Safety and Efficacy of Amyloid-Beta Directed Antibody Therapy in Mild Cognitive Impairment and Dementia with Evidence of Lewy Body Dementia and Amyloid-Beta Pathology (U01 - Clinical Trial Required)

The National Institutes of Health (NIH), in collaboration with the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), is seeking applications for a research funding opportunity under RFA-NS-25-010. The primary objective is to support a Phase 2, randomized, placebo-controlled clinical trial assessing the safety and efficacy of monoclonal antibody therapies targeting amyloid-beta in patients with mild cognitive impairment or dementia presenting with both Alzheimer’s disease (AD) and Lewy Body Dementia (LBD) pathology. This funding aims to fill a significant research gap by focusing on populations with mixed-etiology dementias (MED), specifically those demonstrating both Alzheimer’s biomarkers (such as amyloid-beta deposition or phosphorylated tau) and a clinical diagnosis of LBD, Parkinson’s disease dementia (PDD), or dementia with Lewy bodies (DLB). Applicants are invited to submit projects for trials using FDA-approved or investigational amyloid-beta monoclonal antibodies. The research will examine the efficacy of these therapies within MED populations to determine both therapeutic potential and the risks, especially the occurrence of amyloid-related imaging abnormalities (ARIA). Given the limited representation of LBD patients in prior amyloid antibody trials, there is a pressing need to assess potential adverse effects and identify patient subgroups most likely to benefit. The trials will also emphasize inclusive recruitment that reflects a diversity of race, sex, and geography within the United States, and the proposal must include community engagement cores to foster participation among underrepresented groups and those affected by health disparities. The NIH has allocated a total budget of $10 million for FY25, with the opportunity to fund one award for up to seven years. Project costs are capped at $6.7 million per year, contingent on the NIH’s appropriations and the merit of submitted applications. Applicants must structure the trial design with Bayesian approaches to analyze specific subgroups, along with adaptive randomization strategies where appropriate. This rigorous methodological approach should accommodate a comprehensive set of outcome variables, including secondary endpoints such as cognitive and functional measures. Eligible applicants include higher education institutions, nonprofit organizations, for-profit organizations, and various government entities. Applicants must meet registration requirements through the System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code, eRA Commons, and Grants.gov to ensure eligibility. Proposals should integrate culturally competent engagement strategies to improve recruitment and retention of health-disparity populations. Applications must include a detailed Team Management Plan and a Community Engagement and Research Inclusivity (CERI) Plan, each no longer than two pages. The Team Management Plan should outline multidisciplinary collaboration involving physicians, scientists, community advocates, and stakeholders across relevant fields. The CERI Plan should engage community representatives from the inception through the dissemination of results, emphasizing strategies to include and support populations disproportionately affected by health disparities, as well as compensation for community stakeholders. The application deadline is January 24, 2025, with letters of intent due by December 24, 2024. All applications must adhere strictly to NIH’s guidelines on rigor, reproducibility, and transparency. Selected proposals will undergo a scientific peer review by the NINDS and, if successful, may begin project activities by December 2025. Key review criteria include the scientific significance of the proposed study, innovation, research methodology, and the capacity to manage diverse, multi-site trials efficiently and ethically.