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. 2024 Oct 8;109:105381. doi: 10.1016/j.ebiom.2024.105381

Next-gen spinal cord injury clinical trials: lessons learned and opportunities for future success

Paulina S Scheuren a,b, John LK Kramer a,b,∗
PMCID: PMC11490878  PMID: 39383609

Summary

Despite promising basic science discoveries and a surge in clinical trials, the quest for effective treatments that restore neurological function after spinal cord injury lags on. While “failed” in a conventional sense, emerging solutions to longstanding challenges represent promising steps towards a future with effective interventions. In this personal view, we highlight clinical trials implementing new solutions and their impact on the field. Our perspective is that, ultimately, the integration of shared knowledge, adaptive designs, and a deeper understanding of the intricacies of spinal cord injury holds promise of unlocking of major breakthroughs, leading to improved outcomes for people with spinal cord injury.

Keywords: Spinal cord injury clinical trials, Neurorestorative trials, Adaptive design

Introduction

Spinal cord injury is a devasting neurological condition characterised by varying severities of motor paralysis, as well as sensory and autonomic nervous system deficits.1 While the incidence of spinal cord injury is low, the negative impact on the individual's quality of life is immense,2, 3, 4 as is the cost to and burden on society.5, 6, 7, 8 Despite advanced understanding of molecular and cellular targets involved in protection and repair of the injured spinal cord, an effective neurorestorative intervention remains elusive.9, 10, 11, 12, 13

The absence of an effective intervention that restores neurological function after spinal cord injury was, until recently, attributable in large part to a lack of trying. Between 1980 and 2000, a period of time that saw nearly 100 trials aimed at restoring neurological function in individuals with stroke,14 only a small handful of neurorestorative clinical trials were launched involving individuals with spinal cord injury.15, 16, 17, 18, 19, 20, 21 In the wake of the National Acute Spinal Cord Injury Studies (NASCIS) and Sygen came trials shifting to the management of chronic spinal cord injury—namely those that were investigating the effects of 4-aminopryidine.22,23 Ten years after Sygen were seminal attempts in humans to repair the injured spinal cord with cell-based therapies24,25—trials that were ultimately terminated before reaching their pre-determined endpoints.24,26 Despite concern that early terminations would deter future investment, neurorestorative spinal cord injury trials surged, with many reporting results in the last 4–5 years (Fig. 1).

Fig. 1.

Fig. 1

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The spinal cord injury clinical trial landscape. Clinical trials in spinal cord injury have evolved from a handful of historical trials in the 1980s, followed by the start of the cell-based era, and more recently, a surge in next-gen trials demonstrating emerging opportunities for future success. ∗Note: This illustrates a selection of clinical trials covered in this Personal View, not a complete list of clinical trials in spinal cord injury.

Recently emerging or “next-gen” trials, and those that came before them, represent, on one hand, “failures”—unsuccessful attempts to restore neurological function after spinal cord injury. On the other hand, we argue, they represent progress and invaluable contributions that have provided critical knowledge and framework for future clinical trials. This is because emerging spinal cord injury clinical trials are demonstrating, in the wake of “failing”, key learnings. The aim of this personal view, rather than summarise trial results, is to highlight trial design features that signal advancement and an optimistic future for spinal cord injury.

Search strategy and selection criteria

SCITrialsFinder—a web-based platform that provides curated information about clinical trials in spinal cord injury registered on clinicaltrials.gov—was used to search for interventional, neurorestorative clinical trials in spinal cord injury (www.SCITrialsFinder.net). SCITrialsFinder is primarily intended as a resource for individuals with spinal cord injury, with trial details curated and summarised by experienced spinal cord injury researchers. We extracted and reviewed all curated trials from the SCITrialsFinder website up until March 20th, 2024 (n = 414). A breakdown of study details is illustrated in Fig. 2. The full list of trials can be found in the Supplementary Table S1. Trials that published results prior to the last 5 years (before January 2019) were excluded. From this list, we identified clinical trials that have demonstrated progress related to the conduct and design of clinical trials in spinal cord injury, which will be covered in this Personal View.

Fig. 2.

Fig. 2

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Overview of clinical trials in spinal cord injury. A. The majority of neurorestorative trials are in the United States (231), followed by Canada (41), Switzerland (20), Spain (19), China (18), and the United Kingdom (18). Multi-centre trials that include different countries are counted for each country. B. The most common primary intervention type is technology (e.g., spinal cord stimulation) (223), followed by rehabilitation (83), drug (49), and biological/cell-based trials (23). C. A total of 195 neurorestorative trials are currently recruiting, 27 are recruiting soon, 11 are recruiting by invitation, and 107 have ended. Please note that the numbers displayed in this figure reflect the trials identified in the search criteria described in the ‘Search strategy and selection criteria’ section.

Adaptative designs: the new normal?

Spinal cord injury has historically taken a conventional, randomised controlled trial (RCT) approach. While tried and tested, other fields have turned to innovative study designs. Among them, adaptive designs are an intuitive option, highlighted in recent spinal cord injury trials.27, 28, 29, 30, 31, 32 In the Riluzole in Acute Spinal Cord Injury (RISCIS) Study, investigators adopted a sequential adaptive design that incorporated a pre-specified interim analysis to adjust sample size.29,32 The importance of this design feature lies in accounting for the challenges in estimating the degree of spontaneous recovery in the placebo treated individuals, with small imbalances in injury severity between treated and placebo groups, difficult to predict at the trial onset, masking otherwise meaningful therapeutic effects. Another example of an adaptive design is evidenced in the AXER-204 trial—a seminal study examining the safety and efficacy of Nogo decoy therapy after spinal cord injury.27 In this trial, investigators employed an adaptive seamless design, combining an open-label, single ascending dose (part 1) and randomised, placebo-controlled, double-blinded trial (part 2). The fundamental goal of this approach was to accelerate clinical trial testing, which was achieved, in part, by enroling individuals that participated in part 1 in part 2. This adaptative seamless approach has also been adopted in a recent cell-based trial–Stem Cells in Spinal Cord Injury (SCI2)—with a pre-planned interim analysis as the “phase II study expands into a phase III study” (NCT03935724). Finally, in the SPinal Cord Injury Rho INhibition InvestiGation (SPRING) trial, a planned interim analysis to assess futility30 led to a stoppage in enrolment.31 While unwanted as an outcome, this stoppage reduced burden of research on individuals with spinal cord injury, as well as study sites, opening new opportunities for other trials, and, perhaps more importantly, emphasised the need for trials to “fail fast” in order to succeed.33 These next-gen clinical trials, although “failing” to achieve their primary endpoint, have been successful in implementing adaptive trial designs, paving the way for future spinal cord injury trials and potential success.

Target engagement in the spinal cord

The question of whether novel treatments reach the spinal cord to modify cellular and molecular pathways involved in repair of injured tissue has gone largely overlooked in past trials. The AXER trial, leveraging their access to cerebrospinal fluid (CSF), is notable, then, in that it represents the first to directly assess target engagement.27 To achieve this, investigators employed proteomics and bioinformatic tools (e.g., gene set enrichment analysis), ultimately observing that proteins involved in “gliogenesis and axon guidance”, among others, were differently regulated in CSF of treated individuals—a finding that aligns with the proposed mechanism through which a Nogo decoy was understood to work. Proteomics had been sparingly used in observational studies focused on developing novel biomarkers for diagnosis and prognosis of spinal cord injury,34, 35, 36 but had not seen application in a clinical trial. The collection of serum CSF for the purpose of biomarking target engagement by way of “omics” appears have continued in the completed Nogo Inhibition in Spinal Cord Injury (NISCI) trial, which has yet to report results (NCT03935321). An ongoing trial investigating the neuroprotective effect of Glyburide (NCT05426681) has also incorporated serum and CSF biomarker analyses into the trial design (based on the trial description on clinicaltrials.gov). This demonstrates an encouraging new trend, with the potential for many new trials to follow.

Emerging outcome tools

Proteomics is not the only novel outcome tool integrated into next-gen spinal cord injury clinical trials. Reflecting an increased focus on cervical spinal cord injury, newly developed tools were employed to assess upper limb function. Damage in the cervical spinal cord occurs in approximately half of all cases and is accompanied by deficits in the upper extremities.37,38 Compared to injuries occurring in the thoracic cord, cervical injury provides an intriguing opportunity to detect meaningful treatment effects on motor recovery in spinal segments adjacent to the lesion, whereas thoracic injuries can only be evaluated based on lower extremity function.39 To aid detection of effects in the upper extremities, recent trials including the RISCIS, AXER, and NISCI trials employed the Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP)–a tool only developed in 2011 that incorporates three domains vital to upper extremity function.40 The adoption of GRASSP into clinical trials represents encouraging progress, from first generation clinical trials that relied almost exclusively on the International Standards for the Neurological Classification of Spinal Cord Injury (ISNCSCI)41 to evaluate treatment efficacy. Additional functional outcome measures such as the Spinal Cord Independence Measure (SCIM) have also been introduced into spinal cord injury clinical trials (e.g., NISCI). Assessing treatment efficacy in terms of improvements in motor function that successfully translate into enhanced independence and quality of life may prove particularly important in the context of phase 3 clinical trials. Moreover, there are ongoing efforts to incorporate outcomes that assess the integrity of spinal tissue and pathways (i.e., quantitative MRI and electrophysiological markers), exemplified by the NISCI trial. Electrophysiological measures are also being recognised as valuable tools for identifying individuals who might benefit the most from specific interventions. For instance, they are being used to evaluate the innervation capacity to paralyzed muscles before considering candidates for a multi-centre nerve transfer surgery trial (NCT04023591).

Avoiding controversy: planned sub-group analyses

Arguably the most important shift in trial design has been to the adoption of preplanned sub-group analyses. Historical spinal cord injury trials lacked such plans and, subsequently, faced heavy, “post-mortem” criticism (e.g., methylprednisolone).42 Next-gen spinal cord injury clinical trials have addressed the issue of pre-specified analyses, laying out plans in published study protocols and trial registrations—a move that greatly increases transparency and builds trust in the scientific process. Subgroup analyses in recent trials have specifically examined the role of injury completeness based on clinical testing (e.g., American Spinal Injury Association Impairment Scale (AIS) grades determined by the ISNCSCI).27,32 This reflects the emerging concept that interventions to restore neurological function are translated from preclinical models of “incomplete” injury and will, in turn, be more effective in corresponding human models. Taking sub-group analyses a step further, the NISCI trial has adopted a data-driven stratification approach, digging deeper and going beyond AIS grades.43, 44, 45

Rehabilitation and combination trials

A substantial hurdle in the conduct of a spinal cord injury clinical trial lies in controlling for the effect of rehabilitation. Of notable concern is that some interventions, particularly those that are focused on chronic spinal cord injury, may require rehabilitation to realise the gains of an intervention. Trials incorporating intensive, activity-based rehabilitation are evidenced in emerging neuromodulation studies (e.g., spinal cord stimulation), which have demonstrated encouraging preliminary results,46, 47, 48, 49 making them, effectively, combination therapies. The recently completed Up-LIFT trial49—where the effects of spinal cord stimulation to improve upper limb function in individuals with chronic tetraplegia were investigated—built in a 2-month lead–in phase involving “guided, in-clinic conventional functional task practice” (NCT04697472). Rehabilitation has also been incorporated into recently completed cell-based trials (e.g., Schwann cells).50 Other combinatorial trials are emerging. For instance, the recently completed STIMO-PHARMA trial (NCT04052776) explored the synergistic effects of buspirone and levodopa on enhancing locomotor function in individuals who have undergone spinal cord stimulation. Combination pharmacological therapies are widely thought as critical to improving neurological outcomes after spinal cord injury. This reflects the complexity of repair mechanisms—promoting regeneration of axons, for example, may be meaningless in the absence of a treatment that reduces the glial scar. By no means, a novel concept, pharmacological combinations date back more than 20 years in preclinical models.51 Ongoing trials are also investigating the combination of paired pharmacological agents with spinal cord stimulation (NCT05708274) and acute intermittent hypoxia (NCT05217498). While the results of these trials are still pending, they signify a shift in spinal cord injury clinical trials towards more comprehensive approaches, departing from traditional single-intervention methodologies.

Basic science fuelled clinical trials (plus a case for reverse translation)

The translational arc of treatment success for spinal cord injury has yet to be written. While the utility of preclinical animal models to predict treatment success remains unclear, few alternatives represent viable replacements. To this point in time, much of what has been translated into human clinical trials has evolved from decades of investment in understanding basic mechanisms of spinal cord injury—an outcome we view as a major success. For example, Nogo inhibition has been the target of 2 recent trials, after many decades of development in preclinical models.52, 53, 54, 55, 56, 57 This is important to consider because it means the field has avoided advancing untested therapies of dubious scientific merit based on social and political pressures, which have a high tendency for failure (e.g., liberation therapy for multiple sclerosis).58 An encouraging new trend in translation has taken the approach of combining preclinical results with clinical observations to launch clinical trials. Making use of European Multi-centre study about Spinal Cord Injury (EMSCI) and historical clinical trial data (i.e., Sygen), our group has published a number of studies finding that early exposure to gabapentinoids and baclofen, medications commonly administered in the acute phase of spinal cord injury for neuropathic pain and spasticity, respectively, are associated with greater recovery of neurological function.59, 60, 61, 62 While confounded by indication bias (i.e., benefits may be related to the reason for exposure rather than the exposure, per se), these intriguing results found a potential mechanism in preclinical animal models.63,64 On the basis of these combined clinical and preclinical observations, a recent clinical trial was developed65 and launched in the United States to test the effect of early administration of gabapentin on neurological recovery after spinal cord injury (NCT05302999).

From networks to clinical trials

Multi-centre trials are critical to reaching target enrolment numbers. Until recently, the field of spinal cord injury has achieved this on per case basis, establishing the necessary connections and getting clinical trial “ready” as an intervention emerges. To reduce redundancies, administrative hurdles, and cost, emerging networks, such as the European Multi-centre study about Spinal Cord Injury (EMSCI) and North American Clinical Trials Network (NACTN),66 have served valuable and substantive roles. The ultimate promise of these networks has been only recently realised, both launching an acute interventional trial (see Fig. 1). With the recent completion of next-gen clinical trials (e.g., RISCIS and NISCI), the value of spinal cord injury networks in clinical trials has become increasingly evident.

Remaining challenges and outstanding questions

Old and new challenges remain. The RISCIS study did not meet enrolment targets after their pre-planned interim analysis to adjust sample size (n = +8), despite operating within a network, which serves as evidence of continued struggles to enrol eligible participants. Novel challenges, such as the impact of the COVID-19 pandemic on recruitment in the RISCIS trial, highlight the need for additional, unconventional mitigation strategies. AXER faced the scenario that a gain of function in participants involved in part 2 may have been washed out by the inclusion of participants that had already gained function in part 1—an outcome that may have arisen from a longer than predicted washout time and/or decreased effectiveness of therapy with repeated exposure. Target engagement is a new concept for spinal cord injury clinical trials: are changes in protein expression in the CSF indicative of what is happening in spinal cord tissue? Is it advisable to collect CSF for the sake of such an analysis even if administration occurs systemically (i.e., CSF would otherwise not be acquired)? Despite the logic that interventions may be most beneficial in sub-groups, such analyses are plagued by low statistical power that will yield unreliable results. The implementation and need for standardised rehabilitation in spinal cord injury clinical trials, while an obvious benefit from a theoretical perspective, represents a major practical barrier to the conduct of a clinical trial, greatly increasing cost of research. Emerging trial designs that include rehabilitation also face challenges in interpretating results. For example, in the recently completed Up-LIFT trial,49 some outcomes did not plateau during the lead–in rehabilitation phase, begging the question as to whether more rehabilitation would have similar effects to transcutaneous spinal cord stimulation. Moreover, the absence of a sham control condition opens the possibility that some amount of benefit is attributed to placebo effects. Before the long-term goal of standardised rehabilitation in multi-centre clinical trials can be achieved, robust documentation of rehabilitation practices, whether standardised or unstandardised, would, however, greatly improve the evaluation of these effects in clinical trials. A summary of challenges and potential solutions is illustrated in Fig. 3.

Fig. 3.

Fig. 3

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Current challenges and emerging solutions in spinal cord injury clinical trials. Challenges of traditional clinical trials in spinal cord injury (SCI) (A) and their corresponding solutions that have emerged in Next-gen clinical trials (B) demonstrate fruitful ground for future success in spinal cord injury trials.

Lessons learned and future directions

To address these and other concerns, spinal cord injury clinical trials need to evolve further. A number of opportunities are on the horizon. A very limited number of spinal cord injury trials have incorporated adaptive designs so far, with many options left to consider.67 Following in the footsteps of amyotrophic lateral sclerosis, platform trials rank among particularly enticing adaptive design choices, reducing cost and increasing efficiency (i.e., recruitment and speed).68 New and innovative designs will undoubtedly be needed for new and innovative therapies, such as gene therapy. Objective biomarkers represent an important tool to better stratify injury severity, moving beyond clinical scoring.69 To this end, several biofluid candidates (e.g., glial fibrillary acidic protein and neurofilament light)36,69,70 as well as other quantitative MRI approaches71 have emerged. Whatever the design of acute trials will be, clinical practice guidelines72 concerning the role of timing of surgery and optimal hemodynamic management for acute spinal cord injury will need to be considered. Leveraging historical control data from patient registries or completed clinical trials may also offer promising new avenues to overcome recruitment challenges and expedite throughput. This approach has risen in popularity in other rare diseases and led to the development of a comprehensive roadmap for planning, conducting, analyzing, and reporting of studies that use historical controls.73 Emerging analyses point to the validity of this approach, finding little to suggest that time-dependent changes in practice have impacted the recovery of neurological function after spinal cord injury.38 The widespread adoption of historical controls depends, in large part, on a willingness to share data—a concept that has gained traction in other fields (e.g., amyotrophic lateral sclerosis)74 and, in the field of spinal cord injury, among preclinical scientists.75 The use of biosimulation models in clinical trials has sparked discussions regarding the expedition of early phase investigations, including optimal dosing, safety, and efficacy at the population level.76 Given the heterogeneity of recovery and the multidimensional nature of the neurological dysfunction after spinal cord injury, advanced statistical analyses of clinical trial data are warranted. A recent secondary analysis of the Efficacy of Riluzole in Surgical Treatment for Cervical Spondylotic Myelopathy (CSM-PROTECT) trial has shown the utility of advanced statistical approaches such as global statistical test in detecting multimodal outcomes.77 The value of such approaches in clinical trials for traumatic spinal cord injury remain unexplored. With the anticipated rise in adaptive trial designs, employing advanced statistical approaches in both the analysis and reporting of trial results is imperative (e.g., using adjusted estimators to eliminate or reduce bias).67 This underscores the importance of clinical trial investigators working closely with statisticians throughout all trial stages, from design to the analysis of primary and secondary outcomes.

Conclusion

Spinal cord injury clinical trials have, in our opinion, advanced substantially in recent years, marking important progress in a field that is, by all accounts, relatively young. An effective treatment that restores neurological function has proven evasive, so far. The initial round of failures is difficult to stomach but hardly surprising given the immense challenge of repairing the injured spinal cord—an outcome the spinal cord is programmed to resist. At this critical juncture, trial “failures” are only “failures” if the field stops learning. The biggest failure of them all would be that we stop trying altogether.

Contributors

P.S.S. contributed substantially to the study conceptualisation, data curation, analysis, interpretation, visualization, and manuscript writing–original draft. J.L.K.K. contributed substantially to the study conceptualisation, data curation, interpretation, and manuscript writing–review & editing. Both authors read and approved the final version of the manuscript.

Declaration of interests

P.S.S. is a member of SCITrialsFinder curation group with no financial conflict of interest to declare. J.L.K.K. previously consulted for Axonis. The authors have no other conflicts of interest to declare.

Acknowledgements

P.S.S. is supported by the International Foundation for Research in Paraplegia, Switzerland (P 198 F), the Swiss National Science Foundation, Switzerland (P500PB_214416), and Michael Smith Health Research BC, Canada (RT-2023-3173). J.L.K.K. is supported by grants from Wings for Life, Austria and ICORD, Canada. The funding sources had no role in study design, review, data curation and analysis, interpretation, decision to publish, or preparation of the manuscript.

Footnotes

Appendix A

Supplementary data related to this article can be found at https://doi.org/10.1016/j.ebiom.2024.105381.

Appendix A. Supplementary data

Supplementary Information
mmc1.docx (14.5KB, docx)
Supplementary Table

List of 414 curated clinical trials downloaded from SCITrialsFinder.net on March 20th, 2024. The clinical trials registration number from clinicaltrials.gov (NCTID) is shown in column 1. For multi-center trials, each trial location is listed as an individual row.

mmc2.xlsx (88.7KB, xlsx)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Information
mmc1.docx (14.5KB, docx)
Supplementary Table

List of 414 curated clinical trials downloaded from SCITrialsFinder.net on March 20th, 2024. The clinical trials registration number from clinicaltrials.gov (NCTID) is shown in column 1. For multi-center trials, each trial location is listed as an individual row.

mmc2.xlsx (88.7KB, xlsx)

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