Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001712897
Ethics application status
Approved
Date submitted
13/11/2021
Date registered
14/12/2021
Date last updated
31/01/2023
Date data sharing statement initially provided
14/12/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Non-invasive brain stimulation and exercise for treating knee osteoarthritis
Scientific title
Feasibility and safety of combining repetitive transcranial magnetic stimulation and quadriceps strengthening exercise for chronic pain in knee osteoarthritis – A pilot randomised controlled trial
Secondary ID [1] 305148 0
None
Universal Trial Number (UTN)
U1111-1274-6922
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Knee osteoarthritis 323730 0
Condition category
Condition code
Musculoskeletal 321259 321259 0 0
Osteoarthritis
Physical Medicine / Rehabilitation 321260 321260 0 0
Physiotherapy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Repetitive transcranial magnetic stimulation (rTMS) and quadriceps strengthening exercise. Participants will receive a total of 12 treatment sessions (two sessions per week for six weeks). A qualified and registered physiotherapist with clinical experience in treating knee osteoarthritis will provide exercise therapy. Physiotherapist provides exercise intervention will be blinded to group allocation. For each session, participants will receive active rTMS (15 minutes) followed by supervised exercise (30 minutes).

For active rTMS, high-frequency rTMS will be applied to the motor cortical hotspot of the rectus femoris of the most painful knee using a Magstim Super Rapid2 and a figure-of-eight coil. This TMS machinery is registered on the Australian Register of Therapeutic Goods. For each session, 3000 stimuli (10 Hz, 30 trains of 10 seconds, 20-second intertrain interval) will be delivered at 90% of resting motor threshold. The resting motor threshold will be determined at the beginning of each treatment session.

For exercise, one-to-one quadriceps strengthening exercise will be delivered by the physiotherapist blind to participants’ group allocation to all participants. A standardised set of quadriceps strengthening exercises known to be effective in knee osteoarthritis will be performed using ankle cuff weights or resistance bands. Examples of exercises include seated knee extension, hip abductor strengthening wall squats, sit-to-stand and steps. Exercise intensity will be progressed by the physical therapist as appropriate for each participant. The adherence to the supervised exercise sessions will be monitored using a treatment attendance checklist. The physiotherapist will also develop, monitor and progress a home exercise program that participants will be instructed to perform four times a week during intervention. Each home exercise session will last for 30 minutes. Participants will complete an exercise diary and return to the treating physiotherapist weekly for compliance and adherence to their home exercise program. Any adverse effects of home exercise will be recorded on the exercise diary.
Intervention code [1] 321790 0
Rehabilitation
Intervention code [2] 322322 0
Treatment: Devices
Intervention code [3] 322323 0
Treatment: Other
Comparator / control treatment
Sham rTMS and quadriceps strengthening exercise
Participants will receive a total of 12 treatment sessions (two sessions per week for six weeks). A qualified and registered physiotherapist with clinical experience in treating knee osteoarthritis will provide exercise therapy. Physiotherapist provides exercise intervention will be blinded to group allocation. For each session, participants will receive sham rTMS (15 minutes) followed by supervised exercise (30 minutes).

For sham rTMS, a sham coil that looks identical to a real coil but produces only audible clicks and no magnetic pulse will be used to deliver the stimulation protocol identical to the one used for active rTMS.

For Exercise, one-to-one quadriceps strengthening exercise will be delivered by the physiotherapist blind to participants’ group allocation to all participants. A standardised set of quadriceps strengthening exercises known to be effective in knee osteoarthritis will be performed using ankle cuff weights or resistance bands. Exercise intensity will be progressed by the physical therapist as appropriate for each participant. The physiotherapist will also develop, monitor and progress a home exercise program that participants will be instructed to perform four times a week during intervention. Participants will complete an exercise diary and return to the treating physiotherapist weekly for compliance and adherence to their home exercise program. Any adverse effects of home exercise will be recorded on the exercise diary.
Control group
Active

Outcomes
Primary outcome [1] 329532 0
The number of sessions attended assessed by audit of study database
Timepoint [1] 329532 0
The end of six-week intervention
Primary outcome [2] 329745 0
Willingness of each participant to undergo therapy on an 11-point numerical rating scale with ‘not at all willing’ at 0 and ‘very willing’ at 10
Timepoint [2] 329745 0
The end of six-week intervention
Primary outcome [3] 329746 0
Adverse events documented in accordance with the Common Terminology Criteria for Adverse Events (CTACE5.0) based upon participant self-report
Timepoint [3] 329746 0
The end of six-week intervention
Secondary outcome [1] 403641 0
Primary outcome: Drop-outs assessed by audit of study database
Timepoint [1] 403641 0
The end of six-week intervention
Secondary outcome [2] 403642 0
Primary outcome: Proportion of participants recruited from the total number screened assessed by audit of study database
Timepoint [2] 403642 0
The end of six-week intervention
Secondary outcome [3] 403643 0
Primary outcome: Success of participant/therapist blinding. The success of participant blinding will be assessed at the completion of intervention using a Yes/No response to the question ‘Do you believe you had received the real brain stimulation?’ and an 11-point NRS of the individual’s confidence in that judgement. Participants will also be asked ‘Why do you believe you received the real/sham brain stimulation?’ and ‘Was it divulged to you whether you were receiving real brain stimulation or not?’ The success of blinding outcome assessor and treating physiotherapists will be determined at the completion of the follow-up assessment using a Yes/No response to the question ‘Did you know which intervention group the participant was assigned to before completion of the follow-up assessment?’ and ‘If you answer “yes”, how was it divulged to you?’
Timepoint [3] 403643 0
The end of six-week intervention
Secondary outcome [4] 403644 0
Knee pain will be assessed using an 11-point NRS for pain when walking in the past week
Timepoint [4] 403644 0
The end of six-week intervention
Secondary outcome [5] 403645 0
Knee function will be assessed by the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index (Likert version 3.1) and physical function subscale
Timepoint [5] 403645 0
The end of six-week intervention
Secondary outcome [6] 403646 0
Participant perceived treatment effect will be assessed using the Global Perceived Effect Scale (a 7-point Likert scale ranging from “completely recovered” to “vastly worsened”)
Timepoint [6] 403646 0
The end of six-week intervention
Secondary outcome [7] 403647 0
The presence of neuropathic pain will be assessed using modified painDETECT (7 items, total score = 38)
Timepoint [7] 403647 0
The end of six-week intervention
Secondary outcome [8] 403648 0
Pain catastrophising will be assessed using the Pain Catastrophising Scale, a self-report instrument to assess patients’ thoughts and feelings about pain in the domains of magnification, rumination and helplessness
Timepoint [8] 403648 0
The end of six-week intervention
Secondary outcome [9] 403649 0
The primary motor cortex (M1) function will be measured using an established rapid TMS mapping procedure. Map volume (total quadriceps response) will be used to quantify M1 function.
Timepoint [9] 403649 0
The end of six-week intervention
Secondary outcome [10] 403650 0
Voluntary activation of the quadriceps muscles will be measured using a twitch interpolation technique
Timepoint [10] 403650 0
The end of six-week intervention
Secondary outcome [11] 403651 0
Pressure pain thresholds (PPTs) will be measured using a hand-held pressure algometer at the site of the worst knee pain and ipsilateral thumbnail.
Timepoint [11] 403651 0
The end of six-week intervention
Secondary outcome [12] 403652 0
Conditioned pain modulation will be determined as a change in PPT measured at the medial joint line of the painful knee after pain is induced in the contralateral hand (immersed in cold water of 4ºC for two minutes)
Timepoint [12] 403652 0
The end of six-week intervention

Eligibility
Key inclusion criteria
1. Individuals aged equal or older than 50 years with knee osteoarthritis based on the American College of Rheumatology Clinical Criteria (at least one of the following items: stiffness less than 30 minutes, crepitus, bony tenderness, bony enlargement, no palpable warmth).
2. Knee pain for at least 3 months and on most days of the past month.
3. Average pain intensity equal or greater than 4 on an 11-point numeric rating scale in the past week.
Minimum age
50 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous knee joint replacement or high tibial osteotomy.
2. Knee surgery or joint injection in past six months.
3. Planned surgery in the next nine months.
4. Current or past four weeks oral corticosteroids use.
5. Systemic arthritis.
6. Previous knee fracture or malignancy.
7. Other condition affecting lower limb function.
8. Participation in knee strengthening exercise in past six months.
9. Loss of sensation of the affected lower limb.
10. Neurological or psychiatric disorders.
11. Use of neuroactive drugs.
12. Contraindications to TMS (i.e., epilepsy, metal implant in the skull) based on the TMS safety screening questionnaire.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Within-group changes will be calculated as follow-up minus baseline (mean and standard deviation). To show between-group difference (mean and 95% confidence interval), within-group change of active rTMS + exercise group will be subtracted by within-group change of sham rTMS + exercise group for each outcome measure.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
28/03/2022
Actual
30/06/2022
Date of last participant enrolment
Anticipated
28/07/2023
Actual
Date of last data collection
Anticipated
29/09/2023
Actual
Sample size
Target
30
Accrual to date
10
Final
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 309539 0
Other Collaborative groups
Name [1] 309539 0
Australia & New Zealand Musculoskeletal Clinical Trials Network
Country [1] 309539 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Neuroscience Research Australia
Address
Margarete Ainsworth Building, 139 Barker Street, RANDWICK NSW 2031
Country
Australia
Secondary sponsor category [1] 311206 0
None
Name [1] 311206 0
Address [1] 311206 0
Country [1] 311206 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309320 0
The University of New South Wales Human Research Ethics Committee A
Ethics committee address [1] 309320 0
The University of New South Wales, Sydney NSW 2052
Ethics committee country [1] 309320 0
Australia
Date submitted for ethics approval [1] 309320 0
23/11/2021
Approval date [1] 309320 0
31/01/2022
Ethics approval number [1] 309320 0
HC210954

Summary
Brief summary
Knee osteoarthritis causes persistent pain and difficulty in daily activities. Although exercise is the cornerstone of conservative treatment for knee osteoarthritis, its effects are, at best, moderate. We aim to conduct a ‘proof of concept’ study to explore the use of a novel intervention combining non-invasive brain stimulation and exercise therapy in people with knee osteoarthritis. We hypothesise that this intervention will have a greater effect on the biological mechanisms that contribute to persistent pain and disability in knee osteoarthritis, and therefore provide greater benefits than exercise therapy alone.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113750 0
Dr Wei-Ju Chang
Address 113750 0
Neuroscience Research Australia, Margarete Ainsworth Building, 139 Barker Street, RANDWICK NSW 2031
Country 113750 0
Australia
Phone 113750 0
+61431571312
Fax 113750 0
Email 113750 0
[email protected]
Contact person for public queries
Name 113751 0
Dr Wei-Ju Chang
Address 113751 0
Neuroscience Research Australia, Margarete Ainsworth Building, 139 Barker Street, RANDWICK NSW 2031
Country 113751 0
Australia
Phone 113751 0
+61431571312
Fax 113751 0
Email 113751 0
[email protected]
Contact person for scientific queries
Name 113752 0
Dr Wei-Ju Chang
Address 113752 0
Neuroscience Research Australia, Margarete Ainsworth Building, Barker Street, RANDWICK NSW 2031
Country 113752 0
Australia
Phone 113752 0
+61431571312
Fax 113752 0
Email 113752 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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
SourceTitleYear of PublicationDOI
EmbaseFeasibility and safety of combining repetitive transcranial magnetic stimulation and quadriceps strengthening exercise for chronic pain in knee osteoarthritis: A study protocol for a pilot randomised controlled trial.2022https://dx.doi.org/10.1136/bmjopen-2022-062577
N.B. These documents automatically identified may not have been verified by the study sponsor.