1. ¹Cambridge University Centre for Brain Repair, Robinson Way, Cambridge, UK
2. ²ICORD, University of British Columbia and Vancouver Coastal Health Research Institute, Vancouver, BC, Canada
3. ³WPCMath, Buffalo, NY, USA
4. ⁴Center for Neural Repair, University of California, San Diego, La Jolla, CA, USA
5. ⁵Craig Hospital, Englewood, CO, USA
6. ⁶Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia
7. ⁷Acorda Therapeutics, Hawthorne, NY, USA
8. ⁸Spinal Cord Injury Center, Balgrist University Hospital, Zurich, Switzerland
9. ⁹Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA
10. ¹⁰Department of Neurology, University of California Los Angeles, Geffen School of Medicine, Neurologic Rehabilitation and Research Program, Los Angeles, CA, USA
11. ¹¹Department of Movement & Balance, Division of Neuroscience & Mental Health, Imperial College London, Charing Cross Campus, London, UK
12. ¹²University of Toronto, Krembil Neuroscience Center, Head Spine and Spinal Cord Injury Program, Toronto Western Hospital, Toronto, Ontario, Canada
13. ¹³Institut des Neurosciences – CHU St Eloi, INSERM U-583, Montpellier cedex, France
14. ¹⁴Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA
15. ¹⁵Department of Neurological Surgery, Lois Pope LIFE Center, Miami, FL, USA
16. ¹⁶National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
17. ¹⁷Department of Orthopaedic Surgery, Keio University, School of Medicine, Tokyo, Japan
18. ¹⁸Midlands Centre for Spinal Injuries, Robert Jones and Agnes Hunt Orthopaedic and District Hospital NHS Trust, Oswestry, Shropshire, UK

Correspondence: J Fawcett, Cambridge University Centre for Brain Repair, Robinson Way, Cambridge CB2 2PY, UK

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.