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    Clinical Trial Results:
    Evaluation of effects of chronic dose exposure to cardioselective and non-cardioselective beta blockers on measures of cardiopulmonary function in moderate to severe COPD.

    Summary
    EudraCT number
    		 2011-006008-11
    Trial protocol
    		 GB  
    Global end of trial date
    21 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jul 2017
    First version publication date
    23 Jul 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2012RC01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01656005
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Sponsor R&D Number: 2012RC01
    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
    Professor Brian Lipworth, Scottish Centre for Respiratory Research, 44 01382 383188, b.j.lipworth@dundee.ac.uk
    Scientific contact
    Professor Brian Lipworth, Scottish Centre for Respiratory Research, 44 01382 383188, b.j.lipworth@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
    21 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effects on measures of lung and heart function of two different beta blockers - one that acts mainly on the heart and the other that acts on both the heart and lungs - after chronic dosing.
    Protection of trial subjects
    This study was registered at clinicaltrials.gov under NCT01656005, and had favourable opinion from the East of Scotland Research and Ethics Committee (12/ES/0054). Patients were referred from both primary and secondary care and attended the Scottish Centre for Respiratory Research, Ninewells Hospital & Medical School, Dundee, Scotland, for their visits. Written informed consent was obtained from all participants. Participants were given a PiKO monitor device to record domiciliary FEV1 and FEV6 twice daily in a diary supplied by the department, as well as domiciliary oxygen saturation and HR monitor to be recorded twice daily. They completed a daily diary of reliever use and symptoms and these diaries were reviewed at each study visit. The beta-blocker dose was gradually uptitrated, and the participant informed that should they experience side-effects related to beta-blocker therapy, they should phone the department (during working hours) or the emergency mobile number (out of hours). An action plan would then be formulated by a qualified doctor. Participants were allowed to complete each treatment arm on their maximum tolerated dose of beta-blocker, if this was less than the maximum prescribed dose.
    Background therapy
    		 The beta-blockers were given in combination with sequential step down inhaled therapy: starting with triple inhaler therapy as inhaled corticosteroid /long acting beta-agonist/long acting muscarinic antagonist (ICS+LABA+LAMA), then dual inhaler therapy as ICS/LABA and finally single inhaler therapy as ICS alone – to allow us to dissect out the respective interactions between beta-blockers with LAMA (i.e. ICS/LABA/LAMA vs ICS/LABA) and LABA (i.e. ICS/LABA vs ICS). The three medications used as inhaled therapy were: • Fostair (beclomethasone dipropionate / formoterol) (ICS/LABA) • Spiriva (tiotropium) (LAMA) • Clenil Modulite (beclomethasone dipropionate) (ICS) The lengths of treatment in each treatment arm were as follows: Weeks 1 - 4: Fostair 100/6, 2 puffs bid via a spacer device + Spiriva 18μg od via Handihaler Week 5: Fostair 100/6, 2 puffs bid via a spacer device Week 6: Clenil Modulite 200μg, 2 puffs bid via a spacer device
    Evidence for comparator
    		 Management guidelines clearly reinforce the use of cardioselective beta-blockers in patient with heart failure and COPD. Despite guidelines, beta-blockers remain underused in patients with COPD who have cardiovascular disease, presumably due to concerns regarding possible broncho-constriction, even with cardioselective drugs. It remains unclear if beta-blockers might also have beneficial effects in individuals with COPD who have no history of cardiovascular disease. We elected to perform a study comparing two commonly used selective (bisoprolol) and non-selective (carvedilol) drugs, evaluating cardiopulmonary outcomes. We aimed for realistic target doses of bisoprolol 5mg qd and carvedilol 12·5mg bid, which we identified as being the most commonly tolerated doses in real life for our elderly population
    Actual start date of recruitment
    18 Oct 2012
    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: 45
    Worldwide total number of subjects
    45
    EEA total number of subjects
    45
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    18
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Of the 45 patients screened, 25 were randomised, and 18 completed per protocol.

    Pre-assignment
    Screening details
    		 Moderate to severe stable COPD, GOLD stages 2 & 3, FEV1 30-80% predicted, FEV1/FVC <0·70, >10 pack years, O2 sats ≥92% on room air, no long term domiciliary oxygen, in sinus rhythm, no heart block on ECG. No oral corticosteroids in the past 3 months. No history of uncontrolled hypertension or heart failure (NHYA class III-IV).

    Pre-assignment period milestones
    Number of subjects started
    		 45
    Number of subjects completed
    		 25

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Did not meet inclusion criteria: 18
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Reason: Number of subjects
    		 Screen Failed in Error: 1
    Period 1
    Period 1 title
    Randomised Treatment (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
    Arm description
    		 Bisoprolol for 6 weeks, starting at 1.25 mg qd and uptitrating to a maximum of 5mg qd as tolerated. Uptitration was carried out as follows: Week 1: Bisoprolol 1.25 mg qd Week 2: Bisoprolol 2.5 mg qd Weeks 3-6: Bisoprolol 5.0mg qd Bisoprolol was given in conjunction with three levels of inhaled therapy: (a) triple: inhaled corticosteroid /long acting beta-agonist/long acting muscarinic antagonist (ICS+LABA+LAMA), (b) dual: ICS+LABA, (c) ICS alone. Measurements were made at baseline on no beta-blocker, and after each inhaled step while taking beta-blocker. Cross-over design – Participants received both IMPs (participated in both arms) during the course of the study
    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 was given for 6 weeks, starting at 1.25 mg qd and uptitrating to a maximum of 5mg qd as tolerated. Bisoprolol was given in conjunction with three levels of inhaled therapy as follows: Week 1 : Bisoprolol 1.25 mg qd + Fostair 100/6, 2 puffs bid via a spacer device + Spiriva 18μg od via Handihaler Week 2: Bisoprolol 2.5 mg qd + Fostair 100/6, 2 puffs bid via a spacer device + Spiriva 18μg od via Handihaler Week 3: Bisoprolol 5.0 mg qd + Fostair 100/6, 2 puffs bid via a spacer device + Spiriva 18μg od via Handihaler Week 4: Bisoprolol 5.0 mg qd + Fostair 100/6, 2 puffs bid via a spacer device + Spiriva 18μg od via Handihaler Week 5: Bisoprolol 5.0 mg qd + Fostair 100/6, 2 puffs bid via a spacer device Week 6: Bisoprolol 5.0 mg qd + Clenil Modulite 200μg, 2 puffs bid via a spacer device

    Arm title
    		 Carvedilol
    Arm description
    		 Carvedilol for 6 weeks starting at 3.125 mg bid and uptitrating to a maximum of 12·5 mg bid as tolerated. Uptitration was carried out as follows: Week 1: Carvedilol 3.125 mg bid Week 2: Carvedilol 6.25 mg bid Weeks 3-6: Carvedilol 12.5 mg bid Carvedilol was given in conjunction with three levels of inhaled therapy: (a) triple: inhaled corticosteroid /long acting beta-agonist/long acting muscarinic antagonist (ICS+LABA+LAMA), (b) dual: ICS+LABA, (c) ICS alone. Measurements were made at baseline on no beta-blocker, and after each inhaled step while taking beta-blocker. Cross-over design – Participants received both IMPs (participated in both arms) during the course of the study
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carvedilol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Carvedilol was given for 6 weeks, starting at 3.125 mg bid and uptitrating to a maximum of 12.5mg bid as tolerated. Carvedilol was given in conjunction with three levels of inhaled therapy as follows: Week 1 : Carvedilol 3.125 mg bid + Fostair 100/6, 2 puffs bid via a spacer device + Spiriva 18μg od via Handihaler Week 2: Carvedilol 6.25 mg bid + Fostair 100/6, 2 puffs bid via a spacer device + Spiriva 18μg od via Handihaler Week 3: Carvedilol 12.5 mg bid + Fostair 100/6, 2 puffs bid via a spacer device + Spiriva 18μg od via Handihaler Week 4: Carvedilol 12.5 mg bid + Fostair 100/6, 2 puffs bid via a spacer device + Spiriva 18μg od via Handihaler Week 5: Carvedilol 12.5 mg bid + Fostair 100/6, 2 puffs bid via a spacer device Week 6: Carvedilol 12.5 mg bid + Clenil Modulite 200μg, 2 puffs bid via a spacer device

    Number of subjects in period 1
    		Bisoprolol Carvedilol
    Started
    25
    25
    Completed
    18
    18
    Not completed
    7
    7
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    6
    6

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Randomised Treatment (overall period)
    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 (45). The number of subjects in the baseline period is the number who were then randomised into the study (25). Of these 25 subjects, 18 completed both arms of the cross-over trial and were able to be analysed.
    Reporting group values
    		 Randomised Treatment (overall period) Total
    Number of subjects
    		 25 25
    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)
    		 11 11
        From 65-84 years
    		 14 14
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 5 5
        Male
    		 20 20
    Subject analysis sets

    Subject analysis set title
    Completed Subjects
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Moderate to severe stable COPD, GOLD stages 2 & 3, FEV1 30-80% predicted, FEV1/FVC <0·70, >10 pack years, O2 sats ≥92% on room air, no long term domiciliary oxygen, in sinus rhythm, no heart block on ECG. No oral corticosteroids in the past 3 months. No history of uncontrolled hypertension or heart failure (NHYA class III-IV).

    Subject analysis sets values
    		 Completed Subjects
    Number of subjects
    18
    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)
    9
        From 65-84 years
    9
        85 years and over
    0
    Age continuous
    Units:
        
    ( )
    Gender categorical
    Units: Subjects
        Female
    3
        Male
    15

    End points

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    End points reporting groups
    Reporting group title
    Bisoprolol
    Reporting group description
    		 Bisoprolol for 6 weeks, starting at 1.25 mg qd and uptitrating to a maximum of 5mg qd as tolerated. Uptitration was carried out as follows: Week 1: Bisoprolol 1.25 mg qd Week 2: Bisoprolol 2.5 mg qd Weeks 3-6: Bisoprolol 5.0mg qd Bisoprolol was given in conjunction with three levels of inhaled therapy: (a) triple: inhaled corticosteroid /long acting beta-agonist/long acting muscarinic antagonist (ICS+LABA+LAMA), (b) dual: ICS+LABA, (c) ICS alone. Measurements were made at baseline on no beta-blocker, and after each inhaled step while taking beta-blocker. Cross-over design – Participants received both IMPs (participated in both arms) during the course of the study

    Reporting group title
    Carvedilol
    Reporting group description
    		 Carvedilol for 6 weeks starting at 3.125 mg bid and uptitrating to a maximum of 12·5 mg bid as tolerated. Uptitration was carried out as follows: Week 1: Carvedilol 3.125 mg bid Week 2: Carvedilol 6.25 mg bid Weeks 3-6: Carvedilol 12.5 mg bid Carvedilol was given in conjunction with three levels of inhaled therapy: (a) triple: inhaled corticosteroid /long acting beta-agonist/long acting muscarinic antagonist (ICS+LABA+LAMA), (b) dual: ICS+LABA, (c) ICS alone. Measurements were made at baseline on no beta-blocker, and after each inhaled step while taking beta-blocker. Cross-over design – Participants received both IMPs (participated in both arms) during the course of the study

    Subject analysis set title
    Completed Subjects
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Moderate to severe stable COPD, GOLD stages 2 & 3, FEV1 30-80% predicted, FEV1/FVC <0·70, >10 pack years, O2 sats ≥92% on room air, no long term domiciliary oxygen, in sinus rhythm, no heart block on ECG. No oral corticosteroids in the past 3 months. No history of uncontrolled hypertension or heart failure (NHYA class III-IV).

    Primary: Resistance at 5Hz (R5)

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    End point title
    		 Resistance at 5Hz (R5)
    End point description
    Baseline is after 2 week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA). LAMA= long acting muscarinic receptor antagonist.
    End point type
    Primary
    End point timeframe
    2 weeks
    End point values
    		 Bisoprolol Carvedilol
    Number of subjects analysed
    18
    18
    Units: kPa/L.s
    arithmetic mean (confidence interval 95%)
        baseline
    0.67 (0.52 to 0.82)
    0.67 (0.52 to 0.82)
        ICS/LABA/LAMA
    0.58 (0.47 to 0.69)
    0.61 (0.51 to 0.71)
        ICS/LABA
    0.62 (0.51 to 0.73)
    0.69 (0.58 to 0.8)
        ICS
    0.68 (0.59 to 0.77)
    0.71 (0.6 to 0.81)
    Statistical analysis title
    		 per protocol
    Statistical analysis description
    The study was powered on IOS at >80% to detect a 0·2 kPa/L.s difference in R5 with an SD of 0·23 kPa/L.s requiring a sample size of 18 completed patients per protocol using a cross-over design and alpha error of 0·05 (two-tailed). The data were checked for normality of distribution prior to analysis. Baseline values after run-in and washout were compared; having demonstrated no significant differences for treatment or sequence, the pooled baseline values were used for the purpose of subsequent c
    Comparison groups
    Carvedilol v Bisoprolol
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Secondary: FEV1

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    End point title
    		 FEV1
    End point description
    Baseline is after 2 week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA). LAMA= long acting muscarinic receptor antagonist.
    End point type
    Secondary
    End point timeframe
    2 weeks
    End point values
    		 Bisoprolol Carvedilol
    Number of subjects analysed
    18
    18
    Units: litre(s)
    arithmetic mean (confidence interval 95%)
        baseline
    1.5 (1.2 to 1.79)
    1.5 (1.2 to 1.79)
        ICS/LABA/LAMA
    1.53 (1.21 to 1.84)
    1.47 (1.16 to 1.78)
        ICS/LABA
    1.49 (1.21 to 1.84)
    1.37 (1.06 to 1.68)
        ICS
    1.34 (1.03 to 1.65)
    1.26 (0.94 to 1.59)
    No statistical analyses for this end point

    Secondary: Forced Vital Capacity (FVC)

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    End point title
    		 Forced Vital Capacity (FVC)
    End point description
    Baseline is after 2 week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA). LAMA= long acting muscarinic receptor antagonist.
    End point type
    Secondary
    End point timeframe
    2 weeks
    End point values
    		 Bisoprolol Carvedilol
    Number of subjects analysed
    18
    18
    Units: litre(s)
    arithmetic mean (confidence interval 95%)
        baseline
    3.4 (2.83 to 3.97)
    3.4 (2.83 to 3.97)
        ICS/LABA/LAMA
    3.58 (2.98 to 4.19)
    3.48 (2.9 to 4.07)
        ICS/LABA
    3.57 (2.94 to 4.21)
    3.32 (2.74 to 3.9)
        ICS
    3.17 (2.56 to 3.77)
    2.97 (2.38 to 3.57)
    No statistical analyses for this end point

    Secondary: Relaxed vital capacity (RVC)

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    End point title
    		 Relaxed vital capacity (RVC)
    End point description
    Baseline is after 2 week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA). LAMA= long acting muscarinic receptor antagonist.
    End point type
    Secondary
    End point timeframe
    2 weeks
    End point values
    		 Bisoprolol Carvedilol
    Number of subjects analysed
    18
    18
    Units: litre(s)
    arithmetic mean (confidence interval 95%)
        baseline
    3.56 (2.98 to 4.14)
    3.56 (2.98 to 4.14)
        ICS/LABA/LAMA
    3.73 (3.14 to 4.33)
    3.67 (3.06 to 4.28)
        ICS/LABA
    3.75 (3.19 to 4.31)
    3.54 (2.95 to 4.12)
        ICS
    3.37 (2.81 to 3.93)
    3.16 (2.57 to 3.75)
    No statistical analyses for this end point

    Secondary: Resistance at 20Hz (R20)

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    End point title
    		 Resistance at 20Hz (R20)
    End point description
    Baseline refers to the completion of a 2 week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA). LAMA= long acting muscarinic receptor antagonist.
    End point type
    Secondary
    End point timeframe
    2 weeks
    End point values
    		 Bisoprolol Carvedilol
    Number of subjects analysed
    18
    18
    Units: kPa/L.s
    arithmetic mean (confidence interval 95%)
        pre IMP baseline
    0.39 (0.34 to 0.45)
    0.39 (0.34 to 0.45)
        ICS/LAMA/LAMA
    0.38 (0.32 to 0.44)
    0.39 (0.34 to 0.44)
        ICS/LABA
    0.39 (0.34 to 0.44)
    0.38 (0.33 to 0.44)
        ICS
    0.37 (0.34 to 0.41)
    0.39 (0.33 to 0.44)
    No statistical analyses for this end point

    Secondary: AX

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    End point title
    		 AX
    End point description
    Baseline is after 2 week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA). LAMA= long acting muscarinic receptor antagonist.
    End point type
    Secondary
    End point timeframe
    2 weeks
    End point values
    		 Bisoprolol Carvedilol
    Number of subjects analysed
    18
    18
    Units: kPa/L
    arithmetic mean (confidence interval 95%)
        baseline
    3.01 (2.05 to 3.99)
    3.01 (2.05 to 3.99)
        ICS/LABA/LAMA
    2.6 (1.14 to 3.79)
    2.93 (1.92 to 3.94)
        ICS/LABA
    2.86 (1.8 to 3.91)
    3.86 (2.75 to 4.97)
        ICS
    3.89 (2.8 to 4.98)
    4.3 (3.34 to 5.25)
    No statistical analyses for this end point

    Secondary: X5

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    End point title
    		 X5
    End point description
    Baseline is after 2 week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA). LAMA= long acting muscarinic receptor antagonist.
    End point type
    Secondary
    End point timeframe
    2 weeks
    End point values
    		 Bisoprolol Carvedilol
    Number of subjects analysed
    18
    18
    Units: kPa/L.s
    arithmetic mean (confidence interval 95%)
        baseline
    -0.29 (-0.37 to -0.21)
    -0.29 (-0.37 to -0.21)
        ICS/LABA/LAMA
    -0.25 (-0.34 to 0.17)
    -0.28 (-0.37 to 0.2)
        ICS/LABA
    -0.28 (-0.35 to 0.21)
    -0.36 (-0.44 to 0.27)
        ICS
    -0.35 (-0.47 to -0.23)
    -0.38 (-0.46 to 0.3)
    No statistical analyses for this end point

    Secondary: Resting oxygen saturation (Sp02)

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    End point title
    		 Resting oxygen saturation (Sp02)
    End point description
    Baseline is after 2 week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA). LAMA= long acting muscarinic receptor antagonist.
    End point type
    Secondary
    End point timeframe
    2 weeks
    End point values
    		 Bisoprolol Carvedilol
    Number of subjects analysed
    18
    18
    Units: percent
    arithmetic mean (confidence interval 95%)
        baseline
    96 (96 to 97)
    96 (95 to 97)
        ICS/LABA/LAMA
    96 (95 to 97)
    96 (95 to 97)
        ICS/LABA
    96 (93 to 96)
    94 (91 to 96)
        ICS
    96 (95 to 97)
    96 (95 to 97)
    No statistical analyses for this end point

    Secondary: Exercise oxygen saturation (Sp02)

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    End point title
    		 Exercise oxygen saturation (Sp02)
    End point description
    Baseline is after 2 week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA). LAMA= long acting muscarinic receptor antagonist.
    End point type
    Secondary
    End point timeframe
    2 weeks
    End point values
    		 Bisoprolol Carvedilol
    Number of subjects analysed
    18
    18
    Units: percent
    arithmetic mean (confidence interval 95%)
        baseline
    94 (91 to 96)
    94 (91 to 96)
        ICS/LABA/LAMA
    93 (90 to 96)
    93 (90 to 95)
        ICS/LABA
    93 (90 to 95)
    94 (91 to 96)
        ICS
    93 (90 to 95)
    93 (90 to 95)
    No statistical analyses for this end point

    Secondary: Resting heart rate (HR)

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    End point title
    		 Resting heart rate (HR)
    End point description
    Baseline is after 2 week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA). LAMA= long acting muscarinic receptor antagonist.
    End point type
    Secondary
    End point timeframe
    2 weeks
    End point values
    		 Bisoprolol Carvedilol
    Number of subjects analysed
    18
    18
    Units: bpm
    arithmetic mean (confidence interval 95%)
        baseline
    75 (69 to 82)
    75 (69 to 82)
        ICS/LABA/LAMA
    62 (58 to 66)
    63 (59 to 67)
        ICS/LABA
    60 (56 to 64)
    64 (60 to 68)
        ICS
    60 (55 to 65)
    63 (61 to 66)
    No statistical analyses for this end point

    Secondary: Exercise heart rate (HR)

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    End point title
    		 Exercise heart rate (HR)
    End point description
    Baseline is after 2 week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA). LAMA= long acting muscarinic receptor antagonist.
    End point type
    Secondary
    End point timeframe
    2 weeks
    End point values
    		 Bisoprolol Carvedilol
    Number of subjects analysed
    18
    18
    Units: bpm
    arithmetic mean (confidence interval 95%)
        baseline
    91 (83 to 98)
    91 (83 to 98)
        ICS/LABA/LAMA
    69 (64 to 75)
    71 (67 to 74)
        ICS/LABA
    67 (62 to 72)
    67 (57 to 77)
        ICS
    67 (62 to 73)
    70 (67 to 74)
    No statistical analyses for this end point

    Secondary: Resting systolic blood pressure

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    End point title
    		 Resting systolic blood pressure
    End point description
    Baseline is after 2 week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA). LAMA= long acting muscarinic receptor antagonist.
    End point type
    Secondary
    End point timeframe
    2 weeks
    End point values
    		 Bisoprolol Carvedilol
    Number of subjects analysed
    18
    18
    Units: mmHg
    arithmetic mean (confidence interval 95%)
        baseline
    135 (129 to 142)
    135 (129 to 142)
        ICS/LABA/LAMA
    129 (120 to 138)
    127 (119 to 135)
        ICS/LABA
    127 (118 to 136)
    128 (121 to 138)
        ICS
    127 (119 to 134)
    132 (122 to 142)
    No statistical analyses for this end point

    Secondary: Exercise systolic blood pressure

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    End point title
    		 Exercise systolic blood pressure
    End point description
    Baseline is after 2 week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA). LAMA= long acting muscarinic receptor antagonist.
    End point type
    Secondary
    End point timeframe
    2 weeks
    End point values
    		 Bisoprolol Carvedilol
    Number of subjects analysed
    18
    18
    Units: mmHg
    arithmetic mean (confidence interval 95%)
        baseline
    151 (137 to 166)
    151 (137 to 166)
        ICS/LABA/LAMA
    151 (135 to 167)
    152 (137 to 166)
        ICS/LABA
    149 (132 to 164)
    145 (133 to 157)
        ICS
    145 (133 to 157)
    151 (138 to 163)
    No statistical analyses for this end point

    Secondary: Resting diastolic blood pressure

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    End point title
    		 Resting diastolic blood pressure
    End point description
    Baseline is after 2 week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA). LAMA= long acting muscarinic receptor antagonist.
    End point type
    Secondary
    End point timeframe
    2 weeks
    End point values
    		 Bisoprolol Carvedilol
    Number of subjects analysed
    18
    18
    Units: mmHg
    arithmetic mean (confidence interval 95%)
        baseline
    80 (76 to 84)
    80 (76 to 84)
        ICS/LABA/LAMA
    77 (71 to 83)
    75 (70 to 79)
        ICS/LABA
    72 (67 to 77)
    76 (70 to 81)
        ICS
    73 (68 to 78)
    78 (72 to 83)
    No statistical analyses for this end point

    Secondary: Exercise diastolic blood pressure

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    End point title
    		 Exercise diastolic blood pressure
    End point description
    Baseline is after 2 week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA). LAMA= long acting muscarinic receptor antagonist.
    End point type
    Secondary
    End point timeframe
    2 weeks
    End point values
    		 Bisoprolol Carvedilol
    Number of subjects analysed
    18
    18
    Units: mmHg
    arithmetic mean (confidence interval 95%)
        baseline
    86 (82 to 91)
    86 (82 to 91)
        ICS/LABA/LAMA
    83 (76 to 89)
    86 (81 to 91)
        ICS/LABA
    81 (75 to 87)
    81 (75 to 87)
        ICS
    83 (77 to 89)
    87 (82 to 91)
    No statistical analyses for this end point

    Secondary: 6 minute walk distance

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    End point title
    		 6 minute walk distance
    End point description
    Baseline is after 2 week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA). LAMA= long acting muscarinic receptor antagonist.
    End point type
    Secondary
    End point timeframe
    2 weeks
    End point values
    		 Bisoprolol Carvedilol
    Number of subjects analysed
    18
    18
    Units: meter
    arithmetic mean (confidence interval 95%)
        baseline
    495 (449 to 542)
    495 (449 to 542)
        ICS/LABA/LAMA
    470 (420 to 520)
    489 (449 to 542)
        ICS/LABA
    486 (435 to 536)
    484 (422 to 567)
        ICS
    469 (422 to 515)
    474 (416 to 532)
    No statistical analyses for this end point

    Secondary: St George's Respiratory Questionnaire (SGRQ)

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    End point title
    		 St George's Respiratory Questionnaire (SGRQ)
    End point description
    Baseline is after 2 week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA). LAMA= long acting muscarinic receptor antagonist.
    End point type
    Secondary
    End point timeframe
    2 weeks
    End point values
    		 Bisoprolol Carvedilol
    Number of subjects analysed
    18
    18
    Units: units
    arithmetic mean (confidence interval 95%)
        baseline
    33 (24 to 42)
    33 (24 to 42)
        ICS/LABA/LAMA
    34 (24 to 44)
    36 (27 to 45)
        ICS/LABA
    33 (24 to 42)
    34 (25 to 43)
        ICS
    36 (28 to 44)
    36 (26 to 45)
    No statistical analyses for this end point

    Secondary: Baseline Dyspnoea Index (BDI) & Transition Dyspnoea Index (TDI)

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    End point title
    		 Baseline Dyspnoea Index (BDI) & Transition Dyspnoea Index (TDI)
    End point description
    Baseline is after 2 week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA). LAMA= long acting muscarinic receptor antagonist.
    End point type
    Secondary
    End point timeframe
    2 weeks
    End point values
    		 Bisoprolol Carvedilol
    Number of subjects analysed
    18
    18
    Units: units
    arithmetic mean (confidence interval 95%)
        baseline
    6.7 (5.5 to 7.8)
    6.7 (5.5 to 7.8)
        ICS/LABA/LAMA
    0.83 (-0.24 to 1.69)
    0.22 (-0.82 to 1.27)
        ICS/LAMA
    -0.33 (-1.31 to 0.65)
    0.22 (-0.69 to 1.13)
        ICS
    -1.1 (-2.01 to 0.21)
    -0.83 (-1.92 to 0.25)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs and SAEs were recorded from the time a participant consented to join the study until their last study visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Completed Subjects
    Reporting group description
    		 -

    Serious adverse events
    		 Completed Subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 18 (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
    		 Completed Subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 18 (83.33%)
    Vascular disorders
    Poor circulation in fingers
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Surgical and medical procedures
    Dental Procedures (Crown)
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 18 (22.22%)
         occurrences all number
    4
    Headache
         subjects affected / exposed
    5 / 18 (27.78%)
         occurrences all number
    8
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    3
    Gastrointestinal disorders
    Upset stomach
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Hoarse voice
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    5 / 18 (27.78%)
         occurrences all number
    8
    Cough
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    3
    Wheezing
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    4
    Phlegm
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Nasal congestion
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Psychiatric disorders
    Panic attack
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Painful Lower Limb (foot/leg)
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    3
    Chest pain (muscular)
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Strained Back Muscle
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Joint Pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    5
    Infections and infestations
    Rhinovirus infection
         subjects affected / exposed
    7 / 18 (38.89%)
         occurrences all number
    8
    Chest infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Feb 2015
    REC Amendment - Amendment to notify REC of the use of a patient register as a source for recruiting participants.
    10 Dec 2015
    REC Amendment - Amendment to seek prospective approval of patient-facing documents.

    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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