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

Drug Resistant Partial Onset Seizure Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01963208
• Other study ID #: 1042-0603
• Status: Completed
• Phase: Phase 3
• Start date: October 2013
• Est. completion date: October 2016

Study information

• Verified date: January 2023
• Source: Marinus Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 405
• Est. completion date: October 2016
• Est. primary completion date: May 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Drug Resistant Partial Onset Seizure
• Seizures

Intervention

Drug:
• ganaxolone
200 mg and 225 mg capsules; target dose 1800 mg/day dosed 900mg 2x/day
• Placebo
placebo

Locations

Country	Name	City	State
Australia	Flinders Medical Center	Bedford Park	South Australia
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	St. Vincent's Hospital	Fitzroy	Victoria
Australia	The Florey Institute of Neuroscience and Mental Health	Heidelberg	Victoria
Australia	The Royal Melbourne Hospital	Parkville	Victoria
Australia	The Prince of Wales Hospital	Randwick	New South Wales
Australia	Westmead Hospital	Westmead	New South Wales
Bulgaria	MHAT	Blagoevgrad
Bulgaria	UMHAT Dr. Georgi Stranski Clinic of Neurology	Pleven
Bulgaria	Medical Centre-Teodora	Ruse
Bulgaria	Medical Center Excelsior 4	Sofia
Bulgaria	MHAT Lyulin Department of Neurology	Sofia
Bulgaria	SHATNP	Sofia
Bulgaria	UMHAT Alexandrovska Clinic of Nerve Diseases	Sofia
Bulgaria	Medical Center Ekvita Ltd	Varna
Germany	Epilepsieklinik	Bernau
Germany	Krankenhaus Mara Epilepsie-Zentrum	Bielefeld
Germany	Klinik fur Epileptologie	Bonn
Germany	Neuro-Consil	Dussseldorf
Germany	Universitatsklinikum GieBen und Marburg	Marburg
Germany	Universitatsklin Kum Ulm	Ulm
Poland	Novo-Med	Jaworowa
Poland	Centrum Medycne Dendryt	Katowice
Poland	Indywidualna Praktyka ul Narutowicza	Lublin
Poland	Wojewodzki Szpital Specjalistyczny Oddzial	Lublin
Poland	Fundacja Epileptologii Wiertnicza	Warszawa
Poland	Instytut Psychiatrii i Neurologii	Warszawa
Russian Federation	Kazan State Medical University	Kazan
Russian Federation	City Neurological Center	Novosibirsk
United States	University of Colorado- Anschutz Outpatient Pavilion	Aurora	Colorado
United States	Mid-Atlantic Epilepsy Center	Bethesda	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	University of Alabama Epilepsy Center	Birmingham	Alabama
United States	Consultants in Epilepsy & Neurology	Boise	Idaho
United States	Bringham and Women's Hospital	Boston	Massachusetts
United States	Cooper Medical Center of Rowan University	Camden	New Jersey
United States	Ohio Clinical Research Partners, LLC	Canton	Ohio
United States	Five Towns Neuroscience Research	Cedarhurst	New York
United States	The Comprehensive Epilepsy Care Center for Children and Adults	Chesterfield	Missouri
United States	Ohio State University	Columbus	Ohio
United States	Neurology Consultants of Dallas	Dallas	Texas
United States	Texas Epilepsy Group	Dallas	Texas
United States	Neuro-Pain Medical Center, Inc	Fresno	California
United States	Minneapolis Clinic of Neurology	Golden Valley	Minnesota
United States	Northeast Regional Epilepsy Group	Hackensack	New Jersey
United States	Bluegrass Epilepsy Research, LLC	Lexington	Kentucky
United States	Clinical Trials Inc.	Little Rock	Arkansas
United States	Neuroscience Consulants	Miami	Florida
United States	Northeast Regional Epilepsy Group	Middletown	New York
United States	Winthrop University Hospital	Mineola	New York
United States	New York University Comprehensive Epilepsy Center	New York	New York
United States	Northeast Regional Epilepsy Group	New York	New York
United States	Lynn Health Institute	Oklahoma City	Oklahoma
United States	Sooner Clinical Research	Oklahoma City	Oklahoma
United States	Jefferson Comprehensive Epilepsy Center	Philadelphia	Pennsylvania
United States	Temple University School of Medicine	Philadelphia	Pennsylvania
United States	Xenoscience Inc.	Phoenix	Arizona
United States	Medsol Clinical Research Center	Port Charlotte	Florida
United States	Rainier Clinical Research Center, Inc.	Renton	Washington
United States	Neurological Research Institute	Santa Monica	California
United States	The MORE Foundation	Sun City	Arizona
United States	Wake Forest Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Marinus Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Bulgaria,  Germany,  Poland,  Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Double Blind: Cohort 2: Percent Change From Baseline in 28-day Seizure Frequency During Titration + Maintenance Period	Seizure frequency was based on the number of seizures per 28 days, calculated as the number of seizures over the time interval multiplied by 28 and divided by the number of days in the interval. Baseline 28-day seizure frequency was calculated as the number of seizures in the Baseline period (= 56 days) divided by the number of days with available seizure data in the Baseline period and multiplied by 28. Baseline was defined as non-missing value of last assessment before first dose. Primary analysis was performed using a rank analysis of covariance (ANCOVA).	Baseline and Week 14
Secondary	Double Blind: Cohort 2: Number of Participants With =50% Responder Rate During Titration + Maintenance Period	A 50% responder was a participant who experienced at least a 50% decrease in 28-day seizure frequency compared to Baseline.	Up to Week 14
Secondary	Double Blind: Cohort 2: Change From Baseline in the Number of Seizure Free Days Per 28-day Period During Titration + Maintenance Period	Baseline number of seizure free days per 28-day period was calculated as: the number of seizure free days in the entire Baseline period (<=56 days) divided by the number of days with available seizure data in the baseline period and multiplied by 28. Post-Baseline number of seizure free days per 28-day period was calculated as: the number of seizure free days in the entire treatment period divided by the number of days with available seizure data in the treatment period and multiplied by 28. Change from Baseline in number of seizure free days per 28-day period from Baseline was calculated as: Post-Baseline number of seizure free days per 28-day period minus Baseline number of seizure free days per 28-day period. Baseline was defined as non-missing value of last assessment before first dose.	Baseline and Week 14
Secondary	Double Blind: Cohort 2: Number of Participants With Clinical Global Impression of Change - Improvement (CGI-I) at Week 14	The CGI-I scale is a clinician-rated 7-point Likert scale used to assess the degree to which the participant's epilepsy symptoms have changed relative to Baseline. It was rated as 1. "very much improved"; 2. "much improved"; 3. "minimally improved"; 4. "no change"; 5. "minimally worse"; 6. "much worse"; 7. "very much worse". Higher scores indicated worse condition. Baseline was defined as non-missing value of last assessment before first dose.	At Week 14
Secondary	Double Blind: Cohort 2: Percent Change From Baseline in 28-day Seizure Frequency During Maintenance Period	Seizure frequency was based on the number of seizures per 28 days, calculated as the number of seizures over the time interval multiplied by 28 and divided by the number of days in the interval. Baseline 28-day seizure frequency was calculated as the number of seizures in the Baseline period (= 56 days) divided by the number of days with available seizure data in the Baseline period and multiplied by 28. Baseline was defined as non-missing value of last assessment before first dose.	Baseline and Week 2 to Week 14
Secondary	Double Blind: Cohort 2: Change From Baseline in 28-day Seizure Frequency During Titration + Maintenance Period	Seizure frequency was based on the number of seizures per 28 days, calculated as the number of seizures over the time interval multiplied by 28 and divided by the number of days in the interval. Baseline 28-day seizure frequency was calculated as the number of seizures in the Baseline period (= 56 days) divided by the number of days with available seizure data in the Baseline period and multiplied by 28. Baseline was defined as non-missing value of last assessment before first dose. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.	Baseline and Week 14
Secondary	Double Blind: Cohort 2: Change From Baseline in 28-day Seizure Frequency During Maintenance Period	Seizure frequency was based on the number of seizures per 28 days, calculated as the number of seizures over the time interval multiplied by 28 and divided by the number of days in the interval. Baseline 28-day seizure frequency was calculated as the number of seizures in the Baseline period (= 56 days) divided by the number of days with available seizure data in the Baseline period and multiplied by 28. Baseline was defined as non-missing value of last assessment before first dose. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.	Baseline and Week 2 to Week 14
Secondary	Double Blind: Cohort 2: Change From Baseline in the Number of Seizure Free Days Per 28-day Period During Maintenance Period	Baseline number of seizure free days per 28-day period was calculated as: the number of seizure free days in the entire Baseline period (= 56 days) divided by the number of days with available seizure data in the Baseline period and multiplied by 28. Post-Baseline number of seizure free days per 28-day period was calculated as: the number of seizure free days in the entire treatment period divided by the number of days with available seizure data in the treatment period and multiplied by 28. Change from Baseline in number of seizure free days per 28-day period from Baseline was calculated as: Post-Baseline number of seizure free days per 28-day period minus Baseline number of seizure free days per 28-day period. Baseline was defined as non-missing value of last assessment before first dose.	Baseline and Week 2 to Week 14
Secondary	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	Percentage of participants who had reductions of = 80%, = 60%, = 40%, and = 20% in 28-day seizure frequency from Baseline is presented. A responder is an individual whose reduction of percent change from Baseline in 28-day seizure frequency was = 50%. Baseline was defined as non-missing value of last assessment before first dose.	Up to Week 14
Secondary	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	Percentage of participants who had reductions of = 80%, = 60%, = 40%, and = 20% in 28-day seizure frequency from Baseline is presented. A responder is an individual whose reduction of percent change from Baseline in 28-day seizure frequency was = 50%. Baseline was defined as non-missing value of last assessment before first dose.	Week 2 to Week 14
Secondary	Double Blind: Cohort 2: Percentage of Seizure Free Participants During the Maintenance Period	Percentage of participants who completed the study without any seizures is presented	Week 2 to Week 14
Secondary	Double Blind: Cohort 2: Percentage of Participants Who Experienced at Least One 28-day Seizure Free Period During Titration + Maintenance Phase	Percentage of participants who experienced at least one 28-day seizure free period is presented	Up to Week 14
Secondary	Double Blind: Cohort 2: Longest Percent of Time Spent Seizure-free During Titration + Maintenance Period	The longest period of time seizure-free was defined as the percent of the longest seizure-free period (days) divided by the days with available seizure data, and then multiplied by 100%.	Up to Week 14
Secondary	Double Blind: Cohort 2: Percent Change From Baseline in 28-day Seizure Frequency for Different Subtypes of Seizures During Titration + Maintenance Period	Seizure frequency was based on the number of seizures per 28 days, calculated as the number of seizures over the time interval multiplied by 28 and divided by the number of days in the interval. The analysis was conducted for Partial-Onset Seizure (POS) only which included seizure subtypes: Complex partial seizures (CPS), secondarily generalized tonic-clonic (SGTC) seizures, simple partial seizure with motor/observable component (SPS-Motor) and Simple partial seizure (SPS) without motor/observable component. Baseline 28-day seizure frequency was calculated as the number of seizures in the Baseline period (= 56 days) divided by the number of days with available seizure data in the Baseline period and multiplied by 28. Baseline was defined as non-missing value of last assessment before first dose.	Baseline and Week 14
Secondary	Double Blind: Cohort 2: Number of Participants With Patient Global Impression of Change - Improvement (PGI-I) at Week 8 and Week 14	The PGI-I scale was a 7-point Likert scale completed by the Patient or Caregiver representing the degree to which the participant's epilepsy symptoms had changed relative to Baseline. It was rated as 1. "very much improved"; 2. "much improved"; 3. "minimally improved"; 4. "no change"; 5. "minimally worse"; 6. "much worse"; 7. "very much worse". Higher score indicated worse condition. Baseline was defined as non-missing value of last assessment before first dose.	Week 8 and Week 14
Secondary	Double Blind: Cohort 2: Number of Participants With Clinical Global Impression of Change - Improvement (CGI-I) at Week 8	The CGI-I scale is a clinician-rated 7-point Likert scale used to assess the degree to which the participant's epilepsy symptoms have changed relative to Baseline. It was rated as 1. "very much improved"; 2. "much improved"; 3. "minimally improved"; 4. "no change"; 5. "minimally worse"; 6. "much worse"; 7. "very much worse". Higher scores indicated worse condition. Baseline was defined as non-missing value of last assessment before first dose.	At Week 8