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Trial registered on ANZCTR


Registration number
ACTRN12620001296921
Ethics application status
Approved
Date submitted
23/09/2020
Date registered
30/11/2020
Date last updated
20/05/2024
Date data sharing statement initially provided
30/11/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised controlled trial to investigate the effect of exercise on both the communication between brain and body and symptoms of anxiety
Scientific title
Breathing and anxiety: Understanding the effect of exercise on the possible miscommunication between brain and body in individuals with moderate levels of anxiety
Secondary ID [1] 301684 0
None
Universal Trial Number (UTN)
U1111-1254-6769
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anxiety 318132 0
Condition category
Condition code
Mental Health 316156 316156 0 0
Anxiety

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Measurement sessions before and after intervention:
Two sets of measurements will be performed within a 4 hour session (including breaks) and 1.5 hour session. The first session (4 hours) will involve completing a set of behavioural tasks that consist of answering questions about emotions and body perceptions, two tasks that involve breathing through a sterile system to detect changes in breathing effort, as well as a visual detection task and emotion recognition task (both performed on a computer). One of the breathing tasks will be performed while participants lie in a magnetic resonance imaging (MRI) scanner. The second session (1.5 hours) will involve measurements of resting physiology (e.g. heart rate and breathing rate at rest), lung function tests, physiological and perceptual responses to an inhalation of elevated carbon dioxide, and an incremental exercise test on a bicycle ergometer. The two measurement sessions will take place prior to the randomisation into the study arms, and both of these sessions will then be repeated following 8 weeks of the intervention.

Arm 1: Exercise intervention
Participants with moderate anxiety will be randomised into the exercise or control arms. If entered into the exercise arm, participants will come to the School of Physical Education, Sport and Exercise Sciences on Union Street 2-3 times per week for 8 weeks to participate in supervised small-group exercise training sessions. Exercise training sessions will be prepared and led by a trained member of the study team, and will consist of a mixed intensity exercise program using a range of exercise modalities (such as stationary exercise cycle, treadmill, body weight exercises etc.), with modality options incorporated to accommodate needs of individual participants. Sessions will be progressed in accordance with international best practice (guidelines set out by Exercise and Sports Science Australia, ESSA), beginning with 2 sessions per week and increasing to 3 sessions with progression. Each exercise session will be up to 45 minutes in duration, and intensity level will be assessed in each session using linear rating scales from 0 to 10 (maximal) for each of 5 measures: exertion, breathlessness intensity, anxiety of breathing, leg discomfort and anxiety of leg discomfort. Participants will be monitored at all times to minimise any injury or health risks, and will be pre-screened prior to inclusion in the study using the Physical Activity Readiness Questionnaire (PAR-Q+). Session attendance checklists will be used to record any absences.

Arm 2: Control intervention
If participants are randomised into the control arm, they will complete a matched number of sessions (2-3 times per week for 8 weeks) that consist of a stretching protocol. Participants will be invited to complete these sessions in supervised small-group sessions conducted at the School of Physical Education, Sport and Exercise Sciences, but will additionally have the option to complete any sessions at home following guided instructions. Stretching sessions will be prepared and led by a trained member of the study team, and will comply with international best practice (guidelines set out by Exercise and Sports Science Australia, ESSA). beginning with 2 sessions per week and increasing to 3 sessions with progression. Each stretching session will be up to 45 minutes in duration, and will be targeted to be conducted at a low intensity. Exercise intensity level will also be assessed for each session using linear rating scales from 0 to 10 (maximal) for each of 5 measures: exertion, breathlessness intensity, anxiety of breathing, leg discomfort and anxiety of leg discomfort. Session attendance checklists will be used to record any absences, in conjunction with participant reports if any sessions are completed at home. Once participants have completed the control arm of the study, they will be offered the opportunity to join an exercise training group for a further 8 weeks, to allow all members of the study the option of undergoing the exercise training intervention.
Intervention code [1] 317994 0
Treatment: Other
Comparator / control treatment
The control treatment for the study is described above, where individuals randomised into the control arm will undergo a matched number of sessions to the exercise group, which will consist of a supervised stretching protocol.

An additional cross-sectional control group of individuals with low anxiety will also be measured for comparison, who will not undergo any treatment intervention.
Control group
Active

Outcomes
Primary outcome [1] 324337 0
Change in self-reported anxiety measured using a combination of the Spielberger Trait Anxiety Score, GAD-7 (Generalised Anxiety Disorder Questionnaire) and ASI-3 (Anxiety Sensitivity Index-3)
Timepoint [1] 324337 0
Prior to and 8 weeks post commencement of intervention
Primary outcome [2] 324338 0
Change in breathing perception and related metacognition, measured using a behavioural breathing task (the "Filter Detection Task")
Timepoint [2] 324338 0
Prior to and 8 weeks post commencement of intervention
Primary outcome [3] 324339 0
Change the brain activity associated with interoceptive learning related, measured using a behavioural breathing task (the Breathing Learning Task) paired with functional magnetic resonance imaging
Timepoint [3] 324339 0
Prior to and 8 weeks post commencement of intervention
Secondary outcome [1] 384374 0
Change in exercise performance and perception, as measured by an incremental exercise test
Timepoint [1] 384374 0
Prior to and 8 weeks post commencement of intervention
Secondary outcome [2] 384375 0
Change in both perception and physiology following a hypercapnic challenge, as measured by a controlled intake of carbon dioxide
Timepoint [2] 384375 0
Prior to and 8 weeks post commencement of intervention
Secondary outcome [3] 384376 0
Change in depression measured using the CES-D (Center for Epidemiologic Studies Depression Scale)
Timepoint [3] 384376 0
Prior to and 8 weeks post commencement of intervention
Secondary outcome [4] 384377 0
Change in fatigue measured using the FSS (Fatigue Severity Scale)
Timepoint [4] 384377 0
Prior to and 8 weeks post commencement of intervention
Secondary outcome [5] 384378 0
Change in general mood measured using the PANAS (Positive Affect Negative Affect Schedule) for affective traits
Timepoint [5] 384378 0
Prior to and 8 weeks post commencement of intervention
Secondary outcome [6] 384379 0
Change in general self-reported awareness of body perceptions (interoception) using the MAIA (Interoceptive Awareness Questionnaire)
Timepoint [6] 384379 0
Prior to and 8 weeks post commencement of intervention
Secondary outcome [7] 385030 0
Change in catastrophising of breathing symptoms measured using the PCS-resp (Catastrophic Thinking Scale in Pain, substituting the word “breathlessness” or "breathing" for the word “pain")
Timepoint [7] 385030 0
Prior to and 8 weeks post commencement of intervention
Secondary outcome [8] 386129 0
Change in vigilance towards breathing symptoms measured using the PVAQ-resp (Pain Awareness and Vigilance Scale, substituting the word “breathlessness” or "breathing" for the word “pain”)
Timepoint [8] 386129 0
Prior to and 8 weeks post commencement of intervention
Secondary outcome [9] 386130 0
Change in a visual perception and related metacognition, measured using a visual detection task (the "Perceptual Decision-Making Task")
Timepoint [9] 386130 0
Prior to and 8 weeks post commencement of intervention
Secondary outcome [10] 387207 0
Change in response to emotional faces, measured using an emotional faces task previously developed and reported (the "Facial Expression Recognition Task")
Timepoint [10] 387207 0
Prior to and 8 weeks post commencement of intervention
Secondary outcome [11] 387208 0
Change in lung function, as measured by standard spirometry procedures
Timepoint [11] 387208 0
Prior to and 8 weeks post commencement of intervention
Secondary outcome [12] 402468 0
Change in general self-reported resilience using the CD-RISC questionnaire (Connor Davidson Resilience Scale)
Timepoint [12] 402468 0
Prior to and 8 weeks post commencement of intervention
Secondary outcome [13] 402469 0
Change in general self-efficacy using the GSS questionnaire (General Self-Efficacy Scale)
Timepoint [13] 402469 0
Prior to and 8 weeks post commencement of intervention
Secondary outcome [14] 402470 0
Change in the level of emotional needs, measured using the Institute for Personality-Oriented Management (IPM) algorithm
Timepoint [14] 402470 0
Prior to and 8 weeks post commencement of intervention

Eligibility
Key inclusion criteria
Male or female aged between 18 and 45 years
Ability to provide written and informed consent
Ability to adhere to the study protocol
Spielberger trait anxiety score of greater than or equal to 40 (for moderate anxiety participants) OR less than or equal to 30 (for cross-sectional low anxiety controls)
Engaged in minimal organised sport or fitness activity (<1 per week for the last 6 months or more)
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Evidence of severe acute or chronic medical disorders, including a neurological disorder, current or past history of a severe brain injury or severe respiratory disorder e.g. severe asthma, chronic obstructive pulmonary disease etc.
Past or current diagnoses of schizophrenia, bipolar disorder, drug addiction or psychosis
Colour blindness
Female patients who are pregnant or breastfeeding
Current significant suicidal ideation
Participants must be free of recreational drug and alcohol use at the time of testing
Presence of implanted cardiac pacemakers, hearing aids, insulin pumps or neurostimulators; intracranial metal clips; or metallic bodies in the eye (MRI safety)
Significant levels of smoking or vaping (more than once per week)
Any regular medication (except the oral contraceptive pill for women)
Contraindication to engaging in a progressive exercise program, as determined from a validated health-screening questionnaire (PAR-Q+).

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)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Dynamic (adaptive) random allocation methods such as Minimisation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size:
We will aim to recruit 70 participants with moderate levels of anxiety (greater than or equal to 40 on the Spielberger Trait Anxiety Index) who will be randomised into the exercise or control interventions (35 in each group). Previous work has demonstrated a 12.5% improvement in trait anxiety following 6 weeks of aerobic exercise (initial trait anxiety mean ± SD: 51.80 ± 5.85). Power calculations indicate a sample size of 35 participants in each of two groups (exercise and control) to observe a conservative ~10% improvement (initial trait anxiety: ~42 ± 6) with 90% power and a one-tailed alpha-level of 5%, while 26 participants would be required in each group for a standard level of 80% power. Therefore, to maintain a minimum of 80% power in the final dataset, data collection will continue until at least 26 participants have completed each treatment arm. An additional control group arm of up to 35 participants with low anxiety will be recruited (less than or equal to 30 on the Spielberger Trait Anxiety Index) for a cross-sectional comparison (overall matched for age and gender to moderate anxiety participants), with at least 26 completed participants.

Analysis overview:
Full details of all planned statistical analyses will be documented and time-stamped before being uploaded to an open-access database prior to commencement of any data analysis. Any alterations to these plans will be clearly recorded.
1) Demographic and summary data: Demographic and Background Characteristics: Patient demographic characteristics will be descriptively summarised for all subjects.
2) Questionnaires: Questionnaires will be scored according to their respective manuals. For statistical analysis of this data we will use the statistical analysis software packages of MATLAB, EXCEL or R. For the analysis of questionnaires and other measured variables (below), we will perform analyses in the framework of the General Linear Model (GLM), e.g., multiple regression, analysis of variance (ANOVA), t-tests, and correlation analyses. In these classical (frequentist) statistical analyses, the significance level will be set to an alpha of 0.05 or less, after appropriately correcting for multiple tests.
3) Filter Detection Task (FDT) and Visual Perception Task (VPT)
The FDT and VPT will be analysed using the hierarchical HMeta-d statistical model, with model fits implemented in MATLAB and sampling conducted JAGS. This model firstly utilizes signal detection theory to provide single subject parameter estimates for task difficulty and response bias (akin to symptom over- or under-reporting), as well as using a hierarchical Bayesian formulation of metacognitive efficiency (calculated by fitting metacognitive sensitivity and normalizing by single subject values for sensitivity measures). The task protocol has been designed to generate comparable task difficulty for each participant, by finding the number of filters at which performance was maintained at approximately 75% accuracy.
4) Breathing learning task: To analyse the behavioural data gathered within this task, we will use established generative models of behavioural data, e.g., Hierarchical Gaussian Filter (Mathys et al. 2011) and variants of traditional reinforcement learning models, such as the Rescorla Wagner. Implementation of these models will be carried out in statistically oriented programming languages such as MATLAB, R, or Python.
5) Image pre-processing and analysis will be undertaken using FMRIB’s software library (FSL), following pipelines established in previous work on breathing-related neuroimaging. Structural images will be reoriented to a standard template and brain tissue extracted from raw image files. If automatic brain extraction fails to eliminate all non-brain tissues the excess will be manually removed. Magnitude images will be subjected to the same process, after which brain-extracted images will be eroded to ensure that no voxels containing non-brain tissue such as the skull remain. Fieldmaps will then be created and functional image registration to high resolution structural and MNI152 standard space will be performed using FMRIB's Expert Analysis Tool (FEAT). If registration fails between structural, functional and MNI spaces and is unable to be amended that participant’s data will be removed from further analysis. Additional physiological noise correction and independent component analysis will be used for data de-noising. General linear models will be constructed to analyse the functional task data, informed by model fits and responses recorded within the breathing learning task. Resting state data will be analysed using a combination of independent component analysis and seed-based analyses.
6) Emotional faces task: This task will be analysed using a statistical program such as MATLAB, EXCEL or R. Summary measures from the emotional faces task will be calculated, such as percentage of correct responses (i.e. the number of faces correctly identified as containing any intensity of a particular emotion), percentage of misclassifications (false hits), and reaction times (RTs) (to emotions correctly identified).
7) Lung function measures: Lung function will be assessed with standard measures of absolute and relative (percentage predicted) forced expiratory volumes (FEV) and forced vital capacity (FVC). Maximal voluntary ventilation will also be assessed as previously described, and used as a comparator to maximal values obtained whilst exercising.
8) Hypercapnic reactivity: Both the physiological and perceptual responses to the hypercapnic challenge will be calculated for each participant. The key measures of interest will include the percentage increase in ventilation and heart rate from baseline, the degree of breathlessness intensity and anxiety, the time to return to baseline ventilation and heart rate. All measures will be calculated as the difference between response to the hypercapnic mixture compared to the response to medical air.
9) Exercise measures: Submaximal and maximal physiological and perceptual measures will be calculated from the exercise protocol as previously described. The anaerobic threshold will be determined using the V-slope method, and physiological and perceptual values at both anaerobic threshold and maximal exercise will be utilised to compare across anxiety groups and as a result of an exercise intervention.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/03/2021
Actual
20/05/2021
Date of last participant enrolment
Anticipated
1/11/2025
Actual
Date of last data collection
Anticipated
31/12/2025
Actual
Sample size
Target
125
Accrual to date
18
Final
Recruitment outside Australia
Country [1] 22712 0
New Zealand
State/province [1] 22712 0
Otago

Funding & Sponsors
Funding source category [1] 306121 0
Charities/Societies/Foundations
Name [1] 306121 0
Royal Society of New Zealand
Country [1] 306121 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
Centre for Innovation
Level 1 (East Wing)
87 St David St
Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 306590 0
None
Name [1] 306590 0
Address [1] 306590 0
Country [1] 306590 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306339 0
Central Health and Disability Ethics Committee (HDEC-Expedited Review Pathway)
Ethics committee address [1] 306339 0
Ethics committee country [1] 306339 0
New Zealand
Date submitted for ethics approval [1] 306339 0
18/07/2020
Approval date [1] 306339 0
20/08/2020
Ethics approval number [1] 306339 0
20/CEN/168

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 103542 0
Dr Olivia Harrison
Address 103542 0
School of Pharmacy
University of Otago
Adams Building
18 Frederick Street
Dunedin 9054
Country 103542 0
New Zealand
Phone 103542 0
+64 3 479 4518
Fax 103542 0
Email 103542 0
[email protected]
Contact person for public queries
Name 103543 0
Olivia Harrison
Address 103543 0
School of Pharmacy
University of Otago
Adams Building
18 Frederick Street
Dunedin 9054
Country 103543 0
New Zealand
Phone 103543 0
+64 3 479 4518
Fax 103543 0
Email 103543 0
[email protected]
Contact person for scientific queries
Name 103544 0
Olivia Harrison
Address 103544 0
School of Pharmacy
University of Otago
Adams Building
18 Frederick Street
Dunedin 9054
Country 103544 0
New Zealand
Phone 103544 0
+64 3 479 4518
Fax 103544 0
Email 103544 0
[email protected]

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 (after de-identification)
When will data be available (start and end dates)?
Following completion of data collection and analyses, with no end date
Available to whom?
Researchers who provide sound research proposals
Available for what types of analyses?
All
How or where can data be obtained?
Access subject to approvals by Principal Investigator ([email protected])


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
8396Statistical analysis plan  [email protected] Analysis plans will also be uploaded to public-acc... [More Details]
8397Analytic code  [email protected]



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.