Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000380594p
Ethics application status
Submitted, not yet approved
Date submitted
23/02/2024
Date registered
2/04/2024
Date last updated
2/04/2024
Date data sharing statement initially provided
2/04/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy of transcutaneous spinal cord stimulation combined with locomotor training to improve walking ability in people with chronic spinal cord injury: a multi-centre double-blinded randomised sham-controlled trial (eWALK2.0)
Scientific title
Efficacy of transcutaneous spinal cord stimulation combined with locomotor training to improve walking ability in people with chronic spinal cord injury: a multi-centre double-blinded randomised sham-controlled trial (eWALK2.0)
Secondary ID [1] 311106 0
None
Universal Trial Number (UTN)
U1111-1304-7350
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
spinal cord injury 332261 0
paralysis 332262 0
Condition category
Condition code
Neurological 328978 328978 0 0
Other neurological disorders
Physical Medicine / Rehabilitation 329867 329867 0 0
Other physical medicine / rehabilitation

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 week the participant will attend one session dedicated to overground walking while the other two sessions will be spent walking on the treadmill. Training will be delivered by one experienced spinal physiotherapist or exercise physiologist and up to two assistants as required.

Participants will be allowed 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 participants indicate they need to sit down to rest. The stimulation will be turned back on once the participant is back standing or resumes walking. If participants require 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 stimulation or sham will be turned off. A maximum of 60 minutes will be allotted to complete the 30 minutes of locomotor training regardless of whether 30 minutes of locomotor training with stimulation/sham has been completed..

Speed and body-weight support (BWS) will be adjusted throughout the training program to adapt training intensity. On the first training day, the amount of BWS will be assessed. Excessive knee flexion during stance phase (i.e., > 40°) or toe dragging during swing phase will be indicators of insufficient BWS. The amount of BWS required for overground versus treadmill walking may differ. Body-weight support will be reviewed at the end of each week with the goal of imposing maximum lower extremity weight bearing while maintaining proper locomotor biomechanics. No orthoses or gait aids will be worn while walking on the treadmill..

For overground training sessions, participants will be encouraged to walk at a comfortable pace throughout. 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.

The details of each training session provided to participants will be recorded by the therapist in a training diary. 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 horizontally over the lower abdomen and the cathode (5x10 cm) placed vertically over the lower thoracic/upper lumbar region (T10-L2). Stimulation will consist of an 800 – 1000 microseconds duration biphasic rectangular-wave pulse delivered at 20 Hz. The stimulus intensity will be set to the intensity found to evoke posterior-root muscle (PRM) reflexes in the quadriceps muscles (highest intensity between left and right sides) with a single pulse (i.e. threshold intensity) or to participants’ maximum tolerance, whichever is lowest. The PRM intensity will be re-assessed every four weeks as it can change across sessions. All stimuli will be delivered via a Digitimer Biphasic Constant Current multi-modal stimulator (DS8R) controlled by a custom-made control box designed by NeuRA.
Intervention code [1] 327554 0
Treatment: Devices
Intervention code [2] 327555 0
Rehabilitation
Comparator / control treatment
The sham stimulation group will receive surface spinal stimulation but it will be below the minimal intensity to induce bilateral posterior root-muscle reflex responses. The duration of training will be identical to the stimulation group. All participants will be informed that sensory and muscular responses to the stimulation adapt. 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 spinal cord injury (SCI).
Control group
Placebo

Outcomes
Primary outcome [1] 336802 0
Walking ability with stimulation (for experimental group) or sham (for control group)
Timepoint [1] 336802 0
The primary timepoint is 13 weeks after randomisation. The primary outcome will also be measured at Day 0 (one day after randomisation).
Secondary outcome [1] 429705 0
Walking ability without stimulation or sham
Timepoint [1] 429705 0
Baseline and 13 weeks after randomisation.
Secondary outcome [2] 429706 0
Walking ability without stimulation or sham (self report)
Timepoint [2] 429706 0
Baseline and 13-weeks and 6 months after randomisation.
Secondary outcome [3] 429708 0
Lower extremity motor function with stimulation (for experimental group) or sham (for control group)
Timepoint [3] 429708 0
Day 0 (one day after randomisation) and 13-weeks after randomisation.
Secondary outcome [4] 429709 0
Lower extremity motor function without stimulation or sham
Timepoint [4] 429709 0
Baseline and 13-weeks after randomisation.
Secondary outcome [5] 429710 0
Spasticity with stimulation (for experimental group) or sham (for control group)
Timepoint [5] 429710 0
Day 0 (one day after randomisation) and 13-weeks after randomisation.
Secondary outcome [6] 429711 0
Spasticity without stimulation or sham
Timepoint [6] 429711 0
Baseline and 13-weeks after randomisation.
Secondary outcome [7] 429712 0
Quality of life
Timepoint [7] 429712 0
Baseline and 13-weeks and 6-months after randomisation.
Secondary outcome [8] 429713 0
Independence
Timepoint [8] 429713 0
Baseline and 13-weeks and 6 months after randomisation.
Secondary outcome [9] 429714 0
Participants' impressions of therapeutic benefit of the training
Timepoint [9] 429714 0
13-weeks after randomisation
Secondary outcome [10] 429715 0
Participants' perceptions about their ability to perform self-selected goals
Timepoint [10] 429715 0
Baseline and 13-weeks and 6 months after randomisation
Secondary outcome [11] 429716 0
Neuropathic pain
Timepoint [11] 429716 0
Baseline and 13-weeks and 6 months after randomisation
Secondary outcome [12] 429717 0
Self-reported lower limb spasticity
Timepoint [12] 429717 0
Baseline and 13-weeks and 6 months after randomisation
Secondary outcome [13] 432096 0
Stimulation pain and discomfort
Timepoint [13] 432096 0
At each training session. An average pain rating over the 12-week training period will be calculated for each participant.

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 motor level between C2-T11 on one or both sides
• have a spinally evoked muscle reflex in at least one quadriceps muscle in response to transcutaneous spinal stimulation
• have a total lower limb International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) motor score of at least 4/50
• are willing and able to participate in the training program 3 times a week for 12 weeks, including a follow-up telephone call at 6 months after randomisation
• are able to take at least two steps with no harnessed body weight support. The steps may be completed with assistance (physically swinging the leg through by the therapist is not allowed), braces, gait aids or within parallel bars.
• are able to give informed consent and aged 16 years or over at the time of consent
• are considered by their spinal specialist to be medically stable to undertake the program (including clearance for standing/locomotor training)
Minimum age
16 Years
Maximum age
No limit
Sex
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 50% of the intensity required to evoke a reflex in the quadricep muscle
• 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 multiple long-bone fractures, family history of fragility fracture or any disorders of the bone, such as Paget’s disease
• have a progressive syringomyelia (syrinx) on serial MRI. Radiological findings that have been evaluated by a neurosurgeon as non-progressive may still be eligible
• have had open surgery within the last 3 months
• have severe lower limb spasticity or contracture that will interfere with the training program
• 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 stimulation such as cardiac pacemaker, lower limb fracture, baclofen pump, pregnancy, or implanted electronic devices
• 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)
A secure blocked random-allocation schedule will be computer-generated prior to commencement of the trial by an independent person not directly involved in the trial. The random-allocation schedule will consist of 88 three-digit codes: 44 assigned to the stimulation group and 44 assigned to the sham group. The three-digit codes will be used to program the stimulator control unit. The random allocation schedule will be uploaded to REDCap to allow each study site to randomise participants. To maintain blinded allocation, the REDCap random-allocation schedule will display the three-digit code, not the participant’s allocated group. A participant will be entered into the trial when baseline details are logged and the allocation is provided. Randomisation should occur within 3 weeks of the baseline assessment and after being checked and signed off by the sponsor (NeuRA).
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. The randomisation schedule will not be stratified but will be blocked ensuring equal numbers of sham and experimental participants.
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) linear models. Our primary analysis will use intention to treat. We will also perform a secondary complier average casual effect (CACE) analysis. Compliance will be defined as the number of minutes of stimulation received throughout the 12 weeks.

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

A detailed statistical plan will be developed prior to unblinding and this plan will be made publicly available.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
8/04/2024
Actual
Date of last participant enrolment
Anticipated
10/01/2028
Actual
Date of last data collection
Anticipated
3/07/2028
Actual
Sample size
Target
88
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,WA,VIC

Funding & Sponsors
Funding source category [1] 315362 0
Government body
Name [1] 315362 0
Department of Health and Aged Care - Medical Research Future Fund (MRFF)
Country [1] 315362 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Neuroscience Research Australia
Address
139 Barker St, Randwick
Country
Australia
Secondary sponsor category [1] 318225 0
None
Name [1] 318225 0
Address [1] 318225 0
Country [1] 318225 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 314281 0
The University of New South Wales Human Research Ethics Committee C
Ethics committee address [1] 314281 0
UNSW Sydney High St Kensington NSW 2052 Australia
Ethics committee country [1] 314281 0
Australia
Date submitted for ethics approval [1] 314281 0
04/03/2024
Approval date [1] 314281 0
Ethics approval number [1] 314281 0

Summary
Brief summary
We will conduct a multi-centred, double-blind randomised sham-controlled trial on 88 people with chronic SCI. The primary outcome will be walking ability measured using the Two Minute Walk Test (2MWT) with stimulation. 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 thirty minute 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 quality of life. Outcome measures will be taken at baseline, Day 0, 13-weeks and 6-months after randomisation. Our hypothesis is that spinal stimulation plus locomotor training in chronic SCI will improve walking ability, demonstrated by a clinically important change on the 2 Minute Walk test and that spinal stimulation will be a feasible and safe treatment that can be provided in a community setting.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 131046 0
Prof Jane Butler
Address 131046 0
Neuroscience Research Australia, Barker Street, Randwick, NSW, 2031, Australia
Country 131046 0
Australia
Phone 131046 0
+61 2 9399 1608
Fax 131046 0
Email 131046 0
j.butler@neura.edu.au
Contact person for public queries
Name 131047 0
Prof Jane Butler
Address 131047 0
Neuroscience Research Australia, Barker Street, Randwick, NSW, 2031, Australia
Country 131047 0
Australia
Phone 131047 0
+61 2 9399 1608
Fax 131047 0
Email 131047 0
j.butler@neura.edu.au
Contact person for scientific queries
Name 131048 0
Prof Jane Butler
Address 131048 0
Neuroscience Research Australia, Barker Street, Randwick, NSW, 2031, Australia
Country 131048 0
Australia
Phone 131048 0
+61 2 9399 1608
Fax 131048 0
Email 131048 0
j.butler@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, Jane Butler j.butler@neura.edu.au.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
21436Study protocol    Not yet published
21437Statistical analysis plan    Not yet published
21438Analytic code    Not yet published



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
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