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    Clinical Trial Results:
    A Phase 3b, 2-part, Randomized, Double-blind, Placebo-controlled Crossover Study With a Long term Open-label Period to Investigate Ivacaftor in Subjects With Cystic Fibrosis Aged 3 Through 5 Years Who Have a Specified CFTR Gating Mutation

    Summary
    EudraCT number
    		 2015-001267-39
    Trial protocol
    		 GB   FR  
    Global end of trial date
    08 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Apr 2018
    First version publication date
    29 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VX15-770-123
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02742519
    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)
    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
    13 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Aug 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of Ivacaftor treatment, measured by lung clearance index (LCI) in subjects with cystic fibrosis (CF) who have a specified CF transmembrane conductance regulator (CFTR) gating mutation, and are 3 through 5 years of age at the start of the study.
    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
    04 May 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
    United Kingdom: 7
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Canada: 1
    Worldwide total number of subjects
    14
    EEA total number of subjects
    7
    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)
    14
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Study consisted of 2 parts: Part 1- Double Blind (DB) Crossover Treatment Period and Part 2- Open Label Period.

    Period 1
    Period 1 title
    Part 1: DB Treatment Period
    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
    		 Sequence 1: Ivacaftor First, Then Placebo
    Arm description
    		 Ivacaftor administered every 12 hours for 8 weeks in treatment period 1 followed by placebo matched to Ivacaftor administered every 12 hours for 8 weeks in treatment period 2. Washout period of 8 weeks occurred between treatment period 1 and treatment period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor administered orally every 12 hours for 8 weeks in treatment period 1.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to Ivacaftor administered orally every 12 hours for 8 weeks in treatment period 2.

    Arm title
    		 Sequence 2: Placebo First, Then Ivacaftor
    Arm description
    		 Placebo matched to Ivacaftor administered every 12 hours for 8 weeks in treatment period 1 followed by Ivacaftor administered every 12 hours for 8 weeks in treatment period 2. Washout period of 8 weeks occurred between treatment period 1 and treatment period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to Ivacaftor administered orally every 12 hours for 8 weeks in treatment period 1.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor administered orally every 12 hours for 8 weeks in treatment period 2.

    Number of subjects in period 1
    		Sequence 1: Ivacaftor First, Then Placebo Sequence 2: Placebo First, Then Ivacaftor
    Started
    8
    6
    Completed Treatment Period 1
    8
    6
    Started Treatment Period 2
    8
    6
    Completed
    7
    5
    Not completed
    1
    1
         Availability of commercial drug
    1
    1
    Period 2
    Period 2 title
    Part 2: Open Label Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Ivacaftor
    Arm description
    		 Ivacaftor administered every 12 hours in open label period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor administered every 12 hours in open label period.

    Number of subjects in period 2 [1]
    		Ivacaftor
    Started
    10
    Completed
    0
    Not completed
    10
         Availability of commercial drug
    9
         Unspecified
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Out of 12 subjects who completed double blind crossover treatment period, only 10 subjects entered the Open Label period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence 1: Ivacaftor First, Then Placebo
    Reporting group description
    		 Ivacaftor administered every 12 hours for 8 weeks in treatment period 1 followed by placebo matched to Ivacaftor administered every 12 hours for 8 weeks in treatment period 2. Washout period of 8 weeks occurred between treatment period 1 and treatment period 2.

    Reporting group title
    Sequence 2: Placebo First, Then Ivacaftor
    Reporting group description
    		 Placebo matched to Ivacaftor administered every 12 hours for 8 weeks in treatment period 1 followed by Ivacaftor administered every 12 hours for 8 weeks in treatment period 2. Washout period of 8 weeks occurred between treatment period 1 and treatment period 2.

    Reporting group values
    		 Sequence 1: Ivacaftor First, Then Placebo Sequence 2: Placebo First, Then Ivacaftor Total
    Number of subjects
    		 8 6 14
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 3.6 ( 0.7 ) 4.2 ( 1.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 1 5
        Male
    		 4 5 9

    End points

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    End points reporting groups
    Reporting group title
    Sequence 1: Ivacaftor First, Then Placebo
    Reporting group description
    		 Ivacaftor administered every 12 hours for 8 weeks in treatment period 1 followed by placebo matched to Ivacaftor administered every 12 hours for 8 weeks in treatment period 2. Washout period of 8 weeks occurred between treatment period 1 and treatment period 2.

    Reporting group title
    Sequence 2: Placebo First, Then Ivacaftor
    Reporting group description
    		 Placebo matched to Ivacaftor administered every 12 hours for 8 weeks in treatment period 1 followed by Ivacaftor administered every 12 hours for 8 weeks in treatment period 2. Washout period of 8 weeks occurred between treatment period 1 and treatment period 2.
    Reporting group title
    Ivacaftor
    Reporting group description
    		 Ivacaftor administered every 12 hours in open label period.

    Subject analysis set title
    Placebo (Crossover Part)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo matched to Ivacaftor administered orally every 12 hours for 8 weeks in treatment period 1 or treatment period 2.

    Subject analysis set title
    Ivacaftor (Crossover Part)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Ivacaftor administered orally every 12 hours for 8 weeks in treatment period 1 or treatment period 2.

    Primary: Absolute Change From Baseline in Lung Clearance Index (LCI2.5) Through Week 8

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    End point title
    		 Absolute Change From Baseline in Lung Clearance Index (LCI2.5) Through Week 8
    End point description
    LCI2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value. Full Analysis Set (FAS) was used which included all randomised subjects who had mutation on at least 1 allele, received at least 1 dose of study drug (Ivacaftor or placebo) and had at least 1 post-baseline assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Through Week 8
    End point values
    		 Placebo (Crossover Part) Ivacaftor (Crossover Part)
    Number of subjects analysed
    13
    13
    Units: Lung clearance index
        arithmetic mean (standard deviation)
    -0.07 ( 0.93 )
    -0.53 ( 1.23 )
    Statistical analysis title
    		 Absolute Change From Baseline in LCI2.5
    Statistical analysis description
    As this is a cross-over study, actual number of subjects analysed for the statistical comparison was 13. "Number of subjects included in analysis = 26" is reflected due to EudraCT database limitation.
    Comparison groups
    Ivacaftor (Crossover Part) v Placebo (Crossover Part)
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2121
    Method
    		 paired t-test
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Month 15
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Ivacaftor (Crossover Part)
    Reporting group description
    		 Ivacaftor administered orally every 12 hours for 8 weeks in treatment period 1 or treatment period 2.

    Reporting group title
    Placebo (Crossover Part)
    Reporting group description
    		 Placebo matched to Ivacaftor administered orally every 12 hours for 8 weeks in treatment period 1 or treatment period 2.

    Reporting group title
    Ivacaftor (Open Label Part)
    Reporting group description
    		 Ivacaftor administered orally every 12 hours in open label period.

    Serious adverse events
    		 Ivacaftor (Crossover Part) Placebo (Crossover Part) Ivacaftor (Open Label Part)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Ivacaftor (Crossover Part) Placebo (Crossover Part) Ivacaftor (Open Label Part)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 13 (84.62%)
    11 / 13 (84.62%)
    6 / 10 (60.00%)
    Investigations
    Haemophilus test positive
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Streptococcus test positive
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Bacterial test positive
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Pseudomonas test positive
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 13 (23.08%)
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences all number
    3
    1
    0
    Lethargy
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 13 (23.08%)
    3 / 10 (30.00%)
         occurrences all number
    1
    3
    3
    Constipation
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 13 (23.08%)
    2 / 13 (15.38%)
    4 / 10 (40.00%)
         occurrences all number
    3
    3
    5
    Productive cough
         subjects affected / exposed
    3 / 13 (23.08%)
    3 / 13 (23.08%)
    0 / 10 (0.00%)
         occurrences all number
    3
    3
    0
    Nasal congestion
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 13 (15.38%)
    0 / 10 (0.00%)
         occurrences all number
    1
    3
    0
    Wheezing
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    3 / 13 (23.08%)
    3 / 13 (23.08%)
    3 / 10 (30.00%)
         occurrences all number
    4
    3
    6
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 13 (23.08%)
    1 / 10 (10.00%)
         occurrences all number
    2
    3
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    Bacterial disease carrier
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Otitis media
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Aug 2015
    - Clarified text surrounding liver function testing.
    27 Oct 2016
    - Extended screening period and clarified subject eligibility following multiple breath washout (MBW) assessment.
    12 Apr 2017
    - Decision taken to terminate the study.

    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.
    Vertex terminated the study early because of enrollment futility.
    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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