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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Efficacy of Lumacaftor/Ivacaftor Combination Therapy in Subjects With Cystic Fibrosis Who Have an A455E-CFTR Mutation

    Summary
    EudraCT number
    		 2016-001585-29
    Trial protocol
    		 NL  
    Global end of trial date
    04 Oct 2017

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

    Trial information

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    Trial identification
    Sponsor protocol code
    VX15-809-111
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03061331
    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)
    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 Oct 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of LUM/IVA in subjects with Cystic Fibrosis (CF) 12 years of age and older who have at least one A455E mutation.
    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
    31 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    2
    Adults (18-64 years)
    18
    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 20 subjects were enrolled in this cross-over 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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sequence 1: First LUM/IVA, Then Placebo
    Arm description
    		 Subjects received LUM/IVA fixed dose combination in treatment period 1 followed by placebo matched to LUM/IVA fixed dose combination in treatment period 2. Treatment periods were separated by a wash-out period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LUM/IVA fixed-dose combination
    Investigational medicinal product code
    VX-809/VX-770
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered every 12 hours for 8 weeks.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered every 12 hours for 8 weeks.

    Arm title
    		 Sequence 2: First Placebo, Then LUM/IVA
    Arm description
    		 Subjects received placebo matched to LUM/IVA fixed dose combination in treatment period 1 followed by LUM/IVA fixed dose combination in treatment period 2. Treatment periods were separated by a wash-out period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LUM/IVA fixed-dose combination
    Investigational medicinal product code
    VX-809/VX-770
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered every 12 hours for 8 weeks.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered every 12 hours for 8 weeks.

    Number of subjects in period 1
    		Sequence 1: First LUM/IVA, Then Placebo Sequence 2: First Placebo, Then LUM/IVA
    Started
    10
    10
    Completed
    8
    9
    Not completed
    2
    1
         Adverse event
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence 1: First LUM/IVA, Then Placebo
    Reporting group description
    		 Subjects received LUM/IVA fixed dose combination in treatment period 1 followed by placebo matched to LUM/IVA fixed dose combination in treatment period 2. Treatment periods were separated by a wash-out period.

    Reporting group title
    Sequence 2: First Placebo, Then LUM/IVA
    Reporting group description
    		 Subjects received placebo matched to LUM/IVA fixed dose combination in treatment period 1 followed by LUM/IVA fixed dose combination in treatment period 2. Treatment periods were separated by a wash-out period.

    Reporting group values
    		 Sequence 1: First LUM/IVA, Then Placebo Sequence 2: First Placebo, Then LUM/IVA Total
    Number of subjects
    		 10 10 20
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.2 ( 15.1 ) 34.7 ( 11.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 7 5 12
        Male
    		 3 5 8

    End points

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    End points reporting groups
    Reporting group title
    Sequence 1: First LUM/IVA, Then Placebo
    Reporting group description
    		 Subjects received LUM/IVA fixed dose combination in treatment period 1 followed by placebo matched to LUM/IVA fixed dose combination in treatment period 2. Treatment periods were separated by a wash-out period.

    Reporting group title
    Sequence 2: First Placebo, Then LUM/IVA
    Reporting group description
    		 Subjects received placebo matched to LUM/IVA fixed dose combination in treatment period 1 followed by LUM/IVA fixed dose combination in treatment period 2. Treatment periods were separated by a wash-out period.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo matched to LUM/IVA every 12 hours for 8 weeks in Treatment Period 1 or 2.

    Subject analysis set title
    LUM/IVA
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    LUM/IVA fixed-dose combination every 12 hours for 8 weeks in Treatment Period 1 or 2.

    Primary: Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 8

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    End point title
    		 Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 8
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
    End point type
    Primary
    End point timeframe
    Study Baseline, Through Week 8
    End point values
    		 Placebo LUM/IVA
    Number of subjects analysed
    18
    18
    Units: percentage points
        least squares mean (confidence interval 95%)
    2.6 (0.2 to 4.9)
    2.7 (0.3 to 5.0)
    Statistical analysis title
    		 Absolute Change From Study Baseline in ppFEV1
    Statistical analysis description
    As this is a cross-over study, actual number of subjects analysed for the statistical comparison were 20 (16 of them being counted twice in two treatment periods). "Number of subjects included in analysis = 36 " is incorrect and is reflected due to EudraCT database limitation.
    Comparison groups
    LUM/IVA v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9277
    Method
    		 Mixed Model Repeated Measure (MMRM)
    Parameter type
    		 Least Squares Mean difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 2.7

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 28
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    LUM/IVA
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo LUM/IVA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo LUM/IVA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 18 (72.22%)
    15 / 19 (78.95%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 18 (11.11%)
    3 / 19 (15.79%)
         occurrences all number
    2
    3
    Exercise tolerance decreased
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Menopausal symptoms
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Menstruation irregular
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Sputum increased
         subjects affected / exposed
    3 / 18 (16.67%)
    3 / 19 (15.79%)
         occurrences all number
    3
    3
    Asthma
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    Cough
         subjects affected / exposed
    3 / 18 (16.67%)
    2 / 19 (10.53%)
         occurrences all number
    3
    2
    Dyspnoea
         subjects affected / exposed
    3 / 18 (16.67%)
    2 / 19 (10.53%)
         occurrences all number
    3
    3
    Dysphonia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Paranasal sinus discomfort
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Haemoptysis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    Respiration abnormal
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Sputum discoloured
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Wheezing
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Libido decreased
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Muscle strain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 18 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    0
    4
    Dizziness
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    3
    Dysgeusia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    2
    Paraesthesia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 18 (0.00%)
    8 / 19 (42.11%)
         occurrences all number
    0
    8
    Flatulence
         subjects affected / exposed
    0 / 18 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    0
    4
    Nausea
         subjects affected / exposed
    0 / 18 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    0
    4
    Abdominal pain
         subjects affected / exposed
    3 / 18 (16.67%)
    2 / 19 (10.53%)
         occurrences all number
    3
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    Abdominal discomfort
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Eructation
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Rash pruritic
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Skin exfoliation
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Acne
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Photosensitivity reaction
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    Back pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Arthralgia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 18 (11.11%)
    3 / 19 (15.79%)
         occurrences all number
    2
    3
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 18 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    3
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 19 (10.53%)
         occurrences all number
    2
    2
    Herpes zoster
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Laryngitis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Eye infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Impetigo
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    Sinusitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Tooth infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Wound infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Feb 2017
    - Removed restriction on number of subjects with F508del mutation

    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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