Clinical Trials Register

Summary
EudraCT Number:	2015-004827-30
Sponsor's Protocol Code Number:	RASLOW
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-09-30
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2015-004827-30

A.3

Full title of the trial

RAPID VERSUS SLOW WITHDRAWAL OF ANTIEPILEPTIC MONOTHERAPY IN TWO-YEAR SEIZURE-FREE ADULTS PATIENTS WITH EPILEPSY (RASLOW) STUDY: A PRAGMATIC MULTICENTRE, PROSPECTIVE, RANDOMIZED, CONTROLLED STUDY.

A.3.1

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

Rapid versus slow withdrawal of antiepileptci monotherapy in two-year seizure free patients.

Sospensione rapida contro sospensione lenta della monoterapia con un farmaco antiepilettico in pazienti senza crisi da almeno due anni

A.3.2

Name or abbreviated title of the trial where available

RASLOW

A.4.1

Sponsor's protocol code number

RASLOW

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	AZIENDA OSPEDALIERA "BIANCHI-MELACRINO-MORELLI"
B.1.3.4	Country	Italy
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	Ministero della Salute
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	REGIONE CALABRIA
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IRCCS ISTITUTO DI RICERCHE FARMACOLOGICHE "MARIO NEGRI" DI MILANO
B.5.2	Functional name of contact point	LABORATORIO MALATTIE NEUROLOGICHE
B.5.3	Address:
B.5.3.1	Street Address	VIA LA MASA 19
B.5.3.2	Town/ city	MILANO
B.5.3.3	Post code	20068
B.5.3.4	Country	Italy
B.5.4	Telephone number	0239014604
B.5.5	Fax number	0239001916
B.5.6	E-mail	raslow@marionegri.it

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	KEPPRA - 1000MG-COMPRESSA RIVESTITA CON FILM-USO ORALE BLISTER DIVISIBILE (ALLUMINIO/PVC)-100X1 (DOSE UNITARIA)
D.2.1.1.2	Name of the Marketing Authorisation holder	UCB PHARMA S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.9.2	Current sponsor code	non applicabile
D.3.9.3	Other descriptive name	Antiepileptic drugs
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	0 to 9999
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Epilessia

E.1.1.1

Medical condition in easily understood language

Epilepsy

Epilessia

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	10015046
E.1.2	Term	Epilepsy, unspecified
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 objective of the present study will be to establish whether a slow or a rapid withdrawal schedule of antiepileptic monotherapy influence relapse rate in adult patients with epilepsy, who have been seizure-free for at least two years.

Scopo primario dello studio è quello di stabilire se la sospensione lenta e la sospensione rapida della monoterapia con farmaci antiepilettici influenzano il tasso di ricaduta in pazienti adulti con diagnosi di epilessia liberi da crisi da almeno due anni.

E.2.2

Secondary objectives of the trial

Secondary objectives will be to establish the compliance rates with these two schedules and the differences in terms of severity of relapses, based on occurrence of status epilepticus, seizure-related injuries and death.

Gli obiettivi secondari sono quelli di valutare le differenze tra i due gruppi (sospensione lenta contro sospensione rapida) in termini di compliance con il programma di sospensione, di eventi di stato di male epilettico durante e dopo la sospensione, e di mortalità durante il periodo di studio.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Age at inclusion 18+ years;
2) Diagnosis of epilepsy (according to ILAE 1989 criteria);
3) Age at epilepsy onset of 16 years or older;
4) Seizure freedom for at least 2 years;
5) Current treatment with one of the AEDs available for monotherapy available in Italy (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, valproic acid, zonisamide);
6) Ability to understand and comply with the study requirements and to give written informed consent;
7) Current drug is the active principle contributing to the achievement of seizure remission regardless of the indication and the tolerability profile;
8) Absence of any contraindication and special warning for the current antiepileptic drug.

1) Età superiore a 18 anni;
2) Diagnosi di epilessia (secondo i criteri ILAE 1989 [15]);
3) Età all’esordio dell’epilessia =16 anni;
4) Assenza di crisi da almeno due anni;
5) Attualmente in trattamento con uno dei farmaci antiepilettici disponibili per il trattamento entiepilettico in monoterapia in Italia (carbamazepina, lamotrigina, levetiracetam, oxcarbazepina, fenobarbital, fenitoina, topiramato, acido valproico, zonisamide);
6) Capacità di comprendere e di rispettare tutte le procedure dello studio e di fornire un consenso informato;
7) Il principio attivo attualmente assunto è quello che ha permesso di raggiungere lo stato di remissione indipendentemente dalla sua indicazione e dal profilo di tollerabilità;
8) Assenza di ogni controindicazione e avvertenza speciale per l’antiepilettico in uso.

E.4

Principal exclusion criteria

1) Inability to understand the aims or modalities of the study;
2) Current pregnancy or plans to become pregnant during withdrawal period (e.g. who are not post menopausal, surgically sterile, or using inadequate birth control);
3) History of seizure relapse after discontinuation of treatment;
4) History of psychogenic non-epileptic seizures (PNES);
5) History of status epilepticus;
6) Poor compliance with previous treatments;
7) Experimental treatments in previous 3 months;
8) Men unable to practice contraception for the duration of the treatment.

1) Incapacità a capire gli scopi o le modalità dello studio;
2) Gravidanza in atto o pianificazione di gravidanza durante il periodo di sospensione della terapia (ad esempio, donne che non sono in post menopausa, chirurgicamente sterili o che utilizzano un metodo contraccettivo inadeguato);
3) Storia di recidiva di crisi dopo la sospensione del trattamento;
4) Storia di crisi psicogeniche non epilettiche (PNES);
5) Storia di stato epilettico;
6) Scarsa compliance con i precedenti trattamenti;
7) Uso di farmaci sperimentali nei 3 mesi precedenti;
8) Uomini che non vogliono utilizzare un metodo contraccettivo durante il trattamento.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the time to recurrence of an epileptic seizure.

L’endpoint primario è il tempo alla ricorrenza delle crisi.

E.5.1.1

Timepoint(s) of evaluation of this end point

Anytime during the study

Qualsiasi momento durante lo studio

E.5.2

Secondary end point(s)

Secondary endpoints are the compliance with the assigned withdrawal schedule and the severity of relapses, in terms of seizure-related injuries (contusions, wounds, fractures, strain/sprain, head injury, burns, whiplash), status epilepticus (SE) during or after withdrawal period, and mortality.

Gli endpoint secondari sono la compliance con il trattamento assegnato e la severità delle ricadute, in termini di danni correlati alle crisi (contusioni, ferite, fratture, stiramenti/distorsioni, danni cerebrali, bruciature/ustioni, colpo di frusta), stato di male epilettico durante o dopo il periodo di sospensione e la mortalità.

E.5.2.1

Timepoint(s) of evaluation of this end point

Anytime during the study

In ogni momento durante lo studio

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)

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

1) Sospensione rapida: riduzione del 20% della dose iniziale ogni 15 giorni fino alla sospensione co

1) Rapid withdrawal: reduction by 20% of initial dosage every 15 days until complete discontinuation

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.8.5.1

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

Information not present in EudraCT

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

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

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)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

300

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

350

F.4.2

For a multinational trial

F.4.2.1

In the EEA

350

F.4.2.2

In the whole clinical trial

350

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)

Patients will take the best pharmacological treatment for clinical practice chosen by the neurologist.

Il paziente assumerà la terapia farmacologica che il neurologo riterrà più opportuna per la sua condizione clinica.

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

2016-08-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-03-21

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

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