A clinical study with an investigational drug called ganaxolone in female children with protocadherin 19 (PCDH19)-related epilepsy

Phase 1

• Conditions: protocadherin 19 (PCDH19)-related epilepsy; MedDRA version: 20.0Level: LLTClassification code 10032062Term: Other forms of epilepsy, with intractable epilepsySystem Organ Class: 100000004852; Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

• Registration Number: EUCTR2018-004496-12-IT
• Lead Sponsor: Marinus Pharmaceuticals, Inc

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2021-01-20
• Last Update Posted: 5 April 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: Female
• Target Recruitment: 70

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 antiseizure mediations at therapeutic doses.
5. Have at least 4 countable/witnessed primary seizures per 28 days (average) over an 8-week period prior to the screening visit (prebaseline
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 ß-human chorionic growth hormone (ß-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 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
Are the trial subjects under 18? yes
Number of subjects for this age range:
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this

Exclusion Criteria

Exclusion Criteria:
1. Previous exposure to Ganaxolone (GNX).
2. Pregnant or breastfeeding.
3. Known historical seizure frequency pattern that is highly variable with long remission periods per PI's medical judgment.
4. Patients with = 8 continuous months of seizure freedom over the previous 12 consecutive months.
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 nonregulated cannabidiol (CBD) test (via urine or plasma drug screen) at
the screening visit or a positive result on THC or non-regulated CBD test (vianurine or plasma) at the baseline visit will be excluded from the study. Tetrahydrocannabinol and/or non-regulated 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, or star fruit from diet during the entire clinical trial.
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.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified