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Background: Disparities in posthospitalization outcomes for people with chronic medical conditions and insured by Medicaid are well documented, yet interventions that mitigate them are lacking. Prevailing transitional care interventions narrowly target people aged 65 years and older, with specific disease processes, or limitedly focus on individual-level behavioral change such as self-care or symptom management, thus failing to adequately provide a holistic approach to ensure an optimal posthospital care continuum. This study evaluates the implementation of THRIVE-an evidence-based, equity-focused clinical pathway that supports Medicaid-insured individuals with multiple chronic conditions transitioning from hospital to home by focusing on the social determinants of health and systemic and structural barriers in health care delivery. THRIVE services include coordinating care, standardizing interdisciplinary communication, and addressing unmet clinical and social needs following hospital discharge., Objective: The study's objectives are to (1) examine referral patterns, 30-day readmission, and emergency department use for participants who receive THRIVE support services compared to those receiving usual care and (2) evaluate the implementation of the THRIVE clinical pathway, including fidelity, feasibility, appropriateness, and acceptability., Methods: We will perform a sequential randomized rollout of THRIVE to case managers at the study hospital in 3 steps (4 in the first group, 4 in the second, and 5 in the third), and data collection will occur over 18 months. Inclusion criteria for THRIVE participation include (1) being Medicaid insured, dually enrolled in Medicaid and Medicare, or Medicaid eligible; (2) residing in Philadelphia; (3) having experienced a hospitalization at the study hospital for more than 24 hours with a planned discharge to home; (4) agreeing to home care at partner home care settings; and (5) being aged 18 years or older. Qualitative data will include interviews with clinicians involved in THRIVE, and quantitative data on health service use (ie, 30-day readmission, emergency department use, and primary and specialty care) will be derived from the electronic health record., Results: This project was funded in January 2023 and approved by the institutional review board on March 10, 2023. Data collection will occur from March 2023 to July 2024. Results are expected to be published in 2025., Conclusions: The THRIVE clinical pathway aims to reduce disparities and improve postdischarge care transitions for Medicaid-insured patients through a system-level intervention that is acceptable for THRIVE participants, clinicians, and their teams in hospitals and home care settings. By using our equity-focused case management services and leveraging the power of the electronic medical record, THRIVE creates efficiencies by identifying high-need patients, improving communication across acute and community-based sectors, and driving evidence-based care coordination. This study will add important findings about how the infusion of equity-focused principles in the design and evaluation of evidence-based interventions contributes to both implementation and effectiveness outcomes., International Registered Report Identifier (irrid): DERR1-10.2196/54211., Trial Registration: ClinicalTrials.gov NCT05714605; https://clinicaltrials.gov/ct2/show/NCT05714605., (©J Margo Brooks Carthon, Heather Brom, Marsha Grantham-Murrillo, Kathy Sliwinski, Aleigha Mason, Mindi Roeser, Donna Miles, Dianne Garcia, Jovan Bennett, Michael O Harhay, Emilia Flores, Kelvin Amenyedor, Rebecca Clark. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 26.03.2024.)