Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000787886
Ethics application status
Approved
Date submitted
7/05/2021
Date registered
22/06/2021
Date last updated
27/06/2022
Date data sharing statement initially provided
22/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Can non-invasive brain stimulation enhance the effect of exercise on knee osteoarthritis (OA) pain?
Scientific title
Can a single session of 2mA active transcranial Direct Current Stimulation (tDCS) over the primary motor cortex enhance exercise induced hypoalgesia (EIH) compared to sham tDCS in individuals with knee osteoarthritis (OA)?
Secondary ID [1] 304159 0
None
Universal Trial Number (UTN)
Trial acronym
None
Linked study record
n/a

Health condition
Health condition(s) or problem(s) studied:
knee osteoarthritis 321854 0
Condition category
Condition code
Musculoskeletal 319581 319581 0 0
Osteoarthritis
Physical Medicine / Rehabilitation 319885 319885 0 0
Physiotherapy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The order of interventions (active vs sham tDCS) will be randomised for each participant using a computer generated randomisation such that an equal number of participants have active and sham tDCS in their first session. In this crossover trial, all participants will partake in two treatment sessions, (‘Session 1’ and ‘Session 2’) delivered by a postgraduate qualified physiotherapist, with a minimum 7 day washout. Each of the two treatment sessions will last approximately 1-2 hours and will be closely matched in duration for the intervention and comparison groups. Participant adherence will be monitored during both sessions using a session attendance checklist. Participants will be comfortably seated in a chair while receiving transcranial Direct Current Stimulation (tDCS) and will be asked to remain quiet for the duration of the intervention whilst they watch a nature documentary. Participants in the active (intervention) tDCS group will receive 20 min of 2 mA anodal stimulation. Stimulation will be applied using an HDCell (MagStim Co, UK) and 7 x 5 cm electrodes. The electrode sponges will be soaked in saline solution prior to application. The anode will be placed over the C3 or C4 scalp location according to the International 10–20 EEG system, contralateral to the affected knee. The cathode will be placed over the contralateral supraorbital region. Stimulation intensity will be ramped up to 2 mA over 30s, applied for 20 min and then ramped down to 0 mA over 30s. Immediately following the tDCS participants will complete a bout of isometric exercise where they will be instructed to maintain a target force until failure, defined as unable to sustain 25% of their maximum voluntary contraction for greater than or equal to 5-s, or a maximum of 5 minutes. After a minimum of 7 days, to ensure washout, the participant shall return to receive the crossover sham tDCS intervention.
Intervention code [1] 320496 0
Treatment: Devices
Comparator / control treatment
The order of interventions (active vs sham tDCS) will be randomised for each participant using a computer generated randomisation such that an equal number of participants have active and sham tDCS in their first session. In this crossover trial, all participants will partake in two treatment sessions, (‘Session 1’ and ‘Session 2’) delivered by a postgraduate qualified physiotherapist, with a minimum 7 day washout. Each of the two treatment sessions will last approximately 1-2 hours and will be closely matched in duration for the intervention and comparison groups. Participant adherence will be monitored during both sessions using a session attendance checklist. Participants will be comfortably seated in a chair while receiving transcranial Direct Current Stimulation (tDCS) and will be asked to remain quiet for the duration of the intervention whilst they watch a nature documentary. Participants in the sham (control) tDCS group will receive 20 min of sham stimulation. Stimulation will be applied using an HDCell (MagStim Co, UK) and 7 x 5 cm electrodes. The electrode sponges will be soaked in saline solution prior to application. The anode will be placed over the C3 or C4 scalp location according to the International 10–20 EEG system, contralateral to the affected knee. The cathode will be placed over the contralateral supraorbital region. Participants in the sham (control) tDCS group will receive the same intervention as the anodal (active) tDCS group except that stimulation intensity will be ramped up to 2 mA over 30s and then immediately ramped down to 0 mA over 30s to provide the initial itching sensation. Participants will be informed that they may or may not perceive any sensation during the treatment. This procedure has been shown to effectively blind participants to the stimulation condition. Immediately following the tDCS participants will complete a bout of isometric exercise where they will be instructed to maintain a target force until failure, defined as unable to sustain 25% of their maximum voluntary contraction for greater than or equal to 5-s, or a maximum of 5 minutes. After a minimum of 7 days, to ensure washout, the participant shall return to receive the crossover sham tDCS intervention.
Control group
Placebo

Outcomes
Primary outcome [1] 327443 0
The primary outcome will be change in exercise induced hypalgesia magnitude pre/post isometric exercise. Exercise induced hypalgesia response magnitude will be calculated as the change in pressure pain threshold (PPT) from immediately before to immediately after an acute bout of exercise ( isometric muscle contraction). PPT will be assessed using a hand held pressure algometer (SbMedic, Sweden) with a 1 cm rounded tip and a ramping rate of 30 kpa/s. Participants will be instructed to press a button at the moment they first experience pain from the probe (PPT) and the pressure achieved will be recorded. The average of 3 PPT measurements will be recorded for each site.
Timepoint [1] 327443 0
PPTs shall be assessed for all participants immediately pre and post the combination of real/sham tDCS + isometric exercise on both sessions 1 and 2.
Secondary outcome [1] 395144 0
The secondary outcome measure will be the change in resting knee pain intensity immediately pre and post the combination of real/sham tDCS + isometric exercise on both sessions 1 and 2. Resting knee pain intensity will be captured in sitting, with the knee flexed at 90 degrees. A 0 to 100 numerical rating scale will be used, with anchors of 0 = no pain and 100 = worst pain imaginable.
Timepoint [1] 395144 0
The change in resting knee pain intensity shall be assessed for all participants immediately pre and post the combination of real/sham tDCS + isometric exercise on both sessions 1 and 2.
Secondary outcome [2] 395145 0
An additional outcome measure will be the change in evoked pain intensity via the Staircase-Evoked Pain Procedure (StEPP) before and after isometric exercise.
Timepoint [2] 395145 0
The change in evoked pain intensity shall be assessed for all participants immediately pre and post the combination of real/sham tDCS + isometric exercise on both sessions 1 and 2.

Eligibility
Key inclusion criteria
Participants will be included if they are males and females greater than or equal to 40 years of age, meet The National Institute for Health and Care Excellence clinical criteria for the diagnosis of knee OA, have ongoing knee pain for greater than or equal to 3 months, and have an average pain intensity of greater than or equal to 3/10 numerical rating scale (NRS) in the last week at the time of screening. In the instance where participants have bilateral knee OA, the most painful knee will become the index knee.
Minimum age
40 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will be excluded if they have an inability to speak or write English; conditions preventing safe participation in physical activity (Failed Physical Activity Readiness Questionnaire (PAR-Q), are physically unable to climb 2 flights of stairs, have ever had a total knee replacement, had recent knee surgery (past 6 months), a history of lower limb resistance training (greater than or equal to 2 times per week for a minimum of 6 weeks within the past 6 months); any other form of arthritis (e.g. rheumatoid arthritis); a history of musculoskeletal pain or injury in the lower limb (other than osteoarthritis) in the past 6 months; any neurological condition; any unstable/uncontrolled cardiovascular condition; a current diagnosis of a major psychiatric disorder; any cognitive impairment; contraindications to tDCS (e.g., epilepsy, specific medications, frequent headaches).

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)
The study personnel conducting the recruitment and screening procedures will be unaware of the allocation schedule. Sealed, opaque envelopes will be used to maintain allocation concealment
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The order of interventions (active vs sham tDCS) will be randomised for each participant using a computer generated randomisation such that an equal number of participants have active and sham tDCS in their first session. This balancing will eliminate period and sequence effects.
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
The people analysing the results/data
Intervention assignment
Crossover
Other design features
n/a
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
A total of 27 participants are required to achieve a probability of 80% that the study will detect a difference in EIH between active and sham tDCS at a one-sided 0.05 significance level, with at least a moderate effect size of d = 0.5. There has only been one previous study of tDCS on EIH and, due to the way the data were presented, it was not possible to calculate an effect size. However, previous research (Flood et al., 2016) comparing a single session of active tDCS vs sham tDCS has shown a large effect (d = 0.92) on Conditioned Pain Modulation, another measure of endogenous descending inhibition that is related to EIH. As such, an effect size of d = 0.5 can be considered conservative.
Descriptive statistics will be calculated using IBM SPSS version 25 (IBM Corp, Armonk, NY). Normality of the data will be assessed through visual inspection and using the Shapiro-Wilk statistic. Depending on the distribution of the data and its responsiveness to transformation procedures, a longitudinal analysis of covariance (ANCOVA) or an analysis of variance (ANOVA) will be used to examine between session (active vs sham) differences in: EIH response (relative and absolute), change in evoked pain intensity, and change in pain intensity at rest. The presence of carry-over effects will be tested by including an indicator variable for periods in the statistical model. If carry-over effects are present, data from the first period will be used for the primary analysis whereas data from both the period will be presented in a separate exploratory analysis. A blinding index between 0 (complete unblinding) and 1 (complete blinding) will be calculated and reported. A significance level of 0.05 will be adopted. Secondary outcomes will be corrected for multiple comparisons.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
30/03/2022
Actual
29/03/2022
Date of last participant enrolment
Anticipated
30/03/2023
Actual
Date of last data collection
Anticipated
14/04/2023
Actual
Sample size
Target
27
Accrual to date
14
Final
Recruitment outside Australia
Country [1] 23682 0
New Zealand
State/province [1] 23682 0
Auckland

Funding & Sponsors
Funding source category [1] 308531 0
University
Name [1] 308531 0
Auckland University of Technology, North Shore Campus
Country [1] 308531 0
New Zealand
Primary sponsor type
University
Name
Auckland University of Technology, North Shore Campus
Address
Auckland University of Technology
90 Akoranga Drive, Northcote, Auckland, 0627
New Zealand
Country
New Zealand
Secondary sponsor category [1] 309388 0
None
Name [1] 309388 0
n/a
Address [1] 309388 0
n/a
Country [1] 309388 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308486 0
Health and Disability Ethics Committee
Ethics committee address [1] 308486 0
Ethics committee country [1] 308486 0
New Zealand
Date submitted for ethics approval [1] 308486 0
07/05/2021
Approval date [1] 308486 0
14/06/2021
Ethics approval number [1] 308486 0
21/STH/128

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

Contacts
Principal investigator
Name 110866 0
Dr David Rice
Address 110866 0
School of Clinical Sciences
Auckland University of Technology
Auckland
1142
New Zealand
Country 110866 0
New Zealand
Phone 110866 0
+64992199997032
Fax 110866 0
Email 110866 0
[email protected]
Contact person for public queries
Name 110867 0
David Rice
Address 110867 0
School of Clinical Sciences
Auckland University of Technology
Auckland
1142
New Zealand
Country 110867 0
New Zealand
Phone 110867 0
+64992199997032
Fax 110867 0
Email 110867 0
[email protected]
Contact person for scientific queries
Name 110868 0
David Rice
Address 110868 0
School of Clinical Sciences
Auckland University of Technology
Auckland
1142
New Zealand
Country 110868 0
New Zealand
Phone 110868 0
+64992199997032
Fax 110868 0
Email 110868 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
Participant consent has not been given.


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.