The Journal of Clinical Endocrinology & Metabolism, 2023, 108, 1696–1708

https://doi.org/10.1210/clinem/dgad015
Advance access publication 12 January 2023
Clinical Research Article

Intranasal Carbetocin Reduces Hyperphagia, Anxiousness,

and Distress in Prader-Willi Syndrome: CARE-PWS
Phase 3 Trial
Elizabeth Roof,1 Cheri L. Deal,2 Shawn E. McCandless,3 Ronald L. Cowan,4 Jennifer L. Miller,5

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Jill K. Hamilton,6,7 Elizabeth R. Roeder,8,9 Shana E. McCormack,10,11 Tamanna R. Roshan Lal,12
Hussein D. Abdul-Latif,13 Andrea M. Haqq,14 Kathryn S. Obrynba,15,16 Laura C. Torchen,17
Alaina P. Vidmar,18,19 David H. Viskochil,20,21 Jean-Pierre Chanoine,22 Carol K.L. Lam,22
Melinda J. Pierce,23 Laurel L. Williams,24 Lynne M. Bird,25,26 Merlin G. Butler,27
Diane E. Jensen,28,29 Susan E. Myers,30 Oliver J. Oatman,31 Charumathi Baskaran,32,33
Laura J. Chalmers,34 Cary Fu,1 Nathalie Alos,2 Scott D. McLean,8 Ajay Shah,24
Barbara Y. Whitman,30 Brent A. Blumenstein,35 Sarah F. Leonard,36 Jessica P. Ernest,36
Joseph W. Cormier,36 Sara P. Cotter,36 and Davis C. Ryman36
1
Vanderbilt University, Nashville, TN 37240, USA
2
Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Centre de Recherche, Montréal, Québec H3T 1C5, Canada
3
Department of Pediatrics, Section of Genetics and Metabolism, University of Colorado School of Medicine and Children’s Hospital Colorado,
Aurora, CO 80309, USA
4
Department of Psychiatry, The University of Tennessee Health Science Center College of Medicine, Memphis, TN 37996, USA
5
Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32611, USA
6
Division of Endocrinology, The Hospital for Sick Children, Toronto M5G 1X8, Canada
7
Department of Pediatrics, University of Toronto, Toronto M5G 1X8, Canada
8
Department of Pediatrics, Baylor College of Medicine, San Antonio, TX 78207, USA
9
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
10
Neuroendocrine Center, The Children’s Hospital of Philadelphia Division of Endocrinology and Diabetes, Philadelphia, PA 19104, USA
11
Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
12
Genetics and Metabolism, Children’s National Hospital, Washington, DC 20010, USA
13
Division of Pediatric Endocrinology and Diabetes, Children’s of Alabama, Birmingham, AL 35233, USA
14
Department of Pediatrics, University of Alberta, Edmonton, Alberta T6G 2R3, Canada
15
Division of Endocrinology and Diabetes, Nationwide Children’s Hospital, Columbus, OH 43205, USA
16
Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA
17
Division of Endocrinology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of Medicine, Northwestern University,
Chicago, IL 60208, USA
18
Diabetes & Obesity Program, Center for Endocrinology, Diabetes and Metabolism, Children’s Hospital Los Angeles Department of Pediatrics,
Los Angeles, CA 90027, USA
19
Keck School of Medicine of USC, Los Angeles, CA 90033, USA
20
Department of Pediatrics, Division of Medical Genetics, The University of Utah School of Medicine, Salt Lake City, UT 84112, USA
21
Shriners Hospital for Children, Salt Lake City, UT 84112, USA
22
Department of Pediatrics, Endocrinology and Diabetes Unit, The University of British Columbia, Vancouver V6H 3V4, Canada
23
Diabetes & Endocrinology, Children’s Minnesota—St Paul, St Paul, MN 55404, USA
24
Menninger Department of Psychiatry & Behavioral Sciences, Baylor College of Medicine, Houston, TX 77030, USA
25
Department of Pediatrics, University of California San Diego, San Diego, CA 92037, USA
26
Rady Children’s Hospital, San Diego, CA 92123, USA
27
Department of Psychiatry & Behavioral Sciences, University of Kansas Medical Center, Kansas City, KS 66160, USA
28
Children’s Health Queensland Hospital and Health Services, South Brisbane, Queensland 4101, Australia
29
Centre for Children’s Health Research, University of Queensland, Brisbane, Queensland 4101, Australia
30
Department of Pediatrics, Saint Louis University School of Medicine, Cardinal Glennon Children’s Hospital, Saint Louis, MO 63104, USA
31
Division of Endocrinology and Diabetes, Phoenix Children’s Hospital, Phoenix, AZ 85016, USA
32
Division of Endocrinology, Boston Children’s Hospital, Boston, MA 02115, USA
33
Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA

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.
org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered
or transformed in any way, and that the work properly cited. For commercial re-use, please contact journals.permissions@oup.com
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.

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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
Key Words: Prader-Willi syndrome, carbetocin, oxytocin, vasopressin, hyperphagia, anxiety
Abbreviations: CARE-PWS, Phase 3 Study of Intranasal Carbetocin (LV-101) in Patients With Prader-Willi Syndrome; CGI-C, clinical global impression of
change; CGI-S, clinical global impression of severity; CY-BOCS, Children’s Yale-Brown Obsessive-Compulsive Scale; EC50, half maximal effective
concentration; LTFU, long-term follow-up; HQ-CT, Hyperphagia Questionnaire for Clinical Trials; PADQ, PWS Anxiousness and Distress Behaviors
Questionnaire; PAS, primary analysis set; PCP, placebo-controlled period; PWS, Prader-Willi syndrome; SAS, safety analysis set; V1aR, vasopressin 1A
receptor.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental
genetic disorder with a complex phenotype and no approved
therapies to treat its most serious, life-threatening, and life-
limiting symptoms. It occurs in approximately 1 in 10 000
to 1 in 30 000 births (1, 2). Genetically, PWS is caused by a de­
fect in paternal expression of imprinted genes in the chromo­
some 15q11-q13 region (3).
PWS is characterized by profound hyperphagia, which is an
intense persistent sensation of hunger accompanied by food
preoccupations, an extreme drive to consume food, and
food-related behavior problems. Overt hyperphagia typically
presents by 7 to 8 years of age and is associated with the lack
of a normal satiety response and a low basal metabolic rate
(4-6). Despite adequate energy reserves, these individuals are
subjected to a false state of starvation (7) that can lead to epi­
sodes of food gorging associated with choking or gastric rup­
ture if access to food is not carefully controlled.
Other psychiatric symptoms in PWS include increased lev­
els of anxiousness, obsessive-compulsive tendencies, and
maladaptive behaviors. An analysis of data from 4039 chil­
dren and adolescents with genetic disorders associated with
intellectual disability showed that the prevalence of psychi­
atric symptoms was the highest for PWS (74%) among the
10 disorders evaluated (8). To manage hyperphagia and psy­
chiatric symptoms, caregivers impose strict environmental
controls and constant monitoring of individuals with PWS,
significantly limiting their independence. Assessments of
caregiver burden in PWS exceed those for conditions includ­
ing Alzheimer’s disease and traumatic brain injury (9).
Many of the hallmark features of PWS are thought to involve
deficits in neuroendocrine feedback loops that maintain energy
homeostasis and influence psychosocial, physical, and sexual
development (2). PWS is associated with dysfunction and dys­
regulation of multiple hormones and neuropeptides (reviewed
in 10), which may be causally related to a deficiency in prohor­
mone convertase 1, resulting in impairment of normal process­
ing of multiple prohomones, including the hypothalamic
neuropeptide hormone oxytocin (11). In post mortem brain tis­
sue from individuals with PWS, a 42% decrease in number and
a 54% decrease in volume of oxytocin-expressing neurons have
been reported in the paraventricular nucleus of the hypothal­
amus (12). Mice that are null for Magel2 (one of the genes in
the 15q11-13 PWS locus that is not expressed in PWS) similarly
have decreased levels of oxytocin in the paraventricular nucleus
(11), and perinatal treatment with oxytocin has been shown to
rescue postnatal lethality and social and learning deficits in this
model (13, 14). Although better known for its role in repro­
ductive health, oxytocin is also involved in regulating social
and emotional behaviors and is a potent anorexigenic hormone
involved in the normal satiety response (15).
Carbetocin is an oxytocin analog designed to have im­
proved oxytocin receptor selectivity and longer half-life com­
pared with endogenous oxytocin. It has been approved in
more than 100 countries to prevent uterine atony following
cesarean delivery and has been administered to more
than 11 million women since its first approval in 1997.
Compared with native oxytocin, carbetocin has substantially
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
fects, selective modulation of the oxytocin pathway by carbe­
tocin may offer prosocial and anxiolytic benefits to
individuals with PWS (16) by virtue of reducing off-target
binding to vasopressin receptors and thereby widening the
therapeutic window for treatment in this population.
The results of a phase 2 trial (ClinicalTrials.gov identifier:
NCT01968187) in 37 individuals with PWS showed 9.6 mg
of intranasal carbetocin reconstituted in saline administered
3 times per day with meals to be safe and well-tolerated
(17). Efficacy results over the 14 days of the trial demonstrated
significant improvements in hyperphagia and other behavioral
symptoms in PWS vs the placebo arm, warranting further
study as a potential therapeutic option (17).
This phase 3 study of intranasal carbetocin (LV-101) in pa­
tients with Prader-Willi syndrome (CARE-PWS trial;
ClinicalTrials.gov identifier: NCT03649477) was designed
to evaluate the safety and efficacy of intranasal carbetocin on
behavioral aspects of PWS. CARE-PWS evaluated a novel for­
mulation of the 9.6 mg dose tested in the phase 2 trial and add­
itionally evaluated a lower 3.2 mg dose, as a strategy to avoid
potential off-target effects at higher doses. Efficacy of each
dose arm was compared with a matching placebo (1:1:1) dur­
ing an 8-week placebo-controlled period (PCP). The trial col­
lected safety and efficacy data during a subsequent 56-week
long-term follow-up (LTFU) period during which all partici­
pants received either 9.6 mg or 3.2 mg of carbetocin. After
completion of the LTFU, participants were given the option
to continue to receive carbetocin during an extension period.
Methods
Trial Design
The CARE-PWS trial was a phase 3, randomized, double-
blind, placebo-controlled, parallel-arm, multicenter trial con­
ducted in participants with PWS to evaluate the efficacy and
safety of intranasal carbetocin compared with placebo. The
trial was conducted at 24 hospitals and clinics in the United
States, Canada, and Australia, following approval by inde­
pendent ethics committees or institutional review boards at
each trial center. The trial was conducted in accordance
with Good Clinical Practice and the Declaration of Helsinki.
Informed consent was obtained in writing from the partici­
pant’s parent or legally acceptable representative, and child
assent was obtained, as necessary, before the first trial proced­
ure. Efficacy analyses were completed using a combination of
clinician-reported and caregiver-reported assessments further
detailed later in this article. Safety was assessed by evaluation
of incidence and severity of treatment-emergent adverse
events (TEAEs), laboratory assessments, electrocardiograms,
vital signs, physical examinations, and nasal assessments.
Objectives and Endpoints
The overall objective of the trial was to evaluate the efficacy,
safety, and tolerability of 2 different doses of intranasal carbe­
tocin in participants with PWS. The primary endpoints as­
sessed the efficacy of 9.6 mg of carbetocin 3 times daily vs
placebo in improving hyperphagia and obsessive-compulsive
symptoms during the 8-week PCP, measured by change in to­
tal scores on the Hyperphagia Questionnaire for Clinical
Trials (HQ-CT) and Children’s Yale-Brown Obsessive-
Compulsive Scale (CY-BOCS), respectively. A secondary
endpoint assessed efficacy of the lower, 3.2 mg 3 times daily,
dose of carbetocin vs placebo using these same instruments.
Additional secondary endpoints evaluated efficacy of each
dose (9.6 mg or 3.2 mg 3 times daily) vs placebo in improving
PWS-specific anxiousness and distress behaviors, measured by
the PWS Anxiousness and Distress Behaviors Questionnaire
(PADQ), and evaluated efficacy in improving overall clinical
symptoms of PWS, assessed by clinician-rated clinical global
impression of change (CGI-C) scores. Prespecified secondary
endpoints also further evaluated effects on hyperphagia using
2 different prespecified subsets of the HQ-CT: a subset focus­
ing on items less affected by food-related environmental con­
trols (the HQ-CT subset, including questions 1, 2, 5, 6, 8, and
9) and analysis of scores on HQ-CT question 9 in isolation.
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Prespecified exploratory analyses evaluated improvements
in clinical global impression of severity (CGI-S) scores and
long-term assessments of efficacy observed through the week
64 LTFU trial visit.
Exploratory efficacy objectives included assessments of the
proportion of participants who exhibited clinically meaning­
ful responses to carbetocin vs placebo, and post hoc analyses
included within-participant efficacy comparisons of partici­
pants assigned to placebo and then later to receive 3.2 mg of
carbetocin during the LTFU.
Safety and tolerability objectives were to establish the safety
profile of carbetocin in individuals with PWS. Assessments in­
cluded evaluations of reported TEAEs and frequency of and
reasons for trial discontinuation.
Participants
Key eligibility criteria included genetically confirmed diagnoses
of PWS and age between 7 and 18 years at screening with a total
HQ-CT score ≥13 (18) and total CY-BOCS score ≥9 (19). These
thresholds were selected to ensure the presence of sufficient base­
line scores to detect a potential treatment effect and were not
communicated publicly during the study. Participants were re­
quired to be under the care and observation of a consistent care­
giver; accordingly, those living in group homes were not eligible.
Chronic concomitant medications or supplements were required
to remain stable for at least 3 months before the trial.
Participants were disqualified from participating if they had tak­
en prostaglandins, prostaglandin analogs or agonists, and/or
weight loss medications within 6 months of screening.
Anti-inflammatory medications were allowed. Participants
with a history of oxytocin or carbetocin use were required to
have abstained from use of these medications within 3 months
of screening. Participants were excluded if they had a history
of psychotic symptoms, venous thrombosis or pulmonary em­
bolism, nasal surgery within 6 months of screening, or nasal dis­
orders that could significantly affect drug administration.
Participants were prohibited from adding new food-related in­
terventions (including environmental or dietary restrictions)
within 1 month of screening and during the trial, as well as
use of nasal saline, irrigation, or other nasal medications for
2 weeks before the baseline visit and during the 8-week PCP
of the trial. Participants who completed the 8-week PCP were
given the option to continue to the LTFU portion of the trial.
Randomization and Masking
Trial enrollment began on December 6, 2018, and was closed
prematurely on March 12, 2020, before the target enrollment
number of 175 participants because of the impact of
The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 7
COVID-19. Participants were randomized through an inter­
active web response system. Randomization was performed
before baseline to give adequate time to thaw vials for the first
dose administered at the baseline visit. The randomization ra­
tio was defined to be 2:2:1:1 into 4 trial arms: 9.6 mg carbeto­
cin 3 times daily, during PCP and LTFU; 3.2 mg carbetocin 3
times daily, during PCP and LTFU; placebo 3 times daily dur­
ing the PCP and 9.6 mg carbetocin 3 times daily during LTFU;
and placebo 3 times daily during the PCP and 3.2 mg carbeto­
cin 3 times daily during LTFU. Efficacy analyses of the PCP
pooled the 2 placebo arms together, resulting in a 1:1:1 ran­
domization ratio. The sponsor (Levo Therapeutics), investiga­
tors, caregivers, and participants were blinded to the assigned
treatments during both the PCP and LTFU. To attempt to min­
imize placebo effects to the extent possible, standardized video
training modules aimed at accurate reporting and placebo re­
sponse reduction for caregivers and clinicians were developed
by an organization specialized in mitigating placebo response
in clinical trials (Analgesic Solutions, Wayland, MA).
Following completion of the placebo-controlled period and
unblinding of efficacy results, all participants were transi­
tioned to the 3.2-mg dose in October 2020.
The sponsor completed blinded safety reviews throughout
the trial. An independent data safety monitoring committee
periodically reviewed unblinded safety data. No safety events
were observed during the trial that required unblinding of a
trial participant’s treatment assignment.
Procedures
Investigational product (carbetocin and placebo) was admin­
istered intranasally 3 times per day with meals with a min­
imum of 2.5 hours between doses. The placebo and both
doses of carbetocin were matched for taste and odor to pre­
vent unblinding and were identical in all properties except
for the absence of the active ingredient in the placebo vials.
Each vial provided 3 doses of study drug or placebo that
was to be used with an attachable nasal spray pump. Each
dose consisted of 2 sprays in each nostril, for a total of
4 sprays. Administration was assisted by the caregiver or a
helper (in the event the participant was at school or other ac­
tivities during administration).
Efficacy and safety were assessed at baseline, during the
PCP trial visits at week 2 and week 8, and during the LTFU
period trial visits at weeks 10, 16, 28, 40, 52, and 64.
Caregivers or designees were required to record all doses of
study drug administration on a paper dosing diary and return
diaries to the site staff at trial visits for confirmation of treat­
ment compliance. During the COVID-19 pandemic, trial visits
were conducted remotely via telemedicine, if necessary.
Participants’ hyperphagia symptoms were assessed using
the HQ-CT, which is currently considered the consensus in­
strument for evaluation of hyperphagia behavior in PWS.
The HQ-CT is a 9-item validated questionnaire (total score
range, 0-36) designed to be completed by caregivers of indi­
viduals with PWS and which has been used in other PWS clin­
ical trials (18). Reductions in scores reflect improvements in
hyperphagia. A subset of the HQ-CT items (including ques­
tions 1, 2, 5, 6, 8, and 9), which are less susceptible to envir­
onmental controls imposed by caregivers, was used as a
secondary efficacy endpoint. HQ-CT question 9 asks the care­
giver to rate the overall level of interference that hyperphagia
causes in the daily life of the individual with PWS, can be used
1699
for an overall assessment of improvement, and was also pre­
specified as a secondary endpoint.
Obsessive-compulsive symptoms were assessed using the
CY-BOCS. This scale is a validated, clinician-administered,
semistructured inventory of specific symptoms and severity
with a total score range of 0 to 36. Reductions in scores reflect
improvements in obsessions and compulsions. The scale is va­
lidated for diagnosis and evaluation of pediatric obsessive-
compulsive disorder (19). It has not been validated specifically
for use in the PWS population.
The PADQ was administered to assess PWS-specific anx­
iousness and distress behaviors. The PADQ is a validated
15-item caregiver-reported instrument designed to capture
the observable signs of anxiousness and distress that are com­
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mon among individuals with PWS. The total score of 0 to 56 is
based on responses to the first 14 items, with higher scores in­
dicating greater levels of anxiousness and psychological dis­
tress. The fifteenth question is an overall summary of
caregivers’ observations and is not included in the total score.
The Clinical Global Impression (CGI) scale is among the
most widely used brief assessment tools in psychiatry. The
CGI provides a clinician rating relative to the clinician’s experi­
ence with other individuals with the same diagnosis (20). This
scale measures the current severity of illness (CGI-S) and global
change (CGI-C) in the severity of illness from baseline, each on
a 7-point scale. The CGI-S uses a range of responses from 1
(normal) to 7 (among the most severely ill). The CGI-C uses
a range of responses from 1 (very much improved) to 7 (very
much worse). The CGI-C instrument was used as a secondary
endpoint and the CGI-S was a tertiary endpoint.
Safety was monitored throughout the trial. Safety assessments
included incidence and severity of adverse events, as well as as­
sessment of vital signs, electrocardiograms, physical examina­
tions, nasal examinations, and laboratory assessments
(including chemistry, hematology, coagulation, and urinalysis).
Statistical Analyses
Results from the phase 2 trial of carbetocin in PWS were used
as the basis for powering this trial (17). Planned enrollment of
175 participants would confer ≥90% power for the HQ-CT
and ≥99% power for the CY-BOCS to detect a treatment
arm difference in the total score change from baseline to
week 8 in the 9.6-mg arm vs placebo. The trial type I error
probability (alpha) was specified to be 2-sided 0.05, with
multiplicity control for the 2 primary outcomes using the
Hochberg step-up procedure (21, 22), thereby potentially
leading to primary outcome success if either or both outcomes
met statistical criteria.
Analyses included three analysis sets: the primary analysis
set (PAS), the full analysis set, and the safety analysis set
(SAS). Following consultation with the Food and Drug
Administration and before unblinding, the PAS was defined
to include all participants who completed at least 1 post-base­
line visit (ie, week 2 or week 8) before March 1, 2020, and was
used for all efficacy analyses in the PCP. This data cutoff date
was used to minimize the potential confounding effects of the
onset of the COVID-19 pandemic on behavioral measures in
this sensitive population, resulting in 68% of the intended trial
size. Data from those withdrawing before the cutoff date were
included in the PAS even if no postbaseline visits were re­
corded. The full analysis set included all participants who
were randomized and dosed with study medication and was
1700
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.
used for efficacy analyses in the LTFU period. TEAE incidence
and severity, discontinuations, and other safety measures used
the SAS, which included all participants who received at least
1 dose of study drug.
Efficacy analyses used the constrained longitudinal data
analysis mixed model with repeated measures (23-25) without
imputation. Sensitivity analyses were performed to confirm
robustness of results to missing data and demonstrate consist­
ency in results and conclusions. Statistical comparisons were
conducted using SAS, version 9.4 (SAS Institute, Cary, NC).
Within-participant response to treatment for the HQ-CT
was evaluated as the proportion of participants that achieve
a 7.7-point reduction in total score, a responder threshold de­
fined when validating the HQ-CT instrument (18) and con­
sistent with anchor-based analyses of the CARE-PWS data.
Within-participant response to treatment for the PADQ was
similarly evaluated as the proportion of participants that
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).
For placebo-crossover analyses, mean changes in HQ-CT
and PADQ from baseline to week 8 were compared with
mean changes from week 8 to week 16 in participants that
transitioned from placebo to active treatment arms during
the LTFU period.
All efficacy results analyzed participants according to the
dose arm to which they were originally assigned. Analyses
of safety data included assessments of TEAE incidence rates
and percentages of participants in each arm who experienced
a TEAE, including severity and relatedness to treatment.
Results
A total of 176 participants entered screening and 138 of those
participants were randomized to receive study treatment
(Fig. 1). Because intranasal carbetocin required overnight
thawing before use, randomization occurred after screening,
The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 7
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but before enrollment confirmation at the baseline visit.
Eight randomized participants failed screening criteria or
withdrew consent at the baseline visit and were therefore ex­
cluded from enrollment before receiving the investigational
product, for a total of 130 participants receiving at least
1 dose of the study medication. Of those 130 participants,
128 completed their week 8 visit (2 participants in the
9.6-mg dose arm discontinued before week 8) and 103 com­
pleted the trial (17 participants in the 9.6-mg LTFU dose
arm and 8 participants in the 3.2-mg LTFU dose arm discon­
tinued before their week 64 visit). The PAS included 119
evaluable participants with at least 1 postbaseline visit before
the March 1, 2020, data cutoff date, 104 of which had com­
pleted their week 8 visit before the cutoff date.
Randomization resulted in treatment arms that were gener­
ally well-balanced with respect to baseline demographics as
well as baseline PWS characteristics (Table 1).
Efficacy Outcomes
Participants taking carbetocin showed numerical improve­
ments vs placebo in 11 of the 12 specified primary and second­
ary endpoints (Table 2). The 2 primary endpoints assessing
change in HQ-CT and CY-BOCS for the 9.6-mg carbetocin
arm showed numeric improvements vs placebo that did not
reach statistical significance; therefore, the trial did not meet
its primary endpoint and all other statistical analyses are con­
sidered nominal. Results for the 3.2 mg dose arm showed con­
sistent and nominally significant improvements in multiple
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 =
0.011), anxiousness and distress (PADQ −3.8, P = 0.027), and
clinical global impressions of change (CGI-C −0.5, P = 0.027).
Responder analyses for the 3.2-mg dose further supported the
existence of clinically meaningful improvements in participants’
hyperphagia, anxiousness, and distress symptoms, with
The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 7 1701

Table 1. Baseline demographics and PWS characteristics (primary analysis set)

Placebo-controlled period

3.2 mg 9.6 mg All placebo

(N = 39) (N = 40) (N = 40) P value

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

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Asian 2 (5.1) 2 (5.0) 0
Black/African American 2 (5.1) 1 (2.5) 1 (2.5)
White 33 (84.6) 33 (82.5) 35 (87.5)
Other 2 (5.1) 3 (7.5) 4 (10.0)
Ethnicity, n (%)
Hispanic or Latino 5 (12.8) 3 (7.5) 3 (7.5) 0.643
Not Hispanic or Latino 34 (87.2) 37 (92.5) 37 (92.5)
Baseline weight, kg
Mean (SD) 58.98 (24.5) 61.36 (32.5) 53.59 (25.5) 0.347
Baseline BMI
Mean (SD), kg/m2 26.43 (8.3) 26.30 (9.2) 24.35 (8.8) 0.453
z-score mean (SD) 1.45 (0.96) 1.52 (0.86) 1.14 (1.00) 0.164
Genetic subtype of PWS, n (%)
Deletion type 1 5 (12.8) 2 (5.0) 3 (7.5) 0.858
Deletion type 2 2 (5.1) 5 (12.5) 5 (12.5)
Deletion type unknown 16 (41.0) 19 (47.5) 14 (35.0)
UPD 9 (23.1) 8 (20.0) 9 (22.5)
ID 1 (2.6) 1 (2.5) 3 (7.5)
Unknown 6 (15.4) 5 (12.5) 6 (15.0)
Baseline total scores, mean (SD)
HQ-CT 22.1 (5.1) 23.4 (5.7) 22.4 (4.7) 0.536
CY-BOCS 25.5 (4.1) 28.4 (4.0) 27.8 (6.0) 0.606
PADQ 43.1 (6.9) 42.6 (7.2) 43.9 (6.7) 0.706

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
participants on carbetocin than those on placebo. Responder
thresholds for these instruments were defined using an anchor-
based approach considering changes in CGI-C and correlating
those changes to changes in questionnaire total scores. In the ag­
gregate, these methods provide a range of 4- to 9-point improve­
ments for HQ-CT and a range of 6- to 13-point improvements
in PADQ. Conclusions from responder analyses for HQ-CT to­
tal scores are robust across a range of potential thresholds
(Fig. 3A). Specifically, responder rates for the 3.2-mg dose con­
sistently favored active treatment with odds ratios exceeding 3
for all thresholds and P values (2-sided Fisher exact test) below
0.05 for all but the highest threshold. Responder analyses for
PADQ total scores are shown in Fig. 3B, and again consistently
favored the 3.2-mg dose with P values (2-sided Fisher exact test)
below 0.05 for all but 2 thresholds of improvement.
Participants transitioning from placebo to the 3.2 mg dose
arm at the end of the placebo-controlled period exhibited
substantial improvements in hyperphagia scores in their first
8 weeks on active drug when compared with their experi­
ence during their 8 weeks on placebo (Table 3), consistent
with the observations seen during the PCP for active vs pla­
cebo. The corresponding comparisons for participants tran­
sitioning to 9.6 mg were unremarkable and therefore
consistent with what was observed in the PCP for 9.6 mg
participants.
Improvements from baseline in efficacy assessments per­
sisted throughout the long-term follow-up period (Fig. 4).
Notably, although the 3.2 mg dose continued to provide
equivalent or superior efficacy to that of the 9.6 mg dose,
even participants taking the 9.6 mg dose who chose to stay
in the trial continued to experience substantial, clinically
meaningful, and sustained improvements from baseline
throughout the LTFU period. These observations were con­
sistent across both doses and across multiple efficacy assess­
ments including the HQ-CT (Fig. 4A), CY-BOCS (Fig. 4B),
and PADQ (Fig. 4C). Although there appeared to be a numer­
ically greater improvement in the placebo-to-9.6-mg
1702 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 7

Table 2. Primary and secondary efficacy results

3.2-mg carbetocin 9.6-mg carbetocin Placebo

(N = 39) (N = 40) (N = 40)

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

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Baseline mean (SD) 25.5 (4.10) 28.4 (3.97) 27.8 (6.01)
Change from baseline to week 8
LS mean (SE) −3.1 (0.87) −3.0 (0.86) −2.4 (0.86)
LS mean difference vs placebo −0.8 −0.6 —
(95% CI of LS mean differences) (−3.1 to 1.5) (−2.9 to 1.7) —
Two-sided P value vs placebo 0.514 0.600 —
PADQ
Baseline mean (SD) 43.1 (6.94) 42.6 (7.23) 43.9 (6.74)
Change from baseline to week 8
LS mean (SE) −8.3 (1.26) −4.3 (1.26) −4.5 (1.24)
LS mean difference vs placebo −3.8 0.2 —
(95% CI of LS mean differences) (−7.2 to −0.4) (−3.2 to 3.5) —
Two-sided P value vs placebo 0.027 0.914 —
CGI-C
Week 8 mean (SD) 3.4 (0.95) 3.6 (0.98) 3.9 (0.87)
Week 8
LS mean (SE) 3.4 (0.17) 3.6 (0.17) 3.9 (0.17)
LS mean difference vs placebo −0.5 −0.3 —
(95% CI of LS mean differences) (−0.9 to −0.1) (−0.7 to 0.1) —
Two-sided P value vs placebo 0.027 0.160 —
HQ-CT subset
Baseline mean (SD) 17.4 (3.66) 17.8 (3.76) 17.3 (3.66)
Change from baseline to week 8
LS mean (SE) −4.6 (0.71) −3.3 (0.70) −2.2 (0.69)
LS mean difference vs placebo −2.4 −1.1 —
(95% CI of LS mean differences) (−4.3 to −0.5) (−2.9 to 0.8) —
Two-sided P value vs placebo 0.011 0.248 —
HQ-CT question 9
Baseline mean (SD) 2.8 (1.33) 3.3 (0.88) 3.1 (1.08)
Change from baseline to week 8
LS mean (SE) −0.9 (0.18) −0.5 (0.18) −0.5 (0.18)
LS mean difference vs placebo −0.4 −0.1 —
(95% CI of LS mean differences) (−0.9 to 0.1) (−0.5 to 0.4) —
Two-sided P value vs placebo 0.114 0.832 —

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
period, these data should be interpreted with caution because
of small sample sizes in these subgroups and the confounding
effect of survivor bias, and in particular because the number of
discontinuations was disproportionate among those random­
ized to 9.6 mg. Overall, results were broadly similar for all
participants, including those initially randomized to placebo
(Fig. 4).
Safety Results
In the PCP, 63.2% of participants receiving carbetocin, in­
cluding 60.5% of participants (n = 26) in the 3.2-mg arm
The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 7
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.
and 65.9% of participants (n = 29) in the 9.6-mg arm, re­
ported at least 1 TEAE, compared with 55.8% of participants
(n = 24) in the placebo arm (Table 4). Most TEAEs were mild
to moderate in intensity. Only 1 severe TEAE was reported
during the placebo-controlled period in the 9.6-mg arm
(2.3%); the participant experienced an episode of severe sinus
pain during landing of an airplane flight while suffering from a
sinus infection, which subsequently resolved with oral
antibiotics.
The most frequently reported TEAE by preferred term dur­
ing the PCP was flushing (17.2%), which was mild to moder­
ate in severity. The incidence of flushing was lower in
participants in the 3.2 mg arm (14.0%) compared with the
9.6 mg arm (20.5%), and no participants in the placebo arm
reported a TEAE of flushing. The occurrence of transient
flushing is consistent with previous reports that oxytocin
and oxytocin agonists can be associated with transient periph­
eral vasodilation (26). Flushing was also the most frequently
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,
not serious, and self-limited (generally resolving spontaneous­
ly within 30 minutes).
The most frequently reported TEAEs during the LTFU and
extension periods were nasopharyngitis (10.9% of all partic­
ipants, including 9.4% and 12.1% of participants in the
3.2 mg and the 9.6 mg arms, respectively), headache (11.7%
of all participants, including 15.6% and 7.8% of participants
in the 3.2 mg and the 9.6 mg arms, respectively), and epistaxis
(10.9% of all participants and for both dose arms). In com­
parison, during the placebo-controlled period, the incidence
of nasopharyngitis was 1.1% in the LV-101 all active arm
(0 in the 3.2-mg/dose arm and 2.3% in the 9.6 mg/dose
arm) and 7.0% in the placebo arm.
No deaths or treatment-emergent serious adverse events
were reported during the PCP. No study drug discontinua­
tions were reported during the PCP by participants in the pla­
cebo arm or the 3.2 mg arm. A total of 3 participants (6.8%)
in the 9.6-mg arm reported TEAEs during the PCP that led to
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trial discontinuation (2 of the discontinuations occurred in the
PCP and 1 occurred in the LTFU period).
Although the rates of adverse events were generally similar
between dose arms, discontinuations from behavior-related
adverse events among participants taking 9.6 mg carbetocin
were higher than those taking 3.2 mg (n = 6 vs 2, respectively),
and all reported TEAEs of aggression in both the PCP and
LTFU period were in participants in the 9.6 mg/dose arm
(n = 1 and 3, respectively). This is consistent with discontinu­
ations from the trial generally, which were also more common
among participants receiving 9.6 mg carbetocin vs those re­
ceiving 3.2 mg (n = 19 and 8, respectively; Fig. 1).
Evaluation of additional safety data including laboratory
assessments (hematology, coagulation, clinical chemistry,
and urinalysis), physical examination findings, Tanner sta­
ging, electrocardiograms, weight, body mass index, and vital
signs did not reveal clinically relevant trends associated with
study medication.
Discussion
The therapeutic rationale for investigating carbetocin as a po­
tential treatment for PWS is based on its role as a selective oxy­
tocin receptor agonist with prolonged half-life relative to
native oxytocin itself, potentially enabling replacement of
the functional oxytocin deficiency in PWS while minimizing
off-target effects related to oxytocin’s lack of selectivity that
may have limited previous attempts at treatment.
To date, 5 clinical studies have reported the effects of intra­
nasal oxytocin in PWS (27-31). Oxytocin replacement has
shown varying degrees of efficacy, but has also been associ­
ated with an increase in temper outbursts after 8 weeks of
treatment, driven by significant increases in outbursts ob­
served in participants with PWS receiving higher doses
(27). It has been hypothesized that the off-target effects of
oxytocin binding to vasopressin receptors may be limiting
its therapeutic window in PWS (27). Because of oxytocin’s
lack of selectivity, off-target activation of the vasopressin
1A receptor (V1aR) with high doses of oxytocin may
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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.

Table 3. Placebo-crossover participants

Placebo-to-3.2-mg carbetocin Placebo-to-9.6-mg carbetocin

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
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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

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tract infection
Nasal discomfort 3 (7.0) 2 (4.5) 5 (5.7) 1 (2.3)
Fatigue 3 (7.0) 1 (2.3) 4 (4.6) 0 betocin showed a statistically significant improvement in hy­
Pyrexia 3 (7.0) 0 3 (3.4) 0 perphagia scores, whereas the phase 3 study showed a
Nasopharyngitis 0 1 (2.3) 1 (1.1) 3 (7.0)
Note: A TEAE is defined as an AE occurring after the initial dose of IP;
participants may have more than 1 TEAE per SOC and/or PT. At each level
of participant summarization (SOC and PT), participants who experienced 1
or more AEs within that level are only counted once for that level; the PTs
included are only those reported by ≥5% participants in any treatment, thus,
addition of the numbers in the SOC and/or PT rows does not equal the
number in the “at least 1 TEAE” row.
Abbreviations: AE, adverse event; MedDRA, Medical Dictionary for
Regulatory Activities; IP, Investigational Product; PCP, placebo-controlled
period; PT, Preferred Term; SOC, System Organ Class; TEAE,
treatment-emergent adverse event.
on the encouraging results of an earlier phase 2 trial and sup­
ports that carbetocin can meaningfully improve both hyper­
phagia and anxiousness and distress behaviors in individuals
with PWS while maintaining a favorable safety profile with
chronic use.
Two doses were tested in this phase 3 trial, using the higher
dose of 9.6 mg for the primary endpoints and the lower 3.2 mg
dose for the first secondary endpoints. The primary analysis of
the higher 9.6 mg dose arm demonstrated numeric improve­
ments in HQ-CT and CY-BOCS scores vs placebo, which
did not reach statistical significance in this truncated trial;
therefore, the trial did not meet its primary endpoint.
However, the first secondary endpoint evaluating efficacy of
the 3.2 mg dose arm demonstrated meaningful and nominally
significant improvements in hyperphagia vs placebo. The
3.2 mg dose additionally showed consistent improvements
vs placebo across multiple secondary endpoints, including as­
sessments of anxiousness and distress behaviors. These im­
provements were subsequently maintained throughout the
observed 56-week follow-up period and were clinically mean­
ingful. As additional clinical context, in a natural history
study of individuals with PWS living in the United States
(33), HQ-CT scores were not observed to change significantly
between baseline and 6 months of follow-up, and most indi­
viduals’ HQ-CT score changes were between 0 to 2.
The safety data support that intranasal carbetocin is safe
and well tolerated in participants with PWS, consistent with
the existing favorable safety profile of IV carbetocin in clinical
use for obstetric indications. The most frequent TEAE ob­
served during the placebo-controlled period was flushing,
which was mild and self-limited. Consistent with the hypoth­
esis that the lower 3.2 mg dose may be associated with lower
off-target activity, trial data also suggest a more favorable
long-term tolerability profile for 3.2 mg carbetocin during
false-negative trial result may be obtained.
We note that the previous phase 2 study of 9.6 mg/dose car­
smaller trend for improvement in this dose group that did
not reach significance. Although the potential reasons for
this are difficult to determine definitively, contributing factors
may include greater variability because of increased numbers
of study sites (24 vs 3) and differences in the measurement of
hyperphagia (the HQ-CT vs a different hyperphagia question­
naire, the Hyperphagia in PWS Questionnaire Responsiveness
[HPWSQ-R], which had more and differently worded
questions).
The current study also unexpectedly observed superior effi­
cacy in the 3.2 mg/dose arm relative to the 9.6 mg/dose arm.
Although the reasons for this are not known conclusively,
we note that relevant prior literature regarding use of exogen­
ous oxytocin in PWS suggest that increased off-target vaso­
pressin receptor agonism at high doses may be associated
with increased emotional outbursts, which, in turn, may neg­
ate the ability of an individual to experience the beneficial be­
havioral effect of oxytocin receptor agonism (27).
Cell-based functional reporter assays reveal that carbetocin
has substantially greater affinity for oxytocin receptors com­
pared with vasopressin receptors (half maximal effective con­
centration [EC50] of 0.7, 41, and 172 nM for the oxytocin,
V1a, and V2 receptors, respectively), whereas oxytocin itself
has similar affinities for oxytocin receptors and the V1a and
V2 vasopressin receptor subtypes (EC50 of 2.3, 10, and
7 nM, respectively). In addition to the observed differences
in EC50, carbetocin also appears to have less functional activ­
ity on the V1aR following receptor binding (maximum pos­
sible effect of 24% vs 88% with oxytocin). Although the
enhanced selectivity of carbetocin may mitigate off-target ef­
fects, carbetocin nonetheless has some vasopressin receptor
activity (eg, V1aR) at higher doses, which may mute efficacy
given the overlapping nature of the behaviors measured. As
another potential hypothesis, if higher doses were associated
with greater desensitization of oxytocin receptors, this could
also potentially contribute to the observed difference in effi­
cacy. Such potential unintended effects of oxytocin agonists
at high doses may explain why, although numerical improve­
ments were observed in the 9.6 mg/dose arm, they were lesser
than those observed in the 3.2 mg/dose arm and did not reach
statistical significance.
Despite limitations including an unplanned truncation of
enrollment because of the COVID-19 pandemic, the
CARE-PWS trial demonstrates that 3.2 mg intranasal carbeto­
cin is associated with clinically meaningful and sustained
The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 7
improvements in hyperphagia and behaviors of anxiousness
and distress in individuals with PWS and demonstrates a fa­
vorable safety profile. The highly positive benefit/risk relation­ 9.
ship in the face of substantial unmet medical needs of
individuals with PWS warrant continued investigation of car­
10.
betocin as a potential treatment.
Acknowledgments 11.
Levo Therapeutics and the investigators would like to thank
all of the clinical site support staff who assisted with coordin­ 12.
ation and collection of trial data and, most importantly, the
individuals with PWS and their families who participated in 13.
the trial, as well as Scientific Commercialization for their as­
sistance with medical writing and author review collation.
14.
Disclosures
E.R., C.L.D., S.E.M., R.L.C., J.L.M., J.K.K., E.R.R., S.E.
McCandless, T.R.L., H.D.A., A.M.H., K.S.O., L.C.T.,
A.P.V., D.H.V., J.C., C.K.L., M.P., L.L.W., L.M.B., M.G.B., 15.
D.E.J., S.E. McCormack, O.J.O., C.B., L.J.C., C.F., N.A.,
16.
S.D.M., A.S., and B.Y.W. received research funding to their
institutions from Levo Therapeutics for the conduct of this
study. E.R., S.E. McCandless, C.L.D., and B.A.B. received
consulting fees from Levo Therapeutics. A.M.H. is an investi­ 17.
gator for trials sponsored by Rhythm Pharmaceuticals. S.F.L.,
J.P.E., J.W.C., D.C.R., and S.P.C. were employees of Levo
Therapeutics. 18.
Data Availability
Restrictions apply to the availability of some or all data gen­ 19.
erated or analyzed during this study to preserve patient confi­
dentiality or because they were used under license. The
corresponding author will on request detail the restrictions 20.
and any conditions under which access to some data may be
provided.
21.
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