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    Clinical Trial Results:
    Proof of concept study to assess the differential effects of chronic beta-blockade (celiprolol versus bisoprolol) on cardiopulmonary outcomes at rest and during exercise in chronic obstructive pulmonary disease.

    Summary
    EudraCT number
    		 2015-000207-13
    Trial protocol
    		 GB  
    Global end of trial date
    30 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jun 2021
    First version publication date
    25 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2012RC22
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02380053
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Dundee - NHS Tayside
    Sponsor organisation address
    Residency Block, Level 3, Ninewells Hospital, George Pirie Way, Dundee, United Kingdom, DD1 9SY
    Public contact
    General Enquiries, Scottish Centre for Respiratory Research, +44 1382 383902, scrr@dundee.ac.uk
    Scientific contact
    General Enquiries, Scottish Centre for Respiratory Research, +44 1382 383902, scrr@dundee.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the relative effects on heart and lung (airway) responses at rest and during exercise following beta-blocker treatment with bisoprolol versus celiprolol in COPD patients.
    Protection of trial subjects
    The Sponsor carried out a study risk assessment before issuing approval. The study was approved by the East of Scotland Research Ethics Service (EoSRES) (Ref: 15/ES/0102) and full informed consent was obtained from all participants. Participants were checked against all inclusion and exclusion criteria and were only included if their COPD was stable; those with a low blood pressure or heart rate were not included. A medically-qualified person confirmed the participant’s suitability to receive the study drug according to the study protocol. Participants were given a paper diary card, PiKO device and pulse oximeter for daily a-home monitoring of their lung function, heart rate and oxygen saturation. The beta-blockers (IMP) were given by slowly escalating the dose during each treatment period. Initial beta-blocker dosing started at a low dose and was titrated up halfway through each treatment period. Participants were contacted when they were due to increase their beta-blocker dose and the following items assessed: symptoms attributable to beta-blocker therapy, FEV1, and heart rate. If these were satisfactory, participants progressed to the higher beta-blocker dose for the remainder of the treatment period. Participants were contacted again within 1 week of increasing their dose to repeat the checks. Participants intolerant of higher beta-blockers doses returned to their previous maximum tolerated dose for the remainder of the treatment period. Participants unable to tolerate the minimum beta-blocker dose were withdrawn. Participants were given an instruction leaflet with information on how to measure their lung function, heart rate and oxygen saturation, how to complete their diary cards, potential side effects of study drugs, and how to record adverse events and concomitant medications. Participants were given an out-of-hours mobile number carried by medical staff for advice if they encountered any adverse effects.
    Background therapy
    		 Subjects remained on their usual COPD medications. The IMP was given in addition to their standard treatments.
    Evidence for comparator
    		 Beta-blockers are underused in COPD despite evidence for reducing mortality from cardiovascular comorbidities. Beta-blockers are pharmacologically heterogeneous and the study was designed to assess the clinical consequences of different beta-blockers in COPD. Bisoprolol (BIS) is a beta-1 selective antagonist that may cause bronchoconstriction due to dose related beta-2 blockade. Celiprolol (CEL) is a beta-1 selective antagonist which also exhibits partial beta-2 agonist activity. The study assessed the relative effects of both BIS and CEL in COPD patients to establish whether the proposed benefits on survival with beta-blockers in COPD are reflected in improved cardiovascular and respiratory response to exercise and exercise tolerance.
    Actual start date of recruitment
    07 Jun 2016
    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: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    5
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subject recruitment began 7 June 2016 and the study completed on 30 April 2019. Of the 20 patients screened, 14 were randomised and 11 completed per protocol and were included in the final analysis.

    Pre-assignment
    Screening details
    		 Males and females, 40-80 years, stable COPD (GOLD stage 2/3), post-SABA FEV1 30-80% predicted and FEV1/FVC ratio <70%, no exacerbation in the last month, no hospitalisation for exacerbation in the last 3 months, ≥ 10 pack-years; O2 sats ≥ 92% on room air, sinus rhythm on ECG, average resting systolic BP ≥ 110 mmHg, average resting HR ≥ 55 bpm.

    Pre-assignment period milestones
    Number of subjects started
    		 20
    Number of subjects completed
    		 14 [1]

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Reason: Number of subjects
    		 Elective Intervention Scheduled: 1
    Reason: Number of subjects
    		 Did Not meet Inclusion Criteria: 4
    Notes
    [1] - The number of subjects reported to be in the pre-assignment period is not consistent with the number starting period 1. It is expected that the number completing the pre-assignment period are also present in the arms in period 1.
    Justification: 14 subjects completed run-in and attended a baseline visit. This is a cross-over study where subjects participate in both arms during the course of the study. Bisoprolol arm - 11 patients received at least 1 dose and are counted as participants in this arm. Celiprolol arm - 13 subjects received at least 1 dose and are counted as participants in this arm. 11 subjects completed both arms of this cross-over trial and were able to be analysed.
    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Bisoprolol (BIS)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bisoprolol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Bisoprolol 2.5 mg OD for 2 weeks, followed by 5 mg OD for 2 weeks.

    Arm title
    		 Celiprolol (CEL)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Celiprolol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Celiprolol 200 mg OD for 2 weeks, followed by 400 mg OD for 2 weeks.

    Number of subjects in period 1
    		Bisoprolol (BIS) Celiprolol (CEL)
    Started
    11
    13
    Completed
    11
    11
    Not completed
    0
    2
         IMP Not Tolerated
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Overall Trial
    Reporting group description
    		 -

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The worldwide number enrolled is the number of subjects screened into the study (20). The number of subjects in the baseline period is the number who were randomised into the study (14). Of these 14 subjects, 11 completed both arms of the cross-over trial and were able to be analysed.
    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 14 14
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 5 5
        From 65-84 years
    		 9 9
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.64 ( 7.14 ) -
    Gender categorical
    Units: Subjects
        Female
    		 5 5
        Male
    		 9 9

    End points

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    End points reporting groups
    Reporting group title
    Bisoprolol (BIS)
    Reporting group description
    		 -

    Reporting group title
    Celiprolol (CEL)
    Reporting group description
    		 -

    Subject analysis set title
    Completed Subjects
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    11 subjects who completed both arms of the study per protocol

    Primary: Inspiratory Capacity

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    End point title
    		 Inspiratory Capacity
    End point description
    End point type
    Primary
    End point timeframe
    Inspiratory Capacity was measured at baseline (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Litres
        arithmetic mean (confidence interval 95%)
    2.05 (1.72 to 2.38)
    1.77 (1.42 to 2.12)
    Statistical analysis title
    		 Inspiratory Capacity
    Comparison groups
    Celiprolol (CEL) v Bisoprolol (BIS)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.42
    Method
    		 ANOVA
    Confidence interval

    Primary: DH, dynamic hyperinflation; at exercise isotime 4min

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    End point title
    		 DH, dynamic hyperinflation; at exercise isotime 4min
    End point description
    End point type
    Primary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Litres
        arithmetic mean (confidence interval 95%)
    -0.42 (-0.61 to -0.23)
    -0.67 (-1.12 to -0.23)
    Statistical analysis title
    		 Dynamic Hyperinflation
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.52
    Method
    		 ANOVA
    Confidence interval

    Secondary: Borg Score (Breathing)

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    End point title
    		 Borg Score (Breathing)
    End point description
    End point type
    Secondary
    End point timeframe
    Borg Score (Breathing) was measured at baseline (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: units
        geometric mean (confidence interval 95%)
    6.3 (4.8 to 8.1)
    6.6 (5.2 to 8.2)
    Statistical analysis title
    		 Borg Breathlessness
    Statistical analysis description
    Peak Borg score breathlessness*
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.72
    Method
    		 ANOVA
    Confidence interval

    Secondary: Heart Rate recovery over 3 min n=10

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    End point title
    		 Heart Rate recovery over 3 min n=10
    End point description
    End point type
    Secondary
    End point timeframe
    Heart Rate was measured at baseline (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: beats/min
        arithmetic mean (confidence interval 95%)
    6.7 (5.3 to 8.0)
    4.6 (3.5 to 5.7)
    Statistical analysis title
    		 Heart rate recovery
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 ANOVA
    Confidence interval

    Secondary: Cardiac Output Peak heart rate

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    End point title
    		 Cardiac Output Peak heart rate
    End point description
    End point type
    Secondary
    End point timeframe
    Cardiac Output was measured at baseline (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: L/min
        arithmetic mean (confidence interval 95%)
    102 (96 to 109)
    104 (99 to 108)
    Statistical analysis title
    		 Heart rate
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval

    Secondary: Peak VO2, oxygen uptake

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    End point title
    		 Peak VO2, oxygen uptake
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: litres
        arithmetic mean (confidence interval 95%)
    1.21 (1.00 to 1.42)
    1.24 (1.02 to 1.45)
    Statistical analysis title
    		 Oxygen uptake
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.71
    Method
    		 ANOVA
    Confidence interval

    Secondary: Peak VE, minute ventilation

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    End point title
    		 Peak VE, minute ventilation
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Litres/minute
        arithmetic mean (confidence interval 95%)
    48.2 (41.0 to 55.4)
    48.3 (41.0 to 55.6)
    Statistical analysis title
    		 Minute ventilation
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.31
    Method
    		 ANOVA
    Confidence interval

    Secondary: Peak RR, respiratory rate

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    End point title
    		 Peak RR, respiratory rate
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Breaths/min
        arithmetic mean (confidence interval 95%)
    34 (30 to 38)
    31 (28 to 34)
    Statistical analysis title
    		 Respiratory rate
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.053
    Method
    		 ANOVA
    Confidence interval

    Secondary: Peak O2 Sats*, oxygen saturations

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    End point title
    		 Peak O2 Sats*, oxygen saturations
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Percent
        median (inter-quartile range (Q1-Q3))
    97 (90 to 98)
    97 (91 to 99)
    Statistical analysis title
    		 Oxygen saturations
    Comparison groups
    Celiprolol (CEL) v Bisoprolol (BIS)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6
    Method
    		 ANOVA
    Confidence interval

    Secondary: BR, breathing reserve at peak exercise

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    End point title
    		 BR, breathing reserve at peak exercise
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Percent
        arithmetic mean (confidence interval 95%)
    1.1 (-7.8 to 10.0)
    -3.5 (-14.3 to 7.2)
    Statistical analysis title
    		 Breathing reserve
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25
    Method
    		 ANOVA
    Confidence interval

    Secondary: Total exercise time (min)

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    End point title
    		 Total exercise time (min)
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Minutes
        arithmetic mean (confidence interval 95%)
    6.5 (4.5 to 8.5)
    7.2 (5.4 to 8.9)
    Statistical analysis title
    		 Total exercise time
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.83
    Method
    		 ANOVA
    Confidence interval

    Secondary: Peak Borg score leg discomfort*

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    End point title
    		 Peak Borg score leg discomfort*
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Units
        geometric mean (confidence interval 95%)
    17 (15.8 to 18.3)
    17.4 (16.1 to 18.8)
    Statistical analysis title
    		 Borg Leg Discomfort
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16
    Method
    		 ANOVA
    Confidence interval

    Secondary: FEV1 , forced expiratory volume in 1 second

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    End point title
    		 FEV1 , forced expiratory volume in 1 second
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Percentage of predicted
        arithmetic mean (confidence interval 95%)
    52 (45 to 59)
    52 (45 to 59)
    Statistical analysis title
    		 FEV1
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9
    Method
    		 ANOVA
    Confidence interval

    Secondary: FVC, forced vital capacity

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    End point title
    		 FVC, forced vital capacity
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Percentage of predicted
        arithmetic mean (confidence interval 95%)
    102 (87 to 117)
    100 (88 to 112)
    Statistical analysis title
    		 FVC
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.59
    Method
    		 ANOVA
    Confidence interval

    Secondary: Relaxed vital capacity

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    End point title
    		 Relaxed vital capacity
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Percentage of predicted
        arithmetic mean (confidence interval 95%)
    108 (93 to 124)
    109 (96 to 121)
    Statistical analysis title
    		 Relaxed VC
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.99
    Method
    		 ANOVA
    Confidence interval

    Secondary: Residual Volume/Total Lung Capacity ratio

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    End point title
    		 Residual Volume/Total Lung Capacity ratio
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Percent
        arithmetic mean (confidence interval 95%)
    47.7 (43.3 to 52.0)
    49.6 (44.8 to 54.3)
    Statistical analysis title
    		 RV/TLC ratio
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.06
    Method
    		 ANOVA
    Confidence interval

    Secondary: R5*, resistance at 5 Hertz

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    End point title
    		 R5*, resistance at 5 Hertz
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Percent
        geometric mean (confidence interval 95%)
    144 (124 to 167)
    163 (149 to 179)
    Statistical analysis title
    		 R5
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.04
    Method
    		 ANOVA
    Confidence interval

    Secondary: Ax*, reactance at 5 Hertz

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    End point title
    		 Ax*, reactance at 5 Hertz
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Kilopascals/Litre
        geometric mean (confidence interval 95%)
    1.98 (1.24 to 2.73)
    2.44 (1.74 to 3.13)
    Statistical analysis title
    		 Ax
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 ANOVA
    Confidence interval

    Secondary: Oxygen pulse

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    End point title
    		 Oxygen pulse
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: millilitres per beat
        arithmetic mean (confidence interval 95%)
    11.7 (9.8 to 13.5)
    11.6 (10.0 to 13.3)
    Statistical analysis title
    		 Oxygen pulse
    Comparison groups
    Celiprolol (CEL) v Bisoprolol (BIS)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval

    Secondary: Peak mean arterial blood pressure

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    End point title
    		 Peak mean arterial blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: millimetres of mercury
        arithmetic mean (confidence interval 95%)
    106 (91 to 120)
    106 (93 to 120)
    Statistical analysis title
    		 Mean arterial blood pressure
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 ANOVA
    Confidence interval

    Secondary: Cardiac Outcomes Non-Invasive Cardiac Output Monitor -peak cardiac output

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    End point title
    		 Cardiac Outcomes Non-Invasive Cardiac Output Monitor -peak cardiac output
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Litres/minute
        arithmetic mean (confidence interval 95%)
    11.2 (9.7 to 12.8)
    10.4 (9.4 to 11.4)
    Statistical analysis title
    		 Cardiac output
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7
    Method
    		 ANOVA
    Confidence interval

    Secondary: Cardiac Outcomes Non-Invasive Cardiac Output Monitor - Peak Stroke Volume, n=10

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    End point title
    		 Cardiac Outcomes Non-Invasive Cardiac Output Monitor - Peak Stroke Volume, n=10
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: millilitres/beat
        arithmetic mean (confidence interval 95%)
    122 (102 to 142)
    105 (96 to 113)
    Statistical analysis title
    		 Stroke volume
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 ANOVA
    Confidence interval

    Secondary: Domiciliary Outcomes - Oxygen saturations (AM)

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    End point title
    		 Domiciliary Outcomes - Oxygen saturations (AM)
    End point description
    End point type
    Secondary
    End point timeframe
    Continuous diurnal measurement throughout the study. Mean of last 3 days of each period.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Percent
        arithmetic mean (confidence interval 95%)
    95 (94 to 96)
    95 (94 to 96)
    Statistical analysis title
    		 Oxygen saturations
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.97
    Method
    		 ANOVA
    Confidence interval

    Secondary: Domiciliary Outcomes -oxygen saturations (PM)

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    End point title
    		 Domiciliary Outcomes -oxygen saturations (PM)
    End point description
    End point type
    Secondary
    End point timeframe
    Continuous diurnal measurement throughout the study. Mean of last 3 days of each period.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Percent
        arithmetic mean (confidence interval 95%)
    94 (93 to 96)
    95 (94 to 96)
    Statistical analysis title
    		 Oxygen saturations
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.35
    Method
    		 ANOVA
    Confidence interval

    Secondary: Domiciliary Outcomes - Heart rate (AM)

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    End point title
    		 Domiciliary Outcomes - Heart rate (AM)
    End point description
    End point type
    Secondary
    End point timeframe
    Continuous diurnal measurement throughout the study. Mean of last 3 days of each period.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Beats per minute
        arithmetic mean (confidence interval 95%)
    67 (62 to 72)
    73 (68 to 77)
    Statistical analysis title
    		 Heart rate
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval

    Secondary: Domiciliary Outcomes - Heart rate (PM)

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    End point title
    		 Domiciliary Outcomes - Heart rate (PM)
    End point description
    End point type
    Secondary
    End point timeframe
    Continuous diurnal measurement throughout the study. Mean of last 3 days of each period.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Beats per minute
        arithmetic mean (confidence interval 95%)
    67 (63 to 70)
    74 (70 to 79)
    Statistical analysis title
    		 Heart rate
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval

    Secondary: Domiciliary Outcomes - FEV1 , forced expiratory volume in 1 second (AM)

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    End point title
    		 Domiciliary Outcomes - FEV1 , forced expiratory volume in 1 second (AM)
    End point description
    End point type
    Secondary
    End point timeframe
    Continuous diurnal measurement throughout the study. Mean of last 3 days of each period.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Litres
        arithmetic mean (confidence interval 95%)
    1.24 (0.99 to 1.49)
    1.22 (0.95 to 1.49)
    Statistical analysis title
    		 FEV1
    Comparison groups
    Celiprolol (CEL) v Bisoprolol (BIS)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46
    Method
    		 ANOVA
    Confidence interval

    Secondary: Domiciliary Outcomes - FEV1 , forced expiratory volume in 1 second (PM)

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    End point title
    		 Domiciliary Outcomes - FEV1 , forced expiratory volume in 1 second (PM)
    End point description
    End point type
    Secondary
    End point timeframe
    Continuous diurnal measurement throughout the study. Mean of last 3 days of each period.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Litres
        arithmetic mean (confidence interval 95%)
    1.21 (0.96 to 1.46)
    1.22 (0.92 to 1.52)
    Statistical analysis title
    		 FEV1
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33
    Method
    		 ANOVA
    Confidence interval

    Secondary: Domiciliary Outcomes - FEV1 , forced expiratory volume in 6 second (AM)

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    End point title
    		 Domiciliary Outcomes - FEV1 , forced expiratory volume in 6 second (AM)
    End point description
    End point type
    Secondary
    End point timeframe
    Continuous diurnal measurement throughout the study. Mean of last 3 days of each period.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Litres
        arithmetic mean (confidence interval 95%)
    2.41 (2.01 to 2.81)
    2.41 (1.96 to 2.86)
    Statistical analysis title
    		 FEV6
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.91
    Method
    		 ANOVA
    Confidence interval

    Secondary: Domiciliary Outcomes - FEV1 , forced expiratory volume in 6 second (PM)

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    End point title
    		 Domiciliary Outcomes - FEV1 , forced expiratory volume in 6 second (PM)
    End point description
    End point type
    Secondary
    End point timeframe
    Continuous diurnal measurement throughout the study. Mean of last 3 days of each period.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Litres
        arithmetic mean (confidence interval 95%)
    2.35 (1.89 to 2.80)
    2.38 (1.91 to 2.85)
    Statistical analysis title
    		 FEV6
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4
    Method
    		 ANOVA
    Confidence interval

    Secondary: Domiciliary Outcomes - Symptoms** (AM)

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    End point title
    		 Domiciliary Outcomes - Symptoms** (AM)
    End point description
    End point type
    Secondary
    End point timeframe
    Continuous diurnal measurement throughout the study. Median of last 3 days of each period.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Units (0-3)
        median (inter-quartile range (Q1-Q3))
    0 (0 to 1)
    0 (0 to 1)
    Statistical analysis title
    		 Daily symptoms
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.55
    Method
    		 Friedman’s two-way analysis of variance
    Confidence interval

    Secondary: Domiciliary Outcomes - Symptoms** (PM)

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    End point title
    		 Domiciliary Outcomes - Symptoms** (PM)
    End point description
    End point type
    Secondary
    End point timeframe
    Continuous diurnal measurement throughout the study. Median of last 3 days of each period.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Units (0-3)
        median (inter-quartile range (Q1-Q3))
    1 (0 to 1)
    1 (0 to 1)
    Statistical analysis title
    		 Daily symptoms
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.94
    Method
    		 Friedman’s two-way analysis of variance
    Confidence interval

    Secondary: Domiciliary Outcomes - Reliever use** (AM)

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    End point title
    		 Domiciliary Outcomes - Reliever use** (AM)
    End point description
    End point type
    Secondary
    End point timeframe
    Continuous diurnal measurement throughout the study. Median of last 3 days of each period.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Number of puffs
    0
    0
    Statistical analysis title
    		 Daily reliever use
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.65
    Method
    		 Friedman’s two-way analysis of variance
    Confidence interval

    Secondary: Domiciliary Outcomes - Reliever use** (PM)

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    End point title
    		 Domiciliary Outcomes - Reliever use** (PM)
    End point description
    End point type
    Secondary
    End point timeframe
    Continuous diurnal measurement throughout the study. Median of last 3 days of each period.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Number of puffs
    0
    0
    Statistical analysis title
    		 Daily reliever use
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.54
    Method
    		 Friedman’s two-way analysis of variance
    Confidence interval

    Secondary: Quality of Life Outcome - St Georges Respiratory Questionnaire (SGRQ) GRQ Symptoms

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    End point title
    		 Quality of Life Outcome - St Georges Respiratory Questionnaire (SGRQ) GRQ Symptoms
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Units
        arithmetic mean (confidence interval 95%)
    45 (24 to 47)
    45 (30 to 60)
    Statistical analysis title
    		 SGRQ Symptoms
    Comparison groups
    Celiprolol (CEL) v Bisoprolol (BIS)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.19
    Method
    		 ANOVA
    Confidence interval

    Secondary: Quality of Life Outcome - St Georges Respiratory Questionnaire (SGRQ) SGRQ Activity

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    End point title
    		 Quality of Life Outcome - St Georges Respiratory Questionnaire (SGRQ) SGRQ Activity
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Units
        arithmetic mean (confidence interval 95%)
    60 (47 to 72)
    60 (47 to 73)
    Statistical analysis title
    		 SGRQ Activity
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.96
    Method
    		 ANOVA
    Confidence interval

    Secondary: Quality of Life Outcome - St Georges Respiratory Questionnaire (SGRQ)SGRQ Impacts

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    End point title
    		 Quality of Life Outcome - St Georges Respiratory Questionnaire (SGRQ)SGRQ Impacts
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Units
        arithmetic mean (confidence interval 95%)
    25 (17 to 33)
    25 (16 to 33)
    Statistical analysis title
    		 SGRQ Impacts
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.86
    Method
    		 ANOVA
    Confidence interval

    Secondary: Quality of Life Outcome - St Georges Respiratory Questionnaire (SGRQ)SGRQ Total score

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    End point title
    		 Quality of Life Outcome - St Georges Respiratory Questionnaire (SGRQ)SGRQ Total score
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Units
        arithmetic mean (confidence interval 95%)
    39 (30 to 49)
    37 (29 to 45)
    Statistical analysis title
    		 SGRQ Total score
    Comparison groups
    Celiprolol (CEL) v Bisoprolol (BIS)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6
    Method
    		 ANOVA
    Confidence interval

    Secondary: Biomarker (Venous Blood) Outcomes NT-pro-BNP*, N-terminal pro-B-type natriuretic peptide

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    End point title
    		 Biomarker (Venous Blood) Outcomes NT-pro-BNP*, N-terminal pro-B-type natriuretic peptide
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: picomoles/Litre
        arithmetic mean (confidence interval 95%)
    6.3 (3.2 to 11.6)
    3.97 (1.55 to 8.69)
    Statistical analysis title
    		 NT-pro-BNP
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 ANOVA
    Confidence interval

    Secondary: Biomarker (Venous Blood) Outcomes Galectin-3

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    End point title
    		 Biomarker (Venous Blood) Outcomes Galectin-3
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: nanograms/Litre
        arithmetic mean (confidence interval 95%)
    8.0 (6.3 to 9.7)
    8.5 (7.0 to 10.0)
    Statistical analysis title
    		 Galectin-3
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 ANOVA
    Confidence interval

    Secondary: Beta-2 Adrenceptor activity Creatinine kinase, n=10

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    End point title
    		 Beta-2 Adrenceptor activity Creatinine kinase, n=10
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: Units/Litre
        arithmetic mean (confidence interval 95%)
    112 (78 to 147)
    131 (91 to 171)
    Statistical analysis title
    		 Creatinine kinase
    Comparison groups
    Celiprolol (CEL) v Bisoprolol (BIS)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.27
    Method
    		 ANOVA
    Confidence interval

    Secondary: Beta-2 Adrenceptor activity - Total Cholesterol

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    End point title
    		 Beta-2 Adrenceptor activity - Total Cholesterol
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: millimoles/litre
        arithmetic mean (confidence interval 95%)
    4.8 (4.2 to 5.4)
    4.7 (4.2 to 5.2)
    Statistical analysis title
    		 Total Cholesterol
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.35
    Method
    		 ANOVA
    Confidence interval

    Secondary: Beta-2 Adrenceptor activity - Cholestrol/High Density Lipoprotein ratio

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    End point title
    		 Beta-2 Adrenceptor activity - Cholestrol/High Density Lipoprotein ratio
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: no units
        arithmetic mean (confidence interval 95%)
    3.2 (2.8 to 3.6)
    3.0 (2.6 to 3.3)
    Statistical analysis title
    		 Chol/HDL ratio
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 ANOVA
    Confidence interval

    Secondary: Beta-2 Adrenceptor activity - Potassium

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    End point title
    		 Beta-2 Adrenceptor activity - Potassium
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baselines (pre-beta blocker) and post-beta blocker at 4 weeks.
    End point values
    		 Bisoprolol (BIS) Celiprolol (CEL)
    Number of subjects analysed
    11
    11
    Units: millimoles/litre
        arithmetic mean (confidence interval 95%)
    4.5 (4.3 to 4.6)
    4.4 (4.2 to 4.6)
    Statistical analysis title
    		 Potassium
    Comparison groups
    Bisoprolol (BIS) v Celiprolol (CEL)
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.09
    Method
    		 ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events (AEs) were recorded from the time a participant consented to join the study until the last study visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Received IMP
    Reporting group description
    		 -

    Serious adverse events
    		 Received IMP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Received IMP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 13 (92.31%)
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 13 (38.46%)
         occurrences all number
    7
    Syncope
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Sciatica
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 13 (30.77%)
         occurrences all number
    4
    Lethargy
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Gait disturbance
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Gastrointestinal disorders
    Gastroenteritis
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    5
    Nasopharyngitis
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Rhinorrhoea
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    3
    Sputum increased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Nasal congestion
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Catarrh
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Wheezing
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Sinusitis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Productive cough
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Swelling in Left Hallux
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Neck pain
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1

    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.
    None reported
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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