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 .
there are no approved drugs to foster repair after sci , despite numerous preclinical studies showing the promise of regenerative medicine ( hollis and tuszynski , 2011 ; liu et al .
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 ) .
the most common primary endpoints derived from this neurological assessment are american spinal injury association ( asia ) impairment scale conversion and total motor score .
these 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 significant change in arm and hand control , an area of critical importance to individuals living with quadriplegia after 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 after 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 beneficial , full recovery in fewer muscle groups . as the field 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 .
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 . ,
approximately 12,000 individuals suffer scis each year , most commonly from motor vehicle accidents or falls ( nscisc , 2013 ) .
scis are cervical ( grossman et al . , 2012 ; selvarajah et al . , 2014 ) , and complete cervical sci leads to lifelong quadriplegia ( fawcett et al
individuals with sci also suffer comorbidities , including autonomic dysreflexia , bladder dysfunction , muscle spasticity , and chronic pain ( krassioukov et al . , 2003 ) . the 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 ) .
there are currently no approved treatments to reduce paralysis and improve daily function after sci .
the most common primary endpoints in sci clinical trials are total motor score and asia impairment scale ( ais ) conversion , derivatives of the isncsci assessment ( ditunno et al . , 2005 ; steeves et al . , 2007 )
total motor score and ais conversion were originally designed to assess impairment after sci ( maynard et al . , 1997 ) , but have been subsequently used in clinical trials as measures of drug - based neurological recovery ( steeves et al . , 2007 ) .
both endpoints can increase in a manner that may not signify improved function in cervical subjects .
total motor score ( tms ) measures contraction strength in five upper body muscle groups and five 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 .
the 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 dorsiflexors and in both knee extensors .
a subject could also increase 20 points by improving from full paralysis ( 0 ) to active movement with gravity eliminated ( 2 ) in all ten leg / foot muscle groups , a change offering similarly limited to nonexistent functional benefit for a quadriplegic individual .
the 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 scale ranks 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 . though 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 .
the 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 scientific 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 ) ) .
the need for standardized reporting of functionally meaningful endpoints in such trials is of critical importance for the evaluation of repositioned therapeutics for cervical sci .
the selection of a meaningful primary endpoint for assessing recovery after cervical sci requires an understanding of which drug - based neurological improvements would offer subjects the most functional benefit .
since individuals living with quadriplegia overwhelmingly agree that their quality of life would be most improved by a return of arm / hand function ( anderson , 2004 ) , two isncsci neurological assessment derivatives emerge as valuable endpoints for cervical subjects : ( 1 ) upper extremity motor score ( uems ) and ( 2 ) motor level change .
both endpoints have been used extensively in retrospective analyses of cervical subjects in previous sci clinical trials and databases ( steeves et al . , 2011 , 2012 ;
though these endpoints are not impervious to the limitations seen in tms / ais conversion ( e.g. , increases in uems are also not weighted by comparative functional benefit ) , both offer a more focused measure of functionally meaningful increases in hand and arm control that could better serve as a primary endpoint to support drug approval for cervical sci .
upper extremity motor score ( uems ) measures contraction strength in five 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 correspond directly 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 ) .
the motor level of a cervical sci corresponds to the lowest spinal segment from which extending neurons permit muscle movement against gravity , and above which motor function is normal . in particular , the key muscle group innervated by the  motor level must receive an isncsci motor score of at least 3 ( contraction against gravity alone ) , while all key muscle groups innervated by spinal segments above this level receive a 5 ( normal function ) . since the cervical levels of the spinal cord innervate the arms and hands , the motor level of a cervical subject is a direct measure of arm / hand regions under voluntary control .
the recovery of two or more motor levels in the year following a cervical sci is associated with a significant improvement in functional independence , as measured by the scim self - care subcategory ( personal grooming , feeding , bathing , and dressing ) ( kramer et al . , 2012 ) . 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 .
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 offered a preliminary assessment of efficacy on the traditional sci endpoints of ais grade and total motor score ( fehlings et al . , 2011 ) .
though improvements by cethrin - treated cervical subjects on these endpoints were promising ( mckerracher 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 first year after injury , the sixteen cethrin - treated cervical subjects in all five 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 ) .
the 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 ) .
upper extremity motor score ( uems ) : phase i / iia cethrin trial data vs. historical results . ( a ) change in uems over time . the average change in uems from baseline is displayed at 0 , 0.5 , 6 , 12 , 26 , and 52 week intervals after initial examination for cethrin - treated cervical subjects in the three highest dose groups ( phase i / iia trial : 3 , 6 , and 9 mg doses , n = 9 ) , and at 0 , 4 , 8 , 16 , 26 , and 52 week intervals for historical cervical subjects in the sygen database ( n = 187 , c57 ) .
( b ) change in uems at 1 year after sci . the average change in uems from baseline to 1 year post - injury is displayed for cethrin - treated cervical subjects ( phase i / iia trial : n = 16 for all doses [ 0.3 , 1 , 3 , 6 , 9 mg ] , n = 9 for 3 highest doses 3 , 6 , 9 mg ] ) and comparative historical cervical populations analyzed in the literature ( sygen database [ n = 187 , c57 ] , model systems [ n = 315 ] ) . missing data points for dropouts
error bars represent standard error . the upcoming phase ii / iii cethrin trial will examine the ability of the drug to reduce paralysis and promote functional recovery after acute cervical sci ( nct02053883 ) .
the use of this meaningful primary endpoint for a pivotal trial in cervical sci will help to shift the field toward the choice of functionally relevant endpoints for future cervical trials .
the phase ii / iii cethrin trial will also include secondary endpoints to assess the impact of cethrin on the serious comorbidities of sci , such as respiratory impairment , bowel and bladder dysfunction , pain , muscle spasticity , pressure ulcers , and autonomic dysreflexia ( krassioukov et al .
in addition to the standard international sci data sets , the trial will use a newly developed questionnaire to directly assess personal perceptions of comorbidity severity in cethrin - treated versus placebo subjects . as the field moves forward
, the development and use of other new tools to evaluate sci comorbidities may permit improved clinical assessments ( e.g. , an additional test of the ability to generate an effective cough might enhance standard respiratory assessments of forced expiratory volume ) . by complementing a meaningful primary endpoint ( uems ) with carefully designed secondary tests of sci comorbidities ,
the phase ii / iii cethrin trial will set the tone for a more patient - centric analysis of cervical sci treatments .
with an overall goal of determining the functional benefit 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 . ,
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 specific settings ) by acquiring a relevant adaptive device .
the ideal solution for future clinical testing in acute cervical sci may be the development of a composite endpoint that incorporates both a relevant neurological assessment and a direct test of functional autonomy .
composite endpoints have become increasingly prevalent in clinical trials for other neurological indications ( cutter et al .
, 1999 ; elm and investigators , 2012 ; kozauer and katz , 2013 ) .
for example , the multiple sclerosis functional composite evaluates leg function / ambulation ( via a timed , 25-foot walk ) , arm / hand function ( via a test involving placing pegs in a pegboard ) , and cognitive function ( via a test of the subject 's ability to add numbers heard at 23 second intervals ) ( cutter et al . , 1999 ) .
the use of a well - designed composite for cervical sci could ensure that an approved therapeutic offers neurological improvements conferring direct functional benefit . the upcoming phase
ii / iii cethrin trial will take the first step toward the development of such a composite endpoint .
the trial has been designed to assess whether the following measures of arm and hand recovery can be combined to form a composite primary endpoint : ( 1 ) uems , ( 2 ) graded redefined assessment of strength sensibility and prehension ( grassp ) ( kalsi - ryan et al . , 2012 ) ,
( 3 ) capabilities of upper extremity test ( cue - t ) ( marino et al . , 2012 ) , and ( 4 ) scim iii self - care subscore ( itzkovich et al . , 2007 ) .
grassp and cue - t were recently developed to directly measure the recovery of hand and arm capabilities ( e.g. reaching forward , pushing down , pinching a key ) , and the ability to perform basic functional tasks ( e.g. pouring water , lifting a container ) .
the self - care subsection of scim measures a subject 's ability to perform complex tasks of daily living , such as feeding , dressing , bathing , and grooming .
uems offers a functionally relevant assessment of drug - based neurological changes in arm and hand control .
uems , graasp or cue - t , and the scim self - care subscore could together form a composite endpoint sensitive to drug - based functional improvement that transforms the trajectory of future cervical sci clinical trials .
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 .
 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 . 
Introduction
SCI
Limitations of traditional endpoints for evaluation of cervical SCI
Meaningful endpoints for the evaluation of neurological recovery after cervical SCI
Meaningful endpoint selection in the phase II/III trial of Cethrin for cervical SCI
Developing a composite endpoint for cervical SCI
Conclusions