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    Clinical Trial Results:
    A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and Safety of VX-659 Combination Therapy in Subjects With Cystic Fibrosis Who Are Homozygous for the F508del Mutation (F/F)

    Summary
    EudraCT number
    		 2017-004133-82
    Trial protocol
    		 IE   DE   ES   GB  
    Global end of trial date
    08 Oct 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    26 Jan 2020
    First version publication date
    17 Jul 2019
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Addition of Secondary endpoints

    Trial information

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    Trial identification
    Sponsor protocol code
    VX17-659-103
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03460990
    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
    08 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of VX-659 in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are homozygous for the F508del mutation (F/F)
    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
    01 May 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 17
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Ireland: 10
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    United States: 67
    Worldwide total number of subjects
    116
    EEA total number of subjects
    32
    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)
    29
    Adults (18-64 years)
    87
    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) aged 12 years or older.

    Period 1
    Period 1 title
    Triple Combination Treatment Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TEZ/IVA
    Arm description
    		 Following a run-in period of 4 weeks with TEZ/IVA, subjects received TEZ/IVA for 4 weeks in the TC treatment period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo (matched to VX-659/TEZ/IVA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to VX-659/TEZ/IVA once daily in the morning.

    Investigational medicinal product name
    TEZ/IVA
    Investigational medicinal product code
    VX-661/VX-770
    Other name
    Tezacaftor/Ivacaftor fixed dose combination
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received TEZ 100 mg/IVA 150 mg 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 150 mg once daily in the evening.

    Arm title
    		 VX-659/TEZ/IVA TC
    Arm description
    		 Following a run-in period of 4 weeks with TEZ/IVA, subjects received VX-659/TEZ/IVA for 4 weeks 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-659 240 mg/TEZ 100 mg/IVA 150 mg once daily in the morning.

    Investigational medicinal product name
    Placebo (matched to TEZ/IVA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to 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 150 mg once daily in the evening.

    Number of subjects in period 1 [1]
    		TEZ/IVA VX-659/TEZ/IVA TC
    Started
    57
    54
    Completed
    57
    54
    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 is presented for 111 subjects dosed in the TC treatment period. 5 subjects were included in the run-in period but were not dosed in TC treatment period. Therefore, the total enrolled subjects are 116 whereas the subjects reported in disposition and baseline are 111.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TEZ/IVA
    Reporting group description
    		 Following a run-in period of 4 weeks with TEZ/IVA, subjects received TEZ/IVA for 4 weeks in the TC treatment period.

    Reporting group title
    VX-659/TEZ/IVA TC
    Reporting group description
    		 Following a run-in period of 4 weeks with TEZ/IVA, subjects received VX-659/TEZ/IVA for 4 weeks in the TC treatment period.

    Reporting group values
    		 TEZ/IVA VX-659/TEZ/IVA TC Total
    Number of subjects
    		 57 54 111
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 26.2 ( 9.1 ) 28.3 ( 9.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 33 26 59
        Male
    		 24 28 52
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 1 2
        Not Hispanic or Latino
    		 56 52 108
        Unknown or Not Reported
    		 0 1 1
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 56 54 110
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 1 0 1
    Forced Expiratory Volume in 1 Second (ppFEV1)
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
    Units: Percentage points
        arithmetic mean (standard deviation)
    		 62.9 ( 14.9 ) 62.0 ( 14.8 ) -

    End points

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    End points reporting groups
    Reporting group title
    TEZ/IVA
    Reporting group description
    		 Following a run-in period of 4 weeks with TEZ/IVA, subjects received TEZ/IVA for 4 weeks in the TC treatment period.

    Reporting group title
    VX-659/TEZ/IVA TC
    Reporting group description
    		 Following a run-in period of 4 weeks with TEZ/IVA, subjects received VX-659/TEZ/IVA for 4 weeks in the TC treatment period.

    Primary: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

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    End point title
    		 Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
    End point type
    Primary
    End point timeframe
    From Baseline at Week 4
    End point values
    		 TEZ/IVA VX-659/TEZ/IVA TC
    Number of subjects analysed
    57
    54
    Units: percentage points
        least squares mean (standard error)
    0.3 ( 0.9 )
    10.2 ( 0.9 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    TEZ/IVA v VX-659/TEZ/IVA TC
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed-effects model for repeated measure
    Parameter type
    		 LS Mean Difference
    Point estimate
    10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.4
         upper limit
    		 12.5

    Secondary: Absolute Change in Sweat Chloride (SwCl)

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    End point title
    		 Absolute Change in Sweat Chloride (SwCl)
    End point description
    Sweat samples were collected using an approved collection device.
    End point type
    Secondary
    End point timeframe
    From Baseline at Week 4
    End point values
    		 TEZ/IVA VX-659/TEZ/IVA TC
    Number of subjects analysed
    57
    54
    Units: millimole per liter (mmol/L)
        least squares mean (standard error)
    1.5 ( 1.8 )
    -47.2 ( 1.9 )
    Statistical analysis title
    		 TEZ/IVA vs VX-659/TEZ/IVA TC
    Comparison groups
    TEZ/IVA v VX-659/TEZ/IVA TC
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed-effects model for repeated measure
    Parameter type
    		 LS Mean Difference
    Point estimate
    -48.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -53.9
         upper limit
    		 -43.5

    Secondary: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score

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    End point title
    		 Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score
    End point description
    The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
    End point type
    Secondary
    End point timeframe
    From Baseline at Week 4
    End point values
    		 TEZ/IVA VX-659/TEZ/IVA TC
    Number of subjects analysed
    57
    54
    Units: units on a scale
        least squares mean (standard error)
    3.0 ( 1.7 )
    16.5 ( 1.7 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    TEZ/IVA v VX-659/TEZ/IVA TC
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed-effects model for repeated measure
    Parameter type
    		 LS Mean Difference
    Point estimate
    13.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.8
         upper limit
    		 18.3

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

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    End point title
    		 Safety and Tolerability as Assessed 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 Week 8)
    End point values
    		 TEZ/IVA VX-659/TEZ/IVA TC
    Number of subjects analysed
    57
    54
    Units: Subjects
        Subjects with AEs
    31
    33
        Subjects with SAEs
    0
    2
    No statistical analyses for this end point

    Secondary: Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, TEZ Metabolite (M1-TEZ), and IVA

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    End point title
    		 Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, TEZ Metabolite (M1-TEZ), and IVA
    End point description
    End point type
    Secondary
    End point timeframe
    From Day 1 and Week 4
    End point values
    		 TEZ/IVA VX-659/TEZ/IVA TC
    Number of subjects analysed
    57 [1]
    54
    Units: nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Day 1: VX-659 (n= 0, 0)
    0 ( 0 )
    0 ( 0 )
        Week 4: VX-659 (n= 0, 52)
    99999 ( 99999 )
    720 ( 589 )
        Day 1: TEZ (n= 57, 54)
    1780 ( 832 )
    1590 ( 1020 )
        Week 4: TEZ (n= 56, 53)
    1730 ( 885 )
    1280 ( 594 )
        Day 1: M1-TEZ (n= 57, 54)
    5170 ( 1620 )
    4840 ( 1860 )
        Week 4: M1-TEZ (n= 56, 53)
    5010 ( 1810 )
    4730 ( 1380 )
        Day 1: IVA (n= 57, 54)
    717 ( 616 )
    563 ( 400 )
        Week 4: IVA (n= 56, 53)
    722 ( 642 )
    401 ( 211 )
    Notes
    [1] - "n" in above table signifies subjects evaluable at specified time points and "99999" signifies "NA"
    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 Week 8)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    TEZ/IVA
    Reporting group description
    		 Following a run-in period of 4 weeks with TEZ/IVA, subjects received TEZ/IVA for 4 weeks in the TC treatment period.

    Reporting group title
    VX-659/TEZ/IVA TC
    Reporting group description
    		 Following a run-in period of 4 weeks with TEZ/IVA, subjects received VX-659/TEZ/IVA for 4 weeks in the TC treatment period.

    Serious adverse events
    		 TEZ/IVA VX-659/TEZ/IVA TC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 54 (3.70%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TEZ/IVA VX-659/TEZ/IVA TC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 57 (33.33%)
    23 / 54 (42.59%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 57 (3.51%)
    3 / 54 (5.56%)
         occurrences all number
    2
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 57 (1.75%)
    3 / 54 (5.56%)
         occurrences all number
    1
    3
    C-reactive protein increased
         subjects affected / exposed
    0 / 57 (0.00%)
    4 / 54 (7.41%)
         occurrences all number
    0
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 57 (8.77%)
    3 / 54 (5.56%)
         occurrences all number
    6
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 57 (0.00%)
    4 / 54 (7.41%)
         occurrences all number
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Sputum increased
         subjects affected / exposed
    0 / 57 (0.00%)
    9 / 54 (16.67%)
         occurrences all number
    0
    9
    Cough
         subjects affected / exposed
    3 / 57 (5.26%)
    4 / 54 (7.41%)
         occurrences all number
    3
    4
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    9 / 57 (15.79%)
    2 / 54 (3.70%)
         occurrences all number
    9
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jan 2018
    Updated study drug regimen, dosing guidance and eligibility criteria.
    27 Apr 2018
    Revised exclusion criteria.

    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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    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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