PCDH19-Related Epilepsy
Conditions
Keywords
refractory seizures, epilepsy in children, seizure disorder
Brief summary
A clinical study to evaluate the efficacy, safety, and tolerability of adjunctive ganaxolone therapy compared to placebo for the treatment of seizures in female children and young adults with genetically confirmed PCDH19 gene mutation.
Detailed description
The Violet Study is a global, double-blind, placebo-controlled, Phase 2 clinical trial that plans to enroll approximately 25 female patients between the ages of 1 and 17 with a confirmed disease-related PCDH19 gene variant. Patients will undergo a baseline period before being randomized to receive, in addition to their existing anti-seizure treatment, either ganaxolone or placebo for 17 weeks. Following the treatment period, all patients that meet certain eligibility requirements will have the opportunity to receive ganaxolone in the open label phase of the study. The study's primary efficacy endpoint is percent reduction in seizures. Secondary outcome measures will include non-seizure-related endpoints to capture certain behavioral and sleep disturbances that have been seen in previous clinical studies with ganaxolone.
Interventions
DRUGGanaxolone
active drug
DRUGPlacebo
inactive
Sponsors
Marinus Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
The double-blind phase will randomize subjects to adjunctive ganaxolone or placebo at a 1:1 ratio to standard of care.
Eligibility
Sex/Gender
FEMALE
Age
1 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Molecular confirmation of a pathogenic or likely pathogenic PCDH19 variant * Failure to control seizures despite 2 or more anti-seizure medications * 12 seizures over a 12-week period of primary seizure types prior to screening * On a stable regimen of concomitant AEDs, Ketogenic diets, and modified Atkins diet should be unchanged for 3 months prior to screening)
Exclusion criteria
* Previous exposure to ganaxolone * \> 8 consecutive weeks of seizure freedom during the 12 weeks prior to screening * Concurrent use of strong inducers or inhibitors of CYP3A4/5/7 is not permitted * Use of tetrahydrocannabinol (THC) or non-approved cannabidiol (CBD) is prohibited during the double-blind phase * Exposure to any other investigational drug within 30 days or fewer than 5 half-lives prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Summary of 28-day Seizure Frequency Through 17 Week Post-Baseline Phase (Median Percent Change) | End of the double-blind 17 week treatment period | Summary of 28-Day Seizure Frequency for Seizure Types through 17 week Post-Baseline Phase (Median Percent Change) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summary of 28-day Seizure Frequency for Subjects in the Biomarker-positive Stratum (Median Percent Change) | [Time Frame: End of the double-blind 17 week treatment period] | Summary of 28-day Seizure Frequency for Seizure Types for Subjects in the Biomarker-positive Stratum through 17 weeks (Median Percent Change) |
| 50% Primary Seizure Reduction | End of the double-blind 17 week treatment period | Percent of subjects experiencing a greater than or equal to 50% reduction in 28-day primary seizure frequency relative to the 12-week baseline |
Countries
Hungary, Italy, Netherlands, Poland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo placebo suspension 3x's /day for 17 weeks
Placebo: non-active drug | 11 |
| Ganaxolone ganaxolone suspension (50 mg/ml) 3x's /day for 17 weeks
Ganaxolone: active drug | 10 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Ganaxolone |
|---|---|---|---|
| Age, Continuous | 7.5 years STANDARD_DEVIATION 3.93 | 7.1 years STANDARD_DEVIATION 3.62 | 6.7 years STANDARD_DEVIATION 3.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 10 Participants | 17 Participants | 7 Participants |
| Region of Enrollment Hungary | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Italy | 2 participants | 2 participants | 0 participants |
| Region of Enrollment Netherlands | 2 participants | 4 participants | 2 participants |
| Region of Enrollment Poland | 0 participants | 2 participants | 2 participants |
| Region of Enrollment United States | 6 participants | 12 participants | 6 participants |
| Sex: Female, Male Female | 11 Participants | 21 Participants | 10 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 10 |
| other Total, other adverse events | 11 / 11 | 7 / 10 |
| serious Total, serious adverse events | 5 / 11 | 1 / 10 |
Outcome results
Primary
Summary of 28-day Seizure Frequency Through 17 Week Post-Baseline Phase (Median Percent Change)
Summary of 28-Day Seizure Frequency for Seizure Types through 17 week Post-Baseline Phase (Median Percent Change)
Time frame: End of the double-blind 17 week treatment period
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Summary of 28-day Seizure Frequency Through 17 Week Post-Baseline Phase (Median Percent Change) | -23.97 Median % Change in Number of Seizures |
| Ganaxolone | Summary of 28-day Seizure Frequency Through 17 Week Post-Baseline Phase (Median Percent Change) | -61.52 Median % Change in Number of Seizures |
Secondary
50% Primary Seizure Reduction
Percent of subjects experiencing a greater than or equal to 50% reduction in 28-day primary seizure frequency relative to the 12-week baseline
Time frame: End of the double-blind 17 week treatment period
Population: ITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | 50% Primary Seizure Reduction | 4 Participants |
| Ganaxolone | 50% Primary Seizure Reduction | 5 Participants |
Secondary
Summary of 28-day Seizure Frequency for Subjects in the Biomarker-positive Stratum (Median Percent Change)
Summary of 28-day Seizure Frequency for Seizure Types for Subjects in the Biomarker-positive Stratum through 17 weeks (Median Percent Change)
Time frame: [Time Frame: End of the double-blind 17 week treatment period]
Population: ITT Population specific to subjects in the Biomarker-positive Stratum
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Summary of 28-day Seizure Frequency for Subjects in the Biomarker-positive Stratum (Median Percent Change) | -18.71 Median % Change in Number of Seizures |
| Ganaxolone | Summary of 28-day Seizure Frequency for Subjects in the Biomarker-positive Stratum (Median Percent Change) | -35.90 Median % Change in Number of Seizures |