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    Clinical Trial Results:
    A randomized, double blind placebo-controlled study to assess the safety, tolerability, pharmacokinetics, and preliminary pharmacodynamics of single and multiple ascending doses of QBW251 in healthy subjects and multiple doses in cystic fibrosis patients. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2011-005085-37
    Trial protocol
    		 GB   DE   IE   BE   FR  
    Global end of trial date
    30 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jul 2018
    First version publication date
    12 Jul 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CQBW251X2101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02190604
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    30 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the safety and tolerability of multiple ascending multiple oral doses in CF patients and to evaluate the preliminary efficacy of multiple doses of QBW251 on change from baseline in lung clearance index (LCI) in cystic fibrosis (CF) patients at Day 15.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jul 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 113
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    United States: 17
    Worldwide total number of subjects
    153
    EEA total number of subjects
    136
    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)
    153
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 In parts 1 and 2, participants (Healthy Volunteers) were randomized 3:1 to receive QBW251X or placebo. In part 3, participants (cystic fibrosis (CF) patients) were randomized 3:1 to receive QBW251X or placebo.

    Period 1
    Period 1 title
    Part 1 and 2 (Healthy Volunteers)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1 Cohort 1: QBW251
    Arm description
    		 Single dose of QBW251 10 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBW251
    Investigational medicinal product code
    QBW251
    Other name
    QBW251
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QBW251 10 mg,

    Arm title
    		 Part 1 Cohort 2: QBW251
    Arm description
    		 Single dose of QBW251 25 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBW251
    Investigational medicinal product code
    QBW251
    Other name
    QBW251
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QBW251 25mg orally

    Arm title
    		 Part 1 Cohort 3: QBW251
    Arm description
    		 Single dose of QBW251 75 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBW251
    Investigational medicinal product code
    QBW251
    Other name
    QBW251
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QBW251, 75mg orally

    Arm title
    		 Part 1 Cohort 4: QBW251
    Arm description
    		 Single dose of QBW251 150 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBW251
    Investigational medicinal product code
    QBW251
    Other name
    QBW251
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QBW251, 150mg orally

    Arm title
    		 Part 1 Cohort 5: QBW251
    Arm description
    		 Single dose of QBW251 300 mg in healthy volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBW251
    Investigational medicinal product code
    QBW251
    Other name
    QBW251
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QBW251, 300mg orally

    Arm title
    		 Part 1 Cohort 6: QBW251
    Arm description
    		 Single dose of QBW251 500 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBW251
    Investigational medicinal product code
    QBW251
    Other name
    QBW251
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QBW251, 500mg orally

    Arm title
    		 Part 1 Cohort 7: QBW251
    Arm description
    		 Single dose of QBW251 750 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBW251
    Investigational medicinal product code
    QBW251
    Other name
    QBW251
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QBW251, 750mg orally

    Arm title
    		 Part 1 Cohort 8: QBW251
    Arm description
    		 Single dose of QBW251 1000 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBW251
    Investigational medicinal product code
    QBW251
    Other name
    QBW251
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QBW251, 1000mg orally

    Arm title
    		 Part 1 Placebo
    Arm description
    		 Placebo to QBW251 in all cohorts of part 1 in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Placebo
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, orally

    Arm title
    		 Part 2 Cohort 1: QBW251
    Arm description
    		 Multiple doses of QBW25 150 mg qd in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBW251
    Investigational medicinal product code
    QBW251
    Other name
    QBW251
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QBW251, 150 mg qd

    Arm title
    		 Part 2 Cohort 2: QBW251
    Arm description
    		 Multiple doses of QBW251 400 mg qd in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBW251
    Investigational medicinal product code
    QBW251
    Other name
    QBW251
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QBW251, 450mg qd

    Arm title
    		 Part 2 Cohort 3: QBW251
    Arm description
    		 Multiple doses of QBW251 750 mg qd in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBW251
    Investigational medicinal product code
    QBW251
    Other name
    QBW251
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QBW251, 750mg qd

    Arm title
    		 Part 2 Cohort 4: QBW251
    Arm description
    		 Multiple doses of QBW251 450 mg bid in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBW251
    Investigational medicinal product code
    QBW251
    Other name
    QBW251
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QBW251, 450mg bid

    Arm title
    		 Part 2 Cohort 5: QBW251
    Arm description
    		 Multiple doses of QBW251 750 mg bid in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBW251
    Investigational medicinal product code
    QBW251
    Other name
    QBW251
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QBW251, 750mg bid

    Arm title
    		 Part 2 Placebo
    Arm description
    		 Placebo to QBW251 in all cohorts of part 2 in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Placebo
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo

    Number of subjects in period 1 [1]
    		Part 1 Cohort 1: QBW251 Part 1 Cohort 2: QBW251 Part 1 Cohort 3: QBW251 Part 1 Cohort 4: QBW251 Part 1 Cohort 5: QBW251 Part 1 Cohort 6: QBW251 Part 1 Cohort 7: QBW251 Part 1 Cohort 8: QBW251 Part 1 Placebo Part 2 Cohort 1: QBW251 Part 2 Cohort 2: QBW251 Part 2 Cohort 3: QBW251 Part 2 Cohort 4: QBW251 Part 2 Cohort 5: QBW251 Part 2 Placebo
    Started
    6
    6
    6
    6
    6
    6
    6
    6
    16
    6
    6
    6
    6
    6
    10
    Completed
    6
    6
    6
    6
    6
    6
    6
    6
    16
    6
    6
    6
    6
    5
    8
    Not completed
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    2
         Adverse event, non-fatal
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    2
         Lost to follow-up
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    1
    -
    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: This is an adaptive design parts one and 2 were conducted first then part 3 conducted later . The total equals the ww number.
    Period 2
    Period 2 title
    Part 3 (Patients)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 3 Cohort 1: QBW251
    Arm description
    		 150 mg b.i.d. Multiple doses. Patients having a class III, IV, V, or VI mutation on one allele and any other CFTR mutation on the other allele in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBW251
    Investigational medicinal product code
    QBW251
    Other name
    QBW251
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QBW251, 150mg bid

    Arm title
    		 Part 3 Cohort 2: QBW251
    Arm description
    		 450 mg b.i.d. Multiple doses. Patients having a class III, IV, V, or VI mutation on one allele and any other CFTR mutation on the other allele in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBW251
    Investigational medicinal product code
    QBW251
    Other name
    QBW251
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QBW251, 450mg bid

    Arm title
    		 Part 3 Cohort 3: QBW251
    Arm description
    		 450 mg b.i.d. Multiple doses. Patients who are homozygous for the F508del mutation in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBW251
    Investigational medicinal product code
    QBW251
    Other name
    QBW251
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QBW251, 450mg bid

    Arm title
    		 Part 3 Placebo
    Arm description
    		 Placebo to QBW251 in all cohorts of part 3 in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Placebo
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo

    Number of subjects in period 2 [2]
    		Part 3 Cohort 1: QBW251 Part 3 Cohort 2: QBW251 Part 3 Cohort 3: QBW251 Part 3 Placebo
    Started
    6
    12
    19
    12
    Completed
    6
    12
    19
    12
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: group started after period one and 2 which were with healthy volunteers.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1 Cohort 1: QBW251
    Reporting group description
    		 Single dose of QBW251 10 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

    Reporting group title
    Part 1 Cohort 2: QBW251
    Reporting group description
    		 Single dose of QBW251 25 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

    Reporting group title
    Part 1 Cohort 3: QBW251
    Reporting group description
    		 Single dose of QBW251 75 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

    Reporting group title
    Part 1 Cohort 4: QBW251
    Reporting group description
    		 Single dose of QBW251 150 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

    Reporting group title
    Part 1 Cohort 5: QBW251
    Reporting group description
    		 Single dose of QBW251 300 mg in healthy volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

    Reporting group title
    Part 1 Cohort 6: QBW251
    Reporting group description
    		 Single dose of QBW251 500 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

    Reporting group title
    Part 1 Cohort 7: QBW251
    Reporting group description
    		 Single dose of QBW251 750 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

    Reporting group title
    Part 1 Cohort 8: QBW251
    Reporting group description
    		 Single dose of QBW251 1000 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

    Reporting group title
    Part 1 Placebo
    Reporting group description
    		 Placebo to QBW251 in all cohorts of part 1 in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

    Reporting group title
    Part 2 Cohort 1: QBW251
    Reporting group description
    		 Multiple doses of QBW25 150 mg qd in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

    Reporting group title
    Part 2 Cohort 2: QBW251
    Reporting group description
    		 Multiple doses of QBW251 400 mg qd in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

    Reporting group title
    Part 2 Cohort 3: QBW251
    Reporting group description
    		 Multiple doses of QBW251 750 mg qd in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

    Reporting group title
    Part 2 Cohort 4: QBW251
    Reporting group description
    		 Multiple doses of QBW251 450 mg bid in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

    Reporting group title
    Part 2 Cohort 5: QBW251
    Reporting group description
    		 Multiple doses of QBW251 750 mg bid in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

    Reporting group title
    Part 2 Placebo
    Reporting group description
    		 Placebo to QBW251 in all cohorts of part 2 in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

    Reporting group values
    		 Part 1 Cohort 1: QBW251 Part 1 Cohort 2: QBW251 Part 1 Cohort 3: QBW251 Part 1 Cohort 4: QBW251 Part 1 Cohort 5: QBW251 Part 1 Cohort 6: QBW251 Part 1 Cohort 7: QBW251 Part 1 Cohort 8: QBW251 Part 1 Placebo Part 2 Cohort 1: QBW251 Part 2 Cohort 2: QBW251 Part 2 Cohort 3: QBW251 Part 2 Cohort 4: QBW251 Part 2 Cohort 5: QBW251 Part 2 Placebo Total
    Number of subjects
    		 6 6 6 6 6 6 6 6 16 6 6 6 6 6 10 104
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 6 6 6 6 6 6 6 6 16 6 6 6 6 6 10 104
        From 65-84 years
    		 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 36.3 ± 8.69 35 ± 14.25 43.5 ± 3.39 33.3 ± 9.61 32.7 ± 5.85 44.2 ± 8.23 28.2 ± 9.28 33.2 ± 9.47 30.3 ± 9.18 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
        Male
    		 6 6 6 6 6 6 6 6 16 6 6 6 6 6 10 104
    Age Continuous | Part 2, HV (n=40)
    Units: Years
        arithmetic mean (standard deviation)
    		 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 30.3 ± 5.13 30.5 ± 5.89 29.2 ± 11.62 31.7 ± 13.22 27.8 ± 5 29 ± 6.22 -
    Age Continuous | Part 3, CF patients (n=49)
    Units: Years
        arithmetic mean (standard deviation)
    		 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 0.9999 ± 0.9999 -

    End points

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    End points reporting groups
    Reporting group title
    Part 1 Cohort 1: QBW251
    Reporting group description
    		 Single dose of QBW251 10 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

    Reporting group title
    Part 1 Cohort 2: QBW251
    Reporting group description
    		 Single dose of QBW251 25 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

    Reporting group title
    Part 1 Cohort 3: QBW251
    Reporting group description
    		 Single dose of QBW251 75 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

    Reporting group title
    Part 1 Cohort 4: QBW251
    Reporting group description
    		 Single dose of QBW251 150 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

    Reporting group title
    Part 1 Cohort 5: QBW251
    Reporting group description
    		 Single dose of QBW251 300 mg in healthy volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

    Reporting group title
    Part 1 Cohort 6: QBW251
    Reporting group description
    		 Single dose of QBW251 500 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

    Reporting group title
    Part 1 Cohort 7: QBW251
    Reporting group description
    		 Single dose of QBW251 750 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

    Reporting group title
    Part 1 Cohort 8: QBW251
    Reporting group description
    		 Single dose of QBW251 1000 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

    Reporting group title
    Part 1 Placebo
    Reporting group description
    		 Placebo to QBW251 in all cohorts of part 1 in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

    Reporting group title
    Part 2 Cohort 1: QBW251
    Reporting group description
    		 Multiple doses of QBW25 150 mg qd in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

    Reporting group title
    Part 2 Cohort 2: QBW251
    Reporting group description
    		 Multiple doses of QBW251 400 mg qd in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

    Reporting group title
    Part 2 Cohort 3: QBW251
    Reporting group description
    		 Multiple doses of QBW251 750 mg qd in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

    Reporting group title
    Part 2 Cohort 4: QBW251
    Reporting group description
    		 Multiple doses of QBW251 450 mg bid in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

    Reporting group title
    Part 2 Cohort 5: QBW251
    Reporting group description
    		 Multiple doses of QBW251 750 mg bid in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

    Reporting group title
    Part 2 Placebo
    Reporting group description
    		 Placebo to QBW251 in all cohorts of part 2 in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).
    Reporting group title
    Part 3 Cohort 1: QBW251
    Reporting group description
    		 150 mg b.i.d. Multiple doses. Patients having a class III, IV, V, or VI mutation on one allele and any other CFTR mutation on the other allele in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.

    Reporting group title
    Part 3 Cohort 2: QBW251
    Reporting group description
    		 450 mg b.i.d. Multiple doses. Patients having a class III, IV, V, or VI mutation on one allele and any other CFTR mutation on the other allele in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.

    Reporting group title
    Part 3 Cohort 3: QBW251
    Reporting group description
    		 450 mg b.i.d. Multiple doses. Patients who are homozygous for the F508del mutation in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.

    Reporting group title
    Part 3 Placebo
    Reporting group description
    		 Placebo to QBW251 in all cohorts of part 3 in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.

    Subject analysis set title
    Part 1 cohort 6 FED
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    part 1 cohort 6 had testing done in fasting and fed stat....this data represents the Fed state

    Primary: Part 1 and 2:Number of participants (Healthy Volunteers) with reported adverse events receiving QBW251

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    End point title
    		 Part 1 and 2:Number of participants (Healthy Volunteers) with reported adverse events receiving QBW251 [1]
    End point description
    All adverse events (in healthy volunteers) reported. There were no reporting of serious adverse events or death in part 1 and 2. No statistical analysis was planned for this primary outcome
    End point type
    Primary
    End point timeframe
    Day 1 to Day 36
    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: All end points are verified
    End point values
    		 Part 1 Cohort 1: QBW251 Part 1 Cohort 2: QBW251 Part 1 Cohort 3: QBW251 Part 1 Cohort 4: QBW251 Part 1 Cohort 5: QBW251 Part 1 Cohort 6: QBW251 Part 1 Cohort 7: QBW251 Part 1 Cohort 8: QBW251 Part 1 Placebo Part 2 Cohort 1: QBW251 Part 2 Cohort 2: QBW251 Part 2 Cohort 3: QBW251 Part 2 Cohort 4: QBW251 Part 2 Cohort 5: QBW251 Part 2 Placebo Part 1 cohort 6 FED
    Number of subjects analysed
    6
    6
    6
    6
    6
    6
    6
    6
    16
    6
    6
    6
    6
    6
    10
    5
    Units: Participants
    1
    0
    0
    0
    0
    0
    0
    0
    2
    0
    1
    0
    0
    1
    1
    0
    No statistical analyses for this end point

    Primary: Part 3: Change in Lung Clearance Index (LCI) from baseline to day 15

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    End point title
    		 Part 3: Change in Lung Clearance Index (LCI) from baseline to day 15 [2]
    End point description
    Change in Lung Clearance Index (LCI) will be conducted according to international standards in cystic fibrosis patients. Lung clearance index (LCI) is a measure of ventilation inhomogeneity that is derived from a multiple-breath washout test, A reduction in mean change from baseline for LCI2.5 indicates improvement. No statistical analysis was planned for this primary outcome
    End point type
    Primary
    End point timeframe
    Baseline and Day 15
    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: All end points are verified
    End point values
    Number of subjects analysed
    Units: Ratio
        arithmetic mean (standard deviation)
    No statistical analyses for this end point

    Primary: Part 3: Number of participants (Patients) with reported adverse events receiving QBW251

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    End point title
    		 Part 3: Number of participants (Patients) with reported adverse events receiving QBW251 [3]
    End point description
    All adverse events and serious adverse events (in patients) reported. There were no reporting of death in part 3. No statistical analysis was planned for this primary outcome
    End point type
    Primary
    End point timeframe
    Day 1 to Day 56
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: All end points are verified
    End point values
    Number of subjects analysed
    Units: Participants
        Adverse Events (AE)
        Serious Adverse Events (SAE)
    No statistical analyses for this end point

    Secondary: Part 3:Change in Forced Expiratory Volume in 1 second (FEV1) at day 15

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    End point title
    		 Part 3:Change in Forced Expiratory Volume in 1 second (FEV1) at day 15
    End point description
    Forced Expiratory Volume in 1 second (FEV1) will be measured via spirometer according to international standards. Forced Expiratory Volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation
    End point type
    Secondary
    End point timeframe
    Baseline and Day 15
    End point values
    Number of subjects analysed
    Units: Liters
        least squares mean (standard error)
    No statistical analyses for this end point

    Secondary: Part 3: Change in Cystic Fibrosis Questionnaire-Revised reported outcomes

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    End point title
    		 Part 3: Change in Cystic Fibrosis Questionnaire-Revised reported outcomes
    End point description
    Change in Cystic Fibrosis Questionnaire data will be obtained from patient reported outcomes (CFQ-R PRO). Respiratory Domain, cores range from 0 to 100, with higher scores indicating better health, a change of 4 is considered clinically relevant
    End point type
    Secondary
    End point timeframe
    Baseline and Day 14
    End point values
    Number of subjects analysed
    Units: Units on a scale
        least squares mean (standard error)
    No statistical analyses for this end point

    Secondary: Part 1: AUC0-t in healthy volunteers

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    End point title
    		 Part 1: AUC0-t in healthy volunteers [4]
    End point description
    Pharmacokinetics of QBW251 in plasma: area under the plasma concentration versus time curve from time zero to time of last measurable concentration (AUC0-t). In part one of the study a single dose was administered and samples were collected up to 5 days. As a result the AUC0-t goes from Day 1 to Day 5 (for some lower doses QBW251 concentrations were not measured up to Day 5 as the concentrations were low due to the low dose administered)
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose (i.e. Days 2-5)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All end points are verified
    End point values
    		 Part 1 Cohort 1: QBW251 Part 1 Cohort 2: QBW251 Part 1 Cohort 3: QBW251 Part 1 Cohort 4: QBW251 Part 1 Cohort 5: QBW251 Part 1 Cohort 6: QBW251 Part 1 Cohort 7: QBW251 Part 1 Cohort 8: QBW251 Part 1 Placebo
    Number of subjects analysed
    6
    6
    6
    6
    6
    6
    6
    6
    16
    Units: hr*ng/mL
        arithmetic mean (standard deviation)
    52.5 ± 28.1
    73.7 ± 51.8
    692 ± 389
    1650 ± 907
    5470 ± 1070
    9450 ± 1740
    20200 ± 11500
    35900 ± 9100
    0.9999 ± 0.9999
    No statistical analyses for this end point

    Secondary: Part 1: Maximum concentration (Cmax) in healthy volunteers

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    End point title
    		 Part 1: Maximum concentration (Cmax) in healthy volunteers [5]
    End point description
    Pharmacokinetics of QBW251 in plasma: observed maximum plasma concentration following administration of QBW251. In this analysis Cmax will be reported using blood samples taken on Days 1- 5 are from healthy volunteers
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose (i.e. Days 1 - 5)
    Notes
    [5] - 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: All end points are verified
    End point values
    		 Part 1 Cohort 1: QBW251 Part 1 Cohort 2: QBW251 Part 1 Cohort 3: QBW251 Part 1 Cohort 4: QBW251 Part 1 Cohort 5: QBW251 Part 1 Cohort 6: QBW251 Part 1 Cohort 7: QBW251 Part 1 Cohort 8: QBW251
    Number of subjects analysed
    6
    6
    6
    6
    6
    6
    6
    6
    Units: ug/L
        arithmetic mean (standard deviation)
    21.1 ± 11.9
    24.7 ± 15.9
    186 ± 82.3
    459 ± 267
    1110 ± 330
    1910 ± 413
    2680 ± 1000
    4540 ± 930
    No statistical analyses for this end point

    Secondary: Part 1: Time to maximum concentration (Tmax) in healthy volunteers

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    End point title
    		 Part 1: Time to maximum concentration (Tmax) in healthy volunteers [6]
    End point description
    Pharmacokinetics of QBW251 in plasma: time to reach the maximum concentration after administration of QBW251. In this analysis Tmax will be reported using blood samples taken on Days 1 - 5 from healthy volunteers. In this part of the study a single dose was administered and samples were collected up to 5 days. As a result the Tmax is one value as the concentration-time curve goes to Day 5 (for some lower does QBW251 concentrations were not measured up to Day 5 as the concentrations were low due to the low dose administered).
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose (i.e. Days 1 - 5)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All end points are verified
    End point values
    		 Part 1 Cohort 1: QBW251 Part 1 Cohort 2: QBW251 Part 1 Cohort 3: QBW251 Part 1 Cohort 4: QBW251 Part 1 Cohort 5: QBW251 Part 1 Cohort 6: QBW251 Part 1 Cohort 7: QBW251 Part 1 Cohort 8: QBW251
    Number of subjects analysed
    6
    6
    6
    6
    6
    6
    6
    6
    Units: hr
        arithmetic mean (standard deviation)
    0.756 ± 0.268
    1.25 ± 0.612
    1.33 ± 0.516
    1.5 ± 0.548
    1.5 ± 0.837
    2.17 ± 1.17
    2.52 ± 0.85
    1.83 ± 0.753
    No statistical analyses for this end point

    Secondary: Part 1: T1/2 in healthy volunteers

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    End point title
    		 Part 1: T1/2 in healthy volunteers [7]
    End point description
    Pharmacokinetics of QBW251 in plasma: terminal elimination half-life. In this analysis T1/2 will be reported using blood samples taken on Days 1 - 5 from healthy volunteers. In part one of the study a single dose was administered and samples were collected up to 5 days. As a result the T1/2 goes from Day 1 to Day 5 (for some lower doses QBW251 concentrations were not measured up to Day 5 as the concentrations were low due to the low dose administered).
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose (i.e. Days 1 - 5)
    Notes
    [7] - 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: All end points are verified
    End point values
    		 Part 1 Cohort 1: QBW251 Part 1 Cohort 2: QBW251 Part 1 Cohort 3: QBW251 Part 1 Cohort 4: QBW251 Part 1 Cohort 5: QBW251 Part 1 Cohort 6: QBW251 Part 1 Cohort 7: QBW251 Part 1 Cohort 8: QBW251
    Number of subjects analysed
    6
    6
    6
    6
    6
    6
    6
    6
    Units: hr
        arithmetic mean (standard deviation)
    0.9999 ± 0.9999
    0.9999 ± 0.9999
    10.3 ± 4.24
    10.1 ± 3.35
    12 ± 2.26
    12.7 ± 1.99
    12.8 ± 3.85
    10.7 ± 2.19
    No statistical analyses for this end point

    Secondary: Part 1: AUCinf in healthy volunteers

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    End point title
    		 Part 1: AUCinf in healthy volunteers [8]
    End point description
    Pharmacokinetics of QBW251 in plasma: area under the plasma concentration time curve from time zero to infinity. In this analysis AUCinf will be reported using blood samples taken on Days 1 - 5 from healthy volunteers. In part one of the study a single dose was administered and samples were collected up to 5 days. As a result the AUCinf goes from Day 1 to Day 5 (for some lower doses QBW251 concentrations were not measured up to Day 5 as the concentrations were low due to the low dose administered)
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose (i.e. Days 1 - 5)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All end points are verified
    End point values
    		 Part 1 Cohort 1: QBW251 Part 1 Cohort 2: QBW251 Part 1 Cohort 3: QBW251 Part 1 Cohort 4: QBW251 Part 1 Cohort 5: QBW251 Part 1 Cohort 6: QBW251 Part 1 Cohort 7: QBW251 Part 1 Cohort 8: QBW251
    Number of subjects analysed
    6
    6
    6
    6
    6
    6
    6
    6
    Units: hr*ng/mL
        arithmetic mean (standard deviation)
    0.9999 ± 0.9999
    0.9999 ± 0.9999
    731 ± 387
    1680 ± 903
    5510 ± 1080
    9480 ± 1740
    20300 ± 11500
    36000 ± 9120
    No statistical analyses for this end point

    Secondary: Part 1: CL/F in healthy volunteers

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    End point title
    		 Part 1: CL/F in healthy volunteers [9]
    End point description
    Pharmacokinetics of QBW251 in plasma: apparent systemic clearance from plasma following extravascular administration. In this analysis CL/F will be reported using blood samples taken on Days 1 - 5 from healthy volunteers. In part one of the study a single dose was administered and samples were collected up to 5 days. As a result the CL/F goes from Day 1 to Day 5 (for some lower doses QBW251 concentrations were not measured up to Day 5 as the concentrations were low due to the low dose administered)
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose (i.e. Days 1 - 5)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All end points are verified
    End point values
    		 Part 1 Cohort 1: QBW251 Part 1 Cohort 2: QBW251 Part 1 Cohort 3: QBW251 Part 1 Cohort 4: QBW251 Part 1 Cohort 5: QBW251 Part 1 Cohort 6: QBW251 Part 1 Cohort 7: QBW251 Part 1 Cohort 8: QBW251
    Number of subjects analysed
    6
    6
    6
    6
    6
    6
    6
    6
    Units: L/hr
        arithmetic mean (standard deviation)
    0.9999 ± 0.9999
    0.9999 ± 0.9999
    123 ± 49
    114 ± 63.9
    56.2 ± 11
    54.5 ± 11.9
    45.9 ± 19.9
    29.7 ± 9
    No statistical analyses for this end point

    Secondary: Part 1: Vz/F in healthy volunteers

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    End point title
    		 Part 1: Vz/F in healthy volunteers [10]
    End point description
    Pharmacokinetics of QBW251 in plasma: apparent volume of distribution during the terminal elimination phase following extravascular administration. In this analysis Vz/F will be reported using blood samples taken on Days 1 - 5 from healthy volunteers.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose (i.e. Days 1 - 5)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All end points are verified
    End point values
    		 Part 1 Cohort 1: QBW251 Part 1 Cohort 2: QBW251 Part 1 Cohort 3: QBW251 Part 1 Cohort 4: QBW251 Part 1 Cohort 5: QBW251 Part 1 Cohort 6: QBW251 Part 1 Cohort 7: QBW251 Part 1 Cohort 8: QBW251
    Number of subjects analysed
    6
    6
    6
    6
    6
    6
    6
    6
    Units: Liters
        arithmetic mean (standard deviation)
    0.9999 ± 0.9999
    0.9999 ± 0.9999
    1700 ± 772
    1490 ± 622
    957 ± 151
    995 ± 235
    827 ± 375
    447 ± 112
    No statistical analyses for this end point

    Secondary: Part 2: Ae0-t in healthy volunteers

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    End point title
    		 Part 2: Ae0-t in healthy volunteers [11]
    End point description
    Pharmacokinetics of QBW251 in urine: amount of drug excreted in urine from time zero until last measurable concentration. In this analysis Ae0-t will be reported using urine samples taken on Day 1 from healthy volunteers.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 1
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All end points are verified
    End point values
    		 Part 2 Cohort 1: QBW251 Part 2 Cohort 2: QBW251 Part 2 Cohort 3: QBW251 Part 2 Cohort 4: QBW251 Part 2 Cohort 5: QBW251 Part 2 Placebo
    Number of subjects analysed
    6
    6
    6
    5
    5
    10
    Units: L/hr
        arithmetic mean (standard deviation)
    2.36 ± 1.84
    2.2 ± 1.26
    1.21 ± 0.697
    0.419 ± 0.271
    0.14 ± 0.0936
    0.9999 ± 0.9999
    No statistical analyses for this end point

    Secondary: Part 2: CLr in healthy volunteers

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    End point title
    		 Part 2: CLr in healthy volunteers [12]
    End point description
    Pharmacokinetics of QBW251 in urine: renal clearance following drug administration. In this analysis CLr will be reported using urine samples taken on Day 1 from healthy volunteers.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 1; Day 14 was calculated as urine was only collected up to 12 hours on Day 1 thus CLr cannot be calculated.
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All end points are verified
    End point values
    		 Part 2 Cohort 1: QBW251 Part 2 Cohort 2: QBW251 Part 2 Cohort 3: QBW251 Part 2 Cohort 4: QBW251 Part 2 Cohort 5: QBW251
    Number of subjects analysed
    6
    6
    6
    6
    6
    Units: L/hr
        arithmetic mean (standard deviation)
    2.36 ± 1.84
    2.2 ± 1.26
    1.21 ± 0.697
    0.419 ± 0.271
    0.14 ± 0.0936
    No statistical analyses for this end point

    Secondary: Part 2: AUCtau in healthy volunteers

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    End point title
    		 Part 2: AUCtau in healthy volunteers [13]
    End point description
    Pharmacokinetics of QBW251 in plasma after multiple doses: the area under the plasma concentration-time curve from time zero to end of the dosing interval tau. In this analysis AUCtau will be reported. Samples taken on Days 1 and 14 from healthy volunteers
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 1 and 14; ( If B ID dosing, 12 hours samples will be pre-dosed)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All end points are verified
    End point values
    		 Part 2 Cohort 1: QBW251 Part 2 Cohort 2: QBW251 Part 2 Cohort 3: QBW251 Part 2 Cohort 4: QBW251 Part 2 Cohort 5: QBW251
    Number of subjects analysed
    6
    6
    6
    6
    6
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        Day1
    1800 ± 794
    6170 ± 1250
    16100 ± 8170
    7160 ± 1960
    18800 ± 6360
        Day 14
    2060 ± 708
    7620 ± 1470
    28300 ± 5570
    12100 ± 4930
    80300 ± 56300
    No statistical analyses for this end point

    Secondary: Part 2: Maximum concentration (Cmax) in healthy volunteers

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    End point title
    		 Part 2: Maximum concentration (Cmax) in healthy volunteers [14]
    End point description
    Pharmacokinetics of QBW251 in plasma after multiple doses: observed maximum plasma concentration following QBW251 at steady state. In this analysis Cmax will be reported using blood samples taken on Days 1 and 14 from healthy volunteers.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 1 and 14; ( If B ID dosing, 12 hours samples will be pre-dosed)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All end points are verified
    End point values
    		 Part 2 Cohort 1: QBW251 Part 2 Cohort 2: QBW251 Part 2 Cohort 3: QBW251 Part 2 Cohort 4: QBW251 Part 2 Cohort 5: QBW251
    Number of subjects analysed
    6
    6
    6
    6
    6
    Units: ug/L
    arithmetic mean (standard deviation)
        Day 1
    541 ± 338
    1650 ± 343
    2790 ± 1040
    1650 ± 188
    3720 ± 1530
        Day 14
    430 ± 145
    1500 ± 442
    3840 ± 868
    2190 ± 769
    9420 ± 4330
    No statistical analyses for this end point

    Secondary: Part 2: Time to maximum concentration (Tmax) in healthy volunteers

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    End point title
    		 Part 2: Time to maximum concentration (Tmax) in healthy volunteers [15]
    End point description
    Pharmacokinetics of QBW251 in plasma after multiple doses: time to reach the maximum concentration after administration of QBW251. In this analysis Tmax will be reported using blood samples taken on Days 1 and 14 from healthy volunteers.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 1 and 14; ( If B ID dosing, 12 hours samples will be pre-dosed)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All end points are verified
    End point values
    		 Part 2 Cohort 1: QBW251 Part 2 Cohort 2: QBW251 Part 2 Cohort 3: QBW251 Part 2 Cohort 4: QBW251 Part 2 Cohort 5: QBW251
    Number of subjects analysed
    6
    6
    6
    6
    6
    Units: hr
    arithmetic mean (standard deviation)
        Day 1
    1.67 ± 0.816
    1.17 ± 0.408
    2.33 ± 1.21
    2.68 ± 0.813
    3.67 ± 0.516
        Day 2
    2.17 ± 1.17
    2.17 ± 0.408
    2.33 ± 1.03
    3.25 ± 1.41
    3.8 ± 0.447
    No statistical analyses for this end point

    Secondary: Part 2: AUC0-t

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    End point title
    		 Part 2: AUC0-t [16]
    End point description
    Pharmacokinetics of QBW251 in plasma: area under the plasma concentration versus time curve from time zero to time of last measurable concentration. In this analysis AUC0-t will be reported using blood samples taken on Day 14 are from healthy volunteers.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 14; ( If B ID dosing, 12 hours samples will be pre-dosed)
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All end points are verified
    End point values
    		 Part 2 Cohort 1: QBW251 Part 2 Cohort 2: QBW251 Part 2 Cohort 3: QBW251 Part 2 Cohort 4: QBW251 Part 2 Cohort 5: QBW251 Part 2 Placebo
    Number of subjects analysed
    6
    6
    6
    6
    5
    10
    Units: hr*ng/mL
        arithmetic mean (standard deviation)
    2060 ± 708
    7620 ± 1470
    28300 ± 5570
    12100 ± 4930
    80300 ± 56300
    0.9999 ± 0.9999
    No statistical analyses for this end point

    Secondary: Part 2: Cav in healthy volunteers

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    End point title
    		 Part 2: Cav in healthy volunteers [17]
    End point description
    The average drug concentration in plasma during multiple dosing. In this analysis Cav will be reported using blood samples taken on Days 1 and 14 are from healthy volunteers.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 1 and 14; ( If B ID dosing, 12 hours samples will be pre-dosed)
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All end points are verified
    End point values
    		 Part 2 Cohort 1: QBW251 Part 2 Cohort 2: QBW251 Part 2 Cohort 3: QBW251 Part 2 Cohort 4: QBW251 Part 2 Cohort 5: QBW251
    Number of subjects analysed
    6
    6
    6
    6
    6
    Units: ug/L
        arithmetic mean (standard deviation)
    85.8 ± 29.5
    318 ± 61.1
    1180 ± 232
    0.9999 ± 0.9999
    0.9999 ± 0.9999
    No statistical analyses for this end point

    Secondary: Part 2: CL/F in healthy volunteers

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    End point title
    		 Part 2: CL/F in healthy volunteers [18]
    End point description
    apparent systemic clearance from plasma following extravascular administration. In this analysis CL/F will be reported using blood samples taken on Day 14 from healthy volunteers.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 14; ( If B ID dosing, 12 hours samples will be pre-dosed)
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All end points are verified
    End point values
    		 Part 2 Cohort 1: QBW251 Part 2 Cohort 2: QBW251 Part 2 Cohort 3: QBW251 Part 2 Cohort 4: QBW251 Part 2 Cohort 5: QBW251
    Number of subjects analysed
    6
    6
    6
    6
    6
    Units: L/hr
        arithmetic mean (standard deviation)
    80.8 ± 29.7
    54 ± 9.4
    27.5 ± 5.98
    0.9999 ± 0.9999
    0.9999 ± 0.9999
    No statistical analyses for this end point

    Secondary: Part 2: Vz/F in healthy volunteers

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    End point title
    		 Part 2: Vz/F in healthy volunteers [19]
    End point description
    Apparent volume of distribution during the terminal elimination phase following extravascular administration. In this analysis Vz/F will be reported using blood samples taken on Day 14 from healthy volunteers.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 14; ( If B ID dosing, 12 hours samples will be pre-dosed)
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All end points are verified
    End point values
    		 Part 2 Cohort 1: QBW251 Part 2 Cohort 2: QBW251 Part 2 Cohort 3: QBW251 Part 2 Cohort 4: QBW251 Part 2 Cohort 5: QBW251
    Number of subjects analysed
    6
    6
    6
    6
    6
    Units: Liters
        arithmetic mean (standard deviation)
    1330 ± 550
    1120 ± 395
    608 ± 255
    0.9999 ± 0.9999
    0.9999 ± 0.9999
    No statistical analyses for this end point

    Secondary: Part 2: Racc in healthy volunteers

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    End point title
    		 Part 2: Racc in healthy volunteers [20]
    End point description
    Accumulation ratio (Racc). In this analysis Racc will be reported using blood samples taken on Days 1 - 14 from healthy volunteers.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 1 - 14; ( If B ID dosing, 12 hours samples will be pre-dosed)
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All end points are verified
    End point values
    		 Part 2 Cohort 1: QBW251 Part 2 Cohort 2: QBW251 Part 2 Cohort 3: QBW251 Part 2 Cohort 4: QBW251 Part 2 Cohort 5: QBW251
    Number of subjects analysed
    6
    6
    6
    6
    6
    Units: Ratio
        arithmetic mean (standard deviation)
    1.27 ± 0.425
    1.25 ± 0.199
    2.08 ± 0.913
    1.66 ± 0.386
    3.88 ± 2.07
    No statistical analyses for this end point

    Secondary: Part 2: T1/2 in healthy volunteers

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    End point title
    		 Part 2: T1/2 in healthy volunteers [21]
    End point description
    terminal elimination half-life (T1/2). In this analysis T1/2 will be reported using blood samples taken on Day 14 from healthy volunteers.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4 , 8 hr post-dose at Day 1; 24, 48, 72 and 96 hr post dose Day 14; ( If B ID dosing, 12 hours samples will be pre-dosed)
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All end points are verified
    End point values
    		 Part 2 Cohort 1: QBW251 Part 2 Cohort 2: QBW251 Part 2 Cohort 3: QBW251 Part 2 Cohort 4: QBW251 Part 2 Cohort 5: QBW251
    Number of subjects analysed
    6
    6
    6
    6
    6
    Units: hr
        arithmetic mean (standard deviation)
    11.3 ± 1.44
    14.1 ± 3.8
    15.1 ± 4.4
    0.9999 ± 0.9999
    0.9999 ± 0.9999
    No statistical analyses for this end point

    Secondary: Part 3: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of QBW251 in CF patients

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    End point title
    		 Part 3: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of QBW251 in CF patients
    End point description
    Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast)
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14
    End point values
    Number of subjects analysed
    Units: ng × hr /mL
    arithmetic mean (standard deviation)
        Day 1
        Day 14
    No statistical analyses for this end point

    Secondary: Part 3: Plasma Concentration at the Last Quantifiable Time Point (Clast) of QBW251 in CF patients

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    End point title
    		 Part 3: Plasma Concentration at the Last Quantifiable Time Point (Clast) of QBW251 in CF patients
    End point description
    Blood samples were collected at timepoints prespecified in the study protocol. Tlast of QBW251 was the last time point when blood sample collected was quantifiable
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day2
    End point values
    Number of subjects analysed
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1
        Day 14
    No statistical analyses for this end point

    Secondary: Part 3: Maximum concentration (Cmax) in CF patients

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    End point title
    		 Part 3: Maximum concentration (Cmax) in CF patients
    End point description
    Observed maximum plasma concentration following administration of QBW251. In this analysis Cmax will be reported using blood samples taken on Day 1and day 14 from patients
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14
    End point values
    Number of subjects analysed
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1
        Day 14
    No statistical analyses for this end point

    Secondary: Part 3: Tlast in CF patients

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    End point title
    		 Part 3: Tlast in CF patients
    End point description
    Blood samples were collected at timepoints prespecified in the study protocol. Tlast of QBW251 was the last time point when blood sample collected was quantifiable day 1 and day 14
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14
    End point values
    Number of subjects analysed
    Units: hr
    arithmetic mean (standard deviation)
        Day 1
        Day 14
    No statistical analyses for this end point

    Secondary: Part 3: Time to maximum concentration (Tmax)

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    End point title
    		 Part 3: Time to maximum concentration (Tmax)
    End point description
    Pharmacokinetics of QBW251 in plasma after multiple doses: time to reach the maximum concentration after administration of QBW251. In this analysis Tmax will be reported using blood samples taken on Days 1 and 14 in patients
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hr), 0.25, 0.5, 1, 2, 3, 4, 8 hr post-dose in Day 1, Day 14
    End point values
    Number of subjects analysed
    Units: hr
    arithmetic mean (standard deviation)
        Day 1
        Day 14
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Part 1 QBW251 150 mg
    Reporting group description
    		 Part 1 QBW251 150 mg

    Reporting group title
    Part 1 Placebo
    Reporting group description
    		 Part 1 Placebo

    Reporting group title
    Part 1 QBW251 25 mg
    Reporting group description
    		 Part 1 QBW251 25 mg

    Reporting group title
    Part 1 QBW251 10 mg
    Reporting group description
    		 Part 1 QBW251 10 mg

    Reporting group title
    Part 1 QBW251 750 mg
    Reporting group description
    		 Part 1 QBW251 750 mg

    Reporting group title
    Part 1 QBW251 1000 mg
    Reporting group description
    		 Part 1 QBW251 1000 mg

    Reporting group title
    Part 1 QBW251 500 mg
    Reporting group description
    		 Part 1 QBW251 500 mg

    Reporting group title
    Part 1 QBW251 500 mg (fed)
    Reporting group description
    		 Part 1 QBW251 500 mg (fed)

    Reporting group title
    Part 1 QBW251 300 mg
    Reporting group description
    		 Part 1 QBW251 300 mg

    Reporting group title
    Part 2 QBW251 150 mg
    Reporting group description
    		 Part 2 QBW251 150 mg

    Reporting group title
    Part 2 QBW251 400 mg
    Reporting group description
    		 Part 2 QBW251 400 mg

    Reporting group title
    Part 2 QBW251 750 mg
    Reporting group description
    		 Part 2 QBW251 750 mg

    Reporting group title
    Part 2 Placebo
    Reporting group description
    		 Part 2 Placebo

    Reporting group title
    Part 3 Placebo C1/C2/C3
    Reporting group description
    		 Part 3 Placebo C1/C2/C3

    Reporting group title
    Part 3 QBW251 150 mg b.i.d. C1
    Reporting group description
    		 Part 3 QBW251 150 mg b.i.d. C1

    Reporting group title
    Part 3 QBW251 450 mg b.i.d. C2
    Reporting group description
    		 Part 3 QBW251 450 mg b.i.d. C2

    Reporting group title
    Part 2 QBW251 450 mg bid
    Reporting group description
    		 Part 2 QBW251 450 mg bid

    Reporting group title
    Part 2 QBW251 750 mg bid
    Reporting group description
    		 Part 2 QBW251 750 mg bid

    Reporting group title
    Part 3 QBW251 450 mg b.i.d. C3
    Reporting group description
    		 Part 3 QBW251 450 mg b.i.d. C3

    Serious adverse events
    		 Part 1 QBW251 150 mg Part 1 Placebo Part 1 QBW251 25 mg Part 1 QBW251 10 mg Part 1 QBW251 750 mg Part 1 QBW251 1000 mg Part 1 QBW251 500 mg Part 1 QBW251 500 mg (fed) Part 1 QBW251 300 mg Part 2 QBW251 150 mg Part 2 QBW251 400 mg Part 2 QBW251 750 mg Part 2 Placebo Part 3 Placebo C1/C2/C3 Part 3 QBW251 150 mg b.i.d. C1 Part 3 QBW251 450 mg b.i.d. C2 Part 2 QBW251 450 mg bid Part 2 QBW251 750 mg bid Part 3 QBW251 450 mg b.i.d. C3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    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 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences 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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    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
    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 1 QBW251 150 mg Part 1 Placebo Part 1 QBW251 25 mg Part 1 QBW251 10 mg Part 1 QBW251 750 mg Part 1 QBW251 1000 mg Part 1 QBW251 500 mg Part 1 QBW251 500 mg (fed) Part 1 QBW251 300 mg Part 2 QBW251 150 mg Part 2 QBW251 400 mg Part 2 QBW251 750 mg Part 2 Placebo Part 3 Placebo C1/C2/C3 Part 3 QBW251 150 mg b.i.d. C1 Part 3 QBW251 450 mg b.i.d. C2 Part 2 QBW251 450 mg bid Part 2 QBW251 750 mg bid Part 3 QBW251 450 mg b.i.d. C3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 6 (16.67%)
    8 / 16 (50.00%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    4 / 6 (66.67%)
    2 / 6 (33.33%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    6 / 6 (100.00%)
    3 / 6 (50.00%)
    7 / 10 (70.00%)
    8 / 12 (66.67%)
    5 / 6 (83.33%)
    8 / 12 (66.67%)
    6 / 6 (100.00%)
    4 / 6 (66.67%)
    18 / 19 (94.74%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1
    Chest discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    3 / 12 (25.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    3
    0
    0
    2
    Influenza like illness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    2
    Peripheral swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1
    Sensation of foreign body
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Thirst
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Vessel puncture site bruise
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchial obstruction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Cough
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    2 / 12 (16.67%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    4 / 6 (66.67%)
    0 / 6 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    2
    1
    1
    4
    0
    5
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    0
    0
    0
    0
    Haemoptysis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    3
    Nasal congestion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    2
    Nasal discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Painful respiration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Pulmonary congestion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    2
    Sinus congestion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    1
    Sneezing
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Sputum increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    2 / 12 (16.67%)
    3 / 6 (50.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    5 / 19 (26.32%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    3
    0
    0
    0
    5
    Throat irritation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1
    0
    0
    0
    0
    Tonsillar disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Depression
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Stress
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Investigations
    Adenovirus test positive
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Blood potassium decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Breath sounds abnormal
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Coronavirus test positive
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Ligament sprain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Skin wound
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Congenital, familial and genetic disorders
    Ichthyosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 16 (18.75%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 10 (20.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    3
    0
    0
    0
    2
    0
    0
    0
    0
    0
    0
    2
    0
    0
    3
    1
    0
    1
    Headache
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 16 (12.50%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    4 / 10 (40.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    3 / 12 (25.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    4 / 19 (21.05%)
         occurrences all number
    0
    2
    0
    2
    0
    2
    2
    0
    1
    0
    1
    0
    4
    0
    1
    4
    1
    2
    6
    Hyperaesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Presyncope
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    0
    1
    Tremor
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Ear pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Tinnitus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1
    Abdominal distension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    0
    0
    0
    1
    Abdominal pain lower
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Aphthous stomatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    2
    Faeces discoloured
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 10 (20.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    4 / 6 (66.67%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    1
    4
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Gingival disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    4 / 12 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    1
    4
    0
    0
    2
    Saliva altered
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Salivary gland pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Heat rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Night sweats
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Pruritus generalised
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Rash erythematous
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Rash pruritic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Glycosuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Proteinuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Joint swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1
    Folliculitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Fungal infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    3 / 12 (25.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    3
    1
    0
    0
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    1
    0
    0
    1
    0
    1
    1
    0
    0
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Vitamin d deficiency
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    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
    14 Jun 2012
    The purpose of this amendment was to respond to the MHRA response received on 07-Jun-2012 regarding ‘Discontinuation of study treatment and premature subject withdrawal’, which states the following: Discontinuation of study treatment and subject withdrawal was at the discretion of the Investigator, under the following circumstances: • An SAE that was suspected of being related to study drug • An AE which was severe (Grade 3 or greater) and suspected of being related to study drug MHRA stated the above was unacceptable; if either of the situation under 2 bullets occurred the subject was required to be discontinued from the study medication. Minor typographical errors have been addressed throughout the protocol
    10 Oct 2012
    The purpose of this amendment was to address discrepancies in the assessment schedule with the urine and blood logs in addition to minor clarifications for Parts 1 and Parts 2.
    17 Jul 2013
    The rationale for this amendment was based on the preliminary PK data from the food effect study performed in Part 1, which demonstrated an approximate 21% and 43% reduction in total (AUCinf) and maximal (Cmax) systemic exposure to QBW251, respectively, as compared to the fasted stated. Having demonstrated the impact of food on the PK of QBW251, it was recognized the need to modify protocol language to allow for dose and dosing frequency under food effect conditions to better represent a real-world clinical situation in Parts 2, 3, and 4. Thus this amendment was provided language that was to allow adaptive dose and dosing frequency in order to achieve optimal exposure below the imposed exposure cap.
    12 Aug 2013
    Since the last amendment of this protocol two issues have occurred to justify changes, as follows: 1) The protocol underwent review by both the EU and US Cystic Fibrosis networks, and on the basis of these reviews, the protocol was amended to meet their proposed suggestions. 2) New scientific findings now support the rationale for using specific genotypes of CF patients in the current protocol. The new evidence supported that QBW251 would only benefit CF patients that have a mutation in CFTR that allows trafficking of CFTR to the cell membrane (e.g., class III, IV, V, VI CFTR mutations), but require potentiation of the receptor to repair function. On the basis of the above issues, this amendment implemented these changes relevant to Parts 3 and 4 of the protocol related to CF patients. Furthermore, while Part 2 was ongoing per protocol, the study had completed Part 1 of the study
    15 Apr 2014
    The purpose of this amendment was to address requests from FDA received on 01Apr 2014 regarding: •The maximum clinical exposure (exposure cap) supported by nonclinical data was based on the NOEL in monkeys (i.e., AUC0-24 = 47850 ng.hr/mL) instead of those observed at the rat no-observed-adverse-effect-level (i.e., AUC0-24 = 78850 ng×hr/mL). Healthy Volunteer data demonstrated that the exposure at 450 mg b.i.d. (AUCtau=12,100 ng×hr/mL or AUC0-24 = 24 200 ng×hr/mL), which was the highest dose planned in the study in CF patients, were approximately 2- and 3- fold below the exposures from monkeys and rats, respectively that produced no adverse findings. Based on this data, the highest planned dose in CF patients at 450 mg b.i.d. was still expected to result in exposures less than the new exposure cap of 47 850 ng×hr/mL. •Use of hyperpolarized helium-3 MRI (exploratory objective). This assessment was removed from Part 4 as the 3He MRI methodology is available only at limited number of centers globally. For the type of CF patient population targeted in this protocol, only three 3He MRI centers could potentially be utilized such that the number of subjects receiving the assessment would not be statistically meaningful. Hence this technology was not deployed in this trial. •Dose-escalation stopping rules •Other minor administrative aspects are clarified. A copy of this amended protocol was sent to the IRBs / IECs and Health Authorities for approval prior to implementation
    15 Sep 2014
    The purpose of this amendment was to address requests from the Irish Health Authorities regarding the Screening period that was changed from Day −28 to Day −2 to Day −28 to Day −7. This was done in order to minimize risks of early pregnancy by the urine pregnancy test at Baseline (Day −1) in case Screening visit (formal latest start of contraception) was done less than 7 days prior to Baseline (Day −1). The seven days between end of Screening and first study treatment was sufficient for newly started contraception to be effective, and an early pregnancy would not be missed by a negat ive hCG at baseline visit (Day −1) one day prior to dosing. This amendment also stipulated that patients that were included in Part 3 could not be enrolled in Part 4. At that time, only 28 days of toxicology data was available which was not a sufficient coverage for patients to participate in both, Parts 3 and 4 (total 6 weeks duration). The assessment of effect of QBW251 on height was removed from the exploratory objective. The effect of QBW251 was evaluated on weight and BMI only as we don’t expect to see a change in height in the short period of the study.
    16 Feb 2015
    The purpose of this amendment was to include the assessment of safety, tolerability and efficacy of QBW251 in adult CF patients who are homozygous for the F508del mutation (F508del/F508del). These patients were previously not included in the study due to insufficient pre-clinical data. QBW251 was developed and optimized to potentiate the F508del-CFTR in vitro. Pre-clinical studies had demonstrated that QBW251, as compared to a competitor drug, does not have the same negative effect on cell surface expression and potentiation of human bronchial epithelial cells that express F508del/F508del CFTR (Veit et al 2014 and Cholon et al 2014). In addition, PK studies had showed that QBW251 had an excellent PK profile with lower plasma protein binding and increased free fraction, which supports the notion that a larger proportion of the administered dose may reach the target. Therefore, the inclusion of F508del homozygous patients was based on the rationale that through providing sustained potentiation of F508del-CFTR, QBW251 as monotherapy may provide a clinical benefit to the F508del homozygous patient population without the need to co-administer a corrector to improve surface trafficking of F508del-CFTR. These F508del homozygous patients (n=32) were included in Cohort 3 of Part 3 of the study. Cohort 2 and Cohort 3 of Part 3 of the study were conducted in parallel. In addition to the above rationale for this amendment, this amendment increased the age range for inclusion in Part 3 for Cohort 2 and Cohort 3 from 18 - 55 years to 18 - 65 years. Based on good safety/tolerability profile in 18-55 year olds, and because there was no mechanistic reason to expect a different safety profile in individuals between 55 - 65 years, the upper age limit had been increased to 65 years.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    16 Nov 2015
    An interim analysis was conducted during Part 3 of the study, which demonstrated evidence of efficacy in Cohorts 1 and 2, but futility in cohort 3; hence the study was terminated in Nov 2015 before Cohort 3 was completed.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
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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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