Clinical Trials Register

Summary
EudraCT Number:	2013-000531-27
Sponsor's Protocol Code Number:	NL43510
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2015-03-03
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

2013-000531-27

A.3

Full title of the trial

Corticosteroids or clobazam for ESES syndrome: a European, multicenter,
randomized, controlled clinical trial

Kortikosteroide oder Clobazam für das ESES Syndrom: Eine Europäische, multizentrische, randomisierte, klinische Studie

A.3.1

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

Treatment of ESES syndrome with corticosteroids or clobazam: a European
study

Behandlung des ESES Syndroms mit Kortikosteroiden oder Clobazam: Eine Europäische Studie

A.3.2

Name or abbreviated title of the trial where available

RESCUE ESES

A.4.1

Sponsor's protocol code number

NL43510

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN42686094

A.5.4

Other Identifiers

Name:

DRKS

Number:

DRKS00007126

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	University Medical Center Utrecht
B.1.3.4	Country	Netherlands
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	Dutch national epilepsy fund (NEF)
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Wilhelmina Kinderziekenhuis onderzoeksfonds (WKZ-fund)
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	European Clinical Research Infrastructures Network (ECRIN)
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	University Medical Center Utrecht
B.5.2	Functional name of contact point	Coordinating investigator
B.5.3	Address:
B.5.3.1	Street Address	Lundlaan 6
B.5.3.2	Town/ city	Utrecht
B.5.3.3	Post code	3584 EA
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+318875 73219
B.5.6	E-mail	f.e.jansen@umcutrecht.nl

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	Frisium
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Aventis
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CLOBAZAM
D.3.9.1	CAS number	22316-47-8
D.3.9.4	EV Substance Code	SUB06673MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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.IMP: 2
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.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	prednisolone
D.3.9.3	Other descriptive name	PREDNISOLONE
D.3.9.4	EV Substance Code	SUB10018MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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.IMP: 3
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.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	Powder and solvent for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	methylprednisolone
D.3.9.3	Other descriptive name	METHYLPREDNISOLONE
D.3.9.4	EV Substance Code	SUB08872MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	250
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Encephalopathy with electrical status epilepticus in sleep, also called
ESES syndrome

Encephalopathy mit elektrischem Epilepsiestatus (ESES Syndrom)

E.1.1.1

Medical condition in easily understood language

Sleep epilepsy

Schlafepilepsie

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10032061
E.1.2	Term	Other forms of epilepsy
E.1.2	System Organ Class	100000004852

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 effects on cognition of treatment with either
corticosteroids or clobazam in children with ESES syndrome

Vergleich der kognitiven Behandlungseffekte von Kortisteroiden im Vergleich zu der Behandlung mit Clobazam bei Kindern

E.2.2

Secondary objectives of the trial

- To compare the effects of treatment with corticosteroids or clobazam
on sleep induced spike-wave index in children with ESES syndrome.
- To compare the effects of treatment with corticosteroids or clobazam
on the frequency of seizures in children with ESES syndrome.
- To compare the side-effects and tolerability of treatment with
corticosteroids or clobazam in children with ESES syndrome.
- To compare the effects of treatment with corticosteroids or clobazam in
children with ESES syndrome as measured with a VAS score.
- To assess demographic and disease-related predictive factors,
including immunological factors, of succes of treatment with
corticosteroids or clobazam in children with ESES syndrome.
- To identify a biomarker for disease activity and treatment response.

- Vergleich der Effekte bei der Behandlung des ESES Syndrom bei Kindern mit Kortikosteroiden oder Clobazam auf die den Schlaf induzierten spike-Wave Index
- Vergleich der Effekte bei der Behandlung des ESES Syndrom bei Kindern mit Kortikosteroiden oder Clobazamauf die Häufigkeit der Krämpfe
- Vergleich der Nebeneffekte und Verträglichkeit bei der Behandlung des ESES Syndrom bei Kindern mit Kortikosteroiden oder Clobazam
- Vergleich des Behandlungseffektes der Therapie des ESES Syndrom bei Kindern mit Kortikosteroiden oder Clobazam gemessen mit dem VAS Score
- Bewertung demographischer und krankheitsbezogener prädiktiver Faktoren (einschließlich immunologischer Faktoren), die Einfluss auf den Behandlungserfolg der Therapie mit Korikosteroiden oder mit Clobazam haben
- Indentifikation eines Biomarkers für die Krankheitsaktivität und Ansprache auf die Behandlung.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age 2 up to 12 years (not including children of 12 years old);
• A diagnosis within six months prior to study inclusion (preferably as close to inclusion as possible) of either:
o Bilateral sleep-induced epileptiform activity with SWI in > 85% of nonREM sleep and developmental delay, arrest, or regression (“typical ESES syndrome”);
o Arrest or regression of development and bilateral sleep-induced epileptiform activity with a SWI in > 50%, or unilateral sleep induced epileptiform activity with SWI in > 85% of nonREM sleep (“atypical ESES syndrome”);
o Regression of development and unilateral epileptiform activity with a SWI of > 50% of nonREM sleep (“atypical ESES syndrome”);
• No previous treatment with either corticosteroids or clobazam
• No current treatment nor in the previous three months with carbamazepine, oxcarbazepine, vigabatrin, tiagabine, gabapentin and pregabalin; These drugs are known to possibly worsen the outcome in children with ESES syndrome and may therefore influence treatment result. Furthermore, these drugs can increase the SWI during sleep and may cause an electrographic pattern fulfilling the criteria for ESES. Inclusion of such cases with possible “treatment induced ESES” is not desirable.
• Written informed consent by parents / legal representatives

1. Vorliegen einer schriftlichen Patienten-, bzw. Eltern-Einwilligungserklärung entsprechend den internationalen Richtlinien und den entsprechenden deutschen Rechtsvorschriften;
2. Jungen und Mädchen zwischen 2 und 11 Jahren (einschließlich);
3. Folgende Diagnose innerhalb der letzten 6 Monate vor Einschluss:
o EEG diagnostischer Befund mit einem SWI > 85% der Non-REM-Aktivität und Entwicklungsverzögerung, Stillstand, Regression („Typisches ESES Syndrom“)
o Stillstand oder Regression in der Entwicklung und SWI> 50% oder unilaterale schlafinduzierte Epilepsieaktivität (SWI)> 85 („atypisches ESES Syndrom“)
o Regression der Entwicklung und unilaterale Epilepsieaktivität (SWI) > 50% („atypisches ESES Syndrom“)
4. Keine vorherige Behandlung mit Korticosteroiden oder Clobazam
5. Keine laufende Behandlung oder Behandlung innerhalb der letzten drei Monate mit Carbamazepine, Oxcarbazepine, Vigabatrin, Tiagabine, Gabapentin oder Pregabalin

E.4

Principal exclusion criteria

• Patients with a SWI during wakefulness of > 50%
• Acute or chronic infectious disease (e.g. TB, HIV)
• Immunodeficiency
• Severe osteopenia/osteoporosis
• Diabetes
• Cushing syndrome
• Severe respiratory insufficiency
• Severe liver failure
• Severe ulcera
• Any other condition that, in the investigator’s judgement, contra-indicates the use of corticosteroids or clobazam

1. SWI während der Wachphase > 50%
2. Akute oder chronische Infektionskrankheiten (bspw. TB, HIV)
3. Immunerkrankungen
4. Schwere Osteopenie/Osteoporose
5. Diabetes
6. Cushing Syndrom
7. Schwere Ateminsuffizienz
8. Schweres Leberversagen
9. Schwere Ulcera
10. Jegliche Erkrankung, die – gemäß der Einschätzung des Prüfarztes – eine Kontraindikation für den Einsatz von Kortikosteroiden oder Clobazam darstellt.

E.5 End points

E.5.1

Primary end point(s)

- Intelligence quotient, or developmental quotient
- Cognitive sumscore
Improvement is defined as significant when improved by at least 75% of
the standard deviation.

- Intelligenz quotient oder Entwicklungsquotient
- Kognitiver Summenscore

Verbesserung der Quotinten / Scores wird als siginifikant angesehen, wenn eine Verbesserung mindetesn 75 % über der Standard Abweichung liegen

E.5.1.1

Timepoint(s) of evaluation of this end point

after six months

nach sechs Monaten

E.5.2

Secondary end point(s)

- Individual absolute test results, and IQ scores;
- Spike wave index during non-REM sleep. Improvement is defined as a
rdecrease to less than
25%;
- Seizure frequency. Improvement is defined as a reduction of 50% or
more as compared with
baseline;
- Global improvement of functioning assessed with a VAS score (-5 to 5)
- Safety and tolerability, as assessed by the occurrence of serious
adverse events;
- Differences in pro-inflammatory cytokine levels in patients with ESES
who respond to either treatment strategies compared to nonresponders.

• Individuelle Rohwerte und IQ-Werte (Eine Verbesserung wird als statistisch signifikant betrachtet, wenn diese mindestens 75% der Standardabweichung beträgt).
• Spike-Wave Index während der Non-REM Aktivität (eine Verbesserung ist definiert als ein SWI von weniger als 25%)
• Anfallshäufigkeit (Eine Verbesserung ist definiert als eine Reduktion von 50% oder mehr im Vergleich zur Baseline)
• Bewertung der allgemeinen täglichen Fähigkeiten bewertet mit dem VAS (Visual Analogue Scale) Score (Skala: - 5 bis 5)
• Sicherheit und Verträglichkeit gemessen an dem Auftreten von Serious Adverse Events
• Unterschiede an den pro-inflammatorischen Zytokinspiegeln zwischen Respondern und Non-Respondern

E.5.2.1

Timepoint(s) of evaluation of this end point

after six and 18 months

Nach sechs und achtzehn Monaten

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

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

Yes

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Verblindete Bewertung der Ergebnisse durch Neurophysiologen und Neurpsychologen

Blinded outcome assessment by clinical neurophysiologist and neuropsychologist

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

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:

130

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:

130

F.1.1.6

Adolescents (12-17 years)

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

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

Children

Kinder

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.4.2.1

In the EEA

130

F.4.2.2

In the whole clinical trial

130

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)

Blinded outcome assessment by clinical neurophysiologist and
neuropsychologist

Nach 6 Monaten behandlung kann die Behandlung entsoprechend der Bewertung des behandelnden Arztes fortgesetzt werden

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

2015-10-23

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2022-08-15

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