12 research outputs found
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North American Clinical Trials Network for Spinal Cord Injury Registry: Methodology and Analysis
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 multicenter 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
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The Evolving Profile of Acute Spinal Cord Injury Demographics, Outcomes and Surgical Treatment in North America: Analysis of a Prospective Multicenter Dataset of 989 Patients
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History and Accomplishments of the North American Clinical Trials Network (NACTN) for Spinal Cord Injury, 2004 to 2022
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 Dr. Robert Grossman. Christopher Reeve was an actor who became quadriplegic and started the Christopher and Dana Reeve Foundation, while 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 more than 1000 acute SCI patients documenting the care pathways, including complications. NACTN determined the effectiveness of treatment, including pharmacotherapy and the role and timing of surgery, and barriers to early surgery with a focus on neurological recovery. 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. It has trained many SCI practitioners and has collaborated with many other SCI networks and organizations internationally to promote the care of SCI patients
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Trends in the Use of Corticosteroids in the Management of Acute Spinal Cord Injury in North American Clinical Trials Networks (NACTN) Sites
Immunomodulatory therapeutics represent a potential neuroprotective strategy for the management of acute spinal cord injury (SCI). One of the most intensely debated neuroprotective drugs has been methylprednisolone sodium succinate (MPSS). MPSS was initially investigated for its role in mitigating lipid peroxidation. More recently, the anti-inflammatory/immunomodulatory properties of MPSS have been increasingly appreciated. Over the past two decades, several systematic reviews and clinical practice guidelines related to MPSS use in SCI have been published. The goal of this study was to investigate the temporal changes in the use of steroids at North American Clinical Trials Network (NACTN) centers and to correlate these with the evolution in published literature and guidelines. Data on patients enrolled from 2008 - 2018 in the prospective, multicenter NACTN registry, and in whom information related to the use of steroids was available, were analyzed. Patients were stratified as to whether they received steroids or not. The primary outcome was the change in the rate of steroid use per year between 2008 and 2018. Secondary outcomes included cardiac, gastrointestinal & genitourinary (GIGU), pulmonary and dermatologic complications. We identified 608 patients, of whom 171 (28.1%) were given steroids. In 2008 and 2009, the prevailing paradigm across NACTN centers was in favor of steroid administration and as such 70% (n=56) of patients received steroids in 2008 and 71.9% (n=46) in 2009. An abrupt practice reversal was observed in 2010, whereby only 19.7% of patients (n=14) received steroids, a trend that continued over subsequent years. Increasing literature in the 2000s arguing against the use of steroids culminated in the 2013 CNS/AANS practice guidelines for the management of acute SCI. These guidelines recommended against the use of MPSS for the treatment of acute SCI. Over the following years (2013-2018), steroids continued to be an uncommonly used therapeutic option in NACTN centers (range 3.9-16.9%). Patients receiving steroids had significantly higher rates of pulmonary complications (87%, n=147) compared to those not receiving steroids (73%, n=265; p=0.0003). However, compared to patients receiving steroids, those who did not receive steroids had significantly higher rates of cardiac (40%, [n=146] versus 23%, [n=39]; p=0.0001) and gastrointestinal/genitourinary complications (55%, [n=189], versus 31%, [n=52]; p<0.0001). The 2013 AANS/CNS guidelines and preceding literature appeared to have an impact on dramatically lowering the rates of corticosteroid use for acute SCI in NACTN sites after 2009. Of note, this analysis may not reflect the impact of the 2017 AO Spine Clinical Practice guidelines, which suggested the use of methylprednisolone as a valid practice option for acute SCI, especially for cervical injuries. Enhanced patient involvement in the clinical decision-making process and opportunities to personalize SCI management exist in reference to the use of MPSS in acute SCI
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The RISCIS-PK substudy: 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
To date, no drug therapy has shown significant efficacy in improving functional outcomes in patients with acute spinal cord injury (SCI). Riluzole, an FDA approved sodium channel blocker to attenuate neurodegeneration in amyotrophic lateral sclerosis (ALS), 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 SCI patients. The acute and progressive nature of traumatic SCI and the complexed secondary injury processes alter the pharmacokinetics (PK) of therapeutics. In the PK Sub-study of the multicenter, randomized, placebo-controlled, double-blinded RISCIS Phase II/III trial (ClinicalTrials.gov Identifier: NCT01597518), 32 SCI patients were enrolled, mostly middle-aged Caucasian males with head and neck injuries. PK and pharmacodynamics (PD) of riluzole on motor recovery, were measured by ISNCSCI Motor Score at injury, 3-month and 6-month follow-ups, and axonal injury biomarker, phosphorylated neurofilament heavy chain (pNF-H), during the two-week treatment. PK modeling, PK/PD correlations were developed to identify the potential effective exposure of riluzole for intended PD outcomes. The longitudinal impacts of SCI on the PK of riluzole are characterized. A time-varying population PK model of riluzole is established, incorporating time-varying clearance and volume of distribution from combined data of Phase I and Phase II/III trials. With the model, a rational dosing scheme can be designed with time-dependent modification to preserve the required therapeutic exposure of riluzole. The PD of riluzole of neurological outcomes and PK/PD correlation of the treatment were established. The time courses of efficacy in total motor score improvement (∆TMS) and pNF-H were monitored. A 3D PK/PD correlation was established for ∆TMS at 6 months with overall riluzole exposure, AUCD0-D14, and baseline TMS for individual patients. Patients with baseline TMS of 1 and 36 benefited from the optimal exposure range of 16 - 48 mg*h/ml. The PD models of pNF-H revealed the riluzole efficacy, with diminished increase in progression of pNF-H, indicative of reduced axonal breakdown. The independent parameter of Area Between Effective Curves (ABEC) of pNF-H in placebo and treatment groups was statistically identified as a significant predictor for the treatment effect. A mechanistic CO (Clinical Outcomes)/PD (pNF-H) model was established, and the proposed structure demonstrated the feasibility of PK/PD/CO correlation model. No appreciable hepatic toxicity was observed with the current riluzole treatment regimen. 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 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
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Variability in Early Surgery for Acute Cervical Spinal Cord Injury Patients: An Opportunity for Enhanced Care Delivery
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. Patients in the NACTN SCI registry from 2005 to 2019 with a cervical SCI, excluding Acute Traumatic Central Cord Syndrome, were analyzed for time elapsed from injury to arrival to the hospital, and time to surgery. Two categories were defined: 1) Early Arrival with Early Surgery commenced within 24 hours of injury (EAES) and 2) Early Arrival but Delayed Surgery (EADS) with surgery occurring between 24 to 72 hours post-injury. Patients' demographic features, initial clinical evaluation, medical comorbidities, neurological status, surgical intervention, complications, and outcome data were correlated with respect to the two arrival groups. Of the 222 acute cervical SCI patients undergoing surgery, 163 (73.4%) were EAES, and 59 (26.6%) were EADS. There was no statistical difference in arrival time between the EAES and EADS groups. There was a statistical difference in the median arrival time to surgery between the EAES group (9 hours) compared to the EADS group (31 hours) (p<0.05). There was no statistical difference in race, sex, age, mechanism of injury, APACHE II scores, or medical comorbidities between the two groups but the EAES group did present with a significantly lower systolic blood pressure (p<0.05). EADS patients were more likely to present as an AIS D than EAES (p<0.05). Early surgery was statistically more likely to occur if the injury occurred over the weekend (p<0.05). There were variations in the rates of early surgery between the 8 NACTN sites within the study, ranging from 57% to 100%. Of the 114 patients with 6-month outcome data, there was no significant change between the two groups regarding AIS grade change and motor/pin prick/light touch score recovery. A trend towards improved motor scores with early surgery was not statistically significant (p=0.21). Although there is data that surgery within 24 hours of injury improves outcomes and can be performed safely, there remain variations in care outside of clinical trials. 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 hours 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
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The Importance of Prospective Registries and Clinical Research Networks in the Evolution of Spinal Cord Injury Care
Only 100 years ago, traumatic spinal cord injury (SCI) was commonly lethal. Today, most people who sustain SCI survive with continual efforts to improve their quality of life and neurological outcomes. SCI epidemiology is changing as preventative interventions reduce injuries in younger individuals, and there is an increased incidence of incomplete injuries in aging populations. Early treatment has become more intensive with decompressive surgery and proactive interventions to improve spinal cord perfusion. Accurate data, including specialized outcome measures, are crucial to understanding the impact of epidemiological and treatment trends. Dedicated SCI clinical research and data networks and registries have been established in the United States, Canada, Europe, and several other countries. 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 Study (EMSCI). We compare the registries' focuses, data platforms, advanced analytics use, and impacts. We also describe how registries' data can be combined with EHR 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 like 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 and includes counterfactual analysis, and the creation of digital twins. Registries and other data sources help drive innovation in SCI clinical science
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The bulbocavernosus reflex (BCR) has no prognostic features during the acute evaluation of spinal cord injuries
The bulbocavernosus reflex (BCR) has been used during the initial evaluation of a spinal cord injury patient as a metric to determine prognosis and whether the patient is in "spinal shock". This reflex has been less utilized over the last decade and therefore, a review was performed to assess the value of BCR in patient prognosis. The North American Clinical Trials Network (NACTN) for Spinal Cord Injury is a consortium of tertiary medical centers that includes a prospective SCI registry. The NACTN registry data was analyzed to evaluate the prognostic implication of the BCR during the initial evaluation of a spinal cord injury patient. SCI patients were divided into those with an intact or absent BCR during their initial evaluation. Associations of participants' descriptors and neurological status on follow up were performed followed by associations with the presence of a BCR. 769 registry patients with recorded BCRs were included in the study. The median age was 49 years (32-61 years), majority were male (n=566, 77%), and white (n=519, 73%). Among included patients, high blood pressure was the most common comorbidity (n=230, 31%). Cervical spinal cord injury was the most common (n=470, 76%) with fall (n=320, 43%) being the most frequent mechanism of injury. BCR was present in 311 patients (40.4%), while 458 (59.6%) had a negative BCR within 7 days of injury or before surgery. At 6 months post-injury, 230 patients (29.9%) followed up, of which, 145 had a positive BCR while 85 had a negative BCR, respectively. The presence/absence of BCR was significantly different in patients with cervical (p=0.0015) or thoracic SCI (p=0.0089), or conus medullaris syndrome (p=0.0035), and in those who were AIS grade A (p=0.0313). No significant relationship was observed between BCR results and demographics, AIS grade conversion, motor score changes (p=0.1669), and changes in pin prick (p=0.3795) and light touch scores (p=0.8178). In addition, cohorts were not different in surgery decision (p=0.7762) and injury to surgery time (p=0.0681). In our review of the NACTN spinal cord registry, the BCR did not provide prognostic utility in the acute evaluation of spinal cord injury patients. Therefore, it should not be used as a reliable marker for predicting neurological outcomes post-injury
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Interhospital Transfer delays care for spinal cord injury patients: A Report from the North American Clinical Trials Network for Spinal Cord Injury
The North America Clinical Trials Network (NACTN) for Spinal Cord Injury (SCI) is a consortium of tertiary medical centers that has maintained a prospective SCI registry since 2004, and has espoused that early surgical intervention is associated with improved outcome. It has previously been shown that initial presentation to a lower acuity center and necessity of transfer to a higher acuity center reduce rates of early surgery. The NACTN database was evaluated to examine the association between interhospital transfer (IHT), early surgery, and outcome, taking into account distance traveled and site of origin for the patient. Data from a 15-year period of the NACTN SCI Registry were analyzed (years 2005-2019). Patients were stratified into transfers directly from the scene to a level I trauma center (NACTN site) versus IHT from a level II or III trauma facility. The main outcome was surgery within 24 hours of injury (yes/no) while secondary outcomes were length of stay, death, discharge disposition, and 6-month AIS grade conversion. For the IHT patients, distance traveled for transfer was calculated by measuring the shortest distance between origin and NACTN hospital. Analysis was performed with Brown-Mood test and chi-square tests. Of 724 patients with transfer data, 295 (40%) underwent IHT and 429 (60%) were admitted directly from the scene of accident. Patients who underwent IHT were more likely to have a less severe SCI (AIS D) (p=.002), have a central cord injury (p=.004), and have a fall as their mechanism of injury (p<.0001) than those directly admitted to a NACTN center. Of the 634 patients who had surgery, direct admission to a NACTN site was more likely to result in surgery within 24 hours compared to IHT patients (52% vs. 38%) (p< .0003). Median IHT distance was 28 miles (interquartile range=13-62 miles). There was no significant difference in death, length of stay, discharge to a rehab facility versus home, or 6-month AIS grade conversion rates between the two groups. Patients who underwent IHT to a NACTN site were less likely to have surgery within 24 hours of injury, compared to those directly admitted to the level I trauma facility. While there was no difference in mortality rates, length of stay, or 6-month AIS conversion between groups, patients with IHT were more likely be older with a less severe level of injury (AIS D). This work suggests there are barriers to timely recognition of SCI in the field, appropriate admission to a higher level of care after recognition, and challenges related to the management of individuals with less severe SCI
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Demographics, Mechanism of Injury and Outcomes for Acute Upper and Lower Cervical Spinal Cord Injuries - An Analysis of 470 Patients in the Prospective, Multicenter North American Clinical Trials Network (NACTN) Registry
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. Data were collected prospectively through centers of the North American Clinical Trials Network (NACTN). Data was collected on 470 patients (21% women, mean age 50 years). Cervical vertebral level was analyzed as an ordinal variable to determine a natural demarcation to classify upper versus lower cSCI. For continuous variable analysis, falls were associated with C3 more than C4 vertebral level injuries (60% vs. 42%) (p=0.0126), while motor vehicle accidents (MVA) were associated with C4 more than C3 (40% vs. 29%) (p=0.0962). Motor ISNSCI scores also demonstrated a natural demarcation between C3 and C4, with C3 having higher median ASIA motor scores (40 [4 - 73] vs. 11 [3 - 59], p= 0.0227). There were no differences when comparing C2 to C3 nor C4 to C5. Given the significant differences seen between C3 and C4, but not C2 and C3 nor C4 and C5, upper cSCI was designated as C1-C3, and lower cSCI was designated as C4-C7. Compared to a lower cSCI, patients with an upper cSCI were more likely to have a fall as their mechanism of injury (54% vs. 36%, p= 0.0072). Patients with an ASIA C cSCI were likely to have an upper cervical injury: 23% vs. 11% (p= 0.0226). Additionally, patients with an upper cSCI were more likely to have diabetes prior to injury, 37% vs. 22% respectively (p= 0.0084). Lower cSCI were more likely injured through sports (19% vs. 8%, p= 0.0171) and present with ASIA A (42% vs. 25%, p= 0.0186) neurological grade. Patients with lower cSCI were also significantly more likely to have complications such as shock, pulmonary embolism, and pleural effusion. 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