Clinical Trials Register

Summary
EudraCT Number:	2016-002313-22
Sponsor's Protocol Code Number:	ADV6770-A11CS
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:
Date on which this record was first entered in the EudraCT database:	2016-10-24
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

France - ANSM

A.2

EudraCT number

2016-002313-22

A.3

Full title of the trial

A randomised, active controlled, open-label, 2-way cross-over, multicentre study to investigate the palatability, acceptability, pharmacokinetics, safety and tolerability, and treatment compliance of multidoses of ADV6770 as monotherapy or in combination, in children with childhood absence epilepsy.

Etude multicentrique randomisée, contrôlée, en ouvert, en cross-over, de palatabilité, acceptabilité, pharmacocinétique, sécurité d’emploi et tolérabilité, et de l’observance au traitement d’une nouvelle forme galénique d’ethosuximide (ADV6770, granulés) en monothérapie ou en association chez des enfants présentant une épilepsie-absences en comparaison à la forme sirop (Zarontin®)

A.3.1

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

Study to investigate the palatability, acceptability, pharmacokinetics, safety and tolerability, and treatment compliance of multidoses of ADV6770 as monotherapy or in combination, in children with childhood absence epilepsy.

Kiekids - Etude de palatabilité, acceptabilité, pharmacocinétique, sécurité et tolérance, et de l’observance au traitement d’une nouvelle forme galénique d’ethosuximide (ADV6770, granules) en monothérapie ou en association chez des enfants ayant une épilepsie-absences en comparaison à la forme sirop (Zarontin®).

A.3.2

Name or abbreviated title of the trial where available

KIEKIDS A11CS

A.4.1

Sponsor's protocol code number

ADV6770-A11CS

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/315/2015

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	ADVICENNE PHARMA SA
B.1.3.4	Country	France
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	ADVICENNE PHARMA SA
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Centre d'Investigation Clinique, HCL Lyon
B.5.2	Functional name of contact point	Catherine CORNU
B.5.3	Address:
B.5.3.1	Street Address	Bâtiment les Tilleuls, 59 boulevard Pinel
B.5.3.2	Town/ city	Bron Cedex
B.5.3.3	Post code	69677
B.5.3.4	Country	France
B.5.4	Telephone number	33427857728
B.5.5	Fax number	33472357364
B.5.6	E-mail	catherine.cornu@chu-lyon.fr

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	ethosuximide
D.3.2	Product code	ADV6770
D.3.4	Pharmaceutical form	Granules
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	Ethosuximide
D.3.9.1	CAS number	77-67-8
D.3.9.2	Current sponsor code	ADV-6770
D.3.9.3	Other descriptive name	ETHOSUXIMIDE
D.3.9.4	EV Substance Code	SUB07282MIG
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	125 to 250
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	Yes
D.2.1.1.1	Trade name	Zarontin
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Zarontin
D.3.4	Pharmaceutical form	Syrup
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	Ethosuximide
D.3.9.1	CAS number	77-67-8
D.3.9.3	Other descriptive name	ETHOSUXIMIDE
D.3.9.4	EV Substance Code	SUB07282MIG
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.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

Children with chilhood absence epilepsy.

Enfants ayant une épilepsie-absences.

E.1.1.1

Medical condition in easily understood language

Children with chilhood absence epilepsy.

Enfants ayant une épilepsie-absences.

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	19.0
E.1.2	Level	HLT
E.1.2	Classification code	10000332
E.1.2	Term	Absence seizures
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10034759
E.1.2	Term	Petit mal 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

To assess the palatability of ADV6770 versus ethosuximide syrup.

E.2.2

Secondary objectives of the trial

1) To assess the acceptability of ADV6770 versus ethosuximide syrup.
2) To assess the treatment compliance of ADV6770 versus ethosuximide syrup.
3) To assess the pharmacokinetics of ethosuximide with ADV6770 and syrup formulations.
4) To assess the sustainability of the effects of ADV6770 versus ethosuximide syrup on the absence seizures.
5) To assess pharmacodynamic (PD) profile on gastro-intestinal (GI) tract with Visual Analogue Scales (VAS) for ADV6770 versus ethosuximide syrup.
6) To assess the safety and tolerability of ADV6770 versus ethosuximide syrup.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Subjects, male or female, between 2 and 17 years old inclusive at study entry.
2) Subjects presenting a childhood absence epilepsy (CAE), diagnosed according to the International League Against Epilepsy Proposal for Revised Classification of Epileptic Seizures ILAE), confirmed by EEG.
3) Subjects who have had typical absence seizures only (seizure-free or with persisting seizures).
4) Subjects already treated and stabilised with an anti-epileptic drug: either by ethosuximide in monotherapy or ethosuximide in combination with valproic acid or lamotrigine.
5) Subjects presenting normal safety laboratory values within three months prior to inclusion or at Day 1: absolute neutrophil count ≥ 1500/mm3, platelets count ≥ 120000/mm3, and transaminases ASAT and ALAT levels < 2.5 times the upper limit of normal value.
6) Sexually active female of childbearing potential must agree to use a contraceptive method judged effective by the investigator if sexually active and have a negative pregnancy test at inclusion.
7) Parent/legal guardian(s) who has (have) provided a signed written informed consent for the study.
8) Subjects for whom the assent has been collected or searched, when applicable.

E.4

Principal exclusion criteria

1) Subjects who present other epilepsy syndromes than CAE.
2) Subjects affected by any major disease that may be negatively affected by the study product or that may affect the study product (such as renal impairment, hepatic impairment, haematological disease).
3) Subjects who present contraindications to the administration of the study treatment: known hypersensitivity to succinimides or formulation excipients, rare known hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomatase insufficiency.
4) Subjects treated by medications or consuming products that may interfere with ethosuximide (such as St John’s wort, chelator resins, gastro-intestinal topics, antiacids, adsorbents).
5) Subjects who are not able to evaluate the palatability of the Study treatments.
6) Subjects treated or requiring to be treated with ONLY one EVENING daily dose of ethosuximide at inclusion.
7) Subjects who don’t have coverage by social security.

E.5 End points

E.5.1

Primary end point(s)

The primary outcome is the palatability score (taste rating) measured on a 100-mm visual analogical scale VAS (0 mm indicates a really bad taste, 100 mm indicates a really good taste) incorporating 5 facial hedonic features. The outcome is evaluated by the child himself (with the support of the parents or caregiver if needed), at SP I Day 28 (V2) and SP II Day 28 (V3). The score is determined, for all children, in mm from the left end (mean +/- SD) for each investigational medicinal product (IMP) and represents the opinion of the subject for the treatment period.

E.5.1.1

Timepoint(s) of evaluation of this end point

- Day 28 (V2)
- Day 56 (V3)

E.5.2

Secondary end point(s)

1)Acceptability endpoints
Tests to be done by the children themselves:
- evolution of the score of palatability/”taste”
- number of subjects who rate the palatability of the IMP ≥ 50
- score of after-taste,
- score of easiness of swallowing
- score of appropriateness of the volume/quantity of study product
- score of treatment preference
- score of a spontaneous verbal judgment
- score of easiness of administration
- rate of willingness to consume again the study product

Tests to be done by the parents/caregivers are:
- score of palatability perception
- score of easiness of dose preparation to obtain the right dose
- events of spontaneous rejection or spitting out of the IMP

2) Compliance endpoint
- Rate of compliance based on the patient’s surveillance diary and study drug accountability
- The percentage of days the patient is considered as compliant within a period is also analysed

3) Pharmacokinetics endpoint
Blood PK parameters of ethosuximide, in monotherapy and in combination are calculated after repeated doses, as the average steady-state plasma concentration Cavg and the clearance (Cl)
Cavg = dose / (Tau x Cl), with Tau = time interval between 2 successive administrations

4) Sustained effects endpoints
- Proportion/number of subjects free from treatment failure
- Assessment of the clinical and electroclinical absence seizure condition
- Assessment of the correlation between EEG (30 minute recordings) and video/clinical detection of seizures

5) Pharmacodynamics endpoint
- Score of gastro-intestinal (GI) tolerability

6) Safety & tolerability endpoints4
- Proportion/number of subjects experiencing treatment emergent adverse events (TEAE)
- Changes from baseline in vital signs and laboratory parameters

E.5.2.1

Timepoint(s) of evaluation of this end point

- D14 of first and secund period of treatment : palatability only
- D28 (V2) : all except score of treament preference
- D56 (V3) : all

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

Yes

E.6.7

Pharmacodynamic

Yes

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

Yes

E.6.13.1

Other scope of the trial description

Palatability study
Compliance

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

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

Yes

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

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:

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)

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

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

children from 2 to 17 years old included.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

None

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-10-04

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

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