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    Clinical Trial Results:
    A Phase 3, Randomized, Double-blind, Placebo-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 With a Second CFTR Mutation That Is Not Likely to Respond to VX-661 and/or Ivacaftor Therapy (F508del/NR)

    Summary
    EudraCT number
    		 2014-004787-37
    Trial protocol
    		 AT   DE   ES  
    Global end of trial date
    12 Aug 2016

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

    Trial information

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    Trial identification
    Sponsor protocol code
    VX14-661-107
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02516410
    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, 1 617-341-6777, 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-PIP01-14
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Aug 2016
    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 through Week 12 in subjects with cystic fibrosis (CF) who are heterozygous for the F508del- CF transmembrane conductance regulator (CFTR) gene and with a second CFTR mutation that is not likely to respond to VX-661 and/or ivacaftor therapy (F508del/not responsive [NR]).
    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
    15 Aug 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 States: 89
    Country: Number of subjects enrolled
    Israel: 24
    Country: Number of subjects enrolled
    Australia: 17
    Country: Number of subjects enrolled
    Austria: 16
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Spain: 3
    Worldwide total number of subjects
    168
    EEA total number of subjects
    34
    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)
    37
    Adults (18-64 years)
    131
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted across 38 sites in 7 countries.

    Pre-assignment
    Screening details
    		 A total of 168 subjects were randomized and treated in the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo matched to VX-661 plus Ivacaftor (IVA, VX-770) fixed dose combination (FDC) tablet administered orally in the morning and placebo matched to IVA film-coated tablet administered orally in the evening up to Week 12.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo (matched to VX-661 plus IVA)
    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 supplied as FDC tablet administered orally in the morning up to Week 12.

    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 film-coated tablet administered orally in the evening up to Week 12.

    Arm title
    		 VX-661/IVA
    Arm description
    		 VX-661 100 milligram (mg) plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-661 Plus IVA Fixed Dose Combination
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    VX-661 100 mg plus IVA 150 mg supplied as FDC tablet administered orally in the morning up to Week 12.

    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
    Ivacaftor 150 mg film-coated tablet administered orally in the evening up to Week 12.

    Number of subjects in period 1
    		Placebo VX-661/IVA
    Started
    85
    83
    Completed
    85
    81
    Not completed
    0
    2
         Consent withdrawn by subject
    -
    1
         Adverse event
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to VX-661 plus Ivacaftor (IVA, VX-770) fixed dose combination (FDC) tablet administered orally in the morning and placebo matched to IVA film-coated tablet administered orally in the evening up to Week 12.

    Reporting group title
    VX-661/IVA
    Reporting group description
    		 VX-661 100 milligram (mg) plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.

    Reporting group values
    		 Placebo VX-661/IVA Total
    Number of subjects
    		 85 83 168
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 26 ± 8.8 26.2 ± 9.6 -
    Gender categorical
    Units: Subjects
        Female
    		 42 39 81
        Male
    		 43 44 87

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to VX-661 plus Ivacaftor (IVA, VX-770) fixed dose combination (FDC) tablet administered orally in the morning and placebo matched to IVA film-coated tablet administered orally in the evening up to Week 12.

    Reporting group title
    VX-661/IVA
    Reporting group description
    		 VX-661 100 milligram (mg) plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.

    Primary: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 12

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    End point title
    		 Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 12
    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. 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 through Week 12
    End point values
    		 Placebo VX-661/IVA
    Number of subjects analysed
    85
    82
    Units: percent predicted of FEV1
        least squares mean (standard error)
    -0.1 ± 0.6
    1 ± 0.6
    Statistical analysis title
    		 Change in percent predicted FEV1 Through Week 12
    Comparison groups
    Placebo v VX-661/IVA
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1176
    Method
    		 Mixed-effect repeated measure (MMRM)
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 2.6

    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
    19.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA film-coated tablet administered orally in the evening up to Week 12.

    Reporting group title
    VX-661/IVA
    Reporting group description
    		 VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.

    Serious adverse events
    		 Placebo VX-661/IVA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 85 (16.47%)
    11 / 83 (13.25%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Pulmonary function test decreased
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    0 / 85 (0.00%)
    3 / 83 (3.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    1 / 85 (1.18%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    12 / 85 (14.12%)
    6 / 83 (7.23%)
         occurrences causally related to treatment / all
    2 / 12
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo VX-661/IVA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    63 / 85 (74.12%)
    62 / 83 (74.70%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 85 (8.24%)
    5 / 83 (6.02%)
         occurrences all number
    7
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 85 (4.71%)
    10 / 83 (12.05%)
         occurrences all number
    4
    11
    Pyrexia
         subjects affected / exposed
    5 / 85 (5.88%)
    5 / 83 (6.02%)
         occurrences all number
    6
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    6 / 85 (7.06%)
    6 / 83 (7.23%)
         occurrences all number
    7
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    27 / 85 (31.76%)
    19 / 83 (22.89%)
         occurrences all number
    31
    20
    Haemoptysis
         subjects affected / exposed
    6 / 85 (7.06%)
    8 / 83 (9.64%)
         occurrences all number
    7
    12
    Nasal congestion
         subjects affected / exposed
    8 / 85 (9.41%)
    7 / 83 (8.43%)
         occurrences all number
    8
    9
    Sputum increased
         subjects affected / exposed
    12 / 85 (14.12%)
    7 / 83 (8.43%)
         occurrences all number
    15
    7
    Dyspnoea
         subjects affected / exposed
    7 / 85 (8.24%)
    5 / 83 (6.02%)
         occurrences all number
    7
    5
    Oropharyngeal pain
         subjects affected / exposed
    6 / 85 (7.06%)
    5 / 83 (6.02%)
         occurrences all number
    6
    5
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    15 / 85 (17.65%)
    17 / 83 (20.48%)
         occurrences all number
    19
    21
    Nasopharyngitis
         subjects affected / exposed
    5 / 85 (5.88%)
    2 / 83 (2.41%)
         occurrences all number
    5
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 May 2015
    - Increased the number of planned subjects to account for an interim analysis for futility. - Added washout requirements for subjects who have previously used a commercially available CFTR modulator. - For < 18 years of age, added post-dose spirometry assessments and added ophthalmologic examination at the Early Treatment Termination (ETT) Visit or Safety Follow-up Visit.
    15 Apr 2016
    - Added that ophthalmologic examinations were not required for subjects with documentation of bilateral lens removal. - Specified that the sweat chloride test at screening is optional if the subject’s medical record is used to establish eligibility. - Allowed CFTR genotype information from a previous CFTR genotype laboratory report to be used in cases where results from genotype assessment at screening are not available before randomization. - Removed Pittsburgh Sleep Quality Index (PSQI) assessment at Day 15. - Revised the description of the timing of the spirometry assessment relative to bronchodilator use. - Added a window of ± 15 minutes around the nominal times for all postdose ECG assessments.

    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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