A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy (MIT-E)

Efficacy and Safety Study of Vatiquinone for the Treatment of Mitochondrial Disease Subjects With Refractory Epilepsy

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.

Study Overview

• Status: Terminated
• Conditions: Mitochondrial Diseases; Drug Resistant Epilepsy; Leigh Disease; Leigh Syndrome; Mitochondrial Encephalopathy (MELAS); Pontocerebellar Hypoplasia Type 6 (PCH6); Alpers Disease; Alpers Syndrome
• Intervention / Treatment: Drug: Vatiquinone; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Calgary, Canada, T3B 6A8
    • Alberta Children's Hospital, University of Calgary
• France
  • Angers, France, 49933
    • CHU d'Angers - Service de génétique
  • Montpellier, France, 34295
    • CHU de Montpellier - Hôpital Gui de Chauliac - Département de neuropédiatrie
  • Paris, France, 75015
    • A.P.H.P - Hôpital Necker-Enfants Malades - Service de Neurologie pédiatrique
  • Strasbourg, France, 67200
    • CHU de Strasbourg - Hôpital de Hautepierre - Service de Neuropédiatrie
• Italy
  • Milan, Italy, 20133
    • UOC Neuropsichiatria Infantile, Istituto Neurologico Carlo Besta-Fondazione IRCCS
  • Roma, Italy, 00165
    • U.O.C. Malattie Muscolari e Neurodegenerative, Dipartimento di Scienze Neurologiche e Psichiatriche, Ospedale Pediatrico Bambino Gesù
• Japan
  • Multiple Locations, Japan
    • PTC Clinical Site
• Poland
  • Warsaw, Poland, 04-730
    • Instytut Pomnik-Centrum Zdrowia Dziecka, Centrum Wsparacia Pediatrycznych Badań Klinicznych
• Spain
  • Barcelona, Spain, 08950
    • Hospital Sant Joan de Déu
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28034
    • Hospital Ruber Internacional, Neurology Department, Epilepsy Program
• Sweden
  • Stockholm, Sweden, S-171 76
    • Karolinska University hospital, Astrid Lindgrens Children Hospital
• United Kingdom
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital for Children NHS foundation trust
  • Newcastle upon Tyne, United Kingdom, NE1 4LP
    • The Newcastle Upon Tyne Hospitals NHS Foundation Trust
• United States
  • California
    • San Diego, California, United States, 92123
      • University of California
    • Stanford, California, United States, 94305
      • Stanford University
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale School of Medicine
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Children's National Medical Center - Department Of Neurology
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • John Hopkins Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children Hospital
    • Boston, Massachusetts, United States, 02114-2696
      • Pediatric Genetics Clinic (Main MGH Hospital)
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's of Minnesota
  • Ohio
    • Akron, Ohio, United States, 44308
      • Akron Children's Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Houston, Texas, United States, 77030
      • University of Texas Health Science
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 20 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: Vatiquinone; Vatiquinone will be administered per the treatment arm description.; Other Names: PTC743; EPI-743; Other: Placebo; Vatiquinone-matching placebo will be administered per the treatment arm description
Placebo Comparator: 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.	Other: Placebo; Vatiquinone-matching placebo will be administered per the treatment arm description

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline to Week 24 in the Number of Observable Motor Seizures Per 28 Days During the Double-blind Period	The 28-day motor seizure frequency in the double-blind period was calculated as the (number of motor seizures)/ (the number of valid days where motor seizure count information is present) * 28 within the double-blind period. The baseline of the seizure frequency used the 28 days observations immediately prior to treatment start date for this calculation.	Baseline to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 24 in Number of Disease-Related Hospitalization Days Per 28 Days in Double-Blind Period	The disease-related hospitalization days per 28 days in the double-blind period was calculated as the (number of disease-related hospitalizations)/(the number of days within the double-blind period) * 28. The baseline hospitalization used the 28 days observations immediately prior to treatment start date for this calculation.	Baseline to Week 24
Change From Baseline to Week 72 in Number of Disease-Related Hospitalization Days Per 28 Days in Overall Period	The disease-related hospitalization days per 28 days in the overall period was calculated as the (number of disease-related hospitalizations)/(the number of days within the overall treatment period) * 28. The baseline hospitalization used the 28 days observations immediately prior to treatment start date for this calculation.	Baseline to Week 72
Change From Baseline to Week 24 in Occurrence/Recurrence of Status Epilepticus Per 28 Days in Double-blind Period	The status epilepticus per 28 Days in the double-blind period was calculated as the (number of status epilepticus incidences)/(the number of days in the double-blind period) * 28. The baseline status epilepticus incidences used the 28 days observations immediately prior to treatment start date for this calculation.	Baseline to Week 24
Change From Baseline to Week 72 in Occurrence/Recurrence of Status Epilepticus Per 28 Days in Overall Period	The status epilepticus per 28 Days in the overall period was calculated as the (number of status epilepticus incidences)/(the number of days in the overall period) * 28. The baseline status epilepticus incidences used the 28 days observations immediately prior to treatment start date for this calculation.	Baseline to Week 72
Number of Participants With Disease-Related In-Patient Hospitalizations in Double-Blind Period	In-patient hospitalization per 28 days in the double-blind period was calculated as the (number of in-patient hospitalization)/(the number of days in the double-blind period) * 28. The baseline in-patient hospitalization used the 28 days observations immediately prior to treatment start date for this calculation. Number of participants with in-patient hospitalizations for either seizure or epilepticus per 28 days in double-blind period are reported.	Baseline to Week 24
Number of Participants With Disease-Related In-Patient Hospitalizations in Overall Period	In-patient hospitalization per 28 days in the overall period was calculated as the (number of in-patient hospitalization)/(the number of days in the overall period) * 28. The baseline in-patient hospitalization used the 28 days observations immediately prior to treatment start date for this calculation. Number of participants with in-patient hospitalizations for either seizure or epilepticus per 28 days in overall period are reported.	Baseline to Week 72
Number of Participants With Disease-Related Emergency Room Visits in Double-Blind Period	Disease-related emergency room visits per 28 days in the double-blind period was calculated as the (number of disease-related emergency room visits)/(the number of days in the double-blind period) * 28. The baseline disease-related emergency room visits used the 28 days observations immediately prior to treatment start date for this calculation. Number of participants with disease-related emergency room visits for either seizure or epilepticus per 28 days in double-blind period are reported.	Baseline to Week 24
Number of Participants With Disease-Related Emergency Room Visits in Overall Period	Disease-related emergency room visits per 28 days in the overall period was calculated as the (number of disease-related emergency room visits)/(the number of days in the overall period) * 28. The baseline disease-related emergency room visits used the 28 days observations immediately prior to treatment start date for this calculation. Number of participants with disease-related emergency room visits for either seizure or epilepticus per 28 days in overall period are reported.	Baseline to Week 72
Number of Disease-Related In-Patient Hospitalizations in Double-Blind Period	In-patient hospitalization per 28 days in the double-blind period was calculated as the (number of in-patient hospitalization)/(the number of days in the double-blind period) * 28. The baseline in-patient hospitalization used the 28 days observations immediately prior to treatment start date for this calculation. Number of participants with number of in-patient hospitalizations for either seizure or epilepticus per 28 days in double-blind period are reported.	Baseline to Week 24
Number of Disease-Related In-Patient Hospitalizations in Overall Period	In-patient hospitalization per 28 days in the overall period was calculated as the (number of in-patient hospitalization)/(the number of days in the overall period) * 28. The baseline in-patient hospitalization used the 28 days observations immediately prior to treatment start date for this calculation. Number of participants with number in-patient hospitalizations for either seizure or epilepticus per 28 days in overall period are reported.	Baseline to Week 72
Number of Disease-Related Emergency Room Visits in Double-Blind Period	Disease-related emergency room visits per 28 days in the double-blind period was calculated as the (number of disease-related emergency room visits)/(the number of days in the double-blind period) * 28. The baseline disease-related emergency room visits used the 28 days observations immediately prior to treatment start date for this calculation. Number of participants with number of emergency room visits for either seizure or epilepticus per 28 days in double-blind period are reported.	Baseline to Week 24
Number of Disease-Related Emergency Room Visits in Overall Period	Disease-related emergency room visits per 28 days in the overall period was calculated as the (number of disease-related emergency room visits)/(the number of days in the overall period) * 28. The baseline disease-related emergency room visits used the 28 days observations immediately prior to treatment start date for this calculation. Number of participants with number of emergency room visits for either seizure or epilepticus per 28 days in overall period are reported.	Baseline to Week 72
Percent Change From Baseline to Week 24 in Total Seizure Frequency Per 28 Days in Double-Blind Period	The total seizure frequency per 28 days in the double-blind period was calculated as the (number of total seizures)/(the number of valid days where total seizure count information is present) * 28 within the double-blind period. The baseline of the seizure frequency used the 28 days observations immediately prior to treatment start date for this calculation.	Baseline, Week 24
Percent Change From Baseline to Week 72 in Total Seizure Frequency Per 28 Days in Overall Period	Overall period was defined as the period from the first dosing date of investigational product (IP) during double-blind period to the end of study (double-blind + open-label period). The 28 day total seizure frequency in the overall period was calculated as the (number of total seizures)/(the number of valid days where total seizure count information is present) * 28 within the overall period. The baseline of the seizure frequency used the 28 days observations immediately prior to treatment start date for this calculation.	Baseline, Week 72
Number of Participants Taking Rescue Medications in the Double-blind Period	Number of participants taking rescue medications for epilepsy in double-blind period are reported.	Baseline to Week 24
Number of Participants Taking Rescue Medications in the Overall Period	Number of participants taking rescue medications for epilepsy in overall period are reported.	Baseline to Week 72
Change From Baseline to Week 24 in Health-Related Quality of Life as Measured by the Care-Related Quality of Life of Informal Caregivers (CarerQoL-7D) Questionnaire Score in Double-blind Period	The CarerQol-7D consists of 5 negative and 2 positive dimensions of providing informal care. The negative dimensions are relational problems, mental health problems, problems combining daily activities with care, financial problems and physical health problems because of providing informal care. The 2 positive dimensions are fulfilment from caregiving and support with lending care. For each dimension, there are 3 possible responses: no, some and a lot. Utility tariffs for CarerQol have been developed to calculate a weighted sum score of CarerQol-7D from the responses on the 7 dimensions, ranging from 0 (worst imaginable caregiving situation) to 100 (best imaginable caregiving situation), for which discrete choice experiments were used. Higher sum scores reflect better care-related quality of life.	Baseline, Week 24
Change From Baseline to Week 72 in Health-Related Quality of Life as Measured by the CarerQoL-7D Questionnaire Score in Overall Period	The CarerQol-7D consists of 5 negative and 2 positive dimensions of providing informal care. The negative dimensions are relational problems, mental health problems, problems combining daily activities with care, financial problems and physical health problems because of providing informal care. The 2 positive dimensions are fulfilment from caregiving and support with lending care. For each dimension, there are 3 possible responses: no, some and a lot. Utility tariffs for CarerQol have been developed to calculate a weighted sum score of CarerQol-7D from the responses on the 7 dimensions, ranging from 0 (worst imaginable caregiving situation) to 100 (best imaginable caregiving situation), for which discrete choice experiments were used. Higher sum scores reflect better care-related quality of life.	Baseline, Week 72
Number of Participants With Motor Seizure Clusters in Double-Blind Period	Seizure clusters were defined by "too many to count" entries in the seizure diaries. The motor seizure clusters per 28 days in the double-blind period was calculated as the (number of motor seizure clusters)/(the number of valid days where motor seizure clusters count information was present) * 28 within the double-blind period. The baseline of the seizure frequency used the 28 days observations immediately prior to treatment start date for this calculation.	Baseline to Week 24
Number of Participants With Motor Seizure Clusters in Overall Period	Seizure clusters were defined by "too many to count" entries in the seizure diaries. The motor seizure clusters per 28 days in the overall period was calculated as the (number of motor seizure clusters)/(the number of valid days where motor seizure clusters count information was present) * 28 within the overall period. The baseline of the seizure frequency used the 28 days observations immediately prior to treatment start date for this calculation.	Baseline to Week 72
Number of Participants With >30%, 30% to -30%, < -30% to -60%, < -60% to -100% Reduction in Motor Seizures Per 28 Days During the Double-blind Period	Number of participants whose motor seizure frequency reduction per 28 days was more than the specified percentage compared to baseline were reported.	Baseline to Week 24
Number of Participants With >30%, 30% to -30%, < -30% to -60%, < -60% to -100% Reduction in Total Seizures Per 28 Days During the Double-blind Period	Number of participants whose total seizure frequency reduction per 28 days was more than the specified percentage compared to baseline were reported.	Baseline to Week 24

Collaborators and Investigators

• Sponsor: PTC Therapeutics
• Investigators: Study Director: Vinay Penematsa, MD, PTC Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): September 28, 2020
• Primary Completion (Actual): March 18, 2023
• Study Completion (Actual): December 27, 2023

Study Registration Dates

• First Submitted: May 4, 2020
• First Submitted That Met QC Criteria: May 4, 2020
• First Posted (Actual): May 7, 2020

Study Record Updates

• Last Update Posted (Actual): March 31, 2026
• Last Update Submitted That Met QC Criteria: March 29, 2026
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Oxidative stress; Neurodegeneration; Mitochondrial disease; MELAS; Seizure; Status epilepticus; POLG; polymerase gamma; ALPERS; PCH6; Pontocerebellar hypoplasia type 6; MERRF; intractable epilepsy; Motor seizures; Non-Motor seizures; Refractory epilepsy; Ferroptosis
• Additional Relevant MeSH Terms: Epileptic Syndromes; Neurologic Manifestations; Musculoskeletal Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Muscular Diseases; Pathologic Processes; Neuromuscular Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Myoclonic Epilepsies, Progressive; Epilepsies, Myoclonic; Epilepsy, Generalized; Epilepsy; Carbohydrate Metabolism, Inborn Errors; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Leukoencephalopathies; Pyruvate Metabolism, Inborn Errors; Cerebral Small Vessel Diseases; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Drug Resistant Epilepsy; Seizures; Leigh Disease; Mitochondrial Diseases; Status Epilepticus; MELAS Syndrome; Nerve Degeneration; MERRF Syndrome; Mitochondrial encephalopathy; Diffuse Cerebral Sclerosis of Schilder; Pontocerebellar Hypoplasia Type 6; alpha-tocotrienol quinone
• Other Study ID Numbers: PTC743-MIT-001-EP; 2020-002100-39 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No