Clinical Trials Register

Summary
EudraCT Number:	2012-003750-89
Sponsor's Protocol Code Number:	KKS-186
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-11-21
Trial results	View 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

Germany - BfArM

A.2

EudraCT number

2012-003750-89

A.3

Full title of the trial

A placebo-controlled, double blind, randomised trial with crossover-design investigating the effect of oxytocin nasal spray on neuronal processes of empathy

Placebo-kontrollierte, doppelblinde, randomisierte Studie mit Crossover-Design zur Untersuchung des Effekts von intranasalem Oxytocin auf die neuronalen Prozesse der Empathie

A.3.1

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

Empathy, Autism and Oxytocin – an investigation by means of functional magnetic resonance imaging and moleculargenetic analyses

Empathie, Autismus und Oxytocin - Eine Untersuchung mittels funktioneller Bildgebung und molekulargenetischer Analysen

A.3.2

Name or abbreviated title of the trial where available

empathy-autism-oxytocin

Empathie-Autismus-Oxytocin

A.4.1

Sponsor's protocol code number

KKS-186

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Philipps-University Marburg
B.1.3.4	Country	Germany
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	Deutsche Forschungsgemeinschaft
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Koordinierungszentrum für Klinische Studien der Philipps-Universität Marburg
B.5.2	Functional name of contact point	Katarzyna Piskulak
B.5.3	Address:
B.5.3.1	Street Address	Karl-von-Frisch-Str. 4
B.5.3.2	Town/ city	Marburg
B.5.3.3	Post code	35043
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49064212826503
B.5.5	Fax number	+49064212866517
B.5.6	E-mail	katarzyna.piskulak@kks.uni-marburg.de

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	Yes
D.2.1.1.1	Trade name	Syntocinon® spray
D.2.1.1.2	Name of the Marketing Authorisation holder	Defiante Farmaceutica, Funchal, Portugal
D.2.1.2	Country which granted the Marketing Authorisation	Austria
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Oxytocin nasal spray (Syntocinon® spray)
D.3.4	Pharmaceutical form	Nasal spray
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intranasal use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	oxytocin
D.3.9.1	CAS number	50-56-6
D.3.9.3	Other descriptive name	OXYTOCIN
D.3.9.4	EV Substance Code	SUB09580MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
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	Intranasal use (Noncurrent)

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

high-functioning autism spectrum disorders: autistic disorder (F84.0), Asperger syndrome (F84.5), atypical autism (F 84.1)

hochfunktionale Autismus-Spektrum-Störungen: Frühkindlicher Autismus (F84.0), Asperger-Syndrom (F84.5), Atypischer Autismus (F 84.1)

E.1.1.1

Medical condition in easily understood language

Autism

Autismus

E.1.1.2

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10021737
E.1.2	Term	Infantile autism
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The main aim of the trial is to investigate if the intranasal applied Oxytocin (vs. Placebo) leads to an increased modulation of the neural network of empathy in patients with high-functioning autism dependent on the genotype of the SNP rs53576 in the oxytocin receptor gene.

Führt die Gabe von Oxytocin (vs. Placebo) zu einer verstärkten Modulation neuronaler Prozesse empathischen Erlebens bei bestimmten Genotypen des SNPs rs53576 (G>A) im Oxytocin-Rezeptor-Gen bei ASD?

E.2.2

Secondary objectives of the trial

1. Influence of intranasal applied oxytocin on empathy in patients with high-functioning autism
On the basis of recent publications it is expected, that intranasal applied Oxytocin leads to an attenuated activation of the amygdala and an increased activation of the neural network of empathy compared to placebo.
2. Influence of the genotypes of the SNP rs53576 in the oxytocin receptor gene on the activation of the neural network of empathy in patients with high-functioning autism.
Intranasal applied oxytocin in carriers of the risk allele A of the SNP rs53576 in the OXTR (A/A and G/A) leads to an attenuated activation in the neural network of empathy [anterior insula, ACC (anterior cingulate cortex), amygdala, thalamus, PAG (periaqueductal gray), FG (fusiform gyrus)] during empathic processes.

1: Einfluss von Oxytocin auf Empathienetzwerke bei ASD
Basierend auf neueren Publikationen wird erwartet, dass die Gabe von Oxytocin zu einer generellen Minderaktivierung der Amygdala und zu einer verstärkten Aktivierung des Empathie-Netzwerkes führt (Vergleich Placebo vs. Verum).
2: Einfluss des Genotypen des SNPs rs53576 im Oxytocin-Rezeptor-Gen auf Aktivierung des Empathie-netzwerkes bei ASD
Unter Oxytocingabe kommt es während empathischer Prozesse bei Trägern des Risikoallels A des SNPs rs53576 im Oxytocin-Rezeptor-Gen (A/A und G/A) zu einer weniger starken Aktivierung im Empathie-Netzwerk (anteriore Insula, ACC, Amygdala, Thalamus, PAG, FG).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Diagnosis of autistic disorder (F84.0 according to ICD-10), Asperger syndrome (F84.5 according to ICD-10), atypical autism (F84.1 according to ICD-10)
Male patients
Age 15 ≤ years ≥ 35
German as native language
Right-handedness ( Edinburgh Inventory of Handedness; Oldfield, 1971)
genotyped SNP rs53576 in the oxytocin receptor gene
Signed form of consent (for underage persons: legal guardian)

Patienten mit der Diagnose Frühkindlicher Autismus (F84.0 nach ICD-10), Asperger-Syndrom (F84.5 nach ICD-10) und Atypischer Autismus (F 84.1 nach ICD-10)
Männliches Geschlecht
Alter 15 ≤ Jahre ≥ 35
Deutsch als Muttersprache
Rechtshänder (Edinburgh Händigkeitstest; Oldfield, 1971)
Genotypisierter SNP rs53576 im Oxytocin-Rezeptor-Gen
schriftliche Einwilligung der teilnehmenden Person (bei Minderjährigen der Sorgeberechtigten)

E.4

Principal exclusion criteria

Female
18 ≤ BMI ≥ 30
IQ < 70
traumatic lesions of the brain
serious neurologic diseases (e.g. epilepsy)
incorporated metal
acute suicidal tendency according to the clinical impression
anamnestic known metabolic or endocrinologic disorders
cardiac disorders (anamnesis, electrocardiogram, blood pressure and pulse): 50 ≤ heart rate (bpm) ≥ 90, 100 ≤ blood pressure systolic (mmHg) ≥ 140; 60 ≤ blood pressure diastolic (mmHg) ≥ 90
anamnestic known hypersensitivity to nasal sprays or other drugs
comorbid drug, alcohol or nicotine (no more than 15 cigarettes per day) abuse or dependence
within the 2 hours before the application of oxytocin/placebo intake of food, coffee, beverages (except water), nicotin-consumption as well as excessive fluid intake
cold

Weibliches Geschlecht
18 ≤ BMI ≥ 30
Intelligenzquotient < 70
Traumatische Hirnverletzungen
Schwerwiegende neurologische Erkrankungen (z.B. Epilepsie)
magnetische Metallimplantate
akute Suizidalität gemäß klinischem Eindruck
anamnestisch bekannte metabolische oder endokrinologische Erkrankungen
kardiovaskuläre Erkrankungen (Anamnese, Elektrokardiogramm, Puls- und Blutdruck-Messungen): 50 ≤ Herzfrequenz (bpm) ≥ 90, 100 ≤ Blutdruck systolisch (mmHg) ≥ 140; 60 ≤ Blutdruck diastolisch (mmHg) ≥ 90
anamnestisch bekannte Überempfindlichkeit gegen Nasensprays oder andere Medikamente
Regelmäßiger Konsum von Drogen, Alkohol und Nikotin (nicht mehr als 15 Zig. Pro Tag)
Innerhalb der 2 Stunden vor der Verum/Placebo-Gabe Aufnahme von Nahrung, Kaffee, Getränken (außer Wasser), Nikotin -Konsum sowie exzessives Wassertrinken
Erkältung

E.5 End points

E.5.1

Primary end point(s)

Activation of the neural network of empathy [anterior insula, ACC (anterior cingulate cortex), amygdala, thalamus, PAG (periaqueductal gray), FG (fusiform gyrus)] dependent on the oxytocin-/placebo-application and dependent on the genotype of the SNP rs53576 in the oxytocin receptor gene

Aktivierung des neuronalen Empathie-Netzwerkes aus anteriorer Insula, ACC, Amygdala, Thalamus, PAG, FG in Abhängigkeit von der Oxytocin-/Placebo-Applikation und des Genotyps des SNPs rs53576 im Oxytocin-Rezeptor-Gen.

E.5.1.1

Timepoint(s) of evaluation of this end point

during the 45. and 80. minute after verum/placebo application

zwischen der 45. und 80. Minute nach Verum/Placebo Applikation

E.5.2

Secondary end point(s)

Ascertainment of variables of personality, values of psychopathology and subjective valuation during the task performance.

Erfassung von Persönlichkeitsvariablen, Psychopathologiewerten und subjektiven Einschätzungen während der Bearbeitung der Aufgaben.

E.5.2.1

Timepoint(s) of evaluation of this end point

during the 45. and 80. minute after verum/placebo application

zwischen der 45. und 80. Minute nach Verum/Placebo Applikation

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

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Neuroimaging
Imaging genetics

Neuronale Bildgebung
Genetische Bildgebung

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)

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

E.8.1.6

Cross over

Yes

E.8.1.7

Other

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

Yes

E.8.4

The trial involves multiple sites in the 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

Last Visit of the patient and data base closure

Letze Visite des letzten Patienten und Datenbankschluss

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)

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)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

In the outpatient clinic specializing in children and adolescents with ASD (Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Medical Clinic, Philipps-University Marburg) the focus is on diagnosis and counselling for families. Psychotherapy or treatment aren not undertaken.
After the study patients will be further followed and given advice.

In der Spezialambulanz für Autismus-Spektrum-Störungen der Klinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie der Philipps-Universität Marburg erfolgen Diagnose und Beratung, jedoch keine fortlaufende intensive Psychotherapie und Behandlung der Patienten mit Autismus-Spektrum-Störungen. Nach Studienende, werden die Patienten weiter im Verlauf betreut und beraten.

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

2013-02-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-02-06

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

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