Clinical Trials Register

Summary
EudraCT Number:	2010-018284-42
Sponsor's Protocol Code Number:	LEVVPA
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2012-09-06
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

Netherlands - Competent Authority

A.2

EudraCT number

2010-018284-42

A.3

Full title of the trial

Double-blind randomized trial comparing efficacy, safety and tolerance between Levetiracetam monotherapy and Valproic acid monotherapy in children with newly diagnosed epilepsy

Een dubbelblind gerandomiseerd onderzoek naar effectiviteit, veiligheid en verdraagbaarheid van Levetiracetam monotherapie versus Valproïnezuur monotherapie bij kinderen met nieuw-gediagnosticeerde epilepsie

A.3.1

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

A trial comparing efficacy, safety and tolerance between Levetiracetam and Valproic acid in children with epilepsy

Nieuw vergelijkend onderzoek naar effectiviteit, veiligheid en verdraagbaarheid van Levetiracetam versus Valproïnezuur bij kinderen met epilepsie

A.3.2

Name or abbreviated title of the trial where available

LEVVPA

A.4.1

Sponsor's protocol code number

LEVVPA

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 Centre Groningen
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	ZonMW
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	UMCG
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	UMCG
B.5.2	Functional name of contact point	Dept. of Neurology
B.5.3	Address:
B.5.3.1	Street Address	Hanzeplein 1
B.5.3.2	Town/ city	Groningen
B.5.3.3	Post code	9713 GZ
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	31503612430
B.5.5	Fax number	31503611707
B.5.6	E-mail	o.f.brouwer@umcg.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	No
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	levetiracetam
D.3.4	Pharmaceutical form	Capsule
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	LEVETIRACETAM
D.3.9.1	CAS number	102767-28-2
D.3.9.2	Current sponsor code	LEV
D.3.9.4	EV Substance Code	SUB08459MIG
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	15 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: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	valproic acid
D.3.4	Pharmaceutical form	Capsule
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	VALPROIC ACID
D.3.9.1	CAS number	99-66-1
D.3.9.2	Current sponsor code	VPA
D.3.9.4	EV Substance Code	SUB00015MIG
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	10 to 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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

epilepsy

epilepsie

E.1.1.1

Medical condition in easily understood language

epilepsy, seizures

epileptische aanvallen

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	16.1
E.1.2	Level	PT
E.1.2	Classification code	10015037
E.1.2	Term	Epilepsy
E.1.2	System Organ Class	10029205 - Nervous system disorders

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 objectives of this multi-centre, double-blind, randomized, 2-parallel-groups study are to investigate the efficacy, safety and tolerability of levetiracetam (LEV) monotherapy 15-60mg/kg/day versus valproic acid (VPA) monotherapy 10-40mg/kg/day in 200 children aged 2 to 16 years with newly diagnosed epilepsy.

We investigate whether LEV is just as effective as or even more effective than VPA with less side-effects. If LEV proves to be as effective as VPA with less side-effects, it might even take over its position as the first choice antiepileptic drug in children with epilepsy.

Het doel van deze multicentrum, dubbelblinde, gerandomiseerde, 2-parallel groep studie is de effectiviteit, veiligheid en verdraagbaarheid van levetiracetam (LEV) monotherapie 15-60mg/kg/dag te vergelijken met die van valproinezuur (VPA) monotherapie 10-40mg/kg/dag in 200 kinderen van 2 tot 16 jaar met nieuw-gediagnosticeerde epilepsie.

We onderzoeken of LEV even effectief of zelfs effectiever is dan VPA met minder bijwerkingen. Als LEV even effectief blijkt te zijn als VPA met minder bijwerkingen, zou LEV eerstekeus anti-epilepticum kunnen worden in plaats van VPA bij kinderen met epilepsie.

E.2.2

Secondary objectives of the trial

NVT

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Children of either sex from age 2 until (and including) age 15 years with weight between 13 and 60 kilograms
- New but confident diagnosis of epilepsy made during the last year
- According to the treating physician initiation of antiepileptic medication is indicated

- Kinderen van 2 tot en met 15 jaar met een gewicht tussen 13 en 60 kg
- Minder dan 1 jaar geleden diagnose epilepsie gesteld
- Volgens behandelend arts is behandeling met AED geïndiceerd

E.4

Principal exclusion criteria

- Weight (corrected for length) >+2SD above average as defined in the ‘Groeidiagrammen’ of TNO (2010)
- Treatable underlying cause of epilepsy (e.g. GLUT1-deficiency syndrome)
- Serious pre-existing behavioural disturbances (according to clinician’s judgment) or serious psychiatric disorders requiring hospitalization or medication
- Uncountable seizures (clusters) or history of convulsive status epilepticus or mitochondrial disease (based on clinical characteristics or laboratory tests)
- Earlier treatment with any other AED for seizures, other than emergency treatment, in the year before inclusion
- Earlier treatment with LEV or VPA for any indication at any time
- Participation in another clinical trial with an investigational drug or device within 12 weeks of inclusion, or at any time during this study
- Known presence or history of allergy to the components of LEV or other pyrrolidine derivates or VPA
- Any known disorder or condition that may interfere with the absorption, distribution, metabolisation or excretion of drugs (e.g. end stage renal disease, patients on dialysis, patients with hepatic disease, etc.)
- Pregnancy or at risk of becoming pregnant (in case of active sexual life adequate contraception is obligatory)
- Presence of progressive cerebral disease, any other progressively degenerative neurological disease or cerebral tumours with signs of progression

- Ernstig overgewicht (>+2SD gecorrigeerd voor lengte) zoals gedefinieerd in de Groeidiagrammen van TNO (2010)
- Behandelbare oorzaak voor de epilepsie
- Ernstige preëxistente gedragsstoornissen of psychiatrische aandoening waarvoor behandeling noodzakelijk is
- Ontelbaar aantal aanvallen of status epilepticus of progressieve vorm van epilepsie of mitochondriële aandoening
- Eerdere behandeling met AEDs m.u.v. coupeermedicatie in het laatste jaar voor inclusie
- Eerdere behandeling met LEV of VPA
- Deelname aan ander onderzoek met studiemedicatie gedurende 12 weken vóór inclusie
- Bekende allergie voor ingrediënten van LEV, andere pyrrolidine derivaten of VPA
- Aandoening die invloed heeft op absorptie, distributie, metabolisatie of excretie van medicatie
- Zwangerschap of risico zwanger te worden
- Aanwezigheid progressieve neurologische aandoening

E.5 End points

E.5.1

Primary end point(s)

Retention rate after 52 weeks of treatment comparing LEV versus VPA

Retentie na 52 weken behandeling, waarbij LEV en VPA vergeleken worden

E.5.1.1

Timepoint(s) of evaluation of this end point

after 52 weken

na 52 weken

E.5.2

Secondary end point(s)

- Changes in cognitive development and behaviour
- Terminal remission
- Time to withdrawal from study treatment.
- Percentage of patients being seizure-free after 26 and 52 weeks on antiepileptic drug treatment
- Percentage of patients with >50% seizure reduction (as compared to the last 4 weeks before inclusion) after 52 weeks
- Per epilepsy syndrome: Percentage of patients being seizure-free or with a seizure reduction of more than 50%
- Incidence of side-effects and interactions

- Veranderingen in cognitieve ontwikkeling en gedrag
- Terminale remissie
- Tijd tot staken studiemedicatie
- Percentage aanvalsvrije patiënten na 26 weken en na 52 weken anti-epilepticum gebruik
- Percentage patiënten met >50% aanvalsreductie (vergeleken met laatste 4 weken voor inclusie) na 52 weken
- Per epilepsiesyndroom: percentage aanvalsvrije patiënten of met >50% aanvalsreductie
- Voorkomen bijwerkingen en interacties

E.5.2.1

Timepoint(s) of evaluation of this end point

52 weeks (and some, as indicated, at 26 weeks)

52 weken (en sommige, zoals aangegeven, bij 26 weeks)

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

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

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

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

Yes

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

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:

200

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:

150

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2012-09-06.

Yes

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

Mentally handicapped children

Verstandelijk gehandicapte kinderen

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

200

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)

For each child that completes the 52 weeks follow-up period or that withdraws from the study, the treatment assignment will be unblinded, in order to prescribe a suitable open labelled AED adapted to the efficacy and safety of the treatment received during the study.

Voor elk kind dat de 52-weken follow-up periode voltooit of teruggetrokken wordt uit de studie zal de studiemedicatie gedeblindeerd worden. Zo kan een geschikt open label AED voorgeschreven worden, bepaald door de effectiviteit en veiligheid van de behandeling die tijdens de studie gegeven is.

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

2012-09-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-12-19

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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