Clinical trial NCT01963208: Phase 3 Study of Adjunctive Ganaxolone in Adults With Drug-resistant Partial Onset Seizures and Open-label Extension
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Drug Resistant Partial Onset Seizure
Keywords: partial onset seizures
complex partial seizures
simple partial seizures
anticonvulsant
ganaxolone
neurosteroid
Marinus
epilepsy
Lead sponsor: Marinus Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2013-10-16
Enrollment: 405
Sex: ALL
Minimum age (years): 18
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).

Detailed description: 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

Primary outcomes:
measure: Double Blind: Cohort 2: Percent Change From Baseline in 28-day Seizure Frequency During Titration + Maintenance Period
timeFrame: Baseline and Week 14
Secondary outcomes:
measure: Double Blind: Cohort 2: Number of Participants With ≥50% Responder Rate During Titration + Maintenance Period
timeFrame: Up to Week 14
measure: Double Blind: Cohort 2: Change From Baseline in the Number of Seizure Free Days Per 28-day Period During Titration + Maintenance Period
timeFrame: Baseline and Week 14
measure: Double Blind: Cohort 2: Number of Participants With Clinical Global Impression of Change - Improvement (CGI-I) at Week 14
timeFrame: At Week 14
measure: Double Blind: Cohort 2: Percent Change From Baseline in 28-day Seizure Frequency During Maintenance Period
timeFrame: Baseline and Week 2 to Week 14
measure: Double Blind: Cohort 2: Change From Baseline in 28-day Seizure Frequency During Titration + Maintenance Period
timeFrame: Baseline and Week 14
measure: Double Blind: Cohort 2: Change From Baseline in 28-day Seizure Frequency During Maintenance Period
timeFrame: Baseline and Week 2 to Week 14
measure: Double Blind: Cohort 2: Change From Baseline in the Number of Seizure Free Days Per 28-day Period During Maintenance Period
timeFrame: Baseline and Week 2 to Week 14
measure: Double Blind: Cohort 2: Percentage of Responders Experiencing a ≥R% (80%, 60%, 40%, and 20%) Reduction From Baseline to the End of Treatment Period in 28-day Seizure Frequency During Titration + Maintenance Period
timeFrame: Up to Week 14
measure: Double Blind: Cohort 2: Percentage of Responders Experiencing a ≥R% (80%, 60%, 40%, and 20%) Reduction From Baseline to the End of Treatment Period in 28-day Seizure Frequency During Maintenance Period
timeFrame: Week 2 to Week 14
measure: Double Blind: Cohort 2: Percentage of Seizure Free Participants During the Maintenance Period
timeFrame: Week 2 to Week 14
measure: Double Blind: Cohort 2: Percentage of Participants Who Experienced at Least One 28-day Seizure Free Period During Titration + Maintenance Phase
timeFrame: Up to Week 14
measure: Double Blind: Cohort 2: Longest Percent of Time Spent Seizure-free During Titration + Maintenance Period
timeFrame: Up to Week 14
measure: Double Blind: Cohort 2: Percent Change From Baseline in 28-day Seizure Frequency for Different Subtypes of Seizures During Titration + Maintenance Period
timeFrame: Baseline and Week 14
measure: Double Blind: Cohort 2: Number of Participants With Patient Global Impression of Change - Improvement (PGI-I) at Week 8 and Week 14
timeFrame: Week 8 and Week 14
measure: Double Blind: Cohort 2: Number of Participants With Clinical Global Impression of Change - Improvement (CGI-I) at Week 8
timeFrame: At Week 8
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Epilepsy Center
state: Alabama
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Xenoscience Inc.
state: Arizona
city: Sun City
country: United States
facility: The MORE Foundation
state: Arizona
city: Little Rock
country: United States
facility: Clinical Trials Inc.
state: Arkansas
city: Fresno
country: United States
facility: Neuro-Pain Medical Center, Inc
state: California
city: Santa Monica
country: United States
facility: Neurological Research Institute
state: California
city: Aurora
country: United States
facility: University of Colorado- Anschutz Outpatient Pavilion
state: Colorado
city: Miami
country: United States
facility: Neuroscience Consulants
state: Florida
city: Port Charlotte
country: United States
facility: Medsol Clinical Research Center
state: Florida
city: Boise
country: United States
facility: Consultants in Epilepsy & Neurology
state: Idaho
city: Lexington
country: United States
facility: Bluegrass Epilepsy Research, LLC
state: Kentucky
city: Bethesda
country: United States
facility: Mid-Atlantic Epilepsy Center
state: Maryland
city: Boston
country: United States
facility: Bringham and Women's Hospital
state: Massachusetts
city: Golden Valley
country: United States
facility: Minneapolis Clinic of Neurology
state: Minnesota
city: Chesterfield
country: United States
facility: The Comprehensive Epilepsy Care Center for Children and Adults
state: Missouri
city: Camden
country: United States
facility: Cooper Medical Center of Rowan University
state: New Jersey
city: Hackensack
country: United States
facility: Northeast Regional Epilepsy Group
state: New Jersey
city: Cedarhurst
country: United States
facility: Five Towns Neuroscience Research
state: New York
city: Middletown
country: United States
facility: Northeast Regional Epilepsy Group
state: New York
city: Mineola
country: United States
facility: Winthrop University Hospital
state: New York
city: New York
country: United States
facility: New York University Comprehensive Epilepsy Center
state: New York
city: New York
country: United States
facility: Northeast Regional Epilepsy Group
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest Health Sciences
state: North Carolina
city: Canton
country: United States
facility: Ohio Clinical Research Partners, LLC
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: Lynn Health Institute
state: Oklahoma
city: Oklahoma City
country: United States
facility: Sooner Clinical Research
state: Oklahoma
city: Philadelphia
country: United States
facility: Jefferson Comprehensive Epilepsy Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University School of Medicine
state: Pennsylvania
city: Dallas
country: United States
facility: Neurology Consultants of Dallas
state: Texas
city: Dallas
country: United States
facility: Texas Epilepsy Group
state: Texas
city: Renton
country: United States
facility: Rainier Clinical Research Center, Inc.
state: Washington
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Randwick
country: Australia
facility: The Prince of Wales Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Bedford Park
country: Australia
facility: Flinders Medical Center
state: South Australia
city: Fitzroy
country: Australia
facility: St. Vincent's Hospital
state: Victoria
city: Heidelberg
country: Australia
facility: The Florey Institute of Neuroscience and Mental Health
state: Victoria
city: Parkville
country: Australia
facility: The Royal Melbourne Hospital
state: Victoria
city: Blagoevgrad
country: Bulgaria
facility: MHAT
city: Pleven
country: Bulgaria
facility: UMHAT Dr. Georgi Stranski Clinic of Neurology
city: Ruse
country: Bulgaria
facility: Medical Centre-Teodora
city: Sofia
country: Bulgaria
facility: Medical Center Excelsior 4
city: Sofia
country: Bulgaria
facility: SHATNP
city: Sofia
country: Bulgaria
facility: MHAT Lyulin Department of Neurology
city: Sofia
country: Bulgaria
facility: UMHAT Alexandrovska Clinic of Nerve Diseases
city: Varna
country: Bulgaria
facility: Medical Center Ekvita Ltd
city: Bernau
country: Germany
facility: Epilepsieklinik
city: Bielefeld
country: Germany
facility: Krankenhaus Mara Epilepsie-Zentrum
city: Bonn
country: Germany
facility: Klinik fur Epileptologie
city: Dussseldorf
country: Germany
facility: Neuro-Consil
city: Marburg
country: Germany
facility: Universitatsklinikum GieBen und Marburg
city: Ulm
country: Germany
facility: Universitatsklin Kum Ulm
city: Jaworowa
country: Poland
facility: Novo-Med
city: Katowice
country: Poland
facility: Centrum Medycne Dendryt
city: Lublin
country: Poland
facility: Indywidualna Praktyka ul Narutowicza
city: Lublin
country: Poland
facility: Wojewodzki Szpital Specjalistyczny Oddzial
city: Warszawa
country: Poland
facility: Fundacja Epileptologii Wiertnicza
city: Warszawa
country: Poland
facility: Instytut Psychiatrii i Neurologii
city: Kazan
country: Russian Federation
facility: Kazan State Medical University
city: Moscow
country: Russian Federation
city: Moscow
country: Russian Federation
city: Nizhniy Novgorod
country: Russian Federation
city: Novosibirsk
country: Russian Federation
city: Novosibirsk
country: Russian Federation
facility: City Neurological Center
city: Saint Petersburg
country: Russian Federation
city: Saint Petersburg
country: Russian Federation
city: Saint Petersburg
country: Russian Federation
city: Samara
country: Russian Federation
city: Yaroslavl
country: Russian Federation
Study officials:
References: