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    Clinical Trial Results:
    A Phase 3, 2-Part, Open-label Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Ivacaftor in Subjects With Cystic Fibrosis (CF) Who Are Less Than 24 Months of Age at Treatment Initiation and Have an Ivacaftor-responsive CFTR Mutation

    Summary
    EudraCT number
    		 2015-001997-16
    Trial protocol
    		 GB   IE   DE  
    Global end of trial date
    28 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Jun 2023
    First version publication date
    21 Jun 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VX15-770-124
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02725567
    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-000335-PIP01-08
    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
    25 Jul 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Jun 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety, pharmacokinetics (PK), and pharmacodynamics of ivacaftor in subjects with CF who are less than (<) 24 months of age and have an ivacaftor-responsive CFTR mutation.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jun 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 States: 32
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    Ireland: 5
    Worldwide total number of subjects
    57
    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)
    57
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study was conducted in subjects with cystic fibrosis (CF) who were less than (<) 24 months of age at Day 1 and have an ivacaftor-responsive CF transmembrane conductance regulator (CFTR) mutation.

    Period 1
    Period 1 title
    Overall Trial (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: 3 to < 24 months
    Arm description
    		 Subjects weighing 5 to less than (<) 7 kilogram (kg) received 25 milligram (mg) IVA (ivacaftor), 7 to <14 kg received 50 mg IVA, and those weighing 14 to <25 kg received 75 mg IVA administered every 12 hours (q12h) on Days 1 through 3 and 1 morning dose on Day 4.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IVA
    Investigational medicinal product code
    VX-770
    Other name
    Ivacaftor
    Pharmaceutical forms
    Granules in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received IVA dose every 12 hours.

    Arm title
    		 Part B + A/B: 1 to <24 months
    Arm description
    		 Subjects 4 to <6 months of age and weighing greater than or equal to (≥) 5 kg received 25 mg IVA q12h. At 6 months of age and older, participants weighing 5 to <7 kg received 25 mg IVA, 7 to <14 kg received 50 mg IVA, and those weighing 14 to <25 kg received 75 mg IVA q12h for 24 weeks on Part B. For Part A/B, subjects 1 to <4 months weighing 3 kg to <5 kg received an initial low dose of 5.7 mg q12h IVA and those weighing ≥5 kg received 11.4 mg q12h IVA for the first 15 days of IVA treatment. Doses were maintained or adjusted upward at Day 15 and based on weight and/or age once they reached 4 months of age.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IVA
    Investigational medicinal product code
    VX-770
    Other name
    Ivacaftor
    Pharmaceutical forms
    Granules in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received IVA dose every 12 hours.

    Number of subjects in period 1
    		Part A: 3 to < 24 months Part B + A/B: 1 to <24 months
    Started
    19
    43
    Completed
    19
    40
    Not completed
    0
    3
         Physician decision
    -
    1
         Lost to follow-up
    -
    1
         Withdrawal of Consent (not due to AE)
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: 3 to < 24 months
    Reporting group description
    		 Subjects weighing 5 to less than (<) 7 kilogram (kg) received 25 milligram (mg) IVA (ivacaftor), 7 to <14 kg received 50 mg IVA, and those weighing 14 to <25 kg received 75 mg IVA administered every 12 hours (q12h) on Days 1 through 3 and 1 morning dose on Day 4.

    Reporting group title
    Part B + A/B: 1 to <24 months
    Reporting group description
    		 Subjects 4 to <6 months of age and weighing greater than or equal to (≥) 5 kg received 25 mg IVA q12h. At 6 months of age and older, participants weighing 5 to <7 kg received 25 mg IVA, 7 to <14 kg received 50 mg IVA, and those weighing 14 to <25 kg received 75 mg IVA q12h for 24 weeks on Part B. For Part A/B, subjects 1 to <4 months weighing 3 kg to <5 kg received an initial low dose of 5.7 mg q12h IVA and those weighing ≥5 kg received 11.4 mg q12h IVA for the first 15 days of IVA treatment. Doses were maintained or adjusted upward at Day 15 and based on weight and/or age once they reached 4 months of age.

    Reporting group values
    		 Part A: 3 to < 24 months Part B + A/B: 1 to <24 months Total
    Number of subjects
    		 19 43
    Age categorical
    Units: Subjects
    Age continuous
    There were 57 unique subjects enrolled in the study. Out of 19 subjects from Part A, 5 subjects also participated in Part B.
    Units: months
        arithmetic mean (standard deviation)
    		 10.8 ( 7.18 ) 9.5 ( 5.93 ) -
    Gender categorical
    There were 57 unique subjects enrolled in the study. Out of 19 subjects from Part A, 5 subjects also participated in Part B. The total column for gender represents the sum of Part A, Part B + A/B numbers as the data for unique 57 subjects was not collected separately.
    Units: Subjects
        Female
    		 10 22 32
        Male
    		 9 21 30
    Ethnicity
    There were 57 unique subjects enrolled in the study. Out of 19 subjects from Part A, 5 subjects also participated in Part B.
    Units: Subjects
        Hispanic or Latino
    		 0 1 1
        Not Hispanic or Latino
    		 19 42 56
        Not collected per local regulations
    		 0 0 0
    Race
    There were 57 unique subjects enrolled in the study. Out of 19 subjects from Part A, 5 subjects also participated in Part B.
    Units: Subjects
        White
    		 19 43 57
        Black or African American
    		 0 0 0
        Asian
    		 0 0 0
        American Indian or Alaska Native
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Not collected per local Regulations
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Part A: 3 to < 24 months
    Reporting group description
    		 Subjects weighing 5 to less than (<) 7 kilogram (kg) received 25 milligram (mg) IVA (ivacaftor), 7 to <14 kg received 50 mg IVA, and those weighing 14 to <25 kg received 75 mg IVA administered every 12 hours (q12h) on Days 1 through 3 and 1 morning dose on Day 4.

    Reporting group title
    Part B + A/B: 1 to <24 months
    Reporting group description
    		 Subjects 4 to <6 months of age and weighing greater than or equal to (≥) 5 kg received 25 mg IVA q12h. At 6 months of age and older, participants weighing 5 to <7 kg received 25 mg IVA, 7 to <14 kg received 50 mg IVA, and those weighing 14 to <25 kg received 75 mg IVA q12h for 24 weeks on Part B. For Part A/B, subjects 1 to <4 months weighing 3 kg to <5 kg received an initial low dose of 5.7 mg q12h IVA and those weighing ≥5 kg received 11.4 mg q12h IVA for the first 15 days of IVA treatment. Doses were maintained or adjusted upward at Day 15 and based on weight and/or age once they reached 4 months of age.

    Subject analysis set title
    Part A/B: 1 to <4 months
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects 1 to <4 months weighing 3 kg to <5 kg received an initial low dose of 5.7 mg q12h IVA and those weighing ≥5 kg received 11.4 mg q12h IVA for the first 15 days of IVA treatment. Doses were maintained or adjusted upward at Day 15 and based on weight and/or age once they reached 4 months of age.

    Subject analysis set title
    Part B: 4 to <24 months
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects 4 to <6 months of age and ≥5 kg received 25 mg IVA q12h. At 6 months of age and older, subjects weighing 5 to <7 kg received 25 mg IVA, 7 to <14 kg received 50 mg IVA, and those weighing 14 to <25 kg received 75 mg IVA q12h for 24 weeks on Part B.

    Primary: Part A : 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
    		 Part A : Safety and Tolerability as Assessed by Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious (TEAEs) [1] [2]
    End point description
    Safety Set included all subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Day 1 through Day 70
    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 end point is only applicable for Part A.
    End point values
    		 Part A: 3 to < 24 months
    Number of subjects analysed
    19
    Units: Subjects
        Subjects with TEAEs
    10
        Subjects with Serious TEAEs
    1
    No statistical analyses for this end point

    Primary: Part A: Observed Plasma Concentration of IVA and Their Metabolites (M1-IVA and M6-IVA)

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    End point title
    		 Part A: Observed Plasma Concentration of IVA and Their Metabolites (M1-IVA and M6-IVA) [3] [4]
    End point description
    PK set included subjects who received at least 1 dose of study drug. Here the "n" signifies those subjects who were evaluable at specified time point.
    End point type
    Primary
    End point timeframe
    Pre-dose, 2-4 hours, 6-8 hours, 24-60 hours post-dose
    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 end point is only applicable for Part A.
    End point values
    		 Part A: 3 to < 24 months
    Number of subjects analysed
    19
    Units: nanogram per millitre (ng/ml)
    arithmetic mean (standard deviation)
        Pre dose: IVA (n=19)
    654 ( 531 )
        Pre dose: M1-IVA (n=19)
    1880 ( 1160 )
        Pre dose: M6-IVA (n=19)
    2680 ( 1990 )
        2-4 hrs post dose: IVA (n=19)
    956 ( 497 )
        2-4 hrs post dose: M1-IVA (n=19)
    1990 ( 1160 )
        2-4 hrs post dose: M6-IVA (n=19)
    2460 ( 2110 )
        6-8 hrs post dose: IVA (n=19)
    1040 ( 623 )
        6-8 hrs post dose: M1-IVA (n=19)
    2440 ( 1260 )
        6-8 hrs post dose: M6-IVA (n=19)
    2880 ( 2180 )
        24-60 hrs post dose: IVA (n=18)
    129 ( 68.8 )
        24-60 hrs post dose: M1-IVA (n=18)
    508 ( 228 )
        24-60 hrs post dose: M6-IVA (n=18)
    1100 ( 982 )
    No statistical analyses for this end point

    Primary: Part B + Part A/B: 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
    		 Part B + Part A/B: Safety and Tolerability as Assessed by Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious (TEAEs) [5] [6]
    End point description
    Safety Set included all subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Day 1 through Week 38
    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 end point is only applicable for Part B + A/B.
    End point values
    		 Part B + A/B: 1 to <24 months
    Number of subjects analysed
    43
    Units: Subjects
        Subjects with TEAEs
    38
        ubjects with Serious TEAEs
    6
    No statistical analyses for this end point

    Primary: Part A/B: Observed Plasma Concentration of IVA and Their Metabolites (M1-IVA and M6-IVA)

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    End point title
    		 Part A/B: Observed Plasma Concentration of IVA and Their Metabolites (M1-IVA and M6-IVA) [7]
    End point description
    End point type
    Primary
    End point timeframe
    Day 4 (pre-dose, 2-4 hours, 6-8 hours post-dose); Day 15 (pre-dose); Week 4 (pre-dose); Week 8 (pre-dose, 2-4 hours, 6-8 hours post-dose); Week 12 (pre-dose); Week 18 (pre-dose) and Week 24 (pre-dose)
    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
    End point values
    		 Part A/B: 1 to <4 months
    Number of subjects analysed
    7
    Units: ng/ml
    arithmetic mean (standard deviation)
        Day 4 (pre dose): IVA (n=7)
    348 ( 151 )
        Day 4 (pre dose): M1-IVA (n=7)
    867 ( 412 )
        Day 4 (pre dose): M6-IVA (n=7)
    1570 ( 570 )
        Day 4 (2-4 hrs post dose): IVA (n=7)
    381 ( 135 )
        Day 4 (2-4 hrs post dose): M1-IVA (n=7)
    851 ( 333 )
        Day 4 (2-4 hrs post dose): M6-IVA (n=7)
    1370 ( 450 )
        Day 4 (6-8 hrs post dose): IVA (n=7)
    501 ( 196 )
        Day 4 (6-8 hrs post dose): M1-IVA (n=7)
    1190 ( 420 )
        Day 4 (6-8 hrs post dose): M6-IVA (n=7)
    1670 ( 551 )
        Day 15 (pre dose): IVA (n=6)
    191 ( 134 )
        Day 15 (pre dose): M1-IVA (n=6)
    614 ( 378 )
        Day 15 (pre dose): M6-IVA (n=6)
    1510 ( 1110 )
        Week 4 (pre dose): IVA (n=6)
    316 ( 130 )
        Week 4 (pre dose): M1-IVA (n=6)
    1170 ( 577 )
        Week 4 (pre dose): M6-IVA (n=6)
    3370 ( 2330 )
        Week 8 (pre dose): IVA (n=7)
    449 ( 352 )
        Week 8 (pre dose): M1-IVA (n=7)
    1030 ( 476 )
        Week 8 (pre dose): M6-IVA (n=7)
    2380 ( 1500 )
        Week 8 (2-4 hrs post dose): IVA (n=7)
    523 ( 262 )
        Week 8 (2-4 hrs post dose): M1-IVA (n=7)
    1360 ( 982 )
        Week 8 (2-4 hrs post dose): M6-IVA (n=7)
    2100 ( 1540 )
        Week 8 (6-8 hrs post dose): IVA (n=7)
    438 ( 79.8 )
        Week 8 (6-8 hrs post dose): M1-IVA (n=7)
    1420 ( 606 )
        Week 8 (6-8 hrs post dose): M6-IVA (n=7)
    2320 ( 1330 )
        Week 12 (pre dose): IVA (n=5)
    213 ( 173 )
        Week 12 (pre dose): M1-IVA (n=5)
    906 ( 660 )
        Week 12 (pre dose): M6-IVA (n=5)
    2500 ( 1760 )
        Week 18 (pre dose): IVA (n=6)
    226 ( 153 )
        Week 18 (pre dose): M1-IVA (n=6)
    815 ( 470 )
        Week 18 (pre dose): M6-IVA (n=6)
    2060 ( 1190 )
        Week 24 (pre dose): IVA (n=6)
    276 ( 137 )
        Week 24 (pre dose): M1-IVA (n=6)
    1120 ( 496 )
        Week 24 (pre dose): M6-IVA (n=6)
    2380 ( 799 )
    No statistical analyses for this end point

    Secondary: Part B: Observed Plasma Concentration of IVA and Their Metabolites (M1-IVA and M6-IVA)

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    End point title
    		 Part B: Observed Plasma Concentration of IVA and Their Metabolites (M1-IVA and M6-IVA)
    End point description
    PK set included subjects who received at least 1 dose of study drug. Here the "n" signifies those subjects who were evaluable at specified time point.
    End point type
    Secondary
    End point timeframe
    Week 2 (pre-dose, 2-4 hours, 6-8 hours post-dose); Week 8 (pre-dose,1 hour, 4 hour post-dose); Week 24 (pre-dose, 2-4 hours post dose)
    End point values
    		 Part B: 4 to <24 months
    Number of subjects analysed
    35
    Units: ng/ml
    arithmetic mean (standard deviation)
        Week 2 (pre dose): IVA (n=34)
    457 ( 441 )
        Week 2 (pre dose): M1-IVA (n=34)
    1340 ( 934 )
        Week 2 (pre dose): M6-IVA (n=34)
    1980 ( 1790 )
        Week 2 (2-4 hrs post dose): IVA (n=34)
    812 ( 726 )
        Week 2 (2-4 hrs post dose): M1-IVA (n=34)
    1560 ( 1190 )
        Week 2 (2-4 hrs post dose): M6-IVA (n=34)
    1770 ( 1970 )
        Week 2 (6-8 hrs post dose): IVA (n=32)
    969 ( 705 )
        Week 2 (6-8 hrs post dose): M1-IVA (n=32)
    2210 ( 1360 )
        Week 2 (6-8 hrs post dose): M6-IVA (n=32)
    2140 ( 1880 )
        Week 8 (pre dose): IVA (n=34)
    404 ( 376 )
        Week 8 (pre dose): M1-IVA (n=34)
    1220 ( 782 )
        Week 8 (pre dose): M6-IVA (n=34)
    1720 ( 1110 )
        Week 8 (1 hrs post dose): IVA (n=33)
    466 ( 384 )
        Week 8 (1 hrs post dose): M1-IVA (n=33)
    1100 ( 670 )
        Week 8 (1 hrs post dose): M6-IVA (n=33)
    1500 ( 881 )
        Week 8 (4 hrs post dose): IVA (n=33)
    996 ( 520 )
        Week 8 (4 hrs post dose): M1-IVA (n=33)
    2130 ( 950 )
        Week 8 (4 hrs post dose): M6-IVA (n=33)
    1750 ( 1010 )
        Week 24 (pre dose): IVA (n=35)
    301 ( 204 )
        Week 24 (pre dose): M1-IVA (n=35)
    1050 ( 492 )
        Week 24 (pre dose): M6-IVA (n=35)
    1600 ( 783 )
        Week 24 (2-4 hrs post dose): IVA (n=34)
    794 ( 480 )
        Week 24 (2-4 hrs post dose): M1-IVA (n=34)
    1540 ( 783 )
        Week 24 (2-4 hrs post dose): M6-IVA (n=34)
    1320 ( 592 )
    No statistical analyses for this end point

    Secondary: Part B + Part A/B: Absolute Change in Sweat Chloride

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    End point title
    		 Part B + Part A/B: Absolute Change in Sweat Chloride [8]
    End point description
    Sweat samples were collected using an approved collection device.
    End point type
    Secondary
    End point timeframe
    From Baseline at Week 24
    Notes
    [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 end point is only applicable for Part B + A/B.
    End point values
    		 Part B + A/B: 1 to <24 months
    Number of subjects analysed
    23
    Units: millimole per liter (mmol/L)
        arithmetic mean (standard deviation)
    -62.0 ( 22.2 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 Through Safety Follow-up Period (up to Day 70 for Part A and up to Week 38 for Part B + A/B)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Part A
    Reporting group description
    		 Subjects weighing 5 to <7 kg received 25 mg IVA, 7 to <14 kg received 50 mg IVA, and those weighing 14 to < 25 kg received 75 mg IVA q12h on Days 1 through 3 and 1 morning dose on Day 4.

    Reporting group title
    Part B + A/B
    Reporting group description
    		 Subjects 4 to <6 months of age and weighing ≥5 kg received 25 mg IVA q12h. At 6 months of age and older, participants weighing 5 to <7 kg received 25 mg IVA, 7 to <14 kg received 50 mg IVA, and those weighing 14 to <25 kg received 75 mg IVA q12h for 24 weeks on Part B. For Part A/B, subjects 1 to <4 months weighing 3 kg to <5 kg received an initial low dose of 5.7 mg q12h IVA and those weighing ≥5 kg received 11.4 mg q12h IVA for the first 15 days of IVA treatment.Doses were maintained or adjusted upward at Day 15 and based on weight and/or age once they reached 4 months of age.

    Serious adverse events
    		 Part A Part B + A/B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 19 (5.26%)
    6 / 43 (13.95%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eczema Coxsackium
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eczema herpeticum
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 43 (2.33%)
         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 Part B + A/B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 19 (52.63%)
    34 / 43 (79.07%)
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 19 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    4
    Blood pressure increased
         subjects affected / exposed
    0 / 19 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 19 (0.00%)
    7 / 43 (16.28%)
         occurrences all number
    0
    10
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 19 (0.00%)
    8 / 43 (18.60%)
         occurrences all number
    0
    8
    Pseudomonas test positive
         subjects affected / exposed
    0 / 19 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Head injury
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 19 (0.00%)
    12 / 43 (27.91%)
         occurrences all number
    0
    15
    Gastrointestinal disorders
    Teething
         subjects affected / exposed
    2 / 19 (10.53%)
    2 / 43 (4.65%)
         occurrences all number
    2
    2
    Infantile spitting up
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 19 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Constipation
         subjects affected / exposed
    1 / 19 (5.26%)
    6 / 43 (13.95%)
         occurrences all number
    1
    8
    Vomiting
         subjects affected / exposed
    1 / 19 (5.26%)
    8 / 43 (18.60%)
         occurrences all number
    1
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 19 (21.05%)
    24 / 43 (55.81%)
         occurrences all number
    5
    40
    Nasal congestion
         subjects affected / exposed
    1 / 19 (5.26%)
    6 / 43 (13.95%)
         occurrences all number
    1
    9
    Rhinorrhoea
         subjects affected / exposed
    1 / 19 (5.26%)
    12 / 43 (27.91%)
         occurrences all number
    1
    14
    Wheezing
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Miliaria
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 43 (4.65%)
         occurrences all number
    1
    3
    Eczema
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 43 (2.33%)
         occurrences all number
    1
    1
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 19 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Ear infection
         subjects affected / exposed
    0 / 19 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    7
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 43 (4.65%)
         occurrences all number
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    Otitis media
         subjects affected / exposed
    0 / 19 (0.00%)
    6 / 43 (13.95%)
         occurrences all number
    0
    8
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 19 (5.26%)
    7 / 43 (16.28%)
         occurrences all number
    1
    9
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 19 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Mar 2017
    Amended to add an interim analysis (IA) of safety, PK, and PD data from subjects in Cohorts 1 and 5 after a sufficient number of subjects in Cohort 5 have completed either their Week 12 or Week 24 Visit. Additional IAs for regulatory or operational purposes may also be performed. Added inclusion criterion that the subject’s weight at screening must be within the weight limits as defined for the study drug dose levels. Clarified lower and upper weight limits and added weight limits based on study drug dose levels.
    09 Jun 2020
    Amended to added Part A/B Cohort 8 to study subjects 1 to <4 months of age for 24 weeks. Reduced number of subjects in Part A from 20 to 15 subjects and removed minimum of 5 subjects in Cohort 4 because that age range is included in Part A/B Cohort 8. Part A/B Cohort 8 will be conducted sequentially with no treatment gap. Dosing will be initiated with either a 5.7 mg or 11.4 mg dose depending on age and weight at day 1 and adjusted (if necessary) on day 15 based on PK data collected on day 4.
    29 Jun 2020
    Clarified strengths and route of administration within Investigational Drug Section of Synopsis.

    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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