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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Efficacy and Safety of Ivacaftor and 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 Allele With a CFTR Mutation Predicted to Have Residual Function

    Summary
    EudraCT number
    2014-004788-18
    Trial protocol
    IT   DE   NL   GB   BE  
    Global end of trial date
    16 Feb 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Sep 2017
    First version publication date
    01 Sep 2017
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    VX14-661-108
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02392234
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Vertex Pharmaceuticals Incorporated
    Sponsor organisation address
    50 Northern Avenue, Boston, Massachusetts, United States, 022101862
    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-PIP01-04
    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
    14 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Feb 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 and ivacaftor monotherapy through 8 weeks of treatment in subjects with cystic fibrosis (CF) who are heterozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene and a second allele with a CFTR mutation predicted to have residual function.
    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
    27 Mar 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
    Netherlands: 13
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    France: 23
    Country: Number of subjects enrolled
    Germany: 25
    Country: Number of subjects enrolled
    Italy: 24
    Country: Number of subjects enrolled
    United States: 115
    Country: Number of subjects enrolled
    Australia: 10
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Israel: 7
    Worldwide total number of subjects
    248
    EEA total number of subjects
    109
    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)
    34
    Adults (18-64 years)
    212
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    The study was conducted at 81 sites in 10 countries.

    Pre-assignment
    Screening details
    A total of 248 subjects were randomized to 1 of 6 treatment sequences, each of which included 2 treatment periods and 2 of 3 potential treatments (placebo, VX-661/IVA, IVA).

    Period 1
    Period 1 title
    Treatment Period 1 (8 Weeks)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    First VX-661/IVA, Then IVA - Treatment 1: VX-661/IVA
    Arm description
    VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-661 Plus IVA Combination
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    VX-661 plus IVA Fixed Dose Combination (FDC) in the morning for 8 weeks.

    Investigational medicinal product name
    Placebo (matched to IVA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to IVA in the morning for 8 weeks.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Kalydeco
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    IVA in the evening for 8 weeks.

    Arm title
    First VX-661/IVA, Then Placebo - Treatment 1: VX-661/IVA
    Arm description
    VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-661 Plus IVA Combination
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    VX-661 plus IVA FDC in the morning for 8 weeks.

    Investigational medicinal product name
    Placebo (matched to IVA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to IVA in the morning for 8 weeks.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Kalydeco
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    IVA in the evening for 8 weeks.

    Arm title
    First IVA, Then Placebo - Treatment 1: IVA
    Arm description
    IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo (matched to VX-661 Plus IVA Combination)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to VX-661 plus IVA FDC in the morning for 8 weeks.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Kalydeco
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    IVA in the morning and evening for 8 weeks.

    Arm title
    First IVA, Then VX-661/IVA - Treatment 1: IVA
    Arm description
    IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo (matched to VX-661 Plus IVA Combination)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to VX-661 plus IVA FDC in the morning for 8 weeks.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Kalydeco
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    IVA in the morning and evening for 8 weeks.

    Arm title
    First Placebo, Then VX-661/IVA - Treatment 1: Placebo
    Arm description
    Placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 1 followed by VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (matched to VX-661 Plus IVA Combination)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to VX-661 plus IVA FDC in the morning for 8 weeks.

    Investigational medicinal product name
    Placebo (matched to IVA)
    Investigational medicinal product code
    VX-770
    Other name
    Kalydeco
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to IVA in the morning and evening for 8 weeks.

    Arm title
    First Placebo, Then IVA - Treatment 1: Placebo
    Arm description
    Placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 1 followed by IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (matched to VX-661 Plus IVA Combination)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to VX-661 plus IVA FDC in the morning for 8 weeks.

    Investigational medicinal product name
    Placebo (matched to IVA)
    Investigational medicinal product code
    VX-770
    Other name
    Kalydeco
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to IVA in the morning and evening for 8 weeks.

    Number of subjects in period 1
    First VX-661/IVA, Then IVA - Treatment 1: VX-661/IVA First VX-661/IVA, Then Placebo - Treatment 1: VX-661/IVA First IVA, Then Placebo - Treatment 1: IVA First IVA, Then VX-661/IVA - Treatment 1: IVA First Placebo, Then VX-661/IVA - Treatment 1: Placebo First Placebo, Then IVA - Treatment 1: Placebo
    Started
    41
    43
    40
    42
    41
    41
    Treated
    41
    43
    39
    42
    40
    41
    Completed
    38
    43
    38
    41
    37
    38
    Not completed
    3
    0
    2
    1
    4
    3
         Randomized but not treated
    -
    -
    1
    -
    1
    -
         Adverse event
    1
    -
    1
    -
    1
    1
         Non compliance of study drug
    -
    -
    -
    -
    -
    1
         Pregnancy
    1
    -
    -
    1
    -
    -
         Consent withdrawn by subject
    -
    -
    -
    -
    2
    -
         Unspecified
    1
    -
    -
    -
    -
    -
         Lost to follow-up
    -
    -
    -
    -
    -
    1
    Period 2
    Period 2 title
    Treatment Period 2 (8 Weeks)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    First VX-661/IVA, Then IVA - Treatment 2: IVA
    Arm description
    VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo (matched to VX-661 Plus IVA Combination)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to VX-661 plus IVA FDC in the morning for 8 weeks.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Kalydeco
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    IVA in the morning and evening for 8 weeks.

    Arm title
    First VX-661/IVA, Then Placebo - Treatment 2: Placebo
    Arm description
    VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (matched to VX-661 Plus IVA Combination)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to VX-661 plus IVA FDC in the morning for 8 weeks.

    Investigational medicinal product name
    Placebo (matched to IVA)
    Investigational medicinal product code
    VX-770
    Other name
    Kalydeco
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to IVA in the morning and evening for 8 weeks.

    Arm title
    First IVA, Then Placebo - Treatment 2: Placebo
    Arm description
    IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (matched to VX-661 Plus IVA Combination)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to VX-661 plus IVA FDC in the morning for 8 weeks.

    Investigational medicinal product name
    Placebo (matched to IVA)
    Investigational medicinal product code
    VX-770
    Other name
    Kalydeco
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to IVA in the morning and evening for 8 weeks.

    Arm title
    First IVA, Then VX-661/IVA - Treatment 2: VX-661/IVA
    Arm description
    IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-661 Plus IVA Combination
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    VX-661 plus IVA FDC in the morning for 8 weeks.

    Investigational medicinal product name
    Placebo (matched to IVA)
    Investigational medicinal product code
    VX-770
    Other name
    Kalydeco
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to IVA in the morning for 8 weeks.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Kalydeco
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    IVA in the evening for 8 weeks.

    Arm title
    First Placebo, Then VX-661/IVA - Treatment 2: VX-661/IVA
    Arm description
    Placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 1 followed by VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-661 Plus IVA Combination
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    VX-661 plus IVA FDC in the morning for 8 weeks.

    Investigational medicinal product name
    Placebo (matched to IVA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to IVA in the morning for 8 weeks.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Kalydeco
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    IVA in the evening for 8 weeks.

    Arm title
    First Placebo, Then IVA - Treatment 2: IVA
    Arm description
    Placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 1 followed by IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo (matched to VX-661 Plus IVA Combination)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to VX-661 plus IVA FDC in the morning for 8 weeks.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Kalydeco
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    IVA in the morning and evening for 8 weeks.

    Number of subjects in period 2
    First VX-661/IVA, Then IVA - Treatment 2: IVA First VX-661/IVA, Then Placebo - Treatment 2: Placebo First IVA, Then Placebo - Treatment 2: Placebo First IVA, Then VX-661/IVA - Treatment 2: VX-661/IVA First Placebo, Then VX-661/IVA - Treatment 2: VX-661/IVA First Placebo, Then IVA - Treatment 2: IVA
    Started
    38
    43
    38
    41
    37
    38
    Completed
    37
    43
    38
    41
    37
    38
    Not completed
    1
    0
    0
    0
    0
    0
         Adverse event
    1
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    First VX-661/IVA, Then IVA - Treatment 1: VX-661/IVA
    Reporting group description
    VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.

    Reporting group title
    First VX-661/IVA, Then Placebo - Treatment 1: VX-661/IVA
    Reporting group description
    VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.

    Reporting group title
    First IVA, Then Placebo - Treatment 1: IVA
    Reporting group description
    IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.

    Reporting group title
    First IVA, Then VX-661/IVA - Treatment 1: IVA
    Reporting group description
    IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.

    Reporting group title
    First Placebo, Then VX-661/IVA - Treatment 1: Placebo
    Reporting group description
    Placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 1 followed by VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.

    Reporting group title
    First Placebo, Then IVA - Treatment 1: Placebo
    Reporting group description
    Placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 1 followed by IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.

    Reporting group values
    First VX-661/IVA, Then IVA - Treatment 1: VX-661/IVA First VX-661/IVA, Then Placebo - Treatment 1: VX-661/IVA First IVA, Then Placebo - Treatment 1: IVA First IVA, Then VX-661/IVA - Treatment 1: IVA First Placebo, Then VX-661/IVA - Treatment 1: Placebo First Placebo, Then IVA - Treatment 1: Placebo Total
    Number of subjects
    41 43 40 42 41 41 248
    Age categorical
    Units: Subjects
        <18 Years
    5 6 7 5 5 6 34
        >=18 Years
    36 37 33 37 36 35 214
    Gender categorical
    Units: Subjects
        Female
    23 25 19 21 23 23 134
        Male
    18 18 21 21 18 18 114

    End points

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    End points reporting groups
    Reporting group title
    First VX-661/IVA, Then IVA - Treatment 1: VX-661/IVA
    Reporting group description
    VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.

    Reporting group title
    First VX-661/IVA, Then Placebo - Treatment 1: VX-661/IVA
    Reporting group description
    VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.

    Reporting group title
    First IVA, Then Placebo - Treatment 1: IVA
    Reporting group description
    IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.

    Reporting group title
    First IVA, Then VX-661/IVA - Treatment 1: IVA
    Reporting group description
    IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.

    Reporting group title
    First Placebo, Then VX-661/IVA - Treatment 1: Placebo
    Reporting group description
    Placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 1 followed by VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.

    Reporting group title
    First Placebo, Then IVA - Treatment 1: Placebo
    Reporting group description
    Placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 1 followed by IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.
    Reporting group title
    First VX-661/IVA, Then IVA - Treatment 2: IVA
    Reporting group description
    VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.

    Reporting group title
    First VX-661/IVA, Then Placebo - Treatment 2: Placebo
    Reporting group description
    VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.

    Reporting group title
    First IVA, Then Placebo - Treatment 2: Placebo
    Reporting group description
    IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.

    Reporting group title
    First IVA, Then VX-661/IVA - Treatment 2: VX-661/IVA
    Reporting group description
    IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 1 followed by VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.

    Reporting group title
    First Placebo, Then VX-661/IVA - Treatment 2: VX-661/IVA
    Reporting group description
    Placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 1 followed by VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.

    Reporting group title
    First Placebo, Then IVA - Treatment 2: IVA
    Reporting group description
    Placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in treatment period 1 followed by IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in either treatment period 1 or 2.

    Subject analysis set title
    Ivacaftor
    Subject analysis set type
    Full analysis
    Subject analysis set description
    IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in either treatment period 1 or 2.

    Subject analysis set title
    VX-661/IVA
    Subject analysis set type
    Full analysis
    Subject analysis set description
    VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in either treatment period 1 or 2.

    Primary: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Average of Week 4 and Week 8

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    End point title
    Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Average of Week 4 and Week 8
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male subjects 18 years and older and female subjects 16 years and older. The Wang standard was used for male subjects aged 12 to 17 years and for female subjects aged 12 to 15 years. The average absolute change from baseline in percent predicted FEV1 was derived as: (Average of Week 4 and Week 8 value) minus Baseline value. Full Analysis Set (FAS) included all randomized subjects who received at least 1 dose of study drug. Here 'Number of subjects analysed' signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4 and Week 8 of each treatment period
    End point values
    Placebo Ivacaftor VX-661/IVA
    Number of subjects analysed
    160
    156
    159
    Units: percent predicted of FEV1
        least squares mean (standard error)
    -0.3 ± 0.5
    4.4 ± 0.5
    6.5 ± 0.4
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    For ‘number of subjects included in the analysis’ field: total number of subjects analysed were 160 instead of 316 because this study is a cross-over design and same subjects may have received both the interventions.
    Comparison groups
    Placebo v Ivacaftor
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Linear Mixed Effects Model
    Parameter type
    Least Squares (LS) Mean Difference
    Point estimate
    4.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.7
         upper limit
    5.8
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    For ‘number of subjects included in the analysis’ field: total number of subjects analysed were 160 instead of 319 because this study is a cross-over design and same subjects may have received both the interventions.
    Comparison groups
    Placebo v VX-661/IVA
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Linear Mixed Effects Model
    Parameter type
    LS Mean Difference
    Point estimate
    6.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.7
         upper limit
    7.8

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to Week 28
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo matched to VX-661 plus IVA combination and placebo matched to IVA in the morning, placebo matched to IVA in the evening for 8 weeks in either treatment period 1 or 2.

    Reporting group title
    Ivacaftor
    Reporting group description
    IVA and placebo matched to VX-661 plus IVA combination in the morning, IVA in the evening for 8 weeks in either treatment period 1 or 2.

    Reporting group title
    VX-661/IVA
    Reporting group description
    VX-661 plus IVA combination and placebo matched to IVA in the morning, IVA in the evening for 8 weeks in either treatment period 1 or 2.

    Serious adverse events
    Placebo Ivacaftor VX-661/IVA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 162 (8.64%)
    10 / 157 (6.37%)
    8 / 162 (4.94%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 157 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 162 (0.00%)
    2 / 157 (1.27%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary function test decreased
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 157 (0.00%)
    0 / 162 (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
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 157 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 157 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 162 (1.23%)
    1 / 157 (0.64%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 157 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 157 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 162 (1.23%)
    0 / 157 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 157 (0.64%)
    0 / 162 (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
    Pancreatitis
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 157 (0.64%)
    0 / 162 (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
    Urethral stenosis
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 157 (0.00%)
    0 / 162 (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
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 157 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    8 / 162 (4.94%)
    6 / 157 (3.82%)
    4 / 162 (2.47%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 157 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 162 (1.23%)
    0 / 157 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    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
    Placebo Ivacaftor VX-661/IVA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    125 / 162 (77.16%)
    114 / 157 (72.61%)
    117 / 162 (72.22%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    30 / 162 (18.52%)
    17 / 157 (10.83%)
    23 / 162 (14.20%)
         occurrences all number
    36
    18
    27
    Sputum increased
         subjects affected / exposed
    11 / 162 (6.79%)
    12 / 157 (7.64%)
    14 / 162 (8.64%)
         occurrences all number
    13
    12
    16
    Haemoptysis
         subjects affected / exposed
    12 / 162 (7.41%)
    17 / 157 (10.83%)
    12 / 162 (7.41%)
         occurrences all number
    15
    20
    18
    Dyspnoea
         subjects affected / exposed
    11 / 162 (6.79%)
    3 / 157 (1.91%)
    9 / 162 (5.56%)
         occurrences all number
    11
    3
    11
    Oropharyngeal pain
         subjects affected / exposed
    9 / 162 (5.56%)
    7 / 157 (4.46%)
    9 / 162 (5.56%)
         occurrences all number
    9
    7
    9
    Nasal congestion
         subjects affected / exposed
    9 / 162 (5.56%)
    3 / 157 (1.91%)
    6 / 162 (3.70%)
         occurrences all number
    9
    3
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 162 (8.02%)
    11 / 157 (7.01%)
    18 / 162 (11.11%)
         occurrences all number
    20
    14
    25
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    16 / 162 (9.88%)
    7 / 157 (4.46%)
    12 / 162 (7.41%)
         occurrences all number
    17
    7
    12
    Pyrexia
         subjects affected / exposed
    12 / 162 (7.41%)
    2 / 157 (1.27%)
    8 / 162 (4.94%)
         occurrences all number
    12
    2
    9
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    10 / 162 (6.17%)
    5 / 157 (3.18%)
    13 / 162 (8.02%)
         occurrences all number
    10
    6
    13
    Nausea
         subjects affected / exposed
    10 / 162 (6.17%)
    3 / 157 (1.91%)
    9 / 162 (5.56%)
         occurrences all number
    10
    4
    11
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 162 (3.09%)
    6 / 157 (3.82%)
    13 / 162 (8.02%)
         occurrences all number
    6
    7
    14
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    25 / 162 (15.43%)
    14 / 157 (8.92%)
    19 / 162 (11.73%)
         occurrences all number
    25
    14
    20

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Aug 2015
    - Added additional assessments; - Allowed Screening Period to be extended; - Revised restricted medication list; - Added washout requirements for subjects who previously used commercially available CFTR modulator; - Added details to determine eligible CTFR mutations; - Revised the list of eligible mutations.
    10 Jun 2016
    - Clarified the timing of the Washout Period; - Clarified the inclusion criteria with sweat chloride; - Clarified screening assessments; - Revised the description of assessments; - Revised the testing strategy; - Clarified baseline sweat chloride values.

    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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