Clinical trial NCT03917914: Preventing Adverse Cardiac Events in COPD
Official title: Preventing Adverse Cardiac Events in Chronic Obstructive Pulmonary Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Obstructive Pulmonary Disease
Cardiovascular Diseases
Keywords: COPD
MACE
Lead sponsor: The George Institute
Sponsor class: OTHER
Collaborators: name: National Health and Medical Research Council, Australia
First posted: 2019-04-17
Enrollment: 280
Sex: ALL
Minimum age (years): 40
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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 23 sites in Australia, New Zealand, India and Sri Lanka. 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.

Eligibility criteria: Inclusion Criteria:

Participants will be eligible for this study if they qualify on all of the following:

1. Have provided written informed consent
2. Have COPD defined by the 2019 Global Initiative for Chronic Obstructive Lung Disease (GOLD) diagnostic criteria
3. Aged 40-85 years
4. FEV1 ≥30% and ≤70% predicted post-bronchodilator
5. FEV1/FVC \<0.7 post-bronchodilator
6. Have had a COPD exacerbation in the previous 24 months requiring oral corticosteroid, antibiotics, or both
7. If taking maintenance OCS, dosage is stable and ≤10mg daily for 4 weeks prior to randomisation
8. Resting SBP ≥100mmHg
9. SBP and spirometry criteria must be met after the test dose of bisoprolol of 1.25mg
10. (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:

1. Concurrent therapy with any other β-blocker
2. Resting HR \<60bpm
3. Unstable left HF (i.e. symptomatic and/or necessary change in management in the last 12 weeks, or in clinicians' opinion)
4. Clinically significant pulmonary hypertension, which in the investigator's opinion would be a contraindication for β-blocker therapy
5. Severe end-stage peripheral vascular disease
6. 2nd or 3rd degree heart block
7. Currently using or have been prescribed LTOT or resting saturated oxygen level \<90% when stable
8. 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
9. Clinical instability since a MACE in the previous 12 weeks
10. Lower respiratory tract infection or AECOPD within the last 8 weeks
11. COPD not clinically stable as determined by the investigator
12. 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
13. Females of child-bearing age and capability who are pregnant or breastfeeding or those in this group not using adequate birth control
14. Coexistent illness which precludes participation in the study (poorly controlled diabetes, active malignancy)
15. Severe end-stage liver disease defined by INR\>1.3 and albumin\<30g/L or portal hypertension/ascites
16. High chance in the view of the treating physician that the potential participant will not adhere to study requirements

Primary outcomes:
measure: All-cause mortality
timeFrame: Baseline to 24 months
measure: Hospitalisation for COPD exacerbation
timeFrame: Baseline to 24 months
measure: Hospitalisation for primary cardiac cause (ischaemia, arrhythmia, heart failure or ischaemic stroke)
timeFrame: Baseline to 24 months
measure: Moderate COPD exacerbation - not hospitalised by treated with oral corticosteroids/antibiotics or both
timeFrame: Baseline to 24 months
measure: Cardiac Hospitalisation for cardiac cause other than ischemia, arrythmia or heart failure
timeFrame: Baseline to 24 months
measure: Respiratory hospitalisation for a respiratory cause other than COPD exacerbation
timeFrame: Baseline to 24 months
measure: Decrease in FEV1 or greatest FEV1% drop - largest decrease in FEV1 from post-bronchodiliator spirometry at baseline
timeFrame: Baseline to 24 months
measure: Mild COPD exacerbation - treated with increased inhalers/inhaler technique/addition of theophylline
timeFrame: Baseline to 24 months
measure: Higher SGRQ score (clinically important change >= 4)
timeFrame: Baseline to 12 and 24 months
measure: Higher CAT score (clinically important change >= 2)
timeFrame: Baseline to 12 and 24 months
Secondary outcomes:
measure: Time to first moderate-severe COPD Exacerbation
timeFrame: Baseline to 24 months
measure: Severe (hospital admission) COPD exacerbation rate (annualised)
timeFrame: Baseline to 24 months
measure: Number of events of composite (annualised) cardio-respiratory hospital admissions and MACE
timeFrame: Baseline to 24 months
measure: Quality of life assessed by St George's Respiratory Questionnaire (SGRQ)
timeFrame: Baseline to 24 months
measure: EuroQoL Group 5-5 Dimension self-report questionnaire (EQ-5D-5L) to assess health state utilities
timeFrame: Baseline to 24 months
measure: Healthcare utilisation costs and Quality Adjusted Life Years (QALYs) evaluation of the treatment intervention
timeFrame: Baseline to 24 months
measure: Health status assessed by COPD Assessment Test (CAT)
timeFrame: Baseline to 24 months
measure: Clinic spirometry: post-bronchodilator FEV1 (Forced Expiratory Volume) (L)
timeFrame: Baseline to 24 months
measure: Clinic spirometry: % predicted post-bronchodilator
timeFrame: Baseline to 24 months
measure: Hospital admissions for all respiratory causes
timeFrame: Baseline to 24 months
measure: Hospital admissions for all cardiac causes
timeFrame: Baseline to 24 months
measure: 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.
timeFrame: Baseline to 24 months
measure: Time to a composite outcome (includes any) of: all-case mortality; hospitalisation for COPD exacerbation, hospitalisation for primary cardiac cause (arrytmmia, ischaemia or heart failure) or MACE
timeFrame: Baseline to 24 months
measure: COPD exacerbation rate (annualised)
timeFrame: Baseline to 24 months
Other outcomes:
Locations:
city: Campbelltown
country: Australia
facility: Campbelltown Hospital
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Newcastle
country: Australia
facility: John Hunter Hospital & Hunter Medical Research Institute
state: New South Wales
city: Sydney
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Prince Charles Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Southport
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Washington
city: Perth
country: Australia
facility: TrialsWest Pty Ltd
state: Washington
city: Perth
country: Australia
facility: Institute for Respiratory Health
state: Washington
city: Rohtak
country: India
facility: Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences
state: Haryana
city: Bangalore
country: India
facility: St John's Medical College Hospital
city: Chandigarh
country: India
facility: Postgraduate Institute of Medical Education and Research
city: New Delhi
country: India
facility: All India Institute of Medical Sciences
city: Auckland
country: New Zealand
facility: Middlemore Hospital
city: Christchurch
country: New Zealand
facility: University of Otago
city: Dunedin
country: New Zealand
facility: Dunedin Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Wellington
country: New Zealand
facility: Medical Research Institute of New Zealand
city: Colombo
country: Sri Lanka
facility: Central Chest Clinic - Borella
city: Colombo
country: Sri Lanka
facility: Central Chest Clinic
city: Kandy
country: Sri Lanka
facility: Kandy National Hospital
city: Welisara
country: Sri Lanka
facility: National Institute of Respiratory Diseases
Study officials:
affiliation: The George Institute
name: Prof Christine Jenkins
role: PRINCIPAL_INVESTIGATOR
References:
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.