Caregiver Perspectives: Insights on the COMPASS-PWS Trial

Background

In response to Acadia Pharmaceuticals’ announcement that the COMPASS-PWS Phase 3 trial of intranasal carbetocin did not meet its primary or secondary endpoints and would not advance further, the Foundation for Prader-Willi Research (FPWR) convened a patient forum to gather feedback and patient experience data from families who had participated in the trial. The goal was to better understand parent-reported outcomes, perceived benefits, and challenges in current clinical trial assessments for Prader-Willi syndrome (PWS)-associated behaviors. Approximately twenty families participated in an online meeting and/or submitted written comments about their trial experience. Although the overall outcome of this clinical trial was not positive, several parents reported seeing changes and meaningful improvements in their child’s daily functioning, behavior and level of anxiousness while on carbetocin. Despite the disappointing results overall, the comments and insights provided by these families regarding their trial experience may guide the development of more successful clinical trials for PWS in the future. We are grateful to these families for participating and for sharing their experiences and suggestions for future trials.

Parent-Reported Benefits

When asked to share the most meaningful benefits observed during treatment, parents identified reduced anxiousness, less preoccupation with food and decreased problematic behavior around food as key improvements.

Caregivers of the participants described a general reduction in stress around meals, greater flexibility with food schedules, and a shift in focus away from food-related behaviors. Other noted benefits included improvements in emotional regulation, social engagement, and cognitive function. (see word cloud)

A poll conducted during our Caregiver Forum asked parents to rate carbetocin’s impact on a scale of 1 (low) to 5 (high) across six behavioral and emotional domains. The average composite score across all categories was 3.9 out of 5, with anxiousness rated as showing the most improvement (4.1/5).

Reported Areas of Improvement

1. Hunger and Food Behaviors
   • Decreased hyperphagia
   • Less food talk and fewer food-related obsessions
   • Improved ability to tolerate delays in meals or snacks
   • Reduced urgency around eating and decreased anxiety about food availability
2. Mood and Emotional Regulation
   • Noticeable reduction in anxiety, particularly related to food and schedules
   • Improved ability to pause and think before reacting
   • Fewer emotional “meltdowns” when faced with unexpected changes
3. Social Interaction and Engagement
   • Greater interest in others and a broader range of conversation topics
   • Improved communication and social awareness
4. Executive Function and Cognition
   • Parents observed better reasoning, focus, and problem-solving skills

Participant Analysis of Trial Assessments

Parents provided feedback on the design of the study and assessment tools used in the COMPASS-PWS trial. Many felt that the existing questionnaires did not fully capture meaningful day-to-day changes that they observed during the study. Further, they noted that the study period was too short for them to know if the changes they were observing represented normal day-to-day fluctuations or true changes in behavior related to the treatment.

Commonly Reported Concerns

• Certain questions on the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) were not relevant to all participants; for example, “getting up at night to food seek” may not occur when a child lives in a food-secure environment.
• Parents suggested using rating scales with broader ranges (e.g., 0–7 or 0–10) to allow for greater sensitivity to change.
• Caregivers felt it would be helpful to have a mechanism to share their perceptions of change, which may include insights beyond structured questionnaires.

Recommendations for Future Clinical Trials

Based on participant feedback, FPWR has identified several recommendations for improving future trial design and data collection in PWS clinical trials:

1. Extend Study Duration
   • Lengthen the double-blind, placebo-controlled phase from 12 to at least 16 weeks to allow sufficient time for benefits to emerge.
2. Include a Randomized Withdrawal Phase or Crossover Design
   • Oftentimes, the improvements being assessed in a PWS trial show up as an absence of a negative behavior, which may be difficult to appreciate. Parents noted that behavior differences were most apparent when they stopped the drug; thus, a randomized withdrawal phase or crossover design may allow parents to better compare behaviors on and off the drug. In addition, each phase needs to be of sufficient duration (parents suggested 16 weeks or more) to capture behavior changes.
3. Implement Daily Digital Tracking
   • Parents suggested that shorter-term recall periods may be more accurate than some of the current behavioral assessments. For example, use of daily text prompts to collect brief, real-time caregiver assessments (e.g., amount of food talk, repetitive questioning, number or severity of outbursts related to food) might minimize recall bias.
4. Add Qualitative Pre/Post Interviews
   • Include structured caregiver interviews before and after treatment to capture subjective impressions and contextual insights.
5. Consider additional approaches to reduce placebo effects
   • Placebo Run-In design or additional training for participants and clinical trial staff may help stabilize baseline behaviors and enhance the reliability of subsequent comparisons.
6. Consider Allowing Caregiver-Defined Behaviors of Interest
   • Enable caregivers to define what behaviors are relevant to their child (e.g., repetitive food talk, food-related outbursts), assessed as, for example, a composite endpoint, may allow for more individualized and accurate measurement.
7. Analyze Responder Subgroups
   • Conduct post-hoc analyses to identify characteristics of participants who showed improvement, potentially informing future personalized approaches.

Conclusion

While the COMPASS-PWS trial did not meet its primary endpoint, some participants and their caregivers reported meaningful benefits in anxiety reduction, reduced food focus, emotional regulation, and social functioning. These findings highlight the need for more sensitive, patient-centered outcome measures that reflect the lived experience of individuals with PWS and their families.

FPWR remains committed to advancing research methodologies that better capture the full spectrum of positive, meaningful changes that may occur in a trial and ensuring that the patient voice is integral to the development and evaluation of future PWS treatments.