Oxytocin treatment in neonates and infants aged from 0 to 3 months with prader-willi syndrome: a study of the safety and efficacy on oral and social skills and, feeding behavior of intranasal administrations of oxytocin vs. placebo (phase iii clinical trial)

Prader-Willi syndrome (PWS) is a genetic neurodevelopmental orphan disease
caused by the lack of expression of paternally derived alleles of imprinted
genes in the 15q11-q13 chromosomal region. It is the main cause of syndromic
obesity, with an incidence of around 1/20 000 at birth. From birth to 9 months,
all infants with PWS display severe hypotonia combined with poor appetite
similar to anorexic behavior, poor suck and swallowing troubles that lead to
nasogastric tube feeding in 80% of cases to ensure normal weight gain. Genetic
diagnosis made in the first months of life based on the neonatal phenotype
initiates multidisciplinary care and offers a unique window of opportunity for
early treatment. Both PWS mouse models and patients display a significant
decrease in the number and volume of hypothalamic Oxytocin (OT)-producing
neurons. OT is a neuropeptide which, besides its known actions on uterus and
lactation, is involved in social interactions and mother-infant bonding.
Interestingly, OT has opposite effects throughout life i.e. stimulating food
intake in the neonatal period and then controlling satiety later on. Our
hypothesis is that a deficit of OT may explain the neonatal phenotype with poor
feeding and social cues and may be involved in the lack of satiety later in
life in PWS. We already performed a tolerance study (OTBB1, phase I) and a
proof-of-concept study (OTBB2, phase I/II multiple-ascending dose
safety/efficacy). We showed that OT is well tolerated in neonates/infants with
PWS and improves feeding and social skills when administered early in life.
These results offer promising perspectives for early treatment in
neurodevelopment diseases with feeding problems and prompt us to perform a
phase III study to demonstrate the effect of OT on oral and social skills in
neonates/infants with PWS. This phase III is a multicentric, prospective,
randomized trial which comprises two parts: a part 1 which is an efficacy study
(OT versus Placebo) and a part 2 which is an exploratory study to provide
further information on the use of intranasal OT.

The primary objective is to demonstrate the superiority versus placebo of a 4
weeks intranasal OT administration on oral skills assessed by the Neonatal
Oral-Motor Assessment Scale (NOMAS) in infants with PWS aged less than or equal
to 3 months at inclusion.

The secondary objectives are to document the effects of 1 week and 4 weeks
intranasal OT administration versus Placebo on:
- Sucking/swallowing troubles assessed by videofluoroscopy
- Social withdrawal assessed by Alarm Distress Baby Scale (ADBB)
- Child state, social engagement and mother-infant interactions assessed by
Coding Interactive Behaviour (CIB) subscores *
- Food intake assessed by proficiency score
- Levels of circulating forms of ghrelin
- Parent assessment of feeding
- OT levels
- To document the safety of repeated OT administration for 4 weeks or 8 weeks
with total follow-up over 26 weeks.

The exploratory objectives are to further evaluate the effects of intranasal OT
vs. placebo on:
- Videofluoroscopy total score
- CIB subscores (parental sensitivity, parental intrusiveness, child
withdrawal, dyadic joint negative state)
- Duration of nasogastric tube (NGT) feeding
- Modifications of brain connectivity during resting state (MRI)
- Growth, weight and Head Circumference
- Nutritional phase
- Parental skills
Blood and gut microbiota
- OT circulating levels after OT/placebo administration
- Urinary OT levels Parent observation of feeding (diary-report)
And to
- Compare 4 vs. 8 weeks of intranasal OT administration in terms of NOMAS score
and other criteria.
- Compare delayed vs. non-delayed administration of intranasal OT
administration in terms of NOMAS score and other criteria.
- Evaluate the maintenance of effect in terms of other criteria.

For all these parameters: NOMAS score, ADBB score, CIB subscores, circulating
forms of ghrelin, OT levels, growth and body weight, HC, nutritional phase,
parental skills, blood and gut microbiota:
- Perform correlations on biological and MRI biomarkers, and clinical
endpoints.

Phase III: prospective, randomized, Placebo controlled double blind study for 4
weeks, two-arm superiority trial with parallel groups.

Patients will be allocated in four groups at the time of randomization
according to a randomization scheme per centre that will randomize patients in
a 1:1:1:1 ratio in Group 1, 2, 3 or 4 as described below;
Group 1 will receive OT for 8 weeks then Placebo for 4 weeks
Group 2 will receive OT for 4 weeks then Placebo for 8 weeks
Group 3 will receive Placebo for 4 weeks then OT for 8 weeks
Group 4 will receive Placebo for 4 weeks then OT for 4 weeks then Placebo for 4
weeks
After Week 12, neither OT nor Placebo will be administered.

The investigational medicinal product in this study is intranasal oxytocin. A
matching intranasal placebo solution will also be provided as this is a
double-blind study.

There is no specific treatment for sucking-swallowing problems observed in
neonates/infants with PWS. Based on preliminary results obtained in OTBB2 study
regarding the efficacy of OT not only on sucking-swallowing problems but also
on social behavior and mother-infant interactions without any safety concern,
it is justified to study the safety and the efficacy of OT in a double-blind
Placebo controlled study. As exposure to OT will be extended either to 30 or 60
days depending upon the group of patients allocated at the randomization, we
cannot exclude the onset of adverse event that would not occur during a short
7-day exposure. However, the study design comprises 8 visits from the first OT
administration and safety will be closely monitored. Furthermore, extended
patient follow-up during the 26 weeks study period will be scheduled. Long term
safety will be also monitored during a study for all the children up to 4 years.
The risks of participation in the study are thus minimized and the information
to be gained from 30 to 60 days OT exposure in this cohort of neonates/infants
with PWS is of critical importance. Indeed, should the results confirm our
previous results, the benefit for children with PWS and for their family will
be highly significant. In any case, all patients included will benefit from an
optimal follow-up.