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Diana S. L. Chow, Yang Teng, Elizabeth G. Toups, Bizhan Aarabi, James S. Harrop, Christopher I. Shaffrey, Michele M. Johnson, Maxwell Boakye, Ralph F. Frankowski, Michael G. Fehlings and Robert G. Grossman

Object

The aim of this paper was to characterize individual and population pharmacokinetics of enterally administered riluzole in a Phase 1 clinical trial of riluzole as a neuroprotective agent in adults 18–70 years old with acute spinal cord injury (SCI).

Methods

Thirty-five individuals with acute SCI, American Spinal Injury Association Impairment Scale Grades A–C, neurological levels from C-4 to T-12, who were enrolled in the Phase 1 clinical trial sponsored by the North American Clinical Trials Network for Treatment of Spinal Cord Injury, received 50 mg riluzole twice daily for 28 doses. The first dose was administered at a mean of 8.7 ± 2.2 hours postinjury. Trough plasma samples were collected within 1 hour predose, and peak plasma samples were collected 2 hours postdose on Days 3 and 14 of treatment. Riluzole concentrations were quantified by high-performance liquid chromatography assay. The data were analyzed for individual and population pharmacokinetics using basic structural and covariate models. The pharmacokinetic measures studied were the peak concentration (Cmax), trough concentration (Cmin), systemic exposure (AUC0–12), clearance (CL/F), and volume of distribution (V_F) normalized by the bioavailability (F).

Results

The Cmax and AUC0–12 achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher CL and larger V. The pharmacokinetics of riluzole (Cmax, Cmin, AUC0–12, CL, and V) changed during the acute and subacute phases of SCI during the 14 days of therapy. It was consistently observed in patients at all clinical sites that Cmax, Cmin, and AUC0–12 (128.9 ng/ml, 45.6 ng/ml, and 982.0 ng × hr/ml, respectively) were significantly higher on Day 3 than on Day 14 (76.5 ng/ml, 19.1 ng/ml, and 521.0 ng × hr/ml, respectively). These changes resulted from lower CL (49.5 vs 106.2 L/hour) and smaller V (557.1 vs 1297.9/L) on Day 3. No fluid imbalance or cytochrome P 1A2 induction due to concomitant medications was identified during the treatment course to account for such increases in V and CL, respectively. Possible mechanisms underlying these changes are discussed.

Conclusions

This is the first report of clinical pharmacokinetics of riluzole in patients with SCI. The Cmax and AUC0–12 achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher clearance and larger volume of distribution in SCI patients. The finding in SCI patients of an increase in the clearance and distribution of riluzole between the 3rd and 14th days after SCI, with a lower plasma concentration of riluzole on the 14th day, stresses the importance of monitoring changes in drug metabolism after SCI in interpreting the safety and efficacy of therapeutic drugs that are used in clinical trials in SCI. Clinical trial registration no.: NCT00876889.

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Charles H. Tator, Robin Hashimoto, Annie Raich, Daniel Norvell, Michael G. Fehlings, James S. Harrop, James Guest, Bizhan Aarabi and Robert G. Grossman

There is a need to enhance the pipeline of discovery and evaluation of neuroprotective pharmacological agents for patients with spinal cord injury (SCI). Although much effort and money has been expended on discovering effective agents for acute and subacute SCI, no agents that produce major benefit have been proven to date. The deficiencies of all aspects of the pipeline, including the basic science input and the clinical testing output, require examination to determine remedial strategies. Where has the neuroprotective/pharmacotherapy preclinical process failed and what needs to be done to achieve success? These are the questions raised in the present review, which has 2 objectives: 1) identification of articles that address issues related to the translational readiness of preclinical SCI pharmacological therapies; and 2) examination of the preclinical studies of 5 selected agents evaluated in animal models of SCI (including blunt force trauma, penetrating trauma, or ischemia). The 5 agents were riluzole, glyburide, magnesium sulfate, nimodipine, and minocycline, and these were selected because of their promise of translational readiness as determined by the North American Clinical Trials Network Consortium.

The authors found that there are major deficiencies in the effort that has been extended to coordinate and conduct preclinical neuroprotection/pharmacotherapy trials in the SCI field. Apart from a few notable exceptions such as the NIH effort to replicate promising strategies, this field has been poorly coordinated. Only a small number of articles have even attempted an overall evaluation of the neuroprotective/pharmacotherapy agents used in preclinical SCI trials. There is no consensus about how to select the agents for translation to humans on the basis of their preclinical performance and according to agreed-upon preclinical performance criteria.

In the absence of such a system and to select the next agent for translation, the Consortium has developed a Treatment Strategy Selection Committee, and this committee selected the most promising 5 agents for potential translation. The results show that the preclinical work on these 5 agents has left numerous gaps in knowledge about their preclinical performance and confirm the need for significant changes in preclinical neuroprotection/pharmacotherapy trials in SCI. A recommendation is made for the development and validation of a preclinical scoring system involving worldwide experts in preclinical and clinical SCI.

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James S. Harrop, Robin Hashimoto, Dan Norvell, Annie Raich, Bizhan Aarabi, Robert G. Grossman, James D. Guest, Charles H. Tator, Jens Chapman and Michael G. Fehlings

Object

Using a systematic approach, the authors evaluated the current utilization, safety, and effectiveness of cellular therapies for traumatic spinal cord injuries (SCIs) in humans.

Methods

A systematic search and critical review of the literature published through mid-January 2012 was performed. Articles included in the search were restricted to the English language, studies with at least 10 patients, and those analyzing cellular therapies for traumatic SCI. Citations were evaluated for relevance using a priori criteria, and those that met the inclusion criteria were critically reviewed. Each article was then designated a level of evidence that was developed by the Oxford Centre for Evidence-Based Medicine.

Results

The initial literature search identified 651 relevant articles, which decreased to 350 after excluding case reports and reviews. Evaluation of articles at the title/abstract level, and later at the full-text level, limited the final article set to 12 papers. The following cellular therapies employed in humans with SCI are reviewed: bone marrow mesenchymal and hematopoietic stem cells (8 studies), olfactory ensheathing cells (2 studies), Schwann cells (1 study), and fetal neurogenic tissue (1 study). Overall the quality of the literature was very low, with 3 Grade III levels of evidence and 9 Grade IV studies.

Conclusions

Several different cellular-mediated strategies for adult SCI have been reported to be relatively safe with varying degrees of neurological recovery. However, the literature is of low quality and there is a need for improved preclinical studies and prospective, controlled clinical trials.

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Michael G. Fehlings, Neilank K. Jha, Stephanie M. Hewson, Eric M. Massicotte, Branko Kopjar and Sukhvinder Kalsi-Ryan

Object

Surgical intervention for appropriately selected patients with cervical spondylotic myelopathy (CSM) has demonstrated favorable outcomes. This study evaluates the cost-effectiveness of this type of surgery in terms of cost per quality-adjusted life year (QALY) gained.

Methods

As part of a larger prospective multicenter study, the direct costs of medical treatment for 70 patients undergoing surgery for CSM at a single institution in Canada were retrospectively obtained from the hospital expenses database and physician reimbursement data. Utilities were estimated on the entire sample of 278 subjects enrolled in the multicenter study using SF-6D–derived utilities from 12- and 24-month SF-36v2 follow-up information. Costs were analyzed from the payer perspective. A 10-year horizon with 3% discounting was applied to health-utilities estimates. Sensitivity analysis was performed by varying utility gain by 20%.

Results

The SF-6D utility gain was 0.0734 (95% CI 0.0557–0.0912, p < 0.01) at 12 months and remained unchanged at 24 months. The 10-year discounted QALY gain was 0.64. Direct costs of medical treatment were estimated at an average of CaD $21,066. The estimated cost-utility ratio was CaD $32,916 per QALY gained. The sensitivity analysis showed a range of CaD $27,326–$40,988 per QALY gained. These estimates are within the limits for medical procedures that have an acceptable cost-utility ratio.

Conclusions

Surgical treatment for CSM is associated with significant improvement in health utilities as measured by the SF-6D. The direct cost of medical treatment per QALY gained places this form of treatment within the category deemed by payers to be cost-effective.

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James Guest, James S. Harrop, Bizhan Aarabi, Robert G. Grossman, James W. Fawcett, Michael G. Fehlings and Charles H. Tator

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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Michael G. Fehlings and Aria Fallah

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Michael G. Fehlings and Jefferson R. Wilson

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Sheeraz Qureshi, Vadim Goz, Steven McAnany, Samuel K. Cho, Andrew C. Hecht, Rick B. Delamarter and Michael G. Fehlings

Object

Cost-effectiveness analysis (CEA) of medical interventions has become increasingly relevant to the discussion of optimization of care. The use of utility scales in CEA permits a quantitative assessment of effectiveness of a given intervention. There are no published utility values for degenerative disc disease (DDD) of the cervical spine, anterior cervical discectomy and fusion (ACDF), or cervical disc replacement (CDR). The purpose of this study was to define health utility values for those health states.

Methods

The 36-Item Short Form Health Survey data from the ProDisc-C investigational device exemption study were obtained for single-level DDD at baseline and 24 months postoperatively after ACDF or CDR procedures. Patients in the original study were randomized to either ACDF or CDR. Utilizing a commercially available Short Form–6 dimensions program, utility scores were calculated for each health state using a set of parametric preference weights obtained from a sample of the general population using the recognized valuation technique of standard gamble.

Results

The baseline health state utility (HSU) value for a patient with single-level DDD was 0.54 in both the ACDF and CDR groups. Postoperative changes in HSU values were seen in both intervention groups at 24 months. Cervical disc replacement had a HSU value of 0.72. Anterior cervical discectomy and fusion was found to have a postoperative utility state of 0.71. No statistically significant difference was found in the HSU for ACDF and CDR at 24 months of follow-up.

Conclusions

This study represents the first calculated HSU value for a patient with single-level cervical DDD. Additionally, 2 common treatment interventions for this disease state were assessed. Both treatments were found to have significant impact on the HSU values. These values are integral to future CEA of ACDF and CDR.

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George M. Ghobrial, Christopher M. Maulucci, Mitchell Maltenfort, Richard T. Dalyai, Alexander R. Vaccaro, Michael G. Fehlings, John Street, Paul M. Arnold and James S. Harrop

Object

Thoracolumbar spine injuries are commonly encountered in patients with trauma, accounting for almost 90% of all spinal fractures. Thoracolumbar burst fractures comprise a high percentage of these traumatic fractures (45%), and approximately half of the patients with this injury pattern are neurologically intact. However, a debate over complication rates associated with operative versus nonoperative management of various thoracolumbar fracture morphologies is ongoing, particularly concerning those patients presenting without a neurological deficit.

Methods

A MEDLINE search for pertinent literature published between 1966 and December 2013 was conducted by 2 authors (G.G. and R.D.), who used 2 broad search terms to maximize the initial pool of manuscripts for screening. These terms were “operative lumbar spine adverse events” and “nonoperative lumbar spine adverse events.”

Results

In an advanced MEDLINE search of the term “operative lumbar spine adverse events” on January 8, 2014, 1459 results were obtained. In a search of “nonoperative lumbar spine adverse events,” 150 results were obtained. After a review of all abstracts for relevance to traumatic thoracolumbar spinal injuries, 62 abstracts were reviewed for the “operative” group and 21 abstracts were reviewed for the “nonoperative” group. A total of 14 manuscripts that met inclusion criteria for the operative group and 5 manuscripts that met criteria for the nonoperative group were included.

There were a total of 919 and 436 patients in the operative and nonoperative treatment groups, respectively. There were no statistically significant differences between the groups with respect to age, sex, and length of stay. The mean ages were 43.17 years in the operative and 34.68 years in the nonoperative groups. The majority of patients in both groups were Frankel Grade E (342 and 319 in operative and nonoperative groups, respectively). Among the studies that reported the data, the mean length of stay was 14 days in the operative group and 20.75 in the nonoperative group.

The incidence of all complications in the operative and nonoperative groups was 300 (32.6%) and 21 (4.8%), respectively (p = 0.1065). There was no significant difference between the 2 groups with respect to the incidence of pulmonary, thromboembolic, cardiac, and gastrointestinal complications. However, the incidence of infections (pneumonia, urinary tract infection, wound infection, and sepsis) was significantly higher in the operative group (p = 0.000875). The incidence of instrumentation failure and need for revision surgery was 4.35% (40 of 919), a significant morbidity, and an event unique to the operative category (p = 0.00396).

Conclusions

Due to the limited number of high-quality studies, conclusions related to complication rates of operative and nonoperative management of thoracolumbar traumatic injuries cannot be definitively made. Further prospective, randomized studies of operative versus nonoperative management of thoracolumbar and lumbar spine trauma, with standardized definitions of complications and matched patient cohorts, will aid in properly defining the risk-benefit ratio of surgery for thoracolumbar spine fractures.

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Wai Pui Ng, Michael G. Fehlings, Brian Cuddy, Curtis Dickman, Mahmood Fazl, Barth Green, Patrick Hitchon, Bruce Northrup, Volker Sonntag, Frank Wagner and Charles H. Tator

Acute spinal cord injury (SCI) is a major public health problem for which there is still only limited treatment available. The National Acute Spinal Cord Injury Study-2 (NASCIS-2) and -3 clinical trials demonstrated that the use of acute pharmacotherapy with methylprednisolone can attenuate the secondary injury cascade if administered within 8 hours of acute SCI. However, no trial has been performed to examine whether acute surgical decompressive procedures within this critical 8-hour time window can improve patients' neurological outcome. The purpose of the current prospective Surgical Treatment for Acute Spinal Cord Injury Study (STASCIS) pilot study was to determine the feasibility of obtaining a radiological diagnosis of spinal canal compromise of 25% or more and to perform spinal cord (C3-T1) decompressive procedures by 8 hours postinjury. One of the following three decompressive methods was used: 1) traction alone; 2) traction and surgery; or 3) surgery alone. Twenty-six patients from eight North American centers were entered into the study between 1996 and 1997. Significant difficulties were encountered in many centers in performing immediate magnetic resonance imaging examination in patients with acute SCI. Fewer than 10% of acute cervical SCI patients could be enrolled into this protocol mainly because the combination of the required time for rescue, resuscitation, transport, imaging study, and surgical preparation exceeded the 8-hour injury-to-decompressive surgery window. Eleven patients underwent decompressive procedures initially by being placed in traction at a mean time of 10.9 hours postinjury. Those patients not undergoing this procedure underwent decompressive surgery at a mean time of 40.1 hours. However, the surgical decompressive procedure was completed within 12 hours in seven patients. As a result of these findings, several major changes have been made to the STASCIS protocol for early decompressive therapy.