Clinical Trials Register

Summary
EudraCT Number:	2021-001839-77
Sponsor's Protocol Code Number:	5mille_CT1
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-11-03
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

2021-001839-77

A.3

Full title of the trial

A Multicentric, Drug-Repositioning, Self Controlled Case Series (SCCS) Clinical Trial to Evaluate the Efficacy and Safety of Perampanel in Improving Behavioral Symptoms and Increasing the Quality of Life in Patients with White-Sutton syndrome (POGZRelated Disorder)

Studio multicentrico di ‘riposizionamento del farmaco’ in una serie di pazienti affetti dalla sindrome di White-Sutton (disturbo correlato a POGZ) valutati prima e durante la somministrazione del Perampanel per valutare l'efficacia e la sicurezza del farmaco nel migliorarne i sintomi comportamentali e la qualità della vita.

A.3.1

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

Efficacy and saefety of Perampanel on behaviour and quality of life in Patients with POGZ-Related Disorder

Efficacia e sicurezza del Perampanel sul comportamento e la qualità di vita nei pazienti con sindrome POGZ

A.3.2

Name or abbreviated title of the trial where available

POGZ PER CT

A.4.1

Sponsor's protocol code number

5mille_CT1

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	IRCCS MATERNO INFANTILE BURLO GAROFOLO
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	IRCCS materno infantile Burlo Garofolo
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 Materno Infantile Burlo Garofolo
B.5.2	Functional name of contact point	SCR Epidemiologia e Biostatistica
B.5.3	Address:
B.5.3.1	Street Address	via dell'Istria, 65/1
B.5.3.2	Town/ city	Trieste
B.5.3.3	Post code	34137
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390403785297
B.5.5	Fax number	00390403785411
B.5.6	E-mail	segreteria.irb@burlo.trieste.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.2.1.2	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.3.1	Product name	Fycompa
D.3.2	Product code	[042581037]
D.3.4	Pharmaceutical form	Coated 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	PERAMPANEL
D.3.9.2	Current sponsor code	Perampanel
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 to 4
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.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.2.5	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	perampanel
D.3.2	Product code	[n.a.]
D.3.4	Pharmaceutical form	Coated 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	PERAMPANEL
D.3.9.2	Current sponsor code	perampanel
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	4 to 8
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

Patients with POGZ related disorder

Pazienti con varianti patogenetiche/verosimilmente patogenetiche nel gene POGZ

E.1.1.1

Medical condition in easily understood language

Patients with neurodevelopmental disorder characterized by intellectual disability and/or autism and malformations in different organs of genetic origin

Pazienti con disordini del neurosviluppo caratterizzato da disabilità intellettiva e/o autismo e malformazioni in vari organi di origine monogenica

E.1.1.2

Therapeutic area

Diseases [C] - Symptoms and general pathology [C23]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLGT
E.1.2	Classification code	10037173
E.1.2	Term	Psychiatric and behavioural symptoms NEC
E.1.2	System Organ Class	10037175 - Psychiatric disorders

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

The primary study outcome will be the improvement on the Child Behavior Checklist (CBCL) scores and/or on the Vineland Adaptive Behavior Scales (VABS) scores between before and 6 months after treatment.

Il presente studio mira ad indagare l'efficacia di Perampanel nel migliorare i sintomi comportamentali e i domini funzionali in pazienti con disordine del neurosviluppo correlato a POGZ.

E.2.2

Secondary objectives of the trial

1- To evaluate the improvement on the CBCL scores between before and 12 or 18 months after treatment.
2- To evaluate the improvement on the VABS scores between before and 12 or 18 months after treatment.
3- To evaluate the improvement between before and 12 or 18 months after treatment on scores of neuropsychological tests -selected to evaluate cognitive, motor, speech and language, emotion/reciprocal social interaction areas, attention and executive function- as well as on scores from questionnaires for aggressive behavior, quality of life and psychopathology.
4- To evaluate the frequency and grade of adverse events.
5- To investigate the association between the genotype and the therapeutic outcome.
6- To study epigenetic signature before and during Perampanel treatment.
7- To collect and analyze molecular and clinical data of POGZ-affected subjects.

1- Valutare il miglioramento dei punteggi CBCL tra prima e 12 o 18 mesi dopo il trattamento.
2- Valutare il miglioramento dei punteggi VABS tra prima e 12 o 18 mesi dopo il trattamento.
3- Valutare il miglioramento tra prima e 12 o 18 mesi dopo il trattamento nei punteggi di test neuropsicologici -selezionati per valutare le aree cognitiva, motoria, del linguaggio, delle emozioni/interazione sociale reciproca, attenzione e funzione esecutiva- e nei punteggi dei questionari sul comportamento aggressivo, qualità della vita e psicopatologia.
4- Valutare la frequenza e il grado degli eventi avversi.
5- Indagare l'associazione tra il genotipo e l'esito terapeutico.
6- Studiare la signature epigenetica prima e durante il trattamento con Perampanel.
7- Raccogliere e analizzare dati molecolari e clinici di soggetti affetti da POGZ al fine di ampliare le conoscenze su questa ID sindromica e di indagare ulteriormente sulle associazioni genotipo-fenotipo ad oggi parzialmente rilevate.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age: both pediatric and young adult population are eligible. A minimum age of 4 is required; the maximum age limit is 25 years.
2. Gender: male and/or female. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
3. Type of Patient and Disease Characteristics: a diagnosis of WHSUS (POGZ-related disorder), defined as a molecular identification of a mutation in POGZ and a clinical diagnosis consistent with a neurodevelopmental disorder. Patients diagnosed with either de novo or familial POGZ mutation are eligible for enrollment.
4. Informed Consent: written consent will be given by the patients if capable or by parent(s)/legal representative if minors or incapable of giving informed consent.

1. Età: sono ammissibili sia la popolazione pediatrica che quella adulta. È richiesta un'età minima di 4 anni; il limite superiore di età è 25 anni.
2. Genere: maschile e / o femminile. L'uso di contraccettivi da parte di uomini o donne deve essere coerente con le normative locali relative ai metodi di contraccezione per coloro che partecipano a studi clinici.
3. Tipo di paziente e caratteristiche della malattia: una diagnosi di Disturbo correlato a POGZ, definito come identificazione molecolare di una mutazione in POGZ e una diagnosi clinica coerente con un disordine dello sviluppo neurologico. I pazienti con diagnosi di mutazione POGZ sporadica, de novo o familiare sono eleggibili per l'arruolamento.
4. Consenso informato: il consenso scritto sarà sottoscritto dai pazienti se in grado o dai genitori / rappresentante legale se minorenni o incapaci di dare il consenso informato.

E.4

Principal exclusion criteria

Patients are excluded from the study if any of the following criteria apply:
1. Medical Conditions: other, concomitant diagnosis of a genetic neurodevelopmental disorder.
2. Severe ID.
3. Epilepsy.
4. Pregnancy.
5. Prior adverse effect to non-competitive AMPA receptor agonist/Perampanel.
6. Contraindication to non-competitive AMPA receptor agonist/Perampanel.
7. Being already in therapy with non-competitive AMPA receptor agonist/Perampanel.
8. Therapy with CYP3A inhibitors (clarithromycin, stiripentol, valproate)/inductors (oral steroids, PHT, CBZ, PB, Primidone), unless there is a proper wash out period before stating treatment with Perampanel
9. History of attempted suicide or suicidal ideation, or current suicidal ideation.
10. Other Exclusions: breastfeeding, or intending to conceive during the course of the study.
11. Any condition that in the investigator’s opinion would present an unreasonable risk to the participant.
12. Any participant considered by the investigator unsuitable to receive Perampanel or unable or unlikely to comply with the dosing schedule or the study evaluations.
There is no lifestyle restriction for this study.

I pazienti sono esclusi dallo studio se si applica uno dei seguenti criteri:
1. Condizioni mediche: altra diagnosi concomitante di un disturbo dello sviluppo neurologico genetico.
2. Disabilità Intellettiva severa.
3. Epilessia.
4. Gravidanza.
5. Precedente effetto avverso all'agonista non competitivo del recettore AMPA / Perampanel.
6. Controindicazione all'agonista non competitivo del recettore AMPA / Perampanel.
7. Essere già in terapia con agonista non competitivo del recettore AMPA / Perampanel
8. Storia di tentato suicidio o ideazione suicidaria, o ideazione suicidaria attuale.
7. Altre esclusioni: allattamento al seno o intenzione di concepire durante il corso dello studio.
8. Qualsiasi condizione che, a giudizio dello sperimentatore, presenterebbe un rischio irragionevole per il partecipante.
9. Qualsiasi partecipante ritenuto dallo sperimentatore non idoneo a ricevere Perampanel o incapace o improbabile che rispetti il programma di dosaggio o le valutazioni dello studio.

E.5 End points

E.5.1

Primary end point(s)

The improvement on CBCL is defined as the shifting from ‘Clinical’ to ‘Borderline clinical’ or from ‘Borderline clinical’ to ‘Normal’ in at least one of the CBCL subscales (‘Internalization’, ‘Exteriorization’, ‘Other problems’ and ‘Total’). The improvement on VABS is defined as the shifting from ‘Low’ to ‘Moderately low’ or from ‘Moderately low’ to ‘Normal’) in ate least one of the VABS subscales (among ‘Communication’, ‘Daily living skills’, ‘Socialization’, ‘Motor skills’, or ‘Total’).

L'esito primario dello studio sarà il miglioramento dei punteggi della CBCL e/o dei punteggi delle VABS tra prima e 6 mesi dopo il trattamento.
Il miglioramento della CBCL è definito come il passaggio da "Clinico" a "Borderline clinico" o da "Borderline clinico" a "Normale" in almeno una delle sottoscale CBCL ("Internalizzazione", "Esteriorizzazione", "Altri problemi" e 'Totale'). Il miglioramento su VABS è definito come il passaggio da "Basso" a "Moderatamente basso" o da "Moderatamente basso" a "Normale") in almeno una delle sottoscale VABS (tra "Comunicazione", "Abilità di vita quotidiana", " Socializzazione", "Abilità motorie" o "Totale").

E.5.1.1

Timepoint(s) of evaluation of this end point

At month 6 after the beginning of Perampanel administration

Al 6° mese dall'inizio della somministrazione del farmaco

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

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

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

Serie di casi con controllo di sè stesso

Self controlled case series

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Belgium

Denmark

France

Netherlands

Poland

Switzerland

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

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

Yes

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:

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)

Yes

F.1.2.1

Number of subjects for this age range:

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 2021-11-03.

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

Subject affected by intellectual disability (Severe ID excluded) but with legal representative

Affetti da disabilità intellettiva (esclusi quelli con disabilità intellettiva grave) ma con tutore legale

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

F.4.2.2

In the whole clinical trial

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)

The study does not currently have a long-term follow-up, according to the study design. However, patients who have demonstrated a benefit from the administration of Perampanel will not be precluded from its administration, the methods and management of which can be conducted off-label and is not pertinent to the PI.

Lo studio al momento non prevede un follow-up a lungo termine, come stabilito nel disegno dello studio. Tuttavia, ai pazienti che avranno dimostrato un beneficio dalla somministrazione del Perampanel, non verrà preclusa la sua somministrazione, le cui modalità e la cui gestione potrà essere condotta off-label e non è di pertinenza del PI.

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	ERN ITHACA
G.4.3.4	Network Country	France

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-01-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-04-26

P. End of Trial
P.	End of Trial Status	Ongoing

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