A double-blind, randomized, placebo-controlled study to evaluate the efficacy, safety, and tolerability of intravenous ganaxolone added to standard of care in refractory status epilepticus
- Trial ID
- 2022-502540-12-00
- Protocol
- 1042-SE-3004
- Sponsor
- Marinus Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy**, safety, and tolerability of adjunctive intravenous ganaxolone when added to standard of care (SOC) antiepileptic drugs (AEDs) for the treatment of **Refractory Status Epilepticus (RSE)**. This is clinically relevant as RSE is a severe neurological condition that is often resistant to conventional treatments, and finding effective adjunctive therapies could significantly improve patient outcomes.
Secondary objectives include:
- Evaluating the onset and durability of the effect of adjunctive IV ganaxolone compared to SOC AEDs in RSE, specifically focusing on early cessation of status epilepticus (SE) and the durability of SE control.
- Determining the effect of adjunctive ganaxolone compared to SOC AEDs on healthcare resource utilization in RSE.
Participants
The clinical trial involves a total of **10 participants** diagnosed with **Refractory Status Epilepticus (RSE)**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific criteria, including a diagnosis of status epilepticus (SE) with or without prominent motor features, and prior treatment with benzodiazepines and at least one intravenous antiepileptic drug (AED). The trial population is characterized by individuals who have received adequate doses of these medications to demonstrate efficacy in terminating the current episode of SE. Participants must not be morbidly obese, as indicated by a body mass index (BMI) of less than 40 or an assessment by the investigator. The study includes a vulnerable population, ensuring informed consent is obtained from participants or their legally authorized representatives. Lifestyle factors such as diet and physical activity are not specified in the trial data provided.
Plans and Procedures
The clinical trial is designed as a **double-blind**, **randomized**, **placebo-controlled** study to evaluate the efficacy, safety, and tolerability of intravenous **ganaxolone** in conjunction with standard care for patients with **refractory status epilepticus**. The trial will involve the administration of ganaxolone or a placebo, with the primary objective being the cessation of status epilepticus within 30 minutes of investigational product initiation and no escalation of treatment for persistent or recurrent status epilepticus within 36 hours. The trial is expected to run until November 2025, with recruitment starting in September 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and previous treatment with benzodiazepines and intravenous antiepileptic drugs. Follow-up visits will assess the primary and secondary endpoints, including the time to cessation of status epilepticus, the level of responsiveness, and the incidence of adverse events. The end-of-study visit will evaluate the overall outcomes and safety of the treatment. The expected length of participant involvement is up to 72 hours post-initiation of the investigational product, with conditions for early termination including withdrawal of consent or adverse events that necessitate discontinuation.
Participants must be 18 years or older, with a body mass index of less than 40, and must have experienced a status epilepticus episode meeting specific clinical and electroencephalographic criteria. The trial will exclude individuals who do not meet these criteria or who have conditions that could interfere with the study's objectives. The study will ensure informed consent is obtained from all participants or their legally authorized representatives, with documentation of consent required once participants are capable. The trial will adhere to ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants.
Treatment
The clinical trial involves the administration of **Ganaxolone**, an experimental medication, to evaluate its efficacy, safety, and tolerability in the treatment of refractory status epilepticus. Ganaxolone is provided in a **capsule** form, although for this study, it is administered **intravenously**. The maximum daily dose is 80 mg/h, with a total maximum dose of 80 mg over a treatment period of up to 2 days. The active substance, ganaxolone, is of chemical origin and is developed by Marinus Pharmaceuticals Inc. The administration of Ganaxolone is adjunctive to standard-of-care antiepileptic drugs (SOC AEDs) in this study.
A **placebo** is also utilized in this double-blind, randomized, placebo-controlled study. The placebo is designed to match the investigational product, Ganaxolone, in appearance but does not contain any active substance. The placebo serves as a comparator to assess the true efficacy and safety of Ganaxolone when added to SOC AEDs. The placebo is administered in a manner consistent with the experimental treatment to maintain the study's blinding and integrity.
Efficacy
The efficacy of intravenous **ganaxolone** in the treatment of refractory status epilepticus (RSE) will be assessed through a double-blind, randomized, placebo-controlled clinical trial. The primary efficacy endpoint is the proportion of participants achieving cessation of status epilepticus within 30 minutes of investigational product (IP) initiation, sustained for at least 30 minutes, without escalation of treatment for persistent or recurrent status epilepticus within 36 hours of IP initiation. Secondary endpoints include the proportion of participants achieving cessation of status epilepticus within 30 minutes of IP initiation, sustained for at least 30 minutes, without escalation of treatment within 72 hours, time to cessation of status epilepticus, and various clinical assessments such as the modified Rankin Scale (mRS) at hospital discharge or last assessment, the FOUR Score Scale, and the Richmond Agitation-Sedation Scale (RASS) at specified timepoints (24, 36, and 72 hours following IP initiation).
Data collection will involve the use of validated scales and clinical assessments to measure the level of responsiveness, sedation, and agitation. The Clinical Global Impression-Improvement (CGI-I) scale will also be utilized at 24, 36, and 72 hours following IP initiation and at hospital discharge or final assessment. The trial is designed to ensure rigorous evaluation of the efficacy of ganaxolone as an adjunctive treatment to standard of care antiepileptic drugs (AEDs) in patients with refractory status epilepticus. The study will adhere to a structured schedule for measuring and analyzing these efficacy parameters to ensure the reliability and validity of the results.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Informed consent signature must be obtained from participant or LAR and once capable (per institutional guidelines), there must be documentation of consent by the participant demonstrating they are willing and aware of the investigational nature of the study and related procedures. Where allowed by law, if 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 participant.
- Male or females 18 years of age and older at the time of the first dose of IP.
- SE meeting the following criteria: a. A diagnosis of SE with or without prominent motor features based on clinical and EEG findings according to investigator's judgement, based on the following: i. For SE with prominent motor features: Clinical and EEG seizure activity indicative of convulsive, myoclonic or focal motor SE; ii. For SE without prominent motor features (nonconvulsive SE): Appropriate clinical features and an EEG indicative of NCSE (see modified Salzburg criteria in Appendix 3) iii. For any type of SE: • Approximetaly 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
- Participants must have received a benzodiazepine and at least 1 of the following IV AEDs for treatment of the current episode of SE administered at an adequate dose and for a sufficient duration, in the judgement of the investigator, to demonstrate efficacy. The benzodiazepine and at least 1 of the IV AEDs must have been administered at a dose that would be expected to be effective for the termination of the current episode of SE, as referred to in Section 12.2 (Appendix 2): • IV Fosphenytoin/phenytoin, • IV Valproic acid, • IV Levetiracetam, • IV Lacosamide, • IV Brivaracetam, or • IV Phenobarbital.
- BMI < 40 or, if BMI is not able to be calculated at screening, participant is assessed by investigator as not morbidly obese.
Exclusion Criteria
- Life expectancy of less than 24 hours.
- Anoxic brain injury or an uncorrected, rapidly reversable metabolic condition as the primary cause of SE (eg, hypoglycemia < 50 mg/dL or hyperglycemia > 400 mg/dL).
- Participants who have received high-dose IV anesthetics (eg, 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.
- Clinical condition or advance directive that would NOT permit admission to the ICU or use of IV anesthesia.
- Participants known or suspected to be pregnant
- Participants with known allergy or sensitivity to progesterone or allopregnanolone medications/supplements
- Receiving a concomitant IV product containing Captisol® (marketed products listed in Section 12.4 [Appendix 4]).
- Known or suspected hepatic insufficiency or hepatic failure leading to impaired synthetic liver function.
- Known or suspected stage 3B (moderate to severe; eGFR 44-30 mL/min/1.73 m2), stage 4 (severe; eGFR 29-15 mL/min/1.73 m2), or stage 5 (kidney failure; eGFR < 15 mL/min/1.73 m2 or dialysis) kidney disease.
- 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.
- Known or suspected history or evidence of a medical condition that, in the investigator’s judgment, would expose a participant to an undue risk of a significant adverse event or would interfere with assessments of safety or efficacy during the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 01 Sept 2023 | 6 |
 Belgium | Not Recruiting | 01 Sept 2023 | 5 |
 Croatia | Not Recruiting | 01 Sept 2023 | 3 |
 Czechia | Not Recruiting | 01 Sept 2023 | 6 |
 Denmark | Not Recruiting | 01 Sept 2023 | 3 |
 Finland | Not Recruiting | 01 Sept 2023 | 5 |
 France | Not Recruiting | 01 Sept 2023 | 5 |
 Germany | Not Recruiting | 01 Sept 2023 | 8 |
 Hungary | Not Recruiting | 01 Sept 2023 | 3 |
 Italy | Not Recruiting | 01 Sept 2023 | 5 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Ganaxolone | Test | CAPSULE | INTRAVENOUS | 80 | 2 | PRD2273153 |
Placebo for IMP Ganaxolone | Placebo | N/A | — | — | — | N/A |