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    Clinical Trial Results:
    A Phase 2a, Randomized, Double-blind, Placebo-controlled, Incomplete Block, Crossover Study to Evaluate the Safety and Efficacy of VX-371 in Subjects Aged 12 Years or Older With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation, and Being Treated With Orkambi

    Summary
    EudraCT number
    		 2015-004841-13
    Trial protocol
    		 IE   GB   FR   CZ  
    Global end of trial date
    01 Sep 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    04 Dec 2021
    First version publication date
    29 Apr 2018
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    • Correction of full data set
    To maintain the consistency with CT.gov results, EU results will be updated.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    VX15-371-101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02709109
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Parion Sciences
    Sponsor organisation address
    2800 Meridian Parkway, Durham NC, United States, 27713
    Public contact
    Anita Woodring, Parion Sciences, +1 919-313-1187, awoodring@parion.com
    Scientific contact
    Karl Donn, Parion Sciences, +1 919-313-1185, kdonn@parion.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
    12 Oct 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and efficacy of treatment with VX-371 in hypertonic saline (HS) compared to HS alone in subjects with cystic fibrosis (CF) who are greater than or equal to (>=) 12 years of age, homozygous for the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutation, and being treated with Orkambi.
    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
    10 Feb 2016
    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: 30
    Country: Number of subjects enrolled
    United States: 92
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Ireland: 12
    Worldwide total number of subjects
    142
    EEA total number of subjects
    50
    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)
    55
    Adults (18-64 years)
    87
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects were randomized to 1 of 4 treatment sequences, each of which included 2 treatment periods. Treatment periods were separated by 28 day washout period.

    Period 1
    Period 1 title
    Treatment Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sequence 1 (VX-371 + HS, Then HS): VX-371 + HS
    Arm description
    		 Subjects received VX-371 in combination with 3 milliliter (mL) 4.2% hypertonic saline (HS) in treatment period 1 followed by HS alone in treatment period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-371
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    VX-371 administered twice daily for 28 days in treatment period 1.

    Investigational medicinal product name
    Hypertonic saline (HS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    HS administered twice daily for 28 days in treatment period 1.

    Arm title
    		 Sequence 2 (HS, Then VX-371 + HS): HS
    Arm description
    		 Subjects received 3 mL 4.2% HS in treatment period 1 followed by VX-371 in combination with 3 mL 4.2% HS in treatment period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Hypertonic saline (HS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    HS administered twice daily for 28 days in treatment period 1.

    Arm title
    		 Sequence 3 (VX-371 + placebo, then placebo): VX-371 + placebo
    Arm description
    		 Subjects received VX-371 in combination with placebo (0.17% saline) in treatment period 1 followed by placebo (0.17% saline) alone in treatment period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-371
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    VX-371 administered twice daily for 28 days in treatment period 1.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo (0.17% saline) administered twice daily for 28 days in treatment period 1.

    Arm title
    		 Sequence 4 (Placebo, Then VX-371 + placebo): Placebo
    Arm description
    		 Subjects received placebo (0.17% saline) in treatment period 1 followed by VX-371 in combination with placebo (0.17% saline) in treatment period 2.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo (0.17% saline) administered twice daily for 28 days in treatment period 1.

    Number of subjects in period 1
    		Sequence 1 (VX-371 + HS, Then HS): VX-371 + HS Sequence 2 (HS, Then VX-371 + HS): HS Sequence 3 (VX-371 + placebo, then placebo): VX-371 + placebo Sequence 4 (Placebo, Then VX-371 + placebo): Placebo
    Started
    49
    47
    22
    24
    Completed
    45
    42
    21
    24
    Not completed
    4
    5
    1
    0
         Subject refused further dosing (not due to AE)
    -
    2
    -
    -
         Adverse event
    3
    3
    1
    -
         Noncompliance with study drug
    1
    -
    -
    -
    Period 2
    Period 2 title
    Treatment Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sequence 1 (VX-371 + HS, Then HS): HS
    Arm description
    		 Subjects received VX-371 in combination with 3 mL 4.2% HS in treatment period 1 followed by HS alone in treatment period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Hypertonic saline (HS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    HS administered twice daily for 28 days in treatment period 2.

    Arm title
    		 Sequence 2 (HS, Then VX-371 + HS): VX-371 + HS
    Arm description
    		 Subjects received 3 mL 4.2% HS in treatment period 1 followed by VX-371 in combination with 3 mL 4.2% HS in treatment period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Hypertonic saline (HS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    HS administered twice daily for 28 days in treatment period 2.

    Investigational medicinal product name
    VX-371
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    VX-371 administered twice daily for 28 days in treatment period 2.

    Arm title
    		 Sequence 3 (VX-371 + placebo, then placebo): Placebo
    Arm description
    		 Subjects received VX-371 in combination with placebo (0.17% saline) in treatment period 1 followed by placebo (0.17% saline) alone in treatment period 2.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo (0.17% saline) administered twice daily for 28 days in treatment period 2.

    Arm title
    		 Sequence 4 (Placebo, Then VX-371 + placebo): VX-371 + placebo
    Arm description
    		 Subjects received placebo (0.17% saline) in treatment period 1 followed by VX-371 in combination with placebo (0.17% saline) in treatment period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo (0.17% saline) administered twice daily for 28 days in treatment period 2.

    Investigational medicinal product name
    VX-371
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    VX-371 administered twice daily for 28 days in treatment period 2.

    Number of subjects in period 2 [1]
    		Sequence 1 (VX-371 + HS, Then HS): HS Sequence 2 (HS, Then VX-371 + HS): VX-371 + HS Sequence 3 (VX-371 + placebo, then placebo): Placebo Sequence 4 (Placebo, Then VX-371 + placebo): VX-371 + placebo
    Started
    43
    40
    18
    24
    Completed
    41
    36
    15
    24
    Not completed
    2
    4
    3
    0
         Other noncompliance
    -
    1
    1
    -
         Requires prohibited medication
    -
    -
    1
    -
         Adverse event
    2
    3
    -
    -
         Unspecified
    -
    -
    1
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all the subjects who completed treatment period 1 entered treatment period 2. That is why the number of subjects starting treatment period 2 is not consistent with the number of subjects completing the treatment period 1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period 1
    Reporting group description
    		 -

    Reporting group values
    		 Treatment Period 1 Total
    Number of subjects
    		 142 142
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 23.3 ( 9.08 ) -
    Gender categorical
    Units: Subjects
        Female
    		 55 55
        Male
    		 87 87
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 1 1
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 0 0
        White
    		 139 139
        More than one race
    		 0 0
        Unknown or Not Reported
    		 2 2
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0
        Not Hispanic or Latino
    		 139 139
        Unknown or Not Reported
    		 3 3

    End points

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    End points reporting groups
    Reporting group title
    Sequence 1 (VX-371 + HS, Then HS): VX-371 + HS
    Reporting group description
    		 Subjects received VX-371 in combination with 3 milliliter (mL) 4.2% hypertonic saline (HS) in treatment period 1 followed by HS alone in treatment period 2.

    Reporting group title
    Sequence 2 (HS, Then VX-371 + HS): HS
    Reporting group description
    		 Subjects received 3 mL 4.2% HS in treatment period 1 followed by VX-371 in combination with 3 mL 4.2% HS in treatment period 2.

    Reporting group title
    Sequence 3 (VX-371 + placebo, then placebo): VX-371 + placebo
    Reporting group description
    		 Subjects received VX-371 in combination with placebo (0.17% saline) in treatment period 1 followed by placebo (0.17% saline) alone in treatment period 2.

    Reporting group title
    Sequence 4 (Placebo, Then VX-371 + placebo): Placebo
    Reporting group description
    		 Subjects received placebo (0.17% saline) in treatment period 1 followed by VX-371 in combination with placebo (0.17% saline) in treatment period 2.
    Reporting group title
    Sequence 1 (VX-371 + HS, Then HS): HS
    Reporting group description
    		 Subjects received VX-371 in combination with 3 mL 4.2% HS in treatment period 1 followed by HS alone in treatment period 2.

    Reporting group title
    Sequence 2 (HS, Then VX-371 + HS): VX-371 + HS
    Reporting group description
    		 Subjects received 3 mL 4.2% HS in treatment period 1 followed by VX-371 in combination with 3 mL 4.2% HS in treatment period 2.

    Reporting group title
    Sequence 3 (VX-371 + placebo, then placebo): Placebo
    Reporting group description
    		 Subjects received VX-371 in combination with placebo (0.17% saline) in treatment period 1 followed by placebo (0.17% saline) alone in treatment period 2.

    Reporting group title
    Sequence 4 (Placebo, Then VX-371 + placebo): VX-371 + placebo
    Reporting group description
    		 Subjects received placebo (0.17% saline) in treatment period 1 followed by VX-371 in combination with placebo (0.17% saline) in treatment period 2.

    Subject analysis set title
    VX-371 + Hypertonic Saline
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.

    Subject analysis set title
    Hypertonic Saline
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.

    Subject analysis set title
    VX-371 + Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received 85 mcg VX-371 diluted in 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.

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

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    End point title
    		 Safety and Tolerability as Assessed by Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs [1]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. AEs included abnormal clinically significant findings for spirometry, clinical laboratory parameters, standard 12-lead electrocardiograms (ECGs), vital signs and ophthalmologic examinations. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 112 days (up to 28 days after last dose) that were absent before treatment or that worsened relative to pretreatment state. TEAEs included both serious and non-serious TEAEs. Safety set included all subjects who received at least 1 dose of inhaled study drug.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) up to 28 days post last administration of study drug (up to 112 days)
    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: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 VX-371 + Hypertonic Saline Hypertonic Saline VX-371 + Placebo Placebo
    Number of subjects analysed
    89
    90
    46
    42
    Units: Subjects
        Subjects With TEAEs
    65
    66
    32
    28
        Subjects With Serious TEAEs
    8
    4
    6
    3
    No statistical analyses for this end point

    Primary: Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 28

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    End point title
    		 Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 28
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Study Baseline was defined as the most recent non-missing measurement before the first dose of inhaled study drug in the study. Day 28 measurements after treatment discontinuation from the treatment period in which discontinuation occurred were included in the analysis. The full analysis set (FAS) included all randomised subjects who carried the intended homozygous F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutation and received at least 1 dose of inhaled study drug. Here, "Number of subjects analysed" signifies subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Study baseline, Day 28
    End point values
    		 VX-371 + Hypertonic Saline Hypertonic Saline VX-371 + Placebo Placebo
    Number of subjects analysed
    79
    77
    43
    38
    Units: percentage points
        least squares mean (standard error)
    0.1 ( 0.8 )
    -0.1 ( 0.8 )
    -0.8 ( 1.1 )
    0.8 ( 1.1 )
    Statistical analysis title
    		 VX-371 + Hypertonic Saline Vs Hypertonic Saline
    Statistical analysis description
    As this is a cross-over study, actual number of subjects analysed for the statistical comparison was 79 for " VX-371 + Hypertonic saline" arm and 77 for "Hypertonic saline" arm . "Number of subjects included in analysis =156" is reflected due to EudraCT database limitation of summing up the comparison arm numbers.
    Comparison groups
    VX-371 + Hypertonic Saline v Hypertonic Saline
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8173
    Method
    		 Mixed-effects Model for Repeated Measure
    Parameter type
    		 Least Square (LS) mean difference
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 1.8
    Statistical analysis title
    		 VX-371 + Placebo Vs Hypertonic Saline
    Statistical analysis description
    As this is a cross-over study, actual number of subjects analysed for the statistical comparison was 43 for "VX-371 + Placebo" arm and 77 for "Hypertonic Saline" arm. "Number of subjects included in analysis = 120" is reflected due to EudraCT database limitation of summing up the comparison arm numbers.
    Comparison groups
    VX-371 + Placebo v Hypertonic Saline
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5903
    Method
    		 Mixed-effects Model for Repeated Measure
    Parameter type
    		 LS mean difference
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 1.9
    Statistical analysis title
    		 VX-371 + Hypertonic Saline Vs Placebo
    Statistical analysis description
    As this is a cross-over study, actual number of subjects analysed for the statistical comparison was 79 for " VX-371 + Hypertonic saline" arm and 38 for "Placebo" arm. "Number of subjects included in analysis = 117" is reflected due to EudraCT database limitation of summing up the comparison arm numbers.
    Comparison groups
    VX-371 + Hypertonic Saline v Placebo
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5917
    Method
    		 Mixed-effects Model for Repeated Measure
    Parameter type
    		 LS mean difference
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 1.9
    Statistical analysis title
    		 Hypertonic Saline Vs Placebo
    Statistical analysis description
    As this is a cross-over study, actual number of subjects analysed for the statistical comparison was 77 for "Hypertonic saline (HS)" arm and 38 for "Placebo" arm. "Number of subjects included in analysis = 115" is reflected due to EudraCT database limitation of summing up the comparison arm numbers.
    Comparison groups
    Hypertonic Saline v Placebo
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5021
    Method
    		 Mixed-effects Model for Repeated Measure
    Parameter type
    		 LS mean difference
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 1.8
    Statistical analysis title
    		 VX-371 + Placebo Vs Placebo
    Statistical analysis description
    As this is a cross-over study, actual number of subjects analysed for the statistical comparison was 43 for " VX-371 + Placebo" arm and 38 for "Placebo" arm . "Number of subjects included in analysis =81" is reflected due to EudraCT database limitation of summing up the comparison arm numbers.
    Comparison groups
    VX-371 + Placebo v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1382
    Method
    		 Mixed-effects Model for Repeated Measure
    Parameter type
    		 LS mean difference
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.8
         upper limit
    		 0.5
    Statistical analysis title
    		 VX-371 + Hypertonic Saline, VX-371 + Placebo
    Comparison groups
    VX-371 + Hypertonic Saline v VX-371 + Placebo
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.4962
    Method
    		 Mixed-effects Model for Repeated Measure
    Parameter type
    		 LS mean difference
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 3.5
    Notes
    [2] - As this is a cross-over study, actual number of subjects analysed for the statistical comparison was 79 for "VX-371 + Hypertonic Saline" arm and 43 for "VX-371 + Placebo" arm. "Number of subjects included in analysis = 122" is reflected due to EudraCT database limitation of summing up the comparison arm numbers.

    Secondary: Plasma Concentrations of VX-371

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    End point title
    		 Plasma Concentrations of VX-371
    End point description
    The Pharmacokinetic (PK) analysis set included all subjects who received at least 1 dose of VX-371. Here, "Number of subjects analyzed" signifies subjects evaluable for this endpoint and "n" signifies those subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Pre-dose (90 minutes prior inhaled study drug administration) and 60 minutes post-dose on Days 1, 14 and 28 within treatment period 1 and 2
    End point values
    		 VX-371 + Hypertonic Saline VX-371 + Placebo
    Number of subjects analysed
    89
    45
    Units: picograms per milliliter (pg/mL)
    arithmetic mean (standard deviation)
        Day 1: Pre-dose (n =89, 44)
    0.00 ( 0.00 )
    0.18 ( 1.17 )
        Day 1: Post-dose (n =87, 44)
    2.57 ( 2.35 )
    5.64 ( 4.27 )
        Day 14: Pre-dose (n =86, 43)
    1.63 ( 3.06 )
    2.77 ( 4.77 )
        Day 14: Post-dose (n =81, 42)
    5.81 ( 5.44 )
    11.0 ( 9.74 )
        Day 28: Pre-dose (n =86, 45)
    2.68 ( 4.75 )
    3.67 ( 5.59 )
        Day 28: Post-dose (n =82, 43)
    6.41 ( 6.92 )
    10.9 ( 9.48 )
    No statistical analyses for this end point

    Secondary: Urine Concentrations of VX-371

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    End point title
    		 Urine Concentrations of VX-371
    End point description
    The PK analysis set included all subjects who received at least 1 dose of VX-371. Here, "Number of subjects analyzed" signifies subjects evaluable for this endpoint and "n" signifies those subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Pre-dose (90 minutes prior inhaled study drug administration) and 60 minutes post-dose on Days 1, 14 and 28 within treatment period 1 and 2
    End point values
    		 VX-371 + Hypertonic Saline VX-371 + Placebo
    Number of subjects analysed
    88
    45
    Units: pg/mL
    arithmetic mean (standard deviation)
        Day 1: Pre-dose (n =88, 45)
    0.0745 ( 0.699 )
    0.00 ( 0.00 )
        Day 1: Post-dose (n =88, 45)
    7.78 ( 11.8 )
    22.1 ( 38.4 )
        Day 14: Pre-dose (n =85, 43)
    41.0 ( 97.2 )
    69.6 ( 107 )
        Day 14: Post-dose (n =83, 42)
    38.9 ( 64.8 )
    75.0 ( 98.7 )
        Day 28: Pre-dose (n =84, 45)
    65.3 ( 155 )
    98.6 ( 175 )
        Day 28: Post-dose (n =82, 43)
    49.1 ( 120 )
    75.1 ( 108 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 28 days post last administration of study drug, up to 112 days
    Adverse event reporting additional description
    Safety set included all subjects who received at least 1 dose of inhaled study drug.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    VX-371 + Hypertonic saline (HS)
    Reporting group description
    		 Subjects received 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.

    Reporting group title
    Hypertonic saline (HS)
    Reporting group description
    		 Subjects received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.

    Reporting group title
    VX-371 + Placebo
    Reporting group description
    		 Subjects received 85 mcg VX-371 diluted in 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.

    Serious adverse events
    		 VX-371 + Hypertonic saline (HS) Hypertonic saline (HS) VX-371 + Placebo Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 89 (8.99%)
    4 / 90 (4.44%)
    6 / 46 (13.04%)
    3 / 42 (7.14%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 90 (0.00%)
    0 / 46 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 90 (0.00%)
    0 / 46 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 90 (0.00%)
    0 / 46 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cystic fibrosis related diabetes
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 90 (0.00%)
    0 / 46 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cystic fibrosis respiratory infection suppression
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 90 (0.00%)
    0 / 46 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular torsion
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 90 (0.00%)
    0 / 46 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Small intestinal obstruction
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 90 (1.11%)
    0 / 46 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 90 (0.00%)
    0 / 46 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 89 (0.00%)
    2 / 90 (2.22%)
    1 / 46 (2.17%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 89 (3.37%)
    3 / 90 (3.33%)
    5 / 46 (10.87%)
    3 / 42 (7.14%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
    1 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 VX-371 + Hypertonic saline (HS) Hypertonic saline (HS) VX-371 + Placebo Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 89 (55.06%)
    55 / 90 (61.11%)
    26 / 46 (56.52%)
    20 / 42 (47.62%)
    Investigations
    Pulmonary function test decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    3 / 46 (6.52%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Alanine aminotransferase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 89 (3.37%)
    5 / 90 (5.56%)
    0 / 46 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    3
    5
    0
    4
    Nervous system disorders
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 89 (6.74%)
    8 / 90 (8.89%)
    2 / 46 (4.35%)
    1 / 42 (2.38%)
         occurrences all number
    6
    8
    2
    1
    General disorders and administration site conditions
    Pyrexia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 89 (1.12%)
    5 / 90 (5.56%)
    5 / 46 (10.87%)
    5 / 42 (11.90%)
         occurrences all number
    1
    5
    7
    5
    Gastrointestinal disorders
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 89 (5.62%)
    4 / 90 (4.44%)
    2 / 46 (4.35%)
    1 / 42 (2.38%)
         occurrences all number
    5
    4
    2
    1
    Nausea
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 89 (2.25%)
    3 / 90 (3.33%)
    3 / 46 (6.52%)
    0 / 42 (0.00%)
         occurrences all number
    2
    3
    3
    0
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 89 (1.12%)
    6 / 90 (6.67%)
    1 / 46 (2.17%)
    0 / 42 (0.00%)
         occurrences all number
    1
    6
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative assessment type: Systematic
         subjects affected / exposed
    20 / 89 (22.47%)
    13 / 90 (14.44%)
    13 / 46 (28.26%)
    5 / 42 (11.90%)
         occurrences all number
    29
    13
    15
    7
    Oropharyngeal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    8 / 89 (8.99%)
    6 / 90 (6.67%)
    4 / 46 (8.70%)
    1 / 42 (2.38%)
         occurrences all number
    9
    6
    4
    1
    Nasal congestion
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 89 (7.87%)
    5 / 90 (5.56%)
    2 / 46 (4.35%)
    1 / 42 (2.38%)
         occurrences all number
    8
    5
    3
    1
    Respiration abnormal
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 89 (7.87%)
    6 / 90 (6.67%)
    3 / 46 (6.52%)
    2 / 42 (4.76%)
         occurrences all number
    7
    8
    3
    2
    Wheezing
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 89 (6.74%)
    2 / 90 (2.22%)
    0 / 46 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    6
    2
    0
    1
    Haemoptysis
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 89 (5.62%)
    6 / 90 (6.67%)
    5 / 46 (10.87%)
    5 / 42 (11.90%)
         occurrences all number
    5
    10
    5
    5
    Sputum increased
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 89 (5.62%)
    2 / 90 (2.22%)
    5 / 46 (10.87%)
    2 / 42 (4.76%)
         occurrences all number
    5
    2
    5
    2
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
    alternative assessment type: Systematic
         subjects affected / exposed
    8 / 89 (8.99%)
    12 / 90 (13.33%)
    6 / 46 (13.04%)
    3 / 42 (7.14%)
         occurrences all number
    9
    13
    6
    3
    Nasopharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 89 (0.00%)
    5 / 90 (5.56%)
    2 / 46 (4.35%)
    2 / 42 (4.76%)
         occurrences all number
    0
    5
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Sep 2016
    - Corrected the study restrictions for diuretics and renin-angiotensive drugs - Contraception language changed to align with regulatory requirements

    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
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