E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
SUPER-REFRACTORY STATUS EPILEPTICUS (SRSE) |
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E.1.1.1 | Medical condition in easily understood language |
STATUS EPILEPTICUS NOT RESPONDING TO ANY OF THE CONVENTIONAL THERAPY REGIMEN |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10041962 |
E.1.2 | Term | Status epilepticus |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 cessation of the SAGE-547 or placebo infusion (primary response). |
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E.2.2 | Secondary objectives of the trial |
To compare between SAGE-547 and placebo: time between meeting primary response endpoint and re-institution of any third-line agent for seizure or burst suppression up to V12; secondary response, (success of weaning the subject off all third-line agents before end of the first infusion; time between meeting the secondary response endpoint and re-institution of any third-line agent for seizure or burst suppression up to V12; Change in the Clinical Global Impression scale up to V12; number of days after the end of the first infusion of study drug that the subject does not have status epilepticus, up to V12; number of days after end of the first infusion of study drug that the subject does not have seizures (convulsive and non-convulsive) up to V12; number of separate episodes of status epilepticus occurring up to V12; the proportion of subjects with a new diagnosis of epilepsy after V11. To determine safety and tolerability of a 144-hour infusion of SAGE-547. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenomic sub-study. Included in the main study protocol version amendment 4 dated 29 August 2016.
The objective of this research is to collect and store blood sample for possible DNA extraction and exploratory research into how genes or specific genetic variation may influence response (i.e. distribution, safety, tolerability, and efficacy) to SAGE-547. |
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E.3 | Principal inclusion criteria |
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 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 |
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E.4 | Principal exclusion criteria |
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 GFR low enough to warrant dialysis but for whatever reason, dialysis that would adequately remove Captisol® is not planned; -severe cardiogenic or vasodilatory shock requiring two or more pressors that is not related to third-line agent use; -fulminant hepatic failure; -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 for whom the qualifying wean cannot be completed within 24 hours or who are being administered a third-line agent for indications such as raised intra-cranial pressure that would preclude weaning according to this protocol. 7. Subjects with a living will that does not allow heroic measure. 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). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Success or failure, with success defined as weaning the subject off all third-line agents before completion of the first blinded infusion of SAGE-547 or placebo, and not having to re-institute any third-line agent for seizure or burst suppression during the 24 hours after the end of the first infusion of SAGE-547 or placebo, and concurrent signs of physiologic brain activity as determined by EEG (primary response).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
24 hours after the end of study drug infusion. |
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E.5.2 | Secondary end point(s) |
1. 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. Secondary response, defined as success of weaning the subject off all third-line agents before the end of the first SAGE-547 or placebo infusion; 3. 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. The assessment of clinical status as measured by change in the CGI from Visit 1 (Screening) and to Visit 12; 5. The number of days after the end of the first study drug infusion that the subject does not have status epilepticus, up to Visit 12; 6. The number of days after the end of the first study drug infusion that the subject does not have seizures (convulsive and non-convulsive) up to Visit 12; 7. The number of separate episodes of status epilepticus occurring up to Visit 12; 8. The proportion of subjects with a new diagnosis of epilepsy after Visit 11.
Safety endpoints: 1.Adverse events and medications; 2.Laboratory testing (hematology, serum chemistry, and urinalysis); 3.Vital signs (blood pressure, heart rate, temperature, and weight); 4.ECG parameters; 5.Mortality.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy: up to visit 12 or after visit 11 for end-point # 8. Safety: AEs and medications: V1-V12 ECG and vital signs: V1, V3-V10 Lab tests: V1, V3, V4, V6, V8, V10,V11 Mortality: V12
Retreatment period: AE and medications: V3R-V12R ECG and vital signs: V3R-V10R Lab tests: V3R, V4R, V6R, V8R, V10R, V11R Mortality: V12R |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Canada |
Denmark |
Estonia |
Finland |
France |
Germany |
Hungary |
Israel |
Italy |
Netherlands |
Serbia |
Spain |
Sweden |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |