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
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
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
|
|
||||||||||||||||
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.
|
|||||||||||||||
|
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
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
|
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
||||||||||
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.
|
|||||||||
|
||||||||||
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 |
|
||||||||||
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.
|
|||||||||
|
||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 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 |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
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 |