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    Clinical Trial Results:
    A Phase 3 Study Evaluating the Pharmacokinetics, Safety, and Tolerability of VX-659/TEZ/IVA Triple Combination Therapy in Cystic Fibrosis Subjects 6 Through 11 Years of Age

    Summary
    EudraCT number
    		 2018-001711-67
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    18 Jan 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    29 Apr 2020
    First version publication date
    17 Nov 2019
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Updating for consistency with CT.gov Results

    Trial information

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    Trial identification
    Sponsor protocol code
    VX18-659-106
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03633526
    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-002191-PIP02-17
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the pharmacokinetics (PK) of VX-659 in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis (CF).
    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
    03 Aug 2018
    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: 18
    Worldwide total number of subjects
    18
    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)
    18
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    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 subjects with cystic fibrosis (CF) 6-11 years of age. The study was terminated before start of Part B at Sponsor's discretion.

    Period 1
    Period 1 title
    Triple Combination Treatment Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 VX-659/TEZ/IVA TC
    Arm description
    		 Subjects who received VX-659/TEZ/IVA for 15 days in the TC treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-659/TEZ/IVA
    Investigational medicinal product code
    VX-659/VX-661/VX-770
    Other name
    VX-659/Tezacaftor/Ivacaftor fixed dose combination
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-659/TEZ/IVA once daily in the morning.

    Investigational medicinal product name
    IVA
    Investigational medicinal product code
    VX-770
    Other name
    Ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received IVA once daily in the evening.

    Number of subjects in period 1 [1]
    		VX-659/TEZ/IVA TC
    Started
    16
    Completed
    16
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: In the above disposition summary, data are presented for 16 subjects dosed in the TC treatment period. Two subjects were enrolled but were not dosed in the TC treatment period. Therefore, the total number of enrolled subjects is 18 whereas the number of subjects reported in disposition and baseline is 16.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    VX-659/TEZ/IVA TC
    Reporting group description
    		 Subjects who received VX-659/TEZ/IVA for 15 days in the TC treatment period.

    Reporting group values
    		 VX-659/TEZ/IVA TC Total
    Number of subjects
    		 16 16
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.2 ( 1.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 5 5
        Male
    		 11 11
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 2
        Not Hispanic or Latino
    		 14 14
        Unknown or Not Reported
    		 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 0 0
        White
    		 16 16
        More than one race
    		 0 0
        Unknown or Not Reported
    		 0 0

    End points

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    End points reporting groups
    Reporting group title
    VX-659/TEZ/IVA TC
    Reporting group description
    		 Subjects who received VX-659/TEZ/IVA for 15 days in the TC treatment period.

    Primary: Maximum Observed Concentration (Cmax) of VX-659, TEZ, and IVA

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    End point title
    		 Maximum Observed Concentration (Cmax) of VX-659, TEZ, and IVA [1]
    End point description
    Pharmacokinetic (PK) set included subjects who received at least 1 dose of study drug and for whom the primary PK data were considered to be sufficient and interpretable.
    End point type
    Primary
    End point timeframe
    Day 1 and Day 15
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were planned. No statistical comparisons were planned for primary PK endpoint. PK set included subjects who received at least 1 dose of study drug and for whom the primary PK data were considered to be sufficient and interpretable. Here “n” signifies those subjects who were evaluable at the specified timepoint.
    End point values
    		 VX-659/TEZ/IVA TC
    Number of subjects analysed
    16
    Units: microgram per milliliter (µg/mL)
    arithmetic mean (standard deviation)
        VX-659: Day 1 (n=15)
    1.81 ( 0.858 )
        VX-659: Day 15 (n=15)
    2.55 ( 1.21 )
        TEZ: Day 1 (n=15)
    4.53 ( 1.65 )
        TEZ: Day 15 (n=15)
    5.22 ( 1.69 )
        IVA: Day 1 (n=15)
    0.536 ( 0.208 )
        IVA: Day 15 (n=15)
    0.733 ( 0.256 )
    No statistical analyses for this end point

    Primary: Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, and IVA

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    End point title
    		 Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, and IVA [2]
    End point description
    PK set.
    End point type
    Primary
    End point timeframe
    Day 8 and Day 15
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were planned. No statistical comparisons were planned for primary pharmacokinetic (PK) endpoint. PK set included subjects who received at least 1 dose of study drug and for whom the primary PK data were considered to be sufficient and interpretable. Here “n” signifies those subjects who were evaluable at the specified timepoint.
    End point values
    		 VX-659/TEZ/IVA TC
    Number of subjects analysed
    16
    Units: microgram per milliliter (µg/mL)
    arithmetic mean (standard deviation)
        VX-659: Day 8 (n=16)
    0.358 ( 0.259 )
        VX-659: Day 15 (n=15)
    0.367 ( 0.283 )
        TEZ: Day 8 (n=16)
    0.897 ( 0.488 )
        TEZ: Day 15 (n=15)
    0.740 ( 0.421 )
        IVA: Day 8 (n=16)
    0.289 ( 0.195 )
        IVA: Day 15 (n=15)
    0.283 ( 0.241 )
    No statistical analyses for this end point

    Primary: Area Under the Concentration Versus Time Curve from time 0 to 6 Hours (AUC0-6h) of VX-659, TEZ, and IVA

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    End point title
    		 Area Under the Concentration Versus Time Curve from time 0 to 6 Hours (AUC0-6h) of VX-659, TEZ, and IVA [3]
    End point description
    PK set.
    End point type
    Primary
    End point timeframe
    Day 1 and Day 15
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were planned. No statistical comparisons were planned for primary PK endpoint. PK set included subjects who received at least 1 dose of study drug and for whom the primary PK data were considered to be sufficient and interpretable. Here “n” signifies those subjects who were evaluable at the specified timepoint.
    End point values
    		 VX-659/TEZ/IVA TC
    Number of subjects analysed
    16
    Units: hour*microgram per milliliter (h*µg/mL)
    arithmetic mean (standard deviation)
        VX-659: Day 1 (n=15)
    5.41 ( 3.65 )
        VX-659: Day 15 (n=15)
    8.55 ( 4.50 )
        TEZ: Day 1 (n=15)
    15.5 ( 5.36 )
        TEZ: Day 15 (n=15)
    19.3 ( 7.26 )
        IVA: Day 1 (n=15)
    1.64 ( 0.795 )
        IVA: Day 15 (n=15)
    2.95 ( 1.18 )
    No statistical analyses for this end point

    Secondary: Maximum Observed Concentration (Cmax) of TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA)

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    End point title
    		 Maximum Observed Concentration (Cmax) of TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA)
    End point description
    PK set. Here “n” signifies those subjects who were evaluable at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 15
    End point values
    		 VX-659/TEZ/IVA TC
    Number of subjects analysed
    16
    Units: mcg/mL
    arithmetic mean (standard deviation)
        M1-TEZ: Day 1 (n=15)
    1.63 ( 0.553 )
        M1-TEZ: Day 15 (n=15)
    5.04 ( 1.27 )
        M1-IVA: Day 1 (n=15)
    1.25 ( 0.449 )
        M1-IVA: Day 15 (n=15)
    1.73 ( 0.741 )
    No statistical analyses for this end point

    Secondary: Observed Pre-Dose Concentration (Ctrough) of TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA)

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    End point title
    		 Observed Pre-Dose Concentration (Ctrough) of TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA)
    End point description
    PK set. Here “n” signifies those subjects who were evaluable at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Day 8 and Day 15
    End point values
    		 VX-659/TEZ/IVA TC
    Number of subjects analysed
    16
    Units: mcg/mL
    arithmetic mean (standard deviation)
        M1-TEZ: Day 8 (n=16)
    3.56 ( 1.33 )
        M1-TEZ: Day 15 (n=15)
    3.35 ( 1.23 )
        M1-IVA: Day 8 (n=16)
    0.816 ( 0.491 )
        M1-IVA: Day 15 (n=15)
    0.858 ( 0.672 )
    No statistical analyses for this end point

    Secondary: Area Under the Concentration Versus Time Curve From Time 0 to 6 Hours (AUC0-6h) of TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA)

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    End point title
    		 Area Under the Concentration Versus Time Curve From Time 0 to 6 Hours (AUC0-6h) of TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA)
    End point description
    PK set. Here “n” signifies those subjects who were evaluable at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 15
    End point values
    		 VX-659/TEZ/IVA TC
    Number of subjects analysed
    16
    Units: h*mcg/mL
    arithmetic mean (standard deviation)
        M1-TEZ: Day 1 (n=15)
    5.52 ( 2.87 )
        M1-TEZ: Day 15 (n=15)
    25.2 ( 7.70 )
        M1-IVA: Day 1 (n=15)
    3.60 ( 1.87 )
        M1-IVA: Day 15 (n=15)
    6.98 ( 2.94 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    End point type
    Secondary
    End point timeframe
    From first dose of study drug in TC treatment period up to 28 days after last dose of study drug or to the completion of study participation date, whichever occurs first (up to 6 weeks)
    End point values
    		 VX-659/TEZ/IVA TC
    Number of subjects analysed
    16
    Units: subjects
        Subjects with AEs
    13
        Subjects with SAEs
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug in TC treatment period up to 28 days after last dose of study drug or to the completion of study participation date, whichever occurs first (up to 6 weeks)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    VX-659/TEZ/IVA
    Reporting group description
    		 Subjects who received VX-659/TEZ/IVA for 15 days in the TC treatment period.

    Serious adverse events
    		 VX-659/TEZ/IVA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 16 (6.25%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 VX-659/TEZ/IVA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 16 (81.25%)
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Bacterial test positive
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Human rhinovirus test positive
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    International normalised ratio increased
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Prothrombin time prolonged
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Pulmonary function test decreased
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Respirovirus test positive
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Procedural anxiety
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Vascular disorders
    Hot flush
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 16 (37.50%)
         occurrences all number
    6
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences all number
    4
    Pyrexia
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Post-tussive vomiting
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Nasal discharge discolouration
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    7 / 16 (43.75%)
         occurrences all number
    8
    Oropharyngeal pain
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Paranasal sinus hypersecretion
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Productive cough
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Sputum increased
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Rash papular
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Rash vesicular
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    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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