Optimization of the decision-making process for the selection of therapeutics to undergo clinical testing for spinal cord injury in the North American Clinical Trials Network

2012 ◽  
Vol 17 (Suppl1) ◽  
pp. 94-101 ◽  
Author(s):  
James Guest ◽  
James S. Harrop ◽  
Bizhan Aarabi ◽  
Robert G. Grossman ◽  
James W. Fawcett ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Decision Making ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Clinical Trials ◽  
North American ◽  
Clinical Testing ◽  
Data Set ◽  
The North ◽  
Cord Injury

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.

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

2012 ◽  
Vol 17 (Suppl1) ◽  
pp. 6-10 ◽  
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.

scholarly journals RR14. Spinal Cord Injury after Hybrid Endovascular Repair of Thoracoabdominal Aortic Aneurysms in the North American Complex Abdominal Aortic Debranching (NACAAD) Registry

2012 ◽  
Vol 55 (6) ◽  
pp. 93S-94S ◽  
Author(s):  
Gustavo S. Oderich ◽  
Carlos Timaran ◽  
Mark Farber ◽  
William Quinones-Baldrich ◽  
Guillermo Escobar ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Endovascular Repair ◽  
North American ◽  
Aortic Aneurysms ◽  
The North ◽  
Abdominal Aortic ◽  
Cord Injury

scholarly journals Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP Panel: clinical trial inclusion/exclusion criteria and ethics

Spinal Cord ◽  
2006 ◽  
Vol 45 (3) ◽  
pp. 222-231 ◽  
Author(s):  
M H Tuszynski ◽  
J D Steeves ◽  
J W Fawcett ◽  
D Lammertse ◽  
M Kalichman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Clinical Trials ◽  
Exclusion Criteria ◽  
Cord Injury

Incidence and severity of acute complications after spinal cord injury

2012 ◽  
Vol 17 (Suppl1) ◽  
pp. 119-128 ◽  
Author(s):  
Robert G. Grossman ◽  
Ralph F. Frankowski ◽  
Keith D. Burau ◽  
Elizabeth G. Toups ◽  
John W. Crommett ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Clinical Trials ◽  
Motor Vehicle ◽  
Spinal Injury ◽  
Vehicle Accidents ◽  
The North ◽  
Treatment And Prevention ◽  
Cord Injury ◽  
Study Population

Object The aim of this multicenter, prospective study was to determine the spectrum, incidence, and severity of complications during the initial hospitalization of patients with spinal cord injury. Methods The study was conducted at 9 university-affiliated hospitals that comprise the clinical centers of the North American Clinical Trials Network (NACTN) for Treatment of Spinal Cord Injury. The study population comprised 315 patients admitted to NACTN clinical centers between June 25, 2005, and November 2, 2010, who had American Spinal Injury Association (ASIA) Impairment Scale grades of A–D and were 18 years of age or older. Patients were managed according to a standardized protocol. Results The study population was 79% male with a median age of 44 years. The leading causes of injury were falls (37%) and motor vehicle accidents (28%). The distribution of initial ASIA grades were A (40%), B (16%), C (15%), and D (29%). Fifty-eight percent of patients sustained 1 or more severe, moderate, or mild complications. Complications were associated with more severe ASIA grade: 84% of patients with Grade A and 25% of patients with Grade D had at least 1 complication. Seventy-eight percent of complications occurred within 14 days of injury. The most frequent types of severe and moderate complications were respiratory failure, pneumonia, pleural effusion, anemia, cardiac dysrhythmia, and severe bradycardia. The mortality rate was 3.5% and was associated with increased age and preexisting morbidity. Conclusions Knowledge of the type, frequency, time of occurrence, and severity of specific complications that occur after spinal cord injury can aid in their early detection, treatment, and prevention. The data are of importance in evaluating and selecting therapy for clinical trials.

Pharmacology of riluzole in acute spinal cord injury

2012 ◽  
Vol 17 (Suppl1) ◽  
pp. 129-140 ◽  
Author(s):  
Diana S. L. Chow ◽  
Yang Teng ◽  
Elizabeth G. Toups ◽  
Bizhan Aarabi ◽  
James S. Harrop ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Clinical Trials ◽  
Phase 1 ◽  
Volume Of Distribution ◽  
Plasma Samples ◽  
Phase 1 Clinical Trial ◽  
Cord Injury ◽  
Als Patients

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.

scholarly journals Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial outcome measures

Spinal Cord ◽  
2006 ◽  
Vol 45 (3) ◽  
pp. 206-221 ◽  
Author(s):  
J D Steeves ◽  
D Lammertse ◽  
A Curt ◽  
J W Fawcett ◽  
M H Tuszynski ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Clinical Trials ◽  
Outcome Measures ◽  
Trial Outcome ◽  
Clinical Trial Outcome ◽  
Cord Injury
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