An Introduction to the North American Clinical Trials Network for Spinal Cord Injury Special Edition: Reflections on Accomplishments and a Look to the Future

北美脊髓损伤临床试验网络简介：成就回顾与未来展望

The North American Clinical Trials Network (NACTN) has been established as a network of translational clinical research centers focused on traumatic spinal cord injury (SCI) with the goals of facilitating clinical translational research, promotion of enhanced clinical care protocols including the principle of early surgery for SCI, and improving outcomes for individuals with acute SCI. Since its foundation in 2004 by Dr. Robert Grossman, NACTN has evolved into a powerful multi-stakeholder consortium of eight neurosurgical department faculties at university-affiliated institutions in the United States and Canada, a data management center, and a pharmacological center...

北美临床试验网络(NACTN)是一个专注于创伤性脊髓损伤(SCI)的转化性临床研究中心网络，其目标是促进临床转化性研究，促进包括SCI早期手术原则在内的增强型临床照护方案，并改善急性SCI患者的预后。自2004年由罗伯特·格罗斯曼博士创立以来，NACTN已经发展成为一个强大的多方利益相关者联盟，由美国和加拿大大学附属机构的八个神经外科系、一个数据管理中心和一个药理学中心组成……

REF: Fehlings MG, Neal CJ, Hejrati N, Harrop JS, Toups EG, Guest JD. An Introduction to the North American Clinical Trials Network for Spinal Cord Injury Special Edition: Reflections on Accomplishments and a Look to the Future. J Neurotrauma. 2023;40(17-18):1811-1816. doi:10.1089/neu.2022.0402 PMID: 37668560

由人工翻译修正

North American Clinical Trials Network for Spinal Cord Injury Registry: Methodology and Analysis

北美脊髓损伤登记临床试验网络：方法学与分析

The North American Clinical Trials Network (NACTN) for Spinal Cord Injury (SCI) is a consortium of neurosurgery departments at university affiliated hospitals with medical, nursing, and rehabilitation personnel who are skilled in the assessment, evaluation, and management of SCI. NACTN was established with the goal of consistently advancing the quality of life of people with SCI through clinical trials of new therapies that provide robust evidence of safety and effectiveness. A prospective multi-center Registry was created to collect the natural course of the acute traumatic SCI patient from time of injury to 12 months follow-up. NACTN's network of hospitals enrolls a significant number of patients, defines and adheres to standard protocols, and provides the infrastructure and highly skilled personnel to conduct trials of therapy for SCI. Registry data have been used by academic institutions and by the biotechnology and pharmaceutical sectors to create comparison datasets for Phase I clinical trials of new therapies.

北美脊髓损伤临床试验网络(NACTN)是由大学附属医院的神经外科部门组成的联盟，拥有熟练的脊髓损伤评估、评估和管理的医疗、护理和康复人员。成立NACTN的目的是通过提供强有力的安全性和有效性证据的新疗法的临床试验，持续提高脊髓损伤患者的生活质量。建立一个前瞻性的多中心注册中心，收集急性创伤性脊髓损伤患者从受伤时到12个月随访的自然病程。NACTN的医院网络招收了大量的患者，确定并遵守了标准方案，并提供了进行脊髓损伤治疗试验的基础设施和高技能人员。学术机构以及生物技术和制药部门利用注册数据为新疗法的第一阶段临床试验创建比较数据集。

REF: Toups EG, Ugiliweneza B, Howley SP, et al. North American Clinical Trials Network for Spinal Cord Injury Registry: Methodology and Analysis. J Neurotrauma. 2023;40(17-18):1817-1822. doi:10.1089/neu.2022.0403 PMID: 37125443

由人工翻译修正

History and Accomplishments of the North American Clinical Trials Network for Spinal Cord Injury, 2004–2022

2004-2022年北美脊髓损伤临床试验网络的历史和成就

This is a historical account of the origin and accomplishments of the North American Clinical Trials Network (NACTN) for traumatic spinal cord injury (SCI), which was established in 2004 by Christopher Reeve and Robert Grossman. Christopher Reeve was an actor who became quadriplegic and started the Christopher & Dana Reeve Foundation (CDRF), and Robert Grossman was a neurosurgeon experienced in neurotrauma and a university professor in Houston. NACTN has member investigators at university and military centers in North America and has contributed greatly to the improvement of care, primarily acute care, of patients sustaining traumatic SCI. Its accomplishments are a clinical registry database of >1000 acute SCI patients documenting the care pathways, including complications. NACTN has assessed the effectiveness of treatment, including pharmacotherapy and the role and timing of surgery, and has also identified barriers to early surgery. The principal focus has been on improving neurological recovery. NACTN has trained many SCI practitioners and has collaborated with other SCI networks and organizations internationally to promote the care of SCI patients.

本文回顾了北美创伤性脊髓损伤临床试验网络(NACTN)的起源和成就，该网络由克里斯托弗·里夫和罗伯特·格罗斯曼于2004年建立。克里斯托弗·里夫是一位四肢瘫痪的演员，他创办了克里斯托弗和达纳·里夫基金会(CDRF)，罗伯特·格罗斯曼是一位在神经创伤方面经验丰富的神经外科医生，也是休斯顿的一名大学教授。NACTN在北美的大学和军事中心有成员调查人员，并为改善对遭受创伤性脊髓损伤患者的照护做出了巨大贡献，主要是紧急治疗。它的成就是建立了超过1000名急性脊髓损伤患者的临床登记数据库，记录了包括并发症在内的护理途径。NACTN评估了治疗的有效性，包括药物治疗以及手术的作用和时机，并确定了早期手术的障碍。主要的重点一直是改善神经恢复。NACTN培训了许多SCI从业者，并与国际上其他SCI网络和组织合作，促进对SCI患者的治疗。

REF: Tator CH, Guest JD, Neal CJ, et al. History and Accomplishments of the North American Clinical Trials Network for Spinal Cord Injury, 2004-2022. J Neurotrauma. 2023;40(17-18):1823-1833. doi:10.1089/neu.2022.0404 PMID: 36515162

由人工翻译修正

Importance of Prospective Registries and Clinical Research Networks in the Evolution of Spinal Cord Injury Care

前瞻性登记和临床研究网络在脊髓损伤护理演变中的重要性

We review four registry networks: the North American Clinical Trials Network (NACTN) SCI Registry, the National Spinal Cord Injury Model Systems (SCIMS) Database, the Rick Hansen SCI Registry (RHSCIR), and the European Multi-Center Study about Spinal Cord Injury (EMSCI). We compare the registries' focuses, data platforms, advanced analytics use, and impacts. We also describe how registries' data can be combined with electronic health records (EHRs) or shared using federated analysis to protect registrants' identities. These registries have identified changes in epidemiology, recovery patterns, complication incidence, and the impact of practice changes such as early decompression. They've also revealed latent disease-modifying factors, helped develop clinical trial stratification models, and served as matched control groups in clinical trials. Advancing SCI clinical science for personalized medicine requires advanced analytical techniques, including machine learning, counterfactual analysis, and the creation of digital twins. Registries and other data sources help drive innovation in SCI clinical science.

我们回顾了四个注册网络：北美临床试验网络(NACTN)SCI注册、国家脊髓损伤模型系统(SCIMS)数据库、Rick Hansen SCI注册(RHSCIR)和欧洲脊髓损伤多中心研究(EMSCI)。我们比较了注册中心的关注点、数据平台、高级分析使用情况和影响。我们还描述了如何使用联合分析将登记处的数据与电子健康记录(EHR)相结合或共享，以保护注册者的身份。这些登记已经确定了流行病学、康复模式、并发症发生率以及变化(如早期减压)的影响。他们还揭示了潜在的疾病因素，帮助开发了临床试验分层模型，并在临床试验中充当匹配的对照组。推进SCI临床科学的个性化医学需要先进的分析技术，包括机器学习、反事实分析和数字化的创建。注册表和其他数据来源有助于推动SCI临床科学的创新。

REF: Kelly-Hedrik M, Abd-El-Barr MM, Aarabi B, et al. Importance of Prospective Registries and Clinical Research Networks in the Evolution of Spinal Cord Injury Care. J Neurotrauma. 2023;40(17-18):1834-1848. doi:10.1089/neu.2022.0450 PMID: 36576020

由人工翻译修正

Development of a Systems Medicine Approach to Spinal Cord Injury

脊髓损伤的系统医学治疗方法研究进展

To better understand the evolution from acute SCI to chronic SCI multi-system states, we propose a topological phenotype framework integrating bioinformatics, physiological data, and allostatic load tested against accepted established recovery metrics. This form of correlational phenotyping may reveal critical nodal points for intervention to improve recovery trajectories. This study examines the limitations of current classifications of SCI and how these can evolve through systems medicine.

为了更好地理解从急性脊髓损伤到慢性脊髓损伤多系统状态的演变，我们提出了一个拓扑表型框架，该框架集成了生物信息学、生理数据和针对公认的已建立的恢复指标进行测试的平衡负荷。这种相关表型的形式可能揭示干预措施的关键节点，以改善恢复轨迹。这项研究考察了当前脊髓损伤分类的局限性，以及这些分类如何通过系统医学进化。

REF: Guest JD, Kelly-Hedrick M, Williamson T, et al. Development of a Systems Medicine Approach to Spinal Cord Injury. J Neurotrauma. 2023;40(17-18):1849-1877. doi:10.1089/neu.2023.0024 PMID: 37335060 PMCID: PMC10460697

由人工翻译修正

Safety and Efficacy of Riluzole in Acute Spinal Cord Injury Study (RISCIS): A Multi-Center, Randomized, Placebo-Controlled, Double-Blinded Trial

利鲁唑治疗急性脊髓损伤的安全性和有效性研究(RISCIS)：一项多中心、随机、安慰剂对照的双盲试验

Riluzole is a sodium-glutamate antagonist that attenuates neurodegeneration in amyotrophic lateral sclerosis (ALS). It has shown favorable results in promoting recovery in pre-clinical models of traumatic spinal cord injury (tSCI) and in early phase clinical trials. This study aimed to evaluate the efficacy and safety of riluzole in acute cervical tSCI. An international, multi-center, prospective, randomized, double-blinded, placebo-controlled, adaptive, Phase III trial (NCT01597518) was undertaken. The results of this trial may warrant further investigation to extend these findings. Moreover, guideline development groups may wish to assess the possible clinical relevance of the secondary outcome analyses, in light of the fact that SCI is an uncommon orphan disorder without an accepted neuroprotective treatment.

利鲁唑是一种谷氨酸钠拮抗剂，可减轻肌萎缩侧索硬化症(ALS)的神经退行性变。在创伤性脊髓损伤(TSCI)的临床前模型和早期临床试验中，它已显示出促进康复的良好效果。本研究旨在评价利鲁唑治疗急性颈髓损伤的疗效和安全性。进行了一项国际性、多中心、前瞻性、随机、双盲、安慰剂对照、适应性的III期试验(NCT01597518)。这项试验的结果可能需要进一步调查，以扩大这些发现。此外，指南制定小组希望评估二次结果分析的临床相关性，因为脊髓损伤是一种不常见的孤儿疾病，没有接受神经保护治疗。

REF: Fehlings MG, Moghaddamjou A, Harrop JS, et al. Safety and Efficacy of Riluzole in Acute Spinal Cord Injury Study (RISCIS): A Multi-Center, Randomized, Placebo-Controlled, Double-Blinded Trial. J Neurotrauma. 2023;40(17-18):1878-1888. doi:10.1089/neu.2023.0163 PMID: 37279301 PMCID: PMC10460693

由人工翻译修正

Riluzole in Spinal Cord Injury Study (RISCIS)–Pharmacokinetic (PK) Sub-Study: An Analysis of Pharmacokinetics, Pharmacodynamics, and Impact on Axonal Degradation of Riluzole in Patients With Traumatic Cervical Spinal Cord Injury Enrolled in the RISCIS Phase III Randomized Controlled Trial

利鲁唑在脊髓损伤中的研究(RISCIS)-药代动力学(PK)亚研究：参加RISCIS III期随机对照试验的创伤性颈脊髓损伤患者利鲁唑的药代动力学、药效学和对轴突降解的影响分析

To date, no drug therapy has shown significant efficacy in improving functional outcomes in patients with acute spinal cord injury (SCI). Riluzole is an approved benzothiazole sodium channel blocker to attenuate neurodegeneration in amyotrophic lateral sclerosis (ALS) and is of interest for neuroprotection in SCI. In a Phase I clinical trial (ClinicalTrials.gov Identifier: NCT00876889), riluzole was well tolerated with a 2-week treatment at the dose level approved for ALS and exhibited potential efficacy in patients with SCI. The acute and progressive nature of traumatic SCI and the complexity of secondary injury processes alter the pharmacokinetics (PK) of therapeutics. In the PK sub-study of the multi-center, randomized, placebo-controlled, double-blinded Riluzole in Spinal Cord Injury Study (RISCIS) Phase II/III trial (ClinicalTrials.gov Identifier: NCT01597518), a total of 32 SCI patients were enrolled, and most of our patients were middle-age Caucasian males with head and neck injuries. We studied the PK and pharmacodynamics (PD) of riluzole on motor recovery, measured by International Standards for Neurological Classification of SCI (ISNCSCI) Motor Score at injury and at 3-month and 6-month follow-ups, along with levels of the axonal injury biomarker phosphorylated neurofilament heavy chain (pNF-H), during the 2-week treatment. The development of effective treatment for SCI is challenging. However, the future model-informed and PK-guided drug development and regimen modification can be rationally executed with the optimal dosing regimen design based on the developed 3D PK/PD model. The PK/PD/CO model can serve as a rational guide for future drug development, PKPD model refinement, and extension to other studies in SCI settings.

到目前为止，还没有药物治疗在改善急性脊髓损伤(SCI)患者的功能结果方面显示出显著的疗效。利鲁唑是一种被批准的苯并噻唑钠通道阻滞剂，用于减轻肌萎缩侧索硬化症(ALS)的神经退行性变，对脊髓损伤具有神经保护作用。在I期临床试验(ClinicalTrials.gov：NCT00876889)中，Riluzole耐受性良好，按批准的ALS剂量水平治疗2周，对SCI患者显示出潜在的疗效。创伤性脊髓损伤的急性和渐进性以及继发性损伤过程的复杂性改变了治疗的药代动力学(PK)。在多中心、随机、安慰剂对照、双盲Riluzole用于脊髓损伤研究(RISCIS)II/III期试验(ClinicalTrials.gov ID：NCT01597518)的PK子研究中，共有32名SCI患者入选，我们的患者大多是患有头颈部损伤的中年高加索男性。在2周的治疗中，我们研究了利鲁唑对运动恢复的PK和药效学(PD)，根据国际脊髓损伤神经分类标准(ISNCSCI)在损伤时、3个月和6个月随访时的运动评分，以及轴突损伤生物标记物磷酸化神经丝重链(pNF-H)的水平。开发有效的脊髓损伤治疗方法具有挑战性。然而，基于所建立的三维PK/PD模型的最优给药方案设计可以合理地进行未来模型信息和PK指导的药物开发和方案修改。PK/PD/CO模型可以为未来的药物开发、PKPD模型的完善以及在脊髓损伤环境下的其他研究提供合理的指导。

REF: Chow DS, Nguyen A, Park J, et al. Riluzole in Spinal Cord Injury Study (RISCIS)-Pharmacokinetic (PK) Sub-Study: An Analysis of Pharmacokinetics, Pharmacodynamics, and Impact on Axonal Degradation of Riluzole in Patients With Traumatic Cervical Spinal Cord Injury Enrolled in the RISCIS Phase III Randomized Controlled Trial. J Neurotrauma. 2023;40(17-18):1889-1906. doi:10.1089/neu.2022.0499 PMID: 37130044

由人工翻译修正

Variability in Early Surgery for Acute Cervical Spinal Cord Injury Patients: An Opportunity for Enhanced Care Delivery

急性颈髓损伤患者早期手术的可变性：加强照护提供的机会

Data supporting the benefits of early surgical intervention in acute spinal cord injury (SCI) is growing. For early surgery to be accomplished, understanding the causes of variabilities that effect the timing of surgery is needed to achieve this goal. The purpose of this analysis is to determine factors that affect the timing of surgery for acute cervical SCI within the North American Clinical Trials Network (NACTN) for SCI registry. In the present study of cervical SCI, NACTN achieved its goal of early surgery in 73.4% of patients from 2005-2019 who arrived within 24 h of their injury. Variability in achieving this goal was related to severity of neurological injury, the day of the week, and the treating NACTN center. Evaluating variations within our network improves understanding of potential systemic limitations and our decision-making process to accomplish the goal of early surgery.

支持早期手术治疗急性脊髓损伤(SCI)益处的数据正在增加。为了完成早期手术，需要了解影响手术时机的各种因素的原因，以实现这一目标。这项分析的目的是在北美临床试验网络(NACTN)的SCI注册登记中确定影响急性颈椎SCI手术时机的因素。在目前的颈椎SCI研究中，NACTN在2005-2019年73.4%的患者中实现了早期手术的目标，这些患者在受伤后24小时内到达。实现这一目标的可变性与神经损伤的严重程度、时间以及NACTN治疗中心有关。评估我们网络中的变异可以提高对潜在的系统限制和我们的决策过程的了解，以实现早期手术的目标。

REF: Neal CJ, Ugiliweneza B, Toups EG, et al. Variability in Early Surgery for Acute Cervical Spinal Cord Injury Patients: An Opportunity for Enhanced Care Delivery. J Neurotrauma. 2023;40(17-18):1907-1917. doi:10.1089/neu.2022.0507 PMID: 37125447

由人工翻译修正

Demographics, Mechanism of Injury, and Outcomes for Acute Upper and Lower Cervical Spinal Cord Injuries: An Analysis of 470 Patients in the Prospective, Multi-Center, North American Clinical Trials Network Registry

急性上颈髓和下颈髓损伤的人口学特征、损伤机制和预后：北美前瞻性、多中心、临床试验网络注册的470例患者分析

There is a paucity of data comparing the demographics, mechanism of injury, and outcomes of upper versus lower cervical spinal cord injuries (cSCI). The study objective was to define different clinical manifestations of cSCI. In conclusion, there appears to be a natural demarcation of injury type between C3 and C4. Upper cSCI (C1-C3) was more associated with falls and diabetes, whereas lower cSCI (C4-C7) was more associated with sports, worse ASIA scores, and more complications. Further research will be needed to understand the mechanistic and biological differences between these two groups and whether different treatments may be appropriate for each of these groups.

比较上、下颈髓损伤(CSCI)的人口学特征、损伤机制和预后的数据很少。该研究的目的是明确CSCI的不同临床表现。总而言之，C3和C4之间的损伤类型似乎是自然划分的。较高的CSCI(C1-C3)与跌倒和糖尿病有关，而较低的CSCI(C4-C7)与运动、更差的ASIA评分和更多的并发症更相关。还需要进一步的研究，以了解这两组之间的机制和生物学差异，以及不同的治疗方法是否适合每一组。

REF: Futch BG, Kouam RW, Ugiliweneza B, et al. Demographics, Mechanism of Injury, and Outcomes for Acute Upper and Lower Cervical Spinal Cord Injuries: An Analysis of 470 Patients in the Prospective, Multi-Center, North American Clinical Trials Network Registry. J Neurotrauma. 2023;40(17-18):1918-1927. doi:10.1089/neu.2022.0407 PMID: 36852492

由人工翻译修正