Home » Trials » SLCTR/2021/033


Preventing Adverse Cardiac Events (PACE) in Chronic Obstructive Pulmonary Disease (COPD)

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SLCTR Registration Number

SLCTR/2021/033


Date of Registration

19 Nov 2021

The date of last modification

Nov 18, 2021



Application Summary


Scientific Title of Trial

Preventing Adverse Cardiac Events (PACE) in Chronic Obstructive Pulmonary Disease (COPD)


Public Title of Trial

A double-blind, placebo controlled, randomised trial in participants with COPD to assess the efficacy of proactive treatment with bisoprolol of cardiac risk in people with COPD.


Disease or Health Condition(s) Studied

Respiratory disease


Scientific Acronym

PACE in COPD


Public Acronym

PACE in COPD


Brief title

Preventing Adverse Cardiac Events in COPD


Universal Trial Number

U1111-1270-3082


Any other number(s) assigned to the trial and issuing authority

NCT03917914


Trial Details


What is the research question being addressed?

What is the efficacy of a cardio-selective beta-blocker (bisoprolol) taken in addition to usual care in participants with chronic obstructive pulmonary disease (COPD) over 24 months to reduce combined all-cause mortality, cardiac and respiratory hospital admissions and Major Adverse Cardiovascular Event (MACE) compared to placebo?


Type of study

Interventional


Study design

Allocation

Randomized controlled trial


Masking

Double blinded : Participants, Investigators, Healthcare providers, Outcome assessors


Control

Placebo


Assignment

Parallel


Purpose

Prevention


Study Phase

Phase 3


Intervention(s) planned

Study Setting: National Hospital Sri Lanka, Colombo 08 National Hospital for Respiratory Diseases, Welisara Kandy National Hopital, Kandy This is a Phase III, randomized, double blind, placebo controlled, multi-center, multi-country study to assess the efficacy of proactive treatment of cardiac risk in people with COPD. Participants will be screened for eligibility criteria and then randomized in a 1:1 ratio to one of the two treatment arms, in addition to receiving usual care for their COPD over the study duration of 24 months. Participants will receive either 1.25-5 mg Bisoprolol once daily or 1.25-5 mg Matched placebo (constitute of ProSolv powder) once daily. Randomisation will occur using a secure web-based randomisation system developed and maintained by the study sponsor, using the IBM Clinical Development electronic data capture software. Treatment allocation will be determined by computer-generated random numbers and will be fully automated via a password-protected encrypted website interface. The randomisation list will be concealed and generated centrally using a random combination of 4 by 6 permuted blocks within each stratum. Participants will be stratified for smoking (current or not) and clinical history of cardiac disease requiring current treatment. Up titration of study medication will be undertaken as recommended in the study protocol. From baseline to Visit 2 (4 Weeks), participants will be taking a daily dose of half a tablet of study medication (1.25mg bisoprolol or placebo) once daily. At the 4-week safety visit participants will be up-titrated to one whole tablet (2.5mg bisoprolol or placebo) once daily, provided they have not experienced any of the adverse events (AEs) given in the study protocol. At Visit 3 (12 Weeks) if the participant is not experiencing any AEs as outlined in the study protocol, the dose of study medication will be increased to two whole tablets (5mg bisoprolol or placebo) once daily. If any AEs have occurred, the lower will be maintained until review at the next visit. If any AEs persist throughout the study, the dosage will be reduced as per the study protocol. All dose changes are subject to investigator’s discretion. If between visits, participants experience symptoms suggesting blocker side-effects (light-headedness or falls, other manifestations of hypotension, extreme fatigability, or apparent bronchoconstriction without a clear trigger), their study medication dose will be down-titrated by the investigator. The intervention treatment will continue for 24 months.


Inclusion criteria

  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 (both male and female)
  4. Forced Expiratory Volume in one second (FEV1) ?30% and ?70% predicted post-bronchodilator
  5. FEV1/Forced Vital Capacity (FVC) <0.7 post-bronchodilator
  6. Have had a COPD exacerbation in the previous 12 months requiring oral corticosteroid, antibiotics, or both
  7. If taking maintenance oral corticosteroids (OCS), dosage is stable and ?10mg daily for 4 weeks prior to randomisation
  8. Resting systolic blood pressure (SBP) ?100mmHg
  9. SBP and spirometry criteria must be met after the test dose of bisoprolol of 1.25mg.

Exclusion criteria

  1. Concurrent therapy with any other –? blocker
  2. Resting heart rate (HR) <60bpm
  3. Unstable left HF (i.e. symptomatic and/or necessary change in management in the last 12 weeks, or in investigator’s opinion)
  4. Clinically significant pulmonary hypertension, which in the investigator’s opinion would be a contra-indication for ? -blocker therapy
  5. Severe end-stage peripheral vascular disease
  6. 2nd or 3rd degree heart block
  7. Currently using or have been prescribed long-term oxygen therapy (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 major adverse cardiac event (MACE) in the previous 12 weeks
  10. Lower respiratory tract infection or AECOPD within the last 4 weeks
  11. COPD not clinically stable as determined by the investigator
  12. In the investigator’s opinion, 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 (e.g. 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 opinion of the investigator that the potential participant will not adhere to study requirements.


Primary outcome(s)

1.

All-cause mortality

[

Baseline to 24 months

]
2.

Hospitalisation for COPD exacerbation

[

Baseline to 24 months

]
3.

Hospitalisation for primary cardiac cause (ischaemia, arrhythmia or heart failure)

[

Baseline to 24 months

]
4.

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.

[

Baseline to 24 months

]

Secondary outcome(s)

1.

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)

[

Baseline to 24 months

]
2.

Time to first moderate-severe COPD Exacerbation

[

Baseline to 24 months

]
3.

Severe (hospital admission) COPD exacerbation rate (annualised)

[

Baseline to 24 months

]
4.

Number of events of composite (annualised) cardio-respiratory hospital admissions and MACE.

[

Baseline to 24 months

]
5.

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

]
6.

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

]
7.

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

]
8.

Health status assessed by COPD Assessment Test (CAT)

[

Baseline to 24 months

]
9.

Clinic spirometry: post-bronchodilator FEV1 (Forced Expiratory Volume) (L)

[

Baseline to 24 months

]
10.

Clinic spirometry: % predicted post-bronchodilator

[

Baseline to 24 months

]
11.

Hospital admissions for all respiratory causes.

[

Baseline to 24 months

]
12.

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

]
13.

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

]

Target number/sample size

globally 1164, in Sri Lanka 80 (40 in each arm)


Countries of recruitment

Australia, India, New Zealand


Anticipated start date

2021-12-01


Anticipated end date

2024-12-01


Date of first enrollment


Date of study completion


Recruitment status

Pending


Funding source

National Health and Medical Research Council GPO Box 1421 Canberra ACT 2601 Tel: +61 2 6217 9000 Email: nhmrc@nhmrc.gov.au. Health Research Council of New Zealand PO Box 5541, Victoria Street West, Auckland 1142 Tel: 09 303 5200 Email: i


Regulatory approvals

Pending



State of Ethics Review Approval


Status

Approved


Date of Approval

2021-10-11


Approval number

P/127/09/2021


Details of Ethics Review Committee

Name: Ethics Review Committee, Faculty of Medicine, University of Kelaniya
Institutional Address:Ethics Review Committee, Faculty of Medicine, University of Kelaniya, P.O Box 6, Thalagolla Road, Ragama, Sri Lanka
Telephone:+94 11 2961267
Email: ercmed@kln.ac.lk

Contact & Sponsor Information


Contact person for Scientific Queries/Principal Investigator

Prof. Channa Ranasinha
Specialist Chest Physician
Department of Pharmacology, Faculty of Medicine, University of Kelaniya, Ragama.
+94 11 296 1139
+94 777 449 777

Channa.ranasinha@gmail.com

Contact Person for Public Queries

Prof. Channa Ranasinha
Specialist Chest Physician
Department of Pharmacology, Faculty of Medicine, University of Kelaniya, Ragama.
+94 11 296 1139
+94 777 449 777

Channa.ranasinha@gmail.com


Primary study sponsor/organization

The George Institute for Global Health

Level 5, 1 King St Newtown NSW 2042 Australia
Tel: +61 2 8052 4300
Fax: +61 2 8052 4301

Secondary study sponsor (If any)

The University of Otago

The University of Otago Dunedin New Zealand
+64 3 4797000

university@otago.ac.nz

Trial Completion details


Do the investigators plan to share identified individual clinical trial participant-level data (IPD)?

No


IPD sharing plan description


Study protocol available

Yes


Protocol version and date

Version 07, 25 Feb 2021



Results summary available

No


Date of posting results


Date of study completion


Final sample size


Date of first publication


Link to results


Brief summary of results