The NIDDK High Risk Multi-Center Clinical Study Cooperative Agreement (U01 Clinical Trial Required) invites applications for high-risk, investigator-initiated, multi-center clinical trials focused on diseases within the mission of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Eligible studies must address high-risk therapeutic interventions or involve significant operational complexities across multiple clinical sites. Trials must be hypothesis-driven, aim to improve clinical practice or public health, and demonstrate readiness for immediate participant recruitment upon funding. Applications requiring initial planning should first apply for a U34 planning grant before pursuing this U01 funding opportunity.

The funding opportunity supports trials across a range of diseases, including diabetes, endocrine and metabolic disorders, digestive diseases, nutritional disorders, obesity, and kidney, urologic, and hematologic diseases. Only therapeutic trials are eligible; mechanistic trials and low-risk multi-center studies will not be considered. The studies must demonstrate substantial engagement with affected communities, including meaningful partnerships with patients, community members, and healthcare providers, ensuring cultural appropriateness and alignment with community priorities. The NIDDK emphasizes addressing health disparities and advancing health equity as central objectives of the research.

Eligible applicants include higher education institutions, nonprofits, for-profit organizations, tribal governments, state and local governments, and other public entities. Foreign organizations are not eligible, but foreign components of U.S. organizations may participate. Applications must include a Plan for Enhancing Diverse Perspectives (PEDP) detailing actionable strategies for inclusivity, diversity in research teams, participant recruitment, and engagement with underrepresented groups. Failure to include a PEDP will result in administrative withdrawal of the application.

Applicants must provide detailed plans, including a finalized study protocol, manual of operations, and a timeline with milestones such as regulatory approvals, recruitment goals, training protocols, and anticipated study completion dates. Clear quantifiable performance metrics are required to support progress monitoring. Letters of support from collaborating centers and any co-funding partners are mandatory. Applications should also address data and safety monitoring, recruitment and retention plans, statistical power calculations, and contingency strategies for overcoming recruitment challenges.

Applications will be evaluated based on the significance and innovation of the research, the rigor and feasibility of the proposed approach, the expertise of the research team, and the adequacy of institutional resources. Additional considerations include the inclusion of diverse populations, the clarity of milestone plans, and the potential for the research findings to impact clinical practice or public health. Final funding decisions will consider scientific merit, alignment with NIDDK priorities, and availability of funds.

Key deadlines include submission dates of February 5, June 5, and October 5 annually, with letters of intent due 30 days prior to each submission date. Funding is contingent upon meeting established milestones and demonstrating continued progress throughout the project period, which may last up to five years. Prospective applicants are strongly encouraged to consult with NIDDK program officials early in the application preparation process to ensure alignment with the institute's goals and funding priorities.