Title: A Qualitative Methodology to Support the Evaluation of Novel Treatments for Hyperphagia in People with Prader-Willi Syndrome.Background: Assessing change in symptoms affecting people with Prader Willi Syndrome (PWS), a rare disease, is complicated by the influence of different levels of food security procedures and the impact of immediate circumstances on symptom presentation and severity. We report on the use of qualitative interviews to collect information on behavioral change and on the impact of factors specific to individual participants with PWS in a clinical trial. Methods: Soleno Therapeutics' Phase 3 program consists of a double-blind study, an open-label extension study as well as a sub-study consisting of qualitative interviews collected at baseline, the end of the randomized period, and two points during the open label extension. Interviews were conducted with a semi-structured guide covering specific food-security procedures and three areas of interest: foodrelated behavior, non-food-related behavior, and aspects of daily life. Two coders trained in qualitative analysis singlecoded baseline interview transcripts with a dual-coded subset to confirm reliability. From follow-up interviews mentions of change will be dual-coded, with coders discussing any discrepancies to reach resolution. In future analyses, descriptions of change that also include potential attributions from caregivers will include that contextualization based on a pre-specified adjudication plan. Results:The analysis of the baseline interviews identified a variety of food-security procedures practiced by families of people with PWS participating in the clinical trial, ranging from total lockdown since diagnosis to the absence of any food security or routines. Behaviors that were the subject of the qualitative interview were present at baseline in numbers varying from 17 to 100% of the participants in this study. Specific behaviors reported present in all trial participants varied in their manifestation, for example, frequent conversations about food were described by some families as a negative symptom (arguments, nagging, manipulation) and by others as a positive (productive discussion of food choices). Conclusion:The heterogeneity of the trial participants in the studies of DCCR in people with PWS, as evidenced by the baseline qualitative interviews, supports the need to obtain a further understanding of trial participantspecific experiences before and during a clinical trial. This approach could be used in clinical trials to help support and contextualize treatment efficacy in rare disease populations when used alongside other clinical outcomes.