Abstract
The Spinal Cord Outcomes Partnership Endeavors presented a clinical trials update (CTU) in collaboration with the International Spinal Research Trust as a precourse to their annual meeting. Selected trials adhered to
Introduction
For example, the International Campaign for Cures of Spinal Cord Injury Paralysis panel was initiated by a call to action in 2004. 1 The resulting guidelines addressed trial design, 2 statistical power informed by natural recovery, 3 outcome measures, 4 inclusion and exclusion criteria, and ethical considerations. 5 These article (∼2000 citations in September 2024) influenced the design of subsequent clinical trials. 6 Analyses of ongoing clinical trials offer an opportunity to identify trial design and outcome advances, as well as challenges to address in future trials.7–9
In recent years, there has been a surge in clinical trials employing neurorestorative approaches,
10
defined herein as restoring function through regeneration or plasticity. Per SCITrialsfinder.net, there were 88 neurorestorative trials in 2016 and 273 in 2023. As the last SCOPE-sponsored CTU occurred in 2016 and with several significant neurorestorative clinical trials either in preparation, in progress, or recently completed, SCOPE recognized the critical need for a CTU. The 2023 CTU was held by SCOPE and ISRT in partnership with
Trial Identification and CTU Format
A SCOPE subcommittee (Table 1) identified trials for inclusion in the CTU (considerations for inclusion in Box 1). Seven in-preparation trials were considered, with four presented (Table 2). Twenty-five in-progress and 26 completed trials identified from clinicaltrials.gov were discussed for inclusion; five in-progress (Table 3) and four recently completed trials (Table 4) were presented.
SCOPE Clinical Trial Update Planning Committee Members Represent Academic and Industry Experts in Medicine, Rehabilitation, Clinical Research, and Clinical Trials
SCOPE, Spinal Cord Outcomes Partnership Endeavors.
In-Preparation Trials
DRG, dorsal root ganglion; HSV, herpes-simplex virus; MRI, magnetic resonance imaging; OEC, olfactory ensheathing cells; SCI, spinal cord injury; tSCI, traumatic SCI.
In-Progress Trials
9HPT, 9-hole peg test; 10MWT, 10-min walk test; AIH, acute intermittent hypoxia; AIS, ASIA Impairment Scale; GRASSP, graded redefined assessment of strength sensibility and prehension; LEMS, lower extremity motor score; SCI, spinal cord injury; SCIM, spinal cord independence measure; UEMS, upper extremity motor score.
Recently Completed Clinical Trials
AE, adverse event; AIS, ASIA Impairment Scale; BID, bis in die (twice a day); CUE-T, capabilities of upper extremity test; EQ5D, EuroQol 5-dimension; GRASSP, graded redefined assessment of strength sensibility and prehension; LEMS, lower extremity motor score; NCV, nerve conduction velocity; NLI, neurological level of injury; qol, quality of life; SAE, serious adverse event; SSEP, somatosensory-evoked potential; SCIM, spinal cord independence measure; UEMS, upper extremity motor score.
Focus on neurorestoration (defined as regeneration or plasticity)
Contains an element of novelty in the trial design, analysis, inclusion criteria, or outcome measures as determined by the planning committee
Include trials across drug, cell, and device-based studies
Trial representative able to present
SCI trials listed in Clinical Trials.gov after 2016 (last SCOPE clinical trials update), open for screening prior to September 2023 (in-progress trials), and with results prior to September 2023 (completed trials)
Analytics from SCITrialsFinder.net*
Likely timing of trial initiation (near term preferred)
*SCITrialsFinder.net produces analytics based on the number of clicks on a given trial and direct contact with a clinical trial via the website. Data on user groups differentiating people with SCI, caregivers, researchers, and clinicians are not collected.
To increase the reach of the CTU beyond the 90 in-person attendees, presentations were live-streamed by the I-OSCIRS. Discussions were held offline to facilitate fluid in-person participation.
Presenters were instructed to focus on lessons learned and novelty as opposed to presenting published results. Neither the presentations nor this summary is intended to serve as an exhaustive scientific review of the background and rationale for each trial and, in several areas, reflect the expert opinion of presenters and participants. Preliminary unpublished results reported during the presentations are noted as such. This article reflects trial status at the time of the CTU, and key updates as of November 2024 are provided. For in-preparation and in-progress clinical trials, refer to trial registration (Tables 2–4) for status and relevant publicly available data.
Summary of the CTU
Session 1: A novel biotech perspective
Moderator: Marco Baptista, PhD
Speaker: David Weiner, MD
Dr. Weiner provided a novel perspective on therapeutic drug development for SCI as a consultant working outside SCI. Dr. Weiner, a neurologist trained in neuropharmacology working outside of SCI, has spent 20 years developing innovative therapeutics for multiple neurological disorders and thus provided a novel perspective. He reviewed the well-recognized and urgent need for therapeutics to improve function and address the high burden of care and disability.
Dr. Weiner emphasized that elucidating the underlying biology and pathophysiology is critical to identify relevant targets for therapeutic interventions. Because SCI impacts multiple pathways and cell types, it creates a myriad of opportunities for target identification. However, pathophysiological pathways differ across species, 45 complicating interpretation of results. Researchers must provide a scientific rationale for relevant targets and include evidence that a given intervention engages and modifies the target or biological pathway of interest. As such, target validation, target engagement, pharmacokinetics (PK), and pharmacodynamics (PD) must be assessed at all stages of the development pipeline. To exemplify this process, Dr. Weiner described the development of the neurite outgrowth inhibitor (Nogo-A) pathway as a target for SCI (Table 5).
Key Strategies That Should be Employed in SCI Trials to Improve Chances of Identifying Treatments that Promote Recovery
ASIA, American Spinal Injury Assessment Impairment Scale; CSF, cerebral spinal fluid; IT, intrathecal; MEP, motor-evoked potential; NCV, nerve conduction velocity; SCI, spinal cord injury; SSEP, somatosensory-evoked potential.
Dr. Weiner commented on strategies for establishing therapeutic efficacy. While the translational validity for rodent models of neurological disease is debated, they are useful for defining PK/PD relationships to inform key early clinical trial designs and determine initial target dose(s). Despite a high scientific and regulatory bar for biomarkers as a measure of early efficacy or drug approval, biomarkers offer the potential to correlate initial injury severity with long-term outcomes and enhance prediction models of spontaneous recovery.
Reflecting on future strategies, Dr. Weiner suggested that enhanced predictive capabilities, coupled with refined participant identification methodologies, may improve participant selection. Enrolling likely responders (based on pre-clinical data) in early-stage trials may demonstrate the biological and physiological activity of an intervention. In later-stage trials, prediction and identification models can improve the stratification of larger populations. Ideally, novel clinical outcome measures will be developed, and an immediate goal might be improving existing measures to increase sensitivity and working with regulators on outcomes in registrational trials. A potential opportunity in SCI is regulatory designations to expedite regenerative therapy development and review. For example, Fast Track, Breakthrough Therapy or Device Designation, 52 or Regenerative Therapy Advanced Designation 53 are mechanisms designed to accelerate the availability of therapeutic options. Orphan designation 54 is also an option for approaches with small defined subpopulations (e.g., subacute cervical SCI in ASIA Impairment Scale [AIS] A-C). 1 Future strategies may become clearer given multiple Phase II studies (some of which target the same pathways) with pending clinical results. Developing technologies, such as viral vector-based approaches and extracellular vehicles, may be options for intervention delivery, pending further study.
Session 2: In-preparation clinical trials
Moderator: Armin Curt, MD
Speakers: Armin Blesch, PhD; James St. John, PhD; Cornelia Haag-Molkenteller, MD, PhD; Patrick Freund, MD, PhD
Additional details for all trials in this session are found in Table 2.
I) Embryonic stem cell-derived spinal cord neural stem cells for the formation of neuronal relays—Armin Blesch, UCSD
A large body of pre-clinical literature provides evidence for the generation of neuronal relays by the implantation of spinal neural stem cells (examples55,56). Dr. Blesch focused on scaling up robust pre-clinical strategies (Tuszynski Lab at the University of California at San Diego) into human studies. He described the induction of H9 embryonic stem cells to transition to neuromesodermal progenitor cells, then to neural stem cells, and then dorsal or ventral phenotyping to mimic developmental and anatomical niches.
Dr. Blesch described advances in manufacturing/scale-up practices, safety (including the absence of undifferentiated cells), and cell stability during storage/transport to prepare for clinical use. He showed data describing low variability in cell types produced, consistent genetic markers for appropriate niches, and potency in
Novelty
Anatomical niche-focused cell differentiation.
Treatment consists of multicomponent trophic and survival factors combined with cells.
II) Autologous olfactory ensheathing cell nerve bridge transplantation and intensive rehabilitation for repairing spinal cord injury—James St. John, Griffith University
Dr. St. John described preparation for a clinical trial to assess autologous olfactory ensheathing cells as bioengineered nerve bridges in the SCI lesion. He described improvements in cell identification, viability, and purity 14 and individually customized nerve bridges amenable to implantation without the use of scaffolds, matrices, or gels. Dr. St. John showed unpublished data suggesting these bridges integrate with host tissue, retain their migratory and phagocytic capacity, and consistently display appropriate markers after engineering and implantation. Combining implantation with long-term intensive rehabilitation is theorized to guide axonal growth across the lesion.
Unpublished pre-clinical experiments transplanting bridges into mouse transection models show that 1 week after injury implanted animals show motor and sensory improvement, upregulation of genes associated with neural repair pathways, and downregulation of injury pathways. Preliminary histology reflects the ensheathing of axons by implanted cells and axon guidance across the lesion.
Novelty
Three-dimensional (3D) bioengineering of autologous cells.
Combining implanted bridges and rehabilitation.
III) HSV-1 vector gene therapy for neurogenic bladder—Cornelia Haag-Molkenteller, EG 427
Dr. Haag-Molkenteller described EG 427’s plan for a nonreplicative herpes-simplex virus 1 (nrHSV1) gene therapy vector to target sensory neurons of the bladder. Benefits of nrHSV1 over other vectors include targeted approach, large carrying capacity, absence of neutralizing antibody reactions, repeated dosing, and efficient/reliable large-scale manufacturing.
EG 427 is studying two nonreplicative HSV-1 vectors: EG110A to target bladder dysfunction and EG132A to target spasticity. Following SCI, overstimulation of the afferent type-C fibers can cause neurogenic detrusor overactivity (NDO). NDO results in involuntary bladder contractions and urine leakage, leading to increased bladder pressures, urinary tract infections, and decreased quality of life. 58 After injection into the bladder wall in pre-clinical studies, EG110A travels to the dorsal root ganglia and transduces type C sensory neurons to reduce neurotransmitter release by expression of the light chain of botulinum toxin F. 20 The current treatment for NDO involves direct BOTOX injection into the bladder muscle, requiring repeat injections every 6–9 months. 58 EG110A is projected to lead to multiyear efficacy (3 or more) and specificity to sensory neurons/lack of effect on motor neurons. The EG110A intervention holds promise to reduce urinary incontinence, bladder pressures, urinary tract infections, and urinary retention. EG132A is expected to convert excitatory sensory neurons into inhibitory sensory neurons to target spasticity.
A Phase Ib/IIa trial is planned in the United States and United Kingdom* for 2024 to assess safety/efficacy of EG110A. Importantly, EG 427 will include input from individuals with SCI in the trial design.
Novelty
Intervention specifically targets bladder sensory neurons and bladder dysfunction.
Pinpoint DNA medicine.
*Update
The trial is currently enrolling in the United States (Table 2).
IV) Ibudilast-mediated neuroprotection with enhanced plasticity from early pregabalin administration in acute cervical spinal cord injury—Patrick Freund, Balgrist Hospital
Dr. Freund proposed the repurposing of the drug ibudilast to target chronic inflammation and neurotoxicity, with a primary outcome of reducing lesion volume by 20%* and improving upper extremity motor score (UEMS) by >5 points.
Rodent studies utilizing drugs similar to ibudilast show axonal regeneration after SCI. 17 Human studies in multiple sclerosis demonstrate reduced lesion sizes and increased tissue sparing. 59 Investigators hypothesize that ibudilast mediates neuroprotection via phosphodiesterase 4 (PDE4) inhibition and reduced inflammation. Gabapentin is prescribed for neuropathic pain, and evidence in humans suggests early administration improves motor recovery, 60 potentially via enhanced axonal regeneration by blocking α2δ2, 61 as seen in rodents.
There are no pre-clinical data on ibudilast use in SCI or its combination with gabapentin. But, as both drugs are approved for use in other diseases, this group plans to examine their combined use in SCI. They propose a randomized (1:1) double-blinded Phase IIb trial examining placebo versus ibudilast conducted in the European Multicenter Study about Spinal Cord Injury network to investigate the safety, tolerability, and efficacy of repeated oral doses of Ibudilast (MN-166) in acute traumatic cervical SCI AIS (A–D)*. In addition, they aim to explore additional effects of gabapentinoids as a “standard of care drug” for neuropathic pain (1) within the trial as a secondary objective and (2) in a large associated observational study.
Novelty
Combinatorial repurposed drugs with different proposed mechanisms to modify inflammation.
Magnetic resonance imaging (MRI)-based measure (lesion width) to assess atrophic changes as primary outcome*.
* Update:
Trial will be a feasibility study assessing UEMS as primary outcome.
Challenges and solutions identified during session (i.e., lessons learned)
Several groups described the rigor required to effectively scale up from pre-clinical to clinical deployment, particularly for cell-based interventions. This scale-up is difficult for academic labs and requires significant resources.
Input from individuals with SCI has the potential to improve trial design, enrollment, retention, and participant experience. Early engagement of people with SCI should be included in early trial design to reduce participant burden and focus on outcomes important to people living with SCI.
Utilizing retrospective observational datasets for human data may identify therapeutic approaches that can be evaluated in animal models. Particularly regarding combinatorial approaches, discussion focused on the necessity of a comprehensive understanding of the rationale behind combining treatments and determining the necessary scope and nature of pre-clinical testing for drugs already approved for human use. Historically, human trials have been informed by pre-clinical data in SCI models. Repurposing interventions in the absence of an SCI pre-clinical package may represent a faster path to evaluate potential therapeutics. However, this approach also means trials are initiated with more unknowns, such as mechanisms or interactions, which must be carefully considered. Discussion also focused on strategies to discern the effects of each intervention in trials where randomization of both interventions is not feasible.
Session 3: In-progress clinical trials
Moderator: Linda Jones, PT, PhD
Speakers: James Guest, MD, PhD; Daniel Mikol, MD, PhD; Susan Harkema, PhD; Randy Trumbower, PT, PhD
Additional details for all trials in this session are found in Table 3.
I) Safety and efficacy study of intravenous (IV) administration of Elezanumab to assess change in Upper Extremity Motor Score (UEMS) in adult participants with acute traumatic cervical SCI (ELASCI), Abbvie
II) Study to assess the efficacy and safety of MT-3921 in subjects with acute traumatic cervical SCI, Mitsubishi James Guest, University of Miami
Two trials are examining intravenously delivered monoclonal antibodies designed against repulsive guidance molecule A (RGMa) targets. A primary effect of the antibodies is to disrupt RGMa binding to the neogenin receptor. RGMa signaling is upregulated after SCI and inhibits axonal growth via multiple mechanisms. 22 Further, it affects cell survival and immune responses, making it a potential multimechanistic target. 62 Importantly, RGMa binding of neogenin activates RhoA kinase signaling and subsequently causes growth cone collapse. Thus, interrupting RGMa binding/neogenin signaling is hypothesized to support axonal plasticity and regeneration. 23
The Mitsubishi-sponsored study entails IV injections of antibodies (Unasnemab; MT-3921) within 3 weeks of a traumatic cervical SCI and continuing monthly until day 150 (≈ 6 doses). The Abbvie ELASCI study administers antibodies (Elezanumab; AT-555) within 24 h of traumatic cervical SCI and then every 4 weeks, totaling 13 doses. The Mitsubishi study is of shorter duration and includes individuals with AIS A, B, and C, whereas the Abbvie study enrolls AIS A and B. These differences in trial design will be important considerations when results are available. A subset of sites in the ELASCI trial added serial electrophysiological assessments to motor and functional assessments. Longitudinal plasticity of motor circuits will be assessed by motor-evoked potentials (MEPs) and voluntary electromyography.
Dr. Guest highlighted the unique opportunities created by assessing efficacy in different populations with different inclusion criteria. The resulting analyses will be independent and can serve as reciprocal validation. Furthermore, the antibody in each trial targets different epitopes, permitting assessment of the robustness of the target.
Novelty
Independent trials validate a single therapeutic approach.
Long duration of antibody administration, lasting up to a year with Elezanumab.
Electrophysiology assessments may indicate efficacy by detecting changing signals below clinically measurable motor scores.
Update: both trials active, not recruiting.
III) A Phase Ib/IIa study of NVG-291 in individuals with subacute or chronic SCI—Daniel D. Mikol, NervGen
Protein tyrosine kinase phosphatase sigma (PTPσ) is a receptor of chondroitin sulfate proteoglycans that mediate the inhibition of neural repair. 26 Pre-clinical acute and chronic intervention models of SCI in rodents using intracellular sigma peptide (ISP), a peptide derived from intracellular sequence of rodent PTPσ, demonstrate improved functional (motor, bladder) recovery, with evidence of enhanced plasticity, axonal regeneration, and remyelination.26–28,63 Given that most animal models of SCI are motor incomplete, in this proof-of-concept clinical trial, NVG-291, the human analog of ISP, is being tested in participants with subacute and chronic motor incomplete cervical SCI. Although pre-clinical data showed efficacy in both cervical and thoracic injury models, chronic pre-clinical studies were only conducted in cervical injury to date; thus, the clinical trial includes only participants with cervical SCI.
This is a single-center trial designed to maximize the reliability of electrophysiological assessments (the primary outcome) and the consistency of rehabilitation administered to all participants. Inclusion/exclusion criteria are based on minimal and maximal motor function and MEPs, which must be present in two specific qualifying muscles. The fixed dose selected was determined from pre-clinical and healthy subject dosing studies, with exposures in this trial predicted to overlap with or exceed the broad range of efficacious doses from pre-clinical studies. The anticipated outcome of improved neuronal connectivity is assessed by change in overall motor function (hand function and mobility) and MEPs, a surrogate measure of motor recovery. PK and PD (blood proteomics and transcriptomics) data will be collected.
Novelty
Subacute and chronic SCI.
Electrophysiological assessments (objective, quantitative, continuous, and maximize probability of detecting an efficacy signal) are used to identify potential participants and as outcome measures.
IV) Task-specific epidural stimulation study (TS EPI)—Susan Harkema, formerly University of Louisville, now Kessler Foundation
Studies assessing lumbosacral stimulation for locomotor function after SCI identified multiple off-target effects for therapeutic investigation.64,65 This study utilizes epidural stimulation at subthreshold levels, previously used to enable locomotion. While the primary outcome is cardiovascular function, a secondary hypothesis aims to determine the importance of stimulation parameter specificity for the intended outcome and combinatorial effects of stimulation with rehabilitation.
Dr. Harkema described protocols for implantation and infection reduction. Pre-implant 3D spine and spinal root mapping aids initial implantation at the targeted spinal segment, and pre-surgical imaging and intraoperative neurophysiology offer fine-tuned placement during surgery. Postoperative spatiotemporal mapping identifies appropriate parameters for targeted motor behavior and physiological responses.
Dr. Harkema reported that thus far, all implanted participants (
Novelty
Examining off-target effects as evidence for clinical indication.
V) The BO2ST trial: breathing low oxygen to enhance spinal stimulation training and functional recovery in persons with chronic SCI—Randy Trumbower, Harvard Medical School
Both daily acute intermittent hypoxia (AIH) and transcutaneous spinal cord stimulation (tSTIM) have been evaluated in clinical trials67–69 to induce neural plasticity. The group hypothesizes that combining these interventions will amplify plasticity and enhance the training-related gains of each. The BO2ST trial plans to enroll 64 persons with chronic, motor incomplete SCI to investigate the efficacy (AIH resulting in enduring effects on WALKtSTIM), potency (AIH accelerating the benefits of WALKtSTIM), and safety of this combined approach on overground walking recovery. The trial aims to determine if the combined interventions will amplify or detract from one another and how they should be delivered temporally (e.g., pretreatment or combination). The study includes the intervention plus intense training, with 1- and 2-month follow-ups.
Preliminary unpublished analyses show that while each intervention’s measured effect is short-lived (days to weeks), the combination allows individuals to reach clinically meaningful effects sooner than with either intervention alone and with more significant, longer-lasting (months to years) gains.
Randomly assigning participants to one of three intervention groups permits adequate controls (comparing combo with either intervention individually). The study can improve recruitment by broad inclusion criteria (as pre-clinical data indicate efficacy across broad ranges), a low burden and commitment for participants, and the promise of 1 month of high-intensity training in all groups. Due in part to the broad inclusion criteria, many covariates complicate decision-making and increase experimental noise (e.g., concurrent medication use, measurement error, placebo effects, etc.). Ongoing work with statisticians aims to determine important covariates in baseline data that might impact outcomes and identify physiological factors (e.g., prevalence of sleep-disordered breathing 70 ) common to responders. A second challenge is conducting traditional dosing studies involving combinatorial interventions. As often occurs in stimulation studies, it is hard to control for participants in the stimulation groups who may be aware of the stimulation condition. Finally, the physiological targets underlying the clinical assessments in humans remain unclear.
Novelty
Combining approaches that target complementary mechanisms of neural plasticity may result in greater beneficial effects than either alone.
Consideration of unintended deleterious interactions.
Challenges and solutions identified during session (i.e., lessons learned)
Combinatorial interventions, or the inclusion of intense therapy, creates unique opportunities (such as amplifying task-specific gains) and difficulties (balancing dosing and timing of administration among multiple interventions and differentiating the effects of rehabilitation from the effects of the experimental intervention).
Broad recruitment ranges (e.g., 1–10 years postinjury for chronic SCI in the NVG-291 trial or broad inclusion criteria in the BO2ST trial) assist with enrollment numbers but may require stratified analysis due to the potential for increased noise and/or heterogeneity. One strategy to increase enrollment is to ensure the control arm receives an intervention and thus has a potential benefit (e.g., exercise/training in the NVG-291 trial).
Session 4: Recently completed clinical trials
Moderator: Jane Hsieh, MSc
Speakers: Michael Fehlings, MD, PhD; Norbert Weidner, MD; Gary S. Hogge, DVM, PhD; Edelle Field-Fote, PT, PhD
Additional details for all trials in this session are found in Table 4.
I) Riluzole in spinal cord injury study (RISCIS)—Michael Fehlings, University of Toronto
Riluzole, a sodium-glutamate antagonist, is currently an established neuroprotective medication for amyotrophic lateral sclerosis (ALS). A Phase I/IIa trial was conducted in SCI, and based on these findings, a Phase II/III trial was conducted in cervical SCI. 71
Oral riluzole administration was initiated within 12 hours of injury, a time window infrequently targeted in trials. The trial was terminated before enrollment was complete, but modified subanalyses provided additional information.
Ultimately, 193 patients were randomized into riluzole or placebo with 83% follow-up at 1 year. 50 There were significantly more participants with AIS A injury severity enrolled, possibly due to the rapid transport of more severe injuries to trial sites. The primary outcomes (UEMS and total motor score) were assessed 180 days after injury and showed participants taking riluzole had a mean difference of 1.76 on UEMS and 2.86 on total motor score versus control. 50 Dr. Fehlings also detailed the multiple preplanned secondary analyses, including change in neurological level, independence measures, and mental health scores (Table 4) some of which preliminarily showed positive signal. Dr. Fehlings emphasized the importance of developing and utilizing multiple and alternative methods of analysis to gather as much data as possible from clinical trials.
The rate, relatedness, and severity of adverse events did not differ between riluzole and placebo groups. PK/PD data showed an association between motor recovery and drug levels. Furthermore, riluzole is associated with less elevation in levels of phosphorylated neurofilament heavy chain, a biomarker of axonal degradation, as compared with placebo. 72
Planned alternative and additional analyses include group-based trajectory modeling, recursive partitioning, combining outcome measures to permit global statistical test approaches, examination of MRI findings, and a meta-analysis of Phase I/IIa and II/III.
Novelty
First deployment of a sodium-glutamate antagonist in SCI.
Repurposing a drug with high safety and tolerability that can be easily administered by first responders.
II) Nogo-inhibition in spinal cord injury—first results of a randomized placebo-controlled phase II clinical trial—Norbert Weidner, Heidelberg University Hospital
This multicenter trial evaluated the efficacy of NG101 (anti-Nogo-A antibody) following a Phase I trial that demonstrated safety and feasibility. 49 The current trial used unbiased recursive partitioning (URP) to predict UEMS recovery at 6 months based on standardized neurological assessments at baseline, which permitted balanced inclusion into predefined subgroups who would not likely reach a ceiling effect in the course of natural recovery and potentially be responders to the intervention. This inclusive approach identified eligibility in ∼73% of participants (AIS A–D).
Over 3 years, 126 participants consented to and were randomized into the study (78 experimental and 48 control); an intention-to-treat analysis showed a small nonsignificant increase in the UEMS (primary outcome) with the Nogo-A antibody. A subgroup analysis showed improved UEMS and functional recovery (spinal cord independence measure self-care; secondary outcome) in participants with motor incomplete (AIS C and D) injuries (unpublished).
The mechanisms by which the anti-Nogo antibody is hypothesized to promote axon growth may explain these results. Meaningful regeneration requires an anatomically incomplete injury with preserved neural tissue across the injury site for sprouting collaterals to reach viable targets.
Given the positive findings in the subgroup analysis in the Phase II study, the group plans further studies. Cerebral spinal fluid (CSF) proteomics (unpublished) suggests engagement of a candidate protein important for tissue remodeling, synaptogenesis, and repair, providing an opportunity for validation and mechanistic testing.
Novelty
Effective use of URP to balance participants between treatment arms and identify potential responders.
III) Key learnings from dose escalation studies of OPC1 in subacute spinal cord injury (thoracic and cervical)—Gary Hogge, Lineage Cell Therapeutics
In this approach, pluripotent stem cells are terminally differentiated into oligodendrocyte progenitor cells (OPC1) and implanted into the spinal cord to promote myelination, neurite outgrowth, and neovascularization and to prevent/fill in cavitation. An earlier study (sponsored by Geron Corporation) demonstrated a positive safety profile in thoracic SCI. 73 A Phase I/IIa study (sponsored by Asterias Biotherapeutics) established safety and feasibility in multiple cervical cohorts with escalating doses of cells. 74 Long-term follow-up will continue to 15 years for both studies, and no serious adverse events have been reported related to OPC1 at the 10-year follow-up of the first study.
Following these trials, significant advances were made in manufacturing and implantation protocols. Improvements include large-scale production with no animal reagents, a ready-to-inject formulation to reduce dose-preparation errors, and a fully functional cell line of higher purity. A novel surgical delivery device for implantation was designed, created, and tested to improve usability while enhancing participant safety. A proof-of-concept study to establish the safety and utility of the new surgical device in 5–10 participants was submitted to the U.S. Food and Drug Administration (FDA).
Dr. Hogge noted the importance of recruiting sites with potential for high-capacity enrollment, representing different regions with a wide geographic catchment area. Accommodating feedback from participants, the sponsor plans to use digital study materials (vs. paper), provide stipends (in compliance with established recommendations), and use SCI specific quality of life questionnaires.
The time window for implantation (21–42 days postinjury) was based on biological data from pre-clinical studies but presents challenges for enrollment. Further, a time window for chronic SCI needs to be established. The optimal control group for cell transplantation is challenged by the ethics of sham surgeries. Age at injury and cause of injury are considerations for participant stratification, and incorporation of standardized rehabilitation programs is needed to identify gains beyond spontaneous recovery. Individuals with C4 injuries present a unique challenge given the severity of the injury and functional loss.
Novelty
Person-mounted magnetic needle in surgical device that moves with ventilation removes need to pause ventilation during implantation.
IV) Clinical assessment of upper extremity performance in individuals with spinal cord injury using the LIFT system to deliver noninvasive electrical spinal cord stimulation—Edelle Field-Fote, Shepherd Center
The recently completed Up-LIFT trial assessed the safety and effectiveness of ARCEX therapy, delivered in conjunction with functional task practice training in individuals with tetraplegia. 75 In a run-in study design, participants received 2 months of upper extremity (UE) functional task practice training followed by 2 months of ARCEX therapy combined with UE functional task practice training.
Initially, 65 participants were enrolled, and at the end of the 4-month study, a modified intention-to-treat (mITT) analysis was conducted on 60 individuals who completed all study procedures. The mITT population included individuals with AIS B, C, and D grade injury, with a larger proportion of individuals in the AIS C and D subgroups. Injury chronicity ranged from 1 to 34 years. The stimulation intensity utilized throughout the trial varied among participants but was tolerated well.
The primary effectiveness end-point was met, with 72% of participants achieving clinically significant improvements in at least one strength and one function metric. 75 There were no serious device-related adverse events. The secondary end-points assessed improvements beyond the plateau achieved by rehabilitation alone and suggested further improvements are enhanced with concomitant stimulation. Exploratory analyses revealed a higher responder rate in the AIS C and D subgroups; however, those designated as nonresponders may also receive functional benefits. Dr. Field-Fote described small improvements that did not achieve the threshold for clinically significant improvements but greatly impacted an individual’s quality of life.
Novelty
Choice of end-point—composite responder analysis (clinically significant improvement in at least one strength and one function metric) demonstrating improvement in impairment and function with less likelihood of compensation.
Single-arm run-in study design permits participants to serve as their own control without a crossover design.
Challenges and solutions identified during session (i.e., lessons learned)
Presentations in all sessions commented on the lack of tools to address low enrollment and heterogeneous populations. A focus on secondary measures and tools such as URP to stratify participants illustrates how intelligent data-driven design and analysis can increase the signal-to-noise ratio.
Identifying populations most likely to respond based on pre-clinical data or biomarkers may inform proof-of-concept trial design. Despite difficulties in comparing severities and timelines in pre-clinical studies to human SCI, these studies can inform the severity or injury phase most likely to benefit from the intended intervention. Effective screening will identify participants predicted to be responders for reasons such as less severe injury, specific timepoint postinjury, or key anatomical/morphological biomarker (e.g., preserved tissue substrate). Evaluating efficacy in responders may help determine targets or mechanisms that can be further developed for other populations (e.g., more severe injury or chronic timepoint). A key component of this development is confirming a consistent mechanism of action and target engagement across subpopulations.
Discussion: Challenges and Opportunities
Several significant and long-awaited trials of neuroprotection, regeneration, and neuroplasticity reported findings at this CTU. The in-preparation and in-progress trials are likely to yield vital data in future CTUs. In-person discussions and attendance at meetings provide a critical opportunity to synthesize current efforts and strategize to direct future efforts. A unique feature of this CTU, the online streaming and large virtual audience, suggests there is added utility in increasing the accessibility of CTUs for those who cannot attend in-person meetings. Here, we summarize the discussion and themes that emerged, reflecting the perspectives and opinions of those present. We further contextualize and provide recommendations for consideration for future trials.
Pre-clinical studies
Attendees vigorously debated the type and extent of pre-clinical data necessary to initiate a trial, including the need for pre-clinical efficacy data in SCI models. There was debate regarding the best use of animal studies for establishing efficacy. Considering small versus large animal models, the discussion centered less on the model used but instead on using the data to derisk Phase I studies. The group largely agreed that large animals more closely model key anatomical or functional pathways and may be necessary for key pre-clinical data that cannot be acquired in rodents. Ideally, biomarkers that exhibit consistency across different species will be identified. Animal models can establish PK/PD, mechanisms of target engagement, and therapeutic windows to provide starting points for clinical studies.
Recommendations to derisk the pre-clinical to clinical pipeline
Integrate evidence of mechanistically based target engagement at all stages of the development process.
Provide resources for investigators to access biotechnology/drug development ecosystem.
Concerted funding strategies between multiple funders for late stage pre-clinical and early-stage clinical trials.
Interventions
Combinatorial interventions may approach the same target through different mechanisms or engage different complementary targets. Combinatorial approaches present unique challenges in determining the timing and dosing of all interventions. Consequently, multimodal approaches require a strong scientific rationale with clearly elucidated mechanisms for all modalities. Ideally, multiple levels of inquiry (i.e., cellular, animal, and human studies) provide insight into the target and how the intervention modifies the target. While the potential for amplified effects with combinatorial approaches is encouraging, the potential for negative interactions between interventions requires additional care and management.
Ongoing development of improved technologies (e.g., stimulation methods) and pipelines (e.g., drug screens and compound development) will produce more specific interventions toward precise targets and reveal key aspects of engagement. For example, it may be more desirable to modulate a receptor as opposed to completely blocking it.
Repurposing approved drugs enlarges the pool of potential therapeutics. Repurposing may offer a faster path to clinical trials, reduce barriers to initial safety studies, and support regulatory approval for human use in SCI. 76 Previous work establishing the efficacy of these drugs in other conditions may provide insight and a hypothesis for the mechanism of action that can be validated using SCI animal models. Derisking of studies with previously approved therapeutics with robust evidence may attract interest from investors for SCI clinical trials if new intellectual property potential is present.
Thus far, with small sample sizes and focused inclusion/exclusions criteria, the stimulation trials reported effects in most participants. Importantly, some efficacy is seen across the spectrum of injury severity and chronicity, facilitating mechanistic inquiries in SCI subpopulations. It is important that ongoing and future studies validate mechanisms 77 and inform future work. A remaining challenge in stimulation trials is the difficulty in creating effective placebo conditions to decrease the risk of false positives.
Several studies include targeted rehabilitation. Evidence from pre-clinical and clinical studies suggests that rehabilitation can influence motor outcomes and may amplify functional recovery when combined with other interventions,78,79 although specific mechanisms must still be established.
Recommendations
Identify mechanistically relevant SCI targets for repurposed or combinatorial approaches.
Frameworks are needed to appraise novel and repurposed drugs at all stages (discovery through translation). The Evaluation Subgroup of the SCI Think Tank is eliciting feedback on an evaluation framework for combinatorial approaches.
Explore methods to address placebo effect and devise sham interventions.
Develop protocols that can be harmonized across sites in multicenter trials.
Explore methods to integrate feasible, cost-effective, task-specific rehabilitation into clinical trials.
Trial design
Many presentations highlighted ways to improve recruitment such as providing participant benefits in all arms, where possible, and reducing financial or physical burdens of participation. The difficulty of identifying appropriate controls, such as ethically acceptable controls for surgical interventions, was brought up by several presenters. New control group methods such as historical, 80 registry-matched, or shared controls may improve trial efficiency. Reliable biomarkers may be detectable long before traditional impairment and functionally based measures; they should be considered when designing trials if/when applicable. The incorporation of biomarkers (e.g., fluid-based biomarkers reviewed in 81 ) will facilitate use in some trial designs as an indication of the severity of SCI, recovery, and response to an intervention.
When screening acute or subacute participants, upper and lower bounds are frequently set to prevent ceiling effects and floor effects, excluding participants and potentially causing a loss of valuable data. The growing toolset to address heterogeneous samples was also discussed. Ideally, with these tools, early-stage trials will not require restrictive inclusion criteria. Using
Repeated discussion considered the use of AIS grade as an inclusion criterion. The International Standards for Neurological Classification of SCI (ISNCSCI) exam was developed to promote consistent communication between clinicians and researchers in defining neurological levels and severity of injury and is based on motor and sensory scores, including anal. 83 It has undergone many revisions with input from both clinicians and researchers. 83 Aspects of the ISNCSCI are commonly used for trial inclusion, as recovery predictors and trial outcomes, to describe heterogeneity and for stratification. For neuroprotective studies where interventions must be given within hours of injury, one must consider clinically feasible, accurate alternatives.
The use of change in AIS grades as an outcome measure was also discussed. AIS is an ordinal measure (as with most measures in SCI), with large “categories” that are not always sensitive to change nor reflective of changes in function. Discussion also centered around the use of motor scores, which might not capture meaningful clinical benefits. Improvement in motor scores can be more or less sensitive than existing functional assessments but, depending on the distribution and magnitude of change, might not always correlate with a commensurate change in function. As motor scores may not be sensitive enough, secondary measures may detect additional effects. For example, small improvements of voluntary motor control measured with electromyography that correlate with meaningful quality of life improvement may differ from functional motor control as defined by a prehension score. However, commonly used measures may fail to capture real quality of life effects or unintended effects (positive or negative) of an intervention on other systems. Thus, more holistic measures should be considered in addition to primary outcome measures. Researchers might consider leveraging multiple data sources to validate results. The current climate, wherein multiple completed trials can be analyzed in concert, may signal a nexus point to gather thought leaders to rethink how we analyze and interpret clinical trials, building on lessons learned.
Recommendations
Continue to build large, accessible pre-clinical and clinical trial datasets and registries to:
characterize spontaneous recovery model adaptive trial designs develop precise predictive algorithms explore historical controls or digital twins
84
federate independent datasets
Aggregate clinical trial data, as in ALS, 85 to detect trends and off-target effects that impact recovery, generating novel targets and research questions
Explore and expand novel trial designs (e.g., adaptive and platform trials 86 )
Convene a biostatistical study group to develop recommendations for:
group-based trajectory modeling URP global statistical test approaches on combined outcome measures meta-analyses of Phase I/IIa data
Pursue development, validation, and regulatory approval of biomarkers to provide an objective determination of severity in earlier stages and for early readouts to support adaptive trial designs.
Consider biomarker-focused CTUs/workshops.
Effect sizes and measures
Many studies show small effects using current measures, in part due to heterogeneity of trial participants. A key message was the potential for additive small effects in different body systems to collectively and meaningfully impact quality of life, which might not be detected with functionally based outcomes of clinically meaningful improvements. The need for modification of existing measures or the development of more sensitive measures was discussed. Although linear scales, such as the 10-m and 6-min walk test, are commonly used, many clinical outcome assessments are ordinal with inferred ranking (e.g., task A is more challenging than task B) that cannot ascertain the degree of difference in difficulty between tasks. Despite their established value, ordinal measures are restricted in the type, accuracy, and strength of statistical analyses, and comparing outcomes across differing severities and level of injury is difficult.87,88
Electrophysiology may prove a promising proof-of-concept biomarker in early-stage trials, as changes in electrophysiology may be detectable before clinically detectable motor effects. While these findings should not be overinterpreted, the ability to assess signal in a person with incomplete injury is a key strength. Discussion revolved around strategies to address concerns of quantification and high variability when using electrophysiology assessments as outcome measures, such as photographing electrode placement and regular remapping. Importantly, tracking these changes over time might yield effects and future avenues of research and therapeutics that might ultimately correlate with other clinical features (e.g., force generated).
Enrolling individuals with less severe injuries and more residual tissue may result in larger observed effect sizes, determine mechanisms of improvement, and elucidate better targets for individuals with more severe injuries and less spared tissue. The increased number of trials incorporating electrophysiology and imaging provides an opportunity to learn from these trials.
Recommendations
Use advanced methodologies such as item response theory (IRT), including Rasch analysis,89–92
to evaluate existing measures to assess their underlying constructs, floor and ceiling effects, and gaps in content. IRT may:
develop new measures if warranted. quantify differences in level of difficulty between specific test items and scores in existing measures.
Consider a study group to:
Validate the association of patterns or changes in electrophysiological measures with clinical measures and outcomes. Develop robust protocols to normalize data, reduce noise, and standardize across participants and sites as some research networks have done.
Lived experience perspective
Many presenters reported activities to increase meaningfully incorporation of lived experiences in the research pipeline, including input on trial measures. Funding agencies increasingly recognize the critical importance of lived experience perspective on grant applications, and some now incorporate this perspective on grant review panels. Many of the presentations included descriptions of participant-reported increased quality of life despite results that fell short of clinical significance. Incorporating quality of life and participant perspectives as outcomes may be a way to detect previously undetected effects as well as centralize the lived experience perspective.
Recommendations
The North American SCI Consortium (NASCIC) SCI research advocacy course creates a pool of trained research partners and advisors; investigators should pursue relationships with these partners.
Implement recommendations from upcoming patient-focused drug development (PFDD) meeting with the FDA to express patient preferences for therapeutic development. Ultimately, this PFDD will help inform the field and the FDA of what is important to people living with SCI. Key priorities have been outlined by NASCIC and SCOPE for consideration, including:
small effects (vs. clinical effects) on quality of life population heterogeneity appropriateness of outcomes measures
Identify measures to capture small, meaningful changes outside the primary outcome.
Conclusion
Presentations at the CTU described advances in pre-clinical studies, interventions, trial designs, and measurements. With insights gleaned from recently concluded trials and the advancements in assessment and analysis techniques, the present moment offers an opportunity to comprehensively consider the field’s status and opportunities for advancement, as outlined by points raised in this article.
Trends stemming from completed trials, revised for ongoing trials, and carefully reconsidered for in-preparation trials may signal the need to review and adjust the trajectory for future trials. The lifespans of individuals living with SCI have not improved over the decades, 93 and our research community has not yet achieved substantial, functionally significant improvements in neurorestoration. We have identified new and repurposed potential therapeutics (individually and combined), innovative trial designs, novel methods for data analysis, the need to improve existing outcome measures, and develop more specific and sensitive measures. These are green flags suggesting the need to gather clinicians, researchers, people with lived experience, and organizations to strategize for maximal usage of this emerging knowledge base. As the field begins to assemble to tackle lessons learned, we must prioritize additional ongoing consistent efforts to address the remaining gaps.
Footnotes
Acknowledgments
The authors and contributors wish to acknowledge ISRT, Wings for Life, the Christopher & Dana Reeve Foundation, and SCOPE members for making the CTU possible. The CTU would not have been possible without the efforts of Timea Konya, for which the authors are grateful. The authors thank Dr. Rob Brownstone for providing insightful feedback on this article, Eilah Berlow for her assistance and stellar note taking, Dr. Timothy Friedman for editing, and Oli Hedzelek for his assistance with references. The authors thank Dr. Cedric Geoffroy and the rest of the I-OSCIRS steering committee for their support.
Authors’ Contributions
J.H. and L.J. conceptualized and developed the CTU approach and agenda (in collaboration with the SCOPE committee), coordinated the day’s events, wrote, reviewed, and edited the article; B.R.K. assisted in the CTU and wrote the article; S.R. assisted in the CTU and reviewed and edited the article; A.C. and M.A.S.B moderated sessions in the CTU and reviewed the article; D.W., A.B., J.S.J., C. H-M., P.F., J.G., D.D.M., S.H., R.D.T., M.G.F., N.W., G.S.H., and E.F.-F. presented at the CTU, edited the article, and reviewed the article.
Transparency,Rigor,and Reproducibility Statement
This conference proceeding summarizes presentations and discussions held during the Clinical Trials Update precourse held immediately in advance of the 2023 International Spinal Research Trust yearly meeting. In-person attendance was open to all conference registrants. The online stream was publicly available. Attendees represented people with lived experience, funders, and academic and industry experts in medicine, rehabilitation, clinical research, and clinical trials. The methods for determining presenters are found in the “Approach and Trial Identification” section. Recommendations presented herein have been reviewed by all coauthors and represent the discussions on the day, with additional context from the literature.
Author Disclosure Statement
L.J. is a paid consultant for Lineage, Abbvie, NervGen, and Mitsubishi. J.G. is a consultant to Abbvie and prior DSMB Chair Mitsubishi Tanabe. C.H.-M. is a Chief Medical Officer at EG-427. D.D.M. is an employee of NervGen Pharma. G.S.H. is a paid consultant for Lineage Cell Therapeutics, Inc. P.F. is a paid consultant for Novago. E.F.F is a paid consultant for Onward Medical Inc. and SCI Ventures.
Funding Information
The CTU was made possible by funding from SCOPE, Wings for Life, ISRT, and the Christopher & Dana Reeve Foundation. B.R.K. was supported by a Paralyzed Veterans of America Research Foundation Grant (3195). J.S.J’s research was funded by the Clem Jones Foundation, the Perry Cross Spinal Research Foundation, and the Motor Accident Insurance Commission, which provided funding to Griffith University to support the Clem Jones Centre for Neurobiology and Stem Cell Research to conduct research activities that aim to improve the treatment and rehabilitation of people injured in motor vehicle crashes. R.D.T. was supported by Department of Defense, CDMRP SCIRP. M.G.F. was supported by the Robert Campeau Family Foundation/Dr. C.H. Tator Chair in Brain and Spinal Cord Research at UHN. E.F.F’s research was currently funded by the National Institutes of Health and the National Institute on Disability, Independent Living, and Rehabilitation Research.
1
A number of trial sponsors presented at the CTU received either expedited regulatory designations and/or orphan designation including Abbvie, Lineage, NervGen, Onward, and Mitsubishi.