phase 3 study of adjunctive ganaxolone in adults with drug-resistant partial onset seizures and open-label extension

Conditions: Drug Resistant Partial Onset Seizure

Summary: the study will evaluate the effectiveness and safety of an investigational drug-ganaxolone - on partial seizure frequency in adults with epilepsy taking a maximum of 3 antiepileptic medications (aeds).

this is a 2-cohort study comprised of 2 phases in each cohort. phase 1 is a double-blind (db) phase followed by phase 2, an open-label phase. cohort 1 will provide tolerability, safety, and pk information for ganaxolone 1200 milligram per day (mg/day), 1800 mg/day and placebo. cohort 2 will investigate the efficacy, tolerability and safety of ganaxolone 1800 mg/day compared to placebo. cohort 1 (n= approximately 50) will enroll into a 67-week study comprised of a 4-week prospective baseline period plus 4 week retrospective baseline followed by two treatment phases: a 9-week randomized db placebo-controlled treatment phase followed by a 52-week open label treatment phase. cohort 2 (n=150) will enroll into a 72-week study comprised of a 8-week prospective baseline period followed by two treatment phases: a 14-week randomized db placebo-controlled treatment phase followed by a 52-week open label treatment phase.

Eligibility criteria:
inclusion criteria: * able to give informed consent in writing, or have a legally authorized representative able to do so * willing to enter and participate for the full term of the double blind phase and willing to enter into the open-label phase * male or female outpatients \> 18 years of age * have a confident diagnosis of drug-resistant epilepsy with partial-onset seizures (pos), with or without secondary generalization, for ≥2 years. have residual pos despite having been treated in the past with at least 2 approved anti-epilepsy drugs (aeds) either alone or in combination * based on history, participants would be anticipated to have at least 3 pos during each 4-week baseline period and unlikely to have 21 or more consecutive pos-free days * currently being treated and maintained with a stable regimen of 1, 2, or 3 aeds * able and willing to maintain daily seizure calendar * able and willing to take drug with food twice daily * sexually active women of childbearing potential must use acceptable birth control and have a negative pregnancy test at all visits exclusion criteria: * have had previous exposure to ganaxolone * known sensitivity or allergy to any component in the study drug, progesterone, or other related steroid compounds * exposure to any investigational drug or device \<30 days prior to screening, or plans to take another investigational drug at any time during the study * time of onset of epilepsy treatment \<2 years prior to enrollment * have generalized epilepsy, such as lennox-gastaut syndrome, juvenile myoclonic epilepsy, absence epilepsy, or non-epileptic seizures within the last 12- month period prior to study entry * have less than 3 pos seizures in a 28-day period or more than 21 consecutive seizure-free days during the baseline period * have only simple partial seizures without any observable motor component * have innumerable seizures or status epilepticus within the last 12-months prior to screening * have more than 100 pos per 4-week baseline period * have seizures secondary to illicit drug or alcohol use, infection, neoplasm, demyelinating disease, degenerative neurological disease, or central nervous system (cns) disease deemed progressive, metabolic illness, or progressive degenerative disease * current use of vigabatrin is not permitted. if prior use of vigabatrin, must have documented stable visual fields * current use of ezogabine is not permitted. if prior use, must have been off the medication for at least 3 months prior to screening and have had documented normal fundoscopic exam by ophthalmologist * are planning surgery, or to be evaluated for surgery, during the double-blind phase to control seizures including vns implantation * are suffering from acute or progressive neurological disease, moderate or severe psychiatric disease, or severe mental abnormalities that are likely to require changes in drug therapy during the double-blind portion of the study or interfere with the objectives of the study or the ability to adhere to the protocol requirements * have a history of an actual suicide attempt in the last 5 years or more than 1 lifetime suicide attempt * have a positive urine drug screen at screening or meet criteria for current or historical substance use disorder (dsm-v criteria) within the past 5 years. * have any medical condition that, in the investigator's judgment, is considered to be clinically significant and could potentially affect participant safety or study outcome, including but not limited to: clinically significant cardiac, renal, pulmonary, gastrointestinal, hematologic or hepatic conditions; or a condition that affects the absorption, distribution, metabolism or excretion of drugs * have elevated alt (sgpt) or ast (sgot) greater than 3 times upper limits of normal, or total bilirubin greater than 1.5 times uln * have a history of malignancy within the past 2 years, with the exception of basal cell carcinoma * are currently following or planning to follow a ketogenic diet * use of dietary supplements or herbal preparations are not permitted if participant has been using them consistently for less than 6 months prior to screening, or does not plan on remaining on stable doses for the duration of the double blind phase. use of st. john's wort is not permitted * females who are pregnant, currently breastfeeding or planning to become pregnant during the duration of the study * a history of chronic noncompliance with drug regimens * inability to withhold grapefruit and grapefruit juice from diet during the entire clinical trial

Keywords: partial onset seizures complex partial seizures simple partial seizures anticonvulsant ganaxolone neurosteroid marinus epilepsy