Carbetocin Nasal Spray for the Treatment of Hyperphagia in Prader-Willi Syndrome: Results From the Randomized, Placebo-Controlled, Phase 3 Compass PWS Study.
Carbetocin nasal spray did not show significant efficacy compared to placebo in treating hyperphagia in Prader-Willi Syndrome over a 12-week period.
Where it sits
this study against the rest of the carbetocin corpusSummary and findings
This study evaluated the efficacy of carbetocin nasal spray in treating hyperphagia in individuals with Prader-Willi Syndrome (PWS) over 12 weeks. A total of 175 participants were randomized to receive either carbetocin 3.2 mg TID or placebo. The primary endpoint showed no significant difference in hyperphagia scores between the two groups.
Abstract
<h4>Purpose</h4>Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. The oxytocinergic system represents one of the key neural circuits that is dysfunctional in PWS, making it an attractive therapeutic target. The oxytocin analog carbetocin has a longer half-life and greater receptor selectivity than oxytocin and showed therapeutic potential in the phase 3 CARE-PWS study (ClinicalTrials.gov NCT03649477) based on nominally significant improvements in hyperphagia and anxiousness with the 3 times daily (TID) 3.2-mg dose of intranasal carbetocin over placebo. The phase 3 placebo-controlled COMPASS PWS study was conducted to confirm the potential benefit observed with carbetocin in the CARE-PWS study.<h4>Methods</h4>In the 12-week COMPASS PWS study (ClinicalTrials.gov NCT06173531), 175 participants were randomized 1:1 to carbetocin 3.2 mg TID nasal spray (n = 85) and placebo (n = 90). The primary efficacy endpoint was the change from baseline at week 12 in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Secondary efficacy endpoints were the change in the Clinical Global Impression-Severity (CGI-S) score for PWS, and in the CGI-S for hyperphagia in PWS score from baseline at week 12, the CGI-Change for PWS score at week 12, and the percentage of participants with a treatment response (defined as improvement from baseline ≥8 points) based on the HQ-CT at week 12. Exploratory efficacy endpoints included the change from baseline at week 12 in scores for the PWS Anxiousness and Distress Behaviors Questionnaire.<h4>Findings</h4>The least squares mean change (standard error) from baseline at week 12 in the HQ-CT was -4.8 (0.8) and -5.1 (0.8) in the carbetocin and placebo groups, respectively; the treatment difference of 0.3 (95% confidence interval: -1.8, 2.4; P = 0.79) was not statistically significant. There was no separation between carbetocin and placebo for any secondary or exploratory endpoint. The most frequently reported treatment-emergent adverse events in the carbetocin-treated participants were headache (n = 6 [7.2%]) and pyrexia (n = 5 [6.0%]).<h4>Implications</h4>Carbetocin nasal spray did not demonstrate efficacy compared with placebo for hyperphagia in PWS in the 12-week COMPASS PWS study.
Background
This paper addresses the potential therapeutic role of carbetocin, an oxytocin analog, in managing hyperphagia associated with Prader-Willi Syndrome (PWS). Previous studies suggested that oxytocinergic dysfunction is a key factor in PWS, and carbetocin's longer half-life and receptor selectivity may offer advantages over oxytocin. The COMPASS PWS study aimed to confirm findings from earlier research indicating possible benefits of carbetocin.
Methods
The COMPASS PWS study was a 12-week, randomized, placebo-controlled trial involving 175 participants with PWS, randomized 1:1 to receive either carbetocin 3.2 mg TID nasal spray (n = 85) or placebo (n = 90). The primary outcome measure was the change from baseline in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score at week 12. Secondary outcomes included changes in Clinical Global Impression-Severity (CGI-S) scores and treatment response rates.
Results
At week 12, the least squares mean change in HQ-CT score was -4.8 (0.8) for the carbetocin group and -5.1 (0.8) for the placebo group, resulting in a treatment difference of 0.3 (95% CI: -1.8, 2.4; P = 0.79), which was not statistically significant. No significant differences were observed for secondary or exploratory endpoints.
Interpretation
The findings indicate that carbetocin did not provide a statistically significant benefit over placebo in reducing hyperphagia in PWS. This aligns with previous literature that has shown mixed results for oxytocin-related treatments in hyperphagia. The lack of significant findings, combined with the absence of clinically meaningful effect sizes, raises questions about the utility of carbetocin in this context. Limitations such as the study's design and the relatively small sample size may confound the conclusions.
Key findings
- Least squares mean change in HQ-CT score at week 12: -4.8 (0.8) for carbetocin, -5.1 (0.8) for placebo, treatment difference 0.3 (95% CI: -1.8, 2.4; P = 0.79).
- No statistically significant separation between carbetocin and placebo for any secondary or exploratory endpoint.
- Most frequently reported treatment-emergent adverse events in carbetocin group: headache (n = 6 [7.2%]), pyrexia (n = 5 [6.0%]).
Limitations
- No statistically significant difference in primary endpoint.
- No separation between carbetocin and placebo for secondary or exploratory endpoints.
- Sample size of 175 may limit generalizability.
- 12-week duration may not capture long-term effects.