Tuberous Sclerosis
Conditions
Brief summary
To assess preliminary safety and efficacy of ganaxolone as adjunctive therapy for the treatment of primary seizure types in patients with genetically- or clinically-confirmed TSC-related epilepsy through the end of the 12 week treatment period.
Detailed description
This is an OL proof of concept study of adjunctive GNX treatment in patients with a confirmed clinical diagnosis of TSC and/or a mutation in either the TSC1 or TSC2 gene. The trial consists of two parts: Part A consists of a 4-week baseline period followed by a 12-week treatment period (4-week titration and 8-week maintenance). For patients not continuing in the 24-week OLE period (Part B), a 2-week taper period followed by a 2-week safety period would follow. The main difference between Part A and Part B is the length of treatment, less frequent assessments, and the ability to alter drug doses (both GNX and other antiepileptic drug \[AED\] treatments which includes initiating and stopping other medications) based on investigator evaluation of the patient's clinical course during Part B. Patients with a seizure frequency reduction during the 12-week treatment period in Part A compared to baseline may continue into Part B (OLE eligible), to assess long-term safety, efficacy and tolerability in patients with TSC-related Epilepsy.
Interventions
DRUGGanaxolone
titration followed by maintenance and extension period
Sponsors
Marinus Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
(Part A): * Clinical or mutational diagnosis of TSC * Failure to control seizures despite appropriate trial of 2 or more ASMs at therapeutic doses. * Have at least 8 countable/witnessed primary seizures during the 4-week baseline period with at least 1 primary seizure occurring in at least 3 of the 4 weeks of baseline. Inclusion Criteria (Part B) • Patients have experienced ≥ 35% reduction in primary seizure frequency during the Part A treatment period compared to the 4-week Baseline Period.
Exclusion criteria
(Part A): * Previous exposure to GNX * Pregnant or breastfeeding * Concurrent use of strong inducers or inhibitors of cytochrome P450 (CYP)3A4/5/7. Any strong inhibitor or inducer of CYP3A4/5/7 must be discontinued at least 28 days before Visit 2, study drug initiation. This does not include approved ASMs. * Patients who have been taking felbamate for less than 1 year prior to screening * Patients who test positive for tetrahydrocannabinol (THC) or non-approved cannabidiol (CBD) via plasma drug screen * Chronic use of oral steroid medications, ketoconazole (except for topical formulations), St. John's Wort, or other IPs is not permitted * Have an active CNS infection, demyelinating disease, degenerative neurological disease, or CNS disease deemed progressive. This includes tumor growth which in the opinion of the investigator could affect primary seizure control * Patients with significant renal insufficiency, estimated glomerular filtration rate (eGFR) \< 30 mL/min (calculated using the Cockcroft-Gault formula or Pediatric GFR calculator or Bedside Schwartz), will be excluded from study entry or will be discontinued if the criterion is met post baseline * Have been exposed to any other investigational drug within 30 days or fewer than 5 half lives (whichever is shorter) prior to the screening visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in 28-day Seizure Frequency Through the End of 12-Week Treatment Period | Baseline and Up to Week 12 | Primary seizures include atonic/drop, bilateral clonic, bilateral tonic, focal motor without impairment of consciousness or awareness, focal (motor or non-motor) with impairment of consciousness or awareness, focal to bilateral tonic-clonic, generalized tonic-clonic. Baseline 28-day seizure frequency was calculated as the total number of primary seizures in the Baseline period divided by the number of days with non-missing seizure data in the Baseline period, multiplied by 28. The Baseline Visit was defined as Week 0. Percent change from Baseline in 28-day seizure frequent was calculated as the difference in post-Baseline 28-day seizure frequency and Baseline 28-day seizure frequency, divided by Baseline 28-day seizure frequency, multiplied by 100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing a >=50 Percent Reduction in 28-day Primary Seizure Frequency Through the End of the 12-week Treatment Period Compared to the Baseline Period | Baseline and up to 12 Weeks | Primary seizures include atonic/drop, bilateral clonic, bilateral tonic, focal motor without impairment of consciousness or awareness, focal (motor or non-motor) with impairment of consciousness or awareness, focal to bilateral tonic-clonic, generalized tonic-clonic. Percentage of participants reporting \>=50 percent reduction in seizure frequency has been presented. |
Countries
United States
Participant flow
Recruitment details
This was an open label proof of concept study of adjunctive Ganaxolone treatment in participants with a confirmed clinical diagnosis of Tuberous Sclerosis Complex (TSC). The trial consisted of two parts: 12-Week Treatment period and an open label extension period.
Pre-assignment details
A total of 23 participants were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Period: Ganaxolone Participants \>28 kg were administered with Ganaxolone 1800 milligrams per day (mg/day). Following the Treatment period, participants with a seizure reduction of \>=35 percent compared to the Baseline period and who did not have any other contraindications continued to be treated with Ganaxolone in the Open label extension period. | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period (Up to 12 Weeks) | Adverse Event | 4 | 0 |
| Treatment Period (Up to 12 Weeks) | Lack of Efficacy | 1 | 0 |
| Treatment Period (Up to 12 Weeks) | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Treatment Period: Ganaxolone |
|---|---|
| Age, Continuous | 13.7 Years STANDARD_DEVIATION 8.86 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants |
| Race/Ethnicity, Customized Declined to answer | 1 Participants |
| Race/Ethnicity, Customized Other-Unspecified | 2 Participants |
| Race/Ethnicity, Customized White | 17 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 9 |
| other Total, other adverse events | 20 / 23 | 3 / 9 |
| serious Total, serious adverse events | 3 / 23 | 1 / 9 |
Outcome results
Primary
Percent Change From Baseline in 28-day Seizure Frequency Through the End of 12-Week Treatment Period
Primary seizures include atonic/drop, bilateral clonic, bilateral tonic, focal motor without impairment of consciousness or awareness, focal (motor or non-motor) with impairment of consciousness or awareness, focal to bilateral tonic-clonic, generalized tonic-clonic. Baseline 28-day seizure frequency was calculated as the total number of primary seizures in the Baseline period divided by the number of days with non-missing seizure data in the Baseline period, multiplied by 28. The Baseline Visit was defined as Week 0. Percent change from Baseline in 28-day seizure frequent was calculated as the difference in post-Baseline 28-day seizure frequency and Baseline 28-day seizure frequency, divided by Baseline 28-day seizure frequency, multiplied by 100.
Time frame: Baseline and Up to Week 12
Population: Intention to Treat (ITT) Population comprised of all participants who received at least one dose of Ganaxolone and have at least one post-Baseline efficacy assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Period: Ganaxolone | Percent Change From Baseline in 28-day Seizure Frequency Through the End of 12-Week Treatment Period | -16.61 Percent change |
Secondary
Percentage of Participants Experiencing a >=50 Percent Reduction in 28-day Primary Seizure Frequency Through the End of the 12-week Treatment Period Compared to the Baseline Period
Primary seizures include atonic/drop, bilateral clonic, bilateral tonic, focal motor without impairment of consciousness or awareness, focal (motor or non-motor) with impairment of consciousness or awareness, focal to bilateral tonic-clonic, generalized tonic-clonic. Percentage of participants reporting \>=50 percent reduction in seizure frequency has been presented.
Time frame: Baseline and up to 12 Weeks
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Period: Ganaxolone | Percentage of Participants Experiencing a >=50 Percent Reduction in 28-day Primary Seizure Frequency Through the End of the 12-week Treatment Period Compared to the Baseline Period | 30.4 Percentage of participants |