Phase 3 Study of Adjunctive Ganaxolone in Adults With Drug-resistant Partial Onset Seizures and Open-label Extension

A Multicenter, Double Blind, Randomized, Placebo-Controlled Trial to Determine the Efficacy and Safety of Ganaxolone as Adjunctive Therapy for Adults With Drug-Resistant Partial-Onset Seizures Followed by Long-term Open-Label Treatment

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.

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