Stage I (Years 1-2) Technical Objective 1: Establish a ...

Stage I (Years 1-2) Technical Objective 1: Establish a ...

TBI Endpoints Development A"Collabora) ve"inform for"Advancing" Diagnosis" and" Treatment" of"TBI"" Exploiting the past to the future of clinical outcome assessment Joseph T. Giacino, PhD PI: Geoff Manley, MD, PhD Outcomes Core Lead: Michael McCrea, PhD Co-Leads: Murray Stein, MD, Joseph Giacino, PhD, Harvey Levin, PhD, Sureyya Dikmen, PhD, John Whyte, MD, PhD (DoD CDMRP Award# W81XWH-14-2-0176) Department of Physical Medicine & Rehabilitation Harvard Medical School Spaulding Rehabilitation Hospital Massachusetts General Hospital Brigham & Womens Hospital Current State of the Science

Interventional trials in acute TBI management have been uniformly disappointing: TBI classification crude: Mild, moderate, severe (GCS) Outcome assessment equally crude: Dead, VS, lower severe, upper sev, low moderate, upper mod, good recovery (GOS-E) Studies underpowered, non-standardized procedures, limited multidisciplinary collaboration. No COAs or biomarkers have been validated or qualified for TBI. Consequence: Inability to preferentially target therapies to patients with specific injury mechanisms. The Future of TBI Research To enhance the effectiveness of TBI research, we need clinical outcome assessment measures (COAs) and biomakers that: 1) Permit more accurate disease/condition diagnosis 2) Identify distinct patient subpopulations likely to benefit from therapy/intervention 3) Provide precise outcome assessments to confirm efficacy. TED Aims: Stage I STAGE I Technical Objective 1: Establish a collaborative, multidisciplinary team to: 1) Advance the identification and validation of clinical outcome assessments (COAs) and biomarkers for use as potential FDA-qualified drug development

tools (DDTs) 2) Initiate development of CDISC data standards for trials involving diagnosis and treatment of mTBI to modTBI. TBI Endpoints Development (TED) Project Adult & Pediatric CDE Basic and Core Outcome Measures Sub-Domain Global Outcome Instrument/Scale CDE Level GOS-E/GOS-E-Peds Core DRS Basic Adaptive and Daily Living Skills FIM; WeeFIM/PEDI Basic

Cognitive Activity Limitations FIM-Cog Basic Language and Communication WASI-II Vocabulary Basic Neuropsychological Impairment Adult: WAIS-IV PSI; Trail Making Test; RAVLT/CVLT; Peds: WISC-IV/WPPSI-IV; D-KEFS Verbal Fluency Basic Perceived Health-Related Quality of Life

SWLS; Peds QoL Inventory (Generic) Basic Physical Function FIM-Motor, Rivermead; Peds: WeeFIM-Motor/PEDI- Basic Objective 1.5 Collaborate with the Clinical Data Interchange Standards Consortium (CDISC) to conform TBI Common Data Elements (TBI-CDEs) to CDISC standards for FDA regulatory submission CDISC: A global, open, multidisciplinary, non-profit organization that has established standards to support the acquisition, exchange, submission and archive of clinical research data and metadata. Mission: To develop and support global, platform-independent data standards that enable information system interoperability to improve medical research and related areas of healthcare. TBI Endpoints Development A"Collabora) ve"for"Advancing"Diagnosis"and"Treatment"of"TBI"" The Future of TBI Science

Multi-Dimensional Assessment of TBI Outcome A Collaborative Effort of TRACK-TBI and TED Global Function Level Clinical Phenotype COMPOSITE OUTCOME INDEX STAGE II Technical Objective: 2 Cognitive Domain Neurobehavior al Domain Psychological Health Domain Quality of Life Domain Level Skill Impairment Level

TED Aims: Stage II Memor y Exec Func Languag e Intellig Attentio n Cog Proc Vis-spat Other Judgme nt Anger Soc. Beh Other Impulse Mood Anxiety

PCS Sxs Disinhib PTSD Voc Apathy Personal Other Other Psychos is Locus of C Other Financia l Other Physical Function Domain

Life Satisf Social Motor Sensory Percept Recreat Pain Mobilit y Sleep Other Other Other Validate candidate COAs and biomarkers selected in Stage I, leveraging the existing research infrastructure and clinical study networks of TRACK-TBI, CENC, and CRC for potential qualification as DDTs

Source Variance Level Item Level Responses Item Level Responses Item Level Responses Item Level Responses Item Level Responses Proposed Work Flow: TRACK-TBI and TED COA Working Groups lead and commission SME groups to refine the mutli-dimensional outcome model, and identify core measures in each domain for validation studies, leveraging NINDS CDEs and existing literature. Intended Work Product: empirically-based consensus recommendations on specific measures for TBI trials, and on concept of use (COU) (what measures to use based on acuity, population, setting, and form of intervention under study). TBI Endpoints Development (TED) Project McCrea, Giacino, Dikmen, Manley 2015


Connect Challenges How do we integrate disparate datasets conceptually and technically? What is the best approach to vetting the strength of COAs? Which data analytic procedures are best suited to validating this novel approach to outcome assessment? Opportunities Exploit scope and depth of existing datasets Pursue novel approach to outcome assessment that relies on multi-dimensional modeling of TBI outcomes Develop COA platforms specific to particular TBI phenotypes Synchronize new approach to outcome assessment with FDA COA qualification process to accelerate advances in TBI care Public -Private Partnership Private Partners Not for Profit and Philanthropic Partners Government Partners

TED Academic Partners If you cant win the game, you have to change the rules. Col. Dallas Hack, MD Director, U.S. Army Combat Casualty Care Research Program TBI Endpoints Development for"Advancing"Diagnosis"and"Treatment"of"TBI"" Exploiting the past toA"Collabora) informve"the future of clinical

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