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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Drug Resistant Partial Onset Seizure

Intervention / Treatment
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* Drug: ganaxolone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Double Blind - Cohort 1 - Ganaxolone<br>1200 mg/day and 1800 mg/day + AED | Drug: ganaxolone<br>* 200 mg and 225 mg capsules; target dose 1800 mg/day dosed 900mg 2x/day<br>* Other names: gnx;|
| Placebo Comparator: Double Blind - Cohort 1 - Placebo<br>Placebo + AED | Drug: Placebo<br>* placebo<br>* Other names: pbo;|
| Experimental: Open Label - Ganaxolone in Double-blind phase<br>1800 mg/day + AED | Drug: ganaxolone<br>* 200 mg and 225 mg capsules; target dose 1800 mg/day dosed 900mg 2x/day<br>* Other names: gnx;|
| Experimental: Double Blind - Cohort 2 - Ganaxolone<br>1800 mg/day + AED | Drug: ganaxolone<br>* 200 mg and 225 mg capsules; target dose 1800 mg/day dosed 900mg 2x/day<br>* Other names: gnx;|
| Placebo Comparator: Double Blind - Cohort 2 - Placebo<br>Placebo +AED | Drug: Placebo<br>* placebo<br>* Other names: pbo;|
| Experimental: Open Label - Placebo in Double-blind phase<br>1800 mg/day + AED | Drug: ganaxolone<br>* 200 mg and 225 mg capsules; target dose 1800 mg/day dosed 900mg 2x/day<br>* Other names: gnx;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Marinus, partial onset seizures, complex partial seizures, simple partial seizures, anticonvulsant, ganaxolone, neurosteroid, epilepsy