Exoskeleton Training for Spinal Cord Injury Neuropathic Pain (ExSCIP): Protocol for a Phase 2 Feasibility Randomised Trial

Background and rationale

Traumatic spinal cord injury (SCI) incidence in Ireland is 11.5-13.3 per million per year (Smith et al., 2018), placing it as a rare condition. However, the SCI itself in many cases results in significant physical disability and poses a considerable functional and economic burden at an individual and societal level (McDaid et al., 2019). Pain (nociceptive and neuropathic) is frequently experienced after SCI. Neuropathic pain (NP) type, commonly subdivided into at-level and below level pain, is the most distressing. Following SCI, approximately 53% of people develop neuropathic pain (NP) (Burke et al., 2017; Finnerup et al., 2014). National SCI data identify high pain intensity and pain interference levels with NP presentations and significantly poorer quality of life (QoL) when compared with other pain phenotypes (Burke et al., 2018; Burke et al., 2019). Individuals have described NP as more debilitating than the other consequences of SCI (Hearn et al., 2015), as their most persistent health issue and adequate pain relief as an unmet need (Kennedy et al., 2006). The mainstay of NP treatment after SCI is pharmacotherapy (Loh et al., 2022). Pregabalin/gabapentin, duloxetine, amitriptyline and/or opioids are the first- and second-line treatments recommended (Loh et al., 2022), with high use of non-steroidal anti-inflammatories and paracetamol also reported in survey data (Burke et al., 2019; Cardenas & Jensen, 2006; Jensen et al., 2005). Severe pain remains refractory to these treatments in 2⁄3 sufferers (Guy et al., 2016) and significant, often intolerable, central nervous system side-effects are reported (Siddall et al., 2006). These, together with fear of medication dependency, result in poor adherence to pharmacological regimens leading to a call for non-pharmacological treatment options for people with NP after SCI (Cardenas & Jensen, 2006; Löfgren & Norrbrink, 2012; Siddall et al., 2006; Widerström-Noga et al., 2020).

The intensity of the NP may increase over time after SCI to become a chronic and life-long condition (Finnerup et al., 2014; Siddall, 2009). NP following SCI that emerges within the first year after SCI and tends to become chronic is characterised by sensory deficits, spontaneous or stimulus-evoked pain, including allodynia and hyperalgesia and may be associated with dysesthesia and paraesthesia. Qualitative studies, exploring people’s experiences with NP in daily life after SCI (Buscemi et al., 2018; Widerström-Noga et al., 2017) emphasise the difficult nature of pain, its treatment resistance, and its deleterious effects on QoL. They further identify the need to gain more knowledge and skills in relation to self-management and coping with pain to reduce its impact on their daily life (Henwood et al., 2012; Norrbrink & Löfgren, 2016). The need for better information regarding pain and additional treatment options has been highlighted in the literature by people with SCI, calling for a stronger focus on persistent pain as a consequence of SCI, better access to healthcare providers with expertise in this area (Norman et al., 2010). International data identify the proportional burden of NP following SCI as significant. Ninety-four percent of individuals with SCI NP are prescribed >1 medication, the mean number of physician office visits in a 6-month period due to SCI NP is reported as 2 and the total annualised cost of NP per subject in the United States (US) is reported as $26,270 (direct $8,636, indirect $17,634) (Mann et al., 2013). The presence of pain is further associated with lower return to work rates following injury, and more than a third of individuals with SCI in employment report frequent pain interference with their work (Widerström-Noga et al., 2001). Pain interference with function, health status and work are noted to be significantly worse in individuals with more severe NP (P<0.0005), where overall work impairment is reported at 38% (Widerström-Noga et al., 2001).

NP after SCI is multi-faceted and heterogenous, making isolation of specific mechanisms more challenging. Nonetheless, proposed mechanisms include neuronal hyperexcitability (central and peripheral sensitisation) and corticothalamic maladaptive neuroplasticity (Finnerup et al., 2009). Additionally, NP symptom severity post SCI has been reported to be associated with a combination of residual spinothalamic tract (STT) function below the level of injury and with catastrophising pain coping mechanisms (Widerström-Noga et al., 2016). Our understanding of the mechanistic effects of sensorimotor stimulation on NP in SCI stem from Phantom Limb Pain research where significant reversal of cortical dysfunction in the primary somatosensory cortex is evident (Foell et al., 2014). Similar maladaptive cortical reorganisation is hypothesised to be associated with NP in SCI (Flor, 2008; Wrigley et al., 2009), supported by data garnered from electroencephalography (EEG) studies identifying thalamo-cortical dysrhythmia (Boord et al., 2008; Jensen et al., 2013; Sarnthein & Jeanmonod, 2008; Vuckovic et al., 2018a) and decreased reactivity in alpha band power signals to eye opening (Boord et al., 2008; Vuckovic et al., 2014). Thus, EEG may have application as a biomarker both for current NP and as a predictor of NP development in SCI (Mussigmann et al., 2022; Vuckovic et al., 2018b).

Virtual reality (immersive virtual walking/virtual illusion/imagined walking) has shown promise for reducing NP intensity and interference after SCI (Austin & Siddall, 2021; Gustin et al., 2023; Trost et al., 2022). Virtual illusion interventions show evidence of direct and corrective stimulation to maladaptive sensorimotor reorganisation in SCI patients with NP (Eick & Richardson, 2015; Moseley, 2007), supporting the theory that NP mechanisms are reversible. However, actual sensorimotor intervention studies are inconclusive in SCI at this point (Nees et al., 2017) with limited focus on walking despite compelling preclinical studies showing prevention and /or reversal of SCI neuropathic pain (Dugan & Sagen, 2015; Dugan et al., 2021; Hutchinson et al., 2004). Notably in these animal studies, other exercise modalities such as swimming and stance training had short term or no effect on NP after SCI. This is suggestive of the fact that the characteristics of walking not seen in swimming and stance training, namely the rhythmic stimulation of proprioceptive and mechanosensory afferents combined with weight bearing might be the potential mechanisms that are driving this reduction in NP (Dugan et al., 2021).

Robotic-assisted gait training after SCI is well established in the neurorehabilitation space, notably for motor impairment and gait outcomes in incomplete SCI (Alashram et al., 2021; Stampacchia et al., 2022). However, its mechanistic effects on NP for individuals with SCI have not been well investigated to date. Only two case studies/series employing robotic-assisted gait were identified in the extant literature that mandated participants have NP in the moderate and severe categories prior to using the exoskeleton and results demonstrated meaningful reductions in pain intensity ratings (Cruciger et al., 2016; Kressler et al., 2014). The ExSCIP randomised feasibility trial addresses the current lack of clinical trials in this area, examining exoskeleton-based walking 3 times per week, as a mechanistic-based intervention for NP after SCI. It will test the feasibility and acceptability of an exoskeleton-based walking intervention, and whether it demonstrates positive signals in reduction of NP intensity and interference levels to warrant onward progression to a definitive trial.

Aims and objectives

The overall aim of this study is to examine the feasibility and acceptability of an exoskeleton, mechanistic-targeted, walking intervention for NP in people with SCI.

The primary objectives for the study are:

Study design and setting

The ExSCIP study is a single centre, phase 2 randomised, single blinded, feasibility trial, informed by Bowen’s framework for feasibility studies (Bowen et al., 2009). Given SCI is considered a rare condition, we will apply a randomised feasibility study to allow a better-informed decision on whether to proceed to a larger multi-centre and international trial (Eldridge et al., 2016). This trial protocol has been registered on clinicaltrials.gov (NCT06463418) https://clinicaltrials.gov/study/NCT06463418)

Progression criteria are based on consideration of the primary objectives around feasibility and the potential for effectiveness and implementation in clinical practice. Quantitative and qualitative process evaluation data will be analysed to consider the following continuation criteria.

The intervention will be delivered in the Motion Analysis Laboratory at University College Dublin (UCD).

Participants

Participants will be adults who have sustained a traumatic SCI with confirmed below-level NP. Participants will be recruited from the Spinal Injuries Ireland (SII) national support service via information leaflet and trial advertisement and the outpatient SCI clinic at the National Rehabilitation Hospital (NRH) via advertisement fliers and posters. Interested parties will contact the researcher directly to proceed to the next stage of assessment/screening for the trial as outlined below. Eligibility criteria for participants can be found in Table 1.

Below-level neuropathic pain screening protocol

Stage 1: Telephone screening

NP will be screened for as a minimum criterion initially by phone. This phone screening will do the following:

Stage 2: In-Person assessment

Once informed consent is obtained from candidates, an in-person assessment will be performed by an independent assessor. The assessment will entail the following steps:

Confirmation of presence of moderate to severe below level NP:

Anthropometric and clinical assessment for compatibility for use of exoskeleton:

Stage 3: Data collection

Figure 1. Participant flow through study.

Sample size, randomisation, and blinding

As ExSCIP is a feasibility trial, a sample size calculation will not be conducted. The trial aims to recruit 20 participants to the intervention arm and 20 to the control arm, retaining at least 32 at follow-up. Due to practical considerations including traumatic SCI being a rare condition in Ireland, the strict eligibility criteria in addition to the precedent set by previous RCT’s in this area with considerably smaller sample sizes (Martinez et al., 2018), this number is considered adequate to inform whether sufficient participants can be recruited and retained in the study and to evaluate the feasibility goals outlined.

Following informed consent and baseline evaluation for exoskeleton, recruited participants will then be randomly allocated to the intervention group (ExSCIP) or to the comparator group (receiving a blended relaxation programme devoid of motor imagery). This will be completed by an independent gatekeeper based in the UCD Centre for Support and Training in Analysis and Research (CSTAR), using a pre-generated electronic randomisation schedule stratified by NP severity. Allocation disclosure will be made by telephone by the independent gatekeeper in CSTAR to the trial interventionist after informed consent and baseline evaluation.

To minimise potential biases, all assessments and outcome measures (baseline, post intervention and 6-month follow-up) will be taken by an independent assessor blinded to the treatment allocation. The data analyst will also be blinded to the intervention allocation.

Blinding participants to the ExSCIP intervention is not feasible. The hypothesis of the study will be masked however in the information to subjects. Participants will be informed that the trial is comparing two types of treatment, to avoid higher expectations in the ExSCIP group.

Description of intervention and comparator

Participants will be randomised to either:

Intervention (ExSCIP) group: the intervention group will complete an exoskeleton-based, mechanistic-targeted, progressive walking programme consisting of one-hour sessions of robotic walking 3 times a week for 12 weeks with hands-on supervision provided by a trained, CORU-registered physiotherapist in the UCD Motion Analysis Laboratory. Those randomised to the intervention group will undergo an initial familiarisation trial walking session in the device under the direct supervision of the PI, to optimise device settings to each individual.

Rest periods will be allowed as required and, as individual aerobic capacity will differ, the programme will be individually tailored to increase the number of steps taken and the number of consecutive steps taken without rest during progressive sessions. Total steps taken and the number of overall scheduled sessions attended will be recorded.

Control group: the control group will complete an equally dosed blended relaxation programme, devoid of any motor imagery prompts. It will comprise one face-to-face relaxation class per week alongside 2 online classes over a 12-week period.

Participants in both groups will be permitted to continue with their usual care regimen throughout the duration of the trial. They will not be permitted to participate in additional exoskeleton interventions outside of those provided as part of this study.

Outcomes

Primary outcomes

The primary outcomes will focus on trial feasibility. Full details of these and progression criteria to a multicentre, international RCT can be found in Table 2:

Secondary outcomes

Pain

Changes in NP intensity will be measured using the ISCIPBDS 3.0 pain intensity scale (Widerstrom-Noga et al., 2023). Changes in NP interference as measured in the ISCIPBDS 3.0 pain interference scale and changes in neuropathic pain symptoms will be assessed using the Neuropathic Pain Symptom Inventory (Bouhassira et al., 2004; Wong et al., 2020). In addition, we will use resting EEG as a biomarker for chronic NP. All pain related outcomes will be measured at three timepoints: baseline (week 1/Timepoint 1 (T1)), post intervention (week 13/Timepoint 2 (T2)) and at 6-month follow-up (Timepoint 3 (T3)).

Health Related Quality of Life (HRQoL)

We will assess HRQoL using the EUROQOL EQ-5D-5L (Herdman et al., 2011) at baseline, post-intervention and 6-month follow-up.

Qualitative study

Qualitative focus group discussions with participants and interventionists will be conducted following the intervention to ascertain their experiences of the ExSCIP programme. As pain is multidimensional and often influenced by factors such as attitudes, self-efficacy and thoughts, inclusion of a qualitative study is important to inform additional development and improvement to the intervention.

The qualitative semi-structured question schedule will be developed in collaboration with our PPI panel. A person unknown to the participants will complete the exit discussions. Key areas to be discussed will be:

Qualitative feedback will also be obtained from staff who delivered the ExSCIP intervention to evaluate physiotherapists’ perspectives of delivering an exoskeleton walking programme for pain, with questions addressing.

Qualitative analysis will be underpinned by the principles of phenomenology: open-ended responses from focus group discussions and debriefing interviews will be subject to reflexive thematic analysis. Audio recorded data will be transcribed verbatim by an independent person and transcripts read by two researchers independently. Participant research codes will be used in transcription.

Data/statistical analysis

Baseline demographics of group participants will be presented in two manners. Categorical data will be presented as frequencies & percentages. Continuous data will be presented as means & standard deviations. If there is evidence of skew in continuous data, mean and standard deviation (SD) will be substituted with median and interquartile range.

Outcome variables will be assessed at three time points (baseline, week 13, 6 month follow up). Health related quality of life (HRQoL) as assessed by the EQ-5D-5L will be converted from value scores to index scores for each item which will allow for calculation of a collated index score (Hobbins et al., 2018). Pain intensity, pain interference and HRQoL index scores will be presented as mean and SD at each time point. Within group mean differences and 95% confidence intervals (95% CI) will be calculated at week 13- and 6-month follow-up compared to baseline. Between group differences at each time point will be calculated using repeated measures ANOVAs. The effect sizes of between group differences will be assessed using ETA squared/Omega squared statistics. Statistical significance will be determined α-priori at an alpha level of 0.05. Statistical analysis will be undertaken using IBM SPSS version 29 (IBM, 2023) and conducted as intention-to-treat and per-protocol. Alternatively, this statistical analysis can be performed using the open access R software (R core team, 2024).

Exploratory EEG data analysis will use a multilevel linear mixed model (LMM) to examine differences between the intervention groups over time in the EEG alpha, beta and theta band power. Repeated measures within participants will be modelled as a random effect. Fixed effects in the model, will include group assignment and time. The moderating effects of pain intensity and interference will also be evaluated. The LMM will study both main effects and interaction effects using the R package lme4 (Bates et al., 2015) to fit the models. Models will be compared using Likelihood Ratio Tests (LRT) to assess the significance of effects.

Trial governance and data monitoring

A Trial Steering Committee (TSC) and Trial Management Group (TMG) are established to ensure good governance, trial management and safety monitoring for the duration of the study. The UCD Clinical Research Centre (CRC) team will support the management and conduct of the trial including the development and maintenance of trial documentation according to Good Clinical Practice (GCP) guidelines and UCD CRC Standard Operating Procedures (SOPs).

An independent data monitoring committee (DMC) will also be formed comprising an independent statistician and two independent nominees by the CRC at UCD. They will monitor emergent data in relation to safety and efficacy. Its terms of reference will outline clearly stopping rules and the frequency of the interim data analysis during the recruitment phase. Any adverse events will be monitored by this committee where they will review each event and decide if it is related, might be related or is unrelated to the intervention.

Safety and adverse events

Risk identification and minimisation is essential in an exoskeleton-based walking intervention delivered to a population that is primarily sedentary. Clear exclusion criteria for exoskeleton use will be applied to those who are not suitable for the device use. A trial will be provided prior to programme commencement to further determine suitability and acceptability and appropriate staff training and safety harnessing will be applied.

Adverse events and near misses will be logged throughout the study period and reported to the Data Management Committee, including the date it occurred, the circumstances, assistance provided or onward medical referral (i.e. medical attention required) and what was implemented to prevent this occurring again.

The Project Manager and PI will be advised of each event immediately and will determine what strategies need to occur based on the severity of the event. Serious adverse events (SAEs) will be reported to the SAE oversight committee and the trial will be paused pending investigation.

SAEs will be reported to the UCD HREC within 15 days of occurrence. In relation to COVID-19 and other community transmissible diseases, we will follow public health advice and HSE policies in relation to infection control measures when the study starts.

Dissemination of findings

Study findings will be published in appropriate peer-reviewed journals. We will also present study results at relevant national and international conferences (e.g. Irish Pain Society annual conference, Irish Association of Rehabilitation Medicine Annual Scientific Conference and International Spinal Cord Society Conference)

Our PPI Panel will support with knowledge exchange and dissemination activities that include the preparation of plain language summaries of the study results and their implications for people with spinal cord injury and their families, discussion groups, short video clips, social media messages, media interviews and leveraging existing websites of the PPI panel at Spinal Injuries Ireland (spinalinjuries.ie), Mark Pollock Foundation (markpollock.com) and Helpful Steps Charity (helpfulsteps.ie). We will work with these charities to coordinate knowledge exchange and the dissemination of the study findings, alongside key stakeholders in the organisation and delivery of SCI services in Ireland (the National Spinal Cord System of Care (SCSC) Programme at the NRH and the National Spinal Injuries Unit, Mater Hospital).

Patient Public Involvement

Our PPI Panel was instrumental in developing the grant application for this study and the research protocol, informing both the intervention & control. The panel will continue to work with the researchers during the conduct of the study, working collaboratively to develop the recruitment materials, the interview schedule for the qualitative study and will assist in future dissemination, determining the media, plain language used, and approaches taken in dissemination of findings, including their implications for people with SCI and their families, discussion groups. As co-researchers they will have representation on the Trial Steering committee.

Study status

This study is currently ongoing. The expected study end date is November 2026.