Clinical Trials Register

Summary
EudraCT Number:	2013-000531-27
Sponsor's Protocol Code Number:	NL43510
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-07-03
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

Spain - AEMPS

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

Corticoides o clobazam para el síndrome ESES: un ensayo clínico aleatorizado y controlado multicéntrico europeo.

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

Tratamiento para el síndrome ESES con corticoides: un Estudio Europeo.

A.3.2

Name or abbreviated title of the trial where available

RESCUE ESES

A.4.1

Sponsor's protocol code number

NL43510

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	Fundación para la Investigación hospital Clínico San Carlos
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fundación para la Investigación hospital Clínico San Carlos
B.5.2	Functional name of contact point	UICEC
B.5.3	Address:
B.5.3.1	Street Address	profesor martin lagos s/n
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28040
B.5.3.4	Country	Spain
B.5.4	Telephone number	00349133030002774
B.5.5	Fax number	00349133035153515
B.5.6	E-mail	fibucicec.hcsc@salud.madrid.org

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.2.1.2	Country which granted the Marketing Authorisation	Spain
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/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.5
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	Spain
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	Oral drops
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 STEAGLATE
D.3.9.1	CAS number	5060-55-9
D.3.9.4	EV Substance Code	SUB10019MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	2 to 60
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	Spain
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	Parenteral use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METHYLPREDNISOLONE
D.3.9.1	CAS number	2375-03-3
D.3.9.3	Other descriptive name	METHYLPREDNISOLONE SODIUM HEMISUCCINATE
D.3.9.4	EV Substance Code	SUB26423
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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

Encefalopatía con estatus epiléptico eléctrico del sueño, también llamado sindrome ESES

E.1.1.1

Medical condition in easily understood language

Sleep epilepsy

Epilepsia del sueño

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	17.0
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

comparar los efectos sobre la cognición del tratamiento con corticoides y del tratamiento con clobazam en niños con ESES

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.

- comparar los efectos de ambos tratamientos sobre el índice de puntas y ondas inducidas por el sueño en el EEG.
- comparar entre ambos grupos la incidencia de crisis.
- comparar la seguridad de ambos tratamientos, con el fin de evaluar qué pacientes son los que más se benefician de las terapias.
- estudiar potenciales biomarcadores relacionados con la activación del sistema inmune.

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:
-Bilateral sleep-induced epileptiform activity with SWI in > 85% of nonREM sleep and developmental delay, arrest, or regression (?typical ESES syndrome?)
-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?)
-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

· Edad 2 - 12 años ( sin incluir los niños de 12 años) ;
· Un diagnóstico dentro de los seis meses anteriores a la inclusión de un estudio (preferentemente lo más cerca posible inclusión como
posible ) de cualquiera de :
- actividad epileptiforme inducida Bilateral sueño con patrón EEG caracterizado por ondas y puntas durante más del 85% del sueño no REM y retraso en el desarrollo , la detención o regresión ( "síndrome típico ESES ")
- detención o regresión del desarrollo y de la actividad epileptiforme inducida por el sueño - bilateral con patrón EEG caracterizado por ondas y puntas durante más del 50 % , o unilateral inducida actividad epileptiforme sueño con patrón EEG caracterizado por ondas y puntas durante más del 85% del sueño no REM ( "síndrome ESES atípica ")
- regresión del desarrollo y de la actividad epileptiforme unilateral con patrón EEG caracterizado por ondas y puntas durante más del 50%de sueño no REM ( "síndrome ESES atípica ")
· No tratamiento previo con corticosteroides o clobazam
· No tratamiento actual ni en los tres meses anteriores con carbamazepina , oxcarbazepina, vigabatrina , tiagabina , gabapentina y pregabalina ; Estos medicamentos se sabe que posiblemente empeorará
los resultados en los niños con síndrome de ESES y puede , por tanto, influir en resultado del tratamiento. Además , estos medicamentos pueden aumentar el con patrón EEG caracterizado por ondas y puntas durante el sueño y puede causar un EEG con patrón de cumplimiento de los criterios de ESES . La inclusión de este tipo de casos con tratamiento que posiblemente induzca ESES no es deseable.
· Consentimiento informado por los padres / representantes legales por escrito

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.

. Los pacientes con EEG con patrón puntas y ondas durante la vigilia de> 50%
· Enfermedad infecciosa crónica o aguda(por ejemplo, la tuberculosis, el VIH)
. Inmunodeficiencia
· Severa osteopenia / osteoporosis
· Diabetes
· Síndrome de Cushing
· Insuficiencia respiratoria grave
· Insuficiencia hepática grave
· Úlcera severa
· Cualquier otra condición que, a juicio del investigador, contra-indica el uso de corticosteroides o clobazam.

E.5 End points

E.5.1

Primary end point(s)

Cognitive function at 6 months after starting treatment

funcionamiento cognitivo a los 6 meses del inicio del tratamiento

E.5.1.1

Timepoint(s) of evaluation of this end point

after six months

a los 6 meses

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.

- funcionamiento cognitivo a los 18 meses tras el inicio del tratamiento
- índice de puntas y ondas inducidas por el sueño
- frecuencia de crisis
- seguridad
- tolerabilidad

E.5.2.1

Timepoint(s) of evaluation of this end point

after six and 18 months

a los 18 meses

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

grupos paralelos con control activo y abierto, con evaluador ciego

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

ultima visita del último paciente

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

niños

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.

Tras 6 meses de tratamiento se continuará administrando el cuidado que el médico responsable consideré adecuado

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	ECRIN
G.4.3.4	Network Country	Spain

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-09-19

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

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