BACKGROUNDStroke is the 5th leading cause of death and a leading cause of adult disability in the United States (US). One in four strokes are recurrent events. Stroke patients experience persisting physical and cognitive impairments long-term, and their caregivers/family also experience psychological and health quality impacts. The current standard for stroke care in the US utilizes hospital certifications based on level of available care and include proven acute and in-hospital care processes but offers limited post-discharge care coordination of risk factor management, secondary prevention, and early and continued rehabilitation that have been shown beneficial for recovery; the Joint Commission (JC) Comprehensive Stroke Care (CSC) certification is awarded to hospitals that provide the most advanced level of stroke care. Another model of care in use in the US is a patient-centered, technology-enabled Integrated Stroke Practice Unit (ISPU) that incorporates team-based care components across the continuum. While risk factor management and early rehabilitation occur during hospitalization, these become the focus and are facilitated in the ISPU arm post-discharge. While both models have shown effectiveness, understanding which model yields better outcomes is critical scientific information for the stroke community.METHODSThis paper reports the protocol for the Coordinated, Collaborative, Comprehensive, Family-Based, Integrated, and Technology-Enabled Stroke Care (C3FIT), including rationale, design, and methodology for the study. C3FIT is a pragmatic, multicenter, single masked, Phase III, cluster randomized clinical trial designed to determine effectiveness of two US stroke care models - JC CSC careCSC-Only; control) compared to a model that that layers the ISPU model on top of CSC care (ISPU+CSC; intervention). Up to 23 clinical sites were stratified by geographic region and patient admission volume and randomized at the site level. Participants included patients (or their Legally Authorized Representative) and their caregiver (if available). Participants in each treatment group were followed through in-person, virtual, or phone contact at 3-, 6-, and 12-months post-discharge; participants in the ISPU+CSC arm were also seen at 1-, 2-, 4-, 5-, 7-, 8-, 9-, 10- and 11-months post-discharge. Patient-centered primary outcomes were patient function and quality of life (measured using the simplified modified Rankin Scale and Stroke Impact Scale respectively) at 12-months post-stroke. Treatment differences were assessed using generalized linear mixed models incorporating assessments at 0, 3, 6 and 12 months, with the primary treatment differences evaluated by a contrast statement assessing the 12-month difference.CONCLUSIONResults from C3FIT will help to determine which model of care yields better outcomes for patients and their caregivers, which will build scientific evidence about post-stroke recovery and has the potential to impact post-stroke care across the country.TRIAL REGISTRATIONThis trial is registered at ClinicalTrials.gov (NCT04000971).