Evaluation of Tolerance, Suckling and Food Intake After Repeated Nasals Administrations of Oxytocin in PWS Infants (OTBB2)

The Prader-Willi syndrome (PWS) includes severe neonatal hypotonia with impaired suckling leading to failure to thrive in the most severe cases, subsequently followed by an early onset of morbid obesity with hyperphagia and deficit of satiety, combined with other endocrine dysfunction probably due to hypothalamic dysfunction. The pathophysiological mechanism of the occurrence of the 2 main nutritional phases of PWS is unknown. Swaab reported a deficit in the oxytocin (OT)-producing neurons of the paraventricular nucleus in the brain of these patients. In addition of its well-known anorexigenic effect, OT is involved in establishing and maintaining social codes. Moreover in a PWS mouse model generated from a MAGEL2 KO gene a single OT injection at 5 hr of life prevent the early death observed in 50 % of the new born mice by recovering normal suckling. Interestingly this effect is no longer observed if OT injection takes place later. Our hypothesis is that early administration of OT in babies with PWS may improve suckling and possibly infant-mother interactions. In our recent study (manuscript in preparation), we have shown that a single intranasal administration of OT is well tolerated. This escalating dose study is designed to evaluate the tolerance of repeated intranasal administration of OT in 3 steps (4IU every other day, 4 IU daily, 4IU twice daily) in babies younger than 5 months with PWS.

Study Overview

• Status: Completed
• Conditions: Prader Willi Syndrome
• Intervention / Treatment: Drug: oxytocin

Detailed Description

Prader-Willi syndrome (PWS) is a rare, complex multisystem genetic disorder arising from the lack of expression of paternally inherited imprinted genes on chromosome 15q11-q13. The syndrome includes severe neonatal hypotonia with impaired suckling leading to failure to thrive in the most severe cases, subsequently followed by an early onset of morbid obesity with hyperphagia and deficit of satiety, combined with other endocrine dysfunction probably due to hypothalamic dysfunction. The pathophysiological mechanism of the occurrence of the 2 main nutritional phases of PWS is unknown. Swaab reported a deficit in the oxytocin (OT)-producing neurons of the paraventricular nucleus in the brain of these patients. In addition of its well-known anorexigenic effect, OT is involved in establishing and maintaining social codes. Moreover in a PWS mouse model generated from a MAGEL2 KO gene a single OT injection at 5 hr of life prevent the early death observed in 50 % of the new born mice by recovering normal suckling. Interestingly this effect is no longer observed if OT injection takes place later. Our hypothesis is that early administration of OT in babies with PWS may improve suckling and possibly infant-mother interactions. In our recent study (manuscript in preparation), we have shown that a single intranasal administration of OT is well tolerated. This escalating dose study is designed to evaluate the tolerance of repeated intranasal administration of OT in 3 steps (4IU every other day, 4 IU daily, 4IU twice daily) in babies younger than 5 months with PWS.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Toulouse, France, 31059
    • Centre de réfrence Prader-Willi, Hospital of infants

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 11 months (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Infants with PWS genetically confirmed
• Aged less than 5 months

Exclusion Criteria:

• Infants presenting hepatic insufficiency
• Infants presenting renal insufficiency
• Infants with abnormal ECG

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: first arm; 4IU of oxytocin every other day	Drug: oxytocin; Intranasal administration; Other Names: Oxytocin (Syntocinon)
Active Comparator: second arm; 4 IU of oxytocin daily	Drug: oxytocin; Intranasal administration; Other Names: Oxytocin (Syntocinon)
Active Comparator: third arm; 4 IU of oxytocin twice daily	Drug: oxytocin; Intranasal administration; Other Names: Oxytocin (Syntocinon)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurence of Adverse Event	Occurrence of adverse event, description and quantification of their severity, imputability to repeated intranasal administration of OT (4IU every other day, 4 IU daily, 4IU twice daily) during the 7 days following the first administration.	up to day 8 (Visit 8)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
NOMAS Score	NOMAS score evaluate sucking/swallowing abilitites of infants during feeding; endpoint is the % of infants who reached a NOMAS score <= 10 (normal score)	Before and after 7 days of treatment
Videofluoroscopy of Swallowing Score	Videofluoroscopy of swallowing score (VFSS score)	before and after 7 days of treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic study	Pharmacokinetic study : measurement of circulating oxytocin levels before administration and every 48hrs.	On day 2, 3, 4, 5, 6, 7, 8

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse
• Investigators: Principal Investigator: Maïthé TAUBER, Endocrinologie pédiatrique, Hospital of Toulouse

Publications and helpful links

General Publications

• Tauber M, Boulanouar K, Diene G, Cabal-Berthoumieu S, Ehlinger V, Fichaux-Bourin P, Molinas C, Faye S, Valette M, Pourrinet J, Cessans C, Viaux-Sauvelon S, Bascoul C, Guedeney A, Delhanty P, Geenen V, Martens H, Muscatelli F, Cohen D, Consoli A, Payoux P, Arnaud C, Salles JP. The Use of Oxytocin to Improve Feeding and Social Skills in Infants With Prader-Willi Syndrome. Pediatrics. 2017 Feb;139(2):e20162976. doi: 10.1542/peds.2016-2976.
• Borie AM, Dromard Y, Guillon G, Olma A, Manning M, Muscatelli F, Desarmenien MG, Jeanneteau F. Correction of vasopressin deficit in the lateral septum ameliorates social deficits of mouse autism model. J Clin Invest. 2021 Jan 19;131(2):e144450. doi: 10.1172/JCI144450.
• Viaux-Savelon S, Rosenblum O, Guedeney A, Diene G, Cabal-Berthoumieu S, Fichaux-Bourin P, Molinas C, Faye S, Valette M, Bascoul C, Cohen D, Tauber M. Dyssynchrony and perinatal psychopathology impact of child disease on parents-child interactions, the paradigm of Prader Willi syndrom. J Physiol Paris. 2016 Nov;110(4 Pt B):427-433. doi: 10.1016/j.jphysparis.2017.08.001. Epub 2017 Sep 1.

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): July 1, 2014
• Study Completion (Actual): July 1, 2014

Study Registration Dates

• First Submitted: July 22, 2014
• First Submitted That Met QC Criteria: July 28, 2014
• First Posted (Estimated): July 31, 2014

Study Record Updates

• Last Update Posted (Estimated): February 21, 2024
• Last Update Submitted That Met QC Criteria: January 25, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Prader Willi
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Congenital Abnormalities; Overnutrition; Nutrition Disorders; Overweight; Genetic Diseases, Inborn; Intellectual Disability; Abnormalities, Multiple; Chromosome Disorders; Obesity; Prader-Willi Syndrome; Physiological Effects of Drugs; Reproductive Control Agents; Oxytocics; Oxytocin
• Other Study ID Numbers: 12 391 02; 1239102 (Other Grant/Funding Number: Toulouse University Hospital Funding)