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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2015-002142-31
    Trial protocol
    		 DE   BE   SE   DK   ES   NL   FI   HU   AT   IT  
    Global end of trial date
    11 Aug 2017

    Results information
    Results version number
    		 v1
    This version publication date
    26 Aug 2018
    First version publication date
    26 Aug 2018
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    547-SSE-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02477618
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND number: 117901
    Sponsors
    Sponsor organisation name
    Sage Therapeutics
    Sponsor organisation address
    215 First Street, Cambridge, MA, United States, 02142
    Public contact
    Medical Monitor, SAGE Therapeutics, 001 617-299-8380, info@sagerx.com
    Scientific contact
    Medical Monitor, SAGE Therapeutics, 001 617-299-8380, info@sagerx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Aug 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to determine the response to a 144-hour (6-day) continuous intravenous (IV) infusion of SAGE-547 Injection (hereafter referred to as ‘SAGE-547’) compared to placebo administered to support the weaning of all continuous third-line agents in adult and paediatric subjects with super-refractory status epilepticus (SRSE), and for the response to endure at least 24 hours after cessation of the SAGE-547 or placebo infusion (primary response). Status epilepticus (SE) is a life- threatening condition that involves persistent or recurring seizures. SRSE is a severe form of SE that continues or recurs despite 24 hours or more of anesthetic third-line agents. Subjects with SRSE, who were admitted to the intensive care unit (ICU) and placed into a medically-induced coma, were included in the study. All subjects were critically ill due to a variety of comorbid conditions and had been in status epilepticus for a mean of 17.6 days prior to receiving study drug.
    Protection of trial subjects
    This study was conducted in accordance with applicable International Conference on Harmonisation (ICH) and Good Clinical Practice (GCP) guidelines, as well as local regulations. Because most study subjects were in a state of coma, prior consent was given by a legally authorised representative. Some subjects were able to re-consent upon awakening from the coma.
    Background therapy
    		 Third-line anti-seizure medication and medically induced coma.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Estonia: 1
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    United States: 101
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Serbia: 2
    Worldwide total number of subjects
    132
    EEA total number of subjects
    23
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    15
    Adolescents (12-17 years)
    11
    Adults (18-64 years)
    81
    From 65 to 84 years
    23
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at 122 investigative sites in Canada, United States, Austria, Denmark, Estonia, Finland, France, Germany, Israel, Italy, Serbia, Spain and the United Kingdom from 31 July 2015 to 11 August 2017. Note: The "Subjects Enrolled By Country" table in the "Trial Information" section reflects randomised subjects.

    Pre-assignment
    Screening details
    		 Subjects 2 years of age and older with super-refractory status epilepticus (SRSE) were eligible. The subject population was characterised by having underlying medical conditions, in addition to severe and complex SRSE, with ongoing treatment in a hospital intensive care unit (ICU), and in a medically induced coma.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo
    Arm description
    		 Subjects randomised to placebo received a continuous IV infusion of matching placebo, prepared and administered identically to SAGE-547. Subjects who failed to achieve treatment success during the blinded infusion or within 24 hours of completion of the blinded infusion were potentially eligible to receive open-label SAGE-547 at a higher dose (maximum dose 150 ug/kg/hr).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects randomised to placebo received a continuous IV infusion of matching placebo, prepared and administered identically to SAGE-547. Subjects who failed to achieve treatment success during the blinded infusion or within 24 hours of completion of the blinded infusion were potentially eligible to receive open-label SAGE-547 at a higher dose (maximum dose 150 ug/kg/hr).

    Arm title
    		 SAGE-547
    Arm description
    		 Subjects randomized to SAGE-547 received a continuous IV infusion of SAGE-547 Injection 5 mg/mL for 144 hours. The dose regimen included a 1-hour loading infusion of 300 ug/kg/hr (0-1 hour), then 90 ug/kg/hr (2 to 120 hours), followed by a taper to 65 ug/kg/hr (121 to 128 hours), 45 ug/kg/hr (129 to 136 hours), and 25 ug/kg/hr (137 to 144 hrs). Subjects who failed to achieve treatment success during the blinded infusion or within 24 hours of completion of the blinded infusion were potentially eligible to receive open-label SAGE-547 at a higher dose (maximum dose 150 ug/kg/hr).
    Arm type
    		 Experimental

    Investigational medicinal product name
    SAGE-547
    Investigational medicinal product code
    Other name
    Brexanolone
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects randomized to SAGE-547 received a continuous IV infusion of SAGE-547 Injection 5 mg/mL for 144 hours. The dose regimen included a 1-hour loading infusion of 300 ug/kg/hr (0-1 hour), then 90 ug/kg/hr (2 to 120 hours), followed by a taper to 65 ug/kg/hr (121 to 128 hours), 45 ug/kg/hr (129 to 136 hours), and 25 ug/kg/hr (137 to 144 hrs). Subjects who failed to achieve treatment success during the blinded infusion or within 24 hours of completion of the blinded infusion were potentially eligible to receive open-label SAGE-547 at a higher dose (maximum dose 150 ug/kg/hr).

    Number of subjects in period 1 [1]
    		Placebo SAGE-547
    Started
    66
    66
    Intent-to-Treat Analysis Set
    66
    66
    Completed
    50
    53
    Not completed
    16
    14
         Adverse Event
    1
    1
         Subject erroneously received SAGE- 547
    1
    -
         Death
    11
    11
         Left Study Site for Rehabilitation
    -
    1
         Transferred Away from Study Site
    1
    -
         Completed Visits but Discontinued Drug
    2
    1
    Joined
    0
    1
         Transferred in from other group/arm
    -
    1
    Notes
    [1] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: One subject randomised to placebo was erroneously given SAGE-547 and was, therefore, included in the SAGE-547 group.

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Overall Study
    Reporting group description
    		 -

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One subject randomised to placebo was erroneously given SAGE-547 and was, therefore, included in the SAGE-547 group.
    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 132 132
    Age categorical
    Units: Subjects
    Age continuous
    The Safety Analysis Set included all subjects who had an infusion of blinded study drug initiated. One subject randomised to placebo was erroneously given SAGE-547 and was, therefore, only included in the SAGE-547 group.
    Units: years
        arithmetic mean (standard deviation)
    		 39.6 ( 23.29 ) -
    Gender categorical
    The Safety Analysis Set included all subjects who had an infusion of blinded study drug initiated. One subject randomised to placebo was erroneously given SAGE-547 and was, therefore, only included in the SAGE-547 group.
    Units: Subjects
        Female
    		 65 65
        Male
    		 67 67
    Race
    The Safety Analysis Set included all subjects who had an infusion of blinded study drug initiated. One subject randomised to placebo was erroneously given SAGE-547 and was, therefore, only included in the SAGE-547 group.
    Units: Subjects
        White
    		 92 92
        Black
    		 27 27
        Asian
    		 8 8
        Other
    		 5 5
    Ethnicity
    The Safety Analysis Set included all subjects who had an infusion of blinded study drug initiated. One subject randomised to placebo was erroneously given SAGE-547 and was, therefore, only included in the SAGE-547 group.
    Units: Subjects
        Hispanic or Latino
    		 16 16
        Not Hispanic or Latino
    		 116 116

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects randomised to placebo received a continuous IV infusion of matching placebo, prepared and administered identically to SAGE-547. Subjects who failed to achieve treatment success during the blinded infusion or within 24 hours of completion of the blinded infusion were potentially eligible to receive open-label SAGE-547 at a higher dose (maximum dose 150 ug/kg/hr).

    Reporting group title
    SAGE-547
    Reporting group description
    		 Subjects randomized to SAGE-547 received a continuous IV infusion of SAGE-547 Injection 5 mg/mL for 144 hours. The dose regimen included a 1-hour loading infusion of 300 ug/kg/hr (0-1 hour), then 90 ug/kg/hr (2 to 120 hours), followed by a taper to 65 ug/kg/hr (121 to 128 hours), 45 ug/kg/hr (129 to 136 hours), and 25 ug/kg/hr (137 to 144 hrs). Subjects who failed to achieve treatment success during the blinded infusion or within 24 hours of completion of the blinded infusion were potentially eligible to receive open-label SAGE-547 at a higher dose (maximum dose 150 ug/kg/hr).

    Primary: Percentage of Subjects 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

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    End point title
    		 Percentage of Subjects 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
    End point description
    Third-line agents (TLAs) were anaesthetic 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 subject 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. The Intent-to-Treat Analysis Set included all subjects who had an infusion of blinded study drug initiated.
    End point type
    Primary
    End point timeframe
    7 days
    End point values
    		 Placebo SAGE-547
    Number of subjects analysed
    66
    66
    Units: percentage of subjects
        number (not applicable)
    42.4
    43.9
    Statistical analysis title
    		 Weaning of all third-line agents
    Comparison groups
    Placebo v SAGE-547
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.878
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.056
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.527
         upper limit
    		 2.118

    Secondary: Time Between the Primary Outcome Response and the Re-institution of Any Third-line Agent for Seizure or Burst Suppression

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    End point title
    		 Time Between the Primary Outcome Response and the Re-institution of Any Third-line Agent for Seizure or Burst Suppression
    End point description
    Third-line agents were anaesthetic 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 subject 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. The Intent-to-Treat Analysis Set included all subjects who had an infusion of blinded study drug initiated. Here, overall number of subjects analysed (n) indicates subjects analysed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to 21 days
    End point values
    		 Placebo SAGE-547
    Number of subjects analysed
    28
    29
    Units: days
        median (full range (min-max))
    13.500 (0.06 to 18.00)
    14.000 (0.18 to 16.00)
    Statistical analysis title
    		 Time to event: Re-institution of any TLA
    Comparison groups
    Placebo v SAGE-547
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.636
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.747
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.222
         upper limit
    		 2.507

    Secondary: Percentage of Subjects Able to be Weaned Off All Third-line Agents Before the End of the First SAGE-547 or Placebo Infusion

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    End point title
    		 Percentage of Subjects Able to be Weaned Off All Third-line Agents Before the End of the First SAGE-547 or Placebo Infusion
    End point description
    Third-line agents were anaesthetic 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. The Intent-to-Treat Analysis Set included all subjects who had an infusion of blinded study drug initiated.
    End point type
    Secondary
    End point timeframe
    Day 6
    End point values
    		 Placebo SAGE-547
    Number of subjects analysed
    66
    66
    Units: percentage of subjects
        number (not applicable)
    68.2
    57.6
    Statistical analysis title
    		 Subjects able to be weaned off all TLA: Day 6
    Comparison groups
    Placebo v SAGE-547
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.199
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.623
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.303
         upper limit
    		 1.282

    Secondary: Time Between the Secondary Outcome Measure Response and the Re-institution of Any Third-line Agent for Seizure or Burst Suppression

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    End point title
    		 Time Between the Secondary Outcome Measure Response and the Re-institution of Any Third-line Agent for Seizure or Burst Suppression
    End point description
    Third-line agents were anaesthetic 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. The Intent-to-Treat Analysis Set included all subjects who had an infusion of blinded study drug initiated. Here, overall number of subjects analysed (n) indicates subjects analysed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to 21 days
    End point values
    		 Placebo SAGE-547
    Number of subjects analysed
    45
    38
    Units: days
        median (full range (min-max))
    7.000 (0.00 to 20.00)
    15.000 (0.00 to 19.00)
    Statistical analysis title
    		 Time to event: Re-institution of any TLA
    Comparison groups
    Placebo v SAGE-547
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.328
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.683
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.318
         upper limit
    		 1.466

    Secondary: Change in Clinical Global Impression Scale (CGI)

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    End point title
    		 Change in Clinical Global Impression Scale (CGI)
    End point description
    The CGI scale was used to integrate several sources of information into a single rating of a subject'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 subjects. A negative change from baseline indicates improvement. A positive change from baseline indicates worsening. The Intent-to-Treat Analysis Set included all subjects who had an infusion of blinded study drug initiated. Here, number of subjects analysed (n) indicates subjects with available data at each time point. The study visits followed by “R” indicate the Open-label Treatment Period.
    End point type
    Secondary
    End point timeframe
    Up to 21 days
    End point values
    		 Placebo SAGE-547
    Number of subjects analysed
    66
    66
    Units: units on scale
    arithmetic mean (standard deviation)
        Baseline (n=66, 65)
    6.0 ( 0.89 )
    5.9 ( 1.31 )
        Visit 12 (n=33, 32)
    -1.0 ( 1.42 )
    -0.6 ( 1.91 )
        Visit 12R (n=18, 20)
    -0.7 ( 1.36 )
    -0.5 ( 1.19 )
    No statistical analyses for this end point

    Secondary: Number of Days After the End of the First Study Drug Infusion Without Status Epilepticus, Up to Visit 12

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    End point title
    		 Number of Days After the End of the First Study Drug Infusion Without Status Epilepticus, Up to Visit 12
    End point description
    The Intent-to-Treat Analysis Set included all subjects who had an infusion of blinded study drug initiated. Here, number of subjects analysed (n) indicates subjects with available data at each time point for this outcome measure. The study visits followed by “R” indicate the Open-label Treatment Period.
    End point type
    Secondary
    End point timeframe
    Up to 21 days
    End point values
    		 Placebo SAGE-547
    Number of subjects analysed
    66
    66
    Units: days
    arithmetic mean (standard deviation)
        Visit 12 (n=41,40)
    10.05 ( 6.738 )
    11.15 ( 6.058 )
        Visit 12R (n=25,26)
    11.08 ( 6.557 )
    9.23 ( 6.345 )
    Statistical analysis title
    		 Number of days: Without Status Epilepticus
    Comparison groups
    Placebo v SAGE-547
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.339
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.583
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.193
         upper limit
    		 1.763

    Secondary: Number of Days After the End of the First Study Drug Infusion Without Seizures (Convulsive and Non-convulsive), up to Visit 12

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    End point title
    		 Number of Days After the End of the First Study Drug Infusion Without Seizures (Convulsive and Non-convulsive), up to Visit 12
    End point description
    The Intent-to-Treat Analysis Set included all subjects who had an infusion of blinded study drug initiated. Here, number of subjects analysed (n) indicates subjects with available data at each time point. The study visits followed by “R” indicate the Open-label Treatment Period.
    End point type
    Secondary
    End point timeframe
    Up to 21 days
    End point values
    		 Placebo SAGE-547
    Number of subjects analysed
    66
    66
    Units: days
    arithmetic mean (standard deviation)
        Visit 12 (n=41,40)
    8.22 ( 7.289 )
    7.50 ( 6.626 )
        Visit 12R (n=25,26)
    7.52 ( 7.054 )
    6.08 ( 5.932 )
    Statistical analysis title
    		 Number of days without seizures
    Comparison groups
    Placebo v SAGE-547
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.817
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.086
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.539
         upper limit
    		 2.189

    Secondary: Number of Separate Episodes of Status Epilepticus Up to Visit 12

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    End point title
    		 Number of Separate Episodes of Status Epilepticus Up to Visit 12
    End point description
    The Intent-to-Treat Analysis Set included all subjects who had an infusion of blinded study drug initiated. Here, number of subjects analysed (n) indicates subjects with available data at each time point for this outcome measure. The study visits followed by “R” indicate the Open-label Treatment Period.
    End point type
    Secondary
    End point timeframe
    Up to 21 days
    End point values
    		 Placebo SAGE-547
    Number of subjects analysed
    66
    66
    Units: episodes
    arithmetic mean (standard deviation)
        Visit 12 (n=9,5)
    1.3 ( 0.50 )
    1.4 ( 0.55 )
        Visit 12R (n=5,8)
    2.2 ( 2.17 )
    1.0 ( 0.00 )
    Statistical analysis title
    		 Number of separate episodes of status epilepticus
    Comparison groups
    Placebo v SAGE-547
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.567
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 0.5

    Secondary: Number of Subjects With a New Diagnosis of Epilepsy After Visit 11

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    End point title
    		 Number of Subjects With a New Diagnosis of Epilepsy After Visit 11
    End point description
    The Intent-to-Treat Analysis Set included all subjects who had an infusion of blinded study drug initiated. Here, number of subjects analysed (n) indicates subjects with available data at each time point for this outcome measure. The study visits followed by “R” indicate the Open-label Treatment Period.
    End point type
    Secondary
    End point timeframe
    Up to 21 days
    End point values
    		 Placebo SAGE-547
    Number of subjects analysed
    66
    66
    Units: subjects
        Visit 12 (n=34,34)
    0
    5
        Visit 12R (n=20,23)
    5
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 27 days
    Adverse event reporting additional description
    The Safety Analysis Set included all subjects who had an infusion of blinded study drug initiated. The subject population was characterised by having underlying medical conditions, in addition to severe and complex SRSE, with ongoing treatment in a hospital intensive care unit (ICU), and in a medically induced coma.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects randomised to placebo received a continuous IV infusion of matching placebo, prepared and administered identically to SAGE-547. Subjects who failed to achieve treatment success during the blinded infusion or within 24 hours of completion of the blinded infusion were potentially eligible to receive open-label SAGE-547 at a higher dose (maximum dose 150 ug/kg/hr).

    Reporting group title
    SAGE-547
    Reporting group description
    		 Subjects randomized to SAGE-547 received a continuous IV infusion of SAGE-547 Injection 5 mg/mL for 144 hours. The dose regimen included a 1-hour loading infusion of 300 ug/kg/hr (0-1 hour), then 90 ug/kg/hr (2 to 120 hours), followed by a taper to 65 ug/kg/hr (121 to 128 hours), 45 ug/kg/hr (129 to 136 hours), and 25 ug/kg/hr (137 to 144 hrs). Subjects who failed to achieve treatment success during the blinded infusion or within 24 hours of completion of the blinded infusion were potentially eligible to receive open-label SAGE-547 at a higher dose (maximum dose 150 ug/kg/hr).

    Serious adverse events
    		 Placebo SAGE-547
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 65 (33.85%)
    27 / 67 (40.30%)
         number of deaths (all causes)
    12
    17
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neurogenic shock
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Surgical and medical procedures
    Withdrawal of life support
         subjects affected / exposed
    7 / 65 (10.77%)
    11 / 67 (16.42%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Hypothermia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related thrombosis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoxia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Transaminases increased
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nuclear magnetic resonance imaging brain abnormal
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Brain herniation
         subjects affected / exposed
    3 / 65 (4.62%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    Nerve injury
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Mitochondrial DNA mutation
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    4 / 65 (6.15%)
    5 / 67 (7.46%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 2
    0 / 5
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pulseless electrical activity
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Torsade de pointes
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ventricular fibrillation
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nodal rhythm
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Status epilepticus
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cerebral atrophy
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Mydriasis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pupil fixed
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal ischaemia
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal compartment syndrome
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cirrhosis alcoholic
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angioedema
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Diabetes insipidus
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Septic shock
         subjects affected / exposed
    2 / 65 (3.08%)
    3 / 67 (4.48%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 65 (4.62%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Serratia sepsis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural empyema
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Metabolic acidosis
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Propofol infusion syndrome
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo SAGE-547
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 65 (89.23%)
    60 / 67 (89.55%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 65 (9.23%)
    5 / 67 (7.46%)
         occurrences all number
    6
    5
    Lipase increased
         subjects affected / exposed
    6 / 65 (9.23%)
    5 / 67 (7.46%)
         occurrences all number
    6
    5
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 65 (7.69%)
    4 / 67 (5.97%)
         occurrences all number
    5
    4
    Blood potassium decreased
         subjects affected / exposed
    1 / 65 (1.54%)
    4 / 67 (5.97%)
         occurrences all number
    1
    4
    White blood cell count increased
         subjects affected / exposed
    0 / 65 (0.00%)
    4 / 67 (5.97%)
         occurrences all number
    0
    6
    Electrocardiogram QT prolonged
         subjects affected / exposed
    4 / 65 (6.15%)
    3 / 67 (4.48%)
         occurrences all number
    5
    6
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 65 (9.23%)
    8 / 67 (11.94%)
         occurrences all number
    6
    8
    Hypotension
         subjects affected / exposed
    10 / 65 (15.38%)
    6 / 67 (8.96%)
         occurrences all number
    10
    7
    Deep vein thrombosis
         subjects affected / exposed
    4 / 65 (6.15%)
    3 / 67 (4.48%)
         occurrences all number
    4
    5
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    4 / 65 (6.15%)
    8 / 67 (11.94%)
         occurrences all number
    4
    8
    Atrial fibrillation
         subjects affected / exposed
    2 / 65 (3.08%)
    5 / 67 (7.46%)
         occurrences all number
    2
    10
    Sinus tachycardia
         subjects affected / exposed
    0 / 65 (0.00%)
    4 / 67 (5.97%)
         occurrences all number
    0
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 65 (10.77%)
    12 / 67 (17.91%)
         occurrences all number
    9
    12
    Leukocytosis
         subjects affected / exposed
    3 / 65 (4.62%)
    4 / 67 (5.97%)
         occurrences all number
    3
    6
    Thrombocytopenia
         subjects affected / exposed
    7 / 65 (10.77%)
    3 / 67 (4.48%)
         occurrences all number
    8
    3
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    21 / 65 (32.31%)
    19 / 67 (28.36%)
         occurrences all number
    34
    31
    Hyperthermia
         subjects affected / exposed
    1 / 65 (1.54%)
    5 / 67 (7.46%)
         occurrences all number
    1
    5
    Peripheral swelling
         subjects affected / exposed
    0 / 65 (0.00%)
    4 / 67 (5.97%)
         occurrences all number
    0
    5
    Oedema
         subjects affected / exposed
    4 / 65 (6.15%)
    3 / 67 (4.48%)
         occurrences all number
    4
    3
    Hypothermia
         subjects affected / exposed
    4 / 65 (6.15%)
    1 / 67 (1.49%)
         occurrences all number
    4
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 65 (10.77%)
    12 / 67 (17.91%)
         occurrences all number
    7
    12
    Constipation
         subjects affected / exposed
    8 / 65 (12.31%)
    10 / 67 (14.93%)
         occurrences all number
    11
    12
    Vomiting
         subjects affected / exposed
    2 / 65 (3.08%)
    5 / 67 (7.46%)
         occurrences all number
    2
    5
    Abdominal distension
         subjects affected / exposed
    0 / 65 (0.00%)
    4 / 67 (5.97%)
         occurrences all number
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    8 / 65 (12.31%)
    14 / 67 (20.90%)
         occurrences all number
    9
    14
    Atelectasis
         subjects affected / exposed
    4 / 65 (6.15%)
    5 / 67 (7.46%)
         occurrences all number
    4
    6
    Pulmonary oedema
         subjects affected / exposed
    4 / 65 (6.15%)
    3 / 67 (4.48%)
         occurrences all number
    4
    3
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    8 / 65 (12.31%)
    5 / 67 (7.46%)
         occurrences all number
    10
    5
    Erythema
         subjects affected / exposed
    2 / 65 (3.08%)
    4 / 67 (5.97%)
         occurrences all number
    8
    4
    Rash
         subjects affected / exposed
    2 / 65 (3.08%)
    4 / 67 (5.97%)
         occurrences all number
    2
    4
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    4 / 65 (6.15%)
    5 / 67 (7.46%)
         occurrences all number
    4
    5
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 65 (1.54%)
    4 / 67 (5.97%)
         occurrences all number
    1
    4
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    14 / 65 (21.54%)
    13 / 67 (19.40%)
         occurrences all number
    14
    14
    Pneumonia
         subjects affected / exposed
    11 / 65 (16.92%)
    13 / 67 (19.40%)
         occurrences all number
    12
    15
    Fungal infection
         subjects affected / exposed
    1 / 65 (1.54%)
    4 / 67 (5.97%)
         occurrences all number
    1
    4
    Sepsis
         subjects affected / exposed
    4 / 65 (6.15%)
    3 / 67 (4.48%)
         occurrences all number
    4
    3
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    11 / 65 (16.92%)
    10 / 67 (14.93%)
         occurrences all number
    14
    10
    Hypophosphataemia
         subjects affected / exposed
    6 / 65 (9.23%)
    8 / 67 (11.94%)
         occurrences all number
    6
    8
    Metabolic acidosis
         subjects affected / exposed
    2 / 65 (3.08%)
    8 / 67 (11.94%)
         occurrences all number
    2
    8
    Hypernatraemia
         subjects affected / exposed
    6 / 65 (9.23%)
    6 / 67 (8.96%)
         occurrences all number
    6
    6
    Hyponatraemia
         subjects affected / exposed
    4 / 65 (6.15%)
    5 / 67 (7.46%)
         occurrences all number
    4
    5
    Hyperglycaemia
         subjects affected / exposed
    1 / 65 (1.54%)
    5 / 67 (7.46%)
         occurrences all number
    1
    5
    Hyperammonaemia
         subjects affected / exposed
    0 / 65 (0.00%)
    5 / 67 (7.46%)
         occurrences all number
    0
    5
    Fluid overload
         subjects affected / exposed
    2 / 65 (3.08%)
    4 / 67 (5.97%)
         occurrences all number
    2
    4
    Hypocalcaemia
         subjects affected / exposed
    7 / 65 (10.77%)
    3 / 67 (4.48%)
         occurrences all number
    7
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 May 2015
    • Added Europe to the list of regions with study sites • Added the requirement for maintenance of burst suppression for the first 12 hours of the study drug infusion • Increased the sample size from 126 to 140 (with the intent of obtaining 126 evaluable subjects) • Added that all subjects who failed to complete their randomised treatment infusion or did not have at least one attempt to wean off all TLAs during study treatment were considered “failures” for the primary endpoint • Established the Clinical Standardization Guidelines and Team to assist sites and create consistency with weaning practices across study sites • Added qualifying wean (QW) guidance • Added the collection of Health Economics and Outcome data for subjects who were discharged from intensive care unit (ICU) prior to completion of Visit 12/12R • Added the Status Epilepticus Severity Score assessment during Visit 1
    28 Oct 2015
    • Removed paediatric subjects
    17 Nov 2015
    • Increased the number of study sites to up to 180 sites • Revised the list of accepted TLAs to include thiopental 3 mg/kg/h • Extended the QW EEG for the blinded study drug infusion to cover the 24 hours after the end of TLAs in order to confirm that the QW was a success • Added the consent EEG and blinded infusion EEG to the EEG records to be read centrally to capture the depth of burst suppression prior to QW and during the first 12 hours of the blinded infusion
    22 Apr 2016
    Never implemented.
    12 Aug 2016
    • Added Israel to the list of regions with study sites • Refined exclusion criteria, to exclude subjects who had been treated or randomised in this or any other SAGE-547 study with the intent of allowing subjects previously screened who subsequently met entry criteria • Provided additional guidance for TLA weaning • Extended the time frame from QW failure to when blinded infusion began to 8 hours • Removed an exclusion criterion 5 sub-bullet due to variations of interpretations of a “Do Not Resuscitate” order across sites • Removed the requirement for subjects to be in EEG burst suppression in the 24 hours prior to the QW

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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