Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000372583
Ethics application status
Approved
Date submitted
7/03/2024
Date registered
28/03/2024
Date last updated
28/03/2024
Date data sharing statement initially provided
28/03/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Exercise, immunity and vaccination in chronic obstructive pulmonary disease (COPD)
Scientific title
Exercise as an immunomodulatory intervention and adjuvant to vaccination in people with COPD: feasibility randomised controlled trial
Secondary ID [1] 311692 0
Protocol number: 73014
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Obstructive Pulmonary Disease 333154 0
Condition category
Condition code
Respiratory 329852 329852 0 0
Chronic obstructive pulmonary disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: Exercise training

Participants will undergo a standard outpatient pulmonary rehabilitation program or a telerehabilitation program at the Alfred Hospital in Melbourne. Decision on type of program will be based on participant preference or restrictions on face-to-face services at Alfred Health due to COVID-19. Both programs involve 8 weeks of twice-weekly supervised sessions with health professionals experienced in the delivery of pulmonary rehabilitation.

Participants will undertake at least 30 minutes of lower limb aerobic training each session, which may be completed in shorter intervals if continuous training is limited by symptoms (e.g. 3 × 10 minutes). The training will consist of cycling on a cycle ergometer at a work rate equivalent to a Borg dyspnoea score of 3-4, which will be predicted from the baseline six-minute-walk-test (6MWT) in accordance with our previous research and published equations. Cycle training will be progressed by 5–15 % of the initial workload each week, aiming to maintain a Borg dyspnoea score of 3-4. For those receiving standard outpatient pulmonary rehabilitation this cycling will take place in groups of 8-12 at the Department of Physiotherapy of Alfred Health.

For those receiving telerehabilitation program, participants will provided with all necessary equipment to complete the 8-week rehabilitation period at home. The telerehabilitation equipment ‘kit’ comprises of a step-through exercise bike to maximise safety (Bodyworkx A915), a 4G enabled tablet computer (Apple iPad, Apple, Cupertino, California, USA) with mobile data, fixed to a stand for video conferencing, and a pulse oximeter (Nonin Palmsat 2500A; Nonin Medical, Plymouth, Minnesota, USA) to monitor peripheral oxygen saturation and pulse rate during training and at rest. Their initial exercise training session will be undertaken during a home-visit with an Alfred Health physiotherapist. After the initial home-visit, the remaining 15 telerehabilitation sessions will be conducted in a virtual group of up to 6 participants. At the conclusion of the 8-week rehabilitation period the telerehabilitation equipment ‘kit’ will be removed from the participant's home by Alfred staff. The physiotherapist will conduct all telerehabilitation sessions from a closed office in Alfred Health equipped with a laptop computer and large display screen in line with standard delivery of this clinical service.

Each rehabilitation session (outpatient rehabilitation or telerehabilitation) will also include 30 minutes of resistance exercise. Resistance training will be prescribed as tolerated, to achieve 8–12 repetitions for 3 sets of each exercise. Resistance training for the upper and lower limbs will be prescribed using functional activities. A minimum of four exercises, two each for the upper limb (e.g. wall push-ups, upright row, shoulder press) and lower limb (e.g. squats, sit-to-stand, step-ups), will be prescribed. Once able to perform three sets of 12 repetitions comfortably, weight will be increased. For lower limb exercises, this constituted the addition of hand weights or increasing squat depth as appropriate. Similar to the cycling component, participants completing the rehabilitation at the hospital will complete resistance exercise using equipment at the hospital. For participants in the telerehabilitation group, strength training will utilise appropriate and easily available household items (e.g. tins of soup or bags of rice) to substitute for free weights.

All participants will be encouraged to perform an additional three unsupervised exercise sessions each week (i.e. on different days to the supervised twice-weekly sessions), which will be documented in a home exercise diary and reviewed weekly by the supervising clinician. Participants will be prescribed walking up to 30 minutes daily at the same pace as during the pulmonary rehabilitation program (Borg Dyspneoa score of 3-4). Resistance exercise will also be encouraged in these unsupervised sessions (three days per week) with similar circuit of exercises that are performed during the pulmonary rehabilitation program for up to 30 minutes. Participants receiving telerehabilitation will be free to use the provided equipment during these additional unsupervised sessions. At the end of the 8 weeks participants will be encouraged to continue unsupervised exercise, particularly for the remaining duration of the follow up.


Arm 2: Exercise training + acute exercise
In addition to the 8 weeks of exercise training (described above), participants will complete a single exercise session immediately after vaccination corresponding to the intensity (Borg Dyspneoa score of 3-4) and modality (aerobic and resistance) of the exercise training. This will take place at the Department of Physiotherapy of Alfred Hospital as one-on-one or in groups subject to availability of staff and timing of recruitment of participants. The intention will be to build on the 8 weeks of exercise training by achieving 90 minutes of exercise in this session (e.g. 30-60 minutes of walking and cycling and 30-60 minutes of resistance exercise subject to exercise tolerance) all at a Borg Dyspneoa score of 3-4)


Vaccination: all participants
Given the nature of this study, interventions and comparator treatment arms of the trial will be timed according to the availability of the vaccines. As part of standard care for people with COPD, all participants will receive a single dose of the annual Southern Hemisphere quadrivalent inactivated influenza vaccine or a COVID-19 booster. For the exercise training only group, vaccination will take place on the day following the final exercise session. For the control group, this will occur at the same point . The exercise training only group and the standard care group will receive vaccination at their usual health care facility or pharmacy. They will be instructed to go about their daily routine but avoid exercise on the day of the vaccination.

The exercise training + acute exercise group will receive their vaccination on the day following the final exercise session of the training program but this may be administered by a respiratory nurse at the Alfred hospital (instead of their usual health care facility or pharmacy) in order for participants to complete their 90 minutes of exercise within 30 minutes of receiving the vaccine where possible. Any vaccination by a respiratory nurse at the Alfred Hospital will take place in accordance with usual practice at Alfred Health including under the supervision of a Respiratory Physician where required.

Subject to Australian Technical Advisory Group on Immunisation (ATAGI) advice at the time of vaccination, influenza and COVID-19 vaccine may be co-administered (given on the same day). We will include participants who are yet to receive their influenza, COVID-19 booster or both.
Intervention code [1] 328155 0
Rehabilitation
Comparator / control treatment
Arm 3; Control
Participants will receive 8 weeks of standard care (i.e. no exercise intervention). The control participants will be permitted to enrol on to a pulmonary rehabilitation program or any other exercise program following vaccination. For any participants recruited from the waiting list of pulmonary rehabilitation, they in effect will remain on the waiting list until receipt of the vaccination.
Control group
Active

Outcomes
Primary outcome [1] 337622 0
This will be assessed as a co-primary outcome of Recruitment and Completeness of follow-up
Timepoint [1] 337622 0
End of trial follow-up of all participants
Secondary outcome [1] 432559 0
Adverse events
Timepoint [1] 432559 0
Week 2 (2 weeks following vaccination)
Secondary outcome [2] 432560 0
Antibody titres to influenza strains or COVID-19 variants
Timepoint [2] 432560 0
Week 0 (Before vaccination) and Week 1, 4 and 24 (1 - 24 weeks following vaccination)
Secondary outcome [3] 432561 0
Plasma antigen specific IgG
Timepoint [3] 432561 0
Week 1 and 4 (1 - 4 weeks following vaccination)
Secondary outcome [4] 432562 0
Antibody secreting B cells
Timepoint [4] 432562 0
Week 0 (before vaccination) and Week 1 (1 week following vaccination)
Secondary outcome [5] 432563 0
Antigen specific memory B cells
Timepoint [5] 432563 0
Week 0 (before vaccination) and Week 4 and 24 (4-24 weeks after vaccination)
Secondary outcome [6] 432564 0
Antigen specific CD4+ T memory cells
Timepoint [6] 432564 0
Week 0 (before vaccination) and Week 4 and 24 (4 - 24 weeks after vaccination)
Secondary outcome [7] 432565 0
Antigen specific CD8+ memory cells
Timepoint [7] 432565 0
Week 0 (before vaccination) and Week 4 and 24 (4 - 24 weeks after vaccination)
Secondary outcome [8] 432566 0
Salivary secretory IgA
Timepoint [8] 432566 0
Week -9 (baseline) and Week 0 (before vaccination)
Secondary outcome [9] 433111 0
Ex vivo virus-stimulated production of granzyme B
Timepoint [9] 433111 0
Week -9 (baseline), Week 0 (before vaccination), Week 4 (4 weeks following vaccination)
Secondary outcome [10] 433112 0
Ex vivo virus-stimulated production of cytokines
Timepoint [10] 433112 0
Week -9 (baseline), Week 0 (before vaccination), Week 4 (4 weeks following vaccination)

Eligibility
Key inclusion criteria
- Adults (18 years or over)
- Diagnosis of COPD (according to Global Initiative for Chronic Obstructive Lung Disease criteria: post bronchodilator FEV1/FVC ratio <0.70
- Disease severity classified as either GOLD C or D according to 2017 guidelines (Exacerbations in previous 12 months: greater than or equal to 2 courses of systemic corticosteroids and/or antibiotics or greater than or equal to 1 hospital admission
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Already vaccinated with the influenza vaccine in the study season or not eligible for COVID-19 booster.
- Any history of allergies, suspected hypersensitivity and/or contraindication to vaccines (e.g. egg protein allergy)
- Participation in another clinical trial (use of investigational product or device)
- Current enrolled on a structured physical activity programme or reports completing greater than or equal to 150 minutes of moderate intensity activity or greater than or equal to 75 minutes of vigorous intensity activity per week
- Comorbidities that preclude exercise training
- Clinical instability, defined as experiencing a COPD exacerbation less than 4 weeks prior to baseline visit, as indicated by treatment with systemic corticosteroids and/or antibiotics and/or hospitalisation
- Diagnosis of asthma and/or other relevant lung disease (e.g. history of primary or clinically significant bronchiectasis, cystic fibrosis, bronchiolitis, lung resection, lung cancer, interstitial lung disease [e.g. fibrosis, silicosis, sarcoidosis], active tuberculosis)
- Known alpha-1-antitrypsin deficiency
- Primary immunodeficiency (e.g. common variable immune deficiency, agammaglobulinemia) or severe immunocompromised conditions (active haematological malignancy, long-term haemodialysis or peritoneal dialysis, advanced or untreated HIV)
- Currently taking immunosuppressive medications except inhaled corticosteroids (e.g. prednisolone, cyclosporine, chemotherapy)
- Not enrolled in Medicare
- Unable to read and speak English

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will involve contacting the holder of the allocation schedule who will be independent of the research team.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation with stratification by age (less than or greater than or equal to 65 years) participants via a web-based tool.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety
Statistical methods / analysis
Sample size
We are adopting a recently published framework for informing the progression of this feasibility trial to a definitive trial. This comprises of hypothesis testing of the two co-primary (feasibility) outcomes alongside a traffic light system. There are two progression criteria for this trial:

i) trial will be considered feasible if at least 30% of the participants screened as eligible are recruited to the trial, with the trial considered not feasible if recruitment uptake is less than 15%
ii) trial will be considered feasible if at least 80% of the participants who start the study complete the study protocol, with 60% indicating the main trial is not feasible.

In order to meet these criteria using binomial exact test with 90% power and one-sided 5% alpha, we will need i) for recruitment, the number of people screened for eligibility to be 64; and ii) for completeness of follow-up, number randomised to be 45. Powering at 90% across the two co-primary outcomes will ensure a collective power of 81% (i.e. 0.92), which we consider to be reasonable for this trial. We base our sample size on the primary outcome that requires the greatest number of participants (completeness of follow up). The expected recruitment rate of (30% of 64 screened) would not provide an adequate sample size for hypothesis testing of completeness of follow up. Considering the allocation ratio (1:1:1) for our trial, we will recruit an n of 15 for all groups.

Data analysis
The co-primary outcomes (measures of feasibility) will be analysed and interpreted in order to inform progression to a definitive main trial in accordance with estimates representing thresholds for statistical significance (recruitment uptake: 23.4%; completeness of follow-up 73.3%).

Study estimates for the primary outcomes that fall in red, amber and green zones will be considered unacceptable (statistically non-significant), potentially acceptable (with or without statistical significance) and acceptable (statistically significant) respectively. The research team will decide on overall progression to the main trial using the worst performing criterion. Red will be an indication of STOP and the team will not proceed to the main trial. Green will be an indication of GO and team can progress to the main trial without any changes. Amber indicates changes to the trial design are necessary before progressing to the main trial.

As this is a feasibility study, analyses of all other outcomes will be treated as exploratory. Numerical outcome data will be reported descriptively and presented using numbers and proportions for categorical data, means and standard deviations, medians and interquartile ranges for continuous data. Between group (vaccine-induced immune responses) and within group (immunity before and after exercise training) comparisons will be made using appropriate statistical tests (parametric or non-parametric tests depending on normal distribution).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
5/04/2024
Actual
Date of last participant enrolment
Anticipated
3/10/2025
Actual
Date of last data collection
Anticipated
3/07/2026
Actual
Sample size
Target
45
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 26246 0
The Alfred - Melbourne
Recruitment postcode(s) [1] 42214 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 316020 0
University
Name [1] 316020 0
Monash University
Country [1] 316020 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Country
Australia
Secondary sponsor category [1] 318173 0
None
Name [1] 318173 0
Address [1] 318173 0
Country [1] 318173 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314844 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 314844 0
https://www.alfredhealth.org.au/research/ethics-research-governance
Ethics committee country [1] 314844 0
Australia
Date submitted for ethics approval [1] 314844 0
Approval date [1] 314844 0
16/06/2022
Ethics approval number [1] 314844 0
151/22

Summary
Brief summary
A sudden worsening of respiratory symptoms in Chronic obstructive Pulmonary Disease (COPD) is called a flare up. These flare ups are caused by respiratory infections. Exercise programs can reduce the number of people experiencing a flare up of COPD by as much as 40%. We don’t yet know why this happens.

Key reasons why people with COPD have flare ups include weakened body defences (immune system) against respiratory infections. Measuring responses to safe, but foreign substances like vaccines provide one of the best ways to test how well the immune system defends against infections.

We intend to find out if it is possible to use the flu or COVID-19 booster vaccines to understand how exercise changes the immune system of people with COPD.

The project will recruit 45 volunteers with COPD. The project will split the volunteers into 3 groups:
1) 8 week exercise program before receiving a flu or COVID-19 vaccine;
2) 8 week exercise program before receiving a flu or COVID-19 vaccine and a single exercise session immediately after vaccination;
3) no exercise before or after flu or COVID-19 vaccine.

We will collect blood and saliva from volunteers at the start of the project, before vaccination and on three occasions after vaccination.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 132902 0
Dr Arwel Jones
Address 132902 0
Respiratory Research@Alfred, School of Translational Medicine, Monash University, Level 6 Alfred Centre, 99 Commercial Road, Melbourne, VIC 3004
Country 132902 0
Australia
Phone 132902 0
+61 3 9903 0842
Fax 132902 0
Email 132902 0
arwel.jones@monash.edu
Contact person for public queries
Name 132903 0
Arwel Jones
Address 132903 0
Respiratory Research@Alfred, School of Translational Medicine, Monash University, Level 6 Alfred Centre, 99 Commercial Road, Melbourne, VIC 3004
Country 132903 0
Australia
Phone 132903 0
+61 3 9903 0842
Fax 132903 0
Email 132903 0
arwel.jones@monash.edu
Contact person for scientific queries
Name 132904 0
Arwel Jones
Address 132904 0
Respiratory Research@Alfred, School of Translational Medicine, Monash University, Level 6 Alfred Centre, 99 Commercial Road, Melbourne, VIC 3004
Country 132904 0
Australia
Phone 132904 0
+61 3 9903 0842
Fax 132904 0
Email 132904 0
arwel.jones@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data underlying published results only.
When will data be available (start and end dates)?
Immediately following publication, no end date unless directed by Sponsor or Ethics Commitee.
Available to whom?
Case-by-case basis at the discretion of Primary Sponsor, Principial Investigator and Ethics Committee.
Available for what types of analyses?
Case-by-case basis at the discretion of Primary Sponsor, Principial Investigator and Ethics Committee.
How or where can data be obtained?
Access subject to approvals by Primary sponsor and Principal Investigator (arwel.jones@monash.edu)


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.