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Trial registered on ANZCTR


Registration number
ACTRN12623000588695
Ethics application status
Approved
Date submitted
27/04/2023
Date registered
30/05/2023
Date last updated
28/05/2024
Date data sharing statement initially provided
30/05/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Get A Grip: Spinal stimulation for upper limb and respiratory function in complete tetraplegia
Scientific title
Get A Grip: Spinal stimulation for upper limb and respiratory function in complete tetraplegia
Secondary ID [1] 308659 0
nil
Universal Trial Number (UTN)
U1111-1292-8969
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Spinal Cord Injury- complete tetraplegia 328577 0
Condition category
Condition code
Neurological 325592 325592 0 0
Other neurological disorders
Injuries and Accidents 326836 326836 0 0
Other injuries and accidents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All groups will receive three 30-minute exercise training sessions in combination with transcutaneous spinal stimulation per week for six weeks, in the presence of an experienced exercise physiologist, physio- or occupational therapist. Participants are allocated into groups in an alternating fashion. The targeted upper limb will be chosen by the participant. Tasks will include 3 sets of 8-10 handgrips, wrist contractions and breaths through an inspiratory muscle training device (such as a Philips Threshold IMT) at 70% of the maximal voluntary contraction, which is likely to correspond to a Rating of Perceived Exertion of 7 out of 10, each session. Dexterity tasks using pegs, marbles, cups and other everyday objects will be practiced each session for 15 minutes. Task sets will be alternated in a random order to reduce the need to rest particular muscle groups and increase efficiency of the 30-minute exercise training session. Exercise intensity will be progressed as strength increases over the six weeks.
Transcutaneous spinal stimulation will be applied with two anode electrodes (5x5 cm) placed over left and right acromion processes, and the cathode (2.5x10 cm) placed vertically over the C3-C7 level. A Digitimer Constant Current multi-modal stimulator (DS8R) will be used to deliver the spinal stimulation. The stimulus will be 1ms duration biphasic square-wave pulses, delivered in a train at 30 Hz. Participants allocated to receive kHz frequency stimulation will be presented the same stimulus parameters with an additional carrier frequency of 10kHz. The amplitude of the stimulation will be set at the level of reflex threshold in the wrist extensors (tested with a single pulse for each participant) or below if the participant finds the stimulation uncomfortable (but not below 70% reflex threshold. Delivery of the stimulation will be driven by a control box which the therapist will set to provide stimulation only during active training.
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
Intervention code [1] 325128 0
Treatment: Other
Comparator / control treatment
In this Bayesian Optimal Phase II design study, there is no control group as the trial design does not allow for comparisons across arms. The study has two different arms of electrical stimulation therapy (30Hz or 10kHz), in order to identify which therapeutic strategies are futile or not. This trial will not determine which treatment is `'better`'.
Control group
Active

Outcomes
Primary outcome [1] 333433 0
Signal of benefit for effectiveness in measures of hand and inspiratory function WITH stimulation: The signal of benefit is achieved when at least one of the following thresholds are met: A score of 5.7 in the Action Research Arm Test (ARAT), 5 kg in the hand grip dynamometry (using Jamar dynamometers) and 10cmH20 for maximum inspiratory pressure (tested using a handheld Pro2fit device).
Timepoint [1] 333433 0
Baseline and week 6 post-intervention commencement
Primary outcome [2] 333434 0
Signal of benefit measure of safety: autonomic dysreflexia during training.
Autonomic dysreflexia (AD) occurs in 50-90% of people with a T6 or higher spinal cord injury. An AD episode is a dramatic rise in blood pressure with associated symptoms and signs in response to a noxious precipitant. Blood pressure will be measured using a sphygmomanometer. We will define an AD event as “an increase in systolic blood pressure by 20mmHg, and one of: sweating, chills, “goose flesh”, headache, or flushing” that fails to resolve with the participant’s usual, community interventions". If an AD event occurs that cannot be reversed during two separate therapy sessions, the safety stopping criteria will have been met for that participant.
Timepoint [2] 333434 0
Week 6 assessment post-intervention commencement
Primary outcome [3] 333435 0
Signal of benefit measure of acceptability: measure of adherence to the 6-week exercise training
For any therapy to be effective, recommended dose must be adhered to. Six weeks of exercise training is a typical dose. Adherence with at least 70% of prescribed exercise sessions in a pulmonary rehabilitation program has been demonstrated to deliver sufficient exercise for therapeutic and patient reported outcomes that exceed the minimally important dose. The same threshold will be used in this trial. Therapy attendance will be recorded in participant's training diaries. If adherence is below 70%, an audit of missed training sessions will occur to distinguish between whether participants "could not adhere" (e.g illness or recovering from SCI-related injuries) to the exercise program, or that they "would not adhere" (e.g did not want to attend training sessions or found training sessions of no use).
Timepoint [3] 333435 0
Week 6 assessment post-intervention commencement
Secondary outcome [1] 417100 0
Upper limb dexterity and function WITHOUT stimulation: Action Research Arm Test (ARAT)
The ARAT is a comprehensive test of upper limb function. The test involves 19 items used to assess grasp, grip, pinch and gross movement. Participants are asked to complete the first, most complex task of each domain. If they are able to complete the task, they receive a top score of 3 and move on to the next section. If the participant is not able to undertake the first task, they are scored according to the following criteria:
0= no movement
1= movement, task is partially performed
2= movement, task is completed but takes abnormally long
Timepoint [1] 417100 0
Baseline and week 6 post-intervention commencement
Secondary outcome [2] 417101 0
Hand grip dynamometer (Grip) WITHOUT stimulation: Grip strength will be measured according to a standardised procedure, using the dominant hand.
Timepoint [2] 417101 0
Baseline and week 6 post-intervention commencement
Secondary outcome [3] 419151 0
Maximal inspiratory pressure (MIP) WITHOUT stimulation: respiratory muscle strength will be measured using a Pro2fit device according to standard procedures.
Timepoint [3] 419151 0
Baseline and week 6 post-intervention commencement
Secondary outcome [4] 419153 0
Upper-limb strength WITH stimulation: Pinch grip dynamometry
The test is performed using the dominant hand according to a standardised procedure for lateral pinch test.
Timepoint [4] 419153 0
Baseline and week 6 post-intervention commencement
Secondary outcome [5] 419154 0
Upper-limb strength WITHOUT stimulation: Pinch grip dynamometry
The test is performed using the dominant hand according to a standardised procedure for lateral pinch test.
Timepoint [5] 419154 0
Baseline and week 6 post-intervention commencement
Secondary outcome [6] 419156 0
Upper-limb strength score using manual muscle testing WITH stimulation
Manual muscle testing in five muscles of the trained arm: elbow flexors, wrist extensors, elbow extensors, flexion of the distal phalanx of digit 3 and finger abduction of digit 5. A score from 0-5 will be given for each muscle, from total paralysis to full (normal) strength, the summed across the 5 muscles as a composite measure out of a possible total score of 25.
Timepoint [6] 419156 0
Baseline and week 6 post-intervention commencement
Secondary outcome [7] 419163 0
Upper-limb strength using manual muscle testing WITHOUT stimulation
Manual muscle testing in five muscles of the trained arm: elbow flexors, wrist extensors, elbow extensors, flexion of the distal phalanx of digit 3 and finger abduction of digit 5. A score from 0-5 will be given for each muscle, from total paralysis to full (normal) strength, the summed across the 5 muscles as a composite measure out of 25.
Timepoint [7] 419163 0
Baseline and week 6 post-intervention commencement
Secondary outcome [8] 419164 0
Sniff nasal inspiratory pressure (SNIP) WITH stimulation: SNIP is a standard test of respiratory muscle strength. SNIP will be assessed using a nasal pressure probe inserted into one nostril and connected to a handheld MicroRPM respiratory pressure meter.
Timepoint [8] 419164 0
Baseline and week 6 post-intervention commencement
Secondary outcome [9] 419166 0
Sniff nasal inspiratory pressure (SNIP) WITHOUT stimulation: SNIP is a standard test of respiratory muscle strength. SNIP will be assessed using a nasal pressure probe inserted into one nostril and connected to a handheld MicroRPM respiratory pressure meter.
Timepoint [9] 419166 0
Baseline and week 6 post-intervention commencement
Secondary outcome [10] 419167 0
Sustained maximal inspiratory pressure (SMIP) WITH stimulation: SMIP is a measure of inspiratory muscle performance using a Pro2fit device from residual lung volume to total lung capacity.
Timepoint [10] 419167 0
Baseline and week 6 post-intervention commencement
Secondary outcome [11] 421206 0
Sustained maximal inspiratory pressure (SMIP) WITHOUT stimulation: SMIP is a measure of inspiratory muscle performance using a Pro2fit device from residual lung volume to total lung capacity.
Timepoint [11] 421206 0
Baseline and week 6 post-intervention commencement
Secondary outcome [12] 422196 0
Theoretical Framework of Acceptability questionnaire: A composite measure consisting of 7 component constructs: affective attitude, burden, perceived effectiveness, ethicality, intervention coherence, opportunity cost and self-efficacy. Each question is measured on a scale from 1-5.
Timepoint [12] 422196 0
Week 6 post-intervention commencement
Secondary outcome [13] 422197 0
Goal setting questionnaires: participants will be asked to set one desirable outcome for the 6-week training program. At trial completion, they will be asked to report their progress towards the previously defined goal on a 11-point Likert scale from 0-10.
Timepoint [13] 422197 0
Baseline and week 6 post-intervention commencement
Secondary outcome [14] 428223 0
Capabilities of Upper Extremity Questionnaire: designed to find out how well the participant uses their hand and arms.
Timepoint [14] 428223 0
Baseline and week 6 post-intervention commencement

Eligibility
Key inclusion criteria
- Aged 18 years or older
- Diagnosed with a motor complete spinal cord injury between the levels of C2 and C8 at least one year ago and able to breathe independently
- Willing and able to participate in a training program three times a week for 6 weeks
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Have a history of clinically significant autonomic dysreflexia in response to electrical stimulation
• Unable to elicit reflexes whilst experiencing the stimulation
• Cannot tolerate spinal stimulation at a therapeutic intensity
• Have a progressive neurological disease or other major neurological condition other than the spinal cord injury (e.g., severe traumatic brain injury or stroke)
• Open surgery within the last 3 months
• Syrinx (fluid-filled cyst or cavity in spinal cord) on recent MRI
• Severe upper limb spasticity or contractures
• Any serious medical condition, cognitive impairment (i.e. trouble remembering or learning), drug dependency, psychiatric illness or behavioural problem preventing you from adhering to the protocol
• Cardiac pacemaker or pregnant
• Stem cell or olfactory ensheathing cell therapy within the last 5 years
• Currently taking part, or in the follow-up period, of any other clinical trial

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised 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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Bayesian Optimal Phase II trial design
The Bayesian Optimal Phase II analysis controls for type I and II errors while maintaining power. This analysis prevents the participant exposure to a treatment that may be futile. The null hypothesis is that the true good outcome response rate is 0.3, and the alternative hypothesis is that the true good outcome response rate is 0.6. For each individual trial (Intervention arm) under the umbrella, the rate of promising response will be tested at predefined stopping points; too few good outcomes will result in stopping recruitment for an individual Intervention arm. The BOP II for each Intervention arm trial is conducted in two stages. In Stage 1, participants are allocated to one of two Intervention arms (n=12 each). If there are fewer than 5 good outcomes among the first 12 participants, the Intervention arm is stopped for futility. If the Stage 1 hurdle is passed, the remaining 12 participants per group will be recruited (Stage 2) resulting in a total sample of 24 participants per Intervention arm. If, at the end of Stage 2, there are 11 or more good outcomes among these 24 participants, we reject the null hypothesis, attest that the intervention in that arm “shows promise” and can progress to a seamless Phase IIb/III trial (trial design including interim analyses and sample size calculations can be found at URL: trialdesign.org/one-page-shell.html#BOP2) . The design controls the type I error rate at 0.05 and yields power of 0.92.
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
All outcomes will be analysed with multi-level (i.e. mixed) models. 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 and week 6) and group (injury type, stimulation paradigm) will be fixed factors, and participant 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
2/08/2023
Actual
2/08/2023
Date of last participant enrolment
Anticipated
1/06/2027
Actual
Date of last data collection
Anticipated
14/07/2027
Actual
Sample size
Target
48
Accrual to date
12
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,WA,VIC
Recruitment outside Australia
Country [1] 26350 0
New Zealand
State/province [1] 26350 0
Auckland

Funding & Sponsors
Funding source category [1] 312890 0
Charities/Societies/Foundations
Name [1] 312890 0
Spinal Cure
Country [1] 312890 0
Australia
Primary sponsor type
Other
Name
Neuroscience Research Australia (NeuRA)
Address
139 Barker Street, Randwick, NSW, 2031
Country
Australia
Secondary sponsor category [1] 314572 0
None
Name [1] 314572 0
Address [1] 314572 0
Country [1] 314572 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312167 0
UNSW HREC
Ethics committee address [1] 312167 0
Cnr High Street and Botany Street, UNSW, Sydney, Kensington, NSW, 2052
Ethics committee country [1] 312167 0
Australia
Date submitted for ethics approval [1] 312167 0
24/01/2023
Approval date [1] 312167 0
31/01/2023
Ethics approval number [1] 312167 0
HC220817

Summary
Brief summary
Fifty five percent of all spinal cord injuries result in tetraplegia and with impaired motor and sensory function of arms, hands, legs and respiratory muscles. For people with tetraplegia, restoration of hand and arm function ranks highest of all functional recovery targets, closely followed by improved breathing and coughing. Exercise training is the main treatment for improving upper-limb and respiratory function after spinal cord injury. Emerging evidence from pre-clinical and clinical studies suggest transcutaneous spinal cord neuro-stimulation (TSS), increases spinal cord excitability through increased reflex input. The aim of this study is to explore the efficacy, safety, and acceptability of TSS combined with exercise training for chronic tetraplegia, targeting hand and respiratory function in a multi-centre community-based adaptive Bayesian Optimal Phase (BOP) II trial design across Australia. A BOP trial design allows for early analysis, identifying and ceasing trial arms that prove to be futile to continue. We hypothesise participants with complete SCI may improve in their strength and breathing outcome measures, however, it is not known whether the improvement will reach the pre-determined signal of benefit.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 123710 0
Prof Jane Butler
Address 123710 0
Neuroscience Research Australia
139 Barker Street, Randwick, NSW 2031
Country 123710 0
Australia
Phone 123710 0
+61 02 9399 1608
Fax 123710 0
Email 123710 0
j.butler@neura.edu.au
Contact person for public queries
Name 123711 0
Dr Terry Trinh
Address 123711 0
Neuroscience Research Australia
139 Barker Street, Randwick, NSW 2031
Country 123711 0
Australia
Phone 123711 0
+61 02 9399 1887
Fax 123711 0
Email 123711 0
t.trinh@neura.edu.au
Contact person for scientific queries
Name 123712 0
Prof Jane Butler
Address 123712 0
Neuroscience Research Australia
139 Barker Street, Randwick, NSW 2031
Country 123712 0
Australia
Phone 123712 0
+61 02 9399 1608
Fax 123712 0
Email 123712 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?
Demographic information and primary and secondary outcome assessment data
When will data be available (start and end dates)?
01/05/2023 until 01/12/2027
Available to whom?
Researchers who provide a methodologically sound proposal will be assessed on a case-by-case basis at the discretion of the Principal Investigator, Prof Jane Butler.
Available for what types of analyses?
Any purpose
How or where can data be obtained?
Access subject to approval from Principal Investigator, Prof Jane Butler: j.butler@neura.edu.au


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.