SAGE 547-SSE-301

Principal Investigator: Matthew  Sweney
Keywords: SAGE-547 , Epilepticus Department: Pediatric Administration
IRB Number: 00083538 Co Investigator:  
Specialty: Pediatric Neurology, Pediatric Neurology
Sub Specialties: Pediatric Epilepsy,
Recruitment Status: Recruiting

Contact Information

Priscilla  Cowan
priscilla.rosen@hsc.utah.edu
8012133401

Brief Summary

This is a randomized, double-blind, placebo-controlled trial, designed to evaluate the efficacy and safety of SAGE-547 administered as a continuous intravenous infusion to subjects in Super-refractory status epilepticus (SRSE).

Study Objectives

Primary objective:

To determine the response to a 144-hour (6 day) continuous intravenous infusion of SAGE-547 compared to placebo administered to support the weaning of all third-line agents in adult and pediatric subjects with SRSE, and for the response to endure at least 24 hours after the end of the SAGE-547 or placebo infusion (primary response).

Secondary objectives:
  1. To compare between SAGE-547 and placebo the time between meeting the primary response endpoint and the re-institution of any third-line agent for seizure or burst suppression up to Visit 12;
  2. To compare between SAGE-547 and placebo secondary response, defined as success of weaning the subject off all third-line agents before the end of the first infusion of SAGE-547 or placebo;
  3. To compare between SAGE-547 and placebo the time between meeting the secondary response endpoint, defined in (2) above, and the re-institution of any third-line agent for seizure or burst suppression up to Visit 12;
  4.  To compare the change in the Clinical Global Impression scale (CGI) between SAGE-547 and placebo up to Visit 12;
  5.  To determine the number of days after the end of the first infusion of study drug that the subject does not have status epilepticus, up to Visit 12;
  6. To determine the number of days after the end of the first infusion of study drug that the subject does not have seizures (convulsive and non-convulsive) up to Visit 12;
  7. To determine the number of separate episodes of status epilepticus occurring up to Visit 12;
  8. To determine the proportion of subjects with a new diagnosis of epilepsy after Visit 11

 Safety objectives:

To determine the safety and tolerability of a 144-hour infusion of SAGE-547 in four groups of subjects with SRSE (one infusion of SAGE-547, one infusion of placebo, one infusion of placebo followed by one infusion of SAGE-547, and two infusions of SAGE-547) via:
a. Adverse events and medications;
b. Laboratory testing (hematology, serum chemistry, and urinalysis);
c. Vital signs (blood pressure, heart rate, temperature, and weight);
d. ECG parameters;
e. Mortality.
 
Other objectives:
  1. To evaluate the impact of retreatment with a higher dose SAGE-547 infusion in subjects who initially fail to respond to double blind study medication;
  2. To evaluate the pharmacokinetics of SAGE-547, and present Captisol® and identified SAGE-547 metabolite plasma concentrations;
  3. To correlate QT/QTc interval with plasma concentrations of SAGE-547;
  4. To determine the number of days in the ICU, number of days in hospital, discharge destination from the ICU, discharge destination from the hospital, dischargeability criteria, resource use for subjects discharged from hospital before Visit 12/12R;
  5. To evaluate the Full Outline of UnResponsiveness (FOUR) Score;
  6. To evaluate the Glasgow Outcome Score (GOS);
  7. To evaluate the Supervision Rating Scale (SRS);
  8. To evaluate the Modified Rankin Score (mRS) (age ≥17 years).

 

Inclusion Criteria

Inclusion Criteria
The following inclusion criteria must be met for individuals to be eligible for the trial.
  1. Subjects two (2) years of age and older.
  2. Subjects who have:
• Failed to respond to the administration of at least one first-line agent (e.g., benzodiazepine or other emergent initial AED treatment), according to institution standard of care, and;
• Failed to respond to at least one second-line agent (e.g., phenytoin, fosphenytoin, valproate, phenobarbital, levetiracetam or other urgent control AED), according to institution standard of care, and;
• Not previously been administered a third-line agent but have been admitted to an intensive care unit with the intent of administering at least one third-line agent for at least 24 hours; or who have previously failed zero, one or more wean attempts from third-line agents and are now on continuous intravenous infusions of one or more third-line agent and in an EEG burst or seizure suppression pattern; or who have previously failed one or more wean attempts from third-line agents and are now either not on a continuous intravenous infusion of at least one third-line agent or are on a continuous intravenous infusion of one or more third-line agent but not in an EEG burst or seizure suppression pattern.

Exclusion Criteria

Exclusion Criteria
None of the following exclusion criteria can be met for individuals to be eligible for the trial.
1. Subjects who are pregnant.
2. Subjects with a known allergy to progesterone or allopregnanolone.
3. Subjects with SRSE due to anoxic/hypoxic encephalopathy with highly malignant/malignant EEG features (Westhall, Rosetti et al. 2016).
4. Children (subjects aged less than 17 years) with an encephalopathy due to a rapidly progressing underlying neurological disorder.
5. Subjects who have any of the following:
a. a GFR low enough to warrant dialysis but for whatever reason, dialysis is not planned or non-continuous dialysis planned (that would not adequately remove Captisol®);
b. severe cardiogenic or vasodilatory shock requiring two or more pressors that is not related to third-line agent use;
c. fulminant hepatic failure;
d. no reasonable expectation of recovery (for instance, a likely outcome is persistent vegetative state) or life-expectancy, in the experience of the investigator, is less than 30 days;
6. Subjects who are being administered more than three third-line agents concomitantly or in whom the qualifying wean cannot be completed within 24 hours, or who are being administered a third-line agent for other indications such as management of raised intra-cranial pressure that would preclude weaning according to this protocol.
7. Subjects with a living will that does not allow heroic measures.
8. Subjects who have been exposed to an investigational medication or device within 30 days; the exception to this is that participation in the Established Status Epilepticus Treatment Trial or ESETT within 30 days of screening for the 547-SSE-301 trial is allowed.
9. Subjects who have been treated or randomized in this trial or any other trial employing SAGE-547 previously (i.e., subjects may not have received study drug/placebo and then re-enroll).