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    Clinical Trial Results:
    A Phase 2, 2-panel, Open-label, Randomized Study to Investigate the Pharmacokinetic Interactions Between Simeprevir and Ledipasvir in a Treatment Regimen Consisting of Simeprevir, Sofosbuvir, and Ledipasvir in Treatment-naïve Subjects With Chronic Hepatitis C Virus Genotype 1 Infection

    Summary
    EudraCT number
    		 2015-000459-25
    Trial protocol
    		 BE  
    Global end of trial date
    27 Jan 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jan 2017
    First version publication date
    01 Jan 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TMC435HPC2017
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02421211
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Sciences Ireland UC
    Sponsor organisation address
    Eastgate, Little Island, Cork, Ireland, Belgium, IE-CO T45 A363
    Public contact
    Clinical Registry Group, Janssen Sciences Ireland UC, clinicaltrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Sciences Ireland UC, clinicaltrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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 Jan 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this study were to evaluate the effect of multiple-dose ledipasvir (LDV) 90 milligram (mg) once daily given in combination with sofosbuvir (SOF) 400 mg once daily on the steady-state pharmacokinetics (PK) of SMV 150 mg once daily in chronic hepatitis C virus (HCV) genotype 1 infected participants and to evaluate the effect of multiple-dose SMV 150 mg once daily on the steady-state PK of LDV 90 mg once daily given in combination with SOF 400 mg once daily in chronic HCV genotype 1 infected participants.
    Protection of trial subjects
    Safety evaluations for this study included the monitoring of adverse events (AEs) (including specific toxicities), clinical laboratory tests (hematology, serum chemistry, coagulation, and urinalysis), electrocardiograms (ECGs), vital sign measurements and physical examinations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 May 2015
    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
    Belgium: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 41 participants were enrolled in the study. Among them 40 participants (20 per panel) were randomized and treated. One participant was early terminated from the study, due to withdrawal of consent before randomization to study drug. All randomized participants received study drug and were included in the intent to treat (ITT) population.

    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
    		 Panel 1: SMV 150mg+LDV 90mg/SOF 400mg - 10 Weeks
    Arm description
    		 Participants (Intent-to-treat [ITT] population) received simeprevir (SMV) 150 milligram (mg) capsule and sofosbuvir (SOF) 400 mg tablet, orally, once daily from Day 1 until Day 14. From Day 15 until Day 70, participants received SMV 150 mg capsule and a fixed dose combination (FDC) tablet of 90 mg Ledipasvir (LDV)/400 mg SOF, orally and once daily. ITT population is defined as all enrolled participants who took at least 1 dose of SMV, LDV, or SOF.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Simeprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received SMV 150 mg capsule orally and once daily, from Day 1 until Day 70.

    Investigational medicinal product name
    Sofosbuvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received SOF 400 mg tablet, orally, once daily from Day 1 until Day 14 and a fixed dose combination (FDC) tablet of 90 mg Ledipasvir (LDV)/400 mg SOF, orally and once daily from Day 15 until Day 70.

    Investigational medicinal product name
    Ledipasvir/Sofosbuvir- FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a fixed dose combination tablet of 90 mg LDV/400 mg SOF, orally and once daily from Day 15 until Day 70.

    Arm title
    		 Panel 2: SMV 150mg+LDV 90mg/SOF 400mg - 8 Weeks
    Arm description
    		 Participants (ITT population) received FDC tablet of 90 mg LDV/400 mg SOF, orally, once daily from Day 1 until Day 14. From Day 15 until Day 56, participants received SMV 150 mg capsule and a FDC tablet of 90 mg LDV/400 mg SOF, orally and once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ledipasvir/Sofosbuvir - FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received FDC tablet of 90 mg LDV/400 mg SOF, orally, once daily from Day 1 until Day 56.

    Investigational medicinal product name
    Simeprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received SMV 150 mg capsule orally and once daily from Day 15 until Day 56.

    Number of subjects in period 1
    		Panel 1: SMV 150mg+LDV 90mg/SOF 400mg - 10 Weeks Panel 2: SMV 150mg+LDV 90mg/SOF 400mg - 8 Weeks
    Started
    20
    20
    Completed
    20
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Panel 1: SMV 150mg+LDV 90mg/SOF 400mg - 10 Weeks
    Reporting group description
    		 Participants (Intent-to-treat [ITT] population) received simeprevir (SMV) 150 milligram (mg) capsule and sofosbuvir (SOF) 400 mg tablet, orally, once daily from Day 1 until Day 14. From Day 15 until Day 70, participants received SMV 150 mg capsule and a fixed dose combination (FDC) tablet of 90 mg Ledipasvir (LDV)/400 mg SOF, orally and once daily. ITT population is defined as all enrolled participants who took at least 1 dose of SMV, LDV, or SOF.

    Reporting group title
    Panel 2: SMV 150mg+LDV 90mg/SOF 400mg - 8 Weeks
    Reporting group description
    		 Participants (ITT population) received FDC tablet of 90 mg LDV/400 mg SOF, orally, once daily from Day 1 until Day 14. From Day 15 until Day 56, participants received SMV 150 mg capsule and a FDC tablet of 90 mg LDV/400 mg SOF, orally and once daily.

    Reporting group values
    		 Panel 1: SMV 150mg+LDV 90mg/SOF 400mg - 10 Weeks Panel 2: SMV 150mg+LDV 90mg/SOF 400mg - 8 Weeks Total
    Number of subjects
    		 20 20 40
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 19 20 39
        From 65 to 84 years
    		 1 0 1
        85 years and over
    		 0 0 0
    Title for AgeContinuous
    Units: years
        median (full range (min-max))
    		 50.5 (25 to 70) 51 (26 to 62) -
    Title for Gender
    Units: subjects
        Female
    		 12 10 22
        Male
    		 8 10 18

    End points

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    End points reporting groups
    Reporting group title
    Panel 1: SMV 150mg+LDV 90mg/SOF 400mg - 10 Weeks
    Reporting group description
    		 Participants (Intent-to-treat [ITT] population) received simeprevir (SMV) 150 milligram (mg) capsule and sofosbuvir (SOF) 400 mg tablet, orally, once daily from Day 1 until Day 14. From Day 15 until Day 70, participants received SMV 150 mg capsule and a fixed dose combination (FDC) tablet of 90 mg Ledipasvir (LDV)/400 mg SOF, orally and once daily. ITT population is defined as all enrolled participants who took at least 1 dose of SMV, LDV, or SOF.

    Reporting group title
    Panel 2: SMV 150mg+LDV 90mg/SOF 400mg - 8 Weeks
    Reporting group description
    		 Participants (ITT population) received FDC tablet of 90 mg LDV/400 mg SOF, orally, once daily from Day 1 until Day 14. From Day 15 until Day 56, participants received SMV 150 mg capsule and a FDC tablet of 90 mg LDV/400 mg SOF, orally and once daily.

    Subject analysis set title
    Panel 1: 150 mg SMV + 400 mg SOF (Day 14)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intention-to-treat (ITT) analysis set is defined as all enrolled participants who took at least 1 dose of simeprevir (SMV), ledipasvir (LDV), or sofosbuvir (SOF).

    Subject analysis set title
    Panel 1: SMV 150mg+LDV 90mg/SOF 400mg (Day 28)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT analysis set is defined as all enrolled participants who took at least 1 dose of SMV, LDV, or SOF.

    Subject analysis set title
    Panel 2: 90/400 mg LDV/SOF (Day 14)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT analysis set is defined as all enrolled participants who took at least 1 dose of SMV, LDV, or SOF.

    Subject analysis set title
    Panel 2: SMV 150mg+LDV 90mg/SOF 400mg (Day 28)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT analysis set is defined as all enrolled participants who took at least 1 dose of SMV, LDV, or SOF.

    Primary: Minimum Plasma Concentration (Cmin) of Simeprevir (SMV)

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    End point title
    		 Minimum Plasma Concentration (Cmin) of Simeprevir (SMV)
    End point description
    The Cmin is the minimum observed plasma concentration. The analysis was done on the Intent-to-treat (ITT) population.
    End point type
    Primary
    End point timeframe
    Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours postdose on Day 14 and Day 28
    End point values
    		 Panel 1: 150 mg SMV + 400 mg SOF (Day 14) Panel 1: SMV 150mg+LDV 90mg/SOF 400mg (Day 28)
    Number of subjects analysed
    20
    20
    Units: nanogram per Milliliters (ng/mL)
        arithmetic mean (standard deviation)
    2411 ( 3778 )
    6701 ( 4179 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Panel 1: SMV 150mg+LDV 90mg/SOF 400mg (Day 28) v Panel 1: 150 mg SMV + 400 mg SOF (Day 14)
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Least Square (LS) means ratio
    Point estimate
    4.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 3.4
         upper limit
    		 6.5

    Primary: Maximum Plasma Concentration (Cmax) of SMV

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    End point title
    		 Maximum Plasma Concentration (Cmax) of SMV
    End point description
    The Cmax is the maximum observed plasma concentration. The analysis was done on the ITT population.
    End point type
    Primary
    End point timeframe
    Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours postdose on Day 14 and Day 28
    End point values
    		 Panel 1: 150 mg SMV + 400 mg SOF (Day 14) Panel 1: SMV 150mg+LDV 90mg/SOF 400mg (Day 28)
    Number of subjects analysed
    20
    19 [1]
    Units: ng/mL
        arithmetic mean (standard deviation)
    6767 ( 6362 )
    13691 ( 7775 )
    Notes
    [1] - Here 'N' signifies number of participants analysed for this outcome measure.
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Panel 1: SMV 150mg+LDV 90mg/SOF 400mg (Day 28) v Panel 1: 150 mg SMV + 400 mg SOF (Day 14)
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS means ratio
    Point estimate
    2.3
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 2
         upper limit
    		 2.8

    Primary: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of SMV

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    End point title
    		 Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of SMV
    End point description
    The AUCtau is the measure of the plasma drug concentration from time zero to end of dosing interval. It is used to characterize drug absorption. The analysis was done on the ITT population.
    End point type
    Primary
    End point timeframe
    Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours postdose on Day 14 and Day 28
    End point values
    		 Panel 1: 150 mg SMV + 400 mg SOF (Day 14) Panel 1: SMV 150mg+LDV 90mg/SOF 400mg (Day 28)
    Number of subjects analysed
    20
    19 [2]
    Units: nanogram hour per Milliliters (ng*h/mL)
        arithmetic mean (standard deviation)
    100492 ( 115868 )
    243564 ( 159124 )
    Notes
    [2] - Here 'N' signifies number of participants analysed for this outcome measure.
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Panel 1: SMV 150mg+LDV 90mg/SOF 400mg (Day 28) v Panel 1: 150 mg SMV + 400 mg SOF (Day 14)
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS means ratio
    Point estimate
    3.1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 2.4
         upper limit
    		 3.8

    Primary: Minimum Plasma Concentration (Cmin) of Ledipasvir (LDV)

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    End point title
    		 Minimum Plasma Concentration (Cmin) of Ledipasvir (LDV)
    End point description
    The Cmin is the minimum observed plasma concentration. The analysis was done on the ITT population.
    End point type
    Primary
    End point timeframe
    Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours postdose on Day 14 and Day 28
    End point values
    		 Panel 2: 90/400 mg LDV/SOF (Day 14) Panel 2: SMV 150mg+LDV 90mg/SOF 400mg (Day 28)
    Number of subjects analysed
    20
    18 [3]
    Units: ng/mL
        arithmetic mean (standard deviation)
    319 ( 178 )
    557 ( 307 )
    Notes
    [3] - Here 'N' signifies number of participants analysed for this outcome measure.
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Panel 2: SMV 150mg+LDV 90mg/SOF 400mg (Day 28) v Panel 2: 90/400 mg LDV/SOF (Day 14)
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS means ratio
    Point estimate
    1.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.5
         upper limit
    		 2

    Primary: Maximum Plasma Concentration (Cmax) of LDV

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    End point title
    		 Maximum Plasma Concentration (Cmax) of LDV
    End point description
    The Cmax is the maximum observed plasma concentration. The analysis was done on the ITT population.
    End point type
    Primary
    End point timeframe
    Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours postdose on Day 14 and Day 28
    End point values
    		 Panel 2: 90/400 mg LDV/SOF (Day 14) Panel 2: SMV 150mg+LDV 90mg/SOF 400mg (Day 28)
    Number of subjects analysed
    20
    17 [4]
    Units: ng/mL
        arithmetic mean (standard deviation)
    556 ( 270 )
    930 ( 466 )
    Notes
    [4] - Here 'N' signifies number of participants analysed for this outcome measure.
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Panel 2: SMV 150mg+LDV 90mg/SOF 400mg (Day 28) v Panel 2: 90/400 mg LDV/SOF (Day 14)
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS means ratio
    Point estimate
    1.6
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 1.9

    Primary: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of LDV

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    End point title
    		 Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of LDV
    End point description
    AUCtau is defined as area under the analyte concentration versus time curve during dosing interval tau, calculated by linear-linear trapezoidal summation. The analysis was done on the ITT population.
    End point type
    Primary
    End point timeframe
    Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours postdose on Day 14 and Day 28
    End point values
    		 Panel 2: 90/400 mg LDV/SOF (Day 14) Panel 2: SMV 150mg+LDV 90mg/SOF 400mg (Day 28)
    Number of subjects analysed
    20
    17 [5]
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    9868 ( 4930 )
    17435 ( 8772 )
    Notes
    [5] - Here 'N' signifies number of participants analysed for this outcome measure.
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Panel 2: SMV 150mg+LDV 90mg/SOF 400mg (Day 28) v Panel 2: 90/400 mg LDV/SOF (Day 14)
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS means ratio
    Point estimate
    1.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.6
         upper limit
    		 2

    Secondary: Trough Plasma Concentration (Ctrough) of SMV

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    End point title
    		 Trough Plasma Concentration (Ctrough) of SMV
    End point description
    The (Ctrough) is the plasma concentration before dosing or at the end of the dosing interval of any dose other than the first dose in a multiple dosing regimen. The analysis was done on the ITT population.
    End point type
    Secondary
    End point timeframe
    Predose on Day 14 and Day 28
    End point values
    		 Panel 1: 150 mg SMV + 400 mg SOF (Day 14) Panel 1: SMV 150mg+LDV 90mg/SOF 400mg (Day 28)
    Number of subjects analysed
    19 [6]
    20
    Units: ng/mL
        arithmetic mean (standard deviation)
    3059 ( 4236 )
    8453 ( 6455 )
    Notes
    [6] - Here 'N' signifies number of participants analysed for this outcome measure.
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Plasma Concentration (Tmax) of SMV

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    End point title
    		 Time to Reach Maximum Plasma Concentration (Tmax) of SMV
    End point description
    The Tmax is defined as actual sampling time to reach maximum observed analyte concentration. The analysis was done on the ITT population.
    End point type
    Secondary
    End point timeframe
    Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours postdose on Day 14 and Day 28
    End point values
    		 Panel 1: 150 mg SMV + 400 mg SOF (Day 14) Panel 1: SMV 150mg+LDV 90mg/SOF 400mg (Day 28)
    Number of subjects analysed
    20
    19 [7]
    Units: hour (H)
        median (full range (min-max))
    6 (4 to 12)
    6 (0.47 to 10)
    Notes
    [7] - Here 'N' signifies number of participants analysed for this outcome measure.
    No statistical analyses for this end point

    Secondary: Average Plasma Concentration at Steady State (Cavg,ss) of SMV

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    End point title
    		 Average Plasma Concentration at Steady State (Cavg,ss) of SMV
    End point description
    The Cavg,ss is calculated as area under the plasma concentration-time curve during a dosing Interval (AUC[tau]) divided by the dosing interval (tau). The analysis was done on the ITT population.
    End point type
    Secondary
    End point timeframe
    Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours postdose on Day 14 and Day 28
    End point values
    		 Panel 1: 150 mg SMV + 400 mg SOF (Day 14) Panel 1: SMV 150mg+LDV 90mg/SOF 400mg (Day 28)
    Number of subjects analysed
    20
    19 [8]
    Units: ng/mL
        arithmetic mean (standard deviation)
    4196 ( 4833 )
    10139 ( 6628 )
    Notes
    [8] - Here 'N' signifies number of participants analysed for this outcome measure.
    No statistical analyses for this end point

    Secondary: Fluctuation Index (FI) of SMV

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    End point title
    		 Fluctuation Index (FI) of SMV
    End point description
    Fluctuation index is defined as percentage fluctuation (variation between maximum and minimum concentration at steady state), calculated as: 100*([Cmax Cmin]/Cavg). The analysis was done on the ITT population.
    End point type
    Secondary
    End point timeframe
    Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours postdose on Day 14 and Day 28
    End point values
    		 Panel 1: 150 mg SMV + 400 mg SOF (Day 14) Panel 1: SMV 150mg+LDV 90mg/SOF 400mg (Day 28)
    Number of subjects analysed
    20
    19 [9]
    Units: percentage of fluctuation
        arithmetic mean (standard deviation)
    144 ( 55.5 )
    84.4 ( 36.5 )
    Notes
    [9] - Here 'N' signifies number of participants analysed for this outcome measure.
    No statistical analyses for this end point

    Secondary: Trough Plasma Concentration (Ctrough) of (LDV)

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    End point title
    		 Trough Plasma Concentration (Ctrough) of (LDV)
    End point description
    The (Ctrough) is the plasma concentration before dosing or at the end of the dosing interval of any dose other than the first dose in a multiple dosing regimen. The analysis was done on the ITT population.
    End point type
    Secondary
    End point timeframe
    Predose on Day 14 and Day 28
    End point values
    		 Panel 2: 90/400 mg LDV/SOF (Day 14) Panel 2: SMV 150mg+LDV 90mg/SOF 400mg (Day 28)
    Number of subjects analysed
    20
    18 [10]
    Units: ng/mL
        arithmetic mean (standard deviation)
    376 ( 211 )
    659 ( 406 )
    Notes
    [10] - Here 'N' signifies number of participants analysed for this outcome measure.
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Plasma Concentration (Tmax) of LDV

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    End point title
    		 Time to Reach Maximum Plasma Concentration (Tmax) of LDV
    End point description
    The Tmax is defined as actual sampling time to reach maximum observed analyte concentration. The analysis was done on the ITT population.
    End point type
    Secondary
    End point timeframe
    Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours postdose on Day 14 and Day 28
    End point values
    		 Panel 2: 90/400 mg LDV/SOF (Day 14) Panel 2: SMV 150mg+LDV 90mg/SOF 400mg (Day 28)
    Number of subjects analysed
    20
    17 [11]
    Units: hour
        median (full range (min-max))
    4.07 (1 to 8)
    6 (3.93 to 10)
    Notes
    [11] - Here 'N' signifies number of participants analysed for this outcome measure.
    No statistical analyses for this end point

    Secondary: Average Plasma Concentration at Steady State (Cavg,ss) of LDV

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    End point title
    		 Average Plasma Concentration at Steady State (Cavg,ss) of LDV
    End point description
    The Cavg,ss is calculated as area under the plasma concentration-time curve during a dosing Interval (AUC[tau]) divided by the dosing interval (tau). The analysis was done on the ITT population.
    End point type
    Secondary
    End point timeframe
    Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours postdose on Day 14 and Day 28
    End point values
    		 Panel 2: 90/400 mg LDV/SOF (Day 14) Panel 2: SMV 150mg+LDV 90mg/SOF 400mg (Day 28)
    Number of subjects analysed
    20
    17 [12]
    Units: ng/mL
        arithmetic mean (standard deviation)
    411 ( 207 )
    725 ( 364 )
    Notes
    [12] - Here 'N' signifies number of participants analysed for this outcome measure.
    No statistical analyses for this end point

    Secondary: Fluctuation Index (FI) of LDV

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    End point title
    		 Fluctuation Index (FI) of LDV
    End point description
    Fluctuation index is defined as percentage fluctuation (variation between maximum and minimum concentration at steady state), calculated as: 100*([Cmax Cmin]/Cavg). The analysis was done on the ITT population.
    End point type
    Secondary
    End point timeframe
    Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours postdose on Day 14 and Day 28
    End point values
    		 Panel 2: 90/400 mg LDV/SOF (Day 14) Panel 2: SMV 150mg+LDV 90mg/SOF 400mg (Day 28)
    Number of subjects analysed
    20
    17 [13]
    Units: percentage of fluctuation
        arithmetic mean (standard deviation)
    60.6 ( 19.7 )
    51.2 ( 0.17 )
    Notes
    [13] - Here 'N' signifies number of participants analysed for this outcome measure.
    No statistical analyses for this end point

    Secondary: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The analysis was done on the ITT population.
    End point type
    Secondary
    End point timeframe
    Up to 10 Weeks for Panel 1 and 8 Weeks for Panel 2 (Treatment Phase)
    End point values
    		 Panel 1: SMV 150mg+LDV 90mg/SOF 400mg - 10 Weeks Panel 2: SMV 150mg+LDV 90mg/SOF 400mg - 8 Weeks
    Number of subjects analysed
    20
    20
    Units: number of participants
        Adverse events
    17
    15
        Serious adverse events
    2
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With On-treatment Virologic Response

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    End point title
    		 Percentage of Participants With On-treatment Virologic Response
    End point description
    On-treatment virologic response was determined by hepatitis C virus (HCV) ribonucleic acid (RNA) results satisfying a specified threshold. The following thresholds were considered at any time point: less than (<)LLOQ undetectable, <LLOQ detectable and <LLOQ undetectable/detectable. The ITT analysis set is defined as all enrolled participants who took at least 1 dose of SMV, LDV, or SOF. The scheduled end of treatment visit for Panel 2 was Week 8. The analysis was done on the ITT population.
    End point type
    Secondary
    End point timeframe
    Week 1, up to EOT (Week 10 in Panel 1 and Week 8 in Panel 2)
    End point values
    		 Panel 1: SMV 150mg+LDV 90mg/SOF 400mg - 10 Weeks Panel 2: SMV 150mg+LDV 90mg/SOF 400mg - 8 Weeks
    Number of subjects analysed
    20
    20 [14]
    Units: percentage of participants
    number (not applicable)
        Week 1: >= 15 IU/mL
    65
    60
        Week 1: < 15 IU/mL undetectable/detectable
    35
    40
        Week 1: < 15 IU/mL detectable
    15
    35
        Week 1: < 15 IU/mL undetectable
    20
    5
        Week 2: >= 15 IU/mL
    25
    35
        Week 2: < 15 IU/mL undetectable/detectable
    75
    65
        Week 2: < 15 IU/mL detectable
    30
    30
        Week 2: < 15 IU/mL undetectable (vRVR)
    45
    35
        Week 4: >= 15 IU/mL
    0
    5
        Week 4: < 15 IU/mL undetectable/detectable
    100
    95
        Week 4: < 15 IU/mL detectable
    15
    5
        Week 4: < 15 IU/mL undetectable (RVR)
    85
    90
        Week 6: >= 15 IU/mL
    0
    0
        Week 6: < 15 IU/mL undetectable/detectable
    100
    100
        Week 6: < 15 IU/mL detectable
    0
    5
        Week 6: < 15 IU/mL undetectable
    100
    95
        Week 8: >= 15 IU/mL
    0
    0
        Week 8: < 15 IU/mL undetectable/detectable
    100
    100
        Week 8: < 15 IU/mL detectable
    0
    0
        Week 8: < 15 IU/mL undetectable
    100
    100
        Week 10: >= 15 IU/mL
    0
    999
        Week 10: < 15 IU/mL undetectable/detectable
    100
    999
        Week 10: < 15 IU/mL detectable
    0
    999
        Week 10: < 15 IU/mL undetectable
    100
    999
    Notes
    [14] - In Panel 2, 999 signifies "NA - Not Applicable" because Week 10 is not applicable for Panel 2.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Sustained Virologic Response (SVR) 4 Weeks After the Actual EOT (SVR4) and 12 Weeks After the Actual EOT (SVR12)

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    End point title
    		 Percentage of Participants With Sustained Virologic Response (SVR) 4 Weeks After the Actual EOT (SVR4) and 12 Weeks After the Actual EOT (SVR12)
    End point description
    SVR4 or SVR12 is defined as sustained virologic response 4 or 12 weeks after the actual EOT the participant has HCV RNA <LLOQ detectable or undetectable. The analysis was done on the ITT population.
    End point type
    Secondary
    End point timeframe
    4 weeks after EOT (Week 4 of follow-up phase in Panel 1 and Panel 2) and 12 weeks after EOT (Week 12 of follow-up phase in Panel 1 and Panel 2)
    End point values
    		 Panel 1: SMV 150mg+LDV 90mg/SOF 400mg - 10 Weeks Panel 2: SMV 150mg+LDV 90mg/SOF 400mg - 8 Weeks
    Number of subjects analysed
    20
    20
    Units: percentage of participants
    number (not applicable)
        SVR4
    100
    100
        SVR12
    100
    100
    No statistical analyses for this end point

    Secondary: Percentage of Participants With On-treatment Failure

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    End point title
    		 Percentage of Participants With On-treatment Failure
    End point description
    On-treatment failure is defined as participants who did not achieve SVR12 and with confirmed detectable HCV RNA at the actual end of treatment. This was to include participants with: 1) Viral breakthrough, defined as a confirmed increase of greater than (>)1 log10 in HCV RNA from nadir, or confirmed HCV RNA of >100 international units per Milliliters (IU/mL) in participants whose HCV RNA had previously been <LLOQ while on treatment; 2) Other with confirmed detectable HCV RNA at the actual end of treatment (example, completed, discontinued due to AEs, withdrawal of consent). The analysis was done on the ITT population.
    End point type
    Secondary
    End point timeframe
    Day 70 in Panel 1 and Day 56 in Panel 2
    End point values
    		 Panel 1: SMV 150mg+LDV 90mg/SOF 400mg - 10 Weeks Panel 2: SMV 150mg+LDV 90mg/SOF 400mg - 8 Weeks
    Number of subjects analysed
    20
    20
    Units: percentage of participants
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Viral Relapse

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    End point title
    		 Percentage of Participants With Viral Relapse
    End point description
    Participants who did not achieve SVR12, with undetectable HCV RNA at the actual end of study drug treatment and confirmed HCV RNA greater than or equal to (>=) LLOQ during follow-up. The analysis was done on the ITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 12 follow-up phase after EOT
    End point values
    		 Panel 1: SMV 150mg+LDV 90mg/SOF 400mg - 10 Weeks Panel 2: SMV 150mg+LDV 90mg/SOF 400mg - 8 Weeks
    Number of subjects analysed
    20
    20
    Units: percentage of participants
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants Not Achieving Sustained Virologic Response (SVR) Showing Emerging Mutation in HCV Nonstructural Protein 3/4A (NS3/4A), Nonstructural Protein 5A (NS5A), and Nonstructural Protein 5B (NS5B) Sequence

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    End point title
    		 Number of Participants Not Achieving Sustained Virologic Response (SVR) Showing Emerging Mutation in HCV Nonstructural Protein 3/4A (NS3/4A), Nonstructural Protein 5A (NS5A), and Nonstructural Protein 5B (NS5B) Sequence
    End point description
    The analysis was to be done on the ITT population. All the participants achieved SVR in the study, therefore the data was not collected for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, until end of follow-up phase (Week 12 of follow-up phase) in Panel 1 and Panel 2
    End point values
    		 Panel 1: SMV 150mg+LDV 90mg/SOF 400mg - 10 Weeks Panel 2: SMV 150mg+LDV 90mg/SOF 400mg - 8 Weeks
    Number of subjects analysed
    0 [15]
    0 [16]
    Units: participants
        number (not applicable)
    Notes
    [15] - Data was not collected for this outcome measure.
    [16] - Data was not collected for this outcome measure.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 10 Weeks for Panel 1 and 8 Weeks for Panel 2 (Treatment Phase)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Panel 1: SMV 150mg+LDV 90mg/SOF 400mg - 10 Wks
    Reporting group description
    		 Participants received simeprevir (SMV) 150 milligram (mg) capsule and sofosbuvir (SOF) 400 mg tablet, orally, once daily from Day 1 until Day 14. From Day 15 until Day 70, participants received SMV 150 mg capsule and a fixed dose combination (FDC) tablet of 90 mg Ledipasvir (LDV)/400 mg SOF, orally and once daily.

    Reporting group title
    Panel 2: SMV 150mg+LDV 90mg/SOF 400mg - 8 Wks
    Reporting group description
    		 Participants received FDC tablet of 90 mg LDV/400 mg SOF, orally, once daily from Day 1 until Day 14. From Day 15 until Day 56, participants received SMV 150 mg capsule and a FDC tablet of 90 mg LDV/400 mg SOF, orally and once daily.

    Serious adverse events
    		 Panel 1: SMV 150mg+LDV 90mg/SOF 400mg - 10 Wks Panel 2: SMV 150mg+LDV 90mg/SOF 400mg - 8 Wks
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Tibia fracture
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Panel 1: SMV 150mg+LDV 90mg/SOF 400mg - 10 Wks Panel 2: SMV 150mg+LDV 90mg/SOF 400mg - 8 Wks
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 20 (85.00%)
    15 / 20 (75.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Vasculitis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Catheter site paraesthesia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Asthenia
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Peripheral swelling
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Pyrexia
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Reproductive system and breast disorders
    Breast atrophy
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Headache
         subjects affected / exposed
    1 / 20 (5.00%)
    3 / 20 (15.00%)
         occurrences all number
    1
    3
    Dizziness
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Disturbance in attention
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Presyncope
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Eye disorders
    Eye irritation
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Eyelid oedema
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Photophobia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Vision blurred
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Diarrhoea
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Dyspepsia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Hyperhidrosis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Eczema
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Pruritus
         subjects affected / exposed
    3 / 20 (15.00%)
    3 / 20 (15.00%)
         occurrences all number
    3
    3
    Photosensitivity reaction
         subjects affected / exposed
    11 / 20 (55.00%)
    7 / 20 (35.00%)
         occurrences all number
    17
    12
    Purpura
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Rash
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Muscle spasms
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Angular cheilitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Ear infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Genital abscess
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Laryngitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Tooth infection
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 May 2015
    The amendment 1 included the following changes: prohibit the use of amiodarone from 60 days prior to screening until end of treatment (EOT) (instead of from screening onwards) to allow clearance of amiodarone plasma levels prior to initiation of treatment; include preliminary, in vitro data supporting an inhibitory potential of ledipasvir (LDV) on P-glycoprotein in the gut as well as hepatic organic anion transported protein 1B1/3; and a minor editorial change.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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