Clinical Trials In Spinal Cord Injury Research Articles

Cellular treatments for spinal cord injury: the time is right for clinical trials.

More than 1 million people in the United States live with a spinal cord injury (SCI). Despite medical advances, many patients with SCIs still experience substantial neurological disability, with loss of motor, sensory, and autonomic function. Cell therapy is ideally suited to address the multifactorial nature of the secondary events following SCI. Remarkable advances in our understanding of the pathophysiology of SCI, structural and functional magnetic resonance imaging, image-guided micro-neurosurgical techniques, and transplantable cell biology have enabled the use of cell-based regenerative techniques in the clinic. It is important to note that there are more than a dozen recently completed, ongoing, or recruiting cell therapy clinical trials for SCI that reflect the views of many key stakeholders. The field of regenerative neuroscience has reached a stage in which the clinical trials are scientifically and ethically justified. Although experimental models and analysis methods and techniques continue to evolve, no model will completely replicate the human condition. It is recognized that more work with cervical models of contusive/compressive SCI are required in parallel with clinical trials. It is also important that the clinical translation of advances made through well-established and validated experimental approaches in animal models move forward to meet the compelling needs of individuals with SCI and to advance the field of regenerative neuroscience. However, it is imperative that such efforts at translation be done in the most rigorous and informed fashion to determine safety and possible efficacy, and to provide key information to clinicians and basic scientists, which will allow improvements in regenerative techniques and the validation and refinement of existing preclinical animal models and research approaches. The field of regenerative neuroscience should not be stalled at the animal model stage, but instead the clinical trials need to be focused, safe, and ethical, backed up by a robust, translationally relevant preclinical research strategy.Electronic supplementary materialThe online version of this article (doi:10.1007/s13311-011-0076-7) contains supplementary material, which is available to authorized users.

Spinal cord injury therapies in humans: an overview of current clinical trials and their potential effects on intrinsic CNS macrophages

Introduction: Macrophage activation is a hallmark of spinal cord injury (SCI) pathology. CNS macrophages, derived from resident microglia and blood monocytes, are ubiquitous throughout the injured spinal cord, and respond to signals in the lesion environment by changing their phenotype and function. Depending on their phenotype and activation status, macrophages may initiate secondary injury mechanisms and/or promote CNS regeneration and repair.Areas covered: This review provides a comprehensive overview of current SCI clinical trials that are intended to promote neuroprotection, axon regeneration or cell replacement. None of these potential therapies were developed with the goal of influencing macrophage function; however, it is likely that each will have direct or indirect effects on CNS macrophages. The potential impact of each trial is discussed in the context of CNS macrophage biology.Expert opinion: Activation of CNS macrophages is an inevitable consequence of traumatic SCI. Given that these cells are exquisitely sensitive to changes in microenvironment, any intervention that affects tissue integrity and/or the composition of the cellular milieu will undoubtedly affect CNS macrophages. Thus, it is important to understand how current clinical trials will affect intrinsic CNS macrophages.

Characterization of neurological recovery following traumatic sensorimotor complete thoracic spinal cord injury

Retrospective, longitudinal analysis of sensory, motor and functional outcomes from individuals with thoracic (T2-T12) sensorimotor complete spinal cord injury (SCI). To characterize neurological changes over the first year after traumatic thoracic sensorimotor complete SCI. A dataset of 399 thoracic complete SCI subjects from the European Multi-center study about SCI (EMSCI) was examined for neurological level, sensory levels and sensory scores (pin-prick and light touch), lower extremity motor score (LEMS), ASIA Impairment Scale (AIS) grade, and Spinal Cord Independence Measure (SCIM) over the first year after SCI. AIS grade conversions were limited. Sensory scores exhibited minimal mean change, but high variability in both rostral and caudal directions. Pin-prick and light touch sensory levels, as well as neurological level, exhibited minor changes (improvement or deterioration), but most subjects remained within one segment of their initial injury level after 1 year. Recovery of LEMS occurred predominantly in subjects with low thoracic SCI. The sensory zone of partial preservation (ZPP) had no prognostic value for subsequent recovery of sensory levels or LEMS. However, after mid or low thoracic SCI, ≥3 segments of sensory ZPP correlated with an increased likelihood for AIS grade conversion. The data suggest that a sustained deterioration of three or more thoracic sensory levels or loss of upper extremity motor function are rare events and may be useful for tracking the safety of a therapeutic intervention in early phase acute SCI clinical trials, if a significant proportion of study subjects exhibit such an ascent.

Outcome measures in spinal cord injury: recent assessments and recommendations for future directions.

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. Assessment of current and evolving tools for evaluating human spinal cord injury (SCI) outcomes for both clinical diagnosis and clinical research studies. 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. 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. 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.

Protection and repair of the injured spinal cord: a review of completed, ongoing, and planned clinical trials for acute spinal cord injury

Over the past 2 decades, advances in understanding the pathophysiology of spinal cord injury (SCI) have stimulated the recent emergence of several therapeutic strategies that are being examined in Phase I/II clinical trials. Ten randomized controlled trials examining methylprednisolone sodium succinate, tirilizad mesylate, monosialotetrahexosylganglioside, thyrotropin releasing hormone, gacyclidine, naloxone, and nimodipine have been completed. Although the primary outcomes in these trials were laregely negative, a secondary analysis of the North American Spinal Cord Injury Study II demonstrated that when administered within 8 hours of injury, methylprednisolone sodium succinate was associated with modest clinical benefits, which need to be weighed against potential complications. Thyrotropin releasing hormone (Phase II trial) and monosialotetrahexosylganglioside (Phase II and III trials) also showed some promise, but we are unaware of plans for future trials with these agents. These studies have, however, yielded many insights into the conduct of clinical trials for SCI. Several current or planned clinical trials are exploring interventions such as early surgical decompression (Surgical Treatment of Acute Spinal Cord Injury Study) and electrical field stimulation, neuroprotective strategies such as riluzole and minocycline, the inactivation of myelin inhibition by blocking Nogo and Rho, and the transplantation of various cellular substrates into the injured cord. Unfortunately, some experimental and poorly characterized SCI therapies are being offered outside a formal investigational structure, which will yield findings of limited scientific value and risk harm to patients with SCI who are understandably desperate for any intervention that might improve their function. Taken together, recent advances suggest that optimism for patients and clinicians alike is justified, as there is real hope that several safe and effective therapies for SCI may become available over the next decade.

Neuroplasticity after a spinal cord injury

After a spinal cord injury (SCI) of the cat or rat, neuronal centers below the level of lesion exhibit plasticity than can be exploited by specific training paradigms. In individuals with complete or incomplete SCI, human spinal locomotor centers can be activated and modulated by locomotor training (facilitating stepping movements of the legs using body weight support on a treadmill to provide appropriate sensory cues) (for review see Dietz Nat Rev Neurosci 2002, Clin Neurophysiol 2003). Individuals with incomplete SCI benefit from locomotor training such that they improve their ability to walk over ground. Load- or hip joint-related afferent input seems to be of crucial importance for both the generation of a locomotor pattern and the effectiveness of the training (Dietz et al. Nat Rev Neurosci 2002). However, it may be a critical combination of afferent signals that is needed to generate a locomotor pattern after severe SCI. Mobility of individuals after an SCI can be improved by taking advantage of the plasticity of the central nervous system and can be maintained with persistent locomotor activity. In the future, if regeneration approaches can successfully be applied in human SCI, even individuals with complete SCI may recover walking ability with locomotor training (Curt et al. Spinal Cord 2004). During the past few years, several approaches to spinal cord repair have been successfully established in animal models. For their use in clinical trials of SCI in human beings, specific difficulties that affect the success of clinical trials have to be recognised (Dietz and Curt, Lancet Neurol 2006). First, transection of the spinal cord is commonly applied in animal models, whereas contusion, which generally leads to injury in two to three segments, represents the typical injury mechanism in human beings. Second, the quadrupedal organisation of locomotion in animals and the more complex autonomic functions in human beings, challenge translation of animal behaviour into recovery from SCI in people. Third, the extensive damage of motor neurons and roots associated with spinal cord contusion is little addressed in current translation studies. Fourth, there is increasing evidence for a degradation of neuronal function below the level of the lesion in chronic complete SCI. This degradation might have a considerable impact in chronic SCI subjects for a regeneration-inducing treatment. Therefore, it's relevance needs to be investigated.

Domains of outcomes in spinal cord injury for clinical trials to improve neurological function

Selecting appropriate outcome measures in spinal cord injury clinical trials that aim to improve spinal cord function is a challenging task. Proving that an intervention has the intended effect on neurological functioning is insufficient. Any improvement must be shown to be clinically significant-that is, makes a change in the life of the person. Rehabilitation, which seeks to maximize function despite residual impairments, complicates this task. Small improvements in function due to a spinal cord intervention may be masked by improvements in function due to rehabilitation, particularly in the initial rehabilitation phase of care. Understanding outcome domains in models of disablement will facilitate selection or development of assessment tools appropriate for the trial in question. This article describes an expanded World Health Organization model of functioning that defines the domains of Impairment, Capability/Functional Limitation, and Activity, as well as the subdomains of Capacity and Performance, and gives examples of measurement instruments in use or under development in each domain.

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP Panel: clinical trial inclusion/exclusion criteria and ethics

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.

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: clinical trial design

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.

Methylprednisolone and other confounders to spinal cord injury clinical trials

As our understanding of the pathophysiology of spinal cord injury deepens, novel neuroprotective agents are being developed, some of which have already entered clinical trials. In this Viewpoint, Sipski and Pearse examine the status of translational research in this field, focusing specifically on issues surrounding the concurrent use of methylprednisolone. The authors also discuss other potential confounders of clinical trials for spinal cord injury and suggest possible solutions.

Clinical Trials in Spinal Cord Injury

Progress in promoting axonal plasticity and regeneration in animal models of spinal cord injury (SCI) has led to novel prospects for the initiation of human clinical trials in the near future. This review discusses a number of considerations in the path to translating a preclinical candidate from the laboratory to clinical testing. We will also briefly discuss issues associated with the design, performance, analysis, and reporting of human clinical trials in SCI. It is important, for both the medical community and the spinal cord injured community, that objective scientific and medical standards are adopted in the clinical translation of potentially promising, but as yet unproven, therapies for SCI.

Body Composition Assessment in Spinal Cord Injury Clinical Trials

Body weight and composition impact almost every aspect of rehabilitation and community reintegration for the person with spinal cord injury (SCI), but they have received fairly little attention from the rehabilitation community. In particular, sarcopenia (muscle wasting) and fat accumulation due to paralysis significantly impair activities of daily living, community mobility, cardiopulmonary health, bowel and bladder function, skin integrity, and spasticity and can contribute to morbidities associated with obesity including atherosclerosis, diabetes, dyslipidemia, hypertension, chronic pain, depression, and societal isolation. Usual methods of body composition assessment typically underestimate body fat in SCI and are relatively insensitive to changes that may occur from exercise and nutritional interventions. Current body composition assessment techniques are reviewed for their appropriateness in use with the SCI population, and limitations of those techniques are discussed. Recommendations are made for future investigations to validate clinical assessment tools with the 4-compartment (gold standard) model of body composition assessment and for minimal standards of reporting body weight and composition in clinical trials.

Methodological Issues in Performance of SCI Clinical Trials

Spinal cord injury (SCI) research is at a crossroads for progressing into legitimate science for discovering a cure. To do this, the interventions designed by basic scientists must be applied by translational processes that are planned and performed with systematic standards. Any proposed intervention should be examined under the scrutiny of a randomized, double-blind, placebo-controlled, clinical trial. To support this requirement, the National Institutes of Health has specifically defined the components of a properly run clinical trial. Furthermore, all investigational results should be published according to the Consolidated Standard of Reporting Trials (CONSORT) group, which specifies reporting guidelines for researchers to use. Finally, when it comes to designing and reporting randomized clinical trials for SCI research, unique characteristics of this patient population must be considered to adhere to valid study investigation.

Spinal Cord Injury Clinical Trials for Functional Restoration

Spinal Cord Injury Clinical Trials for Functional Restoration

Spinal Cord Injury Clinical Trials for Neurologic Restoration: Improving Care Through Clinical Research

Spinal Cord Injury Clinical Trials for Neurologic Restoration: Improving Care Through Clinical Research

Spinal Cord Injury Clinical Trials for Functional Restoration

Spinal Cord Injury Clinical Trials for Functional Restoration

An Appraisal of Ongoing Experimental Procedures in Human Spinal Cord Injury

Clinicians and scientists in the field of spinal cord injury research and medicine are poised to begin translating promising new experimental findings into treatments for people. Advances in experimental regeneration research have led to several transplantation strategies that promote axonal regrowth and partial functional recovery in animal models of injury. In this review, we summarize current knowledge regarding various invasive experimental treatments that have been or are now being applied clinically. Various questions about the timeliness, safety, and benefits of the procedures are under discussion within the spinal cord injury (SCI) research community. We also describe guidelines for carrying out optimal clinical trials and efforts to establish specific international guidelines to translate preclinical treatment strategies into clinical trials in SCI. The clinical trial process and the role that clinical professionals have in advising individuals regarding participation in experimental procedures also is discussed.

Neurological and functional capacity outcome measures: Essential to spinal cord injury clinical trials

We intend to demonstrate that future treatment strategies in spinal cord injury (SCI) rehabilitation to restore function (SCI rehabilitation) should be based on the success of rigorous clinical trials with demonstrated effective interventions. Knowing the course of neurological recovery, its mechanism, and its measures will be essential in designing and executing these trials. We reviewed selected recovery outcomes and measures from multicenter studies and a large SCI database. The accuracy of baseline examinations in the first days following injury is critical to demonstrating changes in neurological recovery. Recovery of one neurologic level in subjects with tetraplegia depends on the severity of the injury, the initial level of the injury, and the strength of muscles below the level of injury. Motor recovery of the upper limbs typically correlates with self-care function. Neurological recovery following SCI often correlates with an increase in function and walking in addition to self-care. In subjects with paraplegia, predicting recovery of walking is possible based on the initial 1-week sensory and motor examination. Although initial neurological findings correlate with neurological and functional-recovery outcomes in large populations of 3,500 subjects reported by the Model SCI System centers in the United States, improved outcome measures for walking are needed. The Walking Index for Spinal Cord Injury (WISCI) has recently demonstrated criterion validity and increased sensitivity and responsiveness to change in neurological/walking function in subjects with SCI. The WISCI scale correlated well with measures in use to determine improved walking function regarding walking speed, lower-limb motor scores, and other measures. Demonstrating improved neurologic and functional outcomes following SCI requires accurate neurologic and sensitive functional measures.

Importance of access to research information among individuals with spinal cord injury: results of an evidenced-based questionnaire.

To assess the interests and accessibility of patients with a spinal cord injury (SCI) to information in different areas of SCI. Spinal Program, Toronto Western Hospital, University Health Network. An interest assessment survey and the SF-36 (short form-36) questionnaire were mailed to SCI patients living in the community. The interest assessment examined patients' interest in information in many areas related to SCI, their current knowledge in these areas and the accessibility of different information formats. Fourteen patients (45%) completed the questionnaires. Regardless of physical or mental health status, all patients expressed a high level of interest in SCI research and clinical trials. An Internet website proved to be the most preferred, accessible and comfortable information format for these patients. Patients expressed a lower interest in support groups and organizations. Results from the SF-36 showed poor social functioning was related to interest in support groups, and poor general health perception was related to interest in occupational and physical therapy. The majority of SCI patients have a high interest in accessing SCI research information. The Internet is a favorable, comfortable and accessible tool for providing this information and will benefit all SCI patients. These results suggest that a significant number of patients with SCI would benefit from an accessible Internet-based information database that is relevant to the SCI patients population.