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: Completed
• 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): 60
• 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
  • Milano, 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
  • Warszawa, Poland, 04-730
    • Instytut Pomnik-Centrum Zdrowia Dziecka, Centrum Wsparacia Pediatrycznych Badań Klinicznych
• Spain
  • Barcelona, Spain, 08950
    • Hospital Sant Joan de Deu
  • 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, 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	Time Frame
Percent Change From Baseline to Week 24 in the Number of Observable Motor Seizures per 28 Days	Day 0, Week 24

Secondary Outcome Measures

Outcome Measure	Time Frame
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

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 8, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

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: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Disease; Genetic Diseases, Inborn; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Leukoencephalopathies; Pyruvate Metabolism, Inborn Errors; Epilepsy; Syndrome; Mitochondrial Diseases; Brain Diseases; Drug Resistant Epilepsy; Leigh Disease; Diffuse Cerebral Sclerosis of Schilder
• 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