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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
    		 v2(current)
    This version publication date
    10 Nov 2021
    First version publication date
    22 Feb 2021
    Other versions
    		 v1
    Version creation reason

    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
    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)
    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
    		 The study was conducted in 2 parts, Part A and Part B. All results were planned to be analyzed and reported separately for Part A and Part B of the study.

    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 CF transmembrane conductance regulator gene (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 in Part A received ELX 100 milligrams (mg) once daily (qd)/TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) in the treatment period for 15 days.
    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 (FDC) once daily in the morning.

    Arm title
    		 Part B: ELX/TEZ/IVA
    Arm description
    		 Subjects in Part B weighing less than (<) 30 kilograms (kg) at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and subjects weighing greater than equals to (>=) 30 kg at Day 1 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 FDC once daily in the morning.

    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 in Part A received ELX 100 milligrams (mg) once daily (qd)/TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) in the treatment period for 15 days.

    Reporting group title
    Part B: ELX/TEZ/IVA
    Reporting group description
    		 Subjects in Part B weighing less than (<) 30 kilograms (kg) at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and subjects weighing greater than equals to (>=) 30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h 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
    Ethnicity (NIH/OMB)
    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
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 16 58 63
        Unknown or Not Reported
    		 0 8 8
    Race (NIH/OMB)
    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
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 16 57 62
        More than one race
    		 0 1 1
        Unknown or Not Reported
    		 0 8 8

    End points

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    End points reporting groups
    Reporting group title
    Part A: ELX/TEZ/IVA
    Reporting group description
    		 Subjects in Part A received ELX 100 milligrams (mg) once daily (qd)/TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) in the treatment period for 15 days.

    Reporting group title
    Part B: ELX/TEZ/IVA
    Reporting group description
    		 Subjects in Part B weighing less than (<) 30 kilograms (kg) at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and subjects weighing greater than equals to (>=) 30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.

    Primary: Part A: Maximum Observed Plasma Concentration (Cmax) of ELX, TEZ, and IVA

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    End point title
    		 Part A: Maximum Observed Plasma Concentration (Cmax) of ELX, TEZ, and IVA [1] [2]
    End point description
    PK set for Part A included all subjects who have received at least 1 dose of study drug in Part A. Here, the "n" signifies subjects who were evaluable at the specified time point.
    End point type
    Primary
    End point timeframe
    Part A: Day 15
    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: This endpoint was planned only for Part A arm.
    End point values
    		 Part A: ELX/TEZ/IVA
    Number of subjects analysed
    16
    Units: microgram per milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        ELX (n=15)
    6.13 ± 1.52
        TEZ (n=15)
    6.93 ± 1.96
        IVA (n=15)
    1.01 ± 0.281
    No statistical analyses for this end point

    Primary: Part A: Observed Pre-dose Plasma Concentration (Ctrough) of ELX, TEZ, and IVA

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    End point title
    		 Part A: Observed Pre-dose Plasma Concentration (Ctrough) of ELX, TEZ, and IVA [3] [4]
    End point description
    PK set (Part A). Here, the "n" signifies subjects who were evaluable at the specified time point.
    End point type
    Primary
    End point timeframe
    Part A: Day 15
    Notes
    [3] - 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.
    [4] - 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: This endpoint was planned only for Part A arm.
    End point values
    		 Part A: ELX/TEZ/IVA
    Number of subjects analysed
    16
    Units: mcg/mL
    arithmetic mean (standard deviation)
        ELX (n=15)
    2.86 ± 1.37
        TEZ (n=15)
    1.06 ± 0.366
        IVA (n=15)
    0.297 ± 0.173
    No statistical analyses for this end point

    Primary: Part A: Area Under the Concentration Versus Time Curve From 0 to 24 hours (AUC0-24h) of ELX, TEZ, and IVA

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    End point title
    		 Part A: Area Under the Concentration Versus Time Curve From 0 to 24 hours (AUC0-24h) of ELX, TEZ, and IVA [5] [6]
    End point description
    PK set (Part A).
    End point type
    Primary
    End point timeframe
    Part A: Day 15
    Notes
    [5] - 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.
    [6] - 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: This endpoint was planned only for Part A arm.
    End point values
    		 Part A: ELX/TEZ/IVA
    Number of subjects analysed
    16
    Units: hour*microgram per milliliter (h*mcg/mL)
    arithmetic mean (standard deviation)
        ELX
    107 ± 28.7
        TEZ
    58.4 ± 13.5
        IVA
    8.12 ± 2.93
    No statistical analyses for this end point

    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) [7] [8]
    End point description
    Safety set for Part B included all subjects who received at least 1 dose of study drug in Part B. The safety analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.
    End point type
    Primary
    End point timeframe
    Part B: Day 1 Through Safety Follow-up Visit (up to Week 28)
    Notes
    [7] - 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.
    [8] - 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: This endpoint was planned only for Part B arm.
    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

    Secondary: Part A: Cmax of ELX Metabolite (M23-ELX), TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA)

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    End point title
    		 Part A: Cmax of ELX Metabolite (M23-ELX), TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA) [9]
    End point description
    PK set (Part A). Here, the "n" signifies subjects who were evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Part A: Day 15
    Notes
    [9] - 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: This endpoint was planned only for Part A arm.
    End point values
    		 Part A: ELX/TEZ/IVA
    Number of subjects analysed
    16
    Units: mcg/mL
    arithmetic mean (standard deviation)
        M23-ELX (n=15)
    1.60 ± 0.657
        M1-TEZ (n=15)
    6.26 ± 1.54
        M1-IVA (n=15)
    2.36 ± 0.694
    No statistical analyses for this end point

    Secondary: Part A: Ctrough of ELX Metabolite (M23-ELX), TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA)

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    End point title
    		 Part A: Ctrough of ELX Metabolite (M23-ELX), TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA) [10]
    End point description
    PK set (Part A). Here, the "n" signifies subjects who were evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Part A: Day 15
    Notes
    [10] - 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: This endpoint was planned only for Part A arm.
    End point values
    		 Part A: ELX/TEZ/IVA
    Number of subjects analysed
    16
    Units: mcg/mL
    arithmetic mean (standard deviation)
        M23-ELX (n=15)
    1.30 ± 0.585
        M1-TEZ (n=15)
    4.64 ± 1.36
        M1-IVA (n=15)
    0.890 ± 0.460
    No statistical analyses for this end point

    Secondary: Part A: AUC0-24h of ELX Metabolite (M23-ELX) and TEZ Metabolite (M1-TEZ)

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    End point title
    		 Part A: AUC0-24h of ELX Metabolite (M23-ELX) and TEZ Metabolite (M1-TEZ) [11]
    End point description
    PK set (Part A).
    End point type
    Secondary
    End point timeframe
    Part A: Day 15
    Notes
    [11] - 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: This endpoint was planned only for Part A arm.
    End point values
    		 Part A: ELX/TEZ/IVA
    Number of subjects analysed
    16
    Units: h*mcg/mL
    arithmetic mean (standard deviation)
        M23-ELX
    35.6 ± 13.2
        M1-TEZ
    133 ± 30.4
    No statistical analyses for this end point

    Secondary: Part A: Area Under the Concentration Versus Time Curve From 0 to 6 Hours (AUC0-6h) of IVA Metabolite (M1-IVA)

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    End point title
    		 Part A: Area Under the Concentration Versus Time Curve From 0 to 6 Hours (AUC0-6h) of IVA Metabolite (M1-IVA) [12]
    End point description
    PK set (Part A). The AUC data was analysed for up to 6 hours for IVA metabolite (M1-IVA). Therefore, AUC0-6h is reported for M1-IVA metabolite. Here "number of subjects analysed" signifies subjects who were evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Part A: Day 15
    Notes
    [12] - 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: This endpoint was planned only for Part A arm.
    End point values
    		 Part A: ELX/TEZ/IVA
    Number of subjects analysed
    15
    Units: h*mcg/mL
        arithmetic mean (standard deviation)
    9.41 ± 3.06
    No statistical analyses for this end point

    Secondary: Part A: Safety and Tolerability as Assessed by Number of Subjects With TEAEs and SAEs

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    End point title
    		 Part A: Safety and Tolerability as Assessed by Number of Subjects With TEAEs and SAEs [13]
    End point description
    Safety set for Part A included all subjects who received at least 1 dose of study drug in Part A.
    End point type
    Secondary
    End point timeframe
    Part A: Day 1 Through Safety Follow-up Visit (up to Day 43)
    Notes
    [13] - 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: This endpoint was planned only for Part A arm.
    End point values
    		 Part A: ELX/TEZ/IVA
    Number of subjects analysed
    16
    Units: subjects
        Subjects With TEAEs
    12
        Subjects With SAEs
    0
    No statistical analyses for this end point

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

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    End point title
    		 Part B: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) [14]
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Full analysis set (FAS) for Part B included all enrolled subjects who carry the intended CFTR allele mutation and received at least 1 dose of study drug in Part B. The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.
    End point type
    Secondary
    End point timeframe
    Part B: From Baseline Through Week 24
    Notes
    [14] - 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: This endpoint was planned only for Part B arm.
    End point values
    		 Part B: ELX/TEZ/IVA
    Number of subjects analysed
    66
    Units: percentage points
        least squares mean (confidence interval 95%)
    10.2 (7.9 to 12.6)
    No statistical analyses for this end point

    Secondary: Part B: Absolute Change in Sweat Chloride (SwCl)

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    End point title
    		 Part B: Absolute Change in Sweat Chloride (SwCl) [15]
    End point description
    Sweat samples were collected using an approved collection device. FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.
    End point type
    Secondary
    End point timeframe
    Part B: From Baseline Through Week 24
    Notes
    [15] - 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: This endpoint was planned only for Part B arm.
    End point values
    		 Part B: ELX/TEZ/IVA
    Number of subjects analysed
    66
    Units: millimole per liter (mmol/L)
        least squares mean (confidence interval 95%)
    -60.9 (-63.7 to -58.2)
    No statistical analyses for this end point

    Secondary: Part B: Absolute Change in Cystic Fibrosis Questionnaire Revised (CFQ-R) Respiratory Domain Score

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    End point title
    		 Part B: Absolute Change in Cystic Fibrosis Questionnaire Revised (CFQ-R) Respiratory Domain Score [16]
    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. FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.
    End point type
    Secondary
    End point timeframe
    Part B: From Baseline Through Week 24
    Notes
    [16] - 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: This endpoint was planned only for Part B arm.
    End point values
    		 Part B: ELX/TEZ/IVA
    Number of subjects analysed
    66
    Units: units on a scale
        least squares mean (confidence interval 95%)
    7.0 (4.7 to 9.2)
    No statistical analyses for this end point

    Secondary: Part B: Absolute Change in Body Mass Index (BMI)

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    End point title
    		 Part B: Absolute Change in Body Mass Index (BMI) [17]
    End point description
    BMI was defined as weight in kg divided by squared height in meters (m^2). FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.
    End point type
    Secondary
    End point timeframe
    Part B: From Baseline at Week 24
    Notes
    [17] - 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: This endpoint was planned only for Part B arm.
    End point values
    		 Part B: ELX/TEZ/IVA
    Number of subjects analysed
    66
    Units: kg/m^2
        least squares mean (confidence interval 95%)
    1.02 (0.76 to 1.28)
    No statistical analyses for this end point

    Secondary: Part B: Absolute Change in BMI For-Age Z-Score

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    End point title
    		 Part B: Absolute Change in BMI For-Age Z-Score [18]
    End point description
    BMI was defined as weight in kg divided by squared height in meters (m^2). The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard. FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.
    End point type
    Secondary
    End point timeframe
    Part B: From Baseline at Week 24
    Notes
    [18] - 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: This endpoint was planned only for Part B arm.
    End point values
    		 Part B: ELX/TEZ/IVA
    Number of subjects analysed
    66
    Units: z-score
        least squares mean (confidence interval 95%)
    0.37 (0.26 to 0.48)
    No statistical analyses for this end point

    Secondary: Part B: Absolute Change in Weight

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    End point title
    		 Part B: Absolute Change in Weight [19]
    End point description
    FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.
    End point type
    Secondary
    End point timeframe
    Part B: From Baseline at Week 24
    Notes
    [19] - 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: This endpoint was planned only for Part B arm.
    End point values
    		 Part B: ELX/TEZ/IVA
    Number of subjects analysed
    66
    Units: kg
        least squares mean (confidence interval 95%)
    3.0 (2.5 to 3.5)
    No statistical analyses for this end point

    Secondary: Part B: Absolute Change in Weight-for-age Z-Score

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    End point title
    		 Part B: Absolute Change in Weight-for-age Z-Score [20]
    End point description
    The z-score is a statistical measure to describe whether a mean was above or below the standard. The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard. FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.
    End point type
    Secondary
    End point timeframe
    Part B: From Baseline at Week 24
    Notes
    [20] - 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: This endpoint was planned only for Part B arm.
    End point values
    		 Part B: ELX/TEZ/IVA
    Number of subjects analysed
    66
    Units: z-score
        least squares mean (confidence interval 95%)
    0.25 (0.16 to 0.33)
    No statistical analyses for this end point

    Secondary: Part B: Absolute Change in Height

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    End point title
    		 Part B: Absolute Change in Height [21]
    End point description
    FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.
    End point type
    Secondary
    End point timeframe
    Part B: From Baseline at Week 24
    Notes
    [21] - 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: This endpoint was planned only for Part B arm.
    End point values
    		 Part B: ELX/TEZ/IVA
    Number of subjects analysed
    66
    Units: centimeters (cm)
        least squares mean (confidence interval 95%)
    2.3 (1.9 to 2.7)
    No statistical analyses for this end point

    Secondary: Part B: Absolute Change in Height-for-Age Z-Score

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    End point title
    		 Part B: Absolute Change in Height-for-Age Z-Score [22]
    End point description
    The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard. FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.
    End point type
    Secondary
    End point timeframe
    Part B: From Baseline at Week 24
    Notes
    [22] - 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: This endpoint was planned only for Part B arm.
    End point values
    		 Part B: ELX/TEZ/IVA
    Number of subjects analysed
    66
    Units: z-score
        least squares mean (confidence interval 95%)
    -0.05 (-0.12 to 0.01)
    No statistical analyses for this end point

    Secondary: Part B: Drug Acceptability Assessment Using Modified Facial Hedonic Scale

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    End point title
    		 Part B: Drug Acceptability Assessment Using Modified Facial Hedonic Scale [23]
    End point description
    The study drug acceptability (subject reaction) was assessed by a visual analog scale that incorporates a 5 point facial hedonic scale (Liked it Very Much, Liked it a Little, Not sure, Disliked it a Little, Disliked it Very Much). Number of subjects with the indicated categorical response in the drug acceptability assessment were reported. FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm. Here "number analyzed" signifies those subjects who were evaluable for this outcome.
    End point type
    Secondary
    End point timeframe
    Part B: At Week 24
    Notes
    [23] - 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: This endpoint was planned only for Part B arm.
    End point values
    		 Part B: ELX/TEZ/IVA
    Number of subjects analysed
    33
    Units: subjects
        Liked it Very Much
    16
        Liked it a Little
    6
        Not sure
    10
        Disliked it a Little
    1
        Disliked it Very Much
    0
    No statistical analyses for this end point

    Secondary: Part B: Number of Pulmonary Exacerbations Events

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    End point title
    		 Part B: Number of Pulmonary Exacerbations Events [24]
    End point description
    Pulmonary exacerbation was defined as new or changed treatment with oral, inhaled, or intravenous antibiotics and fulfillment of pre-specified protocol defined criteria. FAS (Part B). The total number of pulmonary exacerbations events across all subjects were reported. The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.
    End point type
    Secondary
    End point timeframe
    Part B: From Baseline Through Week 24
    Notes
    [24] - 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: This endpoint was planned only for Part B arm.
    End point values
    		 Part B: ELX/TEZ/IVA
    Number of subjects analysed
    66
    Units: pulmonary exacerbations events
    4
    No statistical analyses for this end point

    Secondary: Part B: Number of CF Related Hospitalizations

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    End point title
    		 Part B: Number of CF Related Hospitalizations [25]
    End point description
    FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. The total number of CF related hospitalization events across all subjects were reported. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.
    End point type
    Secondary
    End point timeframe
    Part B: From Baseline Through Week 24
    Notes
    [25] - 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: This endpoint was planned only for Part B arm.
    End point values
    		 Part B: ELX/TEZ/IVA
    Number of subjects analysed
    66
    Units: hospitalizations
    0
    No statistical analyses for this end point

    Secondary: Part B: Ctrough of ELX, ELX Metabolite (M23-ELX), TEZ, TEZ Metabolite (M1-TEZ), IVA and IVA Metabolite (M1-IVA)

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    End point title
    		 Part B: Ctrough of ELX, ELX Metabolite (M23-ELX), TEZ, TEZ Metabolite (M1-TEZ), IVA and IVA Metabolite (M1-IVA) [26]
    End point description
    The PK set for Part B included all subjects who have received at least 1 dose of study drug in Part B. Here "n" signifies those subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Part B: At Week 4
    Notes
    [26] - 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: This endpoint was planned only for Part B arm.
    End point values
    		 Part B: ELX/TEZ/IVA
    Number of subjects analysed
    65
    Units: mcg/mL
    arithmetic mean (standard deviation)
        ELX: Week 4 (<30 kg) (n=33)
    2.71 ± 1.77
        ELX: Week 4 (>=30 kg) (n=30)
    5.69 ± 3.00
        M23-ELX: Week 4 (<30 kg) (n=33)
    1.59 ± 1.24
        M23-ELX: Week 4 (>=30 kg) (n=30)
    4.41 ± 2.97
        TEZ: Week 4 (<30 kg) (n=33)
    1.43 ± 1.19
        TEZ: Week 4 (>=30 kg) (n=30)
    2.37 ± 1.07
        M1-TEZ: Week 4 (<30 kg) (n=33)
    5.57 ± 1.78
        M1-TEZ: Week 4 (>=30 kg) (n=30)
    8.12 ± 1.88
        IVA: Week 4 (<30 kg) (n=33)
    0.455 ± 0.681
        IVA: Week 4 (>=30 kg) (n=30)
    0.851 ± 0.489
        M1-IVA: Week 4 (<30 kg) (n=33)
    1.00 ± 0.630
        M1-IVA: Week 4 (>=30 kg) (n=30)
    2.18 ± 1.04
    No statistical analyses for this end point

    Secondary: Part B: Absolute Change in Lung Clearance Index 2.5 (LCI2.5)

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    End point title
    		 Part B: Absolute Change in Lung Clearance Index 2.5 (LCI2.5) [27]
    End point description
    LCI 2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value. FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.
    End point type
    Secondary
    End point timeframe
    Part B: From Baseline Through Week 24
    Notes
    [27] - 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: This endpoint was planned only for Part B arm.
    End point values
    		 Part B: ELX/TEZ/IVA
    Number of subjects analysed
    66
    Units: lung clearance index
        least squares mean (confidence interval 95%)
    -1.71 (-2.11 to -1.30)
    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
    The safety analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm. MedDRA version 21.1 applied for Part A, MedDRA version 23.0 applied for Part B.
    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 in Part A received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h in the treatment period for 15 days.

    Reporting group title
    Part B: ELX/TEZ/IVA
    Reporting group description
    		 Subjects in Part B weighing <30 kg at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and subjects weighing >=30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h 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
    Pyrexia
         subjects affected / exposed
    1 / 16 (6.25%)
    14 / 66 (21.21%)
         occurrences all number
    1
    19
    Fatigue
         subjects affected / exposed
    0 / 16 (0.00%)
    5 / 66 (7.58%)
         occurrences all number
    0
    5
    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
    Diarrhoea
         subjects affected / exposed
    0 / 16 (0.00%)
    7 / 66 (10.61%)
         occurrences all number
    0
    8
    Constipation
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 66 (6.06%)
         occurrences all number
    0
    4
    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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