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    Clinical Trial Results:
    A Phase 3 Study Evaluating the Pharmacokinetics, Safety, and Tolerability of VX-445/TEZ/IVA Triple Combination Therapy in Cystic Fibrosis Subjects 6 Through 11 Years of Age

    Summary
    EudraCT number
    		 2018-001695-38
    Trial protocol
    		 GB   IE  
    Global end of trial date
    07 Aug 2020

    Results information
    Results version number
    		 v1
    This version publication date
    22 Feb 2021
    First version publication date
    22 Feb 2021
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    VX18-445-106
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03691779
    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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002324-PIP01-17
    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
    24 Aug 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Aug 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the pharmacokinetics (PK), safety and tolerability of elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA) when dosed in triple combination (TC).
    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
    02 Oct 2018
    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: 6
    Country: Number of subjects enrolled
    Ireland: 5
    Country: Number of subjects enrolled
    United States: 46
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    Canada: 6
    Worldwide total number of subjects
    71
    EEA total number of subjects
    11
    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)
    71
    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 cystic fibrosis (CF) subjects 6 through 11 years of age who were homozygous for F508del [F/F] genotype or heterozygous for F508del and a CFTR minimal function mutation [F/MF] genotypes.

    Period 1
    Period 1 title
    Triple Combination Treatment Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Part A: ELX/TEZ/IVA
    Arm description
    		 Subjects received ELX/TEZ/IVA in the treatment period for 15 days.
    Arm type
    		 Experimental

    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 (FDC) once daily in the morning.

    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.

    Arm title
    		 Part B: ELX/TEZ/IVA
    Arm description
    		 Subjects received ELX/TEZ/IVA in the treatment period for 24 weeks.
    Arm type
    		 Experimental

    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 FDC once daily in the morning.

    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.

    Number of subjects in period 1
    		Part A: ELX/TEZ/IVA Part B: ELX/TEZ/IVA
    Started
    16
    66
    Completed
    16
    64
    Not completed
    0
    2
         Adverse event
    -
    1
         Withdrawal of consent (not due to AE)
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: ELX/TEZ/IVA
    Reporting group description
    		 Subjects received ELX/TEZ/IVA in the treatment period for 15 days.

    Reporting group title
    Part B: ELX/TEZ/IVA
    Reporting group description
    		 Subjects received ELX/TEZ/IVA in the treatment period for 24 weeks.

    Reporting group values
    		 Part A: ELX/TEZ/IVA Part B: ELX/TEZ/IVA Total
    Number of subjects
    		 16 66 71
    Age categorical
    There were 71 unique subjects enrolled in the study. Out of 16 subjects from Part A, 11 subjects also participated in Part B.
    Units: Subjects
        Children (2-11 years)
    		 16 66 71
    Gender categorical
    There were 71 unique subjects enrolled in the study. Out of 16 subjects from Part A, 11 subjects also participated in Part B. The total column for gender represents the sum of Part A and Part B numbers as the data for unique 71 subjects was not collected separately.
    Units: Subjects
        Female
    		 11 39 50
        Male
    		 5 27 32

    End points

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    End points reporting groups
    Reporting group title
    Part A: ELX/TEZ/IVA
    Reporting group description
    		 Subjects received ELX/TEZ/IVA in the treatment period for 15 days.

    Reporting group title
    Part B: ELX/TEZ/IVA
    Reporting group description
    		 Subjects received ELX/TEZ/IVA in the treatment period for 24 weeks.

    Primary: Part B: 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
    		 Part B: Safety and Tolerability as Assessed by Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [1] [2]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 through Safety Follow-up Visit (up to Week 28)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were planned. No statistical comparisons were planned for this endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only Part B: ELX/TEZ/IVA arm was applicable for this endpoint.
    End point values
    		 Part B: ELX/TEZ/IVA
    Number of subjects analysed
    66
    Units: subjects
        Subjects with TEAEs
    65
        Subjects with SAEs
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 Through Safety Follow-up Visit (up to Day 43 for Part A, up to Week 28 for Part B)
    Adverse event reporting additional description
    MedDRA version for Part A: 21.1, MedDRA version for Part B: 23.0
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1, 23.0
    Reporting groups
    Reporting group title
    Part A: ELX/TEZ/IVA
    Reporting group description
    		 Subjects received ELX/TEZ/IVA in the treatment period for 15 days.

    Reporting group title
    Part B: ELX/TEZ/IVA
    Reporting group description
    		 Subjects received ELX/TEZ/IVA in the treatment period for 24 weeks.

    Serious adverse events
    		 Part A: ELX/TEZ/IVA Part B: ELX/TEZ/IVA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 66 (1.52%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Infections and infestations
    Metapneumovirus infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 66 (1.52%)
         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
    		 Part A: ELX/TEZ/IVA Part B: ELX/TEZ/IVA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 16 (75.00%)
    62 / 66 (93.94%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    7 / 66 (10.61%)
         occurrences all number
    0
    9
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 66 (0.00%)
         occurrences all number
    1
    0
    Human rhinovirus test positive
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 66 (0.00%)
         occurrences all number
    1
    0
    Pulmonary function test decreased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 66 (0.00%)
         occurrences all number
    1
    0
    Transaminases increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 66 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 66 (1.52%)
         occurrences all number
    1
    1
    Craniocerebral injury
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 66 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 16 (0.00%)
    16 / 66 (24.24%)
         occurrences all number
    0
    19
    Lethargy
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 66 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 66 (0.00%)
         occurrences all number
    1
    0
    Chest pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 66 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 16 (0.00%)
    5 / 66 (7.58%)
         occurrences all number
    0
    5
    Pyrexia
         subjects affected / exposed
    1 / 16 (6.25%)
    14 / 66 (21.21%)
         occurrences all number
    1
    19
    Vessel puncture site pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 66 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 16 (6.25%)
    8 / 66 (12.12%)
         occurrences all number
    1
    9
    Abdominal pain upper
         subjects affected / exposed
    1 / 16 (6.25%)
    5 / 66 (7.58%)
         occurrences all number
    1
    5
    Constipation
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 66 (6.06%)
         occurrences all number
    0
    4
    Diarrhoea
         subjects affected / exposed
    0 / 16 (0.00%)
    7 / 66 (10.61%)
         occurrences all number
    0
    8
    Nausea
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 66 (3.03%)
         occurrences all number
    1
    2
    Vomiting
         subjects affected / exposed
    1 / 16 (6.25%)
    7 / 66 (10.61%)
         occurrences all number
    1
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 16 (31.25%)
    28 / 66 (42.42%)
         occurrences all number
    5
    42
    Nasal congestion
         subjects affected / exposed
    2 / 16 (12.50%)
    10 / 66 (15.15%)
         occurrences all number
    3
    14
    Oropharyngeal pain
         subjects affected / exposed
    1 / 16 (6.25%)
    12 / 66 (18.18%)
         occurrences all number
    1
    14
    Productive cough
         subjects affected / exposed
    2 / 16 (12.50%)
    5 / 66 (7.58%)
         occurrences all number
    2
    5
    Respiration abnormal
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 66 (1.52%)
         occurrences all number
    1
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 16 (6.25%)
    8 / 66 (12.12%)
         occurrences all number
    1
    9
    Sinus congestion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 66 (0.00%)
         occurrences all number
    1
    0
    Sputum increased
         subjects affected / exposed
    3 / 16 (18.75%)
    3 / 66 (4.55%)
         occurrences all number
    3
    3
    Skin and subcutaneous tissue disorders
    Pruritus generalised
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 66 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    3 / 16 (18.75%)
    8 / 66 (12.12%)
         occurrences all number
    3
    10
    Rash erythematous
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 66 (4.55%)
         occurrences all number
    1
    3
    Rash maculo-papular
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 66 (3.03%)
         occurrences all number
    1
    3
    Rash papular
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 66 (3.03%)
         occurrences all number
    1
    3
    Infections and infestations
    Croup infectious
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 66 (0.00%)
         occurrences all number
    1
    0
    Ear infection
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 66 (6.06%)
         occurrences all number
    0
    5
    Influenza
         subjects affected / exposed
    0 / 16 (0.00%)
    7 / 66 (10.61%)
         occurrences all number
    0
    8
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 66 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 66 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 66 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 16 (0.00%)
    11 / 66 (16.67%)
         occurrences all number
    0
    14
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 16 (0.00%)
    8 / 66 (12.12%)
         occurrences all number
    0
    8
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 66 (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
    07 Jun 2019
    Amended to update secondary endpoints and incorporate dose justification and weight cutoff based on data from Part A.
    18 Dec 2019
    Amended to update pre-dose assessment window.

    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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