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    Clinical Trial Results:
    A Phase 1/2 Study of VX-121 in Healthy Subjects and in Subjects with Cystic Fibrosis

    Summary
    EudraCT number
    2018-000126-55
    Trial protocol
    NL  
    Global end of trial date
    03 May 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    17 May 2020
    First version publication date
    17 May 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VX17-121-001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03768089
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Vertex Pharmaceuticals Incorporated
    Sponsor organisation address
    50 Northern Avenue, Boston, Massachusetts, United States,
    Public contact
    Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617 341 6777, medicalinfo@vrtx.com
    Scientific contact
    Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617 341 6777, medicalinfo@vrtx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    03 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of single or multiple ascending doses of VX-121 alone or in combination with Tezacaftor/Ivacaftor (TEZ/IVA).
    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
    20 Mar 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
    Netherlands: 109
    Country: Number of subjects enrolled
    United Kingdom: 6
    Worldwide total number of subjects
    115
    EEA total number of subjects
    115
    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)
    0
    Adults (18-64 years)
    115
    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 included 4 parts: Parts A, B, and C were conducted in healthy adult subjects; Part D was conducted in adult cystic fibrosis (CF) subjects.

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Part A: Pooled Placebo (Except Cohorts A3 and A9)
    Arm description
    Subjects received single dose of placebo matched to VX-121 in Cohorts A1 to A5 (Except Cohorts A3 and A9).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (matched to VX-121)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received single dose of placebo matched to VX-121 in Cohorts A1 to A5 (Except Cohorts A3 and A9).

    Arm title
    Part A: VX-121 (Except Cohorts A3 and A9)
    Arm description
    Subjects received single ascending dose of VX-121 in Cohorts A1 to A5 (except Cohorts A3 and A9).
    Arm type
    Experimental

    Investigational medicinal product name
    VX-121
    Investigational medicinal product code
    VX-121
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received single ascending dose of VX-121 in Cohorts A1 to A5 (except Cohorts A3 and A9).

    Arm title
    Part A: VX-121 (Cohort A3)
    Arm description
    Subjects received single dose VX-121 or placebo without milk, followed by open label VX-121 with milk in Cohort A3.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-121
    Investigational medicinal product code
    VX-121
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received single dose VX-121 without milk, followed by VX-121 with milk in Cohort A3.

    Investigational medicinal product name
    Placebo (matched to VX-121)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to VX-121 without milk, followed by VX-121 with milk in Cohort A3.

    Arm title
    Part A: VX-121 (Cohort A9)
    Arm description
    Subjects received single dose of VX-121 suspension, fed on Day 1, VX-121 tablet, fed on Day 9, and then VX-121 tablet, fed with milk on Day 17 in Cohort A9.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-121
    Investigational medicinal product code
    VX-121
    Other name
    Pharmaceutical forms
    Tablet, Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received single dose of VX-121 suspension on Day 1, VX-121 tablet on Day 9, and then VX-121 tablet with milk on Day 17 in Cohort A9.

    Arm title
    Part B: Pooled Placebo
    Arm description
    Subjects received multiple doses of placebo matched to VX-121 for 10 days.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (matched to VX-121)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received multiple doses of placebo matched to VX-121 once daily.

    Arm title
    Part B: VX-121
    Arm description
    Subjects received multiple ascending doses of VX-121 for 10 days.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-121
    Investigational medicinal product code
    VX-121
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received multiple ascending doses of VX-121 once daily.

    Arm title
    Part C: Pooled Placebo
    Arm description
    Subjects received placebo matched to VX-121/TEZ/IVA triple combination (TC) for 14 days.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (matched to VX-121)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to VX-121 suspension once daily.

    Investigational medicinal product name
    Placebo (matched to TEZ/IVA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to TEZ/IVA once daily in the morning.

    Investigational medicinal product name
    Placebo (matched to IVA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to IVA once daily in the evening.

    Arm title
    Part C: VX-121/TEZ/IVA TC
    Arm description
    Subjects received VX-121/TEZ/IVA TC for 14 days.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-121
    Investigational medicinal product code
    VX-121
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-121 suspension once daily.

    Investigational medicinal product name
    TEZ/IVA
    Investigational medicinal product code
    VX-661/VX-770
    Other name
    Tezacaftor/Ivacaftor fixed dose combination
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received TEZ/IVA once daily in the morning.

    Investigational medicinal product name
    IVA
    Investigational medicinal product code
    VX-770
    Other name
    Ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received IVA once daily in the evening.

    Arm title
    Part D: Placebo
    Arm description
    Subjects with CF received placebo matched to VX-121/TEZ/IVA TC for 4 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (matched to VX-121)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects with CF received placebo matched to VX-121 once daily.

    Investigational medicinal product name
    Placebo (matched to TEZ/IVA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects with CF received placebo matched to TEZ/IVA once daily in the morning.

    Investigational medicinal product name
    Placebo (matched to IVA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects with CF received placebo matched to IVA once daily in the evening.

    Arm title
    Part D: VX-121/TEZ/IVA TC
    Arm description
    Subjects with CF received VX-121/TEZ/IVA TC for 4 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-121
    Investigational medicinal product code
    VX-121
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects with CF received VX-121 once daily.

    Investigational medicinal product name
    TEZ/IVA
    Investigational medicinal product code
    VX-661/VX-770
    Other name
    Tezacaftor/Ivacaftor fixed dose combination
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects with CF received TEZ/IVA once daily in the morning.

    Investigational medicinal product name
    IVA
    Investigational medicinal product code
    VX-770
    Other name
    Ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects with CF received IVA once daily in the evening.

    Number of subjects in period 1
    Part A: Pooled Placebo (Except Cohorts A3 and A9) Part A: VX-121 (Except Cohorts A3 and A9) Part A: VX-121 (Cohort A3) Part A: VX-121 (Cohort A9) Part B: Pooled Placebo Part B: VX-121 Part C: Pooled Placebo Part C: VX-121/TEZ/IVA TC Part D: Placebo Part D: VX-121/TEZ/IVA TC
    Started
    8
    23
    6
    8
    9
    24
    6
    19
    3
    9
    Completed
    8
    22
    6
    8
    9
    24
    6
    19
    3
    9
    Not completed
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
         Lost to follow-up
    -
    1
    -
    -
    -
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Part A: Pooled Placebo (Except Cohorts A3 and A9)
    Reporting group description
    Subjects received single dose of placebo matched to VX-121 in Cohorts A1 to A5 (Except Cohorts A3 and A9).

    Reporting group title
    Part A: VX-121 (Except Cohorts A3 and A9)
    Reporting group description
    Subjects received single ascending dose of VX-121 in Cohorts A1 to A5 (except Cohorts A3 and A9).

    Reporting group title
    Part A: VX-121 (Cohort A3)
    Reporting group description
    Subjects received single dose VX-121 or placebo without milk, followed by open label VX-121 with milk in Cohort A3.

    Reporting group title
    Part A: VX-121 (Cohort A9)
    Reporting group description
    Subjects received single dose of VX-121 suspension, fed on Day 1, VX-121 tablet, fed on Day 9, and then VX-121 tablet, fed with milk on Day 17 in Cohort A9.

    Reporting group title
    Part B: Pooled Placebo
    Reporting group description
    Subjects received multiple doses of placebo matched to VX-121 for 10 days.

    Reporting group title
    Part B: VX-121
    Reporting group description
    Subjects received multiple ascending doses of VX-121 for 10 days.

    Reporting group title
    Part C: Pooled Placebo
    Reporting group description
    Subjects received placebo matched to VX-121/TEZ/IVA triple combination (TC) for 14 days.

    Reporting group title
    Part C: VX-121/TEZ/IVA TC
    Reporting group description
    Subjects received VX-121/TEZ/IVA TC for 14 days.

    Reporting group title
    Part D: Placebo
    Reporting group description
    Subjects with CF received placebo matched to VX-121/TEZ/IVA TC for 4 weeks.

    Reporting group title
    Part D: VX-121/TEZ/IVA TC
    Reporting group description
    Subjects with CF received VX-121/TEZ/IVA TC for 4 weeks.

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: There were 115 unique enrolled subjects in the study. One subject was randomized, but not dosed. Therefore, baseline accounts for 114 unique dosed subjects (one subject participated in 2 parts and thus was counted twice in Baseline section).
    Reporting group values
    Part A: Pooled Placebo (Except Cohorts A3 and A9) Part A: VX-121 (Except Cohorts A3 and A9) Part A: VX-121 (Cohort A3) Part A: VX-121 (Cohort A9) Part B: Pooled Placebo Part B: VX-121 Part C: Pooled Placebo Part C: VX-121/TEZ/IVA TC Part D: Placebo Part D: VX-121/TEZ/IVA TC Total
    Number of subjects
    8 23 6 8 9 24 6 19 3 9
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    29.8 ± 10.6 30.3 ± 11.5 25.8 ± 4.16 33.9 ± 11.5 31.7 ± 14.0 29.6 ± 10.5 30.3 ± 12.1 36.6 ± 13.2 22.8 ± 4.9 34.8 ± 12.8 -
    Gender categorical
    Units: Subjects
        Female
    0 2 0 0 1 0 0 1 0 1 5
        Male
    8 21 6 8 8 24 6 18 3 8 109

    End points

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    End points reporting groups
    Reporting group title
    Part A: Pooled Placebo (Except Cohorts A3 and A9)
    Reporting group description
    Subjects received single dose of placebo matched to VX-121 in Cohorts A1 to A5 (Except Cohorts A3 and A9).

    Reporting group title
    Part A: VX-121 (Except Cohorts A3 and A9)
    Reporting group description
    Subjects received single ascending dose of VX-121 in Cohorts A1 to A5 (except Cohorts A3 and A9).

    Reporting group title
    Part A: VX-121 (Cohort A3)
    Reporting group description
    Subjects received single dose VX-121 or placebo without milk, followed by open label VX-121 with milk in Cohort A3.

    Reporting group title
    Part A: VX-121 (Cohort A9)
    Reporting group description
    Subjects received single dose of VX-121 suspension, fed on Day 1, VX-121 tablet, fed on Day 9, and then VX-121 tablet, fed with milk on Day 17 in Cohort A9.

    Reporting group title
    Part B: Pooled Placebo
    Reporting group description
    Subjects received multiple doses of placebo matched to VX-121 for 10 days.

    Reporting group title
    Part B: VX-121
    Reporting group description
    Subjects received multiple ascending doses of VX-121 for 10 days.

    Reporting group title
    Part C: Pooled Placebo
    Reporting group description
    Subjects received placebo matched to VX-121/TEZ/IVA triple combination (TC) for 14 days.

    Reporting group title
    Part C: VX-121/TEZ/IVA TC
    Reporting group description
    Subjects received VX-121/TEZ/IVA TC for 14 days.

    Reporting group title
    Part D: Placebo
    Reporting group description
    Subjects with CF received placebo matched to VX-121/TEZ/IVA TC for 4 weeks.

    Reporting group title
    Part D: VX-121/TEZ/IVA TC
    Reporting group description
    Subjects with CF received VX-121/TEZ/IVA TC for 4 weeks.

    Primary: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) [1]
    End point description
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to safety follow-up visit OR up to 7 days (except Part D)/28 days (Part D) after the last dose date of study drug for subjects who do not have a safety follow-up visit
    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 primary safety endpoint.
    End point values
    Part A: Pooled Placebo (Except Cohorts A3 and A9) Part A: VX-121 (Except Cohorts A3 and A9) Part A: VX-121 (Cohort A3) Part A: VX-121 (Cohort A9) Part B: Pooled Placebo Part B: VX-121 Part C: Pooled Placebo Part C: VX-121/TEZ/IVA TC Part D: Placebo Part D: VX-121/TEZ/IVA TC
    Number of subjects analysed
    8
    23
    6
    8
    9
    24
    6
    19
    3
    9
    Units: Subjects
        Subjects with AEs
    1
    9
    4
    7
    7
    17
    4
    12
    2
    7
        Subjects with SAEs
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to safety follow-up visit OR up to 7 days (except Part D)/28 days (Part D) after the last dose date of study drug for subjects who do not have a safety follow-up visit
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Part A: Pooled Placebo (Except Cohorts A3 and A9)
    Reporting group description
    Subjects received single dose of placebo matched to VX-121 in Cohorts A1 to A5 (Except Cohorts A3 and A9).

    Reporting group title
    Part A: VX-121 (Except Cohorts A3 and A9)
    Reporting group description
    Subjects received single ascending dose of VX-121 in Cohorts A1 to A5 (except Cohorts A3 and A9).

    Reporting group title
    Part A: VX-121 (Cohort A3)
    Reporting group description
    Subjects received single dose VX-121 or placebo without milk, followed by open label VX-121 with milk in Cohort A3.

    Reporting group title
    Part A: VX-121 (Cohort A9)
    Reporting group description
    Subjects received single dose of VX-121 suspension, fed on Day 1, VX-121 tablet, fed on Day 9, and then VX-121 tablet, fed with milk on Day 17 in Cohort A9.

    Reporting group title
    Part B: Pooled Placebo
    Reporting group description
    Subjects received multiple doses of placebo matched to VX-121 for 10 days.

    Reporting group title
    Part B: VX-121
    Reporting group description
    Subjects received multiple ascending doses of VX-121 for 10 days.

    Reporting group title
    Part C: Pooled Placebo
    Reporting group description
    Subjects received placebo matched to VX-121/TEZ/IVA triple combination (TC) for 14 days.

    Reporting group title
    Part C: VX-121/TEZ/IVA TC
    Reporting group description
    Subjects received VX-121/TEZ/IVA TC for 14 days.

    Reporting group title
    Part D: Placebo
    Reporting group description
    Subjects with CF received placebo matched to VX-121/TEZ/IVA TC for 4 weeks.

    Reporting group title
    Part D: VX-121/TEZ/IVA TC
    Reporting group description
    Subjects with CF received VX-121/TEZ/IVA TC for 4 weeks.

    Serious adverse events
    Part A: Pooled Placebo (Except Cohorts A3 and A9) Part A: VX-121 (Except Cohorts A3 and A9) Part A: VX-121 (Cohort A3) Part A: VX-121 (Cohort A9) Part B: Pooled Placebo Part B: VX-121 Part C: Pooled Placebo Part C: VX-121/TEZ/IVA TC Part D: Placebo Part D: VX-121/TEZ/IVA TC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Part A: Pooled Placebo (Except Cohorts A3 and A9) Part A: VX-121 (Except Cohorts A3 and A9) Part A: VX-121 (Cohort A3) Part A: VX-121 (Cohort A9) Part B: Pooled Placebo Part B: VX-121 Part C: Pooled Placebo Part C: VX-121/TEZ/IVA TC Part D: Placebo Part D: VX-121/TEZ/IVA TC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 8 (12.50%)
    9 / 23 (39.13%)
    4 / 6 (66.67%)
    7 / 8 (87.50%)
    7 / 9 (77.78%)
    16 / 24 (66.67%)
    4 / 6 (66.67%)
    12 / 19 (63.16%)
    2 / 3 (66.67%)
    7 / 9 (77.78%)
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    1 / 24 (4.17%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    0
    0
    Catheter site bruise
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    1 / 6 (16.67%)
    3 / 19 (15.79%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    3
    0
    0
    Catheter site erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Catheter site irritation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    2 / 24 (8.33%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    0
    0
    0
    0
    Catheter site pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 23 (4.35%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    2 / 24 (8.33%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    1
    0
    2
    2
    0
    4
    0
    0
    Catheter site pruritus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Chest discomfort
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    1 / 3 (33.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    0
    5
    0
    0
    0
    1
    1
    1
    Feeling cold
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Feeling hot
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Puncture site pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Vessel puncture site bruise
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    3 / 24 (12.50%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    4
    0
    0
    0
    0
    Vessel puncture site pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 9 (11.11%)
    1 / 24 (4.17%)
    0 / 6 (0.00%)
    3 / 19 (15.79%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    0
    3
    0
    0
    Tension
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    2 / 24 (8.33%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    0
    1
    0
    0
    Contusion
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    2 / 24 (8.33%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    0
    1
    0
    0
    Procedural complication
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Faecal volume decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Influenza A virus test positive
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 24 (4.17%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    1 / 3 (33.33%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    1
    3
    Dyspnoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
    1 / 3 (33.33%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    1
    2
    Nasal congestion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    2
    0
    0
    Painful respiration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    2
    Rhinorrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Sputum increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    3 / 9 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    1 / 24 (4.17%)
    2 / 6 (33.33%)
    4 / 19 (21.05%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    3
    4
    0
    0
    Dizziness postural
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Headache
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 23 (8.70%)
    1 / 6 (16.67%)
    4 / 8 (50.00%)
    2 / 9 (22.22%)
    3 / 24 (12.50%)
    1 / 6 (16.67%)
    6 / 19 (31.58%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    2
    1
    4
    2
    3
    2
    7
    0
    1
    Nerve compression
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    1
    0
    0
    Eye disorders
    Eye irritation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    1
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    2
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Constipation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Defaecation urgency
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    4
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 23 (8.70%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    1 / 6 (16.67%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    1
    2
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 23 (4.35%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    1 / 24 (4.17%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    1
    0
    0
    1
    1
    0
    2
    0
    2
    Nausea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    1 / 24 (4.17%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    3
    0
    0
    Oral pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Salivary hypersecretion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Toothache
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    2 / 24 (8.33%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 24 (4.17%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    2
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    3 / 24 (12.50%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    3
    0
    0
    0
    0
    Dermal cyst
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 24 (4.17%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    2
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    0
    0
    Papule
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 24 (4.17%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    2
    0
    0
    Pruritus generalised
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 24 (4.17%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    1
    0
    0
    Rash
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    1 / 24 (4.17%)
    1 / 6 (16.67%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    1
    1
    0
    0
    Rash macular
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    2 / 24 (8.33%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    0
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    2 / 24 (8.33%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    1
    0
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Skin hypertrophy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Skin hypopigmentation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    0
    0
    Skin irritation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    1 / 24 (4.17%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    0
    0
    Swelling face
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    4 / 9 (44.44%)
    2 / 24 (8.33%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    2
    1
    0
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Muscle twitching
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    0
    0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    1 / 3 (33.33%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    1 / 6 (16.67%)
    3 / 19 (15.79%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    3
    0
    0
    Periodontitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 23 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 24 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 May 2018
    Refined study design and revised exclusion criteria
    27 Jul 2018
    Updated dosing guidance and prohibited medications

    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
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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