Clinical Trials Register

Summary
EudraCT Number:	2013-000531-27
Sponsor's Protocol Code Number:	NL43510
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-11-13
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

Denmark - DHMA

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

Kortikosteroider eller clobazam til ESES syndrom : et europæisk , multicenter, randomiseret, kontrolleret klinisk forsøg

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

Behandling af ESES syndrom med kortikosteroider eller clobazam : en europæisk undersøgelse

A.3.2

Name or abbreviated title of the trial where available

RESCUE ESES: Randomized European trial of Steroids vs Clobazam Usage for Encephalopathy with ESES

RESCUE ESES:Randomiseret europæisk forsøg med steroider vs Clobazam til encephalopati med 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:

Dutch CCMO ABR number

Number:

43510

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.4.1	Name of organisation providing support	Martindale Pharma
B.4.2	Country	United Kingdom
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	0031887555555
B.5.5	Fax number	0031887555350
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	clobazam (Frisium®)
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Aventis
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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.2.1.1.1	Trade name	prednisolon DAK
D.2.1.1.2	Name of the Marketing Authorisation holder	Takeda Pharma
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	range
D.3.10.3	Concentration number	2.5 to 25
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.2.1.1.1	Trade name	methylprednisolone
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer BV
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Solution for 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	range
D.3.10.3	Concentration number	40 to 1000
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

Encephalopati med elektrisk status epilepticus under søvn, også kaldet ESES syndrom

E.1.1.1

Medical condition in easily understood language

Sleep epilepsy

Søvn epilepsi

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	18.1
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

At sammenligne effekten på kognition af behandling med enten kortikosteroider eller clobazam hos børn med ESES syndrom

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.

- At sammenligne effekten af behandling med kortikosteroider eller clobazam på søvninduceret spike-wave indeks hos børn med ESES syndrom.
- At sammenligne effekten af behandling med kortikosteroider eller clobazam på hyppigheden af anfald hos børn med ESES syndrom.
- At sammenligne bivirkninger og tolerabilitet af behandling med kortikosteroider eller clobazam hos børn med ESES syndrom.
- At sammenligne effekten af behandling med kortikosteroider eller clobazam hos børn med ESES syndrom målt med en VAS score.
- At vurdere demografiske og sygdomsrelaterede prædiktive faktorer, herunder immunologiske faktorer, ved succes med behandling med kortikosteroider eller clobazam hos børn med ESES syndrom.
- At identificere en biomarkør for sygdomsaktivitet og behandlingsrespons.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Age 2 to 12 years
•A diagnosis within six months prior to study inclusion (preferentially as soon as possible) of either typical or atypical ESES syndrome (as defined in study protocol)
•No previous treatment with either clobazam or steroids
•No current treatment with carbamazepine, oxcarbazepine, vigabatrin, tiagabine, gabapentin and pregabalin and no treatment with any of these drugs in the previous three months;
•Written informed consent by parents/tutors or legal representatives

• Alder 2 til 12 år
• En diagnose inden for seks måneder før studieinklusion påbegyndes (fortrinsvis så hurtigt som muligt) med enten typisk eller atypisk ESES syndrom (som defineret i forsøgsprotokollen)
• Ingen tidligere behandling med enten clobazam eller steroider
• Ingen nuværende behandling med carbamazepin, oxcarbazepin, vigabatrin, tiagabin, gabapentin og pregabalin, og ingen behandling med nogen af disse lægemidler i de foregående tre måneder;
• skriftligt informeret samtykke fra forældremyndighedens indehaver eller værge

E.4

Principal exclusion criteria

•Patients with a spike wave index during wakefulness of > 50%
•Any condition that, in the investigator’s judgement, contraindicates the use of clobazam or steroids.

• Patienter med en spike bølge indeks under vågenhed på > 50%
• Enhver tilstand, der, i følge investigators vurdering, kontraindikerer brug en af clobazam eller steroider.

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.

- Intelligenskvotient, eller udviklingsmæssig kvotient
- Kognitiv sumscore

Forbedring er defineret som signifikant, når der forbedres med mindst 75% af standardafvigelsen.

E.5.1.1

Timepoint(s) of evaluation of this end point

after six months

efter seks måneder

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 absolutte testresultater og IQ score;
- Spike bølge indeks under ikke-REM søvn. Forbedring er defineret som en reduktion til mindre end
25%;
- Frekvens af anfald. Forbedring er defineret som en reduktion på 50% eller mere i forhold til
baseline;
- Samlede forbedring af funktionsmåde vurderet med en VAS score (-5 til 5)
- Sikkerhed og tolerabilitet, som vurderet ud fra forekomsten af alvorlige
bivirkninger;
- Forskelle i pro-inflammatoriske cytokinniveauer hos patienter med ESES
der reagerer på en af behandlingsstrategierne sammenlignet med patienter der ikke reagerer.

E.5.2.1

Timepoint(s) of evaluation of this end point

after six and 18 months

efter seks og 18 måneder

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)

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

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

Blændet resultatvurdering af klinisk neurofysiolog og neuropsykolog

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

Børn

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)

After six months of treatment, the continued care is given according to judgement of the treating physician.

Efter seks måneders behandling, er den fortsatte pleje givet efter bedømmelse af den behandlende læge.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	European Clinical Research Infrastructures Network (ECRIN)
G.4.3.4	Network Country	Netherlands

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-12-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-01-25

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-09-21

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