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Trial registered on ANZCTR


Registration number
ACTRN12620001241921
Ethics application status
Approved
Date submitted
23/09/2020
Date registered
20/11/2020
Date last updated
20/11/2020
Date data sharing statement initially provided
20/11/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
To investigate transcutaneous spinal cord stimulation combined with locomotor training on walking ability in people with chronic spinal cord injury: a multi-centre double-blinded randomised sham-controlled trial (eWALK)
Scientific title
To investigate transcutaneous spinal cord stimulation combined with locomotor training on walking ability in people with chronic spinal cord injury: a multi-centre double-blinded randomised sham-controlled trial
Secondary ID [1] 301269 0
Nil
Universal Trial Number (UTN)
U1111-1251-9618
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
spinal cord injury 317444 0
Condition category
Condition code
Neurological 315535 315535 0 0
Other neurological disorders
Injuries and Accidents 317423 317423 0 0
Other injuries and accidents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All participants will receive three 30 minute locomotor training sessions combined with either spinal stimulation or sham each week over 12 weeks. The locomotor training will consist of walking on a treadmill and overground for 30 minutes. Each participant will attend one session dedicated to overground walking only while the other two sessions will be spent walking on the treadmill. Training will be delivered by one experienced spinal physiotherapist and up to two assistants as required.

Participants will be allowed either seated or standing rests as needed throughout the training session. The rest periods will not contribute to the overall 30 minutes of training. The stimulation/sham will be turned off immediately if a participant indicates they need to sit down to rest. If a participant requires a rest but can stay standing, the stimulation/sham will stay on and a timer will be started by one of the therapists. If the participant does not resume locomotor training within 1 minute, the stimulator will be turned off. A maximum of 60 minutes will be allotted to complete the 30 minutes of locomotor training.

Speed and body-weight support (BWS) are the two parameters that will be adjusted throughout the training program to change training intensity. Body-weight support will be reviewed at the end of each week with the goal of imposing maximum lower extremity weight bearing.

The speed for all participants will start at 0.2m/s on the first training day and will be slowly increased throughout the training session as tolerated. Speed will be decreased if the stepping quality begins to degrade (e.g., excessive knee flexion during stance phase or toe dragging during swing phase).

Orthoses, gait aides, parallel bars or safety harnesses will be used on a case by case basis for optimising safety and will be documented in the participants training diaries along with any changes. However, knee-ankle-foot orthoses will not be used during locomotor training. Manual assistance to the lower limbs will be provided as required to enhance motor learning and improve walking patterns based on established locomotor protocols. When walking on the treadmill, participants will be permitted to hold the side rails for stability while walking. The rails will be positioned at about chest height to prevent weight bearing through the arms. As participants progress, they will be encouraged to add arm swinging if safe to do so.

The details of each training session provided to participants will be recorded by the therapist in a training diary. The training diary will be used to document; whole session time, perceived exertion, braces/gait aids used, amount of body weight support and all other parameters of each training session. If a participant is unable to attend one of the weekly training sessions, a makeup session will be attempted to ensure they attend three sessions a week. Reasons if unable to attend will be documented in the training diary.

Transcutaneous spinal stimulation will be applied with the anode (5 x 10 cm) placed over the lower abdomen and the cathode (3 cm diameter) over the T11-L1 level. The stimulus will be 1ms of a 10kHz biphasic square-wave, pulsed at 15-30 Hz. The stimulus intensity during the intervention will be approximately 5% above the minimal stimulus intensity that induces bilateral posterior root-muscle reflex responses. The intensity will be re-assessed every week as it can decline across sessions. To ensure responses are the result of dorsal root stimulation (rather than direct stimulation of the spinal cord or the anterior roots), paired bursts will be delivered and the presence of post-activation depression verified. Specifically, two pulses with an inter-stimulus interval of 50 ms will be delivered, and the amplitude of the two evoked responses will be compared; dorsal root stimulation should result in the second evoked response being smaller than the first response. All stimuli will be delivered via a Digitimer Biphasic Constant Current multi-modal stimulator (DS8R).
Intervention code [1] 317574 0
Treatment: Devices
Intervention code [2] 317575 0
Rehabilitation
Comparator / control treatment
The sham stimulation group will receive identical stimulation. That is, the electrodes location and stimulus intensity will be determined in the same way. However, when the stimulation is applied at the start of each session, it will be set to 15-30% below the minimal stimulus intensity that induces bilateral posterior root-muscle reflex responses. Then, after 1 minute, the intensity will decay to zero intensity (i.e. 0 mA) over 2 minutes. The stimulus intensity and its decay will be controlled from a specially designed stimulator box, with the electrical stimulation and sham stimulation boxes looking identical. Thus, therapists and participants will be blinded to the form of stimulation delivered. All participants will be informed that sensory and muscular responses to the stimulation adapt. Thus, participants who have sensation at the site of stimulation will not be surprised when the intensity of the stimulation subsides over the first few minutes; the evoked muscle responses in lower extremity muscles are imperceptible and will not be perceived in either the stimulation or sham group. This form of sham stimulation has been used in studies on the therapeutic benefits of transcranial direct current stimulation, including in SCI.
Control group
Placebo

Outcomes
Primary outcome [1] 323784 0
Walking ability with stimulation: Walking ability will be measured using the Walking Index for Spinal Cord Injury II (WISCI II). It considers the amount of physical assistance, braces or devices (parallel bars, walker or cane) required to walk 10 metres. An experienced therapist will rate the participants.
Timepoint [1] 323784 0
Day 1 post-randomisation, 12 weeks (primary timepoint), and 16 weeks post-randomisation
Secondary outcome [1] 382885 0
Walking ability without stimulation: The WISCI II will also be used to assess participants walking ability without the stimulation.
Timepoint [1] 382885 0
Baseline, 12 weeks and 16 weeks post-randomisation
Secondary outcome [2] 382886 0
Lower extremity sensation without stimulation: This will be assessed using the sensory score of the International Standards for Neurological classification of SCI (ISNCSCI), including both pin prick and light touch sensation. Lower extremity sensation (L1 to S4/5) will be assessed using a dermatomal-based sensory examination.

Timepoint [2] 382886 0
Baseline, 12 weeks and 16 weeks post-randomisation
Secondary outcome [3] 382887 0
Lower extremity motor function without stimulation: This will be assessed with the lower extremity motor score from the ISNSCI. This involves performing manual muscle testing in 5 leg muscles bilaterally.
Timepoint [3] 382887 0
Baseline, 12 weeks and 16 weeks post-randomisation
Secondary outcome [4] 382888 0
Lower extremity motor function with stimulation: This will be assessed with the lower extremity motor score from the ISNSCI. This involves performing manual muscle testing in 5 leg muscles bilaterally.
Timepoint [4] 382888 0
Day 1 post-randomisation, 12 weeks and 16 weeks post-randomisation
Secondary outcome [5] 382889 0
Walking speed without stimulation: Walking speed will be measured using the 10 Metre Walk Test (10MWT). The 10MWT is a performance measure used to assess walking speed in metres per second over a short distance. The participant will be instructed to walk as fast as they can safely manage. The total time taken to walk 6 metres will be recorded to the nearest second. 6m is then divided by the total time (in seconds) taken to ambulate and recorded in m/s. Each participant will be allowed two trials at his/her fastest walking speed. The two trials will be averaged. The time is measured for the middle 6m to allow for participant acceleration and deceleration. Participants will be allowed to use any devices or bracing that they are using at the time. At the follow-up assessment, two assessments will be performed, one using their baseline devices and braces and one with their preferred devices and braces. The type of device and/or bracing will be documented. Assistance will be provided to prevent a fall or collapsing (i.e. knee buckling, trunk collapse, etc.). Assistance will not be provided for limb swing, or any other manner in which the assistance is propelling the participant forward.
Timepoint [5] 382889 0
Baseline, 12 weeks and 16 weeks post-randomisation
Secondary outcome [6] 382890 0
Walking speed with stimulation: Walking speed will also be assessed with the stimulation using the 10 Metre Walk Test.

Timepoint [6] 382890 0
Day 1 post-randomisation, 12 weeks and 16 weeks post-randomisation
Secondary outcome [7] 382891 0
Spasticity without stimulation: Lower limb spasticity will be assessed using the Modified Ashworth Scale, a standardised clinical measure of muscle spasticity. For this measure, participants will lie supine on a bed and have their limbs passively moved through range by a physiotherapist who will evaluate the degree of stiffness (tone) using a six-point scale (0-5). Three lower limb muscle groups will be tested; knee extensors, ankle plantarflexors, hip flexors and a total combined score out of 15 will be recorded.
Timepoint [7] 382891 0
Baseline, 12 weeks and 16 weeks post-randomisation
Secondary outcome [8] 388025 0
Spasticity with stimulation: Lower limb spasticity will also be assessed with stimulation using the Modified Ashworth Scale.
Timepoint [8] 388025 0
Day 1 post-randomisation, 12 weeks and 16 weeks post-randomisation
Secondary outcome [9] 388027 0
Bowel function: Bowel function will be assessed using the Neurogenic Bowel Dysfunction (NBD) score, a validated 10-item score commonly used for assessment of bowel symptoms in individuals with SCI. The NBD produces a severity score/47: greater than or equal to 14 severe, 10-13 moderate, 7-9 minor, 0-6 very minor bowel dysfunction.
Timepoint [9] 388027 0
Baseline, 12 weeks and 16 weeks post-randomisation
Secondary outcome [10] 388028 0
Quality of life: Quality of life will be assessed using the EQ-5D-5L which is a standardised preference-based measure of health status that is widely used around the world in clinical trials. The EQ-5D-5L comprises a short descriptive system questionnaire and a visual analogue scale out of 100. The questionnaire provides a simple descriptive profile of a participant’s health state. An index value is then derived by applying a formula that attaches values (weights) to each of the levels in each dimension.
Timepoint [10] 388028 0
Baseline, 12 weeks and 16 weeks post-randomisation

Eligibility
Key inclusion criteria
A person will be eligible to participate if they:
• have a SCI sustained a minimum of 12 months prior to consent
• have a neurological level between T2 and T11
• have a Walking Index for Spinal Cord Injury II (WISCI II) between Level 1 and 5*
• have a reproducible, voluntary muscle flicker/contraction in at least one muscle that flexes or extends the hip, knee, ankle or big toe, on either side of the body
• are willing and able to participate in the stimulation/locomotor training program 3 times a week for 12 weeks, including one follow-up visit at 16 weeks
• are aged 16 years or over at the time of consent and able to give informed consent
• are considered by their spinal specialist to be medically stable to undertake the program (including clearance for standing/locomotor training)

*1 = Ambulates in parallel bars, with braces and physical assistance of two persons, but less than 10 metres
5 = Ambulates in parallel bars, with no braces and no physical assistance, 10 metres
Minimum age
16 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
A person will be ineligible to participate if they:
• have a history of clinically significant autonomic dysreflexia in response to electrical stimulation
• cannot tolerate transcutaneous spinal stimulation at a therapeutic intensity
• have a history of hypotension in response to prolonged standing
• have a progressive neurological disease and any other major neurological lesion additional to the spinal cord injury, e.g., a severe traumatic brain injury or stroke
• have a history of long-bone fracture, family history of fragility fracture or any disorders of the bone, such as Paget’s disease
• have a syringomyelia (syrinx) on recent MRI. Radiological findings such as myelomalacia which have been evaluated by a neurosurgeon as non-progressive may still be eligible
• have had open surgery within the last 3 months
• have absent bilateral patella tendon reflexes suggesting a lower motor neurone lesion
• have severe lower limb spasticity (MAS equal to 4 in any lower limb muscle)
• have extensive lower limb contractures (limiting ROM greater than or equal to 30% within normal ranges required for ambulation)
• have any serious medical condition, cognitive impairment, drug dependency, psychiatric illness or behavioural problem preventing them from adhering to the protocol
• have an existing pressure ulcer Stage 3 or 4 according to the National Pressure Ulcer Advisory Panel classification
• have a previous pressure ulcer treated with a myocutaneous flap using a graft from a locomotor muscle such as the gluteal or hamstring
• have any contraindications to electrical spine or brain stimulation such as cardiac pacemaker, epilepsy, lower limb fracture, baclofen pump, pregnancy, intracranial metal implants or hardware near the stimulation site
• have an upper limb injury preventing prolonged weight bearing through their arms
• have had stem cell or olfactory ensheathing cell therapy within the last 5 years
• are actively participating, or are in the follow-up period, of any other clinical trials

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)
If a participant meets the inclusion criteria, he/she will be invited to participate and given a Participant Information Sheet for consideration.
A secure random-allocation schedule will be computer-generated prior to commencement of the trial by an independent person and kept at a central off-site location. The randomisation schedule will not be stratified but will be blocked ensuring equal numbers of sham and experimental participants. A participant will be entered into the trial when baseline details are logged at the central site and the allocation is provided. The person responsible for central randomisation will notify the researcher, responsible for setting the stimulation parameters, of the treatment assignment. This will not be disclosed to the blinded assessors, participants or therapists.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A secure random-allocation schedule will be computer-generated prior to commencement of the trial by an independent person and kept at a central off-site location. The randomisation schedule will not be stratified but will be blocked ensuring equal numbers of sham and experimental participants. A participant will be entered into the trial when baseline details are logged at the central site and the allocation is provided. The person responsible for central randomisation will notify the researcher, responsible for setting the stimulation parameters, of the treatment assignment. This will not be disclosed to the blinded assessors, participants or therapists.
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
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
All outcomes will be analysed with multi-level (i.e. mixed) models. Ordinal measures with few scale values (e.g. Modified Ashworth Scale) will be assessed using multi-level ordinal logistic regression. Ordinal measures with many scale values (e.g. WISCI II) will be assessed using multi-level linear regression. A strategy will be devised to verify the appropriateness of statistical procedures (diagnostic tests) and propose appropriate alternative analyses (data transformations, alternative models) and the order in which these should be tried.

For all multi-level models, time (baseline, day 1, 12 weeks, 16 weeks) and group (stimulation, sham) will be fixed factors, and participant will be will be a random factor with a random intercept. Baseline values will be included as a covariate.

Contrasts related to our primary and secondary hypotheses will be performed and results reported as mean effects and 95% confidence intervals.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 16660 0
Neuroscience Research Australia (NeuRA) - Randwick
Recruitment outside Australia
Country [1] 22554 0
Spain
State/province [1] 22554 0
Toledo
Country [2] 22555 0
United Kingdom
State/province [2] 22555 0
Glasgow
Country [3] 22556 0
United States of America
State/province [3] 22556 0
Chicago

Funding & Sponsors
Funding source category [1] 306782 0
Charities/Societies/Foundations
Name [1] 306782 0
Spinal Cure
Address [1] 306782 0
Suite 3.04 / 80 Clarence Street Sydney, NSW 2000
Australia
Country [1] 306782 0
Australia
Funding source category [2] 306783 0
Charities/Societies/Foundations
Name [2] 306783 0
Catwalk
Address [2] 306783 0
PO BOX 555, MASTERTON 5840, NEW ZEALAND
Country [2] 306783 0
New Zealand
Primary sponsor type
Other Collaborative groups
Name
Neuroscience Research Australia
Address
139 Barker St, Randwick NSW 2031
Country
Australia
Secondary sponsor category [1] 307334 0
None
Name [1] 307334 0
Address [1] 307334 0
Country [1] 307334 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306736 0
University of New South Wales Research Ethics Committee A
Ethics committee address [1] 306736 0
The University of New South Wales
High St
Kensington NSW 2033
Ethics committee country [1] 306736 0
Australia
Date submitted for ethics approval [1] 306736 0
22/06/2020
Approval date [1] 306736 0
14/08/2020
Ethics approval number [1] 306736 0
HC200478

Summary
Brief summary
We will conduct a multi-centred, double-blind randomised sham-controlled trial on 50 people with chronic SCI. The primary outcome will be walking ability measured using the Walking Index for SCI II (WISCI II). Participants will be randomised to either the Stimulation group or the Sham group. All participants will receive the same intensive locomotor training consisting of three one hour sessions per week, over 12 weeks, in combination with either stimulation or sham stimulation. The secondary outcomes will capture different aspects of recovery, strength, spasticity, and bowel function. Outcome measures will be taken at baseline, 6 weeks, 12 weeks and 16 weeks after randomisation.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 50642 0
Prof Simon Gandevia
Address 50642 0
Neuroscience Research Australia, Barker Street, Randwick, NSW, 2031, Australia
Country 50642 0
Australia
Phone 50642 0
+61 2 93991617
Fax 50642 0
Email 50642 0
s.gandevia@neura.edu.au
Contact person for public queries
Name 50643 0
Prof Simon Gandevia
Address 50643 0
Neuroscience Research Australia, Barker Street, Randwick, NSW, 2031, Australia
Country 50643 0
Australia
Phone 50643 0
+61 2 93991617
Fax 50643 0
Email 50643 0
scirc-team@neura.edu.au
Contact person for scientific queries
Name 50644 0
Prof Simon Gandevia
Address 50644 0
Neuroscience Research Australia, Barker Street, Randwick, NSW, 2031, Australia
Country 50644 0
Australia
Phone 50644 0
+61 2 93991617
Fax 50644 0
Email 50644 0
scirc-team@neura.edu.au

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 will be made available. Demographic data will be presented in summary format.
When will data be available (start and end dates)?
At the completion of the trial once published. There will be no end date to data availability.
Available to whom?
On a case-by-case basis at the discretion of principal investigator.
Available for what types of analyses?
Any purpose
How or where can data be obtained?
Upon request from the principle investigator, Simon Gandevia s.gandevia@neura.edu.au.
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Analytic code
How or where can supporting documents be obtained?
Type [1] 8979 0
Study protocol
Citation [1] 8979 0
Link [1] 8979 0
Email [1] 8979 0
Other [1] 8979 0
Not yet published
Attachment [1] 8979 0
Type [2] 8980 0
Statistical analysis plan
Citation [2] 8980 0
Link [2] 8980 0
Email [2] 8980 0
Other [2] 8980 0
Not yet published.
Attachment [2] 8980 0
Type [3] 8981 0
Analytic code
Citation [3] 8981 0
Link [3] 8981 0
Email [3] 8981 0
Other [3] 8981 0
Not yet published.
Attachment [3] 8981 0
Summary results
No Results