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

    Summary
    EudraCT number
    		 2015-003570-32
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    30 Jun 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-337-1115
    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, United States,
    Public contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-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
    30 Jun 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study was to evaluate the relative bioavailability of a pediatric granules 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 of a pediatric granules 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
    13 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
    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 study sites in the United States. The first participant was screened on 13 May 2015. The last study visit occurred on 30 June 2015.

    Pre-assignment
    Screening details
    		 63 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
    Arm title
    		 Overall Participants
    Arm description
    		 Participants were randomized to 1 of 6 treatment sequences and received each of the following treatments with a 9-day washout interval between each treatment: • Treatment A: Single dose of LDV/SOF tablet administered under fasted conditions • Treatment B: Single dose of LDV/SOF oral granules administered under fasted conditions • Treatment C: Single dose of LDV/SOF oral granules administered under fed conditions
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ledipasvir/sofosbuvir
    Investigational medicinal product code
    Harvoni®; LDV/SOF
    Other name
    Pharmaceutical forms
    Granules, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 90/400 mg tablet or 90/400 mg (8 x 11.25/50 mg units) granules administered orally under fasted or fed conditions

    Number of subjects in period 1
    		Overall Participants
    Started
    42
    Completed
    42

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Participants
    Reporting group description
    		 Participants were randomized to 1 of 6 treatment sequences and received each of the following treatments with a 9-day washout interval between each treatment: • Treatment A: Single dose of LDV/SOF tablet administered under fasted conditions • Treatment B: Single dose of LDV/SOF oral granules administered under fasted conditions • Treatment C: Single dose of LDV/SOF oral granules administered under fed conditions

    Reporting group values
    		 Overall Participants Total
    Number of subjects
    		 42 42
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 42 42
    Gender categorical
    Units: Subjects
        Female
    		 21 21
        Male
    		 21 21
    Race
    Units: Subjects
        Asian
    		 1 1
        Black or African American
    		 2 2
        White
    		 39 39
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 41 41
        Not Hispanic or Latino
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Overall Participants
    Reporting group description
    		 Participants were randomized to 1 of 6 treatment sequences and received each of the following treatments with a 9-day washout interval between each treatment: • Treatment A: Single dose of LDV/SOF tablet administered under fasted conditions • Treatment B: Single dose of LDV/SOF oral granules administered under fasted conditions • Treatment C: Single dose of LDV/SOF oral granules administered under fed conditions

    Subject analysis set title
    Treatment A
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Ledipasvir/sofosbuvir 90/400 mg (1 x 90/400 mg tablet) administered orally under fasted conditions

    Subject analysis set title
    Treatment B
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Ledipasvir/sofosbuvir 90/400 mg (8 x 11.25/50 mg units, LDV/SOF oral granules) administered orally under fasted conditions

    Subject analysis set title
    Treatment C
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Ledipasvir/sofosbuvir 90/400 mg (8 x 11.25/50 mg units, LDV/SOF oral granules) administered orally under fed conditions

    Primary: PK Parameter of LDV as measured by Cmax

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    End point title
    		 PK Parameter of LDV as measured by Cmax
    End point description
    Cmax was defined as maximum observed plasma concentration of drug. PK Analysis Set: participants who received at least 1 dose of study drug and had at least 1 non-missing PK concentration data reported by PK lab for each respective analyte.
    End point type
    Primary
    End point timeframe
    Predose (≤ 5 minutes), 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 on Days 1, 11, and 21
    End point values
    		 Treatment A Treatment B Treatment C
    Number of subjects analysed
    42
    40
    42
    Units: Participants
        geometric mean (confidence interval 95%)
    274.41 (234.5 to 321.1)
    163.9 (145.5 to 184.5)
    216 (200.8 to 232.3)
    Statistical analysis title
    		 LDV: Treatment B/Treatment A for Cmax
    Statistical analysis description
    A parametric mixed effect analysis of variance (ANOVA) model was used to estimate the geometric least-squares mean (GLSM) ratio (Treatment B/Treatment A) of the PK parameter and the corresponding 90% CI. Bioequivalence was concluded if the 90% CIs fell within the prespecified boundaries of 80% to 125%. "Subjects in this analysis" states 82; however, participants analyzed in PK analysis set were 40 for Treatment B and 42 for Treatment A.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    59.53
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 52.71
         upper limit
    		 67.24

    Primary: PK Parameter of GS-331007 (SOF metabolite) as measured by Cmax

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    End point title
    		 PK Parameter of GS-331007 (SOF metabolite) as measured by Cmax
    End point description
    End point type
    Primary
    End point timeframe
    Predose (≤ 5 minutes), 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 on Days 1, 11, and 21
    End point values
    		 Treatment A Treatment B Treatment C
    Number of subjects analysed
    42
    40
    42
    Units: Participants
        geometric mean (confidence interval 95%)
    826.8 (771.6 to 886.1)
    959.8 (890.6 to 1034.5)
    537.6 (507.6 to 569.4)
    Statistical analysis title
    		 GS-331007: Treatment B/Treatment A for Cmax
    Statistical analysis description
    A parametric mixed effect ANOVA model was used to estimate the GLSM ratio (Treatment B/Treatment A) of the PK parameter and the corresponding 90% CI. Bioequivalence was concluded if the 90% CIs fell within the prespecified boundaries of 80% to 125%. "Subjects in this analysis" states 82; however participants in analyzed in PK analysis were 40 for Treatment B and 42 for Treatment A.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    115.31
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 109.31
         upper limit
    		 121.64

    Primary: PK Parameter of LDV as measured by AUClast and AUCinf

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    End point title
    		 PK Parameter of LDV as measured by AUClast and AUCinf
    End point description
    • AUClast was defined as area under the plasma concentration-time curve from time 0 to the last measurable concentration. • AUCinf was defined as area under the plasma concentration-time curve from time zero to infinity.
    End point type
    Primary
    End point timeframe
    Predose (≤ 5 minutes), 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 on Days 1, 11, and 21
    End point values
    		 Treatment A Treatment B Treatment C
    Number of subjects analysed
    42
    40
    42
    Units: Participants
    geometric mean (confidence interval 95%)
        AUClast
    7939.8 (6762.3 to 9322.3)
    4863.9 (4299.4 to 5502.5)
    6451.6 (5956.7 to 69857.5)
        AUCinf
    9257 (7824.5 to 10951.9)
    5763.9 (5044.3 to 6586.1)
    7553.4 (6860.5 to 8316.4)
    Statistical analysis title
    		 LDV: Treatment B/Treatment A for AUClast
    Statistical analysis description
    A parametric mixed effect ANOVA model was used to estimate the GLSM ratio (Treatment B/Treatment A) of the PK parameter and the corresponding 90% CI. Bioequivalence was concluded if the 90% CIs fell within the prespecified boundaries of 80% to 125%. "Subjects in this analysis" states 82; however, participants analyzed in PK analysis set were 40 for Treatment B and 42 for Treatment A.
    Comparison groups
    Treatment B v Treatment A
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    60.96
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 54.72
         upper limit
    		 67.91
    Statistical analysis title
    		 LDV: Treatment C/Treatment B for AUClast
    Statistical analysis description
    A parametric mixed effect ANOVA model was used to estimate the GLSM ratio (Treatment C/Treatment B) of the PK parameter and the corresponding 90% CI. PK equivalence was concluded if the 90% CIs fell within the prespecified boundaries of 70% to 143%. "Subjects in this analysis" states 82; however, participants analyzed in PK analysis set were 42 for Treatment C and 40 for Treatment B.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    134.79
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 123.55
         upper limit
    		 147.05
    Statistical analysis title
    		 LDV: Treatment B/Treatment A for AUCinf
    Statistical analysis description
    A parametric mixed effect ANOVA model was used to estimate the GLSM ratio (Treatment B/Treatment A) of the PK parameter and the corresponding 90% CI. Bioequivalence was concluded if the 90% CIs fell within the prespecified boundaries of 80% to 125%. "Subjects in this analysis" states 82; however, participants analyzed in PK analysis set were 40 for Treatment B and 42 for Treatment A.
    Comparison groups
    Treatment B v Treatment A
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    61.86
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 55.38
         upper limit
    		 69.1
    Statistical analysis title
    		 LDV: Treatment C/Treatment B for AUCinf
    Statistical analysis description
    A parametric mixed effect ANOVA model was used to estimate the GLSM ratio (Treatment C/Treatment B) of the PK parameter and the corresponding 90% CI. PK equivalence was concluded if the 90% CIs fell within the prespecified boundaries of 70% to 143%. "Subjects in this analysis" states 82; however, participants analyzed in PK analysis set were 40 for Treatment C and 42 for Treatment B.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    133.51
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 122.31
         upper limit
    		 145.75

    Primary: PK Parameter of GS-331007 (SOF metabolite) as measured by AUClast and AUCinf

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    End point title
    		 PK Parameter of GS-331007 (SOF metabolite) as measured by AUClast and AUCinf
    End point description
    End point type
    Primary
    End point timeframe
    Predose (≤ 5 minutes), 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 on Days 1, 11, and 21
    End point values
    		 Treatment A Treatment B Treatment C
    Number of subjects analysed
    42
    40
    42
    Units: Participants
    geometric mean (confidence interval 95%)
        AUClast
    10418.5 (9727.2 to 11158.9)
    10897.8 (10121.2 to 11734)
    11999.5 (11330.9 to 12707.5)
        AUCinf
    10958.4 (10257.8 to 11706.8)
    11438.5 (10640 to 12296.9)
    12640.5 (11972.5 to 13345.7)
    Statistical analysis title
    		 GS-331007: Treatment B/Treatment A for AUClast
    Statistical analysis description
    A parametric mixed effect ANOVA model was used to estimate the GLSM ratio (Treatment B/Treatment A) of the PK parameter and the corresponding 90% CI. Bioequivalence was concluded if the 90% CIs fell within the prespecified boundaries of 80% to 125%. "Subjects in this analysis" states 82; however, participants analyzed in PK analysis set were 40 for Treatment B and 42 for Treatment A.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    103.38
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 99.63
         upper limit
    		 107.27
    Statistical analysis title
    		 GS-331007: Treatment C/Treatment B for AUClast
    Statistical analysis description
    A parametric mixed effect ANOVA model was used to estimate the GLSM ratio (Treatment C/Treatment B) of the PK parameter and the corresponding 90% CI. PK equivalence was concluded if the 90% CIs fell within the prespecified boundaries of 80% to 125%. "Subjects in this analysis" states 82; however, participants analyzed in PK analysis set were 42 for Treatment C and 40 for Treatment B.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    111.03
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 106.44
         upper limit
    		 115.83
    Statistical analysis title
    		 GS-331007: Treatment B/Treatment A for AUCinf
    Statistical analysis description
    A parametric mixed effect ANOVA model was used to estimate the GLSM ratio (Treatment B/Treatment A) of the PK parameter and the corresponding 90% CI. Bioequivalence was concluded if the 90% CIs fell within the prespecified boundaries of 80% to 125%. "Subjects in this analysis" states 82; however, participants analyzed in PK analysis set were 40 for Treatment B and 42 for Treatment A.
    Comparison groups
    Treatment B v Treatment A
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    103.13
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 99.5
         upper limit
    		 106.9
    Statistical analysis title
    		 GS-331007: Treatment C/Treatment B for AUCinf
    Statistical analysis description
    A parametric mixed effect ANOVA model was used to estimate the GLSM ratio (Treatment C/Treatment B) of the PK parameter and the corresponding 90% CI. PK equivalence was concluded if the 90% CIs fell within the prespecified boundaries of 80% to 125%. "Subjects in this analysis" states 82; however, participants analyzed in PK analysis set were 42 for Treatment C and 40 for Treatment B.
    Comparison groups
    Treatment B v Treatment C
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    111.45
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 106.89
         upper limit
    		 116.21

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Up to 21 days plus 30 days
    Adverse event reporting additional description
    Safety Analysis Set included all randomized subjects who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Treatment A
    Reporting group description
    		 Ledipasvir/sofosbuvir 90/400 mg (1 x 90/400 mg tablet) administered orally under fasted conditions

    Reporting group title
    Treatment B
    Reporting group description
    		 Ledipasvir/sofosbuvir 90/400 mg (8 x 11.25/50 mg units, LDV/SOF oral granules) administered orally under fasted conditions

    Reporting group title
    Treatment C
    Reporting group description
    		 Ledipasvir/sofosbuvir 90/400 mg (8 x 11.25/50 mg units, LDV/SOF oral granules) administered orally under fed conditions

    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
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: None of the non-serious AE preferred terms occurred to at least 5% of subjects in any of the treatment groups.

    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.
    There were no limitations affecting the analysis or results.
    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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