title: Developing a Cognition Endpoint for Traumatic Brain Injury Clinical Trials.
abstract: Cognitive impairment is a core clinical feature of traumatic brain injury (TBI). After TBI, cognition is a key determinant of post-injury productivity, outcome, and quality of life. As a final common pathway of diverse molecular and microstructural TBI mechanisms, cognition is an ideal endpoint in clinical trials involving many candidate drugs and nonpharmacological interventions. Cognition can be reliably measured with performance-based neuropsychological tests that have greater granularity than crude rating scales, such as the Glasgow Outcome Scale-Extended, which remain the standard for clinical trials. Remarkably, however, there is no well-defined, widely accepted, and validated cognition endpoint for TBI clinical trials. A single cognition endpoint that has excellent measurement precision across a wide functional range and is sensitive to the detection of small improvements (and declines) in cognitive functioning would enhance the power and precision of TBI clinical trials and accelerate drug development research. We outline methodologies for deriving a cognition composite score and a research program for validation. Finally, we discuss regulatory issues and the limitations of a cognition endpoint.
authors.affiliation: 1 Department of Medicine, Division of Physical Medicine and Rehabilitation, University of British Columbia , and GF Strong Rehab Centre, Vancouver, British Columbia, Canada, and Department of Physical Medicine and Rehabilitation, Harvard Medical School, and Red Sox Foundation and Massachusetts General Hospital Home Base Program, Boston, Massachusetts.
authors.forename: Noah D
authors.initials: ND
authors.lastname: Silverberg
authors.affiliation: 2 Department of Medicine, University of Washington , Seattle, Washington.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Crane
authors.affiliation: 3 Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai , New York City, New York.
authors.forename: Kristen
authors.initials: K
authors.lastname: Dams-O'Connor
authors.affiliation: 4 Department of Physical Therapy, University of Delaware , Newark, Delaware.
authors.forename: James
authors.initials: J
authors.lastname: Holdnack
authors.affiliation: 5 Defense and Veterans Brain Injury Center (DVBIC) , Silver Spring, Maryland.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Ivins
authors.affiliation: 6 Defense and Veterans Brain Injury Center (DVBIC) , Walter Reed National Military Medical Center, and National Intrepid Center of Excellence, Bethesda, Maryland.
authors.forename: Rael T
authors.initials: RT
authors.lastname: Lange
authors.affiliation: 7 Department of Neurological Surgery, University of California San Francisco , San Francisco, California.
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Manley
authors.affiliation: 8 Department of Neurosurgery, Medical College of Wisconsin , Milwaukee, Wisconsin.
authors.forename: Michael
authors.initials: M
authors.lastname: McCrea
authors.affiliation: 9 Department of Physical Medicine and Rehabilitation, Harvard Medical School, Spaulding Rehabilitation Hospital, MassGeneral Hospital for Children Sports Concussion Program, and Red Sox Foundation and Massachusetts General Hospital Home Base Program, Boston, Massachusetts, and Defense and Veterans Brain Injury Center, National Intrepid Center of Excellence , Bethesda, Maryland.
authors.forename: Grant L
authors.initials: GL
authors.lastname: Iverson
mesh_terms: D000070642:Brain Injuries, Traumatic / Q000175:diagnosis* / Q000523:psychology; D002986:Clinical Trials as Topic / Q000592:standards*; D003072:Cognition Disorders / Q000175:diagnosis* / Q000523:psychology; D023381:Endpoint Determination / Q000523:psychology / Q000592:standards*; D023261:Glasgow Outcome Scale / Q000592:standards; D006801:Humans; D009483:Neuropsychological Tests / Q000592:standards*; D015203:Reproducibility of Results
keywords: clinical trials; cognition; craniocerebral trauma; neuropsychological tests; outcome assessment; psychometrics