Intranasal carbetocin reduces hyperphagia in individuals with Prader-Willi syndrome

Abstract

Background: Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder of life-threatening hyperphagia, obesity, intellectual deficits, compulsivity, and other behavioral problems. The efficacy and safety of i.n. carbetocin, an oxytocin analog, was evaluated in a prospective, randomized, double-blinded trial in adolescents with PWS.

Methods: Eligible patients aged 10-18 years with genetically confirmed PWS were randomized (1:1) to i.n. carbetocin or placebo 3 times daily for 14 days. The primary efficacy endpoint was change in parent/caregiver-rated Hyperphagia in PWS Questionnaire-Responsiveness (HPWSQ-R) total score. Secondary efficacy endpoints included HPWSQ-R behavior, drive, and severity domains; clinician-rated HPWSQ; Children's Yale-Brown Obsessive-Compulsive Severity Scale; food domain of the Reiss Profile; and Clinical Global Impression-Improvement scale. Endpoints were assessed using analysis of covariance. Relationship between primary and secondary endpoints was assessed using Pearson correlation coefficients. Safety was assessed throughout the study.

Results: Demographics and clinical characteristics were similar between treatment groups (carbetocin, n = 17; placebo, n = 20). Patients receiving carbetocin had statistically significant reductions in HPWSQ-R total score at study end (-15.6) versus patients receiving placebo (-8.9; P = 0.029); several secondary efficacy endpoints also demonstrated significant differences (P < 0.05). Treatment effects for the primary and secondary endpoints were highly correlated (P ≤ 0.0001). Incidence of adverse events (AEs) was similar between treatment groups.

Conclusion: I.n. carbetocin was well tolerated and improved hyperphagia and behavioral symptoms of PWS.

Trial registration: ClinicalTrials.gov: NCT01968187FUNDING. The study was funded by Ferring Pharmaceuticals. Recruitment was aided by ongoing work in PWS performed through Eunice Kennedy Shriver National Institute of Child Health and Human Development grant U54 HD083211.

Keywords: Clinical Trials; Neurodevelopment; Neuroscience.

Conflict of interest statement

Conflict of interest: JM has received research funding from Ferring, Zafgen, and Rhythm Pharmaceuticals. MR is a salaried employee of Ferring and is listed as coinventor on a patent application related to the content of this manuscript, with no financial claims thereof (patent no. WO 2016044131 A1). HTH is the president of Hind T. Hatoum & Company, which had a contractual agreement with Ferring International Pharmascience Center US Inc., the developer of an investigational drug that is the subject of the present manuscript, that involved strategies and the performance of some of the analyses related to data presented in the manuscript. PK was a salaried employee of Ferring and is listed as coinventor on a patent application related to the content of this manuscript, with no financial claims thereof (patent no. WO 2016044131 A1).

Figures

Figure 1. CONSORT diagram of disposition of study patients.

*One patient who did not meet inclusion criteria was mistakenly randomized to treatment with carbetocin but did not receive any study medication. †A total of 19 patients in the placebo group completed the study; however, 1 patient who discontinued the study because of an AE (broken lower arm) was included in the full analysis population and participated in the final efficacy assessment on day 15.

Figure 2. Change from baseline in HPWSQ-R and CY-BOCS at study end (visit 4, day 15).

(A) HPWSQ-R total scores at baseline and study end (visit 4, day 15; primary efficacy endpoint) and least squares (LS) mean change versus baseline for each treatment group and 90% CIs. (B) CY-BOCS total scores at baseline and study end (visit 4, day 15; secondary efficacy endpoint) and LS mean change versus baseline for each treatment group and 90% CIs. Statistical analyses included all participants with assessment scores at baseline and day 15; analyses were performed using an ANCOVA model, with treatment group and study site as fixed effects. Baseline HPWSQ-R total scores served as a covariate. Treatment group differences in total scores were calculated by subtracting LS mean change from baseline in the placebo group from that in the carbetocin group. HPWSQ-R, parent/caregiver-rated Hyperphagia in PWS Questionnaire–Responsiveness.