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Carbetocina Prader
Carbetocina Prader
https://doi.org/10.1210/clinem/dgad015
Advance access publication 12 January 2023
Clinical Research Article
Received: 30 September 2022. Editorial Decision: 9 January 2023. Corrected and Typeset: 3 February 2023
© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.
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The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 7 1697
34
Department of Pediatrics, The University of Oklahoma School of Community Medicine, Tulsa, OK 73117, USA
35
Trial Architecture Consulting, Chevy Chase, MD 20814, USA
36
Levo Therapeutics, Inc., Skokie, IL 60077, USA
Correspondence: Davis C. Ryman, MD, PhD, Aeovian Pharmaceuticals, Inc., 156 2nd St, San Francisco, CA 94105, USA. Email: dryman@aeovian.com.
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.
Prader-Willi syndrome (PWS) is a rare neurodevelopmental Many of the hallmark features of PWS are thought to involve
genetic disorder with a complex phenotype and no approved deficits in neuroendocrine feedback loops that maintain energy
therapies to treat its most serious, life-threatening, and life- homeostasis and influence psychosocial, physical, and sexual
limiting symptoms. It occurs in approximately 1 in 10 000 development (2). PWS is associated with dysfunction and dys
to 1 in 30 000 births (1, 2). Genetically, PWS is caused by a de regulation of multiple hormones and neuropeptides (reviewed
fect in paternal expression of imprinted genes in the chromo in 10), which may be causally related to a deficiency in prohor
some 15q11-q13 region (3). mone convertase 1, resulting in impairment of normal process
PWS is characterized by profound hyperphagia, which is an ing of multiple prohomones, including the hypothalamic
intense persistent sensation of hunger accompanied by food neuropeptide hormone oxytocin (11). In post mortem brain tis
preoccupations, an extreme drive to consume food, and sue from individuals with PWS, a 42% decrease in number and
food-related behavior problems. Overt hyperphagia typically a 54% decrease in volume of oxytocin-expressing neurons have
presents by 7 to 8 years of age and is associated with the lack been reported in the paraventricular nucleus of the hypothal
of a normal satiety response and a low basal metabolic rate amus (12). Mice that are null for Magel2 (one of the genes in
(4-6). Despite adequate energy reserves, these individuals are the 15q11-13 PWS locus that is not expressed in PWS) similarly
subjected to a false state of starvation (7) that can lead to epi have decreased levels of oxytocin in the paraventricular nucleus
sodes of food gorging associated with choking or gastric rup (11), and perinatal treatment with oxytocin has been shown to
ture if access to food is not carefully controlled. rescue postnatal lethality and social and learning deficits in this
Other psychiatric symptoms in PWS include increased lev model (13, 14). Although better known for its role in repro
els of anxiousness, obsessive-compulsive tendencies, and ductive health, oxytocin is also involved in regulating social
maladaptive behaviors. An analysis of data from 4039 chil and emotional behaviors and is a potent anorexigenic hormone
dren and adolescents with genetic disorders associated with involved in the normal satiety response (15).
intellectual disability showed that the prevalence of psychi Carbetocin is an oxytocin analog designed to have im
atric symptoms was the highest for PWS (74%) among the proved oxytocin receptor selectivity and longer half-life com
10 disorders evaluated (8). To manage hyperphagia and psy pared with endogenous oxytocin. It has been approved in
chiatric symptoms, caregivers impose strict environmental more than 100 countries to prevent uterine atony following
controls and constant monitoring of individuals with PWS, cesarean delivery and has been administered to more
significantly limiting their independence. Assessments of than 11 million women since its first approval in 1997.
caregiver burden in PWS exceed those for conditions includ Compared with native oxytocin, carbetocin has substantially
ing Alzheimer’s disease and traumatic brain injury (9). greater selectivity to binding to oxytocin receptors compared
1698 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 7
with vasopressin receptors. In addition to its anorexigenic ef endpoint assessed efficacy of the lower, 3.2 mg 3 times daily,
fects, selective modulation of the oxytocin pathway by carbe dose of carbetocin vs placebo using these same instruments.
tocin may offer prosocial and anxiolytic benefits to Additional secondary endpoints evaluated efficacy of each
individuals with PWS (16) by virtue of reducing off-target dose (9.6 mg or 3.2 mg 3 times daily) vs placebo in improving
binding to vasopressin receptors and thereby widening the PWS-specific anxiousness and distress behaviors, measured by
therapeutic window for treatment in this population. the PWS Anxiousness and Distress Behaviors Questionnaire
The results of a phase 2 trial (ClinicalTrials.gov identifier: (PADQ), and evaluated efficacy in improving overall clinical
NCT01968187) in 37 individuals with PWS showed 9.6 mg symptoms of PWS, assessed by clinician-rated clinical global
of intranasal carbetocin reconstituted in saline administered impression of change (CGI-C) scores. Prespecified secondary
3 times per day with meals to be safe and well-tolerated endpoints also further evaluated effects on hyperphagia using
(17). Efficacy results over the 14 days of the trial demonstrated 2 different prespecified subsets of the HQ-CT: a subset focus
significant improvements in hyperphagia and other behavioral ing on items less affected by food-related environmental con
symptoms in PWS vs the placebo arm, warranting further trols (the HQ-CT subset, including questions 1, 2, 5, 6, 8, and
study as a potential therapeutic option (17). 9) and analysis of scores on HQ-CT question 9 in isolation.
COVID-19. Participants were randomized through an inter for an overall assessment of improvement, and was also pre
active web response system. Randomization was performed specified as a secondary endpoint.
before baseline to give adequate time to thaw vials for the first Obsessive-compulsive symptoms were assessed using the
dose administered at the baseline visit. The randomization ra CY-BOCS. This scale is a validated, clinician-administered,
tio was defined to be 2:2:1:1 into 4 trial arms: 9.6 mg carbeto semistructured inventory of specific symptoms and severity
cin 3 times daily, during PCP and LTFU; 3.2 mg carbetocin 3 with a total score range of 0 to 36. Reductions in scores reflect
times daily, during PCP and LTFU; placebo 3 times daily dur improvements in obsessions and compulsions. The scale is va
ing the PCP and 9.6 mg carbetocin 3 times daily during LTFU; lidated for diagnosis and evaluation of pediatric obsessive-
and placebo 3 times daily during the PCP and 3.2 mg carbeto compulsive disorder (19). It has not been validated specifically
cin 3 times daily during LTFU. Efficacy analyses of the PCP for use in the PWS population.
pooled the 2 placebo arms together, resulting in a 1:1:1 ran The PADQ was administered to assess PWS-specific anx
domization ratio. The sponsor (Levo Therapeutics), investiga iousness and distress behaviors. The PADQ is a validated
tors, caregivers, and participants were blinded to the assigned 15-item caregiver-reported instrument designed to capture
treatments during both the PCP and LTFU. To attempt to min the observable signs of anxiousness and distress that are com
used for efficacy analyses in the LTFU period. TEAE incidence but before enrollment confirmation at the baseline visit.
and severity, discontinuations, and other safety measures used Eight randomized participants failed screening criteria or
the SAS, which included all participants who received at least withdrew consent at the baseline visit and were therefore ex
1 dose of study drug. cluded from enrollment before receiving the investigational
Efficacy analyses used the constrained longitudinal data product, for a total of 130 participants receiving at least
analysis mixed model with repeated measures (23-25) without 1 dose of the study medication. Of those 130 participants,
imputation. Sensitivity analyses were performed to confirm 128 completed their week 8 visit (2 participants in the
robustness of results to missing data and demonstrate consist 9.6-mg dose arm discontinued before week 8) and 103 com
ency in results and conclusions. Statistical comparisons were pleted the trial (17 participants in the 9.6-mg LTFU dose
conducted using SAS, version 9.4 (SAS Institute, Cary, NC). arm and 8 participants in the 3.2-mg LTFU dose arm discon
Within-participant response to treatment for the HQ-CT tinued before their week 64 visit). The PAS included 119
was evaluated as the proportion of participants that achieve evaluable participants with at least 1 postbaseline visit before
a 7.7-point reduction in total score, a responder threshold de the March 1, 2020, data cutoff date, 104 of which had com
fined when validating the HQ-CT instrument (18) and con pleted their week 8 visit before the cutoff date.
sistent with anchor-based analyses of the CARE-PWS data. Randomization resulted in treatment arms that were gener
Within-participant response to treatment for the PADQ was ally well-balanced with respect to baseline demographics as
similarly evaluated as the proportion of participants that well as baseline PWS characteristics (Table 1).
achieve a 10.5-point reduction in total score (the responder
threshold identified when validating the PADQ instrument
and using anchor-based analyses of the CARE-PWS data). Efficacy Outcomes
For placebo-crossover analyses, mean changes in HQ-CT Participants taking carbetocin showed numerical improve
and PADQ from baseline to week 8 were compared with ments vs placebo in 11 of the 12 specified primary and second
mean changes from week 8 to week 16 in participants that ary endpoints (Table 2). The 2 primary endpoints assessing
transitioned from placebo to active treatment arms during change in HQ-CT and CY-BOCS for the 9.6-mg carbetocin
the LTFU period. arm showed numeric improvements vs placebo that did not
All efficacy results analyzed participants according to the reach statistical significance; therefore, the trial did not meet
dose arm to which they were originally assigned. Analyses its primary endpoint and all other statistical analyses are con
of safety data included assessments of TEAE incidence rates sidered nominal. Results for the 3.2 mg dose arm showed con
and percentages of participants in each arm who experienced sistent and nominally significant improvements in multiple
a TEAE, including severity and relatedness to treatment. efficacy assessments compared with placebo (Table 2 and
Fig. 2). Specifically, benefits were observed in symptoms of hy
perphagia (HQ-CT −3.1, P = 0.016; HQ-CT subset −2.4, P =
Results 0.011), anxiousness and distress (PADQ −3.8, P = 0.027), and
A total of 176 participants entered screening and 138 of those clinical global impressions of change (CGI-C −0.5, P = 0.027).
participants were randomized to receive study treatment Responder analyses for the 3.2-mg dose further supported the
(Fig. 1). Because intranasal carbetocin required overnight existence of clinically meaningful improvements in participants’
thawing before use, randomization occurred after screening, hyperphagia, anxiousness, and distress symptoms, with
The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 7 1701
Placebo-controlled period
Age, y
Mean (SD) 12.3 (3.12) 11.7 (3.45) 11.8 (3.52) 0.675
Sex, n (%)
Female 24 (61.5) 19 (47.5) 23 (57.5) 0.432
Male 15 (38.5) 21 (52.5) 17 (42.5)
Race, n (%)
American Indian/Alaska Native 0 1 (2.5) 0 0.820
Abbreviations: BMI, body mass index; CY-BOCS, Children’s Yale-Brown Obsessive-Compulsive Scale; HQ-CT, Hyperphagia Questionnaire for Clinical
Trials; ID, imprinting defect; PADQ, PWS Anxiousness and Distress Behaviors; PWS, Prader-Willi syndrome; UPD, uniparental disomy.
meaningful responses occurring at significantly higher rates in 8 weeks on active drug when compared with their experi
participants on carbetocin than those on placebo. Responder ence during their 8 weeks on placebo (Table 3), consistent
thresholds for these instruments were defined using an anchor- with the observations seen during the PCP for active vs pla
based approach considering changes in CGI-C and correlating cebo. The corresponding comparisons for participants tran
those changes to changes in questionnaire total scores. In the ag sitioning to 9.6 mg were unremarkable and therefore
gregate, these methods provide a range of 4- to 9-point improve consistent with what was observed in the PCP for 9.6 mg
ments for HQ-CT and a range of 6- to 13-point improvements participants.
in PADQ. Conclusions from responder analyses for HQ-CT to Improvements from baseline in efficacy assessments per
tal scores are robust across a range of potential thresholds sisted throughout the long-term follow-up period (Fig. 4).
(Fig. 3A). Specifically, responder rates for the 3.2-mg dose con Notably, although the 3.2 mg dose continued to provide
sistently favored active treatment with odds ratios exceeding 3 equivalent or superior efficacy to that of the 9.6 mg dose,
for all thresholds and P values (2-sided Fisher exact test) below even participants taking the 9.6 mg dose who chose to stay
0.05 for all but the highest threshold. Responder analyses for in the trial continued to experience substantial, clinically
PADQ total scores are shown in Fig. 3B, and again consistently meaningful, and sustained improvements from baseline
favored the 3.2-mg dose with P values (2-sided Fisher exact test) throughout the LTFU period. These observations were con
below 0.05 for all but 2 thresholds of improvement. sistent across both doses and across multiple efficacy assess
Participants transitioning from placebo to the 3.2 mg dose ments including the HQ-CT (Fig. 4A), CY-BOCS (Fig. 4B),
arm at the end of the placebo-controlled period exhibited and PADQ (Fig. 4C). Although there appeared to be a numer
substantial improvements in hyperphagia scores in their first ically greater improvement in the placebo-to-9.6-mg
1702 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 7
HQ-CT
Baseline mean (SD) 22.1 (5.09) 23.4 (5.67) 22.4 (4.74)
Change from baseline to week 8
LS mean (SE) −5.4 (0.96) −3.4 (0.95) −2.2 (0.94)
LS mean difference vs placebo −3.1 −1.2 —
(95% CI of LS mean differences) (−5.7 to −0.6) (−3.7 to 1.3) —
Two-sided P value vs placebo 0.016 0.349 —
CY-BOCS
Primary efficacy endpoints were HQ-CT and CY-BOCS for the 9.6-mg dose; the first secondary endpoints were HQ-CT and CY-BOCS for the 3.2-mg dose. P
values < 0.05 are bolded. Abbreviations: CGI-C, clinician-rated clinical global impression of change; CY-BOCS, Children’s Yale-Brown Obsessive-Compulsive
Scale; HQ-CT = Hyperphagia Questionnaire for Clinical Trials; LS, least squares; PADQ, Prader-Willi Syndrome Anxiousness and Distress Behaviors
Questionnaire; SE, standard error.
subgroup vs the placebo-to-3.2-mg subgroup late in the LTFU participants, including those initially randomized to placebo
period, these data should be interpreted with caution because (Fig. 4).
of small sample sizes in these subgroups and the confounding
effect of survivor bias, and in particular because the number of Safety Results
discontinuations was disproportionate among those random In the PCP, 63.2% of participants receiving carbetocin, in
ized to 9.6 mg. Overall, results were broadly similar for all cluding 60.5% of participants (n = 26) in the 3.2-mg arm
The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 7 1703
and 65.9% of participants (n = 29) in the 9.6-mg arm, re trial discontinuation (2 of the discontinuations occurred in the
ported at least 1 TEAE, compared with 55.8% of participants PCP and 1 occurred in the LTFU period).
(n = 24) in the placebo arm (Table 4). Most TEAEs were mild Although the rates of adverse events were generally similar
to moderate in intensity. Only 1 severe TEAE was reported between dose arms, discontinuations from behavior-related
during the placebo-controlled period in the 9.6-mg arm adverse events among participants taking 9.6 mg carbetocin
(2.3%); the participant experienced an episode of severe sinus were higher than those taking 3.2 mg (n = 6 vs 2, respectively),
pain during landing of an airplane flight while suffering from a and all reported TEAEs of aggression in both the PCP and
sinus infection, which subsequently resolved with oral LTFU period were in participants in the 9.6 mg/dose arm
antibiotics. (n = 1 and 3, respectively). This is consistent with discontinu
The most frequently reported TEAE by preferred term dur ations from the trial generally, which were also more common
ing the PCP was flushing (17.2%), which was mild to moder among participants receiving 9.6 mg carbetocin vs those re
ate in severity. The incidence of flushing was lower in ceiving 3.2 mg (n = 19 and 8, respectively; Fig. 1).
participants in the 3.2 mg arm (14.0%) compared with the Evaluation of additional safety data including laboratory
9.6 mg arm (20.5%), and no participants in the placebo arm assessments (hematology, coagulation, clinical chemistry,
reported a TEAE of flushing. The occurrence of transient and urinalysis), physical examination findings, Tanner sta
flushing is consistent with previous reports that oxytocin ging, electrocardiograms, weight, body mass index, and vital
and oxytocin agonists can be associated with transient periph signs did not reveal clinically relevant trends associated with
eral vasodilation (26). Flushing was also the most frequently study medication.
reported TEAE considered to be possibly related to study
drug by the investigator during the placebo-controlled period.
In all participants, flushing was transient, mild in intensity, Discussion
not serious, and self-limited (generally resolving spontaneous The therapeutic rationale for investigating carbetocin as a po
ly within 30 minutes). tential treatment for PWS is based on its role as a selective oxy
The most frequently reported TEAEs during the LTFU and tocin receptor agonist with prolonged half-life relative to
extension periods were nasopharyngitis (10.9% of all partic native oxytocin itself, potentially enabling replacement of
ipants, including 9.4% and 12.1% of participants in the the functional oxytocin deficiency in PWS while minimizing
3.2 mg and the 9.6 mg arms, respectively), headache (11.7% off-target effects related to oxytocin’s lack of selectivity that
of all participants, including 15.6% and 7.8% of participants may have limited previous attempts at treatment.
in the 3.2 mg and the 9.6 mg arms, respectively), and epistaxis To date, 5 clinical studies have reported the effects of intra
(10.9% of all participants and for both dose arms). In com nasal oxytocin in PWS (27-31). Oxytocin replacement has
parison, during the placebo-controlled period, the incidence shown varying degrees of efficacy, but has also been associ
of nasopharyngitis was 1.1% in the LV-101 all active arm ated with an increase in temper outbursts after 8 weeks of
(0 in the 3.2-mg/dose arm and 2.3% in the 9.6 mg/dose treatment, driven by significant increases in outbursts ob
arm) and 7.0% in the placebo arm. served in participants with PWS receiving higher doses
No deaths or treatment-emergent serious adverse events (27). It has been hypothesized that the off-target effects of
were reported during the PCP. No study drug discontinua oxytocin binding to vasopressin receptors may be limiting
tions were reported during the PCP by participants in the pla its therapeutic window in PWS (27). Because of oxytocin’s
cebo arm or the 3.2 mg arm. A total of 3 participants (6.8%) lack of selectivity, off-target activation of the vasopressin
in the 9.6-mg arm reported TEAEs during the PCP that led to 1A receptor (V1aR) with high doses of oxytocin may
1704 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 7
Baseline to week 8 (n = 20) Week 8 to week 16 (n = 18) Baseline to week 8 (n = 20) Week 8 to week 16 (n = 17)
HQ-CT, LS mean (SE) 0.3 (1.37) −9.1 (1.64) −4.8 (1.41) −5.0 (1.69)
vs first 8 weeks, LS mean −9.3 −0.2
(95% CI) (−14.5 to −4.2) (−5.5 to 5.1)
P value <0.001 0.944
Abbreviations: LS, least squares; HQ-CT, Hyperphagia Questionnaire for Clinical Trials; SE, standard error.
exacerbate PWS behavioral symptoms and mute or negate vasopressin type 2 receptor can be associated with increased
any positive efficacy derived from oxytocin receptor agonism risks of antidiuresis and hyponatremia, which together can
because the V1aR has been implicated in anxiety and depres have significant adverse health consequences. The therapeut
sion (16, 32). Additionally, oxytocin activation of the ic utility of native oxytocin may be further limited by its short
The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 7 1705
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.
half-life of approximately 3 to 5 minutes, making sustained CARE-PWS is the first phase 3 trial of intranasal carbetocin
and selective action at the oxytocin receptor extremely chal in individuals with PWS, and is one of the largest intervention
lenging to achieve. al trials conducted in this population to date. This trial builds
1706 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 7
Table 4. TEAEs reported during the PCP by ≥5% of participants in any long-term treatment, with a substantially lower discontinu
treatment by preferred term ation rate observed in this arm.
As with all clinical studies of potential treatments for PWS,
MedDRA 3.2-mg 9.6-mg All active All placebo statistical power is limited by the number of participants that
preferred term carbetocin carbetocin (N = 87) (N = 43)
can reasonably be enrolled from this rare population.
(N = 43) (N = 44) n (%) n (%)
n (%) n (%) Although the active arms did appear to numerically separate
from placebo, a placebo effect was present, as is commonly
At least 1 TEAE 26 (60.5) 29 (65.9) 55 (63.2) 24 (55.8) observed in clinical trials with behavioral endpoints, making
Flushing 6 (14.0) 9 (20.5) 15 (17.2) 0 statistical significance more challenging to achieve. The sam
Headache 7 (16.3) 4 (9.1) 11 (12.6) 3 (7.0) ple size of CARE-PWS, specifically, was smaller than planned
Epistaxis 1 (2.3) 6 (13.6) 7 (8.0) 1 (2.3) because of needing to prematurely close enrollment at the out
break of the COVID-19 pandemic. In general, smaller sample
Diarrhea 4 (9.3) 2 (4.5) 6 (6.9) 1 (2.3)
sizes make it more difficult to detect treatment differences be
Upper respiratory 3 (7.0) 2 (4.5) 5 (5.7) 2 (4.7)
tween drug and placebo and increase the probability that a
improvements in hyperphagia and behaviors of anxiousness associated with intellectual disability. J Am Acad Child Adolesc
and distress in individuals with PWS and demonstrates a fa Psychiatry. 2020;59(9):1036-1048.
vorable safety profile. The highly positive benefit/risk relation 9. Kayadjanian N, Schwartz L, Farrar E, Comtois KA, Strong TV.
ship in the face of substantial unmet medical needs of High levels of caregiver burden in Prader-Willi syndrome. PLoS
One. 2018;13(3):e0194655.
individuals with PWS warrant continued investigation of car
10. Correa-da-Silva F, Fliers E, Swaab D, Yi C. Hypothalamic neuro
betocin as a potential treatment.
peptides and neurocircuitries in Prader Willi syndrome. J
Neuroendocrinol. 2021;33(7):e12994.
Acknowledgments 11. Burnett L, LeDuc C, Sulsona C, et al. Deficiency in prohormone
convertase PC1 impairs prohormone processing in Prader-Willi
Levo Therapeutics and the investigators would like to thank syndrome. J Clin Invest. 2017;127(1):293-305.
all of the clinical site support staff who assisted with coordin 12. Swaab DF. Prader-Willi syndrome and the hypothalamus. Acta
ation and collection of trial data and, most importantly, the Paediatr Suppl. 1997;86(S423):50-54.
individuals with PWS and their families who participated in 13. Schaller F, Watrin F, Sturny R, Massacrier A, Szepetowski P,
the trial, as well as Scientific Commercialization for their as Muscatelli F. A single postnatal injection of oxytocin rescues the le
31. Tauber M, Mantoulan C, Copet P, et al. Oxytocin may be useful to behavior in vasopressin V1a receptor knockout mice.
increase trust in others and decrease disruptive behaviours in pa Neuropsychopharmacology. 2004;29(3):483-493.
tients with Prader-Willi syndrome: a randomised placebo- 33. Kayadjanian N, Vrana-Diaz C, Bohonowych J, et al.
controlled trial in 24 patients. Orphanet J Rare Dis. 2011;6(1):47. Characteristics and relationship between hyperphagia, anxiety, be
32. Bielsky IF, Hu SB, Szegda KL, Westphal H, Young LJ. Profound havioral challenges and caregiver burden in Prader-Willi syndrome.
impairment in social recognition and reduction in anxiety-like PLoS One. 2021;16(3):e0248739.