Clinical Trials Register

Summary
EudraCT Number:	2015-001324-36
Sponsor's Protocol Code Number:	1042-900
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:	2015-04-16
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2015-001324-36

A.3

Full title of the trial

A Multicenter, Open-Label Proof-of-Concept Trial of Ganaxolone in Children with PCDH19 Female Pediatric Epilepsy

Studio pilota, multicentrico, in aperto con ganaxolone in bambine affette da epilessia infantile associata a mutazione del gene PCDH19

A.3.1

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

Pilot, multicenter study to evaluate the efficacy of the ganaxolone in female children with PCDH19 Pediatric Epilepsy.

Studio di prova, multicentrico per valutare l'efficacia del ganaxolone in bambine affette da epilessia infantile femminile

A.4.1

Sponsor's protocol code number

1042-900

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	Marinus Pharmaceuticals, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Marinus Pharmaceuticals, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Marinus Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Medical Representative
B.5.3	Address:
B.5.3.1	Street Address	142 Temple St. Suite 205
B.5.3.2	Town/ city	New Haven
B.5.3.3	Post code	06510
B.5.3.4	Country	United States
B.5.4	Telephone number	0012039030533
B.5.6	E-mail	gfarfel@marinuspharma.com

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	ganaxolone
D.3.2	Product code	CCD 1042, MD 9150000, Mepalon 1042, SPT316
D.3.4	Pharmaceutical form	Oral suspension
D.3.4.1	Specific paediatric formulation	Yes
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	GANAXOLONE
D.3.9.1	CAS number	38398-32-2
D.3.9.2	Current sponsor code	CCD 1042
D.3.9.3	Other descriptive name	Ganaxolone, SPT3162, MD 9150000, CCD-1042, Mepalon 1042, (3α-hydroxy-3β-methyl-5α-pregnan-20-one)
D.3.9.4	EV Substance Code	SUB07880MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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	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	ganaxolone
D.3.2	Product code	CCD 1042
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	GANAXOLONE
D.3.9.1	CAS number	38398-32-2
D.3.9.2	Current sponsor code	CCD 1042
D.3.9.3	Other descriptive name	Ganaxolone, SPT3162, MD 9150000, CCD-1042, Mepalon 1042, (3α-hydroxy-3β-methyl-5α-pregnan-20-one)
D.3.9.4	EV Substance Code	SUB07880MIG
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	200 to 225
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

PCDH19 Female Pediatric Epilepsy (FPE)

Epilessia infantile associata a mutazione del gene PCDH19

E.1.1.1

Medical condition in easily understood language

PCDH19 Female Pediatric Epilepsy (FPE)

Epilessia infantile associata a mutazione del gene PCDH19

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	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10032062
E.1.2	Term	Other forms of epilepsy, with intractable 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 evaluate the efficacy of open-label ganaxolone as adjunctive therapy for uncontrolled seizures in female children with PCDH19 mutation.

Valutare l’efficacia del Ganaxalone in bambine affette da Epilessia pediatrica associata a mutazione del gene PCDH 19

E.2.2

Secondary objectives of the trial

To evaluate the safety and tolerability of open-label ganaxolone as adjunctive therapy for uncontrolled seizures in female children with PCDH19 mutation.

Valutare la sicurezza e la tollerabilità del Ganaxalone come terapia aggiuntiva per crisi epilettiche incontrollate in bambine con mutazione PCDH19

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Have parent or legal guardian available and willing to give written informed consent, after being properly informed of the nature and risks of the study and prior to engaging in any study-related procedures.
2. Female outpatients > 2 years of age and younger than 11 years of age at time of consent.
3. Have confirmed PCDH19 genetic mutation.
4. Have uncontrolled cluster seizures (approximately 10 or more seconds between seizures), lasting for one hour or more per episode, with inter-cluster episodes of not more than 6 weeks, AND/OR, non-clustered focal dyscognitive or focal convulsive seizures with a frequency ≥4 seizures per 28-day period during baseline.
5. Subjects should be on a stable regimen of AED medication, and generally in good health.
6. Parent or guardian is able and willing to maintain an accurate and complete daily written seizure calendar for the duration of the study.
7. Able and willing to take study medication with food, two or three times daily. Ganaxolone must be administered with food.
8. Subject must be approved to participate by Sponsor and Principal Investigator after review of medical history and baseline seizure calendars.

1. Presenza di genitori o di legale rappresentante che siano disponibili e che vogliano fornire il proprio consenso informato scritto, dopo essere stati appropriatamente informati sulla natura dei rischi legati allo studio e prima che sia effettuata una qualsiasi procedura di studio.
2. Soggetti ambulatoriali di sesso femminile di età > 2 anni e inferiore a 11 anni al momento del consenso.
3. Diagnosi confermata di mutazione del gene PCDH19.
4. Mostrano epilettiche a grappolo (cluster) incontrollate (con un intervallo di circa 10 secondi o più tra le singole crisi), con una durata di un’ora o più per episodio, con intervalli tra i cluster di una durata non superiore alle 6 settimane, E/O, Crisi focali discognitive non-cluster o crisi focali convulsive con una frequenza ≥ 4 crisi per un periodo di 28 giorni durante la baseline.
5. I soggetti dovrebbero trovarsi in regime stabile con farmaci antiepilettici e generalmente in buona salute.
6. I genitori o il rappresentante legale devono essere in grado e avere la volontà di mantenere un accurato e completo diario giornaliero scritto delle crisi per tutta la durata dello studio.
7. I soggetti devono essere in grado e avere la volontà di assumere il farmaco di studio, 2 o 3 volte al giorno. Il Ganaxolone deve essere assunto con dei cibo.
8. La partecipazione dei soggetti deve essere approvata dallo Sponsor e dallo Sperimentatore Principale dopo revisione della anamnesi e del diario delle crisi al baseline.

E.4

Principal exclusion criteria

1. Have had previous exposure to ganaxolone.
2. Known sensitivity or allergy to any component in the study drug, progesterone, or other related steroid compounds.
3. Have SCN1A genetic mutation.
4. Exposure to any investigational drug or device < 90 days prior to screening, or plans to participate in another drug or device trial at any time during the study.
5. Seizures secondary to illicit drug or alcohol use, infection, neoplasm, demyelinating disease, degenerative neurological disease, or central nervous system (CNS) disease deemed progressive, metabolic illness, or progressive degenerative disease.
6. Concurrent use of vigabatrin, tiagabine, ezogabine or finasteride is not permitted, nor use of moderate or severe inducers or inhibitors of CYP3A4/5/7. Individuals with prior use of vigabatrin must have had stable visual fields tested twice over the 12 months after the last dose of vigabatrin. A list of CYP3A4/5/7 inhibitors and inducers is included in the Appendix.
7. Have any medical condition that, in the investigator's judgment, is considered to be clinically significant and could potentially affect subject safety or study outcome, including but not limited to: clinically significant cardiac, renal, pulmonary, gastrointestinal, hematologic or hepatic conditions; or a condition that affects the absorption, distribution, metabolism or excretion of drugs.
8. Have active suicidal plan/intent, or have had active suicidal thoughts in the past 6 months or a suicide attempt in the past 3 years.
9. Have Alanine transferase (ALT; SGPT) or Aspartate transferase (AST; SGOT) levels > 3 times upper limits of normal (ULN), or total bilirubin >1.5 time ULN at the baseline visit.
10. Are currently following or planning to follow a ketogenic diet.
11. Is sexually active or pregnant.
12. Unwilling to forgo grapefruit and grapefruit juice from diet during the entire clinical trial.

1. Che abbiano assunto precedentemente ganaxolone.
2. Con nota ipersensibilità o allergia a qualsiasi componente presente nella formulazione del farmaco di studio, al progesterone o ad altro derivato steroideo.
3. Presentano mutazione del gene SCN1A.
4. Abbiano assunto o utilizzato un farmaco o dispositivo sperimentale nei 90 giorni precedenti lo screening, o che abbiano pianificata la partecipazione ad un altro studio clinico su un farmaco o dispositivo sperimentale in qualsiasi momento durante lo studio clinico.
5. Presentino crisi epilettiche secondarie all’uso di sostanze illecite o alcol, secondarie ad infezione, neoplasia, malattia demielinizzante, malattia neurodegenerativa o malattia a carico del sistema nervoso centrale ritenuta in progressione, malattia metabolica o malattia degenerativa progressiva.
6. L’uso concomitante di vigabatrin, tiagabina, retigabina o finasteride, o l’uso di induttori o inibitori, forti o moderati, del complesso CYP3A4/5/7 non è consentito. Soggetti che abbiano usato precedentemente vigabatrin devono essere risultati stabili a esami del campo visivo per due volte nei 12 mesi successivi all’ultima dose di vigabatrin. Una lista di inibitori e induttori del complesso CYP3A4/5/7 è inclusa nell’appendice al protocollo.
7. Abbia una qualsiasi condizione medica che, secondo il giudizio dello sperimentatore, è considerata clinicamente significativa e potrebbe potenzialmente influenzare la sicurezza del soggetto o l’esito dello studio clinico, incluse ma non limitate a: condizioni cardiache, renali, polmonari, gastrointestinali, ematologiche o epatiche clinicamente significative; o una qualsiasi condizione che possa influire sull’assorbimento, distribuzione, metabolismo o escrezione del farmaco di studio.
8. Che abbia piani o intenti suicidi attivi, o che abbia avuto pensieri suicidari negli ultimi 6 mesi o abbia tentato il suicidio negli ultimi 3 anni.
9. Che mostri livelli di Alanina trasferasi (ALT; SGPT) or Aspartato trasferasi (AST; SGOT) 3 volte superiori al limite superiore di normalità (ULN), o livelli di bilirubina totale 1.5 volte superiore al limite superiore di normalità (ULN) durante la visita basale.
10. Sia attualmente seguendo o pianificando un dieta Ketogenetica.
11. Sia sessualmente attiva o in stato di gravidanza.
12. Che non voglia rinunciare al pompelmo o al succo di pompelmo nella dieta, durante l’intero periodo dello studio clinico.

E.5 End points

E.5.1

Primary end point(s)

Percentage change in seizure (focal dyscognitive or focal convulsive) frequency per 28 days relative to baseline.

Variazione percentuale della frequenza delle crisi (focali discognitive e focali convulsive) rispetto al baseline in un periodo di 28 giorni

E.5.1.1

Timepoint(s) of evaluation of this end point

28 days from calculated baseline.

28 giorni dalla baseline calcolata.

E.5.2

Secondary end point(s)

Efficacy:
Evaluation of inter-cluster interval calculated using daily seizure diary.
Seizure-free interval calculated using daily seizure diary.
Proportion of responders by cohort calculated using daily seizure diary.
Proportion of subjects whose inter-cluster interval increases by cohort calculated using daily seizure diary.
Time to reach baseline number of seizures (per 28 days) calculated using daily seizure diary.
Clinician Global Impression of Change score as assessed by questionnaire. Patient Global Impression of Change score as assessed by questionnaire.

Safety:
Evaluation of safety and tolerability of open-label ganaxolone as adjunctive therapy for uncontrolled seizures in female children with PCDH19 mutation, based on adverse event log and other clinical safety assessments.

Efficacia: intervallo tra i cluster; il tempo per raggiungere il numero di crisi stabilito come riferimento; l’intervallo senza crisi, la proporzione di pazienti con un miglioramento del 50% delle crisi in confronto con la situazione iniziale (Responder), la proporzione di pazienti che aumentano l’intervallo inter-cluster del 50% o più e valutazione dei Questionari “Clinical Global Impression-Improvement Rating” (CGI-I)

Sicurezza: valutazione della sicurezza e della tollerabilità di ganaxolone somministrato in aperto come terapia aggiuntiva per le crisi epilettiche incontrollate in bambine affette da mutazione del gene PCDH19, sulla base del numero di eventi avversi e altri parametri clinici di sicurezza.

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy:
26 weeks

Safety:
30 weeks

Efficacia:
26 settimane

Sicurezza:
30 settimane

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

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

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

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

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

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

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

United States

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

Number of subjects for this age range:

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)

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

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

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

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)

Marinus Pharmaceuticals may offer the opportunity to continue taking ganaxolone.

Marinus Pharmaceuticals potrebbe offrire l'opportunità di continuare con l'assunzione di ganaxolone.

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

2015-06-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-04-01

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

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