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 subjects with SRSE, and for the response to endure at…
ID
Source
Brief title
Condition
- Other condition
- Seizures (incl subtypes)
Synonym
Health condition
Epilepsy
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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).
Secondary outcome
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 reinstitution 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) 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.
Background summary
Epidemiology of SRSE
The incidence of SRSE is very poorly understood, mainly because the diagnostic
codes used for SE do not generally differentiate its nature as responding or
refractory to treatment. Based on the variable reporting of outcomes data, the
incident cases of SRSE could represent between one and two-thirds of the RSE
patients (Novy, Logroscino et al. 2010; Ferlisi and Shorvon 2012; Hocker,
Britton et al. 2013; Sutter, Marsch et al. 2013). More detailed epidemiology
studies are needed to better elucidate the proportion of RSE patients whose
condition becomes super-refractory. A recent review of ICU discharge data in
the USA suggests an annual incidence of approximately 35,000, based on patients
who required at least three days in the ICU for SE [Sage data on file].
Outcomes of SRSE
SE has varying degrees of mortality depending on the underlying etiologies. The
mortality rate of SRSE is estimated to be 30% to 50% using current standard of
care.
The causes of death from SE (and therefore SRSE) are heterogeneous, resulting
from neuronal cell death, complications of underlying medical conditions, or
adverse effects of the current standard treatments. Prognosis worsens and
mortality increases with longer duration of SE, i.e. with SE that develops into
RSE or SRSE (Neligan and Shorvon 2010), and with longer duration of
medically-induced coma (Ferlisi and Shorvon 2012). There is an obvious unmet
medical need to improve upon the current standard of care treatment regimens.
Morbidity is high and survivors have outcomes ranging from poor function to
vegetative state (Shorvon 2011). Approximately one third of patients with RSE
and SRSE will recover, but with chronic neurologic or other deficits (Neligan
and Shorvon 2010; Hocker, Britton et al. 2013). In all, it is estimated that
less than 25-30% of all SRSE patients have a favorable functional outcome.
Unmet Medical Need in Super-refractory Status Epilepticus
Treatment approaches for SRSE consist of diagnosis and treatment of underlying
medical conditions, adding and changing anti-seizure drugs, and repeated
attempts at weaning from IV anesthetic agents. Treatment of SRSE has three aims:
* to prevent excitotoxicity, which begins within 24 hours of SE onset;
* to prevent cerebral damage by initiating neuroprotective burst suppression;
* to prevent the complications of extended periods of anesthesia or
unconsciousness (Shorvon 2011).
Currently, there are no therapies that have been specifically approved for RSE
or SRSE. The primary drugs used to induce coma are continuously infused IV
anesthetics such as propofol, midazolam, or pentobarbital, known as third-line
agents. Use of these drugs to control SRSE has only been studied in small
retrospective reviews or small prospective studies without controls (Hocker,
Britton et al. 2013) therefore there is no agreement on which drug is optimal
nor on an optimal dosing regimen for the treatments that are used.
The most common adverse effect of the third-line agents is hemodynamic
instability; in addition, they are not universally effective, with breakthrough
seizures and withdrawal seizures requiring dose adjustments and changes in
third-line agent(s). The drug thought to be most effective in SRSE,
pentobarbital, is also associated with the most toxic adverse effect profile,
comprising decreased blood pressure and cardiorespiratory collapse (Claassen,
Hirsch et al. 2002). The ability to wean patients successfully off the
third-line agents as quickly as possible is therefore paramount, and an adjunct
to SRSE treatment that enhances the success of the third-line agents and
supports their successful weaning in a short timeframe would be an important
addition to the therapeutic armamentarium. Preliminary clinical data show that
SAGE-547 has been a successful adjunct to third-line therapy in this regard.
For more information refer to the study protocol paragraph 3 page 27.
Study objective
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 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.
Study design
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 SRSE.
Patients will follow one of three paths to entry to the study.
1)The first path is for subjects who are admitted to the intensive care unit at
the study site in status epilepticus, having failed first- and second-line
therapies, with a view to initiating burst or seizure suppression with a
third-line agent.
2)The second path to entry to the study is for subjects who have either been
transferred from another hospital or from within the study site institution and
who are already on a continuous intravenous infusion of thirdline agent with a
burst or seizure suppression pattern on the EEG. These subjects may have had
one or more previous unsuccessful weans and may be on more than one third-line
agent.
3)The third path to entry to the study is for subjects who have either been
transferred from another hospital or from within the study site institution and
who arrive at the study site intensive care unit without a burst or seizure
suppression pattern on the EEG or not on a continuous infusion of at least one
third-line agent. These subjects may have had one or more previous unsuccessful
weans.
Once subjects are deemed to be failures of the QW, they must be randomized to
SAGE-547 or placebo in a 1:1 ratio and the blinded study drug infusion
commenced within eight hours of the investigator*s determination that they
failed the QW.
The randomized portion of the study will be blinded, with the two treatments
(SAGE-547 and placebo) being indistinguishable so that subjects, relatives,
nursing and medical staff, pharmacists and monitors will not be able to
ascertain which subject was allocated to which treatment.
For all subjects in the study, attempts will be made to wean the subject off
all third-line agents starting at hour (H) 49 of the blinded study treatment
infusion, with the aim of completing all weans by hour (H) 120 of the study
treatment infusion.
Those subjects who fail the primary endpoint, and require re-institution of a
third-line agent regimen before the end of the blinded study drug infusion or
within 24 hours of completing the blinded study drug infusion will be eligible
to receive an open-label infusion of SAGE-547 at a dose higher than that
administered in the blinded part of the study.
Intervention
Once subjects are deemed to be failures of the QW, they must be randomized and
the blinded study drug infusion commenced within six hours of the
investigator*s determination that they failed the QW.
Subjects will be randomized to SAGE-547 or placebo in a 1:1 ratio with 70
subjects to be randomized to SAGE-547 and 70 subjects to be randomized to
placebo.
For all subjects in the study, attempts will be made to wean the subject off
all third-line agents starting at hour (H) 49 of the blinded study treatment
infusion, with the aim of completing all weans by hour (H) 120 of the study
treatment infusion. Blinded study treatment infusion is a period 6 days
(144hrs).
Subjects who fail the primary endpoint, and require re-institution of a
third-line agent regimen before the end of the blinded study drug infusion or
within 24 hours of completing the blinded study drug infusion will be eligible
to receive an open-label infusion of SAGE-547 at a dose higher than that
administered in the blinded part of the study.
The same weaning process and study treatment infusion of a period of 6 days
(144hrs) will be applied.
Study burden and risks
There may or may not be a direct benefit to the patient from taking part in
this study. The possible benefits of SAGE-547 may include some level of seizure
control and the ability to help get the patient off the medications to control
their seizures that make him/her unconscious. However, there is no guarantee
that the patient will have any benefit. The information gained from the study
may benefit medical knowledge and other patients in the future.
Taking part in this study may involve some known risks, discomforts, or
inconvenience. There also may be risks that are unknown or unforeseeable.
Significant new findings that might affect the decision to continue the
participation in the study, will be provided to the subject/LAR.
A small number of healthy human patients have received allopregnanolone, the
most common side effects noted in these studies were:
* sleepiness or tiredness
* feelings of intoxication (being drunk)
* flushing (red in the face or neck)
* mild headache
Some of the less common side effects included:
* decreased eye movements
* impaired memory
SAGE-547 has been studied in one study with SRSE patients. Of the 20 patients
treated, there were side effects reported in three (3) patients which the study
doctor thought might be due to SAGE-547:
* One (1) patient had muscle weakness
* One (1) patient had increased platelets in the blood
* One (1) patient had elevated liver enzymes
There is always a chance that an unexpected or serious side effect may happen.
It is also possible to experience a serious allergic reaction which could
become life-threatening or fatal.
The standard anti-seizure medications, as well as the study medication will be
given intravenously throught a catheter, that may cause pain or discomfort.
There is also the risk of infection, bleeding and/or bruising at the insertion
site.
Blood Samples as well will be collected using a catheter; the amount collected
will be about 81 mL or 150 in case the retreatment is necessary. The patient
may have discomfort or pain when blood is collected, and may feel faint or pass
out if they are conscious at the time. There is a risk of infection, bleeding,
soreness, blood clots, tenderness, or bruising at the puncture site. The
patient may develop a small scar at the puncture site where multiple blood
samples are taken.
As part of standard of care, a urinary catheter will be placed during the time
the patient is unconscious. There is a risk of infection with the placement of
a catheter.
First Street 215
Cambridge MA 02142
US
First Street 215
Cambridge MA 02142
US
Listed location countries
Age
Inclusion criteria
1. Subjects 18 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.
Exclusion criteria
1. Subjects who are pregnant.
2. Subjects with a known allergy to progesterone or allopregnanolone or any excipients in SAGE-547.
3. Subjects with SRSE due to anoxic/hypoxic encephalopathy with highly malignant/malignant EEG features (Westhall, Rosetti et al. 2016).
4. Subjects who have any of the following: a. a GFR low enough to warrant dialysis but for whatever reason, dialysis that would adequately remove Captisol® is not planned; 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 opinion of the investigator, of less than 30 days;
5. 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.
6. Subjects with a living will that does not allow heroic measures.
7. 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.
8. 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).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-002142-31-NL |
| ClinicalTrials.gov | NCT02477618 |
| CCMO | NL54982.044.15 |