See the corresponding editorial in this issue, pp 4 5. J Neurosurg Spine (Suppl) 17:6 10, 2012

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1 See the corresponding editorial in this issue, pp 4 5. J Neurosurg Spine (Suppl) 17:6 10, 2012 North American Clinical Trials Network for the Treatment of Spinal Cord Injury: goals and progress Robert G. Grossman, M.D., 1 Elizabeth G. Toups, M.Sc., 1 Ralph F. Frankowski, Ph.D., 2 Keith D. Burau, Ph.D., 2 and Susan Howley, B.A. 3 1 Department of Neurosurgery, The Methodist Hospital; 2 Division of Biostatistics, University of Texas School of Public Health, Houston, Texas; and 3 Christopher Reeve Foundation, Short Hills, New Jersey 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. ( Key Words Spinal Cord Injury Clinical Trials Spinal Cord Injury Registry spinal cord injury complication The NACTN is a consortium of 10 clinical centers composed of neurosurgery department faculty and staff caring for patients with SCIs at university-affiliated hospitals, a Data Management Center, and a Pharmacological Center. The network was established in 2004 to bring basic discoveries in neuroprotection and regeneration to clinical trials and practice. An increasing number of CTNs have been established to accelerate the development of new therapies for many diseases. Clinical Trials Networks Best Practices ( Abbreviations used in this paper: AIS = American Spinal Injury Association Impairment Scale; ASIA = American Spinal Injury Association; CTN = Clinical Trials Network; DMC = Data Management Center; NACTN = North American Clinical Trials Network; SCI = spinal cord injury; SCIM = Spinal Cord Independence Measure. org) is a database with a current listing of over 300 CTNs. The NACTN is listed on this site and on ClinicalTrials. gov ( rm=nactn&recr=open&cond=spinal+cord+injury&ra nk=1). It is the only standing CTN for SCI in North America. It was established with the support of the Christopher Reeve Foundation, which is its sponsoring organization, and since 2006 has been supported by the Telemedicine & Advanced Technology Research Center, US Army Medical Research and Materiel Command. Each NACTN center has one or more principal investigators, and each clinical center has a study coordinator, usually a nurse practitioner, and research assistants. The centers and their principal investigators are listed in the Appendix. The NACTN will add additional clinical centers to conduct specific trials and to achieve wider geographic representation. 6 J Neurosurg: Spine / Volume 17 / September 2012

2 North American Clinical Trials Network NACTN Goals As the NACTN developed, it addressed the major requirements of conducting trials of therapy in SCI. These requirements are as follows: 1) organizing a multicenter network of hospitals capable of enrolling a sufficient number of patients with SCI for conducting Phase I, II, and III studies in 2 3 years of patient enrollment and establishing governance policies and procedures, committees, and a system of communications among centers; 2) creating a Data Management Center (DMC) and a database of the natural history of recovery after SCI, from the time of injury through the multiple stages of repair as a prior control group for evaluating the efficacy of new therapies; 3) creating a database of the incidence and severity of medical and surgical complications that occur during acute and subacute treatment after SCI as a prior control group for evaluating the safety of new therapies; 4) developing sensitive quantitative measures of motor, sensory, and autonomic outcomes; 5) developing standards to evaluate the suitability and feasibility of translating new, basic pharmacological and cell-based discoveries into clinical trials; 6) creating an efficient mechanism to develop the designs and write the protocols for clinical trials of a new therapy; and 7) developing a Pharmacological Center with the ability to perform pharmacokinetic and pharmacodynamic studies of therapeutic drugs. Progress Toward Reaching Goals We here describe the steps that NACTN has taken to reach its goal of addressing the major requirements of conducting clinical trials of new therapies in SCI. Building the network of centers has been accomplished and is described in a chapter in Essentials of Spinal Cord Injury. 1 The NACTN has created a database of the natural history of patients with SCI: the NACTN SCI Registry of the DMC. As of December 31, 2011, 485 patients were enrolled in the SCI Registry. Much of the data presented in the current issue of the Journal of Neurosurgery: Spine is from the DMC registry. The DMC serves two purposes. The first is to provide a statistical and scientific platform to develop the data, logistics, and collaborations necessary to conduct Phase I III clinical trials of emerging neuroprotective and neuroregenerative therapies, especially those that can be administered in the very early stages of injury. A second and equally important purpose is to develop high-quality, standardized, and validated acute care and follow-up data on a representative national sample of adult male and female patients who have suffered an SCI with neurological deficits. These acute care and follow-up data are a unique resource needed to characterize the trajectory (natural history) of individuals who have suffered an SCI. All data are prospectively collected starting at the time of admission to an NACTN clinical center. The registry data include extensive demographic information, medical history, preinjury medication use, circumstances of injury, time of injury, and the time of arrival to the treating NACTN hospital. On admission further details are elicited about the patient s condition by performing a clinical evaluation and by measuring J Neurosurg: Spine / Volume 17 / September 2012 the state of consciousness, based on the Glasgow Coma Scale, and associated injuries, based on the Abbreviated Injury Scale. The ASIA Impairment Scale (AIS) is scored on admission and at key times throughout a patient s hospital and posthospital course. All examiners received training to perform the ASIA examinations and study procedures. Two sessions were held at the University of Louisville Clinical Center to train both the principal investigators and the study coordinators for each center. Physicians and physiotherapists experienced in performing ASIA evaluations supervised the training as well as the actual examination of volunteers (patients with SCI) and checked the results of the examination. Training on study procedures was also provided by the coordinating center. Data on radiographic findings, nonoperative and operative treatments, timing of treatments, and perioperative complications are also collected. The discharge AIS score and the type of facility to which the patient is transferred are recorded. After acute care discharge, long-term follow-up is scheduled at 6 and 12 months. The follow-up registry protocol includes the AIS and, when appropriate, the Functional Independence Measure, Spinal Cord Independence Measure (SCIM), and the Walking Index for Spinal Cord Injury evaluations. As of December 31, 2011, there were 485 completed acute care records in the registry database with an additional 36 acute care records in process. The database also contains 3-, 6-, or 12-month follow-up data for 438 registry patients. Below we summarize the current registry database information for 485 patients with SCI. The majority of registry cases are male (79%) and white (76%), and the median age at injury is 44 years for all registry patients (Table 1). The leading circumstances of injury were falls (37%) and motor vehicle accidents (31%; Table 1). Recreation accidents including sports accounted for 11% of injuries, and diving was responsible for 58% of all sports injuries. Civilian assaults accounted for 5% of all SCIs. For all registry cases, the median arrival time for 58% of injured patients directly to an NACTN center from the scene of injury was approximately 1 hour. For patients transferred from intermediate hospitals, the median arrival time postinjury to an NACTN center was 9.3 hours. The distribution of AIS grades among 410 patients with a score within 7 days of injury is bimodal, with AIS Grade A at 31.1% and AIS Grade D at 24.5%. The majority of SCIs were closed (95%), although 4% were penetrating, primarily bullet injuries. Among the 485 patients, 76% sustained cervical injuries and 18% thoracic injuries (Table 1). Approximately half of all patients with AIS Grades A through D received steroids during acute care. Fiftyfive percent of all patients received both steroid and surgical treatments. Surgeries by AIS Grades A D are reported in Table 2: 91% were surgically treated. The AIS grades were not obtained for a small number of patients, depending on the interval between injury and admission to an NACTN hospital and on the patient s medical condition and ability to cooperate for the examination. Thirty-six patients with spinal column injuries with minor or questionable 7

3 R. G. Grossman et al. TABLE 1: Summary of characteristics in 485 patients with SCI* Characteristic No. (%) sex M 387 (79.8) F 98 (20.2) age in yrs <20 31 (6.4) (80.4) >65 64 (13.2) race white 363 (74.8) other 122 (25.2) circumstance of injury fall 181 (37.3) MVA 151 (31.1) recreation 54 (11.1) motorcycle 42 (8.7) assault 26 (5.4) other 20 (4.1) military 11 (2.3) injury type closed 459 (94.7) penetrating 19 (3.9) other 7 (1.4) injury region cervical 367 (75.7) thoracic 88 (18.1) lumbar/sacral 27 (5.6) SCIWORA 3 (0.6) * MVA = motor vehicle accident; SCIWORA = SCI without radiographic abnormality. Median age at injury 44 years. neurological deficits, AIS Grade E, were entered into the registry and have been kept in the database to compare their clinical course with patients with AIS Grades A D. Surgeries were performed early in the course of treatment, with half of the patients undergoing operation within 35 hours of injury. For patients arriving at an NACTN center without any intermediate hospital transfer, the median time to surgery was 29 hours, and 90% underwent surgery within 5 days of injury. For 367 patients with postsurgery MRI studies, decompression was confirmed in 82%. The duration of acute care hospitalization and discharge status are summarized in Table 3. For 485 patients with SCI, approximately 44% had a hospital stay exceeding 2 weeks. For patients with an AIS Grade A, the median hospital stay during acute care was 19 days; Grade B, 18 days; Grade C, 12 days; Grade D, 11 days; and Grade E, 6 days. Rehabilitation was initiated for 84% of the patients prior to discharge from acute care. More than two-thirds of the patients were discharged to a rehabilitation hospital (69%), and about 6% were transitioned TABLE 2: Spinal surgeries by AIS grade No. of Patients AIS Grade* Posterior Anterior Both None Total A B C D not obtained total * Grade obtained within 7 days of surgery. to either long-term care or a nursing home. Forty-seven patients were discharged as either partially or completely dependent on a ventilator. Table 4 compares AIS grades within 7 days of injury with AIS grades at hospital discharge in 359 patients. It is notable that 88% of patients with an AIS Grade A within 7 days of injury remained at that level at discharge. Although there was improvement within each AIS grade, the improvement was modest. Table 5 summarizes indoor mobility outcomes postinjury based on the SCIM scores obtained in 260 patients at 6 or 12 months postinjury. The SCIM mobility scores are reported by AIS grades obtained within 7 days of injury and differentiates between patients who are unable to walk or who need assistance while walking (SCIM Scores 0 3) and those able to walk independently (SCIM Scores 4 8). Overall, 76 (61%) of the 260 patients regained some ambulation, and clearly ambulation recovery is significantly associated with the initial AIS grade of the SCI. We use the NACTN registry data to determine the incidence and severity of complications that occur during acute and subacute treatment to predict outcomes in individual patients and as a guide for the prevention of complications. A complication was defined as a change in a patient s physiological state or anatomical integrity that requires medical or surgical treatment and/or prolongs the patient s hospitalization. The NACTN principal investigators and clinical coordinators ascertained the oc- TABLE 3: Hospital stay and acute care discharge in 485 patients* Parameter No. (%) hospital LOS (days) <8 128 (26.4) (29.1) (16.3) > (28.2) discharge status rehab hospital 338 (68.6) home care 98 (22.2) nursing home 16 (3.5) long-term care 15 (2.0) in-hospital death 18 (3.7) * LOS = length of stay; rehab = rehabilitation. 8 J Neurosurg: Spine / Volume 17 / September 2012

4 North American Clinical Trials Network TABLE 4: The AIS severity conversion: initial versus acute care discharge AIS Grade at Discharge Initial AIS Grade* A B C D E Total A B C D total * Grade obtained within 7 days of injury. Grade obtained within 14 days of acute care discharge. currence of complications by examining the patient and reviewing the patient s electronic medical record and/ or chart. Complications were categorized as functional disturbances in the following organs or systems: pulmonary, hematological, cardiac, skin, gastrointestinal, and genitourinary. Systemic categories were neuropsychiatric disorders, infections, and death. A picture of the overall distribution of the type, frequency, and incidence of complications for 485 patients is featured in Table 6. Note that the category of infection includes pneumonia, which is by far the most common infection. Further analysis of pulmonary complications is provided in the current issue by Aarabi et al. ( Predictors of pulmonary complications in blunt traumatic spinal cord injury ). The incidence rate of death was 3.7% for the entire group; however, the incidence for patients with AIS Grade A was 8.7% (see article by Grossman et al. in this issue, Incidence and severity of acute complications after spinal cord injury ). Developing sensitive, quantitative measures of motor, sensory, and autonomic outcomes is arguably the most important problem to be solved to obtain meaningful, reproducible outcome data for valid clinical trials. For this purpose the NACTN established a Neurological Outcomes Assessment Task Force, led by Dr. Susan Harkema. Progress toward this goal is reflected in the article by Kun Li et al., Quantitative and sensitive assessment of neurophysiological status after human spinal cord injury, and the article by Boakye et al., Quantitative testing in spinal cord injury: overview of reliability and predictive validity. The development of MRI to obtain surrogate TABLE 5: Spinal Cord Independence Measure, indoor mobility AIS Grade* Able to Walk Independently No. (%) Unable to Walk Independently J Neurosurg: Spine / Volume 17 / September 2012 Total A 1 (1.3) 77 (98.7) 78 B 2 (5.7) 33 (94.3) 35 C 7 (22.6) 24 (77.4) 31 D 48 (49.0) 50 (51.0) 98 E 18 (100.0) 0 (0) 18 total 76 (61) 184 (39) 260 * First grade obtained within 7 days of injury. TABLE 6: Acute care complications: type, frequency, and incidence* Complication Type Frequency (%) Incidence Rate (%) pulmonary 348 (25.3) 36.7 infection 285 (20.7) 33.2 hematology 213 (15.5) 26.6 cardiac 178 (12.9) 25.6 GI/GU 115 (8.4) 17.1 skin 113 (8.2) 16.7 neuropsychiatric 106 (7.7) 19.2 death 18 (1.3) 3.7 * There were 1376 total complications. Abbreviations: GI = gastrointestinal; GU = genitourinary. measures of outcome is reflected in the article by Cadotte et al., A systematic review of spinal fmri research: outlining the elements of experimental design. Prediction of functional outcomes based on neurological and physiological measurements made early in the course of the patient s hospitalization has been another of the NACTN s goals, reflected in the article by Wilson et al., Clinical predictors of neurological outcome, functional status, and survival after traumatic spinal cord injury: a systematic review. To develop standards to evaluate the suitability of translating new pharmacological and cell-based therapies into clinical trials, the NACTN has established a Treatment Strategy Selection Committee, led by Dr. Charles Tator. The deliberations of this committee are reflected in the current issue in the articles by Tator et al. ( Translational potential of preclinical trials of neuroprotection through pharmacotherapy for spinal cord injury ), Harrop et al. ( Evaluation of clinical experience using cellbased therapies in patients with spinal cord injury: a systematic review ), and Guest et al. ( 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 ). The network designed, wrote the protocol for, and initiated its first Phase I clinical trial of a new therapy, riluzole, as a neuroprotective drug. Enrollment of the planned 36 patients has been completed, and the data are being analyzed. The process of planning and executing the trial is detailed in Riluzole for the treatment of acute traumatic spinal cord injury: rationale for and design of the NACTN Phase I clinical trial by Fehlings et al. Performing pharmacological studies of the drugs undergoing trial has been established and is reflected in the article by Chow et al., Pharmacology of riluzole in acute spinal cord injury. Conclusions By addressing the requirements of conducting SCI trials, the NACTN is now prepared to undertake a Phase II trial of riluzole as a neuroprotective agent. The network brings to the trial a large database of the trajectory of recovery from SCI; a database of medical and surgical 9

5 R. G. Grossman et al. complications to be expected during the acute phase of recovery from SCI; experience in trial design and data management; new quantitative measures of motor, sensory, and autonomic outcome; and pharmacokinetic and pharmacodynamic measurements of the therapeutic agent. Appendix NACTN Centers and Investigators Clinical Centers The Methodist Hospital, Houston Coordinating Center Principal Investigator, Robert G. Grossman, M.D. Clinical Trials Manager, Elizabeth Toups, M.Sc., R.N., C.C.R.P. The University of Texas Memorial Hermann Hospital, Houston Investigator, Michele Johnson, M.D. University of Virginia, Charlottesville Investigators, Christopher I. Shaffrey, M.D., and John Jane Sr., M.D., Ph.D. University of Toronto, Toronto Investigators, Michael Fehlings, M.D., Ph.D., and Charles Ta tor, M.D., Ph.D. University of Louisville, Louisville Investigators, Maxwell Boakye, M.D., Susan Harkema, Ph.D., and Jonathan Hodes, M.D. University of Maryland, Baltimore Investigator, Bizhan Aarabi, M.D. Walter Reed National Military Medical Center, Bethesda Investigator, Michael Rosner, M.D. University of Miami, Miami Investigator, James Guest, M.D., Ph.D. Thomas Jefferson University, Philadelphia Investigator, James Harrop, M.D. Brooke Army Medical Center, San Antonio Investigator, Robert Marsh, M.D., Ph.D. Data Management Center The University of Texas School of Public Health, Houston Investigators, Ralph Frankowski, Ph.D., and Keith Burau, Ph.D. Pharmacological Center University of Houston, College of Pharmacy, Houston Investigator, Diana Chow, Ph.D. Disclosure The Christopher and Dana Reeve Foundation sponsored this study, and the Telemedicine & Advanced Technology Research Center, US Army Medical Research and Materiel Command supported this study through Grant Nos. W81XWH and W81XWH Author contributions to the study and manuscript preparation include the following. Conception and design: Grossman, Toups, Frankowski, Burau. Acquisition of data: Grossman, Frankowski, Burau. Analysis and interpretation of data: Grossman, Frankowski, Burau. Drafting the article: Grossman. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Grossman. Statistical analysis: Frankowski, Burau. Administrative/ technical/material support: Grossman, Toups. Study supervision: Grossman. Reference 1. Grossman RG, Toups EG, Frankowski R, Burau K, Howley S: NACTN: building a clinical trials network for spinal cord injury, in Fehlings M, Vaccaro A, Boakye M, et al (eds): Essentials of Spinal Cord Injury. New York: Thieme [in press], 2012 Manuscript submitted January 26, Accepted April 24, Please include this information when citing this paper: DOI: / AOSPINE1294. Address correspondence to: Robert G. Grossman, M.D., Department of Neurosurgery, The Methodist Hospital, 6560 Fannin, Suite 944, Houston, Texas rgrossman@tmhs.org. 10 J Neurosurg: Spine / Volume 17 / September 2012