A Randomized, Controlled Trial of Ganaxolone in Adult Uncontrolled Partial-Onset Seizures
A Randomized, Controlled Trial of Ganaxolone in Adult Uncontrolled Partial-Onset Seizures
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). The study will also evaluate the effectiveness of ganaxolone in females
 with catamenial epilepsy.

 Catamenial epilepsy refers to a relationship between seizure frequency and a woman's
 menstrual cycle, where the number of seizures increases around the time of a woman's
 menstrual cycle.
Subjects will undergo

 -  8-week baseline seizure period

 -  Randomization to ganaxolone or placebo

 -  Dose titrate for 2 weeks followed by 8 weeks of maintenance.

 -  Eligible subjects will be offered participation in the open-label extension study.

 -  Those not entering open-label will undergo a 6-week dose de-escalation to gradually
 taper ganaxolone.
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), subjects
 should have a documented seizure frequency of ≥ 3CPS per 4 weeks on average.

 -  Subjects should not be seizure free for more than 28 consecutive days during treatment
 with a stable dose of AEDs [Note: Subjects 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 subject 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.]

 -  Subjects 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: Subjects 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 subjects who are not sexually active, abstinence is an acceptable form
 of birth control and serum β-HCG must be tested per protocol.

 -  Subjects with a history of depression who are stable an dmay 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: Subjects 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:

 -  Subjects 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 subject 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.

 -  Subject 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.