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Neuroprotection during the Acute Phase of Spinal Cord Injury

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Key Points


Pharmaceutical Agents for Neuroprotection

Clinical Trial Results for Neuroprotective Agents

Mirkowski M, Hsieh JTC, Bailey C, McIntyre A, Teasell RW. (2020). Neuroprotection during the Acute Phase of Spinal Cord Injury. In Eng JJ, Teasell RW, Miller WC, Wolfe DL, Townson AF, Hsieh JTC, Noonan VK, Loh E, McIntyre A, Queree M, editors. Spinal Cord Injury Research Evidence. Version 7.0: p 1-46.


Executive Summary

Despite promising results from preclinical and early phase clinical trials, the neuroprotective properties of pharmacotherapeutic candidates have been difficult to demonstrate when scaled to later phase clinical trials. This could be attributable to several factors. First, there is high variability in the potential for patient recovery, as individuals with cervical injuries tend to recover more neurological function than those with thoracic injuries (Casha et al. 2012, Fehlings et al. 2011). Likewise, patients with incomplete injuries tend to recover more so than those with complete injuries (Bracken et al. 1997, Pitts et al. 1995, Tsutsumi et al. 2006). Recovery also varies depending on age (Burns et al. 1997, Leypold et al. 2007, Pollard & Apple 2003) and whether or not the SCI is penetrating as opposed to non-penetrating (Heary et al. 1997, Levy et al. 1996). Accommodating for these differences through sub-group analysis is hindered with statistical robustness of smaller sample sizes. Second, there has currently been no consensus regarding a method for selecting agents suitable for translation to humans based on preclinical performance. Tator et al. (Tator et al. 2012) suggested that preclinical data should be assessed based on 1) the animal/injury model(s) used; 2) timing of therapy; 3) evidence of beneficial effects of therapy; 4) reproducibility/replication and publication of results; 5) safety/toxicity of the agent; and 6) other factors such as preclinical lab environments. That human injuries are variable in their etiology and are often accompanied by other injuries makes them less straight-forward to treat compared to SCI in well controlled animal models (Sharif-Alhoseini M 2014). Lastly, the efficacy of the drug also depends on the time when it was administered. Although timing of therapy is reported in the preclinical literature, it does not currently reflect feasible timing for treatment in humans (Tator et al. 2012, Wilson & Fehlings 2014).

Along with six criteria proposed by Tator et al. (Tator et al. 2012), only one other publication by Kwon et al. (Kwon et al. 2009) addressing preclinical grading criteria to determine translatability to human trials proposes an objective scoring system to select the most promising candidates for translation. Continued development and validation of a preclinical scoring system involving worldwide experts in preclinical and clinical SCI is the next step towards selecting the next most promising pharmacotherapy for translation to humans (Tator et al. 2012).

In the interim, there is currently no pharmaceutical therapy recognized as the standard of care for neuroprotection during acute SCI. To date, EPO, G-CSF, TRH, and riluzole must be considered carefully due to the small study sample sizes used to investigate these pharmaceutical agents. Alternative study design methods might also be considered to mitigate for the large sample sizes required in a relatively small and heterogenous patient population to reach statistical significance (Tanadini et al. 2014) for a potential pharmacotherapeutic agent to be proven effective as a neuroprotectant in acute SCI.