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.     

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.     

Providing the clinical basis for new interventional therapies: refined diagnosis and assessment of recovery after spinal cord injury

Today, there is accumulating evidence from animal experiments that axonal regeneration and an enhanced level of functional repair can be induced after a spinal cord injury (SCI). Consequently, in the near future, new therapeutic approaches will be developed for the treatment of patients with SCI. The aim of the project presented here is to provide the required clinical basis for the implementation of novel interventional therapies. Refined and combined clinical and neurophysiological measures are needed for a precise qualitative and quantitative assessment of spinal cord function in patients with SCI at an early stage. This represents a basic requirement to recognise any improvement in the recovery of function and to monitor any significant effect of a new treatment. To this aim, five European Spinal Cord Injury Centres involved in the rehabilitation of acute SCI patients have built up a close clinical collaboration to develop a standardised protocol for the assessment of the outcome after SCI and the extent of recovery achieved by actually applied therapies in a larger population of SCI patients. The project's aim is to establish objective, refined tools as a basis for monitoring the effects of new treatment strategies.     

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

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 to 18 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.     

Moving towards multiple site outcomes in spinal cord injury pain clinical trials: An issue of clustered observations in trial design and analysis

Introduction

Pain remains a problem for many with spinal cord injury (SCI), and there is a need for sound, randomized clinical trials examining the efficacy of existing and novel therapeutics. SCI-related pain is complex, as more than one type of pain is often experienced. The purpose of this report is to (i) demonstrate how to design and power calculation of a clinical trial of SCI pain using multiple pain sites per individual; (ii) discuss consequences of failing to adjust for this; and (iii) provide intraclass correlation (ICC) estimates for common pain outcome measures that may be used to power future clinical trials in SCI pain.

Method

Using an existing dataset from a past SCI pain clinical trial, the ICC was calculated for common pain outcome measures to illustrate appropriate corrections for powering, analyzing and interpreting results from multiple pain sites per individual. The problem associated with not accounting for multiple pain sites per individual and the effect on the Type I error rate is also shown.

Results and Discussion

Not accounting for the ICC can lead to (1) incorrect power estimates in the design of a trial, and (2) an inflated Type I error rate with a higher likelihood of misinterpretation of outcomes.

Conclusions

Powering for future SCI pain trials and statistical analysis of trial outcomes may be substantially compromised if methods do not account for the intra-individual associations between pain sites, ultimately affecting study interpretations and evidence-based practice. We present ICC estimates based on SCI pain data for purposes of estimating power for future trials.     

Spasticity outcome measures in spinal cord injury: psychometric properties and clinical utility

STUDY DESIGN: Comprehensive review and systematic analyses. OBJECTIVES: Assess published psychometric evidence for spinal cord injury (SCI) spasticity outcome measures. Considerations about the influence of spasticity on function have also been identified to understand treatment effects and guide service delivery. SETTING: London, Ontario and Vancouver, British Columbia, Canada. METHOD: Review of measures was based on availability of psychometric data, application in clinical settings and evaluated in SCI patients. RESULTS: Ashworth and Modified Ashworth Scales (AS, MAS), Penn Spasm Frequency Scale (PSFS), Spinal Cord Assessment Tool for Spasticity (SCATS), Visual Analogue Scale self-rated scale of spasticity (VAS) and the Wartenberg Pendulum Test (WPT) were included in this review. The most frequently used tools for SCI spasticity measurement include the AS, MAS, PSFS and VAS, of which the latter two are self-report spasticity measures. The SCATS has been partially validated for SCI, but is not widely used. The WPT has been minimally validated despite its use in a large-scale SCI spasticity randomized controlled trial. CONCLUSIONS: Since spasticity is multidimensional, focusing on one or two spasticity outcome measures can misrepresent the extent and influence of spasticity on SCI patients. Different scales measure different aspects of spasticity and individual tools correlate weakly with each other. Spasticity may be better measured with an appropriate battery of tests, including the AS or MAS, along with PSFS. These tools would benefit from further reliability and responsiveness testing. Tools that assess the influence of spasticity on patient activities, participation and quality of life are important, but lacking.     

Functional recovery measures for spinal cord injury: an evidence-based review for clinical practice and research

BACKGROUND/OBJECTIVE: The end goal of clinical care and clinical research involving spinal cord injury (SCI) is to improve the overall ability of persons living with SCI to function on a daily basis. Neurologic recovery does not always translate into functional recovery. Thus, sensitive outcome measures designed to assess functional status relevant to SCI are important to develop. METHOD: Evaluation of currently available SCI functional outcome measures by a multinational work group. RESULTS: The 4 measures that fit the prespecified inclusion criteria were the Modified Barthel Index (MBI), the Functional Independence Measure (FIM), the Quadriplegia Index of Function (QIF), and the Spinal Cord Independence Measure (SCIM). The MBI and the QIF were found to have minimal evidence for validity, whereas the FIM and the SCIM were found to be reliable and valid. The MBI has little clinical utility for use in the SCI population. Likewise, the FIM applies mainly when measuring burden of care, which is not necessarily a reflection of functional recovery. The QIF is useful for measuring functional recovery but only in a subpopulation of people with SCI, and substantial validity data are still required. The SCIM is the only functional recovery outcome measure designed specifically for SCI. CONCLUSIONS: The multinational work group recommends that the latest version of the SCIM (SCIM III) continue to be refined and validated and subsequently implemented worldwide as the primary functional recovery outcome measure for SCI. The QIF may continue to be developed and validated for use as a supplemental tool for the nonambulatory tetraplegic population.     

Identifying and classifying quality of life tools for neurogenic bladder function after spinal cord injury: A systematic review

Objective: To identify and classify quality of life (QoL) tools for assessing the influence of neurogenic bladder after spinal cord injury/disease (SCI).

Design: Systematic Review

Methods: Medline/Pubmed, CINAHL, and PsycInfo were searched using terms related to SCI, neurogenic bladder and QoL. Studies that assessed the influence neurogenic bladder on QoL (or related construct) in samples consisting of?≥50% individuals with SCI were included. Two independent reviewers screened titles and abstracts of 368 identified references; 118 full-text articles were assessed for eligibility, and 42 studies were included. Two reviewers independently classified outcomes as objective (societal viewpoint) or subjective (patient perspective) using a QoL framework.

Results: Ten objective QoL measures were identified, with the Medical Outcomes Short Form (SF-36/SF-12) used most frequently. Fourteen subjective QoL measures were identified; 8 were specific to neurogenic bladder. Psychometric evidence for SCI-specific neurogenic bladder QoL tools was reported for the Quality of Life Index (QLI), Qualiveen, Bladder Complications Scale, Spinal Cord Injury-Quality of Life (SCI-QOL) Bladder Management Difficulties, and the SCI-QOL Bladder Management Difficulties-Short Form. The QLI and Qualiveen showed sensitivity to neurogenic bladder in experimental designs.

Conclusion: Several objective and subjective tools exist to assess the influence of neurogenic bladder on QoL in SCI. The QLI and Qualiveen, both subjective tools, were the only validated SCI-specific tools that showed sensitivity to neurogenic bladder. Further validation of existing subjective SCI-specific outcomes is needed. Research to validate objective measures of QoL would be useful for informing practice and policy related to resource allocation for bladder care post-SCI.     

Outcome Measures for Acute/Subacute Cervical Sensorimotor Complete (AIS-A) Spinal Cord Injury During a Phase 2 Clinical Trial

Effective treatment after cervical spinal cord injury (SCI) is imperative as so many activities of daily living (ADLs) are dependent on functional recovery of arm and hand actions. We focus on defining and comparing neurological and functional endpoints that might be used during acute or subacute Phase 2 clinical trials involving subjects with cervical sensorimotor complete SCI (ASIA Impairment Scale [AIS-A]). For the purposes of this review, the trial would examine the effects of a pharmaceutical small molecule, drug, biologic, or cell transplant on spinal tissue. Thus, neurological improvement is the intended consequence and is most directly measured by assessing neurological impairment (eg, motor aspects of the International Standards Neurological Classification of Spinal Cord Injury [ISNCSCI]). However, changes in neurological function, even if statistically significant, may not be associated with a clear functional impact (ie, a meaningful improvement in individual activity, such as independent self-care ADLs). The challenge is to measure improvement as precisely as possible (change in impairment), but to define a clinically meaningful response in the context of functional improvement (impact on activity limitations). The principal comparisons focused on elements of the ISNCSCI assessment, including upper extremity motor score and motor level. Personal activity capabilities were also examined at various time points. The data suggest that an improvement of 2 or more motor levels after cervical sensorimotor complete SCI may be a clinically meaningful endpoint threshold that could be used for acute and subacute Phase 2 trials with subjects having sensorimotor complete cervical SCI.     

A clinical prediction model for long-term functional outcome after traumatic spinal cord injury based on acute clinical and imaging factors

Abstract To improve clinicians' ability to predict outcome after spinal cord injury (SCI) and to help classify patients within clinical trials, we have created a novel prediction model relating acute clinical and imaging information to functional outcome at 1 year. Data were obtained from two large prospective SCI datasets. Functional independence measure (FIM) motor score at 1 year follow-up was the primary outcome, and functional independence (score ≥6 for each FIM motor item) was the secondary outcome. A linear regression model was created with the primary outcome modeled relative to clinical and imaging predictors obtained within 3 days of injury. A logistic model was then created using the dichotomized secondary outcome and the same predictor variables. Model validation was performed using a bootstrap resampling procedure. Of 729 patients, 376 met the inclusion criteria. The mean FIM motor score at 1 year was 62.9 (±28.6). Better functional status was predicted by less severe initial American Spinal Injury Association (ASIA) Impairment Scale grade, and by an ASIA motor score >50 at admission. In contrast, older age and magnetic resonance imaging (MRI) signal characteristics consistent with spinal cord edema or hemorrhage predicted worse functional outcome. The linear model predicting FIM motor score demonstrated an R-square of 0.52 in the original dataset, and 0.52 (95% CI 0.52,0.53) across the 200 bootstraps. Functional independence was achieved by 148 patients (39.4%). For the logistic model, the area under the curve was 0.93 in the original dataset, and 0.92 (95% CI 0.92,0.93) across the bootstraps, indicating excellent predictive discrimination. These models will have important clinical impact to guide decision making and to counsel patients and families.     

G. Heiner Sell memorial lecture: neuronal plasticity after spinal cord injury: significance for present and future treatments

Recent progress in the understanding of movement control allows us to define more precisely the requirements for successful rehabilitation of patients with neurologic deficits after a spinal cord injury (SCI). Load- and hip joint position-related afferent input seems to be of crucial importance for the generation and success of locomotor training. In addition, there is accumulating evidence from animal experiments that axonal regeneration can be induced after a SCI. Consequently, in the near future, new therapeutic approaches will be developed for the treatment of subjects with SCI. Functional training and regeneration represent complimentary approaches. Regenerating spinal tract fibers needs functional training to make the appropriate connections, and training effects will be enhanced by regenerating fibers. A clinical basis for monitoring the effects of novel interventional therapies is needed. Refined and combined clinical and neurophysiologic measures are needed for a precise qualitative and quantitative assessment of spinal cord function in patients with SCI at an early stage. This is a basic requirement for predicting functional outcome, as well as for recognizing any improvement in the recovery of function caused by a new treatment. To this aim, 14 European spinal cord injury centers involved in the rehabilitation of patients with acute SCI have built a close clinical collaboration using a standardized protocol for the assessment of the outcome after SCI and the extent of recovery achieved by actually applied therapies in a larger population of patients with SCI.     

Clinical canine spinal cord injury provides an opportunity to examine the issues in translating laboratory techniques into practical therapy

STUDY DESIGN: Review. OBJECTIVES: To highlight the value of investigating the effects of putative therapeutic interventions in clinical spinal cord injury (SCI) in domestic dogs. SETTING: England, UK. METHODS: Many experimental interventions in laboratory rodents have been shown to ameliorate the functional deficits caused by SCI; the challenge now is to determine whether they can be translated into useful clinical techniques. Important differences between clinical SCI in human patients and that in laboratory rodents are in the size of the spinal cord and heterogeneity of injury severity. A further key issue is whether the statistical difference in outcome in the laboratory will translate into a useful difference in clinical outcome. Here, we stress the value of investigating the effects of putative therapies in clinical SCI in domestic dogs. The causes of injury, ability to categorise the severity and methods available to measure outcome are very similar between canine and human patients. Furthermore, postmortem tissue more rapidly becomes available from dogs because of their short lifespan than from human patients. RESULTS: The role that investigation of canine SCI might play is illustrated by our preliminary trials on intraspinal transplantation of olfactory glial cells for severe SCI. CONCLUSIONS: This canine translational model provides a means of 'filtering' putative treatments before human application.     

Characterization of a graded cervical hemicontusion spinal cord injury model in adult male rats

Most experimental models of spinal cord injury (SCI) in rodents induce damage in the thoracic cord and subsequently examine hindlimb function as an indicator of recovery. In these models, functional recovery is most attributable to white-matter preservation and is less influenced by grey-matter sparing. In contrast, most clinical cases of SCI occur at the lower cervical levels, a region in which both grey-matter and white-matter sparing contribute to functional motor recovery. Thus experimental cervical SCI models are beginning to be developed and used to assess protective and pharmacological interventions following SCI. The objective of this study was to characterize a model of graded cervical hemicontusion SCI with regard to several histological and behavioral outcome measures, including novel forelimb behavioral tasks. Using a commercially available rodent spinal cord impactor, adult male rats received hemicontusion SCI at vertebral level C5 at 100, 200, or 300 kdyn force, to produce mild, moderate, or severe injury severities. Tests of skilled and unskilled forelimb and locomotor function were employed to assess functional recovery, and spinal cord tissue was collected to assess lesion severity. Deficits in skilled and unskilled forelimb function and locomotion relating to injury severity were observed, as well as decreases in neuronal numbers, white-matter area, and white-matter gliosis. Significant correlations were observed between behavioral and histological data. Taken together, these data suggest that the forelimb functional and locomotor assessments employed here are sensitive enough to measure functional changes, and that this hemicontusion model can be used to evaluate potential protective and regenerative therapeutic strategies.     

Sexual health outcome measures for individuals with a spinal cord injury: a systematic review

STUDY DESIGN: A systematic review of all sexual health outcome measures reporting psychometric properties for a spinal cord injury (SCI) population. OBJECTIVES: To evaluate the psychometric evidence for sexual health outcome measures used in a SCI population in order to (1) determine the clinical relevance of current tools and (2) suggest recommendations for future tool development. SETTING: Vancouver, British Columbia, Canada. METHODS: Electronic databases were searched for articles reporting psychometric properties of sexual health outcome measures used in a SCI population. The search was limited to papers published between January 1986 and January 2006. Hand-searching the references of papers obtained from the electronic search identified additional articles. RESULTS: Four outcome measures met the search criteria: Emotional Quality of the Relationship Scale (EQR), Sexual Activity and Satisfaction Scale (SAS), Sexual Attitude and Information Questionnaire (SAIQ) and Sexual Interest and Satisfaction Scale (SIS). While the clinical utility of these tools may be compromised by their limited scope and advancing age, they may still prove useful for guiding SCI research and clinical practice. CONCLUSION: There is no clinically agreed upon SCI measurement tool for sexual health outcomes. To adequately assess the complex issue of sexual health, it is recommended that future sexual health outcome measures include both quantitative and qualitative data as well as address several key issues.     

Neurological and functional recovery from spinal cord injury. Progress and evaluation standards in paraplegic medicine

Today, there is accumulating evidence from animal experiments that axonal regeneration and an enhanced level of functional repair can be induced after a spinal cord injury (SCI). Consequently, in the near future, new therapeutic approaches will be developed for the treatment of patients with SCI. The aim of the project presented here is to provide the required clinical basis for the implementation of novel interventional therapies. Refined and combined clinical and neurophysiological measures are needed for a precise qualitative and quantitative assessment of spinal cord function in patients with SCI at an early stage. This represents a basic requirement for recognizing any improvement in the recovery of function and to monitor any significant effect of a new treatment. The paper presents objective and refined tools as a basis for monitoring the effects of new treatment strategies.     

Neurologische und funktionelle Erholung nach Querschnittlähmung

Today, there is accumulating evidence from animal experiments that axonal regeneration and an enhanced level of functional repair can be induced after a spinal cord injury (SCI). Consequently, in the near future, new therapeutic approaches will be developed for the treatment of patients with SCI. The aim of the project presented here is to provide the required clinical basis for the implementation of novel interventional therapies. Refined and combined clinical and neurophysiological measures are needed for a precise qualitative and quantitative assessment of spinal cord function in patients with SCI at an early stage. This represents a basic requirement for recognizing any improvement in the recovery of function and to monitor any significant effect of a new treatment. The paper presents objective and refined tools as a basis for monitoring the effects of new treatment strategies.     

Pain after spinal cord injury: an evidence-based review for clinical practice and research. Report of the National Institute on Disability and Rehabilitation Research Spinal Cord Injury Measures meeting

BACKGROUND/OBJECTIVES: To examine the reliability, validity, sensitivity, and practicality of various outcome measures for pain after spinal cord injury (SCI), and to provide recommendations for specific measures for use in clinical trials. DATA SOURCES: Relevant articles were obtained through a search of MEDLINE, EMBASE, CINAHL, and PubMed databases from inception through 2006. STUDY SELECTION: The authors performed literature searches to find articles containing data relevant to the reliability and validity of each pain outcome measure in SCI and selected non-SCI populations. DATA EXTRACTION: After reviewing the articles, an investigator extracted information utilizing a standard template. A second investigator reviewed the chosen articles and the extracted pertinent information to confirm the findings of the first investigator. DATA SYNTHESIS: Taking into consideration both the quantity and quality of the studies analyzed, judgments on reliability and validity of the measures were made by the two investigators. Based upon these judgments, recommendations were formulated for use of specific measures in future clinical trials. In addition, for a subset of measures a voting process by a larger group of SCI experts allowed formulation of recommendations including determining which measures should be incorporated into a minimal dataset of measures for clinical trials and which ones need revision and further validity and reliability testing before use. CONCLUSIONS: A 0-10 Point Numerical Rating Scale (NRS) is recommended as the outcome measure for pain intensity after SCI, while the 7-Point Guy/Farrar Patient Global Impression of Change (PGIC) scale is recommended as the outcome measure for global improvement in pain. The SF-36 single pain interference question and the Multidimensional Pain Inventory (MPI) or Brief Pain Inventory (BPI) pain interference items are recommended as the outcome measures for pain interference after SCI. Brush or cotton wool and at least one high-threshold von Frey filament are recommended to test mechanical allodynia/hyperalgesia while a Peltier-type thermotester is recommended to test thermal allodynia/hyperalgesia. The International Association for the Study of Pain (IASP) or Bryce-Ragnarsson pain taxonomies are recommended for classification of pain after SCI, while the Neuropathic Pain Scale (NPS) is recommended for measuring change in neuropathic pain and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) for quantitating neuropathic and nociceptive pain discrimination.     

A systematic review of functional ambulation outcome measures in spinal cord injury

STUDY DESIGN: Systematic review. OBJECTIVES: To systematically review the psychometric properties of outcome measures used to assess ambulation in people with spinal cord injury (SCI). SETTING: Vancouver, BC, Canada. METHODS: A keyword literature search of original articles that evaluated the psychometric properties of ambulation outcome measures in the SCI population was conducted using multiple databases. Multidimensional scales of function were included if specific data were available on ambulation-related subscales. Reliability, validity and responsiveness values were extracted and conclusions drawn about the psychometric quality of each measure. RESULTS: Seven outcome measures were identified and were broadly categorized into timed and categorical measures of ambulation. Timed measures included timed walking tests that showed excellent reliability, construct validity and responsiveness to change. The psychometric properties of the categorical scales were more variable, but those that were developed specifically for the SCI population had excellent reliability and validity. Categorical scales also exhibited some floor or ceiling effects. CONCLUSION: Excellent tools are available for measuring functional ambulation capacity. Further work is required to develop and evaluate outcome measures to include environmental factors that contribute to the ability to achieve safe, functional ambulation in everyday settings.     

Opinions on the Preclinical Evaluation of Novel Therapies for Spinal Cord Injury: A Comparison between Researchers and Spinal Cord-Injured Individuals

Abstract We previously conducted a survey to gather the opinions and perspectives of scientific and clinical researchers on what levels of preclinical evidence were needed to justify translating a promising neuroprotective or neuroregenerative therapy in spinal cord injury (SCI) into a human clinical trial (Kwon et al., 2010 ). Here we conducted an analogous survey of individuals living with SCI in which we gathered their expectations for the levels of preclinical evidence achieved by researchers in substantiating the neuroprotective and neuroregenerative therapies being offered to them in clinical trials. In total, 214 individuals with SCI completed the survey, and their responses were compared to the responses of the 235 scientists and clinicians who completed our previous survey. SCI individuals were more likely than SCI researchers to opine that demonstrating efficacy and safety in rodent models of SCI alone is sufficient to proceed with clinical trials. However, SCI individuals also reported strong support for large animal and primate model studies, and in the case of the latter, were actually more in agreement for the need for primate studies than researchers. SCI individuals also reported strong support for independent replication studies. In general, individuals with SCI had high expectations for the levels of preclinical evidence required to justify translating novel therapies into clinical trials. These expectations should be considered in the decisions to translate specific experimental therapies for SCI.     

Effect of 4-aminopyridine on gait in ambulatory spinal cord injuries: a double-blind, placebo-controlled, crossover trial

Animal and human research have shown that the drug 4-aminopyridine (4-AP) may improve gait in spinal cord lesions by enhancing nerve transmission to affected muscles. STUDY DESIGN: Prospective, randomized, double-blind, placebo-controlled, crossover trial. OBJECTIVES: To determine the efficacy of 4-AP in improving lower limb muscle strength and biomechanical gait patterns of chronic spinal cord injuries (SCI). SETTING: The Rehabilitation Centre (Ottawa, Canada). METHODS: In all, 15 chronic, ambulatory SCI persons were randomized to an initial 2 weeks of 40 mg/day, oral medication of either placebo or immediate-release, 4-AP and subsequently crossed over to the alternate medication for the following 2 weeks. Evaluations were conducted at baseline (before starting 4-AP or placebo medication), 2 weeks, and 4 weeks. Measures included dynamometer lower limb isometric muscle force and biomechanical gait measures including temporal-spatial parameters, electromyographic activation patterns, joint kinematics and kinetics. Subjective impressions of the drug by the participants were obtained from an exit survey. RESULTS: Despite some positive comments from subjects, statistical and clinical analyses showed no within-subject differences between placebo and 4-AP measures of lower limb muscle force and objective gait analyses (ANOVA statistic P>0.05). CONCLUSION: Results demonstrated the importance of placebo-controlled trials and quantitative outcome measures for the evaluation of 4-AP aimed to enhance gait for chronic, ambulatory SCI persons. Energy expenditure measures and mood may relate more to subjective comments and is suggested for future investigations.