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    Clinical Trial Results:
    A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and Safety of VX-445 Combination Therapy in Subjects With Cystic Fibrosis Who Are Homozygous for the F508del Mutation (F/F)

    Summary
    EudraCT number
    		 2018-000184-89
    Trial protocol
    		 GB   BE   NL  
    Global end of trial date
    28 Dec 2018

    Results information
    Results version number
    		 v1
    This version publication date
    17 Jul 2019
    First version publication date
    17 Jul 2019
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    VX17-445-103
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03525548
    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-002324-PIP01-17
    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
    07 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Dec 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of VX-445 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
    03 Aug 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
    Belgium: 14
    Country: Number of subjects enrolled
    Netherlands: 12
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    United States: 73
    Worldwide total number of subjects
    113
    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)
    33
    Adults (18-64 years)
    80
    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-445/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-445/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/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.

    Arm title
    		 VX-445/TEZ/IVA TC
    Arm description
    		 Following a run-in period of 4 weeks with TEZ/IVA, subjects received VX-445/TEZ/IVA for 4 weeks in the TC treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-445/TEZ/IVA
    Investigational medicinal product code
    VX-445/VX-661/VX-770
    Other name
    VX-445/Tezacaftor/Ivacaftor fixed dose combination
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-445/TEZ/IVA 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 once daily in the evening.

    Number of subjects in period 1 [1]
    		TEZ/IVA VX-445/TEZ/IVA TC
    Started
    52
    55
    Completed
    52
    55
    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 107 subjects dosed in the TC treatment period. 6 subjects were included in the run-in period but were not dosed in TC treatment period. Therefore, the total enrolled subjects are 113 whereas the subjects reported in disposition and baseline are 107.

    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-445/TEZ/IVA TC
    Reporting group description
    		 Following a run-in period of 4 weeks with TEZ/IVA, subjects received VX-445/TEZ/IVA for 4 weeks in the TC treatment period.

    Reporting group values
    		 TEZ/IVA VX-445/TEZ/IVA TC Total
    Number of subjects
    		 52 55 107
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 27.9 ± 10.8 28.8 ± 11.5 -
    Gender categorical
    Units: Subjects
        Female
    		 28 31 59
        Male
    		 24 24 48

    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-445/TEZ/IVA TC
    Reporting group description
    		 Following a run-in period of 4 weeks with TEZ/IVA, subjects received VX-445/TEZ/IVA for 4 weeks in the TC treatment period.

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

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    End point title
    		 Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)
    End point description
    End point type
    Primary
    End point timeframe
    At Week 4
    End point values
    		 TEZ/IVA VX-445/TEZ/IVA TC
    Number of subjects analysed
    52
    55
    Units: percentage points
        least squares mean (standard error)
    0.4 ± 0.9
    10.4 ± 0.9
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    TEZ/IVA v VX-445/TEZ/IVA TC
    Number of subjects included in analysis
    107
    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
    		 12.6

    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
    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-445/TEZ/IVA TC
    Reporting group description
    		 Following a run-in period of 4 weeks with TEZ/IVA, subjects received VX-445/TEZ/IVA for 4 weeks in the TC treatment period.

    Serious adverse events
    		 TEZ/IVA VX-445/TEZ/IVA TC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 52 (1.92%)
    2 / 55 (3.64%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
    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-445/TEZ/IVA TC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 52 (48.08%)
    24 / 55 (43.64%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 52 (7.69%)
    3 / 55 (5.45%)
         occurrences all number
    4
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 52 (3.85%)
    3 / 55 (5.45%)
         occurrences all number
    2
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 55 (3.64%)
         occurrences all number
    3
    2
    Abdominal pain
         subjects affected / exposed
    1 / 52 (1.92%)
    3 / 55 (5.45%)
         occurrences all number
    1
    3
    Nausea
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 55 (1.82%)
         occurrences all number
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Sputum increased
         subjects affected / exposed
    3 / 52 (5.77%)
    3 / 55 (5.45%)
         occurrences all number
    3
    3
    Cough
         subjects affected / exposed
    4 / 52 (7.69%)
    8 / 55 (14.55%)
         occurrences all number
    4
    8
    Haemoptysis
         subjects affected / exposed
    5 / 52 (9.62%)
    2 / 55 (3.64%)
         occurrences all number
    8
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 52 (0.00%)
    4 / 55 (7.27%)
         occurrences all number
    0
    6
    Nasal congestion
         subjects affected / exposed
    1 / 52 (1.92%)
    3 / 55 (5.45%)
         occurrences all number
    1
    3
    Respiration abnormal
         subjects affected / exposed
    0 / 52 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    0
    3
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    5 / 52 (9.62%)
    0 / 55 (0.00%)
         occurrences all number
    5
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 52 (3.85%)
    4 / 55 (7.27%)
         occurrences all number
    2
    4
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 52 (3.85%)
    4 / 55 (7.27%)
         occurrences all number
    2
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Apr 2018
    Updated study drug regimen, dosing guidance, dose and population rationale.
    19 Jul 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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