Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001207808
Ethics application status
Approved
Date submitted
15/07/2021
Date registered
9/09/2021
Date last updated
28/01/2024
Date data sharing statement initially provided
9/09/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The Effect of A Rehabilitation Program on Patients with Multidirectional Instability of the Glenohumeral Joint: A Functional MRI Study
Scientific title
The Effect of A Rehabilitation Program on Brain Structure and Function in Patients with Multidirectional Instability of the Glenohumeral Joint: A Functional MRI Study
Secondary ID [1] 304578 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multidirectional Instability (MDI) of at the Glenohumeral Joint 322467 0
Condition category
Condition code
Physical Medicine / Rehabilitation 320109 320109 0 0
Physiotherapy
Musculoskeletal 320666 320666 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study Design and Allocation:
This study is a non-randomised pre-post intervention study with a control group. The study includes participants with multidirectional instability of the shoulder and age and gender matched controls. All enrolled participants with multidirectional instability of the shoulder will receive the intervention.

Intervention:
The intervention delivered will be a shoulder strengthening program called the Watson Multidirectional Instability (MDI) Program. This program has previously been tested for efficacy in a randomised controlled trial (RCT)(Warby, Ford, Hahne, Watson, & Pizzari, 2016). The Watson MDI program is primarily based around maintaining good scapular (shoulder blade) motor control through all stages of the program and progressing exercises into functional ranges. The program has been standardised for use in a previous RCT, however it provides pathways for clinical decision making regarding the most appropriate selection of exercises for a participant. A detailed outline of the protocol has been previously published(Watson, Warby, Balster, Lenssen, & Pizzari, 2016a, 2016b).

Procedures and who will deliver the intervention:
Participants will attend 18, 30-minute face-to face sessions of physiotherapy over a 24-week period (once a week for 12 weeks and once a fortnight for another 12 weeks) where they will be assessed/reassessed and prescribed/progressed with a specific set of exercises as per the Watson MDI Program. A 24- week intervention period for the treatment of MDI with a rehabilitation program has been shown to result in a large therapeutic benefit (Warby et al., 2016). The physiotherapy treatments will be conducted at the Melbourne Shoulder Group (33 High Street Prahran, 3181) which is a private practice in Melbourne, Australia. Physiotherapists delivering the intervention will have a particular expertise in the treatment of MDI and have a minimum of 4 years post graduate experience.

Materials:
Participants will be instructed to perform their exercises at home and/or in their gym. Equipment for the relevant program (weights and Therabands) will be supplied. Participants will receive treatment free of charge.

The Watson Multidirectional Instability Program:

The Watson MDI program aims to establish motor control, endurance, strength then sports specific control of the scapula and humeral head. The parameters of exercise prescription depend on what stage the participant is completing. The program is standardised, however allows for tailoring of individual patients needs and goals.

Participants with MDI will perform between 1 and 6 exercises, 15 to 30 minutes a day, 1 to 2 times a day, every day of the week.

The stages and exercises for the Watson Multidirectional Instability Program are as follows:

Stage 1:
a) Regaining scapula motor control (example exercises: scapula upward rotation, elevation drills with 0- 1 kg)
b) Regaining humeral head control in 0 degrees of elevation (example exercises: glenohumeral extension, internal and external rotation drills at 0 degrees of elevation with a TheraBand)

Stage 2: Establishing additional posterior muscle control and strength (example exercises: scapula upward rotation drills 2kg +, side lie external rotation, bent over rows, TheraBand extension drills from 0 to 45 degrees of elevation)

Stage 3: Establishing sagittal plane (flexion) control (example exercises: standing flexion drills with a TheraBand to 90 degrees of elevation)

Stage 4: Regaining humeral head control from 45 to 90 degrees of elevation in the sagittal (flexion) and coronal (abduction) plane (example exercises: internal and external rotation at 90 degrees elevation with Therabands. Flexion >90 degrees with Therabands)

Stage 5: Deltoid strength (example exercises: supine and standing flexion with weights, bent over row at 30 and 90 degrees of abduction with weights, short lever abduction with weights)

Stage 6: Sports Specific Function (Part practise of sports specific drills with Therabands integrating into whole practise)


Adherence:
To measure compliance with the home exercise program, upon questioning the participant, the trial physiotherapist will give a compliance score at the end of each session, except for session 1 (i.e.: session 2 to 18) and record this in the clinical notes. These scores will be used to calculate a total compliance score at the end of the 18-session (24 week) intervention period.

References
Ganderton, C., Tirosh, O., Munro, D., Meyer, D., Lenssen, R., Balster, S., . . . Warby, S. (2021). Rehabilitation for atraumatic shoulder instability in circus arts performers: delivered via telehealth. American Journal of Sports Medicine (under review).
Warby, S. A., Ford, J. J., Hahne, A. J., Watson, L. A., & Pizzari, T. (2016). Comparison of two exercise rehabilitation programs for multidirectional instability of the glenohumeral joint: A randomised controlled trial. The American Journal of Sports Medicine (Manuscript under review).
Watson, L., Warby, S. A., Balster, S., Lenssen, R., & Pizzari, T. (2016a). The treatment of multidirectional instability with an exercise program: Part 1. Shoulder & Elbow, 8(4), 271-278. doi:http://dx.doi.org/10.1177/1758573216652086
Watson, L., Warby, S. A., Balster, S., Lenssen, R., & Pizzari, T. (2016b). The treatment of multidirectional instability with an exercise program: Part 2. Shoulder & Elbow, 0(0), 1-8. doi:http://dx.doi.org/10.1177/1758573216652087
Intervention code [1] 320929 0
Rehabilitation
Intervention code [2] 321337 0
Treatment: Other
Comparator / control treatment
Age and gender matched control participants with no history of shoulder problems. Control participants will not receive the intervention (Watson MDI program).
Control group
Active

Outcomes
Primary outcome [1] 327988 0
The primary outcome will be analysis of altered functional brain changes (Functional Magnetic Resonance Imaging [fMRI] signal and connectivity) in MDI participants compared to control participants at baseline, and how this is affected by the therapeutic intervention at follow-up.
Timepoint [1] 327988 0
MDI participants: fMRI measured at baseline and 24 weeks post-intervention commencement.
Controls: fMRI measured at baseline only (no intervention).
Primary outcome [2] 337238 0
The Western Ontario Shoulder Index (WOSI)

MDI only: Baseline, 6, 12 and 24-weeks (primary timepoint)
Timepoint [2] 337238 0
MDI: Baseline, 6, 12 and 24-weeks post intervention commencement

The primary time-point for MDI participants is 24 weeks

Update as of 11/5/23- Controls will not be required to complete the WOSI as they have no shoulder problems are we are not measuring change over time with an intervention. Having controls complete this outcome only increased the burden on their participation.
Primary outcome [3] 337239 0
Melbourne Instability Shoulder Score (MISS)
Timepoint [3] 337239 0
Baseline, 6, 12, 18, 24 weeks follow up

MDI only: 24 weeks is the primary time point
Secondary outcome [1] 397162 0
The TAMPA Scale for Kinesiophobia
Timepoint [1] 397162 0
MDI: Baseline, 6, 12 and 24-weeks post intervention commencement
Controls: Baseline and 24 weeks post baseline measurement.
Secondary outcome [2] 397163 0
Short form Orebro Musculoskeletal Pain Questionnaire
Timepoint [2] 397163 0
MDI: Baseline, 6, 12 and 24-weeks post intervention commencement
Controls: Baseline and 24 weeks post baseline measurement.
Secondary outcome [3] 397164 0
Scapular upward rotation will be measured at rest 30, 45, 60, 90, 120, 135° and end range of motion of glenohumeral abduction with the use of two inclinometers.
Timepoint [3] 397164 0
MDI only: Baseline and 24 weeks post intervention commencement.
Secondary outcome [4] 397165 0
Shoulder muscle strength will be assessed with a handheld dynamometer.
Timepoint [4] 397165 0
MDI only: Baseline and 24 weeks post intervention commencement
Secondary outcome [5] 397166 0
Adverse Events (classified as minor, significant or serious)

Adverse events will be classified in accordance to the adverse events criteria outlined for a previous randomised controlled trial investigating the effect of two rehabilitation programs on multidirectional instability of the shoulder.1 This adverse events classification has been previously published.2 The addition of adverse events relating to the fMRI scanning process have been added to the original classification. The classification of adverse events for this study are as follows:


Minor adverse event
Refers to any symptom or event reported by the participant that may be potentially related to the intervention OR a self-limiting effect of MRI scan. This will include:

• Pain (not fatigue) during or immediately after their home exercise program (HEP) that settled within 48 hours. This may include pain located to the area of the rotator cuff, cervical spine or generalized glenohumeral joint pain.
• Paraesthesia (pins and needles) during or immediately after the HEP that settled remains for > 48 hours.
• Inability to complete scan due to claustrophobia.
• Pain or discomfort when placed in the MRI scanner which resolves on removal from scanner. Includes peripheral nerve stimulation

Significant adverse event
Any symptom or event potentially related to the intervention that interrupts the participant’s ability to continue with the pilot RCT intervention or requires the participant to be referred to a medical practitioner. This does not include routine referrals back to medical practitioners for medication reviews.
OR any symptom or event potentially related to the MRI scan.

This will include:
• Episode of shoulder subluxation during execution of the exercise program that resulted in pain >14 days
• An episode of full shoulder dislocation that spontaneously relocates (requires no hospital admission or visit to GP or other specialist for relocation).
• Extreme pain or ongoing parathesis not settling with medication
• Equipment related pain: Any other injuries sustained to any other body part while performing the home exercise program (e.g.: back pain, injury form dropping weights, TheraBand related injuries).
• Injury/incident, related to the static and gradient fields and radiofrequency waves associated with an MRI scanner, which may require medical attention. Includes panic attack.

Serious adverse event

Any symptom or event potentially related to the intervention or MRI scan related event that requires immediate medical intervention. This will include:




• Report of acute shoulder dislocation associated with HEP that requires relocation by a medical practitioner.
• Injury, requiring urgent medical attention, due to the static and gradient fields and radiofrequency waves associated with an MRI scanner. Includes thermal/electrical burns.

1. Warby SA, Ford JJ, Hahne AJ, et al. Comparison of two exercise rehabilitation programs for multidirectional instability of the glenohumeral joint: A randomised controlled trial. American Journal of Sports Medicine. 2017:1-11.
2. Warby SA, Ford JJ, Hahne AJ, et al. The effect of exercise based management on multidirectional instability of the glenohumeral joint: A pilot randomised controlled trial protocol. BMJ Open. 2016;6(e013083).
Timepoint [5] 397166 0
MDI: Recorded in the clinical notes for every session and formally assessed at 6, 12, 24 weeks post intervention commencement.
Controls: Any adverse events related to the fMRI scanning process (eg: Panic attack). Recorded at the time of 1 x fMRI scan.
Secondary outcome [6] 397167 0
Compliance with home program:
Compliance score given by trial physiotherapist from sessions 2 to 18. The sum of scores from sessions 2 to 12 used to calculate a total compliance score at the end of the 18-session (24 week) program.

The tool to score compliance was specifically developed for use in a previous randomised controlled trial investigating the effect of the Watson MDI program on patients with multidirectional instability of the shoulder.1 The same tool will be used for this study.

1. Warby SA, Ford JJ, Hahne AJ, et al. Comparison of two exercise rehabilitation programs for multidirectional instability of the glenohumeral joint: A randomised controlled trial. American Journal of Sports Medicine. 2017:1-11.
Timepoint [6] 397167 0
MDI only: Session 2 to 18. (All sessions exception session 1)

Eligibility
Key inclusion criteria
Patients with MDI: Inclusion criteria
1. Symptomatic shoulder instability in at least 2 directions (one direction being inferior).
2. Aged 18 to 35 years
3. Female. MDI is more prevalent in the female population and excluding males will limit any bias due to potential gender effects.
4. Right shoulder affected. Participants with a right affected shoulder will be included in this study to limit the potential biases that may result from differences in measuring the left and right sides of the brain from participants with left and right shoulder problems. In this study, fMRI effects of the LEFT brain will be measured from participants with a right sided shoulder problem.
5. No history of trauma to the affected shoulder
6. No structural lesion on a clinical Magnetic Resonance Imaging scan.
7. Ability to understand the English language and willingness to participant in a rehabilitation program.

Aged Matched Control: Inclusion criteria
1. Aged and gender matched controls with no history of shoulder problems for each included MDI participant
Minimum age
18 Years
Maximum age
35 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria for MDI and control groups:
• Male
• Shoulder instability due to trauma, central nervous system lesions, peripheral lesions and any other neurological disorders
• Patients with significant neck (cervical spine) pathology
• Participants will any history of shoulder surgery
• Inability to understand or speak English
• Existence of MRI contraindications
• Participants who are planning surgery between baseline and follow-up FMRI imaging
• Participants who are or are planning to become pregnant
• Patients with contraindications to standard MRI or fMRI

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
Primary Outcome (fMRI):
All pre-processing and statistical analyses of neuroimaging data will be run on the OzStar supercomputing facility at Swinburne University. To avoid registration bias and enhance sensitivity to regional effects due to registration error, a study-specific template (SST) and tissue priors will be created from 50 T1/T2 images from the publicly available ‘Oasis-3’ dataset, matching our groups for age and sex. SST will be created using the ‘multivariateTemplateConstruction2’ algorithm from the Advanced Normalisation Tools (ANTs) that will be registered to Montreal Neurological Institute (MNI) space using the diffeomorphic ‘antsRegistrationSyN’ algorithm. Also, an anatomically-defined parcellation of cortical brain regions will be computed using the ANTs multi-atlas labelling technique for use in T1, DWI and ROI based fMRI analyses: OASIS T1 images pre-labelled by Neuromorphometrics Inc. will be registered to each participant’s T1 image using ‘antsRegistrationSyN’ then joint label fusion will be used to create a final parcellation. Image pre-processing and analyses will include:

T1-weighted imaging:
ANTs tools will be used to probe cortical thickness (CT), volume (CV) and density (CD) within brain parcels, with a focus on ACC and OFC ROIs. T1 images will be processed and registered to the SST using the ANTs CT pipeline (brain extraction, bias-field correction, tissue segmentation, template registration, and registration-based CT estimation). Measures will be: the average thickness within brain parcellations (CT estimates); the intersection volume between parcels and a prior-driven cortical segmentation (CV estimates), and ; the intersection of a 3-class K-means segmentation (with ANTs ‘Atropos’) and parcel (CD estimates).

Diffusion-weighted imaging: MRtrix3 (https://www.mrtrix.org/) will be used to analyse white matter integrity and connectivity cf., with a focus on an M1 ROI defined in task-based analyses. Pre-processing will include denoising, Gibbs ringing removal, correction for non-uniformity bias, eddy currents and movement, as well as susceptibility distortion correction, which affect our frontal ROIs. A multi-shell, multi-tissue constrained spherical deconvolution (CSD) algorithm will be used to model white matter, and exclude cerebrospinal fluid and grey matter signal contributions. Tractogram construction will include generation of 10 million probabilistic streamlines distributed across the brain, and MRtrix3’s SIFT2 algorithm will then be applied to correct tractography biases. Individual connectomes will be computed using brain parcels in native space, with connection strengths computed by summing relevant streamlines. We will examine whole-brain connectomics, and structural connectivity between M1 and the rest of the brain will be assessed using measures of “hubness” such as node strength, betweenness centrality and vulnerability, computed using the Brain Connectivity Toolbox (BCT).

FMRI: we will use ‘fMRIPrep’ pre-processing pipelines that use FSL (motion correction, co-registration, bias-field and susceptibility distortion correction, spatial-smoothing, ICA); ANTs (skull-stripping, registration to SST and MNI space),
and Freesurfer tools; removal of non-BOLD signals using TE-dependent analysis (TEDANA), and; removal of other noise components using a pattern classifier trained on canonical datasets at SUT using ICA-FIX. SPM12 and associated toolboxes will be used for statistical analyses. Resting-state analyses will focus on altered seed-to-voxel connectivity in HD vs controls using an M1 ROI seed defined by task-based analyses using ‘CONN’ Connectivity toolbox. For task fMRI modelling, there will be 6 explicit epoch-based predictors that will model the onset and duration of the six task conditions. The Fixation condition will not be modelled and hence will constitute the implicit model baseline. Each condition will be contrasted with baseline and entered into separate Group x Condition ANOVAs. Generalised psychophysiological interaction (gPPI) analysis will be used to examine whole brain functional connectivity between with the M1 ROI seed. For each participant a deconvolved time series will be extracted from functionally derived M1 ROI to create a physiological variable that will be multiplied by the contrast of interest and added to the original GLM. Contrasts generated from one-sample t-tests on this regressor will be used for group level comparisons.

Secondary Outcomes:
Data analysed will focus on detecting the between-group differences (baseline and -24 weeks) and within-group treatment effects (at all follow-up time points) with effect sizes and 95% CIs (Portney & Watkins, 2009). Primary analyses for the MISS, the WOSI, the TAMPA scale, scapular angles and strength, will be performed using linear mixed models, due to its advantages in modeling repeated measures over time(Bolker et al., 2009; Krueger & Tian, 2004). Mixed models will be adjusted for baseline scores. If the sample size is inappropriate for the use of a linear mixed models (Bolker et al., 2009), repeated measures ANCOVA will be used and adjusted or baseline score (Van Breukelen, 2006).

Compliance with the home exercise program and any adverse events will be reported using descriptive statistics.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/10/2021
Actual
1/02/2022
Date of last participant enrolment
Anticipated
1/07/2024
Actual
Date of last data collection
Anticipated
23/12/2024
Actual
Sample size
Target
60
Accrual to date
26
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 34430 0
3181 - Prahran

Funding & Sponsors
Funding source category [1] 308944 0
University
Name [1] 308944 0
Swinburne University of Technology
Country [1] 308944 0
Australia
Funding source category [2] 309326 0
Commercial sector/Industry
Name [2] 309326 0
Melbourne Shoulder Group
Country [2] 309326 0
Australia
Funding source category [3] 309327 0
Commercial sector/Industry
Name [3] 309327 0
Melbourne Orthopaedic Group
Country [3] 309327 0
Australia
Funding source category [4] 309328 0
Charities/Societies/Foundations
Name [4] 309328 0
Shoulder and Elbow Physiotherapists Australasia
Country [4] 309328 0
Australia
Funding source category [5] 309329 0
Charities/Societies/Foundations
Name [5] 309329 0
Australasian Muskuloskeletal Imaging Group
Country [5] 309329 0
Australia
Primary sponsor type
University
Name
Swinburne University of Technology
Address
John St, Hawthorn VIC 3122
Country
Australia
Secondary sponsor category [1] 310508 0
None
Name [1] 310508 0
Address [1] 310508 0
Country [1] 310508 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308836 0
Swinburne University Human Research Ethics Committee
Ethics committee address [1] 308836 0
Ethics committee country [1] 308836 0
Australia
Date submitted for ethics approval [1] 308836 0
06/11/2020
Approval date [1] 308836 0
18/12/2020
Ethics approval number [1] 308836 0
20212806-6120

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

Contacts
Principal investigator
Name 43498 0
Dr Charlotte Ganderton
Address 43498 0
Swinburne University of Technology, John St, Hawthorn VIC 3122
Country 43498 0
Australia
Phone 43498 0
+6139214 3539
Fax 43498 0
Email 43498 0
[email protected]
Contact person for public queries
Name 43499 0
Sarah Warby
Address 43499 0
Melbourne Shoulder Group, 305 High Street, Prahran, VIC 3181
Country 43499 0
Australia
Phone 43499 0
+61478405258
Fax 43499 0
Email 43499 0
[email protected]
Contact person for scientific queries
Name 43500 0
Sarah Warby
Address 43500 0
Melbourne Shoulder Group, 305 High Street, Prahran, VIC 3181
Country 43500 0
Australia
Phone 43500 0
+61478405258
Fax 43500 0
Email 43500 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?
All data collected (except for patient first and last names) and data analysis scripts will be made available on an open access data repository at the time of submission for publication.
Data shared will include:
1. Participant characteristics
2. fMRI output data at baseline and 24 weeks
3. Secondary outcome data at baseline, 6, 12 and 24 weeks
When will data be available (start and end dates)?
Immediately following publication with no end date determined.
Available to whom?
Any researcher on provision of providing their contact details.
Available for what types of analyses?
Any purpose.
How or where can data be obtained?
Access subject to approvals by Principal Investigators (Charlotte Ganderton; [email protected] or Dr Sarah Warby; [email protected] or [email protected]).


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
12197Study protocol    This has been written and yet to be published. It... [More Details]
12198Ethical approval    365110-(Uploaded-22-06-2021-16-58-25)-Study-related document.pdf



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