The Department of Health and Human Services, through the National Institutes of Health (NIH), is offering a funding opportunity for investigator-initiated, high-risk multi-center clinical trials via the Notice of Funding Opportunity (NOFO) PA-25-147. This grants program, specifically under the U01 cooperative agreement mechanism, invites applications aimed at addressing critical health issues within the mission of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), including diabetes, digestive diseases, and kidney conditions. Proposals must present hypothesis-driven studies with an emphasis on innovative therapeutic interventions, operationally classified as high-risk due to either the intervention's complexity or participant vulnerability. Planning activities must be completed prior to the application, and a Plan for Enhancing Diverse Perspectives (PEDP) is required to ensure inclusivity. Key dates include an application opening on January 3, 2025, with corresponding deadlines for submission. The program encourages early applications to address potential submission errors. Ineligible applications encompass low-risk trials and mechanistic studies, ensuring alignment with NIDDK's mission. NIH will assess proposals based on scientific merit, feasibility, and the integration of diverse perspectives throughout the research process.