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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Marinus Pharmaceuticals Inc., Marinus Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

9 Nov 2023 → 23 Apr 2024

Decision date (initial)

2023-09-04

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Marinus Pharmaceuticals, Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Others

• To evaluate the efficacy, safety, and tolerability of adjunctive IV ganaxolone to SOC AEDs for the treatment of RSE

Secondary objectives 2

1. To evaluate the onset and durability of effect of adjunctive IV ganaxolone compared to SOC AEDs in RSE, specifically: Early cessation of SE; Durability of SE control.
2. Determine the effect of adjunctive ganaxolone compared to SOC AEDs on healthcare resource utilization in RSE

Conditions and MedDRA coding

Refractory Status Epilepticus (RSE)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. 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.
2. Male or females 18 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 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
4. 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.
5. BMI < 40 or, if BMI is not able to be calculated at screening, participant is assessed by investigator as not morbidly obese.

Exclusion criteria 11

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 (eg, hypoglycemia < 50 mg/dL or hyperglycemia > 400 mg/dL).
3. 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.
4. Clinical condition or advance directive that would NOT permit admission to the ICU or 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® (marketed products listed in Section 12.4 [Appendix 4]).
8. Known or suspected hepatic insufficiency or hepatic failure leading to impaired synthetic liver function.
9. 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.
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.
11. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. The proportion of participants having both cessation of status epilepticus (SE) within 30 minutes of IP initiation of at least 30 minutes duration, and no escalation of treatment for persistent or recurrent SE within 36 hours of IP initiation
2. Safety endpoint: Incidence and severity of AEs, SAEs, and withdrawal due to AEs

Secondary endpoints 10

1. The proportion of participants having both of the following: o Cessation of SE within 30 minutes of IP initiation of at least 30 minutes duration, and o No escalation of treatment for persistent or recurrent SE within 72 hours of IP initiation
2. Time to SE cessation
3. Proportion of participants having cessation of SE within 30 minutes of IP initiation of at least 30 min duration without escalation of treatment *
4. No escalation of treatment for persistent or recurrent SE within 36 hours of IP initiation
5. No escalation of treatment for persistent or recurrent SE within 72 hours of IP initiation
6. mRS at the time of hospital discharge or last assessment, whichever is earlier
7. Level of responsiveness as assessed by the FOUR Score Scale at 24, 36, and 72 hours following IP initiation
8. Level of sedation/agitation as assessed by the RASS at 24, 36, and 72 hours following IP initiation
9. Proportion of participants with mRS > 3 at the time of hospital discharge
10. CGI-I at 24, 36, and 72 hours following IP initiation and at hospital discharge (or final assessment)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Marinus Pharmaceuticals Inc.

Sponsor organisation

Marinus Pharmaceuticals Inc.

Address

5 Radnor Corporate Center Suite 500

City

Wayne

Postcode

19087-4535

Country

United States

Scientific contact point

Organisation

Marinus Pharmaceuticals Inc.

Contact name

Erin Abdallah

Public contact point

Organisation

Marinus Pharmaceuticals Inc.

Contact name

Erin Abdallah

Third parties 2

Marinus Pharmaceuticals Inc.

Sponsor organisation

Marinus Pharmaceuticals Inc.

Address

5 Radnor Corporate Center Suite 500

City

Wayne

Postcode

19087-4535

Country

United States

Scientific contact point

Organisation

Marinus Pharmaceuticals Inc.

Contact name

Erin Abdallah

Public contact point

Organisation

Marinus Pharmaceuticals Inc.

Contact name

Erin Abdallah

Third parties 2

Locations

14 EU/EEA countries · 41 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

11 submissions — initial application plus substantial / non-substantial modifications