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    Clinical Trial Results:
    A Phase 2, Randomized, Placebo-Controlled, Double-blind Study to Evaluate the Effect of VX-661 in Combination With Ivacaftor on Chest Imaging Endpoints in Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation

    Summary
    EudraCT number
    		 2019-002189-11
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    24 Jul 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Nov 2019
    First version publication date
    07 Nov 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VX15-661-112
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02730208
    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)
    No
    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
    23 Aug 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the treatment effect of tezacaftor in combination with ivacaftor (TEZ/IVA) on chest imaging endpoints using low-dose computed tomography (LDCT) at Week 72, and to evaluate the safety of TEZ/IVA through Week 72.
    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
    13 Sep 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 41
    Worldwide total number of subjects
    41
    EEA total number of subjects
    0
    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)
    19
    Adults (18-64 years)
    22
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 41 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
    		 TEZ/IVA
    Arm description
    		 Subjects received TEZ/IVA fixed dose combination in the morning and IVA in the evening for 72 weeks.
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    IVA
    Investigational medicinal product code
    VX-770
    Other name
    Ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received IVA 150 mg once daily.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo matched to TEZ/IVA fixed dose combination in the morning and placebo matched to IVA in the evening for 72 weeks.
    Arm type
    		 Placebo

    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.

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

    Number of subjects in period 1
    		TEZ/IVA Placebo
    Started
    20
    21
    Completed
    20
    20
    Not completed
    0
    1
         Withdrawal of consent (not due to AE)
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TEZ/IVA
    Reporting group description
    		 Subjects received TEZ/IVA fixed dose combination in the morning and IVA in the evening for 72 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to TEZ/IVA fixed dose combination in the morning and placebo matched to IVA in the evening for 72 weeks.

    Reporting group values
    		 TEZ/IVA Placebo Total
    Number of subjects
    		 20 21 41
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 20.4 ( 7.5 ) 20.1 ( 9.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 11 10 21
        Male
    		 9 11 20
    Ethnicity (NIH/ OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 20 21 41
        Unknown or Not Reported
    		 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 20 21 41
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Total Brody/ Cystic Fibrosis - Computed Tomography (CFCT) Score
    The exploratory Brody/CF-CT score semi-quantitatively scores the degree of structural lung disease as shown on CT in subjects with CF. The score ranges from a minimum of 0 to a maximum of 219 with higher scores indicating more severe structural lung disease.
    Units: scores on a scale
        arithmetic mean (standard deviation)
    		 38.29 ( 22.91 ) 43.68 ( 33.96 ) -

    End points

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    End points reporting groups
    Reporting group title
    TEZ/IVA
    Reporting group description
    		 Subjects received TEZ/IVA fixed dose combination in the morning and IVA in the evening for 72 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to TEZ/IVA fixed dose combination in the morning and placebo matched to IVA in the evening for 72 weeks.

    Primary: Absolute Change in Total Brody/CF-CT Score

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    End point title
    		 Absolute Change in Total Brody/CF-CT Score
    End point description
    The exploratory Brody/CF-CT score semi-quantitatively scores the degree of structural lung disease as shown on CT in subjects with CF. The score ranges from a minimum of 0 to a maximum of 219 with higher scores indicating more severe structural lung disease. The full analysis set (FAS) included all subjects who were randomized and received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    From Baseline at Week 72
    End point values
    		 TEZ/IVA Placebo
    Number of subjects analysed
    20
    21
    Units: scores on a scale
        least squares mean (standard error)
    0.90 ( 2.09 )
    2.38 ( 2.07 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    TEZ/IVA v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    -1.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.47
         upper limit
    		 4.52
    Notes
    [1] - Treatment effect outcomes are estimates.

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

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    The safety set included all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Week 76
    End point values
    		 TEZ/IVA Placebo
    Number of subjects analysed
    20
    21
    Units: Subjects
        Subjects with AEs
    20
    21
        Subjects with SAEs
    8
    13
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to Week 76
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    TEZ/IVA
    Reporting group description
    		 Subjects received TEZ/IVA fixed dose combination in the morning and IVA in the evening for 72 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to TEZ/IVA fixed dose combination in the morning and placebo matched to IVA in the evening for 72 weeks.

    Serious adverse events
    		 TEZ/IVA Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 20 (40.00%)
    13 / 21 (61.90%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Bacterial test positive
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Type I hypersensitivity
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular torsion
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Atypical mycobacterial lower respiratory tract infection
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    5 / 20 (25.00%)
    6 / 21 (28.57%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection pseudomonal
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TEZ/IVA Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 20 (95.00%)
    20 / 21 (95.24%)
    Investigations
    Bacterial test positive
         subjects affected / exposed
    0 / 20 (0.00%)
    5 / 21 (23.81%)
         occurrences all number
    0
    8
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Fungal test positive
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    3
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Sunburn
         subjects affected / exposed
    1 / 20 (5.00%)
    3 / 21 (14.29%)
         occurrences all number
    1
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 20 (5.00%)
    4 / 21 (19.05%)
         occurrences all number
    1
    9
    Migraine
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    5
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    6
    Fatigue
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Pyrexia
         subjects affected / exposed
    3 / 20 (15.00%)
    2 / 21 (9.52%)
         occurrences all number
    4
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 21 (9.52%)
         occurrences all number
    2
    3
    Constipation
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Nausea
         subjects affected / exposed
    0 / 20 (0.00%)
    4 / 21 (19.05%)
         occurrences all number
    0
    8
    Vomiting
         subjects affected / exposed
    0 / 20 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 20 (40.00%)
    9 / 21 (42.86%)
         occurrences all number
    9
    12
    Epistaxis
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    4
    Haemoptysis
         subjects affected / exposed
    4 / 20 (20.00%)
    2 / 21 (9.52%)
         occurrences all number
    4
    2
    Oropharyngeal pain
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 21 (9.52%)
         occurrences all number
    2
    2
    Productive cough
         subjects affected / exposed
    4 / 20 (20.00%)
    4 / 21 (19.05%)
         occurrences all number
    5
    7
    Rhinorrhoea
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Sputum increased
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    Upper respiratory tract congestion
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    5 / 20 (25.00%)
    9 / 21 (42.86%)
         occurrences all number
    12
    16
    Influenza
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    3 / 20 (15.00%)
    2 / 21 (9.52%)
         occurrences all number
    5
    3
    Nasopharyngitis
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 21 (4.76%)
         occurrences all number
    6
    1
    Pharyngitis
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    Rhinitis
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 20 (20.00%)
    2 / 21 (9.52%)
         occurrences all number
    5
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jan 2016
    Clarified assessment requirements and analysis timing
    15 Dec 2016
    Removed interim analysis, revised assessments, clarified eligibility requirements
    24 Oct 2017
    Clarified visit requirements
    26 Feb 2018
    Clarified visit requirements, added endpoint

    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
    For support, Contact us.
    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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