Clinical trial NCT05814523: To Evaluate the Efficacy, Safety, and Tolerability of Intravenous Ganaxolone Added to Standard of Care in Refractory Status Epilepticus (RSE)
Official title: 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
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE3
Conditions: Refractory Status Epilepticus
Keywords: Refractory status epilepticus
Ganaxolone
Antiepileptic drug
Standard of care
Lead sponsor: Marinus Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2023-04-18
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a multicenter, double-blind, randomized, placebo-controlled study that will evaluate the efficacy, safety, and tolerability of intravenous (IV) ganaxolone versus placebo co-administered with IV antiepileptic drug (AED) according to standard of care for the treatment of RSE. Approximately 70 participants will be randomized in a 1:1 ratio to receive ganaxolone IV solution or placebo IV solution along with standard of care (SOC) IV AED.


Eligibility criteria: Inclusion Criteria:

1. Participant, participant's parent, guardian, or LAR must provide signed 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 participant.
2. Male or females 18 years of age and older at the time of the first dose of IP.
3. SE warranting imminent progression of treatment meeting the following criteria:

   a) A diagnosis of SE, warranting imminent progression of treatment for seizure control, 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.
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.

   * 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 (eg, hypoglycemia \< 50 milligrams per deciliter \[mg/dL\] 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.
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 milliliters per minute per 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.
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 interfere with assessments of safety or efficacy during the study

Primary outcomes:
measure: Percentage of participants who will report cessation of SE within 30 minutes of investigational product (IP) initiation of at least 30 minutes duration
timeFrame: Up to 30 minutes
measure: Percentage of participants who will report no escalation of treatment for persistent or recurrent SE within 36 hours of IP initiation
timeFrame: Up to 36 hours
Secondary outcomes:
measure: Percentage of participants who will report cessation of SE within 30 minutes of IP initiation of at least 30 minutes duration
timeFrame: Up to 30 minutes
measure: Percentage of participants who will report no escalation of treatment for persistent or recurrent SE within 72 hours of IP initiation
timeFrame: Up to 72 hours
measure: Time to SE cessation
timeFrame: Up to 72 hours
measure: Percentage of participants having cessation of SE within 30 minutes of IP initiation of at least 30 minutes duration without escalation of treatment
timeFrame: Up to 30 minutes
measure: Percentage of participants reporting no escalation of treatment for persistent or recurrent SE within 36 hours of IP initiation
timeFrame: Up to 36 hours
measure: Percentage of participants reporting no escalation of treatment for persistent or recurrent SE within 72 hours of IP initiation
timeFrame: Up to 72 hours
measure: Change from Baseline in Modified Rankin Scale (mRS) at the time of hospital discharge
timeFrame: Baseline and Up to Day 31
measure: Change from Baseline in level of responsiveness as assessed by the Full Outline of UnResponsiveness (FOUR) Score scale
timeFrame: Baseline and at 24, 36 and 72 hours
measure: Change from Baseline in level of sedation/ agitation as assessed by Richmond Agitation and Sedation Scale (RASS)
timeFrame: Baseline and at 24, 36 and 72 hours
measure: Percentage of participants with mRS > 3 at the time of hospital discharge
timeFrame: Up to 122 hours
measure: Change from Baseline in Clinical Global Impression-Improvement (CGI-I) following IP initiation and at hospital discharge
timeFrame: Baseline and at 24, 36, and 72 hours
measure: Number of hours on positive pressure ventilation attributable to the episode of SE or its treatment
timeFrame: Up to 4 Weeks
measure: Number of hours on positive pressure ventilation
timeFrame: Up to 4 Weeks
measure: Length of stay (days) in intensive care unit (ICU)
timeFrame: Up to 4 Weeks
measure: Length of stay (days) in hospital
timeFrame: Up to 4 Weeks
measure: Percentage of participants requiring artificial ventilation after initiation of IP
timeFrame: Up to 122 hours
measure: Percentage of participants not requiring IV anesthesia for SE treatment within 36 hours of IP initiation
timeFrame: Up to 36 hours
measure: Percentage of participants not requiring IV anesthesia for SE treatment within 72 hours of IP initiation
timeFrame: Up to 72 hours
measure: Percentage of participants not requiring IV anesthesia for SE treatment through the final study follow-up visit/contact
timeFrame: Up to 4 Weeks
measure: Percentage of participants who do not develop super refractory status epilepticus (SRSE) through the final study follow-up visit/contact
timeFrame: Up to 4 Weeks
measure: Change from Baseline in Euro Quality of Life (five-level EuroQoL five-dimensional [EQ-5D-5L]) score
timeFrame: Baseline and Up to 4 Weeks
measure: Number of AEDs at discharge
timeFrame: Up to 122 hours
measure: Percentage of participants requiring supplemental oxygen after initiation of IP
timeFrame: Up to 4 Weeks
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Medical University of Innsbruck
city: Linz
country: Austria
facility: Kepler University Hospital
city: Linz
country: Austria
facility: Kepler Universitätsklinikum GmbH
city: Salzburg
country: Austria
facility: Paracelsus Medical University Salzburg, Christian Doppler University Hospital, Department of Neurology
city: Wien
country: Austria
facility: Medical University Vienna
city: Bruxelles
country: Belgium
facility: Hôpital Universitaire de Bruxelles - Hôpital Erasme
city: Edegem
country: Belgium
facility: UZA University Hospital Antwerpen
city: Leuven
country: Belgium
facility: University Hospitals Leuven
city: Zagreb
country: Croatia
facility: Dubrava University Hospital
city: Zagreb
country: Croatia
facility: University Hospital Centre Zagreb
city: Brno
country: Czechia
facility: Mazaryk University, Brno,The First Department of Neurology
city: Ostrava
country: Czechia
facility: University Hospital Ostrava
city: Prague
country: Czechia
facility: Motol University Hospital
city: Helsinki
country: Finland
facility: Helsinki University Hospital
city: Kuopio
country: Finland
facility: Kuopio University Hospital
city: Lille
country: France
facility: Hopital R. Salengro
city: Lyon
country: France
facility: Hospices Civils de Lyon
city: Nancy
country: France
facility: CHRU Nancy
city: Toulouse
country: France
facility: Chu de Toulouse
city: Osnabrück
country: Germany
facility: University of Osnabruck, Dep of Neurology, Osnabrück
state: Osnabruck
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen
city: Marburg
country: Germany
facility: Epilepsy Center Hessen
city: Ulm
country: Germany
facility: Universität- und Rehabilitationskliniken Ulm, RKU
city: Budapest
country: Hungary
facility: National Institute of Clinical Neurosciences
city: Be'er Sheva
country: Israel
facility: Soroka Medical Center
state: Beer-Sheva
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
city: Tel Aviv
country: Israel
facility: Sheba Medical Center
city: Tel aviv
country: Israel
facility: Tel-Aviv Sourasky Medical Center
city: Firenze
country: Italy
facility: Azienda Ospedaliero Universitaria Caregg
city: Milan
country: Italy
facility: Università Cattolica del Sacro Cuore
city: Modena
country: Italy
facility: Azienda Ospedaliera Universitaria di Modena
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata di Verona
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital Santaros Klinikos
city: Katowice
country: Poland
facility: Oddział Neurologii z Pododdziałem Udarowym Górnośląskie Centrum Medyczne im. prof. Leszka Gieca Śląskiego Uniwersytetu Medycznego w Katowicach
state: Katowice-Ochojec
city: Kraków
country: Poland
facility: Oddzial Kliniczny Neurologii, Szpital Uniwersytecki w Krakowie
state: Krakow
city: Katowice
country: Poland
facility: Uniwersyteckie Centrum Kliniczne im. prof. K. Gibińskiego w Katowicach
city: Katowice
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Nr 1 im. Prof. Stanisława Szyszko Śląskiego Uniwersytetu
city: Lublin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny
city: Wrocław
country: Poland
facility: WSS im Gromkowskiego
city: Banská Bystrica
country: Slovakia
facility: II. Neurologická klinika SZU Fakultná nemocnica s poliklinikou F. D. Roosevelta Banská Bystrica
city: Bratislava
country: Slovakia
facility: SlovakiaNeurologická klinika SZU a UNB Nemocnica Ružinov Univerzitná nemocnica Bratislava
city: Levoča
country: Slovakia
facility: Neurologické oddelenie Nemocnica Agel Levoča a.s.
city: Trnava
country: Slovakia
facility: Neurologické oddelenie Fakultná nemocnica
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Santa Creu i Sant Pau, Institut de Recerca Biomedica Sant Pau
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos Madrid.
city: Málaga
country: Spain
facility: Hospital Regional Universitario de Málaga
city: Geneva
country: Switzerland
facility: Hôpitaux Universitaires de Genève (HUG)
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois (CHUV)
city: Cardiff
country: United Kingdom
facility: Cardiff and Vale UHB
city: London
country: United Kingdom
facility: King's College Hospital, Department of Neurology
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation Trust
Study officials:
References: