A Study With SAGE-547 for Super-Refractory Status Epilept... | NCT02477618

Status Module

Label	Type	Description	Intervention Names
SAGE-547	Active Comparator	Intravenous	Drug: SAGE-547
Placebo	Placebo Comparator	Intravenous	Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
SAGE-547	Drug		SAGE-547
Placebo

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants Able to be Weaned Off All Third-Line Agents Prior to End of Double-Blind SAGE-547 or Placebo Infusion, and Remain Off All Third-Line Agents for ≥ 24 Hours Following the End of SAGE-547 or Placebo Infusion	Third-line agents were anesthetic agents that were administered in order to reach a seizure or burst suppression electroencephalogram (EEG) pattern. For this study, third-line agents were defined as continuous intravenous infusions of pentobarbital/thiopental, midazolam, propofol, and ketamine at maintenance doses alone or in combination sufficient to produce a burst or seizure suppression pattern on the EEG. A responder was a participant who was able to be weaned off all third-line agents prior to the end of the SAGE-547 or placebo infusion and remain off all third-line agents for >=24 hours after the end of the study drug infusion. The primary analysis was a comparison between SAGE-547 and placebo of the proportion of responders.	7 days

Secondary Outcomes

Measure	Description	Time Frame
Time Between the Primary Outcome Response and the Re-institution of Any Third-line Agent for Seizure or Burst Suppression	Third-line agents were anesthetic agents that were administered in order to reach a seizure or burst suppression EEG pattern. For this study, third-line agents were defined as continuous intravenous infusions of pentobarbital/thiopental, midazolam, propofol, and ketamine at maintenance doses alone or in combination sufficient to produce a burst or seizure suppression pattern on the EEG. A responder was a participant who was able to be weaned off all third-line agents prior to the end of the SAGE-547 or placebo infusion and remain off all third-line agents for >=24 hours after the end of the study drug infusion. The primary analysis was a comparison between SAGE-547 and placebo of the proportion of responders.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Subjects two (2) years of age and older
Subjects who have:
- Failed to respond to the administration of at least one first-line agent (e.g., benzodiazepine or other emergent initial anti-epileptic drug [AED] treatment), according to institution standard of care, and;
- Failed to respond to at least one second-line agent (e.g., phenytoin, fosphenytoin, valproate, phenobarbital, levetiracetam or other urgent control AED), according to institution standard of care, and;
- Not previously been administered a third-line agent but have been admitted to an intensive care unit with the intent of administering at least one third-line agent for at least 24 hours; or who have previously failed zero, one or more wean attempts from third-line agents and are now on continuous intravenous infusions of one or more third-line agent and in an EEG burst or seizure suppression pattern; or who have previously failed one or more wean attempts from third-line agents and are now either not on a continuous intravenous infusion of at least one third-line agent or are on a continuous intravenous infusion of one or more third-line agent but not in an EEG burst or seizure suppression pattern

Exclusion Criteria:

Subjects with SRSE due to anoxic/hypoxic encephalopathy with highly malignant/ malignant EEG features
Children (subjects aged less than 17 years) with an encephalopathy due to a rapidly progressing underlying neurological disorder
Subjects who have any of the following:
1. a glomerular filtration rate (GFR) low enough to warrant dialysis but for whatever reason, dialysis is not planned or non-continuous dialysis planned (that would not adequately remove Captisol®);
2. severe cardiogenic or vasodilatory shock requiring two or more pressors that is not related to third-line agent use;
3. fulminant hepatic failure;
4. no reasonable expectation of recovery (for instance, a likely outcome is persistent vegetative state) or life-expectancy, in the experience of the investigator, is less than 30 days.
Subjects who are being administered more than three third-line agents concomitantly or in whom the qualifying wean cannot be completed per protocol

Name	Affiliation	Role
Eric Rosenthal, MD	Massachusetts General Hospital	Principal Investigator
Mark Wainwright, MD, PhD	Ann & Robert H Lurie Children's Hospital of Chicago	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Sage Investigational Site		Birmingham	Alabama	35233	United States
Sage Investigational Site

Label	URL
Sage Therapeutics	View source

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Placebo	Placebo was administered over the course of 6 days, beginning with a 1-hour dose rate equivalent to 300 micrograms per kilogram per hour (μg/kg/h) of the active arm loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment), which included a step-wise taper during the last 24 hours of treatment.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	May 3, 2017	Apr 11, 2019

Arm/Group Information

ID	Title	Description
BG000	Placebo	Placebo was administered over the course of 6 days, beginning with a 1-hour dose rate equivalent to 300 micrograms per kilogram per hour (μg/kg/h) of the active arm loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment), which included a step-wise taper during the last 24 hours of treatment.
BG001	SAGE-547	SAGE-547 Injection was administered over the course of 6 days, beginning with a 1-hour 300 μg/kg/h loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment) or 150 μg/kg/h (open-label treatment), both of which included a step-wise taper during the last 24 hours of treatment. Eligible participants, who did not respond to blinded study treatment, were allowed to enter an Open-label Treatment Period of identical duration.
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00037.8± 22.69 BG00141.3± 23.89 BG00239.6± 23.29

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00030 BG00135 BG002

Race/Ethnicity, Customized

Count of Participants

Participants

Title

Denominators

Categories

White

Title	Measurements
	BG00047 BG00145 BG002

Race/Ethnicity, Customized

Count of Participants

Participants

Title

Denominators

Categories

Hispanic or Latino

Title	Measurements
	BG00010 BG0016 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Participants Able to be Weaned Off All Third-Line Agents Prior to End of Double-Blind SAGE-547 or Placebo Infusion, and Remain Off All Third-Line Agents for ≥ 24 Hours Following the End of SAGE-547 or Placebo Infusion

Third-line agents were anesthetic agents that were administered in order to reach a seizure or burst suppression electroencephalogram (EEG) pattern. For this study, third-line agents were defined as continuous intravenous infusions of pentobarbital/thiopental, midazolam, propofol, and ketamine at maintenance doses alone or in combination sufficient to produce a burst or seizure suppression pattern on the EEG. A responder was a participant who was able to be weaned off all third-line agents prior to the end of the SAGE-547 or placebo infusion and remain off all third-line agents for >=24 hours after the end of the study drug infusion. The primary analysis was a comparison between SAGE-547 and placebo of the proportion of responders.

The Intent-to-Treat Analysis Set included all participants who had an infusion of blinded study drug initiated.

Posted

Count of Participants

Participants

7 days

ID	Title	Description
OG000	Placebo	Placebo was administered over the course of 6 days, beginning with a 1-hour dose rate equivalent to 300 micrograms per kilogram per hour (μg/kg/h) of the active arm loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment), which included a step-wise taper during the last 24 hours of treatment.
OG001	SAGE-547	SAGE-547 Injection was administered over the course of 6 days, beginning with a 1-hour 300 μg/kg/h loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment) or 150 μg/kg/h (open-label treatment), both of which included a step-wise taper during the last 24 hours of treatment. Eligible participants, who did not respond to blinded study treatment, were allowed to enter an Open-label Treatment Period of identical duration.

Units	Counts
Participants	OG00066 OG00166

Title

Denominators

Categories

Title	Measurements
	OG00028 OG00129

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Regression, Logistic		0.878		Odds Ratio (OR)	1.056			2-Sided	95	0.527	2.118					Superiority

Secondary

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

Third-line agents were anesthetic agents that were administered in order to reach a seizure or burst suppression EEG pattern. For this study, third-line agents were defined as continuous intravenous infusions of pentobarbital/thiopental, midazolam, propofol, and ketamine at maintenance doses alone or in combination sufficient to produce a burst or seizure suppression pattern on the EEG. A responder was a participant who was able to be weaned off all third-line agents prior to the end of the SAGE-547 or placebo infusion and remain off all third-line agents for >=24 hours after the end of the study drug infusion. The primary analysis was a comparison between SAGE-547 and placebo of the proportion of responders.

The Intent-to-Treat Analysis Set included all participants who had an infusion of blinded study drug initiated. Here, overall number of participants analyzed (N) indicates participants analyzed for this outcome measure.

Posted

Median

Full Range

days

Up to 21 days

ID	Title	Description
OG000	Placebo	Placebo was administered over the course of 6 days, beginning with a 1-hour dose rate equivalent to 300 micrograms per kilogram per hour (μg/kg/h) of the active arm loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment), which included a step-wise taper during the last 24 hours of treatment.
OG001	SAGE-547

Secondary

Number of Participants Able to be Weaned Off All Third-line Agents Before the End of the First SAGE-547 or Placebo Infusion

The Intent-to-Treat Analysis Set included all participants who had an infusion of blinded study drug initiated.

Posted

Count of Participants

Participants

Day 6

ID	Title	Description
OG000	Placebo	Placebo was administered over the course of 6 days, beginning with a 1-hour dose rate equivalent to 300 micrograms per kilogram per hour (μg/kg/h) of the active arm loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment), which included a step-wise taper during the last 24 hours of treatment.
OG001	SAGE-547	SAGE-547 Injection was administered over the course of 6 days, beginning with a 1-hour 300 μg/kg/h loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment) or 150 μg/kg/h (open-label treatment), both of which included a step-wise taper during the last 24 hours of treatment. Eligible participants, who did not respond to blinded study treatment, were allowed to enter an Open-label Treatment Period of identical duration.

Secondary

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

Posted

Median

Full Range

days

Up to 21 days

ID	Title	Description
OG000	Placebo	Placebo was administered over the course of 6 days, beginning with a 1-hour dose rate equivalent to 300 micrograms per kilogram per hour (μg/kg/h) of the active arm loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment), which included a step-wise taper during the last 24 hours of treatment.
OG001	SAGE-547	SAGE-547 Injection was administered over the course of 6 days, beginning with a 1-hour 300 μg/kg/h loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment) or 150 μg/kg/h (open-label treatment), both of which included a step-wise taper during the last 24 hours of treatment. Eligible participants, who did not respond to blinded study treatment, were allowed to enter an Open-label Treatment Period of identical duration.

Secondary

Change in Clinical Global Impression Scale (CGI)

The CGI scale was used to integrate several sources of information into a single rating of a participant's condition. The CGI was rated on a 7-point scale, from a minimum of 0 to a maximum of 7, where 0 = Not assessed; 1 = Normal, not at all ill; 2 = Borderline physically ill; 3 = Mildly ill; 4 = Moderately ill; 5 = Markedly ill; 6 = Severely ill; 7 = Among the most extremely ill participants. A negative change from baseline indicates improvement. A positive change from baseline indicates worsening. Here, study visits followed by "R" indicate the Open-label Treatment Period.

The Intent-to-Treat Analysis Set included all participants who had an infusion of blinded study drug initiated. Here, number of participants analyzed (N) indicates participants with available data at each time point for this outcome measure.

Posted

Mean

Standard Deviation

units on scale

Up to 21 days

ID	Title	Description
OG000	Placebo	Placebo was administered over the course of 6 days, beginning with a 1-hour dose rate equivalent to 300 micrograms per kilogram per hour (μg/kg/h) of the active arm loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment), which included a step-wise taper during the last 24 hours of treatment.
OG001	SAGE-547	SAGE-547 Injection was administered over the course of 6 days, beginning with a 1-hour 300 μg/kg/h loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment) or 150 μg/kg/h (open-label treatment), both of which included a step-wise taper during the last 24 hours of treatment. Eligible participants, who did not respond to blinded study treatment, were allowed to enter an Open-label Treatment Period of identical duration.

Secondary

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

Here, study visits followed by "R" indicate the Open-label Treatment Period.

Posted

Mean

Standard Deviation

days

Up to 21 days

ID	Title	Description
OG000	Placebo	Placebo was administered over the course of 6 days, beginning with a 1-hour dose rate equivalent to 300 micrograms per kilogram per hour (μg/kg/h) of the active arm loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment), which included a step-wise taper during the last 24 hours of treatment.
OG001	SAGE-547	SAGE-547 Injection was administered over the course of 6 days, beginning with a 1-hour 300 μg/kg/h loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment) or 150 μg/kg/h (open-label treatment), both of which included a step-wise taper during the last 24 hours of treatment. Eligible participants, who did not respond to blinded study treatment, were allowed to enter an Open-label Treatment Period of identical duration.

Secondary

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

Here, study visits followed by "R" indicate the Open-label Treatment Period.

Posted

Mean

Standard Deviation

days

Up to 21 days

ID	Title	Description
OG000	Placebo	Placebo was administered over the course of 6 days, beginning with a 1-hour dose rate equivalent to 300 micrograms per kilogram per hour (μg/kg/h) of the active arm loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment), which included a step-wise taper during the last 24 hours of treatment.
OG001	SAGE-547	SAGE-547 Injection was administered over the course of 6 days, beginning with a 1-hour 300 μg/kg/h loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment) or 150 μg/kg/h (open-label treatment), both of which included a step-wise taper during the last 24 hours of treatment. Eligible participants, who did not respond to blinded study treatment, were allowed to enter an Open-label Treatment Period of identical duration.

Secondary

Number of Separate Episodes of Status Epilepticus Up to Visit 12

Here, study visits followed by "R" indicate the Open-label Treatment Period.

Posted

Mean

Standard Deviation

episodes

Up to 21 days

ID	Title	Description
OG000	Placebo	Placebo was administered over the course of 6 days, beginning with a 1-hour dose rate equivalent to 300 micrograms per kilogram per hour (μg/kg/h) of the active arm loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment), which included a step-wise taper during the last 24 hours of treatment.
OG001	SAGE-547	SAGE-547 Injection was administered over the course of 6 days, beginning with a 1-hour 300 μg/kg/h loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment) or 150 μg/kg/h (open-label treatment), both of which included a step-wise taper during the last 24 hours of treatment. Eligible participants, who did not respond to blinded study treatment, were allowed to enter an Open-label Treatment Period of identical duration.

Secondary

Number of Participants With a New Diagnosis of Epilepsy After Visit 11

Here, study visits followed by "R" indicate the Open-label Treatment Period.

Posted

Count of Participants

Participants

Up to 21 days

ID	Title	Description
OG000	Placebo	Placebo was administered over the course of 6 days, beginning with a 1-hour dose rate equivalent to 300 micrograms per kilogram per hour (μg/kg/h) of the active arm loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment), which included a step-wise taper during the last 24 hours of treatment.
OG001	SAGE-547	SAGE-547 Injection was administered over the course of 6 days, beginning with a 1-hour 300 μg/kg/h loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment) or 150 μg/kg/h (open-label treatment), both of which included a step-wise taper during the last 24 hours of treatment. Eligible participants, who did not respond to blinded study treatment, were allowed to enter an Open-label Treatment Period of identical duration.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo	Placebo was administered over the course of 6 days, beginning with a 1-hour dose rate equivalent to 300 micrograms per kilogram per hour (μg/kg/h) of the active arm loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment), which included a step-wise taper during the last 24 hours of treatment.	12	65	22	65	58	65
EG001	SAGE-547	SAGE-547 Injection was administered over the course of 6 days, beginning with a 1-hour 300 μg/kg/h loading dose, followed by a maintenance period achieving a maximum of 90 μg/kg/h (double-blind treatment) or 150 μg/kg/h (open-label treatment), both of which included a step-wise taper during the last 24 hours of treatment. Eligible participants, who did not respond to blinded study treatment, were allowed to enter an Open-label Treatment Period of identical duration.	17	67	27	67	60	67

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Cardiac arrest	Cardiac disorders	MedDRA v19.1	Systematic Assessment	EG0004 affected65 at risk EG0015 affected67 at risk
Cardio-respiratory arrest	Cardiac disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0011 affected67 at risk
Pulseless electrical activity	Cardiac disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0011 affected67 at risk
Atrial flutter	Cardiac disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Bradycardia	Cardiac disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Bundle branch block	Cardiac disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Torsade de pointes	Cardiac disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Ventricular fibrillation	Cardiac disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Nodal rhythm	Cardiac disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Ventricular tachycardia	Cardiac disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Mitochondrial DNA mutation	Congenital, familial and genetic disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Diabetes insipidus	Endocrine disorders	MedDRA v19.1	Systematic Assessment	EG0002 affected65 at risk EG0010 affected67 at risk
Mydriasis	Eye disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Pupil fixed	Eye disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Intestinal ischaemia	Gastrointestinal disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0011 affected67 at risk
Abdominal compartment syndrome	Gastrointestinal disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Ileus	Gastrointestinal disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Melaena	Gastrointestinal disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Rectal haemorrhage	Gastrointestinal disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Intra-abdominal haemorrhage	Gastrointestinal disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Hypothermia	General disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Device related thrombosis	General disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Hyperthermia	General disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Multiple organ dysfunction syndrome	General disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Cholestasis	Hepatobiliary disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Cirrhosis alcoholic	Hepatobiliary disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Hepatic failure	Hepatobiliary disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Hepatic function abnormal	Hepatobiliary disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Septic shock	Infections and infestations	MedDRA v19.1	Systematic Assessment	EG0002 affected65 at risk EG0013 affected67 at risk
Pneumonia	Infections and infestations	MedDRA v19.1	Systematic Assessment	EG0003 affected65 at risk EG0011 affected67 at risk
Sepsis	Infections and infestations	MedDRA v19.1	Systematic Assessment	EG0002 affected65 at risk EG0011 affected67 at risk
Pneumonia staphylococcal	Infections and infestations	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Serratia sepsis	Infections and infestations	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Subdural empyema	Infections and infestations	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Urosepsis	Infections and infestations	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Subdural haematoma	Injury, poisoning and procedural complications	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0012 affected67 at risk
Brain herniation	Injury, poisoning and procedural complications	MedDRA v19.1	Systematic Assessment	EG0003 affected65 at risk EG0011 affected67 at risk
Nerve injury	Injury, poisoning and procedural complications	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Transaminases increased	Investigations	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0011 affected67 at risk
Electrocardiogram QT prolonged	Investigations	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Hepatic enzyme increased	Investigations	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Nuclear magnetic resonance imaging brain abnormal	Investigations	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Liver function test abnormal	Investigations	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Metabolic acidosis	Metabolism and nutrition disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0011 affected67 at risk
Hyperkalaemia	Metabolism and nutrition disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Propofol infusion syndrome	Metabolism and nutrition disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Brain oedema	Nervous system disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0012 affected67 at risk
Status epilepticus	Nervous system disorders	MedDRA v19.1	Systematic Assessment	EG0002 affected65 at risk EG0011 affected67 at risk
Cerebral atrophy	Nervous system disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Cerebral infarction	Nervous system disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Posterior reversible encephalopathy syndrome	Nervous system disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Cerebral ischaemia	Nervous system disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Haemorrhage intracranial	Nervous system disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Device dislocation	Product Issues	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Delirium	Psychiatric disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Acute kidney injury	Renal and urinary disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0012 affected67 at risk
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Hypoxia	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Obstructive airways disorder	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Pneumothorax	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Acute respiratory distress syndrome	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Pulmonary oedema	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Respiratory arrest	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Drug reaction with eosinophilia and systemic symptoms	Skin and subcutaneous tissue disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0011 affected67 at risk
Angioedema	Skin and subcutaneous tissue disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk
Withdrawal of life support	Surgical and medical procedures	MedDRA v19.1	Systematic Assessment	EG0007 affected65 at risk EG00111 affected67 at risk
Hypotension	Vascular disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0012 affected67 at risk
Neurogenic shock	Vascular disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0010 affected67 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA v19.1	Systematic Assessment	EG0007 affected65 at risk EG00112 affected67 at risk
Leukocytosis	Blood and lymphatic system disorders	MedDRA v19.1	Systematic Assessment	EG0003 affected65 at risk EG0014 affected67 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA v19.1	Systematic Assessment	EG0007 affected65 at risk EG0013 affected67 at risk
Tachycardia	Cardiac disorders	MedDRA v19.1	Systematic Assessment	EG0004 affected65 at risk EG0018 affected67 at risk
Atrial fibrillation	Cardiac disorders	MedDRA v19.1	Systematic Assessment	EG0002 affected65 at risk EG0015 affected67 at risk
Sinus tachycardia	Cardiac disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0014 affected67 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA v19.1	Systematic Assessment	EG0007 affected65 at risk EG00112 affected67 at risk
Constipation	Gastrointestinal disorders	MedDRA v19.1	Systematic Assessment	EG0008 affected65 at risk EG00110 affected67 at risk
Vomiting	Gastrointestinal disorders	MedDRA v19.1	Systematic Assessment	EG0002 affected65 at risk EG0015 affected67 at risk
Abdominal distension	Gastrointestinal disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0014 affected67 at risk
Pyrexia	General disorders	MedDRA v19.1	Systematic Assessment	EG00021 affected65 at risk EG00119 affected67 at risk
Hyperthermia	General disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0015 affected67 at risk
Peripheral swelling	General disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0014 affected67 at risk
Oedema	General disorders	MedDRA v19.1	Systematic Assessment	EG0004 affected65 at risk EG0013 affected67 at risk
Hypothermia	General disorders	MedDRA v19.1	Systematic Assessment	EG0004 affected65 at risk EG0011 affected67 at risk
Urinary tract infection	Infections and infestations	MedDRA v19.1	Systematic Assessment	EG00014 affected65 at risk EG00113 affected67 at risk
Pneumonia	Infections and infestations	MedDRA v19.1	Systematic Assessment	EG00011 affected65 at risk EG00113 affected67 at risk
Fungal infection	Infections and infestations	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0014 affected67 at risk
Sepsis	Infections and infestations	MedDRA v19.1	Systematic Assessment	EG0004 affected65 at risk EG0013 affected67 at risk
Aspartate aminotransferase increased	Investigations	MedDRA v19.1	Systematic Assessment	EG0006 affected65 at risk EG0015 affected67 at risk
Lipase increased	Investigations	MedDRA v19.1	Systematic Assessment	EG0006 affected65 at risk EG0015 affected67 at risk
Alanine aminotransferase increased	Investigations	MedDRA v19.1	Systematic Assessment	EG0005 affected65 at risk EG0014 affected67 at risk
Blood potassium decreased	Investigations	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0014 affected67 at risk
White blood cell count increased	Investigations	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0014 affected67 at risk
Electrocardiogram QT prolonged	Investigations	MedDRA v19.1	Systematic Assessment	EG0004 affected65 at risk EG0013 affected67 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA v19.1	Systematic Assessment	EG00011 affected65 at risk EG00110 affected67 at risk
Hypophosphataemia	Metabolism and nutrition disorders	MedDRA v19.1	Systematic Assessment	EG0006 affected65 at risk EG0018 affected67 at risk
Metabolic acidosis	Metabolism and nutrition disorders	MedDRA v19.1	Systematic Assessment	EG0002 affected65 at risk EG0018 affected67 at risk
Hypernatraemia	Metabolism and nutrition disorders	MedDRA v19.1	Systematic Assessment	EG0006 affected65 at risk EG0016 affected67 at risk
Hyponatraemia	Metabolism and nutrition disorders	MedDRA v19.1	Systematic Assessment	EG0004 affected65 at risk EG0015 affected67 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0015 affected67 at risk
Hyperammonaemia	Metabolism and nutrition disorders	MedDRA v19.1	Systematic Assessment	EG0000 affected65 at risk EG0015 affected67 at risk
Fluid overload	Metabolism and nutrition disorders	MedDRA v19.1	Systematic Assessment	EG0002 affected65 at risk EG0014 affected67 at risk
Hypocalcaemia	Metabolism and nutrition disorders	MedDRA v19.1	Systematic Assessment	EG0007 affected65 at risk EG0013 affected67 at risk
Agitation	Psychiatric disorders	MedDRA v19.1	Systematic Assessment	EG0004 affected65 at risk EG0015 affected67 at risk
Haematuria	Renal and urinary disorders	MedDRA v19.1	Systematic Assessment	EG0001 affected65 at risk EG0014 affected67 at risk
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Systematic Assessment	EG0008 affected65 at risk EG00114 affected67 at risk
Atelectasis	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Systematic Assessment	EG0004 affected65 at risk EG0015 affected67 at risk
Pulmonary oedema	Respiratory, thoracic and mediastinal disorders	MedDRA v19.1	Systematic Assessment	EG0004 affected65 at risk EG0013 affected67 at risk
Decubitus ulcer	Skin and subcutaneous tissue disorders	MedDRA v19.1	Systematic Assessment	EG0008 affected65 at risk EG0015 affected67 at risk
Erythema	Skin and subcutaneous tissue disorders	MedDRA v19.1	Systematic Assessment	EG0002 affected65 at risk EG0014 affected67 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA v19.1	Systematic Assessment	EG0002 affected65 at risk EG0014 affected67 at risk
Hypertension	Vascular disorders	MedDRA v19.1	Systematic Assessment	EG0006 affected65 at risk EG0018 affected67 at risk
Hypotension	Vascular disorders	MedDRA v19.1	Systematic Assessment	EG00010 affected65 at risk EG0016 affected67 at risk
Deep vein thrombosis	Vascular disorders	MedDRA v19.1	Systematic Assessment	EG0004 affected65 at risk EG0013 affected67 at risk