Dynamic Neural Mechanisms of Brexanolone-induced Antidepressant Effects in Postpartum Depression: a Feasibility Study
Conditions: Postpartum Depression
Sponsor: University of North Carolina, Chapel Hill

Study Title: Dynamic neural mechanisms of brexanolone-induced antidepressant effects in 
postpartum depression 
 
 
UNC Principal Investigator (PI): Susan Girdler, Ph.D. 
UNC PI Department/Division: School of Medicine, Psychiatry 
Number of Sites: 1 
UNC Co-Investigator(s) and Department/Division: David Rubinow, MD; Samantha Meltzer-
Brody, MD; Riah Patterson, MD; Flavio Frohlich, PhD; Justin Riddle, PhD; Alana Campbell, 
PhD; Elizabeth Andersen, PhD (Department of Psychiatry) 
Study Statistician: Kai Xia, PhD (Department of Psychiatry) 
Sponsor:  University of North Carolina at Chapel Hill 
Sources of Funding: Sage Therapeutics (215 First Street, Cambridge, MA., 02142); Buszucki 
Brain Research Fund 
 
NCT Number: NCT05543746 
 
Document Date: 28 SEPTEMBER 2022 
 
 

 Dynamic neural mechanisms of brexanolone-induced antidepressant effects in postpartum depression: A feasibility study 
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Summary of Changes from Previous Version: 
 
Previous  
Version No. 
Affected  
Section(s) 
Summary 
 of Revision(s) 
Reason  
for Change(s) 
V1 
TITLE PAGE; 1.0 
PROTOCOL 
SYNOPSIS; 5.2 
ELIGIBILITY; 6.1 
DRUG PREPARATION 
& 
ADMINISTRATION; 
7.1 TABLE OF 
EVENTS; 7.4 STUDY 
VISITS; 10.1 
RISK/BENEFIT 
ASSESSMENT; 10.2 
ASSESSMENT OF 
SAFETY; 10.3 UP, 
AE, SAE 
TITLE PAGE – SPONSOR IS UNC-CH, SAGE IS SOURCE OF 
FUNDING; 1.0 TARGET POPULATION – ONSET OF PPD 
WITHIN 4 WEEKS OF DELIVERY (RATHER THAN 8); 5.2 – 
RENAL AND HEPATIC IMPAIRMENT (IN ADDITION TO FAILURE) 
ADDED TO LIST OF EXCLUSION CRITERIA;  6.1 – DRUG 
PREPARATION & ADMINISTRATION – UNC WILL DESTROY 
UNUSED STUDY DRUG LOCALLY AT THE END OF THE STUDY 
(RATHER THAN SAGE); 7.1 – AES CHANGED FROM Q4H TO 
Q2H (WHILE AWAKE) DURING INFUSION; 7.4 – MONITORING 
FOR LOSS OF CONSCIOUSNESS IN ADDITION TO EXCESSIVE 
SEDATION; 10.1 – ADDED “SERIOUS RISKS OF BRX” 
LANGUAGE FROM INFORMED CONSENT (IN SECOND PERSON) 
AND ADDITIONAL INFORMATION ABOUT THE TWO CASES OF 
ACCIDENTAL OVERDOSE THAT WERE RECORDED IN THE 
CLINICAL TRIAL UPSI; ADDED “PAIN” TO RISKS ASSOCIATED 
WITH PHLEBOTOMY; 10.2 – ALIGNED LANGUAGE IN RISKS 
ASSOCIATED WITH BRX IN THIS SECTION WITH 10.1; 10.3 – 
ADDED IQVIA EMAIL ADDRESS FOR REPORTING OF AES; 
SUGGESTIONS AFTER INITIAL 
PROTOCOL REVIEW BY SAGE 
THERAPEUTICS 
V2 
ABBREVIATIONS; 
4.3 
MEASUREMENT 
DESIGN; 5.2 
ELIGIBILITY; 5.3 
STRATEGIES FOR 
RECRUITMENT AND 
RETENTION;  6.1 
TEST ARTICLE 
MODIFICATION; 
6.3 INTERVENTION 
PROCEDURAL; 6.4 
CONCOMITANT 
THERAPY; 7.1 
TABLE OF EVENTS; 
7.3-7.7 STUDY 
PROCEDURES; 7.8 
PREMATURE 
DISCONTINUATION; 
9.2 DESCRIPTION 
ABBREVIATIONS – REMOVED UNUSED ABBREVIATIONS (E.G., 
CIOMS, CRO, QA); 4.3 – ADDED COLUMN TO TABLE 1A 
TO INCLUDED SCORING CONVENTIONS AND RANGES OF STUDY 
MEASURES; ADDED TABLES 1B AND 1C TO INCLUDE DETAILS 
SPECIFIC TO EEG AND IMOTIONS SOFTWARE OUTCOMES; 
5.2—REMOVED USE OF ANTI-INFLAMMATORY AGENTS FROM 
EXCLUSION CRITERIA AND CLARIFIED BREASTFEEDING 
CESSATION FOR 4 DAYS OF HOSPITALIZATION (RATHER THAN 
INFUSION) AND ADDED CAREGIVER OF CHILD(REN) TO 
INCLUSION CRITERIA; ADDED RATIONALE FOR HAM-D 
SEVERITY THRESHOLD TO INCLUSION CRITERIA; ADDED 
DOCUMENTED PROOF OF FULL COVID-19 VACCINATION; 
5.3—CLARIFIED THE DIFFERENCE BETWEEN CLINICAL 
PROCEDURES AND RESEARCH PROCEDURES FOR POTENTIAL 
SUBJECTS; PROVIDED EXAMPLES OF RE-SCREENING FOR 
ELIGIBILITY; 6.1 – REMOVED LANGUAGE ABOUT PK ANALYSIS 
IN “MODIFICATION” SECTION; INCLUDED PROTOCOL FOR 
REDUCING INFUSION RATE AND CONTINUING IF INFUSION IS 
STOPPED; 6.3 – INCLUDED REMS TRAINING AND 
CERTIFICATION FOR PRESCRIBERS AND PHARMACISTS; 6.4 – 
SUGGESTIONS FOLLOWING 
PROTOCOL REVIEW BY UNC 
SCIENTIFIC REVIEW COMMITTEE  

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OF STUDY 
COHORT; 10.1 
RISK/BENEFIT 
ASSESSMENT; 10.2 
ASSESSMENT OF 
SAFETY; 10.4 
SAFETY 
MONITORING & 
11.7 CLINICAL 
MONITORING; 
10.5 STUDY 
SUSPENSION & 
11.2 STUDY 
DISCONTINUATION 
AND CLOSURE; 
11.8 QA AND QC; 
11.9.1 DATA 
COLLECTION AND 
MANAGEMENT 
CLARIFIED “MEDICATIONS” AND “PSYCHOTROPIC 
MEDICATIONS”; 7.1 – ITEM “M” IN FOOTNOTES CORRECT TO 
STABLE DOSE OF PSYCHOTROPICS 14 DAYS PRIOR TO 
ENROLLMENT; REVISED H24 TO H28; REMOVED COLUMN 
FOR H48; REMOVED AFFECTIVE STROOP TASK/PROBE FROM 
STUDY PROCEDURES; 7.3-7.7—INCLUDED DETAILS ABOUT 
STUDY VISIT PROCEDURES; 7.8—INCLUDED PROTOCOL IF 
SUICIDALITY IS ENDORSED AT PREMATURE 
DISCONTINUATION; 9.2 – INCLUDED RATIONALE FOR USE OF 
MOOD MEASURES TO DESCRIBE DIFFERENCES IN THE 
TRAJECTORY OF TREATMENT RESPONSE ACROSS INDIVIDUALS; 
10.1 – REMOVED LANGUAGE ABOUT RISKS ASSOCIATED 
WITH AFFECTIVE PROBE TASKS; CLARIFIED SUICIDALITY 
MONITORING RECOMMENDATIONS FOR SUBJECTS WHEN 
THEY ARE OUTPATIENT; ADDED DISCUSSION OF POTENTIAL 
RISK TO INFANT CHILDREN OF SUBJECT AS A RESULT OF 
HOSPITALIZATION AND TEMPORARY CESSATION OF 
BREASTFEEDING; ADDED PROTOCOL FOR SUICIDALITY; 10.2 – 
INCLUDED USE OF NC TRACS IN RECRUITMENT OF 
HISTORICALLY UNDERREPRESENTED IN RESEARCH AND 
INCLUDED CLARIFICATION THAT RECRUITMENT WILL INCLUDE 
PATIENTS FOR WHOM BRX TREATMENT IS ALREADY 
CLINICALLY INDICATED; INCLUDED TABLE 5 TO DESCRIBE 
AROUSAL SCALE TO MONITOR FOR EXCESSIVE SEDATION/ 
LOSS OF CONSCIOUSNESS; 10.4&11.6 – CLARIFIED IQVIA’S 
ROLE IN RECEIVING SAE REPORTS, BUT NOT PROVIDING 
CLINICAL MONITORING; 10.5 & 11.2 – REMOVED CRITERIA 
FOR STUDY STOPPING THAT ARE NOT APPLICABLE (I.E. 
DEMONSTRATION OF EFFICACY AND DETERMINATION THAT 
PRIMARY ENDPOINT HAS BEEN MET); 11.8 – REMOVED 
LANGUAGE SUGGESTING MULTIPLE SITES IN THIS STUDY; 
11.9.1—STUDY COORDINATOR RESPONSIBLE FOR CREATION, 
MAINTENANCE, AND CODING OF REDCAP DATABASE. 
 
V3 
TITLE PAGE, 10.2 
ASSESSMENT OF 
SAFETY; 11.5 KEY 
ROLES AND STUDY 
GOVERNANCE 
DR. RUBINOW WAS REMOVED FROM APPLICABLE SECTIONS 
WHERE HE WAS REFERENCED AS PI AND REPLACED AS CO-I 
SATISFYING UNC IRB 
STIPULATION BASED ON COI 
DETERMINATION 
V4 
PROTOCOL 
SYNOPSIS; 4.3 
MEASUREMENT 
DESIGN; 5.2 
REDUCED HAMD ELIGIBILITY SCORE TO ≥20; REMOVED 
COVID-19 VACCINATION FROM INCLUSION CRITERIA; 
INCREASED POSTPARTUM PERIOD FROM 6 TO ≤8 MONTHS; 
ALLOW FOR OUTSIDE LABORATORY TESTS TO BE USED FOR 
INCREASE RECRUITMENT 
SUCCESS; DECREASE SUBJECT 
BURDEN 

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ELIGIBILITY; 7.1 
TABLE OF EVENTS 
SCREENING IF DONE WITHIN 14 DAYS OF INFUSION; 
REMOVED CLINICAL LAB ASSESSMENTS FROM H72; INCLUDED 
CONTINUOUS HRV MEASURE THROUGHOUT INFUSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
Statement of Compliance ............................................................................................................................... 8 
Abbreviations and Definitions of Terms ......................................................................................................... 9 
1. 
Protocol Synopsis ............................................................................................................................. 11 
2. 
Introduction: Background and Scientific Rationale ........................................................................... 13 
2.1. 
Background Information................................................................................................................ 13 
2.2. 
Supporting Pilot / Unpublished Data ............................................................................................. 14 
2.3. 
Scientific Rationale ........................................................................................................................ 14 
3. 
Objectives ......................................................................................................................................... 16 
3.1. 
Specific Aim................................................................................................................................... 16 
3.2. 
Exploratory Aims ........................................................................................................................... 17 
Exploratory Aim 1 ..................................................................................................................................... 17 
To calculate resting state nodal flexibility from five serial EEG recordings. ................................................. 17 
Exploratory Aim 2 ..................................................................................................................................... 17 
To identify rapid brain state configurations and their probability density function from five serial EEG 
recordings. ................................................................................................................................................ 17 
Exploratory Aim 3 ..................................................................................................................................... 17 
To assess the ability of iMotions Affectiva software to identify affective states using facial expression 
recognition analysis. .................................................................................................................................. 17 
Exploratory Aim 4 ..................................................................................................................................... 17 
To assess the amplitude of left frontal midline theta oscillations by performing spectral analyses of data 
collected from five serial EEG recordings. .................................................................................................. 17 
4. 
Study Design ..................................................................................................................................... 17 
4.1. 
Treatment Design .......................................................................................................................... 17 
4.2. 
Experimental / Observational Design ............................................................................................. 17 
4.3. 
Measurement Design .................................................................................................................... 18 
4.4. 
Outcome Measures ....................................................................................................................... 22 
5. 
Study Participants............................................................................................................................. 23 
5.1. 
Number of Participants ................................................................................................................. 23 
5.2. 
Eligibility ....................................................................................................................................... 23 
5.3. 
Strategies for Recruitment and Retention ..................................................................................... 24 
5.4. 
Consent Process ............................................................................................................................ 25 
6. 
Study Intervention ............................................................................................................................ 26 
6.1. 
Intervention – Test Article ............................................................................................................. 26 

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6.2. 
Assignment Procedures ................................................................................................................. 28 
6.3. 
Intervention – Procedural (if applicable) ........................................................................................ 28 
6.4. 
Concomitant Therapy: ................................................................................................................... 29 
6.5. 
Rescue Medications and Procedures (if applicable) ....................................................................... 29 
6.6. 
Compliance Checks........................................................................................................................ 30 
6.7. 
Withdrawal / Discontinuation of Enrolled Participants .................................................................. 30 
6.8. 
Voluntary Withdrawal (Drop-Out) of Enrolled Participants ............................................................ 30 
7. 
Study Procedures and Schedule........................................................................................................ 31 
7.1. 
Table of Events .............................................................................................................................. 31 
7.2. 
Pre-Screening / Screening (Day -14 to Day 0) ................................................................................. 33 
7.3. 
Enrollment / Baseline (Day 0) ........................................................................................................ 35 
7.4. 
Study Visits (Days 1-4) ................................................................................................................... 36 
7.5. 
Phone Contact............................................................................................................................... 38 
7.6. 
Final Visit (Hour 72) ....................................................................................................................... 38 
7.7. 
Follow-Up Contact (Day 30 ± 3) ..................................................................................................... 39 
7.8. 
Premature Discontinuation ........................................................................................................... 40 
7.9. 
Collection and Management of Tissue Specimens ......................................................................... 40 
8. 
Study Measurements and Evaluations.............................................................................................. 40 
8.1. 
Outcome Measures for Evaluation of Feasibility / Tolerability ....................................................... 41 
8.2. 
Outcome Measures for Evaluation of Efficacy................................................................................ 41 
8.3. 
Outcome Measures for Evaluation of Safety .................................................................................. 41 
8.4. 
Other Outcomes in the Causal Pathway ......................................................................................... 41 
8.5. 
Baseline Characteristics of the Participants ................................................................................... 41 
8.6. 
Variables Representing Treatment ................................................................................................ 41 
9. 
Statistical Analysis Plans ................................................................................................................... 41 
9.1. 
Strategies that Apply to all the Specific Aims ................................................................................. 41 
9.2. 
Description of the Study Cohort .................................................................................................... 42 
9.3. 
Aim-Specific Plans ......................................................................................................................... 42 
9.4. 
Planned Interim Analyses (If Applicable) ........................................................................................ 44 
9.5. 
Plans for Coping with Withdrawals and Loss-To-Follow-Up ............................................................ 44 
9.6. 
Sample Size Rationale.................................................................................................................... 44 
10. 
Safety Monitoring and Management ................................................................................................ 44 
10.1. 
Risk / Benefit Assessment .......................................................................................................... 44 

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10.2. 
Assessment of Safety ................................................................................................................ 47 
10.3. 
Unanticipated Problems, Adverse Events, Serious Adverse Events ............................................. 49 
10.4. 
Safety Monitoring ..................................................................................................................... 53 
10.5. 
Study Suspension / Early Termination of the Study .................................................................... 53 
11. 
Supporting Documentation and Operational Considerations ........................................................... 54 
11.1. 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 54 
11.1.1. 
Informed Consent Process ......................................................................................................... 54 
11.1.1.1. 
Consent/Assent and Other Informational Documents Provided to Participants ..................... 54 
11.1.1.2. 
Consent Procedures and Documentation .............................................................................. 54 
11.2. 
Study Discontinuation and Closure ............................................................................................ 54 
11.3. 
Confidentiality and Privacy ........................................................................................................ 55 
11.4. 
Future Use of Stored Specimens and Data ................................................................................. 56 
11.5. 
Key Roles and Study Governance ............................................................................................... 56 
11.6. 
Safety Oversight ........................................................................................................................ 56 
11.7. 
Clinical Monitoring .................................................................................................................... 56 
11.8. 
Quality Assurance and Quality Control ...................................................................................... 56 
11.9. 
Data Handling and Record Keeping ............................................................................................ 57 
11.9.1. 
Data Collection and Management Responsibilities .................................................................... 57 
11.9.2. 
Study Records Retention ........................................................................................................... 57 
11.10. 
Protocol Deviations ................................................................................................................... 57 
11.11. 
Publication and Data Sharing Policy ........................................................................................... 58 
11.12. 
Conflict of Interest Policy .......................................................................................................... 58 
12. 
Additional Considerations ................................................................................................................ 58 
13. 
References ........................................................................................................................................ 58 
14. 
List of Appendices............................................................................................................................. 67 
 
 
 
 
 
 
 
 

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Statement of Compliance 
This study will be conducted in accordance with the International Conference on Harmonisation 
guidelines for Good Clinical Practice (ICH E6) and the Code of Federal Regulations on the Protection of 
Human Subjects (45 CFR Part 46). The statistical analysis plans will be consistent with guidances such as 
the CONSORT Statement [1] or STROBE Statement [2], ICMJE recommendations [3], the 2016 and 2019 
statements of the American Statistical Association [4,5], and recommendations in Nature [6,7].1 All 
personnel involved in the conduct of this study have completed human subjects protection training. 
 
 
 
 
1 [1] www.consort-statement.org [2] www.strobe-statement.org [3] www.icmje.org [4]  Wasserstein RL, et al. 
(2016), The ASA's Statement on p-Values, The American Statistician, 70:2, 129-133 [5]  Wasserstein RL, et al. 
(2019), Moving to a World Beyond p < 0.05, The American Statistician, 73:sup1, 1-19 [6]  Amrhein, et al. (2019) 
Scientists rise up against statistical significance, Nature 567, 305-307 [7] Editorial (2019) It’s time to talk about 
ditching statistical significance: Looking beyond a much used and abused measure would make science harder, but 
better. Nature 567, 283-283. 

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Abbreviations and Definitions of Terms 
Abbreviation/Acronym Definition 
AE 
Adverse Event/Adverse Experience 
ALLO 
Allopregnanolone 
AMICA 
Adaptive Mixture of Independent Component Analyses 
BIMF 
Barkin Index of Maternal Functioning 
BRX 
Brexanolone 
CI 
Confidence Interval 
CO-I 
Co-Investigator 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTRC 
Clinical & Translational Research Center 
CTSA 
Clinical and Translational Science Awards 
DCC 
Data Coordinating Center 
dFC 
Dynamic Functional Connectivity 
dlPFC 
Dorsolateral Prefrontal Cortex 
DSMB 
Data and Safety Monitoring Board 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EEG 
Electroencephalography 
EPDS 
Edinburgh Postnatal Depression Scale 
FC 
Functional Connectivity 
FDA 
Food and Drug Administration 
fMRI 
Functional Magnetic Resonance Imaging 
FMT 
Frontal Midline Theta 
GABA 
Gamma Aminobutyric Acid 
GCP 
Good Clinical Practice 
HAM-D 
Hamilton Depression Rating Scale 
HIPAA 
Health Insurance Portability and Accountability Act 
HRSA 
Health Resources and Services Administration 
IAPS 
International Affective Picture System 
IB 
Investigator's Brochure 
ICA 
Independent Component Analysis 
ICF 
Informed Consent Form 

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ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IDS-SR 
Inventory of Depression Symptoms – Self-Report 
IDS 
Investigational Drug Services 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IV 
Intravenous Line 
MDD 
Major Depressive Disorder 
N 
Number (typically refers to subjects) 
NC TraCS 
North Carolina Translational and Clinical Sciences Institute 
NIH 
National Institutes of Health  
OB-GYN 
Obstetrics-Gynecology 
OHRP 
Office for Human Research Protections 
PDF 
Probability Density Function 
PFC 
Prefrontal Cortex 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PPD 
Postpartum Depression 
PPIU 
Peripartum Inpatient Unit 
QC 
Quality Control 
REMS 
Risk Evaluation and Mitigation Strategies 
RRS-10 
Rumination Response Scale - 10 
rsEEG 
Resting State Electroencephalography  
SAE 
Serious Adverse Event/Serious Adverse Experience 
SCID-V 
Structured Clinical Interview for DSM-5 Disorders 
SCS 
State Complacency Scale 
SD 
Standard Deviation 
SE 
Standard Error 
SHAPS 
Snaith-Hamilton Pleasure Scale 
SMDDS 
Symptoms of Major Depressive Disorder Scale 
SOP 
Standard Operating Procedures 
STAI 
State-Trait Anxiety Inventory 
STROBE 
STrengthening Reporting of OBservational studies in Epidemiology 
SVM 
Support Vector machines 
UNC-CH SOM 
University of North Carolina at Chapel Hill School of Medicine 
UP 
Unanticipated Problem 

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1. Protocol Synopsis 
 
Study Title 
Dynamic neural mechanisms of brexanolone-induced antidepressant effects 
in postpartum depression 
 
Objectives 
Primary: To evaluate the feasibility of performing five serial EEG recordings 
and frequent affective state assessments over 72 hours in women 
with postpartum depression receiving inpatient brexanolone (BRX) 
infusion treatment. 
Exploratory:  
1. To calculate resting state nodal flexibility from five serial EEG recordings. 
2. To identify rapid brain state configurations and their probability density 
function from five serial EEG recordings. 
3.  To assess the ability of iMotions Affectiva software to identify affective 
states using facial expression recognition analysis. 
4. To assess the amplitude of left frontal midline theta oscillations by 
performing spectral analyses of data collected from five serial EEG 
recordings. 
 
Target Population 
Key Inclusion Criteria  
• 
Women aged 18-45 
• 
Moderate to severe postpartum depression (DSM-V; HAM-D ≥20) 
• 
Onset of PPD in 3rd trimester or within 4 weeks of delivery 
Key Exclusion Criteria 
• 
Current pregnancy 
• 
Pregnancy that resulted in a stillbirth, termination, or child that was 
placed for adoption. 
• 
History of thyroid disorder, renal impairment, hepatic impairment, 
anemia, or seizure disorder 
• 
History of psychotic symptoms, concurrent substance use disorder, 
or suicide attempt this episode. 
• 
Use of anticonvulsant agents or benzodiazepines. 
 
Numbers of 
Participants 
Number to be recruited for screening: n=20 
Number of eligible participants enrolled: n=12 
Clinical Phase 
Not applicable 
 
Intervention 
Enrolled subjects will receive a 60-hour infusion of BRX according to FDA 
approved protocol for administration. A programmable peristaltic infusion 
pump will be used to ensure accurate delivery. 
 
Study Description 
This is a feasibility study of performing repeated EEG recordings and 
assessment of affective states during open-label administration of BRX to 

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women with postpartum depression. Study phases will include screening, 
enrollment, intervention, and follow-up. Subjects will be screened for study 
eligibility criteria through clinical assessments and self-report.  Enrolled 
subjects will be admitted to the UNC Women’s Hospital, where five serial 
EEG recordings will be obtained, along with frequent assessments of 
affective state, before, during, and after a 60-hour IV infusion of BRX. 
Follow-up procedures will include assessments of PPD and affective 
symptoms, as well as an exit interview with the study team. If feasibility 
outcomes are achieved, exploratory EEG analyses will be performed with 
AMICA (adaptive mixture independent component analysis), community 
detection, and microstate assessment. Exploratory analyses of data 
collected by facial expression detection software (iMotions Affectiva) are 
also planned. 
 
Outcome Measures 
Primary outcome measures of feasibility: 
1. Number of successfully analyzed EEG recordings. 
2. Number of subjects completing the entire study protocol through 
the follow-up phase. 
3. Number of subjects withdrawn from the protocol due to adverse 
events and/or participation burden. 
 
Study Duration 
2 years 
 
Subject 
Participation 
Duration 
7 weeks 
Estimated Time to 
Complete 
Enrollment 
20 months  
Statistical Analysis 
Plans 
This study will determine the feasibility of the subject’s participation in the 
protocol. Consequently, we intend to generate descriptive statistics of the 
number of subjects who complete the entire protocol, the number of 
subjects who are withdrawn from the study, and the quality of the EEG 
recordings and affective assessments collected over the course of the 
protocol.  
 
 

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2. Introduction: Background and Scientific Rationale 
2.1. Background Information 
PPD is a great public health problem: it affects approximately 12% of women, adversely impacts mother 
and child, and is the leading cause of maternal death in the first year postpartum1. Recently we 
demonstrated that a 60-hour IV infusion of the neurosteroid (and progesterone metabolite) 
allopregnanolone (ALLO) (the active molecule in brexanolone [BRX]) rapidly (within 8-24 hours) reversed 
the depressed state in hospitalized women with PPD. Moreover, the antidepressant efficacy lasted for at 
least 30 days2,3. These exciting findings introduce an entirely new compound to the antidepressant 
armamentarium (and the first specifically for women with PPD). Several elements of ALLO’s function have 
been identified, notably strong positive allosteric modulation of GABA receptor activity4 and, more 
recently, blockade of proinflammatory immune signaling5–7, but how and if the effects of ALLO on these 
molecular systems translate into its rapid therapeutic efficacy in PPD remain unknown.  
 
GABAergic enhancement by ALLO suggests that its rapid antidepressant effects may be mediated 
through modulation of neuronal networks. Multiple lines of evidence suggest that GABA receptor 
signaling is compromised in depression8. Deficient GABA signaling produces abnormal neural 
synchronization and emergence of dominant network states9. Yet, the network features of a change in 
affective state remain unknown due, in part, to the long timescale of symptom improvement for most 
treatments. The rapid clinical response to ALLO in PPD thus provides a unique opportunity to delineate 
the evolution of network dynamics associated with the affective state switch. Understanding the 
network dynamics of symptom remission is highly significant since it will enable the future design of 
targeted interventions for correcting aberrant network signaling associated with depression. Studies of 
networks with fMRI and EEG have commonly generated summary measures that presume that network 
activity is stationary over time. In contrast, recently developed analytic methods for EEG and fMRI 
identify moment-to-moment brain states, recurrent patterns of interaction between brain regions that 
map onto and predict behavioral states10–12. These dynamic measures have been described as explaining 
more of the variance in cognitive and emotional state than more static measures,13–15,. We propose that 
PPD results from disordered coordination of rapid interactions between widely distributed brain regions, 
and that positive GABAergic modulation by ALLO restores normal network synchronization. We 
hypothesize that BRX-induced rapid emergence from the depressed state in PPD will be accompanied by 
changes in time-varying measures of brain coordination dynamics. 
Significance of the Expected Research Contribution: Upon successful completion of this pilot study, we 
expect our contribution will advance efforts to illuminate the physiology underlying the rapid 
antidepressant actions of a novel neurosteroid treatment for PPD. By studying women while they 
transition between affective states, rather than focusing solely on the symptomatic state, we will gain 
novel and fundamental insight into a transdiagnostic phenomenon - the transition between affective 
states. This pilot study will be the first step in the identification of the disturbed networks and network 
kinetics in women with PPD and restored by ALLO, insights that will ultimately be particularly helpful for 

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developing neuromodulatory therapies designed to destabilize persistent dysphoric states. These 
therapies may be particularly important as alternatives to pharmacotherapies during conditions like 
pregnancy, when medications might otherwise be avoided. 
 
INNOVATION: Studies of the kinetics of brain dynamics during remission from depression – and 
particularly in PPD - are virtually absent from the literature, as are investigations of the physiology 
underlying the transition between markedly different affective states. Our proposed study is innovative 
for several reasons: it employs a novel, rapidly acting, neurosteroid antidepressant in a highly morbid, 
relatively homogeneous form of depression (PPD); its study design exploits the rapidity of response to 
BRX, thus narrowing the window during which changes in both mood state and EEG characteristics are 
anticipated; it focuses on rapid, network dynamics at different temporal scales during induced affective 
state changes. Critically, the unique, within-subject study design creates the opportunity to identify novel 
electrophysiological characteristics of PPD.  
 
2.2. Supporting Pilot / Unpublished Data 
We will use high-density EEG to examine functional interactions via cortical synchronization. Spectral 
analyses are commonly used to infer inter-regional connectivity, with synchrony of neural oscillations in 
specific frequency bands critically involved in long-range communication. Theta (4-8Hz) oscillations link 
PFC and amygdala72, are involved in cognitive regulation of affect73, and are decreased (both power and 
FC) in major depression74. The relevance of this static measure for ALLO is suggested by unpublished 
data from Dr. Jamie Maguire et al showing disturbed theta synchrony activity in the PFC and amygdala in 
animal models that share behavioral features with patients with PPD. Strikingly, administration of ALLO 
restored both normal network activity and normal behavior in these rodent models. Modulation of 
network theta oscillations by ALLO as a potential therapeutic mechanism is also indirectly suggested by 
preliminary findings by CO-I Frohlich showing a positive correlation between increased amplitude of 
frontal midline theta (FMT) oscillations and plasma levels of progesterone, the ALLO precursor. We 
hypothesize an increase in FMT oscillations will be seen in association with remission from the depressed 
state.  
Application of dynamic (rather than aggregate) measures takes greater advantage of the temporal 
precision of EEG. Three methods described in the literature form the basis of the exploratory measures 
to be employed in this pilot study. 
2.3. Scientific Rationale 
The main justification for the proposed pilot study is twofold: 1) Given the severity of the consequences 
of PPD, it is critical that we increase our understanding of the pathophysiology of the disorder; 2) Greater 
understanding of the brain mechanisms underlying the switch between affective states will advance the 
goal of identifying targets for novel therapeutics.  
Modulation of GABAergic signaling by ALLO and implications for network dynamics of affective state in 
PPD: Three early observations support the premise of Exploratory Aim 1, which investigates changes in 

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network dynamics in response to ALLO administered in patients with PPD: 1) Both ALLO levels and GABA 
receptor composition change during pregnancy and postpartum18–20; 2) ALLO (but not benzodiazepines)21 
activates delta subunit-containing GABA receptors, those responsible for tonically inhibiting and 
synchronizing cortical excitatory tone22,23; and 3) knockout of delta subunit-containing GABA receptors 
creates an animal model in which female mice develop depressive-like symptoms restricted to the 
postpartum and deficits in maternal care22, behaviors reversed by an ALLO analogue21. In parallel, recent 
clinical trials showed the antidepressant efficacy of a 60-hour infusion of BRX in women with PPD, with 
50% remitting at 60 hours24. Given both recent conceptualization of depression as a discoordination of 
neural networks25–27  and the ability of ALLO to modulate GABA signaling,4,28, the alteration by ALLO of 
network communication in PPD is a logical but untested inference. Few if any EEG studies of PPD exist, 
but the utility of EEG in studies of depression is well demonstrated by recent machine learning-based 
demonstrations that rsEEG robustly predicts antidepressant response33 and that spatio-temporal network 
dynamics identify susceptibility to depression34. Most fMRI and EEG studies measure average functional 
organization over the entire scan. Convergent evidence suggests, however, that even in the resting state, 
functional brain networks demonstrate significant temporal variability and dynamic reconfiguration not 
captured by aggregate “static” measures35,13,36. Rapid, dynamic fluctuations in time-varying network 
connectivity (dFC) are believed to be essential for continuous updating and efficient flow of neuronal 
information and have been increasingly implicated in a range of cognitive and affective processes and 
psychiatric disorders, including, most recently, depression37–41. Common to these studies is the 
observation that it is the number and characteristics of the dynamic transitions between states that differ 
as a function of diagnosis or behavioral state40,35; i.e., affective behavior arises from the rapid but 
coordinated interactions among multiple brain circuits, not from one, isolated circuit. As shown in our 
preliminary studies of several psychiatric populations (see above), dFC measures offer unparalleled tools 
for mapping the network changes underlying the antidepressant effects of BRX.  
Multiple approaches exist for assessing dFC, each of which segments the time courses from spatial or 
voltage signals into a set of temporal windows, characterizes connectivity (e.g., a correlation matrix) in 
each window, and decomposes information by identifying a smaller number of recurrent patterns. The 
power of these techniques lies in their ability to both preserve the temporal information and yet reduce 
or decompose the data to manageable and interpretable dimensions. Notably, these dynamic techniques 
have only rarely been studied in depression37 and not at all in PPD or during a medication-induced change 
in affective state. We propose, therefore, to apply multiscale (aggregate and time varying/dynamic) EEG 
measures in women with PPD undergoing BRX infusion to identify the network dynamic changes that 
accompany recovery from the depressed state. We will characterize rapid brain state configurations and 
transitions/kinetics at baseline, track changes in state landscape during BRX infusion, and compare 
changed dynamics (nodal flexibility) both pre and post infusion and in those who do and do not remit. By 
interrogating our dataset with these methods, we will have an unprecedented ability to detect the 
formation, dissolution, and reconfiguration of global brain network activity during the transition to a 
remitted state.   
 
The first dynamic method, adaptive mixture independent component analysis (AMICA), can, in an 
unsupervised fashion, detect brain dynamic state changes associated with changes in cognitive state11. 

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AMICA assumes that different segments of the data will be best characterized by distinct ICA models, 
Different models dominate at different time points, and the probabilities of activation and brain source 
characteristics of these models have been shown to successfully identify even rapid changes in behavioral 
state11 We hypothesize that BRX-induced remission will exhibit different model topographies and 
probabilities compared to baseline and to non-remission. 
Network-based community detection (developed by CO-I Mucha)75, generates measures sensitive to 
mood, diagnosis (schizophrenia) and medication-induced change in cognitive states10,38,76. A community 
is a collection of brain regions that preferentially communicate with one another. Community detection 
creates a graph that assesses the reconfiguration of networks over time. This method permits 
determination of how often nodes change networks (network flexibility), which is presumed essential 
for adaptive behavior10,77.  In a novel application of this methodology to model EEG dynamic network 
connectivity, CO-I Campbell has identified differences in the formation, strength, and trajectory of 
networks in response to cognitive tasks in patients with prodromal psychotic symptoms vs. controls. 
Remarkably, the “flexibility” of network nodes (i.e., their joining other networks) over the course of 
several seconds predicts with high precision both individual exposure to stressors and group 
membership (high risk group or controls). We predict an increase in global flexibility 37,78) following BRX 
in those who emerge from the depressed state (remission at hour 60). 
Finally, EEG resting state data can be decomposed into sub-second (60-100ms), transiently stable and 
recurrent components called microstates79. The microstates can be clustered into a small number (usually 
four or five) of canonical classes, which repeatedly recur in individuals and the characteristics of which 
(i.e., specific topography of potentials, sequence, mean duration, number/second) have repeatedly been 
found to be altered in patients with schizophrenia80–82, . We predict the BRX-induced switch will show 
disruption of the depression-associated microstate temporal dynamics, resulting in altered frequency, 
duration and transition probability of the two states described by Koenig83 that have been linked to rsfMRI  
changes in  brain regions pertinent to frontal-amygdala connectivity84,85 .  
 
3. Objectives 
3.1. Specific Aim 
To Evaluate the feasibility of obtaining serial EEG recordings and affective state measures in women 
with PPD who receive inpatient BRX infusion treatment. 

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3.2. Exploratory Aims 
Exploratory Aim 1 
 To calculate resting state nodal flexibility from five serial EEG recordings. 
Exploratory Aim 2 
To identify rapid brain state configurations and their probability density function from five serial EEG 
recordings. 
Exploratory Aim 3 
To assess the ability of iMotions Affectiva software to identify affective states using facial expression 
recognition analysis. 
Exploratory Aim 4 
To assess the amplitude of left frontal midline theta oscillations by performing spectral analyses of 
data collected from five serial EEG recordings.  
4. Study Design 
 
This is a feasibility study of performing repeated EEG recordings and assessments of affective states 
during open-label administration of BRX to women with postpartum depression. Study phases will 
include screening, enrollment, intervention, and follow-up. Subjects will be screened for eligibility 
criteria through clinical assessments and self-report.  Enrolled subjects will be admitted to the UNC 
Women’s Hospital, where five serial EEG recordings will be obtained, along with frequent assessments 
of affective state, before, during, and after a 60-hour IV infusion of BRX. Follow-up procedures will occur 
30 days after completion of the drug infusion, and will include assessments of PPD and affective 
symptoms, as well as an exit interview with the PI. If feasibility outcomes are achieved, exploratory EEG 
analyses will be performed with AMICA (adaptive mixture independent component analysis), 
community detection, and microstate assessment. Exploratory analyses of data collected by facial 
expression detection software (iMotions Affectiva) are also planned. 
4.1. Treatment Design 
Based on an FDA-approved regimen, the 60-hour infusion will be administered as follows: 30 
mcg/kg/hour (Hour 0 to 4), then 60 mcg/kg/hour (Hour 4 to 24), then 90 mcg/kg/hour (Hour 24 to 52), 
followed by 60 mcg/kg/hour (Hour 52 to 56), and 30 mcg/kg/hour (Hour 56 to 60). A programmable 
peristaltic infusion pump will be used to ensure accurate delivery of BRX.  
 
4.2. Experimental / Observational Design 
All enrolled participants receive the same intervention. 
 

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4.3. Measurement Design 
Table 1: Measurement Design 
Name 
Time Frame 
Brief Description 
Scoring 
Hamilton Depression 
Rating Scale (HAM-D) 
Baseline, q4h while 
awake during infusion, 
12 hours post-infusion, 
Day 30 (follow-up) 
17-item rating scale to 
measure severity of 
depression. Will be used 
to define remission as 
scale score equal to or less 
than 7. This assures 
comparability with the 
original clinical trials of 
BRX (which used this scale 
as the primary endpoint). 
Range: 0-55 
Eligibility Score: ≥20 
based on original 
clinical trials of BRX 
Remission Score: ≤7 
Inventory of Depression 
Symptoms – Self Report 
(IDS-SR) 
Baseline; 12 hours post-
infusion 
30 item self-report 
questionnaire that 
assesses depressive 
symptoms, including sad 
mood, irritability, 
lassitude, vegetative 
symptoms, well-being, 
and suicidality. Items 
reflecting anhedonia 
(inverse of the well-being 
items 21 [pleasure], 20 
[energy], 19 
[engagement], and 8 
[reactivity]) will be 
summed to provide a 
subscale of depression 
symptoms 
Range: 0-84 
Total score obtained 
by summing the 
ratings of 28 of the 
30 items. Either 
weight loss or gain, 
appetite loss or gain, 
is scored as only one 
member of each pair 
is applicable to any 
given respondent. 
Each of the 28 items 
is scored on a 0 to 3 
scale (0—absence; 
3—severe pathology) 
Symptoms of Major 
Depressive Disorder Scale 
(SMDDS) 
Baseline, q4h while 
awake during infusion, 
12 hours post-infusion, 
Day 30 (follow-up) 
16-item, rigorously 
developed patient 
reported outcome 
measure for depression, 
the only PRO measure for 
depression approved by 
the FDA to assess clinical 
trial endpoints. 
Range: 0-64 
Total score obtained 
by summing the 
ratings of the 16 
items. Response 
scale for items 1-9: 
Not at all/ A little bit/ 
Moderately/ Quite a 
bit/ Extremely. 
Response scale for 

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items 10-16: Never/ 
Rarely/ Sometimes/ 
Often/ Always 
Edinburgh Postnatal 
Depression Scale (EPDS) 
Baseline, q4h while 
awake during infusion, 
12 hours post-infusion, 
Day 30 (follow-up) 
21 item clinician-rated 
standardized scale 
assessing depressive 
symptom severity in 
women with PPD; widely 
used as a measure of 
symptom change. 
Range: 0-30 
Questions 1,2, &4 
are scored 0, 1, 2, or 
3 in order of 
appearance. 
Questions 3, 5-10 are 
reverse scored.  
Ruminative Responses 
Scale-10 (RRS-10) 
Baseline, 12 hours post-
infusion, Day 30 (follow-
up) 
10-item measure of 
reflective pondering and 
brooding, minus the 
depression items 
contained in the 22-item 
version. Prominent sx of 
PPD; believed related to 
treatment efficacy. 
Range: 10-40 
Response items on a 
scale of 1 “almost 
never” to 4 “almost 
always” are 
summed. Two 
subscales (brooding 
and reflection) 
contain five items 
each. 
Snaith-Hamilton Pleasure 
Scale (SHAPS) 
Baseline, 12 hours post-
infusion, Day 30 (follow-
up) 
A 14-item clinician 
administered scale to 
assess anhedonia, the 
inability to experience 
pleasure. Items cover the 
domains of: social 
interaction, food and 
drink, sensory experience, 
and interests/pastimes.  
Range: 0-14 
Either of the 
“disagree” responses 
receives a score of 1 
and either of the 
“agree” responses 
receives a score of 0. 
A higher score is 
indicative of higher 
levels of anhedonia. 
An “abnormal” score 
is defined as 3 or 
more.   
State Complacency Scale 
(SCS) 
Baseline, q2h while 
awake during infusion, 
12 hours post-infusion, 
Day 30 (follow-up) 
100mm line scale ratings 
for depressed mood, 
anxiety, irritability, mood 
stability, satisfaction with 
current mood, belief that 
mood is about to change 
over time. 
Range: 0-100 for 
each item 

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State-Trait Anxiety 
Inventory (STAI) 
State = Y-1 
Trait = Y-2 
State: Baseline, q4h 
while awake during 
infusion, 12 hours post-
infusion, Day 30 (follow-
up) 
Trait: Baseline, 12 hours 
post-infusion, Day 30 
(follow-up) 
40-item measure used in 
clinical settings to 
diagnose anxiety and 
distinguish it from 
depressive symptoms. 20 
items for assessing trait 
anxiety and 20 items for 
state anxiety. 
Range: 20-80 (each 
form) 
Sum the scoring 
weights (1-4) for 
each response item. 
See manual for 
reverse scoring 
guide. 
Barkin Index of Maternal 
Functioning (BIMF) 
Baseline, 12 hours post-
infusion, Day 30 (follow-
up) 
20-item self-report 
measure to assess overall 
functioning in the context 
of new motherhood. 
Range: 0-120 
Items 16 and 18 are 
reverse scored, then 
all 20 items are 
summed to generate 
the total score. 
Higher total scores 
are associated with 
greater levels of 
functioning. 
Resting State EEG 
Recording (EEG-RS) 
Baseline, during infusion 
(Hours 4, 8, and 28), 12 
hours post-infusion 
8-minute EEG recording 
where subject focuses on 
neutral visual target while 
alternating eyes open and 
closed every 2 minutes 
See Table 1B for 
description of EEG 
outcomes of interest 
iMotion Affectiva Facial 
Expression Analysis 
Software  
Baseline, during infusion 
(Hours 4, 8, and 28), 12 
hours post-infusion 
Software that measures 
20 facial expression 
metrics (e.g., affective 
valence, engagement, 
facial landmarks) known 
to display altered 
configurations that map 
onto emotions. Changes in 
facial expression will 
provide a non- verbal 
complement to self-
ratings in detecting BRX-
induced alterations in 
affective state.  
See Table 1C for 
description of 
iMotions software 
outcomes of interest. 
Semi-structured Interview 
Baseline, during infusion 
(Hours 4, 8, and 28), 12 
hours post-infusion 
Administered 
simultaneously with 
iMotions recording to 
elicit emotional response 
Qualitative 
responses to 
questions about 
recent experiences 

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Table 1B: EEG Outcomes of Interest (Exploratory Aims) 
Exploratory Aim 
Variable of Interest 
Brief Description of 
Measurement 
Calculation of resting state nodal 
flexibility (community detection) 
Nodal flexibility: Frequency with 
which a nodal hub changes its 
community identity 
Measured by allegiance of nodes 
to modules: the number of times 
that each node changes module 
allegiance normalized by the 
total possible number of changes. 
The flexibility of the network as a 
whole is equal to the mean 
flexibility over all the nodes 
Identification of (A) rapid state 
brain configurations (global brain 
states) and (B) their probability 
density function 
(A) Microstate: four quasi-
stable, recurring 
topographic patterns of 
voltage (i.e., different 
configurations of electric 
field lasting 80-120 
milliseconds). 
(B) Duration: frequency of 
occurrence of 
microstates reflects the 
tendency of its 
underlying neural sources 
to become activated 
Frequency = the number of times 
a microstate is present relative to 
the total number of microstates 
recorded. Average duration = 
average time in milliseconds. 
Duration = proportion of time 
that state is activated relative to 
the sampling recording. 
Calculation of amplitude of 
frontal midline theta oscillations 
(spectral analysis) 
Frontal Midline Theta: 4-7 Hz 
reflecting activity from the limbic 
system and hippocampal regions 
Extracted theta power (4-7Hz) 
from FCz electrode during resting 
state recordings. Unit = dB. 
 
Table 1C: iMotions Affectiva Software Outcomes of Interest (Exploratory) 
Exploratory Aim: To assess the ability of iMotions Affectiva software to identify affective states using facial 
expression recognition analysis. 
Variable of Interest 
Brief Description of Measurement 
Unit of Measurement 
in lieu of an affective 
probe task 
of enjoyment, guilt, 
and irritability will be 
compared to 
software output of 
detected facial 
expression (see 
Table 1C). 

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Action Unit (most sensitive level 
of detection) 
Tiny muscular changes in a facial 
expression (e.g., inner brow raiser, 
brow lowered, lip corner depressor, 
etc.) 
Evidence score represents the 
probabilistic odds in 
logarithmic scale (base 10) of 
a target action unit being 
present. 
Emotion Score 
Percent of time spent in a certain 
emotional state (Eckman’s core 7 
emotions) 
The weighted average of 
action units (e.g., cheek raiser, 
lips part, and lip corner puller 
act in concert to create a smile 
during the state of enjoyment) 
Engagement and valence (least 
sensitive levels of analysis) 
Threshold of expressiveness in 
general and positive or negative 
expression 
Probability (percentage) that a 
human assessor would rate 
the emotion equally to the 
software. Expressions that 
don’t meet the predetermined 
thresholds are considered 
“neutral” 
 
4.4. Outcome Measures  
Primary Outcome(s):  
1. Number of successfully analyzed EEG recordings. 
2. Number of subjects completing the entire study protocol through the follow-up phase. 
3. Number of subjects withdrawn from the protocol due to adverse events and/or participation 
burden. 
Tertiary/Exploratory Outcome(s): 
1. Calculation of resting state nodal flexibility (community detection) at H0, 4, 8, 28, 72. 
2. Identification of (A) rapid state brain configurations (global brain states) and (B) their 
probability density function at H0, 4, 8, 28, 72. 
3. Identification of affective states with iMotion Affectiva software at H0, 4, 8, 28, 72. 
4. Calculation of amplitude of frontal midline theta oscillations (spectral analysis) at H0, 4, 8, 
28, 72. 
Other Measures: Baseline Characteristics 
1. Age 
2. Race 
3. Ethnicity 
4. History of depression (SCID-5) 
5. Comorbid anxiety disorder(s) (SCID-5) 

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6. Concurrent psychotropic medication use 
7. Pregnancy history (# pregnancies, # births, methods of delivery, birth complications, past PPD 
episodes) 
5. Study Participants 
5.1. Number of Participants 
Number to be recruited for screening: n=20  
Number of eligible participants enrolled: n=12 women with moderate to severe PPD, medically 
eligible to receive FDA-approved BRX infusion, recruited from current inpatient and outpatient 
population in the Women’s Mood Disorders Clinic at UNC and through local advertisements. Subjects 
recruited from outpatient setting will be individuals for whom BRX is the chosen recommended course of 
treatment. 20 subjects will be screened for eligibility, 12 will be enrolled, and 10 will complete the 
protocol in its entirety. 
5.2. Eligibility 
Inclusion Criteria:  
 
To be eligible to participate in this study, an individual must meet all the following criteria: 
• 
Signed informed consent. 
• 
Ambulatory, female, aged 18-45 
• 
≤ 8 months postpartum 
• 
Agrees to adhere to the study requirements. 
• 
Onset of depression in 3rd trimester or within 4 weeks of delivery 
• 
Meets DSM-V criteria for major depressive disorder with peripartum onset. 
• 
17-item HAM-D total score ≥20 at screening  
• 
Stopped breastfeeding or agrees to temporarily stop for 7 days including 4 days of 
hospitalization and 3 days after 
• 
No new psychotropic drugs during screening and active treatment of study 
• 
Stable use of any current psychotropic drugs for at least 28 days prior to enrollment, with 
stable dosage for at least 14 days prior to enrollment 
• 
Must be on documented contraceptive. 
• 
Must have a caregiver or family member with them to help care for the subject’s child(ren) 
during the infusion and to be in the room with the subject if the child(ren) are present 
during the infusion 
 
Exclusion Criteria:  
 
Any individual who meets one or more of the following criteria will be excluded from participation: 
• 
Positive pregnancy test at screening or day 1 

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• 
Pregnancy that resulted in a stillbirth, termination, or child that was placed for adoption. 
• 
Renal impairment or failure, hepatic impairment or failure, or anemia 
• 
Untreated or inadequately treated hypothyroidism or hyperthyroidism 
• 
Known allergy to progesterone or allopregnanolone. 
• 
Suicide attempt at this episode 
• 
Medical history of schizophrenia, and/or schizoaffective disorder 
• 
Current psychotic symptoms including delusions, hallucinations, or formal thought disorder. 
• 
Concurrent substance abuse 
• 
Exposure to another investigational medication or device within 30 days 
• 
Has previously participated in any study employing brexanolone or SAGE-217. 
• 
Subject is investigative site personnel, sponsor personnel, or an immediate member of their 
family. 
• 
Has received electroconvulsive therapy during current episode. 
• 
History of seizure disorder 
• 
On anticonvulsant agents 
• 
On benzodiazepines 
 
5.3. Strategies for Recruitment and Retention 
Recruitment Strategy:  
Potential subjects will be selected among patients admitted to the PPIU or seen in our Women’s Mood 
Disorders outpatient program, for whom BRX is an appropriate course of treatment. Thus, we will 
capitalize on the existing BRX program at UNC and invite women who are interested and eligible to 
receive BRX treatment for PPD to participate in this research study. The BRX treatment protocol in this 
study will align with the clinical course of treatment at UNC, with the addition of serial EEG recordings, 
affective assessments, iMotions facial expression recordings to satisfy research aims. Should subjects 
decline to participate in the research study, they may still be able to receive BRX treatment through the 
traditional route at UNC.  
Similarly, we will recruit through patients referred as part of our outreach to community OB-GYN 
practices; through advertisements in local newspapers, parent magazines, public transportation and 
online; and through our consultation with the UNC CTSA, the North Carolina Translational and Clinical 
Sciences Institute (NC TraCS). Through the NC TraCS Data Access and Informatics Core, we can identify a 
cohort of UNC Hospital patients for recruitment. UNC uses the EPIC electronic medical record system, 
which enables communication to potential research participants via email and through the MyChart 
patient interface. This makes communication with many potential research participants cost effective 
and highly efficient, because it will enable potential participants to access our online screening tool 
simply by clicking a link in their email or MyChart electronic message. Additionally, we will capitalize on 
the TraCS Research Recruitment Service’s expertise in enrolling members of communities historically 
under-represented in research. We additionally can use the following widely accessed entities: email 

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listservs that are directed to staff, faculty, and students on campus; public transportation in Chapel Hill, 
which is free and widely used; the local newspaper in which we advertise, and online advertising 
through sites like Facebook, which reaches many women of reproductive age.  
Retention Strategy:  
These strategies include the following: providing clear descriptions of all study procedures and burdens; 
enrolling only fully informed subjects; and using a financial bonus linked to completion in full 
compliance. Although we recognize that side effects of any treatment may influence retention, the side 
effects associated with BRX led to no dropouts in our previous experience. Non-compliance should not 
be an issue in this short-term inpatient study. Nonetheless, our sample size of 12 allows for a 20% drop-
out rate. Finally, the study team will conduct exit interviews with participants at the final study visit to 
solicit candid feedback about participants’ experiences in the study. We will use this feedback to make 
improvements to study procedures. Most of past participants have taken advantage of this optional 
session to review their own data and to discuss implications for managing affective symptoms in future 
pregnancies. During the final exit interview, many participants described the opportunities to learn 
more about the effects of hormones on their mood and to help others with similar problems as 
important motivations for their enrolling in and completing the study. We have strategies in place in 
case of unexpected difficulties. The main such strategy will be use of the state-wide, HRSA-funded, 
education and assessment hotline for perinatal depression, the North Carolina Maternal Health Matters 
program. Through this program, staff in the UNC Perinatal Psychiatry Program have access to patients 
and providers throughout the state of North Carolina.  
Screen Failures: 
Of the 20 women screened for eligibility, we anticipate 12 will meet inclusion criteria (60%). Subjects 
who consent to and complete screening protocols (including physical examination, clinical lab 
assessments, ECG, and structured clinical interview for DSM-5 psychiatric disorders) will be 
compensated for their willingness and time, regardless of ultimate eligibility determination. Should 
subjects fail to meet eligibility criteria upon initial screening, re-screening may occur on a case-by-case 
basis, depending on the reason(s) for initial exclusion. Examples may include stabilized regimen of 
psychotropic medications for 28 days and stable dose for 14 days prior to enrollment; cessation of 
breastfeeding; HAM-D score severity in the required range at rescreening.  
5.4. Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent will be obtained by either 
the PI or the study coordinator. The consent process will occur in either the outpatient clinic, the CTRC, 
or the inpatient unit (for subjects recruited after admission). Consent forms will be Institutional Review 
Board (IRB)-approved, and the participant will be asked to read and review the document. The research 
personnel will explain the research study to the participant and answer any questions that may arise. If 
there are unanswered questions, the PI will be available to provide further responses to the participant’s 
questions.  A verbal explanation will be provided in terms suited to the participant’s comprehension of 
the purposes, procedures, and potential risks of the study and of their rights as research participants.  

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Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants will have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document, witnessed by the study personnel, prior to any procedures being done specifically 
for the study. Participants must be informed that participation is voluntary and that they may withdraw 
from the study at any time, without prejudice. A copy of the informed consent document will be given 
to the participants for their records. The informed consent process will be conducted and documented 
in the source document (including the date), and the form signed, before the participant undergoes any 
study-specific procedures. The rights and welfare of the participants will be protected by emphasizing to 
them that the quality of their medical care will not be adversely affected if they decline to participate in 
this study. Each participant will sign a HIPAA authorization form. 
6. Study Intervention 
 
6.1. Intervention – Test Article  
Description:  
As supplied, the brexanolone drug product is a sterile, clear, colorless 5 mg/mL solution of brexanolone 
and 250 mg/mL sulfobutyl-ether-beta-cyclodextrin buffered with 10 mM citrate at a pH of 6.0, supplied 
in single-dose 20 mL vials for IV administration. The composition and pharmaceutical quality of the 
investigational product will be maintained according to the current Good Manufacturing Practice and 
Good Clinical Practice (GCP) guidelines and available for review in the study medication documentation. 
Acquisition:  
Brexanolone will be provided to the site by the sponsor and to the investigator by IDS. 
Formulation/Packaging/Labeling: 
The product is aseptically processed, sterile filtered, and filled into 20 mL Type 1 parenteral glass vials 
with West FluroTec® coated stopper container closure systems, under current Good Manufacturing 
Practice conditions. Brexanolone is intended to be used as a single-use vial. 
Storage and Stability:  
The investigator or designee should refer to the Pharmacy Manual for instructions on acknowledging 
receipt of study drug. 
Study drug vials should be stored under refrigerated conditions (2 to 8°C). The vials must be carefully 
stored safely and separately from other drugs. The study drug may not be used for any purpose other 
than the present study. 
The Investigator or designee will be responsible for ensuring appropriate storage, dispensing, inventory, 
and accountability of all clinical supplies. An accurate, timely record of the disposition of all clinical 
supplies must be maintained. The supplies and inventory must be available for inspection by the 

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designated representatives of the Sponsor or the Sponsor’s representatives on request, and must 
include the information below: 
• The identification of the subject to whom the drug was dispensed 
• The date(s) and quantity of the drug dispensed to the subject 
• The product lot/batch number 
The preparation of the study drugs must be documented on a ‘Drug Preparation and Dispensing Log 
Form’ or similar form. 
The drug inventory and any clinical supplies that have been destroyed must be documented. This 
documentation must include at least the information below or as agreed with the Sponsor: 
• 
The number of prepared units 
• 
The number of administered units 
• 
The number of unused units 
• 
The number of units destroyed at the end of the study 
• 
The date, method, and location of destruction 
Preparation and Administration:  
The Pharmacist or designee will be responsible for preparing study drug for subject 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. 
This is an open-label study. Subjects will receive a 60-hour continuous IV infusion of brexanolone.  
The specific infusion dose of study drug will be calculated based on weight (obtained at screening) for 
each subject and administered according to the dose regimen in Table 2. 
Table 2: Infusion Rate 
Time point 
Day 1 
0 to 4 hours 
Day 1 
4 to 24 hours 
Day 2 to 3 
24 to 52 hours 
Day 3 
52 to 56 hours 
Day 3 
56 to 60 hours 
Dose 
30 mcg/kg/hour 
60 mcg/kg/hr 
90 mcg/kg/hr 
60 mcg/kg/hr 
30 mcg/kg/hr 
 
Dosing will begin in the morning (on Day 1) to avoid the dose increase to 90 mcg/kg/hour late in the day 
and to avoid awakening subjects during the night for completion of study assessments. 
Refer to the Pharmacy Manual for complete details on preparation and administration. 
The pharmacist or designee for drug accountability is to document the date and time of preparation of 
test article and for which subject the study drug was intended (i.e., record subject initials and birth date 
or another unique identifier). 

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At the end of the study, any unused study drug will be destroyed locally per the site’s procedures; 
disposition of study drug will be documented.  
Modification:  
If the UNC Hospitals Arousal Score = 3 (see Table 5), the dose will be reduced by 50% and the doctor will 
be contacted. If there are mild symptoms (e.g., dizzy, lightheaded), the dose will be held at the current 
rate rather than increased. Typically, these mild symptoms will resolve with more time at the lower 
infusion rate, and then subjects can tolerate an increase up to 90mcg/kg. The infusion will be 
immediately stopped if there is loss of consciousness, or if the UNC Hospitals Arousal Scale score is less 
than or equal to 2, or if pulse oximetry reveals hypoxia (oxygen saturation below 90%). 
For patients who do not tolerate the 90 mcg/kg/hour dose, a reduction to 60 mcg/kg/hour may be 
considered during the time that the 90 mcg/kg/hour is scheduled to occur. 
If other intolerable adverse events occur, the infusion will be stopped until the symptoms resolve. The 
infusion may be resumed at the same or lower dose as clinically appropriate.  
Accountability: 
The Pharmacist or designee will maintain accurate records of all investigational drug product supplies 
received, stored, dispensed, and discarded. Accurate records will be kept regarding the volume of study 
drug used for each IV preparation, as well as the required infusion dose (or doses), and the date and 
time of preparation. Reasons for departure from the expected dosing regimen must be recorded. To 
satisfy regulatory requirements regarding drug accountability, all study medication needs to be 
reconciled in full. 
 
6.2. Assignment Procedures 
Matching and Stratification:  
Not applicable 
Randomization, Concealment, and Blinding:  
Not applicable 
Masking (Blinding):  
Not applicable 
 
6.3. Intervention – Procedural (if applicable) 
Description:  

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Refer to the Pharmacy Manual for specific instructions regarding requirements for IV bags and labeling, 
infusion sets, infusion preparation and administration instructions. 
Training on Procedural Intervention:  
For individuals administering, it will be the unit chief from the PPIU, who has extensive experience 
administering brexanolone according to the proposed regimen. Nurses on both the PPIU and the 
Women’s Hospital inpatient unit have extensive experience with exactly the administration regimen 
proposed in this protocol. Prescribers and pharmacists will have been trained and certified in the BRX 
REMS program. 
 
6.4. Concomitant Therapy: 
Subjects may receive standard of care for patients diagnosed with PPD, including psychosocial 
interventions. Any concomitant medication determined medically necessary for the welfare of the 
subject may be given at the discretion of the Investigator at any time during the study, with the caveat 
that changes to psychotropic medications may be made only as outlined in the paragraph below. 
Subjects that are receiving medications administered to treat the symptoms of depression or anxiety 
(such as antidepressants) must have been initiated at least 14 days prior to dosing and must remain at a 
stable dose from at least 14 days prior to dosing until completion of the 72-hour assessments. Any new 
medication for depression or anxiety initiated after the 72-hour assessments are completed must be 
preceded by a discussion with the investigator and designated REMS physician. 
The following interventions will be recorded: 
• All medications taken from 60 days prior to informed consent through the final study visit 
• All psychotropic medications (including anxiolytics or antidepressants) taken in the previous 6 months 
prior to informed consent through the final study visit 
• All medications used to treat the current episode of PPD regardless of timing through the final study 
visit 
• All nonpharmacological interventions used to treat the current episode of PPD regardless of timing 
through the final study visit 
6.5. Rescue Medications and Procedures (if applicable) 
Since subjects will be hospitalized inpatients, and since they will be treated with a GABA positive 
allosteric modulator, which has known anxiolytic effects, it is not anticipated that anyone would 
experience a worsening of symptoms; if there was a concern that rescue was required, the response 
would take the form of decreasing or discontinuing the brexanolone and treating the subject with 
conservative measures until the response to drug discontinuation could be assessed.   

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6.6. Compliance Checks 
Study drug will be prepared by a pharmacist or designee, administered as a continuous IV infusion, and 
the dose received will be documented in the study record. There should be no adjustments in dosing 
except as described in Section 6.1. 
6.7. Withdrawal / Discontinuation of Enrolled Participants 
Enrolled participants may be withdrawn if new or worsening symptoms or any adverse event suggest 
that continued participation would place the subject at risk and not be in the subject’s best interest. 
Subjects may withdraw from the study at any time for any reason without compromising the subject’s 
medical care. The Investigator will also withdraw subjects upon the request of Sage Therapeutics or 
upon termination of the study. 
Subjects who withdraw should, if possible, complete an early termination visit, which includes the 
assessments for the Hour 72 visit (see Table 3). 
The reasons for protocol discontinuation and/or subject withdrawal from the study will be recorded in 
the study record. 
 
6.8. Voluntary Withdrawal (Drop-Out) of Enrolled Participants 
The subjects may voluntarily withdraw participation at any time, for any reason, with no penalty or loss 
of rights. Reasons for discontinuation will be documented in the database. 
 
 

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7. Study Procedures and Schedule 
7.1. Table of Events 
Table 3: Schedule of Events 
Study Procedure 
Screeni
ng 
Period 
Treatment Period/Inpatient Stay (Day 1 to Day 4) 
Follow-
up 
Visit Days 
D-14 to 
1 
D1 
D1 
D1 
D2 
D3 
D4 
D30 
(±3d) 
Hour 
  
H0* 
H4 
H8 
H28 
H60 
H72 
  
Informed Consent 
X 
  
  
  
  
  
  
  
SCID-5 
X 
  
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
  
Medical History 
X 
  
  
  
  
  
  
  
Height 
  
X 
  
  
  
  
  
  
Body Weight 
  
X 
  
  
  
  
  
  
Physical Examinationa 
X 
  
  
  
  
  
  
  
Drug and Alcohol Testb 
X 
X 
  
  
  
  
  
  
Pregnancy Testc 
X 
X 
  
  
  
  
  
  
Clinical lab assessmentsd 
X 
  
  
  
  
  
  
ALLO blood samplee 
  
X 
  
  
X 
  
X 
  
12-lead ECGf 
X 
  
  
  
  
  
  
  
Vital Signsg 
X 
X 
q4h (while awake) during infusion 
X 
  
C-SSRSh 
X 
X 
  
  
  
  
X 
  
HAM-Di 
X 
X 
q4h (while awake) during infusion 
X 
X 
SMDDSi 
  
X 
q4h (while awake) during infusion 
X 
X 
EPDSi 
  
X 
q4h (while awake) during infusion 
X 
X 
STAI (state Y-1)i 
  
X 
q4h (while awake) during infusion 
X 
X 
SCSi 
  
X 
Q4h (while awake) during infusion 
X 
X 
BIMFi 
  
X 
  
  
  
  
X 
X 
IDS-SRi 
  
X 
  
  
  
  
X 
X 
RRS-10i 
  
X 
  
  
  
  
X 
X 
SHAPSi 
  
X 
  
  
  
  
X 
X 
STAI (trait Y-2)i 
  
X 
  
  
  
  
X 
X 
EEG Recordingi 
  
X 
X 
X 
X 
  
X 
  
RS Eyes Open/Closed 
(8min)i,j 
  
X 
X 
X 
X 
  
X 
  

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iMotion Recordingi,j 
  
X 
X 
X 
X 
  
X 
  
Semi-structured 
Interview i,k 
  
X 
X 
X 
X 
  
X 
  
Brexanolone infusion 
  
X 
  
  
Continuous pulse 
oximetryl 
  
X 
  
  
Continuous HRV 
collection 
 
X 
 
 
Adverse Events 
  
q2h (while awake) during infusion 
X 
X 
Monitor for excessive 
sedation 
  
q2h (while awake) during infusion 
  
  
Prior/Concomitant 
medicationsm 
X 
X 
  
  
  
  
X 
X 
Nonpharmological 
interventionsn 
X 
X 
  
  
  
  
X 
X 
Exit Interview 
  
  
  
  
  
  
  
X 
Compensation (total 
$750) 
$50  
$100  
$100  
$100  
$100  
  
$100  
$200  
AE= adverse event; ALLO= allopregnanolone; BIMF= Barkin Index of Maternal Functioning; C-SSRS = 
Columbia-Suicide Severity Rating Scale; D= Day; ECG= electrocardiogram; EEG= 
electroencephalogram; EPDS= Edinburgh Postnatal Depression Scale; HAM-D= Hamilton Depression 
Rating Scale; H=Hour; IDS-SR= Inventory of Depression Symptoms Self-Report; Q= every; RRS-10= 
Ruminative Responses Scale-10; RS= Resting State; SCID-5= Structured Clinical Interview for 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; SCS= State Complacency Scale; 
SHAPS= Snaith-Hamilton Pleasure Scale; SMDDS= Symptoms of Major Depressive Disorder Scale; 
STAI= State-Trait Anxiety Inventory; 
* =  All H0 procedures to be completed prior to dosing 
a Full physical examination at screening. Symptom-directed physical examination may be conducted 
at subsequent time point 
b Drug and alcohol testing will occur at screening and Day 1 (predose; H0). Drug testing will be done 
via urine dipstick; alcohol use will be tested via urine dipstick or breath test. 
c Serum pregnancy test at screening and serum or urine pregnancy test at Day 1 (predose; H0) 
d Safety laboratory tests will include hematology and serum chemistry at all scheduled time points. 
Coagulation to be assessed at screening only. Laboratory assessments documented in subject’s 
medical record will be considered valid for screening purposes if done within 30 days of infusion  
e Laboratory tests for hormone parameters are to be completed within ±30 minutes of the scheduled 
timepoint. 
f Performed within ±1 hour of the scheduled time point on Day 4 
g At all time points, vital signs to include oral temperature (°C), respiratory rate, heart rate, and blood 
pressure. Heart rate and blood pressure to be collected in supine position at all scheduled time 
points. Vital signs collected after the initiation of brexanolone will be obtained within ±30 minutes of 
the scheduled time point, unless the subject is asleep between 23:00 h and 06:00 h.  

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h The "Baseline/Screening" C-SSRS form will be completed at Screening. The "Since Last Visit" C-SSRS 
form will be completed at subsequent time points 
i Hour 0 assessments to be completed on Day 1 prior to the start of the infusion. Subsequent 
assessments during the inpatient period to be initiated within ±1hour of the scheduled time point. 
j Performed during EEG recording 
k Performed during iMotion Affective Facial Expression Analysis Software recording 
l Continuous pulse oximetry to occur for the duration of the infusion. Oxygen saturation need only be 
recorded in the event of hypoxia (<92% SpO2), in which case, the event is to be recorded as an AE 
m At screening to include all medications taken within 60 days, all psychotropic medications taken 
within 6 months, and all medications used to treat the current episode of PPD. At visits subsequent to 
screening all changes to any medication should be captured. To be eligible, subjects must be on a 
stable dose of any psychotropic drugs for at least 14 days prior to enrollment. 
n All nonpharmacological interventions (eg, psychosocial, psychotherapeutic) used to treat the 
current episode of PPD should be captured at screening, and all changes should be captured at 
subsequent visit. 
 
7.2. Pre-Screening / Screening (Day -14 to Day 0) 
PRE-SCREENING: will be performed by research coordinator, either by phone or in person, following 
verbal consent from the participant.  Information obtained will include self-reported information 
relevant to inclusion and exclusion criteria (to be confirmed by objective assessment during screening).  
 
SCREENING* (Day –14 to Day 1): 
*Sequence of screening procedures not pre-defined after informed consent and HIPAA authorization are 
obtained. 
 
Informed Consent and HIPAA Authorization 
To be obtained by PI or Study Coordinator prior to any other procedures listed herein. 
 
Demographic/Medical History 
Medical history will be collected via a checklist completed by the subject. Age, race, and ethnic origin 
will be recorded. The diagnosis of PPD will be determined using the SCID-5. Subjects will be specifically 
asked about the following: depression, anxiety, and other diagnoses per DSM-5. Pregnancy history 
(including number of pregnancies, number of births, methods of delivery, and birth complications) and 
PPD episodes will be recorded. 
Vital Signs 
Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure. Heart rate and 
blood pressure to be collected in supine position at all scheduled time points as well as in the standing 
position at specific time points listed in Table 3.  
Weight, Height and Body Mass Index 

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Body weight and height will be measured; body mass index will be programmatically calculated in the 
study record. 
Physical Examination 
Physical examinations of major body systems will be undertaken and recorded.  Major body systems to 
be included in the screening physical examination are head, eye, ear, nose and throat, heart, lungs, 
abdomen, and extremities; as well, cognitive, neurological, and mental status examinations will be 
performed. 
Electrocardiogram 
Twelve-lead ECGs will be performed. The Investigator will record if the ECG is normal; abnormal, not 
clinically significant; or abnormal, clinically significant (CS). If abnormal, details of the abnormality will be 
provided (e.g., first-degree AV block, bundle branch block). The standard intervals (heart rate, PR, QRS, 
QT, and QTcF) will be recorded for all ECGs. 
Laboratory Assessments 
Blood samples will be collected for hematology, serum chemistry, and coagulation. Analytes to be 
evaluated are summarized in Table 4. 
All blood samples, including those taken for eligibility screening, will be sent to the central laboratory. 
Laboratory assessments obtained by outside medical clinic will be considered valid if collected within 30 
days of infusion start date. 
Table 4: Summary of Laboratory Analytes 
Hematology 
complete blood count (red blood cells, white blood cells with 
differentiation and absolute values, hemoglobin, hematocrit, 
reticulocytes, and platelets) 
Coagulation (at Screening only) 
activated partial thromboplastin time, prothrombin time, and 
international normalized ratio 
Biochemistry 
serum electrolytes (sodium, potassium, chloride, bicarbonate or 
total carbon dioxide, calcium, and phosphorus) renal function tests 
(creatinine and blood urea nitrogen); liver function tests (total 
bilirubin, alkaline phosphatase, aspartate aminotransferase, 
alanine aminotransferase, and gamma glutamyl transferase); 
thyroid stimulating hormone; total protein; albumin and glucose 
(fasting or non-fasting) 
All clinical laboratory test results outside the reference range will be interpreted by the Investigator as 
abnormal, not clinically significant; or abnormal, CS. Screening results considered abnormal, and CS at 
the Screening Visit may make the subject ineligible for the study pending review by the Investigator. 
Clinically significant abnormal results after screening will be considered and reported as AEs. 
Pregnancy Test 
All subjects will be tested for pregnancy by serum or urine human chorionic gonadotropin at the during 
screening.  
Drugs of Abuse and Alcohol 

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Urine assessment for select drugs of abuse will be performed (including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates, and phencyclidine). A positive urine drug screen is 
exclusionary, unless deemed by the investigator to reflect a prescribed medication. Alcohol will be 
assessed via breathalyzer or urine dipstick. 
Hormones and Biochemistry 
Blood samples will be collected and may be analyzed for estrogen, progesterone, progesterone 
metabolites, thyroid function (TSH, T4, T3), and markers of inflammation. 
Columbia-Suicide Severity Rating Scale 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale consists of a 
baseline evaluation that assesses the lifetime experience of the subject with suicidal ideation and 
behavior, and a post-baseline evaluation that focuses on suicidality since the last study visit. The C-SSRS 
includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and behavior as well as numeric 
ratings for severity of ideation, if present (from 1 to 5, with 5 being the most severe). 
The “Baseline/Screening” C-SSRS form will be completed at screening (lifetime history and past 24 
months). The “Since Last Visit” C-SSRS form will be completed at all subsequent time points, as outlined 
in Table 1. 
 
Hamilton Depression Rating Scale 
The HAM-D will be administered by PI or Study Coordinator at screening to confirm eligibility based on a 
score of ≥20, which was the threshold used in the original BRX clinical trials. 
 
Structured Clinical Interview for DSM-V Disorders 
The SCID-V will be administered by PI or Study Coordinator at screening to confirm eligibility based on 
diagnosis of Major Depressive Disorder with Peripartum Onset.  The SCID-V will also be used to diagnose 
and record concurrent anxiety disorders, and to rule out current suicide attempt, concurrent alcohol 
and/or substance use disorder, and history of psychosis or mania. 
 
7.3. Enrollment / Baseline (Day 0) 
Refer to Tables 1 and 3 for schedule of procedures at Baseline. Procedures to be performed by the 
following personnel: PI, Study Coordinator, Research Nurse, and/or EEG technician. 
Baseline (Hour 0) 
• 
Subject will be admitted to UNC Hospital on a Monday or Tuesday morning. Prior to 
administration of drug intervention, the subject will undergo the following procedures: 
o Measure subject’s height and weight, record, and submit to IDS to calculate drug dosage  
o Negative drug/alcohol and pregnancy test (if positive, subject will be withdrawn from 
the study) 
o Baseline blood sample to measure circulating allopregnanolone levels 
o Vital signs 
o Review of current concomitant medications and nonpharmacological interventions 
• 
First EEG recording: 

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o EEG cap will be fitted by technician and electrodes filled with gel solution. Impedance 
will be measured to ensure proper adherence to scalp. Cap set-up will take 
approximately 20 minutes. 
o Recording of 8-minute resting state EEG, eyes alternating open and closed at regular 
intervals. 
o Cap will remain on the subject until the end of the Hour 8 session, so as not to disrupt 
the electrode placement over the course of the serial recordings. EEG will be recorded 
for 8-minute sessions at Hours 4 and 8 on Day 1 (not continuously throughout the day). 
• 
Self-Report measures: Electronic versions of the following surveys will be administered: C-SSRS, 
EPDS; STAI (Y1&Y2); SCS; BIMF; IDS-SR; RRS-10; SHAPS. 
• 
Semi-Structured interview & iMotions Recording: Facing a laptop equipped with a standard 
camera and microphone and iMotions Affectiva software, the subject will be administered a 
semi-structured interview about depressive symptoms and affect by study personnel. Interview 
questions will include the HAM-D and additional questions to assess the subject’s experiences of 
enjoyment, guilt, and irritability. The interview and recording will last 10-20 minutes. A memory 
probe task will be completed, in which a subject will be asked to think of a sad event in her life 
and focus on that memory for 30 seconds while the laptop camera records her facial 
expressions. Then they will be asked to rate their emotional experience during that recall. This 
procedure will be repeated with a prompt to recall a happy memory from her life. Subjects will 
then be asked to come up with a word or phrase that can be used to recall each event during 
later recording sessions. 
• 
Heart Rate Variability: Using a non-invasive device, heart rate variability data will be collected 
throughout the infusion. The device will be adhered to the subject’s torso by two electrodes and 
will begin collecting data once it is adhered to the skin. The device will be removed following 
completion of the brexanolone infusion 
 
7.4. Study Visits (Days 1-4) 
Refer to Tables 1 and 3 for schedule of procedures at study visits following Baseline.  Procedures to be 
performed by the following personnel: PI, Study Coordinator, Research Nurse, and/or EEG technician. 
Hour 4 Visit 
• 
Second EEG recording: With the cap in place from the baseline recording, electrode impedance 
will be measured, and electrode gel refilled to ensure proper fit.  A second EEG will be recorded 
during an 8-minute resting state with eyes opened and closed at regular intervals. The cap will 
remain on the subject until the end of the Hour 8 recording but will not be recording 
continuously between sessions. 
• 
Self-Report measures: Electronic versions of the following surveys will be administered: SMDDS, 
EPDS, STAI (Y1), and SCS. 

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• 
Semi-Structure interview & iMotions Recording: Facing a laptop equipped with a standard 
camera and microphone and iMotions Affectiva software, the subject will be administered a 
semi-structured interview about depressive symptoms and affect by study personnel. Interview 
questions will include a modified version of the HAM-D (items suitable for repeated measure 
within the same day) and additional questions to assess the subject’s experiences of enjoyment, 
guilt, and irritability. The interview and recording will last 10-20 minutes. The memory probe 
task will be completed, in which a subject will be told the predetermined word or phrase to cue 
recall of the sad and happy events, while the camera records her facial expressions for 30 
seconds for each event and the subject rates her emotional experience. 
 
Hour 8 Visit 
• 
Third EEG recording: With the cap in place from the Hour 4 recording, electrode impedance will 
be measured, and electrode gel refilled to ensure proper fit. A third EEG will be recorded during 
an 8-minute resting state with eyes opened and closed at regular interviews. Following 
completion of this recording, the cap will be removed.  
• 
Self-Report measures: Electronic versions of the following surveys will be administered: SMDDS, 
EPDS, STAI (Y1), and SCS. 
• 
Semi-Structured interview and iMotions Recording: Facing a laptop equipped with a standard 
camera and microphone and iMotions Affectiva software, the subject will be administered a 
semi-structured interview about depressive symptoms and affect by study personnel. Interview 
questions will include a modified version of the HAM-D (items suitable for repeated measure 
within the same day) and additional questions to assess the subject’s experiences of enjoyment, 
guilt, and irritability. The interview and recording will last 10-20 minutes. The memory probe 
task will be completed, in which a subject will be told the predetermined word or phrase to cue 
recall of the sad and happy events, while the camera records her facial expressions for 30 
seconds for each event and the subject rates her emotional experience. 
 
Hour 28 Visit (4 hours after highest dose of brexanolone begins) 
• 
Blood sample: to measure and document peak circulating levels of allopregnanolone 
• 
Fourth EEG recording: EEG cap will be fitted by technician and electrodes filled with gel solution. 
Impedance will be measured to ensure proper adherence to scalp. Cap set-up will take 
approximately 20 minutes. A fourth EEG will be recorded dur an 8-minute resting state with 
eyes opened and closed at regular intervals. The cap will be removed following this recording. 
• 
Self-Report measures: Electronic versions of the following surveys will be administered: SMDDS, 
EPDS, STAI (Y1), and SCS. 
• 
Semi-Structured interview and iMotions Recording: Facing a laptop equipped with a standard 
camera and microphone and iMotions Affectiva software, the subject will be administered a 
semi-structured interview about depressive symptoms and affect by study personnel. Interview 
questions will include the HAM-D and additional questions to assess the subject’s experiences of 

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enjoyment, guilt, and irritability. The interview and recording will last 10-20 minutes. The 
memory probe task will be completed, in which a subject will be told the predetermined word 
or phrase to cue recall of the sad and happy events, while the camera records her facial 
expressions for 30 seconds for each event and the subject rates her emotional experience. 
Hour 60 
• 
Brexanolone infusion concludes 
 
SAFETY MONITORING DURING INTERVENTION PHASE (Every 2 hours, while awake, during infusion) 
Continuous Pulse Oximetry 
Subjects will be monitored for hypoxia throughout intervention phase using continuous pulse oximetry 
equipped with an alarm. Oxygen saturation need only be recorded in the event of hypoxia, in which 
case, the event is to be recorded as an AE. The infusion will be immediately stopped if pulse oximetry 
reveals hypoxia. After an episode of hypoxia, the infusion should not be resumed. 
Monitoring for Excessive Sedation and Loss of Consciousness 
For the duration of the infusion, subjects must be assessed for excessive sedation and loss of 
consciousness by a healthcare provider every 2 hours during planned, non-sleep periods. If excessive 
sedation or loss of consciousness 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 as clinically 
appropriate (see Section 6.1), and an AE is to be recorded. 
Vital Signs 
Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure. Heart rate and 
blood pressure to be collected in supine position at all scheduled time points as well as in the standing 
position at specific time points listed in Table 3.  
 
7.5. Phone Contact  
Subjects will be provided phone and email contact information for PI and Study Coordinator, should the 
participant have questions or concerns that may be addressed over the phone between in-person visits. 
7.6. Final Visit (Hour 72) 
Refer to Tables 1 and 3 for schedule of procedures at final inpatient visit. Procedures to be performed by 
the following personnel: PI, Study Coordinator, Research Nurse, and/or EEG technician. 
Hour 72 Visit (12 hours after the end of brexanolone infusion) 
• 
Fifth EEG recording: EEG cap will be fitted by technician and electrodes filled with gel solution. 
Impedance will be measured to ensure proper adherence to scalp. Cap set-up will take 
approximately 20 minutes. A fifth and final EEG will be recorded dur an 8-minute resting state 

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with eyes opened and closed at regular intervals. The cap will be removed following this 
recording. 
• 
Self-Report measures: Electronic versions of the following surveys will be administered: C-SSRS, 
EPDS; STAI (Y1&Y2); SCS; BIMF; IDS-SR; RRS-10; SHAPS. 
• 
Semi-Structured interview and iMotions Recording: Facing a laptop equipped with a standard 
camera and microphone and iMotions Affectiva software, the subject will be administered a 
semi-structured interview about depressive symptoms and affect by study personnel. Interview 
questions will include the HAM-D and additional questions to assess the subject’s experiences of 
enjoyment, guilt, and irritability. The interview and recording will last 10-20 minutes. The 
memory probe task will be completed, in which a subject will be told the predetermined word 
or phrase to cue recall of the sad and happy events, while the camera records her facial 
expressions for 30 seconds for each event and the subject rates her emotional experience. 
• 
Blood sample: to measures and document a return to baseline circulating levels of 
allopregnanolone 
• 
Safety Check prior to discharge from UNC Women’s Hospital 
o Vital signs  
o C-SSRS (“since last visit”) 
o Review of concomitant medications and nonpharmacological interventions 
administered during hospital stay 
In the unlikely event that there is imminent risk of suicidal behavior at the time of the final safety check, 
the subject will be withdrawn from the research study, discharged from the Women’s Hospital, and 
referred to the UNC Emergency Department and/or other appropriate inpatient hospitalization. The 
study doctor will provide referrals for continued care, which may include hospitalization, but will not be 
responsible for providing such care following withdrawal from the research study. 
7.7. Follow-Up Contact (Day 30 ± 3) 
Refer to Tables 1 and 3 for schedule of procedures at final inpatient visit. Procedures to be performed by 
PI and Study Coordinator. 
Day 30 Visit 
This follow-up visit will occur in-person, on the phone, or over HIPAA-secured Zoom call, depending on 
the subject’s preference. 
• 
Self-Report Measures: Electronic versions of the following surveys will be administered: EPDS; STAI 
(Y1&Y2); SCS; BIMF; IDS-SR; RRS-10; SHAPS. 
• 
Semi-Structured interview: Study coordinator or PI will administer the HAM-D 
• 
Exit Interview: an informal interview with PI to include items such as: 
o 
What is your mood like today? 
o 
Do you feel the same as, worse than, or better than you did when you left the hospital? (If 
worse than, when did your mood start to decline?) 
o 
Have you had any trouble with your thinking? 

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o 
How stressed do you feel? Have you had any stressful life events since leaving the hospital? 
o 
Do you have any current illnesses? 
o 
How would you describe your experience participating in this research study? 
o 
Do you have any feedback you’d like to share about your experience in this study or with the 
study drug? 
7.8. Premature Discontinuation 
If a subject withdraws or the investigator discontinues subject participation, the subject will be offered 
the optional exit interview session with PI to discuss her experience in the study protocol and 
assessment conducted while enrolled. Safety assessments will be performed on subjects who withdraw 
prematurely following initiation of brexanolone and include the following: clinical lab assessments, vital 
signs, 12-lead ECG, C-SSRS, and evaluation of adverse events. 
In the unlikely event that there is imminent risk of suicidal behavior at the time of the final safety check, 
the subject will be withdrawn from the research study, discharged from the Women’s Hospital, and 
referred to the UNC Emergency Department and/or other appropriate inpatient hospitalization. The 
study doctor will provide referrals for continued care, which may include hospitalization, but will not be 
responsible for providing such care following withdrawal from the research study. 
 
7.9. Collection and Management of Tissue Specimens 
Sample Preparation:  
Not applicable. 
Record Keeping and Monitoring: 
Record keeping and monitoring will be managed by Study Coordinator using secure, encrypted, and 
HIPAA-compliant data management system (REDCap) provided by UNC. Data will be recorded in real 
time and verified by Study Coordinator for accuracy and completion. Study records and data collection 
will be reviewed in regularly scheduled meetings by Study Coordinator and PI. 
Sample Storage and Security: 
Experimental samples are not applicable. 
8. Study Measurements and Evaluations 
 
See Tables 2-4 for descriptions and schedule of study measurements and evaluations. 
 

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8.1. Outcome Measures for Evaluation of Feasibility / Tolerability 
1. Number of successfully analyzed EEG recordings. 
2. Number of subjects completing the entire study protocol through the follow-up phase. 
3. Number of subjects withdrawn from the protocol due to participation burden. 
 
8.2. Outcome Measures for Evaluation of Efficacy 
Not applicable 
 
8.3. Outcome Measures for Evaluation of Safety 
1. Number of subjects withdrawn from the protocol due to adverse events. 
 
8.4. Other Outcomes in the Causal Pathway 
Not applicable 
 
8.5. Baseline Characteristics of the Participants 
1. Age 
2. Race 
3. Ethnicity 
4. History of depression (SCID-5) 
5. Comorbid anxiety disorder(s) (SCID-5) 
6. Concurrent psychotropic medication use 
7. Pregnancy history (# pregnancies, # births, methods of delivery, birth complications, past PPD 
episodes) 
8.6. Variables Representing Treatment 
Not applicable to feasibility study. 
9. Statistical Analysis Plans 
 
9.1. Strategies that Apply to all the Specific Aims 
To help ensure replicability of the research, the analysis plans will be reviewed and finalized prior to 
collection of data (a priori).  As this is a feasibility study, descriptive rather than inferential statistics will 

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be employed. All statistical estimates of population parameters will be tabulated along with 
corresponding confidence intervals (CI) or standard errors (SE). Where appropriate (i.e., in aggregate 
measures where we might observe a change from pre to post infusion, such as nodal flexibility, spectral 
power, and symptom rating scales) means and confidence intervals will be calculated for the differences 
in means pre and post infusion. Point estimates and CI will be used to inform effect size where 
appropriate.  All missing values and drop-outs will be detailed in the database. Descriptive graphical and 
tabular methods will be used to characterize the participants, visualize the data, and examine 
relationships among variables. 
9.2. Description of the Study Cohort 
Descriptive methods to characterize the study cohort will include use of graphical figures, sample 
means, sample standard deviations, minimum, maximum, frequencies, and counts. Parameters 
examined will include age, parity, history of MDD, latency of onset, symptom rating scales (EPDS, HAM-
D, anhedonia, rumination, complacency state scale, side effects), race, ethnicity, concurrent meds, 
concurrent anxiety disorder. For ordinal or ordered metric variables (symptom ratings), we will estimate 
means and confidence intervals. Mood measures will be used to see if the trajectory of treatment 
response is monotonic or whether it shows different trajectories by different symptom domains across 
individuals. 
 
9.3. Aim-Specific Plans 
Plans for Aim 1:  
To evaluate the feasibility of obtaining serial EEG recordings in women with PPD who receive 
inpatient BRX infusion treatment. Measures obtained will include (1) the number of successfully 
completed EEG recordings, with particular interest in the quality of EEG data from hours 4 to 8 (to assess 
the viability of electrode net for extended time period); (2) the number of subjects who complete the 
entire study protocol through the 30-day follow-up period; and (3) the number of subjects withdrawn 
from the protocol due to adverse events and/or participant burden. (Quality of EEG data is determined 
by visual inspection to identify missing or corrupted signal. An automated process will be used to detect 
poor electrodes and flag them for interpolation. An infomax independent component analysis (ICA) will 
be performed to separate plausible neural activity from eye blinks, eye movement, muscle activity, 
heartbeats, and channel noise.) 
 
 
Plans for Exploratory Aims:  
Exploratory Aim 1: To calculate nodal flexibility at baseline, during, and following BRX infusion. As per 
the published work of Co-I Peter Mucha, nodal flexibility is a measure of how often major neural hubs 
change the networks (communities) in which they participate. We will display, in tabular and graphic 
form, the nodal flexibility during the affective probe and resting state across time points in each subject, 
in the group as a whole, and in the groups of those who do and do not respond to BRX. We will calculate 
and display means and confidence intervals (in tables) and means and standard errors (in graphs). Point 

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estimates and confidence intervals will be used to inform subsequent calculations of effect sizes (pre vs 
post differences in nodal flexibility).  Despite the small sample size, we are confident that we will be able 
generate meaningful population estimates, as prior work by Dr. Mucha and colleagues identified very 
robust effect sizes in small samples of subjects at risk for schizophrenia vs controls. This study included 6 
different conditions (before/after stress by N=0,1,2) with 64 electrodes. Data were time-averaged 
flexibilities calculated from multilayer modularity community detection on the temporal network of 
electrodes defined by theta band correlations over 3 second intervals.  Estimating effect size with 
Cohen’s d with the combined s = sqrt(s1^2+s2^2) of whole-brain flexibility (which averages overall 
electrodes equally) yielded d for each of the 6 tests individually ranging from 0.8 to 1.2. Further, with 
concatenated data, a support vector machine (SVM) supervised classification method successfully 
separated the two subject groups with accuracy 91.2% +/- 9.8%. 
Exploratory Aim 2: To characterize rapid brain state configurations (global brain states) and their 
probability density function at baseline, during, and following the BRX infusion. Brain states will be 
determined with two assessment methods. 1) Microstate analysis generates four canonical patterns of 
correlative voltage distribution. Parameters generated include the duration of each microstate (which 
we will examine) and the sequence of its occurrence (which we will not examine in this pilot). We will 
calculate, and display in a table, means and confidence intervals for the duration of each microstate 
during the affective probe and resting state across time points in the group as a whole and in the groups 
of those who do and do not respond to BRX. 2) AMICA is an unsupervised means of decomposing EEG 
signals to generate recurring, quasi-stable patterns of correlated voltage distribution (global brain state). 
The EEG signal is divided into time windows (one second), each of which serves as a correlation matrix. 
The matrices are decomposed with independent component analysis to yield brain states that account 
for much of the variance in the EEG signal, and the probability of appearance of the models generated is 
then displayed as a probability density function (PDF). We will first create this template, and then 
graphically display the template PDF for each EEG session. 
Exploratory Aim 3: To assess the ability of the iMotions Affectiva software to identify differences in 
affective state (determined by symptom ratings). Our previous data demonstrate delayed self-
recognition of change in affective state, which suggests that affect state changes occur and manifest (to 
others) prior to a subject’s labeling (and recognizing) the state change as having occurred. Affectiva is a 
software that permits detection of emotion in facial expression by examining and integrating key 
alterations in facial musculature. The software calculates emotion scores, or the percent time spent in a 
certain affective state, as the weighted average of action units (tiny musculature changes). We will 
display in tabular form the emotion scores during the affective probe in each session across all five time 
points and will plot the percentage of time spent in each affective state against the HAM-D ratings and 
responses to the semi-structured interview. 
Exploratory Aim 4: To assess the amplitude of left frontal midline theta oscillations by performing 
spectral analyses of data collected from five serial EEG recordings.  Fast Fourier transform will be applied 
to each two-second EEG epoch, and the average spectral power will be calculated within the canonical 
theta frequency band from 4 to 7 Hz. To estimate frontal midline theta (FMT), theta power in electrode 
FCz will be log-transformed and then normalized for each participant using the z-transformation across 
the 90 scalp data channels. Point estimates and CI will be presented in tabular form.  

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9.4. Planned Interim Analyses (If Applicable) 
No interim analyses are planned, but electrode impedance will be assessed at each EEG session to 
decrease the likelihood that degraded signal will be obtained. 
 
9.5. Plans for Coping with Withdrawals and Loss-To-Follow-Up 
Given that these are hospitalized inpatients, we anticipate that no more that 20% (two subjects) will fail 
to complete the study through the inpatient phase (5 EEG sessions). As such, we will recruit 12 subjects 
in order to obtain 10 completers. In the event that subject discontinuation exceeds our expected limits, 
we will calculate and display point estimates for as many sessions as the subject completes. Similarly, in 
the event of unusable EEG data, we will calculate and display point estimates for those sessions with 
reliable EEG readings. 
 
9.6. Sample Size Rationale 
The choice of sample size was based on expert opinion, availability of subjects, and funding limit; we 
predict that 10 participants may be sufficient for two purposes: 1) to determine the feasibility of 
obtaining multiple, high quality EEGs during a BRX infusion; and 2) to provide adequate precision for the 
estimators of variance components and other parameters for which information is needed to plan a 
future study. With a conservative expected drop-out rate of 20%, we will enroll 12 subjects to attain 10 
completers. 
 
10. Safety Monitoring and Management 
10.1. 
Risk / Benefit Assessment 
Potential Risks:  
(Per informed consent form) 
 
Serious Risks of BRX:  
BRX can cause serious side effects, including: 
•Excessive sedation and sudden loss of consciousness: BRX may cause subjects to feel very 
sleepy (excessive sedation) or pass out (loss of consciousness). This is different from normal 
sleep where one drifts into sleep naturally and can wake up easily. Sudden loss of consciousness 
(passing out) can occur in some people.  
•Because this could cause serious harm, a medical professional will monitor the subject for 
symptoms of excessive sleepiness every 2 hours while they are awake. 
•During the infusion, the subject will be instructed to tell the healthcare provider right away if 
they feel like they cannot stay awake during the time they are normally awake or if they feel like 
they are going to pass out. The healthcare provider, under direction of the study doctor, may 
lower the dose or stop the infusion until the symptoms go away. 

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•Subjects must have a caregiver or family member with them to help care for the subject’s 
child(ren) during the infusion and to be in the room with the subject if the child(ren) are present 
during the infusion.  
 
The subject will be directed to tell the healthcare provider if they have any of the following 
symptoms while getting BRX: 
 
• 
Feeling more sleepy than usual (they cannot stay awake when they are trying to stay 
awake) 
• 
Having a hard time paying attention 
• 
Having trouble following simple instructions 
• 
Feeling lightheaded or dizzy or like they are going to pass out 
 
If the subjects start to feel the symptoms listed above, they will be instructed to: 
 
• 
Tell the healthcare provider right away  
• 
If they are holding a baby, to put their baby down 
• 
Sit or lie down 
 
The healthcare provider and study doctor may decide to stop the infusion. During clinical trials, 
once BRX was stopped, patients who passed out woke up after a short time. The subject and the 
study doctor will decide whether to continue BRX.  
 
BRX can cause other serious side effects, including: 
 
• 
Increased risk of suicidal thoughts or actions. BRX and other antidepressant medicines 
may increase suicidal thoughts and actions in some people 24 years of age and younger. 
Depression or other serious mental health illnesses are the most important causes of 
suicidal thoughts or actions.  
 
Subjects will be advised to monitor suicidal thoughts and behaviors while outpatient in the 
following manner: 
• 
Pay close attention to any changes, especially sudden changes in mood, behavior, 
thoughts, or feelings, or if they develop suicidal thoughts or actions.  
• 
Tell the healthcare provider or study doctor right away if they have any new or sudden 
changes in mood, behavior, thoughts, or feelings during the study. 
• 
Keep all follow-up visits with the subject’s regular doctor.  
• 
Contact the study or regular doctor if they have concerns about these symptoms after 
the infusion has been completed. 
 
Subjects will be instructed to tell the study or regular doctor right away if they have any of the 
following symptoms, especially if they are new, worse, or worrying the subject: 
• 
attempts to commit suicide and/or harm themself 
• 
new or worse depression 
• 
other unusual changes in behavior or mood 
 

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If the subject has thoughts of harming themself or others, they will be instructed to go to the 
nearest emergency department (ED) or call 911. They can also call the National Suicide 
Prevention Lifeline 24 hours a day at 1-800-273-8255. 
 
If there is imminent risk of suicidal behavior at the time of the final safety check (Hour 72 prior 
to discharge), the subject will be withdrawn from the research study, discharged from the 
Women’s Hospital, and referred to the UNC Emergency Department and/or other appropriate 
inpatient hospitalization. The study doctor will provide referrals for continued care, which may 
include hospitalization, but will not be responsible for providing such care following withdrawal 
from the research study. 
 
Risks Associated with BRX: The following adverse events in the PPD clinical program are 
considered the most common (more than 1 in 20 people and at least twice the rate of placebo) 
side effects of brexanolone: 
• Sedation (drowsiness) /somnolence (sleepiness) 
• Dry mouth 
• Passing out (loss of consciousness) 
• Flushing of the skin or face (flushing/hot flush) 
 
Other side effects that have occurred in ≥ 2% and > placebo include: 
• Faster than normal heart rate (tachycardia) 
• Diarrhea 
• Upset stomach (dyspepsia) 
• Dizziness, feeling faint (presyncope), feeling of losing one’s balance (vertigo) 
• Mouth and throat pain (oropharyngeal pain) 
 
Two cases of accidental overdosage due to malfunction of the infusion pump were reported 
(Meltzer-Brody et al, Lancet, 392:1058-1070, 2018). The result was a transient loss of 
consciousness, with normal consciousness restored within approximately 15 minutes without 
supportive measures with discontinuation of the infusion. After full resolution of symptoms, both 
patients subsequently resumed and completed treatment. 
 
Risks Associated with EEG: No medical risks are associated with the EEG. There may be slight 
discomfort while the electrodes are attached to the scalp, and subjects may not like the smell of 
the paste or the glue remover. The conductive gel sometimes causes mild scalp irritation. The 
risk level for adverse impact is minimal. 
 
Risks Associated with Phlebotomy: There may be some discomfort, pain and bruising at the site 
of needle entry. There is a very small risk of fainting. Infection in the area of the needle insertion 
is rare. The risk level for adverse impact is low. 
 
Psychological Risks: 1) The structured interview to assess current and lifetime psychiatric illness 
may be associated with some psychological distress. Some items in the questionnaires may 

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provoke some negative emotion in some individuals. 2) Additionally, the frequency of 
administration of mood ratings may prove irritating for some subjects. 3) Subjects may worry 
about the confidentiality of data collected, including the video samples for processing of 
emotion in facial expression. Overall, we believe the risk level for adverse impact to be minimal. 
 
Risks to infant children of the subjects as a result of hospitalization and treatment of the mother 
are mitigated by the requirement of alternative childcare arrangements for the duration of the 
mother’s hospitalization, as outlined in the eligibility criteria of this study. During clinical trials, 
women were not permitted to breastfeed while receiving brexanolone and for four days 
following the end of the infusion. Data show that brexanolone is transferred to breastmilk, 
though the relative infant dose is low (1.3%) and many insurance companies state that 
breastmilk cannot be used for feedings, in line with the clinical trial criteria. For this reason, we 
have included the temporary cessation of breastfeeding in the eligibility criteria for this study. 
 
Potential Benefits: 
 
This study is not designed for the benefit of the individuals participating. The primary purpose of 
this study is to answer research questions. Benefits may accrue, however, as follows: 1) subjects 
will gain access to what is currently an expensive, effective, approved treatment for PPD; 2) 
subjects may also benefit by knowing that they are contributing to research aimed at enhancing 
our understanding of PPD. 
 
10.2. 
Assessment of Safety 
Adequacy of Protection against Risks 
Recruitment and Informed Consent: 
Subjects will be recruited from inpatients on the UNC PPIU or from the UNC Women’s Mood 
Disorder Clinic. Subjects enrolled in this study will be individuals for whom BRX treatment is the 
appropriate and recommended course of treatment. Additionally, subjects will be sought from ads 
seeking volunteers for research on the mechanisms of action of BRX in PPD. For recruitment of 
women from rural North Carolina, recruitment will be made via contacts with regional 
gynecologists, county health departments, and through contacts made via the HRSA-sponsored NC 
Maternal Health MATTERS hotline. Through the NC TraCS Data Access and Informatics Core, we can 
identify a cohort of UNC Hospital patients for recruitment. UNC uses the EPIC electronic medical 
record system, which enables communication to potential research participants via email and 
through the MyChart patient interface. This makes communication with many potential research 
participants cost effective and highly efficient, because it will enable potential participants to access 
our online screening tool simply by clicking a link in their email or MyChart electronic message. 
Additionally, we will capitalize on the TraCS Research Recruitment Service’s expertise in enrolling 
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Trained members of the research team will obtain informed consent from each participant as 
follows: 1) the subject will have the protocol described; 2) the research assistant will be thoroughly 
trained in the procedures administered and will, therefore, be able to answer questions that arise. 
However, if there are unanswered questions, the PI will be available to provide further responses to 
participants' questions; 3) the subject will sign the consent form, witnessed by the research 
assistant. A copy of the consent form will be provided to the subject. Subjects will also be consented 
to access their medical records for information related to relevant medical history. Each will sign a 
HIPAA authorization form. 
Risks Associated with BRX: 
The serious risks of BRX include excessive sedation and sudden loss of consciousness. Other risks are 
described in Section 10.1. These risks will be addressed by the progressive, stepped, infusion rate 
(with lower doses early), with the dose held rather than increased if the subject experiences 
dizziness or profound sedation. Patients will be monitored for the duration of the infusion and will 
also have consistent pulse oximetry to monitor and ensure adequate oxygenation. Additionally, 
possible side effects of BRX will be monitored with a Likert scale (1=Absent, 2=Mild, 3=Moderate, 
4=Severe) that we have used in prior studies of BRX. If the participant reports side-effects of 
Moderate to Severe intensity, the study coordinator or research assistant will contact the study 
nurse to determine if adjustment or cessation of the infusion is required. 
The UNC Hospitals Arousal Scale (see Table 5). will be administered every 2 hours during planned, 
non-sleep periods. If a score is equal to 3 on the Arousal Scale, the dose will be reduced by 50% and 
the inpatient prescriber or psychiatric on-call MD will be notified (216-3834). If the score is less than 
or equal to 2 on the Arousal Scale, the infusion will be discontinued, and the MD will be contacted. 
Table 5: UNC Hospitals Arousal Scale 
5 
Fully awake 
4 
Arouses easily 
3 
Arouses with tactile stimuli 
2 
Arouses to vigorous stimuli 
1 
Responsive to painful stimuli 
0 
Unresponsive 
 
Time 
Score 
Time 
Score 
Hour 0: 
 
Hour 32: 
 
Hour 2: 
 
Hour 34: 
 
Hour 4: 
 
Hour 36: 
 
Hour 6: 
 
Hour 38: 
 
Hour 8: 
 
Hour 40: 
 
Hour 10: 
 
Hour 42: 
 
Hour 12: 
 
Hour 44: 
 
Hour 14: 
 
Hour 46: 
 
Hour 16: 
 
Hour 48: 
 

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Hour 18: 
 
Hour 50: 
 
Hour 20: 
 
Hour 52: 
 
Hour 22: 
 
Hour 54: 
 
Hour 24: 
 
Hour 56: 
 
Hour 26: 
 
Hour 58: 
 
Hour 28: 
 
Hour 60: 
 
Hour 30: 
 
 
 
 
Risks Associated with EEG: The possibility of rash will be addressed by monitoring the scalp for signs 
of irritation. 
Risks Associated with phlebotomy: Subjects will be seated during the procedure to decrease the risk 
of fainting, and sterile technique will be employed to decrease the risk, albeit rare, of infection in 
the area of needle insertion. 
Psychological Risks: 1) Structured interview - The risk of discomfort during assessment will be 
minimized via the use of clinically trained interviewers and highly competent and professional staff. 
2) Mood ratings - The risk of irritation with frequency of administration of mood ratings will be 
addressed by carefully informing potential subjects during the informed consent process about this 
possibility. In our experience, frequent mood ratings have not resulted in any subject wishing to 
discontinue the protocol, in part because most subjects in our studies are very dedicated to 
collecting this information. Subjects will also be informed of their right to withdraw from the study 
at any time. 3) Multiple measures will be undertaken to ensure the confidentiality and integrity of 
the data obtained, including clinical information, mood ratings and video samples. All data collected 
for analysis in this study will be de-identified at collection and will stay on encrypted, password-
protected computers. Only the PI and the study coordinator will have access to individually 
identifiable patient information. Each subject will receive a code number, and the code will be 
stored - separately from data collected - in a locked file the Study Coordinator’s locked office. 
Additionally, the video samples will be obtained on a dedicated, encrypted, password protected 
laptop, which will be returned after use and stored in a locked filing cabinet in the Study 
Coordinator’s locked office. 
 
10.3. 
Unanticipated Problems, Adverse Events, Serious Adverse Events 
Unanticipated Problems:  
 
An unanticipated problem is any incident, experience or outcome that meets all three OHRP 
criteria (1) unexpected (in severity, specificity, frequency, or nature), (2) related or possibly 
related to the research, and (3) suggests the research places subjects or others at greater risk 
than previously known or recognized. Only a subset of adverse events will meet criteria for 
unanticipated problems.   
 

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Adverse Event (AE) Definitions:  
 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
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 product whether or not related to the medicinal 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 an AE that occurs after the first administration of any study drug. The term study 
drug includes any Sage Therapeutics investigational product, a comparator, or a placebo 
administered in a clinical trial. 
 
Serious Adverse Events (SAE) Definition:  
 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is immediately life-threatening (Note: The term “life-threatening” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe.) 
• Requires inpatient 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 subject or may require medical intervention to prevent one 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). 
 
Grading the Severity of Adverse Events and Events of ‘Special Interest’:  
 
We will employ the grading scale adopted by the UNC IRB to grade and report AEs. Adverse 
events will be classified according to severity as either mild, moderate, or severe. 
Mild AE: is defined as having no effect on activities of daily living, such as transient 
lightheadedness or sweating with venipuncture; headache; mild skin irritation; or something of 
equal significance that requires no medical intervention and is of marginal clinical relevance. 
Moderate AE: would be associated with temporary (minutes to a few days) disruption in 
activities of daily living, such as temporary loss of consciousness with venipuncture; worsening 
of migraines or headache that require bed rest; an increase in depressive symptoms above 
baseline of more than five points on the HAM-D; dizziness that precludes ambulation; or 
something of equal significance. 
Severe AE: would include any event that acutely threatens the patient’s health, is life-
threatening, or potentially permanently disabling, or an event of equal significance. 
 

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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 10.3. An AE of severe intensity may 
not be considered serious. 
 
The following events are considered AESIs (Adverse Events of Special Interest) and should be 
reported on the AESI form 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 above. 
 
Relatedness Definition:  
 
The Investigator must make the determination of relationship to the study drug for each AE (not 
related or related). The Investigator should decide whether, in their medical judgment, there is a 
reasonable possibility that the event may have been caused by the drug intervention. If no valid 
reason exists for suggesting a relationship, then the AE should be classified as “not related.” If 
there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the investigational product and the occurrence of the AE, then the AE 
should be considered at least “possibly related.” 
 
Not Related: No relationship between the experience and the administration of study drug; 
related to other etiologies such as concomitant medications or subject’s clinical state. 
Possibly Related: A reaction that follows a plausible temporal sequence from administration of 
the study drug and follows a known response pattern to the suspected study drug. The reaction 
might have been produced by the subject’s clinical state or other modes of therapy 
administered to the subject, but this is not known for sure. 
Probably Related: A reaction that follows a plausible temporal sequence from administration of 
the study drug and follows a known response pattern to the suspected study drug. The reaction 
cannot be reasonably explained by the known characteristics of the subject’s clinical state or 
other modes of therapy administered to the subject. 
 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable”, the event will be considered related to the investigational product for 
the purposes of expedited regulatory reporting. AEs will be reported per Sage Therapeutics 
guidelines as “related” or “not related”. 
 
Expectedness Definition: 
 
The PI will be responsible for determining whether an adverse event is expected or unexpected. 
An AE will be considered unexpected if the nature, severity, or frequency or the event is not 
consistent with the risk information previously described for the study intervention. 
 
AE and SAE Assessment, Follow-up Procedures: 
 

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The study coordinator or research nurse will monitor side effects and AEs every two hours when 
the patient is awake and receiving the infusion. Adverse events forms will also be completed 
after each EEG session and will included the assessment of EEG-related AEs, including 
discomfort and irritation from the EEG net and electrode gel. Side effects consistent with 
moderate or severe AEs or that are troublesome to the subject will also be immediately 
reported to the inpatient unit nurses and to Dr. Patterson, who will be responsible for 
determining the next course of action, which might include slowing or discontinuing the infusion 
or discontinuation of the subject from the study. Dr. Patterson will review all protocol data 
monthly, including enrollment and retention statistics and aggregate reports of side effects/AEs. 
As the contact PI, Dr. Girdler will be the one responsible to report all AEs reported as severe to 
the IRB within one week. The study sponsor will be notified of any study modifications or 
suspension imposed by the local IRB in response to an AE. Finally, it should be noted that the 
subjects will be hospitalized on an inpatient unit during the entire administration of BRX and will 
not be discharged until clinically cleared by the physician. 
 
Reporting and Documentation Procedures:  
 
All SAEs (regardless of causality) will be recorded from the signing of the consent form(s) until 
the final visit of the study for that subject. Serious adverse events occurring after the subject’s 
final study visit should be reported to the Sponsor or Sponsor’s designee only if the investigator 
considers the SAE to be related to study drug. 
 
All SAEs must be reported to Sage Therapeutics, or designee, immediately. A written account of 
the SAE must be sent to Sage Therapeutics within 24 hours of the first awareness of the event 
by the Investigator and/or his/her staff to the IQVIA email address: sage.safety@IQVIA.com. 
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 Therapeutics, or designee. 
 
Additional follow-up information, if required or available, must be sent to Sage Therapeutics, or 
designee. within 24 hours of receipt; a follow-up SAE form should be completed and placed with 
the original SAE information and kept with the appropriate section of the study file. 
 
Sage Therapeutics, or designee, is responsible for notifying the relevant regulatory authorities of 
certain events. It is the Principal Investigator’s responsibility to notify the IRB 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 or from other studies with 
brexanolone. Each site is responsible for notifying its ethics committee of these SUSARs.  
 
Participant Notification of New Information:  
Corrective actions to be considered in response to New Safety Information include: 
• 
Modification of inclusion or exclusion criteria to mitigate the newly identified risks. 
• 
Implementation of additional safety monitoring procedures 

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• 
Suspension of enrollment of new participants or halting of study procedures for enrolled 
participants. 
• 
Modification of informed consent documents to include a description of newly 
recognized risks.  
• 
Provision of additional information about newly recognized risks to previously enrolled 
participants. 
10.4. 
Safety Monitoring 
The proposed research is not a phase III clinical trial requiring a Data and Safety Monitoring Board 
(DSMB), and because it represents an unblinded, small scale, single site, clinical trial involving relatively 
low risk interventions in a non-vulnerable population, the NIH policy on Data and Safety Monitoring 
stipulates that, in most such studies, the PI would be expected to perform some monitoring functions as 
part of the general oversight and scientific leadership of the study. This is the strategy that we intend to 
employ in the proposed research according to the data and safety monitoring plans outlined above. 
IQVIA will receive SAE reports but will not be providing any clinical monitoring. 
10.5. 
Study Suspension / Early Termination of the Study 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator, funding agency, and 
regulatory authorities.  If the study is prematurely terminated or suspended, the Principal Investigator 
(PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will 
provide the reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 

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11. Supporting Documentation and Operational 
Considerations 
11.1. 
Regulatory, Ethical, and Study Oversight Considerations 
11.1.1. 
Informed Consent Process 
11.1.1.1. Consent/Assent and Other Informational Documents Provided 
to Participants 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention. 
 
11.1.1.2. Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
 
11.2. 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator, funding agency, and 
regulatory authorities.  If the study is prematurely terminated or suspended, the Principal Investigator 
(PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will 
provide the reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 

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Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met. 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor and IRB. 
 
11.3. 
Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigator, their staff, 
and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study, or the data will be released to any unauthorized third 
party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
stored in the study database. This will not include the participant’s contact or identifying information. 
Rather, individual participants and their research data will be identified by a unique study identification 
number. The study data entry and study management systems used by research staff will be secured 
and password protected. At the end of the study, all study databases will be de-identified and archived 
at the research site. 
 
Certificate of Confidentiality (if applicable) 
Not appliable. 
 

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11.4. 
Future Use of Stored Specimens and Data 
Not applicable. 
11.5. 
Key Roles and Study Governance 
Principal Investigator 
Susan Girdler, Ph.D. 
UNC-Chapel Hill  
2218 Nelson Hwy Ste 1, 27517 
(919) 623-4469 
Susan_girdler@med.unc.edu 
 
11.6. 
Safety Oversight 
The proposed research is not a phase III clinical trial requiring a Data and Safety Monitoring Board 
(DSMB), and because it represents an unblinded, small scale, single site, clinical trial involving relatively 
low risk interventions in a non-vulnerable population, the NIH policy on Data and Safety Monitoring 
stipulates that, in most such studies, the PI would be expected to perform some monitoring functions as 
part of the general oversight and scientific leadership of the study. This is the strategy that we intend to 
employ in the proposed research according to the data and safety monitoring plans outlined above. 
IQVIA will receive SAE reports but will not be providing any clinical monitoring.  
 
11.7. 
Clinical Monitoring 
Not Applicable. 
 
11.8. 
Quality Assurance and Quality Control  
The study team perform internal quality management of study conduct, data and biological specimen 
collection, documentation, and completion. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system, and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the research team for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted, and data are generated, collected, documented (recorded), and reported in compliance with 
the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), Good 
Laboratory Practices (GLP).  
 

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The investigational site will provide direct access to all trial related source data/documents, and reports 
for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities. 
 
11.9. 
Data Handling and Record Keeping 
11.9.1. 
Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
 
Hardcopies of the study visit worksheets will be converted to electronic records provided for use as 
source document worksheets for recording data for each participant enrolled in the study.  Data 
recorded in the electronic case report form (eCRF) derived from source documents should be consistent 
with the data recorded on the source documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into REDCap, a data capture system provided by the 
North Carolina Translational and Clinical Sciences Institute. The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the source 
documents. The study coordinator will be responsible for programming and computations for data 
management in the REDCap database, with support from consultation services through NC TraCS. 
 
11.9.2. 
Study Records Retention 
Study documents should be retained for a minimum of 3 years have elapsed since the formal 
discontinuation of the study intervention. These documents should be retained for a longer period, 
however, if required by local regulations. No records will be destroyed without the written consent of 
the sponsor, if applicable. It is the responsibility of the sponsor to inform the investigator when these 
documents no longer need to be retained. 
11.10. 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
These practices are consistent with ICH GCP:  

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• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
It is the responsibility of the site investigator to use continuous vigilance to identify and record 
deviations in study source documents. Protocol deviations must be sent to the reviewing Institutional 
Review Board (IRB) per their policies. The site investigator is responsible for knowing and adhering to 
the reviewing IRB requirements. Further details about the handling of protocol deviations will be 
included in the MOP. 
11.11. 
Publication and Data Sharing Policy  
Not applicable. 
11.12. 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with the UNC Office of Human Research Ethics has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. 
12. Additional Considerations 
Not applicable 
 
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14. List of Appendices 
 Not applicable.