E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Genetically determined mitochondrial disease and associated refractory epilepsy |
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E.1.1.1 | Medical condition in easily understood language |
Mitochondrial disease associated with refractory epilepsy |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
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.
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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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Signed informed consent form. • Age <21 years at time of randomization. •Subjects with genetic confirmation of inherited mitochondrial disease with associated epilepsy phenotype (Alpers/POLG, Leigh syndrome, MELAS), or other genetically confirmed mitochondrial diseases secondary to mitochondrial mutations (Pontocerebellar Hypoplasia Type 6 [PCH6], nuclear DNA RARS2 mutation) or myoclonic epilepsy with ragged red fibers (MERRF, mitochondrial DNA [mtDNA] mitochondrially encoded tRNA lysine [MT-TK] mutation) are eligible.
•Despite 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 (except weight-based dose adjustments) during the first 24-week period.
•Documented medical history of epilepsy symptoms associated with mitochondrial disease for at least 6 months prior to screening except for subjects who are <2 years of age at the time of screening (subjects <2 years of age can be considered for enrollment if all other screening criteria are met due to the potential for rapid progression in these subjects). •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 screening visit •Stable regimen of dietary supplements 30 days prior and, if on a ketogenic diet, stable ketogenic diet 90 days prior to the screening visit and for duration of the study. •Electroencephalogram (EEG) at screening or historical EEG up to 6 months prior to screening for diagnostic confirmation of epilepsy. |
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E.4 | Principal exclusion criteria |
•Allergy to vatiquinone or sesame oil. •Aspartate transaminase (AST) or alanine transaminase (ALT) ≥3×ULN at time of screening •INR > 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 and use of artisanal (non-Epidiolex cannabidiol) cannabidiol therapies. •Ongoing treatment with strong cytochrome P450 (CYP) inhibitors such as itraconazole or strong 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 male and female sexually active subjects 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). •Comorbidities that may confound study results (eg, fat malabsorption syndrome, other mitochondrial disorders) in the opinion of the investigator |
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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
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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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
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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 |
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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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
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 |
Australia |
Canada |
Japan |
Russian Federation |
United States |
France |
Germany |
Italy |
Poland |
Sweden |
United Kingdom |
Spain |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
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 |