Alpers Disease, Alpers Syndrome, Drug Resistant Epilepsy, Leigh Disease, Leigh Syndrome, Mitochondrial Diseases, Mitochondrial Encephalopathy (MELAS), Pontocerebellar Hypoplasia Type 6 (PCH6)
Conditions
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
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.
Interventions
DRUGVatiquinone
Vatiquinone will be administered per the treatment arm description.
OTHERPlacebo
Vatiquinone-matching placebo will be administered per the treatment arm description
Sponsors
PTC Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 20 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Week 24 in the Number of Observable Motor Seizures Per 28 Days During the Double-blind Period | Baseline to Week 24 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 72 in Health-Related Quality of Life as Measured by the CarerQoL-7D Questionnaire Score in Overall Period | Baseline, Week 72 | 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. |
| Number of Participants With Motor Seizure Clusters in Double-Blind Period | Baseline to Week 24 | 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. |
| Number of Participants With Motor Seizure Clusters in Overall Period | Baseline to Week 72 | 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. |
| 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 | Baseline to Week 24 | Number of participants whose motor seizure frequency reduction per 28 days was more than the specified percentage compared to baseline were reported. |
| 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 | Baseline to Week 24 | Number of participants whose total seizure frequency reduction per 28 days was more than the specified percentage compared to baseline were reported. |
| Change From Baseline to Week 24 in Number of Disease-Related Hospitalization Days Per 28 Days in Double-Blind Period | Baseline to Week 24 | 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. |
| Change From Baseline to Week 72 in Number of Disease-Related Hospitalization Days Per 28 Days in Overall Period | Baseline to Week 72 | 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. |
| Change From Baseline to Week 24 in Occurrence/Recurrence of Status Epilepticus Per 28 Days in Double-blind Period | Baseline to Week 24 | 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. |
| Change From Baseline to Week 72 in Occurrence/Recurrence of Status Epilepticus Per 28 Days in Overall Period | Baseline to Week 72 | 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. |
| Number of Participants With Disease-Related In-Patient Hospitalizations in Double-Blind Period | Baseline to Week 24 | 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. |
| Number of Participants With Disease-Related In-Patient Hospitalizations in Overall Period | Baseline to Week 72 | 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. |
| Number of Participants With Disease-Related Emergency Room Visits in Double-Blind Period | Baseline to Week 24 | 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. |
| Number of Participants With Disease-Related Emergency Room Visits in Overall Period | Baseline to Week 72 | 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. |
| Number of Disease-Related In-Patient Hospitalizations in Double-Blind Period | Baseline to Week 24 | 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. |
| Number of Disease-Related In-Patient Hospitalizations in Overall Period | Baseline to Week 72 | 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. |
| Number of Disease-Related Emergency Room Visits in Double-Blind Period | Baseline to Week 24 | 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. |
| Number of Disease-Related Emergency Room Visits in Overall Period | Baseline to Week 72 | 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. |
| Percent Change From Baseline to Week 24 in Total Seizure Frequency Per 28 Days in Double-Blind Period | Baseline, Week 24 | 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. |
| Percent Change From Baseline to Week 72 in Total Seizure Frequency Per 28 Days in Overall Period | Baseline, Week 72 | 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. |
| Number of Participants Taking Rescue Medications in the Double-blind Period | Baseline to Week 24 | Number of participants taking rescue medications for epilepsy in double-blind period are reported. |
| 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 | Baseline, Week 24 | 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. |
| Number of Participants Taking Rescue Medications in the Overall Period | Baseline to Week 72 | Number of participants taking rescue medications for epilepsy in overall period are reported. |
Countries
Canada, France, Italy, Japan, Poland, Spain, Sweden, United Kingdom, United States
Contacts
STUDY_DIRECTORVinay Penematsa, MD
PTC Therapeutics
Participant flow
Pre-assignment details
A total of 82 participants were screened, of which 14 were not randomized due to screen failure.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 8.7 years STANDARD_DEVIATION 5.34 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants |
| Number of Observable Motor Seizures per 28 Days | 237.0 motor seizures/28 days |
| Race/Ethnicity, Customized Race American Indian/Alaska Native | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 9 Participants |
| Race/Ethnicity, Customized Race Black/African American | 4 Participants |
| Race/Ethnicity, Customized Race Not Reported | 1 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants |
| Race/Ethnicity, Customized Race White/Caucasian | 44 Participants |
| Sex: Female, Male Female | 34 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 34 | 0 / 34 | 5 / 34 | 2 / 29 |
| other Total, other adverse events | 26 / 34 | 20 / 34 | 30 / 34 | 19 / 29 |
| serious Total, serious adverse events | 18 / 34 | 9 / 34 | 26 / 34 | 16 / 29 |
Outcome results
None listed