E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Genetically determined mitochondrial disease and associated refractory epilepsy |
Enfermedad mitocondrial determinada genéticamente y asociada a la epilepsia farmacorresistente. |
|
E.1.1.1 | Medical condition in easily understood language |
Mitochondrial disease associated with refractory epilepsy |
Epilepsia farmacorresistente asociada a la enfermedad mitocondrial. |
|
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. |
Demostrar el efecto de la vatiquinona (PTC743) sobre la reducción de la frecuencia de crisis motoras observables en sujetos con enfermedad mitocondrial confirmada genéticamente, en su valoración mediante un diario de crisis |
|
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 |
- Evaluar los efectos de la vatiquinona sobre las visitas a Urgencias y las hospitalizaciones por crisis - Evaluar los efectos de la vatiquinona sobre la presentación de status epilepticus - Evaluar los efectos de la vatiquinona sobre el número mensual total de crisis - Evaluar los efectos de la vatiquinona sobre la tasa de respondedores en cuanto a crisis motoras y no motoras - Evaluar los efectos de la vatiquinona sobre el número de medicamentos antiepilépticos de rescate utilizados - Evaluar los efectos de la vatiquinona sobre la calidad de vida relacionada con la salud (utilizando el cuestionario CarerQoL-7D) - Evaluar los efectos de la vatiquinona sobre la producción de crisis en racimo - Evaluar la seguridad de la vatiquinona, en su evaluación mediante los acontecimientos adversos graves relacionados con el fármaco (SAEs), los acontecimientos adversos relacionados con el fármaco (AEs) y las modificaciones de la dosis |
|
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: ◦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. |
- Formulario de consentimiento informado firmado - Confirmación genética de enfermedad mitocondrial hereditaria (secundaria a mutación del ácido desoxirribonucleico nuclear o mitocondrial), con fenotipo de epilepsia asociada
- A pesar del tratamiento en curso con como mínimo 2 fármacos antiepilépticos: -ha presentado >= 6 crisis motoras observadas durante los 28 días anteriores a la visita basal (Dia 0) -ha presentado>=2 crisis motoras observadas en los primeros 14 días y >=2 en los segundos 14 días del periodo de preinclusión - no ha tenido un periodo de 20 días consecutivos sin crisis, y - su diario de crisis contiene como mínimo un 80% de los datos - No se permitirán cambios en el régimen de fármacos antiepilépticos durante el primer periodo de 24 semanas. - Antecedentes médicos documentados de epilepsia asociada a enfermedad mitocondrial durante como mínimo los 6 meses anteriores a la selección - Conformidad en no seguir tratamientos no aprobados durante los 30 días anteriores a la visita basal (día 0) y durante el estudio - Régimen estable de dosis de los medicamentos antiepilépticos durante los 30 días anteriores a la visita basal (día 0) - Régimen estable de suplementos dietéticos durante los 30 días anteriores y, en caso de dieta cetógena, esta se ha mantenido estable durante los 90 días anteriores a la visita basal y se mantendrá durante el estudio - Electroencefalograma (EEG) de la selección o de la historia clínica (tomada en los últimos 30 días) que confirma el diagnóstico de epilepsia |
|
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). |
- Alergia a la vatiquinona o al aceite de sésamo - Aspartato transaminasa (AST) o alanina transaminasa (ALR) >=2× límite superior de la normalidad (ULN) en la selección - Cociente internacional normalizado >=1,5×ULN en la selección - Creatinina sérica >=1,5×ULN en la selección - Participación en otro ensayo clínico intervencional en el plazo de los 60 días anteriores a la aleatorización o durante este ensayo clínico - Tratamiento previo con vatiquinona - Tratamiento concomitante con fármaco(s) no aprobado(s) por las autoridades sanitarias para el tratamiento de enfermedades de origen mitocondrial - Tratamiento en curso con inhibidores del citocromo P450 (CYP), como itraconazol, o inductores de CYP, como rifampicina. El tratamiento con estos agentes deberá haber finalizado como mínimo 4 semanas antes de la entrada en este estudio. - Mujeres embarazadas o en lactancia natural o sujetos sexualmente activos que no desean seguir métodos anticonceptivos adecuados. Las mujeres potencialmente fértiles deben arrojar una prueba de embarazo negativa en la selección y durante la visita basal (Dia 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 |
Cambio porcentual desde la basal a la semana 24 en la frecuencia de crisis motoras observables por 28 días durante la fase controlada con placebo |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 0, Week 24 |
Dia 0, semana 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. Número de días de hospitalización por la enfermedad 2. Número de participantes con presentación o recidiva de status epilepticu 3. Número y porcentaje de sujetos con hospitalizaciones/visitas a Urgencias relacionadas con la enfermedad 4. Número de hospitalizaciones/visitas a Urgencias relacionadas con la enfermedad 5. Cambio porcentual desde la basal a la semana 72 en la frecuencia total de crisis de todos los tipos por 28 días 6. Porcentaje de sujetos con una reducción de las crisis motoras >=25%, >= 50%, >=75% y >=100% 7. Porcentaje de sujetos con una reducción de todo tipo de crisis >=25%, >=50%, >=75% y >=100% 8. Número de medicamentos de rescate para las crisis 9. Calidad de vida relacionada con la salud, medida mediante el cuestionario CarerQoL-7D 10. Número de crisis en racimo |
|
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. Semana 24 y hasta la semana 72 2. Semana 24 y hasta la semana 72 3. Semana 24 y hasta la semana 72 4. Semana 24 y hasta la semana 72 5. Día 0, semana 24, semana 72 6. Semana 24 y hasta la semana 72 7. Semana 24 y hasta la semana 72 8. Semana 24 y hasta la semana 72 9. Semana 24 y hasta la semana 72 10. Semana 24 y hasta la semana 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 | No |
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 |
Ultima visita del último sujeto |
|
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 | 1 |
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 |