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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Ivacaftor-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of VX-661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Heterozygous for the F508del-CFTR Mutation and a Second CFTR Allele With a Gating Defect That Is Clinically Demonstrated to be Ivacaftor Responsive.

    Summary
    EudraCT number
    		 2014-004838-25
    Trial protocol
    		 IT   IE   BE   AT   DE  
    Global end of trial date
    19 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 May 2018
    First version publication date
    20 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VX14-661-109
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02412111
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Vertex Pharmaceuticals Incorporated
    Sponsor organisation address
    50 Northern Avenue, Boston, Massachusetts, United States, 02210-1862
    Public contact
    Medical Monitor, Vertex Pharmaceuticals Incorporated, 1 6173416777, medical_info@vrtx.com
    Scientific contact
    Medical Monitor, Vertex Pharmaceuticals Incorporated, 1 6173416777, medical_info@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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Oct 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of VX-661 in combination with Ivacaftor in subjects with cystic fibrosis (CF) who were heterozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene and a second CFTR allele with a gating defect that was clinically demonstrated to be Ivacaftor responsive
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Jun 2015
    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
    United Kingdom: 21
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    United States: 76
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Ireland: 4
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Australia: 16
    Country: Number of subjects enrolled
    Canada: 7
    Worldwide total number of subjects
    156
    EEA total number of subjects
    57
    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)
    20
    Adults (18-64 years)
    135
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study consisted of 2 periods: an Ivacaftor Run-in Period and an Active Comparator Treatment Period. Subjects were randomized in a ratio of 1:1 to receive either VX-661/ivacaftor combination therapy or ivacaftor monotherapy for 8 weeks during the Active Comparator Treatment Period after completion of 4 weeks Ivacaftor Run-in Period.

    Period 1
    Period 1 title
    Ivacaftor Run-in Period (4 weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Ivacaftor (Run-in period)
    Arm description
    		 Ivacaftor every 12 hours for 4 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor every 12 hours for 4 weeks.

    Number of subjects in period 1
    		Ivacaftor (Run-in period)
    Started
    156
    Completed
    153
    Not completed
    3
         Did not meet eligibility criteria
    1
         Subject refused further dosing
    2
    Period 2
    Period 2 title
    Active Comparator Period (8 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 VX-661 + Ivacaftor
    Arm description
    		 VX-661 and ivacaftor fixed-dose combination once daily in morning and ivacaftor once daily in evening for 8 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-661/Ivacaftor Fixed Dose Combination
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    VX-661 and ivacaftor fixed-dose combination once daily in morning for 8 weeks.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor once daily in evening for 8 weeks.

    Arm title
    		 Ivacaftor monotherapy
    Arm description
    		 Ivacaftor every 12 hours as monotherapy for 8 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor every 12 hours as monotherapy for 8 weeks.

    Number of subjects in period 2 [1]
    		VX-661 + Ivacaftor Ivacaftor monotherapy
    Started
    76
    75
    Full analysis set
    76
    74
    Completed
    75
    69
    Not completed
    1
    6
         Adverse event
    -
    2
         Unspecified
    -
    2
         Other non-compliance
    1
    -
         Lost to follow-up
    -
    1
         Subject refused further dosing
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Two subjects who completed the Run-in period did not enter the active comparator period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ivacaftor (Run-in period)
    Reporting group description
    		 Ivacaftor every 12 hours for 4 weeks.

    Reporting group values
    		 Ivacaftor (Run-in period) Total
    Number of subjects
    		 156 156
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32.1 ( 12.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 68 68
        Male
    		 88 88

    End points

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    End points reporting groups
    Reporting group title
    Ivacaftor (Run-in period)
    Reporting group description
    		 Ivacaftor every 12 hours for 4 weeks.
    Reporting group title
    VX-661 + Ivacaftor
    Reporting group description
    		 VX-661 and ivacaftor fixed-dose combination once daily in morning and ivacaftor once daily in evening for 8 weeks.

    Reporting group title
    Ivacaftor monotherapy
    Reporting group description
    		 Ivacaftor every 12 hours as monotherapy for 8 weeks.

    Primary: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 8

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    End point title
    		 Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 8
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Full Analysis Set was defined as all randomized subjects who have received at least 1 dose of blinded study drug during the active comparator treatment period. Here "Number of subjects analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Through Week 8
    End point values
    		 VX-661 + Ivacaftor Ivacaftor monotherapy
    Number of subjects analysed
    76
    72
    Units: Percent predicted of FEV1
        least squares mean (standard error)
    0.5 ( 0.4 )
    0.2 ( 0.4 )
    Statistical analysis title
    		 Absolute Change From Baseline In ppFEV1
    Comparison groups
    VX-661 + Ivacaftor v Ivacaftor monotherapy
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5846
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 Least Square (LS) mean difference
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 1.4

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 16
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Ivacaftor (Run-in period)
    Reporting group description
    		 Ivacaftor every 12 hours for 4 weeks.

    Reporting group title
    VX-661 + Ivacaftor (Active comparator period)
    Reporting group description
    		 VX-661 and ivacaftor fixed-dose combination once daily in morning and ivacaftor once daily in evening for 8 weeks.

    Reporting group title
    Ivacaftor monotherapy (Active comparator period)
    Reporting group description
    		 Ivacaftor every 12 hours as monotherapy for 8 weeks.

    Serious adverse events
    		 Ivacaftor (Run-in period) VX-661 + Ivacaftor (Active comparator period) Ivacaftor monotherapy (Active comparator period)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 156 (1.28%)
    4 / 76 (5.26%)
    7 / 75 (9.33%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Human rhinovirus test positive
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Idiopathic intracranial hypertension
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 76 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Face oedema
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 76 (1.32%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 76 (1.32%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 76 (1.32%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 76 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    1 / 156 (0.64%)
    2 / 76 (2.63%)
    5 / 75 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 76 (1.32%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 76 (1.32%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ivacaftor (Run-in period) VX-661 + Ivacaftor (Active comparator period) Ivacaftor monotherapy (Active comparator period)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    65 / 156 (41.67%)
    76 / 76 (100.00%)
    53 / 75 (70.67%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 156 (1.28%)
    4 / 76 (5.26%)
    0 / 75 (0.00%)
         occurrences all number
    2
    4
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 156 (2.56%)
    5 / 76 (6.58%)
    2 / 75 (2.67%)
         occurrences all number
    4
    5
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 156 (1.92%)
    0 / 76 (0.00%)
    4 / 75 (5.33%)
         occurrences all number
    3
    0
    4
    Diarrhoea
         subjects affected / exposed
    2 / 156 (1.28%)
    4 / 76 (5.26%)
    1 / 75 (1.33%)
         occurrences all number
    2
    4
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 156 (7.69%)
    12 / 76 (15.79%)
    12 / 75 (16.00%)
         occurrences all number
    12
    13
    13
    Sputum increased
         subjects affected / exposed
    8 / 156 (5.13%)
    4 / 76 (5.26%)
    7 / 75 (9.33%)
         occurrences all number
    8
    5
    8
    Haemoptysis
         subjects affected / exposed
    3 / 156 (1.92%)
    3 / 76 (3.95%)
    4 / 75 (5.33%)
         occurrences all number
    3
    3
    5
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    2 / 156 (1.28%)
    6 / 76 (7.89%)
    4 / 75 (5.33%)
         occurrences all number
    2
    6
    5
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 156 (0.64%)
    4 / 76 (5.26%)
    6 / 75 (8.00%)
         occurrences all number
    1
    4
    6
    Headache
         subjects affected / exposed
    10 / 156 (6.41%)
    6 / 76 (7.89%)
    4 / 75 (5.33%)
         occurrences all number
    10
    6
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jul 2015
    - Specified criteria for sweat chloride assessment at Screening Visit - Added an ophthalmologic examination - Removed some of the study endpoints
    08 Oct 2015
    - Included potential to extend Ivacaftor Run-in Period - Added a window to the Visit during the Ivacaftor Run-in Period
    18 Apr 2017
    - Reduced the planned number of subjects enrolled

    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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