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    Clinical Trial Results:
    A Phase 3, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Lumacaftor in Combination With Ivacaftor in Subjects Aged 6 Through 11 Years With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation

    Summary
    EudraCT number
    		 2015-000543-16
    Trial protocol
    		 GB   DE   SE   DK   BE   FR  
    Global end of trial date
    20 Sep 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Apr 2017
    First version publication date
    19 Apr 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VX14-809-109
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02514473
    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-001582-PIP01-13
    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
    11 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of lumacaftor (LUM) in combination with ivacaftor (IVA) in subjects aged 6 through 11 years with cystic fibrosis (CF), homozygous for the F508del CF transmembrane conductance regulator (CFTR) 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
    23 Jul 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: 103
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    Belgium: 15
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Australia: 28
    Worldwide total number of subjects
    206
    EEA total number of subjects
    58
    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)
    206
    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
    		 A total of 206 subjects were randomized in the study, of which 204 subjects were exposed to study treatment (101 subjects received ‘Placebo’ and 103 subjects received ‘LUM/IVA’).

    Period 1
    Period 1 title
    Overall (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
    		 Placebo
    Arm description
    		 Subjects received placebo matched to lumacaftor (LUM, VX-809) in combination with ivacaftor (IVA, VX-770) fixed-dose combination (FDC) tablet orally every 12 hours (q12h) for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to LUM in combination with IVA FDC tablet q12h for 24 weeks.

    Arm title
    		 LUM/IVA
    Arm description
    		 Subjects received LUM 200 milligram (mg) in combination with IVA 250 mg FDC tablet orally q12h for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lumacaftor/Ivacaftor FDC
    Investigational medicinal product code
    VX-809/VX-770
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LUM 200 mg in combination with IVA 250 mg tablet orally q12h for 24 weeks.

    Number of subjects in period 1 [1]
    		Placebo LUM/IVA
    Started
    101
    103
    Completed
    98
    98
    Not completed
    3
    5
         Consent withdrawn by subject
    2
    1
         Adverse event
    -
    2
         Unspecified
    1
    1
         Lost to follow-up
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 206 subjects were randomized in the study, of which 204 subjects were exposed to study drug (101 subjects received ‘Placebo’ and 103 subjects received ‘LUM/IVA’). Subject Disposition and Baseline Characteristics are presented for the 204 subjects who received the study treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to lumacaftor (LUM, VX-809) in combination with ivacaftor (IVA, VX-770) fixed-dose combination (FDC) tablet orally every 12 hours (q12h) for 24 weeks.

    Reporting group title
    LUM/IVA
    Reporting group description
    		 Subjects received LUM 200 milligram (mg) in combination with IVA 250 mg FDC tablet orally q12h for 24 weeks.

    Reporting group values
    		 Placebo LUM/IVA Total
    Number of subjects
    		 101 103 204
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.9 ± 1.59 8.7 ± 1.6 -
    Gender categorical
    Units: Subjects
        Female
    		 58 63 121
        Male
    		 43 40 83

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to lumacaftor (LUM, VX-809) in combination with ivacaftor (IVA, VX-770) fixed-dose combination (FDC) tablet orally every 12 hours (q12h) for 24 weeks.

    Reporting group title
    LUM/IVA
    Reporting group description
    		 Subjects received LUM 200 milligram (mg) in combination with IVA 250 mg FDC tablet orally q12h for 24 weeks.

    Primary: Absolute Change From Baseline in Lung Clearance Index 2.5 (LCI2.5) Through Week 24

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    End point title
    		 Absolute Change From Baseline in Lung Clearance Index 2.5 (LCI2.5) Through Week 24
    End point description
    Lung clearance index (LCI) is a measure of ventilation inhomogeneity that is derived from a multiple breath washout test using Nitrogen (N2). LCI2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value. Analysis was performed on the Full Analysis Set (FAS), which included all randomized subjects who received any amount of study drug. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline through Week 24
    End point values
    		 Placebo LUM/IVA
    Number of subjects analysed
    99
    99
    Units: Ratio
        least squares mean (standard error)
    0.08 ± 0.13
    -1.01 ± 0.13
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using mixed-effects model for repeated measures (MMRM). The model included treatment, visit and treatment-by-visit interaction as fixed effects; and subject as a random effect with adjustments for weight (less than [<] 25 kilogram [kg] versus greater than or equal to [>=] 25 kg) and percent predicted forced expiratory volume in 1 second (FEV1) severity (<90 versus >=90) at screening.
    Comparison groups
    LUM/IVA v Placebo
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.43
         upper limit
    		 -0.75

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline 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
    		 Subjects received placebo matched to LUM in combination with IVA FDC tablet orally q12h for 24 weeks.

    Reporting group title
    LUM/IVA
    Reporting group description
    		 Subjects received LUM 200 mg in combination with IVA 250 mg FDC tablet orally q12h for 24 weeks.

    Serious adverse events
    		 Placebo LUM/IVA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 101 (10.89%)
    13 / 103 (12.62%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Bacterial test positive
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Procedural anxiety
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Poor venous access
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Drug interaction
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related thrombosis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenitis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    2 / 101 (1.98%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Obstructive airways disorder
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    5 / 101 (4.95%)
    8 / 103 (7.77%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 3
    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
    		 Placebo LUM/IVA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    98 / 101 (97.03%)
    98 / 103 (95.15%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 101 (7.92%)
    8 / 103 (7.77%)
         occurrences all number
    10
    10
    Bacterial test positive
         subjects affected / exposed
    8 / 101 (7.92%)
    7 / 103 (6.80%)
         occurrences all number
    8
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 101 (5.94%)
    6 / 103 (5.83%)
         occurrences all number
    6
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 101 (8.91%)
    13 / 103 (12.62%)
         occurrences all number
    10
    19
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    20 / 101 (19.80%)
    15 / 103 (14.56%)
         occurrences all number
    25
    16
    Fatigue
         subjects affected / exposed
    11 / 101 (10.89%)
    9 / 103 (8.74%)
         occurrences all number
    14
    9
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    7 / 101 (6.93%)
    13 / 103 (12.62%)
         occurrences all number
    7
    13
    Abdominal pain
         subjects affected / exposed
    10 / 101 (9.90%)
    10 / 103 (9.71%)
         occurrences all number
    12
    12
    Nausea
         subjects affected / exposed
    9 / 101 (8.91%)
    10 / 103 (9.71%)
         occurrences all number
    11
    11
    Vomiting
         subjects affected / exposed
    10 / 101 (9.90%)
    10 / 103 (9.71%)
         occurrences all number
    11
    11
    Diarrhoea
         subjects affected / exposed
    4 / 101 (3.96%)
    6 / 103 (5.83%)
         occurrences all number
    4
    6
    Constipation
         subjects affected / exposed
    8 / 101 (7.92%)
    5 / 103 (4.85%)
         occurrences all number
    8
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    47 / 101 (46.53%)
    46 / 103 (44.66%)
         occurrences all number
    71
    64
    Productive cough
         subjects affected / exposed
    6 / 101 (5.94%)
    18 / 103 (17.48%)
         occurrences all number
    7
    21
    Nasal congestion
         subjects affected / exposed
    8 / 101 (7.92%)
    17 / 103 (16.50%)
         occurrences all number
    9
    20
    Oropharyngeal pain
         subjects affected / exposed
    10 / 101 (9.90%)
    15 / 103 (14.56%)
         occurrences all number
    12
    20
    Sputum increased
         subjects affected / exposed
    2 / 101 (1.98%)
    11 / 103 (10.68%)
         occurrences all number
    2
    11
    Rhinorrhoea
         subjects affected / exposed
    5 / 101 (4.95%)
    10 / 103 (9.71%)
         occurrences all number
    6
    14
    Respiration abnormal
         subjects affected / exposed
    4 / 101 (3.96%)
    6 / 103 (5.83%)
         occurrences all number
    4
    8
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 101 (0.99%)
    6 / 103 (5.83%)
         occurrences all number
    1
    6
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    16 / 101 (15.84%)
    13 / 103 (12.62%)
         occurrences all number
    23
    16
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 101 (9.90%)
    13 / 103 (12.62%)
         occurrences all number
    13
    15
    Rhinitis
         subjects affected / exposed
    5 / 101 (4.95%)
    6 / 103 (5.83%)
         occurrences all number
    7
    7
    Nasopharyngitis
         subjects affected / exposed
    8 / 101 (7.92%)
    5 / 103 (4.85%)
         occurrences all number
    13
    7
    Viral upper respiratory tract infection
         subjects affected / exposed
    8 / 101 (7.92%)
    5 / 103 (4.85%)
         occurrences all number
    9
    6
    Influenza
         subjects affected / exposed
    6 / 101 (5.94%)
    4 / 103 (3.88%)
         occurrences all number
    6
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 101 (5.94%)
    3 / 103 (2.91%)
         occurrences all number
    7
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Sep 2015
    Added serial post-dose spirometry assessments; added an additional PK sample.

    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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