Summary: CARE-PWS did not meet either primary efficacy endpoint for intranasal carbetocin 9.6 mg versus placebo at eight weeks. A 3.2-mg regimen showed nominal secondary improvements in hyperphagia and distress, but these findings remain exploratory after the primary analysis failed.
PICO Summary
| Element | Detail |
|---|---|
| Population | Children and adolescents aged 7-18 years with genetically confirmed Prader-Willi syndrome and substantial hyperphagia and obsessive-compulsive symptoms. Of 138 randomised, 130 received treatment; the prespecified pre-pandemic primary analysis included 119 participants. The study involved 24 clinics. |
| Intervention | Intranasal carbetocin three times daily: 9.6 mg/dose or 3.2 mg/dose. Treated populations were 44 and 43 respectively; primary-analysis populations were 40 and 39. Placebo-controlled treatment lasted eight weeks. |
| Comparator | Matching placebo three times daily: 43 treated and 40 in the primary analysis. During subsequent 56-week follow-up, placebo recipients switched to active treatment, so there was no continuing placebo comparison. |
| Outcomes | Primary 9.6-mg versus placebo comparisons failed: HQ-CT hyperphagia difference -1.2 points (95% CI -3.7 to 1.3; P=0.349) and CY-BOCS obsessive-compulsive symptom difference -0.6 (95% CI -2.9 to 1.7; P=0.600). Secondary 3.2-mg findings included HQ-CT difference -3.1 (95% CI -5.7 to -0.6; nominal P=0.016) and PADQ distress difference -3.8 (95% CI -7.2 to -0.4; nominal P=0.027). Flushing occurred in 14.0%, 20.5% and 0% of the lower-dose, higher-dose and placebo groups. No treatment-emergent serious adverse events were reported during the placebo-controlled period; behavioural tolerability and discontinuations remained relevant during longer follow-up. |
| Study Design | Phase 3, randomised, double-blind, placebo-controlled trial; recruitment ended early because of COVID-19. NCT03649477. Sponsored by Levo Therapeutics, with sponsor employees among the authors. Originally published in 2023. |
Expert Commentary
I read CARE-PWS as a negative confirmatory trial with an interesting lower-dose signal. The distinction matters because the title of the original report can sound more conclusive than its primary analysis. Both prespecified high-dose comparisons failed, so the lower-dose findings cannot be promoted to definitive proof by selecting their favourable nominal probabilities. Pandemic-related truncation reduced precision, but does not reverse that hierarchy. Can I use this with my patients? The study can support a specialist discussion about the research programme and the uncertainty surrounding carbetocin; it does not, by itself, establish a routine treatment recommendation. Children with Prader-Willi syndrome and their families need outcomes that reflect daily functioning and safety, not only improvement on one questionnaire. Longer follow-up without a placebo group cannot separate sustained drug effects from selection, expectation or changes in care. I would also distinguish the treated population from the smaller primary analysis set when discussing the strength of the evidence. Sponsor involvement and the greater behavioural tolerability concerns at the higher dose deserve attention. The appropriate next step is a sufficiently powered confirmatory study of the selected lower-dose regimen, with prespecified multiplicity control, meaningful functional outcomes and careful behavioural safety assessment, rather than treating this result as established efficacy.
References
Roof E, Deal CL, McCandless SE, et al. Intranasal Carbetocin Reduces Hyperphagia, Anxiousness, and Distress in Prader-Willi Syndrome: CARE-PWS Phase 3 Trial. J Clin Endocrinol Metab. 2023;108(7):1696-1708. doi:10.1210/clinem/dgad015. PMID: 36633570.
