Minimizing errors in acute traumatic spinal cord injury trials by acknowledging the heterogeneity of spinal cord anatomy and injury severity: an observational Canadian cohort analysis

Abstract

Clinical trials of therapies for acute traumatic spinal cord injury (tSCI) have failed to convincingly demonstrate efficacy in improving neurologic function. Failing to acknowledge the heterogeneity of these injuries and under-appreciating the impact of the most important baseline prognostic variables likely contributes to this translational failure. Our hypothesis was that neurological level and severity of initial injury (measured by the American Spinal Injury Association Impairment Scale [AIS]) act jointly and are the major determinants of motor recovery. Our objective was to quantify the influence of these variables when considered together on early motor score recovery following acute tSCI. Eight hundred thirty-six participants from the Rick Hansen Spinal Cord Injury Registry were analyzed for motor score improvement from baseline to follow-up. In AIS A, B, and C patients, cervical and thoracic injuries displayed significantly different motor score recovery. AIS A patients with thoracic (T2-T10) and thoracolumbar (T11-L2) injuries had significantly different motor improvement. High (C1-C4) and low (C5-T1) cervical injuries demonstrated differences in upper extremity motor recovery in AIS B, C, and D. A hypothetical clinical trial example demonstrated the benefits of stratifying on neurological level and severity of injury. Clinically meaningful motor score recovery is predictably related to the neurological level of injury and the severity of the baseline neurological impairment. Stratifying clinical trial cohorts using a joint distribution of these two variables will enhance a study's chance of identifying a true treatment effect and minimize the risk of misattributed treatment effects. Clinical studies should stratify participants based on these factors and record the number of participants and their mean baseline motor scores for each category of this joint distribution as part of the reporting of participant characteristics. Improved clinical trial design is a high priority as new therapies and interventions for tSCI emerge.

Keywords: bias; motor score; neurological recovery; spinal cord injury; statistical error.

FIG. 1.

The sample size and power was calculated for a hypothetical study based on a 10-unit change in total motor score for three different sampling scenarios. For each graph, the associated standard deviations (SDs) for a ten unit change in motor score are reported based on data from the Rick Hansen Spinal Cord Injury Registry and other published papers. Curve 1 uses simple random sampling, Curve 2 stratifies for conventional patient characteristics (age, gender, American Spinal Injury Association Impairment Scale), and Curve 3 is based on stratifying patients based on the Canadian Classification.