A Randomized, Controlled Trial of Ganaxolone in Adult Uncontrolled Partial-Onset Seizures

Inclusion criteria

• Diagnosis of epilepsy with POS with or without secondary generalized seizures according to the International League Against Epilepsy [ILAE] Classification of Epileptic Seizures (1981). Diagnosis should have been established by clinical history and CT or MRI of the brain to rule out progressive structural lesions and EEG with results consistent with partial-onset epilepsy.
• During the 8 week baseline period preceding randomization visit (Visit 4), participants should have a documented seizure frequency of ≥ 3CPS per 4 weeks on average.
• Participants should not be seizure free for more than 28 consecutive days during treatment with a stable dose of AEDs [Note: Participants with historically sufficiently high seizure frequency who fall short 1 seizure in any 4 weeks period or with a seizure-free period > 28 consecutive days may be allowed to enter the study after discussion with the Medical Monitor. Prolongation of the screening period for questionable cases may also be allowed by the Medical Monitor.]
• Treatment with a stable dose of up to 3 (FDA approved) current AEDs for 1 month prior to screening.
• Maintenance of current AEDs without a change in dosing for the duration of study.

• Concomitant vigabatrin not permitted;
• Felbamate is allowed if the participant has been on felbamate for at least 18 months and has stable laboratory tests) for the course of the study. [Note: A shorter period for stable laboratory results may be allowed by the Medical Monitor, depending on the extent of dose change and the half-life of the AED.]
• Participants receiving treatment with a vagal nerve stimulator (VNS) may be included as long as the VNS has been in place for at least 12 months prior to entry into the study, the VNS battery is not due for replacement during 0600 subject participation, and stimulation parameters have been kept constant for 1 month prior to screening. VNS will be counted as 1 of the 3 concomitant AEDs.
• Male or female, 18 to 69 years of age (inclusive). [Note: Participants who are > 69 years of age but are of good health condition may be allowed to enter the study after discussion with and approval by the Medical Monitor.]
• A 12-lead electrocardiogram (ECG) w/o clinically significant abnormalities.
• Be properly informed of the nature and risks of the study and give informed consent in writing, prior to entering the study.
• Able to participate for the full term of study.
• Able to keep a seizure & medication diary throughout the course of the study.
• Sexually active women of childbearing potential (WCBP) must be using a medically acceptable method of birth control and have a negative qualitative β-human chorionic growth hormone (β-HCG) pregnancy test result from a urine sample collected at the initial screening visit. A woman of 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, surgical sterilization, or adequate barrier methods (e.g., 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 participants who are not sexually active, abstinence is an acceptable form of birth control and serum β-HCG must be tested per protocol.
• Participants with a history of depression who are stable and may be taking 1 anti-depressant medication.

Exclusion criteria

• Presence of non-motor simple partial seizures only.
• History of pseudoseizures in the last 5 years.
• History of a primary generalized seizure in the last 5 years.
• Past use of vigabatrin without stable visual fields tested twice over the 12 months after the last dose of vigabatrin (Concomitant use of vigabatrin is not allowed).
• Seizures secondary to illicit drug or alcohol use, infection, neoplasia, demyelinating disease, degenerative neurological disease, or CNS disease deemed progressive, metabolic illness, or progressive degenerative disease.
• Status epilepticus within the last year prior to randomization.
• Clinically unstable psychiatric disorder within the last 2 years.
• Suicidal attempt within the last 5 years or current significant suicidal ideation.
• History of psychosis within the last 5 years. [Note: Participants who suffered a psychosis that can well be explained by exogenous factors may be allowed to enter the study after discussion with and approval by the Medical Monitor.]
• Current use of neuroleptics for psychosis.
• A significant medical or surgical condition at screening which might compromise the hematologic, cardiovascular, pulmonary, renal, gastrointestinal, or hepatic systems or other conditions that would place the subject at increased risk.
• Known sensitivity or allergy to progesterone or related steroid compounds.
• History of drug use or alcohol abuse within the past 5 years.
• Sexually active WCBP who are unwilling to use a double-barrier method and establish that they are currently not pregnant by submitting to a pregnancy test.
• Females who are currently breastfeeding.
• history of chronic noncompliance with drug regimens.
• Exposure to any other investigational drug or device within 30 days prior to screening.
• Alanine transferase (ALT; SGPT) or Aspartate transferase (AST; SGOT) levels > 3 times upper limits of normal (ULN) at screening.
• Benzodiazepines may be used intermittently for the control of seizure clustering as a one time rescue up to a maximum of 4 occasions as follows:

• Participants who need benzodiazepines for control of seizures more than once per month or more than 4 times total during the Titration and Maintenance Phases will be discontinued.
• Once during the Titration Phase
• No more than once per month during the Maintenance Phase
• Each occasion may be a period of 24 hours, during which up to 3 doses of benzodiazepine may be used.
• If a participant is taking a benzodiazepine chronically for epilepsy and non-epilepsy conditions, it will be counted as 1 of the 3 AEDs and the dose cannot be changed during the study.
• Participant has history of repetitive seizures within the 12-month period preceding study entry where the individual seizures cannot be counted.
• Inability to withhold grapefruit and grapefruit juice from diet for the entire clinical trial.