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    Clinical Trial Results:
    A PHASE II, PARTIAL-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 5-WAY CROSS-OVER CLINICAL PHARMACOLOGY STUDY TO EVALUATE THE PHARMACODYNAMICS OF BDP/B17MP AND FORMOTEROL ACROSS TWO DIFFERENT DOSE LEVELS OF CHF 1535 NEXThaler® DPI AND CHF 1535 pMDI (BOTH FIXED COMBINATION OF BECLOMETHASONE DIPROPIONATE PLUS FORMOTEROL FUMARATE) IN ADULT COPD PATIENTS.

    Summary
    EudraCT number
    2013-002966-38
    Trial protocol
    GB  
    Global end of trial date
    11 Apr 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Jul 2016
    First version publication date
    09 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCD-01535BC1-02
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02000609
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici S.p.A.
    Sponsor organisation address
    Via Palermo, 26/A, Parma, Italy, 43122
    Public contact
    Clinical Trial Transparency Manager, Chiesi Farmaceutici S.p.A., ClinicalTrials_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency Manager, Chiesi Farmaceutici S.p.A., ClinicalTrials_info@chiesi.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
    11 Apr 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Apr 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the average heart rate over 4 hours after administration of BDP and Formoterol using CHF 1535 100/6 NEXThaler® DPI and CHF 1535 100/6 pMDI at two different dose levels
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and local law requirements . Other than routine care, no specific measures for protection of trial subjects were implemented.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Dec 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 49
    Worldwide total number of subjects
    49
    EEA total number of subjects
    49
    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)
    26
    From 65 to 84 years
    23
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Forty-nine COPD patients were randomised and received the study drug. Forty-five (91.8%) randomised and treated patients completed the study. Four (8.2%) patients discontinued the study; 1 (2.0%) patient withdrew consent and 3 (6.1%) patients discontinued due to an AE.

    Pre-assignment
    Screening details
    One hundred and six patients were screened. Fifty-seven patients were not randomised (i.e., screening failures), of whom 43 patients were not eligible to enter the study, 4 patients withdrew consent and 3 patients had an AE during run-in. Seven patients were not randomised for other reasons.

    Period 1
    Period 1 title
    Overall trial by sequence (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Carer, Assessor, Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    A partial-blind treatment allocation approach was applied, meaning that patients and also the Investigator and the Sponsor were aware of the formulation they had taken (CHF 1535 100/6 NEXThaler® or CHF 1535 100/6 pMDI) but did not know the dosage.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sequence T1-T2-P-R1-R2
    Arm description
    - Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 200 μg / FF 12 μg - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 800 μg / FF 48 μg - Treatment P: single dose administration of CHF 1535 100/6 NEXThaler® DPI placebo - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 200 μg / FF 12 μg - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg
    Arm type
    experimental - placebo - active comparator

    Investigational medicinal product name
    CHF1535 Nexthaler DPI (BDP+FF)
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate, formoterol fumarate
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    - Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. Total dose: 200 μg BDP and 12 μg FF. - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. Total dose: 800 μg BDP and 48 μg FF.

    Investigational medicinal product name
    CHF1535 mDPI
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate, formoterol fumarate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. Total dose: 200 μg BDP and 12 μg FF. - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. Total dose: 800 μg BDP and 48 μg FF.

    Investigational medicinal product name
    CHF 1535 Nexthaler DPI placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    - Treatment P: single dose administration via NEXThaler DPI containing placebo.

    Arm title
    Sequence T2-P-T1-R2-R1
    Arm description
    - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 800 μg / FF 48 μg - Treatment P: single dose administration of CHF 1535 100/6 NEXThaler® DPI placebo - Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 200 μg / FF 12 μg - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 200 μg / FF 12 μg - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg
    Arm type
    experimental - placebo - active comparator

    Investigational medicinal product name
    CHF1535 Nexthaler DPI (BDP+FF)
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate, formoterol fumarate
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    - Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. Total dose: 200 μg BDP and 12 μg FF. - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. Total dose: 800 μg BDP and 48 μg FF.

    Investigational medicinal product name
    CHF1535 mDPI
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate, formoterol fumarate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 200 μg / FF 12 μg - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg

    Investigational medicinal product name
    CHF 1535 Nexthaler DPI placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    - Treatment P: single dose administration of CHF 1535 100/6 NEXThaler® DPI placebo

    Arm title
    Sequence R1-R2-T2-T1-P
    Arm description
    - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 200 μg / FF 12 μg - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg - Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 200 μg / FF 12 μg - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 800 μg / FF 48 μg - Treatment P: single dose administration of CHF 1535 100/6 NEXThaler® DPI placebo
    Arm type
    active comparator - experimental - placebo

    Investigational medicinal product name
    CHF1535 Nexthaler DPI (BDP+FF)
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate, formoterol fumarate
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    - Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. Total dose: 200 μg BDP and 12 μg FF. - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. Total dose: 800 μg BDP and 48 μg FF.

    Investigational medicinal product name
    CHF1535 mDPI
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate, formoterol fumarate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 200 μg / FF 12 μg - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg

    Investigational medicinal product name
    CHF 1535 Nexthaler DPI placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    - Treatment P: single dose administration of CHF 1535 100/6 NEXThaler® DPI placebo

    Arm title
    Sequence R2-T1-R1-P-T2
    Arm description
    - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg - Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 200 μg / FF 12 μg - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 200 μg / FF 12 μg -Treatment P: single dose administration of CHF 1535 100/6 NEXThaler® DPI placebo - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 800 μg / FF 48 μg
    Arm type
    active comparator - experimental - placebo

    Investigational medicinal product name
    CHF1535 Nexthaler DPI (BDP+FF)
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate, formoterol fumarate
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    - Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. Total dose: 200 μg BDP and 12 μg FF. - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. Total dose: 800 μg BDP and 48 μg FF.

    Investigational medicinal product name
    CHF1535 mDPI
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate, formoterol fumarate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 200 μg / FF 12 μg - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg

    Investigational medicinal product name
    CHF1535 Nexthaler DPI placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    - Treatment P: single dose administration of CHF 1535 100/6 NEXThaler® DPI placebo

    Arm title
    Sequence P-R1-R2-T2-T1
    Arm description
    - Treatment P: single dose administration of CHF 1535 100/6 NEXThaler® DPI placebo - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 200 μg / FF 12 μg - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg- - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 800 μg / FF 48 μg -Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 200 μg / FF 12 μg
    Arm type
    placebo - active comparator - experimental

    Investigational medicinal product name
    CHF1535 Nexthaler DPI (BDP+FF)
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate, formoterol fumarate
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    - Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. Total dose: 200 μg BDP and 12 μg FF. - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. Total dose: 800 μg BDP and 48 μg FF.

    Investigational medicinal product name
    CHF1535 mDPI
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate, formoterol fumarate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 200 μg / FF 12 μg - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg

    Investigational medicinal product name
    CHF 1535 Nexthaler DPI placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    - Treatment P: single dose administration of CHF 1535 100/6 NEXThaler® DPI placebo

    Number of subjects in period 1
    Sequence T1-T2-P-R1-R2 Sequence T2-P-T1-R2-R1 Sequence R1-R2-T2-T1-P Sequence R2-T1-R1-P-T2 Sequence P-R1-R2-T2-T1
    Started
    10
    10
    10
    9
    10
    Completed
    10
    9
    10
    7
    9
    Not completed
    0
    1
    0
    2
    1
         Adverse event, non-fatal
    -
    -
    -
    2
    1
         Consent withdrawn by subject
    -
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence T1-T2-P-R1-R2
    Reporting group description
    - Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 200 μg / FF 12 μg - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 800 μg / FF 48 μg - Treatment P: single dose administration of CHF 1535 100/6 NEXThaler® DPI placebo - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 200 μg / FF 12 μg - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg

    Reporting group title
    Sequence T2-P-T1-R2-R1
    Reporting group description
    - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 800 μg / FF 48 μg - Treatment P: single dose administration of CHF 1535 100/6 NEXThaler® DPI placebo - Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 200 μg / FF 12 μg - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 200 μg / FF 12 μg - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg

    Reporting group title
    Sequence R1-R2-T2-T1-P
    Reporting group description
    - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 200 μg / FF 12 μg - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg - Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 200 μg / FF 12 μg - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 800 μg / FF 48 μg - Treatment P: single dose administration of CHF 1535 100/6 NEXThaler® DPI placebo

    Reporting group title
    Sequence R2-T1-R1-P-T2
    Reporting group description
    - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg - Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 200 μg / FF 12 μg - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 200 μg / FF 12 μg -Treatment P: single dose administration of CHF 1535 100/6 NEXThaler® DPI placebo - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 800 μg / FF 48 μg

    Reporting group title
    Sequence P-R1-R2-T2-T1
    Reporting group description
    - Treatment P: single dose administration of CHF 1535 100/6 NEXThaler® DPI placebo - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 200 μg / FF 12 μg - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg- - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 800 μg / FF 48 μg -Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 200 μg / FF 12 μg

    Reporting group values
    Sequence T1-T2-P-R1-R2 Sequence T2-P-T1-R2-R1 Sequence R1-R2-T2-T1-P Sequence R2-T1-R1-P-T2 Sequence P-R1-R2-T2-T1 Total
    Number of subjects
    10 10 10 9 10 49
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    61.3 ± 9.56 61.8 ± 8.6 62.2 ± 9.46 61.8 ± 7.38 67 ± 6.31 -
    Gender categorical
    Units: Subjects
        Female
    6 5 7 3 6 27
        Male
    4 5 3 6 4 22

    End points

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    End points reporting groups
    Reporting group title
    Sequence T1-T2-P-R1-R2
    Reporting group description
    - Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 200 μg / FF 12 μg - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 800 μg / FF 48 μg - Treatment P: single dose administration of CHF 1535 100/6 NEXThaler® DPI placebo - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 200 μg / FF 12 μg - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg

    Reporting group title
    Sequence T2-P-T1-R2-R1
    Reporting group description
    - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 800 μg / FF 48 μg - Treatment P: single dose administration of CHF 1535 100/6 NEXThaler® DPI placebo - Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 200 μg / FF 12 μg - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 200 μg / FF 12 μg - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg

    Reporting group title
    Sequence R1-R2-T2-T1-P
    Reporting group description
    - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 200 μg / FF 12 μg - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg - Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 200 μg / FF 12 μg - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 800 μg / FF 48 μg - Treatment P: single dose administration of CHF 1535 100/6 NEXThaler® DPI placebo

    Reporting group title
    Sequence R2-T1-R1-P-T2
    Reporting group description
    - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg - Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 200 μg / FF 12 μg - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 200 μg / FF 12 μg -Treatment P: single dose administration of CHF 1535 100/6 NEXThaler® DPI placebo - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 800 μg / FF 48 μg

    Reporting group title
    Sequence P-R1-R2-T2-T1
    Reporting group description
    - Treatment P: single dose administration of CHF 1535 100/6 NEXThaler® DPI placebo - Treatment R1: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 200 μg / FF 12 μg - Treatment R2: single dose administration of CHF 1535 100/6 pMDI via standard actuator. total dose: BDP 800 μg / FF 48 μg- - Treatment T2: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 800 μg / FF 48 μg -Treatment T1: single dose administration of CHF 1535 100/6 via NEXThaler® DPI. total dose: BDP 200 μg / FF 12 μg

    Subject analysis set title
    Treatment T1 - Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomised patients who received at least one dose of study medication.

    Subject analysis set title
    Treatment T2 - Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomised patients who received at least one dose of study medication.

    Subject analysis set title
    Treatment R1 - Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomised patients who received at least one dose of study medication.

    Subject analysis set title
    Treatment R2 - Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomised patients who received at least one dose of study medication.

    Subject analysis set title
    Treatment P - Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomised patients who received at least one dose of study medication.

    Subject analysis set title
    Treatment T1 - PD
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PD analysis. PD population included all patients from the safety population with available primary endpoint and without any major protocol deviations

    Subject analysis set title
    Treatment T2 - PD
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PD analysis. PD population included all patients from the safety population with available primary endpoint and without any major protocol deviations

    Subject analysis set title
    Treatment R1 - PD
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PD analysis. PD population included all patients from the safety population with available primary endpoint and without any major protocol deviations

    Subject analysis set title
    Treatment R2 - PD
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PD analysis. PD population included all patients from the safety population with available primary endpoint and without any major protocol deviations

    Subject analysis set title
    Treatment P - PD
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PD analysis. PD population included all patients from the safety population with available primary endpoint and without any major protocol deviations

    Primary: Average HR0-4h

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    End point title
    Average HR0-4h
    End point description
    End point type
    Primary
    End point timeframe
    At each visit from Visit 1 (screening) to Visit 6
    End point values
    Treatment T1 - PD Treatment T2 - PD Treatment R1 - PD Treatment R2 - PD Treatment P - PD
    Number of subjects analysed
    44
    45
    44
    45
    45
    Units: bpm
        least squares mean (confidence interval 95%)
    69.31 (68.492 to 70.137)
    75.47 (74.659 to 76.282)
    69.52 (68.701 to 70.345)
    74.88 (74.077 to 75.681)
    67.83 (67.031 to 68.638)
    Statistical analysis title
    Treatment T1 vs Treatment R1
    Comparison groups
    Treatment T1 - PD v Treatment R1 - PD
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.7188
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.349
         upper limit
    0.932
    Statistical analysis title
    Treatment T2 vs Treatment R2
    Comparison groups
    Treatment T2 - PD v Treatment R2 - PD
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.303
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    0.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.538
         upper limit
    1.521
    Statistical analysis title
    Treatment T2 vs Treatment T1
    Comparison groups
    Treatment T2 - PD v Treatment T1 - PD
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    6.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.022
         upper limit
    7.289
    Statistical analysis title
    Treatment R2 vs Treatment R1
    Comparison groups
    Treatment R1 - PD v Treatment R2 - PD
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    5.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.222
         upper limit
    6.49
    Statistical analysis title
    Treatment T1 vs Treatment P
    Comparison groups
    Treatment T1 - PD v Treatment P - PD
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0114
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    1.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.338
         upper limit
    2.622
    Statistical analysis title
    Treatment T2 vs Treatment P
    Comparison groups
    Treatment T2 - PD v Treatment P - PD
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    7.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.512
         upper limit
    8.759
    Statistical analysis title
    Treatment R1 vs Treatment P
    Comparison groups
    Treatment P - PD v Treatment R1 - PD
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0038
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    1.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.554
         upper limit
    2.823
    Statistical analysis title
    Treatment R2 vs Treatment P
    Comparison groups
    Treatment P - PD v Treatment R2 - PD
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    7.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.908
         upper limit
    8.181

    Secondary: Average HR0-1h

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    End point title
    Average HR0-1h
    End point description
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening) to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    47
    46
    45
    46
    47
    Units: bpm
        arithmetic mean (standard deviation)
    70.2 ± 9.81
    74.8 ± 10.22
    69.1 ± 9.6
    73.1 ± 11.32
    68.1 ± 9.66
    No statistical analyses for this end point

    Secondary: Average HR1-2h

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    End point title
    Average HR1-2h
    End point description
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening) to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    47
    46
    45
    46
    47
    Units: bpm
        arithmetic mean (standard deviation)
    69.2 ± 9.76
    75.3 ± 10.77
    68.4 ± 9.77
    73.9 ± 12.15
    66.9 ± 9.42
    No statistical analyses for this end point

    Secondary: Average HR2-3h

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    End point title
    Average HR2-3h
    End point description
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening) to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    47
    46
    45
    46
    47
    Units: bpm
        arithmetic mean (standard deviation)
    68.7 ± 9.56
    74.6 ± 10.55
    68.2 ± 9.45
    73.8 ± 11.33
    67 ± 9.35
    No statistical analyses for this end point

    Secondary: Average HR3-4h

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    End point title
    Average HR3-4h
    End point description
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening) to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    47
    46
    45
    46
    47
    Units: bpm
        arithmetic mean (standard deviation)
    69.6 ± 9.82
    74.8 ± 9.9
    69.2 ± 9.52
    75.3 ± 10.98
    67.9 ± 9.77
    No statistical analyses for this end point

    Secondary: Maximum HR0-4h

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    End point title
    Maximum HR0-4h
    End point description
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening) to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    47
    46
    45
    46
    47
    Units: bpm
        arithmetic mean (standard deviation)
    100 ± 13.23
    104.5 ± 14.65
    100.2 ± 14.59
    103.8 ± 15.4
    98.6 ± 12.75
    Statistical analysis title
    Treatment T1 vs Treatment R1
    Comparison groups
    Treatment T1 - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.4763
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -1.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.447
         upper limit
    2.085
    Statistical analysis title
    Treatment T2 vs Treatment R2
    Comparison groups
    Treatment T2 - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.8215
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    0.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.907
         upper limit
    3.658
    Statistical analysis title
    Treatment T1 vs Treatment P
    Comparison groups
    Treatment T1 - Safety v Treatment P - Safety
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.6849
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.576
         upper limit
    3.912
    Statistical analysis title
    Treatment T2 vs Treatment P
    Comparison groups
    Treatment T2 - Safety v Treatment P - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0004
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    5.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.683
         upper limit
    9.181
    Statistical analysis title
    Treatment R1 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.2663
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    1.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.424
         upper limit
    5.122
    Statistical analysis title
    Treatment R2 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.001
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    5.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.273
         upper limit
    8.839

    Secondary: Average HR0-9 h

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    End point title
    Average HR0-9 h
    End point description
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening) to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    46
    46
    45
    44
    47
    Units: bpm
        arithmetic mean (standard deviation)
    76.4 ± 9.74
    80.7 ± 10.19
    75.8 ± 9.99
    80.1 ± 10.87
    75.1 ± 10.32
    Statistical analysis title
    Treatment T1 vs Treatment R1
    Comparison groups
    Treatment T1 - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.9628
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.286
         upper limit
    1.226
    Statistical analysis title
    Treatment T2 vs Treatment R2
    Comparison groups
    Treatment T2 - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.8994
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.191
         upper limit
    1.354
    Statistical analysis title
    Treatment T1 vs Treatment P
    Comparison groups
    Treatment T1 - Safety v Treatment P - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.1082
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.227
         upper limit
    2.268
    Statistical analysis title
    Treatment T2 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment T2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    5.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.423
         upper limit
    6.903
    Statistical analysis title
    Treatment R1 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0988
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.199
         upper limit
    2.299
    Statistical analysis title
    Treatment R2 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    5.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.308
         upper limit
    6.855

    Secondary: Average HR0-12h

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    End point title
    Average HR0-12h
    End point description
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening) to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    46
    46
    45
    44
    47
    Units: bpm
        arithmetic mean (standard deviation)
    77.7 ± 9.78
    81.7 ± 9.76
    77.3 ± 9.92
    81.2 ± 10.83
    77 ± 10.32
    Statistical analysis title
    Treatment T1 vs Treatment R1
    Comparison groups
    Treatment T1 - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.7786
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -0.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.218
         upper limit
    0.914
    Statistical analysis title
    Treatment T2 vs Treatment R2
    Comparison groups
    Treatment T2 - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.8884
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.157
         upper limit
    1.004
    Statistical analysis title
    Treatment T1 vs Treatment P
    Comparison groups
    Treatment T1 - Safety v Treatment P - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.2816
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.48
         upper limit
    1.639
    Statistical analysis title
    Treatment T2 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment T2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    4.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.709
         upper limit
    5.814
    Statistical analysis title
    Treatment R1 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.1749
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    0.73
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.329
         upper limit
    1.792
    Statistical analysis title
    Treatment R2 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    4.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.758
         upper limit
    5.919

    Secondary: HR at 5 min post-dose

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    End point title
    HR at 5 min post-dose
    End point description
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening) to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    45
    45
    45
    44
    46
    Units: bpm
        arithmetic mean (standard deviation)
    78.72 ± 11.209
    80.29 ± 11.986
    75.86 ± 9.802
    77.18 ± 11.117
    77.87 ± 11.481
    Statistical analysis title
    Treatment T1 vs Treatment R1
    Comparison groups
    Treatment T1 - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0333
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    2.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.176
         upper limit
    4.225
    Statistical analysis title
    Treatment T2 vs Treatment R2
    Comparison groups
    Treatment T2 - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0145
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    2.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.513
         upper limit
    4.595
    Statistical analysis title
    Treatment T1 vs Treatment P
    Comparison groups
    Treatment T1 - Safety v Treatment P - Safety
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.6364
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    0.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.541
         upper limit
    2.514
    Statistical analysis title
    Treatment T2 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment T2 - Safety
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0101
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    2.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    4.669
    Statistical analysis title
    Treatment R1 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0948
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -1.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.728
         upper limit
    0.3
    Statistical analysis title
    Treatment R2 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.9228
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.95
         upper limit
    2.151

    Secondary: PR

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    End point title
    PR
    End point description
    PR, QRS, QTcF were measured at the following time points: 45, 30, 15 minutes pre-dose, 5, 10, 20, 30, 45 minutes post-dose and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12 hours post-dose. Only data referring to 5 minutes post-dose are reported here.
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening) to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    45
    44
    45
    44
    46
    Units: msec
        arithmetic mean (standard deviation)
    153.55 ± 23.937
    153.4 ± 20.534
    156.41 ± 21.649
    155.71 ± 20.831
    154.87 ± 22.006
    No statistical analyses for this end point

    Secondary: QRS

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    End point title
    QRS
    End point description
    PR, QRS, QTcF were measured at the following time points: 45, 30, 15 minutes pre-dose, 5, 10, 20, 30, 45 minutes post-dose and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12 hours post-dose. Only data referring to 5 minutes post-dose are reported here.
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening) to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    45
    45
    45
    44
    46
    Units: msec
        arithmetic mean (standard deviation)
    97.45 ± 10.21
    97.98 ± 10.513
    97.71 ± 10.371
    97.74 ± 10.884
    97.3 ± 10.608
    No statistical analyses for this end point

    Secondary: Change from baseline in QTcF

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    End point title
    Change from baseline in QTcF
    End point description
    PR, QRS, QTcF were measured at the following time points: 45, 30, 15 minutes pre-dose, 5, 10, 20, 30, 45 minutes post-dose and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12 hours post-dose. Only data referring to 5 minutes post-dose are reported here.
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening) to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    45
    45
    45
    44
    46
    Units: msec
        arithmetic mean (standard deviation)
    415.71 ± 19.23
    416.69 ± 19.413
    415.8 ± 19.282
    145.53 ± 17.871
    414.83 ± 17.997
    Statistical analysis title
    Treatment T1 vs Treatment R1
    Comparison groups
    Treatment T1 - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.3064
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    1.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.759
         upper limit
    3.24
    Statistical analysis title
    Treatment T2 vs Treatment R2
    Comparison groups
    Treatment T2 - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.1172
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    1.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.097
         upper limit
    3.928
    Statistical analysis title
    Treatment T1 vs Treatment P
    Comparison groups
    Treatment T1 - Safety v Treatment P - Safety
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.168
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    1.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.324
         upper limit
    3.654
    Statistical analysis title
    Treatment T2 vs Treatment p
    Comparison groups
    Treatment P - Safety v Treatment T2 - Safety
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0136
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    2.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.005
         upper limit
    4.967
    Statistical analysis title
    Treatment R1 vs Treatment P
    Comparison groups
    Treatment R1 - Safety v Treatment P - Safety
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.7244
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    0.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.564
         upper limit
    2.414
    Statistical analysis title
    Treatment R2 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.383
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    1.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.954
         upper limit
    3.094

    Secondary: Premature atrial contractions (PAC) burden 0-12 h

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    End point title
    Premature atrial contractions (PAC) burden 0-12 h
    End point description
    PAC burden was calculated 1 hour pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13 hours post-dose, and over the 0-12 hour post-dose interval. Only data regarding this latter are reported here.
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening) to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    47
    46
    45
    47
    47
    Units: percent
        arithmetic mean (standard deviation)
    -0.0001 ± 0.00188
    -0.0002 ± 0.00552
    0.0002 ± 0.00314
    0.0005 ± 0.00393
    -0.0008 ± 0.00273
    No statistical analyses for this end point

    Secondary: Premature ventricular contractions (PVC) burden 0-12 h

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    End point title
    Premature ventricular contractions (PVC) burden 0-12 h
    End point description
    PVC burden was calculated 1 hour pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13 hours post-dose, and over the 0-12 hour interval. Only data regarding this latter are reported here.
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening) to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    47
    46
    45
    47
    47
    Units: percent
        arithmetic mean (standard deviation)
    0.00197 ± 0.003047
    0.0024 ± 0.004905
    0.00109 ± 0.001671
    0.00141 ± 0.003765
    0.00145 ± 0.003322
    No statistical analyses for this end point

    Secondary: DBP AUC0-8h/8h

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    End point title
    DBP AUC0-8h/8h
    End point description
    SBP and DBP were measured at screening and at Visit 2 to Visit 6, at 45 and 30 min pre-dose, 5, 10, 20, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 h post-drug administration by automated machine.
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening) to Visit 6.
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    47
    46
    45
    47
    47
    Units: bpm
        least squares mean (confidence interval 95%)
    68.66 (67.667 to 69.659)
    65.93 (64.926 to 66.928)
    68.54 (67.519 to 69.56)
    66.3 (65.32 to 67.272)
    70.37 (69.394 to 71.354)
    Statistical analysis title
    Treatment T1 vs Treatment R1
    Comparison groups
    Treatment T1 - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.8631
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    0.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.287
         upper limit
    1.534
    Statistical analysis title
    Treatment T2 vs Treatment R2
    Comparison groups
    Treatment T2 - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.5998
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -0.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.754
         upper limit
    1.016
    Statistical analysis title
    Treatment T1 vs Treatment P
    Comparison groups
    Treatment T1 - Safety v Treatment P - Safety
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0158
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -1.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.096
         upper limit
    -0.326
    Statistical analysis title
    Treatment T2 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment T2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -4.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.826
         upper limit
    -3.069
    Statistical analysis title
    Treatment R1 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0102
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -1.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.228
         upper limit
    -0.441
    Statistical analysis title
    Treatment R2 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -4.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.461
         upper limit
    -2.695

    Secondary: SBP AUC0-8h/8h

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    End point title
    SBP AUC0-8h/8h
    End point description
    SBP and DBP were measured at screening and at Visit 2 to Visit 6, at 45 and 30 min pre-dose, 5, 10, 20, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 h post-drug administration by automated machine.
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening) to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    47
    46
    45
    47
    47
    Units: bpm
        least squares mean (confidence interval 95%)
    120.58 (119.295 to 121.859)
    119.16 (117.856 to 120.463)
    120.17 (118.843 to 121.494)
    119.24 (117.959 to 120.517)
    123.18 (121.906 to 124.461)
    Statistical analysis title
    Treatment T1 vs Treatment R1
    Comparison groups
    Treatment T1 - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.6565
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    0.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.4
         upper limit
    2.216
    Statistical analysis title
    Treatment T2 vs Treatment R2
    Comparison groups
    Treatment T2 - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.9319
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.888
         upper limit
    1.731
    Statistical analysis title
    Treatment T1 vs Treatment P
    Comparison groups
    Treatment T1 - Safety v Treatment P - Safety
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0046
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -2.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.4
         upper limit
    -0.814
    Statistical analysis title
    Treatment T2 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment T2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -4.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.821
         upper limit
    -2.227
    Statistical analysis title
    Treatment R1 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0012
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -3.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.827
         upper limit
    -1.203
    Statistical analysis title
    Treatment R2 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -3.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.756
         upper limit
    -2.135

    Secondary: DBP AUC0-12h/12h

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    End point title
    DBP AUC0-12h/12h
    End point description
    SBP and DBP were measured at screening and at Visit 2 to Visit 6, at 45 and 30 min pre-dose, 5, 10, 20, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 h post-drug administration by automated machine.
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening) to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    47
    46
    45
    47
    47
    Units: bpm
        least squares mean (confidence interval 95%)
    68.78 (67.793 to 69.772)
    66.44 (65.447 to 67.436)
    68.56 (67.542 to 69.57)
    66.55 (65.584 to 67.522)
    70.07 (69.101 to 71.047)
    Statistical analysis title
    Treatment T1 vs Treatment R1
    Comparison groups
    Treatment T1 - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.7505
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    0.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.175
         upper limit
    1.628
    Statistical analysis title
    Treatment T2 vs Treatment R2
    Comparison groups
    Treatment T2 - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.8729
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.488
         upper limit
    1.264
    Statistical analysis title
    Treatment T1 vs Treatment P
    Comparison groups
    Treatment T1 - Safety v Treatment P - Safety
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0656
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -1.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.667
         upper limit
    0.084
    Statistical analysis title
    Treatment T2 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment T2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -3.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.002
         upper limit
    -2.263
    Statistical analysis title
    Treatment R1 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0319
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -1.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.902
         upper limit
    -0.133
    Statistical analysis title
    Treatment R2 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -3.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.895
         upper limit
    -2.146

    Secondary: SBP AUC0-12h/12h

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    End point title
    SBP AUC0-12h/12h
    End point description
    SBP and DBP were measured at screening and at Visit 2 to Visit 6, at 45 and 30 min pre-dose, 5, 10, 20, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 h post-drug administration by automated machine.
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 1 (screening) to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    47
    46
    45
    47
    47
    Units: mmHg
        least squares mean (confidence interval 95%)
    121.22 (119.95 to 122.496)
    120.44 (119.141 to 121.73)
    120.85 (119.533 to 122.165)
    119.88 (118.609 to 121.148)
    123.34 (122.074 to 124.61)
    Statistical analysis title
    Treatment T1 vs Treatment R1
    Comparison groups
    Treatment T1 - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.6816
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    0.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.422
         upper limit
    2.169
    Statistical analysis title
    Treatment T2 vs Treatment R2
    Comparison groups
    Treatment T2 - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.5414
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    0.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.24
         upper limit
    2.354
    Statistical analysis title
    Treatment T1 vs Treatment P
    Comparison groups
    Treatment T1 - Safety v Treatment P - Safety
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0199
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -2.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.899
         upper limit
    -0.339
    Statistical analysis title
    Treatment T2 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment T2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0016
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -2.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.691
         upper limit
    -1.123
    Statistical analysis title
    Treatment R1 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0069
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -2.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.292
         upper limit
    -0.694
    Statistical analysis title
    Treatment R2 vs Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0002
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    -3.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.262
         upper limit
    -1.666

    Secondary: Serum potassium AUC0-4

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    End point title
    Serum potassium AUC0-4
    End point description
    Collection of blood for glucose and potassium determination in serum were performed at the scheduled time: pre-dose, 10, 20, 30, 45 min, 1, 1.5, 2, 3, 4 h post-drug administration.
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 2 to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    47
    46
    45
    47
    47
    Units: mmol*h/L
        geometric mean (confidence interval 95%)
    16 (15.6 to 16.4)
    15.5 (15.1 to 15.9)
    16.2 (15.8 to 16.6)
    15.4 (15 to 15.8)
    16.4 (16 to 16.8)
    Statistical analysis title
    Treatment T1 / Treatment R1
    Comparison groups
    Treatment T1 - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0.4999
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    98.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    95.57
         upper limit
    102.25
    Notes
    [1] - pairwise comparison
    Statistical analysis title
    Treatment T2 / Treatment R2
    Comparison groups
    Treatment T2 - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    P-value
    = 0.7257
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    100.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    97.28
         upper limit
    104.03
    Notes
    [2] - pairwise comparison
    Statistical analysis title
    Treatment T1/ Treatment P
    Comparison groups
    Treatment T1 - Safety v Treatment P - Safety
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    = 0.1442
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    97.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    94.32
         upper limit
    100.87
    Notes
    [3] - pairwise comparison
    Statistical analysis title
    Treatment T2 / Treatment P
    Comparison groups
    Treatment P - Safety v Treatment T2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    other [4]
    P-value
    = 0.0006
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    94.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    91.17
         upper limit
    97.46
    Notes
    [4] - pairwise comparison
    Statistical analysis title
    Treatment R1 / Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    P-value
    = 0.4339
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    98.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    95.41
         upper limit
    102.05
    Notes
    [5] - pairwise comparison
    Statistical analysis title
    Treatment R2 / Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    P-value
    = 0.0002
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    93.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    90.61
         upper limit
    96.89
    Notes
    [6] - pairwise comparison

    Secondary: Serum potassium Cmin

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    End point title
    Serum potassium Cmin
    End point description
    Collection of blood for glucose and potassium determination in serum were performed at the scheduled time: pre-dose, 10, 20, 30, 45 min, 1, 1.5, 2, 3, 4 h post-drug administration.
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 2 to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    47
    46
    45
    47
    47
    Units: mmol/L
        geometric mean (confidence interval 95%)
    3.79 (3.65 to 3.94)
    3.57 (3.44 to 3.72)
    3.77 (3.63 to 3.93)
    3.56 (3.43 to 3.7)
    3.9 (3.75 to 4.05)
    Statistical analysis title
    Treatment T1 / Treatment R1
    Comparison groups
    Treatment T1 - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    P-value
    = 0.8896
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    100.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    95.14
         upper limit
    105.91
    Notes
    [7] - pairwise comparison
    Statistical analysis title
    Treatment T2/ Treatment R2
    Comparison groups
    Treatment T2 - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    other [8]
    P-value
    = 0.8651
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    100.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    95.22
         upper limit
    106
    Notes
    [8] - pairwise comparison
    Statistical analysis title
    Treatment T1/ Treatment P
    Comparison groups
    Treatment T1 - Safety v Treatment P - Safety
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    other [9]
    P-value
    = 0.2989
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    97.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    92.18
         upper limit
    102.55
    Notes
    [9] - pairwise comparison
    Statistical analysis title
    Treatment T2 / Treatment P
    Comparison groups
    Treatment P - Safety v Treatment T2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    other [10]
    P-value
    = 0.0017
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    91.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    86.98
         upper limit
    96.79
    Notes
    [10] - pairwise comparison
    Statistical analysis title
    Treatment R1 / Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    other [11]
    P-value
    = 0.2438
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    96.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    91.78
         upper limit
    102.22
    Notes
    [11] - pairwise comparison
    Statistical analysis title
    Treatment R2 / Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    other [12]
    P-value
    = 0.001
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    91.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    86.56
         upper limit
    96.36
    Notes
    [12] - pairwise comparison

    Secondary: Serum potassium Tmin

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    End point title
    Serum potassium Tmin
    End point description
    Collection of blood for glucose and potassium determination in serum were performed at the scheduled time: pre-dose, 10, 20, 30, 45 min, 1, 1.5, 2, 3, 4 h post-drug administration.
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 2 to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    47
    46
    45
    47
    47
    Units: hours
        median (standard deviation)
    1.53 ± 0
    1.53 ± 0
    1.55 ± 0
    1.53 ± 0
    1.03 ± 0
    Statistical analysis title
    Treatment T1 vs Treatment R1
    Comparison groups
    Treatment T1 - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    other [13]
    P-value
    = 0.3057
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Hodges-Lehmann estimate of shift
    Point estimate
    -0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.78
         upper limit
    0.37
    Notes
    [13] - Pairwise comparison
    Statistical analysis title
    Treatment T2 vs Treatment R2
    Comparison groups
    Treatment T2 - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    other [14]
    P-value
    = 0.7033
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Hodges-Lehmann estimate of shift
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.14
         upper limit
    0.48
    Notes
    [14] - Pairwise comparison

    Secondary: Serum glucose AUC0-4h

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    End point title
    Serum glucose AUC0-4h
    End point description
    Collection of blood for glucose and potassium determination in serum were performed at the scheduled time: pre-dose, 10, 20, 30, 45 min, 1, 1.5, 2, 3, 4 h post-drug administration.
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 2 to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    47
    46
    45
    47
    47
    Units: mg*h/dL
        geometric mean (confidence interval 95%)
    375 (363 to 388)
    415 (402 to 429)
    377 (364 to 390)
    413 (400 to 426)
    371 (359 to 383)
    Statistical analysis title
    Treatment T1 / Treatment R1
    Comparison groups
    Treatment T1 - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    other [15]
    P-value
    = 0.8539
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    99.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    95.07
         upper limit
    104.28
    Notes
    [15] - pairwise comparison
    Statistical analysis title
    Treatment T2 / Treatment R2
    Comparison groups
    Treatment T2 - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    other [16]
    P-value
    = 0.7948
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    100.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    96.09
         upper limit
    105.34
    Notes
    [16] - pairwise comparison
    Statistical analysis title
    Treatment T1 / Treatment P
    Comparison groups
    Treatment T1 - Safety v Treatment P - Safety
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    other [17]
    P-value
    = 0.5978
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    101.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    96.69
         upper limit
    106
    Notes
    [17] - pairwise comparison
    Statistical analysis title
    Treatment T2 / Treatment P
    Comparison groups
    Treatment P - Safety v Treatment T2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    other [18]
    P-value
    < 0.0001
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    112.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    107.1
         upper limit
    117.35
    Notes
    [18] - pairwise comparison
    Statistical analysis title
    Treatment R1 / Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    other [19]
    P-value
    = 0.4772
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    101.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    97.1
         upper limit
    106.47
    Notes
    [19] - pairwise comparison
    Statistical analysis title
    Treatment R2 / Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    other [20]
    P-value
    < 0.0001
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    111.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    106.43
         upper limit
    116.66
    Notes
    [20] - pairwise comparison

    Secondary: Serum glucose Cmax

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    End point title
    Serum glucose Cmax
    End point description
    Collection of blood for glucose and potassium determination in serum were performed at the scheduled time: pre-dose, 10, 20, 30, 45 min, 1, 1.5, 2, 3, 4 h post-drug administration.
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 2 to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    47
    46
    45
    47
    47
    Units: mg/dL
        geometric mean (confidence interval 95%)
    102 (99.6 to 104)
    112 (110 to 114)
    101 (99.2 to 104)
    112 (110 to 115)
    102 (99.9 to 104)
    Statistical analysis title
    Treatment T1 / Treatment R1
    Comparison groups
    Treatment T1 - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    other [21]
    P-value
    = 0.8142
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    100.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    97.46
         upper limit
    103.32
    Notes
    [21] - pairwise comparison
    Statistical analysis title
    Treatment T2 / Treatment R2
    Comparison groups
    Treatment T2 - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    other [22]
    P-value
    = 0.8395
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    99.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    96.83
         upper limit
    102.65
    Notes
    [22] - pairwise comparison
    Statistical analysis title
    Treatment T1 / Treatment P
    Comparison groups
    Treatment T1 - Safety v Treatment P - Safety
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    other [23]
    P-value
    = 0.8543
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    99.73
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    96.88
         upper limit
    102.66
    Notes
    [23] - pairwise comparison
    Statistical analysis title
    Treatment T2 / Treatment P
    Comparison groups
    Treatment P - Safety v Treatment T2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    other [24]
    P-value
    < 0.0001
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    109.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    106.73
         upper limit
    113.12
    Notes
    [24] - pairwise comparison
    Statistical analysis title
    Treatment R1 / Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    other [25]
    P-value
    = 0.6776
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    99.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    96.51
         upper limit
    102.34
    Notes
    [25] - pairwise comparison
    Statistical analysis title
    Treatment R2 / Treatment P
    Comparison groups
    Treatment P - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    other [26]
    P-value
    < 0.0001
    Method
    ANOVA
    Parameter type
    least square mean ratio
    Point estimate
    110.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    107.04
         upper limit
    113.47
    Notes
    [26] - pairwise comparison

    Secondary: Serum glucose Tmax

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    End point title
    Serum glucose Tmax
    End point description
    Collection of blood for glucose and potassium determination in serum were performed at the scheduled time: pre-dose, 10, 20, 30, 45 min, 1, 1.5, 2, 3, 4 h post-drug administration.
    End point type
    Secondary
    End point timeframe
    At each visit from Visit 2 to Visit 6
    End point values
    Treatment T1 - Safety Treatment T2 - Safety Treatment R1 - Safety Treatment R2 - Safety Treatment P - Safety
    Number of subjects analysed
    47
    46
    45
    47
    47
    Units: Hours
        median (standard deviation)
    0.18 ± 0
    1.91 ± 0
    0.18 ± 0
    2.03 ± 0
    0 ± 0
    Statistical analysis title
    Treatment T1 vs Treatment R1
    Comparison groups
    Treatment T1 - Safety v Treatment R1 - Safety
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    other [27]
    P-value
    = 0.2641
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Hodges-Lehmann estimate of shift
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.28
         upper limit
    0
    Notes
    [27] - Pairwise comparison
    Statistical analysis title
    Treatment T2 vs Treatment R2
    Comparison groups
    Treatment T2 - Safety v Treatment R2 - Safety
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    other [28]
    P-value
    = 0.2742
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Hodges-Lehmann estimate of shift
    Point estimate
    -0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.78
         upper limit
    0
    Notes
    [28] - Pairwise comparison

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    At each Visit from visit 0 (pre-screening) and visit 1 (screening) to Visit 6 and afterward at the follow-up (phone call)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Treatment T1- safety population
    Reporting group description
    -

    Reporting group title
    Treatment T2 - safety population
    Reporting group description
    -

    Reporting group title
    Treatment R1 - safety population
    Reporting group description
    -

    Reporting group title
    Treatment R2 - safety population
    Reporting group description
    -

    Reporting group title
    Treatment P - safety population
    Reporting group description
    -

    Serious adverse events
    Treatment T1- safety population Treatment T2 - safety population Treatment R1 - safety population Treatment R2 - safety population Treatment P - safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Treatment T1- safety population Treatment T2 - safety population Treatment R1 - safety population Treatment R2 - safety population Treatment P - safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 47 (12.77%)
    16 / 46 (34.78%)
    8 / 45 (17.78%)
    14 / 47 (29.79%)
    14 / 47 (29.79%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    1 / 47 (2.13%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    0
    1
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    0
    0
    1
    Contusion
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    1 / 45 (2.22%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Excoriation
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 46 (2.17%)
    0 / 45 (0.00%)
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Muscle injury
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 46 (2.17%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Suture related complication
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    0
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    1 / 47 (2.13%)
    1 / 47 (2.13%)
         occurrences all number
    1
    0
    0
    1
    1
    Cough
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    1 / 47 (2.13%)
    2 / 47 (4.26%)
         occurrences all number
    0
    0
    0
    1
    2
    Dyspnoea
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    1 / 45 (2.22%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    0
    1
    Increased upper airway secretion
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    1 / 47 (2.13%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    0
    1
    1
    Wheezing
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 46 (2.17%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 46 (2.17%)
    0 / 45 (0.00%)
    2 / 47 (4.26%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Headache
         subjects affected / exposed
    1 / 47 (2.13%)
    5 / 46 (10.87%)
    2 / 45 (4.44%)
    3 / 47 (6.38%)
    3 / 47 (6.38%)
         occurrences all number
    1
    5
    2
    3
    3
    Migrane
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    0
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    1 / 45 (2.22%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Post herpetic neuralgia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    0
    0
    1
    Presyncope
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Tremor
         subjects affected / exposed
    0 / 47 (0.00%)
    3 / 46 (6.52%)
    0 / 45 (0.00%)
    2 / 47 (4.26%)
    0 / 47 (0.00%)
         occurrences all number
    0
    3
    0
    2
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 46 (2.17%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Catheter site related reaction
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 46 (2.17%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Local swelling
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    2 / 47 (4.26%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Abdominal pain
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    1 / 45 (2.22%)
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Toothache
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    0
    0
    1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 46 (2.17%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 46 (0.00%)
    1 / 45 (2.22%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    0
    0
    1
    Infections and infestations
    Hordeolum
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    1 / 45 (2.22%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Infected bites
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 46 (2.17%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 46 (2.17%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Rash pustular
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    1 / 47 (2.13%)
    2 / 47 (4.26%)
         occurrences all number
    1
    0
    0
    1
    2
    Sinusitis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Skin infection
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 46 (2.17%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 46 (2.17%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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.
    There are no limitations or caveats to this summary of results
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