Super-Refractory Status Epilepticus
Conditions
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).
Interventions
DRUGSAGE-547
DRUGPlacebo
Placebo
Sponsors
Supernus Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects two (2) years of age and older * Subjects who have: * Failed to respond to the administration of at least one first-line agent (e.g., benzodiazepine or other emergent initial anti-epileptic drug \[AED\] 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
* Subjects with SRSE due to anoxic/hypoxic encephalopathy with highly malignant/ malignant EEG features * Children (subjects aged less than 17 years) with an encephalopathy due to a rapidly progressing underlying neurological disorder * Subjects who have any of the following: 1. a glomerular filtration rate (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®); 2. severe cardiogenic or vasodilatory shock requiring two or more pressors that is not related to third-line agent use; 3. fulminant hepatic failure; 4. 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. * Subjects who are being administered more than three third-line agents concomitantly or in whom the qualifying wean cannot be completed per protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Able to be Weaned Off All Third-Line Agents Prior to End of Double-Blind SAGE-547 or Placebo Infusion, and Remain Off All Third-Line Agents for ≥ 24 Hours Following the End of SAGE-547 or Placebo Infusion | 7 days | Third-line agents were anesthetic agents that were administered in order to reach a seizure or burst suppression electroencephalogram (EEG) pattern. For this study, third-line agents were defined as continuous intravenous infusions of pentobarbital/thiopental, midazolam, propofol, and ketamine at maintenance doses alone or in combination sufficient to produce a burst or seizure suppression pattern on the EEG. A responder was a participant who was able to be weaned off all third-line agents prior to the end of the SAGE-547 or placebo infusion and remain off all third-line agents for \>=24 hours after the end of the study drug infusion. The primary analysis was a comparison between SAGE-547 and placebo of the proportion of responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Able to be Weaned Off All Third-line Agents Before the End of the First SAGE-547 or Placebo Infusion | Day 6 | Third-line agents were anesthetic agents that were administered in order to reach a seizure or burst suppression EEG pattern. For this study, third-line agents were defined as continuous intravenous infusions of pentobarbital/thiopental, midazolam, propofol, and ketamine at maintenance doses alone or in combination sufficient to produce a burst or seizure suppression pattern on the EEG. |
| Time Between the Secondary Outcome Measure Response and the Re-institution of Any Third-line Agent for Seizure or Burst Suppression | Up to 21 days | Third-line agents were anesthetic agents that were administered in order to reach a seizure or burst suppression EEG pattern. For this study, third-line agents were defined as continuous intravenous infusions of pentobarbital/thiopental, midazolam, propofol, and ketamine at maintenance doses alone or in combination sufficient to produce a burst or seizure suppression pattern on the EEG. |
| Change in Clinical Global Impression Scale (CGI) | Up to 21 days | The CGI scale was used to integrate several sources of information into a single rating of a participant's condition. The CGI was rated on a 7-point scale, from a minimum of 0 to a maximum of 7, where 0 = Not assessed; 1 = Normal, not at all ill; 2 = Borderline physically ill; 3 = Mildly ill; 4 = Moderately ill; 5 = Markedly ill; 6 = Severely ill; 7 = Among the most extremely ill participants. A negative change from baseline indicates improvement. A positive change from baseline indicates worsening. Here, study visits followed by R indicate the Open-label Treatment Period. |
| Time Between the Primary Outcome Response and the Re-institution of Any Third-line Agent for Seizure or Burst Suppression | Up to 21 days | Third-line agents were anesthetic agents that were administered in order to reach a seizure or burst suppression EEG pattern. For this study, third-line agents were defined as continuous intravenous infusions of pentobarbital/thiopental, midazolam, propofol, and ketamine at maintenance doses alone or in combination sufficient to produce a burst or seizure suppression pattern on the EEG. A responder was a participant who was able to be weaned off all third-line agents prior to the end of the SAGE-547 or placebo infusion and remain off all third-line agents for \>=24 hours after the end of the study drug infusion. The primary analysis was a comparison between SAGE-547 and placebo of the proportion of responders. |
| Number of Days After the End of the First Study Drug Infusion Without Seizures (Convulsive and Non-convulsive), up to Visit 12 | Up to 21 days | Here, study visits followed by R indicate the Open-label Treatment Period. |
| Number of Separate Episodes of Status Epilepticus Up to Visit 12 | Up to 21 days | Here, study visits followed by R indicate the Open-label Treatment Period. |
| Number of Participants With a New Diagnosis of Epilepsy After Visit 11 | Up to 21 days | Here, study visits followed by R indicate the Open-label Treatment Period. |
| Number of Days After the End of the First Study Drug Infusion Without Status Epilepticus, Up to Visit 12 | Up to 21 days | Here, study visits followed by R indicate the Open-label Treatment Period. |
Countries
Austria, Canada, Denmark, Estonia, Finland, France, Germany, Hungary, Israel, Italy, Netherlands, Serbia, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 122 investigative sites in Canada, United States, Austria, Denmark, Estonia, Finland, France, Germany, Israel, Italy, Serbia, Spain and United Kingdom from 31 July 2015 to 11 August 2017.
Pre-assignment details
Participants 2 years of age and older with Super-Refractory Status Epilepticus were eligible. One participant in the placebo group was erroneously given SAGE-547 and was, therefore, included in the SAGE- 547 group.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo was administered over the course of 6 days, beginning with a 1-hour dose rate equivalent to 300 micrograms per kilogram per hour (μg/kg/h) of the active arm loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment), which included a step-wise taper during the last 24 hours of treatment. | 65 |
| SAGE-547 SAGE-547 Injection was administered over the course of 6 days, beginning with a 1-hour 300 μg/kg/h loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment) or 150 μg/kg/h (open-label treatment), both of which included a step-wise taper during the last 24 hours of treatment. Eligible participants, who did not respond to blinded study treatment, were allowed to enter an Open-label Treatment Period of identical duration. | 67 |
| Total | 132 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Completed Visits but Discontinued Drug | 2 | 1 |
| Overall Study | Died in Double-Blind Treatment Period | 11 | 11 |
| Overall Study | Left Study Site for Rehabilitation | 0 | 1 |
| Overall Study | Transferred Away from Study Site | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | SAGE-547 | Total |
|---|---|---|---|
| Age, Continuous | 37.8 years STANDARD_DEVIATION 22.69 | 41.3 years STANDARD_DEVIATION 23.89 | 39.6 years STANDARD_DEVIATION 23.29 |
| Race/Ethnicity, Customized Asian | 3 Participants | 5 Participants | 8 Participants |
| Race/Ethnicity, Customized Black | 14 Participants | 13 Participants | 27 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 10 Participants | 6 Participants | 16 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 55 Participants | 61 Participants | 116 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 4 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 47 Participants | 45 Participants | 92 Participants |
| Sex: Female, Male Female | 30 Participants | 35 Participants | 65 Participants |
| Sex: Female, Male Male | 35 Participants | 32 Participants | 67 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 12 / 65 | 17 / 67 |
| other Total, other adverse events | 58 / 65 | 60 / 67 |
| serious Total, serious adverse events | 22 / 65 | 27 / 67 |
Outcome results
Primary
Number of Participants Able to be Weaned Off All Third-Line Agents Prior to End of Double-Blind SAGE-547 or Placebo Infusion, and Remain Off All Third-Line Agents for ≥ 24 Hours Following the End of SAGE-547 or Placebo Infusion
Third-line agents were anesthetic agents that were administered in order to reach a seizure or burst suppression electroencephalogram (EEG) pattern. For this study, third-line agents were defined as continuous intravenous infusions of pentobarbital/thiopental, midazolam, propofol, and ketamine at maintenance doses alone or in combination sufficient to produce a burst or seizure suppression pattern on the EEG. A responder was a participant who was able to be weaned off all third-line agents prior to the end of the SAGE-547 or placebo infusion and remain off all third-line agents for \>=24 hours after the end of the study drug infusion. The primary analysis was a comparison between SAGE-547 and placebo of the proportion of responders.
Time frame: 7 days
Population: The Intent-to-Treat Analysis Set included all participants who had an infusion of blinded study drug initiated.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Able to be Weaned Off All Third-Line Agents Prior to End of Double-Blind SAGE-547 or Placebo Infusion, and Remain Off All Third-Line Agents for ≥ 24 Hours Following the End of SAGE-547 or Placebo Infusion | 28 Participants |
| SAGE-547 | Number of Participants Able to be Weaned Off All Third-Line Agents Prior to End of Double-Blind SAGE-547 or Placebo Infusion, and Remain Off All Third-Line Agents for ≥ 24 Hours Following the End of SAGE-547 or Placebo Infusion | 29 Participants |
p-value: 0.87895% CI: [0.527, 2.118]Regression, Logistic
Secondary
Change in Clinical Global Impression Scale (CGI)
The CGI scale was used to integrate several sources of information into a single rating of a participant's condition. The CGI was rated on a 7-point scale, from a minimum of 0 to a maximum of 7, where 0 = Not assessed; 1 = Normal, not at all ill; 2 = Borderline physically ill; 3 = Mildly ill; 4 = Moderately ill; 5 = Markedly ill; 6 = Severely ill; 7 = Among the most extremely ill participants. A negative change from baseline indicates improvement. A positive change from baseline indicates worsening. Here, study visits followed by R indicate the Open-label Treatment Period.
Time frame: Up to 21 days
Population: The Intent-to-Treat Analysis Set included all participants who had an infusion of blinded study drug initiated. Here, number of participants analyzed (N) indicates participants with available data at each time point for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Clinical Global Impression Scale (CGI) | Visit 12 | -1.0 units on scale | Standard Deviation 1.42 |
| Placebo | Change in Clinical Global Impression Scale (CGI) | Baseline | 6.0 units on scale | Standard Deviation 0.89 |
| Placebo | Change in Clinical Global Impression Scale (CGI) | Visit 12R | -0.7 units on scale | Standard Deviation 1.36 |
| SAGE-547 | Change in Clinical Global Impression Scale (CGI) | Baseline | 5.9 units on scale | Standard Deviation 1.31 |
| SAGE-547 | Change in Clinical Global Impression Scale (CGI) | Visit 12 | -0.6 units on scale | Standard Deviation 1.91 |
| SAGE-547 | Change in Clinical Global Impression Scale (CGI) | Visit 12R | -0.5 units on scale | Standard Deviation 1.19 |
Secondary
Number of Days After the End of the First Study Drug Infusion Without Seizures (Convulsive and Non-convulsive), up to Visit 12
Here, study visits followed by R indicate the Open-label Treatment Period.
Time frame: Up to 21 days
Population: The Intent-to-Treat Analysis Set included all participants who had an infusion of blinded study drug initiated. Here, number of participants analyzed (N) indicates participants with available data at each time point for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Number of Days After the End of the First Study Drug Infusion Without Seizures (Convulsive and Non-convulsive), up to Visit 12 | Visit 12 | 8.22 days | Standard Deviation 7.289 |
| Placebo | Number of Days After the End of the First Study Drug Infusion Without Seizures (Convulsive and Non-convulsive), up to Visit 12 | Visit 12R | 7.52 days | Standard Deviation 7.054 |
| SAGE-547 | Number of Days After the End of the First Study Drug Infusion Without Seizures (Convulsive and Non-convulsive), up to Visit 12 | Visit 12 | 7.50 days | Standard Deviation 6.626 |
| SAGE-547 | Number of Days After the End of the First Study Drug Infusion Without Seizures (Convulsive and Non-convulsive), up to Visit 12 | Visit 12R | 6.08 days | Standard Deviation 5.932 |
p-value: 0.81795% CI: [0.539, 2.189]Regression, Cox
Secondary
Number of Days After the End of the First Study Drug Infusion Without Status Epilepticus, Up to Visit 12
Here, study visits followed by R indicate the Open-label Treatment Period.
Time frame: Up to 21 days
Population: The Intent-to-Treat Analysis Set included all participants who had an infusion of blinded study drug initiated. Here, number of participants analyzed (N) indicates participants with available data at each time point for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Number of Days After the End of the First Study Drug Infusion Without Status Epilepticus, Up to Visit 12 | Visit 12 | 10.05 days | Standard Deviation 6.738 |
| Placebo | Number of Days After the End of the First Study Drug Infusion Without Status Epilepticus, Up to Visit 12 | Visit 12R | 11.08 days | Standard Deviation 6.557 |
| SAGE-547 | Number of Days After the End of the First Study Drug Infusion Without Status Epilepticus, Up to Visit 12 | Visit 12 | 11.15 days | Standard Deviation 6.058 |
| SAGE-547 | Number of Days After the End of the First Study Drug Infusion Without Status Epilepticus, Up to Visit 12 | Visit 12R | 9.23 days | Standard Deviation 6.345 |
p-value: 0.33995% CI: [0.193, 1.763]Regression, Cox
Secondary
Number of Participants Able to be Weaned Off All Third-line Agents Before the End of the First SAGE-547 or Placebo Infusion
Third-line agents were anesthetic agents that were administered in order to reach a seizure or burst suppression EEG pattern. For this study, third-line agents were defined as continuous intravenous infusions of pentobarbital/thiopental, midazolam, propofol, and ketamine at maintenance doses alone or in combination sufficient to produce a burst or seizure suppression pattern on the EEG.
Time frame: Day 6
Population: The Intent-to-Treat Analysis Set included all participants who had an infusion of blinded study drug initiated.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Able to be Weaned Off All Third-line Agents Before the End of the First SAGE-547 or Placebo Infusion | 45 Participants |
| SAGE-547 | Number of Participants Able to be Weaned Off All Third-line Agents Before the End of the First SAGE-547 or Placebo Infusion | 38 Participants |
p-value: 0.19995% CI: [0.303, 1.282]Regression, Logistic
Secondary
Number of Participants With a New Diagnosis of Epilepsy After Visit 11
Here, study visits followed by R indicate the Open-label Treatment Period.
Time frame: Up to 21 days
Population: The Intent-to-Treat Analysis Set included all participants who had an infusion of blinded study drug initiated. Here, number of participants analyzed (N) indicates participants with available data at each time point for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With a New Diagnosis of Epilepsy After Visit 11 | Visit 12R | 5 Participants |
| Placebo | Number of Participants With a New Diagnosis of Epilepsy After Visit 11 | Visit 12 | 0 Participants |
| SAGE-547 | Number of Participants With a New Diagnosis of Epilepsy After Visit 11 | Visit 12R | 3 Participants |
| SAGE-547 | Number of Participants With a New Diagnosis of Epilepsy After Visit 11 | Visit 12 | 5 Participants |
Secondary
Number of Separate Episodes of Status Epilepticus Up to Visit 12
Here, study visits followed by R indicate the Open-label Treatment Period.
Time frame: Up to 21 days
Population: The Intent-to-Treat Analysis Set included all participants who had an infusion of blinded study drug initiated. Here, number of participants analyzed (N) indicates participants with available data at each time point for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Number of Separate Episodes of Status Epilepticus Up to Visit 12 | Visit 12 | 1.3 episodes | Standard Deviation 0.5 |
| Placebo | Number of Separate Episodes of Status Epilepticus Up to Visit 12 | Visit 12R | 2.2 episodes | Standard Deviation 2.17 |
| SAGE-547 | Number of Separate Episodes of Status Epilepticus Up to Visit 12 | Visit 12 | 1.4 episodes | Standard Deviation 0.55 |
| SAGE-547 | Number of Separate Episodes of Status Epilepticus Up to Visit 12 | Visit 12R | 1.0 episodes | Standard Deviation 0 |
p-value: 0.56795% CI: [-0.9, 0.5]ANCOVA
Secondary
Time Between the Primary Outcome Response and the Re-institution of Any Third-line Agent for Seizure or Burst Suppression
Third-line agents were anesthetic agents that were administered in order to reach a seizure or burst suppression EEG pattern. For this study, third-line agents were defined as continuous intravenous infusions of pentobarbital/thiopental, midazolam, propofol, and ketamine at maintenance doses alone or in combination sufficient to produce a burst or seizure suppression pattern on the EEG. A responder was a participant who was able to be weaned off all third-line agents prior to the end of the SAGE-547 or placebo infusion and remain off all third-line agents for \>=24 hours after the end of the study drug infusion. The primary analysis was a comparison between SAGE-547 and placebo of the proportion of responders.
Time frame: Up to 21 days
Population: The Intent-to-Treat Analysis Set included all participants who had an infusion of blinded study drug initiated. Here, overall number of participants analyzed (N) indicates participants analyzed for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time Between the Primary Outcome Response and the Re-institution of Any Third-line Agent for Seizure or Burst Suppression | 13.500 days |
| SAGE-547 | Time Between the Primary Outcome Response and the Re-institution of Any Third-line Agent for Seizure or Burst Suppression | 14.000 days |
p-value: 0.63695% CI: [0.222, 2.507]Regression, Cox
Secondary
Time Between the Secondary Outcome Measure Response and the Re-institution of Any Third-line Agent for Seizure or Burst Suppression
Third-line agents were anesthetic agents that were administered in order to reach a seizure or burst suppression EEG pattern. For this study, third-line agents were defined as continuous intravenous infusions of pentobarbital/thiopental, midazolam, propofol, and ketamine at maintenance doses alone or in combination sufficient to produce a burst or seizure suppression pattern on the EEG.
Time frame: Up to 21 days
Population: The Intent-to-Treat Analysis Set included all participants who had an infusion of blinded study drug initiated. Here, overall number of participants analyzed (N) indicates participants analyzed for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time Between the Secondary Outcome Measure Response and the Re-institution of Any Third-line Agent for Seizure or Burst Suppression | 7.000 days |
| SAGE-547 | Time Between the Secondary Outcome Measure Response and the Re-institution of Any Third-line Agent for Seizure or Burst Suppression | 15.000 days |
p-value: 0.32895% CI: [0.318, 1.466]Regression, Cox