Clinical Trials Register

Summary
EudraCT Number:	2015-002142-31
Sponsor's Protocol Code Number:	547-SSE-301
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-08-28
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Sweden - MPA

A.2

EudraCT number

2015-002142-31

A.3

Full title of the trial

A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF SAGE-547 INJECTION IN THE TREATMENT OF SUBJECTS WITH SUPER-REFRACTORY STATUS EPILEPTICUS

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

CLINICAL STUDY TO EVALUATE THE EFFICACY AND SAFETY OF A NEW DRUG (SAGE-547) INJECTION IN THE TREATMENT OF SUBJECTS WITH SUPER-REFRACTORY STATUS EPILEPTICUS

A.3.2

Name or abbreviated title of the trial where available

STATUS trial

A.4.1

Sponsor's protocol code number

547-SSE-301

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02477618

A.5.4

Other Identifiers

Name:

IND number

Number:

117901

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Sage Therapeutics
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	SAGE THERAPEUTICS
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	SAGE Therapeutics
B.5.2	Functional name of contact point	Medical Director
B.5.3	Address:
B.5.3.1	Street Address	215 First Street
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	MA 02142
B.5.3.4	Country	United States
B.5.4	Telephone number	001617229-5234

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	SAGE-547
D.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	not available yet
D.3.9.1	CAS number	516-54-1
D.3.9.2	Current sponsor code	SAGE-547
D.3.9.3	Other descriptive name	allopregnanolone
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection/infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

SUPER-REFRACTORY STATUS EPILEPTICUS (SRSE)

E.1.1.1

Medical condition in easily understood language

STATUS EPILEPTICUS NOT RESPONDING TO ANY OF THE CONVENTIONAL THERAPY REGIMEN

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

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 subjects with SRSE, and for the response to endure at least 24 hours after cessation of the SAGE-547 or placebo infusion (primary response).

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.

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 ( adults only - Sweden) dated 18 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.

E.3

Principal 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.

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. Subjects who have any of the following:
-a GFR low enough to warrant dyalisis but for whatever reason, dyalisis 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;
-severe hepatic impairment;
-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.
5. 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.
6. Subjects with a living will that does not allow heroic measure.
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 enrolled treated or randomized in this trial or any other trial employing SAGE-547 previously (i.e., subjects may not withdraw or completehave received study drug/placebo and then re-enroll).

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).

E.5.1.1

Timepoint(s) of evaluation of this end point

24 hours after the end of study drug infusion.

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.

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

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2015-08-28.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

According to Swedish Läkemedelslagen 1992:859, consent will be obtained by both the LAR and the closest relatives of the patients. Only patients with a previously appointed LAR will be included in the study.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

140

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

According to standard of care

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-03-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-10-27

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-08-11

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IMP with orphan designation in the indication
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