PCDH19-related epilepsy
Conditions
Interventions
Investigational product, dose, and mode of administration: Ganaxolone is to be
administered in increments of 15 mg/kg/day up to 63 mg/kg/day given as an oral
suspension with food. Subjects 28 kg wi
Sponsors
Marinus Pharmaceuticals, Inc.
Eligibility
Age
2 Years to 17 Years
Inclusion criteria
Inclusion criteria: 1. Molecular confirmation of a pathogenic or likely pathogenic PCDH19 variant.Genetic mutations will be confirmed by the sponsor*s chosen central laboratory. 2. Female subjects aged 1 through 17 years, inclusive. 3. Subject/parent or LAR willing to give written informed consent/assent, after being properly informed of the nature and risks of the study and prior to engaging in any study related procedures. 4. Failure to control seizures despite appropriate trial of 2 or more anti-seizure mediations at therapeutic doses. 5. Have at least 12 countable/witnessed primary seizures over an 84 day (12 week) period prior to the screening visit (pre-baseline screening). The primary seizure types are defined as countable focal seizures that include progressive hypotonia and impaired awareness, or any countable focal or generalized seizure with a clear motor component. Focal and generalized nonmotor seizures and myoclonic seizures do not count as the primary seizure types. 6. Subject must be approved to participate by sponsor or its designee (eg, Epilepsy Consortium) after review of medical history, genetic testing, seizure classification video (if available), and historical seizure calendars. 7. Ketogenic diets and modified Atkins diets should be unchanged for 3 months prior to screening and must remain stable throughout baseline and the DB phase. 8. Subjects with surgically implanted VNS will be allowed to enter the study provided that all of the following conditions are met: • The VNS has been in place for >= 1 year prior to the screening visit. • The settings must have remained constant for 3 months prior to the screening visit and remain constant throughout baseline and the DB phase. • The battery is expected to last for the duration of baseline and the DB phase. 9. Parent/caregiver is able and willing to maintain an accurate and complete daily seizure diary for the duration of the study. 10. Able and willing to take investigational product (suspension) with food 3 times daily. Ganaxolone must be administered with food. 11. Sexually active female of childbearing potential must be using a medically acceptable method of birth control and have a negative quantitative serum β- human chorionic growth hormone (β-HCG) test collected at the initial screening visit. Childbearing potential is defined as a female who is biologically capable of becoming pregnant. A medically acceptable method of birth control includes intrauterine devices in place for at least 3 months prior to the screening visit, surgical sterilization, or adequate barrier methods (eg, diaphragm or condom and foam). An oral contraceptive alone is not considered adequate for the purpose of this study. Use of oral contraceptives in combination with another method (eg, a spermicidal cream) is acceptable. In subjects who are not sexually active, abstinence is an acceptable form.
Exclusion criteria
Exclusion criteria: 1. Previous exposure to GNX. 2. Pregnant or breastfeeding. 3. Subjects with >8 consecutive weeks (56 consecutive days) of primary seizure freedom during the 12-week pre-baseline screening period. 4. Subjects with 3 × the upper limit of normal (ULN) at screening and if applicable, confirmed by a repeat test. If the subject has another reason to be excluded, repeated liver enzymes are not required. 12. Total bilirubin levels > 1.5 × ULN at screening and if applicable confirmed by a repeat test. In cases of documented, stable medical condition (ie, Gilbert*s Syndrome) resulting in levels of total bilirubin > ULN, the medical monitor can determine if a protocol exception can be made. 13. Subjects with significant renal insufficiency, estimated glomerular filtration rate (eGFR) < 30 mL/min (calculated using the Cockcroft-Gault formula or Pediatric GFR calculator or Bedside Schwartz), will be excluded from study entry or will be discontinued if the criterion is met post baseline. 14. Have been exposed to any other investigational drug within 30 days or fewer than 5 half lives prior to the screening visit. 15. Unwillingness to withhold grapefruit, Seville oranges star fruit, or grapefruit containing products from diet 14 days prior to 1st d
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Criteria for Evaluation: Seizures: All seizure types and frequency will be recorded daily in an eDiary. Days in which no seizures occur will also be noted. Subsets of seizure types will be defined below. Primary Endpoint (seizure control) The primary efficacy endpoint is the percent change in 28-day primary seizure frequency during the 17-week DB phase relative to the baseline. The primary seizure types are defined as countable focal seizures that include progressive hypotonia and impaired awareness, or any countable focal or generalized seizure with a clear motor component. Focal and generalized nonmotor seizures and myoclonic seizures do not count as the primary seizure types for the primary efficacy endpoint. The analyses of the primary endpoint will be performed on the sum of the individual countable seizures and each series of continuous uncountable seizures (each contributes 1 to the sum). Post-baseline 28-day seizure frequency will be calculated as the total number of seizures in the 17-week DB treatment phase divided by the number of days with seizure data in the phase, multiplied by 28. Baseline 28-day seizure frequency will be calculated as the total number of seizures in the baseline phase divided by the number of days with seizure data in the phase, multiplied by 28.The difference between the GNX and placebo groups in the percent changes will be tested using the Wilcoxon Rank-Sum statistic. The primary analysis will be conducted in the TT poulation. If nominal statistical significance is achieved in the ITT population, the primary analysis will be conducted in the biomarker-positive stratum of the ITT population as a secondary endpoint. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary endpoints (seizure control): • The percent change in 28-day primary seizure frequency during the 17-week DB Phase relative to baseline in biomarker-positive subjects • Percentage of subjects experiencing a >= 50% reduction in 28-day primary seizure frequency compared to the baseline Secondary endpoints (behavioral/neuropsychiatric): • Behavior Rating Inventory of Executive Function (BRIEF, preschool version BRIEF-P) • Aberrant Behavior Check - Community (ABC-C) • Children*s Sleep Habit Questionnaire (CHSQ) Exploratory Endpoints: Except for the exploratory endpoints of seizure frequency within the titration and maintenance phases of the DB phase, derived seizure exploratory endpoints will be based on data through the end of the 17-week DB phase relative to the prospective baseline period. • Percent change in 28-day primary seizure frequency during the DB Phase relative to the baseline in biomarker-negative subjects and comparision to biomarker-positive subjects. • Arithmetic change in percentage of seizure-free days, based on all countable focal seizures that include progressive hypotonia and impaired awareness, or any countable focal or generalized seizure with a clear motor component. • Percentage of subjects experiencing a 28-day seizure reduction from baseline >= 25%, and 75% (titration + maintenance and maintenance only). Analysis will be conducted for primary and all seizure types. • Percent change in 28-day seizure frequency through the end of the 4-week titration phase of the DB period relative to the prospective baseline period (all countable focal seizures that include progressive hypotonia and impaired awareness, or any countable focal or generalized seizure with a clear motor component). • Percent change in 28-day seizure frequency during just the maintenance phase of the DB period (ie, from the end of the 4-week titration phase to the end of the 17 week DB phase) relative to the prospective baseline period (all countabl | — |
Countries
Netherlands
Outcome results
None listed