ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12619000629134

Ethics application status

Approved

Date submitted

18/04/2019

Date registered

29/04/2019

Date last updated

13/01/2022

Date data sharing statement initially provided

29/04/2019

Date results information initially provided

13/01/2022

Type of registration

Prospectively registered

Titles & IDs

Public title

The effects of physical exercise on the brain and the immune system in individuals with chronic pain.

Scientific title

The Central Neurobiological and Immunological Effects of Exercise in Individuals with Chronic Pain.

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Whiplash Associated Disorder

Chronic Pain

Condition category

Condition code

Musculoskeletal

Other muscular and skeletal disorders

Neurological

Other neurological disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Participants will be randomised into a staggered baseline of 5, 8, 11, or 14 days. In order to gain an understanding of the variability in clinical outcomes, during this baseline phase three daily questions will assess pain intensity, pain bothersomeness, and disability. The eight-week exercise intervention commences following the completion of the staggered baseline. Through randomisation, participants will be allocated to either the aerobic exercise (intervention) or resistance exercise (comparator) program. Both eight-week programs follow the American College for Sports Medicine Guidelines for Exercise Testing and Prescription.

Aerobic: For the aerobic exercise program, participants will engage in three exercise sessions per week of at least 20 min, focussing on self-chosen, whole-body exercises such as walking, cycling, etc. The target intensity is 40-60% of maximum heart rate (MHR = 220-age) and will be determined using a heart rate monitor (the participant will be provided with one for the study). Participants are asked to refrain from resistance training for the duration of the study.

The total duration of participation in this study is the baseline duration (5, 8, 11, 14 days) + 8 weeks of exercise intervention. For both study arms, adherence to the exercise intervention will be monitored with weekly phone calls.

Intervention code [1]

Rehabilitation

Comparator / control treatment

The comparator is the resistance exercise group:

Participants in the resistance exercise group will engage in three exercise sessions per week, approximately 30 minutes per session. Although no standardised program will be followed, the focus of the exercises will be on strengthening of monoarticular muscle groups away from the neck. Examples of possible resistance exercises are: upper extremities exercises including biceps curl, triceps extension, seated row, lower extremities exercises including squad, lunge, wall sit, calf raises. Training will be performed in 2-3 sets per exercise, and the chosen resistance allows for 8-12 repetitions with proper form per set. The target intensity for each exercise is 40-60% of the 1-repeated maximum (the resistance with which someone can correctly perform one repetition of the exercise). Participants in the resistance exercise group will be provided with a Gymstick in order to perform the exercises. Participants will be asked to refrain from aerobic exercises they would not have normally done for the duration of the study.

Control group

Active

Outcomes

Primary outcome [1]

Pain intensity (0-100 numeric rating scale [NRS], 0=no pain, 100=worst pain imaginable)

Timepoint [1]

Assessed daily in the baseline phase, and daily in the intervention phase, with primary time point being 8 weeks after the start of the exercise intervention. This will be used to determine the effect of the intervention.

Primary outcome [2]

Pain interference (0-100 NRS, 0=no interference, 100=extreme interference)

Timepoint [2]

Primary outcome [3]

Disability (Short Form Health Survey (SF-36) question, scored 1-100, 1=not at all, 100=extremely)

Timepoint [3]

Secondary outcome [1]

o Exercise-induced effects on pain:
- Pressure Pain Threshold before and after 20 min exercise session

Timepoint [1]

Secondary outcome measures are assess three times: At baseline, after 4 weeks of exercise intervention, and after 8 weeks of exercise intervention. The 8-week follow-up data will be used to determine the effect of the intervention.

Secondary outcome [2]

o Sensorimotor control
- Joint position error test

Timepoint [2]

Secondary outcome [3]

o Neurological outcomes (magnetic resonance [MR]):
- Functional connectivity (resting state functional MRI [rs-MRI])

Timepoint [3]

Secondary outcome [4]

o Concentrations of immunological biomarkers
- Blood derived neurotrophic factor (BDNF)

Timepoint [4]

Eligibility

Key inclusion criteria

Inclusion criteria – WAD
- Chronic whiplash associated disorder (>12 weeks duration)
- Aged between 18 and 55 years
o The lower age limit of 18 years will be applied as the brain in children is still in development which could potentially affect the MR outcomes. An upper age limit of 55 years will be applied to limit the possible effect of degenerative changes in the aging brain.
- Moderate neck pain intensity (at least 4/10 on a 0-10 numeric rating scale)
- Pain moderately interferes with daily activities (assessed using one item* from the SF-36 questionnaire)
- Currently low level of physical activity (assessed with the Godin-Shephard activity questionnaire)
- Motivated to commit to an eight-week exercise program
- Able to lie in an MRI scanner on their back for one hour
- Free from metal implants or pacemaker
* During the past 4 weeks, how much did pain interfere with your normal work (including both work outside the home and housework)?

Inclusion criteria – healthy controls
- No current neck pain, nor having had treatment for neck/shoulder complaints in the past 5 years
- No history of injury or trauma to the neck or head
- No current musculoskeletal pain in any body area
- Aged between 18 and 55 years
o The lower age limit of 18 years will be applied as the brain in children is still in development which could potentially affect the MR outcomes. An upper age limit of 55 years will be applied to limit the possible effect of degenerative changes in the aging brain.
- Currently low level of physical activity (assessed with the Godin-Shephard activity questionnaire)
- Motivated to commit to an eight-week exercise program
- Able to lie in an MRI scanner on their back for one hour
- Free from metal implants or pacemaker
- Matched to an individuals with WAD based on sex and age

Minimum age

18 Years

Maximum age

55 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

Exclusion criteria – WAD and healthy individuals
- History of migraine headaches
- Surgery to the neck
- Diabetes
- Posttraumatic stress symptoms (assessed on the PCL-5)
o Individuals with substantial posttraumatic stress symptoms will be excluded from this study as psychological stress may interfere with adherence to the exercise program,58 the neurobiological effects of exercise, and the effects of exercise on health outcomes.
- Currently receiving treatment for their neck pain (e.g., physiotherapy, chiropractic, or similar)
- Comorbidities preventing regular exercise
- Pregnant or breastfeeding
- Claustrophobic

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)

Sealed opaque envelopes with only a number on the outside of the envelope will guarantee allocation concealment.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Participants will be randomised twice: (1) to determine the length of the staggered baseline phase (5, 8, 11, or 14 days), and (2) to determine the type of eight-week exercise intervention (aerobic/resistance). Permuted block randomisation will be used to ensure balance across treatment groups. Both randomisation processes will be performed with a custom written script in MatLab.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people analysing the results/data

Intervention assignment

Parallel

Other design features

Phase

Not Applicable

Type of endpoint/s

Efficacy

Statistical methods / analysis

Descriptive and group baseline data will be analysed using the SPSS package. Intervention effects will be statistically analysed using the single-case randomisation, a test specifically designed (for the R package) for the analysis of data from SCED studies. As visual analysis is an important part of SCED data analysis, pain intensity, pain perception, and disability outcomes will be visually analysed by graphing daily outcomes for the duration of the baseline and intervention.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

20/05/2019

Actual

3/06/2019

Date of last participant enrolment

Anticipated

1/10/2019

Actual

1/10/2019

Date of last data collection

Anticipated

31/12/2019

Actual

31/12/2019

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

QLD

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

NHMRC

Address [1]

16 Marcus Clarke St,
Canberra ACT 2601

Country [1]

Australia

Primary sponsor type

University

Name

The University of Queensland

Address

The University of Queensland
St Lucia, 4072, QLD Australia

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Royal Brisbane and Women's Hospital Human Research Ethics Committee

Ethics committee address [1]

Executive Suites, Lwer Ground Floor
Dr James Mayne Building
Royal Brisbane & Women’s Hospital
Butterfield Street
Herston, 4029, QLD, Australia

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

14/02/2019

Approval date [1]

26/03/2019

Ethics approval number [1]

Ethics committee name [2]

The University of Queensland Human Research Ethics Committee

Ethics committee address [2]

Office of Research Ethics
The University of Queensland
St. Lucia, 4072, QLD Australia

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

26/03/2019

Approval date [2]

15/04/2019

Ethics approval number [2]

2019000769

Summary

Brief summary

While evidence in healthy individuals demonstrates that exercise improves health outcomes and exerts biological effects, the effects in individuals with
chronic pain are poorly understood. Exercise interventions have been suggested useful in reducing pain, however evidence shows that effects vary in
magnitude and direction. This project aims to improve the understanding of the central neurobiological and immunological effects of exercise in individuals
with chronic pain. Individuals with chronic whiplash will participate in either an aerobic or resistance exercise intervention, allowing for a direct comparison
informing on the type and dosage considerations of exercise prescription. Magnetic resonance scans and immunological factor concentrations will inform
on the underlying effects of exercise. A single-case experimental design with sixteen participants allows for an evaluation of the feasibility, as well as the
effectiveness of isolated elements of this intervention. Determining the underlying mechanisms is the first step in understanding the effects of exercise in
individuals with chronic pain. Outcomes will therefore benefit researchers and clinicians aiming to improve health outcomes in individuals with chronic pain.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Rutger de Zoete

Address

288 Herston Rd
Oral Health Building
The University of Queensland
QLD 4006

Country

Australia

Phone

+61 733464787

Fax

[email protected]

Contact person for public queries

Name

Dr Rutger de Zoete

Address

288 Herston Rd
Oral Health Building
The University of Queensland
QLD 4006

Country

Australia

Phone

+61 733464787

Fax

[email protected]

Contact person for scientific queries

Name

Dr Rutger de Zoete

Address

288 Herston Rd
Oral Health Building
The University of Queensland
QLD 4006

Country

Australia

Phone

+61 733464787

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

No individual participant data will be available in order to assure confidentiality.

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
1131	Ethical approval					376317-(Uploaded-18-04-2019-15-42-33)-Study-related document.pdf

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	The effects of physical exercise on structural, functional, and biochemical brain characteristics in individuals with chronic whiplash-associated disorder: A pilot randomized clinical trial.	2023	https://dx.doi.org/10.1111/papr.13240

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically