Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000737437p
Ethics application status
Not yet submitted
Date submitted
24/06/2025
Date registered
11/07/2025
Date last updated
11/07/2025
Date data sharing statement initially provided
11/07/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
Neuromodulatory interventions for reducing neuropathic pain after spinal cord injury
Scientific title
NeuroStim+: Investigating the efficacy of neuromodulation to decrease the severity of neuropathic pain in individuals with a spinal cord injury
Secondary ID [1] 314717 0
none
Universal Trial Number (UTN)
Trial acronym
NeuroStim+
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic neuropathic pain after spinal cord injury 337918 0
Condition category
Condition code
Injuries and Accidents 334245 334245 0 0
Other injuries and accidents
Neurological 334246 334246 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The investigational medical device in this clinical trial includes two devices, electroencephalography (EEG) neurofeedback and transcranial direct current stimulation (tDCS), evaluated individually and in combination.

Group 1: EEG-NF + active tDCS
Group 2: EEG-NF + sham tDCS
Group 3: Active tDCS
Group 4: Sham tDCS

All interventions are home-based and self-administered by participants for 20 sessions over a 6-week period, with one session completed per day. Each session will last approximately 60 min for Groups 1 and 2, and 30 min for Groups 3 and 4. Adherence is assessed through automatic logging of device usage and completion data, which are uploaded in real time to a secure, study-specific dashboard accessible only to the research team. This system allows for continuous monitoring of session completion and engagement across all study arms.

Active tDCS will be delivered using the Sooma Duo tDCS device. The device will be pre-programmed to provide active stimulation at 2 mA for the entire treatment session, with a gradual ramp-up to 2 mA at a rate of 0.1 mA/s at the beginning and a ramp-down to 0 mA at the same rate at the end of the tDCS session. Stimulation will be delivered through 5 × 5 cm circular rubber electrodes, prepared by soaking sponge pads in saline and securing them within the electrode perimeter. An impedance threshold of 50 kiloohms must be met for the stimulation to begin. If impedance exceeds this threshold, participants will be instructed to apply additional saline solution beneath the electrodes. Using a customized electrode montage, the anodal electrode will be placed on the vertex of the head and held in place using a 3D printed headset. The cathodal electrode will be positioned on the shoulder and kept in place with a shoulder band.

The EEG neurofeedback intervention is based on brain-computer interface (BCI) technology. We will be using an OpenBCI system with 3D printed headset. OpenBCI products are used as open-source tools for BCI systems. This EEG headset will be completed by a customised software and gaming interface in Unity game engine (Unity Technologies, USA). Our game scenario provides neurofeedback in an interactive, goal-directed, virtual gaming environment. The EEG headset records brain activity from C1 and C2 electrode sites (over the sensorimotor cortex), with reference electrode placed on the left ear and ground electrode on the right ear. To set up, participants will insert two pre-soaked sponge electrodes into the C1 and C2 electrode holders, then place the headset on their head. They will then play a game on a Surface Pro tablet, where they will view a gaming object (rocket, jellyfish, bird, or plane) that moves based on changes in EEG rhythms. The EEG-NF protocol aims to suppress theta (4–7 Hz) and high-beta (20–30 Hz) bands, while reinforcing the sensorimotor rhythms (SMR, 10–15 Hz). When participants successfully regulate all three bands in the desired direction, the object of the game will move faster or higher, and the background colour will change to give participants visual feedback. At the end of each round, participants will receive feedback on their progress through points. Each EEG neurofeedback session will consist of 5 rounds of neurofeedback games, each lasting 2.5 minutes, with a 30-second break between rounds.
Intervention code [1] 331325 0
Treatment: Devices
Comparator / control treatment
Participants in Groups 2 and 4 will receive sham tDCS, which will be delivered using the Sooma Duo tDCS device. The device will be pre-programmed to provide a brief ramp-up to 2 mA over 20 seconds, followed by an immediate ramp-down to 0 mA, to mimic the initial sensation of active tDCS without delivering ongoing stimulation.
During the sham session, every 5 minutes the following contact checking will also occur:
i. Current is ramped up to 0.1mA (at a rate of 0.1mA/s)
ii. Current is held at 0.1mA for 2 seconds
iii. Current is ramped down to 0mA (at a rate of 0.1mA/s)
Control group
Placebo

Outcomes
Primary outcome [1] 341913 0
Pain severity
Timepoint [1] 341913 0
Pain severity will be measured at baseline, 6, 16, 26, and 52 weeks post-randomisation. However, the primary endpoint is 6 weeks post-randomisation.
Secondary outcome [1] 448983 0
Pain at its worst
Timepoint [1] 448983 0
Baseline, 6, 16, 26, and 52 weeks post-randomisation
Secondary outcome [2] 448984 0
Sleep disturbance
Timepoint [2] 448984 0
Baseline, 6, 16, 26, and 52 weeks post-randomisation
Secondary outcome [3] 448987 0
Depression
Timepoint [3] 448987 0
Baseline, 6, 16, 26, and 52 weeks post-randomisation
Secondary outcome [4] 448988 0
Quality of life
Timepoint [4] 448988 0
Baseline, 6, 16, 26, and 52 weeks post-randomisation

Eligibility
Key inclusion criteria
· Have a complete or incomplete cervical, thoracic, or lumbar spinal cord injury,
· Can breathe independently,
· More than 6 months post-injury,
· Have had ongoing nerve (neuropathic) pain at or below your injury level for more than three months,
· Have an average pain level of at least 4 out of 10 over the past week,
· Have an endorsement of more than 2 items on a 7-item Spinal Cord Injury Pain Instrument (SCIPI),
· Are 18 years of age or older,
· Can read and understand English,
· Able to fully engage in the NeuroStim+ intervention by self-administering the tDCS and EEG headsets or by receiving assistance from a caregiver.,
· Willing and able to complete one NeuroStim+ intervention session per day, for 20 days over a 5-week period.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
· Have implanted devices such as cardiac pacemaker, cochlear implant, or deep brain stimulation,
· Have a personal history of seizures, or someone in their immediate family (such as a parent, sibling, or child) has experienced seizures,
· Have a history of a serious head injury (e.g., concussion) or illness (e.g., stroke) resulting in brain damage,
· Have metal inside the head including surgical clips or fragments from welding/metalwork,
· Have a diagnosed neurological disorder associated with cognitive impairment (e.g., dementia), or a psychiatric disorder such as schizophrenia,
· Have serious or unstable medical conditions, including uncontrolled hypertension or significant cardiovascular or vascular disease.,
· Are pregnant/lactating,
· Are located outside of Australia.

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)
Following screening for eligibility, informed consent, and completion of demographic and baseline questionnaires, each participant will be randomly allocated to one of four groups (Groups 1, 2, 3, or 4) at a ratio of 1:1:1:0.5. The allocation schedule will not be accessible to other trial staff until the trial is completed, ensuring that allocation is concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A statistician who is not involved in participant recruitment or assessment will use a random number generator to create a randomisation schedule, assigning each participant ID to one of the groups.
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Factorial
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Primary Objectives
Objective 1: To evaluate the average causal effect of EEG-NF compared to no EEG-NF on pain severity at 6 weeks post-randomisation (primary endpoint).
Objective 2: To evaluate the average causal effect of active tDCS compared to sham tDCS on pain severity at 6 weeks post-randomisation.
Objective 3: To evaluate the average causal effect of combined EEG-NF + active tDCS compared to active tDCS alone, or EEG-NF + sham tDCS, on pain severity at 6 weeks post-randomisation.

Statistical Analysis
The primary estimands are the average marginal causal effects (i.e., the mean differences between the potential outcome under intervention and the potential outcome with the comparator) of the intention to provide the interventions on BPI-Pain Severity measured six weeks after randomisation in the trial population. As the objective is to assess the effects of intending to administer the interventions (a “treatment policy strategy”), outcome data from all trial participants will be included in the analysis, regardless of treatment-modifying events. That is, the primary analysis will be by intention to treat.

Primary Analysis
Objectives 1 and 2 seek to estimate, respectively, the average marginal causal effects of EEG-NF compared to no EEG-NF and the average marginal causal effect of active tDCS compared to sham tDCS. These effects will be estimated using the strategy recommended by Kahan and colleagues. In that strategy, the estimate of effect is the marginal effect of each of the interventions (that is, the effect of active EEG-NF compared to no EEG-NF averaged across the active tDCS and sham tDCS groups, and the effect of active tDCS compared to sham tDCS averaged across the EEG-NF and no EEG-NF groups). To examine the extent to which assumptions about the independence of treatments, implicit in the estimation of marginal effects, may have biased estimates of effect, we will also estimate (a) the interaction between the treatments, and (b) the conditional treatment effects (i.e., the effects of each intervention within each level of the other intervention). The estimates of the marginal effects, as well as of the interactions and the conditional effects, will all be obtained from the same statistical model. The model will be a mixed effects linear regression model in which the dependent variable is the BPI-Pain Severity score, the fixed independent variables are a dummy coded variable for each of the interventions, a dummy-coded factor variable for time, and the interactions between these variables, and there are random intercepts for individuals. For the primary analysis of efficacy, we will extract from the model estimates of effects on BPI-Pain Severity at 6 weeks using the “stratification” approach described by Morris et al.
Point estimates of the effects and their 95% confidence intervals will be reported, and these will be supplemented with two-sided hypothesis tests. As the primary justification for the factorial trial was to conduct “two trials for the cost of one”, the alpha level will be set at 0.05. Thus, these hypothesis tests will not be adjusted for multiple comparisons, just as would have occurred if the hypothesis tests had been conducted in two separate trials.
Objective 3 seeks to estimate the effect of combined EEG-NF + active tDCS compared to active tDCS alone or EEG-NF + sham tDCS. The effects will be estimated using the same model as used for Objectives 1 and 2. The Bonferroni procedure will be used to adjust for multiple comparisons, so the alpha will be set at 0.05 / 2 = 0.025 for each of these two comparisons.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/12/2025
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
231
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 319272 0
Government body
Name [1] 319272 0
Medical Research Future Fund (MRFF) - Australian Government, Department of Health, Disability and Ageing
Country [1] 319272 0
Australia
Primary sponsor type
University
Name
University of New South Wales
Address
Country
Australia
Secondary sponsor category [1] 321743 0
None
Name [1] 321743 0
Address [1] 321743 0
Country [1] 321743 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 317847 0
The University of New South Wales Research Ethics Committee A
Ethics committee address [1] 317847 0
Ethics committee country [1] 317847 0
Australia
Date submitted for ethics approval [1] 317847 0
31/07/2025
Approval date [1] 317847 0
Ethics approval number [1] 317847 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 142342 0
Prof Sylvia Gustin
Address 142342 0
NeuroRecovery Research Hub, level 1, Biological Sciences Building, Gate 10, UNSW, Kensington, NSW 2052
Country 142342 0
Australia
Phone 142342 0
+61 2 9348 0846
Fax 142342 0
Email 142342 0
[email protected]
Contact person for public queries
Name 142343 0
Sylvia Gustin
Address 142343 0
NeuroRecovery Research Hub, level 1, Biological Sciences Building, Gate 10, UNSW, Kensington, NSW 2052
Country 142343 0
Australia
Phone 142343 0
+61 2 9348 0846
Fax 142343 0
Email 142343 0
[email protected]
Contact person for scientific queries
Name 142344 0
Sylvia Gustin
Address 142344 0
NeuroRecovery Research Hub, level 1, Biological Sciences Building, Gate 10, UNSW, Kensington, NSW 2052
Country 142344 0
Australia
Phone 142344 0
+61 2 9348 0846
Fax 142344 0
Email 142344 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
• Researchers
Conditions for requesting access:
• Yes, conditions apply:
• Requires review on a case-by-case basis by the trial custodian, sponsor or data sharing committee
• Requires a scientifically sound proposal or protocol
• Requires approval by an ethics committee
• Requires a data sharing agreement between data requester and trial custodian or sponsor
What individual participant data might be shared?
• De-identified individual participant data:
• Published results
What types of analyses could be done with individual participant data?
• Systematic reviews and meta-analyses
• Studies exploring new research questions
When can requests for individual participant data be made (start and end dates)?
From:
After publication of main results
To:
A finite period of: 7 years
Where can requests to access individual participant data be made, or data be obtained directly?
• Email of trial custodian, sponsor or committee: [email protected]

Are there extra considerations when requesting access to individual participant data?
No


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.