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.     

Behavioral testing after spinal cord injury: congruities, complexities, and controversies

Selection and implementation of behavioral tests in spinal cord injury research is an important process, and yet few papers have focused on these issues. The critical component of any behavioral experiment is the ability to produce reliable, reproducible, and worthwhile data. Unfortunately, the difference between worthwhile and worthless data is often subtle. This paper describes factors that must be considered in order to select the most sensitive behavioral tests to match the hypothesis of the experiment and apply any test in a standardized, consistent manner. Classifications of behavioral tests, their strengths and limitations, as well as methods to overcome these limitations are discussed. Recent work in translating behavioral tests from rats to mice is also provided. The purpose of this article is to provide a framework by which behavioral testing can be standardized within and across spinal cord injury labs.     

Clinical studies in spinal cord injury: moving towards successful trials

Spinal cord injury is a devastating condition for which there is still no cure. Many new therapies have emerged in the past few decades that have attempted to improve the outcome after injury, with varying levels of supporting experimental and clinical data. Most studies have been preliminary and have lacked control groups, but positive results can often be embraced by clinicians and patients who are faced without an alternative, despite the poor design and bias of many studies. This article is a review of clinical studies in spinal cord injury and discusses guidelines for future clinical trial design.     

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.     

Bridging the gap: from discovery to clinical trials in spinal cord injury

Recently, the Kent Waldrep National Paralysis Foundation initiated a think tank intended to bridge several gaps and achieve several goals in regard to spinal cord injury (SCI) research and funding. Affiliated with the need to bridge a pathophysiological gap in spinal parenchyma and/or reorganize remaining circuitry after injury is a need to bridge resource gaps for timely funding for translational research, gaps in knowledge between researchers, and between researchers/clinicians and SCI patients. The epistemology of cure was examined and redefined to include transitional recoveries and advances. Modes and mechanisms of funding have been evaluated and where deficits were perceived, suggestions have been made to expedite and increase the number and breadth of funding opportunities. Innovative infrastructure changes are submitted. We discuss the progression of clinical trials as well as offer suggestions to facilitate benchtop-to-bedsite translation of valuable research to the customer. Highlights of recently completed, in progress, and future trials are detailed. Finally, we submit five essential processes required to promote advances to the SCI patient population: discovery, development, clinical trials, evaluation, and rehabilitation. These ideas are intended to facilitate entry of serious dialogue and to ultimately improve the lives of patients living with SCI.     

颈脊髓损伤并迟发性窒息

目的:探讨颈脊髓严重损伤引起迟发性窒息的临床特点和危险因素。方法:对6例颈脊髓严重损伤引起迟发性窒息的各种因素进行回顾性分析。结果:MKI显示窒息病人脊髓受累节段弥散,多累及以节段,大多数病人伤后出现一过性心动过缓和呼吸困难,5例窒息发生于睡眠中。结论:临床表现稳定的严重颈脊髓损伤患者仍有发生迟发性窒息的危险。弥漫性脊髓损伤后出现心动过缓及呼吸困难,即使是一过性或自限性的,均应视为危险因素,夜间睡眠期间发生迟发性窒息的可能性大,应密切监护。     

Clinical trials in wound care. II: Achieving statistical significance

Clinical trials must be well designed in order to produce statistically and clinically significant results. This article describes the randomisation techniques that can prevent bias, the importance of sample size and the concept of power analysis.     

无骨折脱位型颈脊髓损伤15例临床分析

随着交通运输业和建筑业的发展 ,颈椎外伤随之增多。颈椎骨折脱位常合并脊髓损伤 ,但临床上有时只有颈脊髓损伤表现 ,而无颈椎骨折脱位影像学表现。这是一种特殊类型的脊髓损伤 ,即无骨折脱位型颈脊髓损伤。 1998年至 2 0 0 0年 10月 ,作者对 15例无骨折脱位型颈脊髓损伤病人的临床表现、影像学检查及其治疗方法进行回顾性总结和分析 ,现报告如下。1　临床资料1 1　一般资料　本组病人 15例 ,男 11例 ,女 4例 ;年龄 16～6 3岁 ,平均 4 8 5岁。受伤原因 :交通伤 7例 ,高处坠落伤 3例 ,骑自行车摔伤 2例 ,一般轻外伤 3例。临床表现 :(1)颈部疼…     

Extraparotid Warthin's tumor: Clinical manifestations, challenges, and controversies

Extraparotid Warthin's tumors continue to challenge the head and neck surgeon's diagnostic and therapeutic skills. A series of six extraparotid Warthin's tumors are presented to illustrate the need to keep a high index of suspicion for this lesion in the workup of cystic masses involving cervical levels II and III or in the event of a concomitant neck mass and a parotid Warthin's tumor. Discussion of the debate surrounding the embryogenesis and histogenesis of extraparotid Warthin's tumors follows. Clinical guidelines are suggested for the diagnosis, treatment, and follow-up of patients with extraparotid Warthin's tumors. (Otolaryngol Head Neck Surg 1996;114:732-5.)     

Overview of the national spinal cord injury statistical center database

OBJECTIVE: An evaluation of the history, design, and status of the database of the National Spinal Cord Injury Statistical Center (NSCISC) was undertaken to identify its continued relevance. RESEARCH DESIGN: A systematic review was conducted of goals, content, and quality control procedures, as well as its suitability and public availability for conducting future epidemiologic and health services research. RESULTS: The NSCISC database contains information on approximately 29,000 persons injured since 1973 and treated at any regional model spinal cord injury system within 1 year of injury. The NSCISC database is structured longitudinally with data collected at discharge, 1 year after injury, 5 years after injury, and every 5 years thereafter. The database includes information on demographics, injury severity, medical complications, surgical procedures, types and amounts of therapy, length of stay, charges, and both short-term and long-term treatment outcomes. Strengths include large sample size, use of valid and reliable measures, geographic and patient diversity, comprehensiveness, availability of long-term prospective follow-up information, good case identification, and rigorous quality control procedures. Limitations include lack of population basis, inclusion of only model system patients, losses to follow-up, and other missing data. Recent content additions include detailed information on each treatment phase, depression, substance abuse, environmental barriers to community integration, and patient identifying information. A process exists for researchers to gain access to the data. CONCLUSIONS: The database remains a valuable resource. Future plans include linkage to other databases to enhance research capability, a published research compendium, and development of a user's guide to facilitate database usage.     

骨盆骨折伴颈脊髓损伤的临床分析

目的 探讨伴有颈脊髓损伤的骨盆骨折的临床特征。方法 总结和分析187例骨盆骨折患者中伴有颈脊髓损伤的48例骨盆骨折的临床特征。结果 按照损伤机制分型，以前后挤压型骨盆骨折中伴休克和颈髓损伤最多；颈髓损伤平面上移和程度加重以伴有休克者最明显；低钠血症是此类损伤早期常见的并发症。结论 重视此类损伤的病史特点。详细的颈部检查，了解其损伤的机制分型，严格控制液体入量，尽早应用抗再灌注损伤的药物，严密监测低钠血症的相关数据，则有助于此类损伤的早期救治。     

Current status of clinical trials for acute spinal cord injury

Acute spinal cord injury (ASCI) occurs as a result of physical disruption of spinal cord axons through the epicenter of injury leading to deficits in motor, sensory, and autonomic function. This is a debilitating neurological disorder common in young adults that often requires life-long therapy and rehabilitative care, placing a significant burden on our healthcare system. While no cure exists, research has identified various pharmacological compounds that specifically antagonize primary and secondary mechanisms contributing to the etiology of ASCI. Several compounds including methylprednisolone (MPSS), GM-1 ganglio-side, thyrotropin releasing hormone (TRH), nimodipine, and gacyclidine have been tested in prospective randomized clinical trials of ASCI. MPSS and GM-1 ganglioside have shown evidence of modest benefits. Clearly trials of improved neuroprotective agents are required. Promising potential therapies for ASCI include riluzole, minocycline, erythropoietin, and the fusogen polyethylene glycol, as well as mild hypothermia.     

不同程度颈脊髓损伤后低钠血症的临床分析

 目的回顾性总结急性颈脊髓损伤后低钠血症的发生特点,并分析其可能的发生原因,以及脊髓损伤严重程度、性别、年龄等因素对血钠变化的影响。方法研究对象为2005年6月至2011年3月急诊收治的一组颈椎外伤患者,排除合并颅脑外伤及慢性疾病的患者,入选病例分为完全性脊髓损伤组、不完全性脊髓损伤组及无神经功能障碍组,回顾性分析各组病例的血钠变化情况。结果入选病例共102例,男83例,女19例;年龄17~68岁,平均45.6岁。完全性脊髓损伤组23例,不完全性脊髓损伤组60例,无神经功能障碍组19例。共发生低钠血症共39例,完全性脊髓损伤组15例(65%),不完全性脊髓损伤组23例(38%),无神经功能障碍组1例(5%)。低钠血症发生率在三组间两两比较,差异有统计学意义,完全性脊髓损伤组低钠血症的发生率明显高于不完全性脊髓损伤组和无神经功能障碍组。Logistic逐步回归分析结果显示低钠血症与患者脊髓损伤程度有明确相关关系,而与患者的年龄、性别、脊髓损伤节段无相关关系。结论急性颈脊髓损伤后具有较高的低钠血症发生率,虽然影响钠盐平衡的因素及相互作用非常复杂,但颈脊髓损伤致自主神经功能障碍、神经内分泌功能异常以及血液动力学改变可能是导致颈脊髓损伤后电解质系统异常的重要原因。     

Clinical trials without statistical significance. Importance of type II error

A randomized clinical trial is a prospective experiment to compare one or more interventions against a control group, in order to determine the effectiveness of the interventions. A clinical trial may compare the value of a drug vs. placebo. It may compare surgical with medical interventions. The principles apply to any situation in which the issue of who is exposed to which condition is under the control of the experimenter, and that the method of assignment is through randomization. A negative clinical trial is that in which no significant difference is found between the comparison groups. Results without statistical difference may be useful either to discard useless treatments or to demonstrate that one intervention is as effective as the one it was compared with. Eliminating useless treatments may be adequate. However, if this is the result of studies with methodological errors, new interventions that are actually useful may not be available for patients. In this review we present some of the possible methodological errors that may lead to false negative results in clinical trials.