Clinical Trials Register

Summary
EudraCT Number:	2020-002100-39
Sponsor's Protocol Code Number:	PTC743-MIT-001-EP
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-02-25
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

2020-002100-39

A.3

Full title of the trial

Efficacy and Safety Study of Vatiquinone for the Treatment of Mitochondrial Disease Subjects With Refractory Epilepsy (MIT-E)

Étude évaluant l’efficacité et la sécurité d’emploi de la vatiquinone pour le traitement de patients atteints d’une maladie mitochondriale avec épilepsie réfractaire (MIT-E)

A.3.1

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

A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy

Étude évaluant l’efficacité et la sécurité d’emploi de la vatiquinone pour le traitement de patients atteints d’une maladie mitochondriale avec épilepsie réfractaire

A.3.2

Name or abbreviated title of the trial where available

MIT-E

A.4.1

Sponsor's protocol code number

PTC743-MIT-001-EP

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04378075

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	PTC THERAPEUTICS, 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	PTC THERAPEUTICS, 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	PTC THERAPEUTICS, INC.
B.5.2	Functional name of contact point	Patient Advocacy
B.5.3	Address:
B.5.3.1	Street Address	100 CORPORATE COURT
B.5.3.2	Town/ city	SOUTH PLAINFIELD
B.5.3.3	Post code	NJ 07080
B.5.3.4	Country	United States
B.5.4	Telephone number	+1 866-282-5873
B.5.6	E-mail	medinfo@ptcbio.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	Vatiquinone
D.3.2	Product code	PTC743
D.3.4	Pharmaceutical form	Oral solution
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	VATIQUINONE
D.3.9.1	CAS number	1213269-98-7
D.3.9.2	Current sponsor code	PTC743
D.3.9.3	Other descriptive name	EPI743; alpha-tocotrienol quinone
D.3.9.4	EV Substance Code	SUB188275
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	100
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Oral solution
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Genetically determined mitochondrial disease and associated refractory epilepsy

Maladie mitochondriale génétiquement définie et épilepsie réfractaire associée

E.1.1.1

Medical condition in easily understood language

Mitochondrial disease associated with refractory epilepsy

Maladie mitochondriale associée à une épilepsie réfractaire

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	10077953
E.1.2	Term	Refractory epilepsy
E.1.2	System Organ Class	100000004852

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10052637
E.1.2	Term	Genetic mitochondrial abnormalities NEC
E.1.2	System Organ Class	100000004850

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 demonstrate the effect of vatiquinone (PTC743) on reduction in observable motor seizure frequency in subjects with genetically confirmed mitochondrial disease, as assessed by a seizure diary.

L’objectif principal de l’étude est de démontrer l’effet de la vatiquinone (PTC743) sur la réduction
de la fréquence des crises motrices observables chez des patients atteints d’une maladie mitochondriale génétiquement confirmée, telle qu’évaluée par un journal des crises.

E.2.2

Secondary objectives of the trial

● To demonstrate the effects of vatiquinone on seizure-related emergency room visits and hospitalizations
● To demonstrate the effects of vatiquinone on occurrence of status epilepticus
● To demonstrate the effects of vatiquinone in monthly total seizure count
● To demonstrate the effects of vatiquinone in responder rate in motor and non-motor seizures
● To demonstrate the effects of vatiquinone on number of rescue antiepileptic medications used
● To demonstrate the effects of vatiquinone on health-related quality of life (using the CarerQoL-7D questionnaire)
● To demonstrate the effects of vatiquinone on occurrence of seizure clusters
● To demonstrate the safety of vatiquinone as assessed by drug-related SAEs, drug-related adverse events (AEs), and dose modifications

● Démontrer les effets de la vatiquinone sur les consultations aux urgences et les hospitalisations liées aux crises.
● Démontrer les effets de la vatiquinone sur la survenue de l’état de mal épileptique.
● Démontrer les effets de la vatiquinone sur le nombre total mensuel de crises.
● Démontrer les effets de la vatiquinone dans le taux de patients répondeurs dans les crises motrices et non motrices.
● Démontrer les effets de la vatiquinone sur le nombre de médicaments antiépileptiques de secours utilisés.
● Démontrer les effets de la vatiquinone sur la qualité de vie liée à la santé (à l’aide du questionnaire CarerQoL-7D).
● Démontrer les effets de la vatiquinone sur la survenue de crises répétitives.
● Démontrer la sécurité d’emploi de la vatiquinone, telle qu’évaluée par les EIG liés au médicament, les événements indésirables (EI) liés au médicament et les modifications de dose.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Signed informed consent form.
•Genetic confirmation of inherited mitochondrial disease (secondary to either nuclear or mitochondrial DNA mutation) with associated epilepsy phenotype

•Despite ongoing treatment with at least 2 antiepileptic drugs:
◦have ≥6 observed motor seizures occurring during the 28 days prior to the baseline visit (Day 0).
◦have ≥2 observed motor seizures in the first 14 days and ≥2 in the second 14 days of the Run-in period (Day -14).
◦do not have a consecutive 20-day seizure free period.
◦have at least 80% of seizure diary data.
No changes to the AED regimen will be allowed during the first 24-week period.

•Documented medical history of epilepsy symptoms associated with mitochondrial disease for at least 6 months prior to screening.
•Consent to abstain from non-approved therapies for 30 days prior to the baseline visit (Day 0) and for the duration of the study.
•Stable dose regimen of antiepileptic therapies 30 days prior to the baseline visit (Day 0).
•Stable regimen of dietary supplements 30 days prior and, if on a ketogenic diet, stable ketogenic diet 90 days prior to the baseline visit (Day 0) and for duration of the study.
•Electroencephalogram (EEG) at screening or historical EEG (taken within the last 30 days) for diagnostic confirmation of epilepsy.

• Consentement éclairé signé
• Confirmation génétique d’une maladie mitochondriale héréditaire (secondaire à une mutation nucléaire ou mitochondriale de l’ADN) avec phénotype d’épilepsie associé

• Malgré un traitement en cours avec au moins 2 MAE :
○ Présentent ≥ 6 crises motrices observées au cours des 28 jours précédant la visite de référence
○ Présentent ≥ 2 crises motrices observées au cours des 14 premiers jours et ≥ 2 au cours des 14 jours suivants de la période de pré-inclusion
○ N’ont pas de période sans crise de 20 jours consécutifs
○ Ont au moins 80 % des données dans le journal des crises
Aucune modification du schéma posologique du MAE ne sera autorisée pendant la première période de 24 semaines.

• Antécédents médicaux documentés d’épilepsie associée à une maladie mitochondriale depuis au moins 6 mois avant la sélection
• Consentement à s’abstenir de suivre des thérapies non approuvées pendant 30 jours avant la visite de référence et pendant toute la durée de l’étude
• Schéma posologique stable de thérapies antiépileptiques 30 jours avant la visite de référence
• Régime stable de compléments alimentaires 30 jours avant et, si régime cétogène, régime cétogène stable 90 jours avant la visite de référence et pendant toute la durée de l’étude
• Électroencéphalogramme (EEG) à la sélection ou antécédent d’EEG pour la confirmation diagnostique de l’épilepsie

E.4

Principal exclusion criteria

•Allergy to vatiquinone or sesame oil.
•Aspartate transaminase (AST) or alanine transaminase (ALT) ≥2 × upper level of normal (ULN) at time of screening.
•International normalized ratio (INR) ≥1.5 × ULN at time of screening.
•Serum creatinine ≥1.5 × ULN at time of screening.
•Participation in another interventional clinical trial 60 days prior to randomization or for the duration of this clinical trial
•Previously received vatiquinone.
•Concomitant treatment with drug(s) that have not received regulatory agency approval for the treatment of mitochondrial diseases.
•Ongoing treatment with cytochrome P450 (CYP) inhibitors such as itraconazole or CYP inducers such as rifampin. Treatment with these agents must be completed at least 4 weeks prior to enrollment.
•Pregnant or lactating participants or those sexually active participants who are unwilling to comply with proper birth control methods. Females of childbearing potential must have a negative pregnancy test at screening and during the baseline visit (Day 0).

•Allergie à la vatiquinone ou à l’huile de sésame
•Taux d’aspartate aminotransférase (ASAT) ou d’alanine aminotransférase (ALAT) ≥ 2 × limite supérieure de la normale (LSN) au moment de la sélection
•INR ≥ 1,5 × LSN au moment de la sélection
•Créatinine sérique ≥ 1,5 × LSN au moment de la sélection
•Participation à un autre essai clinique interventionnel 60 jours avant la randomisation ou pendant la durée de cet essai clinique
•A déjà reçu de la vatiquinone
•Traitement concomitant par médicament(s) n’ayant pas reçu l’approbation de l’agence réglementaire pour le traitement des maladies mitochondriales
•Traitement concomitant par idébénone
•Traitement en cours par des inhibiteurs du cytochrome P450 (CYP) tels que l’itraconazole ou des inducteurs du CYP tels que la rifampicine. Le traitement par ces agents doit être terminé au moins 4 semaines avant l’inclusion.
•Les patientes enceintes ou qui allaitent ou les patientes sexuellement actives qui ne souhaitent pas se conformer aux méthodes de contraception appropriées. Les femmes en âge de procréer doivent présenter un test de grossesse négatif à la sélection et lors de la visite de référence.

E.5 End points

E.5.1

Primary end point(s)

Percent change from Baseline to Week 24 in the Number of Observable Motor Seizures per 28 Days during the placebo-controlled phase

Le pourcentage de variation par rapport à la référence jusqu'à semaine 24 , de la fréquence des crises motrices observables par période de 28 jours pendant la phase contrôlée par placebo

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 0, Week 24

Jour 0, semaine 24

E.5.2

Secondary end point(s)

1.Number of Disease-Related Hospital Days
2.Number of Participants with Occurrences or Recurrence of Status Epilepticus
3.Number of Participants with Disease-Related In-Patient Hospitalizations or Emergency Room Visits
4.Number of Disease-Related In-Patient Hospital Admissions or Emergency Room Visits
5.Change from Baseline to Week 72 in Total Seizure Frequency (All Types) per 28 Days
6.Percentage of Participants with ≥25%, ≥50%, ≥75%, and 100% Reduction in Motor Seizures
7.Percentage of Participants with ≥25%, ≥50%, ≥75%, and 100% Reduction in Total Seizures (All Types)
8.Number of Participants Who Require Rescue Seizure Medication
9.Health-Related Quality of Life as Measured by the Care-Related Quality of Life of Informal Caregivers (CarerQoL-7D) Questionnaire
10.Number of Participants with Seizure Clusters

1.Nombre de jours d’hospitalisation liés à la maladie
2.Survenue ou récurrence d’un état de mal épileptique
3.Nombre et pourcentage de patients ayant effectué une hospitalisation/des visites aux urgences liées à leur maladie
4.Nombre d’hospitalisations/de visites aux urgences liées à la maladie des patients
5.Variation en pourcentage par rapport à la référence jusqu'à semaine 72 de la fréquence totale des crises par période de 28 jours de tous les types
6. Proportion de patients présentant une réduction de ≥ 25 %, ≥ 50 %, ≥ 75 % et 100 % des crises motrices
7.Proportion de patients présentant une réduction de ≥ 25 %, ≥ 50 %, ≥ 75 % et 100 % des crises totales
8.Nombre de médicaments de secours contre les crises
9.Qualité de vie liée à la santé telle que mesurée par le questionnaire CarerQoL-7D
10.Nombre de crises répétitives définies par les entrées « trop nombreuses à compter » dans les journaux des crises

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Week 24 and up to Week 72
2. Week 24 and up to Week 72
3. Week 24 and up to Week 72
4. Week 24 and up to Week 72
5. Day 0, Week 24, Week 72
6. Week 24 and up to Week 72
7. Week 24 and up to Week 72
8. Week 24 and up to Week 72
9. Week 24 and up to Week 72
10. Week 24 and up to Week 72

1. Semaine 24 et jusqu'à semaine 72
2. Semaine 24 et jusqu'à semaine 72
3. Semaine 24 et jusqu'à semaine 72
4. Semaine 24 et jusqu'à semaine 72
5. Jour 0, semaine 24, semaine 72
6. Semaine 24 et jusqu'à semaine 72
7. Semaine 24 et jusqu'à semaine 72
8. Semaine 24 et jusqu'à semaine 72
9.Semaine 24 et jusqu'à semaine 72
10.Semaine 24 et jusqu'à semaine 72

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

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)

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)

E.8.2.2

Placebo

Yes

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

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

France

Germany

Italy

Spain

United Kingdom

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

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

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)

None

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

2021-04-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-10-04

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2023-12-27

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IMP with orphan designation in the indication
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