Back to resultsPreventing Adverse Cardiac Events in COPD
Primary Purpose
Chronic Obstructive Pulmonary Disease, Cardiovascular Diseases
Status
Active
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Bisoprolol
Placebo Oral Tablet
Sponsored by
About this trial
This is an interventional prevention trial for Chronic Obstructive Pulmonary Disease focused on measuring COPD
Eligibility Criteria
Inclusion Criteria:
Participants will be eligible for this study if they qualify on all of the following:
- Have provided written informed consent
- Have COPD defined by the 2019 Global Initiative for Chronic Obstructive Lung Disease (GOLD) diagnostic criteria
- Aged 40-85 years
- FEV1 ≥30% and ≤70% predicted post-bronchodilator
- FEV1/FVC <0.7 post-bronchodilator
- Have had a COPD exacerbation in the previous 12 months requiring oral corticosteroid, antibiotics, or both
- If taking maintenance OCS, dosage is stable and ≤10mg daily for 4 weeks prior to randomisation
- Resting SBP ≥100mmHg
- SBP and spirometry criteria must be met after the test dose of bisoprolol of 1.25mg
- (New Zealand only) A history of cardiovascular disease, including heart failure, ischaemic heart disease, tachyarrhythmias, and hypertension
Exclusion Criteria:
Participants will be ineligible for the study if they have any of the following:
- Concurrent therapy with any other β-blocker
- Resting HR <60bpm
- Unstable left HF (i.e. symptomatic and/or necessary change in management in the last 12 weeks, or in clinicians' opinion)
- Clinically significant pulmonary hypertension, which in the investigator's opinion would be a contraindication for β-blocker therapy
- Severe end-stage peripheral vascular disease
- 2nd or 3rd degree heart block
- Currently using or have been prescribed LTOT or resting saturated oxygen level <90% when stable
- Expected survival is less than 12 months, or in the investigator's opinion, the person has such unstable disease (of any type) that maintaining 12 months' participation would be unlikely
- Clinical instability since a MACE in the previous 12 weeks
- Lower respiratory tract infection or AECOPD within the last 8 weeks
- COPD not clinically stable as determined by the investigator
- In the clinician's view, have asthma-COPD overlap or co-existent asthma are present; or an improvement in FEV1 ≥400mL post-bronchodilator is observed on two occasions
- Females of child-bearing age and capability who are pregnant or breastfeeding or those in this group not using adequate birth control
- Coexistent illness which precludes participation in the study (poorly controlled diabetes, active malignancy)
- Severe end-stage liver disease defined by INR>1.3 and albumin<30g/L or portal hypertension/ascites
- High chance in the view of the treating physician that the potential participant will not adhere to study requirements
Sites / Locations
- Campbelltown Hospital
- Liverpool Hospital
- John Hunter Hospital & Hunter Medical Research Institute
- Concord Repatriation General Hospital
- Westmead Hospital
- Prince Charles Hospital
- Princess Alexandra Hospital
- Gold Coast University Hospital
- Fiona Stanley Hospital
- TrialsWest Pty Ltd
- Institute for Respiratory Health
- Greenlane Clinical Centre, Auckland District Health Board
- Middlemore Hospital
- University of Otago
- Dunedin Hospital
- Waikato Hospital
- Medical Research Institute of New Zealand
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Bisoprolol
Placebo
Arm Description
1.25, 2.5 or 5mg of bisoprolol daily
1.25, 2.5 or 5mg of matched placebo daily
Outcomes
Primary Outcome Measures
All-cause mortality
Hospitalisation for COPD exacerbation
Hospitalisation for primary cardiac cause (ischaemia, arrhythmia or heart failure)
Major Adverse Cardiovascular Event (MACE)
Major Adverse Cardiovascular Event (MACE) includes myocardial infarction, sudden death, cardiac death or a fatal event in system organ classes for cardiac and vascular disorders, and serious and non-serious stroke.
Secondary Outcome Measures
COPD exacerbation rate (annualised)
Exacerbations will be defined as worsening respiratory symptoms resulting in treatment with antibiotics or systemic glucocorticoids. Exacerbation severity will be graded (secondary outcome) according to the following scale:
i. moderate (requiring oral corticosteroids, antibiotics or both without hospital admission) ii. severe (requiring above treatment and hospital admission)
Time to first moderate-severe COPD Exacerbation
Severe (hospital admission) COPD exacerbation rate (annualised)
Number of events of composite (annualised) cardio-respiratory hospital admissions and MACE
Quality of life assessed by St George's Respiratory Questionnaire (SGRQ)
The SGRQ is a 50-item questionnaire developed to measure health status (quality of life) in patients with diseases of airways obstruction.
Scores are calculated for three domains:
Symptoms, Activity and Impacts (Psycho-social) as well as a total score.
Psychometric testing has demonstrated its repeatability, reliability and validity. Sensitivity has been demonstrated in clinical trials.
A minimum change in score of 4 units was established as clinically relevant after patient and clinician testing. The SGRQ has been used in a range of disease groups including asthma, chronic obstructive pulmonary disease (COPD) and bronchiectasis, and in a range of settings such as randomised controlled therapy trials and population surveys.
EuroQoL Group 5-5 Dimension self-report questionnaire (EQ-5D-5L) to assess health state utilities
EQ-5D-5L consists of 2pg: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS).
Five dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression.
Each dimension 5 levels: no problems, slight problems, moderate problems, severe problems, extreme problems.
Patient indicates their health state by ticking most appropriate statement in each of the five dimensions.
This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state.
EQ VAS records patient's self-rated health on a vertical visual analogue scale. Endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement.
Healthcare utilisation costs and Quality Adjusted Life Years (QALYs) evaluation of the treatment intervention
Mean differences in healthcare utilisation costs and Quality Adjusted Life Years between both treatment groups will be estimated.
Costs will be ascertained from participants and study records. Health care utilisation will be on the basis of self-reported GP and hospital attendances and changes in concomitant medication. Health state utilities will be estimated via the EQ-5D-5L and will be used to weight survival up to 24 months to determine Quality Adjusted Life Years.
Health status assessed by COPD Assessment Test (CAT)
Clinic spirometry: post-bronchodilator FEV1 (Forced Expiratory Volume) (L)
Clinic spirometry: % predicted post-bronchodilator
Hospital admissions for all respiratory causes
Hospital admissions for all cardiac causes
All cardiac causes includes ischaemia, arrhythmia, heart failure, acute arrhythmia, non-ST-elevation myocardial infarction, urgent revascularisation (stent/angioplasty/coronary artery bypass grafting), and MACE events (includes myocardial infarction, sudden death, cardiac death or a fatal event in system organ classes for cardiac and vascular disorders, and serious and non-serious stroke).
Total Number of cardiac events: MACE plus acute arrhythmia, Non-ST-elevation myocardial infarction (NSTEMI), urgent revascularisation (stent/angioplasty/Coronary artery bypass grafting [CABGs]) and clinically diagnosed heart failure episodes.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03917914
Brief Title
Preventing Adverse Cardiac Events in COPD
Official Title
Preventing Adverse Cardiac Events in Chronic Obstructive Pulmonary Disease
Study Type
Interventional
2. Study Status
Record Verification Date
May 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
June 30, 2020 (Actual)
Primary Completion Date
March 2025 (Anticipated)
Study Completion Date
March 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The George Institute
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
A double-blind, randomised controlled trial in participants with COPD to assess the efficacy of proactive treatment of cardiac risk in people with COPD. We hypothesise that treating known and undiagnosed CVD in COPD participants will improve both cardiac and respiratory outcomes.
Detailed Description
Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of global health-related morbidity and mortality. Heart disease in COPD is a known but neglected comorbidity and cardiovascular disease (CVD) accounts for 30-50% of deaths in COPD participants. Studies repeatedly show that CVD in COPD participants is under-recognised and under-treated yet participants with COPD are frequently excluded from clinical trials of drugs which reduce cardiac morbidity and mortality. This has led to under-treatment of CVD in COPD participants. A particular concern is low use of β-blockers. These have previously been considered to be contra-indicated in COPD and no RCTs have been conducted in this population. There is now observational evidence that cardioselective β-blockers are safe and may improve mortality, but this data is limited to retrospective analyses of cohorts of COPD participants. Contrary to previous concerns, retrospective analyses also suggest that cardioselective β-blockers may reduce the risk of COPD exacerbations. The proposed study will focus on treating CVD in COPD participants to reduce mortality and morbidity.
The study will be conducted in approximately 20 sites in Australia and New Zealand, and possibly 1-2 international sites. Participants with COPD will be randomised to one of two treatment arms in addition to receiving usual care for their COPD over the study duration of 24 months.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Obstructive Pulmonary Disease, Cardiovascular Diseases
Keywords
COPD
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
280 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Bisoprolol
Arm Type
Active Comparator
Arm Description
1.25, 2.5 or 5mg of bisoprolol daily
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
1.25, 2.5 or 5mg of matched placebo daily
Intervention Type
Drug
Intervention Name(s)
Bisoprolol
Intervention Description
As in arm description
Intervention Type
Drug
Intervention Name(s)
Placebo Oral Tablet
Intervention Description
As in arm description
Primary Outcome Measure Information:
Title
All-cause mortality
Time Frame
Baseline to 24 months
Title
Hospitalisation for COPD exacerbation
Time Frame
Baseline to 24 months
Title
Hospitalisation for primary cardiac cause (ischaemia, arrhythmia or heart failure)
Time Frame
Baseline to 24 months
Title
Major Adverse Cardiovascular Event (MACE)
Description
Major Adverse Cardiovascular Event (MACE) includes myocardial infarction, sudden death, cardiac death or a fatal event in system organ classes for cardiac and vascular disorders, and serious and non-serious stroke.
Time Frame
Baseline to 24 months
Secondary Outcome Measure Information:
Title
COPD exacerbation rate (annualised)
Description
Exacerbations will be defined as worsening respiratory symptoms resulting in treatment with antibiotics or systemic glucocorticoids. Exacerbation severity will be graded (secondary outcome) according to the following scale:
i. moderate (requiring oral corticosteroids, antibiotics or both without hospital admission) ii. severe (requiring above treatment and hospital admission)
Time Frame
Baseline to 24 months
Title
Time to first moderate-severe COPD Exacerbation
Time Frame
Baseline to 24 months
Title
Severe (hospital admission) COPD exacerbation rate (annualised)
Time Frame
Baseline to 24 months
Title
Number of events of composite (annualised) cardio-respiratory hospital admissions and MACE
Time Frame
Baseline to 24 months
Title
Quality of life assessed by St George's Respiratory Questionnaire (SGRQ)
Description
The SGRQ is a 50-item questionnaire developed to measure health status (quality of life) in patients with diseases of airways obstruction.
Scores are calculated for three domains:
Symptoms, Activity and Impacts (Psycho-social) as well as a total score.
Psychometric testing has demonstrated its repeatability, reliability and validity. Sensitivity has been demonstrated in clinical trials.
A minimum change in score of 4 units was established as clinically relevant after patient and clinician testing. The SGRQ has been used in a range of disease groups including asthma, chronic obstructive pulmonary disease (COPD) and bronchiectasis, and in a range of settings such as randomised controlled therapy trials and population surveys.
Time Frame
Baseline to 24 months
Title
EuroQoL Group 5-5 Dimension self-report questionnaire (EQ-5D-5L) to assess health state utilities
Description
EQ-5D-5L consists of 2pg: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS).
Five dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression.
Each dimension 5 levels: no problems, slight problems, moderate problems, severe problems, extreme problems.
Patient indicates their health state by ticking most appropriate statement in each of the five dimensions.
This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state.
EQ VAS records patient's self-rated health on a vertical visual analogue scale. Endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement.
Time Frame
Baseline to 24 months
Title
Healthcare utilisation costs and Quality Adjusted Life Years (QALYs) evaluation of the treatment intervention
Description
Mean differences in healthcare utilisation costs and Quality Adjusted Life Years between both treatment groups will be estimated.
Costs will be ascertained from participants and study records. Health care utilisation will be on the basis of self-reported GP and hospital attendances and changes in concomitant medication. Health state utilities will be estimated via the EQ-5D-5L and will be used to weight survival up to 24 months to determine Quality Adjusted Life Years.
Time Frame
Baseline to 24 months
Title
Health status assessed by COPD Assessment Test (CAT)
Time Frame
Baseline to 24 months
Title
Clinic spirometry: post-bronchodilator FEV1 (Forced Expiratory Volume) (L)
Time Frame
Baseline to 24 months
Title
Clinic spirometry: % predicted post-bronchodilator
Time Frame
Baseline to 24 months
Title
Hospital admissions for all respiratory causes
Time Frame
Baseline to 24 months
Title
Hospital admissions for all cardiac causes
Description
All cardiac causes includes ischaemia, arrhythmia, heart failure, acute arrhythmia, non-ST-elevation myocardial infarction, urgent revascularisation (stent/angioplasty/coronary artery bypass grafting), and MACE events (includes myocardial infarction, sudden death, cardiac death or a fatal event in system organ classes for cardiac and vascular disorders, and serious and non-serious stroke).
Time Frame
Baseline to 24 months
Title
Total Number of cardiac events: MACE plus acute arrhythmia, Non-ST-elevation myocardial infarction (NSTEMI), urgent revascularisation (stent/angioplasty/Coronary artery bypass grafting [CABGs]) and clinically diagnosed heart failure episodes.
Time Frame
Baseline to 24 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Participants will be eligible for this study if they qualify on all of the following:
Have provided written informed consent
Have COPD defined by the 2019 Global Initiative for Chronic Obstructive Lung Disease (GOLD) diagnostic criteria
Aged 40-85 years
FEV1 ≥30% and ≤70% predicted post-bronchodilator
FEV1/FVC <0.7 post-bronchodilator
Have had a COPD exacerbation in the previous 24 months requiring oral corticosteroid, antibiotics, or both
If taking maintenance OCS, dosage is stable and ≤10mg daily for 4 weeks prior to randomisation
Resting SBP ≥100mmHg
SBP and spirometry criteria must be met after the test dose of bisoprolol of 1.25mg
(New Zealand only) A history of cardiovascular disease, including heart failure, ischaemic heart disease, tachyarrhythmias, and hypertension
Exclusion Criteria:
Participants will be ineligible for the study if they have any of the following:
Concurrent therapy with any other β-blocker
Resting HR <60bpm
Unstable left HF (i.e. symptomatic and/or necessary change in management in the last 12 weeks, or in clinicians' opinion)
Clinically significant pulmonary hypertension, which in the investigator's opinion would be a contraindication for β-blocker therapy
Severe end-stage peripheral vascular disease
2nd or 3rd degree heart block
Currently using or have been prescribed LTOT or resting saturated oxygen level <90% when stable
Expected survival is less than 12 months, or in the investigator's opinion, the person has such unstable disease (of any type) that maintaining 12 months' participation would be unlikely
Clinical instability since a MACE in the previous 12 weeks
Lower respiratory tract infection or AECOPD within the last 8 weeks
COPD not clinically stable as determined by the investigator
In the clinician's view, have asthma-COPD overlap or co-existent asthma are present; or an improvement in FEV1 ≥400mL post-bronchodilator is observed on two occasions
Females of child-bearing age and capability who are pregnant or breastfeeding or those in this group not using adequate birth control
Coexistent illness which precludes participation in the study (poorly controlled diabetes, active malignancy)
Severe end-stage liver disease defined by INR>1.3 and albumin<30g/L or portal hypertension/ascites
High chance in the view of the treating physician that the potential participant will not adhere to study requirements
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Prof Christine Jenkins
Organizational Affiliation
The George Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Campbelltown Hospital
City
Campbelltown
State/Province
New South Wales
ZIP/Postal Code
2560
Country
Australia
Facility Name
Liverpool Hospital
City
Liverpool
State/Province
New South Wales
ZIP/Postal Code
2170
Country
Australia
Facility Name
John Hunter Hospital & Hunter Medical Research Institute
City
Newcastle
State/Province
New South Wales
ZIP/Postal Code
2305
Country
Australia
Facility Name
Concord Repatriation General Hospital
City
Sydney
State/Province
New South Wales
ZIP/Postal Code
2139
Country
Australia
Facility Name
Westmead Hospital
City
Sydney
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
Facility Name
Prince Charles Hospital
City
Brisbane
State/Province
Queensland
ZIP/Postal Code
4032
Country
Australia
Facility Name
Princess Alexandra Hospital
City
Brisbane
State/Province
Queensland
ZIP/Postal Code
4102
Country
Australia
Facility Name
Gold Coast University Hospital
City
Southport
State/Province
Queensland
ZIP/Postal Code
4215
Country
Australia
Facility Name
Fiona Stanley Hospital
City
Murdoch
State/Province
Western Australia
ZIP/Postal Code
6150
Country
Australia
Facility Name
TrialsWest Pty Ltd
City
Perth
State/Province
Western Australia
ZIP/Postal Code
6000
Country
Australia
Facility Name
Institute for Respiratory Health
City
Perth
State/Province
Western Australia
ZIP/Postal Code
6009
Country
Australia
Facility Name
Greenlane Clinical Centre, Auckland District Health Board
City
Auckland
ZIP/Postal Code
1142
Country
New Zealand
Facility Name
Middlemore Hospital
City
Auckland
ZIP/Postal Code
2025
Country
New Zealand
Facility Name
University of Otago
City
Christchurch
ZIP/Postal Code
8011
Country
New Zealand
Facility Name
Dunedin Hospital
City
Dunedin
ZIP/Postal Code
9054
Country
New Zealand
Facility Name
Waikato Hospital
City
Hamilton
ZIP/Postal Code
3240
Country
New Zealand
Facility Name
Medical Research Institute of New Zealand
City
Wellington
ZIP/Postal Code
6021
Country
New Zealand
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
34452971
Citation
Martin A, Hancox RJ, Chang CL, Beasley R, Wrobel J, McDonald V, Dobler CC, Yang IA, Farah CS, Cochrane B, Hillis GS, Scowcroft CP, Aggarwal A, Di Tanna GL, Balicki G, Galgey S, Jenkins C. Preventing adverse cardiac events (PACE) in chronic obstructive pulmonary disease (COPD): study protocol for a double-blind, placebo controlled, randomised controlled trial of bisoprolol in COPD. BMJ Open. 2021 Aug 27;11(8):e053446. doi: 10.1136/bmjopen-2021-053446.
Results Reference
derived
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Preventing Adverse Cardiac Events in COPD
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