Preventing Adverse Cardiac Events in COPD

Preventing Adverse Cardiac Events in Chronic Obstructive Pulmonary Disease

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Cardiovascular Diseases; Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Drug: Bisoprolol; Drug: Placebo Oral Tablet

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.

• Study Type: Interventional
• Enrollment (Actual): 280
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Dr Allison Humphries; Phone Number: +61 2 8052 4383; Email: ahumphries@georgeinstitute.org.au
• Study Contact Backup: Name: Zoe Calleja; Phone Number: +61 2 8052 4404; Email: ZCalleja@georgeinstitute.org.au

Study Locations

• Australia
  • New South Wales
    • Campbelltown, New South Wales, Australia, 2560
      • Campbelltown Hospital
    • Liverpool, New South Wales, Australia, 2170
      • Liverpool Hospital
    • Newcastle, New South Wales, Australia, 2305
      • John Hunter Hospital & Hunter Medical Research Institute
    • Sydney, New South Wales, Australia, 2145
      • Westmead Hospital
    • Sydney, New South Wales, Australia, 2139
      • Concord Repatriation General Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4102
      • Princess Alexandra Hospital
    • Brisbane, Queensland, Australia, 4032
      • Prince Charles Hospital
    • Southport, Queensland, Australia, 4215
      • Gold Coast University Hospital
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Fiona Stanley Hospital
    • Perth, Western Australia, Australia, 6000
      • TrialsWest Pty Ltd
    • Perth, Western Australia, Australia, 6009
      • Institute for Respiratory Health
• New Zealand
  • Auckland, New Zealand, 2025
    • Middlemore Hospital
  • Auckland, New Zealand, 1142
    • Greenlane Clinical Centre, Auckland District Health Board
  • Christchurch, New Zealand, 8011
    • University of Otago
  • Dunedin, New Zealand, 9054
    • Dunedin Hospital
  • Hamilton, New Zealand, 3240
    • Waikato Hospital
  • Wellington, New Zealand, 6021
    • Medical Research Institute of New Zealand

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 38 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Bisoprolol; 1.25, 2.5 or 5mg of bisoprolol daily	Drug: Bisoprolol; As in arm description
Placebo Comparator: Placebo; 1.25, 2.5 or 5mg of matched placebo daily	Drug: Placebo Oral Tablet; As in arm description

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospitalisation for COPD exacerbation		Baseline to 24 months
All-cause mortality	Composite outcome of the following that will be analysed using a win-ratio apprach according to clinical importance	Baseline to 24 months
Hospitalisation for primary cardiac cause (ischaemia, arrhythmia, heart failure or ischaemic stroke)		Baseline to 24 months
Moderate COPD exacerbation - not hospitalised by treated with oral corticosteroids/antibiotics or both		Baseline to 24 months
Cardiac Hospitalisation for cardiac cause other than ischemia, arrythmia or heart failure		Baseline to 24 months
Respiratory hospitalisation for a respiratory cause other than COPD exacerbation		Baseline to 24 months
Decrease in FEV1 or greatest FEV1% drop - largest decrease in FEV1 from post-bronchodiliator spirometry at baseline		Baseline to 24 months
Mild COPD exacerbation - treated with increased inhalers/inhaler technique/addition of theophylline		Baseline to 24 months
Higher SGRQ score (clinically important change >= 4)		Baseline to 12 and 24 months
Higher CAT score (clinically important change >= 2)		Baseline to 12 and 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to first moderate-severe COPD Exacerbation		Baseline to 24 months
Severe (hospital admission) COPD exacerbation rate (annualised)		Baseline to 24 months
Number of events of composite (annualised) cardio-respiratory hospital admissions and MACE		Baseline to 24 months
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.	Baseline to 24 months
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.	Baseline to 24 months
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.	Baseline to 24 months
Health status assessed by COPD Assessment Test (CAT)		Baseline to 24 months
Clinic spirometry: post-bronchodilator FEV1 (Forced Expiratory Volume) (L)		Baseline to 24 months
Clinic spirometry: % predicted post-bronchodilator		Baseline to 24 months
Hospital admissions for all respiratory causes		Baseline to 24 months
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).	Baseline to 24 months
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.		Baseline to 24 months
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		Baseline to 24 months
COPD exacerbation rate (annualised)		Baseline to 24 months

Collaborators and Investigators

• Sponsor: The George Institute
• Investigators: Principal Investigator: Prof Christine Jenkins, The George Institute

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 30, 2020
• Primary Completion (Estimated): March 1, 2025
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: April 10, 2019
• First Submitted That Met QC Criteria: April 15, 2019
• First Posted (Actual): April 17, 2019

Study Record Updates

• Last Update Posted (Estimated): January 18, 2024
• Last Update Submitted That Met QC Criteria: January 15, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: COPD
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Disease Attributes; Chronic Disease; Cardiovascular Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Bisoprolol
• Other Study ID Numbers: PACE in COPD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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