Clinical Outcome Assessment Endpoints in Nephrotic Syndrome Drug Development: Research Partner Feedback on Patient-Centered Trial Design

Introduction: Nephrotic syndrome (NS) clinical trials often rely on biomarkers or clinical measures as primary endpoints, but these may not fully capture the treatment benefits that matter most to patients. Edema-related swelling, a central manifestation of NS, profoundly affects patients' health-related quality of life, including physical function, severe physical and mental symptoms, and ability to participate in routine activities, highlighting the need for clinical outcome assessments (COAs) that directly measure its severity and impact. The PREPARing a clinical outcomes assessment set for Nephrotic Syndrome (Prepare-NS) project, supported by the United States Food and Drug Administration's Center for Drug Evaluation and Research Pilot Grant Program, aims to address this unmet need. Methods: We conducted qualitative interviews with and surveyed clinical trialists from industry, academia, and patient advocacy organizations. Each queried participants on how COAs, including patient- and observer-reported outcomes, could be used to demonstrate treatment benefit in trials. Participants were asked about preferences for timing, frequency, and format of COA assessment, as well as how COA-based endpoints could best capture swelling impacts, and how these might relate to other trial endpoints. Results: Participants expressed strong support for COA-based endpoints to complement clinical or biomarker endpoints, noting that the impact of disease as represented by proteinuria does not fully capture potential treatment benefit to patients. We identified multiple endpoints to operationalize swelling COAs in clinical trials. Additional key considerations included optimal timing of assessments, feasibility of daily diaries (i.e., daily symptom ratings), potential confounding factors, and alignment of COAs with proteinuria or other endpoints. Conclusions: Collectively, these insights inform the Prepare-NS initiative's ongoing development and validation efforts. Incorporating standardized COAs in NS clinical trials could expand efficacy endpoints and pave the way for patient-centered NS drug development.