Conditions: Acute Respiratory Distress Syndrome COVID-19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 29
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the efficacy and safety of brexanolone in participants on ventilator support for acute respiratory distress syndrome (ARDS) due to COVID-19.

Detailed description:

Arms:
arm 1: Participants receiving mechanical ventilation as standard of care were randomized to receive a 60-hour single continuous intravenous (IV) infusion of brexanolone-matching placebo. arm 2: Participants receiving mechanical ventilation as standard of care were randomized to receive a 60-hour single continuous IV infusion of brexanolone at 70 micrograms per kilogram per hour (mcg/kg/h) for 58 hours followed by a 2-hour taper of brexanolone at 35 mcg/kg/h.

Interventions: intervention 1: Brexanolone intervention 2: Placebo
Intervention descriptions: intervention 1: Administered as IV infusion. intervention 2: Administered as IV infusion.

Protocol document:
Prot_000.pdf: 
Official Title: 
A Study of Brexanolone for Acute Respiratory Distress Syndrome 
due to COVID-19
NCT Number: 
NCT04537806
Document Date: 
Protocol Version 5.0: 26 February 2021


DocuSign Envelope ID: 7361CE63-33A6-48FA-AA00-78E25461A2F7 
A STUDY OF BREXANOLONE FOR ACUTE 
RESPIRATORY DISTRESS SYNDROME DUE TO 
COVID-19 
PROTOCOL NUMBER: 547-ARD-301 
Investigational Product 
Brexanolone 
Clinical Phase 
3 
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Sage Contact and Medical Monitor 
 PhD 
Phone:
Date of Original Protocol 
Date of Amendment 1 
Date of Amendment 2 
Date of Amendment 3 
Date of Amendment 4 
07 April 2020; Version 1 
30 June 2020; Version 2 
23 July 2020; Version 3 
18 August 2020, Version 4 
24 February 2021, Version 5 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or consultant for 
review by you, your staff, and the applicable Institutional Review Board/Independent Ethics Committee. 
Your acceptance of this document constitutes agreement that you will not disclose the information 
contained herein to others without written authorization from Sage Therapeutics, Inc. 






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INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for brexanolone. I have read the 
547-ARD-301 protocol and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
Signature of Investigator 
 
 
 
Date (DD/MMM/YYYY) 




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2. 
SYNOPSIS 
 
Name of Sponsor/Company: 
Sage Therapeutics, Inc. (hereafter referred to as Sage Therapeutics, or Sage) 
Name of Investigational Product: 
Brexanolone 
Name of Active Ingredient: 
Brexanolone (USAN), also known as allopregnanolone (scientific name) 
Title of Study: 
A Study of Brexanolone for Acute Respiratory Distress Syndrome Due to COVID-19 
Number of Sites and Study Location: Up to 15 healthcare sites in the US 
Phase of Development: 3 
Planned Duration for each Study Participant: 
The planned study period will be approximately 1 month. This includes up to 2 days for screening 
(Visit 1), a 60-hour treatment period (Visit 2 through Visit 6), and follow-up visits through Day 28 
(Visit 11). 
Objectives and Endpoints: 
Primary Objective 
• 
To evaluate the effect of brexanolone in participants on ventilator support for acute 
respiratory distress syndrome (ARDS) due to COVID-19 
Secondary Objective 
• 
To evaluate the safety of brexanolone in participants on ventilator support for ARDS due 
to COVID-19 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Endpoint 
• 
Proportion of participants alive and free of respiratory failure at Day 28 
Secondary Endpoint 
• 
Incidence of treatment-emergent adverse events 


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• 
All-cause mortality through Day 28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Change from baseline in vital signs, 
, clinical laboratory parameters, and 
12-lead ECG 
 
 
 
 
 
Study Description: 
This is a randomized, double-blind, placebo-controlled study designed to evaluate treatment with 
brexanolone in approximately 100 participants with ARDS due to COVID-19. Participants and their 
family or caregivers, clinicians, site staff, and sponsor personnel will be masked to treatment 
allocation. 
Patients with ARDS and SARS-CoV-2 infection who give informed consent (or for whom consent is 
given by a proxy) and who are currently intubated and receiving mechanical ventilation as part of 
standard of care for no longer than 48 hours before signing informed consent or who are on an 
immediate clinical plan to receive such intervention, will be eligible for screening. All participants 
must have mechanical ventilation in place prior to randomization, and randomization must occur 
within 48 hours of signing informed consent. Eligible participants will be stratified by age (<70 or ≥70 
years) and randomized 1:1 within each stratum to receive either brexanolone plus standard of care or 
placebo plus standard of care. 
Participants will receive continued standard of care in addition to a continuous intravenous (IV) 
infusion of brexanolone or placebo for 60 hours. The infusion must be initiated within 6 hours from the 
time of randomization. The blinded 60-hour infusion will be administered at a dose of 70 mcg/kg/h for 
58 hours followed by a 2-hour taper at 35 mcg/kg/h. Transfer out of the ICU is not an indication to 
discontinue the infusion of investigational product (IP). 
Because brexanolone is a GABAA receptor positive allosteric modulator, it is possible that the sedating 
properties of co-administered anesthetics may be potentiated in the presence of brexanolone. Thus, 
during brexanolone infusion, lower doses of co-administered sedative agents may achieve the same 
anesthetic effects. During IP infusion, if sedation levels are deeper than intended, the dose(s) of 
sedative anesthetics should be titrated to the desired effect rather than adjusting the dose of IP. 


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In the scenario that a participant is experiencing unplanned sedation/somnolence when no longer on 
any sedating agents, but still receiving blinded IP, the IP infusion may be stopped or the dose may be 
reduced to 35 mcg/kg/h until the symptoms resolve. 
The IP infusion may also be stopped, or the dose may be reduced to 35 mcg/kg/h if the participant 
experiences an intolerable AE determined by the investigator to be related to IP. 
If the infusion is stopped and symptoms resolve, the IP infusion may be resumed at the same or lower 
dose as clinically appropriate. Each time the decision is made to stop the IP infusion or reduce the dose 
for AEs, the Richmond Agitation Sedation Scale (RASS) will be administered and if RASS ≥ -3, the 
Confusion Assessment Method for the intensive care unit (CAM-ICU) will be administered as well. 
In this study, reintubation events, delirium, unplanned sedation/somnolence, altered mental status, and 
sudden loss of consciousness will be recorded as adverse events of special interest (AESI) and should 
be reported in an expedited manner as outlined in Section 12.2.3. 
Follow-up assessments will be conducted as summarized in Figure 1; limited assessments will be 
collected by phone if the participant has been discharged from inpatient care. All participants will have 
measures of pulmonary function assessed throughout the study. Unless the clinical condition of the 
participant dictates otherwise, ventilation guidelines for ARDS due to COVID-19 should be followed. 
An independent data monitoring committee (DMC) will monitor the clinical data for safety and will 
meet at least monthly throughout the duration of the study. In order to perform their monitoring 
function, the DMC will have access to unblinded safety and efficacy data to ensure the safety of the 
participants in the study. The DMC will also review the results of the planned interim analysis and 
provide recommendations for continuing or stopping the study for safety and/or futility in accordance 
with the DMC charter. 
Number of Participants (planned): Approximately 100 participants 
Eligibility Criteria: 
Inclusion Criteria 
Each eligible participant must: 
1.
Be confirmed positive for SARS-CoV-2 infection as determined by polymerase chain reaction
at screening or within 2 weeks prior to screening
2.
Be aged 18 years or older
3.
Be able to provide written informed consent, signed by participant or by proxy (legally
acceptable representative)
4.
Have a presumptive diagnosis of ARDS at screening and PaO2/FiO2 (PF ratio) <300 within 48
hours prior to randomization
5.
Be intubated and receiving mechanical ventilation prior to randomization. Note that
participants must have initiated mechanical ventilation within 48 hours prior to written
informed consent, or have an immediate clinical plan for such intervention at time of written
informed consent
6.
Be likely to survive, in the opinion of the investigator, for at least 72 hours from the time of
written informed consent
Exclusion Criteria: 
Each eligible participant must not: 


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1. Be concurrently participating in another clinical study for an investigational product or device 
at screening 
2. Be pregnant, based on a positive pregnancy test at screening 
3. Be in fulminant hepatic failure at screening 
4. Have end stage renal disease at screening 
5. Have a known allergy to progesterone, allopregnanolone, or any excipients in the brexanolone 
injection 
Investigational Product Dosage and Mode of Administration: 
Brexanolone or placebo will be administered as a single, continuous, IV infusion for 60 hours at 
70 mcg/kg/h for 58 hours followed by a 2-hour taper at 35 mcg/kg/h. 
Duration of Treatment: 
Each participant will receive a single IV infusion of brexanolone or placebo for 60 hours. 
Statistical Methods: 
Detailed methodology for summary and statistical analyses of the data collected in this study will be 
documented in a statistical analysis plan, which will be finalized and approved prior to database lock 
for the planned interim analysis. 
General Considerations 
Unless otherwise specified in the statistical analysis plan, baseline is defined as the last measurement 
prior to the start of IP infusion. 
Continuous variables will be summarized with n, mean, standard deviation, median, minimum and 
maximum, Q1, and Q3. Change from baseline values for continuous endpoints will be calculated at 
each time point and descriptively summarized as described above. For all categorical endpoints, 
summaries will include counts and percentages. Out of range safety endpoints may be categorized as 
low or high, where applicable. 
Analysis Sets 
The Randomized Set is defined as all randomized participants (based on treatment as randomized). 
The Full Analysis Set is defined as all randomized participants who initiated IV infusion of 
brexanolone or placebo (based on treatment as randomized). 
The Per Protocol (PP) Set is defined as all randomized participants (based on treatment as randomized) 
with no major protocol deviations. This is a subset of the Randomized Set. 
The Safety Set will include all participants who initiated IV infusion of brexanolone or placebo (based 
on actual treatment received). 
Safety Analysis 
The incidence of treatment-emergent adverse events, changes from baseline in vital signs, 
 
, clinical laboratory evaluations, and 12-lead ECG will be summarized. 
Efficacy Analysis 
The primary endpoint of proportion of participants alive and free of respiratory failure at Day 28 will 
be summarized using a logistic regression, adjusting for age group. The odds ratio and difference in 
proportions will be estimated. The secondary endpoint of all-cause mortality through Day 28 will be 
analyzed using both the Kaplan-Meier method for time to death and the logistic regression model for 
the proportion of deaths. 
 






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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
TITLE ........................................................................................................................... 1 
2. 
SYNOPSIS .................................................................................................................... 6 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ................ 12 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................. 17 
5. 
INTRODUCTION ...................................................................................................... 19 
5.1. 
Dose Justification ........................................................................................................ 20 
6. 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 21 
6.1. 
Objectives .................................................................................................................... 21 
6.1.1. 
Primary Objective ....................................................................................................... 21 
6.1.2. 
Secondary Objective ................................................................................................... 21 
 
 21 
6.2. 
Endpoints .................................................................................................................... 21 
6.2.1. 
Primary Endpoint ........................................................................................................ 21 
6.2.2. 
Secondary Endpoint .................................................................................................... 21 
 
 21 
7. 
INVESTIGATIONAL PLAN ..................................................................................... 23 
7.1. 
Overall Study Design .................................................................................................. 23 
7.2. 
Number of Participants ............................................................................................... 24 
7.3. 
Treatment Assignment ................................................................................................ 24 
7.4. 
Dose Adjustment Criteria ............................................................................................ 24 
7.4.1. 
Data Monitoring Committee ....................................................................................... 24 
7.4.2. 
Safety Criteria for Adjustment or Stopping Doses ...................................................... 24 
7.5. 
Criteria for Study Termination ..................................................................................... 25 
8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS ..................................... 26 
8.1. 
Participant Inclusion Criteria ....................................................................................... 26 
8.2. 
Participant Exclusion Criteria ..................................................................................... 26 
8.3. 
Screen Failures ............................................................................................................ 26 
8.4. 
Investigational Product Discontinuation and Early Termination from the 


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Study ...........................................................................................................................27 
8.4.1. 
Investigational Product Discontinuation .....................................................................27 
8.4.2. 
Early Termination from the Study ..............................................................................27 
8.4.3. 
Loss to Follow-up .......................................................................................................27 
8.4.4. 
Replacement of Participants ........................................................................................27 
9. 
TREATMENT OF PARTICIPANTS .........................................................................28 
9.1. 
Description of Investigational Product ........................................................................28 
9.2. 
Prior Medications, Concomitant Medications and Restrictions ..................................28 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ...........................................28 
9.2.2. 
Prohibited Medications ...............................................................................................28 
9.2.3. 
Other Restrictions ........................................................................................................28 
9.3. 
Intervention after the End of the Study .......................................................................28 
9.4. 
Treatment Adherence ..................................................................................................29 
9.5. 
Randomization and Blinding ......................................................................................29 
9.5.1. 
Emergency Unblinding ...............................................................................................29 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT ..............30 
10.1. 
Investigational Product ...............................................................................................30 
10.2. 
Investigational Product Packaging and Labeling ........................................................30 
10.3. 
Investigational Product Storage ..................................................................................30 
10.4. 
Investigational Product Preparation ............................................................................30 
10.5. 
Investigational Product Administration.......................................................................30 
10.6. 
Investigational Product Accountability, Handling, and Disposal ...............................31 
10.7. 
Product Complaints .....................................................................................................31 
11. 
EFFICACY AND CLINICAL PHARMACOLOGY ASSESSMENTS .....................32 
11.1. 
Efficacy Assessments ..................................................................................................32 
 
32 
 
32 
 
.32 
 
.32 
 
33 
11.1.6. 
Prone Positioning ........................................................................................................33 
11.1.7. 
Data Collection at Follow-Up .....................................................................................33 
 
 33 


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 33 
 
 
 
 34 
 
 34 
 
 34 
12. 
SAFETY ASSESSMENTS ......................................................................................... 35 
12.1. 
Safety Parameters ........................................................................................................ 35 
12.1.1. 
Demography and Medical History .............................................................................. 35 
12.1.2. 
Weight and Height ...................................................................................................... 35 
12.1.3. 
Vital Signs ................................................................................................................... 35 
 
 35 
12.1.5. 
Electrocardiogram ....................................................................................................... 36 
12.1.6. 
Laboratory Assessments .............................................................................................. 36 
12.1.6.1. 
Screening ..................................................................................................................... 36 
12.1.6.2. 
Visit 2 (Hour 0) through Visit 9 (Day 7) ..................................................................... 36 
12.1.6.3. 
After Visit 9 (Day 8 through Day 28) ......................................................................... 36 
12.1.6.4. 
Pregnancy Screen ........................................................................................................ 36 
12.1.7. 
Richmond Agitation Sedation Scale ........................................................................... 36 
12.1.8. 
Confusion Assessment Method for the Intensive Care Unit ....................................... 36 
12.2. 
Adverse and Serious Adverse Events ......................................................................... 37 
12.2.1. 
Adverse Event Definition ............................................................................................ 37 
12.2.2. 
Serious Adverse Event Definition ................................................................................ 37 
12.2.3. 
Definition of Adverse Events of Special Interest (AESI) ........................................... 38 
12.2.4. 
Relationship to Investigational Product ...................................................................... 39 
12.2.5. 
Recording Adverse Events .......................................................................................... 39 
12.2.6. 
Reporting Serious Adverse Events ............................................................................. 40 
12.3. 
Pregnancy .................................................................................................................... 41 
12.4. 
Overdose ..................................................................................................................... 42 
13. 
STATISTICS .............................................................................................................. 43 
13.1. 
Data Analysis Sets ....................................................................................................... 43 
13.2. 
Handling of Missing Data ........................................................................................... 43 
13.3. 
General Considerations ............................................................................................... 43 
13.4. 
Demographics and Baseline Characteristics ............................................................... 43 


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13.5. 
Efficacy Analysis ........................................................................................................ 44 
13.6. 
Safety Analyses ........................................................................................................... 44 
13.6.1. 
Adverse Events ............................................................................................................ 44 
13.6.2. 
Clinical Laboratory Evaluations................................................................................... 44 
13.6.3. 
Vital Signs ................................................................................................................... 45 
13.6.4. 
12-Lead Electrocardiogram ......................................................................................... 45 
 
. 45 
13.6.6. 
Prior and Concomitant Medications ............................................................................ 45 
 
 46 
13.8. 
Sample Size and Power ............................................................................................... 46 
13.8.1. 
Interim and Data Monitoring Committee Analyses .................................................... 46 
13.8.1.1. 
Interim Analysis .......................................................................................................... 46 
13.8.1.2. 
Data Monitoring Committee Analysis ........................................................................ 47 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ......................................... 48 
14.1. 
Study Monitoring ........................................................................................................ 48 
14.2. 
Audits and Inspections ................................................................................................ 48 
14.3. 
Institutional Review Board or Independent Ethics Committee ................................... 49 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................... 50 
16. 
ETHICS....................................................................................................................... 51 
16.1. 
Ethics Review ............................................................................................................. 51 
16.2. 
Ethical Conduct of the Study ....................................................................................... 51 
16.3. 
Written Informed Consent .......................................................................................... 51 
17. 
DATA HANDLING AND RECORDKEEPING ........................................................ 53 
17.1. 
Inspection of Records .................................................................................................. 53 
17.2. 
Retention of Records ................................................................................................... 53 
18. 
PUBLICATION POLICY ........................................................................................... 54 
19. 
LIST OF REFERENCES ............................................................................................ 55 
LIST OF TABLES 
Table 1: 
Contact Information ......................................................................................................5 


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Table 2: 
Common Terminology Criteria for Adverse Events ...................................................39 
Table 3: 
List of Common ICU Comorbidities ...........................................................................41 
Table 4: 
Summary of Clinical Laboratory Analytes .................................................................45 
 
LIST OF FIGURES 
Figure 1: 
Schedule of Assessments ............................................................................................11 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
ARDS 
acute respiratory distress syndrome 
CAM-ICU 
Confusion Assessment Method for the intensive care unit 
CFR 
Code of Federal Regulation 
COVID-19 
A syndrome caused by infection with the SARS-CoV-2 virus 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
data monitoring committee 
ECG 
Electrocardiogram 
ECMO 
extracorporeal membrane oxygenation 
ET 
early termination 
FDA 
Food and Drug Administration 
FiO2 
fraction of inspired oxygen 
GABA 
gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICU 
Intensive care unit 
IEC 
Independent Ethics Committee 
IP 
investigational product 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
IV 
Intravenous 
LAR 
legally authorized representative 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
 
 
PaO2 
partial pressure of arterial oxygen 




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5. 
INTRODUCTION 
Multiple approaches should be sought to mitigate the clinical and public health impact of 
COVID-19. While several approaches are being investigated with an aim to lower viral load and 
develop vaccines, an approach to improving respiratory function in COVID-19 patients with 
respiratory failure is urgently needed. Brexanolone (ZulressoTM) is an FDA-approved 
intravenous (IV) infusion for the treatment of postpartum depression (PPD) in adults. Extensive 
safety experience in Intensive Care Unit (ICU) was gained during development of a separate 
indication for super-refractory status epilepticus (SRSE). Based on its unique pharmacology 
targeting multiple subtypes of GABAA receptors, brexanolone has the potential to attenuate the 
impact of COVID-19 in ventilated patients through multiple mechanisms of action. Preclinical 
evidence to date suggests that brexanolone is likely to have the following beneficial effects in the 
clinic: anti-inflammatory and fluid clearance effects via direct action on GABAA receptors 
located in human alveolar epithelial cells; anti-inflammatory and antiviral effects via inhibition 
of toll-like receptors and reduction in proinflammatory cytokines; and direct effects on 
pulmonary function through direct effects on smooth muscle in the lung, reducing shunting and 
improving partial pressure of arterial oxygen (PaO2). 
Severe forms of infection with SARS-CoV-2 produce significant impairment of respiratory 
function, including acute lung inflammation and acute respiratory distress syndrome (ARDS) 
(Wujtewicz 2020). Although epidemiological data are rapidly evolving, preliminary reports show 
that pulmonary impact severe enough to warrant critical care treatment is occurring in 3 to 6% of 
infected patients (CDC COVID-19 Response Team 2020; Wujtewicz 2020). Data from United 
Kingdom and from Seattle both suggest that of patients with COVID-19 in critical care, >75% 
require mechanical ventilation and up to approximately 50% do not survive (Bhatraju 2020; 
ICNARC 2020). The respiratory symptoms associated with morbidity are driven by factors 
including vasoconstriction, pulmonary edema, and inflammation secondary to cytokine 
activation. In addition to viral-induced respiratory trauma, ventilator support that is provided to 
address ARDS can also exacerbate lung damage and lead to a negative spiral that further 
contributes to morbidity and mortality. 
Brexanolone is chemically identical to allopregnanolone, an endogenous member of a family of 
molecules known as neuroactive steroids. There is substantial literature suggesting that 
brexanolone could act to improve airway flow and overall lung function under pathological 
conditions, including those conditions associated with ARDS, namely an elevated inflammatory 
response and fluid accumulation in the lungs. Notably, a recent analysis of 323 hospitalized 
patients with COVID-19 found that patients receiving the GABAA receptor partial agonist 
zopiclone had significantly better survival. In critically ill patients in the study, the 
administration of zopiclone in addition to standard ventilator support was associated with a 
favorable clinical outcome in 67% of patients versus 13% of patients not on zopiclone 
(Hu 2020). 
While approved for the treatment of PPD, brexanolone has been investigated for the treatment of 
several disorders, including SRSE. SRSE is status epilepticus that does not respond to standard 
treatments and which has a mortality rate of 30-40%. In the clinical development program for 
SRSE, the safety and tolerability of a 6-day continuous IV infusion of brexanolone with doses up 
to 150 mcg/kg/h was established in unconscious patients on mechanical ventilators in 
(neuro)critical care units. These patients had serious comorbidities, had been on mechanical 


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ventilation for several days to several weeks, and were receiving multiple concomitant 
medications including IV barbiturates, benzodiazepines, anticonvulsants, and general anesthetics. 
In the studies of patients with SRSE, no important risks or safety signals related to brexanolone 
infusion were observed and the safety profile was similar to placebo (ie, standard of care), 
supporting the potential for investigational use of brexanolone in patients with COVID-19- 
related ARDS. 
In preclinical studies, IV-administered brexanolone distributed to all tissues, including lung, with 
a lung-to-plasma ratio of approximately 1.5 to 2.3. Other data showed good persistence in lung 
after systemic administration. 
 
5.1. 
Dose Justification 
The brexanolone dose regimen to be used in this study (70 mcg/kg/h for 58 hours followed by a 
2-hour taper at 35 mcg/kg/h) was chosen for this patient population based on the following 
considerations: 
• Acceptable safety and tolerability profile defined in pivotal nonclinical toxicology 
studies (see brexanolone Investigator’s Brochure for additional details) 
• Brexanolone is an endogenous compound that increases during pregnancy, 
culminating in plasma concentrations of approximately 150 nM at the end of the third 
trimester. These plasma concentrations are in a similar range as is predicted for an 
infusion of 70 mcg/kg/h of brexanolone. 
• The dosing regimen approximates the total dose and duration approved for the 
treatment of postpartum depression 
• The dosing regimen is intended to simplify dosing in intensive care units and to 
maintain steady-state plasma concentrations for the maximum amount of time over 
the course of the infusion in participants with ARDS due to COVID-19 
• Participants will be already unconscious prior to or at start of the infusion; therefore, 
titration (intended to reduce the incidence of dizziness and somnolence in conscious 
patients) is not considered necessary 
• Brexanolone is rapidly cleared; therefore, a short taper is incorporated to slow the 
decline in plasma concentrations during discontinuation 






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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, double-blind, placebo-controlled study designed to evaluate treatment with 
brexanolone in approximately 100 participants with ARDS due to COVID-19. Participants and 
their family or caregivers, clinicians, site staff, and sponsor personnel will be masked to 
treatment allocation. 
Patients with ARDS and SARS-CoV-2 infection who give informed consent (or for whom 
consent is given by a proxy) and who are currently intubated and receiving mechanical 
ventilation as part of standard of care for no longer than 48 hours before signing written 
informed consent or who are on an immediate clinical plan to receive such intervention will be 
eligible for screening. All participants must have mechanical ventilation in place prior to 
randomization, and randomization must occur within 48 hours of signing informed consent. 
Eligible participants will be stratified by age (<70 or ≥70 years) and randomized 1:1 within each 
stratum to receive either brexanolone plus standard of care or placebo plus standard of care. 
Participants will receive continued standard of care in addition to a continuous IV infusion of 
brexanolone or placebo for 60 hours. The infusion must be initiated within 6 hours from the time 
of randomization. The blinded 60-hour infusion will be administered at a dose of 70 mcg/kg/h 
for 58 hours followed by a 2-hour taper at 35 mcg/kg/h. Transfer out of the ICU is not an 
indication to discontinue the infusion of IP. 
Brexanolone may potentiate the sedative effects of co-administered anesthetics. During IP 
infusion, if sedation levels are deeper than intended, the dose(s) of sedative anesthetics should be 
titrated to the desired effect rather than adjusting the dose of IP (see Section 7.4 for additional 
details). 
Dose adjustment is permitted in the event that a participant is experiencing unplanned 
sedation/somnolence when no longer on any sedating agents or if the participant experiences an 
intolerable AE determined by the investigator to be related to IP. Details regarding dose 
adjustment criteria and procedures are provided in Section 7.4. 
Follow-up assessments will be conducted as summarized in Figure 1; limited assessments will be 
collected by phone if the participant has been discharged from inpatient care. All participants 
will have measures of pulmonary function assessed throughout the study. Unless the clinical 
condition of the participant dictates otherwise, the ventilation guidelines for ARDS due to 
COVID-19 should be followed. 
An independent data monitoring committee (DMC) will monitor the clinical data for safety and 
will meet at least monthly throughout the duration of the study. In order to perform their 
monitoring function, the DMC will have access to unblinded safety and efficacy data to ensure 
the safety of the participants in the study. The DMC will also review the results of the planned 
interim analysis and provide recommendations for continuing or stopping the study for safety 
and/or futility in accordance with the DMC charter. Refer to Section 7.4.1 and Section 13.8.1.2 
for additional details. 


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7.2. 
Number of Participants 
Approximately 100 participants may participate. 
 
7.3. 
Treatment Assignment 
Eligible participants will be stratified by age (<70 or ≥70 years) and randomized 1:1 to receive 
either brexanolone plus standard of care or placebo plus standard of care. See Section 10.5 for 
details regarding IP administration. Additional details on randomization and blinding are 
provided in Section 9.5. 
 
7.4. 
Dose Adjustment Criteria 
Because brexanolone is a GABAA receptor positive allosteric modulator, it is possible that the 
sedating properties of co-administered anesthetics may be potentiated in the presence of 
brexanolone. Thus, during brexanolone infusion, lower doses of co-administered sedative agents 
may achieve the same anesthetic effects. During IP infusion, if sedation levels are deeper than 
intended, the dose(s) of sedative anesthetics should be titrated to the desired effect rather than 
adjusting the dose of IP. 
After the anesthetic agents are stopped, patients will remain sedated for varying amounts of time 
as the anesthetic agents wash out of lipid tissues. Additionally, in patients who are candidates for 
extubation, it is common to continue mild sedation using drugs that do not affect respiratory 
drive (eg, dexmedetomidine) after discontinuing the anesthetic agent(s), in order to facilitate a 
spontaneous breathing trial. 
In the scenario that a participant is experiencing unplanned sedation/somnolence when no longer 
on any sedating agents, but still receiving blinded IP, the IP infusion may be stopped or the dose 
may be reduced to 35 mcg/kg/h until the symptoms resolve. 
The IP infusion may also be stopped or the dose may be reduced to 35 mcg/kg/h if the participant 
experiences an intolerable AE determined by the investigator to be related to IP. 
If the infusion is stopped and symptoms resolve, the IP infusion may be resumed at the same or 
lower dose as clinically appropriate. Each time the decision is made to stop the IP infusion or 
reduce the dose for AEs, the Richmond Agitation Sedation Scale (RASS) will be administered, 
and if RASS ≥-3, the Confusion Assessment Method for the intensive care unit (CAM-ICU) will 
be administered as well (see Section 12.1.7). 
7.4.1. 
Data Monitoring Committee 
The DMC will review available unblinded safety data regularly (at least every month). The DMC 
will also have access to unblinded efficacy data as necessary. Refer to Section 13.8.1.2 for 
additional details. The DMC will be comprised of experienced members and will apply medical 
and statistical judgment during the performance of their activities according to a DMC charter. 
The DMC will be provided with all SAEs (including fatalities) and AESIs on an ongoing basis. 
 
7.4.2. 
Safety Criteria for Adjustment or Stopping Doses 
Enrollment in the study will be discontinued if the DMC determines that any of the following 
criteria have been met: 


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1. 
there is an increased risk of mortality due to brexanolone 
2. 
there is an increased risk of ICU delirium due to brexanolone 
3. 
there is an increased risk of prolonged intubation due to brexanolone 
4. 
there is an increased risk of reintubation due to brexanolone 
After each data review, the DMC may recommend that the study continue without modifications, 
continue with modifications, or be terminated, or that study treatment or enrollment is 
suspended. The DMC may also recommend stopping the study for futility at the time of interim 
analysis. 
 
7.5. 
Criteria for Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons including the occurrence of SAEs or other findings suggesting unacceptable risk to 
participants, or for administrative reasons. In the event of study termination, Sage Therapeutics 
will provide written notification to the investigator. Investigational sites must promptly notify 
their IRB/independent ethics committee (IEC), where required, and initiate withdrawal 
procedures for participants. 


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8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
Eligible participants must fulfill all inclusion criteria and none of the exclusion criteria. Results 
from standard of care assessments may be used for screening if they occur within the time 
windows specified in Figure 1. 
 
8.1. 
Participant Inclusion Criteria 
Each eligible participant must: 
1. Be confirmed positive for SARS-CoV-2 infection as determined by polymerase chain 
reaction at screening or within 2 weeks prior to screening 
2. Be aged 18 years or older 
3. Be able to provide written informed consent, signed by participant or by proxy (legally 
acceptable representative) 
4. Have a presumptive diagnosis of ARDS at screening and PaO2/FiO2 (PF ratio) <300 
within 48 hours prior to randomization 
5. Be intubated and receiving mechanical ventilation prior to randomization. Note that 
participants must have initiated mechanical ventilation within 48 hours prior to written 
informed consent, or have an immediate clinical plan for such intervention at time of 
written informed consent 
6. Be likely to survive, in the opinion of the investigator, for at least 72 hours from the time 
of written informed consent 
 
8.2. 
Participant Exclusion Criteria 
Each eligible participant must not: 
1. Be concurrently participating in another clinical study for an investigational product or 
device at screening 
2. Be pregnant, based on a positive pregnancy test at screening 
3. Be in fulminant hepatic failure at screening 
4. Have end stage renal disease at screening 
5. Have a known allergy to progesterone, allopregnanolone, or any excipients in the 
brexanolone injection 
 
8.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information will be 
collected, including demography, screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened. 


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8.4. 
Investigational Product Discontinuation and Early Termination from 
the Study 
A participant may withdraw from the study at any time at their own request (or by proxy/legally 
authorized representative [LAR]) for any reason. The investigator may discontinue a participant 
from IP for safety, behavioral, compliance, or administrative reasons, however, participants will 
remain in the study unless they withdraw consent. 
The reason for IP discontinuation and/or the reason for early termination from the study must be 
documented in the participant’s study record and recorded in the participant’s case report form 
(CRF). 
The investigator must notify the sponsor and/or the medical monitor when a participant stops 
participation in the study for any reason. 
 
8.4.1. 
Investigational Product Discontinuation 
If it is necessary to discontinue the IP earlier than planned and consent is not withdrawn, 
participants will remain in the study and be followed per protocol to capture safety and efficacy 
assessments for the duration of the study period. 
The reason for IP discontinuation must be documented in the participant’s study record and 
recorded in the appropriate CRF. 
 
8.4.2. 
Early Termination from the Study 
At the time of early study termination/stopping study participation, if possible, an early 
termination visit should be conducted. The participant will be permanently discontinued both 
from the IP and from the study at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor will retain 
and continue to use any data collected before such a withdrawal of consent. If a participant 
withdraws from the study, he/she may request destruction of any samples taken and not tested, 
and the investigator must document this in the site study records. 
 
8.4.3. 
Loss to Follow-up 
A participant will be deemed lost to follow-up after 3 attempts at contacting the participant have 
been unsuccessful. 
 
8.4.4. 
Replacement of Participants 
Participants will not be replaced. 


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9. 
TREATMENT OF PARTICIPANTS 
9.1. 
Description of Investigational Product 
Brexanolone is a sterile, clear, colorless solution that must be diluted prior to administration as 
an IV infusion. Placebo will be identical to brexanolone without the active ingredient. In this 
study, brexanolone or placebo will be administered as a single, continuous, IV infusion for 
60 hours. Additional details on IP administration are in Section 10.5 and additional IP 
description details can be found in Section 10 and in the brexanolone IB. 
 
9.2. 
Prior Medications, Concomitant Medications and Restrictions 
9.2.1. 
Prior and Concomitant Medications and/or Supplements 
Participants should receive standard of care treatment for ARDS due to COVID-19, and any 
concomitant medication deemed medically necessary for the welfare of the participant may be 
given at the discretion of the investigator at any time during the study. All concomitant 
medications, including central nervous system (CNS) depressants, agents employed to sedate 
participants and drugs administered to treat or prevent ICU delirium, administered from the time 
of informed consent through the end of the study should be recorded on the appropriate CRF. 
Details such as the start and stop dates and times, dose, and indication will be recorded. 
As noted in Section 7.4, brexanolone may potentiate the sedative effects of anesthetic drugs such 
as propofol and midazolam; the doses of these drugs should be titrated to the desired level of 
sedation during the infusion of brexanolone. Any change to dose(s) of sedative drugs, CNS 
depressants, and drugs administered to treat or prevent ICU delirium, in addition to the date and 
time of each dosage change, will be recorded throughout the duration of the study. 
Brexanolone contains betadex sulfobutyl ether sodium (SBECD) as a solubilizer. SBECD relies 
on renal clearance for elimination and may accumulate in participants with decreased renal 
function. Total daily dose of SBECD should be taken into consideration when other agents 
containing SBECD (including certain antifungals and antivirals, including remdesivir) are 
coadministered with IP. 
 
9.2.2. 
Prohibited Medications 
Not applicable 
 
9.2.3. 
Other Restrictions 
Participants may not participate in another clinical trial for an investigational product or device 
through the end of the study. 
Phenytoin or propofol may not be coadministered with IP in the same line. For other IV 
medications, infusion may occur via a port system, with separate ports for each infusion to avoid 
mixing medications in the long lines from the bags. 
 
9.3. 
Intervention after the End of the Study 
Not applicable 


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9.4. 
Treatment Adherence 
IP will be administered to participants by site staff, as described in Section 10.5. The 
investigator(s) or designated staff will record the time and dose of IP administration in the source 
documents. Any reasons for nonadherence will also be documented. Deviation(s) from the 
prescribed dosage regimen will be documented. Details on IP accountability are included in 
Section 10.6. 
9.5. 
Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled study. Participants and their family or 
caregivers, clinicians, site staff, and sponsor personnel will be blinded to treatment allocation. 
An independent DMC (see Section 13.8.1) will have access to unblinded safety data monthly and 
efficacy data as necessary. Participants who meet the eligibility criteria will be randomized in a 
stratified manner based on age (<70 or ≥70 years). Participants will be randomized 1:1 within 
each stratum to receive brexanolone plus standard of care or placebo plus standard of care. 
Randomization will be performed centrally via an interactive response technology (IRT) system. 
Randomization schedules will be generated by an independent statistician. The allocation to 
treatment group will be based on the randomization schedule. The randomization schedules will 
be kept strictly confidential, accessible only to authorized personnel until the time of unblinding. 
The blinding of the study will be broken after the database has been locked. 
Randomization must occur within 48 hours of written informed consent. 
 
9.5.1. 
Emergency Unblinding 
During the study, the blind is to be broken only when the safety of a participant is at risk and the 
treatment plan is dependent on the study treatment received. Unless a participant is at immediate 
risk, the investigator should make attempts to contact Sage prior to unblinding the study 
treatment administered to a participant. Requests from the investigator about the treatment 
administered to study participants should be discussed with the Sage medical monitor. If the 
unblinding occurs without Sage’s knowledge, the investigator must notify Sage within 24 hours 
of breaking the blind. All circumstances surrounding a premature unblinding must be clearly 
documented in the source records. 
In all cases where the IP allocation for a participant is unblinded (such as for SUSARs), pertinent 
information (including the reason for unblinding) must be documented in the participant’s 
records and on the CRF. 


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10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational Product 
Brexanolone is a sterile, clear, colorless, and preservative-free solution. It is hypertonic and must 
be diluted prior to administration as an IV infusion. Each mL of solution contains 5 mg of 
brexanolone, 250 mg of betadex sulfobutyl ether sodium (SBECD) as solubilizer, citric acid and 
sodium citrate as buffering agents, and Water for Injection, USP. Hydrochloric acid or sodium 
hydroxide may be used during manufacturing to adjust pH. 
Placebo will be identical to brexanolone and provided in identical vials. Placebo will be 
manufactured in a similar way to brexanolone and will consist of the same formulation without 
the active ingredient. 
 
10.2. 
Investigational Product Packaging and Labeling 
Brexanolone and placebo will be provided to the sites. 
The IP is sterile-filtered and aseptically filled into 20 mL clear glass vials with a stopper 
container closure system. IP is intended to be used as a single-use vial. 
Blinded IP labels with all required information and conforming to all applicable FDA Code of 
Federal Regulations and Good Manufacturing Practices/Good Clinical Practices guidelines will 
be prepared by the sponsor. 
Additional information regarding the packaging and labeling is provided in the Pharmacy 
Manual. 
 
10.3. 
Investigational Product Storage 
IP vials should be stored under refrigerated conditions (2 to 8°C) and suitably protected from 
light. The vials must be carefully stored safely and separately from other drugs. The IP may not 
be used for any purpose other than the present study. 
Additional information regarding IP storage is provided in the brexanolone Investigator’s 
Brochure. 
 
10.4. 
Investigational Product Preparation 
The pharmacist or designee will be responsible for preparing IP for dosing. The prepared 
admixture will be administered at room temperature. 
Refer to the Pharmacy Manual for specific instructions regarding requirements for IV bags and 
labeling, infusion sets, infusion preparation and administration instructions. 
 
10.5. 
Investigational Product Administration 
IP will be administered as a single, continuous, IV infusion for 60 hours. Initiation of the 
infusion must occur within 6 hours of randomization. 


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The specific infusion dose of IP will be calculated based on weight (obtained at screening) for 
each participant and will be administered as a single continuous IV infusion for 60 hours at 
70 mcg/kg/h for 58 hours followed by a 2-hour taper at 35 mcg/kg/h. Placebo infusion rates will 
be matched to the brexanolone infusion rates. 
Transfer out of the ICU is not an indication to discontinue the infusion of IP. The IP infusion 
may be stopped or the dose reduced due to an AE as described in Section 7.4. 
 
10.6. 
Investigational Product Accountability, Handling, and Disposal 
Upon receipt of IP, the investigator(s), or the responsible pharmacist or designee, will inspect the 
IP and complete and follow the instructions regarding receipt and storage in the Investigator’s 
Brochure and (where applicable) in the Pharmacy Manual. A copy of the shipping 
documentation will be kept in the study files. 
The IP provided is for use only as directed in this protocol. The investigator or designee must 
keep a record of all IP received, used and returned/discarded. Accurate records will be kept 
regarding the volume of IP used for each IV preparation, as well as the required infusion dose (or 
doses), the date and time of preparation and for which participant the IP was intended (ie, record 
participant initials and birth date or another unique identifier). Reasons for departure from the 
expected dosing regimen must be recorded. 
Sage Therapeutics will be permitted access to the study supplies at any time with appropriate 
notice during or after completion of the study to perform drug accountability reconciliation. 
The investigator, pharmacist, or qualified designee is responsible for drug accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final disposition records). 
At the end of the study, any unused IP will be returned to Sage Therapeutics for destruction or 
destroyed locally per the site’s procedures; disposition of IP will be documented. 
 
10.7. 
Product Complaints 
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution. 
In the course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 
forwarding the product complaint information via the contact information listed in Table 1. 
Where possible, personnel should segregate and retain any product, materials, or packaging 
associated with the product complaint until further instruction is provided by Sage or its 
designated representative(s). 










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12.1.5. 
Electrocardiogram 
A 12-lead ECG will be recorded at all scheduled time points. The standard intervals (heart rate, 
PR, QRS, QT, and QTcF) as well as any rhythm abnormalities will be recorded. Brief descriptive 
text should be included if the trace morphology is abnormal. 
 
12.1.6. 
Laboratory Assessments 
Hematology, clinical chemistry, and coagulation panels collected are to be recorded at the 
timepoints specified in Figure 1 and as noted below. 
 
12.1.6.1. Screening 
Standard of care hematology, clinical chemistry, and coagulation panels are to be collected 
within 12 hours prior to initiating IP. 
 
12.1.6.2. Visit 2 (Hour 0) through Visit 9 (Day 7) 
Hematology and clinical chemistry panels are to be recorded daily; panels collected per standard 
of care may be used. Additionally, coagulation parameters should be recorded at the time points 
indicated in Figure 1. 
 
12.1.6.3. After Visit 9 (Day 8 through Day 28) 
Hematology and clinical chemistry panels are to be recorded on Day 14 and Day 28; panels 
collected per standard of care may be used. Additional hematology and clinical chemistry panels 
collected per standard of care between Day 8 and Day 28 should also be recorded. 
 
12.1.6.4. Pregnancy Screen 
A serum or urine pregnancy test will be conducted for all female participants at screening. 
 
12.1.7. 
Richmond Agitation Sedation Scale 
The RASS is a tool validated to assess sedation and agitation in ICU patients (Sessler 2002). 
RASS is a 10-point scale, with 4 levels of anxiety or agitation (+1 to +4 [combative]), one level 
to denote a calm and alert state (0), and 5 levels of sedation (-1 to -5) culminating in unarousable 
(-5). 
The RASS will be administered once daily at the scheduled time points. In addition, the RASS 
will be administered within 2 hours after extubation. The RASS will also be administered each 
time the decision is made to stop the IP infusion or reduce the dose (see Section 7.4). 
 
12.1.8. 
Confusion Assessment Method for the Intensive Care Unit 
The CAM-ICU score is a validated score to assess delirium in mechanically ventilated patients 
using standardized nonverbal assessments (Ely 2001). 
The CAM-ICU will be administered every time RASS is assessed if RASS score ≥-3. 


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12.2. 
Adverse and Serious Adverse Events 
Nonserious AEs will be collected per the procedure described in Section 12.2.1. AESIs will be 
collected per the procedures described in Section 12.2.3. 
SAEs will be collected per the procedures described in Section 12.2.2 and Section 12.2.6. 
 
12.2.1. 
Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical investigation participant 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a 
medicinal (investigational) product whether or not related to the medicinal (investigational) 
product. In clinical studies, an AE can include an undesirable medical condition occurring at any 
time, including baseline or washout periods, even if no study treatment has been administered. 
A TEAE is defined as an adverse event with onset after the start of IP, or any worsening of a 
pre-existing medical condition/adverse event with onset after the start of IP and throughout the 
study. The term IP includes any Sage IP, a comparator, or a placebo administered in a clinical 
trial. 
Laboratory abnormalities and changes from baseline in vital signs, and ECGs are considered AEs 
if they result in discontinuation or interruption of study treatment, require therapeutic medical 
intervention, meet protocol specific criteria (if applicable) or if the investigator considers them to 
be clinically significant. Any abnormalities that meet the criteria for an SAE should be reported 
in an expedited manner. Laboratory abnormalities and changes from baseline in vital signs and 
ECGs that are clearly attributable to another AE do not require discrete reporting (eg, electrolyte 
disturbances in the context of dehydration, chemistry and hematologic disturbances in the 
context of sepsis). 
Participants who discontinue the IP due to an AE, regardless of investigator-determined 
causality, should be followed until the event is resolved, considered stable, or the investigator 
determines the event is no longer clinically significant. Any AEs that are unresolved at the 
participant’s last AE assessment in the study are followed up by the investigator for as long as 
medically indicated, but without further recording in the CRF. The sponsor or its representative 
retains the right to request additional information for any participant with ongoing 
AE(s)/SAE(s)/AESIs at the end of the study, if judged necessary. 
12.2.2. 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence that, at any dose: 
• Results in death 
• Places the participant at immediate risk of death (a life-threatening event); however, 
this does not include an event that, had it occurred in a more severe form, might have 
caused death 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 




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12.2.4. 
Relationship to Investigational Product 
The investigator must make the determination of relationship to the IP for each AE (not related, 
related). The following definitions should be considered when evaluating the relationship of AEs 
SAEs, and AESIs to the IP. 
 
Not Related 
An AE will be considered “not related” to the use of the IP if there is not a reasonable 
possibility that the event has been caused by the IP. Factors pointing towards this 
assessment include but are not limited to: the lack of temporal relationship between 
administration of the IP and the event, the presence of biologically implausible 
relationship between the product and the AE, or the presence of a more likely 
alternative explanation for the AE 
Related 
An AE will be considered “related” to the use of the IP if there is a reasonable 
possibility that the event may have been caused by the product under investigation. 
Factors that point towards this assessment include but are not limited to: a positive 
rechallenge, a reasonable temporal sequence between administration of the drug and 
the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the 
drug and the AE, or a lack of alternative explanation for the AE 
For AESIs deemed “not related” to IP, the suspected cause of the event should be recorded on 
the AESI form. 
 
12.2.5. 
Recording Adverse Events 
Adverse events spontaneously reported by the participant and/or in response to an open question 
from the study personnel or observed will be recorded during the study at the investigational site. 
The AE term should be reported in standard medical terminology when possible. For each AE, 
the investigator will evaluate and report the onset and resolution (date and time), intensity, 
causality, seriousness criterion(ia), action taken, and outcome (if applicable), and whether the AE 
resulted in IP dose reduction, discontinuation of the IP or withdrawal from the study. 
Intensity will be assessed according to the guidelines for the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0. The CTCAE provides a grading 
(severity) scale for AEs, with unique clinical descriptions of severity based on the general 
guidance listed below: 
Table 2: 
Common Terminology Criteria for Adverse Events 
 
Grade 
Criteria 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
2 
Moderate; minimal, local, or noninvasive intervention such as packing or cautery 
indicated, limiting age-appropriate instrumental activities of daily living (ADL) 
3 
Severe; or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL 


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Grade 
Criteria 
4 
Life-threatening consequences; urgent indications indicated 
5 
Death related to adverse event 
It is important to distinguish between seriousness and severity. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.2. An AE of severe intensity 
may not necessarily be considered serious. 
 
12.2.6. 
Reporting Serious Adverse Events 
Except as specified below, in order to adhere to all applicable laws and regulations for reporting 
an SAE(s), the study site must notify Sage or designee within 24 hours of the study site staff 
becoming aware of the SAE(s). The investigator must complete, sign and date the SAE reporting 
form, verify the accuracy of the information recorded on the SAE reporting form with the 
corresponding source documents, and send a copy to Sage or designee. 
Additional follow-up information, if required or available, should all be sent to Sage or designee 
within 24 hours of receipt on a follow-up SAE reporting form and placed with the original SAE 
information and kept with the appropriate section of the CRF and/or study file. 
SAEs occurring after the designated follow-up time for the study, should be reported to Sage or 
designee according to the timelines noted above only if the investigator considers the SAE 
related to IP. 
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the principal investigator’s responsibility to notify the IRB/IEC of all SAEs that 
occur at his or her site. Investigators will also be notified of all suspected unexpected serious 
adverse reactions (SUSARs) that occur during the clinical study. IRBs/IECs will be notified of 
SAEs and/or SUSARs as required by local law. 
Exceptions to the Standard SAE Reporting Requirements 
Unless otherwise noted below, if the event is included in Table 3, an SAE reporting form does 
not need to be completed, but the event should be recorded on the CRF. The following 
exceptions apply: 
• Please Note: If the event is on the list and if the event was considered by the 
investigator to be related to IP then the SAE reporting form will be completed, and 
the SAE will be reported to Sage per standard SAE reporting requirements. The SAE 
form for such an event has to be sent to Sage or designee within 24 hours of the site 
becoming aware of the SAE. 
• Please Note: If the event is on the list, but the outcome is fatal, the mortality CRF will 
be completed, the SAE reporting form will be completed, and the SAE will be 
reported to Sage per standard SAE reporting requirements. The SAE form for such an 
event has to be sent to Sage or designee within 24 hours of the site becoming aware 
of the SAE. The mortality CRF will capture the actual cause of death as well as the 
category of the cause of death. 


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Table 3: 
List of Common ICU Comorbidities 
 
Complications of Mechanical Ventilatory 
Support 
Infectious Complications 
Pulmonary barotrauma / pneumothorax 
Skin and soft tissue infection 
Ventilator associated pneumonia 
Sepsis or bacteremia 
Cardiac and Vascular Events 
Septic shock 
Tachyarrhythmias such as: 
Pneumonia 
Atrial fibrillation 
Urinary tract infection or urosepsis 
Ventricular tachycardia 
Catheter site infections 
Ventricular fibrillation 
Gastrointestinal 
Pulmonary embolism 
Esophageal, gastric or duodenal ulcer 
Thromboembolic event (other than pulmonary) 
Gastrointestinal bleeding 
Myocardial infarction 
Other 
Stroke / cerebrovascular accident 
Acute renal failure 
Hypotension 
Complications of procedures 
 
12.3. 
Pregnancy 
If a participant becomes pregnant after initiating IP, pregnancy information must be collected 
and recorded on the pregnancy form and submitted to the sponsor within 24 hours of learning of 
the pregnancy. Details will be collected for all pregnancies for which conception was likely to 
have occurred after the start of IP administration until 5 terminal half-lives following the last 
administration of IP or until the completion of the study whichever is longer. Any pregnancy 
occurring in that time frame will be followed until delivery or termination of the pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The outcome of all 
pregnancies (eg, spontaneous abortion, elective abortion, normal birth) must be followed and 
documented even if the participant was discontinued from the study. The investigator will collect 
follow-up information on the participant and the neonate, and the information will be forwarded 
to Sage or designee. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date. Any termination of pregnancy will be reported, regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an IP may have 
interfered with the effectiveness of a contraceptive medication. Any complication during 
pregnancy (eg, anemia, infections, pre-eclampsia) should be reported as an AE/SAE. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
spontaneous abortion, stillbirth, neonatal death), the Investigator should follow the procedures 
for reporting an SAE. 


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12.4. 
Overdose 
An overdose will be considered to have occurred if the infusion rate exceeds the recommended 
rate by 10% at any point during the infusion and/or the total dose administered exceeds 10% of 
the protocol-defined total dose. Overdoses are not considered AEs and should not be recorded as 
an AE on the CRF; however, all overdoses must be recorded on an Overdose form and sent to 
Sage or designee within 24 hours of the site becoming aware of the overdose. An overdose must 
be reported to Sage or designee even if the overdose does not result in an AE. 


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13. 
STATISTICS 
Detailed description of the interim and final analyses to be performed in the study will be 
provided in the statistical analysis plan (SAP). To avoid a potentially biased estimate of the event 
rate in each arm at the time of the interim analysis, both the interim analyses and final analysis 
will incorporate all available data from all participants in the study in the analysis population, 
regardless of whether participants have reached Day 28. The SAP will be finalized and approved 
prior to database lock of the interim analysis. Any changes/additions to the SAP following 
database lock will be described in detail in the clinical study report. 
 
13.1. 
Data Analysis Sets 
The Randomized Set is defined as all randomized participants (based on treatment as 
randomized). 
The Full Analysis Set is defined as all randomized participants who initiated IV infusion of 
brexanolone or placebo (based on treatment as randomized). 
Per Protocol (PP) Set is defined as all randomized participants (based on treatment as 
randomized) with no major protocol deviations. This is a subset of the Randomized Set. 
The Safety Set will include all participants who initiated IV infusion of brexanolone or placebo 
(based on actual treatment received). 
 
13.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All participants, including those with missing 
data, will be used in the analyses, as per the analysis sets defined in Section 13.1. The primary 
analysis method will use all nonmissing data available. In addition, tipping-point analyses will be 
conducted as sensitivity analyses to assess the impact of missing data. 
 
13.3. 
General Considerations 
All participant data, including those that are derived, that support the tables and figures will be 
presented in the participant data listings. Some data may be presented only in participant data 
listing, some may be presented with a corresponding table or figure; these will be indicated in 
relevant sections below. Unless otherwise specified in the SAP, baseline is defined as the last 
measurement prior to the start of IP infusion. 
Continuous endpoints will be summarized with number (n), mean, standard deviation, median, 
minimum, and maximum. In addition, change from baseline values will be calculated at each 
time point and summarized descriptively. For categorical endpoints, descriptive summaries will 
include counts and percentages. 
 
13.4. 
Demographics and Baseline Characteristics 
Demographic data, such as age, race, and ethnicity, and baseline characteristics, such as height 
and weight will be summarized using the Safety Set. 
Medical history will be listed by participant. 








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A detailed description of the interim analysis is included in the SAP. 
 
13.8.1.2. Data Monitoring Committee Analysis 
An independent DMC will monitor the clinical data for safety and will meet at least monthly 
throughout the duration of the study. The DMC will provide recommendations for continuing or 
stopping the study for safety in accordance with the DMC charter. Stopping criteria are presented 
in Section 7.4.2 and Section 13.8.1.1. 
In order to perform their monitoring function, the DMC will have access to unblinded safety data 
to ensure the safety of the participants in the study. Efficacy data will also be delivered to the 
DMC as needed to perform their functions. The DMC will also review the results of the planned 
interim analysis (see Section 13.8.1.1). 
Only descriptive analysis will be performed (ie, no statistical hypothesis testing will be 
performed). All analyses will be performed by a designated clinical research organization 
independent of Sage. 


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
During the COVID-19 pandemic, travel and site visit restrictions are in place to protect the safety 
of participants, staff, and to minimize the spread of disease. While these COVID-19 restrictions 
are in place, oversight of the study sites will comprise phone calls and information provided by 
sites to Sage, as appropriate. Once the travel and site visit restrictions are lifted, Sage or a Sage 
representative may conduct in-person site visits, as appropriate. 
Before an investigational site can enter a participant into the study, a representative of Sage 
Therapeutics may visit or otherwise contact the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Sage Therapeutics or its representatives. 
This will be documented in a Clinical Trial Agreement between Sage Therapeutics and 
the investigator. 
During the study, a monitor from Sage Therapeutics or representative will have regular contacts 
with the investigational site, for the following: 
• Provide information and support to the investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that IP accountability checks are being 
performed 
• Perform source data verification. This includes a comparison of the data in the case report 
forms with the participant’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each 
participant (eg, clinic charts). 
• Record and report any protocol deviations not previously sent to Sage Therapeutics 
• Confirm AEs have been properly documented on CRFs and confirm any AESIs and 
SAEs have been forwarded to Sage Therapeutics as specified in Section 12.2.3 and 
Section 12.2.6, respectively, and those SAEs that met criteria for reporting have been 
forwarded to the IRB or IEC 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
 
14.2. 
Audits and Inspections 
Sage Therapeutics or authorized representatives of Sage Therapeutics, a regulatory authority, or 
an IEC or an IRB may visit the site to perform an audit(s) or inspection(s), including source data 
verification. The purpose of a Sage Therapeutics audit or a regulatory authority inspection is to 
systematically and independently examine all study-related activities and documents to 


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determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, GCP/ICH GCP guidelines, and any applicable 
regulatory requirements. The investigator should contact Sage Therapeutics immediately if 
contacted by a regulatory agency or IRB/IEC about an inspection. 
 
14.3. 
Institutional Review Board or Independent Ethics Committee 
The principal investigator must obtain IRB (or IEC) approval for the clinical study prior to 
enrolling a participant. Initial IRB (or IEC) approval, and all materials approved by the IRB (or 
IEC) for this study including the participant consent form and recruitment materials must be 
maintained by the Investigator and made available for inspection. 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practice (GCP) and all applicable regulatory 
requirements, Sage Therapeutics may conduct a quality assurance audit(s) at the clinical site. 
Please see Section 14.2 for more details regarding the audit process. 
The investigator must have adequate quality control practices to ensure that the study is 
performed in a manner consistent with the protocol, GCP/ICH GCP guidelines, and applicable 
regulatory requirements. The investigator is responsible for reviewing all identified protocol 
deviations. Significant protocol deviations should be reported to the IRB/IEC per the IRB/IEC’s 
written procedures. 
The investigator is responsible for supervising any individual or party to whom the investigator 
delegates trial-related duties and functions conducted at the trial site. When the investigator 
retains the services of any individual or party to perform trial-related duties and functions, the 
investigator must ensure the individual or party is qualified to perform trial-related duties and 
functions and should implement procedures to ensure the integrity of the trial-related duties and 
functions performed, and any data generated. 
The investigator must maintain adequate and accurate source documents and trial records that 
include all pertinent observations on each of the site’s trial participants. Source data must be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data 
should be traceable, should not obscure the original entry, and should be explained, if necessary 
to provide clarification. 


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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be given a written and 
dated approval or favorable opinion by an IRB or IEC as appropriate. The investigator must 
obtain and document approval before he or she can enroll any participant into the study. The IRB 
or IEC must supply to the sponsor a list of the IRB/IEC membership and a statement to confirm 
that the IRB/IEC is organized and operates according to GCP and applicable laws and 
regulations. 
The principal investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit participants for the study. The protocol must be re-approved by the 
IRB or IEC upon receipt of amendments and annually, as local regulations require. 
The principal investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the IP. Sage 
Therapeutics will provide this information to the principal investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. In addition, the principal investigator must 
inform the IRB/IEC and sponsor of any changes significantly affecting the conduct of the trial 
and/or increasing the risk to participants (eg, violations to the protocol or urgent safety measures 
taken for participant safety). 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH and GCP guidelines, as well as all 
applicable regional or national regulatory requirements. 
 
16.3. 
Written Informed Consent 
Prior to enrolling a trial participant, the investigator(s) will ensure that the participant and/or the 
legally authorized representative is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study. Participants and/or their 
representatives must also be notified that they are free to discontinue from the study at any time. 
The participant and/or their representative should be given the opportunity to ask questions and 
allowed time to consider the information provided. 
When the participant decides to participate in the trial, the participant (or the participant’s LAR) 
must provide signed and dated informed consent. The written consent must be obtained before 
conducting any study procedures. The investigator must document the consent process in the 
participant’s source records. The investigator must maintain the original, signed ICF. A copy of 
the signed ICF must be given to the participant or to the participant’s LAR. 
Participants may be unable to give consent. Therefore, consent will be given by proxy by a LAR. 
Should a participant gain the ability to sufficiently comprehend the situation and consent during 
the course of the study, written informed consent or verbal assent will be documented as required 


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or recommended by the institution’s IRB. The form of consent to be obtained will depend on the 
condition of the participant as determined by the principal investigator. 
Throughout the trial, participants should be informed of any changes made to the study and as 
new safety and or risk information becomes known. The provision of this information will be 
documented in the participant’s source records, and when applicable, an updated ICF will be 
provided. 


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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Sage Therapeutics or its representative(s) will be allowed to conduct site visits at the 
investigation facilities for the purpose of monitoring any aspect of the study (Section 14.1). The 
investigator agrees to allow the monitor to inspect the facility, drug storage area, drug 
accountability records, participant charts and study source documents, and other records relative 
to study conduct. 
Inspection of the study by a Regulatory Authority may occur at any time. The investigator must 
agree to the inspection of study-related records and source documents by the Regulatory 
Authority representative(s). 
 
17.2. 
Retention of Records 
The principal investigator must maintain all documentation relating to the study for the period 
outlined in the site contract, or for a period of 2 years after the last marketing application 
approval, and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the IP. Sage is responsible to inform the investigator/institution as to when study documents 
no longer need to be retained. 


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18. 
PUBLICATION POLICY 
All information concerning brexanolone is considered confidential and shall remain the sole 
property of Sage Therapeutics. The investigator agrees to use this information only in conducting 
the study and shall not use it for any other purposes without written approval from Sage 
Therapeutics. No publication or disclosure of study results will be permitted except as specified 
in a separate, written, agreement between Sage Therapeutics and the investigator. 


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19. 
LIST OF REFERENCES 
ARDS Definition Task Force, Ranieri, VM, Rubenfeld, GD, et al. Acute respiratory distress 
syndrome: the Berlin Definition. JAMA. 2012;307(23), 2526-2533. 
Beigel JH, Tomashek, KM, Dodd, LE, Mehta, AK, Zingman, BS, et al. Remdesivir for the 
Treatment of COVID-19 – Preliminary Report. NEJM. 2020. DOI: 10.1056/NEJMoa2007764. 
Bhatraju, PK, Ghassemieh, BJ, Nichols, M, et al. Covid-19 in Critically Ill Patients in the Seattle 
Region - Case Series. N Engl J Med. 2020. doi:10.1056/NEJMoa2004500 
CDC COVID-19 Response Team. Severe Outcomes Among Patients with Coronavirus Disease 
2019 (COVID-19) — United States, February 12–March 16, 2020. MMWR Morb Mortality 
Wkly Rpt. 2020;(69), 343-346. 
Ely EW, Inouye SK, Bernard GR, Gordon S, Francis J, May L, et al. Delirium in Mechanically 
Ventilated Patients: Validity and Reliability of the Confusion Assessment Method for the 
Intensive Care Unit (CAM-ICU). JAMA. 2001 Dec 5;286(21):2703-10. 
Howell MD, Davis AM. Management of ARDS in Adults. JAMA. 2018; Feb 20;319(7):711-712. 
Hu, L, Chen, S, Fu, Y, Gao, Z, Long, H, Ren, HW. Risk Factors Associated with Clinical 
Outcomes in 323 COVID-19 Patients in Wuhan, China. 2020. Preprint available through 
medRxiv. 
Intensive Care National Audit and Research Centre. ICNARC Report on COVID-19 in Critical 
Care 27 March 2020. icnarc.org. 2020; Mar 27. 
Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O'Neal PV, Keane KA, et al. The Richmond 
Agitation-Sedation Scale: Validity and Reliability in Adult Intensive Care Unit Patients. Am J 
Respir Crit Care Med. 2002 Nov 15;166(10):1338-44. 
Wujtewicz, M, Dylczyk-Sommer, A, Aszkielowicz, A, Zdanowski, S, Piwowarczyk, S, Owczuk, 
R. COVID-19 - what should anaethesiologists and intensivists know about it? Anaesthesiol 
Intensive Ther. 2020;52(1), 34-41. 


 
 
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SAP_001.pdf: 
Official Title: 
A Study of Brexanolone for Acute Respiratory Distress Syndrome 
due to COVID-19
NCT Number: 
NCT04537806
Document Date: 
SAP Version 1.0: 23 November 2021


DocuSign Envelope ID: 13C3E8B4-E995-4D1E-89E1-CADE1F9A1C15 
STATISTICAL ANALYSIS PLAN 
METHODS 
PROTOCOL NUMBER 547-ARD-301 
A STUDY OF BREXANOLONE FOR ACUTE RESPIRATORY DISTRESS 
SYNDROME DUE TO COVID-19 
Author of SAP: 
 
Version: 1.0 
Version Date of SAP: 19 November 2021 
Sponsor: 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, Massachusetts 02142 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure 
without the prior written consent of Sage Therapeutics, Inc. is strictly prohibited except to the 
extent required under applicable laws or regulations. Persons to whom the information is 
disclosed must be informed that the information is confidential and may not be further 
disclosed by them. 




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Statistical Analysis Plan Methods Version 1.0 19 November 2021 
Sage Therapeutics, Inc. 
Protocol Number: 547-ARD-301 (Version 5.0 24 February 2021) 
 
CONFIDENTIAL 
 
TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS ................................................................... 7 
2. 
INTRODUCTION .................................................................................... 9 
3. 
STUDY OBJECTIVES ........................................................................... 10 
3.1. 
Primary Objective ................................................................................... 10 
3.2. 
Secondary Objective ............................................................................... 10 
 
 10 
4. 
STUDY ENDPOINTS ............................................................................ 11 
4.1. 
Efficacy Endpoints .................................................................................. 11 
4.1.1. 
Primary Efficacy Endpoint ...................................................................... 11 
4.1.2. 
Key Secondary Efficacy Endpoint .......................................................... 11 
4.1.3. 
Estimand for the Primary and Key Secondary Efficacy Endpoints ........ 11 
 
 11 
4.2. 
Safety Endpoints ...................................................................................... 12 
 
 12 
5. 
STUDY DESIGN .................................................................................... 13 
5.1. 
Overall Design ........................................................................................ 13 
5.2. 
Sample Size and Power ........................................................................... 14 
5.3. 
Randomization ........................................................................................ 14 
5.4. 
Blinding and Unblinding ......................................................................... 14 
6. 
MODIFICATIONS ................................................................................. 15 
6.1. 
Modifications from the Approved Clinical Study Protocol .................... 15 
6.1.1. 
Per-Protocol Analysis Population ........................................................... 15 
6.1.2. 
Concomitant Medications ....................................................................... 15 
 
 15 
6.1.4. 
Efficacy Analyses ................................................................................... 15 
6.1.5. 
Tipping Point Analyses ........................................................................... 16 
6.1.6. 
Interim Analysis ....................................................................................... 16 
 
 16 
6.2. 
Modifications from the Approved Statistical Analysis Plan ................... 16 
6.3. 
Modifications from the Approved DMC Charter .................................... 16 






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APPENDIX D. PROCEDURAL TERMS USED IN THE IDENTIFICATION OF 
RESPIRATORY FAILURE AND UNSUCCESSFUL EXTUBATION46 




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Abbreviation 
Definition 
SARS-CoV-2 
the novel coronavirus responsible for COVID-19 
 
 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 


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2. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the planned statistical analyses and data 
presentations for the final analysis of the 547-ARD-301 study and is based on the study 
protocol, version 5.0, dated 24 February 2021. This study is being terminated early due to 
Sponsor decision, not for safety reasons. Please see Section 6.1 for additional details. 
All analyses and data presentations will be generated using SAS® Version 9.4 or 
higher Software (SAS Institute, Cary, North Carolina, USA). This SAP will be finalized and 
approved before the clinical database lock for the planned final analysis. Any changes made 
to the SAP after the clinical database lock for the final analysis has occurred will be 
documented and discussed in the clinical study report for this study. 








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5. 
STUDY DESIGN 
5.1. 
Overall Design 
This is a randomized, double-blind, placebo-controlled study designed to evaluate treatment 
with brexanolone in approximately 100 participants with ARDS due to COVID-19. 
Participants and their family or caregivers, clinicians, site staff, and sponsor personnel will be 
masked to treatment allocation. 
Participants with ARDS and SARS-CoV-2 infection who give informed consent (or for 
whom consent is given by a proxy) and who are currently intubated and receiving mechanical 
ventilation as part of standard of care or who are on an immediate clinical plan to receive 
such intervention will be eligible for screening. All participants must have mechanical 
ventilation in place prior to randomization. Eligible participants will be stratified by age (<70 
or ≥70 years) and randomized 1:1 within each stratum to receive either brexanolone plus 
standard of care or placebo plus standard of care. 
Participants will receive continued standard of care in addition to a continuous intravenous 
(IV) infusion of investigational product (IP) – brexanolone or placebo for 60 hours. The 
infusion must be initiated within 6 hours from the time of randomization. The blinded 60- 
hour infusion will be administered at a dose of 70 mcg/kg/h for 58 hours followed by a 2- 
hour taper at 35 mcg/kg/h. Transfer out of the ICU is not an indication to discontinue the 
infusion of investigational product. 
Brexanolone may potentiate the sedative effects of co-administered anesthetics. During IP 
infusion, if sedation levels are deeper than intended, the dose(s) of sedative anesthetics 
should be titrated to the desired effect rather than adjusting the dose of IP (see Section 7.4 of 
the study protocol for additional details). 
Dose adjustment is permitted in the event that a participant is experiencing unplanned 
sedation/somnolence when no longer on any sedating agents or if the participant experiences 
an intolerable adverse event (AE) determined by the investigator to be related to IP. Details 
regarding dose adjustment criteria and procedures are provided in Section 7.4 of the study 
protocol. 
Follow-up assessments will be conducted as summarized in the Protocol, limited assessments 
will be collected by phone if the participant has been discharged from inpatient care. All 
participants will have measures of pulmonary function assessed throughout the study. Unless 
the clinical condition of the participant dictates otherwise, the ventilation guidelines for 
ARDS due to COVID-19 should be followed. 
An independent data monitoring committee (DMC) will monitor the clinical data for safety 
and will meet at least monthly throughout the duration of the study. In order to perform their 
monitoring function, the DMC will have access to data to ensure the safety of the participants 
in the study. The DMC will provide recommendations for continuing or stopping the study 
for safety or futility in accordance with the DMC charter. Refer to Section 7.4.1 and 
Section 13.8.1.2 of the study protocol for additional details. 


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5.2. 
Sample Size and Power 
The sample size of approximately 100 participants would provide 80% power to detect a 
treatment difference of 27% in proportion of participants alive and free of respiratory failure 
at Day 28. The sample size is computed assuming proportion of 50% for the placebo group 
and 77% for the brexanolone group using Chi-square test with a two-sided Type I error rate 
(alpha) of 0.05. 
5.3. 
Randomization 
This is a randomized, double-blind, placebo-controlled study. Participants who meet the 
eligibility criteria will be randomized in a stratified manner based on age (<70 or ≥70 years). 
Participants will be randomized in a 1:1 ratio within each stratum to receive brexanolone plus 
standard of care or placebo plus standard of care. Randomization will be performed centrally 
via an interactive response technology system. Randomization schedules will be generated by 
an independent statistician outside Sage. 
5.4. 
Blinding and Unblinding 
Participants and their family or caregivers, clinicians, site staff, and sponsor personnel will be 
blinded to treatment allocation. An independent DMC will have access to unblinded data as 
described in the DMC charter. 
The randomization schedules will be kept strictly confidential, accessible only to authorized 
personnel until the time of unblinding. The blinding of the study will be broken after the 
database has been locked. 
During the study, the blind is to be broken only when the safety of a participant is at risk and 
the treatment plan is dependent on the study treatment received. Unless a participant is at 
immediate risk, the investigator should make attempts to contact Sage prior to unblinding the 
study treatment administered to a participant. Requests from the investigator about the 
treatment administered to study participants should be discussed with the Sage medical 
monitor. If the unblinding occurs without Sage’s knowledge, the investigator must notify 
Sage within 24 hours of breaking the blind. All circumstances surrounding a premature 
unblinding must be clearly documented in the source records. 
In all cases where the IP allocation for a participant is unblinded (such as for suspected 
unexpected serious adverse reactions (SUSARs)), pertinent information (including the reason 
for unblinding) must be documented in the participant’s records. 








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8. 
STATISTICAL ANALYSIS 
8.1. 
General Considerations 
Unless otherwise specified, continuous endpoints will be summarized with n, mean, standard 
deviation (SD), median, minimum (min) and maximum (max). The min and max will be 
reported with the same number of decimal places as the source (raw) data. Mean and median 
will be reported to 1 decimal place more than the source (raw) data and standard deviation 
will be reported to 2 decimal places more than the source (raw) data, but no more than 4 
decimal places. Any values that require transformation to standard units (metric or SI) will 
be converted with the appropriate corresponding precision. 
Categorical variables (eg, presence of an AE) will be summarized using counts and 
percentages. Percentages will be presented to 1 decimal place unless otherwise specified. 
All participant data, including those derived, that support the tables and figures will be 
presented in the participant data listings. Some data may be presented only in participant data 
listing with an underlying table or figure; these will be indicated in relevant sections below. 
All summaries will be provided by treatment – either by treatment assigned at randomization, 
or actual treatment received. Actual treatment is defined as: 
- 
Brexanolone – if the participant was exposed to brexanolone; 
- 
Placebo – if the participant received placebo and not a single dose of brexanolone. 
For the purpose of all safety and efficacy analyses, baseline is defined as the last non-missing 
measurement on or prior to the initiation of IP, unless stated otherwise. 
P-values will be reported to four decimal places, with p-values less than 0.0001 reported as 
“<0.0001”. P-values larger than 0.9999 will be reported as “>0.9999”. 
 
8.1.1. 
Definition of Study Day 
For the purpose of the efficacy and safety data summaries, Study Day 1 is defined as the date 
of first dose of study treatment. For visits (or events) that occur on or after the date of first 
dose of study treatment, Study Day is defined as: 
(date of visit [event] − date of first dose of study treatment + 1). 
For visits (or events) that occur prior to the date of first dose of study treatment, Study Day is 
defined as: 
(date of visit [event] − date of first dose of study treatment). There is no Study Day 0. 
 
8.1.2. 
Visit Windows 
Visit windows are defined in Table 2. It is noted that certain specific endpoints might have 
slightly different analysis visit rules. If an endpoint will be analyzed using the visit windows, 
as specified in the corresponding sections of the applicable endpoints, all assessments within 
the window, regardless if the assessment is scheduled or unscheduled, will be included. A 






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8.2.2. 
Protocol Deviations 
Protocol deviations identified during the study will be captured and categorized by the study 
team review as major or minor deviations in blinded fashion on an ongoing basis until 
database lock. 
The major protocol deviations will be summarized for all randomized participants using the 
FAS. All protocol deviations (major and minor) will be included in a data listing. 
 
8.2.3. 
Demographics and Baseline Characteristics 
The following analyses will be provided separately for the Safety Analysis Set (using actual 
treatment received), and the FAS (using randomized treatment). 
Demographic data (age at informed consent date, race, sex, ethnicity) and baseline 
characteristics, such as height, weight, and body mass index (BMI), will be summarized by 
treatment group (randomized for FAS and actual for Safety Analysis Set) and overall. 
 
8.2.4. 
Pregnancy Tests 
A serum or urine pregnancy test will be conducted for all female participants at screening. 
These data will be listed by participant. 
 
8.2.5. 
Medical/Surgical History 
Listings and tabulations associated with Medical and/or Surgical History will use the Safety 
Analysis Set. 
Medical/surgical history collected at screening will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA), Version 23.0 or later. Medical/surgical history data 
will be summarized by system organ class (SOC) and preferred term (PT). 
In addition to medical/surgical history collected at screening, listings will also include 
COVID-19 symptom onset date, COVID-19 vaccination history (including dates of 
administration and manufacturer), 
 date of diagnosis 
of ARDS, severity of ARDS at screening (per Berlin Criteria; ARDS Definition Task Force), 
date and time of initial intubation, and the date and time of initiation of mechanical 
ventilation. Protocol version will be included in these listings. 
 
8.2.6. 
Prior and Concomitant Medications 
Listings and tabulations associated with Prior and Concomitant Medications will use the 
Safety Analysis Set. 
All medications taken and procedures undergone during the study will be recorded. All 
medications will be coded using World Health Organization-Drug (WHO) Global B3 
September 2020 or later. 
Medications will be presented according to whether they are being taken prior to and/or 
during the study (concomitant). Prior medications are defined as those taken prior to the 
initiation of the IP. Concomitant medications are defined as those with a start date and time 
on or after the initiation of IP or those with a start date and time before the initiation of IP 


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that are ongoing or with a stop date/time on or after the initiation of IP. If medication 
date/time is incomplete and it is not clear whether the medication was concomitant, it will be 
assumed concomitant. For imputation of missing concomitant medication dates, please refer 
to Appendix A. Note that it is possible for a medication to be both ‘prior’ and ‘concomitant’ 
when a medication has start date and time before the initiation of IP and end date and time 
either missing or after the initiation of IP. 
Concomitant procedures are recorded on a separate electronic case report form (eCRF) page; 
this will be presented in a listing by participant. The study day for the end date of the 
procedure will be provided, when a complete end date is available. 
Concomitant medication data will be tabulated for the following classes of medications using 
a standard concomitant medication table format. Medications in the following categories 
will also be listed: 
• CNS depressants (eg, benzodiazepines, opioids/opiates, barbiturates, propofol); 
• other agents utilized for sedation effects (eg, dexmedetomidine); 
• drugs administered to treat or prevent ICU delirium (eg, antipsychotics, atypical 
antipsychotics, or other agents intended for delirium treatment). 
Please see Section 8.4.2 for details regarding the ATC Level 3 codes corresponding to these 
medication classes. There will be no prohibited medications defined for this study. 
 
8.2.7. 
Investigational Product Exposure 
The total exposure (in mcg/kg) to IP is defined as the total mcg/kg for brexanolone that was 
received during the study. Total drug exposure for participants randomized to placebo is 
zero, unless the participant received brexanolone by mistake, in which case the total exposure 
comes from brexanolone exposure. 
The exposure duration to IP is defined as total number of hours treated with study drug 
during the study, which is calculated as (end time of infusion – start time of infusion [in 
seconds])/3600. Note that this does not exclude the time when the dose has been interrupted. 
The total exposure and exposure duration to IP will be summarized by descriptive statistics, 
using the Safety Analysis Set. 
 
8.2.8. 
Investigational Product Adherence 
IP adherence (%) is calculated as [Actual total dose (in mcg/kg)/Planned total dose (in 
mcg/kg) x 100]. Actual total dose will account for the tapering period. IP adherence will be 
summarized using the Safety Analysis Set. 
 
8.3. 
Efficacy Analysis 
The Full Analysis Set will be used for all efficacy analyses. When referencing “Day 28” in 
efficacy analyses, it is understood that this refers to Visit 11. 








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produce estimated treatment differences (ie, differences in proportions). A sample SAS code 
is as follows: 
proc genmod data=indata; 
class trt01p agegr1; 
model aval = trt01p agegr1 / dist=binomial link=identity; 
lsmeans trt01p / diff cl; 
run; 
 
Please see Appendix D for a detailed breakdown of the Procedural terms used to identify 
subjects with lack of respiratory failure. 
 
8.3.3. 
Analysis of Key Secondary Efficacy Endpoint 
The proportion of participants who died for any cause (all-cause mortality) by Visit 11 (Day 
28 ± 3 days) is the key secondary endpoint. 
• If a participant dies prior to Visit 11, the participant will be assigned a value of “yes” 
for the key secondary endpoint 
• Participants having Visit 11 (either in-person or via phone call) will be assigned a 
value of “no” for the key secondary endpoint 
• Participants having follow-up assessments on/after Day 25 and known to be alive for 
those assessments and for whom Visit 11 was not performed will be assigned a value 
of “no” for the key secondary endpoint 
• Participants with early study termination (ET) for reasons other than death and prior 
to Visit 11 will not be included in the primary analysis. 
The difference in the proportions between brexanolone and placebo will be analyzed using 
the SAS procedure GENMOD. In this model, the proportion will be the response variable, 
and the predictor variables will be treatment arm and age group (<70 or ≥70 years). 
Participants will be analyzed according to their actual age group, regardless of the age group 
used for randomization purposes. The proportion will be directly modeled using the binomial 
distribution with identity link. The point estimate, confidence interval, and p-value for the 
difference in the fitted proportions will be obtained using the “LSMEANS” statement to 
produce estimated treatment differences (ie, differences in proportions). The sample SAS 
code presented in Section 8.3.2 will be adapted for this purpose. 
8.3.3.1. 
Multiplicity Adjustment 
No adjustment for multiplicity will be done. 








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Table 3: 
Safety Endpoints and Variables in the Summary Tables 
 
Safety 
Evaluation 
Incidence 
Raw 
Value 
Change 
from 
Baseline 
Normal Range 
Shift from 
Baseline 
Potentially 
Clinically 
Significant 
(PCS) 
Abnormality/ 
Clinical 
Significance 
AEs 
X 
Labs 
X 
X 
X 
X 
* 
ECG 
X 
X 
X 
* 
Vital Signs 
X 
X 
X 
<define all abbreviations and shorthand (eg, “labs”) used in the table> 
X = Safety Assessment will be summarized in tables 
* = Safety Assessment will be summarized in individual participant data listings 
 
8.4.1. 
Adverse Events 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 23.0 or higher. A treatment-emergent adverse event (TEAE) is defined as an adverse 
event with onset after the initiation of IP. The analysis of adverse events will be based on the 
concept of TEAEs. 
If the date of an adverse event is incomplete and an unambiguous determination could not be 
made with respect to its onset time versus the first dose of IP and/or last dose of IP, the 
adverse event will be assumed to be a TEAE and a treatment period TEAE. For imputation 
of missing AE dates, please refer to Appendix A. 
The incidence of all TEAEs and non-serious TEAE’s will be separately summarized by SOC 
and preferred term PT. In addition, summaries will be provided by maximum severity (mild, 
moderate, severe, life-threatening, death) and by relationship (related, not related) to IP. Any 
TEAEs leading to discontinuation of treatment or withdrawal from the study and any 
treatment-emergent serious adverse events will also be summarized, sorted by descending 
frequency in SOC and PT. 
For maximum severity, participants will be counted only once within each SOC and PT at the 
maximum severity in the following order: severe > moderate > mild; an AE with missing 
severity will be omitted from severity presentation. A participant will be counted only once 
within each SOC and PT at the strongest relationship to IP in the following order: related > 
not related. The incidences will be presented by descending frequency of SOC in the 
brexanolone group and then, within a SOC, by descending frequency of PT based on the 
participant count, and in alphabetical order of PT if the incidence within a PT is a tie. 
The following table documents events considered to be AESI in this study, and the MedDRA 
preferred terms and lower-level terms (i.e., LLTs) in the right-hand column will be used to screen 
adverse events for possible AESI status. Where LLTs are specified, they take precedence in the 
determination of AESI’s; when LLTs are left unspecified, it is understood that MedDRA 
preferred terms will take precedence: 


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AESI Term 
MedDRA Preferred Term(s) 
Loss of Consciousness 
1. Loss of consciousness 
2. Altered state of consciousness 
3. Syncope 
Excessive sedation 
1. Sedation 
2. Somnolence 
3. Sedation complication (note: this 
corresponds to the LLT of “Sedation 
excessive) 
Reintubation events 
1. Endotracheal 
intubation 
(note: 
this 
corresponds to the LLT of “Reintubate”) 
2. Endotracheal intubation complication 
(note: this corresponds to the LLT of 
“endotracheal reintubation”) 
Delirium 
1. Delirium 
2. Intensive care unit delirium 
3. Anesthetic complication neurological 
(note: this corresponds to the LLT of 
“Delirium on emergence”) 
Altered mental status 
1. Mental status changes (note: this 
corresponds to the LLTs of “Acute mental 
status changes” and “Mental status 
changes” 
2. Mini mental status examination abnormal 
 
The process for identification of AESI is to screen for MedDRA terms in the right-hand 
column and to query once any adverse events have been identified as meeting these broad 
criteria. AESI’s will be tabulated separately from all TEAE’s, using the same SOC x PT 
format. 
All AEs, AESI and SAEs (including those with onset or worsening before the start of IP) 
through the end of the study will be listed. In addition, a listing containing individual 
participant’s AE data for participants who died, and participants with SAEs leading to 
treatment discontinuation will be provided, separately. 
 
8.4.2. 
Concomitant Medications 
Concomitant medications will be coded using WhoDD dictionary Global B3 September 2020 
or later. 


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Concomitant medications are defined as those with a start date and time on or after the 
initiation of IP or those with a start date and time before the initiation of IP that are ongoing 
or with a stop date/time on or after the initiation of IP. If medication date/time is incomplete 
and it is not clear whether the medication was concomitant, it will be assumed concomitant. 
For imputation of missing concomitant medication dates, please refer to Appendix A. 
A standard table of concomitant medications will be generated, showing both treatment 
groups as well as a total column, for the Safety Population. This table will show ATC Level 
3 x Preferred Name and participants with multiple occurrences of a drug class or drug will be 
counted only once in the specific ATC classification or preferred name, respectively. 
Concomitant medications will also be listed. 
Additionally, the following overlapping classes of medications will be separately tabulated 
using the same format as a standard concomitant medication table and will be restricted to 
the study days associated with ICU stay for each participant. Days in ICU occurring during 
any long-term safety follow-up will be included. For this purpose, medications of special 
interest are all qualifying medications with start dates that not only occur on or after the 
initiation of investigational product but also must occur during an ICU stay. There are no 
restrictions on medication stop date(s): 
• CNS depressants (eg, benzodiazepines, opioids/opiates, barbiturates, propofol); 
• other agents utilized for sedation effects (eg, dexmedetomidine); 
• drugs administered to treat or prevent ICU delirium (eg, antipsychotics, atypical 
antipsychotics, or other agents intended for delirium treatment). 
These classes of medications will be identified via the following ATC Level 3 codes: 
• N01A (anesthetics, general) 
• N02A (opiods) 
• N03A (antiepileptics) 
• N05A (antipsychotics) 
• N05B (anxiolytics) 
• N05C (hypnotics and sedatives) 
A separate listing of these medications will be generated and will at minimum include dose, 
dose frequency, route of administration, and duration. 
 
8.4.3. 
Clinical Laboratory 
The clinical laboratory tests to be performed in this study are listed in Table 4. 


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Table 4: 
Summary of Clinical Laboratory Analytes 
 
Biochemistry 
Renal Panel: glucose, calcium, phosphorus, blood urea nitrogen, creatinine, 
sodium, potassium, chloride, bicarbonate 
Hepatic Panel: albumin, alanine aminotransferase, aspartate aminotransferase, 
total bilirubin, direct bilirubin, indirect bilirubin, alkaline phosphatase, total 
protein, lactate dehydrogenase, gamma glutamyl transferase, c-reactive protein 
Hematology 
red blood cell count, hemoglobin, hematocrit, white blood cell count (i.e., 
leukocytes) with differential, platelet count, erythrocyte sedimentation rate 
Coagulation 
Activated partial thromboplastin time, prothrombin time, and international 
normalized ratio (INR) 
For the laboratory results that is “< or = x”, where x is a number as collected in the data, the 
numeric part of the result will be used in the calculation in the summary tables. The same is 
true if the result is presented as below limit of quantification (BLQ) and a lower limit of 
quantification (LLOQ) value is provided – LLOQ value will be used for calculation in the 
summary tables. The actual results as collected will be presented in the listings. The analysis 
summary will be performed for the scheduled laboratory values only. The unscheduled 
laboratory values will be presented in the listings. 
All statistical analyses of laboratory values will be performed using SI units. Numerical 
values and change from baseline values will be summarized by actual treatment group at 
each windowed visit. If a normal range is provided for the parameter, the out-of-range values 
will be flagged as low or high, where applicable, in the participant data listings. Shift tables 
will also be generated. 
The number and percentage of participants with potentially clinically significant (PCS) 
values will be provided in separate listings in hematology, serum chemistry, and liver 
function tests. PCS values will be identified for specific laboratory parameters as outlined in 
Table 5. The summaries will be based on all post-baseline values, including both scheduled 
and unscheduled data. Percentages for PCS tables will be based on the number of subjects 
contributing observations. 
Liver function tests will be monitored closely for PCS values, and will be summarized for 
occurrence any time post-baseline for the following parameters for these PCS threshold (for 
condition involving more than one parameter, the results need to be from the same 
timepoint): 
Alanine Aminotransferase: >3xULN, 
Aspartate Aminotransferase: >3xULN, Alanine Aminotransferase or Aspartate 
Aminotransferase: >3xULN, 
Alkaline Phosphatase: >3xULN, 
Total Bilirubin: >2xULN 
Total Bilirubin > 2xULN AND (Alanine Aminotransferase or Aspartate Aminotransferase 
>3xULN) 
Total Bilirubin >2xULN AND Alkaline Phosphatase >3xULN AND (Alanine 
Aminotransferase or Aspartate Aminotransferase >3xULN) 


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Any lab results considered clinically significant by the investigator will be captured as 
adverse events, hence will show up in AE listings and/or tabulations. 
Table 5: 
Potentially Clinically Significant Values for Specific Laboratory 
Parameters 
 
Laboratory 
Parameter 
Units 
Criteria for PCS Values (Observed values) 
High 
Low 
Hemoglobin -male 
g/L 
>185 
<115 
Hemoglobin -female 
g/L 
>170 
<100 
Hematocrit-male 
Fraction of 1 
>0.55 
<0.385 
Hematocrit-female 
Fraction of 1 
>0.49 
<0.345 
Platelet count 
10^9/L 
>600 
<125 
Leukocytes 
10^9/L 
>15 
<2.5 
Basophils 
10^9/L 
>0.5 
NA 
Eosinophils 
10^9/L 
>1.5 
NA 
Neutrophils 
10^9/L 
NA 
<1.5 
Lymphocytes 
10^9/L 
>6.0 
<0.5 
Monocytes 
10^9/L 
>1.4 
NA 
Albumin 
g/L 
>70 
<28 
Blood urea nitrogen 
mmol/L 
>10.71 
NA 
Calcium 
mmol/L 
>2.75 
<2.0 
Chloride 
mmol/L 
>120 
<90 
Creatinine 
mmol/L 
>3xULN or >3x Baseline 
Gamma Glutamyl 
Transferase 
U/L 
>3xULN 
Glucose 
mmol/L 
>13.9 
<2.8 
Sodium 
mmol/L 
>150 
<132 
Potassium 
mmol/L 
>5.4 
<3.3 
Protein 
g/L 
<45 
Bicarbonate 
mmol/L 
>34 
<18 
Phosphorus 
mmol/L 
>1.94 
<0.61 
Liver Function Tests 
(LFT) 


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Laboratory 
Parameter 
Units 
Criteria for PCS Values (Observed values) 
High 
Low 
Bilirubin 
μmol/L 
>2xULN 
NA 
Aspartate 
Aminotransferase 
U/L 
>3xULN 
NA 
Alanine 
Aminotransferase 
U/L 
>3xULN 
NA 
Alkaline Phosphatase 
U/L 
>3xULN 
NA 
Coagulation 
International 
Normalized Ratio 
(INR) 
NA 
>1.5x ULN 
NA 
Partial thromboplastin 
time (PTT) 
sec 
>1.5x ULN 
NA 
 
8.4.4. 
Vital Signs 
Vital signs include systolic and diastolic blood pressure, heart rate, temperature, and 
respiratory rate (if not on mechanical ventilation). Systolic and diastolic blood pressure and 
heart rate are to be collected supine or prone. Respiratory rate and temperature are collected 
once in any position. Descriptive summaries of observed values and changes from baseline 
will be provided for vital sign parameters - by windowed visit and treatment group. 
Additionally, the number and percentage of participants with PCS and PCS values will be 
summarized. PCS values will be identified for vital sign parameters as outlined in Table 6. 
Table 6: 
Potentially Clinically Significant Values for Vital Sign Parameters 
 
Vital Sign 
Units 
Criteria for PCS Values 
(Observed values) 
Criteria for Change from 
Baseline values (PCSC) 
High 
Low 
Increase 
Decrease 
Heart rate (supine and prone) 
Beats/min 
>120 
<40 
NA 
NA 
Systolic Blood Pressure (supine 
and prone) 
mmHg 
>180 
<90 
≥30 
≥30 
Diastolic Blood pressure 
(supine and prone) 
mmHg 
>110 
<50 
≥20 
≥20 
 
8.4.5. 
Electrocardiogram 
A 12-lead ECG will be performed at all scheduled time points. The standard intervals (heart 
rate, PR, QRS, QT, and QTcF) as well as any rhythm abnormalities will be recorded. Brief 
descriptive text should be included if the trace morphology is abnormal. 


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Example: 
The observed value at each windowed visit and change from baseline at each post-baseline 
windowed visit will be summarized. Each ECG is evaluated by investigator as ‘normal’, 
‘abnormal, not clinically significant’ and ‘abnormal, clinically significant’ in the eCRF; the 
number and percentage of participants with ‘abnormal, clinically significant’ or ‘abnormal, 
not clinically significant’ will be provided at baseline and each post-baseline windowed visit. 
The number and percentage of participants with PCS and PCSC values will be summarized. 
PCS values will be identified for ECG parameters as outlined in Table 7. In addition, the 
maximum value of QTcF if within any of the PCS criteria will be summarized. 
Table 7:    Potentially Clinically Significant Values and Change for ECG Parameters 
 
ECG 
Units 
Criteria for PCS Values (Observed values) 
Criteria for PCSC values 
(Change from Baseline) 
High 
Low 
Increase 
Decrease 
QTcF 
Interval 
msec 
>450 but <=480 
>480 but <=500 
>500 
NA 
>=30 to 60 
>60 
NA 
 
8.4.6. 
Richmond Agitation Sedation Scale 
The RASS is a tool validated to assess sedation and agitation in ICU participants. RASS is a 
10-point scale, with 4 levels of anxiety or agitation (+1 to +4 [combative]), one level to 
denote a calm and alert state (0), and 5 levels of sedation (-1 to -5) culminating in 
unarousable (-5). 
The RASS will be administered once daily to all participants at the scheduled time points. In 
addition, the unscheduled RASS will be administered within 2 hours after each extubation. 
The unscheduled RASS will also be administered each time the decision is made to stop the 
IP infusion or reduce the dose. 
Descriptive summaries of observed values will be provided for RASS- by windowed visit, 
and summarized by timepoint and treatment group. The unscheduled values will be presented 
in the listings. 
 
8.4.7. 
Confusion Assessment Method for the Intensive Care Unit 
The CAM-ICU score is a validated score to assess delirium in mechanically ventilated 
participants using standardized nonverbal assessments. The overall score is either “CAM- 
ICU Positive” or “CAM-ICU Negative”. The CAM-ICU will be administered every time 
RASS is assessed if RASS score ≥-3. 
The listings of the observed values will be provided for CAM-ICU. 




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9. 
SUMMARY OF INTERIM AND DMC ANALYSES 
9.1.1.1. 
Interim Analysis 
The originally planned Interim Analysis will not be performed due to Sponsor decision to 
stop the study early. 
 
9.1.1.2. 
Data Monitoring Committee Analysis 
An independent DMC will monitor the clinical data for safety and efficacy and will meet at 
least monthly throughout the duration of the study. The DMC will provide recommendations 
for continuing or stopping the study for safety or futility in accordance with the DMC 
charter. Stopping criteria are prespecified in study protocol Section 7.4.2 and Section 
13.8.1.1. 
In order to perform their monitoring function, the DMC will have access to unblinded safety 
to ensure the safety of the participants in the study. Efficacy data will be delivered to the 
DMC as needed to perform their functions. The DMC will also review the results of the 
planned interim analysis. 
Only descriptive analysis will be performed (ie, no statistical hypothesis testing will be 
performed). All analyses will be performed by a designated clinical research organization 
independent of Sage. 
Sage team will remain blinded for all the DMC and interim analysis data until the end of 
study. 
Please refer to the DMC Charter for additional details. 


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10. 
REFERENCES 
Include a list of references, as appropriate. 
Beigel JH, Tomashek, KM, Dodd, LE, Mehta, AK, Zingman, BS, et al. Remdesivir for the 
Treatment of COVID-19 – Preliminary Report. NEJM. 2020. DOI: 
10.1056/NEJMoa2007764. 


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11. 
LIST OF APPENDICES 


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APPENDIX A. HANDLING OF MISSING DATES 
Dates missing the day or both the day and month of the year will adhere to the following 
conventions in order to classify TEAEs and to classify prior and concomitant medications. 
In general, listings will present the actual partial or missing values rather than the imputed 
values that may be used in derivation. In instances where imputed values will be presented, 
imputed values will be flagged. 
Adverse Events 
If the AE start date is completely missing, do not impute a date but consider it as TEAE, 
unless the AE end date is before the initiation of treatment, in which case the AE will be 
considered prior. 
For partial AE start dates: 
• When the year is known, but the month and day is unknown, then: 
− If the year matches the year of initiation of study drug and the end date (if 
present) is after the initiation of study drug, or AE is ongoing, then impute as 
the month and day of the initiation of the study drug date + 1 day. 
− If the year of AE onset < year of initiation of the treatment, then the month 
and day will be set to December 31st. 
− If the year of AE onset > the year of initiation of treatment, then the month 
and day will be set to January 1st. 
• If the year and month are known, but the day is unknown, then: 
− If the year of AE onset = the year of initiation of the treatment and: 
− the month of AE onset = the month of initiation of the treatment, then the day 
will be set to the day of initiation of the treatment. 
− the month of AE onset < the month of initiation of the treatment, then the day 
will be set to the last day of month. 
− if the month of AE onset > the month of initiation of the treatment, then the 
day will be set to the 1st day of month. 
− If the year of AE onset < the year of initiation of the treatment, then the day 
will be set to the last day of month. 
− If the year of AE onset > the year of initiation of the treatment, then the day 
will be set to the 1st day of month. 
If the imputed AE onset date is after the AE stop date, then the onset date will be set to the 
stop date. 


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• When the year and day are present and the month is missing, treat it as if the day 
is missing, and only year is present. Follow the imputation rules for “year is 
known, but the month and day is unknown”. 
• When the year is missing, but the month and/or day is known, treat this date as 
missing; do not impute. 
Dates in Disease History (Dates of diagnosis, current episode, first episode) 
• If the year is present and the month and day are missing, then the month and day 
will be set to January 1. 
• If the year and day are present and the month is missing, then the month will be 
set to January. 
• If the year and month are present and the day is missing, then the day will be set 
to the 1st day of month 
Prior and Concomitant Medications 
For the partial start date of medication: 
• If the year is present and the month and day are missing, then the month and day 
will be set to January 1. 
• If the year and day are present and the month is missing, then the month will be 
set to January. 
• If the year and month are present and the day is missing, then the day will be set 
to the 1st day of month. 
• If the imputed start date of medication is after the non-imputed end date of 
medication, then the start date will be set to the end date of medication. 
For the partial end date of medication: 
• If the year is present and the month and day are missing, then the month and day 
will be set to December 31. 
• If the year and day are present and the month is missing, then the month will be 
set to December. If the year and month are present and the day is missing, then 
the day will be set to the last day of the month. 
• If the year and day are present and the month is missing, then treat it as if the day 
is also missing. Set the month and day to be December 31. 


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APPENDIX B. LIST OF DISPLAYS 
 
 
 
 


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APPENDIX D. PROCEDURAL TERMS USED IN THE IDENTIFICATION OF RESPIRATORY 
FAILURE AND UNSUCCESSFUL EXTUBATION 
 
 
Verbatim Procedural 
Term † 
Interpretation Relative to Respiratory 
Failure 
Interpretation Relative to Extubation 
1. Bronchoscopy 
No impact on determination of respiratory 
failure 
No impact on determination of unsuccessful 
extubation 
2. Chest Tube Insertion 
No impact on determination of respiratory 
failure 
No impact on determination of unsuccessful 
extubation 
3. CPR 
No impact on determination of respiratory 
failure 
No impact on determination of unsuccessful 
extubation 
4. ECMO 
Respiratory failure 
Extubation considered unsuccessful if within 48 
hours of extubation 
5. Initiation of Non- 
Invasive Positive 
Pressure Ventilation 
Respiratory failure 
Extubation considered unsuccessful if within 48 
hours of extubation 
6. Initiation of Oxygen 
Delivery by High- 
Flow Nasal Cannula 
Respiratory failure 
No impact on determination of unsuccessful 
extubation 
7. Intubation 
Respiratory failure 
Extubation considered unsuccessful if within 48 
hours of extubation 


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8. Intubation/ 
Brochoscopy/ 
Cauterization 
Respiratory failure 
Extubation considered unsuccessful if within 48 
hours of extubation 
9. Mechanical 
Ventilation 
Respiratory failure 
Extubation considered unsuccessful if within 48 
hours of extubation 
10. None: Extubated to 
4L NC 
Respiratory failure 
No impact on determination of unsuccessful 
extubation 
11. Pneumothorax, Right No impact on determination of respiratory 
failure 
No impact on determination of unsuccessful 
extubation 
12. PS/CPAP 
Respiratory failure 
Extubation considered unsuccessful if within 48 
hours of extubation 
13. Reintubation 
Respiratory failure 
Extubation considered unsuccessful if within 48 
hours of extubation 
14. Tracheostomy 
No impact on determination of respiratory 
failure 
No impact on determination of unsuccessful 
extubation 
†Mis-spellings present in the clinical database are displayed as-is in this table 


 
 
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