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    Clinical Trial Results:
    A Phase 1, Open-label, Randomized, Crossover Study to Evaluate the Relative Bioavailability of a Granule Formulation of Tezacaftor and Ivacaftor Compared to a Fixed-dose Combination Tablet in Healthy Adult Subjects

    Summary
    EudraCT number
    		 2020-000689-40
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    08 Nov 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Nov 2021
    First version publication date
    19 Nov 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VX19-661-012
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Vertex Pharmaceuticals Incorporated
    Sponsor organisation address
    50 Northern Avenue, Boston, Massachusetts, United States,
    Public contact
    Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617-341-6777, medicalinfo@vrtx.com
    Scientific contact
    Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617-341-6777, medicalinfo@vrtx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001640-PIP01-14
    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
    07 Dec 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Nov 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Nov 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the relative bioavailability (BA) of a granule formulation of tezacaftor (TEZ)/ivacaftor (IVA) compared to a reference fixed-dose combination (FDC) tablet of TEZ/IVA.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the International Council on Harmonization (ICH) Guideline for Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Oct 2020
    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: 16
    Worldwide total number of subjects
    16
    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)
    16
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study was conducted in healthy subjects 19 to 55 years of age.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TEZ/IVA Sequence 1: First Granules Then Tablet
    Arm description
    		 Subjects received TEZ 50 milligrams (mg)/IVA 75 mg granules on Day 1 in dosing period 1 followed by TEZ 50 mg/IVA 75 mg fixed-dose combination (FDC) tablet on Day 15 in dosing period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TEZ/IVA
    Investigational medicinal product code
    VX-661/VX-770
    Other name
    Tezacaftor/Ivacaftor
    Pharmaceutical forms
    Granules, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of TEZ/IVA granule and tablet formulation in the fed state in dosing period 1 and 2 as per the sequence.

    Arm title
    		 TEZ/IVA Sequence 2: First Tablet Then Granules
    Arm description
    		 Subjects received TEZ 50 mg/IVA 75 mg FDC tablet on Day 1 in dosing period 1 followed by TEZ 50 mg/IVA 75 mg granules on Day 15 in dosing period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TEZ/IVA
    Investigational medicinal product code
    VX-661/VX-770
    Other name
    Tezacaftor/Ivacaftor
    Pharmaceutical forms
    Tablet, Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of TEZ/IVA granule and tablet formulation in the fed state in dosing period 1 and 2 as per the sequence.

    Number of subjects in period 1
    		TEZ/IVA Sequence 1: First Granules Then Tablet TEZ/IVA Sequence 2: First Tablet Then Granules
    Started
    8
    8
    Completed
    8
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TEZ/IVA Sequence 1: First Granules Then Tablet
    Reporting group description
    		 Subjects received TEZ 50 milligrams (mg)/IVA 75 mg granules on Day 1 in dosing period 1 followed by TEZ 50 mg/IVA 75 mg fixed-dose combination (FDC) tablet on Day 15 in dosing period 2.

    Reporting group title
    TEZ/IVA Sequence 2: First Tablet Then Granules
    Reporting group description
    		 Subjects received TEZ 50 mg/IVA 75 mg FDC tablet on Day 1 in dosing period 1 followed by TEZ 50 mg/IVA 75 mg granules on Day 15 in dosing period 2.

    Reporting group values
    		 TEZ/IVA Sequence 1: First Granules Then Tablet TEZ/IVA Sequence 2: First Tablet Then Granules Total
    Number of subjects
    		 8 8 16
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 39.5 ( 5.5 ) 41.8 ( 6.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 5 9
        Male
    		 4 3 7

    End points

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    End points reporting groups
    Reporting group title
    TEZ/IVA Sequence 1: First Granules Then Tablet
    Reporting group description
    		 Subjects received TEZ 50 milligrams (mg)/IVA 75 mg granules on Day 1 in dosing period 1 followed by TEZ 50 mg/IVA 75 mg fixed-dose combination (FDC) tablet on Day 15 in dosing period 2.

    Reporting group title
    TEZ/IVA Sequence 2: First Tablet Then Granules
    Reporting group description
    		 Subjects received TEZ 50 mg/IVA 75 mg FDC tablet on Day 1 in dosing period 1 followed by TEZ 50 mg/IVA 75 mg granules on Day 15 in dosing period 2.

    Subject analysis set title
    TEZ/IVA Granules
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who received TEZ 50 mg/IVA 75 mg granules formulation in sequence 1 or 2.

    Subject analysis set title
    TEZ/IVA FDC Tablet
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who received TEZ 50 mg/IVA 75 mg tablet formulation in sequence 1 or 2.

    Primary: Maximum Observed Plasma Concentration (Cmax) of TEZ and IVA

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of TEZ and IVA
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 up to 144 hours post-dose
    End point values
    		 TEZ/IVA Granules TEZ/IVA FDC Tablet
    Number of subjects analysed
    16
    16
    Units: microgram per milliliter (mcg/mL)
    geometric mean (geometric coefficient of variation)
        TEZ
    2.63 ( 24.6 )
    3.23 ( 34.4 )
        IVA
    0.333 ( 50.0 )
    0.339 ( 58.7 )
    Statistical analysis title
    		 TEZ: Granules vs TEZ: Tablet
    Statistical analysis description
    As this is a cross-over study, actual number of subjects analysed for the statistical comparison was “16” for TEZ/IVA Granules arm and TEZ/IVA FDC Tablet arm. “Number of subjects included in analysis = 32” is reflected due to EudraCT database limitation of summing up the comparison arm numbers.
    Comparison groups
    TEZ/IVA Granules v TEZ/IVA FDC Tablet
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric Least Squares Mean Ratio
    Point estimate
    81.5
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 71.4
         upper limit
    		 93.1
    Statistical analysis title
    		 IVA: Granules vs IVA: Tablet
    Statistical analysis description
    As this is a cross-over study, actual number of subjects analysed for the statistical comparison was “16” for TEZ/IVA Granules arm and TEZ/IVA FDC Tablet arm. “Number of subjects included in analysis = 32” is reflected due to EudraCT database limitation of summing up the comparison arm numbers.
    Comparison groups
    TEZ/IVA FDC Tablet v TEZ/IVA Granules
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric Least Squares Mean Ratio
    Point estimate
    98.2
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 85.5
         upper limit
    		 113

    Primary: Area Under the Concentration Versus Time Curve From the Time of Dosing Extrapolated to Infinity [AUC(0 - inf)] of TEZ and IVA

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    End point title
    		 Area Under the Concentration Versus Time Curve From the Time of Dosing Extrapolated to Infinity [AUC(0 - inf)] of TEZ and IVA
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 up to 144 hours post-dose
    End point values
    		 TEZ/IVA Granules TEZ/IVA FDC Tablet
    Number of subjects analysed
    16
    16
    Units: hours*microgram per milliliter(h*mcg/mL)
    geometric mean (geometric coefficient of variation)
        TEZ
    48.4 ( 27.3 )
    51.8 ( 27.8 )
        IVA
    4.31 ( 67.0 )
    4.10 ( 61.3 )
    Statistical analysis title
    		 TEZ: Granules vs TEZ: Tablet
    Statistical analysis description
    As this is a cross-over study, actual number of subjects analysed for the statistical comparison was “16” for TEZ/IVA Granules arm and TEZ/IVA FDC Tablet arm. “Number of subjects included in analysis = 32” is reflected due to EudraCT database limitation of summing up the comparison arm numbers.
    Comparison groups
    TEZ/IVA Granules v TEZ/IVA FDC Tablet
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric Least Squares Mean Ratio
    Point estimate
    93.4
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 88.4
         upper limit
    		 98.7
    Statistical analysis title
    		 IVA: Granules vs IVA: Tablet
    Statistical analysis description
    As this is a cross-over study, actual number of subjects analysed for the statistical comparison was “16” for TEZ/IVA Granules arm and TEZ/IVA FDC Tablet arm. “Number of subjects included in analysis = 32” is reflected due to EudraCT database limitation of summing up the comparison arm numbers.
    Comparison groups
    TEZ/IVA Granules v TEZ/IVA FDC Tablet
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric Least Squares Mean Ratio
    Point estimate
    105
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 90.7
         upper limit
    		 122

    Primary: Area Under the Concentration Versus Time Curve From the Time of Dosing to the Last Measurable Concentration [AUC(0-tlast)] of TEZ and IVA

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    End point title
    		 Area Under the Concentration Versus Time Curve From the Time of Dosing to the Last Measurable Concentration [AUC(0-tlast)] of TEZ and IVA
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 up to 144 hours post-dose
    End point values
    		 TEZ/IVA Granules TEZ/IVA FDC Tablet
    Number of subjects analysed
    16
    16
    Units: h*mcg/mL
    geometric mean (geometric coefficient of variation)
        TEZ
    42.9 ( 27.8 )
    45.7 ( 27.7 )
        IVA
    4.22 ( 68.2 )
    4.01 ( 62.5 )
    Statistical analysis title
    		 TEZ: Granules vs TEZ: Tablet
    Statistical analysis description
    As this is a cross-over study, actual number of subjects analysed for the statistical comparison was “16” for TEZ/IVA Granules arm and TEZ/IVA FDC Tablet arm. “Number of subjects included in analysis = 32” is reflected due to EudraCT database limitation of summing up the comparison arm numbers.
    Comparison groups
    TEZ/IVA Granules v TEZ/IVA FDC Tablet
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric Least Squares Mean Ratio
    Point estimate
    93.9
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 88.6
         upper limit
    		 99.5
    Statistical analysis title
    		 IVA: Granules vs IVA: Tablet
    Statistical analysis description
    As this is a cross-over study, actual number of subjects analysed for the statistical comparison was “16” for TEZ/IVA Granules arm and TEZ/IVA FDC Tablet arm. “Number of subjects included in analysis = 32” is reflected due to EudraCT database limitation of summing up the comparison arm numbers.
    Comparison groups
    TEZ/IVA Granules v TEZ/IVA FDC Tablet
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric Least Squares Mean Ratio
    Point estimate
    105
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 90.6
         upper limit
    		 123

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to Day 21
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    TEZ/IVA Granules
    Reporting group description
    		 All subjects who received TEZ 50 mg/IVA 75 mg granules formulation in sequence 1 or 2.

    Reporting group title
    TEZ/IVA FDC Tablet
    Reporting group description
    		 All subjects who received TEZ 50 mg/IVA 75 mg tablet formulation in sequence 1 or 2.

    Serious adverse events
    		 TEZ/IVA Granules TEZ/IVA FDC Tablet
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 16 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TEZ/IVA Granules TEZ/IVA FDC Tablet
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 16 (50.00%)
    6 / 16 (37.50%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Abdominal pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    6 / 16 (37.50%)
    3 / 16 (18.75%)
         occurrences all number
    6
    3
    Dyspepsia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Lip dry
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 16 (6.25%)
         occurrences all number
    2
    1
    Pruritus
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1

    More information

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

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

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