Cervical spinal cord injury: tailoring clinical trial endpoints to re flect meaningful functional improvements

Lisa M. Bond, Lisa McKerracher

1 McGill University, Department of Neurology and Neurosurgery, Montreal, Quebec, Canada

2 BioAxone BioSciences, Inc., Cambridge, MA, USA

Cervical spinal cord injury: tailoring clinical trial endpoints to re flect meaningful functional improvements

Lisa M. Bond2, Lisa McKerracher1,2

1 McGill University, Department of Neurology and Neurosurgery, Montreal, Quebec, Canada

2 BioAxone BioSciences, Inc., Cambridge, MA, USA

Cervical spinal cord injury (SCI) results in partial to full paralysis of the upper and lower extremities. Traditional primary endpoints for acute SCI clinical trials are too broad to assess functional recovery in cervical subjects, raising the possibility of false positive outcomes in trials for cervical SCI. Endpoints focused on the recovery of hand and arm control (e.g.,upper extremity motor score, motor level change) show the most potential for use as primary outcomes in upcoming trials of cervical SCI. As the field moves forward, the most reliable way to ensure meaningful clinical testing in cervical subjects may be the development of a composite primary endpoint that measures both neurological recovery and functional improvement.

spinal cord injury; SCI; cervical; clinical trial; endpoint; Cethrin; UEMS

Bond LM, McKerracher L. Cervical spinal cord injury： tailoring clinical trial endpoints to reflect meaningful functional improvements. Neural Regen Res. 2014;9(16)：1493-1497.

Introduction

Acute spinal cord injury (SCI) is a serious unmet medical need. A traumatic lesion to the spinal cord results in sensory and motor impairment below the level of the injury and spontaneous recovery is very limited in neurologically complete injuries (Fawcett et al., 2007). Cervical SCI, the most devastating and most common type of SCI (Grossman et al., 2012), leaves individuals with impaired or absent function of the upper extremities (arms and hands) in addition to the lower body paralysis seen after thoracic/lumbar/sacral SCI.ere are no approved drugs to foster repair aer SCI, despite numerous preclinical studies showing the promise of regenerative medicine (Hollis and Tuszynski, 2011; Liu et al., 2011; Filli and Schwab, 2012; Dickendesher et al., 2013; Watzlawick et al., 2014).

Unlike other neurotrauma indications, there have been few clinical trials in SCI, and only very recent trials have focused exclusively on cervical SCI (NCT01828203, NCT01502631, NCT01597518). Clinical trials have traditionally used the International Standards for the Neurological Classification of Spinal Cord Injury (ISNCSCI) to broadly track motor/ sensory changes in subjects after injury (Ditunno et al., 2005).e most common primary endpoints derived from this neurological assessment are American Spinal Injury Association (ASIA) Impairment Scale conversion and total motor score.ese broad endpoints have limited value for the assessment of recovery after cervical injury, as conversion between grades or change in total motor score may occur without signi fi cant change in arm and hand control, an area of critical importance to individuals living with quadriplegia aer cervical SCI (Anderson, 2004).

As the number of compounds entering late-stage clinical testing for SCI grows, the selection of meaningful primary endpoints for the evaluation of recovery aer cervical injury becomes increasingly important. At present, two endpoints used in retrospective analyses of previous studies show the most promise: (1) Upper extremity motor score (UEMS) and (2) motor level change. These endpoints better reflect meaningful recovery in the arms and hands, but can still fail to distinguish functional benefit. For example, very small changes in multiple muscle groups may produce the same overall increase in UEMS score as a more bene fi cial, full recovery in fewer muscle groups. As the fi eld moves forward, the development of a composite endpoint directly sensitive to both neurological recovery and functional improvement may permit a more meaningful evaluation of drugs for acute cervical SCI.

SCI

Traumatic SCI is a global problem. A SCI can instantly transform an otherwise healthy individual into a person facing a lifetime of disability, and more than 175,000 spinal cord injuries occur globally every year (Lee et al., 2014). In the United States, approximately 12,000 individuals suffer SCIs each year, most commonly from motor vehicle accidents or falls (NSCISC, 2013). Approximately 57-75% of U.S. SCIs are cervical (Grossman et al., 2012; Selvarajah et al., 2014), and complete cervical SCI leads to lifelong quadriplegia (Fawcettet al., 2007). Individuals with SCI also su ff er comorbidities, including autonomic dysre flexia, bladder dysfunction, muscle spasticity, and chronic pain (Krassioukov et al., 2003).e combination of these medical complications and corresponding challenges for personal autonomy and community involvement lead individuals with SCI to consistently report a lower quality of life than the nondisabled community (Dijkers, 1997).ere are currently no approved treatments to reduce paralysis and improve daily function aer SCI.

Limitations of traditional endpoints for evaluation of cervical SCI

Total motor score (TMS)measures contraction strength in fi ve upper body muscle groups and fi ve lower body muscle groups on either side of the body from 0 (total paralysis) to 5 (normal movement), for a total possible score of 100.e score does not weigh muscle groups by their functional potential or assess the functional value of a score increase. Clinical trial participants could therefore achieve a significant, 20 point improvement in total motor score over placebo in the year following injury due to an isolated recovery from paralysis (0) to normal function (5) in both ankle dorsi flexors and in both knee extensors. A subject could also increase 20 points by improving from full paralysis (0) to active movementwith gravity eliminated(2) in all ten leg/foot muscle groups, a change offering similarly limited to nonexistent functional bene fi t for a quadriplegic individual.e use of a TMS endpoint could thus result in a false positive outcome in a clinical trial for cervical SCI, based on isolated large increases or widely dispersed small increases in lower body muscle groups.

The ASIA Impairment Scaleranks impairment according to body-wide ISNCSCI motor/sensory results, from AIS A (complete paralysis, no motor or sensory function below the level of the injury) to AIS B (complete motor paralysis, sensory function below injury level), AIS C (incomplete motor paralysis, more than half of key muscles below injury level score ＜ 3), AIS D (incomplete motor paralysis, more than half of key muscles below injury level score ≥ 3), or AIS E (normal motor and sensory function). Transitions to higher AIS grades may similarly lack association with functional independence. For example, a two grade transition from AIS A to AIS C, generally regarded as a meaningful clinical outcome, could be due simply to an increase in sensation and the regain in normal control of one large toe (e.g.,extensor hallucis longus: 0 to 5).

Both TMS and AIS grade can thus improve based on isolated or widely dispersed increases in lower body control.ough subtle changes in lower body control can hold meaning for individuals with an incomplete SCI or those with paraplegia from a thoracic injury, these changes may have little functional value for an individual with quadriplegia from a cervical SCI. In addition, such changes may simply reflect an incorrect classification of complete paralysis rather than incomplete paralysis during initial baseline measurements.e reliability of baseline measurements is a particular concern in trials of neuroprotective drugs that must be given within 12 hours of injury (Tadie et al., 2003; Casha et al., 2012; Grossman et al., 2014), as baseline assessments for these trials must be conducted while the spinal cord is still in a state of spinal shock (Ditunno et al., 2005). Overall, TMS and AIS conversion are unreliable outcome measures for assessing functional recovery in cervical subjects.

The limitations of these endpoints must be considered with particular care when designing or evaluating trials for drug repositioning, as primary endpoint analysis and scienti fi c reporting in these trials may result in recommendations without the same robust regulatory oversight ensured during the approval process for a new drug. The clinical trial of methylprednisolone as a repositioned treatment for SCI reported total motor score recovery and remains controversial today (Bracken, 2001; Tator, 2006). More recent SCI clinical trials for drug repositioning have also reported primary analyses of total motor score and/or AIS conversion (e.g.,the minocycline trial (Casha et al., 2012) and the riluzole trial (Grossman et al., 2014)).e need for standardized reporting of functionally meaningful endpoints in such trials is of critical importance for the evaluation of repositioned therapeutics for cervical SCI.

Meaningful endpoints for the evaluation of neurological recovery after cervical SCI

Upper extremity motor score (UEMS)measures contraction strength in fi ve key arm and hand muscle groups on either side of the body from 0 (total paralysis) to 5 (active movement), for a maximal possible score of 50. UEMS correlates more closely than total motor score or lower extremity motor score with improvements in self-care and mobility measured by the Functional Independence Measure (FIM) (Marino and Graves, 2004). Increases in UEMS also corresponddirectly to improvements in functional activities of daily living and self-care measured with the Spinal Cord Independence Measure (SCIM) (Kramer et al., 2012). Furthermore, individuals with a higher UEMS have an increased capacity for self-feeding, as measured by the Quadriplegia Index of Function (QIF) (Marino et al., 1995).

As more compounds move into later-stage clinical trials for SCI, the importance of evaluating cervical subjects based on such functionally meaningful primary endpoints must be emphasized. To date, only one trial including acute cervical SCI subjects has selected a primary endpoint with the capacity to measure functional arm and hand recovery (NCT01502631, ≥ 2 motor level recovery). Standardized reporting of a primary UEMS endpoint in future SCI clinical trials will allow assessment of meaningful recovery in cervical subjects and facilitate comparative analyses of drug efficacy between trials. Such reporting will be particularly important for repositioned drug trials, where presented analyses of UEMS recovery have previously been secondary or absent (Bracken et al., 1997; Casha et al., 2012; Grossman et al., 2014).

Meaningful endpoint selection in the phase II/III trial of Cethrin for cervical SCI

The biologic drug Cethrin is a Rho antagonist designed to promote neuroregeneration and neuroprotection when delivered as a topical adjunct to decompression surgery after SCI (McKerracher and Guertin, 2013). An open-label, phase I/IIa trial demonstrated that Cethrin was well-tolerated, and o ff ered a preliminary assessment of e ffi cacy on the traditional SCI endpoints of AIS grade and total motor score (Fehlings et al., 2011).ough improvements by Cethrin-treated cervical subjects on these endpoints were promising (McK-erracher and Anderson, 2013), it is clear that an increase in AIS grade conversion or total motor score may not signify improved daily function.

To permit a more meaningful assessment of phase I/IIa Cethrin trial results, the original ISNCSCI assessment data was recently re-analyzed on the endpoint of upper extremity motor score (McKerracher and Anderson, 2013). During the fi rst year aer injury, the sixteen Cethrin-treated cervical subjects in all fi ve tested dose groups (0.3, 1, 3, 6, 9 mg) improved an average of 12.2 ± 2.6 points in UEMS from a baseline of complete paralysis (Figure 1).e nine cervical subjects in the three highest dose groups (3, 6, and 9 mg) demonstrated an average UEMS recovery of 14 ± 2.4 points. These improvements would confer functional benefit over the expected spontaneous recovery of 8.8 ± 0.5 points (Model Systems (Marino et al., 2011)) to 9.6 ± 0.4 points (Sygen database (Steeves et al., 2011)) seen in historical cervical individuals with complete paralysis. Even a two point improvement in UEMS recovery can result in increases in hand and arm strength with a tremendous functional impact for subjects with cervical SCI (Steeves et al., 2012).

Developing a composite endpoint for cervical SCI

With an overall goal of determining the functional bene fi t of a trial therapeutic for cervical SCI, the natural complement to selecting an appropriate neurological assessment is the additional use of a direct test to measure functional ability. Tests of functional independence, such as FIM and, more recently, SCIM, have been incorporated as secondary endpoints in SCI clinical trials ((Bracken et al., 1997; Casha et al., 2012), NCT01828203). However, these tests are unsuited for independent use as primary endpoints for cervical SCI, as improvement in a specific category may reflect external factors/rehabilitation, rather than drug-based improvements in body control. For example, a cervical subject could advance in the dressing category of SCIM from a score of (1) (requiring partial assistance with clothing without buttons, zippers, or laces) to a score of (2) (independent with clothing without buttons, zippers, or laces; requires adaptive devices and/or speci fi c settings) by acquiring a relevant adaptive device.

Figure 1 Upper extremity motor score (UEMS): Phase I/IIa Cethrin trial datavs.historical results.

Conclusions

Traditional primary endpoints for acute SCI clinical trials do not adequately assess functional recovery in cervical subjects, raising the possibility of false positive outcomes in trials for cervical SCI. Endpoints focused on the recovery of hand/arm control (UEMS, motor level change) show the most potential for use as primary outcomes for cervical SCI in the immediate future. Selection of the upper extremity motor score as the primary endpoint for the upcoming phase II/III trial of Cethrin will set the tone for the use of this endpoint in clinical development programs. The most reliable way to ensure meaningful clinical testing in acute cervical SCI may be the development of a composite primary endpoint that directly measures both neurological recovery and functional improvement.

Acknowledgments:The authors would like to thank Dr. Kim Anderson-Erisman (Miami Project to Cure Paralysis; University of Miami, USA) for her helpful comments on the manuscript. We are also grateful to Dr. John Ditunno and Dr. Ralph Marino of Thomas Jefferson University for useful discussions on SCI trial endpoints.

Author statements:The intellectual property for Cethrin is owned by BioAxone BioSciences, Inc. Dr. McKerracher L is the inventor of Cethrin and the Founder and CEO of BioAxone Bio-Sciences. Dr. Bond LM is the Director of Scientific and Regulatory Affairs at BioAxone. The authors thus have commercial and proprietary interests in Cethrin.

Anderson KD (2004) Targeting recovery: priorities of the spinal cord-injured population. J Neurotrauma 21:1371-1383.

Bracken MB (2001) Methylprednisolone and acute spinal cord injury: an update of the randomized evidence. Spine 26:S47-54.

Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, Fehlings M, Herr DL, Hitchon PW, Marshall LF, Nockels RP, Pascale V, Perot PL, Jr., Piepmeier J, Sonntag VK, Wagner F, Wilberger JE, Winn HR, Young W (1997) Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA 277:1597-1604.

Casha S, Zygun D, McGowan MD, Bains I, Yong VW, Hurlbert RJ (2012) Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. Brain 135:1224-1236.

Cutter GR, Baier ML, Rudick RA, Cookfair DL, Fischer JS, Petkau J, Syndulko K, Weinshenker BG, Antel JP, Confavreux C, Ellison GW, Lublin F, Miller AE, Rao SM, Reingold S, Thompson A, Willoughby E (1999) Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain 122:871-882.

Dickendesher TL, Duan Y, Giger RJ (2013) Chapter 8: Axon Regeneration. Cellullar Migration and Formation of Neuronal Connections. Academic Press 2:151-176.

Dijkers M (1997) Quality of life after spinal cord injury: a meta analysis of the effects of disablement components. Spinal Cord 35:829-840.

Ditunno JF, Jr., Burns AS, Marino RJ (2005) Neurological and functional capacity outcome measures: essential to spinal cord injury clinical trials. J Rehabil Res Dev 42:35-41.

Elm JJ, Investigators NN-P (2012) Design innovations and baseline findings in a long-term Parkinson’s trial: the National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson’s Disease Long-Term Study-1. Mov Disord 27:1513-1521.

Fawcett J, Curt A, Steeves J, Coleman W, Tuszynski M, Lammertse D, Bartlett P, Blight A, Dietz V, Ditunno J (2007) Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord 45:190-205.

Fehlings M, Theodore N, Harrop J, Maurais G, Kuntz C, Shaffrey CI, Kwon BK, Chapman JR, Yee A, Tighe A, McKerracher L (2011) A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury. J Neurotrauma 28:787-796.

Filli L, Schwab ME (2012) The rocky road to translation in spinal cord repair. Ann Neurol 72:491-501.

Grossman RG, Frankowski RF, Burau KD, Toups EG, Crommett JW, Johnson MM, Fehlings MG, Tator CH, Shaffrey CI, Harkema SJ (2012) Incidence and severity of acute complications after spinal cord injury. J Neurosurg Spine 17:119-128.

Grossman RG, Fehlings MG, Frankowski RF, Burau KD, Chow DS, Tator C, Teng A, Toups EG, Harrop JS, Aarabi B, Shaffrey CI, Johnson MM, Harkema SJ, Boakye M, Guest JD, Wilson JR (2014) A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury. J Neurotrauma 31:239-255.

Hollis ER, 2nd, Tuszynski MH (2011) Neurotrophins: potential therapeutic tools for the treatment of spinal cord injury. Neurotherapeutics 8:694-703.

Itzkovich M, Gelernter I, Biering-Sorensen F, Weeks C, Laramee MT, Craven BC, Tonack M, Hitzig SL, Glaser E, Zeilig G, Aito S, Scivoletto G, Mecci M, Chadwick RJ, El Masry WS, Osman A, Glass CA, Silva P, Soni BM, Gardner BP, Savic G, Bergstrom EM, Bluvshtein V, Ronen J, Catz A (2007) The Spinal Cord Independence Measure (SCIM) version III: reliability and validity in a multi-center international study. Disabil Rehabil 29:1926-1933.

Kalsi-Ryan S, Curt A, Verrier MC, Fehlings MG (2012) Development of the Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP): reviewing measurement speci fi c to the upper limb in tetraplegia. J Neurosurg Spine 17:65-76.

Kozauer N, Katz R (2013) Regulatory innovation and drug development for early-stage Alzheimer’s disease. N Engl J Med 368:1169-1171.

Kramer JL, Lammertse DP, Schubert M, Curt A, Steeves JD (2012) Relationship between motor recovery and independence after sensorimotor-complete cervical spinal cord injury. Neurorehabil Neural Repair 26:1064-1071.

Krassioukov AV, Furlan JC, Fehlings MG (2003) Medical co-morbidities, secondary complications, and mortality in elderly with acute spinal cord injury. J Neurotrauma 20:391-399.

Lee BB, Cripps RA, Fitzharris M, Wing PC (2014) The global map for traumatic spinal cord injury epidemiology: update 2011, global incidence rate. Spinal Cord 52:110-116.

Liu K, Tedeschi A, Park KK, He Z (2011) Neuronal intrinsic mechanisms of axon regeneration. Annu Rev Neurosci 34:131-152.

Marino RJ, Graves DE (2004) Metric properties of the ASIA motor score: subscales improve correlation with functional activities. Arch Phys Med Rehabil 85:1804-1810.

Marino RJ, Rider-Foster D, Maissel G, Ditunno JF (1995) Superiority of motor level over single neurological level in categorizing tetraplegia. Paraplegia 33:510-513.

Marino RJ, Burns S, Graves DE, Leiby BE, Kirshblum S, Lammertse DP (2011) Upper- and lower-extremity motor recovery after traumatic cervical spinal cord injury: an update from the national spinal cord injury database. Arch Phys Med Rehabil 92:369-375.

Marino RJ, Patrick M, Albright W, Leiby BE, Mulcahey M, Schmidt-Read M, Kern SB (2012) Development of an objective test of upper-limb function in tetraplegia: the capabilities of upper extremity test. Am J Phys Med Rehabil 91:478-486.

Maynard FM, Jr., Bracken MB, Creasey G, Ditunno JF, Jr., Donovan WH, Ducker TB, Garber SL, Marino RJ, Stover SL, Tator CH, Waters RL, Wilberger JE, Young W (1997) International standards for neurological and functional classi fi cation of spinal cord injury. American Spinal Injury Association. Spinal Cord 35:266-274.

McKerracher L, Anderson KD (2013) Analysis of recruitment and outcomes in the phase I/IIa Cethrin clinical trial for acute spinal cord injury. J Neurotrauma 30:1795-1804.

McKerracher L, Guertin P (2013) Rho as a target to promote repair: translation to clinical studies with cethrin. Curr Pharm Des 19:4400-4410.

NSCISC (2013) Spinal Cord Injury. Facts and Figures at a Glance. National Spinal Cord Injury Statistics Center Birmingham, Alabama, United States:1-2.

Selvarajah S, Hammond ER, Haider AH, Abularrage CJ, Becker D, Dhiman N, Hyder O, Gupta D, Black JH, 3rd, Schneider EB (2014) The burden of acute traumatic spinal cord injury among adults in the United States: an update. J Neurotrauma 31:228-238.

Steeves JD, Lammertse D, Curt A, Fawcett JW, Tuszynski MH, Ditunno JF, Ellaway PH, Fehlings MG, Guest JD, Kleitman N, Bartlett PF, Blight AR, Dietz V, Dobkin BH, Grossman R, Short D, Nakamura M, Coleman WP, Gaviria M, Privat A, International Campaign for Cures of Spinal Cord Injury P (2007) Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial outcome measures. Spinal Cord 45:206-221.

Steeves J, Kramer J, Fawcett J, Cragg J, Lammertse D, Blight A, Marino R, Ditunno J, Coleman W, Geisler F (2011) Extent of spontaneous motor recovery after traumatic cervical sensorimotor complete spinal cord injury. Spinal Cord 49:257-265.

Steeves JD, Lammertse DP, Kramer JLK, Kleitman, N., Kalsi-Ryan S, Jones L, Curt A, Blight AR, Anderson KD (2012) Outcome measures for acute/subacute cervical sensorimotor complete (AIS-A) spinal cord injury during a phase 2 clinical trial. Top Spinal Cord Inj Rehabil 18:1-14.

Stein DM, Menaker J, McQuillan K, Handley C, Aarabi B, Scalea TM (2010) Risk factors for organ dysfunction and failure in patients with acute traumatic cervical spinal cord injury. Neurocrit Care 13:29-39.

Tadie M, Gaviria M, Mathe J-F, Menthonnex P, Loubert G, Lagarrigue J, Saint-Marc C, Argenson C, Kempf C, D’Arbigny P, Kamenka J-M, Privat A, Carli P (2003) Early care and treatment with a neuroprotective drug, gacyclidine, in patients with acute spinal cord injury. Rachis 15:363-376.

Tator CH (2006) Review of treatment trials in human spinal cord injury: issues, dif fi culties, and recommendations. Neurosurgery 59:957-982; discussion 982-957.

Watzlawick R, Sena ES, Dirnagl U, Brommer B, Kopp MA, Macleod MR, Howells DW, Schwab JM (2014) Effect and reporting bias of RhoA/ROCK-blockade intervention on locomotor recovery after spinal cord injury: a systematic review and meta-analysis. JAMA Neurol 71:91-99.

Lisa M Bond, Ph.D., Director of Scientific and Regulatory Affairs, BioAxone BioSciences, Inc., One Kendall Square, Building 200, Suite 2203, Cambridge, MA 02139, USA, lisa.bond@bioaxonebio.com.

10.4103/1673-5374.139470

http://www.nrronline.org/

Accepted: 2014-07-18