E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Genetically determined mitochondrial disease and associated refractory epilepsy |
Malattia mitocondriale determinata geneticamente ed associata ad epilessia refrattaria |
|
E.1.1.1 | Medical condition in easily understood language |
Mitochondrial disease associated with refractory epilepsy |
Malattia mitocondriale associata ad epilessia refrattaria |
|
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 | No |
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. |
Dimostrare l’effetto di vatiquinone (PTC743) sulla riduzione della frequenza delle convulsioni motorie osservabili in soggetti con malattia mitocondriale geneticamente confermata, valutato mediante un diario delle crisi. |
|
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 |
- Dimostrare gli effetti di vatiquinone sulle visite in pronto soccorso e sulle ospedalizzazioni correlate alle crisi convulsive - Dimostrare gli effetti di vatiquinone sull’insorgenza di stato epilettico - Dimostrare gli effetti di vatiquinone sul numero totale di crisi mensili - Dimostrare gli effetti di vatiquinone sul tasso di risposta nelle convulsioni motorie e non motorie - Dimostrare gli effetti di vatiquinone sul numero di farmaci antiepilettici di emergenza utilizzati - Dimostrare gli effetti di vatiquinone sulla qualità di vita correlata alla salute (usando il questionario CarerQoL-7D) - Dimostrare gli effetti di vatiquinone sull’insorgenza di convulsioni a grappolo - Dimostrare la sicurezza di vatiquinone valutata in base a eventi avversi seri (SAE) farmaco-correlati, eventi avversi (AE) farmaco-correlati e modificazioni della dose |
|
E.2.3 | Trial contains a sub-study | No |
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: a) have >or= 6 observed motor seizures occurring during the 28 days prior to the baseline visit (Day 0). b) have >or= 2 observed motor seizures in the first 14 days and >or= 2 in the second 14 days of the Run-in period (Day -14). c) do not have a consecutive 20-day seizure free period. d) 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 |
- Aver firmato il consenso informato - Malattia mitocondriale ereditaria geneticamente confermata (secondaria a mutazione del DNA nucleare o mitocondriale) con fenotipo epilettico associato - Nonostante il trattamento in corso con almeno 2 farmaci anti-epilettici(FAE): a) avere >0= 6 convulsioni motorie nei 28 giorni precedenti la visita basale (Giorno 0); b) avere >0= 2 convulsioni motorie osservate nei primi 14 giorni e >0= 2 nei secondi 14 giorni del periodo di Run-in (Giorno -14); c) assenza di un periodo libero da crisi per 20 giorni consecutivi; d) almeno l’80% del diario delle crisi compilato. Durante le prime 24 settimane non saranno consentite modifiche al regime FAE. - Anamnesi documentata di epilessia associata a malattia mitocondriale da almeno 6 mesi nel periodo precedente lo Screening - Consenso a non assumere terapie non approvate nei 30 giorni precedenti la Visita basale e per la durata dello studio - Terapie antiepilettiche a regime posologico stabile nei 30 giorni precedenti la Visita basale - Integratori alimentari a regime stabile nei 30 giorni precedenti e, nel caso di una dieta chetogenica, dieta chetogenica stabile nei 90 giorni precedenti la Visita basale e per la durata dello studio - Elettroencefalogramma (EEG) allo Screening o precedente EEG a conferma della diagnosi di epilessia |
|
E.4 | Principal exclusion criteria |
- Allergy to vatiquinone or sesame oil. - Aspartate transaminase (AST) or alanine transaminase (ALT) >or= 2 × upper level of normal (ULN) at time of screening. - International normalized ratio (INR) >or= 1.5 × ULN at time of screening. - Serum creatinine >or= 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). |
- Allergia a vatiquinone o all’olio di sesamo - Aspartato transaminasi o alanina transaminasi >o= 2×il limite superiore della norma (ULN) allo Screening - Rapporto internazionale randomizzato >o= 1,5×ULN allo Screening - Creatinina sierica >o= 1,5×ULN allo Screening - Partecipazione a un altro studio clinico interventistico nei 60 giorni precedenti la randomizzazione o nel corso di questo studio clinico - Precedente trattamento con vatiquinone - Trattamento concomitante con farmaci non approvati dalle agenzie regolatorie per il trattamento delle malattie mitocondriali - Trattamento concomitante con inibitori del citocromo P450 (CYP) come itraconazolo o induttori del CYP come rifampina. Il trattamento con questi farmaci deve essere completato almeno 4 settimane prima dell’arruolamento. - Soggetti in gravidanza o allattamento o soggetti sessualmente attivi non disposti a utilizzare metodi contraccettivi appropriati. I soggetti di sesso femminile in età fertile devono presentare un risultato negativo al test di gravidanza effettuato allo Screening e alla Visita basale (Giorno 0). |
|
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 |
Variazione percentuale dal Basale alla Settimana 24 nella frequenza delle convulsioni motorie osservabili in 28 giorni durante la fase controllata verso placebo |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 0, Week 24 |
Giorno 0, Settimana 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 >or= 25%, >or= 50%, >or= 75%, and 100% Reduction in Motor Seizures 7. Percentage of Participants with >or= 25%, >or= 50%, >or= 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. Numero di giorni di ospedalizzazione correlata alla malattia 2. Insorgenza o recidiva di stato epilettico 3. Numero e percentuale di soggetti ricoverati/presentatisi in pronto soccorso a causa della malattia 4. Numero di ricoveri o visite in pronto soccorso correlati/e alla malattia 5. Variazione percentuale rispetto al Basale nella frequenza di tutti i tipi di convulsioni in 28 giorni 6. Percentuale di soggetti con una riduzione delle convulsioni motorie >o= 25%, >o= 50%, >o= 75%, e 100% 7.Percentuale di soggetti con una riduzione delle convulsioni totali (di tutti i tipi) >o= 25%, >o= 50%, >o= 75%, e 100% 8.Numero di partecipanti che necessitano Rescue Medication per l'epilessia 9.Qualità della vita correlata allo stato di salute come misurato con il questionario Care-Related Quality of Life of Informal Caregivers (CarerQoL-7D) 10.Numero di partecipanti con convulsioni a grappolo |
|
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. Settimana 24 e fino alla settimana 72 2. Settimana 24 e fino alla settimana 72 3. Settimana 24 e fino alla settimana 72 4. Settimana 24 e fino alla settimana 72 5. Giorno 0, settimana 24, settimana 72 6. Settimana 24 e fino alla settimana 72 7. Settimana 24 e fino alla settimana 72 8. Settimana 24 e fino alla settimana 72 9. Settimana 24 e fino alla settimana 72 10. Settimana 24 e fino alla settimana 72 |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
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) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |