Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials

Abstract

The International Campaign for Cures of Spinal Cord Injury Paralysis (ICCP) supported an international panel tasked with reviewing the methodology for clinical trials in spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the first of four papers. Here, we examine the spontaneous rate of recovery after SCI and resulting consequences for achieving statistically significant results in clinical trials. We have reanalysed data from the Sygen trial to provide some of this information. Almost all people living with SCI show some recovery of motor function below the initial spinal injury level. While the spontaneous recovery of motor function in patients with motor-complete SCI is fairly limited and predictable, recovery in incomplete SCI patients (American spinal injury Association impairment scale (AIS) C and AIS D) is both more substantial and highly variable. With motor complete lesions (AIS A/AIS B) the majority of functional return is within the zone of partial preservation, and may be sufficient to reclassify the injury level to a lower spinal level. The vast majority of recovery occurs in the first 3 months, but a small amount can persist for up to18 months or longer. Some sensory recovery occurs after SCI, on roughly the same time course as motor recovery. Based on previous data of the magnitude of spontaneous recovery after SCI, as measured by changes in ASIA motor scores, power calculations suggest that the number of subjects required to achieve a significant result from a trial declines considerably as the start of the study is delayed after SCI. Trials of treatments that are most efficacious when given soon after injury will therefore, require larger patient numbers than trials of treatments that are effective at later time points. As AIS B patients show greater spontaneous recovery than AIS A patients, the number of AIS A patients requiring to be enrolled into a trial is lower. This factor will have to be balanced against the possibility that some treatments will be more effective in incomplete patients. Trials involving motor incomplete SCI patients, or trials where an accurate assessment of AIS grade cannot be made before the start of the trial, will require large subject numbers and/or better objective assessment methods.

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

“…Depending on the location and severity of the injury, deficits can range from weakness of limb movement to total paralysis and ventilator-assisted respiration. Spontaneous functional recovery is limited, but can and often does occur in patients with initial sparing of sensorimotor function [2]. This recovery, which plateaus between 12 to 18 months, is very likely due to sparing and sprouting of axons within the zone of partial preservation, an area where some motor function remains intact, immediately adjacent to the lesion site [2].…”

“…Spontaneous functional recovery is limited, but can and often does occur in patients with initial sparing of sensorimotor function [2]. This recovery, which plateaus between 12 to 18 months, is very likely due to sparing and sprouting of axons within the zone of partial preservation, an area where some motor function remains intact, immediately adjacent to the lesion site [2].Approximately 40% of humans that sustain spinal cord injury (SCI) exhibit improvement from their early postinjury baseline, and this spontaneous recovery can range from modest to extensive [2]. Spontaneous recovery primarily appears to depend on the extent of tissue sparing at the injury site, allowing compensatory axonal sprouting and systems reorganization at levels ranging from the spinal cord to the cerebral cortex [3][4][5][6][7][8][9][10].…”

Diagnostic criteria of traumatic central cord syndrome. Part 2: A Questionnaire Survey among Spine Specialists

“…21 This finding is supported by a panel of SCI experts from the International Campaign for Cures of Spinal Cord Injury Paralysis, who published four reference works appraising methodological issues for the conduct of clinical trials in SCI. [22][23][24] Referring to higher spontaneous rates of overall sensory and motor recovery in TCCS, the expert panel considered TCCS patients 'not being the best subjects to be included with other types of traumatic SCI during a phase 1 or phase 2 trial, as they could increase the variability of the outcome data'. 24 To examine the hypothesis that TCCS patients truly have a higher rate of neurological recovery, the use of a clear diagnostic criterion may be of great benefit.…”

“…This led us to the development of the questions of this study. An interactive pilot questionnaire survey was created and a group of 22 participants of the 48th International Spinal Cord Society annual scientific meeting in Florence, [21][22][23][24] October 2009, were found to participate. Based On the answers, comments and suggestions of these 22 participants, a definitive online survey version was created using Quizmaker '09 (Articulate, New York, NY, USA).…”

Assessment of the sympathetic level of lesion in patients with spinal cord injury

“…Without taking into account spontaneous neurological recovery in complete tetra-or paraplegic patients, the conclusion that complete sympathetic and somatic lesions are associated, is questionable. 3 Despite raised questions, we praise the efforts that have been made by Previnaire et al 1 We found the SkARV test useful in clinical practice and easy to perform. However, it would be more appropriate to retest SkARV and ASIA after certain time intervals and to clarify definitions of autonomic disorders in patients with SCI.…”