Status Epilepticus
Conditions
Keywords
Seizure, Status Epilepticus, Convulsive Status Epilepticus, Non-Convulsive Status Epilepticus, Epilepsy
Brief summary
This study evaluated the effectiveness and safety of an investigational product (IP), intravenous (IV) ganaxolone, to treat participants with status epilepticus (SE).
Detailed description
This is a double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of IV ganaxolone in status epilepticus. Investigational product was added to standard of care following failure of any two or more antiseizure medications (benzodiazepine and one IV antiepileptic drug (AED) or two IV AEDs. Participants were screened for inclusion/exclusion criteria prior to receiving investigational product by continuous IV infusion. Participants were followed for approximately 4 weeks. Participants who are known to be at risk for SE were consented or assented prior to an SE event.
Interventions
DRUGGanaxolone
Ganaxolone will be administered.
DRUGPlacebo
Placebo will be administered.
Sponsors
Marinus Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participant, participant's parent, guardian, or legal authorized representative (LAR) must provide signed of informed consent/assent, and once capable (per institution guidelines), there must be documentation of consent/assent by the participant demonstrating they are willing and aware of the investigational nature of the study and related procedures. Where allowed by law, where the participant lacks the capacity to make informed decisions regarding his/her medical treatment options, the treating clinician may follow their deferred consenting practices. The clinician will make the final decision based on the best interests of the particiapant. 2. Male or females 12 years of age and older at the time of the first dose of IP 3. SE meeting the following criteria: a. A diagnosis of SE with or without prominent motor features based on clinical and EEG findings: i. Diagnosis is established by: * For SE with prominent motor features: Clinical and EEG seizure activity indicative of convulsive, myoclonic or focal motor SE. * For SE without prominent motor features (nonconvulsive SE): Appropriate clinical features and an EEG indicative of non-convulsive status epilepticus (NCSE) ii. For any type of SE: * At least 6 minutes of cumulative seizure activity over a 30-minute period within the hour before IP initiation, AND * Seizure activity during the 30 minutes immediately prior to IP initiation b. The treating clinician(s) anticipate that IV anesthesia is likely to be the next treatment for SE that persists following initiation of IP 4. Participants must have received any two or more of the following agents for treatment of the current episode of SE administered at an adequate dose and for a sufficient duration, in the judgment of the investigator, to demonstrate efficacy * Benzodiazepines, * IV Fosphenytoin/phenytoin, * IV Valproic acid, * IV Levetiracetam, * IV Lacosamide, * IV Brivaracetam, or * IV Phenobarbital 5. Body mass index (BMI) \< 40 or, if BMI is not able to be calculated at screening, participant is assessed by investigator as not morbidly obese
Exclusion criteria
1. Life expectancy of less than 24 hours 2. Anoxic brain injury or an uncorrected rapidly reversable metabolic condition as the primary cause of SE (e.g., hypoglycemia \< 50 milligram per deciliter \[mg/dL\] or hyperglycemia \> 400 mg/dL) 3. Participants who have received high-dose IV anesthetics (e.g., midazolam, propofol, thiopental, or pentobarbital) during the current episode of SE for more than 18 hours, or who continue to have clinical or electrographic evidence of persistent seizures while receiving high-dose IV anesthetics. 4. Clinical condition or advance directive that would NOT permit use of IV anesthesia 5. Participants known or suspected to be pregnant 6. Participants with known allergy or sensitivity to progesterone or allopregnanolone medications/supplements 7. Receiving a concomitant IV product containing Captisol® 8. Known or suspected hepatic insufficiency or hepatic failure leading to impaired synthetic liver function. 9. Known or suspected stage 3B (moderate to severe; estimated glomerular filtration rate \[eGFR\] 44-30 milliliter/minutes/1.73-meter square \[mL/min/1.73m\^2\]), stage 4 (severe; eGFR 29-15 mL/min/1.73m\^2), or stage 5 (kidney failure; eGFR \< 15 mL/min/1.73m\^2 or dialysis) kidney disease 10. Use of an investigational product for which less than 30 days or 5 half-lives have elapsed from the final product administration. Participation in a non-interventional clinical study does not exclude eligibility.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With SE Cessation Within 30 Minutes of Investigational Product (IP) Initiation Without Medications for the Acute Treatment of SE | Up to 30 minutes | SE cessation was determined by the investigator based on clinical and electroencephalography (EEG). Medications for the acute treatment of SE were defined as antiepileptic drugs (AEDs) administered to abort ongoing SE or prevent imminent recurrence of SE based on clinical or EEG evidence. |
| Percentage of Participants With no Progression to Intravenous (IV) Anesthesia for 36 Hours Following Investigational Product (IP) Initiation | Up to 36 hours after IP initiation | Percentage of participants with no progression to IV anesthesia for 36 hours following IP initiation SE cessation was based on investigator report with confirmation by assessment of concomitant medication data. |
| Number of Participants With Treatment Emergent Adverse Events | Up to 4 weeks after IP initiation | An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant who has been administered a pharmaceutical product; it does not necessarily have a causal relationship with this treatment. Treatment-emergent adverse event (TEAE) is defined as an AE that occurred or worsened at the time of or following IP initiation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Treatment Escalation in the First 24 Hours Following IP Initiation | Up to 24 hours after IP initiation | For time to treatment escalation (any mediation used for acute treatment of SE), the estimates are based descriptive statistics on participants with treatment escalation in the first 24 hours following IP initiation. For participants without treatment escalation, the time to treatment escalation was censored at IP completion, or discontinuation from the study or death, whichever occurs earlier. The median time to treatment escalation has been presented. |
| Time to Initiation of Anesthesia for SE Treatment Through the Final Study Follow-up Visit/Contact | Up to 4 Weeks following IP initiation | Time to initiation of anesthesia for SE treatment through the final study follow-up visit/contact, were calculated based on descriptive statistics. The estimate was censored at study discontinuation, death, or last follow-up of the participant, whichever occurs first. The median time to initiation of anesthesia has been presented. |
| Percentage of Participants With no Progression to IV Anesthesia for 72 Hours Following IP Initiation | Up to 72 hours after IP initiation | Percentage of participants with no progression to IV anesthesia for 72 hours following IP initiation SE cessation was assessed by the investigator based on clinical and EEG features. |
| Percent Change From Baseline in Seizure Burden Through 72 Hours Following IP Initiation | Up to 72 hours after IP initiation | The seizure burden through 72 hours following IP initiation is described as the percent of time during which there is electrographic seizure activity from IP initiation to 72 hours. The change from baseline of seizure burden was summarized using descriptive statistics by treatment group. The baseline seizure burden is defined for 30 minutes prior to IP initiation. |
| Percentage of Participants Who Develop Super Refractory Status Epilepticus (SRSE) Through the Final Study Follow-up Visit/Contact | Up to 4 Weeks following IP initiation | Percentage of participants who developed SRSE through the final study follow-up visit/contact was provided for each treatment group. |
| Time to SE Cessation Following IP Initiation | Up to 72 hours after IP initiation | Time to SE cessation was assessed for the first 72 hours following IP using the Kaplan-Meier method. |
| Percentage of Participants With Any Escalation of Treatment in the First 24 Hours Following IP Initiation | Up to 24 hours after IP initiation | SE cessation will be determined by the investigator based on clinical and EEG. Percentage of participants with any escalation of treatment in the first 24 hours following IP initiation, i.e. any medication other than IP administered for the acute treatment of SE in the first 24 hours following IP initiation was summarized |
Countries
Australia, Canada, United States
Participant flow
Recruitment details
This was a double-blind, randomized, placebo-controlled study that evaluated the efficacy and safety of ganaxolone intravenous (IV) solution in status epilepticus (SE).
Pre-assignment details
A total of 100 participants were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Ganaxolone Ganaxolone IV administered with a 30-milligrams (mg) bolus dose with initiation of a 36-hour continuous infusion followed by a 12-hour taper | 51 |
| Placebo Placebo IV administered with a bolus and infusion equivalent to volume of IV ganaxolone | 49 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 15 | 10 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 3 | 2 |
| Overall Study | Participant discharged prematurely | 1 | 0 |
| Overall Study | Participant discharged to hospice facility | 0 | 1 |
| Overall Study | Participant family decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Ganaxolone |
|---|---|---|---|
| Age, Continuous | 57.0 years STANDARD_DEVIATION 19.03 | 57.5 years STANDARD_DEVIATION 19.13 | 57.9 years STANDARD_DEVIATION 19.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 13 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 43 Participants | 86 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 27 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 7 Participants | 4 Participants |
| Race (NIH/OMB) White | 32 Participants | 66 Participants | 34 Participants |
| Sex: Female, Male Female | 19 Participants | 40 Participants | 21 Participants |
| Sex: Female, Male Male | 30 Participants | 60 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 11 / 49 | 15 / 51 |
| other Total, other adverse events | 39 / 49 | 43 / 51 |
| serious Total, serious adverse events | 18 / 49 | 19 / 51 |
Outcome results
Primary
Number of Participants With Treatment Emergent Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant who has been administered a pharmaceutical product; it does not necessarily have a causal relationship with this treatment. Treatment-emergent adverse event (TEAE) is defined as an AE that occurred or worsened at the time of or following IP initiation.
Time frame: Up to 4 weeks after IP initiation
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ganaxolone | Number of Participants With Treatment Emergent Adverse Events | Serious TEAEs | 19 Participants |
| Ganaxolone | Number of Participants With Treatment Emergent Adverse Events | TEAE leading to withdrawal | 2 Participants |
| Ganaxolone | Number of Participants With Treatment Emergent Adverse Events | TEAE Leading to study drug discontinuation | 1 Participants |
| Ganaxolone | Number of Participants With Treatment Emergent Adverse Events | TEAE resulting in death | 11 Participants |
| Ganaxolone | Number of Participants With Treatment Emergent Adverse Events | Any TEAE | 48 Participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events | TEAE resulting in death | 11 Participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events | Any TEAE | 43 Participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events | Serious TEAEs | 18 Participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events | TEAE Leading to study drug discontinuation | 2 Participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events | TEAE leading to withdrawal | 0 Participants |
Primary
Percentage of Participants With no Progression to Intravenous (IV) Anesthesia for 36 Hours Following Investigational Product (IP) Initiation
Percentage of participants with no progression to IV anesthesia for 36 hours following IP initiation SE cessation was based on investigator report with confirmation by assessment of concomitant medication data.
Time frame: Up to 36 hours after IP initiation
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ganaxolone | Percentage of Participants With no Progression to Intravenous (IV) Anesthesia for 36 Hours Following Investigational Product (IP) Initiation | 63.27 Percentage of participants |
| Placebo | Percentage of Participants With no Progression to Intravenous (IV) Anesthesia for 36 Hours Following Investigational Product (IP) Initiation | 51.06 Percentage of participants |
p-value: 0.1619fixed weight combination test
Primary
Percentage of Participants With SE Cessation Within 30 Minutes of Investigational Product (IP) Initiation Without Medications for the Acute Treatment of SE
SE cessation was determined by the investigator based on clinical and electroencephalography (EEG). Medications for the acute treatment of SE were defined as antiepileptic drugs (AEDs) administered to abort ongoing SE or prevent imminent recurrence of SE based on clinical or EEG evidence.
Time frame: Up to 30 minutes
Population: Intent-To-Treat (ITT) population comprised of all randomized participants in the double-blind phase of the study who received IP and had at least one non-missing efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ganaxolone | Percentage of Participants With SE Cessation Within 30 Minutes of Investigational Product (IP) Initiation Without Medications for the Acute Treatment of SE | 79.59 Percentage of participants |
| Placebo | Percentage of Participants With SE Cessation Within 30 Minutes of Investigational Product (IP) Initiation Without Medications for the Acute Treatment of SE | 12.77 Percentage of participants |
p-value: 0fixed weight combination test
Secondary
Percentage of Participants Who Develop Super Refractory Status Epilepticus (SRSE) Through the Final Study Follow-up Visit/Contact
Percentage of participants who developed SRSE through the final study follow-up visit/contact was provided for each treatment group.
Time frame: Up to 4 Weeks following IP initiation
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ganaxolone | Percentage of Participants Who Develop Super Refractory Status Epilepticus (SRSE) Through the Final Study Follow-up Visit/Contact | 22.45 Percentage of participants |
| Placebo | Percentage of Participants Who Develop Super Refractory Status Epilepticus (SRSE) Through the Final Study Follow-up Visit/Contact | 25.53 Percentage of participants |
Secondary
Percentage of Participants With Any Escalation of Treatment in the First 24 Hours Following IP Initiation
SE cessation will be determined by the investigator based on clinical and EEG. Percentage of participants with any escalation of treatment in the first 24 hours following IP initiation, i.e. any medication other than IP administered for the acute treatment of SE in the first 24 hours following IP initiation was summarized
Time frame: Up to 24 hours after IP initiation
Population: Intent-To-Treat (ITT) population comprised of all randomized participants in the double-blind phase of the study who received IP and had at least one non-missing efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ganaxolone | Percentage of Participants With Any Escalation of Treatment in the First 24 Hours Following IP Initiation | 55.10 Percentage of participants |
| Placebo | Percentage of Participants With Any Escalation of Treatment in the First 24 Hours Following IP Initiation | 80.85 Percentage of participants |
p-value: 0.0075fixed weight combination test
Secondary
Percentage of Participants With no Progression to IV Anesthesia for 72 Hours Following IP Initiation
Percentage of participants with no progression to IV anesthesia for 72 hours following IP initiation SE cessation was assessed by the investigator based on clinical and EEG features.
Time frame: Up to 72 hours after IP initiation
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ganaxolone | Percentage of Participants With no Progression to IV Anesthesia for 72 Hours Following IP Initiation | 51.02 Percentage of participants |
| Placebo | Percentage of Participants With no Progression to IV Anesthesia for 72 Hours Following IP Initiation | 46.81 Percentage of participants |
p-value: 0.2097fixed weight combination test
Secondary
Percent Change From Baseline in Seizure Burden Through 72 Hours Following IP Initiation
The seizure burden through 72 hours following IP initiation is described as the percent of time during which there is electrographic seizure activity from IP initiation to 72 hours. The change from baseline of seizure burden was summarized using descriptive statistics by treatment group. The baseline seizure burden is defined for 30 minutes prior to IP initiation.
Time frame: Up to 72 hours after IP initiation
Population: ITT population. Participants with percent change from Baseline in seizure burden through 72 hours has been presented.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ganaxolone | Percent Change From Baseline in Seizure Burden Through 72 Hours Following IP Initiation | -59.1 Percent change | Standard Deviation 88.98 |
| Placebo | Percent Change From Baseline in Seizure Burden Through 72 Hours Following IP Initiation | -93.9 Percent change | Standard Deviation 19.79 |
Secondary
Time to Initiation of Anesthesia for SE Treatment Through the Final Study Follow-up Visit/Contact
Time to initiation of anesthesia for SE treatment through the final study follow-up visit/contact, were calculated based on descriptive statistics. The estimate was censored at study discontinuation, death, or last follow-up of the participant, whichever occurs first. The median time to initiation of anesthesia has been presented.
Time frame: Up to 4 Weeks following IP initiation
Population: ITT population. Participants who initiated anesthesia for SE treatment were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ganaxolone | Time to Initiation of Anesthesia for SE Treatment Through the Final Study Follow-up Visit/Contact | 15.00 hours |
| Placebo | Time to Initiation of Anesthesia for SE Treatment Through the Final Study Follow-up Visit/Contact | 3.17 hours |
Secondary
Time to SE Cessation Following IP Initiation
Time to SE cessation was assessed for the first 72 hours following IP using the Kaplan-Meier method.
Time frame: Up to 72 hours after IP initiation
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ganaxolone | Time to SE Cessation Following IP Initiation | 0.07 hours |
| Placebo | Time to SE Cessation Following IP Initiation | 2.85 hours |
p-value: 0Log Rank
Secondary
Time to Treatment Escalation in the First 24 Hours Following IP Initiation
For time to treatment escalation (any mediation used for acute treatment of SE), the estimates are based descriptive statistics on participants with treatment escalation in the first 24 hours following IP initiation. For participants without treatment escalation, the time to treatment escalation was censored at IP completion, or discontinuation from the study or death, whichever occurs earlier. The median time to treatment escalation has been presented.
Time frame: Up to 24 hours after IP initiation
Population: ITT population. Participants with treatment escalation following IP initiation were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ganaxolone | Time to Treatment Escalation in the First 24 Hours Following IP Initiation | 5.42 hours |
| Placebo | Time to Treatment Escalation in the First 24 Hours Following IP Initiation | 2.32 hours |