Fighting for recovery on multiple fronts: The past, present, and future of clinical trials for spinal cord injury

Abstract

Through many decades of preclinical research, great progress has been achieved in understanding the complex nature of spinal cord injury (SCI). Preclinical research efforts have guided and shaped clinical trials, which are growing in number by the year. Currently, 1,149 clinical trials focused on improving outcomes after SCI are registered in the U.S. National Library of Medicine at ClinicalTrials.gov. We conducted a systematic analysis of these SCI clinical trials, using publicly accessible data downloaded from ClinicalTrials.gov. After extracting all available data for these trials, we categorized each trial according to the types of interventions being tested and the types of outcomes assessed. We then evaluated clinical trial characteristics, both globally and by year, in order to understand the areas of growth and change over time. With regard to clinical trial attributes, we found that most trials have low enrollment, only test single interventions, and have limited numbers of primary outcomes. Some gaps in reporting are apparent; for instance, over 75% of clinical trials with “Completed” status do not have results posted, and the Phase of some trials is incorrectly classified as “Not applicable” despite testing a drug or biological compound. When analyzing trials based on types of interventions assessed, we identified the largest representation in trials testing rehab/training/exercise, neuromodulation, and behavioral modifications. Most highly represented primary outcomes include motor function of the upper and lower extremities, safety, and pain. The most highly represented secondary outcomes include quality of life and pain. Over the past 15 years, we identified increased representation of neuromodulation and rehabilitation trials, and decreased representation of drug trials. Overall, the number of new clinical trials initiated each year continues to grow, signifying a hopeful future for the clinical treatment of SCI. Together, our work provides a comprehensive glimpse into the past, present, and future of SCI clinical trials, and suggests areas for improvement in clinical trial reporting.

Ethics and accountability for clinical trials

“…Significant gaps in the ClinicalTrials.gov database have been documented in the past [ 1 ]. We are particularly concerned about clinical trials for people living with spinal cord injury (SCI) for whom biomedical innovation is regularly featured in news media, and who may turn to the database for scientific details and opportunities for enrollment in trials themselves.…”

“…The Not Applicable Phase category, defined as “ trials without FDA-defined phases, including trials of devices or behavioral interventions ” presents further ambiguity. It accounts for a majority of SCI clinical trial studies [ 1 ]. However, there is a lack of clarity about what type of intervention qualifies for a Not Applicable Phase study versus Phase I, or if a successful trial in the Not Applicable Phase moves to a Phase I or to directly a Phase IV designation.…”

Current Spinal Cord Injury Animal Models are Too Simplistic for Clinical Translation

“…Many preclinical animal studies focus on SCI in young adult rodents. This neglects to account for the increasing number of older SCI patients, often owing to fall-induced tetraplegic injury [15]. It should not be assumed that young adults respond similarly to older adults after SCI.…”

“…Although there are more male SCI patients, with a ratio of approximately 3.6 : 1 (males : females) [15], much of the preclinical rodent research focuses on females. This is mostly due to their relative practical benefits, including manual bladder emptying following SCI.…”

Reanalysis of published histological data can help to characterize neuronal death after Spinal Cord Injury

“…SCI causes extensive alterations in the Central Nervous System (CNS) leading to impaired motor, sensory, and autonomic functions. Research efforts devoted during the past 40 years have yielded multiple therapies, several of which have been tested in clinical trials (Dietz et al, 2022). However, to date, only early surgery interventions, intensive care management, and rehabilitation remain the cornerstones for SCI treatment (Ahuja et al ., 2017; Donovan & Kirshblum, 2018).…”