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    Clinical Trial Results:
    A Phase 3, Open-label Study Evaluating the Long-term Safety and Efficacy of VX-445/TEZ/IVA Combination Therapy in Subjects With Cystic Fibrosis Who Are 6 Years of Age and Older

    Summary
    EudraCT number
    		 2019-001827-11
    Trial protocol
    		 GB   IE  
    Global end of trial date
    24 Feb 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Sep 2024
    First version publication date
    07 Sep 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VX19-445-107
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04183790
    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
    20 Mar 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Feb 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Feb 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the long-term safety and tolerability of elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are 6 years of age and older
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Feb 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 45 Months
    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
    Canada: 6
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    United States: 39
    Worldwide total number of subjects
    64
    EEA total number of subjects
    5
    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)
    64
    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
    		 The study was conducted in two parts, Part A and Part B. Subjects of both Parts A and B received the same treatment (ELX,TEZ,IVA). Therefore, results were planned to be collected and analyzed for the overall population of the study.

    Pre-assignment
    Screening details
    		 Subjects from parent study VX18-445-106 Part B (NCT03691779) were enrolled in this study. A total of 64 subjects were enrolled in this study.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 ELX/TEZ/IVA
    Arm description
    		 Subjects greater than or equal to (≥) 6 years and less than (<) 12 years of age and weighing <30 kilograms (kg) received ELX (elexacaftor) 100 milligram (mg) once daily (qd) /TEZ (tezacaftor) 50 mg qd/IVA (ivacaftor) 75 mg every 12 hours (q12h) and those weighing (≥) 30 kg received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg in the treatment period for 192 week. Subjects ≥ 12 years of age received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 192 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Elexacaftor/Tezacaftor/Ivacaftor
    Investigational medicinal product code
    VX-445/VX-661/VX-770
    Other name
    ELX/TEZ/IVA
    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
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    IVA
    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
    		ELX/TEZ/IVA
    Started
    64
    Part A completed
    60
    Rollover to Part B
    48
    Part B completed
    39
    Completed
    39
    Not completed
    25
         Subjects did not rollover to Part B
    12
         Adverse event
    1
         Withdrawal of Consent (not due to AE)
    6
         Commercial drug is available for subject
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Period
    Reporting group description
    		 Baseline data was analyzed on Full analysis set (FAS) which is defined as all subjects who received at least 1 dose of study drug.

    Reporting group values
    		 Overall Period Total
    Number of subjects
    		 64 64
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.3 ( 1.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 39 39
        Male
    		 25 25

    End points

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    End points reporting groups
    Reporting group title
    ELX/TEZ/IVA
    Reporting group description
    		 Subjects greater than or equal to (≥) 6 years and less than (<) 12 years of age and weighing <30 kilograms (kg) received ELX (elexacaftor) 100 milligram (mg) once daily (qd) /TEZ (tezacaftor) 50 mg qd/IVA (ivacaftor) 75 mg every 12 hours (q12h) and those weighing (≥) 30 kg received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg in the treatment period for 192 week. Subjects ≥ 12 years of age received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 192 weeks.

    Primary: 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) [1]
    End point description
    Safety Set is defined as all subjects who received at least 1 dose of study drug in the study.
    End point type
    Primary
    End point timeframe
    Day 1 up to Week 196
    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.
    End point values
    		 ELX/TEZ/IVA
    Number of subjects analysed
    64
    Units: Subjects
        Subjects with TEAEs
    64
        Subjects with SAEs
    7
    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 196
    Adverse event reporting additional description
    Safety set included all subjects who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    ELX/TEZ/IVA
    Reporting group description
    		 Subjects ≥6 years and <12 years of age and weighing <30kg received ELX 100 mg qd /TEZ 50 mg qd/IVA 75 mg q12h and those weighing ≥30 kg received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg in the treatment period for 192 weeks. Subjects ≥ 12 years of age received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 192 weeks

    Serious adverse events
    		 ELX/TEZ/IVA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 64 (10.94%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Haematuria traumatic
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Idiopathic intracranial hypertension
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 64 (4.69%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ELX/TEZ/IVA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    62 / 64 (96.88%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 64 (9.38%)
         occurrences all number
    9
    Bacterial test positive
         subjects affected / exposed
    7 / 64 (10.94%)
         occurrences all number
    12
    SARS-CoV-2 test positive
         subjects affected / exposed
    8 / 64 (12.50%)
         occurrences all number
    8
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    7
    Injury, poisoning and procedural complications
    Immunisation reaction
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    26 / 64 (40.63%)
         occurrences all number
    39
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    28 / 64 (43.75%)
         occurrences all number
    52
    Fatigue
         subjects affected / exposed
    10 / 64 (15.63%)
         occurrences all number
    11
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    6
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    5
    Abdominal pain
         subjects affected / exposed
    14 / 64 (21.88%)
         occurrences all number
    16
    Constipation
         subjects affected / exposed
    10 / 64 (15.63%)
         occurrences all number
    15
    Diarrhoea
         subjects affected / exposed
    10 / 64 (15.63%)
         occurrences all number
    16
    Nausea
         subjects affected / exposed
    6 / 64 (9.38%)
         occurrences all number
    10
    Vomiting
         subjects affected / exposed
    17 / 64 (26.56%)
         occurrences all number
    33
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    40 / 64 (62.50%)
         occurrences all number
    103
    Epistaxis
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    4
    Nasal congestion
         subjects affected / exposed
    23 / 64 (35.94%)
         occurrences all number
    43
    Oropharyngeal pain
         subjects affected / exposed
    24 / 64 (37.50%)
         occurrences all number
    43
    Productive cough
         subjects affected / exposed
    11 / 64 (17.19%)
         occurrences all number
    23
    Rhinorrhoea
         subjects affected / exposed
    21 / 64 (32.81%)
         occurrences all number
    36
    Sinus congestion
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    9
    Infections and infestations
    COVID-19
         subjects affected / exposed
    18 / 64 (28.13%)
         occurrences all number
    21
    Ear infection
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    4
    Hordeolum
         subjects affected / exposed
    9 / 64 (14.06%)
         occurrences all number
    16
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    8 / 64 (12.50%)
         occurrences all number
    8
    Influenza
         subjects affected / exposed
    7 / 64 (10.94%)
         occurrences all number
    7
    Nasopharyngitis
         subjects affected / exposed
    10 / 64 (15.63%)
         occurrences all number
    22
    Pharyngitis streptococcal
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    6
    Sinusitis
         subjects affected / exposed
    6 / 64 (9.38%)
         occurrences all number
    9
    Upper respiratory tract infection
         subjects affected / exposed
    19 / 64 (29.69%)
         occurrences all number
    61
    Viral upper respiratory tract infection
         subjects affected / exposed
    7 / 64 (10.94%)
         occurrences all number
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jun 2021
    Amended to extend treatment period by adding Part B (additional 96 weeks of treatment duration) and updated monitoring text to include flexibility for remote monitoring.

    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.
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    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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