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    Clinical Trial Results:
    A Phase 3b, Randomized, Double blind, Controlled Study Evaluating the Efficacy and Safety of VX-445/Tezacaftor/Ivacaftor in Cystic Fibrosis Subjects, Homozygous for F508del

    Summary
    EudraCT number
    		 2019-001735-31
    Trial protocol
    		 GB   BE  
    Global end of trial date
    24 Jul 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    04 Sep 2021
    First version publication date
    06 Feb 2021
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Addition of secondary endpoints

    Trial information

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    Trial identification
    Sponsor protocol code
    VX18-445-109
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04105972
    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
    11 Aug 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jul 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of VX-445/TEZ/IVA in cystic fibrosis subjects, homozygous for F508del (F/F).
    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
    03 Oct 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 88
    Country: Number of subjects enrolled
    Australia: 30
    Country: Number of subjects enrolled
    Belgium: 20
    Country: Number of subjects enrolled
    Germany: 38
    Worldwide total number of subjects
    176
    EEA total number of subjects
    146
    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)
    0
    Adolescents (12-17 years)
    53
    Adults (18-64 years)
    123
    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 aged 12 years or older.

    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
    		 TEZ/IVA
    Arm description
    		 Following TEZ/IVA run-in period of 4 weeks, subjects received TEZ 100 milligrams (mg) once daily (qd)/IVA 150 mg every 12 hours (q12h) in the treatment period for 24 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    TEZ/IVA
    Investigational medicinal product code
    VX-661/VX-770
    Other name
    Tezacaftor/Ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 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
    		 ELX/TEZ/IVA
    Arm description
    		 Following TEZ/IVA run-in period of 4 weeks, subjects 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
    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 [1]
    		TEZ/IVA ELX/TEZ/IVA
    Started
    88
    87
    Completed
    86
    86
    Not completed
    2
    1
         Adverse Event
    2
    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 176 subjects enrolled in the study. Out of those 176 subjects, 1 subject was randomized but not dosed in the treatment period. Therefore, only 175 subjects are included in the subject disposition and baseline section.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TEZ/IVA
    Reporting group description
    		 Following TEZ/IVA run-in period of 4 weeks, subjects received TEZ 100 milligrams (mg) once daily (qd)/IVA 150 mg every 12 hours (q12h) in the treatment period for 24 weeks.

    Reporting group title
    ELX/TEZ/IVA
    Reporting group description
    		 Following TEZ/IVA run-in period of 4 weeks, subjects received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.

    Reporting group values
    		 TEZ/IVA ELX/TEZ/IVA Total
    Number of subjects
    		 88 87 175
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 27.8 ( 11.0 ) 27.9 ( 11.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 45 43 88
        Male
    		 43 44 87
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 1 3
        Not Hispanic or Latino
    		 83 85 168
        Unknown or Not Reported
    		 3 1 4
    Ethnicity/Race
    Units: Subjects
        Asian
    		 0 2 2
        White
    		 88 84 172
        White, Asian
    		 0 1 1
    CF Questionnaire-Revised (CFQ-R) Respiratory Domain Score
    The CFQ-R is a validated subject-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 73.1 ( 17.6 ) 71.2 ( 19.6 ) -

    End points

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    End points reporting groups
    Reporting group title
    TEZ/IVA
    Reporting group description
    		 Following TEZ/IVA run-in period of 4 weeks, subjects received TEZ 100 milligrams (mg) once daily (qd)/IVA 150 mg every 12 hours (q12h) in the treatment period for 24 weeks.

    Reporting group title
    ELX/TEZ/IVA
    Reporting group description
    		 Following TEZ/IVA run-in period of 4 weeks, subjects received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.

    Primary: Absolute Change in CF Questionnaire-Revised (CFQ-R) Respiratory Domain Score

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    End point title
    		 Absolute Change in CF Questionnaire-Revised (CFQ-R) Respiratory Domain Score
    End point description
    The CFQ-R is a validated subject-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Full analysis set (FAS) included all randomized subjects who carried the intended CF transmembrane conductance regulator (CFTR) allele mutation and received at least 1 dose of study drug in treatment period.
    End point type
    Primary
    End point timeframe
    From Baseline Through Week 24
    End point values
    		 TEZ/IVA ELX/TEZ/IVA
    Number of subjects analysed
    88
    87
    Units: units on scale
        least squares mean (standard error)
    1.2 ( 1.5 )
    17.1 ( 1.5 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    ELX/TEZ/IVA v TEZ/IVA
    Number of subjects included in analysis
    175
    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
    15.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.7
         upper limit
    		 20.1

    Secondary: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

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    End point title
    		 Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. FAS.
    End point type
    Secondary
    End point timeframe
    From Baseline Through Week 24
    End point values
    		 TEZ/IVA ELX/TEZ/IVA
    Number of subjects analysed
    88
    87
    Units: percentage points
        least squares mean (standard error)
    1.0 ( 0.7 )
    11.2 ( 0.7 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    TEZ/IVA v ELX/TEZ/IVA
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed-effects Model for Repeated Measure
    Parameter type
    		 LS Mean Difference
    Point estimate
    10.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.2
         upper limit
    		 12.1

    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
    		 TEZ/IVA ELX/TEZ/IVA
    Number of subjects analysed
    88
    87
    Units: millimole per liter (mmol/L)
        least squares mean (standard error)
    -3.4 ( 1.2 )
    -46.2 ( 1.3 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    TEZ/IVA v ELX/TEZ/IVA
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    -42.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -46.2
         upper limit
    		 -39.3

    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
    From Day 1 in the Treatment Period up to 28 Days After the Last Dose of Study Drug or to the Completion of Study Participation Date, Whichever Occurs First (up to Week 28)
    End point values
    		 TEZ/IVA ELX/TEZ/IVA
    Number of subjects analysed
    88
    87
    Units: subjects
        Subjects With TEAEs
    81
    77
        Subjects With SAEs
    14
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 in the Treatment Period up to 28 Days After Last Dose of Study Drug or to the Completion of Study Participation Date, Whichever Occurs First (up to Week 28)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    TEZ/IVA
    Reporting group description
    		 Following TEZ/IVA run-in period of 4 weeks, subjects received TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.

    Reporting group title
    ELX/TEZ/IVA
    Reporting group description
    		 Following TEZ/IVA run-in period of 4 weeks, subjects received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.

    Serious adverse events
    		 TEZ/IVA ELX/TEZ/IVA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 88 (15.91%)
    5 / 87 (5.75%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Extrasystoles
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 87 (1.15%)
         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
    1 / 88 (1.14%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obsessive-compulsive disorder
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 87 (1.15%)
         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
    9 / 88 (10.23%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 3 diabetes mellitus
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 87 (1.15%)
         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
    		 TEZ/IVA ELX/TEZ/IVA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    72 / 88 (81.82%)
    59 / 87 (67.82%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 88 (1.14%)
    6 / 87 (6.90%)
         occurrences all number
    2
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 88 (0.00%)
    5 / 87 (5.75%)
         occurrences all number
    0
    6
    Bacterial test positive
         subjects affected / exposed
    5 / 88 (5.68%)
    1 / 87 (1.15%)
         occurrences all number
    8
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 88 (20.45%)
    25 / 87 (28.74%)
         occurrences all number
    26
    38
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 88 (7.95%)
    4 / 87 (4.60%)
         occurrences all number
    10
    6
    Diarrhoea
         subjects affected / exposed
    7 / 88 (7.95%)
    8 / 87 (9.20%)
         occurrences all number
    8
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    23 / 88 (26.14%)
    11 / 87 (12.64%)
         occurrences all number
    32
    17
    Haemoptysis
         subjects affected / exposed
    6 / 88 (6.82%)
    3 / 87 (3.45%)
         occurrences all number
    8
    3
    Nasal congestion
         subjects affected / exposed
    0 / 88 (0.00%)
    6 / 87 (6.90%)
         occurrences all number
    0
    6
    Oropharyngeal pain
         subjects affected / exposed
    7 / 88 (7.95%)
    11 / 87 (12.64%)
         occurrences all number
    8
    12
    Productive cough
         subjects affected / exposed
    3 / 88 (3.41%)
    8 / 87 (9.20%)
         occurrences all number
    4
    10
    Sputum increased
         subjects affected / exposed
    16 / 88 (18.18%)
    10 / 87 (11.49%)
         occurrences all number
    18
    10
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 88 (0.00%)
    7 / 87 (8.05%)
         occurrences all number
    0
    8
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    32 / 88 (36.36%)
    10 / 87 (11.49%)
         occurrences all number
    38
    12
    Nasopharyngitis
         subjects affected / exposed
    13 / 88 (14.77%)
    17 / 87 (19.54%)
         occurrences all number
    18
    19
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 88 (5.68%)
    9 / 87 (10.34%)
         occurrences all number
    6
    11

    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
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    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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