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    Clinical Trial Results:
    A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-440 Combination Therapy in Subjects Aged 12 Years and Older With Cystic Fibrosis

    Summary
    EudraCT number
    		 2016-000454-36
    Trial protocol
    		 GB   AT   DK   DE   BE   ES   NL   IT  
    Global end of trial date
    09 Aug 2017

    Results information
    Results version number
    		 v1
    This version publication date
    14 Dec 2018
    First version publication date
    14 Dec 2018
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    VX15-440-101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02951182
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Vertex Pharmaceuticals Incorporated
    Sponsor organisation address
    50 Northern Avenue, Massachusetts, Boston, United States, 02210-1862
    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
    07 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety, tolerability and efficacy of VX-440 in dual and triple combination with tezacaftor (TEZ) and ivacaftor (IVA)
    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
    09 Nov 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
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    United States: 45
    Worldwide total number of subjects
    74
    EEA total number of subjects
    19
    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)
    74
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Four parts were planned for the study, but only Parts 1 and 2 were conducted. Part 3 was removed from the protocol in Version 2.0. Part 4 was not conducted at the Sponsor’s discretion.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1: Placebo - Cohort 1A and 1B Combined
    Arm description
    		 Subjects received placebo matched to VX-440, placebo matched to tezacaftor (TEZ; VX-661) and placebo matched to ivacaftor (IVA, VX-770) triple combination administered orally for 4 weeks in part 1.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched with VX-440, TEZ, and IVA triple combination in part 1.

    Arm title
    		 Part 1 Cohort 1A: Triple Combination (TC)
    Arm description
    		 Subjects received VX-440 at a dose of 200 milligram (mg) along with TEZ 100 mg and IVA 150 mg triple combination administered orally up to Week 4.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-440
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-440 at a dose of 200 mg administered every 12 hours (q12h) up to 4 weeks.

    Investigational medicinal product name
    TEZ
    Investigational medicinal product code
    VX-661
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received TEZ at a dose of 100 mg administered once daily (qd) up to 4 weeks.

    Investigational medicinal product name
    IVA
    Investigational medicinal product code
    VX-770
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received IVA at a dose of 150 mg administered q12h up to 4 weeks.

    Arm title
    		 Part 1 Cohort 1B: TC Low Dose
    Arm description
    		 Subjects received VX-440 at a dose of 200 mg along with TEZ 50 mg and IVA 150 mg triple combination administered orally up to Week 4.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-440
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-440 at a dose of 200 mg administered q12h up to 4 weeks.

    Investigational medicinal product name
    TEZ
    Investigational medicinal product code
    Other name
    VX-661
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received TEZ at a dose of 50 mg administered every q12h up to 4 weeks.

    Investigational medicinal product name
    IVA
    Investigational medicinal product code
    Other name
    VX-770
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received IVA at a dose of 150 mg administered q12h up to 4 weeks.

    Arm title
    		 Part 1 Cohort 1B: TC High Dose
    Arm description
    		 Subjects received VX-440 at a dose of 600 mg along with TEZ 50 mg and IVA 300 mg triple combination administered orally up to Week 4.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-440
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-440 at a dose of 600 mg administered q12h up to 4 weeks.

    Investigational medicinal product name
    TEZ
    Investigational medicinal product code
    VX-661
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received TEZ at a dose of 50 mg administered every q12h up to 4 weeks.

    Investigational medicinal product name
    IVA
    Investigational medicinal product code
    VX-770
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received IVA at a dose of 300 mg administered q12h up to 4 weeks.

    Arm title
    		 Part 2: TEZ/IVA
    Arm description
    		 Following a 4-week run-in period on TEZ/IVA, subjects received TEZ 100 mg and IVA 150 mg administered orally up to Week 8.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    TEZ
    Investigational medicinal product code
    VX-661
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received TEZ at a dose of 100 mg administered once daily up to 12 weeks.

    Investigational medicinal product name
    IVA
    Investigational medicinal product code
    VX-770
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received IVA at a dose of 150 mg administered q12h up to 12 weeks.

    Arm title
    		 Part 2: TC-2
    Arm description
    		 Following a 4-week run-in period on TEZ/IVA, subjects received VX-440 at a dose of 600 mg for 4 weeks along with TEZ 50 mg and IVA 300 mg administered orally up to Week 8.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TEZ
    Investigational medicinal product code
    VX-661
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received TEZ at a dose of 50 mg administered q12 up to 12 weeks.

    Investigational medicinal product name
    IVA
    Investigational medicinal product code
    VX-770
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received IVA at a dose of 300 mg administered q12h up to 12 weeks.

    Investigational medicinal product name
    VX-440
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-440 at a dose of 600 mg administered q12h up to 4 weeks.

    Number of subjects in period 1 [1]
    		Part 1: Placebo - Cohort 1A and 1B Combined Part 1 Cohort 1A: Triple Combination (TC) Part 1 Cohort 1B: TC Low Dose Part 1 Cohort 1B: TC High Dose Part 2: TEZ/IVA Part 2: TC-2
    Started
    11
    9
    9
    18
    6
    20
    Completed
    11
    9
    9
    18
    6
    20
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of the 74 subjects enrolled (47 subjects in Part 1 and 27 subjects in Part 2 Run-in Period), 1 subject from Run-in period discontinued before randomization at the start of the Treatment Period because continuation criteria were not met.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Placebo - Cohort 1A and 1B Combined
    Reporting group description
    		 Subjects received placebo matched to VX-440, placebo matched to tezacaftor (TEZ; VX-661) and placebo matched to ivacaftor (IVA, VX-770) triple combination administered orally for 4 weeks in part 1.

    Reporting group title
    Part 1 Cohort 1A: Triple Combination (TC)
    Reporting group description
    		 Subjects received VX-440 at a dose of 200 milligram (mg) along with TEZ 100 mg and IVA 150 mg triple combination administered orally up to Week 4.

    Reporting group title
    Part 1 Cohort 1B: TC Low Dose
    Reporting group description
    		 Subjects received VX-440 at a dose of 200 mg along with TEZ 50 mg and IVA 150 mg triple combination administered orally up to Week 4.

    Reporting group title
    Part 1 Cohort 1B: TC High Dose
    Reporting group description
    		 Subjects received VX-440 at a dose of 600 mg along with TEZ 50 mg and IVA 300 mg triple combination administered orally up to Week 4.

    Reporting group title
    Part 2: TEZ/IVA
    Reporting group description
    		 Following a 4-week run-in period on TEZ/IVA, subjects received TEZ 100 mg and IVA 150 mg administered orally up to Week 8.

    Reporting group title
    Part 2: TC-2
    Reporting group description
    		 Following a 4-week run-in period on TEZ/IVA, subjects received VX-440 at a dose of 600 mg for 4 weeks along with TEZ 50 mg and IVA 300 mg administered orally up to Week 8.

    Reporting group values
    		 Part 1: Placebo - Cohort 1A and 1B Combined Part 1 Cohort 1A: Triple Combination (TC) Part 1 Cohort 1B: TC Low Dose Part 1 Cohort 1B: TC High Dose Part 2: TEZ/IVA Part 2: TC-2 Total
    Number of subjects
    		 11 9 9 18 6 20 73
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.2 ( 9.2 ) 36.3 ( 13.2 ) 30.6 ( 13.3 ) 29.3 ( 6.7 ) 33.2 ( 3.7 ) 30.8 ( 5.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 1 3 1 0 4 11
        Male
    		 9 8 6 17 6 16 62

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Placebo - Cohort 1A and 1B Combined
    Reporting group description
    		 Subjects received placebo matched to VX-440, placebo matched to tezacaftor (TEZ; VX-661) and placebo matched to ivacaftor (IVA, VX-770) triple combination administered orally for 4 weeks in part 1.

    Reporting group title
    Part 1 Cohort 1A: Triple Combination (TC)
    Reporting group description
    		 Subjects received VX-440 at a dose of 200 milligram (mg) along with TEZ 100 mg and IVA 150 mg triple combination administered orally up to Week 4.

    Reporting group title
    Part 1 Cohort 1B: TC Low Dose
    Reporting group description
    		 Subjects received VX-440 at a dose of 200 mg along with TEZ 50 mg and IVA 150 mg triple combination administered orally up to Week 4.

    Reporting group title
    Part 1 Cohort 1B: TC High Dose
    Reporting group description
    		 Subjects received VX-440 at a dose of 600 mg along with TEZ 50 mg and IVA 300 mg triple combination administered orally up to Week 4.

    Reporting group title
    Part 2: TEZ/IVA
    Reporting group description
    		 Following a 4-week run-in period on TEZ/IVA, subjects received TEZ 100 mg and IVA 150 mg administered orally up to Week 8.

    Reporting group title
    Part 2: TC-2
    Reporting group description
    		 Following a 4-week run-in period on TEZ/IVA, subjects received VX-440 at a dose of 600 mg for 4 weeks along with TEZ 50 mg and IVA 300 mg administered orally up to Week 8.

    Subject analysis set title
    Part 1: TC-1A/ TC-1B-low Pooled
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Sub-group analysis for primary efficacy endpoint: All subjects pooled together for Part 1: TC-1A arm and Part 1: TC-1B low dose arm.

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

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    End point title
    		 Number of Subjects With Treatment-Emergent 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 in the Treatment Period through 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 data was planned to be analysed for this endpoint. No statistical comparisons were planned.
    End point values
    		 Part 1: Placebo - Cohort 1A and 1B Combined Part 1 Cohort 1A: Triple Combination (TC) Part 1 Cohort 1B: TC Low Dose Part 1 Cohort 1B: TC High Dose Part 2: TEZ/IVA Part 2: TC-2
    Number of subjects analysed
    11
    9
    9
    18
    6
    20
    Units: Subjects
    number (not applicable)
        AEs
    9
    9
    9
    15
    6
    15
        SAEs
    0
    0
    0
    2
    2
    1
    No statistical analyses for this end point

    Primary: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Day 29

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    End point title
    		 Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Day 29 [2] [3]
    End point description
    FEV1 is the volume of air that can forcibly be blown out in first second, after full inspiration.
    End point type
    Primary
    End point timeframe
    Baseline, Through Day 29
    Notes
    [2] - 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: Pooled Data for Part 1: TC-1A arm and Part 1: TC-1B low dose arm was planned to be reported for primary efficacy end point.
    [3] - 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: Pooled Data for Part 1: TC-1A arm and Part 1: TC-1B low dose arm was planned to be reported for primary efficacy end point.
    End point values
    		 Part 1: Placebo - Cohort 1A and 1B Combined Part 1 Cohort 1B: TC High Dose Part 2: TEZ/IVA Part 2: TC-2 Part 1: TC-1A/ TC-1B-low Pooled
    Number of subjects analysed
    11
    18
    6
    19
    18
    Units: Percentage of predicted FEV1
        least squares mean (confidence interval 95%)
    1.4 (-2.5 to 5.5)
    12.0 (8.8 to 15.2)
    -2.5 (-7.2 to 2.2)
    9.5 (6.9 to 12.2)
    10.0 (6.9 to 13.2)
    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 in the Treatment Period through Safety Follow-up Visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Part 1: Placebo - Cohort 1A and 1B Combined
    Reporting group description
    		 -

    Reporting group title
    Part 1 Cohort 1A: Triple Combination (TC)
    Reporting group description
    		 -

    Reporting group title
    Part 1 Cohot 1B: TC Low Dose
    Reporting group description
    		 -

    Reporting group title
    Part 1 Cohort 1B: TC High Dose
    Reporting group description
    		 -

    Reporting group title
    Part 2: TEZ/IVA
    Reporting group description
    		 -

    Reporting group title
    Part 2: TC-2
    Reporting group description
    		 -

    Serious adverse events
    		 Part 1: Placebo - Cohort 1A and 1B Combined Part 1 Cohort 1A: Triple Combination (TC) Part 1 Cohot 1B: TC Low Dose Part 1 Cohort 1B: TC High Dose Part 2: TEZ/IVA Part 2: TC-2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 18 (11.11%)
    2 / 6 (33.33%)
    1 / 20 (5.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    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
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    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 1: Placebo - Cohort 1A and 1B Combined Part 1 Cohort 1A: Triple Combination (TC) Part 1 Cohot 1B: TC Low Dose Part 1 Cohort 1B: TC High Dose Part 2: TEZ/IVA Part 2: TC-2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 11 (81.82%)
    9 / 9 (100.00%)
    9 / 9 (100.00%)
    15 / 18 (83.33%)
    6 / 6 (100.00%)
    15 / 20 (75.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Chills
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hypersensitivity
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Reproductive system and breast disorders
    Testicular cyst
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 11 (36.36%)
    3 / 9 (33.33%)
    1 / 9 (11.11%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    5 / 20 (25.00%)
         occurrences all number
    4
    3
    1
    1
    0
    5
    Sputum increased
         subjects affected / exposed
    3 / 11 (27.27%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    3 / 20 (15.00%)
         occurrences all number
    3
    1
    1
    1
    1
    3
    Haemoptysis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    1
    0
    2
    Dyspnoea
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    Paranasal sinus hypersecretion
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    Respiration abnormal
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    Dysphonia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Lower respiratory tract congestion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Productive cough
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Wheezing
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Increased viscosity of bronchial secretion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Paranasal sinus discomfort
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Pulmonary pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Rales
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Sinus disorder
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Sinus pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Throat irritation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Mood swings
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    1
    0
    1
    2
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    2
    0
    1
    Blood urine present
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Blood bilirubin unconjugated increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Blood chloride increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Blood pressure increased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Crystal urine present
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Lipase decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Monocyte count increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pulmonary function test decreased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Anaesthetic complication neurological
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Contusion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Joint injury
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Ligament rupture
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Post procedural swelling
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Post-traumatic neck syndrome
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Procedural nausea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Sunburn
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    1
    0
    0
    1
    Dizziness
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    Lethargy
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Presyncope
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    4 / 20 (20.00%)
         occurrences all number
    1
    1
    1
    5
    0
    4
    Abdominal pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 18 (11.11%)
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Abnormal faeces
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Flatulence
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Anorectal discomfort
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Faeces pale
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Alopecia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Blister
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Night sweats
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Skin disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Arthralgia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Flank pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Muscle twitching
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Tendon discomfort
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Tendonitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    2 / 11 (18.18%)
    6 / 9 (66.67%)
    0 / 9 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    2
    7
    0
    2
    0
    3
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    2 / 18 (11.11%)
    2 / 6 (33.33%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    2
    2
    2
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    0
    2
    0
    2
    Folliculitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Increased appetite
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 May 2016
    - Sample size was reduced - Clarification in the study drug interruption and discontinuation - Modified contraception 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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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