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    Clinical Trial Results:
    A multi-center, non-blinded, randomized cross-over study to compare the acute tolerability and pharmacokinetics of BAYQ6256 (iloprost; Ventavis) inhalation using the I-Neb nebulizer and the FOX nebulizer in subjects with pulmonary arterial hypertension

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2013-002783-12
    Trial protocol
    		 DE   AT  
    Global end of trial date
    29 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Jul 2016
    First version publication date
    21 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAYQ006256/16483
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02032836
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, D-51368 Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Sep 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess, in subjects with pulmonary arterial hypertension, the acute tolerability of 5 microgram (mcg) iloprost inhaled as Ventavis 20 microgram per milliliter (mcg/mL) solution through a FOX nebulizer* with that of 5 mcg iloprost inhaled as Ventavis 10 mcg/mL solution through the I-Neb nebulizer. * FOX or FOX Bavent nebuliser used for Ventavis® meanwhile carries the product name Breelib™
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 Individual therapy of underlying pulmonary arterial hypertension (PAH) and other comorbidities. Inhalative therapy with 5 mcg iloprost using the I-Neb nebulizer until Day 2 (before first cross-over dosing).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Mar 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Ethical reason
    Long term follow-up duration
    		 39 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Germany: 27
    Worldwide total number of subjects
    28
    EEA total number of subjects
    28
    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)
    18
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at five study centers in Germany and one in Austria in healthy male and female subjects between 10 March 2014 (first subject first visit) and 27 July 2017 (last subject last visit for study part 4).

    Pre-assignment
    Screening details
    		 Overall, 28 subjects were screened and randomized into the study, of which 1 subject never received study drug. Of 27 subjects, 26 received iloprost using I-Neb nebulizer and 27 received iloprost using FOX nebulizer in a cross-over fashion during Part 2 and Part 3 of the study. Of these subjects, 25 entered Part 4 and were included in the analysis.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 I-Neb – FOX
    Arm description
    		 Part 1: Subjects received single inhalation of 1.25 mcg iloprost using 10 mcg/ml iloprost solution (Ventavis 10) and then 2.5 mcg iloprost using Ventavis 10, both using the FOX nebulizer on Day 1. Part 2: On Day 2, subjects received single inhalation of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer; followed by single inhalation of 5 mcg iloprost using 20 mcg/ml iloprost solution (Ventavis 20) with the FOX nebulizer in a cross-over fashion. A washout period of at least 2 hours was maintained between treatments in Part 1 and Part 2. Part 3: Continued on Day 2, and through until Day 30, subjects received multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer for 2 weeks; followed by multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 20 with the FOX nebulizer for 2 weeks in a cross-over fashion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Iloprost 1.25 mcg via Iloprost 10 mcg/mL with FOX nebulizer (Experimental)
    Investigational medicinal product code
    BAYQ6256
    Other name
    Ventavis
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received single inhalation of 1.25 mcg iloprost using 10 mcg/ml iloprost solution (Ventavis 10) with the FOX nebulizer in Part 1.

    Investigational medicinal product name
    Iloprost 2.5 mcg via Iloprost 10 mcg/mL with FOX nebulizer (Experimental)
    Investigational medicinal product code
    BAYQ6256
    Other name
    Ventavis
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received single inhalation of 2.5 mcg iloprost using Ventavis 10 with the FOX nebulizer in Part 1.

    Investigational medicinal product name
    Iloprost 5 mcg via Iloprost 10 mcg/mL with I-neb nebulizer (Active comparator)
    Investigational medicinal product code
    BAYQ6256
    Other name
    Ventavis
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received single inhalation of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer in Part 2.

    Investigational medicinal product name
    Iloprost 5 mcg via Iloprost 20 mcg/mL with FOX nebulizer (Experimental)
    Investigational medicinal product code
    BAYQ6256
    Other name
    Ventavis
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received single inhalation of 5 mcg iloprost using 20 mcg/ml iloprost solution (Ventavis 20) with the FOX nebulizer in Part 2.

    Investigational medicinal product name
    Iloprost 5 mcg via Iloprost 10 mcg/mL with I-Neb nebulizer (Active comparator)
    Investigational medicinal product code
    BAYQ6256
    Other name
    Ventavis
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer for 2 weeks in Part 3.

    Investigational medicinal product name
    Iloprost 5 mcg via Iloprost 20 mcg/mL with FOX nebulizer (Experimental)
    Investigational medicinal product code
    BAYQ6256
    Other name
    Ventavis
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 20 with the FOX nebulizer for 2 weeks in Part 3.

    Arm title
    		 FOX - I-Neb
    Arm description
    		 Part 1: Subjects received single inhalation of 1.25 mcg iloprost using 10 mcg/ml iloprost solution (Ventavis 10) and then 2.5 mcg iloprost using Ventavis 10, both using the FOX nebulizer on Day 1. Part 2: On Day 2, subjects received single inhalation of 5 mcg iloprost using 20 mcg/ml iloprost solution (Ventavis 20) with the FOX nebulizer; followed by single inhalation of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer in a cross-over fashion. A wash-out period of at least 2 hours was maintained between treatments in Part 1 and Part 2. Part 3: Continued on Day 2, and through until Day 30, subjects received multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 20 with the FOX nebulizer for 2 weeks; followed by multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer for 2 weeks in a cross-over fashion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Iloprost 1.25 mcg via Iloprost 10 mcg/mL with FOX nebulizer (Experimental)
    Investigational medicinal product code
    BAYQ6256
    Other name
    Ventavis
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received single inhalation of 1.25 mcg iloprost using 10 mcg/ml iloprost solution (Ventavis 10) with the FOX nebulizer in Part 1.

    Investigational medicinal product name
    Iloprost 2.5 mcg via Iloprost 10 mcg/mL with FOX nebulizer (Experimental)
    Investigational medicinal product code
    BAYQ6256
    Other name
    Ventavis
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received single inhalation of 2.5 mcg iloprost using Ventavis 10 with the FOX nebulizer in Part 1.

    Investigational medicinal product name
    Iloprost 5 mcg via Iloprost 10 mcg/mL with I-neb nebulizer (Active comparator)
    Investigational medicinal product code
    BAYQ6256
    Other name
    Ventavis
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received single inhalation of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer in Part 2.

    Investigational medicinal product name
    Iloprost 5 mcg via Iloprost 20 mcg/mL with FOX nebulizer (Experimental)
    Investigational medicinal product code
    BAYQ6256
    Other name
    Ventavis
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received single inhalation of 5 mcg iloprost using 20 mcg/ml iloprost solution (Ventavis 20) with the FOX nebulizer in Part 2.

    Investigational medicinal product name
    Iloprost 5 mcg via Iloprost 10 mcg/mL with I-Neb nebulizer (Active comparator)
    Investigational medicinal product code
    BAYQ6256
    Other name
    Ventavis
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer for 2 weeks in Part 3.

    Investigational medicinal product name
    Iloprost 5 mcg via Iloprost 20 mcg/mL with FOX nebulizer (Experimental)
    Investigational medicinal product code
    BAYQ6256
    Other name
    Ventavis
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 20 with the FOX nebulizer for 2 weeks in Part 3.

    Number of subjects in period 1 [1]
    		I-Neb – FOX FOX - I-Neb
    Started
    13
    14
    Completed
    13
    13
    Not completed
    0
    1
         Non-compliance with study drug
    -
    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: Not all the enrolled subjects were treated with study drugs. As baseline only included treated subjects, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    I-Neb – FOX
    Reporting group description
    		 Part 1: Subjects received single inhalation of 1.25 mcg iloprost using 10 mcg/ml iloprost solution (Ventavis 10) and then 2.5 mcg iloprost using Ventavis 10, both using the FOX nebulizer on Day 1. Part 2: On Day 2, subjects received single inhalation of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer; followed by single inhalation of 5 mcg iloprost using 20 mcg/ml iloprost solution (Ventavis 20) with the FOX nebulizer in a cross-over fashion. A washout period of at least 2 hours was maintained between treatments in Part 1 and Part 2. Part 3: Continued on Day 2, and through until Day 30, subjects received multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer for 2 weeks; followed by multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 20 with the FOX nebulizer for 2 weeks in a cross-over fashion.

    Reporting group title
    FOX - I-Neb
    Reporting group description
    		 Part 1: Subjects received single inhalation of 1.25 mcg iloprost using 10 mcg/ml iloprost solution (Ventavis 10) and then 2.5 mcg iloprost using Ventavis 10, both using the FOX nebulizer on Day 1. Part 2: On Day 2, subjects received single inhalation of 5 mcg iloprost using 20 mcg/ml iloprost solution (Ventavis 20) with the FOX nebulizer; followed by single inhalation of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer in a cross-over fashion. A wash-out period of at least 2 hours was maintained between treatments in Part 1 and Part 2. Part 3: Continued on Day 2, and through until Day 30, subjects received multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 20 with the FOX nebulizer for 2 weeks; followed by multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer for 2 weeks in a cross-over fashion.

    Reporting group values
    		 I-Neb – FOX FOX - I-Neb Total
    Number of subjects
    		 13 14 27
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.8 ( 17.1 ) 56.4 ( 14.5 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 10 11 21
        Male
    		 3 3 6

    End points

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    End points reporting groups
    Reporting group title
    I-Neb – FOX
    Reporting group description
    		 Part 1: Subjects received single inhalation of 1.25 mcg iloprost using 10 mcg/ml iloprost solution (Ventavis 10) and then 2.5 mcg iloprost using Ventavis 10, both using the FOX nebulizer on Day 1. Part 2: On Day 2, subjects received single inhalation of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer; followed by single inhalation of 5 mcg iloprost using 20 mcg/ml iloprost solution (Ventavis 20) with the FOX nebulizer in a cross-over fashion. A washout period of at least 2 hours was maintained between treatments in Part 1 and Part 2. Part 3: Continued on Day 2, and through until Day 30, subjects received multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer for 2 weeks; followed by multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 20 with the FOX nebulizer for 2 weeks in a cross-over fashion.

    Reporting group title
    FOX - I-Neb
    Reporting group description
    		 Part 1: Subjects received single inhalation of 1.25 mcg iloprost using 10 mcg/ml iloprost solution (Ventavis 10) and then 2.5 mcg iloprost using Ventavis 10, both using the FOX nebulizer on Day 1. Part 2: On Day 2, subjects received single inhalation of 5 mcg iloprost using 20 mcg/ml iloprost solution (Ventavis 20) with the FOX nebulizer; followed by single inhalation of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer in a cross-over fashion. A wash-out period of at least 2 hours was maintained between treatments in Part 1 and Part 2. Part 3: Continued on Day 2, and through until Day 30, subjects received multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 20 with the FOX nebulizer for 2 weeks; followed by multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer for 2 weeks in a cross-over fashion.

    Subject analysis set title
    Safety Analysis Set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received any treatment with the study medication (with the I-Neb or the FOX nebulizer, or with both) were included.

    Subject analysis set title
    Hemodynamic Set (HDS-1)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who were treated in both treatment periods at Visit 2 (Part 2), for whom no major deviations from protocol were recorded, who had any quantifiable iloprost plasma concentrations in both periods and for whom pre-inhalation blood-pressure and heart rate measurement and at least one post-inhalation blood-pressure and heart rate measurement were available for both periods were included.

    Subject analysis set title
    Hemodynamic Set (HDS-2)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects valid for HDS-1 and who had no shift in basic heart rhythm during Visit 2 (Part 2), and who did not have a heart rhythm that was primarily driven by a pacemaker, were included.

    Subject analysis set title
    Pharmacokinetic Set for dose-linearity analysis (PKS-1)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who completed Visit 1 (Part 1) and who had two valid pharmacokinetic (PK) profiles (as judged by the responsible PK expert) using the FOX nebulizer (2.5 mcg in Part 1 and 5 mcg in Part 2) were included.

    Subject analysis set title
    Pharmacokinetic Set for Visit 2 (PKS-2)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who completed Visit 2 (Part 2) and who had valid pharmacokinetic profiles In both treatment periods were included.

    Subject analysis set title
    Iloprost 5 mcg, I-Neb nebulizer – HDS-1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received single inhalation of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer in Part 2.

    Subject analysis set title
    Iloprost 5 mcg, FOX nebulizer – HDS-1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received single inhalation of 5 mcg iloprost using 20 mcg/ml iloprost solution (Ventavis 20) with the FOX nebulizer in Part 2.

    Subject analysis set title
    Iloprost 2.5 mcg, FOX nebulizer – PKS-1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received single inhalation of 2.5 mcg iloprost using Ventavis 10 with the FOX nebulizer on Day 1.

    Subject analysis set title
    Iloprost 5 mcg, FOX nebulizer – PKS-1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received single inhalation of 5 mcg iloprost using Ventavis 20 with the FOX nebulizer in Part 2.

    Subject analysis set title
    Iloprost 5 mcg, I-Neb nebulizer – PKS-2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received single inhalation of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer in Part 2.

    Subject analysis set title
    Iloprost 5 mcg, FOX nebulizer – PKS-2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received single inhalation of 5 mcg iloprost using Ventavis 20 with the FOX nebulizer in Part 2.

    Primary: Percentage of subjects with a meaningful maximum increase (i.e. >=25%) in heart rate and/or a meaningful maximum decrease (i.e. >=20%) in systolic blood pressure within the 30 minutes after the completion of inhalation

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    End point title
    		 Percentage of subjects with a meaningful maximum increase (i.e. >=25%) in heart rate and/or a meaningful maximum decrease (i.e. >=20%) in systolic blood pressure within the 30 minutes after the completion of inhalation [1]
    End point description
    Maximum increase in heart rate between post-inhalation and pre-inhalation measurements within the 30 minutes after inhalation. Relative change (% change) were calculated as ΔHR = 100 * ΔHR / HR pre inhalation. Maximum decrease in systolic blood pressure between post-inhalation and pre-inhalation measurements within the 30 minutes after inhalation. Relative change (% change) were calculated as ΔSBP = 100 * ΔSBP / SBP pre inhalation. Percentage of subjects with relative increase in “all QRS” heart rate > 25% OR relative decrease in systolic blood pressure > 20% were reported.
    End point type
    Primary
    End point timeframe
    Within the 30 minutes after the completion of inhalation
    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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Iloprost 5 mcg, I-Neb nebulizer – HDS-1 Iloprost 5 mcg, FOX nebulizer – HDS-1
    Number of subjects analysed
    24 [2]
    24 [3]
    Units: Percentage of subjects
        number (not applicable)
    4.2
    16.7
    Notes
    [2] - HDS-1
    [3] - HDS-1
    No statistical analyses for this end point

    Secondary: Absolute decrease in systolic blood pressure within 30 minutes after end of inhalation

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    End point title
    		 Absolute decrease in systolic blood pressure within 30 minutes after end of inhalation
    End point description
    Systolic blood pressures (SBP) were measured over a two-hour interval after inhalation of iloprost using either the FOX inhaler or in randomized order the I-Neb nebulizer. Changes in the systolic blood pressure as decreases are shown. (i.e., a positive number means a decrease in blood pressure.)
    End point type
    Secondary
    End point timeframe
    Up to 2 hours after start of each inhalation
    End point values
    		 Iloprost 5 mcg, I-Neb nebulizer – HDS-1 Iloprost 5 mcg, FOX nebulizer – HDS-1
    Number of subjects analysed
    24 [4]
    24 [5]
    Units: millimeter of mercury (mmHg)
        arithmetic mean (standard deviation)
    10.125 ( 9.1429 )
    12.7917 ( 9.8289 )
    Notes
    [4] - HDS-1
    [5] - HDS-1
    No statistical analyses for this end point

    Secondary: Absolute decrease in diastolic blood pressure within 30 minutes after end of inhalation

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    End point title
    		 Absolute decrease in diastolic blood pressure within 30 minutes after end of inhalation
    End point description
    Diastolic blood pressures (DBP) were measured over a two-hour interval after inhalation of iloprost using either the FOX inhaler or in randomized order the I-Neb nebulizer. Changes in the diastolic blood pressure as decreases are shown. (i.e., a positive number means a decrease in blood pressure.)
    End point type
    Secondary
    End point timeframe
    Up to 2 hours after start of each inhalation
    End point values
    		 Iloprost 5 mcg, I-Neb nebulizer – HDS-1 Iloprost 5 mcg, FOX nebulizer – HDS-1
    Number of subjects analysed
    24 [6]
    24 [7]
    Units: mmHg
        arithmetic mean (standard deviation)
    9.5833 ( 5.9411 )
    10.3333 ( 7.8997 )
    Notes
    [6] - HDS-1
    [7] - HDS-1
    No statistical analyses for this end point

    Secondary: Absolute decrease in mean arterial blood pressure within 30 minutes after end of inhalation

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    End point title
    		 Absolute decrease in mean arterial blood pressure within 30 minutes after end of inhalation
    End point description
    Mean arterial blood pressure was calculated as a linear combination of systolic and diastolic blood pressures. Changes in the mean arterial blood pressure as decreases are shown. (i.e., a positive number means a decrease in blood pressure.)
    End point type
    Secondary
    End point timeframe
    Up to 2 hours after start of each inhalation
    End point values
    		 Iloprost 5 mcg, I-Neb nebulizer – HDS-1 Iloprost 5 mcg, FOX nebulizer – HDS-1
    Number of subjects analysed
    24 [8]
    24 [9]
    Units: mmHg
        arithmetic mean (standard deviation)
    8.75 ( 4.9395 )
    10.1111 ( 8.4308 )
    Notes
    [8] - HDS-1
    [9] - HDS-1
    No statistical analyses for this end point

    Secondary: Absolute increase in heart rate (all QRS) within 30 minutes after end of inhalation

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    End point title
    		 Absolute increase in heart rate (all QRS) within 30 minutes after end of inhalation
    End point description
    The subjects' heart rate was measured over a two-hour interval after inhalation of iloprost using either the FOX inhaler or in randomized order the I-Neb nebulizer. Changes in the heart rate as increases are shown. (i.e., a positive number means an increase in heart rate.)
    End point type
    Secondary
    End point timeframe
    Up to 2 hours after start of each inhalation
    End point values
    		 Iloprost 5 mcg, I-Neb nebulizer – HDS-1 Iloprost 5 mcg, FOX nebulizer – HDS-1
    Number of subjects analysed
    24 [10]
    24 [11]
    Units: beats/minute
        arithmetic mean (standard deviation)
    2.3333 ( 3.9636 )
    6.5417 ( 4.5871 )
    Notes
    [10] - HDS-1
    [11] - HDS-1
    No statistical analyses for this end point

    Secondary: Absolute decrease in oxygen saturation within 30 minutes after end of inhalation

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    End point title
    		 Absolute decrease in oxygen saturation within 30 minutes after end of inhalation
    End point description
    During visit 2, peripheral arterial oxygen saturation will be monitored by finger pulse oxymetry (locally available devices).
    End point type
    Secondary
    End point timeframe
    Up to 2 hours after start of each inhalation
    End point values
    		 Iloprost 5 mcg, I-Neb nebulizer – HDS-1 Iloprost 5 mcg, FOX nebulizer – HDS-1
    Number of subjects analysed
    24 [12]
    24 [13]
    Units: percentage of oxygen saturation
        arithmetic mean (standard deviation)
    2.2917 ( 3.445 )
    2.375 ( 1.3772 )
    Notes
    [12] - HDS-1
    [13] - HDS-1
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration versus time curve from zero to infinity [AUC] of iloprost in plasma

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    End point title
    		 Area under the plasma concentration versus time curve from zero to infinity [AUC] of iloprost in plasma
    End point description
    Area under the concentration versus time curve from zero to infinity after single (first) dose. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    End point type
    Secondary
    End point timeframe
    0, 2, 5, 10, 20, 30 and 45 minutes after inhalation on Day 1 and 0, 2, 5, 10, 20, 30, 45 and 60 minutes after inhalation on Day 2
    End point values
    		 Iloprost 2.5 mcg, FOX nebulizer – PKS-1 Iloprost 5 mcg, FOX nebulizer – PKS-1 Iloprost 5 mcg, I-Neb nebulizer – PKS-2 Iloprost 5 mcg, FOX nebulizer – PKS-2
    Number of subjects analysed
    7 [14]
    8 [15]
    5 [16]
    7 [17]
    Units: ng·h/L
        geometric mean (geometric coefficient of variation)
    44.975 ( 11.88 )
    63.057 ( 42.44 )
    44.564 ( 27.11 )
    61.848 ( 45.7 )
    Notes
    [14] - PKS-1
    [15] - PKS-1
    [16] - PKS-2
    [17] - PKS-2
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The relative bioavailability of iloprost administered through the I-Neb and FOX nebulizers devices was investigated by comparing AUC for each subject in turn. Thereafter, the geometric least-squares mean for these ratios was derived.
    Comparison groups
    Iloprost 5 mcg, FOX nebulizer – PKS-2 v Iloprost 5 mcg, I-Neb nebulizer – PKS-2
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Least squares mean
    Point estimate
    2.3048
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.5053
         upper limit
    		 10.513

    Secondary: Area under the plasma concentration versus time curve from zero to the last data point [AUC(0-tlast)] of iloprost in plasma

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    End point title
    		 Area under the plasma concentration versus time curve from zero to the last data point [AUC(0-tlast)] of iloprost in plasma
    End point description
    As AUC could be determined reliably only for a minority of subjects, owing to the rapid decrease of plasma concentrations below lower limit of quantification (LLOQ) after the end of inhalation. Therefore, according to the rules set out prospectively, AUC(0–tlast) was used as primary PK arameter instead. Area under the plasma concentration versus time curve from zero to the last data point. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    End point type
    Secondary
    End point timeframe
    0, 2, 5, 10, 20, 30 and 45 minutes after inhalation on Day 1 and 0, 2, 5, 10, 20, 30, 45 and 60 minutes after inhalation on Day 2
    End point values
    		 Iloprost 2.5 mcg, FOX nebulizer – PKS-1 Iloprost 5 mcg, FOX nebulizer – PKS-1 Iloprost 5 mcg, I-Neb nebulizer – PKS-2 Iloprost 5 mcg, FOX nebulizer – PKS-2
    Number of subjects analysed
    24 [18]
    24 [19]
    24 [20]
    24 [21]
    Units: ng·h/L
        geometric mean (geometric coefficient of variation)
    23.487 ( 76.51 )
    46.6096 ( 77.84 )
    29.0543 ( 67.4 )
    40.9102 ( 81.45 )
    Notes
    [18] - PKS-1
    [19] - PKS-1
    [20] - PKS-2
    [21] - PKS-2
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The relative bioavailability of iloprost administered through the I-Neb and FOX nebulizers devices was investigated by comparing AUC(0–tlast) for each subject in turn. Thereafter, the geometric least-squares mean for these ratios was derived.
    Comparison groups
    Iloprost 5 mcg, FOX nebulizer – PKS-2 v Iloprost 5 mcg, I-Neb nebulizer – PKS-2
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Least squares mean
    Point estimate
    1.4239
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.0441
         upper limit
    		 1.9417

    Secondary: Half-life associated with the terminal slope [t1/2] of iloprost in plasma

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    End point title
    		 Half-life associated with the terminal slope [t1/2] of iloprost in plasma
    End point description
    Half-life associated with the terminal slope. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    End point type
    Secondary
    End point timeframe
    0, 2, 5, 10, 20, 30 and 45 minutes after inhalation on Day 1 and 0, 2, 5, 10, 20, 30, 45 and 60 minutes after inhalation on Day 2
    End point values
    		 Iloprost 2.5 mcg, FOX nebulizer – PKS-1 Iloprost 5 mcg, FOX nebulizer – PKS-1 Iloprost 5 mcg, I-Neb nebulizer – PKS-2 Iloprost 5 mcg, FOX nebulizer – PKS-2
    Number of subjects analysed
    11 [22]
    10 [23]
    5 [24]
    9 [25]
    Units: hour
        geometric mean (geometric coefficient of variation)
    0.2041 ( 27.32 )
    0.1746 ( 23.93 )
    0.1482 ( 27.73 )
    0.1697 ( 23.48 )
    Notes
    [22] - PKS-1
    [23] - PKS-1
    [24] - PKS-2
    [25] - PKS-2
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration versus time curve from start to end of inhalation [AUC(0-t1)] of iloprost in plasma

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    End point title
    		 Area under the plasma concentration versus time curve from start to end of inhalation [AUC(0-t1)] of iloprost in plasma
    End point description
    Area under the plasma concentration versus time curve from start to end of inhalation. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    End point type
    Secondary
    End point timeframe
    0, 2, 5, 10, 20, 30 and 45 minutes after inhalation on Day 1 and 0, 2, 5, 10, 20, 30, 45 and 60 minutes after inhalation on Day 2
    End point values
    		 Iloprost 2.5 mcg, FOX nebulizer – PKS-1 Iloprost 5 mcg, FOX nebulizer – PKS-1 Iloprost 5 mcg, I-Neb nebulizer – PKS-2 Iloprost 5 mcg, FOX nebulizer – PKS-2
    Number of subjects analysed
    24 [26]
    24 [27]
    24 [28]
    24 [29]
    Units: ng·h/L
        geometric mean (geometric coefficient of variation)
    1.1122 ( 94.96 )
    1.6375 ( 84.77 )
    6.8297 ( 66.03 )
    1.4627 ( 87.91 )
    Notes
    [26] - PKS-1
    [27] - PKS-1
    [28] - PKS-2
    [29] - PKS-2
    No statistical analyses for this end point

    Secondary: Maximum observed drug concentration in plasma [Cmax] after single dose administration of iloprost

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    End point title
    		 Maximum observed drug concentration in plasma [Cmax] after single dose administration of iloprost
    End point description
    Maximum observed drug concentration in plasma. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    End point type
    Secondary
    End point timeframe
    0, 2, 5, 10, 20, 30 and 45 minutes after inhalation on Day 1 and 0, 2, 5, 10, 20, 30, 45 and 60 minutes after inhalation on Day 2
    End point values
    		 Iloprost 2.5 mcg, FOX nebulizer – PKS-1 Iloprost 5 mcg, FOX nebulizer – PKS-1 Iloprost 5 mcg, I-Neb nebulizer – PKS-2 Iloprost 5 mcg, FOX nebulizer – PKS-2
    Number of subjects analysed
    24 [30]
    24 [31]
    24 [32]
    24 [33]
    Units: ng/L
        geometric mean (geometric coefficient of variation)
    89.1 ( 47.21 )
    176.27 ( 58.49 )
    90.23 ( 54.54 )
    158.7 ( 59.7 )
    Notes
    [30] - PKS-1
    [31] - PKS-1
    [32] - PKS-2
    [33] - PKS-2
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The relative bioavailability of iloprost administered through the I-Neb and FOX nebulizers devices was investigated by comparing Cmax for each subject in turn. Thereafter, the geometric least-squares mean for these ratios was derived.
    Comparison groups
    Iloprost 5 mcg, FOX nebulizer – PKS-2 v Iloprost 5 mcg, I-Neb nebulizer – PKS-2
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Least squares mean
    Point estimate
    1.7723
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.3647
         upper limit
    		 2.3018

    Secondary: Time to reach maximum drug observed concentration in plasma [tmax] after single dose of iloprost

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    End point title
    		 Time to reach maximum drug observed concentration in plasma [tmax] after single dose of iloprost
    End point description
    Time to reach maximum drug observed concentration in plasma. Median and full range were reported.
    End point type
    Secondary
    End point timeframe
    0, 2, 5, 10, 20, 30 and 45 minutes after inhalation on Day 1 and 0, 2, 5, 10, 20, 30, 45 and 60 minutes after inhalation on Day 2
    End point values
    		 Iloprost 2.5 mcg, FOX nebulizer – PKS-1 Iloprost 5 mcg, FOX nebulizer – PKS-1 Iloprost 5 mcg, I-Neb nebulizer – PKS-2 Iloprost 5 mcg, FOX nebulizer – PKS-2
    Number of subjects analysed
    24 [34]
    24 [35]
    24 [36]
    24 [37]
    Units: hour
        median (full range (min-max))
    0.11667 (0.0667 to 0.1833)
    0.11667 (0.0667 to 0.15)
    0.21667 (0.1167 to 0.4)
    0.1 (0.0667 to 0.15)
    Notes
    [34] - PKS-1
    [35] - PKS-1
    [36] - PKS-2
    [37] - PKS-2
    No statistical analyses for this end point

    Secondary: Time to reach maximum observed drug concentration in plasma at steady state [tmax,end] after single dose administration of iloprost

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    End point title
    		 Time to reach maximum observed drug concentration in plasma at steady state [tmax,end] after single dose administration of iloprost
    End point description
    Time to reach maximum observed drug concentration in plasma at steady state. Median and full range were reported.
    End point type
    Secondary
    End point timeframe
    0, 2, 5, 10, 20, 30 and 45 minutes after inhalation on Day 1 and 0, 2, 5, 10, 20, 30, 45 and 60 minutes after inhalation on Day 2
    End point values
    		 Iloprost 2.5 mcg, FOX nebulizer – PKS-1 Iloprost 5 mcg, FOX nebulizer – PKS-1 Iloprost 5 mcg, I-Neb nebulizer – PKS-2 Iloprost 5 mcg, FOX nebulizer – PKS-2
    Number of subjects analysed
    24 [38]
    24 [39]
    24 [40]
    24 [41]
    Units: hour
        median (full range (min-max))
    0.0614 (0.0252 to 0.1108)
    0.07065 (0.0406 to 0.1111)
    0.03735 (0.0056 to 0.0986)
    0.06365 (0.0406 to 0.1072)
    Notes
    [38] - PKS-1
    [39] - PKS-1
    [40] - PKS-2
    [41] - PKS-2
    No statistical analyses for this end point

    Secondary: Time of last concentration above lower limit of quantification (LLOQ), directly taken from analytical data [tlast] after single dose administration of iloprost

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    End point title
    		 Time of last concentration above lower limit of quantification (LLOQ), directly taken from analytical data [tlast] after single dose administration of iloprost
    End point description
    Time of last concentration above lower limit of quantification (LLOQ), directly taken from analytical data. Median and full range were reported.
    End point type
    Secondary
    End point timeframe
    0, 2, 5, 10, 20, 30 and 45 minutes after inhalation on Day 1 and 0, 2, 5, 10, 20, 30, 45 and 60 minutes after inhalation on Day 2
    End point values
    		 Iloprost 2.5 mcg, FOX nebulizer – PKS-1 Iloprost 5 mcg, FOX nebulizer – PKS-1 Iloprost 5 mcg, I-Neb nebulizer – PKS-2 Iloprost 5 mcg, FOX nebulizer – PKS-2
    Number of subjects analysed
    24 [42]
    24 [43]
    24 [44]
    24 [45]
    Units: hour
        median (full range (min-max))
    0.56667 (0.2167 to 0.8333)
    0.68333 (0.2 to 1.1)
    0.6 (0.2667 to 1.2833)
    0.56667 (0.2 to 1.0667)
    Notes
    [42] - PKS-1
    [43] - PKS-1
    [44] - PKS-2
    [45] - PKS-2
    No statistical analyses for this end point

    Secondary: Percentage of area under the plasma concentration versus time curve from the last data point to infinity [%AUC(tlast-inf)] after single dose administration of iloprost

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    End point title
    		 Percentage of area under the plasma concentration versus time curve from the last data point to infinity [%AUC(tlast-inf)] after single dose administration of iloprost
    End point description
    Percentage of AUC from the last data point above LLOQ to infinity. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    End point type
    Secondary
    End point timeframe
    0, 2, 5, 10, 20, 30 and 45 minutes after inhalation on Day 1 and 0, 2, 5, 10, 20, 30, 45 and 60 minutes after inhalation on Day 2
    End point values
    		 Iloprost 2.5 mcg, FOX nebulizer – PKS-1 Iloprost 5 mcg, FOX nebulizer – PKS-1 Iloprost 5 mcg, I-Neb nebulizer – PKS-2 Iloprost 5 mcg, FOX nebulizer – PKS-2
    Number of subjects analysed
    7 [46]
    8 [47]
    5 [48]
    7 [49]
    Units: percentage of AUC
        geometric mean (geometric coefficient of variation)
    15.1 ( 22.9 )
    8.84 ( 32.5 )
    12.5 ( 49.3 )
    8.82 ( 35.3 )
    Notes
    [46] - PKS-1
    [47] - PKS-1
    [48] - PKS-2
    [49] - PKS-2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the start of study treatment until end of study Part 4, over a period up to 3 years
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    1.25 UG FOX
    Reporting group description
    		 Iloprost 1.25 mcg, FOX nebulizer - Part 1

    Reporting group title
    2.5 UG FOX
    Reporting group description
    		 Iloprost 2.5 mcg, FOX nebulizer - Part 1

    Reporting group title
    5 UG I-NEB SD
    Reporting group description
    		 Iloprost 5 mcg Single Dose (SD), I-Neb nebulizer - Part 2

    Reporting group title
    5 UG FOX SD
    Reporting group description
    		 Iloprost 5 mcg Single Dose (SD), FOX nebulizer - Part 2

    Reporting group title
    5 UG I-NEB MD
    Reporting group description
    		 Iloprost 5 mcg Multiple Dose (MD), I-Neb nebulizer - Part 3

    Reporting group title
    5 UG FOX MD PART 3
    Reporting group description
    		 Iloprost 5 mcg Multiple Dose (MD), FOX nebulizer - Part 3

    Reporting group title
    5 UG FOX MD PART 4
    Reporting group description
    		 Iloprost 5 mcg, MD, FOX nebulizer - Part 4

    Serious adverse events
    		 1.25 UG FOX 2.5 UG FOX 5 UG I-NEB SD 5 UG FOX SD 5 UG I-NEB MD 5 UG FOX MD PART 3 5 UG FOX MD PART 4
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 26 (7.69%)
    2 / 27 (7.41%)
    20 / 25 (80.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    5
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    5
    Vascular disorders
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 1
    Surgical and medical procedures
    Lung transplant
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Therapy change
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 1
    Oedema peripheral
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Pulmonary artery aneurysm
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Pulmonary congestion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Pulmonary hypertension
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    5 / 25 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Catheterisation cardiac
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colonoscopy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transplant evaluation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Rib fracture
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Spinal compression fracture
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Device use error
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Right ventricular failure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    5 / 25 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    5 / 25 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Retinal tear
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Visual acuity reduced
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    2 / 25 (8.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Melaena
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Large intestine polyp
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Acute kidney injury
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Gastroenteritis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Gastrointestinal infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Pneumonia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Abscess jaw
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Respiratory tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    3 / 25 (12.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 1.25 UG FOX 2.5 UG FOX 5 UG I-NEB SD 5 UG FOX SD 5 UG I-NEB MD 5 UG FOX MD PART 3 5 UG FOX MD PART 4
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 11 (27.27%)
    6 / 27 (22.22%)
    3 / 26 (11.54%)
    4 / 27 (14.81%)
    6 / 26 (23.08%)
    12 / 27 (44.44%)
    24 / 25 (96.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenoma benign
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Tracheal neoplasm
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Vascular disorders
    Blood pressure fluctuation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Flushing
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    Haematoma
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Hypertensive crisis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    Hypotension
         subjects affected / exposed
    2 / 11 (18.18%)
    3 / 27 (11.11%)
    1 / 26 (3.85%)
    4 / 27 (14.81%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    2
    3
    1
    4
    0
    0
    4
    Phlebitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Hot flush
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Surgical and medical procedures
    Endodontic procedure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Intestinal polypectomy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Cataract operation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Oxygen therapy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Chest discomfort
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    3
    Chills
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Extravasation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    3
    Feeling abnormal
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Gait disturbance
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    11 / 25 (44.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    13
    Pyrexia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    General physical health deterioration
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Exercise tolerance decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Medical device site reaction
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Puncture site pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Seasonal allergy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Mite allergy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Social circumstances
    Postmenopause
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Reproductive system and breast disorders
    Nipple pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Cough
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    3 / 27 (11.11%)
    6 / 25 (24.00%)
         occurrences all number
    0
    1
    1
    0
    0
    3
    10
    Dysphonia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    9 / 25 (36.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    15
    Epistaxis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    6 / 25 (24.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    11
    Nasal congestion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Pleural effusion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Pleurisy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Pulmonary artery aneurysm
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Pulmonary hypertension
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Pulmonary oedema
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Throat irritation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Nocturnal dyspnoea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Restlessness
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Sleep disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    Stereotypy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Stress
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Hepatic steatosis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    Blood potassium decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Blood sodium abnormal
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    3
    Catheterisation cardiac
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    International normalised ratio increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    PCO2 increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Pulmonary arterial pressure increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Serum ferritin decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Brain natriuretic peptide increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    4 / 25 (16.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    5
    Neurological examination abnormal
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Walking distance test abnormal
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Myocardial necrosis marker increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Head injury
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Laceration
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Rib fracture
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Spinal compression fracture
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Limb injury
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Procedural nausea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Hereditary haemorrhagic telangiectasia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    1
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Bradycardia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Bundle branch block right
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Cardiac failure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Cardiovascular disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Cyanosis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Extrasystoles
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
    6 / 25 (24.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    6
    Pericardial effusion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Sinus bradycardia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    8 / 25 (32.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    10
    Bradyarrhythmia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    7 / 25 (28.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    9
    Dizziness exertional
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Head discomfort
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 26 (7.69%)
    4 / 27 (14.81%)
    6 / 25 (24.00%)
         occurrences all number
    1
    1
    0
    0
    2
    4
    7
    Memory impairment
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Migraine
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    11
    Paraesthesia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    Polyneuropathy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Tremor
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    7 / 25 (28.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    11
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Vertigo
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Hypoacusis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    External ear pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Periorbital oedema
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Visual acuity reduced
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Visual impairment
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    Eyelid haematoma
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Anorectal disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Ascites
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Constipation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    5 / 25 (20.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    6
    Dental caries
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    5 / 25 (20.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    9
    Diverticulum
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Diverticulum intestinal
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Flatulence
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Gastritis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Gastrointestinal pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Melaena
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    Nausea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    9 / 25 (36.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    15
    Vomiting
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    6
    Large intestine polyp
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Bowel movement irregularity
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Reactive gastropathy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Eczema
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Erythema
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Hirsutism
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Milia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Petechiae
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Dermatosis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Renal and urinary disorders
    Acute prerenal failure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Incontinence
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Nocturia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Renal failure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    5
    Urinary incontinence
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Renal impairment
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Acute kidney injury
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Arthritis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Back pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    4 / 25 (16.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    5
    Bursitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    5
    Musculoskeletal pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Osteoarthritis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Pain in jaw
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    4 / 25 (16.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    Tendonitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Tendon calcification
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Spinal pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    6
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    3
    Conjunctivitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Fungal infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Gastrointestinal infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    4 / 25 (16.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    Periodontitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    Rhinitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Subcutaneous abscess
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    4 / 25 (16.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    6
    Viral infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    9 / 25 (36.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    15
    Gastrointestinal fungal infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Abscess jaw
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Lung infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
    10 / 25 (40.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    19
    Herpes dermatitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Infective glossitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Diabetes mellitus
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    Gout
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    Hyperuricaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    8 / 25 (32.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    16
    Hyponatraemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    3
    Iron deficiency
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Metabolic alkalosis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Hyperlipidaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Dec 2013
    The German Competent Authority BfArM requested that the method of contraception for women of child-bearing potential shall be highly-effective and follow the “Note for guidance on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals (CPMP/ICH/286/95, modification)”.
    21 Jul 2014
    Modification 1: Clarification of measurements of heart rate and blood pressure at Visit 1 and Visit 2. Modification 2: Clarification that multiple heart-rate and blood-pressure measurements were to be performed starting at the end of the inhalation. Modification 3: Minor adaptations.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Occurrence of "±” in relation with geometric CV is auto-generated and cannot be deleted. Decimal places were automatically truncated if last decimal equals zero.
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