ANZCTR - Registration

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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

28/03/2023

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

Secondary ID [1]

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

Condition category

Condition code

Neurological

Other neurological disorders

Injuries and Accidents

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 fortnightly as it can decline across sessions. All stimuli will be delivered via a Digitimer Biphasic Constant Current multi-modal stimulator (DS8R).

Intervention code [1]

Treatment: Devices

Intervention code [2]

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 SCI.

Control group

Placebo

Outcomes

Primary outcome [1]

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]

Day 1 post-randomisation, 12 weeks (primary timepoint), and 16 weeks post-randomisation

Secondary outcome [1]

Walking ability without stimulation: The WISCI II will also be used to assess participants walking ability without the stimulation.

Timepoint [1]

Baseline, 12 weeks and 16 weeks post-randomisation

Secondary outcome [2]

Sensory function 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. Sensation (C2 to S4/5) will be assessed using a dermatomal-based sensory examination.

Timepoint [2]

Baseline, 12 weeks and 16 weeks post-randomisation

Secondary outcome [3]

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]

Baseline, 12 weeks and 16 weeks post-randomisation

Secondary outcome [4]

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]

Day 1 post-randomisation, 12 weeks and 16 weeks post-randomisation

Secondary outcome [5]

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 [5]

Baseline, 12 weeks and 16 weeks post-randomisation

Secondary outcome [6]

Spasticity with stimulation: Lower limb spasticity will also be assessed with stimulation using the Modified Ashworth Scale.

Timepoint [6]

Day 1 post-randomisation, 12 weeks and 16 weeks post-randomisation

Secondary outcome [7]

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 [7]

Baseline, 12 weeks and 16 weeks post-randomisation

Secondary outcome [8]

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 [8]

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 bilateral motor levels between T1 and T11
• have a Walking Index for Spinal Cord Injury II (WISCI II) between Level 1 and 6*
• 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
6 = Ambulates with walker, with braces and physical assistance of one person, 10 metres

Minimum age

16 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

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
• unable to elicit reflexes whilst experiencing the stimulation suggesting a lower motor neurone lesion
• have severe lower limb spasticity (MAS = 4 in any lower limb muscle)
• have extensive lower limb contractures preventing 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 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)

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

Recruiting

Date of first participant enrolment

Anticipated

8/03/2021

Actual

10/03/2021

Date of last participant enrolment

Anticipated

16/12/2024

Actual

Date of last data collection

Anticipated

16/04/2025

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,VIC

Recruitment hospital [1]

Neuroscience Research Australia (NeuRA) - Randwick

Recruitment hospital [2]

Swinburne University of Technology - Hawthorn

Recruitment postcode(s) [1]

3122 - Hawthorn

Recruitment outside Australia

Country [1]

Spain

State/province [1]

Toledo

Country [2]

United Kingdom

State/province [2]

Glasgow

Country [3]

United States of America

State/province [3]

Chicago

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Spinal Cure

Address [1]

Suite 3.04 / 80 Clarence Street Sydney, NSW 2000
Australia

Country [1]

Australia

Funding source category [2]

Charities/Societies/Foundations

Name [2]

Catwalk

Address [2]

PO BOX 555, MASTERTON 5840, NEW ZEALAND

Country [2]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

University of New South Wales Research Ethics Committee A

Ethics committee address [1]

The University of New South Wales
High St
Kensington NSW 2033

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

22/06/2020

Approval date [1]

14/08/2020

Ethics approval number [1]

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, 12 weeks and 16 weeks after randomisation.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Simon Gandevia

Address

Neuroscience Research Australia, Barker Street, Randwick, NSW, 2031, Australia

Country

Australia

Phone

+61 2 93991617

Fax

[email protected]

Contact person for public queries

Name

Simon Gandevia

Address

Neuroscience Research Australia, Barker Street, Randwick, NSW, 2031, Australia

Country

Australia

Phone

+61 2 93991617

Fax

[email protected]

Contact person for scientific queries

Name

Simon Gandevia

Address

Neuroscience Research Australia, Barker Street, Randwick, NSW, 2031, Australia

Country

Australia

Phone

+61 2 93991617

Fax

[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 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 [email protected].

What supporting documents are/will be available?

Doc. No.	Type	Other Details
8979	Study protocol	Not yet published
8980	Statistical analysis plan	Not yet published.
8981	Analytic 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

Source	Title	Year of Publication	DOI
Embase	Transcutaneous spinal cord stimulation combined with locomotor training to improve walking ability in people with chronic spinal cord injury: study protocol for an international multi-centred double-blinded randomised sham-controlled trial (eWALK).	2022	https://dx.doi.org/10.1038/s41393-021-00734-1

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically