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    Clinical Trial Results:
    A Phase 3b, Randomized, Placebo-controlled Study Evaluating the Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Subjects 6 Through 11 Years of Age Who Are Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF)

    Summary
    EudraCT number
    		 2019-003554-86
    Trial protocol
    		 DE   DK   GB   FR   NL  
    Global end of trial date
    17 May 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    14 Aug 2022
    First version publication date
    29 Nov 2021
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    VX19-445-116
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04353817
    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
    14 Jun 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 May 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    17 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) in subjects 6 through 11 years of age with cystic fibrosis (CF), heterozygous for F508del and a minimal function (MF) mutation (F/MF).
    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
    19 Jun 2020
    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: 11
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Israel: 5
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 31
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Switzerland: 12
    Country: Number of subjects enrolled
    United Kingdom: 17
    Worldwide total number of subjects
    121
    EEA total number of subjects
    63
    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)
    121
    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
    		 This study was conducted in CF subjects 6 through 11 years of age.

    Period 1
    Period 1 title
    Triple Combination Treatment Period (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 ELX/TEZ/IVA and placebo matched to IVA in the treatment period for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo (matched to ELX/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 ELX/TEZ/IVA once daily in the morning.

    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 in the evening.

    Arm title
    		 ELX/TEZ/IVA
    Arm description
    		 Subjects weighing less than (<) 30 kilograms (kg) at screening received ELX 100 mg once daily (qd)/TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) and subjects weighing greater than equals to (>=) 30 kg at screening received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
    Arm type
    		 Experimental

    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 once daily in the evening.

    Investigational medicinal product name
    ELX/TEZ/IVA
    Investigational medicinal product code
    VX-445/VX-661/VX-770
    Other name
    Elexacaftor/Tezacaftor/Ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received ELX/TEZ/IVA fixed-dose combination once daily in the morning.

    Number of subjects in period 1
    		Placebo ELX/TEZ/IVA
    Started
    61
    60
    Completed
    61
    59
    Not completed
    0
    1
         Adverse Event
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to ELX/TEZ/IVA and placebo matched to IVA in the treatment period for 24 weeks.

    Reporting group title
    ELX/TEZ/IVA
    Reporting group description
    		 Subjects weighing less than (<) 30 kilograms (kg) at screening received ELX 100 mg once daily (qd)/TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) and subjects weighing greater than equals to (>=) 30 kg at screening received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.

    Reporting group values
    		 Placebo ELX/TEZ/IVA Total
    Number of subjects
    		 61 60 121
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.2 ( 1.7 ) 9.1 ( 1.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 35 35 70
        Male
    		 26 25 51
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 1 1
        Not Hispanic or Latino
    		 42 48 90
        Unknown or Not Reported
    		 19 11 30
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 0 1 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 1 1
        White
    		 42 45 87
        More than one race
    		 0 1 1
        Unknown or Not Reported
    		 19 11 30
    Lung Clearance Index2.5 (LCI2.5)
    The LCI2.5 index is the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting values and is calculated by dividing the sum of exhaled tidal breaths (cumulative exhaled volume (CEV)) by simultaneously measured functional residual capacity (FRC). An LCI of 7.5 and below is normal; values greater than 7.5 are abnormal. LCI is able to detect abnormalities in lung function earlier than more traditional modalities such as spirometry.
    Units: index
        arithmetic mean (standard deviation)
    		 9.75 ( 1.95 ) 10.26 ( 2.22 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to ELX/TEZ/IVA and placebo matched to IVA in the treatment period for 24 weeks.

    Reporting group title
    ELX/TEZ/IVA
    Reporting group description
    		 Subjects weighing less than (<) 30 kilograms (kg) at screening received ELX 100 mg once daily (qd)/TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) and subjects weighing greater than equals to (>=) 30 kg at screening received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.

    Primary: Absolute Change in Lung Clearance Index (LCI) 2.5

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    End point title
    		 Absolute Change in Lung Clearance Index (LCI) 2.5
    End point description
    The LCI2.5 index is the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting values and is calculated by dividing the sum of exhaled tidal breaths (cumulative exhaled volume (CEV)) by simultaneously measured functional residual capacity (FRC). An LCI of 7.5 and below is normal; values greater than 7.5 are abnormal. LCI is able to detect abnormalities in lung function earlier than more traditional modalities such as spirometry. Full analysis set (FAS) included all randomized subjects who carry the intended CFTR allele mutation and receive at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    From Baseline Through Week 24
    End point values
    		 Placebo ELX/TEZ/IVA
    Number of subjects analysed
    61
    60
    Units: index
        least squares mean (standard error)
    -0.02 ( 0.16 )
    -2.29 ( 0.16 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    ELX/TEZ/IVA v Placebo
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed-effects Model for Repeated Measure
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    -2.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.71
         upper limit
    		 -1.81

    Secondary: Absolute Change in Sweat Chloride (SwCl)

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    End point title
    		 Absolute Change in Sweat Chloride (SwCl)
    End point description
    Sweat samples were collected using an approved collection device. FAS.
    End point type
    Secondary
    End point timeframe
    From Baseline Through Week 24
    End point values
    		 Placebo ELX/TEZ/IVA
    Number of subjects analysed
    61
    60
    Units: millimole per liter (mmol/L)
        least squares mean (standard error)
    -0.9 ( 1.5 )
    -52.1 ( 1.5 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    ELX/TEZ/IVA v Placebo
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Mixed-effects Model for Repeated Measure
    Parameter type
    		 LS Mean Difference
    Point estimate
    -51.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -55.3
         upper limit
    		 -47.1
    Notes
    [1] - This is the nominal p-value without multiplicity controlled.

    Secondary: Safety and Tolerability as Assessed by Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Safety and Tolerability as Assessed by Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    End point description
    Safety set included all subjects who received at least 1 dose of study drug in the treatment period.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Week 28
    End point values
    		 Placebo ELX/TEZ/IVA
    Number of subjects analysed
    61
    60
    Units: subjects
        Subjects With TEAEs
    57
    48
        Subjects With SAEs
    9
    4
    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 28
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    ELX/TEZ/IVA
    Reporting group description
    		 Subjects weighing <30 kg at screening received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and subjects weighing >=30 kg at screening received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to ELX/TEZ/IVA and placebo matched to IVA in the treatment period for 24 weeks.

    Serious adverse events
    		 ELX/TEZ/IVA Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 60 (6.67%)
    9 / 61 (14.75%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Bacterial test positive
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 61 (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
    0 / 60 (0.00%)
    1 / 61 (1.64%)
         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
    General physical health deterioration
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intussusception
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
         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
    Nasal polyps
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    0 / 60 (0.00%)
    3 / 61 (4.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella zoster virus infection
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
         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
    		 ELX/TEZ/IVA Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 60 (76.67%)
    53 / 61 (86.89%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 61 (1.64%)
         occurrences all number
    3
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 60 (8.33%)
    3 / 61 (4.92%)
         occurrences all number
    9
    4
    Bacterial test positive
         subjects affected / exposed
    0 / 60 (0.00%)
    4 / 61 (6.56%)
         occurrences all number
    0
    4
    Forced expiratory volume decreased
         subjects affected / exposed
    0 / 60 (0.00%)
    4 / 61 (6.56%)
         occurrences all number
    0
    4
    Staphylococcus test positive
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 61 (1.64%)
         occurrences all number
    4
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 60 (30.00%)
    12 / 61 (19.67%)
         occurrences all number
    22
    20
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 60 (0.00%)
    5 / 61 (8.20%)
         occurrences all number
    0
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 60 (8.33%)
    17 / 61 (27.87%)
         occurrences all number
    9
    27
    Diarrhoea
         subjects affected / exposed
    4 / 60 (6.67%)
    6 / 61 (9.84%)
         occurrences all number
    4
    6
    Abdominal pain upper
         subjects affected / exposed
    4 / 60 (6.67%)
    5 / 61 (8.20%)
         occurrences all number
    4
    7
    Steatorrhoea
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 61 (0.00%)
         occurrences all number
    4
    0
    Nausea
         subjects affected / exposed
    1 / 60 (1.67%)
    5 / 61 (8.20%)
         occurrences all number
    1
    6
    Vomiting
         subjects affected / exposed
    3 / 60 (5.00%)
    4 / 61 (6.56%)
         occurrences all number
    4
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 60 (23.33%)
    26 / 61 (42.62%)
         occurrences all number
    17
    40
    Nasal polyps
         subjects affected / exposed
    0 / 60 (0.00%)
    4 / 61 (6.56%)
         occurrences all number
    0
    5
    Nasal congestion
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 61 (4.92%)
         occurrences all number
    3
    4
    Productive cough
         subjects affected / exposed
    7 / 60 (11.67%)
    6 / 61 (9.84%)
         occurrences all number
    8
    7
    Rhinorrhoea
         subjects affected / exposed
    7 / 60 (11.67%)
    7 / 61 (11.48%)
         occurrences all number
    9
    7
    Oropharyngeal pain
         subjects affected / exposed
    3 / 60 (5.00%)
    12 / 61 (19.67%)
         occurrences all number
    4
    14
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    4 / 60 (6.67%)
    0 / 61 (0.00%)
         occurrences all number
    5
    0
    Rash
         subjects affected / exposed
    6 / 60 (10.00%)
    3 / 61 (4.92%)
         occurrences all number
    6
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 60 (1.67%)
    4 / 61 (6.56%)
         occurrences all number
    2
    4
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    1 / 60 (1.67%)
    14 / 61 (22.95%)
         occurrences all number
    1
    16
    Nasopharyngitis
         subjects affected / exposed
    7 / 60 (11.67%)
    9 / 61 (14.75%)
         occurrences all number
    8
    12
    Rhinitis
         subjects affected / exposed
    3 / 60 (5.00%)
    5 / 61 (8.20%)
         occurrences all number
    3
    5
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 60 (5.00%)
    5 / 61 (8.20%)
         occurrences all number
    4
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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