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Trial registered on ANZCTR


Registration number
ACTRN12623000793617
Ethics application status
Approved
Date submitted
10/07/2023
Date registered
24/07/2023
Date last updated
28/05/2024
Date data sharing statement initially provided
24/07/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Get A Grip: Spinal stimulation for upper limb and respiratory function in incomplete tetraplegia
Scientific title
Get A Grip: Spinal stimulation for upper limb and respiratory function in incomplete tetraplegia: a Bayesian Optimal Phase II trial
Secondary ID [1] 309824 0
None
Universal Trial Number (UTN)
U1111-1294-6663
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Spinal Cord Injury- Incomplete tetraplegia 330240 0
Condition category
Condition code
Neurological 327109 327109 0 0
Other neurological disorders
Injuries and Accidents 327521 327521 0 0
Other injuries and accidents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All groups will be prescribed 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. Only one target upper limb will be trained which will be chosen by the participant. Tasks will include 3 sets of 8-10 handgrips, wrist extension contractions and breaths through an inspiratory muscle training device at 70% of their maximal voluntary contraction. Dexterity tasks using pegs, marbles, cups and other everyday objects will be practiced each session for 15 minutes. Task sets will be alternated in 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 spinous processes. 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 (conventional). Participants allocated to receive kHz frequency stimulation will be presented the same stimulus parameters with an additional carrier frequency of 10kHz (high frequency). Participants will be allocated in an alternating fashion based on grip strength. 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. Reasons if unable to attend will be documented in the training diary.
Intervention code [1] 326256 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 conventional or 10kHz burst modulated stimulation), 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] 334977 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] 334977 0
Baseline and week 6 post-intervention commencement
Primary outcome [2] 334978 0
Signal of benefit measure of safety: autonomic dysreflexia during training.
Blood pressure will be measured using a sphygmomanometer. We will define an autonomic dysreflexic 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 autonomic dysreflexic event occurs that cannot be reversed during two separate therapy sessions, the safety stopping criteria will have been met for that participant.
Timepoint [2] 334978 0
Safety will be assessed continuously throughout all sessions.
Primary outcome [3] 334979 0
Signal of benefit measure of acceptability: measure of adherence to the 6-week exercise training program.
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 complications) 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). The latter will only count towards missed sessions.
Timepoint [3] 334979 0
Week 6 assessment post-intervention commencement
Secondary outcome [1] 423142 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] 423142 0
Baseline and week 6 post-intervention commencement
Secondary outcome [2] 423143 0
Hand grip dynamometry (Grip) WITHOUT stimulation: Grip strength of the target limb will be measured according to a standardised procedure using a Jamar Dynamometer.
Timepoint [2] 423143 0
Baseline and week 6 post-intervention commencement
Secondary outcome [3] 423144 0
Maximal inspiratory pressure (MIP) WITHOUT stimulation: respiratory muscle strength will be measured using a handheld Pro2fit device according to standard procedures.
Timepoint [3] 423144 0
Baseline and week 6 post-intervention commencement
Secondary outcome [4] 423145 0
Upper-limb strength WITH stimulation: Pinch grip dynamometry. The test is performed by the target limb according to a standardised procedure for lateral pinch test.
Timepoint [4] 423145 0
Baseline and week 6 post-intervention commencement
Secondary outcome [5] 423146 0
Upper-limb strength WITHOUT stimulation: Pinch grip dynamometry: The test is performed by the target limb according to a standardised procedure for lateral pinch test using a Jamar Dynamometer.
Timepoint [5] 423146 0
Baseline and week 6 post-intervention commencement
Secondary outcome [6] 423147 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 will be performed. A score from 0-5 will be given for each muscle, and a total score out of 25 will be recorded.
Timepoint [6] 423147 0
Baseline and week 6 post-intervention commencement
Secondary outcome [7] 423148 0
Upper-limb strength score 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 will be performed. A score from 0-5 will be given for each muscle, and a total score out of 25 will be recorded.
Timepoint [7] 423148 0
Baseline and week 6 post-intervention commencement
Secondary outcome [8] 423149 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] 423149 0
Baseline and week 6 post-intervention commencement
Secondary outcome [9] 423150 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] 423150 0
Baseline and week 6 post-intervention commencement
Secondary outcome [10] 423151 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] 423151 0
Baseline and week 6 post-intervention commencement
Secondary outcome [11] 423152 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] 423152 0
Baseline and week 6 post-intervention commencement
Secondary outcome [12] 423161 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] 423161 0
Week 6 post-intervention commencement
Secondary outcome [13] 423164 0
Goal setting questionnaires: participants will be asked to set one upper limb goal and one breathing goal they would like to achieve by the end of 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] 423164 0
Baseline and week 6 post-intervention commencement
Secondary outcome [14] 423785 0
Neuropathic pain question:
Participants will be asked to rate the average amount of neuropathic pain experienced over the past 7 days from 0-10 on a visual analogue scale.
Timepoint [14] 423785 0
Baseline and week 6 post-intervention commencement
Secondary outcome [15] 423788 0
Spasticity severity question:
Participants will be asked to rate the overall severity of spasticity over the past 7 days from 0-10 on a visual analogue scale.
Timepoint [15] 423788 0
Baseline and week 6 post-intervention commencement
Secondary outcome [16] 424233 0
Spasticity impact question:
Participants will be asked to rate the overall impact of spasticity on daily life over the past 7 days from 0-10 on a visual analogue scale.
Timepoint [16] 424233 0
Baseline and week 6 post-intervention commencement
Secondary outcome [17] 424234 0
Capabilities of upper extremity questionnaire
A 17-item questionnaire to measure upper extremity function in people with tetraplegia. Participants are asked how well they perform each task using their target/trained arm on a scale from 1-7, whereby 1 represents "totally limited" and 7 representing "not limited at all"
Timepoint [17] 424234 0
Week 6 post-intervention commencement

Eligibility
Key inclusion criteria
- Aged 18 years or older
- Have a motor incomplete (American Spinal Injury Association (ASIA) Impairment Scale (AIS) C or D) spinal cord injury sustained a minimum of 12 months prior to consent.
- Able to breathe independently
- Have an injury level between C2 and C8 neurological levels.
- 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
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
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.

Although BOP II design does not allow for comparisons between study groups, forced allocation based on grip strength will allow for the two groups to be balanced. Participants are stratified based on grip strength (grip/ no grip), and then allocated in an alternating fashion into one of two stimulating frequency groups.
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
31/07/2023
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
14
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,WA,VIC
Recruitment outside Australia
Country [1] 26349 0
New Zealand
State/province [1] 26349 0
Auckland

Funding & Sponsors
Funding source category [1] 314009 0
Charities/Societies/Foundations
Name [1] 314009 0
SpinalCure Australia
Country [1] 314009 0
Australia
Primary sponsor type
Other
Name
Neuroscience Research Australia (NeuRA)
Address
139 Barker Street, Randwick, NSW, 2031
Country
Australia
Secondary sponsor category [1] 315895 0
None
Name [1] 315895 0
Address [1] 315895 0
Country [1] 315895 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313146 0
UNSW HREC
Ethics committee address [1] 313146 0
Cnr High Street and Botany Street, UNSW, Sydney, Kensington, NSW, 2052
Ethics committee country [1] 313146 0
Australia
Date submitted for ethics approval [1] 313146 0
24/01/2023
Approval date [1] 313146 0
31/01/2023
Ethics approval number [1] 313146 0
HC220817

Summary
Brief summary
Fifty five percent of all spinal cord injuries result in tetraplegia 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 suggests 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. The study will be a multi-centred 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 incomplete tetraplegia will improve in their strength and breathing outcome measures, to reach the pre-determined signal of benefit.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 127150 0
Prof Jane Butler
Address 127150 0
Neuroscience Research Australia 139 Barker Street, Randwick, NSW 2031
Country 127150 0
Australia
Phone 127150 0
+61 02 9399 1608
Fax 127150 0
Email 127150 0
j.butler@neura.edu.au
Contact person for public queries
Name 127151 0
Dr Terry Trinh
Address 127151 0
Neuroscience Research Australia 139 Barker Street, Randwick, NSW 2031
Country 127151 0
Australia
Phone 127151 0
+61 02 9399 1887
Fax 127151 0
Email 127151 0
t.trinh@neura.edu.au
Contact person for scientific queries
Name 127152 0
Prof Jane Butler
Address 127152 0
Neuroscience Research Australia 139 Barker Street, Randwick, NSW 2031
Country 127152 0
Australia
Phone 127152 0
+61 02 9399 1608
Fax 127152 0
Email 127152 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)?
17/07/2023- no end date determined
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.