E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
protocadherin 19 (PCDH19)-related epilepsy |
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E.1.1.1 | Medical condition in easily understood language |
protocadherin 19 (PCDH19)-related epilepsy |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10032061 |
E.1.2 | Term | Other forms of epilepsy |
E.1.2 | System Organ Class | 100000004852 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary:
To assess the efficacy of Ganaxolone (GNX) compared with Placebo, in biomarker-positive subjects, as adjunctive therapy for the treatment of primary seizure types in children with genetically-confirmed PCDH19-related epilepsy at the end of the 17-week double-blind (DB) phase. |
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E.2.2 | Secondary objectives of the trial |
Secondary:
• To assess the effect of GNX on primary seizure rate in biomarker negative subjects.
• To assess behavioral/neuropsychiatric changes in subjects receiving GNX compared with subjects receiving PBO as adjunctive therapy at the end of the 17-week DB phase
• To assess the safety and tolerability of GNX compared with PBO as adjunctive therapy at the end of the 17-week DB phase.
• To assess pharmacokinetic (PK) parameters in subjects receiving GNX doses up to 63 mg/kg/day ( or 1800 mg/day maximum) throughout the study.
• To assess the long-term efficacy of GNX when administered as adjunctive therapy throughout the open-label (OL) phase.
•To assess the long-term safety and tolerability of GNX when administered as adjunctive therapy throughout the OL phase. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion Criteria:
1. Molecular confirmation of a pathogenic or likely pathogenic PCDH19 variant. The principal investigator (PI) must review the results of the genetic analysis and confirm that the causal relationship to the epilepsy syndrome is likely. If the subject has a de novo variant of unknown significance (VUS) then the central assessor, PI, and Sponsor will review study inclusion. 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 a 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. Subjects should be on a stable regimen of anti-seizure medications, if any, for ≥ 1 month prior to the screening visit, without a foreseeable change in dosing for the duration of baseline and the DB phase. Vagus nerve stimulator (VNS), ketogenic diet, and modified Atkins diet should be unchanged for 3 months prior to screening
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 electronic 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 |
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E.4 | Principal exclusion criteria |
Exclusion Criteria:
1. Previous exposure to Ganaxolone (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 primary seizures during the 12-week baseline period.
5. Concurrent use of strong inducers or inhibitors of CYP3A4/5/7 is not permitted. Any strong inhibitor or inducer of CYP3A4/5/7 must be discontinued at least 28 days before Randomization Visit. This does not include approved AEDs.
6. Subjects with a positive result on tetrahydrocannabinol (THC) or non-approved cannabidiol (CBD) test (via plasma drug screen) Tetrahydrocannabinol and/or non-approved CBD will be allowed in the OL phase.
7. Chronic use of oral steroid medications, ketoconazole (except for topical formulations), St. John’s Wort, or other investigational products is not permitted.
8. Changes in any chronic medications within the last month prior to the screening visit. All chronic concomitant medications must be stable in dose for at least 1-month prior to the screening visit unless otherwise noted.
9. Have an active CNS infection, demyelinating disease, degenerative neurological disease, or CNS disease deemed progressive as evaluated by brain imaging (magnetic resonance imaging [MRI]).
10. Have any disease or condition (medical or surgical; other than PCDH19) at the screening visit that might compromise the hematologic, cardiovascular, pulmonary, renal, gastrointestinal, or hepatic systems; or other conditions that might interfere with the absorption, distribution, metabolism, or excretion of the investigational product, or would place the subject at increased risk.
11. An aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase [SGOT]) or alanine aminotransferase (ALT/serum glutamic pyruvic transaminase [SGPT]) > 3 × the upper limit of normal (ULN) at screening or baseline visits and confirmed by a repeat test.
12. Total bilirubin levels > 1.5 × ULN at screening or baseline visit and 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 dose and for the duration of the study.
16. Unwillingness to withhold alcohol throughout the entire clinical trial.
17. Have active suicidal plan/intent or have had active suicidal thoughts in the past 6 months or a suicide attempt in the past 3 years.
18. Known sensitivity or allergy to any component in the investigational product(s), progesterone or other related steroid compounds.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Endpoint (seizure control)
The primary efficacy endpoint is the percent change in 28-day primary seizure frequency at the end of the 17-week DB phase relative to the baseline. The primary seizure types are defined as 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The analyses of the primary endpoint will be performed on the sum of the individual countable seizures and uncountable series of 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. |
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E.5.2 | Secondary end point(s) |
Secondary endpoints (seizure control):
•Percentage of subjects experiencing a ≥ 50% reduction in 28-day primary seizure frequency compared to the 12 week 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)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Seizure Frequency - Week -12 Screening Visit (start of Baseline); Wk0 baseline, Wks 1-5, 9, 13, 17
and behavioral/neuropsychiatric
Week 0 and 17 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Open label - 17 weeks double blinded followed by approximately 3 years open label |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 36 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Czech Republic |
Denmark |
France |
Germany |
Hungary |
Israel |
Italy |
Netherlands |
Poland |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |