Clinical trial NCT03228394
Conditions: Depression Depressive Disorder Depression, Postpartum Behavioral Symptoms Mood Disorders Mental Disorders Puerperal Disorders Pregnancy Complications Postpartum PPD
Keywords: Postpartum Care Postpartum Depression
Sponsor: Marinus Pharmaceuticals
Start date: 2017-06-27; Completion date: 2020-05-10
Enrollment: 91 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the Safety, Pharmacokinetics and Efficacy of IV Administration of Ganaxolone in Women with Postpartum Depression

Detailed description:
This study will explore whether ganaxolone is safe and well tolerated in women suffering from PPD. In addition, ganaxolone's efficacy in treating depressive symptoms will be assessed through a set of exploratory analyses. Plasma levels of ganaxolone will be determined through pharmacokinetic analysis. The study results will be used to select a ganaxolone dose and dosing regimen for further development in PPD.

Arms: arm 1: Intravenous arm 2: Intravenous
Interventions: intervention 1: Ganaxolone intervention 2: Placebo
Intervention descriptions: intervention 1: Ganaxolone IV intervention 2: Placebo IV

Protocol documents:
Prot_002.pdf: 
 
  
 
PROTOCOL: 1042-PPD-2002 
TITLE: 
A Phase 2A, Double-blind, Placebo-controlled, Multiple-dose 
Escalation Study to Evaluate Safety, Pharmacokinetics and 
Efficacy of Intravenously and Orally Administered Ganaxolone in 
Women with Postpartum Depression 
DRUG: 
Ganaxolone (CCD 1042:3α-hydroxy-3β-methyl-5α-pregnan-20-one) 
IND: 
106,104 
SPONSOR:  
Marinus Pharmaceuticals, Inc. 
170 N. Radnor Chester Road 
Suite 250 
Radnor, PA 19087  
USA 
 
INITIAL VERSION (V 1.0):  
05 December 2016 
AMENDMENT 1 (V 2.0):  
 
15 February 2017 
AMENDMENT 2 (V 3.0): 
 
10 October 2017 
AMENDMENT 3 (V 4.0): 
 
19 October 2017 
AMENDMENT 4 (V 5.0) 
 
01 February 2018 
AMENDMENT 5 (V 6.0) 
 
28 February 2018 
AMENDMENT 6 (V 7.0) 
 
09 May 2018 
AMENDMENT 7 (V 8.0) 
 
08 Oct 2018 
 
 
 
 
 
 
 
 
This document contains confidential and proprietary information of Marinus and is disclosed pursuant to 
confidentiality and non-disclosure obligations. This information should be used solely for the purposes for which it 
was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Marinus. 


Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2002 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Marious) Approval 
. 
.. 
.. ,, .. 
Signature: 
Date: 
MD 
~.U?t~~! !?ev,el~pm~.!_lt a_Qd ~JJ~a~o_v~giJa!l~ 
Investigator's Acknowledgement 
I have read this protocol for Marinus Study l 042-PPD-2002. 
Version 8.0 / 08 Oct 2018 
Title: A Phase 2A, Double-blind, Placebo-controlled, Multiple-dose Escalation Study to Evaluate 
Safety, Pharmacokinetics and Efficacy oflntravenously and OraJly Administered Ganaxolone in 
Women with Postpartum Depression 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed. 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject ~,1ethical and safety coosiderations and guidelines, and to conduct the study in 
accor~ce with International Conference on Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
\ 
:. ... , .. , 
. ·~.,·... 
'\ 
(please hand print or type) 
,··. 
·, 
Signature: 
Date: 
---------- - - - ---
CONFIDENTIAL 
Page 2 of 104 


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EMERGENCY CONTACT INFORMATION 
 
 
SERIOUS ADVERSE EVENT REPORTING:  
In the event of a serious adverse event (SAE), the investigator must e-mail or fax the Marinus 
Clinical Study Serious Adverse Event Form within 24 hours to Marinus Safety Department at:  
Email: safetyPPD2002@marinuspharma.com  
Fax: 484-679-2138  
SPONSOR CONTACTS:  
Sponsor Operational Contact:  
 BS 
 Clinical Operations 
Telephone:
Email: 
 
 
Sponsor Medical Contact and Medical Monitor:  
 MD 
Telephone:
Email:


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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................................2 
EMERGENCY CONTACT INFORMATION ................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES .........................................................................................................................10 
LIST OF FIGURES .......................................................................................................................10 
LIST OF APPENDICES ................................................................................................................10 
ABBREVIATIONS .......................................................................................................................11 
STUDY SYNOPSIS ......................................................................................................................12 
1.0 
BACKGROUND INFORMATION ..................................................................................16 
1.1 
Postpartum Depression (PPD) .....................................................................................16 
1.2 
Product Background and Clinical Information ............................................................16 
 
Ganaxolone Summary of Safety ........................................................................16 
1.2.1
1.2.1.1 
Summary of Adverse Events .....................................................................17 
1.2.1.2 
Summary of safety of IV ganaxolone ........................................................17 
1.2.1.3 
Other ganaxolone safety information .........................................................18 
1.2.1.4 
Preliminary safety information from the current trial (1042-PPD-2002) ..19 
2.0 
STUDY OBJECTIVES AND PURPOSE .........................................................................20 
2.1 
Rationale for the Study ................................................................................................20 
2.2 
Study Objectives ..........................................................................................................20 
 
Safety Objective ................................................................................................20 
2.2.1
 
Efficacy Objective .............................................................................................20 
2.2.2
 
Pharmacokinetic Objective ................................................................................20 
2.2.3
3.0 
STUDY DESIGN...............................................................................................................21 
3.1 
Study Design and Study Population ............................................................................21 
3.2 
Rationale for Study Design ..........................................................................................21 
3.3 
Blinding Scheme ..........................................................................................................22 
3.4 
Dose Selection .............................................................................................................22 
 
Cohort 1 .............................................................................................................22 
3.4.1
 
Cohort 2 .............................................................................................................23 
3.4.2
 
Cohort 3 .............................................................................................................23 
3.4.3
 
Cohorts 4 and 5 ..................................................................................................23 
3.4.4
 
Cohort 6 .............................................................................................................24 
3.4.5
 
Dose justification in context of previous experience with IV ganaxolone ........24 
3.4.6
3.5 
Justification for Placebo as a Control Group ...............................................................25 
3.6 
Study Duration .............................................................................................................25 
3.7 
Interim Analyses ..........................................................................................................25 


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3.8 
Definition of Completion .............................................................................................26 
3.9 
Sites and Regions .........................................................................................................26 
4.0 
STUDY POPULATION ....................................................................................................27 
4.1 
Inclusion Criteria .........................................................................................................27 
4.2 
Exclusion Criteria ........................................................................................................27 
4.3 
Reproductive Potential .................................................................................................29 
 
Female Contraception ........................................................................................29 
4.3.1
4.4 
Discontinuation of Subjects .........................................................................................29 
 
Subject Withdrawal Criteria ..............................................................................29 
4.4.1
 
Decisions to discontinue the study will be made at each participating site 
4.4.2
by the Principal Investigator.  If feasible, the reason for discontinuation 
should be discussed with the Medical Monitor. Reasons for 
Discontinuation .................................................................................................30 
 
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .............................30 
4.4.3
5.0 
PRIOR AND CONCOMITANT TREATMENT ..............................................................31 
5.1 
Prior Pharmacological Treatment ................................................................................31 
5.2 
Concomitant Pharmacological Treatment....................................................................31 
5.3 
Concomitant Psychological Treatment ........................................................................31 
 
Permitted Treatment ..........................................................................................31 
5.3.1
5.3.1.1 
Permitted Psychological Treatments..........................................................31 
5.3.1.2 
Permitted Antidepressant Treatments ........................................................31 
5.3.1.3 
Other Permitted Treatments .......................................................................32 
 
Prohibited Treatments .......................................................................................32 
5.3.2
6.0 
INVESTIGATIONAL PRODUCT ....................................................................................34 
6.1 
Identity of Investigational Product ...............................................................................34 
 
Ganaxolone IV infusion solution ......................................................................34 
6.1.1
 
Placebo IV control solution ...............................................................................34 
6.1.2
 
Ganaxolone oral capsules ..................................................................................34 
6.1.3
 
Placebo oral capsules .........................................................................................34 
6.1.4
6.2 
Administration of Investigational Product(s) ...............................................................34 
 
Interactive Voice/Web Response System (IxRS) Technology for 
6.2.1
Investigational Product Management ................................................................35 
 
Allocation of Subjects to IP ...............................................................................35 
6.2.2
 
Dosing ...............................................................................................................36 
6.2.3
 
Dose Adjustments ..............................................................................................37 
6.2.4
 
Blinding .............................................................................................................37 
6.2.5
 
Unblinding the Treatment Assignment .............................................................37 
6.2.6
6.3 
Labeling, Packaging, Storage, and Handling ...............................................................38 
 
Labeling .............................................................................................................38 
6.3.1


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Packaging ..........................................................................................................38 
6.3.2
6.3.2.1 
IV ganaxolone ............................................................................................38 
6.3.2.2 
Ganaxolone and placebo oral capsules ......................................................38 
 
Storage ...............................................................................................................39 
6.3.3
6.4 
Drug Accountability.....................................................................................................39 
6.5 
Drug Administration ....................................................................................................40 
 
Administration of IV IP (Cohorts 1-6) ..............................................................40 
6.5.1
 
Administration of oral ganaxolone or placebo capsules (Cohort 6) ..................40 
6.5.2
7.0 
STUDY PROCEDURES ...................................................................................................41 
7.1 
Screening Visit and Screening Period (day -14 to -1) – Cohorts 1-6 ..........................42 
7.2 
Admission to the Unit (Day 0) – Cohorts 1-6 ..............................................................43 
7.3 
Infusion Days (+ 1 to + 4) – Cohorts 1-5 .....................................................................43 
 
Before Infusion (Morning of Day + 1) ..............................................................43 
7.3.1
 
During Infusion (Days +1 to +4) .......................................................................44 
7.3.2
7.4 
Post Discharge Follow-up Period (Days +5 to +30) – Cohorts 1-5 .............................45 
 
First Post-discharge Visit 7 Days After Discharge from the Unit (Day 
7.4.1
+11; visit window) .............................................................................................45 
 
Second Post-discharge Visit 30 Days After Discharge From the Unit 
7.4.2
(Day +34) ..........................................................................................................45 
7.5 
Infusion (Day +1) – Cohort 6 (Screening and Admission visits for Cohort 6 
described in Section 7.1 and 7.2, respectively) ............................................................48 
 
Before Infusion (Morning of Day +1; Baseline) ...............................................48 
7.5.1
 
During the Infusion and Evening of Day +1 (Day +1)......................................48 
7.5.2
 
Day + 2 (Discharge and transition to outpatient treatment) ..............................49 
7.5.3
7.6 
Outpatient treatment phase (Days + 3 – +29) - Cohort 6 .............................................49 
 
Safety phone calls (Days +3, +5, +10 and +13) ................................................49 
7.6.1
 
Visit 3 HAMD Call (Day +4 ±1 day) ................................................................49 
7.6.2
 
Visit 4 (Day +8) .................................................................................................50 
7.6.3
 
Visit 5 HAMD Call (Day +11 ±1 day) ..............................................................50 
7.6.4
 
Visit 6 (Day +15 ±2 days) .................................................................................50 
7.6.5
 
Visit 7 (Day +22 ±3 days) .................................................................................51 
7.6.6
 
Visit 8 (Day +29 ±3 days) .................................................................................51 
7.6.7
7.7 
Post–treatment Follow-up Period (Days +29 to +71) – Cohort 6 ................................52 
 
First Post-treatment Follow-up Visit - 7 days After the Last On-treatment 
7.7.1
Visit (Day +36) ..................................................................................................52 
 
Second Post-treatment Follow-up Visit - 28 days After the Last On-
7.7.2
treatment Visit (Day +57) ..................................................................................53 
 
Third Post-treatment Follow-up Visit - 42 days After the Last On-
7.7.3
treatment Visit (Day +71) ..................................................................................53 


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7.8 
Study Evaluations and Procedures ...............................................................................56 
 
Demographic, Medical History and Other Baseline Characteristics .................56 
7.8.1
 
Informed Consent ..............................................................................................56 
7.8.2
 
Eligibility Review ..............................................................................................56 
7.8.3
 
Prior Medication, Concomitant Medication and Concomitant Therapy 
7.8.4
Review ...............................................................................................................56 
 
Physical Examination ........................................................................................56 
7.8.5
7.8.5.1 
12-lead Electrocardiogram .........................................................................57 
7.8.5.2 
Clinical Safety Laboratory Evaluations .....................................................57 
7.8.5.3 
Adverse Event Collection ..........................................................................58 
7.8.5.4 
Vital Signs ..................................................................................................58 
 
Interviews, Questionnaires and Scales ..............................................................59 
7.8.6
7.8.6.1 
Mini International Neuropsychiatric Interview 7.0 ...................................59 
7.8.6.2 
The Hamilton Depression Rating Scale .....................................................59 
7.8.6.3 
Stanford Sleepiness Scale ..........................................................................59 
7.8.6.4 
Clinical Global Impression-Improvement (CGI-I) and Clinical Global 
Impression-Severity (CGI-S) .................................................................59 
7.8.6.5 
Edinburgh Postnatal Depression Scale (EPDS) .........................................60 
7.8.6.6 
Spielberg Trait-State Anxiety Inventory, 6 item version ...........................60 
7.8.6.7 
SAFER interview .......................................................................................60 
 
Columbia Suicide Severity Rating Scale (CSSRS) ...........................................60 
7.8.7
 
Pharmacokinetic Sampling ................................................................................60 
7.8.8
 
Neurosteroid levels ............................................................................................60 
7.8.9
 
Volume of Blood to Be Drawn from Each Subject ...........................................61 
7.8.10
8.0 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ...............................62 
8.1 
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events ...........................................................................................................................62 
 
Severity Categorization .....................................................................................62 
8.1.1
 
Causality Categorization ...................................................................................63 
8.1.2
 
Variables ............................................................................................................63 
8.1.3
 
Symptoms of the Disease Under Study .............................................................63 
8.1.4
 
Adverse Events Based on Clinical Laboratory and Other Safety 
8.1.5
Evaluations ........................................................................................................63 
 
Adverse Events Based on Signs and Symptoms ...............................................64 
8.1.6
 
Pregnancy ..........................................................................................................64 
8.1.7
8.2 
Serious Adverse Event Procedures ..............................................................................64 
 
Reference Safety Information ...........................................................................64 
8.2.1
 
Reporting Procedures ........................................................................................64 
8.2.2
 
Serious Adverse Event Definition .....................................................................65 
8.2.3


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Serious Adverse Event Collection Time Frame ................................................65 
8.2.4
 
Serious Adverse Event Onset and Resolution Dates .........................................66 
8.2.5
 
Fatal Outcome ...................................................................................................66 
8.2.6
 
Regulatory Agency, Institutional Review Board, Ethics Committee, and 
8.2.7
Site Reporting ....................................................................................................66 
9.0 
DATA MANAGEMENT AND STATISTICAL METHODS ..........................................67 
9.1 
Data Collection ............................................................................................................67 
9.2 
Clinical Data Management ..........................................................................................67 
9.3 
Data Handling Considerations .....................................................................................67 
9.4 
Handling of Missing and Incomplete Data ..................................................................67 
9.5 
Statistical Analysis Plan ...............................................................................................68 
 
Planned Interim Analysis ..................................................................................68 
9.5.1
 
Justification for Sample Size .............................................................................68 
9.5.2
 
Study Population ...............................................................................................69 
9.5.3
 
Demographic and Baseline Characteristics .......................................................69 
9.5.4
 
Investigational Medicinal Product .....................................................................69 
9.5.5
 
Concomitant Medication ...................................................................................70 
9.5.6
 
Safety Analyses .................................................................................................70 
9.5.7
 
Efficacy Analyses ..............................................................................................70 
9.5.8
9.5.8.1 
Primary Endpoint .......................................................................................70 
9.5.8.2 
Secondary Endpoints .................................................................................70 
 
 
9.5.8.4 
Statistical Methods .....................................................................................71 
 
Other Analyses ..................................................................................................71 
9.5.9
 
Pharmacokinetic Analyses ................................................................................71 
9.5.10
10.0 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ......................................72 
10.1 
Sponsor’s Responsibilities ...........................................................................................72 
 
Good Clinical Practice Compliance ..................................................................72 
10.1.1
 
Public Posting of Study Information .................................................................72 
10.1.2
 
Study Suspension, Termination, and Completion .............................................72 
10.1.3
10.2 
Investigator’s Responsibilities .....................................................................................73 
 
Good Clinical Practice Compliance ..................................................................73 
10.2.1
 
Protocol Adherence and Investigator Agreement..............................................73 
10.2.2
 
Documentation and Retention of Records .........................................................73 
10.2.3
10.2.3.1 
Case Report Forms .....................................................................................73 
10.2.3.2 
Recording, Access, and Retention of Source Data and Study 
Documents ..............................................................................................74 
10.2.3.3 
Audit/Inspection .........................................................................................74 
10.2.3.4 
Financial Disclosure ...................................................................................74 


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10.3 
Ethical Considerations .................................................................................................75 
 
Informed Consent ..............................................................................................75 
10.3.1
 
Institutional Review Board or Ethics Committee ..............................................75 
10.3.2
10.4 
Privacy and Confidentiality .........................................................................................75 
10.5 
Study Results and Publication Policy ..........................................................................76 
11.0 
REFERENCES ..................................................................................................................77 
12.0 
APPENDICES ...................................................................................................................79 
 
 
 


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LIST OF TABLES 
Table 1. Schedule of Assessments – Cohorts 1-5 ....................................................................46 
Table 2. Schedule of Assessments – Cohort 6 .........................................................................54 
Table 3. Volume of Blood to Be Drawn from Each Subject (Cohorts 1-5) .............................61 
Table 4. Volume of Blood to Be Drawn from Each Subject (Cohort 6) .................................61 
 
LIST OF FIGURES 
Figure 1: 
Study Design Flow Chart ..............................................................................42 
 
LIST OF APPENDICES 
Appendix 1. Prohibited Strong CYP3A4 Inhibitors and Inducers ...........................................79 
Appendix 2. Scales and Assessments ......................................................................................80 
Appendix 3. Protocol History and Summary of Changes ........................................................80 
 
 


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ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine Aminotransferase 
AST 
aspartate Aminotransferase 
BP 
blood pressure 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
Cmax 
peak plasma concentration 
CRF 
case report form 
CRO 
contract research organization 
CSSRS 
Columbia Suicide Severity Rating Scale 
CTNI 
Massachusetts General Hospital Clinical Trials Network and Institute  
ECG 
electrocardiogram 
EPDS 
Edinburgh Postnatal Depression Scale 
FDA 
Food and Drug Administration 
GABA 
gamma Aminobutyric Acid 
GCP 
Good Clinical Practice 
HAMD17 
Hamilton Depression Rating Scale 17-item version 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IV 
Intravenous 
PK 
Pharmacokinetic 
PO 
Orally 
PPD 
Postpartum Depression 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SNRIs 
serotonin and norepinephrine reuptake inhibitors 
SRC 
safety review committee 
SSRIs 
selective serotonin reuptake inhibitors 
SSS 
Stanford Sleepiness Scale 
STAI 
Spielberger State-Trait Anxiety Inventory 


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STUDY SYNOPSIS 
Protocol number:  
1042-PPD-2002 
Drug:  
Ganaxolone IV, Ganaxolone Oral Capsules 
Title of the study: A Phase 2A, Double-blind, Placebo-controlled, Multiple-dose Escalation Study to Evaluate 
Safety, Pharmacokinetics and Efficacy of Intravenously and Orally Administered Ganaxolone in Women with 
Postpartum Depression  
Number of subjects (total and for each treatment arm): This is a Phase 2A, double-blind, placebo-
controlled, multiple-dose escalation study consisting of up to 6 cohorts (Cohorts 1-6). Approximately 200 
women with PPD 18 to 45 years of age will be screened to randomize up to 100 subjects across up to 6 cohorts. 
Approximately 10-30 subjects will be randomized into each cohort.  Randomized subjects will receive the 
investigational product (IP), ganaxolone or matching placebo in a 1:1 ratio.  In Cohorts 1-5 the IP will be 
administered intravenously over 60 hours. In Cohort 6 the dosing is initiated with a 6-hour intravenous (IV) 
infusion followed by oral dosing for 28 days plus 3-day taper.  
Site(s) and Region(s): Approximately 20 investigative sites in the United States  
Study period (planned): 
March 2017 to June 2019 
Clinical phase:  
Phase 2A 
 
Objectives: 
Safety objective: To assess the safety and tolerability of escalating doses of intravenously and orally 
administered ganaxolone as determined by adverse events and changes from baseline in laboratory measures, 
vital signs, Columbia Suicide Severity Rating Scale (CSSRS), electrocardiogram (ECG), Stanford Sleepiness 
Scale (SSS), and physical examination.  
Efficacy objective: To explore the efficacy of escalating doses of intravenously and orally administered 
ganaxolone in the treatment of PPD with the Hamilton Depression Rating Scale 17-item version (HAMD17), 
Edinburgh Postnatal Depression Scale (EPDS), Spielberger State-Trait Anxiety Inventory 6-item version 
(STAI6) and Clinical Global Impression-Improvement (CGI-I) scale.  
Pharmacokinetic objective:  To collect samples of blood for pharmacokinetic analysis after administration of 
IV and oral ganaxolone. 
Rationale: Rapidly declining plasma levels of allopregnanolone and other neurosteroids, after childbirth are 
thought to be linked to triggering depression in women who are vulnerable to develop this condition.  
Ganaxolone, a synthetic analog of allopregnanolone, may provide benefit to these women.  
Investigational product, dose, and mode of administration: Ganaxolone IV or IV placebo.   
Cohort 1: ganaxolone is infused at a rate of 4 mg/h (16 ml/h of ganaxolone 0.25 mg/ml solution) for 48 hours 
and then at a rate of 2 mg/h for the next 12 hours. The infusion is stopped at 60 hours. 
Cohort 2: ganaxolone is infused at a rate of 8 mg/h (16 ml/h of ganaxolone 0.5 mg/ml solution) for 48 hours 
and then at a rate of 4 mg/h for the next 12 hours. The infusion is stopped at 60 hours. 
Cohort 3: Twelve mg bolus of ganaxolone is initially given over 2 minutes followed by ganaxolone infusion at 
a rate of 12 mg/h (24 ml/h of ganaxolone 0.5 mg/ml solution) for 48 hours. The rate is then reduced to 6 mg/h 
for the next 12 hours. The infusion is stopped at 60 hours.  
Cohorts 4-5: Cohorts 4 and 5 are optional and will be utilized only if further dose exploration is warranted. 
Ganaxolone infusion rate will be decided based on the results of Cohorts 1-3. However, the initial bolus dose 
will not exceed 16 mg over 2 minutes and the maximum infusion rate will not exceed 16 mg/h.  
Cohort 6: In this cohort dosing is initiated with ganaxolone infusion at a rate of 20 mg/h (40 ml/h of 
ganaxolone 0.5 mg/ml solution or matching placebo) for 6 hours followed by ganaxolone 900 mg or matching 
placebo capsules given orally at dinner time for 28 days followed by a 3-day taper.   
 


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Methodology:  
The screening period for each cohort will be up to 2 weeks.  
For Cohorts 1-5, following the screening period, there will be a 4-day inpatient treatment phase at a hospital or 
clinical pharmacology unit during which a 60-hour infusion of ganaxolone or placebo will be administered.  The 
subjects will be discharged from the unit on the morning of Day 4. There will be 2 safety follow-up visits after 
inpatient discharge on post-treatment Weeks 1 and 4.  
In Cohort 6, following the screening period, there will be a 1-day inpatient treatment phase at a hospital or 
clinical pharmacology unit. The study drug will be administered intravenously over a period of 6 hours followed 
by administration of the first dose of the oral study drug (ganaxolone 900 mg or matching placebo) at dinner 
time. The subjects will be discharged home the next morning (Day 2), and oral dosing will be continued at home 
for 27 days (Days 2-28 at dinner time daily followed by a 3-day taper. There will be 3 safety follow-up visits 
after the last dose on post-treatment Weeks 1, 4, and 6.  
Inclusion Criteria:  
1. An understanding of and ability, and willingness to fully comply with study procedures and restrictions.  
2. Ability to voluntarily provide written, signed, and dated informed consent as applicable to participate in the 
study. 
3. Female aged 18 to 45 years, inclusive, at the Screening Visit 
4. Experiencing a Major Depressive Episode, which started between the start of the third trimester and 
4 weeks following delivery.  The Major Depressive Episode must be diagnosed according to MINI 7.0 
interview  
5. Given birth in the last 12 months 
6. HAMD17 score of ≥ 26 at screening (HAMD17 must be ≥ 22 per CTNI rating at Admission to the Unit on 
Day 0) 
7. The diagnosis of PPD and severity of depression must be supported by the SAFER interview 
8. Must agree to stop breastfeeding from start of study treatment to 45 days after end of study treatment 
9. Must agree to use acceptable contraceptive methods during the study period 
 
Exclusion Criteria 
1. Current or past history of any psychotic illness, including Major Depressive Episode with psychotic 
features 
2. Any psychiatric condition that, in the investigator’s judgment, is considered clinically significant and could 
affect subject safety or study outcome including eating disorder, panic disorder, obsessive-compulsive 
disorder, or post-traumatic stress disorder   
3. History of suicide attempt within the past 3 years (actual attempt, interrupted or aborted attempt, 
preparatory acts or behavior) 
4. Active suicidal ideation (e.g. answering “yes” to questions 4 or 5 in the CSSRS suicidal ideation section) 
5. History of severe bipolar I disorder (e.g. hospitalization due to the illness, lifetime history of psychosis or 
suicide attempt)   
6. Uncontrolled seizure disorder  
7. Current or history within the past 3 years of any substance use disorder, with the exception of tobacco or 
caffeine 


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8. Positive drug screen for any illicit substances or prescription drugs at screening or randomization.  If the 
drug screen is positive for a prescription drug that has the potential to be abused (e.g. amphetamine, 
benzodiazepine), legitimate use of the drug must be verified by the subject’s providing the current pill 
bottle, prescription for the drug, or a note from the prescribing physician.  Cannabis use is prohibited, and 
subjects with positive drug screen for cannabis are excluded. However, occasional users of cannabis may be 
re-tested if the subject is willing to refrain from consuming cannabis-based products during the trial. If the 
re-test sample is negative at screening the subject can be considered eligible. If the re-test sample is positive 
for cannabis the investigator may ask for determination of the urine or blood levels of ∆9-
tetrahydrocannabinol (THC), and its metabolites 11-hydroxy-THC and, 9-carboxy-THC. If the levels of 
THC are not detectable the subject may be considered eligible for the trial.   
9. Current or relevant history of any medical disorder that may require treatment or make the subject unlikely 
to be able to complete the study, or any condition that presents undue risk from the investigational product 
or procedure point of view 
10. Any clinically significant abnormality identified on physical examination, ECG or laboratory tests that in 
the judgment of the investigator would compromise the subject’s safety or successful participation in the 
clinical study 
11. Subject has untreated or uncontrolled hypothyroidism  
12. Known or suspected intolerance or hypersensitivity to the investigational product(s) or allopregnanolone, or 
any of the stated ingredients 
13. Use of another investigational product within 60 days prior to the first dose of investigational product  
14. Has alanine transferase (ALT) or aspartate transferase (AST) greater than 2.5 times upper limit of normal or 
total bilirubin greater than 1.5 times upper limit of normal (unless elevation is due to Gilbert’s syndrome) 
15. Screening QTcF > 470 msec 
16. Unwillingness to withhold grapefruit, Seville oranges, star fruit, or citrus derived products from diet 
between screening and discharge from the study unit  
17. Receiving concomitant treatment with strong CYP3A4 inducers or strong CYP3A4 inhibitors 
18. Body mass index (BMI) ≥ 40 
19. Subject is pregnant 
20. Subject is using prohibited medications as specified in Section 5.3.2 
Maximum duration of subject involvement in the study: Approximately 12 weeks 
Safety: Adverse events, vital signs, Columbia Suicide Severity Rating Scale (CSSRS), electrocardiogram 
(ECG), Stanford Sleepiness Scale (SSS), and physical examination.  
 
Efficacy: Hamilton Depression Rating Scale (HAMD17), Edinburgh Postnatal Depression Scale (EPDS), 
Spielberger State-Trait Anxiety Inventory six item version (STAI6) and Clinical Global 
Impression-Improvement (CGI-I) scale. 
 
Pharmacokinetics: Six samples will be collected for pharmacokinetic analysis in Cohorts 1-5 and 12 samples 
in Cohort 6.  Maximal plasma concentration (Cmax), concentration at steady-state (Css, determined by the mean 
concentrations once steady-state is achieved by visual inspection), AUC0-24 (calculated as Css multiplied by 24 
hours) will be estimated. Seven samples will be collected during the inpatient phase of Cohort 6 (including 6 
samples on Day 1) followed by collection of 5 samples during the outpatient phase during the study visits for a 
total of 12 samples in Cohort 6.  
 
Statistical Methods:  
Sample size: No formal hypothesis testing will be performed, and the sample size is not based on statistical 
power considerations.  A population of about 6 to 10 subjects per dose is commonly tested in studies which aim 
to establish a tolerability range for a new compound or a new formulation. 


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Analysis Populations: The Screened Set will consist of all subjects who have signed an informed consent. The 
Randomized Set will consist of subjects randomized. The Safety Set will consist of all subjects who received IP. 
The modified Intent to Treat Set (mITT) will consist of all subjects in the Safety Set who have at least 1 post-
baseline efficacy assessment.  The Per-Protocol Set will consist of all subjects in the mITT set who do not have 
major protocol deviations that may affect key efficacy endpoints. The Infusion Completer Set will consist of all 
subjects in the Safety Set who completed the 60-hour infusion in Cohorts 1-5, and who completed the 6-hour 
infusion in Cohort 6. The Completer Set will consist of all subjects in the Safety Set who completed the 60-hour 
infusion and attended the final safety follow-up visit in Cohorts 1-5, and who completed the 6-hour infusion and 
oral dosing period and attended all outpatient visits including the safety follow-up visits in Cohort 6. 
Analysis Methods: Data analyses will primarily be descriptive. Continuous variables will be summarized as 
numbers of observations, means, measures of variance (e.g., standard deviation), and percentiles (e.g., median, 
minimum, maximum).  Categorical variables will be summarized as numbers of observations and percentages. 
Results from exploratory statistical analyses of efficacy endpoints may be presented but only to aid in 
interpretation.   
 
 


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1.0 
BACKGROUND INFORMATION 
1.1 
Postpartum Depression (PPD) 
Postpartum depression (PPD) is a mood disorder that occurs in about 7% of women following 
the birth of a child.4  Common symptoms include feelings of extreme sadness, hopelessness, 
suicidal ideation, anxiety, and fatigue, which mirror those of a major depressive episode with the 
additional criteria that the onset of depression occurs within 4 weeks of childbirth.  PPD can 
affect a mother’s ability to care for her child and may negatively affect a child’s cognitive 
development.8  
Rapid changes in the levels of endogenous neurosteroids during pregnancy are thought to be 
related to the development of PPD.  Plasma levels of allopregnanolone, which is a metabolite of 
progesterone and an endogenous gamma-aminobutyric acid (GABA) modulator, are known to 
increase throughout pregnancy and then precipitously drop after delivery.10, 5  It is thought that 
these rapid hormonal changes are linked to triggering depression in women who are vulnerable 
to develop this condition.  Serotonin Selective Reuptake Inhibitors (SSRIs) are known to 
increase allopregnanolone, and it has been suggested that this mechanism could explain why 
SSRIs have shown therapeutic effect in the treatment of PPD.6  However, there have been a 
limited number of placebo-controlled randomized clinical trials testing the efficacy of SSRIs, or 
any other medication, in the treatment of PPD.15, 6 
Data were recently published that demonstrated that a continuous infusion of allopregnanolone 
rapidly alleviates symptoms of depression in women with PPD.7  In this open-label study, 4 
women with severe PPD received a 60-hour infusion of allopregnanolone.  The mean Hamilton 
Depression Rating Scale for Depression (HAMD) before the infusion was 26.5 indicating that 
the women were severely depressed.  Mean HAMD total score showed robust reductions even at 
the earliest time point measured (Mean HAMD 4.8 at Hour 12) and remained substantially lower 
through the end of infusion (Mean HAMD 3.3 at Hour 24, 1.8 at Hour 36, 2.3 at Hour 48, and 
1.8 at Hour 60).  Other end points showed similar improvements.  
1.2 
Product Background and Clinical Information 
Ganaxolone is the 3β-methylated synthetic analog of the progesterone metabolite 
allopregnanolone.  Allopregnanolone exhibits potent anxiolytic, antidepressant, antiepileptic, and 
sedative activity by virtue of its GABAA receptor modulating properties.  As with 
allopregnanolone, ganaxolone potentiation of the GABAA receptor occurs at a site distinct from 
the benzodiazepine site.  However, unlike allopregnanolone, ganaxolone cannot be converted to 
a hormonally active steroid.1  Ganaxolone is currently under study for treatment of chronic 
neurologic and neuropsychiatric conditions such as epilepsy and behavioral problems associated 
with Fragile X Syndrome.  
 
Ganaxolone Summary of Safety  
1.2.1
As of October 10, 2017, 1557 unique subjects have received ganaxolone ranging in duration 
from 1 day to more than 2 years using doses from 50 to 2000 mg/day in completed studies. Of 
these subjects, 1527 subjects received oral ganaxolone and 30 subjects received IV ganaxolone. 


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In 20 completed Phase 1 studies, 319 healthy subjects received GNX oral doses of 50 to 2,000 
mg/day for periods of up to 2 weeks or IV bolus doses ranging from 10 to 30 mg over durations 
of 2 minutes to 1 hour or a bolus dose of 6 mg over 5 minutes followed with a continuous 
infusion of 20 mg per hour for 4 hours.  
 
In the 20 completed Phase 2/3 clinical studies, 1238 unique subjects have received oral 
ganaxolone in studies of adult subjects with epilepsy, pediatric subjects with seizure disorders, 
pediatric subjects with FXS, adult subjects with PTSD, and adult subjects with migraine.  
 
1.2.1.1 
Summary of Adverse Events 
In clinical trials of ganaxolone, adverse events (AEs) related to the GABAergic mechanism of 
action in the CNS were reported more commonly in subjects receiving ganaxolone than placebo. 
In general, the frequency of these events has been dose related. Most of these effects were 
reported as mild or moderate and were reversible after dose decrease or drug discontinuation.   
In all completed placebo-controlled studies, 61.7% (613/993) of subjects who received 
ganaxolone and 51.8% (330/637) of subjects who received placebo experienced at least 1 
treatment emergent adverse event (TEAE). In these studies, the most frequently reported (i.e., in 
≥5% of subjects) TEAEs in ganaxolone-treated subjects were CNS-related: somnolence (22.0% 
ganaxolone, 6.4% placebo), dizziness (13.0% ganaxolone, 4.2% placebo), fatigue (9.7% 
ganaxolone, 5.2% placebo), and headache (5.5% ganaxolone, 7.7% placebo). All of these events, 
except headache, occurred more frequently in ganaxolone-treated subjects than placebo subjects.  
In placebo-controlled studies adverse event of rash led to discontinuations in GNX-treated 
subjects in 6 cases (6/993; 0.6%) compared to no cases (0/637; 0%) in placebo-treated subjects. 
One of the events was also reported as an SAE. In addition, in the ongoing study 1042-0900, an 
additional event of rash was reported as an SAE. Both SAEs resolved after discontinuation of the 
study drug. There have been no cases of Stevens-Johnson syndrome, toxic epidermal necrolysis 
or any other clinically important rashes reported in the clinical development program. Marinus 
considers rash as a potential rare adverse event associated with GNX.  
 
1.2.1.2 
Summary of safety of IV ganaxolone  
Preclinical studies and a study in 36 healthy volunteers assessing safety, pharmacokinetics and 
pharmacodynamics of intravenously administered ganaxolone has been completed.  Preclinical 
toxicity studies showed intravenous (IV) ganaxolone to be generally safe and adverse events 
consistent with expected dose-related sedation.  In rats continuously dosed with IV ganaxolone 
for 14 days no ganaxolone-related changes were noted in clinical pathology parameters or 
histopathology examination.  There was no evidence of local irritation when ganaxolone was 
given intra- or perivenously in preclinical studies.  Furthermore, IV ganaxolone did not cause 
hemolysis and was compatible with human plasma.  
The safety, pharmacokinetics and pharmacodynamics of IV ganaxolone were investigated in 
healthy 36 volunteers in Study 1042-0405, in which ganaxolone was administered as a bolus 
dosing (Stage 1) or as a bolus dose followed by a continuous infusion (Stage 2).  Ten of the 
36 subjects enrolled were women.  


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• Stage 1 enrolled and dosed subjects in 4 cohorts (A-D): 6 subjects in Cohort A (10 mg 
ganaxolone IV bolus in 3 subjects and 30 mg ganaxolone bolus in 3 subjects over 
5-minutes), 8 subjects in Cohort B (20 mg ganaxolone bolus over 2-minutes), 8 subjects 
in Cohort C (30 mg ganaxolone bolus over 1-hour) and 8 subjects in Cohort D (10 mg 
ganaxolone bolus over 1-hour). Cohorts B, C and D included 2 placebo subjects in each 
cohort.  
• Stage 2 of the study dosed a total of 6 subjects with a 6 mg bolus followed by a 4-hour 
infusion at 20 mg/h.  Ten of the 36 subjects enrolled in Study 1042-0405 were women.  
A total of 35 of the 36 subjects enrolled in Stages 1 and 2 completed the study as planned while 
1 subject withdrew their consent.  
Six subjects reported treatment emergent AEs in Stage 1 and 2.  No single AE was seen twice. 
Only one event, headache, was considered by the investigator to be related to ganaxolone. None 
of the treatment emergent AEs was serious, and all were of mild intensity. No clinically 
meaningful mean changes in laboratory test results, vital signs, or ECG parameters occurred in 
any cohort.  
Pharmacokinetic data from Study 1042-0405 showed that a bolus infusion of 30 mg ganaxolone 
over 5-minutes led to peak concentration levels (Cmax) of > 1,000 ng/ml with no safety concerns 
(except sedation). Infusion of 30 mg/h for 1 hour, 20 mg over 2 minutes and 20 mg/h for 4 hours 
led to peak concentrations of 258 ng/mL, 441 ng/mL and 215 ng/mL, respectively, again without 
any safety concerns. This is consistent with findings from previous studies with the oral 
formulation of ganaxolone, in which Cmax levels of up to 200 to 300 ng/mL were commonly 
observed and were not associated with major safety findings or toxicity (apart from sedation-
related effects).   
1.2.1.3 
Other ganaxolone safety information  
Ganaxolone is metabolized by CYP3A4/5, and in vitro data and human PK data from subjects 
taking strong CYP inducers (carbamazepine and phenytoin) has shown increased ganaxolone 
clearance with approximately a 45% lowering in overall ganaxolone levels and exposure. 
Marinus considers interaction with strong inducers and inhibitors as a potential risk associated 
with the use of ganaxolone.  
 
In the ganaxolone development program overall, no clinically significant trends in 
electrocardiogram (ECG) intervals, vital signs, or physical or neurological examinations have 
been noted, and no mean changes from baseline in clinical laboratory results have been 
identified.  In the completed placebo-controlled Phase 1, 2, and 3studies, 0.32% of subjects who 
received GNX and 0.46% of subjects who received placebo developed elevated LFTs during the 
study (>3x ULN AST and/or ALT). A subject participating in the ganaxolone pediatric epilepsy 
study 1042-0900 developed liver failure, which was not considered to be related to ganaxolone. 
The subject was diagnosed with short bowel syndrome, liver steatosis and IgG-cholangitis, 
which were considered to be the causal factors for the subject’s liver failure. There have been no 
other cases of Hy’s Law or liver failure in the ganaxolone development program.  
 


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It is not known if ganaxolone is excreted to breast milk. After cessation of the dosing, plasma 
ganaxolone levels are expected to drop rapidly, but it is possible that low sub-therapeutic levels 
persist for several days as ganaxolone is slowly released from tissues. Therefore, a washout 
period of 45 days is required following cessation of ganaxolone treatment before breast-feeding.  
Previous toxicology studies in animals focusing on prenatal and neonatal development have not 
demonstrated toxicities associated with ganaxolone. Ganaxolone has been administered to 
infants with severe forms of epilepsy as early as 4 months of age.  
In clinical trials involving administration of ganaxolone over several weeks, the study drug has 
been tapered off over a 1 to 2-week period.  There have been no reports of withdrawal symptoms 
emerging after cessation of ganaxolone.  
 
1.2.1.4 
Preliminary safety information from the current trial (1042-PPD-2002) 
Cohort 1 
Dosing for the Cohort 1 of this study has been completed. In this cohort ganaxolone was infused 
at a rate of 4 mg/h for 48 hours after which the rate was lowered to 2 mg/h for the next 12 hours. 
The infusion was stopped at 60 hours. 
. There were 
no serious adverse events or adverse events leading to discontinuation, and no subject needed a 
dose adjustment. The DRC deemed the Cohort 1 dose to be well-tolerated and recommended 
increasing the dose from 4 mg/h (Cohort 1) to 8 mg/h for Cohort 2.  
Cohort 2 
 
 
. In this cohort 
ganaxolone was infused at a rate of 8 mg/h for 48 hours after which the rate was lowered to 4 
mg/h for the next 12 hours. The infusion was stopped at 60 hours. There have been no serious 
adverse events or adverse events leading to discontinuation, and no subject has needed a dose 
adjustment. The DRC has evaluated preliminary adverse event data from these 12 subjects and 
deemed this dosing regimen to be well-tolerated. The DRC has recommended increasing the 
dose to 12 mg/h for Cohort 3.  
 
Cohort 3 
 
 
 and respective data 
reviewed by the DRC. In this cohort ganaxolone (or matching placebo) was given as 12 mg IV 
bolus over 2 minutes followed by IV infusion at a rate of 12 mg/h for 48 hours after which the 
rate was lowered to 6 mg/h for the final 12 hours. The infusion was stopped at 60 hours. There 
have been no serious adverse events or adverse events leading to discontinuation, and no subject 
has needed a dose adjustment. The DRC has evaluated preliminary adverse event data from these 
13 subjects and deemed this dosing regimen to be well-tolerated. The DRC has recommended 
that enrollment into Cohort 3 be completed with 20 subjects.  
 


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2.0 
STUDY OBJECTIVES AND PURPOSE 
2.1 
Rationale for the Study 
Rapidly declining plasma levels of allopregnanolone and other neurosteroids, after childbirth are 
thought to be linked to triggering depression in women who are vulnerable to development of 
this condition.  Ganaxolone, a synthetic analog of allopregnanolone, may provide benefit to these 
women.  
This study will explore whether ganaxolone is safe and well tolerated in women suffering from 
PPD. In addition, ganaxolone’s efficacy in treating depressive symptoms will be assessed 
through a set of exploratory analyses.  Plasma levels of ganaxolone will be determined through 
pharmacokinetic analysis.  The study results will be used to select a ganaxolone dose and dosing 
regimen for further development in PPD.  
2.2 
Study Objectives 
 
Safety Objective 
2.2.1
To assess the safety and tolerability of escalating doses of IV ganaxolone as determined by AEs 
and changes from baseline in laboratory measures, vital signs, Columbia Suicide Severity Rating 
Scale (CSSRS), electrocardiogram (ECG), Stanford Sleepiness Scale (SSS), and physical 
examination. In Cohort 6 the safety of IV dosing followed by oral dosing is investigated using 
the same assessments as in Cohorts 1-5.  
 
Efficacy Objective 
2.2.2
To explore the efficacy of escalating doses of IV ganaxolone in the treatment of PPD with the 
17-item Hamilton Depression Rating Scale (HAMD17), Edinburgh Postnatal Depression Scale 
(EPDS), Spielberger State-Trait Anxiety Inventory six item version (STAI6) and Clinical Global 
Impression-Improvement (CGI-I) scale. In Cohort 6 the efficacy of IV dosing followed by oral 
dosing is explored using the same assessments as in Cohorts 1-5.  
 
Pharmacokinetic Objective 
2.2.3
To collect samples of blood for pharmacokinetic analysis to assess ganaxolone plasma exposure 
after administration of intravenous and oral ganaxolone. 


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3.0 
STUDY DESIGN 
3.1 
Study Design and Study Population 
This is a Phase 2A, double-blind, placebo-controlled, multiple-dose escalation study consisting 
of up to 6 cohorts (Cohorts 1-6).  
Approximately 200 women with PPD 18–45 years of age will be screened to randomize up to 
100 subjects across up to 6 cohorts.  Approximately 10-30 subjects will be randomized into each 
cohort.  
In Cohorts 1-5, the treatment is administered intravenously over 60 hours. Randomized subjects 
will receive IV ganaxolone or matching IV placebo in a 1:1 ratio. More specifically, the dosing 
for Cohorts 1-5 is as follows:  
Cohort 1: ganaxolone is infused at a rate of 4 mg/h (16 ml/h of ganaxolone 0.25 mg/ml solution) 
for 48 hours and then at a rate of 2 mg/h for the next 12 hours. The infusion is stopped at 60 
hours. 
 
Cohort 2: ganaxolone is infused at a rate of 8 mg/h (16 ml/h of ganaxolone 0.5 mg/ml solution) 
for 48 hours and then at a rate of 4 mg/h for the next 12 hours. The infusion is stopped at 60 
hours. 
 
Cohort 3: Twelve mg bolus of ganaxolone is initially given over 2 minutes followed by 
ganaxolone infusion at a rate of 12 mg/h (24 ml/h of ganaxolone 0.5 mg/ml solution) for 48 
hours. The rate is then reduced to 6 mg/h for the next 12 hours. The infusion is stopped at 60 
hours.  
 
Cohorts 4 and 5: Cohorts 4 and 5 are optional and will be utilized only if further dose 
exploration is warranted. Ganaxolone infusion rate will be decided based on the results of 
Cohorts 1-3. However, the initial bolus dose will not exceed 16 mg over 2 minutes and the 
maximum infusion rate will not exceed 16 mg/h.  
 
In Cohort 6, subjects randomized to ganaxolone will receive an initial IV infusion of 20 mg/h 
(40 ml/h of ganaxolone 0.5 mg/ml solution) for 6 hours followed by 900 mg (4 capsules) 
ganaxolone capsules administered orally at dinner time for 28 days followed by a 3-day taper (3, 
2, and 1 capsules per day, respectively). Subjects randomized to placebo will receive an initial IV 
infusion of matching placebo (at 40 ml/h) followed by 4 placebo capsules administered orally at 
dinner time for 28 days followed by a 3-day taper (3, 2, and 1 capsules per day, respectively). 
Randomization will allocate subjects to the ganaxolone arm or placebo arm in 1:1 ratio.  
3.2 
Rationale for Study Design  
Rapid changes in allopregnanolone and other neurosteroid levels during and after pregnancy are 
thought to contribute to the biological underpinnings of PPD.  There are also data suggesting that 


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the sensitivity of the GABA system is altered during pregnancy and after childbirth, possibly as a 
result of changes in the circulating neurosteroid levels, and that there may be a state of 
neurosteroid withdrawal after pregnancy.11  Ganaxolone may alleviate PPD by increasing 
neurosteroid activity.  
Although ganaxolone has been administered to more than 1,500 subjects there have been no 
prior studies establishing the safety or efficacy of ganaxolone in clinical studies of PPD or other 
mood disorders in women.  This study is designed to establish the safety profile of intravenous 
ganaxolone in women with PPD.  The safety of transition from IV treatment to oral treatment is 
investigated in Cohort 6. Potential efficacy signals will also be explored.  These data will be used 
to select a dose (or doses) and dosing regimen for further development of ganaxolone in PPD.    
3.3 
Blinding Scheme 
Within cohorts, subjects will be randomized to ganaxolone or placebo in a 1:1 ratio. The 
randomization scheme will be prepared by an independent third-party vendor. Treatment 
assignments will be obtained by the investigator (or designee) via an Interactive Voice and/or 
Web Response System (IxRS). Subjects who are randomized to receive ganaxolone in Cohorts 1-
5 will receive ganaxolone as an intravenous infusion for 60 hours with or without an intravenous 
ganaxolone bolus dose.  Subjects who are randomized to placebo will receive matching placebo 
infusion for 60 hours (0.9% saline) with or without a matching intravenous placebo bolus dose.  
The placebo infusion is identical to ganaxolone in its appearance.  In Cohort 6, subjects 
randomized to ganaxolone will receive an initial infusion of 20 mg/h (40 ml/h of ganaxolone 0.5 
mg/ml solution) for 6 hours followed by treatment with oral doses of 900 mg ganaxolone (4 
capsules per dose) for 28 days followed by a 3-day taper (3, 2, and 1 capsules per day, 
respectively). Subjects randomized to placebo will receive an initial infusion with matching IV 
placebo (at 40 ml/hr) followed by matching oral placebo (4 capsules per dose) for 28 days 
followed by a 3-day taper (3, 2, and 1 capsules per day, respectively). The placebo infusion and 
placebo capsules are identical to the ganaxolone infusion and ganaxolone capsules, respectively, 
in their appearance.  An unblinded study pharmacist at the investigative site will prepare the 
ganaxolone and placebo IV solutions and allocate capsule supply for Cohort 6. Members of the 
DRC will be unblinded at scheduled DRC meetings. All other study personnel, including persons 
involved in the evaluation of the study subjects (e.g. investigators, sub-investigators, and 
physicians/nurses), will remain blinded at all times, except in case of an emergency.  Subjects 
will be blinded.   
3.4 
Dose Selection  
 
Cohort 1 
3.4.1
For Cohort 1, the targeted ganaxolone plasma concentration at steady state (Css) will be 
52 ng/ml, which is estimated to be achieved with a ganaxolone infusion rate of 4 mg/hr (16 ml/h 
of ganaxolone 0.25 mg/ml solution).  Steady state is expected to be achieved within 24 hours.  
For Cohort 1, the infusion rate is lowered to 2 mg/h after + 48 hours of infusion and stopped at 
+ 60 hours.  This is done to minimize any risks for withdrawal or rebound of anxiety and 
depression symptoms.  


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The target ganaxolone exposure level of approximately 52 ng/ml for Cohort 1 was chosen to 
achieve a level similar to that of allopregnanolone at the end of pregnancy.  Allopregnanolone 
levels increase gradually throughout pregnancy reaching a peak mean concentration at the end of 
pregnancy of about 15 to 60 ng/ml.  The levels then drop precipitously after the delivery.10, 5, 14  
We hypothesize that substitution of the low allopregnanolone levels with ganaxolone would 
alleviate or reverse the symptoms of PPD.  
 
Cohort 2 
3.4.2
For Cohort 2, the ganaxolone infusion rate will be 8 mg/hr (16 ml/h of ganaxolone 0.5 mg/ml 
solution). The infusion rate will be lowered to 4 mg/h (8 ml/h of ganaxolone 0.5 mg/ml solution) 
after + 48 hours of infusion and will be stopped at + 60 hours.  This is done to minimize any 
risks for withdrawal or rebound of anxiety and depression symptoms. This dose will 
approximately double the expected plasma exposure as compared to Cohort 1 at steady state 
(Cohort 2 expected plasma concentration ~ 100-120 ng/mL). 
 
Cohort 3 
3.4.3
For Cohort 3, an initial 12 mg bolus of ganaxolone will be given over 2 minutes, followed by 
ganaxolone infusion at a rate of 12 mg/h (24 ml/h of ganaxolone 0.5 mg/ml solution) for 48 
hours. The rate will be reduced to 6 mg/h for the next 12 hours, which is done to minimize any 
risks for withdrawal or rebound of anxiety and depression symptoms. The infusion is stopped at 
60 hours.  
This dose will increase the expected maximum plasma exposure by about 1.5-fold as compared 
to Cohort 2 at steady state during the infusion. The expected maximum plasma concentrations 
will be ~ 180 ng/ml during the infusion. During the initial 2-minute ganaxolone bolus, the peak 
plasma concentrations are expected to increase up to 300 ng/ml transiently, and then falling 
rapidly below 100 ng/ml after the bolus dose has been completed.  
The bolus dose is justified to provide a rapid loading dose of ganaxolone, which is hypothesized 
to expedite the onset of antidepressant activity.  
Based on prior studies with the oral formulation and results from Phase 1 Study 1042-0405 in 
healthy volunteers using the IV formulation of ganaxolone, the Cohort 3 dose and associated 
plasma exposure is expected to be generally safe and well tolerated.   
 
Cohorts 4 and 5  
3.4.4
Cohorts 4 and 5 are optional and will be utilized only if further dose exploration is warranted. 
Ganaxolone infusion rate will be decided based on the results from previous cohorts. However, 
no bolus doses higher than 16 mg over 2 minutes will be administered. The cap for the maximum 
infusion rate in Cohorts 4 and 5 will be 16 mg/h (not including any ganaxolone given by bolus). 
Ganaxolone was administered to healthy volunteers in Study 1042-0405 at these dose levels and 
above without any safety concerns (see below for details). With this maximum bolus and 
infusion rate the amount of Captisol® infused over 24 hours will not exceed the maximum levels 
achieved with Carnexiv®, an approved IV carbamazepine product.   
 


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Cohort 6  
3.4.5
For Cohort 6, the goal of initiation of treatment with IV infusion followed by oral capsules is to 
maximize the speed of onset of antidepressant activity while providing the convenience of oral 
dosing for the remainder of the treatment period. Under this IV-oral dosing schedule there may 
not be a need for a prolonged inpatient observation.  
This initial infusion is targeted to provide a fast onset of antidepressant activity by delivery of 
rapid plasma exposures to ganaxolone. At dinner time of Day 1 the subjects will take their first 
oral dose of ganaxolone 900 mg or matching placebo (4 capsules). This dose is expected to 
provide mean Cmax plasma concentrations of approximately 250-300 ng/mL and mean steady-
state levels between 90 and 150 ng/mL, which may be mildly sedating. In previous studies 
ganaxolone has been given up to a daily dose of 2000 mg, and at single doses of 1000 mg. Based 
on the previous experience this dose is expected to be safe.  
At subsequent nights (Days 2-28), the target dose is ganaxolone 900 mg or matching placebo (4 
capsules) at dinner time followed by a 3-day taper (3, 2, and 1 capsule/s per day, respectively). 
However, based on the assessment of the investigator the dose may be maintained at 675 mg or 
450 mg (or matching placebo) in case of adverse events, such as grogginess in the morning. In 
the case of 3 capsules per day on day 28 the taper will consist of 2, 2, and 1 capsule/s on days 29, 
30, and 31, respectively. In the case of 2 capsules per day on day 28 the taper will consist of 1 
capsule on days 29, 30, and 31. If the subject cannot tolerate 450 mg (or matching placebo) per 
dose the investigator will contact the Medical Monitor to discuss dosing options.  
Subjects will be provided with a diary to capture the details of dose administration and 
associated food intake throughout the treatment period. Subjects will document the number of 
capsules taken and whether a fatty meal/snack (e.g., fatty yogurt, nuts, avocado) was consumed 
±15 minutes of taking the capsules. 
The mechanism by which ganaxolone is postulated to be efficacious under this dosing regimen is 
restructuring of sleep architecture.2  Preclinical studies have shown that allopregnanolone has the 
capacity to modulate sleep, and disturbed sleep architecture is one of the hallmarks of 
depression.  
 
Dose justification in context of previous experience with IV ganaxolone  
3.4.6
In Study 1042-0405, which was a Phase 1 study in healthy volunteers investigating the safety of 
IV ganaxolone, infusion of 30 mg/h for 1 hour, 20 mg over 2 minutes and 20 mg/h for 4 hours 
led to peak concentrations of 258, 441 and 215 ng/mL, respectively, without any safety concerns. 
Sedation was assessed using the Modified Observers Assessment of Alertness/Sedation 
(MOAAS) scale. On this scale, score 5 indicates no sedation (responds readily to name spoken in 
normal tone) while score 1 indicates deep sedation (responds only after painful trapezius 
squeeze). In these cohorts, vast majority of the scores were 5 with few exceptions of 4 (lethargic 
response to name spoken in normal tone) and 3 (responds only after name is called loudly or 
repeatedly). The sedation scores reversed quickly after the infusion was stopped. The highest 
bolus dose tested was 30 mg, which was infused over 5-minutes. This dose led to peak 
concentration levels (Cmax) of > 1,000 ng/mL with no safety concerns (except sedation).   


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Six subjects reported treatment emergent AEs.  No single AE was seen twice. Only one event, 
headache, was considered by the investigator to be related to ganaxolone. None of the treatment 
emergent AEs was serious, and all were of mild intensity. No clinically meaningful mean 
changes in laboratory test results, vital signs, or ECG parameters occurred in any cohort.  
This safety profile is consistent with findings from previous studies with the oral formulation of 
ganaxolone, in which Cmax levels of up to 200 to 300 ng/mL were commonly observed and were 
not associated with major safety findings or toxicity (apart from sedation-related effects).  
3.5 
Justification for Placebo as a Control Group 
There are no approved treatments for PPD although SSRIs and serotonin and norepinephrine 
reuptake inhibitors (SNRIs) are commonly used off-label to manage PPD.  All subjects whether 
randomized to the placebo or control group will be allowed to remain on their current 
antidepressants provided that they have not had a recent change in the medication regimen (for 
details, please see Section 5.3.2 for prohibited treatments).  The add-on design minimizes subject 
risks because the current medications are not withdrawn, since that could exacerbate depressive 
symptoms.  The duration of the double-blind treatment phase in Cohorts 1-5 of the study is short 
(60 hours) and is conducted in an inpatient setting, which further minimizes risks to the subjects. 
The Cohort 6 treatment period is initiated in an inpatient setting, which allows observation of the 
effects of the IV infusion and first dose effects of the oral medication during the approximately 
48-hour stay on the unit.  
3.6 
Study Duration  
The screening period for each cohort will be up to 2 weeks. In Cohorts 1-5 the screening period 
is followed by a 60-hour infusion treatment with or without initial bolus dosing during the 4-day 
inpatient treatment phase at a hospital or clinical pharmacology unit.  The subjects will be 
discharged from the unit on the morning of Day-4.  There will be 2 safety follow-up visits after 
inpatient discharge on post-treatment Weeks 1 and 4.  The total duration of the study will be up 
to 7 weeks for Cohorts 1-5. For Cohort 6 there will be an initial infusion treatment and oral dose 
during the approximately 24-hour inpatient dosing phase followed by 27 days of oral treatment 
as outpatient. There will be 3 safety follow-up visits after the outpatient treatment period on post-
treatment Weeks 1,4, and 6.  The total duration of the study will be up to 12 weeks for subjects 
participating in Cohort 6.  
3.7 
Interim Analyses 
The study team physician and the clinical operations lead will monitor emerging blinded safety 
data from each subject periodically throughout the duration of the study.  
In addition, safety and efficacy data from each cohort will be unblinded, and analyses will be 
conducted for the purpose of dose selection for the next cohort.  The dose for the next cohort will 
be decided based on these interim data analyses.  The decision how to adjust the dose and/or the 
duration of the infusion will be made based on recommendations by a Data Review Committee 
(DRC) composed of the sponsor’s Chief Medical Officer, and at least 2 other external 
physicians.  At least one of the members will have special expertise in the clinical care of women 
with depression or postpartum depression.  One of the members will have expertise in the 


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conduct of clinical trials or analysis of clinical trial data. The study team and all parties other 
than the DRC will remain blinded.  
The dose for the subsequent cohorts will be selected with the goal of gaining additional 
information on ganaxolone’s tolerability and dose-response profile.  
A separate DRC guidance document outlines the principles for dose selection.  Marinus may 
decide to stop the study, or make the data public, after completion of any cohort.  
3.8 
Definition of Completion   
A cohort is considered complete when the final subject in the cohort has completed the final 
protocol-defined assessment, including follow-up visits, for the cohort. 
The Study Completion Date is defined as the date the final subject, across all sites, completes her 
final protocol-defined assessment, including follow-up visits, for the final cohort.   
3.9 
Sites and Regions 
The study will be conducted in the United States at approximately 20 investigative sites.  


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4.0 
STUDY POPULATION 
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed. 
4.1 
Inclusion Criteria 
The subject will not be considered eligible for the study without meeting all of the criteria below. 
1. An understanding of and ability, and willingness to fully comply with study procedures and 
restrictions.  
2. Ability to voluntarily provide written, signed, and dated informed consent as applicable to 
participate in the study. 
3. Female aged 18 to 45 years, inclusive, at the Screening Visit 
4. Experiencing a Major Depressive Episode, which started between the start of the third 
trimester and 4 weeks following delivery.  The Major Depressive Episode must be diagnosed 
according to MINI 7.0 interview  
5. Given birth in the last 12 months 
6. HAMD17 score of ≥ 26 at screening (HAMD17 must be ≥ 22 per CTNI rating at Admission 
to the Unit on Day 0) 
7. The diagnosis of PPD and severity of depression must be supported by the SAFER interview 
8. Must agree to stop breastfeeding from start of study treatment to 45 days after end of study 
treatment 
9. Must agree to use acceptable contraceptive methods during the study period 
 
4.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following exclusion criteria are met:  
1. Current or past history of any psychotic illness, including Major Depressive Episode with 
psychotic features 
2. Any psychiatric condition that, in the investigator’s judgment, is considered clinically 
significant and could affect subject safety or study outcome including eating disorder, panic 
disorder, obsessive-compulsive disorder, or post-traumatic stress disorder   
3. History of suicide attempt within the past 3 years (actual attempt, interrupted or aborted 
attempt, preparatory acts, or behavior) 
4. Active suicidal ideation (e.g. answering “yes” to questions 4 or 5 in the CSSRS suicidal 
ideation section) 
5. History of severe bipolar I disorder (e.g. hospitalization due to the illness, lifetime history of 
psychosis or suicide attempt)   


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6. Uncontrolled seizure disorder  
7. Current or history within the past 3 years of any substance use disorder, with the exception of 
tobacco or caffeine 
8. Positive drug screen for any illicit substances or prescription drugs at screening or 
randomization.  If the drug screen is positive for a prescription drug that has the potential to 
be abused (e.g. amphetamine, benzodiazepine), legitimate use of the drug must be verified by 
the subject’s providing the current pill bottle, prescription for the drug, or a note from the 
prescribing physician.  Cannabis use is prohibited and subjects with positive drug screen for 
cannabis are excluded. However, occasional users of cannabis may be re-tested if the subject 
is willing to refrain from consuming cannabis-based products during the trial. If the re-test 
sample is negative at screening the subject can be considered eligible. If the re-test sample is 
positive for cannabis the investigator may ask for determination of the urine or blood levels 
of ∆9-tetrahydrocannabinol (THC), and its metabolites 11-hydroxy-THC and, 9-carboxy-
THC. If the levels of THC are not detectable the subject may be considered eligible for the 
trial.   
9. Current or relevant history of any medical disorder that may require treatment or make the 
subject unlikely to be able to complete the study, or any condition that presents undue risk 
from the investigational product or procedure point of view 
10. Any clinically significant abnormality identified on physical examination, ECG or laboratory 
tests, that in the judgment of the investigator would compromise the subject’s safety or 
successful participation in the clinical study 
11. Subject has untreated or uncontrolled hypothyroidism  
12. Known or suspected intolerance or hypersensitivity to the investigational product(s) or 
allopregnanolone, or any of the stated ingredients 
13. Use of another investigational product within 60 days prior to the first dose of investigational 
product  
14. Has alanine transferase (ALT) or aspartate transferase (AST) greater than 2.5 times upper 
limit of normal or total bilirubin greater than 1.5 times upper limit of normal (unless 
elevation is due to Gilbert’s syndrome) 
15. Screening QTcF > 470 msec 
16. Unwillingness to withhold grapefruit, Seville oranges, star fruit, or citrus derived products 
from diet between screening and discharge from the study unit  
17. Receiving concomitant treatment with strong CYP3A4 inducers or strong CYP3A4 inhibitors 
18. Body mass index (BMI) ≥ 40 
19. Subject is pregnant 
20. Subject is using prohibited medications as specified in Section 5.3.2 


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4.3 
Reproductive Potential 
 
Female Contraception 
4.3.1
Sexually active females of childbearing potential should be using an acceptable form of 
contraception throughout the study period between screening and last follow-up visit.  
Acceptable methods of contraception are: 
• Intrauterine device plus condoms (If the subject has a hormone-releasing intrauterine device 
(IUD) this must have been in place for a minimum of 30 days) 
• Double-barrier methods (e.g. condoms with spermicidal gel, foam or sponge, diaphragm with 
spermicidal gel, foam or sponge) 
• Hysterectomy or tubal ligation at or after delivery 
4.4 
Discontinuation of Subjects 
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The investigator or sponsor may 
withdraw the subject at any time (e.g. in the interest of subject safety).  The investigator is 
encouraged to discuss withdrawal of a subject from the investigational product with the medical 
monitor when possible. Withdrawn subjects who have not received IP will be replaced. 
If the investigational product is discontinued, regardless of the reason, the evaluations listed for 
Day 4 are to be performed as completely as possible for Cohort 1-5, and Day 28 evaluations for 
Cohort 6. Whenever possible, all discontinued subjects should also undergo the protocol-
specified follow-up.  Comments (spontaneous or elicited), complaints or AEs reported by the 
subject must be recorded in the source documents.  The reason for discontinuation and the date 
and time of discontinuation of the investigational product must be recorded in the case report 
form (eCRF) and source documents.  
 
Subject Withdrawal Criteria 
4.4.1
All subjects reserve the right to withdraw from the clinical study at any time, as stated in the 
informed consent form (ICF).  The Investigator may discontinue subjects from the clinical study 
for any of the following reasons: 
1. ECG evidence of QT prolongation (QTcF > 530 msec, or an increase of QTcF > 60 msec 
above baseline to a value > 480 msec on the 12-lead ECG, confirmed on a repeat 12-lead 
ECG taken after resting at least 5 minutes in a supine or semi-recumbent position after 
the original finding of prolonged QTcF).  
2. It is the Investigator’s opinion that it is not in the subject’s best interest to continue in the 
study. 
3. Any subject who exhibits any Suicidal Behavior or Suicidal Ideation (e.g. subject 
answers “yes” to question 4 or 5 in the Suicidal Ideation section of the CSSRS).  These 
subjects should be evaluated by a psychiatrist immediately. 


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4. Rash that is clinically significant and considered to be related to the study drug (e.g. 
morbiliform, urticarial, papular).  
5. Subject experiences an SAE considered to be related to the study drug 
 
Decisions to discontinue the study will be made at each participating site by 
4.4.2
the Principal Investigator.  If feasible, the reason for discontinuation should be 
discussed with the Medical Monitor. Reasons for Discontinuation 
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the eCRF.  If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the eCRF.  
Reasons for discontinuation include but are not limited to: 
• AE 
• Protocol deviation 
• Withdrawal of consent by subject 
• Lost to follow-up 
• Lack of efficacy 
• Other (If “Other” is selected, the investigator must specify the reason on the eCRF) 
 
 
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit 
4.4.3
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact).  At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that she 
return to the site for final safety evaluations.  If a contact is made but the subject refuses or is 
unable to come to the final safety evaluation it should be documented in the eCRF.  


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5.0 
PRIOR AND CONCOMITANT TREATMENT 
All non-study treatments (including herbal treatments, vitamins, and non-pharmacological 
treatments) received within 60 days prior to the screening visit (Visit 1) and through the final 
study contact (including protocol-defined follow-up period) must be recorded on the appropriate 
eCRF page. 
5.1 
Prior Pharmacological Treatment 
Prior pharmacological treatment includes all treatments (including herbal treatments and 
vitamins) that the subject received and stopped within 60 days of the date of the screening visit.  
For example, if the subject had been treated with sertraline during pregnancy but it was 
discontinued 3 weeks prior to the screening visit, this medication would be recorded on the prior 
medication eCRF page.  
5.2 
Concomitant Pharmacological Treatment  
Concomitant treatment refers to all treatments (including herbal treatment and vitamins) taken 
between the screening visit and the end of the follow-up period regardless of the start date of the 
concomitant medication.  For example, if the subject was started on a prenatal vitamin and it was 
continued through the study period, this treatment would be recorded on the concomitant 
medication eCRF page.  
5.3 
Concomitant Psychological Treatment 
Concomitant psychological treatment refers to all psychological care the subject is receiving 
between the screening visit and the end of the follow-up period regardless of the start date of the 
concomitant psychological treatment.  Concomitant psychological treatment information must be 
recorded on the concomitant psychological treatments eCRF page. 
 
Permitted Treatment 
5.3.1
5.3.1.1 
Permitted Psychological Treatments 
The subject may continue their current form of psychological treatment (e.g. Cognitive 
Behavioral Therapy, Psychodynamic Psychotherapy, Supportive Psychotherapy) throughout the 
treatment period.  However, initiation of a new therapy (a new treatment modality or switching a 
therapist) is prohibited between screening and discharge from the inpatient unit.  
5.3.1.2 
Permitted Antidepressant Treatments  
The subject may continue their current SSRI, SNRI or bupropion or other serotonin or 
norepinephrine modulating antidepressant (e.g. vortioxetine, mirtazapine) treatment provided the 
regimen conforms to the standard of care and the medication was started at least 21 days before 
the screening visit, and there has not been a dose change within 7 days of the screening visit.  
The antidepressant medication must have been approved for treatment of major depressive 


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disorder by the United States (US) Food and Drug Administration (FDA).  Monoamine 
Inhibitors are prohibited (including all formulations of selegiline).  Tricyclic antidepressant 
medications will be decided on a case-by-case basis with the medical monitor.  
5.3.1.3 
Other Permitted Treatments 
The subject may continue her current non-psychiatric medications with the exception of 
medications that are strong inducers or inhibitors of CYP3A4 (Appendix 1).  
The subject may use diphenhydramine 25 to 50 mg, trazodone 25 to 50 mg or doxepin 3 to 5 mg 
during the inpatient or outpatient phase for severe insomnia as needed.  Only 1 dose of 1 of the 
medications is allowed per night.  It is recommended to use the same medication each night.  To 
minimize carryover effects there should be a minimum of 10-hour interval between 
administration of an allowed hypnotic and any efficacy assessment.  Other hypnotics, such as 
zolpidem or zaleplon, are prohibited.  
If the subject is treated with an atypical antipsychotic medication that was started with the 
purpose of augmenting the therapeutic effect of an antidepressant (i.e. the antipsychotic is not 
intended for treatment of psychosis or mood stabilization), she may continue this treatment 
throughout the study period.  Examples of such treatments would be quetiapine 50 mg at bedtime 
and aripiprazole 15 mg daily.  However, the antipsychotic medication must have been started at 
least 21 days before the screening, and there should not have been a dose change within 7 days 
of screening.  
Other medications and medication combinations should be discussed with the medical monitor 
before enrolling the subject in the study.  
After the subject completes the study treatment period, any changes to the antidepressant or 
antianxiety medication regimen are not prohibited, but investigators are encouraged to maintain 
such drugs at stable doses if possible.  Any changes in the medication regimen must be recorded 
on the concomitant medication eCRF page.   
 
Prohibited Treatments 
5.3.2
The following classes of medications and treatments are prohibited during the study treatment 
period.  If the subject has been taking any of these medications before enrollment, there should 
be a medication-free period of a minimum of 5 days or 5 half-lives of that medication, whichever 
is longer, before admission to the unit.  In general, subjects who require extensive washouts may 
not be candidates for participation and those cases should be discussed with the medical monitor.  
• Benzodiazepines and barbiturates 
• Gabapentin and pregabalin 
• Anticonvulsants and mood stabilizers 
• All hypnotics and sleep aids (with the exception of low-dose diphenhydramine, doxepin, 
and trazodone as described above) 
• Opioids  


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• Cannabis  
• Electroconvulsive Therapy (ECT), rapid transcranial magnetic stimulation (rTMS), vagal 
nerve stimulation 
• Experimental (including hormonal and herbal) treatments of postpartum depression 
• Strong inhibitors and inducers of CYP3A4 (Appendix 1) 


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6.0 
INVESTIGATIONAL PRODUCT 
6.1 
Identity of Investigational Product 
 
Ganaxolone IV infusion solution 
6.1.1
Manufacturer:  Particle Sciences Inc. 
Vehicle:  Captisol® containing sterile IV solution  
Formulation:  IV 
Strength:  3 mg/ml solution in a glass vial, which is to be diluted with 0.9% saline for the 
infusion.  For details regarding preparation of the infusion solution please see pharmacy manual.  
Route of administration:  IV 
 
Placebo IV control solution 
6.1.2
Placebo name:  0.9% saline physiological sterile IV solution 
Formulation:  IV solution matching ganaxolone in appearance 
Strength:  not applicable 
Route of administration:  IV 
 
Ganaxolone oral capsules  
6.1.3
Ganaxolone capsules will be provided in size 00 white/opaque gelatin capsules packaged in 
HDPE bottles with a foil induction seal and child resistant closure.  Each bottle will contain 70 
capsules.  Each capsule contains 225 mg ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-
one), and hydroxypropyl methylcellulose, sucrose, polyethylene glycol 3350, polyethylene 
glycol 400, sodium lauryl sulfate, sodium benzoate, citric acid anhydrous, sodium methyl 
paraben, microcrystalline cellulose, 30% Simethicone Emulsion, gelatin capsules, polysorbate 
80, and sodium chloride. 
 
Placebo oral capsules 
6.1.4
Placebo formulation is comprised of sucrose spheres of comparable size to the ganaxolone spray 
layered spheres encapsulated in a size 00 white/opaque gelatin capsule.  The weights of placebo 
capsules are matched to ganaxolone capsules.  The placebo capsules will be provided to the sites 
in bottles identical to the active drug.  
6.2 
Administration of Investigational Product(s) 
For administration of the IV investigational product (IP; ganaxolone or matching placebo [0.9% 
saline solution]) the investigator needs to use the Sponsor-approved Captisol®-compatible 


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intravenous infusion bags and infusion sets which are prepared according to the Pharmacy 
manual.  Any substitutions and deviations from the Pharmacy manual need to be approved by the 
sponsor.  
Ganaxolone or matching placebo capsules (Cohort 6 only) will be administered orally with food. 
Ganaxolone or matching placebo capsules should be taken ±15 minutes of a fatty meal or snack 
(e.g., fatty yogurt, nuts, avocado) and with 240 mL (8 oz) of water at dinner time.   
Subjects will be provided with a diary to capture the details of dose administration and 
associated food intake throughout the treatment period. Subjects will document the number of 
capsules taken and whether a fatty meal/snack (e.g., fatty yogurt, nuts, avocado) was consumed 
±15 minutes of taking the capsules.  
 
Interactive Voice/Web Response System (IxRS) Technology for 
6.2.1
Investigational Product Management 
The name and address of the Interactive Voice/Web Response System (IxRS) for this study will 
be maintained in the Investigator’s files at each study site. 
Interactive response technology will be used for the following investigational product tasks: 
• 
Randomization 
• 
Communication of treatment assignment to sites 
• 
Supply management 
• 
Inventory management and supply ordering 
• 
Expiration date tracking 
• 
Returns 
• 
Emergency unblinding 
 
 
Allocation of Subjects to IP 
6.2.2
This is a double-blind, placebo-controlled study.  The actual IP given to individual subjects is 
determined by a randomization schedule. prepared by an independent third-party vendor. Within 
cohorts, subjects will be randomized to ganaxolone or placebo in a 1:1 ratio 
Subject numbers are assigned to all subjects as they consent to take part in the study.  Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.  
The randomization number represents a unique number corresponding to IP kit number allocated 
to the subject, once eligibility has been determined.  
After being randomized a subject will be replaced only if she discontinues prior to receiving IP. 
The replacement subject will receive the same IP assignment as the replaced subject. 


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Dosing 
6.2.3
Subjects entering the study will be randomized to ganaxolone or matching placebo at the 
Baseline Visit.  The goal of Cohorts 1-6 is to determine safety, tolerability, PK and efficacy of 
the IV formulation (and in Cohort 6, the IV formulation followed by oral formulation) of 
ganaxolone in PPD subjects administered at a predicted dose regimen mimicking the levels of 
allopregnanolone at the end of pregnancy, or higher.10, 5, 14  
Infusion rates for ganaxolone IV will be the same as for placebo IV. Cohort 1  
The infusion rate for Cohort 1 will be 4 mg/h (16 ml/h of ganaxolone 0.25 mg/ml solution).  The 
infusion rate (4 mg/ml or 16 ml/h) is maintained constant until + 48 hours when the rate is 
reduced to 2 mg/h and then stopped at + 60 hours.  
The infusion rate of 4 mg/ml is estimated to produce a ganaxolone steady state level of about 
52 ng/ml after about 24 hours of infusion. 
Cohort 2 
The infusion rate for Cohort 2 will be 8 mg/h (16 ml/h of ganaxolone 0.5 mg/ml solution).  The 
infusion rate (8 mg/ml or 16 ml/h of ganaxolone 0.5 mg/ml solution) is maintained constant until 
+ 48 hours when the rate is reduced to 4 mg/h (8 ml/h of ganaxolone 0.5 mg/ml solution) and 
then stopped at + 60 hours.  
The infusion rate of 8 mg/h is estimated to produce a ganaxolone steady state level of about 100 
ng/ml after about 24 hours of infusion.  
Cohort 3 
For Cohort 3, an initial 12 mg bolus of ganaxolone will be given over 2 minutes, followed by 
ganaxolone infusion administered at a rate of 12 mg/h (24 ml/h of ganaxolone 0.5 mg/ml 
solution) for 48 hours. The rate is then reduced to 6 mg/h for the next 12 hours. The infusion is 
stopped at 60 hours.  
Cohort 4 and 5  
Cohort 4 and 5 are optional and will be utilized only if further dose exploration is warranted. The 
dosing regimen for Cohort 4 and 5 will be decided based on the results of the Cohorts 1-3 and 
the recommendation of the DRC. However, no bolus doses higher than 16 mg over 2 minutes 
will be administered. The cap for the maximum infusion rate in Cohorts 4 and 5 will be 16 mg/h.  
Cohort 6 
For Cohort 6, an initial IV infusion 20 mg/h (40 ml/h of ganaxolone 0.5 mg/ml solution or 
matching placebo) for 6 hours will be followed by oral dose of 900 mg ganaxolone or matching 
placebo (4 capsules) at dinner time (Day 1). On subsequent nights (Day 2-28) the subject will 
take 900 mg of ganaxolone, or matching placebo (4 capsules), at dinner time followed by a 3-day 


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taper (3, 2, and 1 capsule/s per day, respectively (unless the dose is adjusted as per the 
instructions from the investigator in which case the taper follows instructions in section 3.4.6).  
 
Dose Adjustments 
6.2.4
Sedation and dizziness are known effects of ganaxolone at higher doses.  If a subject experiences 
excessive sedation or dizziness the investigator may adjust the dosing by stopping the infusion 
for a minimum of 1 hour or until the effects resolve and then restarting the dosing at half the rate 
prescribed for the cohort (for Cohorts 1-5).  For example, if the rate prescribed for the cohort is 4 
mg/h (16 ml/h), the investigator may stop the infusion for 1 hour and then restart the infusion at 
2 mg/h (8 ml/h).  If the dose is adjusted, this must be recorded in the source documentation and 
eCRF.  Under these circumstances the subject must be monitored closely for recurrence of 
sedation.  
If the subject experiences excessive sedation or dizziness during the administration of the bolus 
dose, the dosing should be stopped immediately. The investigator should wait for a minimum of 
1 hour or until the effects resolve and then starting the infusion at the rate prescribed for the 
cohort.  Under these circumstances the subject must be monitored closely for recurrence of 
sedation. The dose of the oral medication in Cohort 6 may be adjusted by lowering the dose from 
900 mg to 675 mg or 450 mg, or matching placebo at dinner time if the subject experiences 
adverse effects, such as sedation in the morning. If the dose is adjusted, this must be recorded in 
the eCRF. Other dosing adjustments may be possible, but they should be discussed with the 
medical monitor.  
 
Blinding 
6.2.5
The site pharmacy personnel who dispenses the study drug will not be blinded and will not be 
involved in any study assessments.  All other participating staff involved in the evaluation and 
execution of the study will remain blinded to subject’s study drug treatment.  
 
Unblinding the Treatment Assignment 
6.2.6
The treatment assignment must not be broken during the study except in emergency situations in 
which the identification of the investigational product is required for further treatment of the 
subject.  The investigator should contact the medical monitor before unblinding, if possible.  
However, this should not delay unblinding in case of an emergency.  The investigator should 
contact the medical monitor as soon as possible after the investigator has been unblinded.  
In the event that the treatment assignment is broken, the date, the signature of the person who 
broke the code, and the reason for breaking the code are recorded on the source documents.  
Upon breaking the blinding, the subject is withdrawn from the study, but should be followed up 
for safety purposes.  Any code-breaks that occur must be reported to the Contract Research 
Organization (CRO) and sponsor.  


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6.3 
Labeling, Packaging, Storage, and Handling 
Further information regarding labeling, packaging, storage and handling can be found in the 
Pharmacy Manual.  
 
Labeling 
6.3.1
Each stock solution vial contains 88 mL of ganaxolone at a concentration of 3 mg/mL. A label is 
applied to each vial with information on strength, manufacturing batch number, manufacturing 
date, storage conditions, name of the manufacturer, and a warning that the drug is intended for 
research only.  
The site pharmacy will prepare the IV bags, which will include at minimum the subject ID, 
protocol number, and time and date of IV bag preparation.  No information which could 
potentially unblind the study drug should be visible to the subject or staff, and no packaging 
information should allude to the contents of the IV bag (e.g., “drug lot number”).  Further details 
are provided in the pharmacy manual. 
The Site Pharmacy will dispense the IV bag to a qualified blinded staff member who will 
administer the study drug to the subject.   
For Cohort 6 the medication bottles (placebo and ganaxolone) will be labeled before shipping to 
the sites.  
 
Packaging 
6.3.2
6.3.2.1 
 IV ganaxolone 
The sponsor will provide stock study drug solution which will be diluted by an unblinded 
research pharmacist at the investigative site.  The sponsor will also provide or approve IV bags 
and empty syringes which are to be used for infusion and bolus dosing of the study drug and 
placebo.  All packaging and labeling operations will be performed according to good 
manufacturing practice (GMP) and good clinical practice (GCP) guidelines.  The study drugs 
will be prepared and supplied according to the randomization plan.  Investigational products are 
prepared and distributed by the unblinded pharmacist.  The pharmacist will enter the unique 
subject identifier on the investigational product as the product is distributed to the staff members 
managing administration of the study drug.  Further details can be found in the pharmacy manual  
6.3.2.2 
Ganaxolone and placebo oral capsules 
For Cohort 6 ganaxolone capsules and matching placebos will be provided in HDPE bottles. 
All packaging and labeling operations will be performed according to good manufacturing 
practice (GMP) and good clinical practice (GCP) guidelines.  Investigational products are 
prepared and distributed by the site pharmacist or delegated staff.   


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The site pharmacy or delegated site staff will be responsible for dispensing the study treatment to 
the subject.  A sufficient number of capsules will be provided to the subject until the next study 
visit plus at least 3-day overage.  
Detailed instructions when to take the medication and a reminder to take the study medication 
with fatty food (meal or snack, e.g., fatty yogurt, nuts, avocado) at dinner time and with 240 mL 
(8 oz) of water will be provided to the subject along with a medication diary to document intake 
of IP and fatty meal/snack ±15 minutes. 
 
Storage 
6.3.3
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location.  Limited responsibility may be delegated to the pharmacist, but 
this delegation must be documented.  
The ganaxolone stock solution investigational product will be stored at refrigerated temperature 
2ºC to 8ºC (36ºF to 46ºF).   
The 0.3-micron ganaxolone capsules (225 mg) and matching placebos are stored in HDPE 
bottles with a foil induction seal and child resistant closure at room temperature (60oF to 75oF).  
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range.  The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained.  The temperature should be monitored continuously through use of either 
an in-house system, a mechanical recording device such as a calibrated chart recorder, or by 
manual means, such that both minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required.  The sponsor or sponsor’s delegate must be 
notified immediately upon discovery of any excursion from the established range.  Temperature 
excursions will require site investigation as to cause and remediation.  The sponsor will 
determine the ultimate impact of excursions on the investigational product and will provide 
supportive documentation as necessary.  Under no circumstances should the product be 
dispensed to subjects until the impact has been determined and the product is deemed appropriate 
for use by the sponsor. 
The sponsor or sponsor’s delegate should be notified immediately if there are any changes to the 
storage area of the investigational product that could affect the integrity of the product(s), e.g. 
fumigation of a storage room. 
6.4 
Drug Accountability 
Drug kits containing the study drug (ganaxolone stock vials for the IV solution, ganaxolone 225 
mg capsules and matching placebo capsules) and supplies needed for each subject for the entire 
study will be supplied to the investigative site by the sponsor or a distributor on behalf of the 
sponsor.  The pharmacist will inventory and acknowledge receipt of all shipments of the kits.  
The study drugs must be kept in a locked area with restricted access and stored and handled in 
accordance with the manufacturers’ instructions.  The pharmacist will also keep accurate records 


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of the quantities of study drug dispensed and used.  The pharmacist is responsible for all drug 
supplies; written documentation is mandatory.  The study monitor will periodically check the 
supplies of the study drug held by the pharmacist to verify accountability of all kits used.  The 
pharmacist will dispense the kits according to the dosing plan.  Upon receiving kits, the Principal 
Investigator and the team members will administer them only to the identified subjects in this 
study, following the procedures described in this study protocol and documented in the 
appropriate eCRF.  At the conclusion of the study, all unused study drug will be returned or 
destroyed per the site’s Standard Operating Procedures or instructions from the sponsor.  The 
sponsor will verify that a final report of drug accountability to the unit-dose level is prepared and 
maintained in the Principal Investigator’s study file. 
6.5 
Drug Administration 
 
Administration of IV IP (Cohorts 1-6)  
6.5.1
The IP will be administered IV via an indwelling catheter inserted in a vein on the arm or hand.  
The IP should be given as continuous infusion as instructed.  If the study drug is stopped 
temporarily (e.g. catheter change) the infusion may be re-started at the same rate as before.  A 
new infusion bag should be prepared every 24 hours.  The catheter should be flushed with saline 
at the same time when the tubing is changed.  The catheter site should be inspected for 
inflammation at least twice a day.  For details please see pharmacy manual.  
 
Administration of oral ganaxolone or placebo capsules (Cohort 6) 
6.5.2
Oral doses of ganaxolone or matching placebo should be taken at dinner time with fatty food 
(±15 minutes of a fatty meal or snack, e.g., fatty yogurt, nuts, avocado) and with 240 mL (8 oz) 
of water at home.   
Subjects participating in Cohort 6 will be informed about possible side effects from the study 
medication and cautioned to avoid quick postural changes.  They should not carry the baby or 
sleep with the baby in the same bed due to the possible side-effect of dizziness and sedation.  
Subjects will be advised not to drive, operate heavy machinery, or participate in any potentially 
hazardous activity during the study that requires full mental alertness until they are sure the 
medication is not affecting alertness.  They will also be cautioned that non-adherence to the 
dosing instructions (e.g. increasing the dose, taking the study medication doses too close 
together) could produce side effects.  
The interaction between alcohol and ganaxolone is not known.  Alcohol use is prohibited during 
the treatment period.  
The subjects participating in Cohort 6 must have a reliable family member, significant other or a 
trusted friend who can take the role for being the primary childcare provider and a support 
person at home (including at nighttime) while the subject is participating in the trial.  


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7.0 
STUDY PROCEDURES 
This is a Phase 2A, double-blind, placebo-controlled, multiple-dose escalation study consisting 
of up to 6 cohorts. In Cohorts 1-5 the IV formulation of ganaxolone will be used while in Cohort 
6 both IV and oral formulations will be used. Approximately 200 women with PPD 18 to 45 
years of age will be screened to randomize approximately 100 subjects across the up to 
6 cohorts. Approximately 10-30 subjects will be randomized into each cohort.  Randomized 
subjects will receive ganaxolone or placebo in a 1:1 ratio.  In Cohorts 1-5 the treatment is 
administered intravenously (with or without an initial bolus) over 60 hours. In Cohort 6 the 
treatment is initiated with a 6-hour intravenous (IV) infusion followed by oral ganaxolone or 
matching placebo. Additional subjects may be included into these cohorts or additional cohorts 
may be added, but will not exceed 100 randomized subjects for the study. 
The screening period for each cohort will be up to 2 weeks. Following the screening period, there 
will be a 4-day inpatient treatment phase at a hospital or clinical pharmacology unit for Cohorts 
1-5 during which a 60-hour infusion of ganaxolone or placebo will be administered (with or 
without bolus dosing).  The subjects will be discharged from the unit on the morning of Day 4. 
There will be 2 safety follow-up visits after inpatient discharge on post-treatment Weeks 1 and 4.  
In Cohort 6, following the screening period, there will be a 1-day inpatient treatment phase at a 
hospital or clinical pharmacology unit during which a 6-hour infusion of ganaxolone or matching 
placebo will be administered initially from 9 am to 3 pm (±1 hour) before oral dosing is started at 
7 pm (±1 hour). The subjects will be admitted on Day 0 and discharged from the unit in the 
morning of Day 2. The first dose of oral ganaxolone (4 capsules; 900 mg) or matching placebo 
will be administered at dinner time (around 7 pm) of Day 1, 4 hours after the end of infusion on 
Day 1. Oral dosing is continued as outpatient on Days 2-28. The dosing regimen during the 
outpatient phase of Cohort 6 is 900 mg or placebo (4 capsules) at dinner time daily. A 3-day 
taper will follow at days 29, 30, and 31, as described in Section 3.4.6. There will be 3 safety 
follow-up visits after the last dose on post-treatment Weeks 1,4, and 6.  
On Day 1 subjects will have 6 PK samplings: at 1 hour after the end of the 6-hour infusion (i.e., 
at 4 pm), at 7 pm (just prior to the oral dosing), and at 1, 2, 3, and 4 hours post oral dosing (at 8, 
9, 10, and 11 pm) as well at 8 am the following morning (on Day 2) prior to discharge. 
The subjects will take a 900 mg dose or placebo (4 caps) on the evening of Day 1 at dinner time 
and continue with the 900 mg dose or matching placebo at dinner time on Days 2-28. A 3-day 
taper will follow as described in Section 3.4.6.  
 


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Page 42 of 104 
A schematic of the study design if provided in Figure 1.  
Figure 1: Study Design Flow Chart 
 
 
7.1 
Screening Visit and Screening Period (day -14 to -1) – Cohorts 1-6 
• Obtain written informed consent  
• Collect demographics, medical history, review prior medications, review of concomitant 
medications and therapies,  
• Assess CGI-S 
• Conduct MINI international neuropsychiatric interview  
• Conduct Hamilton Depression Rating Scale 17-item version (HAMD17) interview 
• Edinburgh Postnatal Depression Scale (EPDS) 
• Spielberger State-Trait Anxiety Inventory (STAI6) 
• Perform a physical examination  
• Collect vital signs (BP, pulse, temperature, pulse oximetry, respiratory rate) 
• Collect ECG 
• Collect urine sample for urinalysis, drug screen and urine pregnancy test  
• Collect safety laboratory tests  
• Measure height and weight  
• Conduct CSSRS interview  
• Review inclusion and exclusion criteria.  Screen failure is defined as a subject who has 
given informed consent, and failed to meet the inclusion criteria and/or met the exclusion 
criteria 
• Schedule a SAFER interview if the subject meets the eligibility criteria.  The SAFER 
interview will be conducted during the screening period.  The investigative site must wait 
for the results of the SAFER interview before admitting the subject on the unit.  
Cohorts 1-5 
----GNX n = 5 -15 
Cohorts 6 
GNX n = 5-15 
_____ 
111 IV Bolus (in Cohort 3 only) I 
I 60 hour IV Infusion 
6-hour 40 ml/hr IV infusion + 28 day 4 capsules at dinner 
(= GNX 120 mg IV+ 28 day 900 mg PO at dinner 
-----41 0R matching placebo) 
Followed by 3-day taper 
...._---PBO n = 5 - 15 
PBO n = 5-15 


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• Screening period may be extended to 21 days with approval from the medical monitor 
(e.g. a laboratory sample was hemolysed which had to be repeated causing a delay). 
• 
The subject may stay on the inpatient unit voluntarily between screening visit and 
admission to the study (Day 0) provided that close monitoring of the subject can be 
ensured. The gap between the screening visit and admission (Day 0) should be kept as 
short as possible, preferably no more than 2 days. Q15 minute health checks should be 
implemented during the gap period. The SAFER interview will be done during the gap 
period. The sponsor should be informed of this decision.  
 
7.2 
Admission to the Unit (Day 0) – Cohorts 1-6  
• Review concomitant medications and therapies  
• Admission to the unit.  The subject arrives on the unit the day before the start of the 
infusion (Day 1) to complete assessments and accommodate to the unit.  
• Collect vital signs (BP, pulse, temperature, pulse oximetry, respiratory rate) 
• Collect ECG 
• Collect urine sample for urinalysis, drug screen and urine pregnancy test 
• Collect safety laboratory tests 
• Collect neurosteroid level 
• Measure weight 
• CTNI to conduct HAMD17 interview 
• Collect AEs 
• Conduct CSSRS interview  
• Review inclusion and exclusion criteria (including hematology and chemistry from the 
screening visit); HAMD17 (conducted by CTNI) must be ≥ 22 for randomization. 
• Start Q15 minutes health checks (e.g. to observe general wellbeing and behavior, monitor 
infusion)  
• If the subject is breastfeeding, she is encouraged to “pump and dump” while inpatient and 
for 45 days after the discharged from the unit.  She should be provided with a breast 
pump. 
7.3 
Infusion Days (+ 1 to + 4) – Cohorts 1-5 
 
Before Infusion (Morning of Day + 1)  
7.3.1
• Review concomitant medications  
• CTNI to conduct HAMD17 interview 
• EPDS 


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• STAI6 
• Assess CGI-S 
• Collect AEs 
• Collect vital signs (BP, pulse, temperature, pulse oximetry, respiratory rate) 
• Stanford Sleepiness Scale (SSS) 
• Conduct CSSRS interview 
• Randomization 
• Start monitoring of pulse oximetry 
• The subject’s bed should be placed close to the nursing station in an area that allows 
visual observation of the subject throughout the infusion period.  
 
During Infusion (Days +1 to +4)  
7.3.2
• Start bolus/infusion in the morning of Day +1 (0h) after baseline assessments are 
completed 
• CTNI to conduct interviews for HAMD17 (+12h, +24h, +48h, +60h, +72h) 
• Conduct interviews for CGI-I (+12h, +24h, +48h, +60h, +72h) 
• EPDS (+60h) 
• STAI6 (+12h, +24h, +48h, +60h, +72h) 
• Collect AEs 
• Collect ECG (+12h, +24h, +48h, +72h) 
• Collect VS (BP, pulse, respiratory rate, pulse oximetry, temperature): (+4, +8h, +12, 
+18h, +24h, +32h, +40h, +48h, +56h, +60h, +72h) 
• Collect SSS (+8h, +32h, +56h, +72h) 
• Collect pharmacokinetic samples (+12h, +24h, +48h, +72h) 
• Record concomitant medications  
• Lower the infusion rate to half what was prescribed for the cohort (for example, lower the 
infusion rate from 4 mg/h to 2 mg/h) (+48h) 
• Collect safety laboratory tests (+48h) 
• Collect neurosteroid level (+48h) 
• End infusion (+60h) 
• Collect urine sample for urinalysis, drug screen and urine pregnancy test (+72h) 
• Conduct CSSRS interview (+12h, +36h, +60h, +72h) 
• Perform a physical examination (+72h) 


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• Stop monitoring of pulse oximetry and Q15 min health checks (+72h) 
• Discharge subject (+72h) 
7.4 
Post Discharge Follow-up Period (Days +5 to +30) – Cohorts 1-5  
 
First Post-discharge Visit 7 Days After Discharge from the Unit (Day +11; 
7.4.1
visit window)  
• Review concomitant medications and therapies  
• Collect vital signs (BP, pulse, temperature, pulse oximetry, respiratory rate) 
• Collect safety laboratory tests.  
• Collect neurosteroid level 
• Collect pharmacokinetic sample 
• Collect urine sample for urinalysis, drug screen and urine pregnancy test  
• Measure weight 
• Conduct interviews for HAMD17 (CTNI) and CGI-I  
• EPDS 
• STAI6 
• Conduct CSSRS interview 
• Collect AEs 
 
Second Post-discharge Visit 30 Days After Discharge From the Unit 
7.4.2
(Day +34)  
• Review concomitant medications and therapies  
• Collect vital signs (BP, pulse, temperature, pulse oximetry, respiratory rate) 
• Measure weight 
• Collect urine sample for urinalysis, drug screen and urine pregnancy test,  
• Collect pharmacokinetic sample  
• Conduct CSSRS interview 
• Collect AEs 
• Conduct interviews for HAMD17 (CTNI) and CGI-I  
• EPDS 
• STAI6 
 


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Table 1. Schedule of Assessments – Cohorts 1-5 
Day 
Day -14 to 
-1 
Day 0 
Day 1 (Start 
Infusion in 
AM, 0h) 
Day 2  
Day 3 (End 
Infusion in 
PM) 
Day 4 
(Discharge) 
Day 11 (Day 7 
Post Discharge)  
Day 34 (Post 
Discharge 
Day 30) 
VISIT 
Screening 
Admission 
Infusion 
Infusion 
Infusion 
Discharge 
Follow-up 
Follow-up 
 
 
 
0h-24 
24-48h 
48-72 
72h 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics,  Medical History 
X 
 
 
 
 
 
 
 
MINI neuropsychiatric interview 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
 
Concomitant Meds and Therapy Review 
X 
X 
X 
X 
X 
X 
X 
X 
Admission to the unit 
 
X 
 
 
 
 
 
 
Discharge from the unit 
 
 
 
 
 
X 
 
 
Physical examination  
X 
 
 
 
 
X 
 
 
SAFER Interview (during screening) 
X 
 
 
 
 
 
 
 
Vital signs (BP, Pulse, pO2, RR, temp) 
X 
X 
X 
X 
X 
X 
X 
X 
Height (screening only) and weight  
X 
X 
 
 
 
 
X 
X 
ECGs 
X 
X 
X 
X 
X 
X 
 
 
Safety Laboratory Tests 
X 
X 
 
 
X 
 
X 
 
Neurosteroid level  
 
X 
 
 
X 
 
X 
 
Urinalysis, Drug Screen and Pregnancy Tests 
X 
X 
 
 
 
X 
X 
X 
CSSRS 
X 
X 
X 
X 
X 
X 
X 
X 
Record AEs  
 
X 
X 
X 
X 
X 
X 
X 
Randomization  
 
 
X 
 
 
 
 
 
Start bolus/infusion (0h) 
 
 
X 
 
 
 
 
 
Lower the infusion rate to half (+48h) 
 
 
 
 
X 
 
 
 
End infusion (+60h) 
 
 
 
 
X 
 
 
 
PK sample collection 
 
 
X 
X 
X 
X 
X 
X 
HAMD17 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
CGI-S 
X 
 
X 
 
 
 
 
 
EPDS 
X 
 
X 
 
X 
 
X 
X 
SSS 
 
 
X 
X 
X 
X 
 
 
STAI6 
X 
 
X 
X 
X 
X 
X 
X 
Q15 min health checks & pulse ox 
 
 
throughout 
 
 


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Specific timepoints for assessments on days +1, +2, +3 and +4: - Cohorts 1-5 
PK samples: +12h, +24h, +48h, +72h 
HAMD17: before start of infusion, +12h, +24h, +48h, +60h, +72h all done by CTNI 
CGI-I: +12h, +24h, +48h, +60h, +72h  
CGI-S: before start of infusion 
EPDS: before start of infusion, +60h  
STAI6: before start of infusion, +12h, +24h, +48h, +60h, +72h  
ECG: +12h, +24h, +48h, +72h  
Vital Signs: (BP/P/pO2/RR/Temp): before start of infusion, +4, +8h, +12, +18h, +24h, +32h, +40h, +48h, +56h, +60h, +72h  
SSS: before start of infusion, +8h, +32h, +56h, +72h  
CSSRS: before start of infusion, +12h, +36h, +60, +72h  
Safety laboratory tests and neurosteroid level: +48h  
Urinalysis drug and pregnancy test: +72h  
Physical examination: +72h 
AEs and concomitant medications are collected throughout the inpatient stay.  
Q15min health checks are done from the time of admission to the time of discharge.  Pulse oximetry (pO2) must be monitored throughout the infusion, including 
during the night when the subject is sleeping.  The subject should be awakened if pulse oximetry falls < 91%.   
The following priority order will be in effect when more than 1 assessment is required at a particular time point: 1) HAMD17 2) CGI-I/CGI-S 3) EPDS 4) STAI6 
5) SSS 6) CSSRS 7) vital signs 8) ECG 9) safety labs and neurosteroid level 10) PK sample 11) neurosteroid level 12) urinalysis drug screen and pregnancy test 
13) physical examination 
Day 11 and Day 34 visits have visit windows of ± 3 and ± 5 days, respectively 
 


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7.5 
Infusion (Day +1) – Cohort 6 (Screening and Admission visits for Cohort 6 
described in Section 7.1 and 7.2, respectively) 
 
Before Infusion (Morning of Day +1; Baseline)  
7.5.1
• CTNI to conduct HAMD17 interview 
• EPDS 
• STAI6 
• Assess CGI-S 
• Review concomitant medications  
• Collect vital signs (BP, pulse, temperature, pulse oximetry, respiratory rate),  
• Stanford Sleepiness Scale (SSS) 
• Conduct CSSRS interview 
• Collect AEs 
• Randomization  
• The subject’s bed should be placed close to the nursing station in an area that allows 
visual observation of the subject  
• Start monitoring of pulse oximetry 
 
 
During the Infusion and Evening of Day +1 (Day +1) 
7.5.2
• Start 6-hour infusion at 40 mL/hr at 9 am of Day +1 (0h) after baseline assessments are 
completed (listed above) 
• End 6-hour infusion 
• Complete +6h assessments after the end of the 6-hour infusion CTNI to conduct 
interviews for HAMD17 (+6h) 
• Conduct interviews for CGI-I (+6h) 
• EPDS (+6h) 
• STAI6 (+6h) 
• Collect AEs 
• Collect ECG (+6h) 
• Collect VS (BP, pulse, respiratory rate, pulse oximetry, temperature): (+6h) 
• Collect SSS (+6h) 
• Collect pharmacokinetic samples (+7h [i.e., 1 hour after the end of the infusion], at +10h 
[i.e., just before the oral dose], and at 1, 2, 3, and 4 hours after the oral dose 
• Collect neurosteroid level (+6h) 
• Record concomitant medications  
• Conduct CSSRS interview (+6h)  


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• Administer the IP: 900 mg of ganaxolone, or matching placebo (four 225 mg capsules or 
four placebo capsules), at dinner time (i.e., at 7 pm) ±15 minutes of a fatty meal or snack 
(e.g., fatty yogurt, nuts, avocado) 
• Continue monitoring of pulse oximetry and Q15 min health checks  
 
 
Day + 2 (Discharge and transition to outpatient treatment) 
7.5.3
• The assessments listed below are completed before discharge 
• CTNI to conduct interviews for HAMD17  
• Conduct interviews for CGI-I  
• EPDS  
• STAI6  
• Collect AEs  
• Collect ECG 
• Collect VS (BP, pulse, respiratory rate, pulse oximetry, temperature) 
• Collect SSS  
• Collect a pharmacokinetic sample at 8 am (23h) 
• Collect neurosteroid level  
• Record concomitant medications  
• Conduct CSSRS interview 
• Perform physical examination 
• Dispense medication bottle 
• Provide the subject with dosing instructions and subject diary completion. 
• Subject will take the IP (900 mg dose of ganaxolone, or matching placebo) at dinner time 
(four 225 mg capsules, or matching placebo capsules) 
7.6 
Outpatient treatment phase (Days + 3 – +29) - Cohort 6 
 
Safety phone calls (Days +3, +5, +10 and +13) 
7.6.1
• A safety phone call is made on days +3, +5, +10, and +13 by the PI (or the sub-I). The 
subject is asked about her general wellbeing. AEs are recorded.  
 
 
Visit 3 HAMD Call (Day +4 ±1 day) 
7.6.2
• CTNI to conduct HAMD17 interview 
 


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Visit 4 (Day +8) 
7.6.3
• CTNI to conduct HAMD17 interview 
• EPDS 
• STAI6 
• Assess CGI-I 
• Review concomitant medications and therapies  
• Collect vital signs (BP, pulse, temperature, pulse oximetry, respiratory rate),  
• Collect ECG 
• Collect urine sample for urinalysis, drug screen and urine pregnancy test 
• Collect safety laboratory tests 
• Collect neurosteroid level 
• Collect a pharmacokinetic sample  
• Stanford Sleepiness Scale (SSS) 
• Conduct CSSRS interview 
• Collect AEs 
• Dispense study medication with a supply to last until the next visit (+ 3 days overage to 
cover for unexpected need to re-schedule a study visit or weekends).  Provide the subject 
with dosing instructions. IP return and accountability. 
• Subject will continue to take study drug (900 mg of ganaxolone, or matching placebo) at 
dinner time (unless the dose is lowered to 675 mg, or 450 mg, or matching placebo at 
dinner time as per instructions from the investigator) 
 
 
Visit 5 HAMD Call (Day +11 ±1 day) 
7.6.4
• CTNI to conduct HAMD17 interview 
 
Visit 6 (Day +15 ±2 days)  
7.6.5
• CTNI to conduct HAMD17 interview 
• EPDS 
• STAI6 
• Assess CGI-I 
• Review concomitant medications and therapies  
• Collect vital signs (BP, pulse, temperature, pulse oximetry, respiratory rate),  
• Collect ECG 


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• Collect urine sample for urinalysis, drug screen and urine pregnancy test 
• Collect safety laboratory tests 
• Collect neurosteroid level 
• Collect a pharmacokinetic sample  
• Measure weight 
• Stanford Sleepiness Scale (SSS) 
• Conduct CSSRS interview 
• Collect AEs 
• Dispense study medication with a supply to last until the next visit (+ 3 days overage to 
cover for unexpected need to re-schedule a study visit or weekends).  Provide the subject 
with dosing instructions. IP return and accountability. 
• Perform physical examination  
 
 
Visit 7 (Day +22 ±3 days) 
7.6.6
• CTNI to conduct HAMD17 interview 
• EPDS 
• STAI6 
• Assess CGI-I 
• Review concomitant medications and therapies  
• Collect vital signs (BP, pulse, temperature, pulse oximetry, respiratory rate),  
• Collect ECG 
• Collect urine sample for urinalysis, drug screen and urine pregnancy test 
• Collect neurosteroid level 
• Collect a pharmacokinetic sample  
• Stanford Sleepiness Scale (SSS) 
• Conduct CSSRS interview 
• Collect AEs 
• Dispense study medication with a supply to last until the next visit (+ 3 days overage to 
cover for unexpected need to re-schedule a study visit or weekends).  Provide the subject 
with dosing instructions. IP return and accountability. 
 
 
Visit 8 (Day +29 ±3 days) 
7.6.7
• CTNI to conduct HAMD17 interview 


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• EPDS 
• STAI6 
• Assess CGI-I 
• Review concomitant medications and therapies  
• Collect vital signs (BP, pulse, temperature, pulse oximetry, respiratory rate),  
• Collect ECG 
• Collect urine sample for urinalysis, drug screen and urine pregnancy test 
• Collect safety laboratory tests 
• Collect a pharmacokinetic sample  
• Measure weight 
• Stanford Sleepiness Scale (SSS) 
• Conduct CSSRS interview 
• Collect AEs 
• Dispense study medication with a supply to last through the taper period. Provide the 
subject with dosing instructions. IP return and accountability. 
• Begin 3-day taper (3 capsules on Day 29, 2 capsules on Day30, 1 capsule on Day31, or, if 
Day 28 dose is other than ganaxolone 900 mg or placebo, follow instructions in section 
3.4.6) 
• Perform physical examination 
 
7.7 
Post–treatment Follow-up Period (Days +29 to +71) – Cohort 6 
 
First Post-treatment Follow-up Visit - 7 days After the Last On-treatment 
7.7.1
Visit (Day +36) 
• The Follow-up Visit 1 should occur about 1 week after the Day 29 visit.  
• CTNI to conduct interviews for HAMD17  
• Perform EPDS 
• Perform STAI6 
• Assess CGI-I  
• Review concomitant medications and therapies  
• Collect vital signs (BP, pulse, temperature, RR) 
• Collect ECG Collect neurosteroid level  
• Collect a pharmacokinetic sample 
• Collect urine sample for urinalysis, drug screen and urine pregnancy test  
• Measure weight  


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• Conduct CSSRS interview 
• Collect SSS 
• Collect AEs  
• IP return and accountability 
 
 
Second Post-treatment Follow-up Visit - 28 days After the Last On-
7.7.2
treatment Visit (Day +57) 
• The Follow-up Visit 2 should occur about 28 days after the Day 29 visit.  
• CTNI to conduct interviews for HAMD17  
• Perform EPDS 
• Perform STAI6 
• Assess CGI-I  
• Review concomitant medications and therapies  
• Collect vital signs (BP, pulse, temperature, RR) 
• Collect safety laboratory tests  
• Collect urine sample for urinalysis, drug screen and urine pregnancy test  
• Measure weight  
• Conduct CSSRS interview 
• Collect SSS 
• Collect AEs  
 
 
Third Post-treatment Follow-up Visit - 42 days After the Last On-treatment 
7.7.3
Visit (Day +71) 
• The Follow-up Visit 3 should occur about 42 days after the Day 29 visit.  
• CTNI to conduct interviews for HAMD17  
• Perform EPDS 
• Perform STAI6 
• Assess CGI-I  
• Review concomitant medications and therapies  
• Collect vital signs (BP, pulse, temperature, RR) 
• Collect urine sample for urinalysis, drug screen and urine pregnancy test  
• Measure weight  
• Conduct CSSRS interview 
• Collect SSS 
• Collect AEs  
 
 


Marinus Phannaceuticals, Inc. 
Protocol 1042-PPD-2002 
Table 2. Schedule of Assessments - Cohort 6 
Day 
Day -14 
Day 0 
to -1 
Admission 
VISIT 
Scl'eenin 
g 
Informed consent 
X 
Demographics, Medical History 
X 
iMINI neuropsychiatric interview 
X 
l!nc!usion/Exclusion criteria 
X 
X 
Concomitant Meds and Therapy Review 
X 
X 
Admission to the unit 
X 
Discharge from the unit 
Physical examination 
X 
SAFER Interview (during screening) 
X 
Vital signs (BP, Pulse, pO2, RR, temp) 
X 
X 
Height ( screening only) and weight 
X 
X 
ECGs 
X 
X 
Safety Laboratory Tests 
X 
X 
Neurosteroid level 
X 
Urinalysis, Drug Screen and Pregnancy Tests 
X 
X 
CSSRS 
X 
X 
Record AEs 
X 
Randomization 
Start infusion (Oh; 9 am ±lh) • 
End infusion (6h) 
PK sample collection° 
HAMD17 ' 
X 
X 
CGI-1 
CGI-S 
X 
EPDS 
X 
sss 
STAI6 
X 
Dispense medication/return accountability 
Oral dosing ( at dinner time) 
Q 15 min health checks & pulse ox• 
X 
Start 3-day taper 
CONFIDENTIAL 
Day 1 
Day l' 
Day 2 
Days3 
&5 
Baseline 
Disc.hal'ge Safety 
Post-BL 
& 
Outpatient 
call 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
throughout the inpatient period 
Version 8.0 / 08 Oct 2018 
Day 4 
Day 8 Days 10 Day 11 
Day lS 
Day 22 
Day 29 Day 36 Day 57 Day71 
&13 
V3 
Safety 
VS 
l" 
2-
3•• 
HAMD V4 outpt 
HAI\ID V6 outpt V7 outpt VS outpt Follow- Follow- Follow-
Call 
call 
Call 
UP 
UP 
UP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
throughout the outpatient period 
X 
Page 54 of 104 


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a Infusion starts at 9 am and ends 6 hours later at 3 pm and is administered at a constant rate of 40 mL/hr.  
b Twelve pharmacokinetic samples are collected in Cohort 6:  
On Day 1 subjects will have 6 PK samplings: at 1 hour after the end of the 6-hour infusion (i.e., at 4 pm), at 7 pm (just prior to the oral dosing), and at 1, 2, 3, and 
4 hours post oral dosing (at 8, 9, 10, and 11 pm) as well at 8 am the following morning (on Day 2) prior to discharge. 
A pharmacokinetic sample is also collected on Days 8, 15, 22, 29, and 36 during the study visit.  
c All HAMD17 ratings, except the one done at screening, will be conducted by CTNI raters. 
d Q15min health checks are done from the time of start of the infusion to the time of discharge.  Pulse oximetry (pO2) must be monitored from the start of the 
infusion throughout the inpatient period, including during the night when the subject is sleeping.  The subject should be awakened if pulse oximetry falls < 91%.   
e On Day +1 all efficacy assessments should be conducted first before lab draws, if possible.  
f All Day +2 assessments, including PK and neurosteroid levels, are to be done before the subject is discharged from the unit. 
The following priority order will be in effect when more than 1 assessment is required at a particular time point: 1) HAMD17 2) CGI-I/CGI-S 3) EPDS 4) STAI6 
5) SSS 6) CSSRS 7) vital signs 8) ECG 9) safety labs and neurosteroid level 10) PK sample 11) neurosteroid level 12) urinalysis drug screen and pregnancy test 
13) physical examination 
 
All outpatient visits have a ± 3-day visit window, except Visits 3 and 5 which have just a ± 1-day visit window and Visits 4 and 6 which have a ± 2-day visit 
window.  
 
 


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7.8 
Study Evaluations and Procedures 
 
Demographic, Medical History and Other Baseline Characteristics 
7.8.1
Demographic and Other Baseline Characteristics will be collected and recorded on the 
appropriate sections of the eCRF at the time of the screening visit.  
 
Informed Consent 
7.8.2
The nature of the study and its risks and benefits will be explained to the subject by the principal 
investigator or designated study personnel.  The purpose of placebo control design and the 
chances of receiving placebo in this study will be discussed with the subject.  
 
Eligibility Review 
7.8.3
An eligibility review will be conducted by the investigator at the visits specified in Table 1 or 2 
using the subject inclusion and exclusion criteria below.  
 
Prior Medication, Concomitant Medication and Concomitant Therapy 
7.8.4
Review 
At screening, prospective subjects will be asked about medications they have taken in the 
previous 60 days, including prescription medications, non-prescription medications, vitamins and 
supplements.  At subsequent visits, the subjects will be asked about medications taken since the 
last visit.  During the inpatient treatment phase concomitant medications taken by the subject 
will be recorded.  
The medications that were taken within the past 60 days will be recorded.  The medications that 
were taken within the past 60 days but stopped before the screening visit are recorded on the 
prior medications eCRF page.  The medications that were taken during the study period between 
the screening visit and last follow-up visit, regardless of whether the medication was started 
during the study period or before the study period, are recorded on the concomitant medications 
eCRF page.  
The following data will be recorded for all medications used by the subject:  drug name, dose, 
regimen, route of administration, start and stop dates, and the indication for use.  
The type of psychological counseling the patient is receiving at the time of screening will be 
recorded on the Concomitant Psychological Treatment eCRF page.  
 
Physical Examination 
7.8.5
A complete physical examination will be performed at screening, before discharge from the unit, 
and during visits 6 and 8 (outpatient visits) of Cohort 6.  
The physical examination will include a review of the following body systems: 
• 
General appearance 


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• 
Skin 
• 
Head, Eyes, Ears, Nose, Mouth and Throat 
• 
Neck/Thyroid/Breastfeeding status  
• 
Musculoskeletal 
• 
Respiratory 
• 
Cardiovascular 
• 
Neurological 
• 
Abdomen 
The physical examination will be documented in the subject’s source documents and on the 
physical examination eCRF.  If a new clinically significant abnormal finding (i.e. not noted at 
screening) occurs after the screening examination, it must be captured as an AE and documented 
on the appropriate AE eCRF page.  
7.8.5.1 
12-lead Electrocardiogram  
A 12-lead ECG will be conducted at the time points described in Table 1 or 2.  Before each 
measurement the subject should be resting in a supine or semi-recumbent position for 
10 minutes.  RR, PR, QRS, QTcF and QTcB will be collected.  ECGs will be measured with 
equipment calibrated as per the ECG vendor’s standard operating procedure.  The ECG results 
will be assessed by a qualified clinician.  The Investigator’s assessment of Normal or Abnormal 
will be recorded and entered in the eCRF page.  If a new clinically significant abnormal finding 
(i.e. not noted at Screening) occurs after the Screening examination, it must be captured as an AE 
or SAE (if it meets criteria for an SAE – see Section 8.0) and documented on the appropriate AE 
eCRF page and, if an SAE, submitted to Marinus Safety Department on the SAE form.   
7.8.5.2 
Clinical Safety Laboratory Evaluations  
The name and address of the central clinical laboratory for this study will be maintained in the 
Investigator’s files at each study site.  
All clinical laboratory assays will be performed according to the laboratory’s normal procedures 
as described in Table 1 or 2.  
Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes.  The investigator 
should assess out-of-range clinical laboratory values for clinical significance, indicating if the 
values are clinically significant or not.  Abnormal clinical laboratory values, which are 
unexpected or not explained by the subject’s clinical condition, may, at the discretion of the 
investigator or sponsor, be repeated as soon as possible until confirmed, explained, or resolved. 
The following clinical laboratory assessments will be performed:  


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Biochemistry  
Sodium, potassium, glucose, chloride, carbon dioxide, creatinine, total protein, blood urea 
nitrogen, albumin, total bilirubin (with reflex fractionation to direct and indirect bilirubin if total 
bilirubin is elevated and outside of the normal range), alanine aminotransferase, aspartate 
transferase, alkaline phosphatase, thyroid stimulating hormone (with reflex to free T4 if thyroid 
stimulating hormone (TSH) is outside of the normal range).  The PI may determine serum βHCG 
levels to confirm or exclude pregnancy.  
Hematology 
Hematocrit, hemoglobin, red blood cell count, mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, platelet count, white blood cell count 
with differential.  
Subjects are not required to be fasting prior to collection of the blood samples. 
Urine analysis including pregnancy test and urine drug screen 
Leukocytes, nitrites, protein, blood, specific gravity, glucose, ketones, urine pregnancy test, urine 
drug screen (cannabis, opioids [including oxycodone, methadone and buprenorphine], cocaine, 
benzodiazepines, barbiturates, alcohol [ethanol], and phencyclidine).  
Confirmatory testing of positive drug screen findings using for example gas chromatography 
mass spectroscopy (GCMS) may be conducted.  
7.8.5.3 
Adverse Event Collection 
Please refer to Section 8.0, Adverse and Serious Adverse Events Assessment. 
7.8.5.4 
Vital Signs 
Vital signs including blood pressure, pulse, respirations, temperature (recorded in Celsius [°C]) 
and pulse oximetry will be monitored at the time points as outlined above.  Vital signs should be 
collected after the subject has been supine for 5 minutes.  If a vital sign measurement is 
scheduled at the same time as a blood draw, vital signs should be collected prior to the blood 
draw.  Blood pressure should be determined by an appropriately-sized cuff (using the same 
method, the same arm and in the same position throughout the study).  Any abnormal screening 
vital sign results considered to be clinically significant should be repeated to confirm the finding.  
Height (in centimeters) will be collected at the screening visit.  Weight (in kilograms) will be 
collected at the screening and 2 follow-up visits. 
During the inpatient phase while the subject is receiving study drug subjects should be monitored 
for pulse oximetry continually, including during the nights.  Monitoring may be interrupted for 
bathroom breaks, lunch etc.  


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If pulse oximetry drops below 91% the patient should be wakened and assessed for excessive 
sedation.  
Any clinically significant deviations from baseline vital signs that are deemed clinically 
significant in the opinion of the investigator are to be recorded as an AE.  
 
Interviews, Questionnaires and Scales 
7.8.6
The scales and assessments are listed in Appendix 2.  A separate file containing each 
scale/assessment will be provided to the site. 
7.8.6.1 
Mini International Neuropsychiatric Interview 7.0 
The Mini International Neuropsychiatric Interview (MINI) is a short, clinician-administered, 
structured diagnostic interview, with an administration time of approximately 15 minutes.  The 
MINI will be administered at the screening visit.  
7.8.6.2 
The Hamilton Depression Rating Scale  
The Hamilton Depression Rating Scale (HAMD) is a commonly-used semi-structured 
clinician-rated instrument which assess the range of symptoms that are most frequently observed 
in subjects with major depression.  HAMD has undergone a considerable amount of 
psychometric study and is accepted as a valid standard of symptom outcome assessment in 
studies of major depression.  In this study the symptoms of depression will be scored using the 
original 17-item HAMD scale (HAMD17).  The 6-item version of this scale, known as HAMD6, 
will be derived from these data and used as an additional measure of changes in symptoms of 
depression.  The items on the HAMD6 scale are as follows:  depressed mood, work and interests, 
general somatic symptoms (tiredness), anxiety, guilt feelings, and psychomotor retardation.  
Both HAMD6 and HAMD17 have been validated and used in many clinical trials of 
antidepressant medications.9  The use of the 6-item scale is justified because many items on the 
17-item version cannot be expected to change over short period of time (e.g. weight or sleep). 
All HAMD17 ratings, except the one done at screening, will be conducted by CTNI raters. 
7.8.6.3 
Stanford Sleepiness Scale 
Stanford Sleepiness Scale (SSS) is a simple 8-item self-rated scale measuring level of sleepiness 
the subject is feeling.  Level 1 is “feeling active, vital, alert or wide-awake” level 7 is “no longer 
fighting sleep, sleep onset soon; having dream-like thoughts”; level 8 is sleeping.   
7.8.6.4 
Clinical Global Impression-Improvement (CGI-I) and Clinical Global 
Impression-Severity (CGI-S) 
The Clinical Global Impression – Improvement scale (CGI-I) is a 7-point scale that asks 
the clinician to assess how much the subject's illness has improved or worsened relative to a 
baseline state at the beginning of the intervention.  It is rated as:  1, very much improved; 
2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 
7, very much worse.  The Clinical Global Impression – Severity scale (CGI-S) is a 7-point scale 


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Page 60 of 104 
that asks the clinician to rate the severity of the subject's depression at the time of assessment, 
relative to the clinician's past experience with subjects who have the same diagnosis.  
Considering total clinical experience, a subject is assessed on severity of depression at the time 
of rating 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 
5, markedly ill; 6, severely ill; or 7, extremely ill. 
7.8.6.5 
Edinburgh Postnatal Depression Scale (EPDS) 
The (EPDS) is a 10-question self-rated instrument for assessment symptoms of PPD, such as 
worry, sleep, mood and enjoyment.  Two questions assessing obsessive thoughts are added to 
this questionnaire (“How much of your time is occupied by obsessive thoughts over the past 
24h?” and “How much distress do your obsessive thoughts cause you?), but they are not counted 
towards the total score in the statistical analysis.  These 2 questions are rated on a 5-point scale.  
7.8.6.6 
Spielberg Trait-State Anxiety Inventory, 6 item version  
The Spielberg Trait-State Anxiety Inventory, six item version (STAI6) is a short questionnaire 
evaluating anxiety state.  The STAI6 has 6 questions, such as “I feel calm” and “I feel tense,” 
which the subject rates on a scale corresponding to “not at all,” “somewhat,” “moderately,” and 
“very much.”12  
7.8.6.7 
SAFER interview 
Staff psychiatrists or psychologists at the Massachusetts General Hospital Clinical Trials 
Network and Institute (CTNI) will perform independent remote SAFER interview (State versus 
trait; Assessability; Face validity; Ecological Validity; and Rule of 3 Ps (pervasive, persistent, 
and pathological)) for the screened subjects who are deemed eligible for randomization to 
confirm validity of the diagnosis of PPD and eligibility for the study from depression 
perspective.  
 
Columbia Suicide Severity Rating Scale (CSSRS) 
7.8.7
The CSSRS is a unique, simple, and short method of assessing both behavior and ideation that 
tracks all suicidal events, and provides a summary of suicidality.13  It assesses the lethality of 
attempts and other features of ideation (frequency, duration, controllability, reasons for ideation, 
and deterrents) that are significantly predictive of completed suicide. 
 
Pharmacokinetic Sampling 
7.8.8
Blood samples for pharmacokinetic analysis will be drawn at the times specified in Tables 1 and 
2 to allow determination of ganaxolone plasma levels.  
 
Neurosteroid levels  
7.8.9
A sample for determination of neurosteroid levels (allopregnanolone and possibly other 
progesterone metabolites) will be drawn at the times specified in Tables 1 and 2.  


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Volume of Blood to Be Drawn from Each Subject 
7.8.10
Table 3. Volume of Blood to Be Drawn from Each Subject (Cohorts 1-5) 
Assessment 
Approximate Sample 
Volume (mL)a 
Number of 
Samples 
Approximate Total 
Volume (mL) 
Pharmacokinetic samples 
6 
6 
36 
Safety hematology  
3 
4 
12 
Safety chemistry 
7 
4 
28 
Neurosteroid level 
6 
3 
18 
Total mL 
 
 
94 
During this study, approximately 94 mL of blood will be drawn from all subjects during the 
study (Cohorts 1-5). 
Table 4. Volume of Blood to Be Drawn from Each Subject (Cohort 6) 
Assessment 
Approximate Sample 
Volume (mL)a 
Number of 
Samples 
Approximate Total 
Volume (mL) 
Pharmacokinetic samples 
6 
12 
72 
Safety hematology  
3 
6 
18 
Safety chemistry 
7 
6 
42 
Neurosteroid level 
6 
7 
42 
Total mL 
 
 
174 
Approximately 174 mL of blood will be drawn from all subjects during the study (Cohort 6). 
 


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8.0 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT 
8.1 
Definition of Adverse Events, Period of Observation, Recording of Adverse Events 
An AE is any untoward medical occurrence in a 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 
(investigational) product, whether or not related to the medicinal (investigational) product 
(ICH Guidance E2A 1995).  
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (e.g. “Have you had any health problems since the previous 
visit/you were last asked?”).  All AEs are collected from the time the informed consent is signed 
until the end of the follow-up period.  This includes events occurring during the screening phase 
of the study, regardless of whether or not investigational product is administered.  Where 
possible, a diagnosis rather than a list of symptoms should be recorded.  If a diagnosis has not 
been made, then each symptom should be listed individually.  All AEs should be captured on the 
appropriate AE pages in the eCRF and in source documents.  In addition to untoward AEs, 
unexpected benefits outside the investigational product indication should also be captured on the 
AE eCRF. 
All AEs must be followed to closure, regardless of whether the subject is still participating in the 
study.  Closure indicates that an outcome is reached (AE has resolved), stabilization achieved 
(the investigator does not expect any further improvement or worsening of the event), or the 
event is otherwise explained.  When appropriate, medical tests and examinations are performed 
so that resolution of event(s) can be documented. 
 
Severity Categorization 
8.1.1
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity.  Any changes in the severity of the AE must be recorded. 
The medical assessment of severity is determined by using the following definitions: 
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual activities of daily 
living. 
Moderate: A type of AE that is usually alleviated with specific therapeutic intervention.  The 
event interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the research subject. 
Severe: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 


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Causality Categorization 
8.1.2
The investigator will assess causal relationship between the investigational product and each AE 
(i.e., their relationship to study drug), and answer “yes” or “no” to the question, “Do you 
consider that there is a reasonable possibility that the event may have been caused by the 
investigational product?”  
 
Variables 
8.1.3
The following variables will be collected for each AE: 
• AE  
• The date and time when the AE started and stopped 
• Maximum intensity or intensity or changes in intensity 
• Whether the AE is serious or not 
• Investigator causality rating against the study drug (yes or no) 
• Action taken with regard to investigational product (none, dose reduced, interrupted, 
withdrawn)  
• AE caused subject’s discontinuation from study (yes or no) 
• Outcome (fatal, not recovered/not resolved, recovered/resolved with sequelae, 
recovering/resolving, recovered/resolved, unknown) 
 
Symptoms of the Disease Under Study 
8.1.4
Symptoms of the disease under study (e.g. depression) should not be classified as AEs as long as 
they are within the normal day-to-day fluctuation or expected progression of the disease and are 
part of the efficacy data to be collected in the study; however, significant worsening of the 
symptoms should be recorded as an AE. 
 
Adverse Events Based on Clinical Laboratory and Other Safety Evaluations 
8.1.5
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the investigational product, a shift 
of a parameter is observed from a normal value to an abnormal value, or a there is a further 
worsening of an already abnormal value.  When evaluating such changes, the extent of deviation 
from the reference range, the duration until return to the reference range, either while continuing 
treatment or after the end of treatment with the investigational product, and the range of variation 
of the respective parameter within its reference range, must be taken into consideration. 
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (e.g. concomitant disease) is found for the 
abnormal values. 


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Page 64 of 104 
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE. 
 
Adverse Events Based on Signs and Symptoms 
8.1.6
All AEs spontaneously reported by the subject or reported in response to the open question from 
the study personnel: “Have you had any health problems since the previous visit/you were last 
asked?” or revealed by observation, will be collected and recorded in the eCRF. 
 
Pregnancy 
8.1.7
All pregnancies are to be reported from the time informed consent is signed until the end of the 
follow-up period. 
Any report of pregnancy for any study participant must be reported within 24 hours to Marinus 
Safety Department or its delegate using the Pregnancy Report Form (and any applicable 
follow-up reports).  The study participant must be withdrawn. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant.  It is the responsibility of the investigator to obtain this information 
within 30 calendar days after the initial notification and approximately 30 calendar days 
postpartum.  
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Marinus Serious Adverse Event Form.  
Note:  An elective abortion is not considered an SAE. 
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Marinus Serious Adverse Event Form to Marinus Safety 
Department.  The test date of the first positive serum/urine β-human chorionic gonadotropin 
(β-HCG) test or ultrasound result will determine the pregnancy onset date. 
8.2 
Serious Adverse Event Procedures 
 
Reference Safety Information 
8.2.1
The reference for safety information for this study is the Investigator’s Brochure, which the 
sponsor has provided under separate cover to all investigators. 
 
Reporting Procedures 
8.2.2
All initial and follow-up SAE reports must be reported by the investigator to Marinus Safety 
Department within 24 hours of the first awareness of the event.  
The investigator must complete, sign, and date the Marinus Serious Adverse Event Forms and 
verify the accuracy of the information recorded on the form with the corresponding source 
documents and fax or e-mail the form to:  


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Email:  safetyPPD2002@marinuspharma.com  
Fax:  484-679-2138  
Note:  The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication errors unless they result in an SAE.  
 
Serious Adverse Event Definition 
8.2.3
A serious adverse event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose: 
• Results in death 
• Is life-threatening.  Note:  The term “life-threatening” in the definition of “serious” 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 that hypothetically might have caused death if it was more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization.  Note:  
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs.  For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as an SAE(s). 
• Results in persistent or significant disability/incapacity 
• Is a congenital abnormality or birth defect  
• Is an important medical event.  
Note:  Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 1 
of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home; blood 
dyscrasias or convulsions that do not result in inpatient hospitalization; or the development of 
drug dependency or drug abuse.  
 
Serious Adverse Event Collection Time Frame 
8.2.4
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the end of the follow-up period and must be reported to the Marinus 
Safety Department or its delegate within 24 hours of the first awareness of the event.  In 
addition, the Marinus medical monitor should be informed of the event within 24 hours via either 
email or a phone call.  
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Marinus Safety 
Department within 24 hours of the first awareness of the event.  


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Serious Adverse Event Onset and Resolution Dates 
8.2.5
The onset date of the SAE is defined as the date the event meets serious criteria.  The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic.  In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively. 
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate. 
 
Fatal Outcome 
8.2.6
Any SAE that results in the subject’s death (i.e. the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the resolution 
date.  For all other events ongoing at the time of death that did not contribute to the subject’s 
death, the outcome should be considered not resolved, without a resolution date recorded. 
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (e.g. drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received the investigational product).  The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.  
 
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
8.2.7
Reporting 
The sponsor or its delegate is responsible for notifying the relevant regulatory authorities of 
related, unexpected SAEs. 
In addition, the sponsor or its delegate is responsible for notifying active sites of all related, 
unexpected SAEs occurring during all interventional studies across the ganaxolone clinical 
development program.  
The investigator is responsible for notifying the local Institutional Review Board (IRB), local 
Ethics Committee (EC), or the relevant local regulatory authority of all SAEs that occur at his or 
her site as required. 


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9.0 
DATA MANAGEMENT AND STATISTICAL METHODS 
9.1 
Data Collection 
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRFs.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  Once a subject is enrolled, it is expected that site personnel 
will complete the eCRF entry within approximately 2 business days of the subject’s visit.  
During the inpatient phase the site must complete the eCRF entry daily (every evening) to allow 
monitoring of the data.  
9.2 
Clinical Data Management 
Data are to be entered into a clinical database as specified in the eCRF completion guidelines or 
data management plan.  Quality control and data validation procedures are applied to ensure the 
validity and accuracy of the clinical database. 
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures.  Data queries requiring clarification are 
to be communicated to the site for resolution.  Only authorized personnel will make corrections 
to the clinical database, and all corrections are documented in an auditable manner. 
9.3 
Data Handling Considerations 
Data that may potentially unblind the treatment assignment (i.e. investigational product serum 
concentrations, treatment allocation, and investigational product preparation/accountability data) 
will be handled with special care during the data cleaning and review process.  These data will be 
handled in such a way that, prior to unblinding, any data that may unblind study team personnel 
will be presented as blinded information or otherwise will not be made available.  If applicable, 
unblinded data may be made available to quality assurance representatives for the purposes of 
conducting independent drug audits.  
9.4 
Handling of Missing and Incomplete Data 
While every attempt must be made by the Investigator to provide complete data, there are cases 
in which this may not always be possible (e.g. incomplete subject recall of start and stop dates).  
Unrecorded values will be treated as missing, except for severity and relationship to 
investigational medicinal product for AEs.  If the severity or relationship to investigational 
medicinal product is missing for an AE, which occurred post administration of investigational 
medicinal product, the event will be regarded as severe and related to investigational medicinal 
product, respectively. 


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The appropriateness of the method(s) described for handling missing data for other variables will 
be reassessed at data reviews.  Any necessary changes or refinements will be documented in the 
Statistical Analysis Plan (SAP).  Depending on the extent of missing values, further investigation 
may be made into the sensitivity of the analysis results, to the method(s) specified. 
9.5 
Statistical Analysis Plan 
Data analyses will primarily be descriptive.  The purpose of this study is to identify a ganaxolone 
dose and exposure level that is safe and well tolerated.  Efficacy data will be collected but will be 
considered hypothesis-generating i.e., there are no a priori hypotheses on which the study was 
powered. Results from exploratory statistical analyses may be presented but only to aid in 
interpretation.   
The SAP will provide the statistical methods and definitions for the analysis of the safety and 
efficacy data, and it will describe the approaches to be taken for summarizing other study 
information such as subject disposition, demographics and baseline characteristics, 
investigational product exposure, and prior and concomitant medications.  The SAP will also 
include a description of how missing, or unused data will be addressed.  
The SAP will be finalized prior to completion of the first cohort to preserve the integrity of the 
statistical analysis and study conclusions. This will not preclude amendments to the SAP before 
database lock. 
 
Planned Interim Analysis  
9.5.1
Safety and efficacy data from each cohort will be unblinded, and analyses will be conducted for 
the purpose of dose selection for the next cohort.  The dose for the next cohort will be decided 
based on these interim data analyses.  The decision how to adjust the dose and/or the duration of 
the infusion will be made based on recommendations by a Data Review Committee (DRC) 
composed of the sponsor’s Chief Medical Officer, and at least 2 other external physicians.  At 
least one of the members will have special expertise in the clinical care of women with 
depression or postpartum depression.  One of the members will have expertise in the conduct of 
clinical trials or analysis of clinical trial data. The study team and all parties other than the DRC 
will remain blinded.  
The dose for the subsequent cohorts will be selected with the goal of gaining additional 
information on ganaxolone’s tolerability and dose-response profile.  
A separate DRC guidance document outlines the principles for dose selection.  Marinus may 
decide to stop the study, or make the data public, after completion of any cohort.  
 
Justification for Sample Size 
9.5.2
No formal hypothesis testing will be performed and the sample size is not based on statistical 
power considerations.  The sample size was chosen based on experience with other studies 
conducted with compounds in early clinical development.  A population of about 6 to 10 subjects 
per dose is commonly tested in studies which aim to establish a tolerability range for a new 
compound or a new formulation, and is used as a guide for a minimum cohort size for this study.  


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Similar study design was recently used to assess safety and identify an efficacy signal in major 
depressive disorder for NSI-189.3  
 
Study Population 
9.5.3
The Screened Set will consist of all subjects who have signed an informed consent. 
The Randomized Set will consist of all subjects randomized. 
The Safety Set will consist of all subjects who received IP.  
The modified Intent to Treat Set (mITT) will consist of all subjects in the Safety Set who have 
at least 1 post-randomization efficacy assessment. 
The Per-Protocol Set will consist of all subjects in the mITT set who do not have major protocol 
deviations that may affect key efficacy endpoints.  
The Infusion Completer Set will consist of all subjects in the Safety Set who completed the 60-
hour infusion in Cohort 1-5, and who completed the initial infusion in Cohort 6.  
The Completer Set will consist of all subjects in the Safety Set who completed the 60-hour 
infusion and attended the final safety follow-up visit in Cohorts 1-5. In Cohort 6 the completer 
set will consist of subjects who completed the initial infusion and oral IP dosing period with at 
least 80% oral dosing compliance and attended all outpatient visits including the safety follow-
up visits.  
 
Demographic and Baseline Characteristics 
9.5.4
Descriptive summaries of demographic and baseline characteristics as well as subject disposition 
will be presented by treatment group. 
Baseline characteristics will include a summary of the following: 
• 
Subject demographics 
• 
Pre-existing medical conditions 
• 
Prior therapies. 
Continuous variables such as age, weight, and height will be summarized using number of 
observations, mean, standard deviation, median, minimum, and maximum values.  Categorical 
variables, like sex and race, will be summarized using number of observations and percentages. 
Medical history will be summarized by treatment group using the number of observations and 
percentages of subjects reporting each category. 
 
Investigational Medicinal Product 
9.5.5
Summary statistics for the duration of exposure to investigational medicinal product will be 
presented by treatment group. 


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Concomitant Medication 
9.5.6
Concomitant medications will be listed and summarized by preferred drug name and treatment 
group. 
 
Safety Analyses 
9.5.7
Reported AE terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The incidence of Treatment Emergent AEs (TEAEs), defined as any AE that started 
or worsened after first administration of IP, will be summarized by treatment group, system 
organ class preferred terms, severity and relatedness for each cohort.  SAEs and AEs leading to 
discontinuation of the study drug will be listed separately for each cohort.  
The absolute values and change from baseline in laboratory tests, vital signs, SSS, ECGs and 
CSSRS will be summarized by treatment group for each cohort.  
Potentially clinically important findings will be included in AE summaries and listings.  
Results of the physical examination (baseline and discharge) will be listed.  
 
Efficacy Analyses 
9.5.8
9.5.8.1 
  Primary Endpoint 
The primary efficacy endpoint will be HAMD17 total score change from baseline to 60 hours 
post-infusion (on Day 3) for Cohorts 1-3 and to Day 29 for Cohort 6. The primary analysis in 
each cohort will be done using the mITT set. Although the trial is not powered for inferential 
analysis and there is no consideration for control of type 1 error across multiple cohorts, a 
clinically meaningful numeric difference in means of 3-4 points between ganaxalone and placebo 
treatment groups would be considered an indication of efficacy and will be the most influential 
outcome in the overall assessment of the efficacy of ganaxalone in treating PPD. 
9.5.8.2 
Secondary Endpoints 
The trial will also evaluate the following secondary endpoints at each post-baseline data 
collection time point to provide additional evidence of the efficacy of ganaxalone in treating 
PPD: 
• Change from baseline in HAMD17 total score other than at 60 hours post-infusion (on Day 
3) for Cohorts 1-3 and to Day 29 for Cohort 6 
• HAMD17 response defined as at least a 50% reduction from baseline in total score 
• HAMD17 remission defined as total score <= 7 
• Change from baseline in EPDS total score 
• Change from baseline in STAI6 
• CGI-I 
 


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9.5.8.3 
Explorato1y Endpoints 
I 
I 
I 
I 
I 
9.5.8.4 
Statistical Methods 
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Observed values and changes from baseline for HAMD 17, EPDS, and STAI6 total scores, 
subscales, and individual items will be summarized by visit. The categorical outcomes of 
HAMD 17 response, HAMD 17 remission, and CGI-1 will be summarized by visit. 
The prefen ed approach for explorato1y analysis of continuous efficacy variables will be mixed 
model repeated measures (MMRM) but other approaches such as t-tests, analysis of covariance, 
or non-parametric methods may be used if necessaiy or more practical. Similarly, the prefe1Ted 
approach for analysis of categorical efficacy variables will be repeated measures (e.g., 
generalized estimating equations) but other approaches such as chi squai·e or Fisher's exact tests 
maybe used. 
9.5.9 
Other Analyses 
No other analyses ai·e planned in this study. 
9. 5 .10 
Pharmacokinetic Analyses 
The following phan nacokinetics parameters will be estimated for each subject receiving 
ganaxolone, if sufficient data are available: Maximal plasma concentration (Cmax), concentration 
at steady-state (Css, detennined by the mean concentrations once steady-state is achieved by 
visual inspection), AUCo.24 (calculated as Css multiplied by 24 hours). PK samples will be 
collected from subjects pa1t icipating in Cohort 6 after the IV infusion, before and during the oral 
dosing po1tion of the study. 
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10.0 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This study is conducted in accordance with current applicable regulations, International 
Conference on Harmonisation (ICH), European Union (EU) Directive 2001/20/EC and its 
updates, and local ethical and legal requirements.  
The name and address of each third-party vendor (e.g. CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate. 
10.1 
Sponsor’s Responsibilities 
 
Good Clinical Practice Compliance 
10.1.1
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), EU Directive 2001/20/EC, as 
well as all applicable national and local laws and regulations. 
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines.  Records and data may additionally be 
reviewed by auditors or by regulatory authorities. 
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study.  The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site. 
 
Public Posting of Study Information 
10.1.2
The sponsor is responsible for posting appropriate study information on applicable websites.  
Information included in clinical study registries may include participating investigators’ names 
and contact information.  
 
Study Suspension, Termination, and Completion 
10.1.3
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason.  
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate.  Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly. 


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10.2 
Investigator’s Responsibilities 
 
Good Clinical Practice Compliance 
10.2.1
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines. 
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
personnel are available at the site prior to commitment to participate in this study.  The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period. 
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification.  Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study. 
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study. 
 
Protocol Adherence and Investigator Agreement 
10.2.2
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document.  The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria.  Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol. 
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation.  The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor.  Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations. 
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement. 
 
Documentation and Retention of Records 
10.2.3
10.2.3.1 
Case Report Forms 
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor. 
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 


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observations and other data pertinent to the clinical investigation.  CRFs must be completed by 
the investigator or designee as stated in the site delegation log. 
All data will have separate source documentation; no data will be recorded directly onto the 
eCRF.  All data sent to the sponsor must be endorsed by the investigator. 
The Clinical Research Associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan.  If the data are unclear or contradictory, queries are sent for 
corrections or verification of data. 
10.2.3.2 
Recording, Access, and Retention of Source Data and Study Documents 
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, including past psychiatric history.  
The investigator must permit authorized representatives of the sponsor; the IRB/EC; and auditors 
to inspect facilities and to have direct access to original source records relevant to this study, 
regardless of media. 
The CRA/study monitor will check the eCRF entries against the source documents.  The consent 
form includes a statement by which the subject agrees to the monitor/auditor from the sponsor or 
its representatives, national or local regulatory authorities, or the IRB/EC, having access to 
source data (e.g. subject’s medical file, appointment books, original laboratory reports, X-rays 
etc.).  
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (e.g. the US FDA) or 
an auditor. 
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor. 
10.2.3.3 
Audit/Inspection 
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare Products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site. 
10.2.3.4 
Financial Disclosure 
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor.  The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 


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ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998). 
10.3 
Ethical Considerations 
 
Informed Consent 
10.3.1
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments.  All consent 
documentation must be in accordance with applicable regulations and GCP.  Each subject is 
requested to sign and date the subject informed consent form or a certified translation if 
applicable, after the subject has received and read the written subject information and received 
an explanation of what the study involves, including but not limited to: the objectives, potential 
benefits and risk, inconveniences, and the subject’s rights and responsibilities.  A copy of the 
informed consent documentation (i.e., a complete set of subject information sheets and fully 
executed signature pages) must be given to the subject.  This document may require translation 
into the local language.  Signed consent forms must remain in each subject’s study file and must 
be available for verification at any time. 
If local IRB/EC is used, the principal investigator provides the sponsor or its delegate with a 
copy of the consent that was reviewed by the IRB/EC and received their favorable 
opinion/approval.  A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor prior to the start of the study unless it is agreed to 
and documented prior to study start that another party (i.e., CRO or coordinating principal 
investigator) is responsible for this action.  Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor or delegate. 
 
Institutional Review Board or Ethics Committee 
10.3.2
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement. 
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue. 
Investigational product supplies will not be released until the sponsor or its delegate has received 
written IRB/EC approval of and copies of revised documents. 
The investigator is responsible for keeping the IRB/EC apprised of the progress of the study and 
of any changes made to the protocol, but in any case at least once a year.  The investigator must 
also keep the local IRB/EC informed of any serious and significant AEs. 
10.4 
Privacy and Confidentiality 
All sites and laboratories or entities providing support for this study, must, where applicable, 
comply with the HIPAA act of 1996.  A site that is not a covered entity as defined by HIPAA 
must provide documentation of this fact to the sponsor or its delegate. 


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The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After subjects have consented to take part in the study, the sponsor and/or its representatives may 
review their medical records and data collected during the study.  These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; national or local regulatory authorities; and the IRB/EC which 
gave approval for the study to proceed.  The sponsor and/or its representatives accessing the 
records and data will take all reasonable precautions in accordance with applicable laws, 
regulations, and guidelines to maintain the confidentiality of subjects’ identities. 
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor in verifying the accuracy of the data (e.g. to 
confirm that laboratory results have been assigned to the correct subject).  
The results of studies - containing subjects’ unique identifying number, relevant medical records, 
and possibly initials and dates of birth – will be recorded.  They may be transferred to, and used 
in, other countries which may not afford the same level of protection that applies within the 
countries where this study is conducted.  The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities. 
10.5 
Study Results and Publication Policy 
Marinus will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative.  
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, public presentations to the investors in the company, invited lectures, 
opinion pieces, book chapters, electronic postings on medical/scientific or company website, or 
other disclosure of the study results, in printed, electronic, oral or other form.  The results may be 
made public after completion of any cohort.  


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11.0 
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3. Fava M, Johe K, Ereshefsky LG et al. A Phase 1B, randomized, double blind, placebo 
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7. Kanes S, Colquhoun H, Gunduz-Bruce H et al., Sage-547 (allopregnanolone) and Sage-217: 
Investigational Neuroactive Steroid Targeting the GABAA Receptors for treatment of CNS 
Disorders. ASCP Annual Meeting Abstract Book TH25. 2016. 
8. Kaplan PS, Danko CM, Kalinka CJ, et al. A developmental decline in the learning-promoting 
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of depression. Infant Behav Dev. 2012;35:369–79.  
9. Kyle PR, Lemming OM, Timmerby N et al. The Validity of the Different Versions of the 
Hamilton Depression Scale in Separating Remission Rates of Placebo and Antidepressants in 
Clinical Trials of Major Depression. J Clin Psychopharmacol. 2016;36:453-6. 
10. Luisi S, Petraglia F, Benedetto C, et al. Serum allopregnanolone levels in pregnant women: 
changes during pregnancy, at delivery, and in hypertensive patients. J Clin Endocrinol Metab. 
2000;85:2429–33.  
11. Maguire J and Mody I. Steroid hormone fluctuations and GABAAR plasticity. 
Neuropsychoendocrinology. 2009;34:S84-S90. 
12. Marteau TM and Bekker H. The development of a six item short-form of the Spielberger 
Stait-Trait Anxiety Inventory. British Journal of Clinical Psychology. 1992;31:301-6. 


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13. Posner K, Oquendo MA, Gould M et al. Columbia classification algorithm of suicide 
assessment (C-CASA): classification of suicidal events in the FDA’s pediatric suicidal risk 
analysis of antidepressants. Am J Psychiatry. 2007;164:1035-43. 
14. Turkmen S, Backstrom T, Wahlstrom G. Tolerance to allopregnanolone with focus on the 
GABAA receptor. British Journal of Pharmacology. 2011;162:311–27. 
15. Yonkers K, Lin H, Howell HB et al. Pharmacological Treatment of Postpartum Women with 
New Onset Major Depressive Disorder: A Randomized Controlled Trial with Paroxetine. 
Journal of Clinical Psychiatry. 2008;69: 659–65. 
16. Helmreich I, Wagner S, Mergl R, et al. Sensitivity to changes during antidepressant 
treatment: a comparison of unidimensional subscales of the Inventory of Depressive 
Symptomatology (IDS-C) and the Hamilton Depression Rating Scale (HAMD) in patients 
with mild major, minor or subsyndromal depression. Eur Arch Psychiatry Clin Neurosci. 
2012 Jun;262(4):291-304 
17. Boessen R1, Groenwold RH, Knol MJ, et al. Comparing HAMD(17) and HAMD subscales 
on their ability to differentiate active treatment from placebo in randomized controlled trials. 
J Affect Disord. 2013 Mar 5;145(3):363-9. 
18. Thase ME, Chen D, Edwards J, Ruth A. Efficacy of vilazodone on anxiety symptoms in 
patients with major depressive disorder. Int Clin Psychopharmacol. 2014 Nov;29(6):351-6. 


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12.0 
APPENDICES 
Appendix 1. Prohibited Strong CYP3A4 Inhibitors and Inducers  
Prohibited strong inhibitors 
Prohibited strong inducers 
Indinavir 
Efavirenz 
Nelfinavir 
Nevirapine 
Ritonavir 
Barbiturates 
Clarithromycin 
Carbamazepine 
Itroconazole 
Enzalutamide 
Ketoconazole 
Glucocorticoids 
Nefazadone 
Modafinil 
Saquinavir 
Oxcarbazepine 
Suboxone 
Phenobarbital 
Telithromycin 
Phenytoin 
Grapefruit juice 
Pioglitazone 
 
Rifabutin 
 
Rifampin 
 
St. John’s Wort 
 
Troglitazone 
 
Source:  The Flockhart Table (http://medicine.iupui.edu/clinpharm/ddis/main-table) 
 
 


Marinus Phannaceuticals, Inc. 
Protocol 1042-PPD-2002 
Appendix 2. Scales and Assessments 
Version 8.0 / 08 Oct 2018 
The following scales/assessments will be utilized in this study: 
Full Title of Scale/Assessment 
Version 
Hamilton Depression Rating Scale (HAMD 17) 
17-item version 
Spielberg Trait-State Anxiety Invento1y 
6-item version 
Edinburgh Postnatal Depression Scale (EPDS) 
Two obsession items are added to the 
standard EPDS questionnaire 
Columbia Suicide Severity Rating Scale 
Baseline and since last visit (standard) 
Stanford Sleepiness Scale 
NA 
Mini International Neuropsychiatric Assessment 
Version 7.0 
Clinical Global Impression - Improvement 
NA 
Clinical Global Impression - Severity 
NA 
A separate master file containing each scale/assessment listed above will be provided to the site. 
Updates to scales/assessments during the study (if applicable) will be documented in the table 
above and a new master file containing the revised scale/assessment will be provided to the site. 
Appendix 3. Protocol History and Summary of Changes 
Document 
Date 
Global/Country/Site Specific 
Original Protocol 
05 Dec 2016 
us 
Amendment 1 (V 2.0) 
15 February 2017 
us 
Amendment 2 (V 3.0) 
10 October 2017 
us 
Amendment 3 (V 4.0) 
19 October 2017 
us 
Amendment 4 (V 5.0) 
01 February 2018 
us 
Amendment 5 (V 6.0) 
28 February 2018 
us 
Amendment 6 (V 7.0) 
09 May 2018 
us 
Amendment 7 (V 8.0) 
08 Oct 2018 
us 
CONFIDENTIAL 
Page 80 of 104 


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Amendment 7 (V 8.0) Summary of Changes: 
Page 
Section, Title, 
Paragraph, 
Line 
Original Text 
Revised Text 
All 
Header 
Version 7.0 / 09 May 2018 
Version 8.0 / 08 Oct 2018 
1 
Cover Page 
Blank 
AMENDMENT 7 (V 8.0)  
08 Oct 2018 
Reason for Change: Updated amendment / version details 
2 
Protocol Signature 
Page 
, MD, PhD, 
 
Clinical Development 
 MD 
 Clinical Development and 
Pharmacovigilance 
Reason for Change:  Marinus contact change 
3 
 
  
 MD, PhD 
, Clinical Development 
Medical Monitor 
Telephone: 
Email: 
  
 MD 
Telephone: 
Email: 
 
Reason for Change: Marinus contact change 
11 
Study Synopsis 
Number of subjects (total and for 
each treatment arm): This is a Phase 
2A, double-blind, placebo-controlled, 
multiple-dose escalation study 
consisting of up to 6 cohorts (Cohorts 
1-6). Approximately 200 women with 
PPD 18 to 45 years of age will be 
screened to randomize up to 100 
subjects across up to 6 cohorts. 
Approximately 10-30 subjects will be 
randomized into each cohort.  
Randomized subjects will receive 
ganaxolone or placebo in a 1:1 ratio.  
In Cohorts 1-5 the treatment will be 
administered intravenously over 60 
hours. In Cohort 6 the treatment is 
initiated with an intravenous (IV) 
infusion followed by a transition to oral 
ganaxolone for 14 days. 
Number of subjects (total and for each 
treatment arm): This is a Phase 2A, 
double-blind, placebo-controlled, multiple-
dose escalation study consisting of up to 6 
cohorts (Cohorts 1-6). Approximately 200 
women with PPD 18 to 45 years of age will 
be screened to randomize up to 100 subjects 
across up to 6 cohorts. Approximately 10-
30 subjects will be randomized into each 
cohort.  Randomized subjects will receive 
the investigational product (IP), 
ganaxolone or matching placebo in a 1:1 
ratio.  In Cohorts 1-5 the IP will be 
administered intravenously over 60 hours. 
In Cohort 6 the dosing is initiated with a 6-
hour intravenous (IV) infusion followed by 
oral dosing for 28 days plus 3-day taper. 
Reason for Change:  Updated details for Cohort 6 
11 
Study Synopsis 
Study period 
(planned) 
Study period (planned): 
March 2017 to December 2018 
Study period (planned): 
March 2017 to June 2019 
Reason for Change: Updated timeline estimate 


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11 
Study Synopsis 
Investigational 
product, dose, and 
mode of 
administration 
Cohort 6: In this cohort treatment is 
initiated with an initial ganaxolone 
infusion followed by a transition to 
treatment with oral ganaxolone 
capsules for 14 days given at bedtime 
(QHS). The exact duration and dose of 
the infusion will be decided based on 
the results of previous cohorts. The 
first oral dose is administered 
following the IV dosing at 450 mg 
QHS. At subsequent days ganaxolone 
is administered at 675 mg QHS. 
Cohort 6: In this cohort dosing is initiated 
with ganaxolone infusion at a rate of 20 
mg/h (40 ml/h of ganaxolone 0.5 mg/ml 
solution or matching placebo) for 6 hours 
followed by ganaxolone 900 mg or 
matching placebo capsules given orally at 
dinner time for 28 days followed by a 3-
day taper.   
Reason for Change: Updated details for Cohort 6 
12 
Study Synopsis 
Methodology 
In Cohort 6, following the screening 
period, there will be a 1-day inpatient 
treatment phase at a hospital or clinical 
pharmacology unit. The study drug will 
be administered intravenously over a 
period of ≤ 12 hours (exact dose and 
duration to be determined based on the 
results from previous cohorts), 
followed by administration of the first 
dose of the oral study drug (450 mg) at 
bedtime (HS). The subjects will be 
discharged home the next morning 
(Day 2), and oral dosing will be 
continued at home for 13 days (Days 2-
14) at bedtime daily (QHS). There will 
be 2 safety follow-up visits after the 
last dose on post-treatment Weeks 1 
and 4. 
In Cohort 6, following the screening period, 
there will be a 1-day inpatient treatment 
phase at a hospital or clinical pharmacology 
unit. The study drug will be administered 
intravenously over a period of 6 hours 
followed by administration of the first dose 
of the oral study drug (ganaxolone 900 mg 
or matching placebo) at dinner time. The 
subjects will be discharged home the next 
morning (Day 2), and oral dosing will be 
continued at home for 27 days (Days 2-28 
at dinner time daily followed by a 3-day 
taper. There will be 3 safety follow-up 
visits after the last dose on post-treatment 
Weeks 1, 4, and 6.  
Reason for Change: Updated details for Cohort 6 
12 
Study Synopsis 
Inclusion Criteria 
6. 
HAMD17 score of ≥ 26 at 
screening (HAMD17 must be ≥ 22 at 
Admission to the Unit on Day 0) 
7. 
The diagnosis of PPD and 
severity of depression must be 
supported by the SAFER interview 
8. 
Must agree to stop 
breastfeeding from start of study 
treatment to 45 days after infusion 
6. HAMD17 score of ≥ 26 at screening 
(HAMD17 must be ≥ 22 per CTNI 
rating at Admission to the Unit on Day 
0) 
7. The diagnosis of PPD and severity of 
depression must be supported by the 
SAFER interview 
8. Must agree to stop breastfeeding from 
start of study treatment to 45 days after 
end of study treatment 
Reason for Change:  Clarification of HAMD rating responsibility and breastfeeding timing 
13 
Study Synopsis 
Pharmacokinetics 
Pharmacokinetics: Six samples will 
be collected for pharmacokinetic 
analysis in Cohorts 1-5.  Maximal 
plasma concentration (Cmax), 
concentration at steady-state (Css, 
determined by the mean concentrations 
once steady-state is achieved by visual 
inspection), AUC0-24 (calculated as Css 
Pharmacokinetics: Six samples will be 
collected for pharmacokinetic analysis in 
Cohorts 1-5 and 12 samples in Cohort 6.  
Maximal plasma concentration (Cmax), 
concentration at steady-state (Css, 
determined by the mean concentrations 
once steady-state is achieved by visual 
inspection), AUC0-24 (calculated as Css 


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multiplied by 24 hours) will be 
estimated. Four samples will be 
collected during the inpatient phase of 
Cohort 6 followed by collection of 2 
samples during the outpatient phase 
during the study visits.  
multiplied by 24 hours) will be estimated. 
Seven samples will be collected during the 
inpatient phase of Cohort 6 (including 6 
samples on Day 1) followed by collection 
of 5 samples during the outpatient phase 
during the study visits for a total of 12 
samples in Cohort 6.  
Reason for Change: Updated details for Cohort 6 
13 
 
Study Synopsis 
Statistical Methods 
Primarily descriptive 
Sample size: No formal hypothesis testing 
will be performed, and the sample size is 
not based on statistical power 
considerations.  A population of about 6 
to 10 subjects per dose is commonly 
tested in studies which aim to establish a 
tolerability range for a new compound or 
a new formulation. 
Analysis Populations: The Screened Set 
will consist of all subjects who have 
signed an informed consent. The 
Randomized Set will consist of subjects 
randomized. The Safety Set will consist of 
all subjects who received IP. The 
modified Intent to Treat Set (mITT) will 
consist of all subjects in the Safety Set 
who have at least 1 post-baseline efficacy 
assessment.  The Per-Protocol Set will 
consist of all subjects in the mITT set 
who do not have major protocol 
deviations that may affect key efficacy 
endpoints. The Infusion Completer Set 
will consist of all subjects in the Safety 
Set who completed the 60-hour infusion 
in Cohorts 1-5, and who completed the 6-
hour infusion in Cohort 6. The 
Completer Set will consist of all subjects 
in the Safety Set who completed the 60-
hour infusion and attended the final 
safety follow-up visit in Cohorts 1-5, and 
who completed the 6-hour infusion and 
oral dosing period and attended all 
outpatient visits including the safety 
follow-up visits in Cohort 6. 
Analysis Methods: Data analyses will 
primarily be descriptive. Continuous 
variables will be summarized as numbers 
of observations, means, measures of 
variance (e.g., standard deviation), and 
percentiles (e.g., median, minimum, 
maximum).  Categorical variables will be 
summarized as numbers of observations 
and percentages. Results from 
exploratory statistical analyses of efficacy 
endpoints may be presented but only to 
aid in interpretation.   


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Reason for Change:  Added details for statistical analysis 
18 
1.2.1.4  Preliminary 
safety information 
from the current 
trial (1042-PPD-
2002) 
Blank 
Cohort 3 
13 subjects in Cohort 3 have completed 
dosing as of September 5th, 2018 and 
respective data reviewed by the DRC. In 
this cohort ganaxolone (or matching 
placebo) was given as 12 mg IV bolus 
over 2 minutes followed by IV infusion at 
a rate of 12 mg/h for 48 hours after which 
the rate was lowered to 6 mg/h for the 
final 12 hours. The infusion was stopped 
at 60 hours. There have been no serious 
adverse events or adverse events leading 
to discontinuation, and no subject has 
needed a dose adjustment. The DRC has 
evaluated preliminary adverse event data 
from these 13 subjects and deemed this 
dosing regimen to be well-tolerated. The 
DRC has recommended that enrollment 
into Cohort 3 be completed with 20 
subjects.  
 
Reason for Change:  Added safety data from Cohort 3 
20 
3.1  Study Design 
and Study 
Population 
In Cohort 6, subjects randomized to 
ganaxolone will receive an initial IV 
infusion of ganaxolone followed by a 
transition to oral ganaxolone capsules 
administered at 450 mg QHS the first 
day and then at 675 mg QHS on Days 
2-14. The exact duration and dose of 
the initial infusion will be decided 
based on the results of previous cohorts 
but will be less than 12 hours. Subjects 
randomized to placebo will receive an 
initial IV infusion of placebo followed 
by a transition to oral placebo capsules 
administered QHS for 14 days. 
Randomization will allocate subjects to 
the ganaxolone arm or placebo arm in 
1:1 ratio.  
 
In Cohort 6, subjects randomized to 
ganaxolone will receive an initial IV 
infusion of 20 mg/h (40 ml/h of ganaxolone 
0.5 mg/ml solution) for 6 hours followed 
by 900 mg (4 capsules) ganaxolone 
capsules administered orally at dinner 
time for 28 days followed by a 3-day 
taper (3, 2, and 1 capsules per day, 
respectively). Subjects randomized to 
placebo will receive an initial IV infusion of 
matching placebo (at 40 ml/h) followed by 
4 placebo capsules administered orally at 
dinner time for 28 days followed by a 3-
day taper (3, 2, and 1 capsules per day, 
respectively). Randomization will allocate 
subjects to the ganaxolone arm or placebo 
arm in 1:1 ratio.  
Reason for Change:  Updated details for Cohort 6 
21 
3.3  Blinding 
Scheme 
Subjects who are randomized to 
receive ganaxolone in Cohorts 1-5 will 
receive ganaxolone as an intravenous 
infusion for 60 hours with or without 
an intravenous ganaxolone bolus dose.  
Subjects who are randomized to 
placebo will receive placebo infusion 
for 60 hours (0.9% saline) with or 
without an intravenous placebo bolus 
Within cohorts, subjects will be 
randomized to ganaxolone or placebo in 
a 1:1 ratio. The randomization scheme 
will be prepared by an independent 
third-party vendor. Treatment 
assignments will be obtained by the 
investigator (or designee) via an 
Interactive Voice and/or Web Response 
System (IxRS). Subjects who are 


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dose.  The placebo infusion is identical 
to ganaxolone in its appearance.  In 
Cohort 6 subjects randomized to 
ganaxolone will receive an initial 
infusion of ganaxolone followed by a 
transition to treatment with oral 
ganaxolone capsules for 14 days. 
Subjects randomized to placebo will 
receive an initial infusion with IV 
placebo followed by a transition to 
treatment with oral placebo capsules 
for 14 days. The placebo infusion and 
placebo capsules are identical to the 
ganaxolone infusion and capsules in 
their appearance.  An unblinded study 
pharmacist at the investigative site will 
prepare the ganaxolone and placebo IV 
solutions, and allocate capsule supply 
for Cohort 6. Persons involved in the 
evaluation of the study subjects (e.g. 
investigators, sub investigators, and 
physicians/nurses), will remain blinded 
at all times, except in case of an 
emergency.  Subjects are blinded. 
randomized to receive ganaxolone in 
Cohorts 1-5 will receive ganaxolone as an 
intravenous infusion for 60 hours with or 
without an intravenous ganaxolone bolus 
dose.  Subjects who are randomized to 
placebo will receive matching placebo 
infusion for 60 hours (0.9% saline) with or 
without a matching intravenous placebo 
bolus dose.  The placebo infusion is 
identical to ganaxolone in its appearance.  
In Cohort 6, subjects randomized to 
ganaxolone will receive an initial infusion 
of 20 mg/h (40 ml/h of ganaxolone 0.5 
mg/ml solution) for 6 hours followed by 
treatment with oral doses of 900 mg 
ganaxolone (4 capsules per dose) for 28 
days followed by a 3-day taper (3, 2, and 
1 capsules per day, respectively). Subjects 
randomized to placebo will receive an 
initial infusion with matching IV placebo 
(at 40 ml/hr) followed by matching oral 
placebo (4 capsules per dose) for 28 days 
followed by a 3-day taper (3, 2, and 1 
capsules per day, respectively). The 
placebo infusion and placebo capsules are 
identical to the ganaxolone infusion and 
ganaxolone capsules, respectively, in their 
appearance.  An unblinded study pharmacist 
at the investigative site will prepare the 
ganaxolone and placebo IV solutions and 
allocate capsule supply for Cohort 6. 
Members of the DRC will be unblinded 
at scheduled DRC meetings. All other 
study personnel, including persons 
involved in the evaluation of the study 
subjects (e.g. investigators, 
sub-investigators, and physicians/nurses), 
will remain blinded at all times, except in 
case of an emergency.  Subjects will be 
blinded.   
Reason for Change: Updated details for Cohort 6 
23 
3.4.5  Cohort 6 
For Cohort 6, the infusion rate for the 
initial infusion on Day 1 will be 
decided based on the results of the 
previous cohorts. The goal of initiation 
of treatment with IV infusion followed 
by transition to oral capsules is to 
maximize the speed of onset of 
antidepressant activity while providing 
the convenience of oral dosing for the 
remainder of the treatment period. 
Under this IV-oral dosing schedule 
there may not be a need for a 
prolonged inpatient observation.  
For Cohort 6, the goal of initiation of 
treatment with IV infusion followed by 
oral capsules is to maximize the speed of 
onset of antidepressant activity while 
providing the convenience of oral dosing 
for the remainder of the treatment 
period. Under this IV-oral dosing 
schedule there may not be a need for a 
prolonged inpatient observation.  
This initial infusion is targeted to provide 
a fast onset of antidepressant activity by 
delivery of rapid plasma exposures to 
ganaxolone. At dinner time of Day 1 the 


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This initial infusion is targeted to 
provide a fast onset of antidepressant 
activity by delivery of rapid plasma 
exposures to ganaxolone. At bedtime 
of Day 1 the patient will take their first 
oral dose of ganaxolone of 450 mg (2 
capsules). This dose is expected to 
provide mean Cmax plasma 
concentrations of approximately 150 
ng/ml, which may be mildly sedating. 
In previous studies ganaxolone has 
been given up to a daily dose of 2000 
mg, and at single doses of 1000 mg. 
Based on the previous experience this 
dose is expected to be safe.  
At subsequent nights (Days 2-14), the 
target dose is 675 mg (3 capsules) 
QHS. However, based on the 
assessment of the investigator the dose 
may be maintained at 450 mg in case 
of adverse events, such as grogginess 
in the morning. The mechanism by 
which ganaxolone is postulated to be 
efficacious under this dosing regimen 
is restructuring of sleep architecture.2  
Preclinical studies have shown that 
allopregnanolone has the capacity to 
modulate sleep, and disturbed sleep 
architecture is one of the hallmarks of 
depression.   
subjects will take their first oral dose of 
ganaxolone 900 mg or matching placebo 
(4 capsules). This dose is expected to 
provide mean Cmax plasma 
concentrations of approximately 250-300 
ng/mL and mean steady-state levels 
between 90 and 150 ng/mL, which may 
be mildly sedating. In previous studies 
ganaxolone has been given up to a daily 
dose of 2000 mg, and at single doses of 
1000 mg. Based on the previous 
experience this dose is expected to be 
safe.  
At subsequent nights (Days 2-28), the 
target dose is ganaxolone 900 mg or 
matching placebo (4 capsules) at dinner 
time followed by a 3-day taper (3, 2, and 
1 capsule/s per day, respectively). 
However, based on the assessment of the 
investigator the dose may be maintained 
at 675 mg or 450 mg (or matching 
placebo) in case of adverse events, such 
as grogginess in the morning. In the case 
of 3 capsules per day on day 28 the taper 
will consist of 2, 2, and 1 capsule/s on 
days 29, 30, and 31, respectively. In the 
case of 2 capsules per day on day 28 the 
taper will consist of 1 capsule on days 29, 
30, and 31. If the subject cannot tolerate 
450 mg (or matching placebo) per dose 
the investigator will contact the Medical 
Monitor to discuss dosing options.  
Subjects will be provided with a diary to 
capture the details of dose administration 
and associated food intake throughout 
the treatment period. Subjects will 
document the number of capsules taken 
and whether a fatty meal/snack (e.g., 
fatty yogurt, nuts, avocado) was 
consumed ±15 minutes of taking the 
capsules. 
The mechanism by which ganaxolone is 
postulated to be efficacious under this 
dosing regimen is restructuring of sleep 
architecture.2  Preclinical studies have 
shown that allopregnanolone has the 
capacity to modulate sleep, and disturbed 
sleep architecture is one of the hallmarks 
of depression.  
Reason for Change: Updated details for Cohort 6 


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24 
3.5  Justification 
for Placebo as a 
Control Group 
The Cohort 6 treatment period is 
initiated in an inpatient setting, which 
allows observation of the effects of the 
IV infusion and first dose effects of the 
oral medication during the 
approximately 24-hour stay on the unit.  
The Cohort 6 treatment period is initiated in 
an inpatient setting, which allows 
observation of the effects of the IV infusion 
and first dose effects of the oral medication 
during the approximately 48-hour stay on 
the unit.  
Reason for Change: Updated details for Cohort 6 
24 
3.6  Study Duration 
For Cohort 6 there will be an initial 
infusion treatment during the 
approximately 24-hour inpatient 
treatment phase followed by 13 days of 
treatment as outpatient. There will be 2 
safety follow-up visits after the 
outpatient treatment period on post-
treatment Weeks 1 and 4.  The total 
duration of the study will be up to 9 
weeks for subjects participating in 
Cohort 6.  
For Cohort 6 there will be an initial infusion 
treatment and oral dose during the 
approximately 24-hour inpatient dosing 
phase followed by 27 days of oral treatment 
as outpatient. There will be 3 safety follow-
up visits after the outpatient treatment 
period on post-treatment Weeks 1,4, and 6.  
The total duration of the study will be up to 
12 weeks for subjects participating in 
Cohort 6.  
Reason for Change: Updated details for Cohort 6 
24 
3.7  Interim 
Analyses 
In addition, safety and efficacy data 
from each cohort will be unblinded, 
and an analysis will be conducted for 
the purpose of dose selection for the 
next cohort.  The dose for the next 
cohort will be decided based on these 
interim data analyses.  The decision 
how to adjust the dose and/or the 
duration of the infusion will be made 
based on recommendations by a Data 
Review Committee (DRC) composed 
of the sponsor’s Chief Medical Officer, 
and at least 2 other external physicians.  
At least one of the members will have 
special expertise in the clinical care of 
women with depression or postpartum 
depression.  One of the members will 
have expertise in the conduct of 
clinical trials or analysis of clinical trial 
data.  
In addition, safety and efficacy data from 
each cohort will be unblinded, and analyses 
will be conducted for the purpose of dose 
selection for the next cohort.  The dose for 
the next cohort will be decided based on 
these interim data analyses.  The decision 
how to adjust the dose and/or the duration 
of the infusion will be made based on 
recommendations by a Data Review 
Committee (DRC) composed of the 
sponsor’s Chief Medical Officer, and at 
least 2 other external physicians.  At least 
one of the members will have special 
expertise in the clinical care of women with 
depression or postpartum depression.  One 
of the members will have expertise in the 
conduct of clinical trials or analysis of 
clinical trial data. The study team and all 
parties other than the DRC will remain 
blinded.  
Reason for Change: Clarification on the Interim Analysis 
25 
3.8  Definition of 
Completion   
The Study Completion Date is defined 
as the date the final subject, across all 
sites, completes her final protocol-
defined assessment for the final cohort.  
Please note that this includes all 
follow-up visits.  
 
A cohort is considered complete when the 
final subject in the cohort has completed 
the final protocol-defined assessment, 
including follow-up visits, for the cohort. 
The Study Completion Date is defined as 
the date the final subject, across all sites, 
completes her final protocol-defined 
assessment, including follow-up visits, for 
the final cohort.   
Reason for Change: Clarification of study completion 


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26 
4.1  Inclusion 
Criteria 
6. 
HAMD17 score of ≥ 26 at 
screening (HAMD17 must be ≥ 22 at 
Admission to the Unit on Day 0) 
7. 
The diagnosis of PPD and 
severity of depression must be 
supported by the SAFER interview 
8. 
Must agree to stop 
breastfeeding from start of study 
treatment to 45 days after infusion 
6. HAMD17 score of ≥ 26 at screening 
(HAMD17 must be ≥ 22 per CTNI 
rating at Admission to the Unit on Day 
0) 
7. The diagnosis of PPD and severity of 
depression must be supported by the 
SAFER interview 
8. Must agree to stop breastfeeding from 
start of study treatment to 45 days after 
end of study treatment 
Reason for Change: Clarification of HAMD rating responsibility and breastfeeding timing 
28 
4.4  
Discontinuation of 
Subjects 
The investigator is encouraged to 
discuss withdrawal of a subject from 
the investigational product with the 
medical monitor when possible. 
If the investigational product is 
discontinued, regardless of the reason, 
the evaluations listed for Day 4 are to 
be performed as completely as possible 
for Cohort 1-5, and Day 14 evaluations 
for Cohort 6. 
The investigator is encouraged to discuss 
withdrawal of a subject from the 
investigational product with the medical 
monitor when possible. Withdrawn 
subjects who have not received IP will be 
replaced. 
If the investigational product is 
discontinued, regardless of the reason, the 
evaluations listed for Day 4 are to be 
performed as completely as possible for 
Cohort 1-5, and Day 28 evaluations for 
Cohort 6. 
Reason for Change: Clarification on discontinuation of subjects 
30 
5.0  PRIOR AND 
CONCOMITANT 
TREATMENT 
All non-study treatments (including 
herbal treatments and vitamins) 
received within 30 days prior to the 
screening visit (Visit 1) and through 
the final study contact (including 
protocol-defined follow-up period) 
must be recorded on the appropriate 
eCRF page. 
All non-study treatments (including herbal 
treatments, vitamins, and non-
pharmacological treatments) received 
within 60 days prior to the screening visit 
(Visit 1) and through the final study contact 
(including protocol-defined follow-up 
period) must be recorded on the appropriate 
eCRF page. 
Reason for Change: Clarification on concomitant treatments and timing for data collection 
30 
5.3  Concomitant 
Psychological 
Treatment 
Concomitant psychological treatment 
refers to all psychological care the 
patient is receiving at the time of the 
screening visit.  Concomitant 
psychological treatment information 
must be recorded on the concomitant 
psychological treatments eCRF page. 
 
Concomitant psychological treatment refers 
to all psychological care the subject is 
receiving between the screening visit and 
the end of the follow-up period regardless 
of the start date of the concomitant 
psychological treatment.  Concomitant 
psychological treatment information must 
be recorded on the concomitant 
psychological treatments eCRF page. 
Reason for Change: Clarification of the timing for collection of psychological treatment 
31 
5.3.1.3  Other 
Permitted 
Treatments 
After the subject is discharged from the 
unit, any changes to the antidepressant 
or antianxiety medication regimen are 
not prohibited, but investigators are 
encouraged to maintain such drugs at 
stable doses if possible.  Any changes 
After the subject completes the study 
treatment period, any changes to the 
antidepressant or antianxiety medication 
regimen are not prohibited, but investigators 
are encouraged to maintain such drugs at 
stable doses if possible.  Any changes in the 


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in the medication regimen must be 
recorded on the concomitant 
medication eCRF page.   
medication regimen must be recorded on 
the concomitant medication eCRF page.   
Reason for Change: Clarification on the timing for permitted treatments 
31 
5.3.2  Prohibited 
Treatments 
The following classes of medications 
and treatments are prohibited during 
the inpatient study period.   
The following classes of medications and 
treatments are prohibited during the study 
treatment period. 
Reason for Change: Clarification on the timing for prohibited treatments 
33 
6.2 Administration 
of Investigational 
Product(s) 
For administration of the IV 
investigational product and IV placebo 
the investigator needs to use the 
Sponsor-approved Captisol®-
compatible intravenous infusion bags 
and infusion sets which are prepared 
according to the Pharmacy manual.  
Any substitutions and deviations from 
the Pharmacy manual need to be 
approved by the sponsor.  
Ganaxolone oral capsules (Cohort 6 
only) will be administered orally with 
food.  Ganaxolone should be taken just 
before or together with a meal or snack 
and with 240 mL (8 oz) of water at 
bedtime.   
For administration of the IV investigational 
product (IP; ganaxolone or matching 
placebo [0.9% saline solution]) the 
investigator needs to use the Sponsor-
approved Captisol®-compatible intravenous 
infusion bags and infusion sets which are 
prepared according to the Pharmacy 
manual.  Any substitutions and deviations 
from the Pharmacy manual need to be 
approved by the sponsor.  
Ganaxolone or matching placebo capsules 
(Cohort 6 only) will be administered orally 
with food. Ganaxolone or matching 
placebo capsules should be taken ±15 
minutes of a fatty meal or snack (e.g., 
fatty yogurt, nuts, avocado) and with 240 
mL (8 oz) of water at dinner time.   
Subjects will be provided with a diary to 
capture the details of dose administration 
and associated food intake throughout 
the treatment period. Subjects will 
document the number of capsules taken 
and whether a fatty meal/snack (e.g., 
fatty yogurt, nuts, avocado) was 
consumed ±15 minutes of taking the 
capsules.  
Reason for Change: Updated details for Cohort 6 
34 
6.2.1  Interactive 
Voice/Web 
Response System 
(IxRS) Technology 
for Investigational 
Product 
Management 
The name and address of the 
IVRS/Interactive Web Response 
System (IWRS) for this study will be 
maintained in the Investigator’s files at 
each study site. 
Interactive response technology will be 
used for the following investigational 
product tasks: 
• 
Randomization 
 
The name and address of the Interactive 
Voice/Web Response System (IxRS) for 
this study will be maintained in the 
Investigator’s files at each study site. 
Interactive response technology will be used 
for the following investigational product 
tasks: 
• 
Randomization 
• 
Communication of treatment 
assignment to sites 
Reason for Change: Clarification of IxRS management 


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34 
6.2.2  Allocation of 
Subjects to IP 
This is a double-blind, placebo-
controlled study.  The actual treatment 
given to individual subjects is 
determined by a randomization 
schedule. 
Subject numbers are assigned to all 
subjects as they consent to take part in 
the study.  Within each site (numbered 
uniquely within a protocol), the subject 
number is assigned to subjects 
according to the sequence of 
presentation for study participation.  
The randomization number represents a 
unique number corresponding to 
investigational product allocated to the 
subject, once eligibility has been 
determined.  
After being randomized a patient will 
be replaced only if she discontinues 
prior to receiving study treatment. 
This is a double-blind, placebo-controlled 
study.  The actual IP given to individual 
subjects is determined by a randomization 
schedule prepared by an independent 
third-party vendor. Within cohorts, 
subjects will be randomized to 
ganaxolone or placebo in a 1:1 ratio. 
Subject numbers are assigned to all subjects 
as they consent to take part in the study.  
Within each site (numbered uniquely within 
a protocol), the subject number is assigned 
to subjects according to the sequence of 
presentation for study participation.  
The randomization number represents a 
unique number corresponding to IP kit 
number allocated to the subject, once 
eligibility has been determined.  
After being randomized a subject will be 
replaced only if she discontinues prior to 
receiving IP. The replacement subject will 
receive the same IP assignment as the 
replaced subject. 
Reason for Change: Clarification on allocation and replacement of subjects 
35 
6.2.3  Dosing 
Subjects entering the study will be 
randomized to ganaxolone or placebo 
at the Baseline Visit.  The goal of 
Cohort 1 is to determine safety, 
tolerability, PK and efficacy of the IV 
formulation of ganaxolone in PPD 
subjects administered at a predicted 
dose mimicking the levels of 
allopregnanolone at the end of 
pregnancy, or higher. 
Subjects entering the study will be 
randomized to ganaxolone or matching 
placebo at the Baseline Visit.  The goal of 
Cohorts 1-6 is to determine safety, 
tolerability, PK and efficacy of the IV 
formulation (and in Cohort 6, the IV 
formulation followed by oral 
formulation) of ganaxolone in PPD 
subjects administered at a predicted dose 
regimen mimicking the levels of 
allopregnanolone at the end of pregnancy, 
or higher.10, 5, 14 Infusion rates for 
ganaxolone IV will be the same as for 
placebo IV.  
Reason for Change: Updated details for Cohort 6 
35 
6.2.3 Cohort 6 
The rate and duration for the initial 
ganaxolone infusion will be decided 
based on the previous results. 
However, the duration of the infusion 
will not exceed 12 hours. Following 
completion of the infusion the patient 
will be administered a 450 mg dose (2 
caps) of ganaxolone at bedtime (Day 
1). On subsequent nights (Day 2-14) 
the patient will take 675 mg of 
ganaxolone QHS (unless the dose is 
adjusted as per the instructions from 
the investigator).  
 
For Cohort 6, an initial IV infusion 20 
mg/h (40 ml/h of ganaxolone 0.5 mg/ml 
solution or matching placebo) for 6 hours 
will be followed by oral dose of 900 mg 
ganaxolone or matching placebo (4 
capsules) at dinner time (Day 1). On 
subsequent nights (Day 2-28) the subject 
will take 900 mg of ganaxolone, or 
matching placebo (4 capsules), at dinner 
time followed by a 3-day taper (3, 2, and 
1 capsule/s per day, respectively (unless 
the dose is adjusted as per the 
instructions from the investigator in 
which case the taper follows instructions 
in section 3.4.6). 


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Reason for Change: Updated details for Cohort 6 
36 
6.2.4  Dose 
Adjustments 
The dose of the oral medication in 
Cohort 6 may be adjusted by lowering 
the dose from 675 mg QHS to 450 mg 
QHS if the patient experiences adverse 
effects, such as sedation in the 
morning. If the dose is adjusted, this 
must be recorded in the eCRF. Other 
dosing adjustments may be possible 
but they should be discussed with the 
medical monitor. 
The dose of the oral medication in Cohort 6 
may be adjusted by lowering the dose from 
900 mg to 675 mg or 450 mg, or matching 
placebo at dinner time if the subject 
experiences adverse effects, such as 
sedation in the morning. If the dose is 
adjusted, this must be recorded in the eCRF. 
Other dosing adjustments may be possible, 
but they should be discussed with the 
medical monitor.  
Reason for Change: Updated details for Cohort 6 
37 
6.3.1  Labeling 
The site pharmacy will prepare the IV 
bags, which will include at minimum 
the subject ID, protocol number, and 
time and date of IV bag preparation.  
No information should be visible to the 
subject or staff, which could potentially 
unblind the study drug, or allude to the 
contents of the IV bag (e.g. “drug lot 
number”).  Further details are provided 
in the pharmacy manual. 
The site pharmacy will prepare the IV bags, 
which will include at minimum the subject 
ID, protocol number, and time and date of 
IV bag preparation.  No information which 
could potentially unblind the study drug 
should be visible to the subject or staff, 
and no packaging information should 
allude to the contents of the IV bag (e.g., 
“drug lot number”).  Further details are 
provided in the pharmacy manual. 
Reason for Change: Clarification of IV bag labeling 
37 
6.3.2.2  
Ganaxolone and 
placebo oral 
capsules 
The site pharmacy or delegated site 
staff will be responsible for dispensing 
the study treatment to the subject.  
Sufficient amount of capsules will be 
provided to the patient until the next 
study visit.  
Detailed instructions when to take the 
medication and a reminder to take the 
study medication with food (with a 
meal or snack) at bedtime and with 240 
mL (8 oz) of water will be provided to 
the patient. 
 
The site pharmacy or delegated site staff 
will be responsible for dispensing the study 
treatment to the subject.  A sufficient 
number of capsules will be provided to the 
subject until the next study visit plus at 
least 3-day overage.  
Detailed instructions when to take the 
medication and a reminder to take the study 
medication with fatty food (meal or snack, 
e.g., fatty yogurt, nuts, avocado) at 
dinner time and with 240 mL (8 oz) of 
water will be provided to the subject along 
with a medication diary to document 
intake of IP and fatty meal/snack ±15 
minutes. 
Reason for Change: Updated details for Cohort 6 
39 
6.5.1  
Administration of 
IV ganaxoloneIP 
(Cohorts 1-6) 
The study drug will be administered IV 
via an indwelling catheter inserted in a 
vein on the arm or hand.  The study 
drug should be infused as instructed 
throughout the study period.  If the 
study drug is stopped temporarily (e.g. 
catheter change) the infusion may be 
re-started at the same rate as before.  A 
new infusion bag should be prepared 
every 24 hours.  The catheter should be 
flushed with saline at the same time 
when the tubing is changed.  The 
The IP will be administered IV via an 
indwelling catheter inserted in a vein on the 
arm or hand.  The IP should be given as 
continuous infusion as instructed.  If the 
study drug is stopped temporarily (e.g. 
catheter change) the infusion may be re-
started at the same rate as before.  A new 
infusion bag should be prepared every 24 
hours.  The catheter should be flushed with 
saline at the same time when the tubing is 
changed.  The catheter site should be 
inspected for inflammation at least twice a 


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catheter site should be inspected for 
inflammation at least twice a day.  For 
details please see pharmacy manual.  
day.  For details please see pharmacy 
manual.  
Reason for Change: Clarification of administration of IV  
39 
6.5.2 
Administration of 
oral ganaxolone or 
placebo capsules 
(Cohort 6) 
Oral doses of ganaxolone should be 
taken at bedtime with food (just before 
or with a meal or snack) and with 240 
mL (8 oz) of water at home.   
 
Oral doses of ganaxolone or matching 
placebo should be taken at dinner time 
with fatty food (±15 minutes of a fatty 
meal or snack, e.g., fatty yogurt, nuts, 
avocado) and with 240 mL (8 oz) of water 
at home.   
Reason for Change: Clarification of oral dosing 
40 
7.0  STUDY 
PROCEDURES 
In Cohort 6 the treatment is initiated 
with an intravenous (IV) infusion 
followed by a transition to oral 
ganaxolone. Additional patients may be 
included into these cohorts or 
additional cohorts may be added, but 
will not exceed 100 randomized 
subjects for the study. 
The screening period for each cohort 
will be up to 2 weeks. Following the 
screening period, there will be a 4-day 
inpatient treatment phase at a hospital 
or clinical pharmacology unit for 
Cohorts 1-5 during which a 60-hour 
infusion of ganaxolone or placebo will 
be administered (with or without bolus 
dosing).  The subjects will be 
discharged from the unit on the 
morning of Day 4. There will be 2 
safety follow-up visits after inpatient 
discharge on post-treatment Weeks 1 
and 4.  
In Cohort 6, following the screening 
period, there will be a 1-day inpatient 
treatment phase at a hospital or clinical 
pharmacology unit during which an 
infusion of ganaxolone or placebo will 
be administered initially before oral 
dosing is started. The subjects will be 
admitted in the morning of Day 1 
(infusion day) and discharged from the 
unit in the morning of Day 2. The first 
dose of oral ganaxolone (2 capsules; 
450 mg) will be administered following 
the infusion at bedtime (HS) of Day 1. 
Oral dosing is continued as outpatient 
on Days 2-14. The dosing regimen 
during the outpatient phase of Cohort 6 
is 675 (3 capsules) mg at bedtime daily 
(QHS). There will be 2 safety follow-
up visits after the last dose on post-
In Cohort 6 the treatment is initiated with a 
6-hour intravenous (IV) infusion followed 
by oral ganaxolone or matching placebo. 
Additional subjects may be included into 
these cohorts or additional cohorts may be 
added, but will not exceed 100 randomized 
subjects for the study. 
The screening period for each cohort will be 
up to 2 weeks. Following the screening 
period, there will be a 4-day inpatient 
treatment phase at a hospital or clinical 
pharmacology unit for Cohorts 1-5 during 
which a 60-hour infusion of ganaxolone or 
placebo will be administered (with or 
without bolus dosing).  The subjects will be 
discharged from the unit on the morning of 
Day 4. There will be 2 safety follow-up 
visits after inpatient discharge on post-
treatment Weeks 1 and 4.  
In Cohort 6, following the screening period, 
there will be a 1-day inpatient treatment 
phase at a hospital or clinical pharmacology 
unit during which a 6-hour infusion of 
ganaxolone or matching placebo will be 
administered initially from 9 am to 3 pm 
(±1 hour) before oral dosing is started at 7 
pm (±1 hour). The subjects will be 
admitted on Day 0 and discharged from the 
unit in the morning of Day 2. The first dose 
of oral ganaxolone (4 capsules; 900 mg) or 
matching placebo will be administered at 
dinner time (around 7 pm) of Day 1, 4 
hours after the end of infusion on Day 1. 
Oral dosing is continued as outpatient on 
Days 2-28. The dosing regimen during the 
outpatient phase of Cohort 6 is 900 mg or 
placebo (4 capsules) at dinner time daily. 
A 3-day taper will follow at days 29, 30, 
and 31, as described in Section 3.4.6. 
There will be 3 safety follow-up visits after 
the last dose on post-treatment Weeks 1,4, 


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treatment Weeks 1 and 4.  
Following the analysis of the data from 
the first 10 subjects in Cohort 6, the 
Data Review Committee may 
recommend that after completion of the 
infusion of the study drug on Day 1 the 
subjects can be discharged home based 
on the assessment of the investigator, 
and the subjects begin taking the oral 
doses of the study medication at home. 
The subjects will take a 450 mg dose (2 
caps) on Day 1 (QHS) and continue 
with the 675 mg dose on Days 2-14. 
Those subjects who are discharged 
home on Day 1 will come back for a 
study visit in the Morning of Day 2 (for 
Day 2 assessments; Table 3). 
Following completion of the Day 2 
assessment they will continue the visit 
and assessment schedule as outlined in 
Table 2.  
 
and 6.  
On Day 1 subjects will have 6 PK 
samplings: at 1 hour after the end of the 
6-hour infusion (i.e., at 4 pm), at 7 pm 
(just prior to the oral dosing), and at 1, 2, 
3, and 4 hours post oral dosing (at 8, 9, 
10, and 11 pm) as well at 8 am the 
following morning (on Day 2) prior to 
discharge. 
The subjects will take a 900 mg dose or 
placebo (4 caps) on the evening of Day 1 
at dinner time and continue with the 900 
mg dose or matching placebo at dinner 
time on Days 2-28. A 3-day taper will 
follow as described in Section 3.4.6.  
Reason for Change: Updated details for Cohort 6 
47 
7.5  Admission to 
the Unit and 
Infusion (Day +1) – 
Cohort 6 
(Screening and 
Admission visits 
for Cohort 6 
described in 
Section 7.1 and 7.2, 
respectively) 
7.5.1 
Before Infusion (Morning of 
Day +1; Baseline)  
• 
Admission to the unit.  The 
patient arrives on the unit on the day of 
the infusion (Day +1) to complete 
assessments and accommodate to the 
unit.  
• 
Conduct HAMD17 interview 
• 
EPDS 
• 
STAI6 
• 
Assess CGI-S 
• 
Review concomitant 
medications and therapies  
• 
Collect vital signs (BP, pulse, 
temperature, pulse oximetry, 
respiratory rate),  
• 
Collect ECG 
• 
Collect urine drug screen and 
urine pregnancy test 
• 
Collect safety laboratory tests 
• 
Collect neurosteroid level 
• 
Measure weight 
• 
Stanford Sleepiness Scale 
(SSS) 
• 
Conduct CSSRS interview 
• 
Collect AEs 
• 
Review inclusion and 
exclusion criteria (including 
hematology and chemistry from the 
screening visit); HAMD17 must be ≥ 
22 for randomization. 
7.5.1 
Before Infusion (Morning of Day 
+1; Baseline)  
• 
CTNI to conduct HAMD17 
interview 
• 
EPDS 
• 
STAI6 
• 
Assess CGI-S 
• 
Review concomitant medications  
• 
Collect vital signs (BP, pulse, 
temperature, pulse oximetry, respiratory 
rate),  
• 
Stanford Sleepiness Scale (SSS) 
• 
Conduct CSSRS interview 
• 
Collect AEs 
• 
Randomization  
• 
The subject’s bed should be 
placed close to the nursing station in an 
area that allows visual observation of the 
subject  
• 
Start monitoring of pulse 
oximetry 
 
7.5.2 
During the Infusion and Evening 
of Day +1 (Day +1) 
• 
Start 6-hour infusion at 40 
mL/hr at 9 am of Day +1 (0h) after 
baseline assessments are completed 
(listed above) 
• 
End 6-hour infusion 
• 
Complete +6h assessments after 
the end of the 6-hour infusion CTNI to 


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• 
Randomization  
• 
The patient’s bed should be 
placed close to the nursing station in an 
area that allows visual observation of 
the patient throughout the infusion 
period.  
• 
Start monitoring of pulse 
oximetry 
• 
Start Q15 minutes health 
checks (e.g. to observe general 
wellbeing and behavior, monitor 
infusion)  
• 
If the patient is breastfeeding, 
she is encouraged to “pump and dump” 
while inpatient and for 45 days after 
the end of the outpatient study period.  
She should be provided with a breast 
pump. 
7.5.2 
During the Infusion and 
Evening of Day +1(Day +1) 
• 
Start infusion in the early 
afternoon of Day +1 (0h) after baseline 
assessments are completed (listed 
above) 
• 
Conduct interviews for 
HAMD17 (+6h) 
• 
Conduct interviews for CGI-I 
(+6h) 
• 
EPDS (+6h) 
• 
STAI6 (+6) 
• 
Collect AEs 
• 
Collect ECG (+6h) 
• 
Collect VS (BP, pulse, 
respiratory rate, pulse oximetry, 
temperature): (+6h) 
• 
Collect SSS (+6h) 
• 
Collect a pharmacokinetic 
sample (+6h; before the infusion is 
turned off) 
• 
Collect neurosteroid level 
(+6h) 
• 
Record concomitant 
medications  
• 
Conduct CSSRS interview 
(+6h) 
• 
Stop the infusion after all +6h 
assessments have been completed 
• 
Collect a pharmacokinetic 
sample before administration of the 
oral study drug  
• 
Administer 450 mg of 
ganaxolone at bedtime with a snack 
(two 225 mg capsules or two placebo 
capsules) 
• 
Collect a pharmacokinetic 
sample 1 hour after taking the oral dose 
conduct interviews for HAMD17 (+6h) 
• 
Conduct interviews for CGI-I 
(+6h) 
• 
EPDS (+6h) 
• 
STAI6 (+6h) 
• 
Collect AEs 
• 
Collect ECG (+6h) 
• 
Collect VS (BP, pulse, 
respiratory rate, pulse oximetry, 
temperature): (+6h) 
• 
Collect SSS (+6h) 
• 
Collect pharmacokinetic samples 
(+7h [i.e., 1 hour after the end of the 
infusion], at +10h [i.e., just before the 
oral dose], and at 1, 2, 3, and 4 hours 
after the oral dose 
• 
Collect neurosteroid level (+6h) 
• 
Record concomitant medications  
• 
Conduct CSSRS interview (+6h)  
• 
Administer the IP: 900 mg of 
ganaxolone, or matching placebo (four 
225 mg capsules or four placebo 
capsules), at dinner time (i.e., at 7 pm) 
±15 minutes of a fatty meal or snack (e.g., 
fatty yogurt, nuts, avocado) 
• 
Continue monitoring of pulse 
oximetry and Q15 min health checks  
 
7.5.3 
Day + 2 (Discharge and 
transition to outpatient treatment) 
• 
The assessments listed below are 
completed before discharge 
• 
CTNI to conduct interviews for 
HAMD17  
• 
Conduct interviews for CGI-I  
• 
EPDS  
• 
STAI6  
• 
Collect AEs  
• 
Collect ECG 
• 
Collect VS (BP, pulse, 
respiratory rate, pulse oximetry, 
temperature) 
• 
Collect SSS  
• 
Collect a pharmacokinetic 
sample at 8 am (23h) 
• 
Collect neurosteroid level  
• 
Record concomitant medications  
• 
Conduct CSSRS interview 
• 
Perform physical examination 
• 
Dispense medication bottle 
• 
Provide the subject with dosing 
instructions and subject diary 
completion. 
• 
Subject will take the IP (900 mg 
dose of ganaxolone, or matching placebo) 
at dinner time (four 225 mg capsules, or 


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• 
Continue monitoring of pulse 
oximetry and Q15 min health checks 
7.5.3 
Day + 2 (Discharge and 
transition to outpatient treatment) 
• 
The assessments listed below 
are completed before discharge 
• 
Conduct interviews for 
HAMD17  
• 
Conduct interviews for CGI-I  
• 
EPDS  
• 
STAI6  
• 
Collect AEs  
• 
Collect ECG 
• 
Collect VS (BP, pulse, 
respiratory rate, pulse oximetry, 
temperature) 
• 
Collect SSS  
• 
Collect a pharmacokinetic 
sample  
• 
Collect neurosteroid level  
• 
Record concomitant 
medications  
• 
Conduct CSSRS interview 
• 
Dispense outpatient 
medication supply 
• 
Patient will take a 675 mg 
dose of ganaxolone at bedtime (three 
225 mg capsules) 
7.6 
Outpatient treatment phase 
(Days + 3 – +14) - Cohort 6 
7.6.1 
Safety phone calls (Days +3, 
+5, +9 and +11) 
• 
A safety phone call is made 
on days +3, +5, +9, and +11 by the PI 
(or the sub-I). The patient is asked 
about her general wellbeing. AEs are 
recorded.  
7.6.2 
Visit 3 (Day +7) 
• 
Conduct HAMD17 interview 
• 
EPDS 
• 
STAI6 
• 
Assess CGI-I 
• 
Review concomitant 
medications and therapies  
• 
Collect vital signs (BP, pulse, 
temperature, pulse oximetry, 
respiratory rate),  
• 
Collect ECG 
• 
Collect urine drug screen and 
urine pregnancy test 
• 
Collect safety laboratory tests 
• 
Collect neurosteroid level 
• 
Collect a pharmacokinetic 
sample  
• 
Stanford Sleepiness Scale 
(SSS) 
matching placebo capsules) 
7.6 
Outpatient treatment phase 
(Days + 3 – +29) - Cohort 6 
7.6.1 
Safety phone calls (Days +3, +5, 
+10 and +13) 
• 
A safety phone call is made on 
days +3, +5, +10, and +13 by the PI (or 
the sub-I). The subject is asked about her 
general wellbeing. AEs are recorded.  
 
7.6.2 
Visit 3 HAMD Call (Day +4 ±1 
day) 
• 
CTNI to conduct HAMD17 
interview 
 
7.6.3 
Visit 4 (Day +8) 
• 
CTNI to conduct HAMD17 
interview 
• 
EPDS 
• 
STAI6 
• 
Assess CGI-I 
• 
Review concomitant medications 
and therapies  
• 
Collect vital signs (BP, pulse, 
temperature, pulse oximetry, respiratory 
rate),  
• 
Collect ECG 
• 
Collect urine sample for 
urinalysis, drug screen and urine 
pregnancy test 
• 
Collect safety laboratory tests 
• 
Collect neurosteroid level 
• 
Collect a pharmacokinetic 
sample  
• 
Stanford Sleepiness Scale (SSS) 
• 
Conduct CSSRS interview 
• 
Collect AEs 
• 
Dispense study medication with 
a supply to last until the next visit (+ 3 
days overage to cover for unexpected 
need to re-schedule a study visit or 
weekends).  Provide the subject with 
dosing instructions. IP return and 
accountability. 
• 
Subject will continue to take 
study drug (900 mg of ganaxolone, or 
matching placebo) at dinner time (unless 
the dose is lowered to 675 mg, or 450 mg, 
or matching placebo at dinner time as 
per instructions from the investigator) 
 
7.6.4 
Visit 5 HAMD Call (Day +11 ±1 
day) 
• 
CTNI to conduct HAMD17 
interview 
7.6.5 
Visit 6 (Day +15 ±2 days)  


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• 
Conduct CSSRS interview 
• 
Collect AEs 
• 
Dispense outpatient 
medication supply  
• 
Patient will continue to take 
675 mg of ganaxolone QHS (unless the 
dose is lowered to 450 mg QHS as per 
instructions from the investigator) 
7.6.3 
Visit 4 (Day +14) 
• 
Conduct HAMD17 interview 
• 
EPDS 
• 
STAI6 
• 
Assess CGI-I 
• 
Review concomitant 
medications and therapies  
• 
Collect vital signs (BP, pulse, 
temperature, pulse oximetry, 
respiratory rate),  
• 
Collect ECG 
• 
Collect urine drug screen and 
urine pregnancy test 
• 
Collect safety laboratory tests 
• 
Collect neurosteroid level 
• 
Collect a pharmacokinetic 
sample  
• 
Measure weight 
• 
Stanford Sleepiness Scale 
(SSS) 
• 
Conduct CSSRS interview 
• 
Collect AEs 
• 
Perform physical examination  
7.7 
Post–treatment Follow-up 
Period (Days +15 to +44) – Cohort 6 
7.7.1 
First Post-treatment Follow-
up Visit - 7 days After the Last On-
treatment Visit (Day +21) 
• 
The Follow-up Visit 1 should 
occur about 1 week after the Day 14 
visit.  
• 
Conduct interviews for 
HAMD17  
• 
Perform EPDS 
• 
Perform STAI6 
• 
Assess CGI-I  
• 
Review concomitant 
medications and therapies  
• 
Collect vital signs (BP, pulse, 
temperature, RR) 
• 
Collect safety laboratory tests  
• 
Collect neurosteroid level  
• 
Collect urine drug screen and 
urine pregnancy test  
• 
Measure weight  
• 
Conduct CSSRS interview 
• 
Collect SSS 
• 
Collect AEs  
• 
CTNI to conduct HAMD17 
interview 
• 
EPDS 
• 
STAI6 
• 
Assess CGI-I 
• 
Review concomitant medications 
and therapies  
• 
Collect vital signs (BP, pulse, 
temperature, pulse oximetry, respiratory 
rate),  
• 
Collect ECG 
• 
Collect urine sample for 
urinalysis, drug screen and urine 
pregnancy test 
• 
Collect safety laboratory tests 
• 
Collect neurosteroid level 
• 
Collect a pharmacokinetic 
sample  
• 
Measure weight 
• 
Stanford Sleepiness Scale (SSS) 
• 
Conduct CSSRS interview 
• 
Collect AEs 
• 
Dispense study medication with 
a supply to last until the next visit (+ 3 
days overage to cover for unexpected 
need to re-schedule a study visit or 
weekends).  Provide the subject with 
dosing instructions. IP return and 
accountability. 
• 
Perform physical examination  
 
7.6.6 
Visit 7 (Day +22 ±3 days) 
• 
CTNI to conduct HAMD17 
interview 
• 
EPDS 
• 
STAI6 
• 
Assess CGI-I 
• 
Review concomitant medications 
and therapies  
• 
Collect vital signs (BP, pulse, 
temperature, pulse oximetry, respiratory 
rate),  
• 
Collect ECG 
• 
Collect urine sample for 
urinalysis, drug screen and urine 
pregnancy test 
• 
Collect neurosteroid level 
• 
Collect a pharmacokinetic 
sample  
• 
Stanford Sleepiness Scale (SSS) 
• 
Conduct CSSRS interview 
• 
Collect AEs 
• 
Dispense study medication with 
a supply to last until the next visit (+ 3 
days overage to cover for unexpected 
need to re-schedule a study visit or 


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Version 8.0 / 08 Oct 2018 
 
CONFIDENTIAL 
 
Page 97 of 104 
 
7.7.2 
Second Post-treatment 
Follow-up Visit - 30 days After the 
Last On-treatment Visit (Day +44) 
• 
The Follow-up Visit 2 should 
occur about 30 days after the Day 14 
visit.  
• 
Conduct interviews for 
HAMD17  
• 
Perform EPDS 
• 
Perform STAI6 
• 
Assess CGI-I  
• 
Review concomitant 
medications and therapies  
• 
Collect vital signs (BP, pulse, 
temperature, RR) 
• 
Collect urine drug screen and 
urine pregnancy test  
• 
Measure weight  
• 
Conduct CSSRS interview 
• 
Collect SSS 
• 
Collect AEs 
 
weekends).  Provide the subject with 
dosing instructions. IP return and 
accountability. 
 
7.6.7 
Visit 8 (Day +29 ±3 days) 
• 
CTNI to conduct HAMD17 
interview 
• 
EPDS 
• 
STAI6 
• 
Assess CGI-I 
• 
Review concomitant medications 
and therapies  
• 
Collect vital signs (BP, pulse, 
temperature, pulse oximetry, respiratory 
rate),  
• 
Collect ECG 
• 
Collect urine sample for 
urinalysis, drug screen and urine 
pregnancy test 
• 
Collect safety laboratory tests 
• 
Collect a pharmacokinetic 
sample  
• 
Measure weight 
• 
Stanford Sleepiness Scale (SSS) 
• 
Conduct CSSRS interview 
• 
Collect AEs 
• 
Dispense study medication with 
a supply to last through the taper period. 
Provide the subject with dosing 
instructions. IP return and 
accountability. 
• 
Begin 3-day taper (3 capsules on 
Day 29, 2 capsules on Day30, 1 capsule on 
Day31, or, if Day 28 dose is other than 
ganaxolone 900 mg or placebo, follow 
instructions in section 3.4.6) 
• 
Perform physical examination 
 
7.7 
Post–treatment Follow-up 
Period (Days +29 to +71) – Cohort 6 
7.7.1 
First Post-treatment Follow-up 
Visit - 7 days After the Last On-
treatment Visit (Day +36) 
• 
The Follow-up Visit 1 should 
occur about 1 week after the Day 29 visit.  
• 
CTNI to conduct interviews for 
HAMD17  
• 
Perform EPDS 
• 
Perform STAI6 
• 
Assess CGI-I  
• 
Review concomitant medications 
and therapies  
• 
Collect vital signs (BP, pulse, 
temperature, RR) 
• 
Collect ECG Collect 
neurosteroid level  


Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2002 
Version 8.0 / 08 Oct 2018 
 
CONFIDENTIAL 
 
Page 98 of 104 
• 
Collect a pharmacokinetic 
sample 
• 
Collect urine sample for 
urinalysis, drug screen and urine 
pregnancy test  
• 
Measure weight  
• 
Conduct CSSRS interview 
• 
Collect SSS 
• 
Collect AEs  
• 
IP return and accountability 
 
7.7.2 
Second Post-treatment Follow-
up Visit - 28 days After the Last On-
treatment Visit (Day +57) 
• 
The Follow-up Visit 2 should 
occur about 28 days after the Day 29 
visit.  
• 
CTNI to conduct interviews for 
HAMD17  
• 
Perform EPDS 
• 
Perform STAI6 
• 
Assess CGI-I  
• 
Review concomitant medications 
and therapies  
• 
Collect vital signs (BP, pulse, 
temperature, RR) 
• 
Collect safety laboratory tests  
• 
Collect urine sample for 
urinalysis, drug screen and urine 
pregnancy test  
• 
Measure weight  
• 
Conduct CSSRS interview 
• 
Collect SSS 
• 
Collect AEs  
 
7.7.3 
Third Post-treatment Follow-up 
Visit - 42 days After the Last On-
treatment Visit (Day +71) 
• 
The Follow-up Visit 3 should 
occur about 42 days after the Day 29 
visit.  
• 
CTNI to conduct interviews for 
HAMD17  
• 
Perform EPDS 
• 
Perform STAI6 
• 
Assess CGI-I  
• 
Review concomitant medications 
and therapies  
• 
Collect vital signs (BP, pulse, 
temperature, RR) 
• 
Collect urine sample for 
urinalysis, drug screen and urine 
pregnancy test  
• 
Measure weight  
• 
Conduct CSSRS interview 
• 
Collect SSS 


Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2002 
Version 8.0 / 08 Oct 2018 
 
CONFIDENTIAL 
 
Page 99 of 104 
• 
Collect AEs 
 
 
Reason for Change: Updated details for Cohort 6 
54 
Table 2 Schedule of 
Assessments – 
Cohort 6 
 
Updated schedule based on details in 
section 7.5 
Reason for Change: Updated details for Cohort 6 
56 
7.8.5 Physical 
Examination 
A complete physical examination will 
be performed at screening and before 
discharge from the unit.  
A complete physical examination will be 
performed at screening, before discharge 
from the unit, and during visits 6 and 8 
(outpatient visits) of Cohort 6.  
Reason for Change: Updated details for Cohort 6 
59 
7.8.6.2  The 
Hamilton 
Depression Rating 
Scale 
The Hamilton Depression Rating Scale 
(HAMD) is a commonly-used semi-
structured clinician-rated instrument 
which assess the range of symptoms 
that are most frequently observed in 
subjects with major depression.  
HAMD has undergone a considerable 
amount of psychometric study and is 
accepted as a valid standard of 
symptom outcome assessment in 
studies of major depression.  In this 
study the symptoms of depression will 
be scored using the original 17-item 
HAMD scale (HAMD17).  The 6 item 
version of this scale, known as 
HAMD6, will be derived from these 
data and used as an additional measure 
of changes in symptoms of depression.  
The items on the HAMD6 scale are as 
follows:  depressed mood, work and 
interests, general somatic symptoms 
(tiredness), anxiety, guilt feelings, and 
psychomotor retardation.  Both 
HAMD6 and HAMD17 have been 
validated and used in many clinical 
trials of antidepressant medications.9  
The use of the 6-item scale is justified 
because many items on the 17-item 
version cannot be expected to change 
over short period of time (e.g. weight 
or sleep).  
The Hamilton Depression Rating Scale 
(HAMD) is a commonly-used semi-
structured clinician-rated instrument which 
assess the range of symptoms that are most 
frequently observed in subjects with major 
depression.  HAMD has undergone a 
considerable amount of psychometric study 
and is accepted as a valid standard of 
symptom outcome assessment in studies of 
major depression.  In this study the 
symptoms of depression will be scored 
using the original 17-item HAMD scale 
(HAMD17).  The 6-item version of this 
scale, known as HAMD6, will be derived 
from these data and used as an additional 
measure of changes in symptoms of 
depression.  The items on the HAMD6 scale 
are as follows:  depressed mood, work and 
interests, general somatic symptoms 
(tiredness), anxiety, guilt feelings, and 
psychomotor retardation.  Both HAMD6 
and HAMD17 have been validated and used 
in many clinical trials of antidepressant 
medications.9  The use of the 6-item scale is 
justified because many items on the 17-item 
version cannot be expected to change over 
short period of time (e.g. weight or sleep). 
All HAMD17 ratings, except the one done 
at screening, will be conducted by CTNI 
raters. 
Reason for Change: Clarification of HAMD17 rating responsibilities 


Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2002 
Version 8.0 / 08 Oct 2018 
 
CONFIDENTIAL 
 
Page 100 of 104 
61 
Table 4. Volume of 
Blood to Be Drawn 
from Each Subject 
(Cohort 6) 
 
Updated to include additional volume of 
blood draws for Cohort 6 
Reason for Change: Updated details for Cohort 6 
68 
9.5  Statistical 
Analysis Plan 
Statistical analyses will be mostly 
descriptive.  The purpose of this study 
is to identify a ganaxolone dose and 
exposure level that is safe and well 
tolerated.  Efficacy data will be 
collected but they are considered 
exploratory because of the small 
sample size.   
The SAP will provide the statistical 
methods and definitions for the 
analysis of the safety and efficacy data, 
and it will describe the approaches to 
be taken for summarizing other study 
information such as subject disposition, 
demographics and baseline 
characteristics, investigational product 
exposure, and prior and concomitant 
medications.  The SAP will also 
include a description of how missing, 
or unused data will be addressed.  
The SAP will be finalized prior to 
completion of the first cohort to 
preserve the integrity of the statistical 
analysis and study conclusions.  
 
Data analyses will primarily be 
descriptive.  The purpose of this study is to 
identify a ganaxolone dose and exposure 
level that is safe and well tolerated.  
Efficacy data will be collected but will be 
considered hypothesis-generating i.e., 
there are no a priori hypotheses on which 
the study was powered. Results from 
exploratory statistical analyses may be 
presented but only to aid in 
interpretation.   
The SAP will provide the statistical 
methods and definitions for the analysis of 
the safety and efficacy data, and it will 
describe the approaches to be taken for 
summarizing other study information such 
as subject disposition, demographics and 
baseline characteristics, investigational 
product exposure, and prior and 
concomitant medications.  The SAP will 
also include a description of how missing, 
or unused data will be addressed.  
The SAP will be finalized prior to 
completion of the first cohort to preserve 
the integrity of the statistical analysis and 
study conclusions. This will not preclude 
amendments to the SAP before database 
lock. 
Reason for Change: Added details for statistical analysis 
68 
9.5.1  Planned 
Interim Analysis 
An interim unblinded analysis of safety 
and efficacy data will be conducted for 
each cohort.  Based on these data the 
dose for the next cohort will be 
decided.  The dose recommendation 
will be made by a Data Review 
Committee (DRC) comprised of the 
sponsor’s Chief Medical Officer and 2 
external physicians familiar with the 
clinical care of women with major 
depression or PPD and with experience 
in conducting clinical trials.  A separate 
guidance document will outline the 
functions and membership of the DRC. 
The Marinus and the CRO study teams 
will remain blinded until the database 
lock of each cohort.  
Safety and efficacy data from each cohort 
will be unblinded, and analyses will be 
conducted for the purpose of dose selection 
for the next cohort.  The dose for the next 
cohort will be decided based on these 
interim data analyses.  The decision how 
to adjust the dose and/or the duration of 
the infusion will be made based on 
recommendations by a Data Review 
Committee (DRC) composed of the 
sponsor’s Chief Medical Officer, and at 
least 2 other external physicians.  At least 
one of the members will have special 
expertise in the clinical care of women 
with depression or postpartum depression.  
One of the members will have expertise 
in the conduct of clinical trials or analysis 
of clinical trial data. The study team and 


Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2002 
Version 8.0 / 08 Oct 2018 
 
CONFIDENTIAL 
 
Page 101 of 104 
 
all parties other than the DRC will 
remain blinded.  
The dose for the subsequent cohorts will 
be selected with the goal of gaining 
additional information on ganaxolone’s 
tolerability and dose-response profile.  
A separate DRC guidance document 
outlines the principles for dose selection.  
Marinus may decide to stop the study, or 
make the data public, after completion of 
any cohort.  
Reason for Change: Clarification of planned interim analyses 
69 
9.5.3  Study 
Population 
The Screened Set will consist of all 
subjects who have signed an informed 
consent. 
The Safety Set will consist of all 
subjects who received ganaxolone.  
The modified Intent to Treat Set 
(mITT) will consist of all subjects in 
the Safety Set who have at least 1 post-
randomization efficacy assessment. 
The Per-Protocol Set will consist of 
all subjects in the mITT set who do not 
have major protocol deviations that 
may affect key efficacy endpoints.  
The Infusion Completer Set will 
consist of all subjects in the Safety Set 
who completed the 60 hour infusion in 
Cohort 1-5, and who completed the 
initial infusion in Cohort 6.  
The Completer Set will consist of all 
subjects in the Safety Set who 
completed the 60 hour infusion and 
attended the final safety follow-up visit 
in Cohorts 1-5. In Cohort 6 the 
completer set will consist of subjects 
who completed the initial infusion and 
oral treatment period and attended all 
outpatient visits including the safety 
follow-up visits.  
The Screened Set will consist of all 
subjects who have signed an informed 
consent. 
The Randomized Set will consist of all 
subjects randomized. 
The Safety Set will consist of all subjects 
who received IP.  
The modified Intent to Treat Set (mITT) 
will consist of all subjects in the Safety Set 
who have at least 1 post-randomization 
efficacy assessment. 
The Per-Protocol Set will consist of all 
subjects in the mITT set who do not have 
major protocol deviations that may affect 
key efficacy endpoints.  
The Infusion Completer Set will consist of 
all subjects in the Safety Set who completed 
the 60-hour infusion in Cohort 1-5, and who 
completed the initial infusion in Cohort 6.  
The Completer Set will consist of all 
subjects in the Safety Set who completed 
the 60-hour infusion and attended the final 
safety follow-up visit in Cohorts 1-5. In 
Cohort 6 the completer set will consist of 
subjects who completed the initial infusion 
and oral IP dosing period with at least 
80% oral dosing compliance and attended 
all outpatient visits including the safety 
follow-up visits.  
Reason for Change: Clarification of study population 
70 
9.5.7  Safety 
Analyses 
Reported AEs terms will be coded 
using the Medical Dictionary for 
Regulatory Activities (MedDRA).  The 
incidence of Treatment Emergent AEs 
(TEAEs) will be summarized by 
treatment group, system organ class 
preferred terms, severity and 
Reported AE terms will be coded using the 
Medical Dictionary for Regulatory 
Activities (MedDRA).  The incidence of 
Treatment Emergent AEs (TEAEs), defined 
as any AE that started or worsened after 
first administration of IP, will be 
summarized by treatment group, system 


Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2002 
Version 8.0 / 08 Oct 2018 
 
CONFIDENTIAL 
 
Page 102 of 104 
relatedness for each cohort.  SAEs and 
AEs leading to discontinuation of the 
study drug will be summarized by 
treatment group for each cohort.  
The absolute values and change from 
baseline in laboratory tests, vital signs, 
SSS, ECGs and CSSRS will be 
summarized by treatment group for 
each cohort.  
Potentially clinically important 
findings will be summarized or listed. 
 
organ class preferred terms, severity and 
relatedness for each cohort.  SAEs and AEs 
leading to discontinuation of the study drug 
will be listed separately for each cohort.  
The absolute values and change from 
baseline in laboratory tests, vital signs, SSS, 
ECGs and CSSRS will be summarized by 
treatment group for each cohort.  
Potentially clinically important findings will 
be included in AE summaries and 
listings.  
Reason for Change: Clarification of safety analyses 
70 
9.5.8  Efficacy 
Analyses 
Data for efficacy-related variables (e.g. 
HAMD17, HAMD6, STAI6, EPDS) 
will be summarized by visit and by 
change from baseline.  Items related to 
sleep and anxiety within the HAMD17 
and EPDS scales may be tabulated 
separately.  
 
9.5.8.1  Primary Endpoint 
The primary efficacy endpoint will be 
HAMD17 total score change from 
baseline to 60 hours post-infusion (on 
Day 3) for Cohorts 1-3 and to Day 29 for 
Cohort 6. The primary analysis in each 
cohort will be done using the mITT set. 
Although the trial is not powered for 
inferential analysis and there is no 
consideration for control of type 1 error 
across multiple cohorts, a clinically 
meaningful numeric difference in means 
of 3-4 points between ganaxalone and 
placebo treatment groups would be 
considered an indication of efficacy and 
will be the most influential outcome in 
the overall assessment of the efficacy of 
ganaxalone in treating PPD. 
9.5.8.2  Secondary Endpoints 
The trial will also evaluate the following 
secondary endpoints at each post-
baseline data collection time point to 
provide additional evidence of the 
efficacy of ganaxalone in treating PPD: 
• 
Change from baseline in HAMD17 
total score other than at 60 hours 
post-infusion (on Day 3) for Cohorts 
1-3 and to Day 29 for Cohort 6 
• 
HAMD17 response defined as at least 
a 50% reduction from baseline in 
total score 
• 
HAMD17 remission defined as total 
score <= 7 
• 
Change from baseline in EPDS total 
score 
• 
Change from baseline in STAI6 
• 
CGI-I 




Marinus Phannaceuticals, Inc. 
Protocol 1042-PPD-2002 
Reason for Change: Clarification of efficacy analysis 
71 
9.5.10 
Pha1macokinetic 
Analyses 
Tue following phannacokinetics 
parameters will be estimated for each 
subject receiving ganaxolone, if 
sufficient data are available: Maximal 
plasma concentration (Cmax), 
concentration at steady-state (Css, 
dete1mined by the mean concentrations 
once steady-state is achieved by visual 
inspection), AUC0_24 (calculated as Css 
multiplied by 24 hours). PK samples 
will be collected from subjects 
participating in Cohort 6 during the IV 
and oral dosing portion of the study. 
Reason for Change: Updated PK sampling and timing 
77 
11.0 
REFERENCES 
Blank 
Reason for Change: Added references 
Version 8.0 / 08 Oct 2018 
Tue following phannacokinetics parameters 
will be estimated for each subject receiving 
ganaxolone, if sufficient data are available: 
Maximal plasma concentration (Cmax), 
concentration at steady-state (Css, 
detennined by the mean concentrations 
once steady-state is achieved by visual 
inspection), AUC0_24 (calculated as c •• 
multiplied by 24 hours). PK samples will be 
collected from subjects participating in 
Cohort 6 after the IV infusion, before and 
during the oral dosing portion of the study. 
16-
Helmreich I, Wagne1· S, Mergl 
R, et al. Sensitivity to changes during 
antidepressant treatment: a comparison 
of unidimensional sub scales of the 
Invento1·y of Depressive Symptomatology 
(IDS-C) and the Hamilton Depression 
Rating Scale (HAMD) in patients with 
mild major, mino1· or subsyndromal 
depression. Em· Arch Psychiatry Clin 
Neurosci. 2012 Jun;262(4):291-304 
17. 
Boessen Rl, Groenwold RH, 
Knol MJ , et al. Compa1-ing HAMD(l 7) 
and HAMD subscales on their ability to 
differentiate active treatment from 
placebo in randomized controlled trials. J 
Affect Disord. 2013 Mar 5;145(3):363-9. 
18. 
Thase ME, Chen D, Edwards J , 
Ruth A. Efficacy of vilazodone on anxiety 
symptoms in patients with major 
depressive disorder. Int Clin 
Psychopharmacol. 2014 Nov;29(6):351-6. 
Additional grallllllatical, typographical e1rnrs and fonnatting revisions have been made in the document but are not 
identified here. 
CONFIDENTIAL 
Page 104 of 104 

SAP_003.pdf: 
DocuSign Envelope ID: 1C62FF80 611 F 48EF 88EB 4801 F50DF810 
* 
PRAHEALTHSCIENCES 
Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN GNXLNE 
Protocol No.: 1042 PPD 2002 
Version Date: 06 Jun 2019 
Sponsor: 
Protocol No: 
PRA Project Id: 
Version Date: 
Version No.: 
Title: 
CRF Version No./Date: 
SAP No. 
1.0 Approvals 
Sponsors 
Sponsor Name: 
Representative/ Title 
(Co-Owner): 
Signature /Date: 
Representative/ Title: 
Signature /Date: 
PRA 
Project Manager/Title: 
Signature /Date: 
Biostatistician / Title 
(Co-Owner): 
Signature /Date: 
EDSREP 009 T 01 F 
Statistical Analysis Plan 
Marinus Pharmaceuticals 
1042-PPD-2002 
MRSGNXLN-GNXLNE 
22 October 2018 
8.0 (Amendment 7) 
A Phase 2A, Double-blind, Placebo-controlled, Multiple-dose Escalation Study to 
Evaluate Safety, Pharmacokinetics and Efficacy of Intravenously and Orally 
Administered Ganaxolone in Women with Postpartum Depression 
2.0 I 09AUG2018 
3.1 (Amendment to 2.0) 
Marinus Pharmaceuticals 
gned by Janice M. Pogoda, 
7-06-2019 I 11:07 AM PDT 
Page 1 of 35 


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
EDSREP 009 T 01 F 
Page 2 of 35 
 
Table of Contents 
 Approvals ............................................................................................................................................................................ 1 
Table of Contents ..................................................................................................................................................................... 2 
 Purpose ................................................................................................................................................................................ 4 
 Scope ..................................................................................................................................................................................... 4 
 Introduction ....................................................................................................................................................................... 4 
4.1 Changes from Protocol .............................................................................................................................................. 4 
 Study Objectives ............................................................................................................................................................... 4 
 Study Design ....................................................................................................................................................................... 5 
6.1 General Description .................................................................................................................................................. 5 
6.2 Sample Size Considerations .................................................................................................................................. 10 
6.3 Randomization ........................................................................................................................................................... 10 
6.4 Blinding ......................................................................................................................................................................... 11 
 Study Variables and Covariates ................................................................................................................................ 11 
7.1 Efficacy ........................................................................................................................................................................... 11 
7.1.1 HAMD17 ............................................................................................................................................................... 11 
7.1.2 HAMD6 .................................................................................................................................................................. 11 
7.1.3 Edinburgh Postnatal Depression Scale (EPDS) .................................................................................... 11 
7.1.4 Spielberger Trait-State Anxiety Inventory, 6 item version ............................................................. 12 
7.1.5 Clinical Global Impression-Improvement (CGI-I) ............................................................................... 12 
7.2 Safety .............................................................................................................................................................................. 12 
7.2.1 Adverse Events (AE) ........................................................................................................................................ 12 
7.2.2 Laboratory Measures ...................................................................................................................................... 12 
7.2.3 Vital Signs, Height, and Weight ................................................................................................................... 13 
7.2.4 Columbia-Suicide Severity Rating Scale (C-SSRS) ............................................................................... 13 
7.2.5 Stanford Sleepiness Scale (SSS) .................................................................................................................. 13 
7.2.6 12-lead Electrocardiogram (ECG) .............................................................................................................. 14 
7.2.7 Physical Examination ...................................................................................................................................... 14 
 Definitions ......................................................................................................................................................................... 14 
8.1 Treatment/Subject Grouping Definition ......................................................................................................... 14 
8.2 Other Definitions ....................................................................................................................................................... 15 
8.3 Imputation .................................................................................................................................................................... 16 
8.4 Analysis Time Point/Visit Windows ................................................................................................................. 16 
 Analysis Sets ..................................................................................................................................................................... 17 
 Analyses ........................................................................................................................................................................... 18 
10.1 Data Review Committee (DRC) ......................................................................................................................... 18 
10.2 Analyses After Cohorts 1-3 ................................................................................................................................. 19 
10.3 Final Analysis ........................................................................................................................................................... 19 
 Data Review ................................................................................................................................................................... 20 
11.1 Data Handling and Transfer ............................................................................................................................... 20 
11.2 Data Screening ......................................................................................................................................................... 20 
 Statistical Methods ...................................................................................................................................................... 20 
12.1 Subject Disposition ................................................................................................................................................ 20 
12.2 Important Protocol Deviations ......................................................................................................................... 20 
12.3 Treatments ................................................................................................................................................................ 21 
12.3.1 Extent of Study Drug Exposure ................................................................................................................ 21 


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
EDSREP 009 T 01 F 
Page 3 of 35 
12.3.2 Concomitant Medications ........................................................................................................................... 23 
12.4 Demographic and Baseline Characteristics ................................................................................................. 23 
12.4.1 Demographics .................................................................................................................................................. 23 
12.4.2 Medical History ............................................................................................................................................... 23 
12.4.3 Prior Medications ........................................................................................................................................... 23 
12.4.4 Mini International Neuropsychiatric Interview 7.0 ......................................................................... 23 
12.4.5 SAFER Interview ............................................................................................................................................. 23 
12.4.6 Clinical Global Impression – Severity Scale ......................................................................................... 24 
12.5 Efficacy Analyses ..................................................................................................................................................... 24 
12.5.1 Primary Efficacy Endpoint ......................................................................................................................... 25 
12.5.2 Secondary Efficacy Endpoints ................................................................................................................... 25 
 
12.6 Safety Analyses ........................................................................................................................................................ 26 
12.6.1 Adverse Events ................................................................................................................................................ 26 
12.6.2 Laboratory Data .............................................................................................................................................. 26 
12.6.3 Vital Signs .......................................................................................................................................................... 27 
12.6.4 Physical Examinations, 12-Lead ECGs, and Other Observations Related to Safety ............ 27 
 Validation ........................................................................................................................................................................ 28 
Appendix 1 Glossary of Abbreviations ......................................................................................................................... 29 
Appendix 2 Adverse Event Start/Stop Date Imputation ....................................................................................... 31 
Appendix 3 Tables, Figures, Listings, and Supportive SAS Output Appendices .......................................... 32 
 


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
EDSREP 009 T 01 F 
Page 4 of 35 
 Purpose 
This statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Marinus Pharmaceuticals Protocol 1042-PPD-2002. 
 Scope 
This SAP was first created during the trial start-up and, per protocol, was signed off by the Sponsor prior to 
completion of the first cohort of the trial. The SAP can be amended, as needed, up to unblinding. Each 
amendment must be approved and signed off by Sponsor. If an amendment to the SAP requires updates 
to analysis data set or TFL (table, figure and listing) programming, the amendment must be signed off by 
the Sponsor prior to programming changes being made. 
 Introduction 
This SAP should be read in conjunction with the study protocol and case report form (CRF). This SAP 
amendment is based on Protocol Version 8.0, Amendment 7 dated 08Oct2018 and CRF dated 09Aug2018. 
Any further changes to the protocol or CRF may necessitate updates to the SAP. 
Analyses presented to the Data Review Committee (DRC), as well as the pharmacokinetic (PK) and 
neurosteroid analyses, will not be detailed in this SAP. 
This SAP supersedes the statistical considerations identified in the protocol; where considerations are 
substantially different, they will be so identified in Section 4.1. Any post-hoc or unplanned analyses not 
included in this SAP, or significant changes from the planned analysis in this SAP, will be clearly identified 
in Section 9.8.2 of the clinical study report (CSR). Changes to planned analyses after database lock do not 
require an updated SAP but should be included in the CSR. 
4.1 Changes from Protocol 
• 
Protocol Synopsis and Sections 2.2.1 and 7.8.7: Change from baseline analysis for the Columbia- 
Suicide Severity Rating Scale (C-SSRS) will not be performed.  Instead, the number of subjects 
who answered “yes” to the 5 suicidal ideation questions and the 5 suicidal behavior questions of 
the C-SSRS will be tabulated. 
• 
Protocol Synopsis and Section 2.2.1: Change from baseline analysis for physical examinations will 
be performed. Details of the physical examination will be listed only. 
• 
Section 9.5.3: The Per Protocol Set will consist of all subjects in the mITT (modified Intent to Treat) 
set who do not have protocol deviations that may affect key efficacy endpoints, whether or not the 
deviations are classified as major. 
 Study Objectives 
The study objectives are as follows. 
Safety objective: To assess the safety and tolerability of escalating doses of intravenously administered 
ganaxolone as determined by adverse events, physical examination, C-SSRS, and change since baseline 
in: 
1) laboratory measures,  
2) vital signs,  
3) electrocardiogram (ECG), and 
4) Stanford Sleepiness Scale (SSS). 
Efficacy objective: To explore the efficacy of escalating doses of intravenously administered ganaxolone 
in the treatment of postpartum depression (PPD) by:  


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
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Page 5 of 35 
1) Hamilton Depression Rating Scale 17-item version (HAMD17),  
2) Edinburgh Postnatal Depression Scale (EPDS),  
3) Spielberger State-Trait Anxiety Inventory 6-item version (STAI6) and  
4) Clinical Global Impression-Improvement (CGI-I) scale. 
Pharmacokinetic objective: To collect samples of blood for pharmacokinetic analysis after administration 
of intravenous (IV) ganaxolone.  Pharmacokinetic analyses will be not be performed by PRA; as such, PK 
analysis details are beyond the scope of this SAP. 
 Study Design 
6.1 General Description 
This is a Phase 2A, double-blind, placebo-controlled, multiple-dose escalation study consisting of up 
to 6 cohorts (Cohort 1 to 6).  
Approximately 200 women with PPD 18–45 years of age will be screened to randomize up to 100 
subjects across up to 6 cohorts, with Cohorts 4 and 5 optional. Approximately 10-30 subjects will be 
randomized into each cohort. Randomized subjects will receive ganaxolone or matching placebo in 
a 1:1 ratio.  The study will be conducted in the United States at approximately 15 investigative sites.  
 
 
Figure 1 Study Design. 
 
 
 
6.0 
PRAHEALTHSCIENCES 
Cohorts 1- 5 
----- GNX n = 5 -15 
Cohorts 6 
GNX n = 5-15 
_____ 
1l 1v Bolus (in Cohort 3 only) I 
I 60 hour IV Infusion 
6-hour 40 ml/hr IV infusion + 28 day 4 capsules at dinner 
-----• (= GNX 120 mg IV + 28 day 900 mg PO at dinner 
OR matching placebo) 
Followed by 3-day taper 
-----PBO n = 5 -15 
PBO n = 5-15 


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
EDSREP 009 T 01 F 
Page 6 of 35 
Table 1. Schedule of Assessments – Cohorts 1-5 
Day 
Day -14 to -1 
Day 0 
Day 1 
(Start 
Infusion in 
AM, 0h) 
Day 2  
Day 3 
(End 
Infusion 
in PM) 
Day 4 
(Discharge) 
Day 11 (Day 7 
Post Discharge) 
Day 34 (Post 
Discharge 
Day 30) 
VISIT 
Screening 
Admission 
Infusion 
Infusion 
Infusion 
Discharge 
Follow-up 
Follow-up 
 
 
 
0h-24 
24-48h 
48-72 
72h 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics,  Medical History 
X 
 
 
 
 
 
 
 
MINI neuropsychiatric interview 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
 
Concomitant Meds and Therapy 
X 
X 
X 
X 
X 
X 
X 
X 
Admission to the unit 
 
X 
 
 
 
 
 
 
Discharge from the unit 
 
 
 
 
 
X 
 
 
Physical examination  
X 
 
 
 
 
X 
 
 
SAFER Interview (during screening) 
X 
 
 
 
 
 
 
 
Vital signs (BP, Pulse, pO2, RR, temp) 
X 
X 
X 
X 
X 
X 
X 
X 
Height (screening only) and weight  
X 
X 
 
 
 
 
X 
X 
ECGs 
X 
X 
X 
X 
X 
X 
 
 
Safety Laboratory Tests 
X 
X 
 
 
X 
 
X 
 
Neurosteroid level  
 
X 
 
 
X 
 
X 
 
Urinalysis Drug Screen and Pregnancy 
X 
X 
 
 
 
X 
X 
X 
CSSRS 
X 
X 
X 
X 
X 
X 
X 
X 
Record AEs  
 
X 
X 
X 
X 
X 
X 
X 
Randomization  
 
 
X 
 
 
 
 
 
Start bolus/infusion (0h) 
 
 
X 
 
 
 
 
 
Lower the infusion rate to half (+48h) 
 
 
 
 
X 
 
 
 
End infusion (+60h) 
 
 
 
 
X 
 
 
 
PK sample collection 
 
 
X 
X 
X 
X 
X 
X 
HAMD17 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
CGI-S 
X 
 
X 
 
 
 
 
 
EPDS 
X 
 
X 
 
X 
 
X 
X 
SSS 
 
 
X 
X 
X 
X 
 
 


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
EDSREP 009 T 01 F 
Page 7 of 35 
Table 1. Schedule of Assessments – Cohorts 1-5 
Day 
Day -14 to -1 
Day 0 
Day 1 
(Start 
Infusion in 
AM, 0h) 
Day 2  
Day 3 
(End 
Infusion 
in PM) 
Day 4 
(Discharge) 
Day 11 (Day 7 
Post Discharge) 
Day 34 (Post 
Discharge 
Day 30) 
VISIT 
Screening 
Admission 
Infusion 
Infusion 
Infusion 
Discharge 
Follow-up 
Follow-up 
STAI6 
X 
 
X 
X 
X 
X 
X 
X 
Q15 min health checks & pulse ox 
 
 
throughout 
 
 
Specific timepoints for assessments on days +1, +2, +3 and +4: - Cohorts 1-5 
PK samples: +12h, +24h, +48h, +72h 
HAMD17: before start of infusion, +12h, +24h, +48h, +60h, +72h all done by CTNI 
CGI-I: +12h, +24h, +48h, +60h, +72h  
CGI-S: before start of infusion 
EPDS: before start of infusion, +60h  
STAI6: before start of infusion, +12h, +24h, +48h, +60h, +72h  
ECG: +12h, +24h, +48h, +72h  
Vital Signs: (BP/P/pO2/RR/Temp): before start of infusion, +4, +8h, +12, +18h, +24h, +32h, +40h, +48h, +56h, +60h, +72h  
SSS: before start of infusion, +8h, +32h, +56h, +72h  
CSSRS: before start of infusion, +12h, +36h, +60, +72h  
Safety laboratory tests and neurosteroid level: +48h  
Urinalysis drug and pregnancy test: +72h  
Physical examination: +72h 
AEs and concomitant medications are collected throughout the inpatient stay.  
Q15min health checks are done from the time of admission to the time of discharge.  Pulse oximetry (pO2) must be monitored throughout the infusion, 
including during the night when the subject is sleeping.  The subject should be awakened if pulse oximetry falls < 91%.   
The following priority order will be in effect when more than 1 assessment is required at a particular time point: 1) HAMD17 2) CGI-I/CGI-S 3) EPDS 4) 
STAI6 5) SSS 6) CSSRS 7) vital signs 8) ECG 9) safety labs and neurosteroid level 10) PK sample 11) neurosteroid level 12) urinalysis drug screen and 
pregnancy test 13) physical examination 
Day 11 and Day 34 visits have visit windows of ± 3 and ± 5 days, respectively 
 
 


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
EDSREP 009 T 01 F 
Page 8 of 35 
 
 
PRAHEALTHSCIENCES 
Table 2. S('heclule of Assessments - Coho1·t 6 
Day 
Da.--U 
Da.-0 
Day l 
Dayl° 
Day 2' 
Da.-s 3 
Day~ 
Day 8 
Days 10 Day 11 
Da~-1~ 
Day 2.2 
Da~- 29 
Day .16 Day 57 Day 7l 
t~ -I 
Admission 
&5 
&B 
Screenin 
Baseline 
Disl'hal'ge Safety 
Y3 
Safe~-
Y5 
l'' 
2"" 
.l"' 
nsn 
Post-BL 
& 
RAJ.ID \ -.,i outpt 
HAMD Y6 outp 11 ontpt YB outpt Follow- Follow- Follow-
" 
call 
call 
., 
Outpatieu.t 
Call 
Call 
up 
up 
up 
Informed consent 
X 
Demographics, Medical History 
X 
MINI neuropsychiatric inteiview 
X 
lnclusion/Exdusion criteria 
X 
X 
Concomitant Meds and Therapy Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Admission to the unit 
X 
Discharge from the unit 
X 
Physic.al examination 
X 
X 
X 
X 
SAFER Interview (during screening) 
X 
Vital igns (B P, Pulse, p02, RR, temp) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height (screening only) and weight 
X 
X 
X 
X 
X 
X 
X 
ECG;; 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Laboratory Tests 
X 
X 
X 
X 
X 
X 
Neurosteroid lei·el 
X 
X 
X 
X 
X 
X 
X 
Urinalysis, Dmg Screen and Pregnan.cy Tes ts 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CSSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record A.Es 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
X 
Start infusion (Oh; 9 am ± l h) • 
X 
End infusion (6h) 
X 
PK sample collection ' 
X 
X 
X 
X 
X 
X 
X 
HM,ID17' 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-S 
X 
X 
EPDS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
sss 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
STAI6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense medication/return accountability 
X 
X 
X 
X 
X 
Oral dosing (at dimm time) 
X 
throughout the outpatient period 
Q15 min health checks & pulse ox • 
X 
throughout lhe inpatient period 
Start 3-day taper 
X 


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
EDSREP 009 T 01 F 
Page 9 of 35 
PRAHEALTHSCIENCES 
• Infusion st~rts at 9 am and ends 6 hours later at 3 pm and is administered at a constant rate of 40 mL/hr. 
b Twelve pham1acoki11etic samples are collected in Cohort 6: 
On Day 1 subjects will have 6 PK samplings: at l hour after the end of the 6-hour infusion (i.e., at 4 pm), at 7 pm (just prior to the oral dosing), and at l , 2, 3, and 
4 hours post oral dosing (at 8, 9, 10, and 11 pm) as well at 8 am the following morning (on Day 2) prior to discl1a1ge. 
A pharmacokinetic sample is also collected on Days 8, 15, 22, 29, and 36 during the study visit. 
c All H.AMDl 7 ratings, except the one done at screening, will be conducted by CTNI raters. 
d Q 1 Smin health checks are done from the tin1e of start of the infusion to the time of discha1ge. Pulse oximetry (p02) must be monitored from the st~rt of the 
infusion throughout the inpatient period, including during the night when the subject is sleeping. The subje.ct should be awakened if pulse oximetry falls < 91 %. 
• On Day+ 1 all efficacy assessments should be conducte.d first before lab draws, if possible. 
f All Day +2 assessments, including PK and neurosteroid levels, a1e to be done before the subject is discharged from the unit. 
The following priority order will be in effect when more than 1 assessment is required at a particular time point: l) H.AMD17 2) CGI-1/CGI-S 3) EPDS 4) STAI6 
5) SSS 6) CSSRS 7) vital signs 8) ECG 9) safety fabs and neurosteroid level 10) PK sample 11) neurosteroid level 12) urinalysis drng screen and pregnancy test 
13) physical examination 
All outpatient. visits have a± 3-day visit window, except Visits 3 and 5 which have just a± 1-day visit window and Visits 4 and 6 which have a± 2-day visit 
ivi11dow. 


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
PRS 005 T 17 F 
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Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
 
 
 
 
 
Cohorts 1-5 will involve IV infusions only, henceforth referred to as IV only cohorts, while Cohort 6 will 
involve both IV and oral study drug, henceforth referred to as the IV-to-oral cohort.  
The IV only cohorts will include a screening visit followed by a screening period up to 2 weeks, a 
baseline/randomization visit followed by an inpatient 4-day treatment phase during which the subjects will 
receive a 60-hour infusion of ganaxolone or placebo (with or without bolus). The subject will be discharged 
from the unit on the morning of Day 4. There will be a follow-up period of 30 days after discharge during 
which the subject will have safety visits at week 1 (Day 11) and week 4 (Day 34). An unblinded interim 
safety and efficacy analysis will be conducted by the DRC after each cohort for the purpose of dose 
selection for the next cohort. The total duration of study participation will be up to 7 weeks. 
The IV-to-oral cohort (Cohort 6) will include a screening visit followed by a screening period up to 2 weeks, 
a baseline/randomization visit followed by an inpatient 1-day treatment phase during which the subjects will 
receive a 6-hour infusion of ganaxolone or placebo from approximately 9 am to 3 pm followed by the start 
of oral dosing at approximately 7 pm. The subjects will be admitted 1 day prior to Day 1 (infusion day) and 
discharged from the unit in the morning of Day 2. Oral dosing is continued as outpatient on Days 2-28. 
There will be 3 safety follow-up visits after the last dose, at Weeks 1, 4, and 6. The total duration of study 
participation will be up to 12 weeks. 
The dosing regimen for each cohort is as follows: 
Cohort 1: ganaxolone is infused at a rate of 4 mg/h (16 ml/h of ganaxolone 0.25 mg/ml solution) for 
48 hours and then at a rate of 2 mg/h for the next 12 hours. The infusion is stopped at 60 hours. 
Cohort 2: ganaxolone is infused at a rate of 8 mg/h (16 ml/h of ganaxolone 0.5 mg/ml solution) for 
48 hours and then at a rate of 4 mg/h for the next 12 hours. The infusion is stopped at 60 hours. 
Cohort 3: Twelve mg bolus of ganaxolone is initially given over 2 minutes followed by ganaxolone 
infusion at a rate of 12 mg/h (24 ml/h of ganaxolone 0.5 mg/ml solution) for 48 hours. The rate is 
then reduced to 6 mg/h for the next 12 hours. The infusion is stopped at 60 hours.  
Cohorts 4-5: Cohorts 4 and 5 are optional and will be utilized only if further dose exploration is 
warranted. Ganaxolone infusion rate will be decided based on the results of Cohorts 1-3. However, 
the initial bolus dose will not exceed 16 mg over 2 minutes and the maximum infusion rate will not 
exceed 16 mg/h.  
Cohort 6: subjects randomized to ganaxolone will receive an initial IV infusion of 20 mg/h (40 ml/h 
of ganaxolone 0.5 mg/ml solution) for 6 hours followed by 900 mg (4 capsules) ganaxolone 
capsules administered orally at dinner time for 28 days followed by a 3-day taper (3, 2, and 1 
capsules per day, respectively). Subjects randomized to placebo will receive an initial IV infusion 
of matching placebo (at 40 ml/h) followed by 4 placebo capsules administered orally at dinner time 
for 28 days followed by a 3-day taper (3, 2, and 1 capsules per day, respectively). 
6.2 Sample Size Considerations 
No formal hypothesis testing will be performed, and the sample size is not based on statistical power 
considerations. The sample size was chosen based on experience with other studies conducted with 
compounds in early clinical development and on DRC recommendations. A population of about 6 to 10 
subjects per dose is commonly tested in studies which aim to establish a tolerability range for a new 
compound or a new formulation and is used as a guide for a minimum cohort size for this study. 
6.3 Randomization 
Approximately 200 women 18–45 years of age will be screened, and approximately 10-30 of those with 
PPD will be randomized within cohorts on Day 1 to receive ganaxolone or placebo in a 1:1 ratio with 1 block 


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
PRS 005 T 17 F 
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Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
 
 
 
 
 
of 4 for each cohort, while the rest of the blocks are of size 2. Treatment assignment will be determined by 
a randomization schedule prepared by PAREXEL. Randomization will not be stratified. Treatment 
assignments will be obtained by the investigator (or designee) via an Interactive Voice and/or Web 
Response System (IxRS). Subject numbers will be assigned sequentially as subjects consent to participate 
in the study. After being randomized a subject will be replaced only if she discontinues prior to receiving 
investigational product (IP). The replacement subject will receive the same IP assignment as the replaced 
subject. 
6.4 Blinding 
The unblinded pharmacist, unblinded medical monitor, independent reporting statistician/programmers, as 
well as the DRC are provided the treatment information prior to unblinding in order to ensure the optimal 
conduct of the study. In addition, any data transferred into PRA are processed by an unblinded database 
developer in order to ensure any potentially unblinding information is masked to the study team. All other 
study personnel remain blinded to treatment assignment until unblinding. 
The unblinded statistician and programming team are external to PRA and have limited communication 
with the blinded statistician and programmers during the conduct of this study.  
 Study Variables and Covariates 
7.1 Efficacy 
7.1.1 HAMD17 
The Hamilton Depression Rating Scale (HAMD) is a commonly-used semi-structured clinician-rated 
instrument which assesses the range of symptoms that are most frequently observed in subjects with major 
depression.  All items are scored on an ordinal scale between 0 and 4 (8 items) or 0 and 2 (9 items) of 
increasing severity. A total score is derived by summing over all individual items. Improvement is indicated 
by negative change scores and this will be footnoted in the TFLs. The 17-item version of this scale 
(HAMD17) will be used in this trial and will be assessed at each in-person study visit . The Day 1 
assessment before IP infusion will be the Baseline observation. 
7.1.2 HAMD6 
Some items on the HAMD scale (such as weight) are not expected to have meaningful changes over the 
first 72 hours. The 6-item version of the HAMD, known as HAMD6, will be used as an additional measure 
of changes in symptoms of depression. The items on the HAMD6 scale are as follows: depressed mood, 
work and interests, general somatic symptoms (tiredness), anxiety, guilt feelings, and psychomotor 
retardation. The HAMD6 is considered to be responsive to more immediate changes in depression 
symptoms. Improvement is indicated by negative change scores and this will be footnoted in the TFLs. 
7.1.3 Edinburgh Postnatal Depression Scale (EPDS) 
The EPDS is a 10-question self-rated instrument for assessment of symptoms of PPD such as worry, sleep, 
mood and enjoyment, which are rated on a 4-point scale (0 to 3) of increasing severity.  The EPDS total 
score is the sum of the scores of these 10 questions.  Improvement is indicated by negative change scores 
and this will be footnoted in the TFLs. 
Two questions assessing obsessive thoughts were added to this questionnaire (“How much of your time is 
occupied by obsessive thoughts over the past 24h?” and “How much distress do your obsessive thoughts 


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
PRS 005 T 17 F 
Page 12 of 35 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
 
 
 
 
 
cause you?), but they are not counted towards the total EPDS score. These 2 questions are rated on a 5-
point scale (0 to 4) of increasing severity. 
The responses will be assessed at Screening, Day 1, +60h, Day 11, and Day 34 for the IV only cohorts and 
at each in-person visit for the IV to oral cohort. The Day 1 assessment before IP infusion will be the Baseline 
observation. 
7.1.4 Spielberger Trait-State Anxiety Inventory, 6 item version  
The Spielberger Trait-State Anxiety Inventory, six item version (STAI6), is a short questionnaire evaluating 
anxiety state. The STAI6 has 6 questions: 1) “I feel calm”, 2) “I am tense”, 3) “I feel upset”, 4) “I am relaxed”, 
5) “I feel content”, and 6) “I am worried".  Each of these questions are rated as a) “not at all” b) “somewhat”, 
c) “moderately”, and d) “very much.”  For questions 2, 3, and 6, the scoring is a=1, b=2, c=3, and d=4.  For 
the other 3 questions, the scoring is a=4, b=3, c=2, and d=1.  The STAI6 score is the result of first totaling 
the 6 individual item scores, and then prorating it by a multiplication factor of 20/6 to acquire a range of 20 
to 80, inclusive (Marteau 1992). Improvement is indicated by negative change scores and this will be 
footnoted in the TFLs.     
The responses will be assessed at each post-baseline in-person visit except Day 0 (admission). The Day 
1 assessment before IP infusion will be the Baseline observation. 
7.1.5 Clinical Global Impression-Improvement (CGI-I) 
The Clinical Global Impression – Improvement scale (CGI-I) is a 7-point scale that asks the clinician to 
assess how much the subject's illness has improved or worsened relative to a baseline state at the 
beginning of the intervention. It is rated as: 1, very much improved; 2, much improved; 3, minimally 
improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. 
CGI-I responses will be assessed at each post-baseline in-person visit. 
7.2 Safety 
7.2.1 Adverse Events (AE) 
An AE is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical 
product and that does not necessarily have a causal relationship with this treatment. Data on AEs will be 
collected at each visit from the time the informed consent is signed until the end of the follow-up period. 
This includes AEs occurring during the screening phase of the study, regardless of whether or not 
investigational product has been administered.  AEs will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) 20.0.  Rules for partial dates are provided in Appendix 2. 
7.2.2 Laboratory Measures  
Laboratory measures will be assessed at Screening, Day 0, +48h, and Day 11 for the IV only cohorts and 
at Screening and Days 0, 8, 15, 29, and 57 for the IV to oral cohort. Urine pregnancy tests and drug 
screens will be conducted at Screening, Day 0, +72h, and Days 11 and 34 for the IV only cohorts and at 
Screening and at Days 0, 8, 15, 22, 29, 36, 57, and 71. The Day 0 assessment will be the Baseline 
observation. Neurosteroid levels and PK data will be analyzed separately by other third-party vendors and 
thus will not be described in this SAP.  Per protocol, the following assessments will be done. 
• 
Chemistry: Sodium, potassium, glucose, chloride, carbon dioxide, creatinine, total protein, blood 
urea nitrogen, albumin, total bilirubin (with reflex fractionation to direct and indirect bilirubin if total 
bilirubin is elevated and outside of the normal range), alanine aminotransferase, aspartate 
transferase, alkaline phosphatase, thyroid stimulating hormone (with reflex to free T4 if thyroid 


Statistical Analysis Plan 
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Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
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Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
 
 
 
 
 
stimulating hormone (TSH) is outside of the normal range), β-HCG (Human Chorionic 
Gonadotropin) 
• 
Hematology: Hematocrit, hemoglobin, red blood cell count, mean corpuscular volume, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, white 
blood cell count with differential 
• 
Urinalysis: Leukocytes, nitrites, protein, blood, specific gravity, glucose, ketones 
• 
Urine Drug Screen: Cannabis, oxycodone, methadone, buprenorphine, cocaine, 
benzodiazepines, barbiturates, alcohol (ethanol) and phencyclidine 
Urine pregnancy results will only be provided in a data listing. 
7.2.3 Vital Signs, Height, and Weight 
Vital signs will be assessed at each in-person study visit . The following measurements will be taken:. 
a. Systolic blood pressure (mmHg) 
b. Diastolic blood pressure (mmHg) 
c. 
Pulse rate (beats/min) 
d. Oral body temperature (degrees Celsius) 
e. Respiratory rate (breaths/min) 
f. 
Pulse Oximetry (%) 
g. 
Height (cm) (collected only at Screening) 
h. Weight (kg) (collected only at Screening and Days 0, 11, and 34 for the IV only cohorts and at 
Screening and Days 15, 29, 36, 57, and 71 for the IV to oral cohort) 
a. Body Mass Index (kg/m2)  
The Day 1 assessment before IP infusion will be the Baseline observation for vital signs. For weight, the 
Day 0 assessment will be the Baseline observation. 
7.2.4 Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a unique, simple, and short method of assessing both behavior and ideation that tracks all 
suicidal events and provides a summary of suicidality. It assesses the lethality of attempts and other 
features of ideation (frequency, duration, controllability, reasons for ideation, and deterrents) that are 
significantly predictive of completed suicide. 
C-SSRS will be assessed at each in-person study visit. The Day 1 assessment before IP infusion will be 
the Baseline observation. 
7.2.5 Stanford Sleepiness Scale (SSS) 
Stanford Sleepiness Scale (SSS) is a self-rated scale (1 to 8 of increasing sleepiness) measuring level of 
sleepiness the subject is feeling. Level 1 is “feeling active, vital, alert or wide-awake” level 7 is “no longer 
fighting sleep, sleep onset soon; having dream-like thoughts”; level 8 is sleeping. 
The responses will be assessed at Day 1 before infusion, +8h, +32h, +56h, and +72h for the IV only cohorts 
and at Day 1 before infusion, +6h and at Days 2, 8, 15, 22, 29, 36, 57, and 71 for the IV to oral cohort. The 
Day 1 assessment before IP infusion will be the Baseline observation. 


* PRAHEALTHSCIENCES 
Statistical Analysis Plan 
PRA Protocol ID MRSGNXLN-GNXLNE 
Protocol No. 1042-PPD-2002 
Version Date: 06-Jun-2019 
7.2.6 12-lead Electrocardiogram (ECG) 
A 12-lead ECG will be conducted at Screening, Day 0, Day 1 before infusion, +12h, +24h, +48h, and +72h 
for the IV only cohorts and at Screening, +6h, and at Days 0, 2, 8, 15, 22, 29, and 36 for the IV to oral 
cohort. The Day 1 assessment before IP infusion will be the Baseline observation for the IV only cohorts. 
For the IV to oral cohort, the Day O assessment will be the Baseline observation. RR, PR, ORS, QTcF and 
QTcB will be collected. Continuous measures will be imported from an external vendor database. The data 
will undergo vendor specific edit checks. Reconciliations with EDC will be performed upon import of data 
to PRA. 
7.2.7 Physical Examination 
A complete physical examination will be performed at Screening and + 72h for the IV only cohorts and at 
Screening and at Days 2, 15, and 29 for the IV to oral cohort. 
The physical examination will include a review of the following body systems: 
• 
Autoimmune 
• 
Cardiovascular 
• 
Dermatological 
• 
Ears, Nose, Throat 
• 
Endocrine/Metabolic 
• 
Gastrointestinal 
• 
Genito-urinary 
• 
Musculoskeletal 
• 
Respiratory 
• 
Central Nervous System 
8.0 Definitions 
8.1 Treatment/Subject Grouping Definition 
Throughout this SAP treatment refers to active or placebo. Dose refers to the dose level of the active 
treatment. 
PRS 005 T 17 F 
Ganaxolone or Placebo 
Cohort 1: ganaxolone is infused at a rate of 4 mg/h (16 ml/h of ganaxolone 
0.25 mg/ml solution) for 48 hours and then at a rate of 2 mg/h for the next 
12 hours. The infusion is stopped at 60 hours. 
Cohort 2: ganaxolone is infused at a rate of 8 mg/h (16 ml/h of ganaxolone 
0.5 mg/ml solution) for 48 hours and then at a rate of 4 mg/h for the next 12 
hours. The infusion is stopped at 60 hours. 
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Statistical Analysis Plan 
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Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
PRS 005 T 17 F 
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Cohort 3: Twelve mg bolus of ganaxolone is initially given over 2 minutes 
followed by ganaxolone infusion at a rate of 12 mg/h (24 ml/r of ganaxolone 
0.5 mg/ml solution) for 48 hours. The rate is then reduced to 6 mg/h for the 
next 12 hours. The infusion is stopped at 60 hours.  
Cohorts 4-5: Cohorts 4 and 5 are optional and will be utilized only if further 
dose exploration is warranted. Ganaxolone infusion rate will be decided 
based on the results of Cohorts 1-3. However, the initial bolus dose will not 
exceed 16 mg over 2 minutes and the maximum infusion rate will not exceed 
16 mg/h.  
Cohort 6: Subjects randomized to ganaxolone will receive an initial IV 
infusion of 20 mg/h (40 ml/h of ganaxolone 0.5 mg/ml solution) for 6 hours 
followed by 900 mg (4 capsules) ganaxolone capsules administered orally 
at dinner time for 28 days followed by a 3-day taper (3, 2, and 1 capsules 
per day, respectively). Subjects randomized to placebo will receive an 
initial IV infusion of matching placebo (at 40 ml/h) followed by 4 placebo 
capsules administered orally at dinner time for 28 days followed by a 3-day 
taper (3, 2, and 1 capsules per day, respectively). Randomization will 
allocate subjects to the ganaxolone arm or placebo arm in 1:1 ratio. 
 
8.2 Other Definitions  
+72h 
72 hours after start of infusion (0hr) based on visit window.  If a subject is discontinued from the study 
during the inpatient treatment phase (Day 1 through Day 4), all assessments scheduled at +72h will be 
collected at the time of study exit, but the assessments will be allocated to analysis visits based on visit 
windows detailed in Section 8.4.      
Age 
The following SAS® code will be used to calculate subject age (years): 
Age = floor ([intck{‘month’, birth date, screen date} - {day(informed consent date) < day(birth date)}] / 12), 
where intck is a SAS® function counting integer days. 
 
Baseline 
Baseline is defined as the last non-missing assessment prior to the first dose of study drug.  The last 
observation can be an unscheduled/repeated measurement. In most cases, the time point just before “start 
of infusion” or “0hr” will be treated as the baseline, but if this observation is missing in a given period then 
the screening value may be used. 
Change from Baseline 
Change from baseline (CFB) will be calculated as (post-baseline – baseline).     
Discontinuation of study 
A subject will be considered discontinued from the study when a Study Exit CRF page is completed 
indicating primary reason for discontinuation.  
Protocol deviation 
Potential planned or unplanned protocol deviations noted during clinical monitoring will be documented by 
category (i.e., inclusion criteria, exclusion criteria, study drug, safety assessment, efficacy assessment, visit 
window, informed consent, prohibited medication, and other) and by whether or not the deviation excludes 


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
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the subject from the per protocol analysis set. All deviations will be reviewed, categorized, and finalized 
prior to database lock.  
Relationship to study treatment 
AEs related to study treatment will be defined as those entered as Related or Not Related. If relationship is 
missing, then it will be considered as related to study treatment. 
Study day 
Study day is defined relative to the date of the first dose of study drug. For assessments that occur after 
this visit date, study day is calculated as (assessment date – study drug first dose date + 1). For 
assessments that occur prior to study drug first dose date, study day will be calculated as (assessment 
date – study drug first dose date); there is no Study Day 0. 
Study time 
Study time (in minutes) is defined relative to the time of the first dose of study drug (0 hour on the morning 
of Day 1).  
8.3 Imputation 
While every attempt must be made by the investigator to provide complete data, there are cases in which 
this may not always be possible (e.g., incomplete subject recall of start and stop dates).  Unrecorded values 
will be treated as missing in summaries and analyses unless otherwise noted. 
8.4 Analysis Time Point/Visit Windows 
For data summarized on a per time point or per visit basis, the windows used for analyses are defined 
below unless stated otherwise. 
For the IV only cohorts (cohorts 1-5), the following analysis time points and visit windows will be used.  
Protocol 
Visit 
Window Description 
(Target Day/Time 
Point) 
Protocol Window 
(with respect to Visit 
Day as defined in the 
protocol) 
Analysis Window (with respect to 
Study Day and Study Time in 
minutes as defined in this SAP) 
Screening 
Screening 
Day -14 to -1 
 Study Day < -1 
Day 0 
Day 0 (Admission) 
Day 0 
Study Day = -1 
Day +1 
Day 1 (Pre-Infusion) 
N/A 
Study Day = 1 and Study Time < 0  
Day +1 
Day 1 (+4h)  
N/A 
0 <= Study Time < 360 
Day +1 
Day 1 (+8h)  
N/A 
360 <= Study Time < 600 
Day +1 
Day 1 (+12h)  
N/A 
600 <= Study Time < 900 
Day +1 
Day 1 (+18h) 
N/A 
900 <= Study Time < 1260 
Day +2 
Day 2 (+24h) 
N/A 
1260 <= Study Time < 1680 
Day +2 
Day 2 (+32h) 
N/A 
1680 <= Study Time < 2160 
Day +2 
Day 2 (+40h) 
N/A 
2160 min <= Study Time < 2640 min 
Day +3 
Day 3 (+48h) 
N/A 
2640 min <= Study Time < 3120 min 
Day +3 
Day 3 (+56h)  
N/A 
3120 min <= Study Time < 3480 min 
Day +3 
Day 3 (+60h)  
N/A 
3480 min <= Study Time < 3960 min 
Day +4 
Day 4 (+72h)  
N/A 
3960 min <= Study Time < 2 days 
after 72 hr timepoint 


Statistical Analysis Plan 
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Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
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Protocol 
Visit 
Window Description 
(Target Day/Time 
Point) 
Protocol Window 
(with respect to Visit 
Day as defined in the 
protocol) 
Analysis Window (with respect to 
Study Day and Study Time in 
minutes as defined in this SAP) 
Day 11 
Day 11  
Day 8 to 14 
5 <= Study Day < 23 
Day 34 
Day 34 
Day 29 to Day 39 
23 < Study Day < 45  
 
For the IV to oral cohort (cohort 6), the following analysis time points and visit windows will be used.  
Protocol 
Visit 
Window 
Description (Target 
Day/Time Point) 
Protocol Window (with 
respect to Visit Day as 
defined in the protocol) 
Analysis Window (with respect to 
Study Day and Study Time in 
minutes as defined in this SAP) 
Screening 
Screening 
Day -14 to -1 
 Study Day < -1 
Day 0 
Day 0 (Admission) 
Day 0 
Study Day = -1 
Day +1 
Day 1 (Pre-
Infusion) 
N/A 
Study Day = 1 and Study Time < 0  
Day +1 
Day 1 (Post-
Infusion)  
N/A 
Study Day = 1 and Study Time >= 0 
Day 2 
Day 2 (Discharge) 
N/A 
Study Day = 2 
Day 4 
Day 4 (HAMD Call) 
Day 3 to 5 
3 <= Study Day <= 5  
for HAMD only 
Day 8 
Day 8 
Day 6 to 10 
6 <= Study Day <= 9 for HAMD, 
3 <= Study Day <= 11 otherwise 
Day 11 
Day 11 (HAMD Call) 
Day 10 to 12 
10 <= Study Day <= 12  
for HAMD only 
Day 15 
Day 15 
Day 12 to 18 
13 <= Study Day <=18 for HAMD, 
12 <= Study Day <= 18 otherwise 
Day 22 
Day 22  
Day 19 to 25 
19 <= Study Day <= 25 
Day 29 
Day 29 
Day 26 to 32 
26 <= Study Day <= 32 
Day 36 
Day 36  
Day 33 to 39 
33 <= Study Day <= 46 
Day 57 
Day 57 
Day 54 to 60 
47 <= Study Day <= 64 
Day 71 
Day 71 
Day 68 to 74 
65 <= Study Day <= 77 
 
The analysis windows are aligned with, but wider than, those specified by the schedule of visits and 
procedures in the protocol in order to include in analyses of all study data (including unscheduled visit data) 
that fall outside of protocol visit windows.  If multiple data points are observed within a single analysis 
window, the latest observation will be used for analysis.  
 Analysis Sets 
The Screened Set will consist of all subjects who have signed an informed consent. 
The Randomized Set will consist of all subjects who were randomized. 


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
PRS 005 T 17 F 
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The Safety Set will consist of all subjects who received IP.  
The modified Intent to Treat Set (mITT) will consist of all subjects in the Safety Set who have at least 1 
post-randomization efficacy assessment. 
The Per Protocol (PP) Set will consist of all subjects in the mITT set who do not have protocol deviations 
that may affect key efficacy endpoints.  
The Infusion Completer Set will consist of all subjects in the IV only cohorts (cohorts 1-5) who completed 
the 60-hour infusion and all subjects in the IV to oral cohort (cohort 6) who completed the initial infusion.  
The Completer Set will consist of all subjects in the IV only cohorts who completed the 60-hour infusion 
and attended all outpatient visits, and all subjects in the IV to oral cohort who completed the initial infusion 
and oral IP dosing period with at least 80% oral dosing compliance and attended all outpatient visits. 
Subjects in the Safety Set will be analyzed according to the actual treatment received. Subjects in the 
Randomized, mITT, and both completer sets will be analyzed according to assigned treatment regardless 
of actual treatment received. 
 Analyses 
10.1 Data Review Committee (DRC)  
Interim unblinded analyses of safety and efficacy data will be conducted by a Data Review Committee 
(DRC) during the study, separate from the blinded study team. The DRC is composed of the Marinus 
Chief Medical Officer and at least two other external physicians. At least one of the members will have 
special expertise in the clinical care of women with depression or postpartum depression. One of the 
members will have expertise in the conduct of clinical trials and analysis of clinical trial data. Additional 
expert members will include an independent contractor statistician (DRC statistician) and a 
pharmacokineticist (DRC pharmacokineticist).  
 
It is the DRC’s responsibility to weigh the risks and benefits of ganaxolone after each interim analysis and 
make a recommendation on whether the study or cohort should be continued or stopped. The DRC will 
also provide a recommendation for the next dosing regimen with the goal of gaining additional 
information on ganaxolone’s tolerability and dose-response profile. A separate DRC guidance document 
outlines the principles for dose selection. Marinus may decide to stop the study, or make the data public, 
after completion of any cohort. 
 
For the purpose of the DRC meetings, a snapshot of the clinical trial database will be delivered to the 
DRC statistician who will generate necessary tables, figures and listings (TFLs) needed for the DRC data 
review. These analyses will be specified in a separate document agreed upon between the DRC and 
Marinus. The randomization list will be delivered directly to the DRC statistician, who will perform 
unblinding. The Marinus and PRA study teams will remain blinded until after each cohort database lock.  
 
Pharmacokinetic data will be transferred to the DRC pharmacokineticist directly from the pharmacokinetic 
analysis vendor (QPS Inc) using a password protected file.  
 
The TFLs generated for the DRC meetings are separate from the TFLs prepared following each database 
lock, as described below.  


Statistical Analysis Plan 
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Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
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10.2 Analyses After Cohorts 1-3  
An unblinded analysis of efficacy and safety data for Cohorts 1-3 will be conducted after the last patient in 
Cohort 3 has completed her final visit (or withdrawn from the study), all clinical data have been entered 
into the data capture system, AE and concomitant medication data have been coded, quality control 
checks have been completed, all data queries have been resolved, protocol deviations and the per 
protocol analysis set have been identified, and the database has been locked. TFLs for subject 
disposition, demographics and baseline characteristics, efficacy, and AEs will be produced external to 
PRA.   
 
The continuing trial subsequent to Cohort 3 will again be conducted in a double-blind fashion. 
10.3 Final Analysis 
The unblinded final analysis will occur when all subjects in the final cohort have completed their final visit 
(or withdrawn from the study), all clinical data have been entered into the data capture system, AE and 
concomitant medication data have been coded, quality control checks have been completed, all data 
queries have been resolved, protocol deviations and the per protocol analysis set have been identified, 
and the database has been locked. However, Sponsor may decide to stop the study, or make all or a 
portion of the data public, at any time during any cohort.  
 
If Sponsor chooses to unblind and/or make public all or any portion of the data before database lock, the 
following processes will be in place: 
 
• 
A cutoff date or study visit will be established, referred to as the “cutoff time point.” 
• 
A database freeze procedure will be performed in a blinded manner for data collected up to and 
including the cutoff time point. Documentation of the database freeze procedure will include a 
detailed description of the specific data that were cleaned prior to the freeze, the timing of 
temporarily eliminating site access to the database for additional data entry during the freeze, the 
duration of the freeze, the specific portions of the database that will be unfrozen so that data 
entry can continue, and procedures for validating that the data up to and including the cutoff time 
point were not changed post freeze.   
• 
Key personnel required to produce SDTMs, ADaMs, and TFLs will be unblinded at the subject 
level after database freeze. This will include programmers and statisticians but not other 
members of the data management team, nor any other members of the clinical team, nor any 
other representatives of Sponsor. Specific personnel who are unblinded at this stage will be 
documented. Data listings produced for quality control purposes will not display unblinded 
treatment assignments from cohorts for which hard lock has not yet occurred. 
• 
Any data summaries or other trial-level data presentations containing unblinded data will consist 
only of data from the frozen portion of the database until the complete database has been 
locked. 
• 
Any study personnel with exposure to unfrozen, unblinded data prior to database lock will not be 
involved in decisions that result in changes to the data or the analysis plan until the complete 
database has been locked and the study has been formally unblinded. 
• 
Three sets of summaries and analyses will be produced: (1) a topline set that includes data only 
up to and including the cutoff time point to be delivered before database lock and formal 
unblinding, (2) the same topline set rerun and revalidated after database lock and formal 


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
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unblinding, and (3) a complete set that includes all data, to be delivered after database lock and 
formal unblinding. 
• 
Analyses of primary and secondary endpoints will consist only of data up to and including the 
cutoff time point. Any analysis that includes data that were not part of the frozen portion of the 
database will be exploratory. 
 Data Review 
11.1 Data Handling and Transfer 
PRA will provide data handling and transfer in accordance with Data Management Plan and Data Transfer 
Plan both dated 12Nov2018. 
11.2 Data Screening 
Beyond the data screening built into the PRA Data Management Plan, the PRA programming of analysis 
datasets, tables, figures, and listings (TFL) provides additional data screening. Presumed data issues will 
be output into SAS logs identified by the word “Problem” and extracted from the logs by a SAS macro and 
sent to Data Management. 
Reviews of a pre-lock TFL run (if included in the study contract) allow for further data screening prior to 
lock. The PRA statistician and the sponsor must approve database lock. 
 Statistical Methods 
Data analyses will primarily be descriptive. The purpose of this study is to identify a ganaxolone dose and 
exposure level that is safe and well tolerated. Efficacy data will be collected but will be considered 
hypothesis-generating; i.e., there are no a priori hypotheses on which the study was powered. Results from 
exploratory statistical analyses may be presented but only to aid in interpretation. 
Unless otherwise indicated, continuous variables will be summarized with the following descriptive 
statistics: n (number of observations), (arithmetic) mean, standard deviation (SD), first and third quartiles 
(Q1 and Q3), minimum (min) value, median, and maximum (max) value.  The minimum and maximum 
values will be displayed to the same level of precision as the raw data, the median and mean to a further 
decimal place and the SD to two additional decimal places – up to 4 decimal places total. 
Categorical data will be summarized with frequencies and percentages. Percentages by categories will be 
based on the number of subjects exposed within a treatment.  Percentages will be rounded to one decimal 
place. 
All analyses will use SAS version 9.4 or higher.  Tables will present data summarized by treatment group 
within cohort. For each summary table, corresponding supportive listing(s) will be provided. 
12.1 Subject Disposition 
The summary of subject disposition will include number and percentage of subjects in each analysis set, 
subject status at the end of the trial (completed or discontinued), and reason for discontinuation.   
12.2 Important Protocol Deviations 
Per PRA processes, protocol deviations will be entered into our Clinical Trials Management System 
(CTMS). The study team and the sponsor will conduct on-going reviews of the deviation data from CTMS 


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Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
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and the resulting set of evaluable subjects throughout the study, adjusting the deviation criteria as seems 
appropriate. The Per Protocol set must be finalized at the post-freeze data review meeting (or earlier), prior 
to database lock. 
Protocol deviations (see definition in Section 8) for subjects in the Safety Set will be summarized by 
category. Examples of categories that may be used are inclusion criteria, exclusion criteria, study drug, 
safety assessment, lab/endpoint data, visit window, informed consent, prohibited medication, 
overdose/misuse, and other. 
12.3 Treatments 
12.3.1 Extent of Study Drug Exposure 
12.3.1.1 IV Only Cohorts 
For each IV only cohort, duration of IV exposure (hours), total dose (mg), and mean daily dose (mg) will 
be summarized for the Safety set, calculated as follows: 
 
Duration of Exposure = ∑𝑡𝑡𝑣𝑣+ ∑𝑡𝑡𝑏𝑏−∑𝑡𝑡𝑖𝑖 where: 
tv = all IV/infusion administration time intervals, calculated as end date/time – start date/time (hrs) 
tb = all bolus administration time intervals, calculated as end date/time – start date/time (hrs)  
ti = all IV/infusion interruption time intervals, calculated as stop time – start time (hrs). Note: ∑𝑡𝑡𝑖𝑖= Total 
Duration of Interruptions 
Note: Since interruption start/end times but not start/end dates are collected, if end time > start time, it will 
be assumed that start date = end date; otherwise, it will be assumed that end date = start date + 1. 
Total Dose = ∑(𝑡𝑡𝑣𝑣𝑟𝑟𝑣𝑣𝑐𝑐) + ∑𝑣𝑣𝑏𝑏𝑐𝑐−∑(𝑡𝑡𝑖𝑖𝑟𝑟𝑖𝑖𝑐𝑐) where: 
tv and ti are as defined above (hr) 
rv = infusion rate (mL/h) 
ri = infusion rate at start of interruption (mL/h) Note: since neither infusion rate nor date at start of 
interruption is collected, it will be assumed that ri is the same as infusion rate at end of interruption (which 
is collected), unless otherwise instructed by Sponsor. 
c = concentration (mg/mL) Note: Concentration for subjects treated with ganaxolone is cohort-dependent. 
Concentration for placebo subjects is 0.  
vb = volume of bolus injected (mL) 
Mean Daily Dose = 
Total Dose
Overall Days Exposed where:  
Overall Days Exposed = last end date of last IV/infusion or bolus administration – first start date of first 
IV/infusion or bolus administration + 1. 
 
Details of infusion interruptions and early discontinuations will be listed.   
 


Statistical Analysis Plan 
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Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
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12.3.1.2 IV to Oral Cohort 
For the IV to oral cohort, duration of IV exposure (hours), duration of oral exposure (days), total duration 
of exposure (days), IV dose (mg), oral dose (mg), total dose (mg), mean daily IV dose (mg), mean daily 
oral dose (mg), and mean daily total dose (mg) will be summarized for the Safety set, calculated as 
follows: 
 
Duration of IV Exposure = ∑𝑡𝑡𝑣𝑣−∑𝑡𝑡𝑖𝑖 where 
tv = all IV/infusion administration time intervals, calculated as end date/time – start date/time (hrs) 
ti = all IV/infusion interruption time intervals, calculated as stop date/time – start date/time (hrs). 
Note: ∑𝑡𝑡𝑖𝑖= Total Duration of Interruptions 
Duration of Oral Exposure = date of last oral exposure – date of first oral exposure + 1 
Total Duration of Exposure = date of last exposure – date of first exposure + 1 
IV Dose = ∑(𝑡𝑡𝑣𝑣𝑟𝑟𝑣𝑣𝑐𝑐) −∑(𝑡𝑡𝑖𝑖𝑟𝑟𝑖𝑖𝑐𝑐) where: 
tv and ti are as defined above (hr) 
rv = infusion rate (mL/h) 
ri = infusion rate at start of interruption 
c = concentration (mg/mL) Note: Concentration for subjects treated with ganaxolone is cohort-
dependent. Concentration for placebo subjects is 0.  
Oral Dose = ∑𝑘𝑘𝑣𝑣𝑐𝑐 where: 
kv = number of capsules taken during the vth interval of oral dosing, where each interval is 
defined by a fixed number of capsules taken per day 
c = concentration (mg) Note: Concentration for placebo subjects is 0.  
Total Dose = IV dose + oral dose 
Mean Daily IV Dose = 
IV Dose
Days Exposed to IV Dose where:  
Days Exposed to IV Dose = last end date of last IV/infusion– first start date of first IV/infusion + 1. 
Mean Daily Oral Dose = 
Oral Dose
Days Exposed to Oral Dose where:  
Days Exposed to Oral Dose = date of last oral exposure – date of first oral exposure + 1. 
Mean Daily Total Dose = 
Total Dose
Total Days Exposed where:  
Total Days Exposed = date of last exposure – date of first exposure + 1. 
Details of infusion interruptions and discontinuations will be listed.   
Oral compliance will be summarized and will be calculated as: 
100 x ൤Total Actual Oral Dose
Total Expected Oral Dose൨ 
 
where Actual Oral Dose will be based on returned capsule count. 


Statistical Analysis Plan 
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12.3.2 Concomitant Medications 
A concomitant medication is defined as any medication taken between the screening visit and the end of 
the follow-up period (i.e., the end date is on or after the screening visit date, or the subject is still taking the 
medication at the end of the follow-up period) regardless of the start date of the medication. Medications 
recorded with insufficient exposure dates to determine whether or not they were concomitant will be 
considered concomitant.   
Concomitant medications will be categorized by preferred term according to WHO (World Health 
Organization) Drug Dictionary (Version 01DEC2017 Drug Dictionary Enhanced (DDE)) and will be 
summarized for the Safety Set. The number and percentage of subjects using each medication will be 
displayed for each preferred term. 
12.4 Demographic and Baseline Characteristics 
12.4.1 Demographics 
The following demographic and other baseline characteristics will be summarized for the Safety Set: 
• 
Sex (female) 
• 
Age (years) 
• 
Race (White, Black or African American, Asian, American Indian or Alaska Native,  Native 
Hawaiian or Other Pacific Islander, Other) 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• 
Weight (kg) 
• 
Height (cm) 
• 
Body mass index (kg/m2) 
 
12.4.2 Medical History 
Medical history will be tabulated for the Safety Set by System Organ Class (SOC) and Preferred Term (PT) 
according to MedDRA Version 20.0. 
12.4.3 Prior Medications 
Prior medications are defined as medications with an end date prior to the screening visit date.  If a partial 
date allows a medication to be considered a prior medication, it will be categorized as such. 
Prior medications will be categorized by preferred term according to WHO Drug Dictionary (Version 
01DEC2017 DDE) and will be summarized for the Safety Set. The number and percentage of subjects 
using each medication will be displayed for each preferred term. 
12.4.4 Mini International Neuropsychiatric Interview 7.0 
The Mini International Neuropsychiatric Interview (MINI) is a short, clinician-administered, structured 
diagnostic interview, with an administration time of approximately 15 minutes conducted only at the 
screening visit.  MINI data will not be summarized but will be presented in a data listing. 
12.4.5 SAFER Interview 
Staff psychiatrists or psychologist at the Massachusetts General Hospital Clinical Trials Network and 
Institute will perform independent remote SAFER interview (State versus trait; Assessability; Face validity; 
Ecological Validity; and Rule of 3 Ps (pervasive, persistent, and pathological)) for the screened patients 


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
PRS 005 T 17 F 
Page 24 of 35 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
 
 
 
 
 
who are deemed eligible for randomization to confirm validity of the diagnosis of PPD and eligibility for the 
study from depression perspective.  
Time of SAFER interview and whether a subject is eligible based on inclusion criteria will be listed. 
12.4.6 Clinical Global Impression – Severity Scale 
The Clinical Global Impression – Severity scale (CGI-S) is a 7-point scale that asks the clinician to rate the 
severity of the subject's depression at the time of assessment, relative to the clinician's past experience 
with subjects who have the same diagnosis. Considering total clinical experience, a subject is assessed on 
severity of depression at the time of rating 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, 
moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill. 
CGI-S responses will be assessed at Screening and Day 1 before infusion (Baseline) and will be 
summarized. 
12.5 Efficacy Analyses 
Statistical analysis of efficacy endpoints will primarily be done using the mITT set and will be done only to 
aid in interpretation as the trial was not powered for inferential hypothesis testing. As such, there will be no 
adjustments for inflation of type 1 error due to multiplicity.  
For efficacy endpoints expressed as continuous variables, summary tables will show continuous summary 
statistics for each time point of data collection (visit) as well as least squares (LS) means with standard 
errors (SEs) and associated p-values from mixed model repeated measures (MMRM) analysis. Summary 
statistics by time point will also be displayed graphically using bar and/or line charts. MMRM models will 
include fixed effects for treatment, visit, and the treatment-by-visit interaction, and the baseline observation 
will be included as a covariate. Repeated measurements are made on each subject. Residuals will be 
evaluated for substantial departure from normality and independent and constant variance. Methods such 
as data transformation, detecting and assessing the influence of outliers, and alternative analytical 
approaches (e.g., non-parametric) may be used to address assumption deviations. An unstructured 
covariance will be the default covariance structure but other structures (e.g., compound symmetry) may be 
used to evaluate sensitivity to the choice of structure or, if necessary, to achieve convergence. MMRM 
assumes missing observations are missing at random (MAR);  i.e., missingness depends only on variables 
other than the outcome that are available in the database. Because the MAR assumption is not testable, 
and because it seems possible that subjects with poorer outcome may be more likely to miss trial 
assessments, a sensitivity analysis may be done in which all missing data will be imputed. Conservatively, 
multiple imputation with a pattern-mixture model will be used; specifically, for all subjects with missing 
observations regardless of treatment assignment, imputation will be based only on subjects randomized to 
placebo. The imputation method will be fully conditional specification (FCS) regression with 25 imputations. 
Variables in the imputer’s model will be observed values at each time point included in the MMRM analysis, 
including baseline. 
For efficacy endpoints expressed as categorical (including binary) variables, summary tables will show 
frequencies and percentages of subjects in each category as well as adjusted event rates with SEs and 
associated p-values using general estimating equations (GEE). Summary statistics by time point will also 
be displayed graphically using bar charts. GEE models will include main effects for treatment and visit and 
an interaction term for treatment-by-visit. Baseline will be included as a covariate where applicable. 
Unstructured covariance will be specified but alternative structures (e.g., CS) or alternative statistical 
methods (e.g., chi square tests of association) may be used if GEE convergence cannot be achieved. GEE 
assumes missing observations are missing completely at random (MCAR); i.e., missingness is independent 
of all other information whether it was collected or not. A sensitivity analysis based on multiple imputation, 
as described above, may be done in which FCS logistic regression would be the imputation method. 


* PRAHEALTHSCIENCES 
12.5.1 Primary Efficacy Endpoint 
Statistical Analysis Plan 
PRA Protocol ID MRSGNXLN-GNXLNE 
Protocol No. 1042-PPD-2002 
Version Date: 06-Jun-2019 
The primary efficacy endpoint will be HAMD17 total score change from baseline to 60 hours post-infusion 
(on Day 3) for the IV only cohorts and to Day 29 for the IV to Oral cohort. Although the trial is not powered 
for inferential analysis and there is no consideration for control of type 1 error across multiple cohorts, a 
clinically meaningful numeric difference in means of 3-4 points between ganaxalone and placebo treatment 
groups would be considered an indication of efficacy and will be the most influential outcome in the overall 
assessment of the efficacy of ganaxalone in treating PPD. 
12.5.2 Secondary Efficacy Endpoints 
The trial will also evaluate the following secondary endpoints at each post-baseline data collection time 
point to provide additional evidence of the efficacy of ganaxalone in treating PPD: 
• 
Change from baseline in HAMD17 total score other than at 60 hours post-infusion (on Day 3) for 
Cohorts 1-3 and to Day 29 for Cohort 6 
• 
HAMD17 response defined as at least a 50% reduction from baseline in total score 
• 
HAMD17 remission defined as total score<= 7 
• 
Change from baseline in EPDS total score 
• 
Change from baseline in ST Al6 
• 
CGl-I rating 
12.5.3 Exploratory Efficacy Endpoints and Analyses 
PRS 005 T 17 F 
Page 25 of35 
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* PRAHEALTHSCIENCES 
I 
12.6 Safety Analyses 
Statistical Analysis Plan 
PRA Protocol ID MRSGNXLN-GNXLNE 
Protocol No. 1042-PPD-2002 
Version Date: 06-Jun-2019 
Unless otherwise stated in the subsections below, the following safety variables will presented in listings 
and analyzed in summary tables containing summary statistics and change from baseline by treatment 
arms for each study time point. All safety analyses will be based on the Safety Set. 
1) 
Laboratory measures, including urine drug screen 
2) 
Vital signs 
3) 
Electrocardiogram (ECG) 
4) 
Stanford Sleepiness Scale (SSS). 
12.6.1 Adverse Events 
AEs reported from screening through EOS will be coded according to MedDRA® (Medical Dictionary for 
Regulatory Activities) version 20.0 or greater. Each reported AE will be mapped to a Preferred Term (PT) 
and a System Organ Class (SOC). 
A treatment-emergent AE (TEAE) will be defined as an AE that began or worsened after the first dose of 
IP and no later than 30 days after the last dose of IP. AEs with insufficient date or time information to 
determine whether or not they were treatment-emergent will be considered treatment-emergent. 
All TEAEs will be listed. In addition, separate listings will be done for non-treatment-emergent AEs and 
serious AEs (SAEs), treatment-emergent SAEs, and TEAEs that resulted in death, IP discontinuation, IP 
interruption, or dose reduction. Listings will include reported term, PT, and SOC; start and stop date; 
whether or not the AE was serious; severity; whether or not the AE was related to IP; action taken; and 
outcome. 
Incidence and number of TEAEs will be summarized by SOC and PTs within SOCs. Summaries will include 
assessments of severity and relationship to IP. Missing severity will be considered severe and missing 
relationship will be considered related. Only the most related TEAE per subject for a given PT will be 
counted in summaries by relationship; similarly, only the most severe TEAE will be counted in summaries 
by severity. Separate summaries will be done for TEAEs related to IP and TEAEs resulting in IP 
discontinuation or interruption, or dose reduction. Summaries will be done separately for (a) all TEAEs and 
(b) treatment-emergent SAEs only. 
12.6.2 Laboratory Data 
In addition to change from baseline summary tables for quantitative lab parameters, out of range lab 
observations will be determined using reference ranges provided by MedPace Laboratory and will be 
flagged in data listings. 
Over the course of the study, there may be some lab tests performed that are not mentioned in the protocol. 
These tests will not be summarized but will be included in the listings. 
Neurosteroid levels will be not be performed by PRA, as such, neurosteroid levels analysis details are 
beyond the scope of this statistical analysis plan. 
PRS 005 T 17 F 
Page 26 of35 
Strictly Confidential. © 2004-2015, PRA Health Sciences. All rights reserved. 


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
PRS 005 T 17 F 
Page 27 of 35 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
 
 
 
 
 
12.6.3 Vital Signs 
Vital signs will be analyzed as continuous variables.  In addition to change from baseline summary tables, 
potentially clinically significant (PCS) observations will be flagged in data listings based on the criteria given 
in Table 3. 
TABLE 3. VITAL SIGNS PCS CRITERIA 
Vital Sign 
Unit 
Low PCS Criteria 
High PCS Criteria 
Heart rate 
bpm 
≤50 and decrease of ≥15 from 
baseline 
≥120 and increase of ≥15 from 
baseline 
Systolic blood 
Pressure 
mmHg 
≤90 and decrease of ≥20 from 
baseline 
≥180 and increase of ≥20 from 
baseline 
Diastolic 
blood 
Pressure 
mmHg 
≤50 and decrease of ≥15 from 
baseline 
≥105 and increase of ≥15 from 
baseline 
Respiratory 
rate 
Breaths/m
inute 
≤8 and decrease of ≥4 from baseline 
≥30 and increase of ≥10 from 
baseline 
Body 
Temperature 
Degree 
Celsius 
≤36 and decrease of ≥1 from 
baseline 
≥38.3 and increase of ≥1 from 
baseline 
Body Weight 
% 
Decrease of ≥7 from baseline 
Increase of ≥7 from baseline 
Oximetry 
% 
≤90% 
N/AA 
 
12.6.4 Physical Examinations, 12-Lead ECGs, and Other Observations Related to 
Safety 
12.6.4.1 Physical Examination 
Physical examination results will not be summarized but will be provided in a listing. 
12.6.4.2 12-Lead ECG 
12-lead ECG parameters will be analyzed and transferred externally to PRA. These parameters will be 
summarized as continuous variables.  In addition to summary tables PCS ECG observations will be flagged 
in data listings based on the criteria given in Table 4. 
TABLE 4. ECG PCS CRITERIA 
ECG 
Parameter 
Unit 
Low PCS Criteria 
High PCS Criteria 
Heart rate 
bpm 
≤50 and decrease of ≥15 from 
baseline 
≥120 and increase of ≥15 from 
baseline 
PR Interval 
ms 
<120 and baseline value ≥120 
>210 and baseline value ≤200 
QRS Complex 
ms 
None 
>110 and baseline value ≤110 
QTcF 
ms 
None 
Prolongation >30 from baseline 
 


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
PRS 005 T 17 F 
Page 28 of 35 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
 
 
 
 
 
12.6.4.3 Pregnancy  
All pregnancy results will be listed. 
12.6.4.4 Stanford Sleepiness Scale (SSS) 
A summary of SSS will show frequency and percentage of subjects at each rating level, and a plot showing 
mean (SE) SSS at each applicable study time point will be provided. 
12.6.4.5 Columbia-Suicide Severity Rating Scale (C-SSRS) 
For the 5 suicidal ideation questions (“Wish to be dead,” “Non-specific active suicidal thoughts,” “Active 
suicidal ideation with any methods (not plan) without intent to act,” “Active suicidal ideation with some intent 
to act, without specific plan,” “Active suicidal ideation with specific plan and intent”) and the 5 suicidal 
behavior questions (“Preparatory acts or behavior,” “Aborted attempt,” “Interrupted attempt,” “Suicide 
attempt,” “Suicide behavior”) of the C-SSRS, the number of subjects who answered “yes” will be tabulated 
for each applicable study time point.  Other data collected on the C-SSRS (e.g., ideation intensity measures) 
will be provided in data listings only. 
 Validation 
Quality control procedures will be documented separately in the study specific quality control plan.  
 
 


* PRAHEALTHSCIENCES 
Statistical Analysis Plan 
PRA Protocol ID MRSGNXLN-GNXLNE 
Protocol No. 1042-PPD-2002 
Version Date: 06-Jun-2019 
Appendix 1 Glossary of Abbreviations 
Glossary of Abbreviations: 
AE 
CFB 
CGl-I 
CGI-S 
CRF 
CSR 
C-SSRS 
CTMS 
DDE 
DRC 
ECG 
EDPS 
FCS 
GEE 
GNX 
HAMD 
HAMD6 
HAMD17 
HCG 
IP 
IV 
lxRS 
MAR 
MCAR 
MedDRA 
MINI 
mlTT 
MMRM 
PBO 
PCS 
PRS 005 T 17 F 
Adverse event 
Change from Baseline 
Clinical Global Impression - Improvement 
Clinical Global Impression - Severity 
Case Report Form 
Clinical Study Report 
Columbia-Suicide Severity Rating Scale 
Clinical Trials Management System 
Drug Dictionary Enhanced 
Data Review Committee 
Electrocardiogram 
Edinburgh Postnatal Depression Scale 
Fully Conditional Specification 
General Estimating Equations 
Ganaxolone 
Hamilton Depression Rating Scale 
Hamilton Depression Rating Scale 6-item version 
Hamilton Depression Rating Scale 17-item version 
Human Chorionic Gonadotropin 
lnvestigational Product 
Intravenous 
Interactive Voice and/or Web Response System 
Missing at Random 
Missing Completely at Random 
Medical Dictionary for Regulatory Actvitites 
Mini International Neuropsychiatric Interview 
Modified Intention-to-treat 
Mixed Model Repeated Measures 
Placebo 
Potentially Clinically Significant 
Strictly Confidential. © 2004-201 5, PRA Health Sciences. All rights reserved. 
Page 29 of 35 


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
PRS 005 T 17 F 
Page 30 of 35 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
 
 
 
 
 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PPD 
Postpartum Depression 
PT 
Preferred Term 
Q1/Q3 
First Quartile/Third Quartile 
SAE 
Serious Adverse Event 
SAFER 
State versus trait; Assessability; Face validity; Ecological Validity; and Rule of 3 Ps 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class  
SSS 
Stanford Sleepiness Scale 
STAI6 
Spielberger State-Trait Anxiety Inventory 6-item version 
TEAE 
Treatment-Emergent AE 
TFL 
Table, figure and listing 
TSH 
Thyroid Stimulating Hormone 
WHO 
World Health Organization 


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
PRS 005 T 17 F 
Page 31 of 35 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
 
 
 
 
 
Appendix 2 Adverse Event Start/Stop Date Imputation 
 
Imputation Rules for Partial Dates (D = day, M = month, Y = year) 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date for 
AEs 
D 
M and Y same as M and Y of first dose 
of study drug 
Date of first dose of study drug 
M and/or Y not same as date of first 
dose of study drug 
First day of month 
D and M 
Y same as Y of first dose of study drug 
Date of first dose of study drug 
Y prior to Y of first dose of study drug 
but same as Y of screening date 
Date of screening date 
D, M, Y 
None - date completely missing 
Date of first dose of study drug 
Stop date for 
AEs 
D 
M and Y same as M and Y of last dose 
of study drug 
Date of last dose of study drug 
M and/or Y not same as date of last 
dose of study drug 
Use last day of month 
D and M 
Y same as Y of last dose of study drug 
Date of last dose of study drug 
Y not same as Y of last dose of study 
drug 
Use Dec 31 
D, M, Y 
None - date completely missing 
No imputation, but assume 
ongoing 
Note:  In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date 
month. 
Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of the start day 
month. 
 


* PRAHEALTHSCIENCES 
Statistical Analysis Plan 
PRA Protocol ID MRSGNXLN-GNXLNE 
Protocol No. 1042-PPD-2002 
Version Date: 06-Jun-2019 
Appendix 3 Tables, Figures, Listings, and Supportive SAS Output 
Appendices 
List of Post-Text Tables, Figures : 
Output 
Table 14.1.1 
Table 14.1.2.1 
Table 14.1.3.X 
Table 14.1.4.X 
Table 14.1.5.X 
Table 14.2.1.1.1.1 
Table 14.2.1.1.2.1 
Table 14.2.1.1.3.1 
Table 14.2.1.1.4.1 
Table 14.2.1.2.1.1 
Table 14.2.1.3.1.1 
Table 14.2.2.1.1.1 
Table 14.2.2.1.2.1 
Table 14.2.3.1.1.1 
Table 14.2.4.1.1 
Table 14.3.1.X 
Table 14.3.1.3 
Table 14.3.2.1 
Table 14.3.2.2.1 
Table 14.3.2.2.2 
Table 14.3.2.2.3 
Table 14.3.2.2.4 
Table 14.3.2.2.5 
Table 14.3.2.3.1 
PRS 005 T 17 F 
Title 
mil 
Subject Disposition 
Randomized 
Baseline Characteristics 
Safety 
Medical History by System Organ Class and Preferred Term 
_____ 
Safety 
Prior Medications by WHO Drug Dictionary Preferred Term 
___ 
Safety 
Concomitant Medications by WHO Drug Dictionary Preferred Term 
Safety 
Observed Values and Changes From Baseline in HAMD17 Total Score 
mlTT 
Observed Values and Changes From Baseline in HAMD17 Bech Subscale 
mlTT 
(HAMD6) 
Observed Values and Changes From Baseline in HAMD17 Anxiety/Somatization 
mlTT 
Subscale 
Observed Values and Changes From Baseline in HAMD17 Gibbons Subscale 
mlTT 
HAMD17 Total Score - Response 
______________ 
mlTT 
HAMD17 Total Score - Remission 
mlTT 
Observed Values and Changes From Baseline in EPDS Total Score 
mlTT 
Observed Values and Changes From Baseline in EPDS Anxiety Subscale 
Observed Values and Changes From Baseline in STAIG Total Score 
CG I-Improvement 
Treatment Exposure (IV/Infusion) 
Treatment Exposures 
Summary of Treatment-Emergent Adverse Events (TEAEs) 
Incidence and Number of Treatment-Emergent Adverse Events 
Incidence and Number of Treatment-Emergent Adverse Events Related to 
lnvestigational Product 
Incidence and Number of Treatment-Emergent Adverse Events Resulting in 
lnvestigational Product Discontinuation 
Incidence and Number of Treatment-Emergent Adverse Events Resulting in 
lnvestigational Product Dose Reduction or Interruption 
Incidence of Treatment-Emergent Adverse Event Preferred Terms in Order of 
Descending Incidence Among All Subjects 
Incidence and Number of Treatment-Emergent Serious Adverse Events 
mlTT 
mlTT 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 
Page 32 of35 
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Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
PRS 005 T 17 F 
Page 33 of 35 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
 
 
 
 
 
Table 14.3.2.3.2 
Incidence and Number of Treatment-Emergent Serious Adverse Events Related 
to Investigational Product 
Safety 
Table 14.3.2.3.3 
Incidence and Number of Treatment-Emergent Serious Adverse Events 
Resulting in Investigational Product Discontinuation 
Safety 
Table 14.3.2.3.4 
Incidence and Number of Treatment-Emergent Serious Adverse Events 
Resulting in Investigational Product Dose Reduction or Interruption 
Safety 
Table 14.3.2.3.5 
Incidence of Treatment-Emergent Serious Adverse Event Preferred Terms  
in Order of Descending Incidence Among All Subjects 
Safety 
Table 14.3.3.1.X 
Hematology Results by Time Point  
Safety 
Table 14.3.3.2.X 
Biochemistry Results by Time Point  
Safety 
Table 14.3.3.3.X 
Urinalysis Results by Time Point  
Safety 
Table 14.3.3.4.X 
Urine Drug Screen by Time Point 
Safety 
Table 14.3.4.X 
Vital Sign Results by Time Point 
Safety 
Table 14.3.5.X 
Electrocardiogram Results 
Safety 
Table 14.3.6 
Stanford Sleepiness Scale 
Safety 
Table 14.3.7.X 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Suicidal Ideation and 
Behavior by Time Point 
Safety 
Figure 14.2.1.1.1.1.1 
Mean (SE) HAMD17 Total Score 
mITT 
Figure 14.2.1.1.1.3.1 
Mean (SE) HAMD17 Total Score 
mITT 
Figure 14.2.1.1.2.1.1 
Mean (SE) HAMD17 Bech Subscale (HAMD6) 
mITT 
Figure 14.2.1.1.2.3.1 
Mean (SE) HAMD17 Bech Subscale (HAMD6) 
mITT 
Figure 14.2.1.1.3.1.1 
Mean (SE) HAMD17 Anxiety Subscale 
mITT 
Figure 14.2.1.1.3.3.1 
Mean (SE) HAMD17 Anxiety Subscale 
mITT 
Figure 14.2.1.1.4.1.1 
Mean (SE) HAMD17 Gibbons Subscale 
mITT 
Figure 14.2.1.1.4.3.1 
Mean (SE) HAMD17 Gibbons Subscale 
mITT 
Figure 14.2.1.1.5.4.1 
Mean HAMD17 Individual Items 
mITT 
Figure 14.2.1.2.1.1 
HAMD17 Total Score - Response 
mITT 
Figure 14.2.1.3.1.1 
HAMD17 Total Score - Remission 
mITT 
Figure 14.2.2.1.1.1.1 
Mean (SE) EPDS Total Score 
mITT 
Figure 14.2.2.1.1.3.1 
Mean (SE) EPDS Total Score 
mITT 
Figure 14.2.2.1.2.1.1 
Mean (SE) EPDS Anxiety Subscale 
mITT 
Figure 14.2.2.1.2.3.1 
Mean (SE) EPDS Anxiety Subscale 
mITT 
Figure 14.2.2.1.3.4.1 
Mean EPDS Individual Items 
mITT 
Figure 14.2.3.1.1.1.1 
Mean (SE) STAI6 Total Score 
mITT 
Figure 14.2.3.1.1.3.1 
Mean (SE) STAI6 Total Score 
mITT 
Figure 14.2.3.1.2.4.1 
Mean STAI6 Individual Items 
mITT 


* PRAHEALTHSCIENCES 
Statistical Analysis Plan 
PRA Protocol ID MRSGNXLN-GNXLNE 
Protocol No. 1042-PPD-2002 
Version Date: 06-Jun-2019 
Figure 14.2.4.1.1.1 
Figure 14.2.4.2.3.1 
Figure 14.3.6 
CG I-Improvement 
CG I-Improvement 
Stanford Sleepiness Scale 
List of End of Text Listings: 
Output 
Listing 16.1. 7 .X 
Listing 16.2.1 
Listing 16.2.2.X 
Listing 16.2.3.X 
Listing 16.2.4.1 
Listing 16.2.4.2.X 
Listing 16.2.4.3.X 
Listing 16.2.4.4.X 
Listing 16.2.4.5.X 
Listing 16.2.5.1.X 
Listing 16.2.5.2.X 
Listing 16.2.5.3.3 
Listing 16.2.6.1 
Listing 16.2.6.2 
Listing 16.2.6.3 
Listing 16.2.6.4 
Listing 16.2.6.5 
Listing 16.2. 7 .1 
Listing 16.2.7.2 
Listing 16.2.7.3 
Listing 16.2.7.4 
Listing 16.2.7.5 
Listing 16.2.7.6.1 
Listing 16.2.7.6.2 
Listing 16.2.8.1.X 
Listing 16.2.8.2.X 
PRS 005 T 17 F 
Title 
Randomization Assignments 
Subject Disposition 
Protocol Deviations 
Subject Analysis Sets 
Baseline Characteristics 
Medical History 
Prior and Concomitant Medications 
Mini International Neuropsychiatric Interview (MINI) 
SAFER Interview 
Study Drug Administration (IV/Infusion) 
Study Drug Interruption (IV/Infusion) 
Study Drug Administration (Bolus) 
Hamilton Depression Rating Scale 17-ltem Version (HAMD17) 
Edinburgh Postnatal Depression Scale (EPDS) 
Spielberg Trait-State Anxiety Inventory 6-ltem Version (STAl6) 
Clinical Global Impression - Improvement (CGl-I) 
Obsessive Thoughts 
Treatment-Emergent Adverse Events 
Treatment-Emergent Serious Adverse Events 
Treatment Emergent Adverse Events Resulting in IP 
Discontinuation 
Treatment Emergent Adverse Events Resulting in IP Dose 
Reduction or Interruption 
Treatment-Emergent Adverse Events Resulting in Death 
Non-Treatment-Emergent Adverse Events 
Non-Treatment-Emergent Serious Adverse Events 
Hematology Results (Quantitative Parameters) 
Biochemistry Results (Quantitative Parameters) 
Strictly Confidential. © 2004-201 5, PRA Health Sciences. All rights reserved. 
Analysis Set 
Screened 
Randomized 
Randomized 
Randomized 
Randomized 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 
Randomized 
Randomized 
Randomized 
Randomized 
Randomized 
Safety 
Safety 
Safety 
Safety 
Safety 
Screened 
Screened 
Safety 
Safety 
mlTT 
mlTT 
Safety 
-
----
Page 34 of 35 
d 


Statistical Analysis Plan 
PRA Protocol ID: MRSGNXLN-GNXLNE 
Protocol No.: 1042-PPD-2002 
Version Date: 06-Jun-2019  
PRS 005 T 17 F 
Page 35 of 35 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
 
 
 
 
 
Listing 16.2.8.3.X 
Urinalysis Results (Quantitative Parameters) 
Safety 
Listing 16.2.8.4.X 
Clinical Laboratory Results (Semi-Quantitative and Qualitative 
Parameters) 
Safety 
Listing 16.2.8.5.X 
Urine Pregnancy Test Results 
Safety 
Listing 16.2.9.X 
Vital Signs 
Safety 
Listing 16.2.10.1.X 
Electrocardiogram Results Part 1 
Safety 
Listing 16.2.10.2.X 
Electrocardiogram Results Part 2 
Safety 
Listing 16.2.11.X 
Physical Examinations 
Safety 
Listing 16.2.12 
Stanford Sleepiness Scale 
Safety 
Listing 16.2.13.X 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Safety