North American Clinical Trials Network (NACTN) for Treatment of Spinal Cord Injury: A Consortium of Military, Veterans Administration, and Civilian Hospitals

The North American Clinical Trials Network (NACTN) includes 9 clinical centers funded by the US Department of Defense and the Christopher Reeve Paralysis Foundation. Its purpose is to accelerate clinical testing of promising therapeutics in spinal cord injury (SCI) through the development of a robust interactive infrastructure. This structure includes key committees that serve to provide longitudinal guidance to the Network. These committees include the Executive, Data Management, and Neurological Outcome Assessments Committees, and the Therapeutic Selection Committee (TSC), which is the subject of this manuscript. The NACTN brings unique elements to the SCI field. The Network's stability is not restricted to a single clinical trial. Network members have diverse expertise and include experts in clinical care, clinical trial design and methodology, pharmacology, preclinical and clinical research, and advanced rehabilitation techniques. Frequent systematic communication is assigned a high value, as is democratic process, fairness and efficiency of decision making, and resource allocation. This article focuses on how decision making occurs within the TSC to rank alternative therapeutics according to 2 main variables: quality of the preclinical data set, and fit with the Network's aims and capabilities. This selection process is important because if the Network's resources are committed to a therapeutic, alternatives cannot be pursued. A proposed methodology includes a multicriteria decision analysis that uses a Multi-Attribute Global Inference of Quality matrix to quantify the process. To rank therapeutics, the TSC uses a series of consensus steps designed to reduce individual and group bias and limit subjectivity. Given the difficulties encountered by industry in completing clinical trials in SCI, stable collaborative not-for-profit consortia, such as the NACTN, may be essential to clinical progress in SCI. The evolution of the NACTN also offers substantial opportunity to refine decision making and group dynamics. Making the best possible decisions concerning therapeutics selection for trial testing is a cornerstone of the Network's function.

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North American Clinical Trials Network for the Treatment of Spinal Cord Injury: goals and progress

Journal of Neurosurgery Spine ◽

10.3171/2012.4.aospine1294 ◽

2012 ◽

Vol 17 (Suppl1) ◽

pp. 6-10 ◽

Cited By ~ 19

Author(s):

Robert G. Grossman ◽

Elizabeth G. Toups ◽

Ralph F. Frankowski ◽

Keith D. Burau ◽

Susan Howley

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Clinical Trials ◽

Phase I ◽

Data Management ◽

North American ◽

Conducting Phase ◽

The North ◽

Number Of Patients ◽

Cord Injury

The North American Clinical Trials Network (NACTN) for the Treatment of Spinal Cord Injury is a consortium of 10 neurosurgery departments, a data management center, and a pharmacological center. The NACTN was established with the goal of bringing recent molecular and cell-based discoveries in neuroprotection and regeneration from the laboratory into clinical trials that optimize meaningful data outcomes and maximum safety to patients. The requirements of planning and executing clinical trials in spinal cord injury (SCI) and the steps that the NACTN has taken to address these requirements are discussed and illustrated in articles in this issue of the Journal of Neurosurgery: Spine. The progress that the NACTN has made in meeting these goals can be summarized as organizing a network of hospitals capable of enrolling a sufficient number of patients for conducting Phase I and II trials; creating a Data Management Center and a database of the natural history of recovery after SCI (at the time of this writing 485 patients were enrolled in the database); creating a database of the incidence and severity of complications that occur during acute and subacute treatment after SCI; developing a Pharmacological Center capable of performing pharmacokinetic and pharmacodynamic studies of therapeutic drugs; completing enrollment of 36 patients in NACTN's first clinical trial, a Phase I study of riluzole, a neuroprotective drug; and performing pharmacokinetic and pharmacodynamic studies of riluzole in acute SCI.

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North American Clinical Trials Network: Building a Clinical Trials Network for Spinal Cord Injury

Essentials of Spinal Cord Injury ◽

10.1055/b-0034-83871 ◽

2013 ◽

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Clinical Trials ◽

North American ◽

Network Building ◽

Cord Injury

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Extracorporeal shockwave therapy in spinal cord injury, early to advance to clinical trials? A systematic review and meta-analysis on animal studies

The Neuroradiology Journal ◽

10.1177/19714009211026899 ◽

2021 ◽

pp. 197140092110268

Author(s):

Seyedeh Niloufar Rafiei Alavi ◽

Arian Madani Neishaboori ◽

Mahmoud Yousefifard

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Clinical Trials ◽

Animal Models ◽

Meta Analysis ◽

Mean Difference ◽

Extracorporeal Shockwave Therapy ◽

Extracorporeal Shockwave ◽

Shockwave Therapy ◽

Cord Injury

Background As there is no consensus over the efficacy of extracorporeal shockwave therapy in the management of spinal cord injury complications, the current meta-analysis aims to investigate preclinical evidence on the matter. Methods The search strategy was developed based on keywords related to ‘spinal cord injury’ and ‘extracorporeal shockwave therapy’. A primary search was conducted in Medline, Embase, Scopus and Web of Science until the end of 2020. Studies which administered extracorporeal shockwave therapy on spinal cord injury animal models and evaluated motor function and/or histological findings were included. The standardised mean difference with a 95% confidence interval (CI) were calculated. Results Seven articles were included. Locomotion was significantly improved in the extracorporeal shockwave therapy treated group (standardised mean difference 1.68, 95% CI 1.05–2.31, P=0.032). It seems that the efficacy of extracorporeal shockwave therapy with an energy flux density of 0.1 mJ/mm2 is higher than 0.04 mJ/mm2 ( P=0.044). Shockwave therapy was found to increase axonal sprouting (standardised mean difference 1.31, 95% CI 0.65, 1.96), vascular endothelial growth factor tissue levels (standardised mean difference 1.36, 95% CI 0.54, 2.18) and cell survival (standardised mean difference 2.49, 95% CI 0.93, 4.04). It also significantly prevents axonal degeneration (standardised mean difference 2.25, 95% CI 1.47, 3.02). Conclusion Extracorporeal shockwave therapy significantly improves locomotor recovery in spinal cord injury animal models through neural tissue regeneration. Nonetheless, in spite of the promising results and clinical application of extracorporeal shockwave therapy in various conditions, current evidence implies that designing clinical trials on extracorporeal shockwave therapy in the management of spinal cord injury may not be soon. Hence, further preclinical studies with the effort to reach the safest and the most efficient treatment protocol are needed.

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AAV2-mediated and hypoxia response element-directed expression of bFGF in neural stem cells showed therapeutic effects on spinal cord injury in rats

Cell Death and Disease ◽

10.1038/s41419-021-03546-6 ◽

2021 ◽

Vol 12 (3) ◽

Author(s):

Sipin Zhu ◽

Yibo Ying ◽

Jiahui Ye ◽

Min Chen ◽

Qiuji Wu ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Clinical Trials ◽

Control Group ◽

Therapeutic Effects ◽

Hypoxia Response Element ◽

Neurofilament Protein ◽

Response Element ◽

Hypoxia Response ◽

Cord Injury

AbstractNeural stem cell (NSCs) transplantation has been one of the hot topics in the repair of spinal cord injury (SCI). Fibroblast growth factor (FGF) is considered a promising nerve injury therapy after SCI. However, owing to a hostile hypoxia condition in SCI, there remains a challenging issue in implementing these tactics to repair SCI. In this report, we used adeno-associated virus 2 (AAV2), a prototype AAV used in clinical trials for human neuron disorders, basic FGF (bFGF) gene under the regulation of hypoxia response element (HRE) was constructed and transduced into NSCs to yield AAV2-5HRE-bFGF-NSCs. Our results showed that its treatment yielded temporally increased expression of bFGF in SCI, and improved scores of functional recovery after SCI compared to vehicle control (AAV2-5HRE-NSCs) based on the analyses of the inclined plane test, Basso–Beattie–Bresnahan (BBB) scale and footprint analysis. Mechanistic studies showed that AAV2-5HRE-bFGF-NSCs treatment increased the expression of neuron-specific neuronal nuclei protein (NeuN), neuromodulin GAP43, and neurofilament protein NF200 while decreased the expression of glial fibrillary acidic protein (GFAP) as compared to the control group. Further, the expressions of autophagy-associated proteins LC3-II and Beclin 1 were decreased, whereas the expression of P62 protein was increased in AAV2-5HRE-bFGF-NSCs treatment group. Taken together, our data indicate that AAV2-5HRE-bFGF-NSCs treatment improved the recovery of SCI rats, which is accompanied by evidence of nerve regeneration, and inhibition of SCI-induced glial scar formation and cell autophagy. Thus, this study represents a step forward towards the potential use of AAV2-5HRE-bFGF-NSCs for future clinical trials of SCI repair.

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From Discovery to Clinical Trials: Treatment Strategies for Central Neuropathic Pain after Spinal Cord Injury

Current Pharmaceutical Design ◽

10.2174/1381612053507864 ◽

2005 ◽

Vol 11 (11) ◽

pp. 1411-4120 ◽

Cited By ~ 40

Author(s):

Claire Hulsebosch

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Clinical Trials ◽

Neuropathic Pain ◽

Treatment Strategies ◽

Central Neuropathic Pain ◽

Cord Injury

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Review of clinical trials of neuroprotection in acute spinal cord injury

Neurosurgical FOCUS ◽

10.3171/foc.1999.6.1.11 ◽

1999 ◽

Vol 6 (1) ◽

pp. E10 ◽

Cited By ~ 8

Author(s):

Charles H. Tator ◽

Michael G. Fehlings

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Clinical Trials ◽

Treatment Time ◽

Time Window ◽

Current Knowledge ◽

Acute Spinal Cord Injury ◽

Randomized Controlled Studies ◽

Cord Injury ◽

Therapeutic Time Window

In this paper the authors review the clinical trials of neuroprotection that have been performed for the treatment of acute spinal cord injury (SCI). The biological rationale for the selection of each treatment modality is discussed with reference to current knowledge of the principles in the management of acute SCI as well as the primary and secondary injury mechanisms identified by experimental and clinical studies of the pathophysiology of acute SCI. The trials are evaluated with regard to the availability and use of accurate clinical outcome measures, and the methodologies of the trials are critically evaluated with an emphasis on prospective randomized controlled studies. A detailed description and critical analysis are provided of the results of the 10 clinical trials conducted to date in which a randomized prospective controlled design has been used. The issue of the therapeutic time window in acute SCI is discussed. To date, methylprednisolone is the only effective neuroprotective agent that has been established for use in human SCI, and the only therapeutic time window established in human SCI is a maximum trauma-to-treatment time of 8 hours.

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