Intranasal Carbetocin Reduces Hyperphagia, Anxiousness, and Distress in Prader-Willi Syndrome: CARE-PWS Phase 3 Trial

Abstract

Context: Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. Intranasal carbetocin, an oxytocin analog, was investigated as a selective oxytocin replacement therapy.

Objective: To evaluate safety and efficacy of intranasal carbetocin in PWS.

Design: Randomized, double-blind, placebo-controlled phase 3 trial with long-term follow-up.

Setting: Twenty-four ambulatory clinics at academic medical centers.

Participants: A total of 130 participants with PWS aged 7 to 18 years.

Interventions: Participants were randomized to 9.6 mg/dose carbetocin, 3.2 mg/dose carbetocin, or placebo 3 times daily during an 8-week placebo-controlled period (PCP). During a subsequent 56-week long-term follow-up period, placebo participants were randomly assigned to 9.6 mg or 3.2 mg carbetocin, with carbetocin participants continuing at their previous dose.

Main outcome measures: Primary endpoints assessed change in hyperphagia (Hyperphagia Questionnaire for Clinical Trials [HQ-CT]) and obsessive-compulsive symptoms (Children's Yale-Brown Obsessive-Compulsive Scale [CY-BOCS]) during the PCP for 9.6 mg vs placebo, and the first secondary endpoints assessed these same outcomes for 3.2 mg vs placebo. Additional secondary endpoints included assessments of anxiousness and distress behaviors (PWS Anxiousness and Distress Behaviors Questionnaire [PADQ]) and clinical global impression of change (CGI-C).

Results: Because of onset of the COVID-19 pandemic, enrollment was stopped prematurely. The primary endpoints showed numeric improvements in both HQ-CT and CY-BOCS which were not statistically significant; however, the 3.2-mg arm showed nominally significant improvements in HQ-CT, PADQ, and CGI-C scores vs placebo. Improvements were sustained in the long-term follow-up period. The most common adverse event during the PCP was mild to moderate flushing.

Conclusions: Carbetocin was well tolerated, and the 3.2-mg dose was associated with clinically meaningful improvements in hyperphagia and anxiousness and distress behaviors in participants with PWS.

Clinical trials registration number: NCT03649477.

Keywords: Prader-Willi syndrome; anxiety; carbetocin; hyperphagia; oxytocin; vasopressin.

Figure 1.

CARE-PWS study CONSORT diagram. Participants were screened, randomized, and enrolled in an 8-week placebo-controlled study period followed by a subsequent 56-week long-term follow-up period. A total of 130 participants received carbetocin or placebo.

Figure 2.

Effects of 3.2 mg/dose carbetocin vs placebo across efficacy assessments in the placebo-controlled period. Changes from baseline to week 8 in study efficacy assessments are shown for the carbetocin 3.2-mg group compared with placebo. Note: questionnaires are of differing scales. Abbreviations: CGI-Change, clinical global impression of change; CY-BOCS, Children's Yale-Brown Obsessive-Compulsive Scale; HQ-CT, Hyperphagia Questionnaire for Clinical Trials; PADQ, PWS Anxiousness and Distress Behaviors Questionnaire.

Figure 3.

HQ-CT and PADQ responders to carbetocin. Proportions of participants reaching various thresholds of change from baseline to week 8 in (A) HQ-CT and (B) PADQ scores are shown for the carbetocin 3.2-mg group compared with placebo. Note: all participants with missing week 8 data are considered nonresponders at all thresholds (even if because of the March 1, 2020, COVID-19 cutoff date). Abbreviations: HQ-CT, Hyperphagia Questionnaire for Clinical Trials; PADQ, PWS Anxiousness and Distress Behaviors Questionnaire.

Figure 4.

Long-term efficacy data from week 8 through week 64. Data from study efficacy questionnaires (A) HQ-CT, (B) CY-BOCS, and (C) PADQ throughout the long-term follow-up period are shown for each treatment group. Abbreviations: CY-BOCS, Children's Yale-Brown Obsessive-Compulsive Scale; HQ-CT, Hyperphagia Questionnaire for Clinical Trials; PADQ, PWS Anxiousness and Distress Behaviors Questionnaire.