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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.

Objectives: To develop a comprehensive set of common data elements (CDEs), data definitions, case report forms and guidelines for use in spinal cord injury (SCI) clinical research, as part of the CDE project at the National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health. Setting: International Working Groups. Methods: Nine working groups composed of international experts reviewed existing CDEs and instruments, created new elements when needed and provided recommendations for SCI clinical research. The project was carried out in collaboration with and cross-referenced to development of the International Spinal Cord Society (ISCoS) International SCI Data Sets. The recommendations were compiled, subjected to internal review and posted online for external public comment. The final version was reviewed by all working groups and the NINDS CDE team before release. Results: The NINDS SCI CDEs and supporting documents are publically available on the NINDS CDE website and the ISCoS website. The CDEs span the continuum of SCI care and the full range of domains of the International Classification of Functioning, Disability and Health. Conclusion: Widespread use of CDEs can facilitate SCI clinical research and trial design, data sharing and retrospective analyses. Continued international collaboration will enable consistent data collection and reporting, and will help ensure that the data elements are updated, reviewed and broadcast as additional evidence is obtained.

An international panel reviewed the methodology for clinical trials of spinal cord injury (SCI), and provided recommendations for the valid conduct of future trials. This is the second of four papers. It examines clinical trial end points that have been used previously, reviews alternative outcome tools and identifies unmet needs for demonstrating the efficacy of an experimental intervention after SCI. The panel focused on outcome measures that are relevant to clinical trials of experimental cell-based and pharmaceutical drug treatments. Outcome measures are of three main classes: (1) those that provide an anatomical or neurological assessment for the connectivity of the spinal cord, (2) those that categorize a subject's functional ability to engage in activities of daily living, and (3) those that measure an individual's quality of life (QoL). The American Spinal Injury Association impairment scale forms the standard basis for measuring neurologic outcomes. Various electrophysiological measures and imaging tools are in development, which may provide more precise information on functional changes following treatment and/or the therapeutic action of experimental agents. When compared to appropriate controls, an improved functional outcome, in response to an experimental treatment, is the necessary goal of a clinical trial program. Several new functional outcome tools are being developed for measuring an individual's ability to engage in activities of daily living. Such clinical end points will need to be incorporated into Phase 2 and Phase 3 trials. QoL measures often do not correlate tightly with the above outcome tools, but may need to form part of Phase 3 trial measures.

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the third of four papers. It examines inclusion and exclusion criteria that can influence the design and analysis of clinical trials in SCI, together with confounding variables and ethical considerations. Inclusion and exclusion criteria for clinical trials should consider several factors. Among these are (1) the enrollment of subjects at appropriate stages after SCI, where there is supporting data from animal models or previous human studies; (2) the severity, level, type, or size of the cord injury, which can influence spontaneous recovery rate and likelihood that an experimental treatment will clinically benefit the subject; and (3) the confounding effects of various independent variables such as pre-existing or concomitant medical conditions, other medications, surgical interventions, and rehabilitation regimens. An issue of substantial importance in the design of clinical trials for SCI is the inclusion of blinded assessments and sham surgery controls: every effort should be made to address these major issues prospectively and carefully, if clear and objective information is to be gained from a clinical trial. The highest ethical standards must be respected in the performance of clinical trials, including the adequacy and clarity of informed consent.

Study design: Review by the spinal cord outcomes partnership endeavor (SCOPE), which is a broad-based international consortium of scientists and clinical researchers representing academic institutions, industry, government agencies, not-for-profit organizations and foundations. Objectives: Assessment of current and evolving tools for evaluating human spinal cord injury (SCI) outcomes for both clinical diagnosis and clinical research studies. Methods: a framework for the appraisal of evidence of metric properties was used to examine outcome tools or tests for accuracy, sensitivity, reliability and validity for human SCI. Results: Imaging, neurological, functional, autonomic, sexual health, bladder/bowel, pain and psychosocial tools were evaluated. Several specific tools for human SCI studies have or are being developed to allow the more accurate determination for a clinically meaningful benefit (improvement in functional outcome or quality of life) being achieved as a result of a therapeutic intervention. Conclusion: Significant progress has been made, but further validation studies are required to identify the most appropriate tools for specific targets in a human SCI study or clinical trial.

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the fourth of four papers. Here, we examine the phases of a clinical trial program, the elements, types, and protocols for valid clinical trial design. The most rigorous and valid SCI clinical trial would be a prospective double-blind randomized control trial utilizing appropriate placebo control subjects. However, in specific situations, it is recognized that other trial procedures may have to be considered. We review the strengths and limitations of the various types of clinical trials with specific reference to SCI. It is imperative that the design and conduct of SCI clinical trials should meet appropriate standards of scientific inquiry to insure that meaningful conclusions about efficacy and safety can be achieved and that the interests of trial subjects are protected. We propose these clinical trials guidelines for use by the SCI clinical research community.

Objectives: To develop consistent variable names and a common database structure for the data elements in the International Spinal Cord Injury (SCI) Data Sets. Setting: National Institute of Neurological Disorders and Stroke (NINDS) Common Data Elements (CDE) Project and The Executive Committee of the International SCI Standards and Data Sets committees (ECSCI). Methods: The NINDS CDE team creates a variable name for each defined data element in the various International SCI Data Sets. Members of the ECSCI review these in an iterative process to make the variable names logical and consistent across the data sets. Following this process, the working group for the particular data set reviews the variable names, and further revisions and adjustments may be made. In addition, a database structure for each data set is developed allowing data to be stored in a uniform way in databases to promote sharing data from different studies. Results: The International SCI Data Sets variable names and database specifications will be available through the web sites of the International Spinal Cord Society ( http://www.iscos.org.uk ), the American Spinal Injury Association ( http://www.asia-spinalinjury.org ) and the NINDS CDE project web site ( http://www.CommonDataElements.ninds.nih.gov ). Conclusion: This process will continue as additional International SCI Data Sets fulfill the requirements of the development and approval process and are ready for implementation.

The effects of two antiinflammatory and neuroprotective agents, methylprednisolone (MP) and interleukin-10 (IL-10), singly and in combination on tissue damage, axonal preservation and functional recovery were studied in the contused adult Fischer rat thoracic spinal cord 12 weeks after injury. MP (30 mg/kg at 5 min, and 2 and 4 h after injury) was administered intravenously and IL-10 (15 or 30 μg/kg at 30 min after injury), intraperitoneally. MP, IL-10, or the combination significantly reduced the volume of damaged tissue (including cavities) compared to control animals. The loss of spinal tissue (cavities) was reduced after treatment with MP alone or combined with IL-10, but not with IL-10 alone. The reduction in tissue damage was confined to spinal gray matter; at the level of the lesion epicenter, the thickness of the lateral white matter columns was similar in all groups. Retrograde tracing using fast blue revealed that the number of spared propriospinal and supraspinal projections was similar in all groups at 12 weeks after the contusion. The open-field BBB-test showed no significant difference in hindlimb locomotion between groups. Our results demonstrate that all tested antiinflammatory treatments significantly increase the volume of spared spinal gray matter 3 months after a moderate contusion of the Fischer rat thoracic spinal cord, but none of the treatments improved axonal preservation or functional recovery.