Clinical trial NCT00465517: A Randomized, Controlled Trial of Ganaxolone in Adult Uncontrolled Partial-Onset Seizures
Official title: A Double-blind, Randomized, Placebo-controlled Study to Evaluate the Safety, Tolerability, and Efficacy of Ganaxolone as add-on Therapy in Adult Subjects With Epilepsy Consisting of Uncontrolled Partial-onset Seizures.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Partial Epilepsy
Catamenial Epilepsy
Keywords: Partial onset seizures
Complex-partial seizures
Anticonvulsant
Partial seizures
Catamenial epilepsy
Lead sponsor: Marinus Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2007-04-25
Enrollment: 147
Sex: ALL
Minimum age (years): 18
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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). 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Mean Weekly Log-transformed Seizure Frequency During Weeks 1 Through 10
timeFrame: Week 1 through Week 10
Secondary outcomes:
measure: Mean Weekly Log-transformed Seizure Frequency During Weeks 3 Through 10
timeFrame: Week 3 through Week 10
measure: Change From Baseline in Mean Weekly Seizure Frequency During Weeks 1 Through 10
timeFrame: Baseline and at Week 1 through Week 10
measure: Change From Baseline in Mean Weekly Seizure Frequency During Weeks 3 Through 10
timeFrame: Baseline and at Week 3 through Week 10
measure: Percent Change From Baseline in Mean Weekly Seizure Frequency During Weeks 1 Through 10
timeFrame: Baseline and at Week 1 through Week 10
measure: Percent Change From Baseline in Mean Weekly Seizure Frequency During Weeks 3 Through 10
timeFrame: Baseline and at Week 3 through Week 10
measure: Mean Weekly Seizure Frequency for Each Week After Dosing During Weeks 1 to 10
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10
measure: Percent Change From Baseline in Mean Weekly Seizure Frequency by Subtype During Weeks 1 Through 10
timeFrame: Baseline and at Week 1 through Week 10
measure: Number of Responders During Weeks 1 Through 10
timeFrame: Baseline and at Week 1 through Week 10
measure: Number of Responders During Weeks 3 Through 10
timeFrame: Baseline and at Week 3 through Week 10
measure: Number of Seizure-free Participants Up to Week 2
timeFrame: Up to Week 2
measure: Number of Seizure-free Participants During Weeks 3 Through 10
timeFrame: Week 3 through Week 10
measure: Number of Seizure-free Participants During Weeks 1 Through 10
timeFrame: Week 1 through Week 10
measure: Number of Seizure-free Days Up to Week 2
timeFrame: Up to Week 2
measure: Number of Seizure-free Days During Week 3 Through 10
timeFrame: Week 3 through Week 10
measure: Number of Seizure-free Days During Week 1 Through 10
timeFrame: Week 1 through Week 10
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Epilepsy Program
state: Arkansas
city: Los Angeles
country: United States
facility: University of Southern California Adult Comprehensive Epilepsy Center
state: California
city: Sacramento
country: United States
facility: University of California-Davis
state: California
city: Aurora
country: United States
facility: Anchutz Outpatient Pavillion Neurosciences Clinic/ University of Colorado Hospital
state: Colorado
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida McKnight Brain Institute
state: Florida
city: Sarasota
country: United States
facility: Intercoastal Medicine
state: Florida
city: Atlanta
country: United States
facility: Emory HealthCare
state: Georgia
city: Springfield
country: United States
facility: Southern Illinois University Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky, Dept. of Neurology
state: Kentucky
city: Bethesda
country: United States
facility: Mid-Atlantic Epilepsy and Sleep Center
state: Maryland
city: Detroit
country: United States
facility: 2799 West Grand blvd. CFP 071
state: Michigan
city: Saint Paul
country: United States
facility: Minnesota Epilepsy Group, PA
state: Minnesota
city: Chesterfield
country: United States
facility: Comprehensive Epilepsy Care Center for Children and Adults
state: Missouri
city: Hackensack
country: United States
facility: Overlook Hospital and Hackensack Medical Center
state: New Jersey
city: Albany
country: United States
facility: Neurosciences Institute at Albany Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
city: Media
country: United States
facility: Riddle Health Care Center for Neuroscience
state: Pennsylvania
city: Philadelphia
country: United States
facility: Drexel University / Hahneman Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Ctr
state: Tennessee
city: Dallas
country: United States
facility: Neurological Clinic of Texas, P.A.
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
Study officials:
References:
citation: Maguire MJ, Nevitt SJ. Treatments for seizures in catamenial (menstrual-related) epilepsy. Cochrane Database Syst Rev. 2021 Sep 16;9(9):CD013225. doi: 10.1002/14651858.CD013225.pub3.