Clinical trial NCT04378075: A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
Official title: Efficacy and Safety Study of Vatiquinone for the Treatment of Mitochondrial Disease Subjects With Refractory Epilepsy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Mitochondrial Diseases
Drug Resistant Epilepsy
Leigh Disease
Leigh Syndrome
Mitochondrial Encephalopathy (MELAS)
Pontocerebellar Hypoplasia Type 6 (PCH6)
Alpers Disease
Alpers Syndrome
Keywords: POLG
polymerase gamma
ALPERS
MELAS
PCH6
Pontocerebellar hypoplasia type 6
MERRF
intractable epilepsy
Mitochondrial disease
Oxidative stress
Motor seizures
Non-Motor seizures
Seizure
Refractory epilepsy
Status epilepticus
Ferroptosis
Neurodegeneration
Lead sponsor: PTC Therapeutics
Sponsor class: INDUSTRY
First posted: 2020-05-07
Enrollment: 68
Sex: ALL
Maximum age (years): 20
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Percent Change From Baseline to Week 24 in the Number of Observable Motor Seizures per 28 Days
timeFrame: Day 0, Week 24
Secondary outcomes:
measure: Number of Disease-Related Hospital Days
timeFrame: Week 24 and up to Week 72
measure: Number of Participants with Occurrences or Recurrence of Status Epilepticus
timeFrame: Week 24 and up to Week 72
measure: Number of Participants with Disease-Related In-Patient Hospitalizations or Emergency Room Visits
timeFrame: Week 24 and up to Week 72
measure: Number of Disease-Related In-Patient Hospital Admissions or Emergency Room Visits
timeFrame: Week 24 and up to Week 72
measure: Percent Change From Baseline to Week 72 in Total Seizure Frequency per 28 Days
timeFrame: Day 0, Week 24, Week 72
measure: Percentage of Participants with ≥25%, ≥50%, ≥75%, and 100% Reduction in Motor Seizures
timeFrame: Week 24 and up to Week 72
measure: Percentage of Participants with ≥25%, ≥50%, ≥75%, and 100% Reduction in Total Seizures
timeFrame: Week 24 and up to Week 72
measure: Number of Participants Who Require Rescue Seizure Medication
timeFrame: Week 24 and up to Week 72
measure: Health-Related Quality of Life as Measured by the Care-Related Quality of Life of Informal Caregivers (CarerQoL-7D) Questionnaire
timeFrame: Week 24 and up to Week 72
measure: Number of Participants with Seizure Clusters
timeFrame: Week 24 and up to Week 72
Other outcomes:
Locations:
city: San Diego
country: United States
facility: University of California
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: New Haven
country: United States
facility: Yale School of Medicine
state: Connecticut
city: Washington
country: United States
facility: Children's National Medical Center - Department Of Neurology
state: District of Columbia
city: Baltimore
country: United States
facility: John Hopkins Medicine
state: Maryland
city: Boston
country: United States
facility: Pediatric Genetics Clinic (Main MGH Hospital)
state: Massachusetts
city: Boston
country: United States
facility: Boston Children Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: Children's of Minnesota
state: Minnesota
city: Akron
country: United States
facility: Akron Children's Hospital
state: Ohio
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science
state: Texas
city: Seattle
country: United States
facility: Seattle Children's hospital
state: Washington
city: Calgary
country: Canada
facility: Alberta Children's Hospital, University of Calgary
city: Angers
country: France
facility: CHU d'Angers - Service de génétique
city: Montpellier
country: France
facility: CHU de Montpellier - Hôpital Gui de Chauliac - Département de neuropédiatrie
city: Paris
country: France
facility: A.P.H.P - Hôpital Necker-Enfants Malades - Service de Neurologie pédiatrique
city: Strasbourg
country: France
facility: CHU de Strasbourg - Hôpital de Hautepierre - Service de Neuropédiatrie
city: Milano
country: Italy
facility: UOC Neuropsichiatria Infantile, Istituto Neurologico Carlo Besta-Fondazione IRCCS
city: Roma
country: Italy
facility: U.O.C. Malattie Muscolari e Neurodegenerative, Dipartimento di Scienze Neurologiche e Psichiatriche, Ospedale Pediatrico Bambino Gesù
city: Multiple Locations
country: Japan
facility: PTC Clinical Site
city: Warszawa
country: Poland
facility: Instytut Pomnik-Centrum Zdrowia Dziecka, Centrum Wsparacia Pediatrycznych Badań Klinicznych
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Déu
city: Madrid
country: Spain
facility: Hospital Ruber Internacional, Neurology Department, Epilepsy Program
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Stockholm
country: Sweden
facility: Karolinska University hospital, Astrid Lindgrens Children Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children NHS Foundation Trust
city: Newcastle Upon Tyne
country: United Kingdom
facility: The Newcastle Upon Tyne Hospitals NHS Foundation Trust
Study officials:
affiliation: PTC Therapeutics
name: Vinay Penematsa, MD
role: STUDY_DIRECTOR
References: