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

Phase 2

Terminated

Conditions: Alpers Disease
Mitochondrial Diseases
Mitochondrial Encephalopathy (MELAS)
Pontocerebellar Hypoplasia Type 6 (PCH6)
Drug Resistant Epilepsy
Leigh Disease
Leigh Syndrome
Alpers Syndrome

Interventions: Drug: Vatiquinone
Other: Placebo

Registration Number: NCT04378075

Lead Sponsor: PTC Therapeutics

Brief Summary: This is a parallel-arm, double-blind, placebo-controlled study with a screening phase that includes a 28-day run-in phase to establish baseline seizure frequency, followed by a 24-week, randomized, placebo-controlled phase. After completion of the randomized, placebo-controlled phase, participants may enter a 48-week, long-term, extension phase during which they will receive open-label treatment with vatiquinone.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 68

Inclusion Criteria

Signed informed consent form.
Participant or parent/legal guardian is able and willing to complete seizure diaries for the duration of the study.
Genetic confirmation of inherited mitochondrial disease with associated epilepsy phenotype (Alpers/polymerase subunit gamma [POLG], Leigh syndrome, mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes [MELAS]), or other genetically confirmed mitochondrial disease 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).
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.
Documented medical history of epilepsy associated with mitochondrial disease for at least 6 months prior to screening except for participants who are <2 years of age at the time of screening (participants <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 participants).
Consent to abstain from non-approved therapies for 30 days prior to the screening visit 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 seizures.

Exclusion Criteria

Allergy to vatiquinone or sesame oil.
Aspartate transaminase (AST) or alanine transaminase (ALT) ≥3 × upper level of normal (ULN) at time of screening.
International normalized ratio (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.
Concomitant treatment with idebenone.
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.During the study, participants should not use grapefruit/grapefruit juice or St John's wort extract.
Pregnant or lactating participants or those male or female sexually active participants who are unwilling to comply with proper birth control methods from the time consent is signed until 30 days after treatment discontinuation. 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 (for example, fat malabsorption syndrome, other mitochondrial disorders) in the opinion of the investigator.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Vatiquinone	Vatiquinone	15 milligrams/kilogram (mg/kg) if body weight \<13 kg, and 200 mg if body weight ≥13 kg, administered orally, 3 times per day (TID) or up to 72 weeks
Vatiquinone	Placebo	15 milligrams/kilogram (mg/kg) if body weight \<13 kg, and 200 mg if body weight ≥13 kg, administered orally, 3 times per day (TID) or up to 72 weeks
Placebo	Placebo	Vatiquinone-matching placebo, administered orally, TID for up to 24 weeks followed by vatiquinone 15 mg/kg if body weight \<13 kg, and 200 mg if body weight ≥13 kg, administered orally, TID for up to 48 weeks.

Primary Outcome Measures

Name	Time	Method
Percent Change From Baseline to Week 24 in the Number of Observable Motor Seizures per 28 Days	Day 0, Week 24

Secondary Outcome Measures

Name	Time	Method
Number of Disease-Related Hospital Days	Week 24 and up to Week 72
Number of Participants with Occurrences or Recurrence of Status Epilepticus	Week 24 and up to Week 72
Number of Participants with Disease-Related In-Patient Hospitalizations or Emergency Room Visits	Week 24 and up to Week 72
Number of Disease-Related In-Patient Hospital Admissions or Emergency Room Visits	Week 24 and up to Week 72
Percent Change From Baseline to Week 72 in Total Seizure Frequency per 28 Days	Day 0, Week 24, Week 72
Percentage of Participants with ≥25%, ≥50%, ≥75%, and 100% Reduction in Motor Seizures	Week 24 and up to Week 72
Percentage of Participants with ≥25%, ≥50%, ≥75%, and 100% Reduction in Total Seizures	Week 24 and up to Week 72
Number of Participants Who Require Rescue Seizure Medication	Week 24 and up to Week 72
Health-Related Quality of Life as Measured by the Care-Related Quality of Life of Informal Caregivers (CarerQoL-7D) Questionnaire	Week 24 and up to Week 72
Number of Participants with Seizure Clusters	Week 24 and up to Week 72

Trial Locations

Locations (27): John Hopkins Medicine
🇺🇸
Baltimore, Maryland, United States
Akron Children's Hospital
🇺🇸
Akron, Ohio, United States
Pediatric Genetics Clinic (Main MGH Hospital)
🇺🇸
Boston, Massachusetts, United States
Boston Children Hospital
🇺🇸
Boston, Massachusetts, United States
University of California
🇺🇸
San Diego, California, United States
Children's of Minnesota
🇺🇸
Minneapolis, Minnesota, United States
Baylor College of Medicine
🇺🇸
Houston, Texas, United States
University of Texas Health Science
🇺🇸
Houston, Texas, United States
Yale School of Medicine
🇺🇸
New Haven, Connecticut, United States
Stanford University
🇺🇸
Stanford, California, United States
Children's National Medical Center - Department Of Neurology
🇺🇸
Washington, District of Columbia, United States
Alberta Children's Hospital, University of Calgary
🇨🇦
Calgary, Canada
CHU d'Angers - Service de génétique
🇫🇷
Angers, France
CHU de Strasbourg - Hôpital de Hautepierre - Service de Neuropédiatrie
🇫🇷
Strasbourg, France
CHU de Montpellier - Hôpital Gui de Chauliac - Département de neuropédiatrie
🇫🇷
Montpellier, France
A.P.H.P - Hôpital Necker-Enfants Malades - Service de Neurologie pédiatrique
🇫🇷
Paris, France
PTC Clinical Site
🇯🇵
Multiple Locations, Japan
UOC Neuropsichiatria Infantile, Istituto Neurologico Carlo Besta-Fondazione IRCCS
🇮🇹
Milano, Italy
Instytut Pomnik-Centrum Zdrowia Dziecka, Centrum Wsparacia Pediatrycznych Badań Klinicznych
🇵🇱
Warszawa, Poland
U.O.C. Malattie Muscolari e Neurodegenerative, Dipartimento di Scienze Neurologiche e Psichiatriche, Ospedale Pediatrico Bambino Gesù
🇮🇹
Roma, Italy
Hospital Sant Joan de Déu
🇪🇸
Barcelona, Spain
Hospital Ruber Internacional, Neurology Department, Epilepsy Program
🇪🇸
Madrid, Spain
Great Ormond Street Hospital for Children NHS Foundation Trust
🇬🇧
London, United Kingdom
Karolinska University hospital, Astrid Lindgrens Children Hospital
🇸🇪
Stockholm, Sweden
Hospital Universitario 12 de Octubre
🇪🇸
Madrid, Spain
The Newcastle Upon Tyne Hospitals NHS Foundation Trust
🇬🇧
Newcastle Upon Tyne, United Kingdom
Seattle Children's hospital
🇺🇸
Seattle, Washington, United States