Drug Resistant Partial Onset Seizure
Conditions
Keywords
Partial Onset Seizures, complex partial seizures, simple partial seizures, anticonvulsant, ganaxolone, neurosteroid, Marinus, epilepsy
Brief summary
A follow-on, two-year open-label extension study of ganaxolone as add-on therapy in adult patients with drug-resistant partial-onset seizures
Detailed description
This study is a 2-year, open-label continuation for those patients benefiting from ganaxolone treatment after completing Protocol 1042-0603.
Interventions
DRUGganaxolone
225 mg capsules 450 mg to 900 mg 2x/day
Sponsors
Marinus Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects who have completed all scheduled clinical study visits in the previous protocol 1042-0603 and have shown a minimum 35% improvement in mean 28-day seizure frequency over the last three 28-day periods in study 1042-603 as compared to the baseline of study 1042-603. * Subjects whose daily study drug compliance in Study 1042-0603 was 90% or greater, and for whom the investigator feels that the subject was compliant with the full dose as prescribed. * Able to give informed consent in writing, or have a legally authorized representative able to do so, after being properly informed of the nature and risks of the study and prior to engaging in any study-related procedures. * Currently being treated and maintained with a stable regimen of 1, 2, or 3 anti-epileptic drugs (AED) at a consistent dose for one month prior to study entry. * Implanted Vagus Nerve Stimulator (VNS) is permitted and will not count towards the number of concomitant AEDs. * Able and willing to maintain an accurate and complete daily written seizure calendar or has a caregiver who is able and willing to maintain an accurate and complete daily written seizure calendar. * Able and willing to take drug with food twice daily. Ganaxolone must be administered with food. * Sexually active women of childbearing potential (WCBP) must be using a medically acceptable method of birth control and have a negative pregnancy test at Visit 1 and at subsequent visits.
Exclusion criteria
* Have any medical condition that, in the investigator's judgment, is considered to be clinically significant and could potentially affect subject safety or study outcome * Experienced a Serious Adverse Event or a moderate or severe medically important adverse event judged probably or definitely related to open-label ganaxolone in the previous study, 1042-0603 * Have Alanine transferase (ALT; SGPT) or Aspartate transferase (AST; SGOT) levels \> 3 times upper limits of normal (ULN), or total bilirubin \>1.5 time ULN during Study 1042-0603. * Have a history of malignancy within the past 2 years, with the exception of basal cell carcinoma. * 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. * Have active suicidal plan/intent, or have had active suicidal thoughts in the past 6 months. Have a history of an actual suicide attempt in the last 5 years or more than 1 lifetime actual suicide attempt as classified by the Columbia-Suicide Severity Rating Scale (C-SSRS). * Have a history of drug or alcohol abuse within the past 5 years. As with other AEDs, the use of alcohol is not advised. * Are currently following or planning to follow a ketogenic diet. * Current use of vigabatrin or ezogabine (retigabine; Potiga; Trobalt) is not permitted. * Females who are pregnant, currently breastfeeding or planning to become pregnant during the study. * Inability/unwillingness to withhold grapefruit and grapefruit juice from diet during the entire clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in 28-day Seizure Frequency | Baseline and at Day 28 | Baseline 28-day seizure frequency was calculated as the number of seizures in the Baseline period of Study 1042-0603 (less than or equal to 56 days) divided by the number of days with available seizure data in the Baseline period and multiplied by 28. Post-baseline 28-day seizure frequency was calculated as the number of seizures in the entire treatment period divided by the number of days with available seizure data in the treatment period and multiplied by 28. Baseline was defined as the last non-missing value obtained before the first treatment in the preceding Study 1042-0603. The calculation for percent change from Baseline in 28-day seizure frequency was done as follows for each participant: post-Baseline 28-day seizure frequency minus Baseline 28-day seizure frequency whole divided by Baseline 28-day seizure frequency multiplied by 100 percent. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Showed Greater Than or Equal to 50% Reduction in 28-day Seizure Frequent From Baseline | Baseline and at Day 28 | A 50% responder is an individual whose reduction of percent change from Baseline to the end of the open label extension period in 28-day partial-onset seizure (POS) seizure frequency is greater than or equal to 50%. |
| Number of Participants With Clinical Global Impression of Improvement (CGI-I) Scores | At Week 104 | The CGI-I scale is a clinician-rated 7-point scale used to assess how much the participant's illness had improved or worsened relative to a Baseline state at the beginning of the intervention. 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. Participants who showed CGI improvement at Week 104 (End of treatment) has been presented. |
| Number of Participants With Patient/Caregiver Global Impression of Improvement (PGI-I) Scores | At Week 104 | The participant is asked to rate the total improvement of their partial-onset seizures whether or not in the participant's judgment it is due entirely to drug treatment based on a 7-point scale using the markers very much improved, much improved, slightly improved, no change, slightly worse, much worse, or very much worse (1 = very much improved; 7 = very much worse). Higher scores indicated worse condition. Participants who showed PGI improvement at Week 104 (End of treatment) has been presented. |
Countries
United States
Participant flow
Recruitment details
This was an open-label extension of Study 1042-0603, providing a two-year adjunctive ganaxolone treatment to adult participants with epilepsy consisting of partial-onset seizures (POS).
Pre-assignment details
A total of 26 participants moved in from 1042-0603 (NCT01963208) study. As Ganaxolone missed its primary endpoint in the double-blind portion of the 1042-0603 study, the study was terminated.
Participants by arm
| Arm | Count |
|---|---|
| Ganaxolone Participants entered the study at their current dose of ganaxolone (450 milligrams \[mg\] to 900 mg twice daily; up to a maximum dose of 1800 mg per day) from Study 1042-0603 (NCT01963208). The dose of ganaxolone has been adjusted for tolerability and response. | 26 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Study Termination | 19 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Ganaxolone |
|---|---|
| Age, Continuous | 44.3 Years STANDARD_DEVIATION 15.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 26 |
| other Total, other adverse events | 10 / 26 |
| serious Total, serious adverse events | 1 / 26 |
Outcome results
Primary
Percent Change From Baseline in 28-day Seizure Frequency
Baseline 28-day seizure frequency was calculated as the number of seizures in the Baseline period of Study 1042-0603 (less than or equal to 56 days) divided by the number of days with available seizure data in the Baseline period and multiplied by 28. Post-baseline 28-day seizure frequency was calculated as the number of seizures in the entire treatment period divided by the number of days with available seizure data in the treatment period and multiplied by 28. Baseline was defined as the last non-missing value obtained before the first treatment in the preceding Study 1042-0603. The calculation for percent change from Baseline in 28-day seizure frequency was done as follows for each participant: post-Baseline 28-day seizure frequency minus Baseline 28-day seizure frequency whole divided by Baseline 28-day seizure frequency multiplied by 100 percent.
Time frame: Baseline and at Day 28
Population: Full Analysis Population included participants who returned at least 25 days of seizure calendar data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ganaxolone | Percent Change From Baseline in 28-day Seizure Frequency | -41.86 Percent change | Standard Deviation 44.913 |
Secondary
Number of Participants Who Showed Greater Than or Equal to 50% Reduction in 28-day Seizure Frequent From Baseline
A 50% responder is an individual whose reduction of percent change from Baseline to the end of the open label extension period in 28-day partial-onset seizure (POS) seizure frequency is greater than or equal to 50%.
Time frame: Baseline and at Day 28
Population: Full Analysis Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ganaxolone | Number of Participants Who Showed Greater Than or Equal to 50% Reduction in 28-day Seizure Frequent From Baseline | 14 Participants |
Secondary
Number of Participants With Clinical Global Impression of Improvement (CGI-I) Scores
The CGI-I scale is a clinician-rated 7-point scale used to assess how much the participant's illness had improved or worsened relative to a Baseline state at the beginning of the intervention. 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. Participants who showed CGI improvement at Week 104 (End of treatment) has been presented.
Time frame: At Week 104
Population: Safety Population included all participants who signed informed consent and took one dose of study medication in this study. Only those participants with data available at indicated timepoints has been presented.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ganaxolone | Number of Participants With Clinical Global Impression of Improvement (CGI-I) Scores | Very much improved | 1 Participants |
| Ganaxolone | Number of Participants With Clinical Global Impression of Improvement (CGI-I) Scores | Much improved | 9 Participants |
| Ganaxolone | Number of Participants With Clinical Global Impression of Improvement (CGI-I) Scores | Minimally improved | 11 Participants |
| Ganaxolone | Number of Participants With Clinical Global Impression of Improvement (CGI-I) Scores | No change | 2 Participants |
| Ganaxolone | Number of Participants With Clinical Global Impression of Improvement (CGI-I) Scores | Minimally worse | 0 Participants |
| Ganaxolone | Number of Participants With Clinical Global Impression of Improvement (CGI-I) Scores | Much worse | 0 Participants |
| Ganaxolone | Number of Participants With Clinical Global Impression of Improvement (CGI-I) Scores | Very much worse | 0 Participants |
Secondary
Number of Participants With Patient/Caregiver Global Impression of Improvement (PGI-I) Scores
The participant is asked to rate the total improvement of their partial-onset seizures whether or not in the participant's judgment it is due entirely to drug treatment based on a 7-point scale using the markers very much improved, much improved, slightly improved, no change, slightly worse, much worse, or very much worse (1 = very much improved; 7 = very much worse). Higher scores indicated worse condition. Participants who showed PGI improvement at Week 104 (End of treatment) has been presented.
Time frame: At Week 104
Population: Safety Population. Only those participants with data available at indicated time points has been presented.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ganaxolone | Number of Participants With Patient/Caregiver Global Impression of Improvement (PGI-I) Scores | Very much improved | 4 Participants |
| Ganaxolone | Number of Participants With Patient/Caregiver Global Impression of Improvement (PGI-I) Scores | Much improved | 8 Participants |
| Ganaxolone | Number of Participants With Patient/Caregiver Global Impression of Improvement (PGI-I) Scores | Minimally improved | 10 Participants |
| Ganaxolone | Number of Participants With Patient/Caregiver Global Impression of Improvement (PGI-I) Scores | No change | 1 Participants |
| Ganaxolone | Number of Participants With Patient/Caregiver Global Impression of Improvement (PGI-I) Scores | Minimally worse | 0 Participants |
| Ganaxolone | Number of Participants With Patient/Caregiver Global Impression of Improvement (PGI-I) Scores | Much worse | 0 Participants |
| Ganaxolone | Number of Participants With Patient/Caregiver Global Impression of Improvement (PGI-I) Scores | Very much worse | 0 Participants |