Clinical trial NCT02052739: Study to Evaluate SAGE-547 Injection as Adjunctive Therapy for the Treatment of Super-Refractory Status Epilepticus
Official title: An Open-Label Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of SAGE-547 Injection as Adjunctive Therapy for the Treatment of Super-Refractory Status Epilepticus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Super-refractory Status Epilepticus
Keywords: Status Epilepticus
Refractory status epilepticus
Super-refractory status epilepticus
SAGE-547
SAGE
Sage Therapeutics
Lead sponsor: Sage Therapeutics
Sponsor class: INDUSTRY
First posted: 2014-02-03
Enrollment: 25
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety and tolerability of SAGE-547 in participants in super-refractory status epilepticus (SRSE).

Detailed description: This is an open-label study consisting of a screening period (1 day), 4-day treatment period (96 hours) followed by a 1-day dose taper period (24 hours), a 2-day acute follow-up period, and a 3 week extended follow-up period.

On Day 1 of treatment SRSE participants under seizure suppression or burst-suppression with a continuous intravenous (IV) anti-epileptic drug (AED) (third-line agent) were given a 1-hour IV loading infusion of SAGE-547 followed by a maintenance infusion. After 48 hours of SAGE-547 treatment, the continuous IV AED (third-line agent) was weaned while continuing SAGE-547 at the maintenance infusion for the remainder of the treatment period. After 96 hours (4 days) of therapy with SAGE-547, the dose was to be tapered and discontinued over 24 hours.

The participants would have routine continuous electroencephalogram (EEG) monitoring during the screening period, and continuing until 48 hours after SAGE-547 treatment had completed. Participants would then have follow-up examinations weekly for the next 3 weeks (Days 8, 15, 22, and 29), during which safety and functional assessments would be obtained. Apart from treatment with SAGE-547, all participants would receive the standard of care for adults in SRSE along with ongoing treatment for all underlying medical conditions.

Eligibility criteria: Inclusion Criteria:

* Participants 2 years of age and older.
* Participants with an EEG-confirmed SRSE diagnosis under concomitant therapy with a continuous IV AED (third-line agent) for ≥ 24 hours. For this study, SRSE is defined by the following criteria and in accordance with those used at major epilepsy treatment centers:

  * Failure 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
  * Failure 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
  * Presence of one or more breakthrough seizures \> 6 hours after initiation of the continuous IV AED/third-line agent (e.g., pentobarbital, midazolam, propofol).

Exclusion Criteria:

* Participants with SRSE due to anoxic/hypoxic encephalopathy, children (participants aged less than 18 years) with an encephalopathy due to an underlying progressive neurological disorder.
* Participants with clinically significant electrocardiogram abnormalities.
* Participants with a significant medical or surgical condition that may compromise vital organ systems, or other conditions that would place the participants at increased risk such as dialysis or acute respiratory distress syndrome, severe cardiogenic or vasodilatory shock requiring 2 or more pressors, fulminant hepatic failure, etc.
* Participants who are receiving a continuous IV AED (third-line agent) for seizure suppression or burst-suppression that would require greater than 24 hours to wean.

Primary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Up to Day 29
measure: Change From Baseline (CFB) in National Institutes of Health Stroke Scale (NIH-SS) Total Score
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Vital Sign Parameter: Body Weight
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Vital Sign Parameter: Heart Rate
timeFrame: Baseline (Screening) to infusion at 0-24 hours: Loading-predose and at 15,30,45 minutes;1,2,4,8 and 24 hour;25-48: 48 hour;49-72:72 hours;73-96: 96 hour;97-120:120 hours;Acute follow-up at 121-144,145-168 hours; Extended Follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Vital Sign Parameter: Blood Pressure - SBP and DBP
timeFrame: Baseline (Screening) to infusion at 0-24 hours:Loading-predose and at 15,30,45 minutes;1,2,4,8 and 24 hour;25-48: 48 hour;49-72: 72 hour;73-96: 96 hour;97-120:120 hour;Acute follow-up at 121-144,145-168 hours;Extended follow-up at Days 8,15,22 and 29
measure: Change From Baseline in Vital Sign Parameter: Respiratory Rate
timeFrame: Baseline (Screening) to infusion at 0-24 hours:Loading-predose and at 15,30,45 minutes;1,2,4,8 and 24 hour;25-48: 48 hour;49-72:72 hours;73-96: 96 hour;97-120:120 hours;Acute follow-up at 121-144,145-168 hours;Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Vital Sign Parameter: Body Temperature
timeFrame: Baseline (Screening) to infusion at 0-24 hours: Loading-predose and at 15,30,45 minutes;1,2,4,8 and 24 hour;25-48: 48 hour;49-72:72 hours;73-96: 96 hour;97-120:120 hours;Acute follow-up at 121-144,145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Vital Sign Parameter: Oxygen Saturation
timeFrame: Baseline (Screening) to infusion at 0-24 hours: Loading-predose and at 15,30,45 minutes;1,2,4,8 and 24 hour;25-48: 48 hour;49-72:72 hours;73-96: 96 hour;97-120:120 hours;Acute follow-up at 121-144,145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Serum Chemistry Parameter: Alanine Aminotransferase Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Serum Chemistry Parameter: Albumin Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Serum Chemistry Parameter: Aspartate Aminotransferase Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Serum Chemistry Parameter: Bicarbonate Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Serum Chemistry Parameter: Bilirubin Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Serum Chemistry Parameter: Blood Urea Nitrogen Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Serum Chemistry Parameter: Calcium Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Serum Chemistry Parameter: Chloride Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Serum Chemistry Parameter: Creatine Kinase Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Serum Chemistry Parameter: Creatinine Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Serum Chemistry Parameter: Glucose Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Serum Chemistry Parameter: Lipase Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Serum Chemistry Parameter: Magnesium Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Serum Chemistry Parameter: Potassium Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Serum Chemistry Parameter: Protein Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Serum Chemistry Parameter: Sodium Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Hematology Parameter: Basophil Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Hematology Parameter: Basophils to Leukocytes Ratio Reported in Percentage of Cells
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Hematology Parameter: Eosinophil Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Hematology Parameter: Eosinophils to Leukocytes Ratio Reported in Percentage of Cells
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin Concentration Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Hematology Parameter: Erythrocyte Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Hematology Parameter: Hematocrit Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Hematology Parameter: Hemoglobin Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Hematology Parameter: Leukocyte Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Hematology Parameter: Lymphocyte Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Hematology Parameter: Lymphocytes to Leukocytes Ratio Reported in Percentage of Cells
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Hematology Parameter: Monocyte Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Hematology Parameter: Monocytes to Leukocytes Ratio Reported in Percentage of Cells
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Hematology Parameter: Neutrophil Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Hematology Parameter: Neutrophils to Leukocytes Ratio Reported in Percentage of Cells
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Hematology Parameter: Platelet Levels
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Electrocardiogram (ECG) Parameter: Heart Rate
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Electrocardiogram (ECG) Parameters: PR Interval, QRS Interval, QT Interval and QTc Interval
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Number of Participants With Prior Anti-epileptic Drugs (AEDs) and Pressors Usage
timeFrame: Up to Day 29
Secondary outcomes:
measure: Number of Participants With Relapse - Re-Initiation of Third-Line Agent
timeFrame: Up to Day 29
measure: Number of Participants With Treatment Response (Treatment Responders)
timeFrame: Up to 96 hours
measure: Duration of Response
timeFrame: Up to Day 29
measure: Maximum Plasma Concentration (Cmax) of SAGE-547
timeFrame: Pre-dose (0 hours), 1, 2, 4, 8, 24, 48, 72, 96, 104, 112, 120 and 144 hours post-dose
measure: Time to Attain Maximum Observed Plasma Concentration (Tmax) of SAGE-547
timeFrame: Pre-dose (0 hours), 1, 2, 4, 8, 24, 48, 72, 96, 104, 112, 120 and 144 hours post-dose
measure: Areas Under the Plasma SAGE-547 Concentration Time Curves From the Start of the Infusion Until the Time to the Last Sample (AUClast)
timeFrame: Pre-dose (0 hours), 1, 2, 4, 8, 24, 48, 72, 96, 104, 112, 120 and 144 hours post-dose
measure: Area Under the Plasma SAGE-547 Concentration-Time Curve in a 24 Hour Period (AUC24)
timeFrame: Pre-dose (0 hours), 1, 2, 4, 8 and 24 hours post-dose
measure: Area Under the Plasma SAGE-547 Concentration-Time Curve (AUC1-96)
timeFrame: Pre-dose (0 hours), 1, 2, 4, 8, 24, 48, 72 and 96 hours post-dose
measure: Average Plasma Concentration (Cav) of SAGE-547
timeFrame: Pre-dose (0 hours), 1, 2, 4, 8, 24, 48, 72 and 96 hours post-dose
measure: Plasma Clearance (CL) of SAGE-547
timeFrame: Pre-dose (0 hours), 1, 2, 4, 8, 24, 48, 72, 96, 104, 112, 120 and 144 hours post-dose
measure: Change From Baseline in Modified Rankin Scale (mRS-9Q) Scores
timeFrame: Baseline (Screening) to Infusion at 49-72 hour, 73-96 hour; Extended follow-up at Day 8, 15, 22 and 29
measure: Change From Baseline in Clinical Global Impression: Severity Scale (CGI-S)
timeFrame: Baseline (Screening), Extended follow-up at Days 8, 15, 22, and 29
measure: Clinical Global Impression: Improvement Scale (CGI-I) Scores
timeFrame: Infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Glasgow Coma Scale (GCS) Scores
timeFrame: Baseline (Screening) to infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Change From Baseline in Richmond Agitation Sedation Scale (RASS) Score
timeFrame: Baseline (Screening) to Infusion at 0-24, 25-48, 49-72, 73-96, 97-120 hours; Acute follow-up at 121-144, 145-168 hours; Extended follow-up at Days 8, 15, 22 and 29
measure: Number of Participants Who Survived
timeFrame: Up to Day 29
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Sage Investigational Site
state: Alabama
city: Sarasota
country: United States
facility: Sage Investigational Site
state: Florida
city: Chicago
country: United States
facility: Sage Investigational Site
state: Illinois
city: Wichita
country: United States
facility: Sage Investigational Site
state: Kansas
city: New Orleans
country: United States
facility: Sage Investigational Site
state: Louisiana
city: Boston
country: United States
facility: Sage Investigational Site
state: Massachusetts
city: Boston
country: United States
facility: Sage Investigational Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: Sage Investigational Site
state: Michigan
city: Detroit
country: United States
facility: Sage Investigational Site
state: Michigan
city: New York
country: United States
facility: Sage Investigational Site
state: New York
city: Rochester
country: United States
facility: Sage Investigational Site
state: New York
city: Durham
country: United States
facility: Sage Investigational Site
state: North Carolina
city: Winston-Salem
country: United States
facility: Sage Investigational Site
state: North Carolina
city: Philadelphia
country: United States
facility: Sage Investigational Site
state: Pennsylvania
city: Nashville
country: United States
facility: Sage Investigational Site
state: Tennessee
city: Dallas
country: United States
facility: Sage Investigational Site
state: Texas
city: Temple
country: United States
facility: Sage Investigational Site
state: Texas
Study officials:
affiliation: Sage Therapeutics
name: Robert Lasser, MD, MBA
role: STUDY_CHAIR
References:
citation: Rosenthal ES, Claassen J, Wainwright MS, Husain AM, Vaitkevicius H, Raines S, Hoffmann E, Colquhoun H, Doherty JJ, Kanes SJ. Brexanolone as adjunctive therapy in super-refractory status epilepticus. Ann Neurol. 2017 Sep;82(3):342-352. doi: 10.1002/ana.25008. Epub 2017 Sep 11.