Clinical Trials Register

Summary
EudraCT Number:	2021-000094-91
Sponsor's Protocol Code Number:	RC31/20/0518
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-04-01
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2021-000094-91

A.3

Full title of the trial

EFFECT OF INTRANASAL OXYTOCIN ON DYSPHAGIA RELATED TO OROPHARYNGO-OESOPHAGEAL DYSMOTILITY TRANSIT IN CHILDREN AND ADOLESCENTS WITH PRADER-WILLI SYNDROME: A PHASE 3 STUDY (DYSMOT)

EFFETS DE L’ADMINISTRATION INTRANASALE D’OCYTOCINE SUR LA DYSPHAGIE LIÉE À UN TROUBLE DE LA MOTILITE OROPHARYNGO-ŒSOPHAGIENNE CHEZ DES ENFANTS ET DES ADOLESCENTS PORTEURS D’UN SYNDROME DE PRADER-WILLI : ÉTUDE DE PHASE 3 (DYSMOT)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

EFFECT OF INTRANASAL OXYTOCIN ON DYSPHAGIA IN CHILDREN AND ADOLESCENTS WITH PRADER WILLI SYNDROME

EFFETS DE L’ADMINISTRATION INTRANASALE D’OCYTOCINE SUR LA DYSPHAGIE CHEZ LES ENFANTS ET ADOLESCENTS ATTEINTS D’UN SYNDROME DE PRADER-WILLI

A.3.2

Name or abbreviated title of the trial where available

DYSMOT

A.4.1

Sponsor's protocol code number

RC31/20/0518

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Toulouse University Hospital
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	OT4B
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Centre de référence Prader-Willi
B.5.2	Functional name of contact point	TAUBER
B.5.3	Address:
B.5.3.1	Street Address	330 avenue de Grande-Bretagne
B.5.3.2	Town/ city	Toulouse
B.5.3.3	Post code	31059
B.5.3.4	Country	France
B.5.4	Telephone number	+330534 55 85 51
B.5.5	Fax number	+330534 55 85 58
B.5.6	E-mail	tauber.mt@chu-toulouse.fr

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/141302
D.3 Description of the IMP
D.3.1	Product name	OXYTOCIN
D.3.2	Product code	H01BB02
D.3.4	Pharmaceutical form	Nasal spray, solution
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Nasal use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Nasal spray
D.8.4	Route of administration of the placebo	Nasal use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Prader-Willi Syndrome

Syndrome de Prader-Willi

E.1.1.1

Medical condition in easily understood language

Prader-Willi Syndrome

Syndrome de Prader-Willi

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To compare the effect of a 12-week intranasal administration of OT versus (vs) placebo on dysphagia related to OPOD in children and adolescents with PWS.

Comparer l’effet de l’administration intranasale d’ocytocine pendant 12 semaines versus placebo sur la dysphagie liée à un trouble de la motilité oropharyngo-œsophagienne chez des enfants et des adolescents présentant un SPW.

E.2.2

Secondary objectives of the trial

To compare the effect of a 12-week intranasal administration of OT vs placebo on:
• Swallowing symptoms;
• Gastrointestinal disorders;
• Feeding events
• Behavioural problems such as:
o Temper outbursts;
o Skin picking;
• Patient global improvement.
To document the effect of 12-week OT treatment withdrawal on dysphagia related to OPOD and other efficacy parameters.
To document the maintenance of efficacy over a 24 week-intranasal administration of OT.
To document the long-term efficacy up to 48-weeks of intranasal administration of OT.

Comparer l’effet de l’administration intranasale d’ocytocine pendant 12 semaines à un placebo selon les critères suivants :
• Troubles de la déglutition ;
• Troubles digestifs ;
• Evènements particuliers au cours des repas et notamment l’étouffement ;
• Troubles comportementaux, tels que:
o Accès de colère ;
o Grattage compulsif de la peau ;
• Amélioration globale du patient.
Documenter l’effet de l’arrêt du traitement par ocytocine sur la dysphagie reliée à l’OPOD et sur les autres paramètres d’efficacité.
Documenter le maintien d’efficacité de l’administration intranasale d’ocytocine pendant 24 semaines.
Documenter l’efficacité à long terme (jusqu’à 48 semaines) de l’administration intranasale d’ocytocine

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patients aged between 2 and 17,5 years.
2. Genetically confirmed diagnosis of PWS.
3. Parents (or legal representative) have signed the informed consent form and are willing to comply with all study procedures.

1. Patients masculins et féminins âgés de 2 à 17ans et demi.
2. Diagnostic de SPW confirmé génétiquement.
3. Les parents (ou le représentant légal) ont signé le formulaire de consentement éclairé et acceptent de se conformer à toutes les procédures de l’étude.

E.4

Principal exclusion criteria

1. A history of hypersensitivity to the study drug or drugs with similar chemical structures, to excipients of the product, or to latex;
2. Intolerance of intranasal administrations (including when due to a major behavioural problem);
3. Hyponatremia (clinically relevant at the discretion of the investigator);
4. Hypokalaemia (clinically relevant at the discretion of the investigator);
5. Prolongation of the QT interval and/or family history of prolongation of the QT interval;
6. Concomitant treatment prolonging the QT interval;
7. History of abnormal electrocardiogram (ECG) (validated by a cardiologist);
8. Pregnant girls; (for girls aged 14 years of above who do not have contraception and are sexually active, a negative pregnancy test will be required)
9. Patient with clinical signs in the context of contact with SARs-COV2 infected person
10. Patient included in another study protocol on a medicinal product within the last 6 months
11. Administrative problems:

1. Antécédents d’hypersensibilité au médicament à l’étude ou à des médicaments avec des structures chimiques similaires, aux excipients du produit, ou au latex ;
2. Intolérance aux administrations intranasales (y compris celles dues à un problème comportemental majeur) ;
3. Hyponatrémie ;
4. Hypokaliémie ;
5. Allongement de l’intervalle QT et/ou antécédents familiaux d’allongement de l’intervalle QT ;
6. Traitements concomitants allongeant l’intervalle QT ;
7. Antécédents d’électrocardiogramme (ECG) anormal (validé par un cardiologue) ;
8. Femmes enceintes (pour les filles âgées de 14 ans et plus sans contraception et sexuellement actives, a test de grossesse negatf sera requis)
8. Patient inclus dans un autre protocole d’étude portant sur un médicament au cours des 6 derniers mois ;
9. Problèmes administratifs

E.5 End points

E.5.1

Primary end point(s)

The percentage of patients showing normalisation of at least 1 of the following abnormal OPOD subscores after 12 weeks OT / placebo at V2 (groups 1 and 3 vs group 2):
• Oral and pharyngeal propulsion;
• Initiation and synchronisation of swallowing;
• Oesophageal motility.

Pourcentage de patients présentant une normalisation d’au moins un des 3 sous-scores relatifs à l’OPOD anormaux après 12 semaines de traitement par ocytocine vs placebo lors de la V2 (groupes 1 & 3 versus group 2) :
• Propulsion buccale et pharyngée ;
• Initiation et synchronisation de la déglutition ;
• Motilité œsophagienne.

E.5.1.1

Timepoint(s) of evaluation of this end point

visit 2 and (visit 3 for complementary analysis)

visite 2 et (visite 3 pour analyse complémentaire)

E.5.2

Secondary end point(s)

Secondary Endpoints Secondary Efficacy Endpoints:
The following parameters will be assessed for differences between OT and placebo at V2 or change from baseline (groups 1 and 3 vs group 2):
• Swallowing symptoms
• Digestive questionnaire
• Occurrence of feeding events –
• Bristol stool scale
• Temper outbursts questionnaire
• Percentage of patients with improvement in CGI score
•Percentage of patients with improvement in parent/caregiver’s global impression score (overall and by level of improvement);
• Percentage of patients with improvement in CGI specific for skin picking (overall and by level of improvement).

The percentage of normalised OPOD subscores at V2 which became abnormal at V3, in Group 1. All above parameters presented, as percentage of patients at V3 and as change from baseline to V3 vs change from V2 to V3 in Group 1 (withdrawal effect).

The percentage of normalised OPOD subscores at V2 which remains
normal at V3, in Group 3; all above parameters presented, as percentage of patients and as change from baseline to V3 vs change from V2 to V3 in Group 3. (Maintenance of efficacy)

All parameters presented, as percentage of patients and as change from baseline to V4 in all groups (48 weeks for group 3, 36 weeks for group 2 and 24 weeks for group 1) (long-term efficacy).

Other Endpoints:
Plasma OT at V1, V2 and V3.
Acylated ghrelin (AG), unacylated ghrelin (UAG), AG/UAG at V1, V2 and V3.
Safety Endpoints:
• Adverse events;
• Laboratory safety parameters at V1, V2, V3 and V4;
• Vital signs (SBP, DBP and HR) at V1, V2, V3 and V4;
• ECG at V1, V2, and V3.

Critères d’efficacité secondaires :
Les paramètres suivants seront évalués afin de déterminer les différences entre l’ocytocine et le placebo lors de la V2 ou changement par rapport aux valeurs initiales (groupes 1&3 vs groupe 2) :
• Troubles de la déglutition
• Questionnaire digestif
• Evènements particuliers au cours des repas
• Échelle des selles de Bristol
• Questionnaire sur les accès de colère
• CGI
• score des impressions globales
• CGI spécifiques du grattage

Pourcentage des sous-scores, relatifs à l’OPOD, lors de la V2 devenant anormaux lors de la V3 dans le groupe 1. Tous les paramètres ci-dessus présentés en pourcentage de patients lors de la V3 et en changement par rapport aux valeurs initiales lors de la V3 versus changement entre la V2 et la V3 dans le groupe 1 (effet de l’interruption du traitement).

Tous les paramètres ci-dessus présentés en pourcentage de patients et en changement par rapport aux valeurs initiales lors de la V4 dans tous les groupes (48 semaines pour le groupe 3, 36 semaines pour le groupe 2 et 24 semaines pour le groupe 1) (efficacité à long terme).

Autres critères d’évaluation :
Taux d’ocytocine plasmatique lors des visites V1, V2 et V3.
Ghréline acétylée (AG), ghréline non acétylée (UAG), AG/UAG lors des visites V1, V2 et V3.

Critères de sécurité d’emploi :
• Événements indésirables ;
• Paramètres biologiques de sécurité d’emploi lors des visites V1, V2, V3 et V4 ;
• Signes vitaux (PAS, PAD et FC) lors des visites V1, V2, V3 et V4 ;
• ECG lors des visites V1, V2 et V3.

E.5.2.1

Timepoint(s) of evaluation of this end point

Visit 2, Visit 3 and Visit 4

Visite 2 Visite 3 et Visite 4

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

a first period with double blind versus placebo and a second period open label for all patients

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

Dernière visite du dernier patient

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Most patients SPW who will become adults during the trial won't be able to give their consent personnally

La plupart des patients SPW qui deviendront adultes durant l'étude ne pourront pas donner leur consentement eux-mêmes.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

There will be one-month clinical trial exclusion period for the patients enrolled in this study.

Un mois de periode d'exclusion à l'issue de la dernière visite.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-01-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-04-27

P. End of Trial
P.	End of Trial Status	Completed

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