Clinical trial NCT05645432
Conditions: Tinnitus
Keywords: Tinnitus
Sponsor: Sage Therapeutics
Start date: 2023-05-10; Completion date: 2023-11-21
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to evaluate the safety and tolerability of brexanolone in participants with tinnitus following a single 6-hour continuous intravenous (IV) infusion.

Detailed description:

Arms: arm 1: Participants will receive a 6-hour single continuous intravenous (IV) infusion of brexanolone at 30 micrograms per kilogram per hour (mcg/kg/hour) for 0 to 0.5 hours, at 60 mcg/kg/hour for 0.5 to 1 hour, and at 90 mcg/kg/hour for 1 to 6 hours, on Day 1 of the Treatment Period.
Interventions: intervention 1: Brexanolone
Intervention descriptions: intervention 1: Brexanolone IV infusion

Protocol documents:
Prot_000.pdf: 
Official Title: 
An Open-Label Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of Brexanolone in the Treatment of 
Adult Participants With Tinnitus 
NCT Number: 
NCT05645432 
Document Date: 
Protocol Amendment 2: 17 Oct 2023


1 
 
 
 
 
 
AN OPEN-LABEL STUDY EVALUATING THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS, AND EFFICACY OF 
BREXANOLONE IN THE TREATMENT OF ADULT 
PARTICIPANTS WITH TINNITUS 
(AN OPEN-LABEL STUDY EVALUATING BREXANOLONE IN 
ADULTS WITH TINNITUS) 
PROTOCOL NUMBER: 547-TRM-201 
IND NUMBER: 162652 
 
Investigational Product 
Brexanolone 
Clinical Phase 
Phase 2 
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Sponsor Contact 
 
Phone: 
 
email: 
 
Sponsor Medical Monitor 
, MD 
 
Phone/text: 
 
email:
 
Sponsor Translational Lead 
, PhD 
Phone: 
 
email: 
 
Date of Original Protocol 
31 August 2022 
Date of Amendment 1 
18 July 2023 
Date of Amendment 2 
13 October 2023 
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. 


Clinical Protocol 
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INVESTIGATOR’S AGREEMENT 
I have received and read the investigator’s brochure for brexanolone. I have read the 
547-TRM-201 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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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Sage Study Physician  
, MD 
 
Phone/text: 
 
email: 
 
24-Hour Emergency Contact 
, MD 
 
E-mail: 
 
Phone: Mobile: 
 
Main Switchboard: 
 
Serious Adverse Event (SAE) 
Reporting Contact 
IQVIA Lifecycle Safety  
4820 Emperor Boulevard 
Durham, NC 27703 
E-mail: Sage.Safety@iqvia.com 
Fax: +1-855-638-1674 
SAE Hotline: +1-855-564-2229 
Sage Study Physician 
, MD 
 
E-mail: 
 
MD 
 
E-mail: 
 
Phone: Mobile: 
 
Main Switchboard: 
 
Product Complaint Contact 
Sage Therapeutics 
E-mail: productcomplaints@sagerx.com 
Phone: +1-833-554-7243 
 




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• Change from baseline in vital signs, 
electrocardiogram (ECG), and clinical 
laboratory parameters  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Study Description: 
This is an open-label study to evaluate the safety, tolerability, 
, and efficacy of brexanolone in 
adults with tinnitus following a single 6-hour continuous intravenous (IV) infusion. The study design 
is presented in Figure 1. 


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Figure 1: 
Study Design 
 
This study includes a Screening Period of up to 28 days, a 1-day Treatment Period, and a 6-day 
Follow-up Period. After providing informed consent, participants will undergo screening assessments 
as outlined in Table 2 to determine eligibility.  
Screening Period: 
The Screening Period begins with the signing of the informed consent form (ICF). Eligible 
participants will complete additional eligibility and baseline assessments as specified in the Schedule 
of Assessments (Table 2).  
Starting 7 days before administration of investigational product (IP) (Day -7), participants will have 
twice daily remote predose assessments as indicated in Table 2. Participants will receive training on 
how to perform all remote assessments during Screening. The participant will be contacted by the site 
on Day -7 through Day -1 to remind them to begin remote assessments. Assessments will be 
performed remotely by the participant on Day -7 through Day -1. Ratings for both VAS-L and 
VAS-A will be done twice daily, once each in the morning and evening.  
Participants will be excluded from dosing if they do not successfully perform at least 10 of the 
14 remote VAS assessments. 
Treatment Period: 
A continuous, 6-hour IV infusion of IP will be administered at the Clinic Treatment Visit on Day 1. 
Assessments will be performed as indicated in Table 3.  
The participant will spend approximately 9 hours in the clinic on Day 1: 1 hour for setup of IV pump 
and assessments performed prior to administration of IP, 6 hours for the IP infusion, and 2 hours for 
safety observation at the conclusion of the IP infusion. At the discretion of the investigator, 
participants may stay in the clinic overnight after the end of infusion. 
Due to the risk of excessive sedation and sudden loss of consciousness, for the duration of the 
infusion, participants will be monitored for hypoxia using continuous pulse oximetry equipped with 
an alarm and will be assessed for excessive sedation 
 by a 
healthcare provider. If excessive sedation occurs at any time during the infusion, the infusion will be 
stopped until the symptoms resolve. The infusion may be resumed at the same or lower dose per 
protocol guidance. The infusion will be immediately stopped if pulse oximetry reveals hypoxia, 


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specifically if this occurs in the context of excessive sedation or sudden loss of consciousness. After 
an episode of confirmed hypoxia, the infusion should not be resumed.  
For lactating subjects, the investigator and subject should weigh the developmental and health 
benefits of breastfeeding during the infusion against any potential adverse effects on the breastfed 
child from brexanolone or from the underlying maternal condition. Subjects may continue to 
breastfeed or express milk to feed their infant during the infusion if the benefit is deemed to outweigh 
the risk. During the study, a qualified lactation consultant will be made available to subjects upon 
request. 
In this study, excessive sedation, loss of consciousness, and any sedation-related AE that leads to dose 
reduction, interruption, or termination will be recorded as an adverse event of special interest (AESI). 
A fall precaution protocol must be in place for the duration of the brexanolone infusion. 
At the conclusion of the IP infusion, if deemed medically appropriate by the investigator, participants 
will be released from the clinic after the 2-hour safety observation period and completion of 
assessments. Participants will be cautioned against engaging in potentially hazardous activities 
requiring mental alertness, including driving, until any sedative effects have dissipated. A designated 
companion must drive the participant when they are discharged from the clinic. 
Follow-Up Period:  
Assessments for the Follow-up Period will be performed as indicated in Table 3. The participant will 
be contacted by the site on Day 2 through Day 6 to remind them to begin remote assessments. 
Follow-up assessments will be conducted remotely on Day 2 through Day 6. Ratings for both VAS-L 
and VAS-A will be done twice daily, once each in the morning and evening. 
Participants will return to the clinic approximately 6 days after the last dose of IP (Day 7±1 day) for 
efficacy and safety monitoring. The EOS Visit will be conducted at the time of discontinuation if this 
occurs at any time before Day 7±1 day (see Section 8.4.2). 
Number of Participants (planned): Up to 24 participants will be dosed to achieve approximately 
20 study completers, assuming a 20% study discontinuation rate among dosed participants.  
Eligibility Criteria:  
Inclusion Criteria: 
Participants must meet all of the following criteria to qualify for participation in this study: 
1. Participant has signed an ICF before any study-specific procedure is started. 
2. Participant is ambulatory and is 18 to 65 years of age, inclusive, at the time informed consent is 
obtained. 
3. Participant has a designated companion for the Clinic Treatment Visit who will drive them when 
they leave the clinic.  
4. Participant is in good physical health and has no clinically significant findings (excluding 
tinnitus), as determined by the investigator on medical history and physical examination, 
including neurologic and mental status examinations, 12-lead ECG, or clinical laboratory tests.  
5. Participant has a diagnosis of subjective, idiopathic, unilateral or bilateral, non-pulsatile tinnitus 
(eg, not due to medical disease) of ≥6 months and <10 years duration. 
6. Participant has mild to severe tinnitus distress according to Tinnitus Handicap Inventory (THI) 
score of 24 to 68 at Screening. 
7. Participant is willing and able to safely discontinue the use of central nervous system (CNS) 
depressants (eg, opioids and benzodiazepines), antidepressants, anticonvulsants, CNS stimulants 
(with the exception of caffeine), aspirin, other nonsteroidal anti-inflammatory drugs, and 


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aminoglycosides at least 14 days or 5 half-lives (whichever is longer) prior to receiving IP and 
through completion of the study.  
8. Female participant agrees to use at least one method of highly effective contraception during 
participation in the study and for 30 days following the last dose of IP, unless she is 
postmenopausal, permanently sterile, or does not engage in sexual relations which carry a risk of 
pregnancy (see Section 9.2.5).  
9. Male participant with a partner who is of childbearing potential agrees to use an acceptable 
method of effective contraception for the duration of the study and for 13 weeks after receiving 
the IP, unless the participant does not engage in sexual relation(s) which carry a risk of 
pregnancy in his female partner(s). Acceptable methods of effective contraception are listed in 
Section 9.2.5.  
10. Male participant is willing to abstain from sperm donation for the duration of the study and for 
13 weeks after receiving the IP. 
Exclusion Criteria: 
Participants who meet any of the following criteria are disqualified from participation in this study: 
1. Participant has history or presence of any neurologic disease or condition, including, but not 
limited to, unexplained loss of consciousness, seizure disorder including a prior nonfebrile 
seizure, and closed head trauma with clinically significant sequelae. 
2. Participant has a history of sleep apnea or any clinically significant respiratory conditions that 
may predispose the participant to hypoxia during the infusion. 
3. Participant intends to start or discontinue a pharmacological or nonpharmacological therapy (eg, 
psychotherapy, sound therapy, masking, transcranial magnetic stimulation [TMS]) for tinnitus 
during the course of the study.  
4. Participant has currently active and medically significant or uncontrolled hepatic, renal, 
cardiovascular, pulmonary, gastrointestinal, hematological, immunologic, metabolic disease 
(hypothyroidism with stable thyroid replacement is acceptable).  
5. Participant’s tinnitus can be modulated by maneuvers of the temporomandibular joint, head and 
neck, eyes, or limbs, or otherwise attributed to somatosensory cause or has had prior otoscopic 
surgeries or cholesteatoma.  
6. Participants has current unilateral or bilateral hearing loss of 30 dB or greater (mild hearing loss) 
in one or more tested frequencies (500 Hz, 1000 Hz, 2000 Hz, and 4000 Hz), 60 dB or greater at 
6000 Hz and 8000 Hz, asymmetry of 30 dB or greater in two or more tested frequencies or uses a 
cochlear implant or hearing aid. 
7. Participant has history of chronic otitis media (>3 per year during past 5 years). 
8. Participant has a total score of 15 or greater (ie, moderately severe) on the Patient Health 
Questionnaire-9 (PHQ-9) at Screening.  
9. Participant has diagnosis of moderate or severe substance use disorder (excluding nicotine 
dependence) within 12 months of Screening, has a positive screen for drugs of abuse including 
tetrahydrocannabinol (THC) on Day 1 prior to dosing, or has a positive screen for alcohol on Day 
1 prior to dosing. 
10. Participant has a known allergy to progesterone, allopregnanolone, or any IP excipient.  
11. Female participant has a positive pregnancy test or a confirmed pregnancy at Screening or prior 
to dosing on Day 1 
12. Participant has had exposure to another investigational drug or device within 30 days or 5 half-
lives of the investigational drug, whichever is longer, prior to the Day 1 visit. 


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13. Participant has a history of suicidal behavior within 2 years or answers “YES” to Questions 3, 4, 
or 5 on the C-SSRS at Screening or at Day 1 or is currently at risk of suicide in the opinion of the 
investigator. 
14. Participant has donated 1 or more units (1 unit = 450 mL) of blood or experienced acute loss of 
an equivalent amount of blood within 60 days prior to Day 1.  
15. Participant has any condition, comorbidity, or lifestyle consideration that in the opinion of the 
investigator would limit or interfere with the participant’s ability to complete or partake in the 
study. 
16. Participant is unwilling or unable to comply with study procedures and the required training 
during the Baseline Period. The participant must complete 10 VAS assessments remotely prior to 
Day 1. 
17. Participant is unable to complete participation in the study, eg, due to preplanned event including 
elective surgery. 
18. Participant is investigative site personnel, sponsor personnel, or a member of their 
immediate families (spouse, parent, child, or sibling whether biological or legally 
adopted).  
Investigational Product, Dosage and Mode of Administration: 
Brexanolone will be administered as a single, continuous, 6-hour IV infusion, administered according 
to the following dosing regimen: 
Time point 
Day 1 
0 to 0.5 hours 
Day 1 
0.5 to 1 hour 
Day 1 
1 to 6 hours 
Dose 
30 mcg/kg/hour 
60 mcg/kg/hour 
90 mcg/kg/houra 
a A reduction in dosage to 60 mcg/kg/hour should be considered for participants who do not tolerate 
90 mcg/kg/hour. No reductions below 60 mcg/kg/hour are permitted. 
Duration of Treatment:  
Each participant will receive a single 6-hour intravenous infusion of brexanolone. 
Statistical Methods: 
A detailed description of the analyses to be performed in the study will be provided in the statistical 
analysis plan (SAP). The SAP will be finalized and approved prior to database lock. 
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 listings, 
whereas other data may be presented in both listings and corresponding table(s) or figure(s). 
For in-clinic assessments, baseline is defined as the most recent value immediately prior to the start of 
IP infusion. For remote daily assessments, baseline is defined as the average of all available 
preinfusion values per participant. 
Continuous data will be summarized, at minimum, with number (n), mean, standard deviation (SD), 
median, Q1, Q3, minimum, and maximum. Categorical data will be summarized, at minimum, with 
counts and percentages. Change from baseline is calculated as the baseline value minus the post-
baseline value, unless defined otherwise for specific assessments and/or endpoints.  
Summary tables will generally summarize values at each timepoint and change from baseline at each 
post-baseline time point. 


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Analysis Sets  
Efficacy Set 
The Efficacy Set will be defined as all participants who received any amount of IP and have at least 
one post-baseline efficacy evaluation.  
 
 
Safety Set 
The Safety Set is defined as all participants who received any amount of IP.  
Statistical Methods 
Statistical methods will be described in detail in the statistical analysis plan (SAP). 
Descriptive statistics will be generated for safety, efficacy, and 
data; participant listings will be 
provided in all cases.  
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA®). At 
minimum, TEAEs will be displayed by System Organ Class and preferred term. Vital signs, clinical 
laboratory measures, ECG, 
 data will be summarized. Out-of-range safety 
endpoints may be categorized as low or high, where applicable. 
 
 
 
. 
  


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Table 2: 
Schedule of Assessments: Screening Period 
Study Procedure 
Screening Period 
 
Clinic Assessments 
Remote Assessments 
Visit Day 
-28 to -8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
Clinic Visit 
X 
 
 
 
 
 
 
 
Remote 
 
X 
X 
X 
X 
X 
X 
X 
Informed consent process 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical historya 
X 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
Physical examination b  
X 
 
 
 
 
 
 
 
Body weight 
X 
 
 
 
 
 
 
 
Clinical laboratory assessments c 
X 
 
 
 
 
 
 
 
Drug and alcohol test d 
X 
 
 
 
 
 
 
 
Pregnancy test (WOCBP only) e 
X 
 
 
 
 
 
 
 
Vital signs f 
X 
 
 
 
 
 
 
 
12-lead ECG g 
X 
 
 
 
 
 
 
 
Audiology Diagnostics i 
X 
 
 
 
 
 
 
 
VAS loudness and annoyance j 
 
X 
X 
X 
X 
X 
X 
X 


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Study Procedure 
Screening Period 
 
Clinic Assessments 
Remote Assessments 
Visit Day 
-28 to -8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
Clinic Visit 
X 
 
 
 
 
 
 
 
Remote 
 
X 
X 
X 
X 
X 
X 
X 
Remote Assessment Reminderk 
 
X 
X 
X 
X 
X 
X 
X 
Participant training l 
X 
 
 
 
 
 
 
 
Adverse events m 
X 
Prior/concomitant medications n 
X 
Nonpharmacological interventions o 
X 
Abbreviations: 
; 
; ECG = electrocardiogram; 
; TMS = transcranial magnetic stimulation; 
VAS = Visual Analogue Scale; VAS-A = VAS annoyance; VAS-L = VAS loudness; WOCBP = women of childbearing potential. 
Note: Clinic-based screening assessments must occur within 28 days prior to IP administration and results must be reported by Day -8. 
Note: When scheduled at the same timepoint, assessments will be performed in the following order: vitals, VAS, 
. 
a Tinnitus-related medical history will be obtained by structured interview. 
 b Full physical examination at Screening. Symptom-directed physical examination may be conducted at subsequent time points. 
 c Safety laboratory tests will include hematology, serum chemistry, and urinalysis at all scheduled time points. Coagulation to be assessed at Screening only.  
d Drug and alcohol testing will occur at Screening (see Section 12.1.6 or a list of analytes). Drug testing will be on a urine specimen via urine dipstick. Alcohol 
use will be tested either on a urine specimen dipstick or breath test. A failed Screening drug or alcohol test does not exclude participation in the study if test is 
negative at Day 1. 
e Serum pregnancy test at screening. 
f Vital signs to include temperature (°C), respiratory rate, heart rate, and blood pressure. Heart rate and blood pressure to be collected in semi-inclined position.  
g ECGs must be performed after the participant has been in a supine position for at least 5 minutes.  
  
  
 i A full audiological examination will be conducted at Screening including pure tone audiogram. The audiologist will perform a physical exam of ears and obtain 
clinical history to evaluate duration and quality (whether unilateral/bilateral, pulsatile/non-pulsatile). A healthcare professional trained to perform movement tests 
will evaluate whether tinnitus can be attributed to a somatosensory cause.  


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 j Ratings for both VAS-L and VAS-A will be done twice daily, once each in the morning and evening, on Day -7 through Day -1. 
k The participant will be contacted by the site on Day -7 through Day -1 to remind them to begin remote assessments. 
 l Participants will be trained by study personnel on the procedures for all remote assessments. 
 mA phone call to follow up on any AE(s) will be conducted, if deemed appropriate by the investigator, to review the current status of the participant. 
 n To include all medications taken within 60 days, all psychotropic medications taken within 6 months, and all medications used to treat tinnitus regardless of 
timing. Participants will be asked about any changes during clinic visits. 
o Nonpharmacological interventions: eg, psychotherapy, sound therapy, masking, TMS. Participants will be asked about changes during clinic visits. 


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Table 3: 
Schedule of Assessments – Treatment Period and Follow-up Period 
Study Procedure 
Treatment Period 
Follow-up Period 
Clinic Treatment Visit 
 
EOS 
Visita 
Visit Day 
1 
2 
3 
4 
5 
6 
7 
±1 
Hour From Start of Infusion Pre-
dose b 
0 
0.5 
1 
2 
3 
4 
5 
6 
8 
 
 
 
 
 
 
Clinic Visit 
X 
 
 
 
 
 
X 
Remote 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Clinical laboratory assessments c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy test (WOCBP only) d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs e 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
Drug and alcohol test f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
VAS loudness and annoyance j 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 


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Study Procedure 
Treatment Period 
Follow-up Period 
Clinic Treatment Visit 
 
EOS 
Visita 
Visit Day 
1 
2 
3 
4 
5 
6 
7 
±1 
Hour From Start of Infusion Pre-
dose b 
0 
0.5 
1 
2 
3 
4 
5 
6 
8 
 
 
 
 
 
 
Clinic Visit 
X 
 
 
 
 
 
X 
Remote 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Safety phone call 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Remote Assessment Reminderl 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Continuous pulse oximetry m 
 
X 
 
 
IP infusion  
 
X 
 
 
Admission to clinic 
X 
 
 
 
 
 
 
 
 
 
 
Discharge from clinic o 
 
 
 
 
 
 
 
 
 
X 
 
Adverse events p 
X 
Prior/concomitant medications q 
X 
Nonpharmacological interventions r 
X 
Abbreviations: 
; 
; 
; ECG = electrocardiogram; EOS = End of Study; IP = investigational product; 
; 
; 
; 
TMS = transcranial magnetic stimulation; VAS = Visual Analogue Scale; VAS-A = VAS annoyance; VAS-L = VAS loudness; WOCBP = women of 
childbearing potential. 
Note: For Day 1 assessments, assessments at 0.5 and 1 hour must be collected within 10 minutes prior to the dose increase. Assessments at timepoints 2, 3, 4, 5, 
6, and 8 hours may be completed within ±10 minutes of the scheduled time point.  




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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............17 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................22 
5. 
INTRODUCTION ......................................................................................................24 
5.1. 
Study Rationale ...........................................................................................................24 
5.2. 
Effects of GABAA Receptors in the Auditory Pathway .............................................25 
5.3. 
Support for Use of Brexanolone in Tinnitus ...............................................................25 
5.4. 
Dose Justification ........................................................................................................26 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................27 
7. 
INVESTIGATIONAL PLAN .....................................................................................29 
7.1. 
Overall Study Design ..................................................................................................29 
7.2. 
Number of Participants ...............................................................................................31 
7.3. 
Treatment Assignment ................................................................................................31 
7.4. 
Dose Escalation and Adjustment Criteria ...................................................................31 
7.5. 
Criteria for Study Termination ...................................................................................31 
7.6. 
End of Study Definition ..............................................................................................31 
8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS.....................................32 
8.1. 
Participant Inclusion Criteria ......................................................................................32 
8.2. 
Participant Exclusion Criteria .....................................................................................32 
8.3. 
Screen Failures ............................................................................................................34 
8.4. 
Investigational Product Discontinuation and Early Termination from the 
Study ...........................................................................................................................34 
8.4.1. 
Investigational Product Discontinuation .....................................................................34 
8.4.2. 
Early Termination from the Study ..............................................................................34 
8.4.3. 
Loss to Follow-up .......................................................................................................35 
8.4.4. 
Replacement of Participants .......................................................................................35 
9. 
TREATMENT OF PARTICIPANTS .........................................................................36 
9.1. 
Description of Investigational Product .......................................................................36 


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9.2. 
Prior and Concomitant Medications, Nonpharmacological Interventions, 
Restrictions, and Contraception Requirements ...........................................................36 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................36 
9.2.2. 
Nonpharmacological Interventions .............................................................................36 
9.2.3. 
Prohibited Medications ...............................................................................................36 
9.2.4. 
Other Restrictions .......................................................................................................36 
9.2.5. 
Acceptable Forms of Contraception ...........................................................................36 
9.3. 
Intervention after the End of the Study .......................................................................37 
9.4. 
Treatment Adherence ..................................................................................................38 
9.5. 
Randomization and Blinding ......................................................................................38 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............39 
10.1. 
Investigational Product ...............................................................................................39 
10.2. 
Investigational Product Packaging and Labeling .......................................................39 
10.3. 
Investigational Product Storage ..................................................................................39 
10.4. 
Investigational Product Preparation ............................................................................39 
10.5. 
Investigational Product Administration ......................................................................39 
10.6. 
Investigational Product Accountability, Handling, and Disposal ...............................40 
10.7. 
Product Complaints ....................................................................................................40 
11. 
EFFICACY 
41 
11.1. 
Efficacy Assessments .................................................................................................41 
 
41 
11.1.2. 
Visual Analog Scales ..................................................................................................41 
 
 
 
42 
 
42 
 
42 
 
42 
 
42 
 
43 
12. 
SAFETY ASSESSMENTS ........................................................................................44 
12.1. 
Safety and Tolerability Assessments ..........................................................................44 
12.1.1. 
Demography and Medical History ..............................................................................44 
12.1.2. 
Weight and Height ......................................................................................................44 






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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Assessments: Screening Period ..............................................................11 
Table 3: 
Schedule of Assessments – Treatment Period and Follow-up Period ........................14 
Table 4: 
Abbreviations and Specialist Terms ...........................................................................22 
Table 5: 
Infusion Rate ...............................................................................................................40 
Table 6: 
Summary of Clinical Laboratory Analytes .................................................................45 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................6 
Figure 2: 
Study Design ...............................................................................................................29 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 4: 
Abbreviations and Specialist Terms  
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
 
 
 
 
 
 
 
BMI 
body mass index 
 
 
 
 
 
 
 
 
 
 
CNS 
central nervous system 
 
 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
End of Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
independent ethics committee 
IP 
investigational product 
IRB 
institutional review board 
IV 
intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
 
 
 
 


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Abbreviation 
Definition 
QTcF 
QT corrected according to Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SPL 
sound pressure level 
TEAE 
treatment-emergent adverse event 
 
 
 
 
 
 
TMS 
transcranial magnetic stimulation 
UP 
unanticipated problem 
USM 
urgent safety measure 
VAS 
Visual Analog Scale 
VAS-A 
VAS annoyance 
VAS-L 
VAS loudness 
WOCBP 
woman of childbearing potential 
 


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5. 
INTRODUCTION 
Individuals with tinnitus hear sounds, ringing, buzzing, humming, clicking or other noises that 
usually originate in the auditory pathway rather than from an internal or external source. Tinnitus 
can be caused by either an underlying medical condition, such as noise trauma or age-related 
hearing loss, ear injury, or cardiovascular disease, or other causes, including medication use. 
Tinnitus is estimated to occur in approximately 1 in 10 adults in the US population 
(Bhatt et al 2016). 
The presentation of tinnitus varies greatly among individuals. Most individuals with tinnitus 
experience subjective tinnitus, which is defined as the perception of sound(s) in the absence of a 
corresponding external or internal sound source. The duration of tinnitus symptoms after its 
initial onset is also used to classify the condition, and expert guidance defines tinnitus as acute if 
experienced for less than 3 months, as sub-acute after 3 months, and “chronic” for periods of 
6 months or longer (Cima et al 2019). Tinnitus can also affect quality of life, and the term 
“bothersome” tinnitus designates cases in which the perception of the characteristic sound 
becomes very disturbing, and may be associated with anxiety, depression, sleep disturbances, 
and maladaptive psychological reactions that impede daily function (Cima 2018). 
Disruption in γ-aminobutyric acid (GABA)ergic signaling affects the critical balance between 
excitatory and inhibitory inputs to central auditory pathways in both normal hearing and tinnitus. 
The GABAA receptor is expressed in the auditory system, particularly concentrated in the 
cochlea, and specific receptor subunits appear associated with long-term maintenance of hair 
cells and neurons in the inner ear (Maison et al 2006). Reductions in auditory cortex GABA 
levels occur with older age and correspond to elevated pure-tone hearing thresholds in humans 
(Gao et al 2015). The inhibitory function of the GABA-gated chloride channel (GABAA) 
receptor is also thought to be critical for auditory processing, including sound segmentation and 
multi-sensory integration, by modulating input/output, frequency tuning, and temporal response 
accuracy (Wang et al 2008).  
There are currently no Food and Drug Administration (FDA)-approved pharmacological or 
nonpharmacological treatments for tinnitus. However, attenuation of some tinnitus symptoms has 
been reported with a variety of GABAergic drugs, including benzodiazepine derivatives 
alprazolam (Johnson et al 1993) and clonazepam (Bahmad et al 2006), and the GABA homolog 
gabapentin (Zapp 2001; Shulman et al 2002; Bauer and Brozoski 2006) under select 
circumstances. Considering the inconsistent effects of conventional GABAergic drugs, agents 
that significantly potentiate extrasynaptic GABAA receptors may offer unique benefit in the 
management of tinnitus relative to drugs with low affinity at extrasynaptic GABAA receptors 
(Witkin et al 2022). Therefore, the investigation of the use of brexanolone, a positive allosteric 
modulator of synaptic and extra-synaptic GABAA receptors, in the treatment of tinnitus is 
supported by both nonclinical and clinical data. 
5.1. 
Study Rationale 
Brexanolone is a potent positive allosteric modulator of synaptic and extra-synaptic GABAA 
receptors and has potential to enhance both phasic and tonic inhibition in the brain. Brexanolone 
was formulated to be chemically identical to allopregnanolone, a metabolite of progesterone and 
endogenous neuroactive steroid.  


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Tonic conductance of extrasynaptic GABAA receptors is considered critical to producing 
shunting inhibition that regulates neuronal network excitability. By this rationale, it has been 
proposed that neurosteroids, including brexanolone, may show unique potential in the 
management of tinnitus when compared to drugs with selective affinity for synaptic GABAA 
receptors.  
5.2. 
Effects of GABAA Receptors in the Auditory Pathway 
GABA is an amino acid that functions as an important inhibitory neurotransmitter for the CNS 
(Watanabe et al 2002). Disruption in GABAergic signaling affects the critical balance between 
excitatory and inhibitory inputs to central auditory pathways in both normal hearing and tinnitus. 
The GABAA receptor is expressed in the auditory system, particularly concentrated in the 
cochlea, and specific receptor subunits appear associated with long-term maintenance of hair 
cells and neurons in the inner ear (Maison et al 2006). Reductions in auditory cortex GABA 
levels occur with older age and correspond to elevated pure-tone hearing thresholds in humans 
(Gao et al 2015). The inhibitory function of the GABAA receptor is also thought to be critical for 
auditory processing, including sound segmentation and multi-sensory integration, by modulating 
input/output, frequency tuning, and temporal response accuracy (Wang et al 2008).  
Loss of inhibition in the GABA pathway and specific potassium pathways plays a role in the 
pathology of tinnitus in animal models (Yang et al 2011; Li et al 2013). Studies in humans 
support the findings in animal models. A significant decrease in GABAA receptor density in the 
medial temporal cortex in patients with severe disabling tinnitus and hearing loss was observed 
with single-photon emission computed tomography (Sedley et al 2015). An investigation using 
two-dimensional J-resolved spectroscopy identified lower glutamate and GABA concentrations 
in auditory cortices of tinnitus patients, as well as a correlation between glutamate concentration 
and perceived tinnitus loudness, suggesting the influence of excessive excitatory activity (Isler et 
al 2022).  
5.3. 
Support for Use of Brexanolone in Tinnitus 
Although no medications are approved for use in tinnitus management, and current guidelines 
discourage their use (Tunkel et al 2014), attenuation of some tinnitus symptoms has been 
reported with a variety of GABAergic drugs, including benzodiazepine derivatives alprazolam 
(Johnson et al 1993) and clonazepam (Bahmad et al 2006), and the GABA homolog gabapentin 
(Zapp 2001; Shulman et al 2002; Bauer and Brozoski 2006) under select circumstances.  
Considering the inconsistent results for conventional GABAergic drugs in tinnitus, agents that 
significantly potentiate extrasynaptic GABAA receptors may offer unique benefit in the 
management of tinnitus relative to drugs with low affinity at extrasynaptic GABAA receptors 
(Witkin et al 2022). The GABAergic compound gaboxadol, which selectively activates 
extrasynaptic GABAA receptors, has successfully ameliorated tinnitus in animal studies 
(reviewed in Richardson et al 2012). This selective activation of extrasynaptic GABAA receptors 
by low concentrations of gaboxadol reduces spontaneous and evoked firing rates of sensory 
thalamic neurons involved in tinnitus. Such reductions in excitability of auditory 
thalamus/medial geniculate body (MGB) neurons following activation of extrasynaptic GABAA 
receptors in tinnitus could prove advantageous in reducing the transmission of hyperexcitability 
to the auditory cortex (Herd et al 2009).  


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While brexanolone is approved for the treatment of postpartum depression (PPD), its efficacy 
has also been examined in the management of super-refractory status epilepticus (SRSE). SRSE 
is a life-threatening form of status epilepticus that recurs despite 24 hours or more of continuous 
intravenous (IV) administration of anesthetic third-line agents. In a Phase 2, open-label study 
using a targeted burst-suppression regimen (the STATUS study), brexanolone was associated 
with a statistically significant increase in quantitative EEG suppression ratio (qSR) during the 
initial 1-hour loading infusion (which targeted a plasma concentration of 150 nM). Moreover, 
initial qSR increase was positively correlated with brexanolone plasma concentrations over first 
9 hours of infusion (maintenance infusion of 86 mcg/kg/hour). These findings support the 
potential of brexanolone to enhance neural inhibition in presence of aberrant excitatory activity 
with brief exposure (Rosenthal et al 2015a; Rosenthal et al 2015b).  
Based on the data for GABAergic compounds in tinnitus, suppression of aberrant excitatory 
activity by brexanolone in SRSE, and the potential role of GABA in the pathogenesis of this 
disorder, brexanolone, a positive allosteric modulator of synaptic and extra-synaptic GABAA 
receptors, is being evaluated in the treatment of patients with tinnitus. 
5.4. 
Dose Justification 
Brexanolone, administered as a 60-hour infusion, is approved for the treatment of postpartum 
depression (PPD) in patients 15 years and older with a maintenance infusion rate of 
90 mcg/kg/hour for 28 hours. In the present study, a 5-hour duration infusion given at 
90 mcg/kg/hour following a period of up-titration in otherwise healthy participants with tinnitus 
is thought to allow adequate time to approach steady-state levels of brexanolone and anticipated 
to rapidly achieve plasma concentrations of brexanolone in the range experienced during therapy 
for PPD and during a clinical study for burst suppression in patients with SRSE (Section 5.3). 
Moreover, 90 mcg/kg/hour given as a short-term infusion (ie, 4 hours) was generally 
well-tolerated in the brexanolone ADME/mass balance study (547-CLP-101). 
 




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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is an open-label study to evaluate the safety, tolerability, 
, and efficacy of brexanolone in 
adults with tinnitus following a single 6-hour continuous IV infusion. The study design is 
presented in Figure 2. 
Figure 2: 
Study Design 
 
 
This study includes a Screening Period of up to 28 days, a 1-day Treatment Period, and a 6-day 
Follow-up Period. After providing informed consent, participants will undergo screening 
assessments as outlined in Table 2 to determine eligibility. 
Screening Period: 
The Screening Period begins with the signing of the informed consent form (ICF). Eligible 
participants will complete additional eligibility and baseline assessments as specified in the 
Schedule of Assessments (Table 2).  
Starting 7 days before administration of investigational product (IP) (Day -7), participants will 
have twice daily remote predose assessments as indicated in Table 2. Participants will receive 
training on how to perform all remote assessments during Screening. The participant will be 
contacted by the site on Day -7 through Day -1 to remind them to begin remote assessments. 
Assessments will be performed remotely by the participant on Day -7 through Day -1. Ratings 
for both VAS-L and VAS-A will be done twice daily, once each in the morning and evening. 
Participants will be excluded from dosing if they do not successfully perform at least 10 of the 
14 remote VAS assessments. 


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Treatment Period: 
A continuous, 6-hour IV infusion of IP will be administered at the Clinic Treatment Visit on 
Day 1. Assessments will be performed as indicated in Table 3.  
The participant will spend approximately 9 hours in the clinic on Day 1: 1 hour for setup of IV 
pump and assessments performed prior to administration of IP, 6 hours for the IP infusion, and 
2 hours for safety observation at the conclusion of the IP infusion. At the discretion of the 
investigator, participants may stay in the clinic overnight after the end of infusion. 
Due to the risk of excessive sedation and sudden loss of consciousness, for the duration of the 
infusion, participants will be monitored for hypoxia using continuous pulse oximetry equipped 
with an alarm and will be assessed for excessive sedation 
by 
a healthcare provider. If excessive sedation occurs at any time during the infusion, the infusion 
will be stopped until the symptoms resolve. The infusion may be resumed at the same or lower 
dose per protocol guidance. The infusion will be immediately stopped if pulse oximetry reveals 
hypoxia, specifically if this occurs in the context of excessive sedation or sudden loss of 
consciousness. After an episode of confirmed hypoxia, the infusion should not be resumed.  
For lactating subjects, the investigator and subject should weigh the developmental and health 
benefits of breastfeeding during the infusion against any potential adverse effects on the 
breastfed child from brexanolone or from the underlying maternal condition. Subjects may 
continue to breastfeed or express milk to feed their infant during the infusion if the benefit is 
deemed to outweigh the risk. During the study, a qualified lactation consultant will be made 
available to subjects upon request. 
In this study, excessive sedation, loss of consciousness, and any sedation-related AE that leads to 
dose reduction, interruption, or termination will be recorded as an adverse event of special 
interest (AESI). 
A fall precaution protocol must be in place for the duration of the brexanolone infusion. 
At the conclusion of the IP infusion, if deemed medically appropriate by the investigator, 
participants will be released from the clinic after the 2-hour safety observation period and 
completion of assessments. Participants will be cautioned against engaging in potentially 
hazardous activities requiring mental alertness, including driving, until any sedative effects have 
dissipated. A designated companion must drive the participant when they are discharged from 
the clinic. 
Follow-Up Period:  
Assessments for the Follow-up Period will be performed as indicated in Table 3. The participant 
will be contacted by the site on Day 2 through Day 6 to remind them to begin remote 
assessments. Follow-up assessments will be conducted remotely on Day 2 through Day 6. 
Ratings for both VAS-L and VAS-A will be done twice daily, once each in the morning and 
evening.  
Participants will return to the clinic approximately 6 days after the last dose of IP (Day 7±1 day) 
for efficacy and safety monitoring at the EOS Visit. The EOS Visit will also be conducted at the 
time of study discontinuation if this occurs at any time before Day 7 ±1 day (see Section 8.4.2). 


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7.2. 
Number of Participants 
Up to 24 participants will be dosed to achieve approximately 20 study completers, assuming a 
20% study discontinuation rate among dosed participants.  
7.3. 
Treatment Assignment 
In this open-label study, all participants will receive a single 6-hour continuous IV infusion of 
brexanolone on Day 1. 
7.4. 
Dose Escalation and Adjustment Criteria 
  
If excessive sedation 
 occurs at any time during the infusion, the infusion will 
be stopped until the symptoms resolve. The infusion may be resumed at the same or lower dose 
per protocol guidance. The infusion will be immediately stopped if pulse oximetry reveals 
hypoxia. After an episode of confirmed hypoxia, the infusion should not be resumed. 
If other intolerable AEs occur, the infusion will be stopped until the symptoms resolve. The 
infusion may be resumed at the same or lower dose as clinically appropriate. 
For participants who do not tolerate the 90 mcg/kg/hour dose for reasons other than hypoxia, a 
reduction to 60 mcg/kg/hour should be considered. No reductions below 60 mcg/kg/hour are 
permitted. 
Any sedation-related AEs that lead to dose interruption, termination, or reduction should be 
recorded as AESIs, and should be reported in an expedited manner as outlined in Section 12.2.3. 
A plasma sample for 
 should be drawn during the time when the pump is stopped. 
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 AEs 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 institutional review board (IRB)/independent ethics committee (IEC), where required, and 
initiate withdrawal procedures for participating participants.  
7.6. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study.  
A participant is considered to have completed the study if he/she has completed the EOS Visit. 


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8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
8.1. 
Participant Inclusion Criteria 
Participants must meet all of the following criteria to qualify for participation in this study: 
1. Participant has signed an ICF before any study-specific procedure is started. 
2. Participant is ambulatory and is 18 to 65 years of age, inclusive, at the time informed 
consent is obtained. 
3. Participant has a designated companion for the Clinic Treatment Visit who will drive 
them when they leave the clinic.  
4. Participant is in good physical health and has no clinically significant findings (excluding 
tinnitus), as determined by the investigator on medical history and physical examination, 
including neurologic and mental status examinations, 12-lead ECG, or clinical laboratory 
tests.  
5. Participant has a diagnosis of subjective, idiopathic, unilateral or bilateral, non-pulsatile 
tinnitus (eg, not due to medical disease) of ≥6 months and <10 years duration. 
6. Participant has mild to severe tinnitus distress according to Tinnitus Handicap Inventory 
(THI) score of 24 to 68 at Screening. 
7. Participant is willing and able to safely discontinue the use of central nervous system 
(CNS) depressants (eg, opioids and benzodiazepines), antidepressants, anticonvulsants, 
CNS stimulants (with the exception of caffeine), aspirin, other nonsteroidal anti-
inflammatory drugs, and aminoglycosides at least 14 days or 5 half-lives (whichever is 
longer) prior to receiving IP and through completion of the study.  
8. Female participant agrees to use at least one method of highly effective contraception 
during participation in the study and for 30 days following the last dose of IP, unless she 
is postmenopausal, permanently sterile, or does not engage in sexual relations which 
carry a risk of pregnancy (see Section 9.2.5).  
9. Male participant with a partner who is of childbearing potential agrees to use an 
acceptable method of effective contraception for the duration of the study and for 
13 weeks after receiving the IP, unless the participant does not engage in sexual 
relation(s) which carry a risk of pregnancy in his female partner(s). Acceptable methods 
of effective contraception are listed in Section 9.2.5.  
10. Male participant is willing to abstain from sperm donation for the duration of the study 
and for 13 weeks after receiving the IP. 
8.2. 
Participant Exclusion Criteria 
Participants who meet any of the following criteria are disqualified from participation in this 
study: 
1. Participant has history or presence of any neurologic disease or condition, including, but 
not limited to, unexplained loss of consciousness, seizure disorder including a prior 
nonfebrile seizure, and closed head trauma with clinically significant sequelae. 


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2. Participant has a history of sleep apnea or any clinically significant respiratory conditions 
that may predispose the participant to hypoxia during the infusion. 
3. Participant intends to start or discontinue a pharmacological or nonpharmacological 
therapy (eg, psychotherapy, sound therapy, masking, transcranial magnetic stimulation 
[TMS]) for tinnitus during the course of the study. 
4. Participant has currently active and medically significant or uncontrolled hepatic, renal, 
cardiovascular, pulmonary, gastrointestinal, hematological, immunologic, metabolic 
disease (hypothyroidism with stable thyroid replacement is acceptable).  
5. Participant’s tinnitus can be modulated by maneuvers of the temporomandibular joint, 
head and neck, eyes, or limbs, or otherwise attributed to somatosensory cause or has had 
prior otoscopic surgeries or cholesteatoma.  
6. Participants has current unilateral or bilateral hearing loss of 30 dB or greater (mild 
hearing loss) in one or more tested frequencies (500 Hz, 1000 Hz, 2000 Hz, and 
4000 Hz), 60 dB or greater at 6000 Hz and 8000 Hz, asymmetry of 30 dB or greater in 
two or more tested frequencies or uses a cochlear implant or hearing aid. 
7. Participant has history of chronic otitis media (>3 per year during past 5 years). 
8. Participant has a total score of 15 or greater (ie, moderately severe) on the Patient Health 
Questionnaire-9 (PHQ-9) at Screening.  
9. Participant has diagnosis of moderate or severe substance use disorder (excluding 
nicotine dependence) within 12 months of Screening, has a positive screen for drugs of 
abuse including tetrahydrocannabinol (THC) on Day 1 prior to dosing, or has a positive 
screen for alcohol on Day 1 prior to dosing. 
10. Participant has a known allergy to progesterone, allopregnanolone, or any IP excipient.  
11. Female participant has a positive pregnancy test or a confirmed pregnancy at Screening 
or prior to dosing on Day 1. 
12. Participant has had exposure to another investigational drug or device within 30 days or 
5 half-lives of the investigational drug, whichever is longer, prior to the Day 1 visit. 
13. Participant has a history of suicidal behavior within 2 years or answers “YES” to 
Questions 3, 4, or 5 on the C-SSRS at Screening or at Day 1 or is currently at risk of 
suicide in the opinion of the investigator. 
14. Participant has donated 1 or more units (1 unit = 450 mL) of blood or experienced acute 
loss of an equivalent amount of blood within 60 days prior to Day 1.  
15. Participant has any condition, comorbidity, or lifestyle consideration that in the opinion 
of the investigator would limit or interfere with the participant’s ability to complete or 
partake in the study. 
16. Participant is unwilling or unable to comply with study procedures and the required 
training during the Baseline Period. The participant must complete 10 VAS assessments 
remotely prior to Day 1. 


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17. Participant is unable to complete participation in the study, eg, due to preplanned event 
including elective surgery. 
18. Participant is investigative site personnel, sponsor personnel, or a member of their 
immediate families (spouse, parent, child, or sibling whether biological or legally 
adopted). 
8.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently dosed. A minimal set of screen failure information will be collected, including 
demography, screen failure details, eligibility criteria, and any serious adverse event (SAE). 
Individuals who screen fail may not be rescreened except for failure of inclusion criterion 7 
and/or exclusion criteria 12, 14, and 17 (after clinical recovery from the preplanned event). An 
individual who qualifies may only be rescreened once. Rescreened participants will be assigned a 
new participant number. 
A failed Screening drug or alcohol test does not exclude participation in the study if test is 
negative at Day 1. However, participants with a failed drug or alcohol test on Day 1 are excluded 
from participation in the study and may not be rescreened. 
8.4. 
Investigational Product Discontinuation and Early Termination from 
the Study 
A participant may withdraw from the study at any time at his/her own request for any reason. 
The investigator may discontinue a participant from the study and/or from IP for safety, 
behavioral, compliance, or administrative reasons.  
The investigator must notify the sponsor and/or the medical monitor when a participant 
discontinues IP and/or stops participation in the study for any reason.  
8.4.1. 
Investigational Product Discontinuation 
When a participant is discontinued from IP, the participant should continue, if willing, to 
participate in the remainder of the study by attending all scheduled visits per the SOA (Table 3). 
The reason for IP discontinuation and/or the reason for early termination from the study must be 
documented in the participant’s source documentation and recorded in the participant’s 
electronic case report form (eCRF) 
8.4.2. 
Early Termination from the Study 
At the time of study withdrawal/stopping study participation, if possible, the EOS Visit should be 
conducted. The participant will be permanently discontinued both from the IP 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. 


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Reasons for study discontinuation include, but are not limited to, the following:  
• Adverse event 
• Pregnancy 
• Protocol deviation 
• Non-compliance with study drug 
• Lost to follow-up 
• Withdrawal by subject 
• Screen failure 
• Study terminated by sponsor 
8.4.3. 
Loss to Follow-up 
A participant will be deemed lost to follow-up after unsuccessful documented attempts to contact 
the participant.  
8.4.4. 
Replacement of Participants 
Participants who initiate the IP infusion and who subsequently withdraw for any reason will not 
be replaced. See Section 8.3 regarding rescreening of screen failure participants. 


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9. 
TREATMENT OF PARTICIPANTS 
9.1. 
Description of Investigational Product 
Participants will be administered a single continuous 6-hour IV infusion of brexanolone. 
9.2. 
Prior and Concomitant Medications, Nonpharmacological 
Interventions, Restrictions, and Contraception Requirements 
9.2.1. 
Prior and Concomitant Medications and/or Supplements 
The start and end dates, route, dose/units, frequency, and indication for all medications and/or 
supplements taken within 60 days, all psychotropic medications taken within 6 months, and all 
medications used to treat tinnitus regardless of timing prior to signing the informed consent 
through the first dose of IP will be recorded.  
All medications and/or supplements taken from the first dose of IP through the Day 7 (±1 days) 
visit (including start and end dates route, dose/units, frequency, and indication) will be recorded 
on the eCRF. Any concomitant medication determined necessary for the welfare of the 
participant may be given at the discretion of the investigator at any time during the study.  
9.2.2. 
Nonpharmacological Interventions 
The start and end dates for all nonpharmacological interventions for tinnitus prior to signing the 
informed consent will be recorded. Nonpharmacological interventions include, but are not 
limited to, psychotherapy, sound therapy masking, and transcranial magnetic stimulation (TMS). 
9.2.3. 
Prohibited Medications 
Participant must discontinue the use of central nervous system (CNS) depressants (eg, opioids 
and benzodiazepines), antidepressants, anticonvulsants, CNS stimulants (with the exception of 
caffeine), aspirin, other nonsteroidal anti-inflammatory drugs, and aminoglycosides at least 
14 days or 5 half-lives (whichever is longer) prior to receiving IP and through completion of the 
study.  
9.2.4. 
Other Restrictions 
The participant should not engage in potentially hazardous activities requiring mental alertness 
and should not drive a car until after completion of the brexanolone infusion and until any 
feelings of sedation have dissipated. A designated companion must drive the participant when 
they are discharged from the clinic.  
Alcohol consumption while receiving brexanolone is prohibited. 
IV medications may not be coadministered with brexanolone in the same infusion line. 
9.2.5. 
Acceptable Forms of Contraception 
As per the Clinical Trials Facilitation and Coordination Group (CTFG), a woman is considered 
of childbearing potential (WOCBP), ie, fertile, following menarche and until becoming 


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postmenopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.  
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used 
to confirm a postmenopausal state in females not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.  
A male is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
Acceptable forms of highly effective contraception (ie, can achieve a failure rate of <1% per year 
when used consistently and correctly) for participants of childbearing potential or for a male 
participant’s partner of childbearing potential include: 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation  
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion or bilateral tubal ligation (performed at least 3 months prior 
to screening) 
• Vasectomized partner (performed at least 3 months prior to screening) 
• Sexual abstinence (no sexual intercourse) 
Acceptable forms of contraception for male participants include: 
• Sexual abstinence (no sexual intercourse) 
• History of vasectomy (performed at least 3 months prior to screening) 
• Condom with spermicide used together with highly effective female contraceptive 
methods if the female partner(s) is of childbearing potential (see above for list of 
acceptable female contraceptive methods) 
Acceptable forms of contraception which may not be considered as highly effective include: 
• Oral progestogen-only hormonal contraception, where inhibition of ovulation is not 
the primary mode of action  
• Male or female condom with or without spermicide  
• Cap, diaphragm, or sponge with spermicide  
• A combination of male condom with either cap, diaphragm, or sponge with 
spermicide (double barrier methods) are also considered acceptable 
9.3. 
Intervention after the End of the Study 
Not applicable 


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9.4. 
Treatment Adherence 
Brexanolone will be administered to participants as a single 6-hour continuous IV infusion 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 non-adherence 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 an open-label study in which all participants will receive brexanolone. 


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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 as a 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. 
The composition and pharmaceutical quality of the study drug will be maintained according to 
the current Good Manufacturing Practice and Good Clinical Practice (GCP) guidelines and 
available for review in the IP documentation.  
10.2. 
Investigational Product Packaging and Labeling 
Brexanolone is sterile-filtered and aseptically filled into 20 mL Type 1 parenteral glass vials with 
West FluroTec® coated stopper container closure system under current Good Manufacturing 
Practice conditions. Brexanolone is intended to be used as a single-use vial. 
IP labels with all required information and conforming to all applicable FDA Code of Federal 
Regulations and Good Manufacturing Practices/Good Clinical Practices (GCP) 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 
Upon receipt of the IP, the investigator, the responsible pharmacist, or designee will inspect the 
product and acknowledge receipt in accordance with the pharmacy manual.  
IP vials should be stored under refrigerated conditions (2 to 8°C). 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.  
10.4. 
Investigational Product Preparation 
The pharmacist or designee will be responsible for preparing brexanolone for participant 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 
Participants will receive a 6-hour continuous IV infusion of brexanolone on Day 1.  
The specific infusion dose of IP will be calculated based on weight (obtained at Screening) for 
each participant and administered according to the dose regimen in Table 5. 


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Table 5: 
Infusion Rate 
Time point 
Day 1 
0 to 0.5 hours 
Day 1 
0.5 to 1 hour 
Day 1 
1 to 6 hours 
Dose 
30 mcg/kg/hour 
60 mcg/kg/hour 
90 mcg/kg/houra 
a A reduction in dosage to 60 mcg/kg/hour should be considered for participants who do not tolerate 
90 mcg/kg/hour. No reductions below 60 mcg/kg/hour are permitted. 
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 and in 
the Pharmacy Manual. 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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11. 
EFFICACY 
 
 
11.1. 
Efficacy Assessments 
For in-clinic assessments, baseline is defined as the most recent value immediately prior to the 
start of IP infusion. For remote daily assessments, baseline is defined as the average of all 
available preinfusion values per participant. 
 
 
 
 
 
 
  
11.1.2. 
Visual Analog Scales 
The VAS loudness (VAS-L) and annoyance (VAS-A) are subject-rated scales for evaluating 
tinnitus (Adamchic et al 2012). Scoring for both is along a linear vertical scale, with the left side 
being not audible/not annoying (score of 0) and the right side being extremely loud or annoying 
(score of 100). Intermediate scores are determined by extrapolation between the two sides of the 
scales.  
To assess tinnitus loudness (VAS-L), participants will answer the question “How loud is your 
tinnitus now?” on a horizontal scale anchored on left by “not audible” and on right by “extremely 
loud” . 
To assess tinnitus annoyance (VAS-A), participants will answer the question “How much is your 
tinnitus annoying you now?” on a horizontal scale anchored on left by “not annoying” and on 
right by “extremely annoying”.  
 
 
 


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12. 
SAFETY ASSESSMENTS 
12.1. 
Safety and Tolerability Assessments 
Safety and tolerability of brexanolone will be evaluated by incidence of treatment-emergent 
adverse events as well as changes from baseline in vital signs measurements, ECGs, and clinical 
laboratory parameters, 
.  
The following assessments will be conducted according to the Schedules of Assessments 
(Table 2 and Table 3). 
12.1.1. 
Demography and Medical History 
Demographic characteristics (age, race, sex, ethnicity) and a full medical history will be 
documented. Tinnitus-related medical history will be obtained by structured interview. Mild to 
severe tinnitus will be determined using the 
 Participants will also be asked about 
unexplained loss of consciousness, seizure disorder including a prior nonfebrile seizure, and 
closed head trauma with clinically significant sequelae. 
12.1.2. 
Weight and Height 
Height and weight will be measured and documented. Body mass index (BMI) will be calculated 
and documented.  
12.1.3. 
Physical Examination 
Whenever possible, the same individual should perform all physical examinations. Physical 
examinations will include assessment of body systems (eg, head, eye, ear, nose, and throat; heart; 
lungs; abdomen; and extremities) as well as cognitive and neurological examination and mental 
status examination, as performed per local standard of care. Unscheduled physical examinations 
may also be conducted per the investigator’s discretion. 
Any abnormality in physical examinations will be interpreted by an investigator as abnormal, not 
clinically significant (NCS); or abnormal, clinically significant (CS) in source documents.  
12.1.4. 
Vital Signs 
Vital signs comprise heart rate, respiratory rate, temperature, and blood pressure. Heart rate and 
systolic and diastolic blood pressure are to be measured after the participant has been semi-
inclined for at least 5 minutes prior to the measurement.  
Any abnormality in vital signs will be interpreted by an investigator as abnormal, not clinically 
significant (NCS); or abnormal, clinically significant (CS) in source documents. 
12.1.5. 
Electrocardiogram  
A 12-lead ECG will be performed. The standard intervals (heart rate, PR, QRS, QT, and QTcF) 
as well as any rhythm abnormalities will be recorded. 
Electrocardiograms will be performed after the participant has been resting in a position for at 
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All abnormal ECGs will be interpreted by an investigator as abnormal NCS, or abnormal CS in 
source documents. 
12.1.6. 
Laboratory Assessments 
Blood samples will be collected for hematology, serum chemistry, and coagulation. Analytes to 
be evaluated are summarized in Table 6. 
Table 6: 
Summary of Clinical Laboratory Analytes 
Biochemistry 
Renal Panel: glucose, calcium, phosphorus, blood urea nitrogen, creatinine, 
sodium, potassium, chloride, bicarbonate 
Hepatic Panel: albumin, ALT, AST, total bilirubin and if elevated, reflex 
fractionation for direct and indirect bilirubin alkaline phosphatase, total protein, 
lactate dehydrogenase, gamma glutamyl transferase 
Coagulation 
(Screening only) 
Activated partial thromboplastin time, prothrombin time, and international 
normalized ratio only on subjects determined to be high clinical risk for bleeding 
Hematology 
Red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell count with 
differential, and platelet count. 
Urinalysis 
Specific gravity, pH, protein, glucose, ketones, occult blood, leukocyte esterase, 
nitrite, bilirubin, and urobilinogen. If protein, leukocyte, occult blood, and/or 
nitrites are positive, a microscopic examination will be performed. 
 
All clinical laboratory test results outside the reference range will be interpreted by the 
investigator as abnormal NCS or abnormal CS in source documents. Screening results 
considered abnormal, CS at the Screening Visit may make the subject ineligible for the study 
pending review by the investigator or medical monitor. Clinically significant abnormal results 
after screening will be considered and reported as AEs. 
Follicle stimulating hormone testing will be conducted to confirm whether a participant with 
≥12 months of spontaneous amenorrhea meets the protocol-defined criteria for being post-
menopausal (Section 8.1). 
12.1.6.1. Drugs of Abuse, Alcohol, Cotinine 
Urine assessment for select drugs of abuse will be performed (including amphetamines, 
barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, and phencyclidine).  
Alcohol will be assessed via breathalyzer or urine dipstick.  
12.1.6.2. Pregnancy Screen 
A serum pregnancy test will be conducted for all WOCBP at Screening; a urine pregnancy test 
will be conducted for all WOCBP at all other scheduled timepoints.  
12.1.7. 
Continuous Pulse Oximetry 
Subjects will be monitored during the infusion for hypoxia using continuous pulse oximetry 
equipped with an alarm. Oxygen saturation should be recorded prior to dose escalation at 
0.5 hour and 1 hour. Otherwise, it need only be recorded in the event of hypoxia, in which case, 




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• If the answer is “yes”, the following questions are asked: 
− Did you have a test? If yes, was the result positive, negative, or inconclusive? 
− Were you isolated? If yes, what were the dates of isolation? 
− Were you hospitalized? If yes, what were the dates of hospitalization? 
2. Did you receive the COVID-19 vaccine? 
• If the answer is “no”, no further questions. 
• If the answer is “yes”, the following questions are asked: 
− What is the reported name of the COVID-19 vaccine you received? 
− Who is the manufacturer of the COVID-19 vaccine you received? 
− On what date(s) did you receive the COVID-19 vaccine? 
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Adverse Event Definition 
An adverse event (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 treatment-emergent adverse event (TEAE) is defined as an AE 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 study.  
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 a serious adverse event 
(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). 
All AEs that occur after any participant has signed the informed consent and throughout the 
duration of the study, whether or not they are related to the study, must be reported to Sage 
Therapeutics. 
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 


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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 eCRF. The sponsor or its representative 
retains the right to request additional information for any patient with ongoing AE(s)/SAE(s) 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 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the investigator 
may jeopardize the participant or may require medical intervention to prevent 1 of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any participant has signed the ICF and throughout the duration of the 
study, whether or not they are related to the study, must be recorded on the SAE report form 
provided by Sage Therapeutics. Any SAE that is ongoing when the participant completes their 
final study visit, will be followed by the investigator until the event has resolved, stabilized, 
returned to baseline status, or until the participant dies or is lost to follow up. 
A prescheduled or elective procedure or routinely scheduled treatment will not be considered an 
SAE, even if the participant is hospitalized. The site must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or on a waiting list to be scheduled) prior to obtaining the participant’s 
consent to participate in the study. 
• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of an 
investigator, between the participant’s consent to participate in the study and at the 
time of the procedure or treatment. 
12.2.3. 
Definition of Adverse Events of Special Interest  
An adverse event of special interest (AESI) is an AE/SAE of scientific and/or medical concern, 
specific to the product or program for which ongoing monitoring and rapid communication by 
the investigator to the sponsor is required. Such adverse events normally require thorough 
documentation and investigation in order to characterize them.  


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The following events are considered AESIs and should be reported on the AESI form to Sage 
and designee within 72 hours: 
• Excessive sedation  
• Loss of consciousness 
• Any sedation-related AE that leads to dose reduction, interruption, or termination 
If the AESI also qualifies as an SAE, an SAE form should be submitted per the guidelines per 
Section 12.2.7. 
12.2.4. 
Definition of Urgent Safety Measure and Unanticipated Problem  
In accordance with Article 10(b) of Directive 2001/20/EC, some reported events may result in an 
urgent safety measure (USM), defined as an action that the sponsor and investigator may take in 
order to protect the participants of a study against any immediate hazard to their health or safety. 
Examples of USMs include: 
• Suspension of enrollment due to significantly higher incidence of death at one site 
• Additional clinical or non-clinical investigations performed due to increased 
frequency of AEs 
• Halting a clinical study for safety reasons 
In accordance with FDA Guidance 21 CFR Part 312.66, some reported events may qualify as an 
unanticipated problem (UP), defined as any incident, experience, or outcome that meets all of the 
following criteria: 
• Unexpected (in terms of nature, severity, or frequency) given (i) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (ii) the 
characteristics of the population being studied; related or possibly related to an 
individual’s participation in the study; and 
• Suggests the study may place the participant or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) related to the study 
than was previously known or recognized. 
Any UP must be reported within 24 hours of awareness via email to Sage and designee due to the 
urgent reporting requirements to regulators and IRB(s)/IECs(s). 
12.2.5. 
Relationship to Investigational Product 
The investigator must make the determination of relationship to the IP for each adverse event 
(not related, related). The following definitions should be considered when evaluating the 
relationship of AEs and SAEs 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 


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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 
12.2.6. 
Recording Adverse Events 
Adverse events spontaneously reported by the participant and/or in response to an open question 
from the study personnel or revealed by observation 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 (date and time), 
resolution (date and time), intensity, causality, action taken, outcome and seriousness (if 
applicable), and whether or not it caused the participant to discontinue the IP or withdraw early 
from the study. 
Intensity will be assessed according to the following scale: 
• Mild: symptom(s) barely noticeable to participant or does not make participant 
uncomfortable; does not influence performance or functioning; prescription drug not 
ordinarily needed for relief of symptom(s)  
• Moderate: symptom(s) of a sufficient severity to make participant uncomfortable; 
performance of daily activity is influenced; participant is able to continue in study; 
treatment for symptom(s) may be needed 
• Severe: symptom(s) cause severe discomfort; symptoms cause incapacitation or 
significant impact on participant’s daily life; severity may cause cessation of 
treatment with IP; treatment for symptom(s) may be given and/or participant 
hospitalized  
It is important to distinguish between serious and severe AEs. 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. 
12.2.7. 
Reporting Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE(s), the study site 
must notify Sage and designee within 24 hours of the study site staff becoming aware of the 
SAE(s). The investigator must complete, sign and date the SAE report form, verify the accuracy 
of the information recorded on the SAE report form with the corresponding source documents, 
and send a copy to Sage and designee.  


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Additional follow-up information, if required or available, should all be sent to Sage and 
designee within 24 hours of receipt on a follow-up SAE report form and placed with the original 
SAE information and kept with the appropriate section of the eCRF and/or study file. 
Serious adverse events occurring after the designated follow up time for the study, should be 
reported to Sage and 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. 
In addition, appropriate personnel in Sage Drug Safety and Pharmacovigilance or designee will 
unblind SUSARs for the purpose of regulatory reporting. Sage or designee will submit SUSARs 
(in blinded or unblinded fashion) to regulatory agencies according to local law. Sage, or 
designee, will submit SUSARS to investigators in a blinded fashion. 
12.3. 
Pregnancy 
If a participant becomes pregnant after the first administration of IP, pregnancy information must 
be collected and recorded on the Pregnancy form and submitted to Sage and designee 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 investigator will also attempt to collect pregnancy information 
on any participant’s partner who becomes pregnant after the participant has received the first 
administration of IP. After obtaining the necessary signed informed consent from the pregnant 
partner directly, the investigator will follow the same pregnancy reporting procedures specified 
for pregnant participants.  
The participant or participant’s partner 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 or participant’s partner and 
the neonate, and the information will be forwarded to Sage and designee within 24 hours of 
awareness. 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 
Overdose is described in Section 12.5.  
12.5. 
Special Considerations 
Drug abuse is the persistent or sporadic, intentional excessive use of IP which is accompanied by 
harmful physical or psychological effects in the participant. If an event of drug abuse occurs 
during the study, it must be reported to the sponsor and/or designee using the Special 
Considerations Form within 24 hours of the site becoming aware of the event(s). If the drug 
abuse results in an AE or SAE, the AE or SAE must also be recorded and reported as described 
in Section 12.2.6 and Section 12.2.7, respectively. 
Drug misuse refers to situations where IP is intentionally and inappropriately used not in 
accordance with the intended use as specified in the protocol. If an event of drug misuse occurs 
during the study, it must be reported to the sponsor and/or designee using the Special 
Considerations Form within 24 hours of the site becoming aware of the event(s). If the drug 
misuse results in an AE or SAE, the AE or SAE must also be recorded and reported as described 
in Section 12.2.6 and Section 12.2.7, respectively. 
An overdose is any dose of study treatment given to a participant or taken by a participant that 
exceeds the dose described in the protocol. Overdoses are not considered AEs and should not be 
recorded as an AE on the CRF; however, all overdoses must be recorded on the Special 
Considerations Form and sent to Sage and/or designee within 24 hours of the site becoming 
aware of the overdose. An overdose must be reported to Sage and designee even if the overdose 
does not result in an AE. If an overdose results in an AE or SAE, the AE or SAE must also be 
recorded and reported as described in Section 12.2.6 and Section 12.2.7, respectively. 
A medication error is any preventable event that may cause or lead to inappropriate medication 
use or participant harm while the medication is in the control of the healthcare professional, 
participant, or consumer. All medication errors must be recorded on the Special considerations 
form and sent to the sponsor and/or designee within 24 hours of the site becoming aware of the 
medication error. The medication error must be reported to the sponsor and/or designee even if 
the medication error does not result in an AE. If a medication error results in an AE or SAE, the 
AE or SAE must also be recorded and reported as described in Section 12.2.6 and Section 12.2.7, 
respectively. 


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13. 
STATISTICS 
A detailed description of the analyses to be performed in the study will be provided in the 
statistical analysis plan (SAP). The SAP will be finalized and approved prior to database lock.  
13.1. 
Data Analysis Sets 
The Efficacy Set will be defined as all participants who received any amount of IP and have at 
least one post-baseline efficacy evaluation.  
  
The Safety Set is defined as all participants who received any amount of IP.  
13.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All participants will be used in the analyses, 
as per the analysis populations, using all non-missing data available. No imputation process will 
be used to estimate 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 listings, 
whereas other data may be presented in both listings and corresponding table(s) or figure(s).  
For the Screening period and Days 2-7, not more than one (1) set of remote morning VAS 
components and one (1) set of remote evening VAS components per timepoint will be used in 
the statistical analysis of data for a given study participant. However, morning and evening VAS 
component data may be displayed and descriptively summarized.  
For in-clinic VAS component assessments (VAS-A and VAS-L, Section 11.1.2), baseline is 
defined as the most recent VAS component value immediately prior to the start of IP infusion.  
For remote daily VAS-A assessments, baseline is defined as the arithmetic mean of Screening 
VAS-A values per participant; likewise, for remote daily VAS-L assessments, baseline is defined 
as the arithmetic mean of Screening VAS-L values per participant.  
Continuous data will be summarized, at minimum, with number (n), mean, standard deviation 
(SD), median, Q1, Q3, minimum, and maximum. Categorical data will be summarized, at 
minimum, with counts and percentages. Change from baseline is calculated as the baseline value 
minus the post-baseline value, unless defined otherwise for specific assessments and/or 
endpoints.  
Summary tables will generally summarize values at each timepoint and change from baseline at 
each post-baseline time point. 
13.4. 
Demographics and Baseline Characteristics 
Demographic data, such as age, race, and ethnicity, and baseline characteristics, such as height, 
weight, and BMI, will be summarized using the Safety Set.  


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Pregnancy test results and drug screen results will be listed but not summarized.  
Medical history will be listed by participant.  
13.5. 
Efficacy Analysis  
Efficacy analyses will primarily be based on the Efficacy Set. 
The two secondary endpoints of this study are (a) tinnitus perception during brexanolone 
infusion based on the VAS and (b) tinnitus perception after brexanolone infusion based on VAS. 
For remote assessments, ratings for both VAS-L and VAS-A will be obtained twice daily, once 
each in the morning and evening, during the both the Screening Period and on Day 2 to Day 7.  
The daily arithmetic means of remote VAS-A and VAS-L ratings obtained during the Screening 
Period will be computed and used descriptively. The daily arithmetic means of remote VAS-A 
and VAS-L ratings obtained on Days 2-7 will be used both descriptively and in statistical 
modeling. 
Each component of VAS for tinnitus will have change from baseline score (see Section 13.3 for 
a description of appropriate baseline for a given schedule of assessment timepoint) at each 
postbaseline assessment (whether during brexanolone infusion or post-brexanolone infusion) 
computed. Descriptive statistics of both VAS component scores and VAS component change 
from baseline scores will be summarized. 
Each VAS component score will be analyzed separately for each secondary endpoint. This will 
be done separately for Day 1 (ie, during treatment) and Days 2 to 7 (ie, after treatment). The 
during-infusion Day 1 VAS component data will consist of VAS components obtained at 0.5, 1, 
2, 3, 4, 5, and 6 hours. The post-infusion Days 2 to 7 VAS component data will consist of daily 
arithmetic component means.  
Each analysis will utilize a mixed effects model for repeated measures. Each repeated measures 
model will include (a) the change from baseline score of the appropriate VAS component as the 
dependent variable and (b) both baseline VAS component value and visit as fixed effect 
independent variables. Participants will be treated as random effects. 
Model- based point estimates (ie, least squares means, their 95% confidence intervals, and 
associated p-values) at each time point (visit) will be reported where applicable. Line plots of 
change from baseline scores will be plotted with standard error bars. Additional analyses will be 
detailed in the SAP. 
13.5.1. 
Multiplicity Adjustment 
Not applicable. 
13.5.2. 
Sensitivity Analyses 
Sensitivity analyses are not described in the protocol. Sensitivity analyses may be discussed in 
the SAP. 


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13.6. 
Safety Analyses 
The primary endpoint of this study is the incidence of TEAEs. This will be primarily assessed 
with TEAE tables presenting per-participant frequency counts and percentages within each 
unique combination of System Organ Class and Preferred Term. Please see Section 13.6.1 for 
additional detail. 
Generally, safety and tolerability of brexanolone will be evaluated by incidence of TEAEs and 
SAEs, as well as changes from baseline in vital signs measurements, ECGs, and clinical 
laboratory parameters, 
.  
Safety data will be listed by participant and summarized by treatment group. All safety 
summaries will be performed on the Safety Set using treatment received.  
13.6.1. 
Adverse Events 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 25.0 or higher. A treatment-emergent adverse event (TEAE) is defined as an AE with 
onset or worsening of severity after the first dose of brexanolone.  
The proportion of participants experiencing TEAEs will be displayed by treatment group and by 
system organ class and preferred term. Summaries will be provided by severity (mild, moderate, 
severe) and by causality (related, not related to IP). TEAEs leading to discontinuation or 
interruption of treatment or withdrawal from the study and any treatment-emergent SAEs will be 
summarized. All AEs and SAEs through the end of the study will be listed. 
13.6.2. 
Clinical Laboratory Evaluations 
Results of clinical laboratory parameters in each scheduled visit and mean changes from baseline 
will be summarized in standard units. Normal ranges for each parameter will be provided by the 
laboratory; shift from baseline to post-baseline values in abnormality of results will be provided. 
Potentially clinically significant values will be summarized by treatment. Clinical laboratory 
results will be listed by participant and timing of collection.  
13.6.3. 
Physical Examinations 
The occurrence of a physical examination (yes/no) and the date performed will be listed by 
participant. 
13.6.4. 
Vital Signs 
Vital sign results at each visit and mean changes from baseline will be summarized by scheduled 
visit. Potentially clinically significant values will be summarized by treatment. Vital sign results 
will be listed by participant and timing of collection. 
13.6.5. 
12-Lead Electrocardiogram 
The following ECG parameters will be listed for ECGs for each participant: heart rate, PR, QRS, 
QT, and QTcF. ECG data will be summarized by visit. Electrocardiogram findings will be listed 
by participant and visit. 




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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Unless otherwise waived or addressed in another forum (eg, investigator meeting), before an 
investigational site can enter a participant into the study, a representative of Sage will visit the 
investigational study site to: 
• Confirm the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, IP management, GCP/ International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP compliance, 
and the responsibilities of Sage or its representatives. Agreed upon site responsibilities 
will be documented in a Clinical Trial Agreement between Sage and the investigator. 
During the study, a monitor from Sage 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 eCRF, and that IP accountability checks are being performed 
• Perform source data verification. This includes a comparison of the data in the eCRF 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, 
medical records, source documents, clinic charts). 
• Record and report any protocol deviations not previously sent to Sage Therapeutics. 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to Sage Therapeutics, 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 IRB/IEC 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 
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. 


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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 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. Protocol deviations that harm or increase the possibility of harm to the rights and 
welfare of a participant, or a deviation made without prior IRB/IEC approval to eliminate an 
immediate hazard to the participant 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 study-related duties and functions conducted at the study site. When the investigator 
retains the services of any individual or party to perform study-related duties and functions, the 
investigator must ensure the individual or party is qualified to perform study-related duties and 
functions and should implement procedures to ensure the integrity of the study-related duties and 
functions performed, and any data generated.  
The investigator must maintain adequate and accurate source documents and study records that 
include all pertinent observations on each of the site’s study 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 Informed Consent Form, 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 study 
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 study participant, the investigator(s) will ensure that the participant is given 
full and adequate oral and written information about the nature, purpose, possible risk and 
benefit of the study. Participants must also be notified that they are free to discontinue from the 
study at any time. The participant should be given the opportunity to ask questions and allowed 
time to consider the information provided. 
When the participant decides to participate in the study, the participant (or the participant’s, 
parent or legally authorized representative) 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 documentation. 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 parent or legally authorized representative. 
Throughout the study, 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 


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documented in the participant’s source records, and when applicable, an updated ICF will be 
provided. 
16.4. 
 Data Protection 
• Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 
• The participant must be informed that his/her personal study-related data (including 
but not limited to, retained biological samples, images and/or recordings) will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for 
their data to be used as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Sage Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 


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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 visits at the investigation 
site and/or supporting facilities for the purpose of monitoring any aspect of the study. The 
investigator agrees to allow the monitor to inspect the facility, drug storage area, drug 
accountability records, participant medical records 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 investigational product. 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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Zapp JJ. Gabapentin for the treatment of tinnitus: a case report. Ear, nose, and throat journal. 
2001;80(2):114-116. 


Signature Page for VV-CLIN-003013 v1.0
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547-TRM-201 Protocol Summary of Changes 
Sage Therapeutics 
Version 2.0, Amendment 1  
 
 
1 
Protocol 547-TRM-201, Amendment 1 
Summary of Changes 
Date of Amendment: 18 July 2023 
An Open-Label Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy 
of Brexanolone in the Treatment of Adult Participants with Tinnitus 
Rationale for Protocol Amendment 1 
Changes to the protocol include: 
• Updated Inclusion Criterion #5 to increase the allowable duration of tinnitus 
diagnosis prior to Screening from <5 to <10 years (Synopsis, Section 8.1). 
• Clarified schedule of assessments footnote a to state that clinic-based screening 
assessments must be reported by Day -8 (Table 2). 
• Made minor editorial wording updates or clarifications to align with the protocol 
template (Synopsis, Section 8.1, Section 9.2.5, Section 12.2.7). 
• Clarified that the infusion will be immediately stopped if pulse oximetry reveals 
hypoxia, specifically in the context of excessive sedation or sudden loss of 
consciousness (Synopsis, Section 7.1). 
• Clarified that contact information in the event of a product complaint can be found in 
the Pharmacy Manual (Section 10.7). 
• Updated Section 12.4 Overdose and added Section 12.5 Special Considerations with 
new language for “abuse” and “misuse” to align with the Regulation (EU) 
No 536/2014 Of the European Parliament and Of The Council (Section 12.4, 
Section 12.5). 
• Moved language regarding medication errors from Section 10.7 to Section 12.5. 
Administrative changes, including personnel updates, have also been made. 


547-TRM-201 Protocol Summary of Changes 
Sage Therapeutics 
Version 3.0, Amendment 2  
 
 
1 
Protocol 547-TRM-201, Amendment 2 
Summary of Changes 
Date of Amendment: 13 October 2023 
An Open-Label Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy 
of Brexanolone in the Treatment of Adult Participants with Tinnitus 
Protocol Amendment 2 reflects the following changes:  
• The Sponsor Contact has changed from: 
 
Phone:
 
email: 
 
to: 
 
Phone: 
 
email: 
 
 
• The Sponsor Medical Monitor and Study Physician have changed from:  
, MD 
 
Phone/text: 
 
email: 
 
to: 
, MD 
 
Phone/text: 
 
email: 
 
• The Sponsor Approval page was deleted to align with current Sage process and template. 
• For clarity, editorial changes were made to a secondary endpoint (Section 6), the 
description of the Analysis Sets (Section 13.1), the description of the mixed effects model 
(Section 13.5) and corresponding sections of Section 2, Synopsis.   
• Minor formatting changes 

SAP_001.pdf: 
Official Title: 
An Open-Label Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of Brexanolone in the Treatment of 
Adult Participants With Tinnitus 
NCT Number: 
NCT05645432 
Document Date: 
Final Version: 01 Feb 2024


 
 
 
 
 
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SAP text Version 2.0 31-Jan-2024 
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Filing requirements: TMF 
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Statistical Analysis Plan for Interventional Studies 
Text only 
Sponsor Name: Sage Therapeutics, Inc. 
 
Protocol Number: 547-TRM-201 
Protocol Title: An Open-Label Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy 
of Brexanolone in the Treatment of Adult Participants with Tinnitus 
 
Protocol Version and Date: Amendment 2.0, Version 3.0, dated 13-Oct-2023 
 
Syneos Health Project Code: 7043647  
 
Authors:
 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Sage Therapeutics, Inc. 
Acceptance of this document constitutes agreement by the recipient that no information contained herein 
will be published or disclosed without prior written authorization from an official of Sage Therapeutics, Inc. 
However, this document may be disclosed to appropriate Institutional Review Board and Ethics 
Committees or duly authorized representatives of a national regulatory authority under the condition that 
they are requested to keep it confidential. In the event of an actual or suspected breach of this obligation, 
Syneos Health should be notified promptly. 
 
 
 
 
 
 
 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Sage Therapeutics, Inc.; Protocol No.: 547-TRM-201 
 
 
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Table of Contents 
Revision History ...............................................................................................................................2 
Approvals ........................................................................................................................................3 
1. 
Glossary of Abbreviations .......................................................................................................8 
2. 
Purpose ................................................................................................................................ 10 
2.1. 
Responsibilities ........................................................................................................ 10 
2.2. 
Timings of Analyses ................................................................................................. 10 
3. 
Study Objectives .................................................................................................................. 11 
3.1. 
Primary Objective ..................................................................................................... 11 
3.2. 
Secondary Objectives .............................................................................................. 11 
 
 11 
 
 11 
4. 
Study Details/Design............................................................................................................ 12 
4.1. 
Brief Description ....................................................................................................... 12 
4.2. 
Participant Selection ................................................................................................ 12 
4.2.1. 
Inclusion Criteria ................................................................................................... 12 
4.2.2. 
Exclusion Criteria .................................................................................................. 13 
4.3. 
Determination of Sample Size ................................................................................. 13 
4.4. 
Treatment Assignment and Blinding ....................................................................... 13 
4.5. 
Administration of Study Medication ......................................................................... 13 
4.6. 
Study Procedures and Flowchart ............................................................................ 13 
5. 
Endpoints ............................................................................................................................. 15 
5.1. 
Primary Endpoint ..................................................................................................... 15 
5.2. 
Secondary Endpoints ............................................................................................... 15 
 
 15 
 
 15 
6. 
Analysis Sets........................................................................................................................ 16 
6.1. 
Screened Set ........................................................................................................... 16 
6.2. 
Enrolled Set.............................................................................................................. 16 
6.3. 
Efficacy Set .............................................................................................................. 16 
6.4. 
Safety Set ................................................................................................................. 16 
6.5. 
Protocol Deviations .................................................................................................. 16 
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Statistical Analysis Plan for Interventional Studies 
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7. 
General Aspects for Statistical Analysis .............................................................................. 17 
7.1. 
General Methods ..................................................................................................... 17 
7.2. 
Key Definitions ......................................................................................................... 17 
7.2.1. 
Baseline ................................................................................................................ 17 
7.2.2. 
Study Day ............................................................................................................. 17 
7.3. 
Missing Data ............................................................................................................ 17 
7.3.1. 
Adverse Events (AE) ............................................................................................ 17 
7.3.2. 
Dates in Disease History (Dates of diagnosis, current episode, first episode) .... 18 
7.3.3. 
Prior and Concomitant Medications ..................................................................... 18 
7.4. 
Visit Windows ........................................................................................................... 19 
7.5. 
Pooling of Centers ................................................................................................... 19 
7.6. 
Subgroups ................................................................................................................ 19 
8. 
Demographic, Other Baseline Characteristics and Medication .......................................... 20 
8.1. 
Participant Disposition and Withdrawals ................................................................. 20 
8.2. 
Protocol Deviations .................................................................................................. 20 
8.3. 
Demographic and Baseline Characteristics ............................................................ 20 
8.4. 
Medical History ........................................................................................................ 20 
8.5. 
Tinnitus Medical History ........................................................................................... 20 
8.6. 
Prior and Concomitant Medications ........................................................................ 20 
8.7. 
Extent of Exposure................................................................................................... 21 
8.8. 
Treatment Compliance ............................................................................................ 21 
9. 
Efficacy ................................................................................................................................. 22 
9.1. 
Visual Analog Scales ............................................................................................... 22 
 
 23 
 
 24 
 
 24 
 
 24 
 
 25 
10. 
Safety ................................................................................................................................... 26 
10.1. 
Adverse Events ........................................................................................................ 26 
10.1.1. 
Treatment-Emergent Adverse Event (TEAE) ....................................................... 26 
10.1.2. 
Adverse Event of Special Interest (AESI) ............................................................. 27 
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Statistical Analysis Plan for Interventional Studies 
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10.2. 
Laboratory Evaluations ............................................................................................ 27 
10.3. 
Vital Signs, Weight, and Height ............................................................................... 30 
10.4. 
ECG .......................................................................................................................... 31 
10.5. 
Physical Examination ............................................................................................... 32 
 
 32 
 
 32 
11. 
Interim Analyses .................................................................................................................. 33 
12. 
Changes from Analysis Planned in Protocol ....................................................................... 34 
13. 
Reference List ...................................................................................................................... 35 
14. 
Quality Control ..................................................................................................................... 36 
15. 
Index of Tables, Figures, and Listings ................................................................................. 37 
16. 
Appendices .......................................................................................................................... 38 
16.1. 
Appendix A: Schedule of Assessments for Screening Period ................................ 38 
16.2. 
Appendix B: Schedule of Assessments for Treatment Period and Follow-up Period
.................................................................................................................................. 39 
 
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Statistical Analysis Plan for Interventional Studies 
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1. 
Glossary of Abbreviations 
Abbreviation 
Description 
AE 
Adverse Event 
AESI 
Adverse event of special interest 
ALT 
Alanine Transaminase 
AST 
Aspartate Transferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body mass index 
CI 
Confidence interval 
 
 
 
 
CS 
Clinically Significant 
 
 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
EOS 
End of study 
ICF 
Informed consent form 
IP 
Investigational product 
IV 
Intravenous 
LS 
Least squares 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
 
 
NA 
Not applicable 
NCS 
Not Clinically Significant  
 
 
 
 
PT 
Preferred Term 
Q1 
First quartile 
Q3 
Third quartile 
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Abbreviation 
Description 
QC 
Quality Control 
QTcF 
QT corrected according to Fridericia’s formula 
RBC 
Red Blood Cells 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDTM 
Study Data Tabulation Model 
SOC 
System organ class 
SOP 
Standard Operating Procedure 
SPL 
Sound pressure level 
SS 
Safety Set 
TEAE 
Treatment-emergent adverse event 
 
 
TFL 
Table, Figure and Listing 
 
 
TMS 
Transcranial magnetic stimulation 
UN 
Unstructured Covariance Matrix 
VAS 
Visual Analog Scale 
VAS-A 
VAS annoyance 
VAS-L 
VAS loudness 
WOCBP 
Woman of childbearing potential 
WHO 
World Health Organization 
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Statistical Analysis Plan for Interventional Studies 
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2. 
Purpose 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables and 
figures which will be produced, and the statistical methodologies which will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives. 
2.1. 
Responsibilities 
Syneos Health will perform the statistical analyses and is responsible for the production and quality 
control (QC) of all tables, figures and listings related to the safety, tolerability, and efficacy of Brexanolone 
in the treatment of adult participants with tinnitus. All clinical pharmacology assessments, including 
assessments, will be detailed in a separate modeling and assessment plan. 
qPharmetra will prepare individual 
 estimates utilizing the existing 
for Brexanolone and 
transfer to Sage. 
.  
2.2. 
Timings of Analyses 
The primary analysis of safety, tolerability, and efficacy is planned after all participants complete the final 
study visit or terminate early from the study. 
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Statistical Analysis Plan for Interventional Studies 
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3. 
Study Objectives 
3.1. 
Primary Objective 
The primary objective is to evaluate the safety and tolerability of brexanolone in adult participants with 
tinnitus.  
3.2. 
Secondary Objectives 
The secondary objectives are: 
• 
To assess subjective tinnitus perception during brexanolone infusion based on Visual Analog 
Scales (VAS). 
• 
To assess subjective tinnitus perception after brexanolone infusion based on VAS.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan for Interventional Studies 
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4. 
Study Details/Design 
4.1. 
Brief Description 
This is an open-label study to evaluate the safety, tolerability, 
, and efficacy of brexanolone in adults 
with tinnitus following a single 6-hour continuous intravenous (IV) infusion. 
This study includes a Screening Period of up to 28 days, a 1-day Treatment Period, and a 6-day Follow-
up Period. After providing informed consent, participants will undergo screening assessments as outlined 
in Study Protocol Table 2 to determine eligibility.   
Screening Period: 
The Screening Period begins with the signing of the informed consent form (ICF). Eligible 
participants will complete additional eligibility and baseline assessments as specified in the Schedule 
of Assessments (Study Protocol Table 2). 
Starting 7 days before administration of investigational product (IP) (Day -7), participants will have 
twice daily remote predose assessments as indicated in Study Protocol Table 2. Participants will receive 
training on how to perform all remote assessments during Screening. The participant will be contacted by 
the site on Day -7 through Day -1 to remind them to begin remote assessments. Assessments will be 
performed remotely by the participant on Day -7 through Day -1. Ratings for both Visual Analog Scale-
Loudness (VAS-L) and Visual Analog Scale-Annoyance (VAS-A) will be done twice daily, once each in 
the morning and evening. Participants will be excluded from dosing if they do not successfully perform at 
least 10 of the 14 remote VAS assessments. 
Treatment Period: 
A continuous, 6-hour IV infusion of IP will be administered at the Clinic Treatment Visit on Day 1. 
Assessments will be performed as indicated in Study Protocol Table 3.The participant will spend 
approximately 9 hours in the clinic on Day 1: 1 hour for setup of IV pump and assessments performed 
prior to administration of IP, 6 hours for the IP infusion, and 2 hours for safety observation at the 
conclusion of the IP infusion. At the discretion of the investigator, participants may stay in the clinic 
overnight after the end of infusion. 
 Follow-Up Period: 
Assessments for the Follow-up Period will be performed as indicated in Study Protocol Table 3. The 
participant will be contacted by the site on Day 2 through Day 6 to remind them to begin remote 
assessments. Follow-up assessments will be conducted remotely on Day 2 through Day 6. Ratings for 
both VAS-L and VAS-A will be done twice daily, once each in the morning and evening. 
Participants will return to the clinic approximately 6 days after the last dose of IP (Day 7±1 day) for 
efficacy and safety monitoring. The End of Study (EOS) Visit will be conducted at the time of 
discontinuation if this occurs at any time before Day 7±1 day (see Study Protocol Section 8.4.2).  
4.2. 
Participant Selection 
4.2.1. 
Inclusion Criteria 
Participants must meet all of the inclusion criteria listed in Study Protocol Section 8.1 to qualify for 
participation in this study.  
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4.2.2. 
Exclusion Criteria 
Participants who meet any of the exclusion criteria listed in Study Protocol Section 8.2 will be disqualified 
from participation in this study.  
4.3. 
Determination of Sample Size 
Up to 24 participants will be dosed to achieve approximately 20 study completers, assuming a 20% study 
discontinuation rate among dosed participants.  
4.4. 
Treatment Assignment and Blinding 
This is an open-label study in which all participants will receive a continuous, 6-hour IV infusion of 
brexanolone administered at the Clinic Treatment Visit on Day 1. 
4.5. 
Administration of Study Medication 
Participants will receive a 6-hour, continuous IV infusion of brexanolone on Day 1.  
The specific infusion dose of IP will be calculated based on weight (obtained at Screening) for each 
participant and administered according to the dose regimen in Table 1. 
Table 1. Infusion Rate 
Time point 
Day 1 
0 to 0.5 hours 
Day 1 
0.5 to 1 hour 
Day 1 
1 to 6 hours 
Dose 
30 mcg/kg/hour 
60 mcg/kg/hour 
90 mcg/kg/houra 
 a reduction in dosage to 60 mcg/kg/hour should be considered for participants who do not tolerate 90 mcg/kg/hour. No reductions 
below 60 mcg/kg/hour are permitted.  
Due to the risk of excessive sedation and sudden loss of consciousness, for the duration of the infusion, 
participants will be monitored for hypoxia using continuous pulse oximetry equipped with an alarm and 
will be assessed for excessive sedation (with the 
) by a healthcare provider. If excessive sedation 
occurs at any time during the infusion, the infusion will be stopped until the symptoms resolve. The 
infusion may be resumed at the same or lower dose per protocol guidance. The infusion will be 
immediately stopped if pulse oximetry reveals hypoxia. After an episode of confirmed hypoxia, the 
infusion should not be resumed. 
In this study, excessive sedation, loss of consciousness, and any sedation-related adverse event (AE) 
that leads to dose reduction, interruption, or termination will be recorded as an adverse event of special 
interest (AESI).  
4.6. 
Study Procedures and Flowchart 
The study design is summarized in the flow chart below. Reference Protocol Schedule of Assessments 
(Tables 2 and 3) for the complete Schedule of Activities. 
 
 
 
 
 
Figure 1. Study Design 
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5. 
Endpoints   
5.1. 
Primary Endpoint 
• 
Incidence of treatment-emergent adverse events (TEAEs) 
5.2. 
Secondary Endpoints 
• 
Change from baseline to Hour 6 of infusion in VAS-L ratings 
• 
Change from baseline to Hour 6 of infusion in VAS-A ratings 
• 
Change from baseline to post-infusion in VAS-L ratings measured via daily diary over multiple 
days 
• 
Change from baseline to post-infusion in VAS-A ratings measured via daily diary over multiple 
days 
 
 
 
 
 
 
• 
Change from baseline in vital signs, electrocardiogram (ECG), and clinical laboratory parameters 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6. 
Analysis Sets 
Details on the process for defining analysis datasets are located in the Data Review and Definition of 
Analysis Sets SOP (3911).  
6.1. 
Screened Set 
The Screened Set will include all participants who were screened for participation in this study.  
6.2. 
Enrolled Set 
The Enrolled Set will include all participants who provided written informed consent and passed the 
inclusion and exclusion criteria for study participation. Screen failures will not be included in this set.  
6.3. 
Efficacy Set 
The Efficacy Set will be defined as all participants who received any amount of IP and have at least one 
post-baseline efficacy evaluation.    
6.4. 
Safety Set  
The Safety Set (SS) will include all participants who received any amount of IP. The SS will be used for 
all analyses of safety endpoints.  
6.5. 
Protocol Deviations 
Protocol deviations identified during the study will be captured in the Electronic Data Capture (EDC) 
system. Protocol deviation management at Syneos Health is detailed in Protocol Deviation and Non-
compliance Management (3101.W02). 
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7. 
General Aspects for Statistical Analysis 
7.1. 
General Methods 
• Continuous variables will be summarized using the number of observations (n), mean, standard 
deviation (SD), median, minimum, maximum, first quartile (Q1), and third quartile (Q3). In addition, 
change from baseline values will be calculated at each time point and summarized descriptively.  
• For categorical variables, descriptive summaries will include counts and percentages. 
• All relevant participant data will be included in listings. All participants entered into the database will 
be included in participant data listings 
7.2. 
Key Definitions 
7.2.1. 
Baseline 
For in-clinic assessments, baseline is defined as the most recent value immediately prior to the start of IP 
infusion. For remote daily assessments, baseline is defined as the average of all available preinfusion 
values per participant.  Change from Baseline is defined as the measurement at each timepoint minus the 
Baseline value.  
7.2.2. 
Study Day  
Study Day is calculated relative to the start date of study treatment and defined as follows: 
• 
The day of participant receiving the IP infusion is designated as Day 1. 
• 
For visit days after Day 1, study day = visit date – Day 1 date + 1. 
• 
For visit days prior to Day 1, study day = visit date – Day 1 date. Thus, study days for screening 
visits are negative numbers. There is no “Day 0”. 
7.3. 
Missing Data 
All participants will be used in the analysis using all non-missing data available. No imputation process 
will be used to estimate missing data.  
Dates missing the day, or both the day and month of the year will adhere to the following conventions 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. 
7.3.1. 
Adverse Events (AE) 
If an AE start date is completely missing, do not impute the date but consider it as a 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: 
o 
If the year matches the year of first dose and the end date (if present) is after first dose 
date, or AE is ongoing, then impute as the month and day of earlier date of (the first dose 
date + 1 day, last dose date). 
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o 
If the year of AE onset < year of initiation of the treatment, then the  month and day will 
be set to December 31st.  
o 
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: 
o 
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 of the particular year. 
▪ 
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. 
o 
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 of the particular year. 
o 
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. 
o 
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.” 
o 
When the year is missing, but the month and/or day is known, treat this date as missing; 
do not impute.  
7.3.2. 
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. 
7.3.3. 
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 end date (imputed date if applicable) 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 
either December 31 or date of death, whichever is earlier. 
• 
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 or month of death.  
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• 
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 either December 31 or date of death, whichever is earlier. 
7.4. 
Visit Windows 
There will be no windowing for visits. 
7.5. 
Pooling of Centers 
Not applicable. 
7.6. 
Subgroups 
No subgroup analysis is planned for this study. 
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8. 
Demographic, Other Baseline Characteristics and Medication 
8.1. 
Participant Disposition and Withdrawals 
The summaries of participant disposition will include the number and percentages of participants who 
were screened, screen failed, treated, completed treatment, discontinued IP prematurely with primary 
reasons for discontinuing IP, completed the study, and prematurely withdrew from the study with primary 
reasons for not completing the study. All percentages will be calculated based on the participants who 
were enrolled, unless otherwise stated. If a participant is rescreened because the participant has been a 
screen failure the first time, the status of the participant will be determined from the second screening. In 
the count of screened participants, such a participant will be counted only once. Participants of all 
analysis sets will be summarized (eg, number and percentages of participants in Screening Set, Enrolled 
Set, Efficacy Set, and Safety Set)..  
A listing will be provided for participants screen failed with primary reason and a disposition listing will be 
provided for all enrolled participants. A separate listing will be provided for the Safety Set and reported for 
participants who prematurely discontinued IP, prematurely withdrew from the study with reasons, and 
date of withdrawal from the study. 
8.2. 
Protocol Deviations 
All major protocol deviations will be summarized using the Safety Set. All protocol deviations (major and 
minor) will be included in a data listing for the Enrolled Set. 
Any violation of inclusion/exclusion criteria will also be presented in a separate data listing using the 
Screened Set.   
8.3. 
Demographic and Baseline Characteristics 
Demographic data including age, sex, race, ethnicity, and baseline characteristics (e.g., weight, height, 
BMI, childbearing potential), will be summarized and listed using the Safety Set. The below conversions 
will be used if needed. 
Body mass index (BMI) (kg/m2) = Weight(kg)/[Height(m)2] 
8.4. 
Medical History 
Medical history collected at screening will be analyzed using the Safety Set and coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology. The summary will be presented by primary 
system organ class (SOC) and preferred term (PT). A participant will be counted once within each level of 
summarization. Medical history will be presented in a corresponding listing.  
8.5. 
Tinnitus Medical History 
Tinnitus medical history will be analyzed for the Safety Set and will include at a minimum information 
related to initial onset, tinnitus pulse, perception, loudness, sound, awareness, conditions that worsen 
symptoms, hearing aid use, and sound tolerability. Tinnitus medical history will be tabulated and a 
corresponding listing provided.     
8.6. 
Prior and Concomitant Medications 
Medications will be recorded throughout the duration of the study and will be coded using World Health 
Organization (WHO) Drug Dictionary Global B3 September 2022, or later.  
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Medications taken prior to the initiation of the start of IP will be denoted “Prior”. Those medications taken 
prior to the initiation of the IP and continuing beyond the initiation of the IP, or those medications started 
at the same time or after the initiation of IP will be denoted “Concomitant”. 
Both prior and concomitant medications will be separately summarized by anatomical therapeutic 
chemical (ATC Level 3) class and preferred term.  Note that medication taken before the initial dosing of 
the IP and continued after the initial dosing will be categorized as a prior medication and, separately, as a 
concomitant medication. All prior and concomitant medications will be listed. Medications will be 
presented according to whether they are “Prior” or “Concomitant”, as defined above. If medication dates 
are incomplete and it is not clear whether the medication was concomitant, it will be assumed to be 
concomitant. Missing date imputation rules are provided in Section 7.3.3. 
Concomitant procedures are recorded on a separate electronic case report form (eCRF) page; this will be 
presented in a listing by participant.  
The Safety Set will be used for all tables and listings.  
8.7. 
Extent of Exposure 
The number and percentage of treated participants receiving 6 hours of infusion will be tabulated.  
Detailed information regarding the infusion timepoints, planned doses, actual infusion rates, infusion 
interruptions, infusion discontinuations, and dose changes will be listed for each participant in the Safety 
Set. 
Study drug exposure will be summarized using actual infusion duration, dose changes, infusion rate 
changes, and interruptions lasting more than 5 minutes. Actual infusion duration is the elapsed time 
between start time and stop time of study drug administration, defined as stop time (HH:MM) – start time 
(HH:MM), and will not include any dose interruptions lasting more than 5 minutes. Actual cumulative 
infusion duration is the sum of all actual infusion durations. The total length of interruption is the elapsed 
time between end time of one infusion and the start time of the next recorded infusion.  
Detailed information regarding the infusion timepoints, planned dose, actual infusion rate, infusion 
interruption, and permanent infusion discontinuation will be listed for each participant in the Safety Set by 
timepoint. Actual cumulative infusion duration and cumulative length of infusion interruption lasting more 
than 5 minutes will be tabulated, along with number of unique infusion interruptions among treatment 
completers.   
8.8. 
Treatment Compliance  
The planned dose of 30, 60, or 90 mcg/kg/hour will be captured in the EDC system. The actual infusion 
rate will also be captured in the EDC in mL/hour, and converted to actual dose mcg/kg/hour using the 
following formula: 
1000 mcg/hour * (actual flow rate from infusion pump in mL/hour) / (participant weight in kg) 
Treatment compliance will be calculated as: 
(actual dose / planned dose) * 100 
Planned dose, actual infusion rate, actual dose, and percent compliance will be listed for each participant 
in the Safety Set by timepoint.  Overall treatment compliance will be tabulated. 
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9. 
Efficacy 
All efficacy analyses will be based on the Efficacy Set.  
9.1. 
Visual Analog Scales 
The VAS-L and VAS-A are participant-rated scales for evaluating tinnitus (Adamchic et al 2012). Scoring 
for both is along a linear horizontal scale, with the left side anchor (score of 0) representing the lowest 
severity and the right side anchor (score of 100) representing the highest severity of the rated tinnitus 
experience. Intermediate scores are determined by extrapolation between the two sides of the scales. 
To assess tinnitus loudness (VAS-L), participants will answer the question “How loud is your tinnitus 
now?” on a horizontal scale anchored on left by “not audible” and on right by “extremely loud”. To assess 
tinnitus annoyance (VAS-A), participants will answer the question “How much is your tinnitus annoying 
you now?” on a horizontal scale anchored on left by “not annoying” and on right by “extremely annoying”.  
The VAS-L and VAS-A will be administered both as remote and as in-clinic measures at different times of 
this study. Remote VAS data collection will occur from Day -7 to Day -1 (preinfusion) and from Day 2 to 
Day 7 (postinfusion). For remote assessments, ratings for both VAS-L and VAS-A will be obtained twice 
daily, once each in the morning and once in the evening. And the daily arithmetic means of VAS-L and 
VAS-A ratings will be computed separately for remote measures obtained during pre- and postinfusion 
periods. -. For remote assessments, the daily arithmetic mean will be calculated by averaging the morning 
and evening scores ([morning score + evening score] / 2).  If a participant is missing either a morning or 
evening score, then the single available score will be used as the mean for that day.  
The VAS-L and VAS-A will be obtained in-clinic during the treatment period ( Day 1) , administered once 
prior to start of infusion and then repeated at hours 0.5, 1, 2, 3, 4, 5 and 6 of the infusion. .  
For the treatment period (Day 1), baseline is defined as the most recent value immediately prior to the 
start of IP infusion, or predose. For the postinfusion remote assessment  period (Days 2 through 7), 
baseline is defined as the average of all available preinfusion values per participant collected from Day -7 
through Day -1.  This will be calculated by summing the daily arithmetic means and dividing by the total 
number of non-missing days. If a participant is missing either a morning or evening score, then the single 
available score will be used as the mean for that day Missing day or partial missing day VAS ratings will 
not be imputed. 
Descriptive statistics of both VAS component scores and VAS component change from baseline scores 
will be tabulated.  Considering the small sample size, unbiased Hedge’s g will be used to compare the 
effect size of the post baseline score at each timepoint to the baseline score.  Hedge’s g will be calculated 
for pre-post scores in one group using the following formula: 
 𝑔= 𝑑  × 𝐽  
Where 𝑑  =
(𝑝𝑜𝑠𝑡−𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑚𝑒𝑎𝑛)−(𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑚𝑒𝑎𝑛)
𝑆𝐷𝑤𝑖𝑡ℎ𝑖𝑛
 and 𝐽= 1 −
3
4(2𝑛−2)−1 
SDwithin can be computed from the standard deviation of the change from baseline (SDCFB) as  
𝑆𝐷𝑤𝑖𝑡ℎ𝑖𝑛= 𝑆𝐷𝐶𝐹𝐵/√2(1 −𝑟),  
r is the correlation between baseline and post-baseline, n is the number of pairs. 
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10. 
Safety 
The Safety Set (SS) will be used for all safety analyses. Safety and tolerability of brexanolone will be 
evaluated by incidence of treatment-emergent adverse events 
 
. Listings for discharge and safety phone call will also be included. 
10.1. 
Adverse Events 
An Adverse Event (AE) is defined as any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of IP, whether or not related 
to IP. Adverse events will be coded using MedDRA Version 25.1 or higher.  
10.1.1. Treatment-Emergent Adverse Event (TEAE) 
A TEAE is defined as an AE 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. If the date of an adverse 
event is incomplete and an unambiguous determination could not be made with respect to its onset time 
versus administration of IP, the adverse event will be assumed to be a TEAE. For imputation of missing 
AE dates, please refer to Section 7.3.1. 
An overview summary table of TEAEs will present the number and percentage of participants as well as 
the number of events for the following:   
• 
TEAEs 
• 
TEAEs by maximum severity (severe>moderate>mild) 
• 
Study drug-related TEAEs 
• 
Treatment-emergent serious adverse events (SAEs) 
• 
TEAEs leading to interruption of IP 
• 
TEAEs leading to withdrawal of IP 
• 
TEAEs leading to discontinuation from the study 
• 
Treatment-emergent AESIs 
• 
TEAEs leading to death 
Incidence of TEAEs in following categories will be provided by SOC and PT. A participant is counted only 
once under each SOC and PT in case of multiple occurrences of the same AE. These tables will be 
sorted by overall descending frequency of SOC and then, within a SOC, by overall descending frequency 
of PT.  
• 
TEAEs 
• 
TEAEs by maximum severity (severe>moderate>mild) 
• 
Study drug-related TEAEs 
• 
Treatment-emergent SAEs 
• 
TEAEs leading to interruption of IP 
• 
TEAEs leading to withdrawal of IP 
• 
TEAEs leading to discontinuation from the study 
• 
TEAEs leading to death 
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 
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severity presentation. For relationship to IP, participants will be counted only once within each SOC and 
PT at the strongest relationship to IP in the following order: related>not related; an AE with relationship 
missing is treated as related. 
All AEs through the end of the study will be listed including, but not limited to, verbatim term, PT, SOC, 
relationship to study drug, start and end date, seriousness, action taken, and outcome. Separate listings 
will be provided for SAEs, AEs leading to death, AEs leading to  treatment discontinuation, AEs leading to 
study withdrawal, and AEs leading to dose reduction. TEAEs will be flagged in the listing. 
10.1.2. Adverse Event of Special Interest (AESI) 
An AESI is an AE/SAE of scientific and/or medical concern, specific to the product or program for which 
ongoing monitoring and rapid communication by the investigator to the sponsor is required. The following 
events are considered AESIs and collected as an AESI: 
• 
Excessive sedation 
• 
Loss of consciousness 
• 
Any sedation-related AE that leads to dose reduction, interruption, or termination 
Treatment-emergent AESIs will be summarized. All AESIs (including those with onset or worsening 
before the start of IP) will be separately listed, in addition to being included in the primary TEAE tables 
discussed above. Excessive sedation and loss of consciousness will be reported in a listing for the 
information including the timepoint, whether the participant was assessed for excessive sedation, and the 
date and time.  
10.2. 
Laboratory Evaluations 
Urinalysis samples will be collected. Blood samples will be collected for hematology, serum chemistry, 
and coagulation. Analytes to be evaluated are summarized in Table 2. 
Table 2: Summary of Clinical Laboratory Analytes 
Biochemistry 
Renal Panel: glucose, calcium, phosphorus, blood urea nitrogen, creatinine, 
sodium, potassium, chloride, bicarbonate 
Hepatic Panel: albumin, alanine transaminase (ALT), aspartate transferase (AST), 
total bilirubin and if elevated, reflex fractionation for direct and indirect bilirubin 
alkaline phosphatase, total protein, lactate dehydrogenase, gamma glutamyl 
transferase 
Coagulation 
(Screening only) 
Activated partial thromboplastin time, prothrombin time, and international 
normalized ratio only on participants determined to be high clinical risk for bleeding 
Hematology 
Red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell count with 
differential, and platelet count 
Urinalysis 
Specific gravity, pH, protein, glucose, ketones, occult blood, leukocyte esterase, 
nitrite, bilirubin, and urobilinogen. If protein, leukocyte, occult blood, and/or nitrites 
are positive, a microscopic examination will be performed 
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All clinical laboratory test results outside the reference range will be interpreted by the investigator as 
abnormal, not clinically significant (abnormal NCS) or abnormal, clinically significant (abnormal CS) in 
source documents. Clinically significant abnormal results after screening will be considered and reported 
as AEs. 
Baseline value, post-baseline value and change from baseline in hematology, serum chemistry, and 
urinalysis lab results will be tabulated separately at screening and EOS visit. Coagulation will be tabulated 
at screening. Corresponding by participant listings will be presented. A shift table for hematology, serum 
chemistry and urinalysis lab shift from baseline to post-baseline values in abnormality of results will be 
provided. A summary table of potentially clinically significant values by visit will also be provided.     
Follicle stimulating hormone testing will be conducted to confirm whether a participant with ≥12 months of 
spontaneous amenorrhea meets the protocol-defined criteria for being post-menopausal (see Study 
Protocol Section 8.1). Test results will be presented in a by participant listing.  
A serum pregnancy test will be conducted for all woman of childbearing potential (WOCBP) at Screening; 
a urine pregnancy test will be conducted for all WOCBP at all other scheduled timepoints. Serum and 
urine pregnancy test results will be presented in a by participant listing.   
Urine assessment for select drugs of abuse will be performed (including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates, and phencyclidine). Alcohol will be assessed via 
breathalyzer or urine dipstick. Drug and alcohol test results will be presented in a by participant listing.   
Table 3:  Criteria for Identifying PCS Values for Laboratory Evaluations 
Laboratory Evaluation 
Sex 
Units 
Criteria for PCS Values 
(Observed values) 
Criteria for 
PCSC 
values 
(Change 
from 
Baseline) 
Criteria for 
PCSC 
values 
(Change 
from 
Baseline) 
Parameter 
Chemistry 
 
 
High  
Low  
  
  
Albumin  
Both 
g/L  
>70  
<28  
NA  
NA  
Blood urea nitrogen (aka Urea 
Nitrogen and Nitrogen) 
Both 
mmol/L 
>10.71 
NA 
NA  
NA  
Calcium 
Both 
mmol/L 
>2.75 
<2.0 
NA  
NA  
Chloride 
Both 
mmol/L 
>120 
<90 
NA  
NA  
Creatinine 
Both 
mmol/L 
>3xULN or 
>3x 
Baseline 
  
NA  
NA  
Gamma Glutamyl Transferase 
Both 
  
>3xULN 
  
NA  
NA  
Glucose 
Both 
mmol/L 
>13.9 
<2.8 
NA  
NA  
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Sodium  
Both 
mmol/L  
>150 
<132  
NA  
NA  
Potassium  
Both 
mmol/L  
>5.4  
<3.3  
NA  
NA  
Protein (aka total 
protein)  Chemistry results only 
Both 
g/L 
  
<45 
NA  
NA  
Bicarbonate (HCO3 may also 
be reported as CO2) 
Both 
mmol/L  
>34  
<18  
NA  
NA  
Phosphorus (aka Phosphate) 
Both 
mmol/L 
>1.94 
<0.61 
NA  
NA  
Bilirubin (total) 
Both 
μmol/L 
>2xULN 
NA 
NA  
NA  
Aspartate Aminotransferase 
Both 
U/L  
>3xULN 
NA 
NA  
NA  
Alanine Aminotransferase 
Both 
U/L  
>3xULN 
NA 
NA  
NA  
Alkaline Phosphatase 
Both 
U/L  
>1.5xULN 
NA 
NA  
NA  
Lactate Dehydrogenase 
Both 
U/L  
>2xULN 
NA 
NA  
NA  
 
 
 
 
 
 
 
Coagulation 
 
 
 
 
  
 
Prothrombin time (PT) 
Both 
sec 
>=1.11 x 
ULN 
Not 
Specified 
NA  
NA  
Partial thromboplastin time 
(PTT) 
Both 
sec 
>1.5 xULN 
Not 
Specified 
NA  
NA  
 
 
 
 
 
 
 
Hematology 
 
 
High  
Low  
NA  
NA  
Hemoglobin                     
Male 
g/L  
>185 
<115 
NA  
NA  
Hemoglobin                     
Female 
g/L  
>170 
<100 
NA  
NA  
Hematocrit    
Male 
Fraction 
of 1 
>0.55 
<0.385 
NA  
NA  
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Hematocrit    
Female 
Fraction 
of 1 
>0.49 
<0.345 
NA  
NA  
Platelet count  
Both 
10^9/L  
>600 
<125 
NA  
NA  
White blood cell 
Both 
10^9/L  
>15  
<2.5  
NA  
NA  
Basophils  
Both 
10^9/L  
>0.5 
NA 
NA  
NA  
Eosinophils 
Both 
10^9/L  
>1.5 
NA 
NA  
NA  
Neutrophils  
Both 
10^9/L  
NA  
<1.5  
NA  
NA  
Lymphocytes  
Both 
10^9/L  
>6.0  
<0.5  
NA  
NA  
Monocytes  
Both 
10^9/L  
>1.4 
NA 
NA  
NA  
 
10.3. 
Vital Signs, Weight, and Height  
Vital signs (heart rate, respiratory rate, temperature, and blood pressure), weight, and height will be 
measured according to the Protocol Schedule of Assesments (Tables 2 and 3) and collected on the 
eCRF. BMI will be calculated and documented on the eCRF. Descriptive summaries (number of 
participants, mean, standard deviation, median, minimum, maximum, Q1, Q3) of actual values and 
changes from baseline of vital signs will be presented for each visit using the Safety Set. 
Temperature will be summarized in Celsius (C) units.  
Any abnormality in vital signs will be interpreted by an investigator as abnormal, not clinically significant 
(NCS); or abnormal, clinically significant (CS) in source documents.  
Baseline for vital signs on Day 1 is defined as Day 1 pre-dose. Baseline for vital signs at EOS is defined 
as the screening values. Baseline value, post-baseline value and change from baseline in vital signs will 
be tabulated by visit. Vital sign data will be listed chronologically by participant and visit for each vital sign 
parameter. Potentially clinically significant values will be summarized by treatment. Weight, height, and 
BMI data will be listed by participant and visit. Pulse oximetry will be listed separately by participant and 
visit. 
Table 4: Criteria for Identifying PCS Values for Vital Sign Parameters 
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Vital Sign Parameter 
Sex 
Units 
Criteria for PCS Values 
(Observed values) 
Criteria for PCSC values 
(Change from Baseline 
values) 
  
  
  
High  
Low  
Increase  
Decrease  
Heart rate (supine and 
standing) 
Both 
Beats/min  
>120  
<40  
NA 
NA 
Systolic Blood Pressure 
(supine and standing)  
Both 
mmHg  
>180 
<90  
≥30 
≥30 
Diastolic Blood pressure 
(supine and standing)  
Both 
mmHg  
>110 
<50  
≥20 
≥20  
Respiratory Rate 
Both 
breaths/min >20 
<8 
NA  
NA  
 
10.4. 
ECG 
A 12-lead ECG will be performed according to the Protocol Schedule of Assesments (Tables 2 and 3). 
The standard intervals (heart rate, PR, QRS, QT, and QT corrected according to Fridericia’s formula 
[QTcF]), as well as any rhythm abnormalities, will be recorded.  
All abnormal ECGs will be interpreted by an investigator as abnormal NCS or abnormal CS in source 
documents. 
Baseline value, post-baseline value and change from baseline in ECG parameters will be tabulated at 
screening and EOS visit. A by participant listing will be provided, including each ECG parameter: 
ventricular heart rate (beats per minute [bpm]), PR Interval [msec], QT Interval [msec], QTcF Interval 
[msec], and central reader’s interpretation, including clinical significance and abnormal description. 
Table 5: Criteria for Identifying PCS Values for ECG Parameters 
ECG Parameter 
  
  
Criteria for PCS Values 
(Observed values) 
Criteria for 
PCSC 
values 
(Change 
from 
Baseline) 
Criteria for 
PCSC 
values 
(Change 
from 
Baseline) 
  
Sex 
Units 
High  
Low  
Increase  
Decrease  
QTcF Interval 
Both 
msec 
>450 but 
<=480 
NA  
>=30 to 60  
NA  
QTcF Interval 
Both 
msec 
>480 but 
<=500  
NA  
>60 
NA  
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QTcF Interval 
Both 
msec 
>500 
NA  
NA 
NA  
 
10.5. 
Physical Examination 
Physical examinations will include assessments of body systems (e.g., head, eye, ear, nose, and throat; 
heart; lungs; abdomen; and extremities) as well as cognitive and neurological examination and mental 
status examination, as performed per local standard of care. Unscheduled physical examinations may 
also be conducted per the investigator’s discretion.  
Any abnormality in physical examinations will be interpreted by an investigator as abnormal NCS or 
abnormal CS in source documents.  
Physical examination performed (Yes/No), not done reason, date and time of the examination will be 
listed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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11. 
Interim Analyses 
There is no formal interim analysis planned for this study. 
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12. 
Changes from Analysis Planned in Protocol 
Approximately 10 participants will be dosed instead of the expected 24 participants from the protocol.  
A screened analysis set will be identified to include all participants who were screened for participation in 
this study. This analysis set will be used in a listing of inclusion and exclusion criteria violations, including 
the primary reason for exclusion. 
An enrolled analysis set will be identified to include all participants who provided written informed consent 
and passed the inclusion and exclusion criteria for study participation. Screen failures will not be included 
in this set. This analysis set will be used to list protocol deviations. 
 
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13. 
Reference List 
Adamchic A, Langguth B, Hauptmann C, Tess PA. Psychometric Evaluation of Visual Analog 
Scale for the Assessment of Chronic Tinnitus. Am J Audiometry. 2012; 21:215-225. 
Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Introduction to Meta-Analysis. 2009: Chapter 4, 
Effect Sizes Based on Means. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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14. 
Quality Control 
SAS programs are developed to produce output such as analysis data sets, summary tables, data 
listings, figures or statistical analyses. Syneos Health Standard Operating Procedure (SOPs) Developing 
Statistical Programming and Validation Plan (3920), End-to-End Process of the Production of Study Data 
Tabulation Model (SDTM) (3921), and End-to-End Process of the Production of Analysis Datasets and 
Tables, Figures, and Listings (3922) describe the quality control procedures that are performed for all 
SAS programs and output. Quality control is defined here as the operational techniques and activities 
undertaken to verify that the SAS programs produce the output by checking for their logic, efficiency and 
commenting and by review of the produced output. 
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15. 
Index of Tables, Figures, and Listings 
Table, figure, and listing shells are provided in separate documents. 
All tables, figures and listings (TFLs), and statistical analyses will be generated using SAS for Windows, 
Release 9.4 (SAS Institute Inc., Cary, NC, USA). Computer-generated TFL output will adhere to the 
specifications detailed in the table, figure, and listing shell documents. 
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16. 
Appendices 
16.1. 
Appendix A: Schedule of Assessments for Screening Period 
Study Procedure 
Screening Period 
 
Clinic Assessments 
Remote Assessments 
Visit Day 
-28 to -8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
Clinic Visit 
X 
 
 
 
 
 
 
 
Remote 
 
X 
X 
X 
X 
X 
X 
X 
Informed consent process 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History a 
X 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
Physical examination b 
X 
 
 
 
 
 
 
 
Body weight 
X 
 
 
 
 
 
 
 
Clinical laboratory assessments c 
X 
 
 
 
 
 
 
 
Drug and alcohol test d 
X 
 
 
 
 
 
 
 
Pregnancy test (WOCBP only) e 
X 
 
 
 
 
 
 
 
Vital signs f 
X 
 
 
 
 
 
 
 
12-lead ECG g 
X 
 
 
 
 
 
 
 
Audiology Diagnostics i 
X 
 
 
 
 
 
 
 
VAS loudness and annoyance j 
 
X 
X 
X 
X 
X 
X 
X 
Remote Assessment Reminder k 
 
X 
X 
X 
X 
X 
X 
X 
Participant training l 
X 
 
 
 
 
 
 
 
Adverse events m 
X 
Prior/concomitant medications n 
X 
Nonpharmacological interventions o 
X 
Abbreviations:
; 
; ECG = 
electrocardiogram; 
 
; TMS = transcranial magnetic stimulation; VAS = Visual Analogue Scale; VAS-A = VAS annoyance; VAS-L = VAS 
loudness; WOCBP = women of childbearing potential. 
Note: Screening assessments must occur within 28 days prior to IP administration and results must be reported by Day -8. 
Note: When scheduled at the same timepoint, assessments will be performed in the following order: vitals, VAS, 
. 
a Tinnitus-related medical history will be obtained by structured interview. 
b Full physical examination at Screening. Symptom-directed physical examination may be conducted at subsequent time points. 
c Safety laboratory tests will include hematology, serum chemistry, and urinalysis at all scheduled time points. Coagulation to be 
assessed at Screening only. 
d Drug and alcohol testing will occur at Screening (see Study Protocol Section12.1.6 for a list of analytes). Drug testing will be on a 
urine specimen via urine dipstick. Alcohol use will be tested either on a urine specimen dipstick or breath test. A failed Screening 
drug or alcohol test does not exclude participation in the study if test is negative at Day 1. 
e Serum pregnancy test at screening. 
f Vital signs to include temperature (°C), respiratory rate, heart rate, and blood pressure. Heart rate and blood pressure to be 
collected in semi-inclined position. 
g ECGs must be performed after the participant has been in a supine position for at least 5 minutes. 
 
. 
i A full audiological examination will be conducted at Screening including pure tone audiogram. The audiologist will perform a 
physical exam of ears and obtain clinical history to evaluate duration and quality (whether unilateral/bilateral, pulsatile/non-pulsatile). 
A healthcare professional trained to perform movement tests will evaluate whether tinnitus can be attributed to a somatosensory 
cause. 
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j Ratings for both VAS-L and VAS-A will be done twice daily, once each in the morning and evening, on Day -7 through Day -1. 
k The participant will be contacted by the site on Day -7 through Day -1 to remind them to begin remote assessments. 
l Participants will be trained by study personnel on the procedures for all remote assessments. 
m A phone call to follow up on any AE(s) will be conducted, if deemed appropriate by the investigator, to review the current status of 
the participant. 
n To include all medications taken within 60 days, all psychotropic medications taken within 6 months, and all medications used to 
treat tinnitus regardless of timing. Participants will be asked about any changes during clinic visits. 
o Nonpharmacological interventions: eg, psychotherapy, sound therapy, masking, TMS. Participants will be asked about changes 
during clinic visits. 
16.2. 
Appendix B: Schedule of Assessments for Treatment Period and Follow-up Period 
Study Procedure 
Treatment Period 
Follow-up Period 
Clinic Treatment Visit 
 
EOS 
Visita 
Visit Day 
1 
2 
3 
4 
5 
6 
7±1 
Hour From Start of 
Infusion 
Pre-
doseb 
0 
0.5 
1 
2 
3 
4 
5 
6 
8 
 
 
 
 
 
 
Clinic Visit 
X 
 
 
 
 
 
X 
Remote 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Clinical laboratory 
assessments c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy test 
(WOCBP only) d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs e 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
Drug and alcohol 
test f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
VAS loudness and 
annoyance j 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Safety phone call 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Remote 
Assessment 
Reminder l 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Continuous pulse 
oximetry m 
 
X 
 
 
IP infusion 
 
X 
 
 
Admission to clinic 
X 
 
 
 
 
 
 
 
 
 
 
Discharge from 
clinic o 
 
 
 
 
 
 
 
 
 
X 
 
Adverse events p 
X 
Prior/concomitant 
medications q 
X 
Nonpharmacoligical 
interventions r 
X 
Abbreviations: 
 
; EOS = End of Study; IP = investigational product; 
 
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; TMS = transcranial magnetic stimulation; VAS = Visual Analogue 
Scale; VAS-A = VAS annoyance; VAS-L = VAS loudness; WOCBP = women of childbearing potential. 
Note: For Day 1 assessments, assessments at 0.5 and 1 hour must be collected within 10 minutes prior to the dose increase. 
Assessments at timepoints 2, 3, 4, 5, 6, and 8 hours may be completed within ±10 minutes of the scheduled time point. 
Note: Preferred order of assessments at all timepoints: 
 VAS-L, VAS-A, vital signs (temperature [°C], respiratory rate, heart 
rate, and blood pressure), 
. 
a The EOS Visit will be conducted at the time of discontinuation if this occurs at any time before Day 7 ±1 day. 
b All predose assessments must be completed prior to IP administration. 
c Safety laboratory tests will include hematology, serum chemistry, and urinalysis at all scheduled time points. 
d Urine pregnancy test at all scheduled time points. 
e Heart rate and blood pressure to be collected in semi-inclined position at all scheduled time points. Predose (Hour 0) vital signs will 
be collected within 60 minutes prior to dosing. 
f Drug and alcohol testing will occur prior to dosing on Day 1(see Study Protocol Section 12.1.6 for a list of analytes). Drug testing 
will be on a urine specimen via urine dipstick. Alcohol use will be tested either on a urine specimen dipstick or breath test. 
Participants with a failed drug or alcohol test on Day 1 are excluded from participation in the study. 
g ECGs must be performed after the participant has been in a supine position for at least 5 minutes. 
 
 
 
 
 
j for both VAS-L and VAS-A will be done twice daily, once each in the morning and evening, on Day 2 through Day 6 and on the 
morning of Day 7. 
 
 
 
 
l The participant will be contacted by the site on Day 2 through Day 6 to remind them to begin remote assessments. 
m Continuous pulse oximetry to occur for the duration of the infusion. Oxygen saturation should be recorded prior to dose escalation 
at 0.5 hour and 1 hour. Otherwise, it need only be recorded in the event of confirmed hypoxia, in which case, the event is to be 
recorded as an AE. 
 
 
 
o If deemed medically appropriate by the investigator, participants will be released from the clinic after the 2-hour safety 
assessments have been completed. Participants will be cautioned against engaging in potentially hazardous activities requiring 
mental alertness, including driving, until any sedative effects have dissipated. A designated companion must drive the participant 
when they are discharged from the clinic. 
p A phone call to follow up on any AE(s) will be conducted, if deemed appropriate by the investigator, to review the current status of 
the participant. 
q All changes to any medication should be captured. Participants will be asked about any changes during clinic visits. 
r Nonpharmacological interventions: eg, psychotherapy, sound therapy, masking, TMS. Participants will be asked about any 
changes during clinic visits. 
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to you through the DocuSign system during and immediately after the signing session and, if you 
elect to create a DocuSign account, you may access the documents for a limited period of time 
(usually 30 days) after such documents are first sent to you. After such time, if you wish for us to 
send you paper copies of any such documents from our office to you, you will be charged a 
$0.00 per-page fee. You may request delivery of such paper copies from us by following the 
procedure described below. 
 
Withdrawing your consent  
If you decide to receive notices and disclosures from us electronically, you may at any time 
change your mind and tell us that thereafter you want to receive required notices and disclosures 
only in paper format. How you must inform us of your decision to receive future notices and 
disclosure in paper format and withdraw your consent to receive notices and disclosures 
electronically is described below. 
 
Consequences of changing your mind  
If you elect to receive required notices and disclosures only in paper format, it will slow the 
speed at which we can complete certain steps in transactions with you and delivering services to 
you because we will need first to send the required notices or disclosures to you in paper format, 
and then wait until we receive back from you your acknowledgment of your receipt of such 
paper notices or disclosures. Further, you will no longer be able to use the DocuSign system to 
receive required notices and consents electronically from us or to sign electronically documents 
from us. 
 
All notices and disclosures will be sent to you electronically  
Electronic Record and Signature Disclosure created on: 10-Aug-2020 | 10:12
Parties agreed to: 


Unless you tell us otherwise in accordance with the procedures described herein, we will provide 
electronically to you through the DocuSign system all required notices, disclosures, 
authorizations, acknowledgements, and other documents that are required to be provided or made 
available to you during the course of our relationship with you. To reduce the chance of you 
inadvertently not receiving any notice or disclosure, we prefer to provide all of the required 
notices and disclosures to you by the same method and to the same address that you have given 
us. Thus, you can receive all the disclosures and notices electronically or in paper format through 
the paper mail delivery system. If you do not agree with this process, please let us know as 
described below. Please also see the paragraph immediately above that describes the 
consequences of your electing not to receive delivery of the notices and disclosures 
electronically from us. 
 
How to contact Sage Therapeutics - Part 11:  
You may contact us to let us know of your changes as to how we may contact you electronically, 
to request paper copies of certain information from us, and to withdraw your prior consent to 
receive notices and disclosures electronically as follows: 
To contact us by email send messages to: marcel@sagerx.com 
 
To advise Sage Therapeutics - Part 11 of your new email address  
To let us know of a change in your email address where we should send notices and disclosures 
electronically to you, you must send an email message to us at marcel@sagerx.com and in the 
body of such request you must state: your previous email address, your new email address.  We 
do not require any other information from you to change your email address.  
If you created a DocuSign account, you may update it with your new email address through your 
account preferences.  
 
To request paper copies from Sage Therapeutics - Part 11  
To request delivery from us of paper copies of the notices and disclosures previously provided 
by us to you electronically, you must send us an email to marcel@sagerx.com and in the body of 
such request you must state your email address, full name, mailing address, and telephone 
number. We will bill you for any fees at that time, if any. 
 
To withdraw your consent with Sage Therapeutics - Part 11  
To inform us that you no longer wish to receive future notices and disclosures in electronic 
format you may: 


i. decline to sign a document from within your signing session, and on the subsequent page, 
select the check-box indicating you wish to withdraw your consent, or you may; 
ii. send us an email to marcel@sagerx.com and in the body of such request you must state your 
email, full name, mailing address, and telephone number. We do not need any other information 
from you to withdraw consent..  The consequences of your withdrawing consent for online 
documents will be that transactions may take a longer time to process.. 
 
Required hardware and software  
The minimum system requirements for using the DocuSign system may change over time. The 
current system requirements are found here: https://support.docusign.com/guides/signer-guide-
signing-system-requirements.  
 
Acknowledging your access and consent to receive and sign documents electronically  
To confirm to us that you can access this information electronically, which will be similar to 
other electronic notices and disclosures that we will provide to you, please confirm that you have 
read this ERSD, and (i) that you are able to print on paper or electronically save this ERSD for 
your future reference and access; or (ii) that you are able to email this ERSD to an email address 
where you will be able to print on paper or save it for your future reference and access. Further, 
if you consent to receiving notices and disclosures exclusively in electronic format as described 
herein, then select the check-box next to ‘I agree to use electronic records and signatures’ before 
clicking ‘CONTINUE’ within the DocuSign system. 
By selecting the check-box next to ‘I agree to use electronic records and signatures’, you confirm 
that: 
 
You can access and read this Electronic Record and Signature Disclosure; and 
 
You can print on paper this Electronic Record and Signature Disclosure, or save or send 
this Electronic Record and Disclosure to a location where you can print it, for future 
reference and access; and 
 
Until or unless you notify Sage Therapeutics - Part 11 as described above, you consent to 
receive exclusively through electronic means all notices, disclosures, authorizations, 
acknowledgements, and other documents that are required to be provided or made 
available to you by Sage Therapeutics - Part 11 during the course of your relationship 
with Sage Therapeutics - Part 11.