Clinical trial NCT03460756
Conditions: Depressive Disorder Depression Depression, Postpartum Behavioral Symptoms Mood Disorders Mental Disorder Pregnancy Complications Postpartum Blues PPD Postpartum Disorder
Keywords: Postpartum Care Postpartum Depression
Sponsor: Marinus Pharmaceuticals
Start date: 2017-12-28; Completion date: 2019-07-05
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A clinical study to evaluate safety, tolerability and efficacy of oral administration of ganaxolone in women with postpartum depression

Detailed description:

Arms: arm 1: Oral arm 2: Oral
Interventions: intervention 1: Ganaxolone intervention 2: Placebo
Intervention descriptions: intervention 1: Oral intervention 2: Oral

Protocol documents:
Prot_002.pdf: 
TITLE: 
DRUG: 
IND: 
SPONSOR: 
Document 
M(t\R1Nl.Js 
PHARMACEUTICALS 
PROTOCOL: 1042-PPD-2003 
A Phase 2, Double-blind, Placebo-controlled, Multicenter Study 
to Evaluate Safety, Tolerability and Efficacy of IV and Oral 
Administration of Ganaxolone in Women with Postpartum 
Depression 
Ganaxolone (CCD 1042:3a-hydroxy-3 ~-methyl-5a-pregnan-20-one) 
135256 
Marinus Phannaceuticals, Inc. 
170 N. Radnor Chester Road 
Suite 250 
Radnor, PA 19087 
USA 
Date 
Global/Country/Site Specific 
Original Protocol - Version 1 
09 Jun 2017 
Global 
Amendment 1 - Version 2 
15 Aug 2017 
Global 
Amendment 2 - Version 3 
25 Jan 2018 
Global 
Amendment 3 - Version 4 
05 Jun 2018 
Global 
Amendment 4 - Version 5 
22 Oct 2018 
Global 
This document contains confidential and proprietary infonnation 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. 


IND No. 135256 
Protocol l 042-PPD-2003 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Marinus) Approval 
Date: 
Investigator's Acknowledgement 
I have read this protocol for Marinus Study 1042-PPD-2003. 
Marinus Phannaceutica1s, Inc. 
Version 5.0 /22 Oct 2018 
Title: A Phase 2, Double-blind, Placebo-controlled, Multi center Study to Evaluate Safety, 
Tolerability and Efficacy ofJV and Oral Administration ofGanaxolone 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, pennissible 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 to ethical and safety considerations and guidelines, and to conduct the study in accordance 
with International Council on Hannonisation 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 
tennination 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~) 
Signature: ---------------
Confidential 
Date: 
Page 2 of 131 


IND No. 135256 
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Protocol 1042-PPD-2003 
 
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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:  safetyPPD2003@marinuspharma.com  
Fax:  484-679-2138  
SPONSOR CONTACTS:  
Sponsor Operational Contact:  
 
Telephone: 
 
Email: 
Sponsor Medical Contact and Medical Monitor:  
 MD  
 
Marinus Pharmaceuticals Inc. 
Telephone: 
Email: 
 


IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
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Page 4 of 131 
TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ................................................................................................. 2 
EMERGENCY CONTACT INFORMATION ............................................................................... 3 
TABLE OF CONTENTS ................................................................................................................ 4 
LIST OF TABLES .......................................................................................................................... 8 
LIST OF FIGURES ......................................................................................................................... 9 
LIST OF APPENDICES ................................................................................................................. 9 
ABBREVIATIONS ....................................................................................................................... 10 
STUDY SYNOPSIS ...................................................................................................................... 13 
1 
BACKGROUND INFORMATION ....................................................................................... 18 
1.1 
Postpartum Depression (PPD) ........................................................................................... 18 
1.2 
Product Background and Clinical Information ................................................................. 18 
1.2.1 
Ganaxolone:  Oral Administration .............................................................................. 19 
1.2.2 
Ganaxolone:  Intravenous Administration .................................................................. 20 
2 
STUDY OBJECTIVES AND PURPOSE .............................................................................. 22 
2.1 
Rationale for the Study ...................................................................................................... 22 
2.2 
Study Objectives ................................................................................................................ 22 
2.2.1 
Objectives of the Open-label Safety Part .................................................................... 22 
2.2.1.1 
Safety Objective .................................................................................................... 22 
2.2.1.2 
Dosing Objective ................................................................................................... 22 
2.2.1.3 
Efficacy Objective ................................................................................................. 22 
2.2.1.4 
Pharmacokinetic Objective .................................................................................... 22 
2.2.2 
Objectives of the Double-blind Part ............................................................................ 23 
2.2.3 
Efficacy Objective ....................................................................................................... 23 
2.2.4 
Safety Objective .......................................................................................................... 23 
2.2.5 
Pharmacokinetic Objective .......................................................................................... 23 
3 
STUDY DESIGN ................................................................................................................... 24 
3.1 
Study Design and Study Population .................................................................................. 24 
3.2 
Rationale for Study Design ............................................................................................... 25 
3.3 
Dose Selection ................................................................................................................... 26 
3.4 
Study Duration .................................................................................................................. 28 
3.5 
Planned Analyses .............................................................................................................. 28 
3.5.1 
Analysis After Completion of the Open Label Part .................................................... 28 
3.5.2 
Analyses After Completion of the Double-blind Placebo-controlled Part .................. 28 
3.6 
Definition of Completion .................................................................................................. 29 
3.7 
Sites and Regions .............................................................................................................. 29 
4 
STUDY POPULATION ........................................................................................................ 30 
4.1 
Inclusion Criteria ............................................................................................................... 30 
4.2 
Exclusion Criteria .............................................................................................................. 30 
4.3 
Reproductive Potential ...................................................................................................... 32 


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4.3.1 
Female Contraception .................................................................................................. 32 
4.4 
Discontinuation of Subjects ............................................................................................... 32 
4.4.1 
Subject Withdrawal Criteria ........................................................................................ 32 
4.4.2 
Reasons for Discontinuation ....................................................................................... 33 
4.4.3 
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit ....................................... 33 
5 
PRIOR AND CONCOMITANT TREATMENT ................................................................... 34 
5.1 
Prior Pharmacological Treatment ...................................................................................... 34 
5.2 
Concomitant Pharmacological Treatment ......................................................................... 34 
5.3 
Concomitant Psychological Treatment ............................................................................. 34 
5.3.1 
Permitted Treatment .................................................................................................... 34 
5.3.1.1 
Permitted Psychological Treatments ..................................................................... 34 
5.3.1.2 
Permitted Antidepressant Treatments ................................................................... 34 
5.3.1.3 
Other Permitted Treatments .................................................................................. 35 
5.3.2 
Prohibited Treatments ................................................................................................. 35 
6 
INVESTIGATIONAL PRODUCTS ...................................................................................... 37 
6.1 
Identity of Investigational Products .................................................................................. 37 
6.1.1 
Ganaxolone Immediate Release Oral Capsules (0.3 Micron Formulation) ................ 37 
6.1.2 
Ganaxolone IV Infusion Solution ................................................................................ 37 
6.1.3 
Ganaxolone Oral Suspension ...................................................................................... 37 
6.2 
Administration of Investigational Product(s) .................................................................... 38 
6.2.1 
Allocation of Subjects to Treatment ............................................................................ 38 
6.2.2 
Dosing for the Open-label Treatment Part – OL TID Group ...................................... 38 
6.2.3 
Dosing for the Open-Label Treatment Part – OL QHS Group ................................... 41 
6.2.4 
Dosing for the Open-Label Treatment Part – OL QHS Group – 4 Week ................... 43 
6.2.5 
Dosing for the Open-Label Treatment Part – OL 1,125 mg Group ............................ 45 
6.2.6 
Dosing for the Open-Label Treatment Part – OL Bolus-Oral Group .......................... 46 
6.2.7 
Dose Adjustments During Open-label ........................................................................ 47 
6.2.8 
Blinding ....................................................................................................................... 48 
6.3 
Labeling, Packaging, and Storage ..................................................................................... 48 
6.3.1 
Labeling ....................................................................................................................... 48 
6.3.2 
Packaging and Dispensing the Study Drug ................................................................. 48 
6.3.3 
Storage ......................................................................................................................... 49 
6.4 
Drug Accountability .......................................................................................................... 49 
6.5 
Drug Administration .......................................................................................................... 50 
7 
STUDY PROCEDURES ....................................................................................................... 51 
7.1 
Screening Period (Day -14 to -1) for OL TID and OL QHS ............................................. 52 
7.1.1 
Screening Visit (Visit 1) .............................................................................................. 52 
7.2 
Treatment Period (Day 1 to Day 14; Visits 2 to 5) for OL TID and OL QHS .................. 52 
7.2.1 
Start of the Open-label Safety Period (Day 1; Visit 2) ................................................ 52 
7.2.2 
Treatment Visits (Days 4, 7, 10) (+ 3 days) for OL TID and OL QHS ...................... 53 


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Protocol 1042-PPD-2003 
 
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7.3 
Follow-up Visit 1 (Day 17 ± 2) and Follow-up Visit 2 (Day 38 ± 4) for OL TID 
and OL QHS.................................................................................................................... 54 
7.4 
Screening Period (Day -14 to -1) for OL QHS 4 week ..................................................... 56 
7.4.1 
Screening Visit (Visit 1) .............................................................................................. 56 
7.5 
Treatment Period (Day 1 to Day 28; Visits 2 to 7) for OL QHS 4 week .......................... 56 
7.5.1 
Start of the Open-label Safety Period (Enrollment Visit for the OL QHS 4 
week) (Day 1) ............................................................................................................. 56 
7.5.2 
Treatment Visits (Days 2, 8, 15, 22, 29) for OL QHS 4 week .................................... 57 
7.6 
Follow-up Visit 1 (Day 36 ± 2), Follow-up Visit 2 (Day 59 ± 2), Follow-up Visit 3 
(Day 89 ± 4), and Follow-up Visit 4 (Day 119 ± 4) for the OL QHS 4 week group ...... 58 
7.7 
Screening Period (Day -14 to -1) for OL 1,125 mg and OL Bolus-Oral groups ............... 60 
7.7.1 
Screening Visit (Visit 1) .............................................................................................. 60 
7.8 
Treatment Period (Day 1 to Day 29; Visits 2 to 7) for OL 1,125 mg and OL Bolus-
Oral groups ...................................................................................................................... 60 
7.8.1 
Start of the Open-label Safety Period (Enrollment Visit for the OL 1,125 mg 
and OL Bolus-Oral groups) (Day 1) .......................................................................... 60 
7.8.2 
Treatment Visits (Days 2, 8, 15, 22, 29 ± 3 days [except Day 2]) for OL 1,125 
mg and OL Bolus-Oral groups ................................................................................... 62 
7.9 
Follow-up Visit 1 (Day 36 ± 3), Follow-up Visit 2 (Day 57 ± 3), and Follow-up 
Visit 3 (Day 71 ± 3) for the OL 1,125 mg and OL Bolus-Oral groups ........................... 63 
7.10 
Study Evaluations and Procedures .................................................................................... 66 
7.10.1 
Demographics, Medical History, and Other Baseline Characteristics ........................ 66 
7.10.2 
Informed Consent ........................................................................................................ 66 
7.10.3 
Eligibility Review ........................................................................................................ 66 
7.10.4 
Prior Medication, Concomitant Medication and Concomitant Therapy Review ........ 66 
7.10.5 
Physical Examination .................................................................................................. 66 
7.10.5.1 
12-lead Electrocardiogram .................................................................................... 67 
7.10.5.2 
Clinical Safety Laboratory Evaluations ................................................................ 67 
7.10.5.3 
Adverse Event Collection ...................................................................................... 68 
7.10.5.4 
Vital Signs ............................................................................................................. 68 
7.10.6 
Interviews, Questionnaires, and Scales ....................................................................... 68 
7.10.6.1 
Mini International Neuropsychiatric Interview 7.0 ............................................... 68 
7.10.6.2 
The Hamilton Depression Rating Scale ................................................................ 69 
7.10.6.3 
Stanford Sleepiness Scale ...................................................................................... 69 
7.10.6.4 
Clinical Global Impression-Improvement and Clinical Global 
Impression-Severity ............................................................................................... 69 
7.10.6.5 
Edinburgh Postnatal Depression Scale (EPDS) .................................................... 69 
7.10.6.6 
Spielberg Trait-State Anxiety Inventory, 6 Item Version ..................................... 69 
7.10.6.7 
SAFER Interview .................................................................................................. 70 
7.10.6.8 
Columbia Suicide Severity Rating Scale (CSSRS) ............................................... 70 
7.10.7 
Pharmacokinetic Sampling .......................................................................................... 70 
7.10.8 
Neurosteroid Levels .................................................................................................... 70 


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7.10.9 
Volume of Blood to Be Drawn from Each Subject ..................................................... 71 
7.10.10 
Safety Plan for Medical Emergencies ......................................................................... 72 
8 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT .................................... 73 
8.1 
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events .............................................................................................................................. 73 
8.1.1 
Severity Categorization ............................................................................................... 73 
8.1.2 
Causality Categorization ............................................................................................. 74 
8.1.3 
Variables ...................................................................................................................... 74 
8.1.4 
Symptoms of the Disease Under Study ....................................................................... 74 
8.1.5 
Adverse Events Based on Clinical Laboratory and Other Safety Evaluations ............ 74 
8.1.6 
Adverse Events Based on Signs and Symptoms ......................................................... 75 
8.1.7 
Pregnancy .................................................................................................................... 75 
8.2 
Serious Adverse Event Procedures .................................................................................... 75 
8.2.1 
Reference Safety Information ..................................................................................... 75 
8.2.2 
Reporting Procedures .................................................................................................. 75 
8.2.3 
Serious Adverse Event Definition ............................................................................... 76 
8.2.4 
Serious Adverse Event Collection Time Frame .......................................................... 76 
8.2.5 
Serious Adverse Event Onset and Resolution Dates ................................................... 77 
8.2.6 
Fatal Outcome ............................................................................................................. 77 
8.2.7 
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting .................................................................................................................... 77 
9 
DATA MANAGEMENT AND STATISTICAL METHODS .............................................. 78 
9.1 
Data Collection .................................................................................................................. 78 
9.2 
Clinical Data Management ................................................................................................ 78 
9.3 
Statistical Analysis Plan .................................................................................................... 78 
9.3.1 
Data Review Committee (DRC) and Recommendations for Dosing .......................... 78 
9.3.2 
Justification for Sample Size ....................................................................................... 79 
9.3.3 
Study Population ......................................................................................................... 79 
9.4 
Analysis Methods .............................................................................................................. 79 
9.4.1 
Demographic and Baseline Characteristics ................................................................. 79 
9.4.2 
Subject Disposition ...................................................................................................... 80 
9.4.3 
Investigational Medicinal Product ............................................................................... 80 
9.4.4 
Concomitant Medication ............................................................................................. 80 
9.4.5 
Safety Analyses ........................................................................................................... 80 
9.4.6 
Efficacy Analyses ........................................................................................................ 80 
9.4.6.1 
Primary Endpoint .................................................................................................. 80 
9.4.6.2 
Secondary Endpoints ............................................................................................. 81 
 
 
9.4.6.4 
Statistical Methods ................................................................................................ 81 
9.4.7 
Other Analyses ............................................................................................................ 82 
9.4.8 
Handling of Missing and Incomplete Data .................................................................. 82 


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9.4.9 
Pharmacokinetic Analyses .......................................................................................... 82 
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ........................................... 83 
10.1 
Sponsor’s Responsibilities ................................................................................................ 83 
10.1.1 
Good Clinical Practice Compliance ............................................................................ 83 
10.1.2 
Public Posting of Study Information ........................................................................... 83 
10.1.3 
Study Suspension, Termination, and Completion ....................................................... 83 
10.2 
Investigator’s Responsibilities .......................................................................................... 83 
10.2.1 
Good Clinical Practice Compliance ............................................................................ 83 
10.2.2 
Protocol Adherence and Investigator Agreement........................................................ 84 
10.2.3 
Documentation and Retention of Records ................................................................... 84 
10.2.3.1 
Case Report Forms ................................................................................................ 84 
10.2.3.2 
Recording, Access, and Retention of Source Data and Study Documents ........... 85 
10.2.3.3 
Audit/Inspection .................................................................................................... 85 
10.2.3.4 
Financial Disclosure .............................................................................................. 85 
10.3 
Ethical Considerations ....................................................................................................... 86 
10.3.1 
Informed Consent ........................................................................................................ 86 
10.3.2 
Institutional Review Board or Ethics Committee ........................................................ 86 
10.4 
Privacy and Confidentiality ............................................................................................... 87 
10.5 
Study Results and Publication Policy ................................................................................ 87 
11 REFERENCES ....................................................................................................................... 88 
12 APPENDICES ........................................................................................................................ 90 
 
LIST OF TABLES 
Table 1. 
Study Drug Dosing Schedule – Open-Label TID Group ...................................... 40 
Table 2. 
Study Drug Dosing Schedule – Open-Label QHS Group ..................................... 42 
Table 3. 
Study Drug Dosing Schedule – Open-Label QHS 4 Week Group ........................ 44 
Table 4. 
Study Drug Dosing Schedule – Open-label 1,125 mg Group ............................... 45 
Table 5. 
Study Drug Dosing Schedule – Open-label Bolus-oral Group ............................. 46 
Table 6. 
Schedule of Assessments for the Open-label OL TID and OL QHS and Double-
blind Groups .......................................................................................................... 55 
Table 7. 
Schedule of Assessments for the Open-label OL QHS 4 Week Group ................ 59 
Table 8. 
Schedule of Assessments for the Open-label OL 1,125 mg and OL Bolus-oral 
Groups ................................................................................................................... 64 
Table 9. 
Volume of Blood to Be Drawn from Each Subject for the OL TID, OL QHS and 
Double-blind Groups ............................................................................................. 71 
Table 10. 
Volume of Blood to Be Drawn from Each Subject for the OL QHS 4 Week, OL 
1,125 mg, and OL Bolus-oral groups .................................................................... 71 
Table 11. 
Volume of Blood to Be Drawn from Each Subject for the PK Subgroup of OL 
1,125 mg Group ..................................................................................................... 71 


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Protocol 1042-PPD-2003 
 
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Table 12. 
Volume of Blood to Be Drawn from Each Subject for the PK Subgroup of OL 
Bolus-Oral Group .................................................................................................. 71 
 
LIST OF FIGURES 
Figure 1-A:  Design of Open-Label Part ....................................................................................... 14 
Figure 1-B:  Design of the Double-Blind Placebo-Controlled Part .............................................. 14 
 
LIST OF APPENDICES 
Appendix 1.   Prohibited Strong CYP3A4 Inhibitors and Inducers ............................................ 90 
Appendix 2.   Scales and Assessments ........................................................................................ 91 
Appendix 3.   Protocol History ................................................................................................... 92 
 
 
 


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Protocol 1042-PPD-2003 
 
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ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC0-24 
area under the concentration curve 
-HCG 
-human chorionic gonadotropin 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
Cmax 
maximum plasma concentration 
Cmin 
Minimum plasma concentration 
CNS 
central nervous system 
CRA 
clinical research associate 
CRC 
child-resistant closure 
CRO 
contract research organization 
Css 
concentration at steady-state 
CSSRS 
Columbia Suicide Severity Rating Scale 
CTNI 
Clinical Trial Network Institute of Massachusetts General Hospital 
CYP 
Cytochrome P 
DBPC 
Double-blind placebo-controlled 
DRC 
Data Review Committee 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECT 
Electroconvulsive Therapy  
eCRF 
electronic case report form 
EMA 
European Medicines Agency  
EPDS 
Edinburgh Postnatal Depression Scale 
EU 
European Union 
FDA 
Food and Drug Administration 
GABA 
gamma Aminobutyric Acid 
GCP 
Good Clinical Practice 
GCMS 
gas chromatography mass spectroscopy 
GMP 
Good Manufacturing Practices 


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HAMD 
Hamilton Depression Rating Scale 
hCG 
human chorionic gonadotropin 
HDPE 
high-density polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IP 
Investigational product 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 7.0 
Mini International Neuropsychiatric Interview 7.0 
mITT 
modified Intent to Treat 
OL 
open-label 
PCDH19 
protocadherin 19 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPD 
postpartum depression 
PTSD 
Post-traumatic stress disorder 
QID 
4 times daily 
Q4H 
every 4 hours 
QHS 
nightly at bedtime 
QTcF 
QT interval Fridericia’s correction 
rTMS 
rapid transcranial magnetic stimulation  
SAE 
serious adverse event 
SAFER 
State versus trait; Assessability; Face validity; Ecological Validity; and 
Rule of 3 Ps 
SAP 
statistical analysis plan 
SOP 
standard operating procedure 
SSRIs 
selective serotonin reuptake inhibitors 
SSS 
Stanford Sleepiness Scale 
STAI 
Spielberger State-Trait Anxiety Inventory 
TEAE 
Treatment Emergent AEs 
TID 
3 times daily 
TSH 
thyroid stimulating hormone 


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ULN 
upper limit of normal 
US 
United States 


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STUDY SYNOPSIS 
Protocol number:  
1042-PPD-2003 
Drug:  
Ganaxolone IV, oral suspension, and oral capsule formulations 
Title of the study:  A Phase 2, Double-blind, Placebo-controlled, Multicenter Study to Evaluate Safety, Tolerability 
and Efficacy of IV and Oral Administration of Ganaxolone in Women with Postpartum Depression 
Design:  
This is a Phase 2, multicenter study in women with postpartum depression (PPD) consisting of 2 parts:  An Open 
Label Part with multiple ascending doses focused on safety and tolerability in 5 groups that differ by total daily 
dosing and formulation of study drug; and a Double-blind Placebo-controlled (DBPC) part focused on safety, 
tolerability and efficacy in one group.  The DBPC Part will begin after the Open Label Part dosing is completed.  The 
dosing, treatment duration and timing of evaluations for the double-blind portion of the study will be decided based 
on the results of the Open Label Part and recommendations of the Data Review Committee (DRC).  The DRC is 
comprised of Marinus’ Chief Medical Officer and 2 external physician experts.   
Figure 1-A and Figure 1-B depict the design for each subject group in the Open Label and DBPC Parts, respectively. 
Number of subjects and dose regimen for each treatment arm:  
For the Open Label Part, approximately 176 women aged 18 to 48 years with PPD will be screened to enroll 
approximately 88 subjects.   
The first group (called open-label 3 times daily [OL TID]) of approximately 8 subjects will receive oral ganaxolone 
(capsules) titrated to a daily dose of 900 mg/day over 10 days, followed by a taper over 4 days.   
The second group (called open-label administered at bedtime [OL QHS]) of approximately 20 subjects will receive 
oral ganaxolone (capsules) at bedtime (QHS), titrated to a dose of 675 mg QHS over 4 days and maintained until 
Day 10, followed by a taper over 4 days.  
The third group (called OL QHS 4-week) of approximately 20 subjects will be administered oral ganaxolone 
(capsules) at a dose of 675 mg QHS for 28 days, followed by a taper over 4 days.  
The fourth group (called OL 1,125 mg group) of approximately 20 subjects will receive on the first 2 days, oral 
ganaxolone capsules at a dose of 675 mg at approximately 7 pm (with dinner) and 675 mg at 10 pm (with a fatty 
snack), followed by 26 days of ganaxolone 1,125 mg at dinner time, and a taper over 4 days.  Approximately 6 
subjects will participate in pharmacokinetics (PK) collection that requires an overnight stay on Day 1. 
The fifth group (called OL Bolus-oral) of approximately 20 subjects will receive ganaxolone starting with a single 
intravenous (IV) 12 mg bolus over 2 minutes at approximately 4 pm of Day 1, followed by ganaxolone oral 
suspension 750 mg at 6pm (with a fatty meal), and 750 mg at 10pm (with a fatty snack).  On Day 2, subjects will 
receive ganaxolone oral suspension 750 mg at dinner time and 750 mg at bedtime, followed by 26 days of 
ganaxolone oral suspension 1,000 mg at dinner time.  Treatment will then be tapered over 4 days.  Approximately 6 
subjects will participate in PK collection that requires an overnight stay on Day 1. 


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Figure 1-A:  Design of Open-Label Part 
 
For DBPC part, approximately 100 women with PPD aged 18 to 48 years will be screened to randomize 50 women in 
a 1:1 ratio to receive ganaxolone or matching placebo for 14 days.  The dosing, treatment duration and timing of 
evaluations for the double-blind portion of the study will be decided based on the results of the Open Label Part and 
recommendations of the DRC.  The total daily dose will not exceed 1,600 mg.  Randomization will be stratified by 
the use of concomitant antidepressants so that the number of subjects who are treated with antidepressants and who 
are not treated with antidepressants will be similar in each treatment group.   
Figure 1-B:  Design of the Double-Blind Placebo-Controlled Part 
 
 
 
 
 
The investigator has the flexibility to adjust the dose and/or timing of the dose if the subject experiences sedation, 
dizziness or other untoward effects in each dosing group, by reducing the dose first to a lower level and possibly 
increasing it later if tolerance develops to the untoward effects (see Section 6.2.7). 
Site(s) and Region(s): Approximately 30 investigational sites in the United States  
Screening 
2 wks 
DB dosing 
2wk 
GNX n=25 
PLA n=25
30 Day  
Follow-up 
Taper 
4 days
OL TID 
----------;--------------------- GNX n N 8 
I 
, 
C: 
Screening OL dosing 
30 Day 
2 wk 
2wk 
Follow-up 
OLQHS 
----------,--------------------- GNX n N 20 
" 
I 
I 
2 wk 
2wk 
OL QHS 4-week 
I 
30 Day 
Follow-up 
C: 
Screening OL dosing 
---------
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
GNX n N 20 
C: 
Screening 
2 wk 
OL dosing 
4wk 
OL Oral 1,125 mg 
----------- ----- ---
OL dosing 
4wk 
C: 
Screening 
2 wk 
OL IV Bolus-Oral 
., 
----------- ----- ---
Screening 
2 wk 
,, 
OL dosing 
4wk 
l 
T 
6week 
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y 
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-
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GNXnN20 
• GNX n N 20 
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~----------------
-----------.___I -
-
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Dosing; 
On days 1 and 2: 
PO 675 mg at dinner time and 
675 mg at bedtime 
1,125 mg with dinner days 3-28; 
Taper: days 29-32 
Dosing: 
IV bolus 12 mg/2 min on day 1 at N4 pm 
PO 750 mg at dinner time and 
750 mg at bedtime on days 1 and 2 
1000 mg with dinner on days 3-28; 
Taper: days 29-32 


IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
Confidential 
Page 15 of 131 
Study period (planned): 
September 2017 to June 2019 
Clinical phase:  Phase 2 
Objectives:  
Open-Label Part:  Safety, dosing, efficacy and pharmacokinetics 
1. To assess the safety and tolerability of ganaxolone in women with PPD as determined by adverse events (AEs), 
changes from baseline in laboratory measures, vital signs, Columbia Suicide Severity Rating Scale (CSSRS), 
electrocardiogram (ECG), Stanford Sleepiness Scale (SSS), and physical examination.  
2. To develop an optimal dosing regimen for the double-blind part.  Adverse events and other safety data, including 
sedation and dosing changes will be adjudicated by the DRC before proceeding to the double-blind part of the 
study.   
3. To assess the efficacy of ganaxolone using 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-Severity and Improvement (CGI-S and CGI-I) scales.  
4. To collect samples of blood for PK analysis after administration of oral and IV ganaxolone to use in 
population-PK analyses, the results of which will be reported separately by the Sponsor. 
Double-Blind placebo controlled (DBPC) Part:  Safety, efficacy, and pharmacokinetics 
Safety objective:  To assess the safety and tolerability of ganaxolone vs placebo in women with PPD as determined 
by AEs and changes from baseline in laboratory measures, vital signs, CSSRS, ECG, SSS, and physical examination.   
Efficacy objective:  To assess the efficacy of ganaxolone vs placebo using the HAMD17, EPDS, STAI6 and CGI-S 
and CGI-I scales.  
The primary efficacy variable in this study is change from baseline in the HAMD17 total score on Day 10 of the 
DBPC part between ganaxolone and matching placebo.   
Pharmacokinetic objective:  To collect samples of blood for PK analyses after administration of oral ganaxolone to 
use in population-PK analyses, the results of which will be reported separately by the Sponsor. 
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.  This study is intended to test the safety and 
efficacy of ganaxolone in the treatment of PPD. 
Investigational product, dose, and mode of administration:  Ganaxolone IV, oral suspension, and oral capsule 
(225 mg/capsule) formulations and matching placebo will be used.   
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 48 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 International 
Neuropsychiatric Interview (MINI) 7.0 interview  
5. Given birth in the last 12 months 
6. HAMD17 score of ≥ 20 at screening rated by a certified site rater. 


IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
Confidential 
Page 16 of 131 
7. HAMD17 ≥ 18 (rated by CTNI) on Day 1 prior to study drug administration  
8. The diagnosis of PPD and severity of depression must be supported by the State versus trait; Assessability; Face 
validity; Ecological Validity; and Rule of 3 Ps (SAFER) interview 
9. Must agree to stop breastfeeding from start of study treatment until 45 days after receiving the last dose of the 
study drug 
10. Must agree to use acceptable contraceptive methods during the study period 
11. Must have a reliable family member, significant other or a trusted friend who can take a role as the primary 
childcare provider and support person at home (including during the night) while the subject is participating in 
the trial 
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 
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 alcohol or 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 after 5 days 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 blood levels of ∆9-tetrahydrocannabinol (THC), and its metabolites 11-hydroxy-
THC and 9-carboxy-THC.  If THC is not detectable, the subject is 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 QT interval Fridericia’s correction (QTcF) > 470 msec 
16. Unwillingness to withhold grapefruit, Seville oranges, star fruit, or concentrated citrus derived products from diet 
between screening and last on-treatment visit  
17. Receiving concomitant treatment with strong cytochrome P (CYP)3A4 inducers or strong CYP3A4 inhibitors 
18. Body mass index (BMI) ≥ 40 


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Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
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Page 17 of 131 
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 7 weeks for the OL TID and OL QHS 
groups and the DBPC part.  The duration for the OL QHS 4-week group is approximately 18 weeks and the duration 
for the OL 1,125 mg and OL Bolus-oral groups is approximately 12 weeks.  
Key variables: 
Safety:  Adverse events, laboratory measures, vital signs, CSSRS, ECG, SSS, and physical examination. 
Efficacy:  HAMD17, EPDS, STAI6, CGI-I and CGI-S scales. 
Pharmacokinetics:  For the OL TID and OL QHS groups, a total of 5 samples of blood will be collected to 
determine ganaxolone plasma concentrations during the study.  Samples will be collected on 3 occasions during 
treatment with ganaxolone to determine trough concentrations in plasma.  An additional 2 samples of blood will be 
collected at follow up visits, after ganaxolone treatment has been completed, to monitor the disappearance of 
ganaxolone following cessation of treatment.  For the OL QHS 4-week, OL 1,125 mg, and OL Bolus-oral groups, 
6 samples of blood will be collected to determine ganaxolone plasma concentrations during the study.  Samples will 
be collected on 4 occasions during treatment in the OL QHS 4 weeks group and on 5 occasions during treatment in 
the OL 1,125 mg and OL Bolus-oral groups to determine ganaxolone trough concentrations in plasma.  Two 
additional samples of blood will be collected in the first 2 follow up visits in the OL QHS 4 weeks group and 
1 additional sample will be collected in the OL 1,125 mg, and OL Bolus-oral groups at the first follow up visit after 
ganaxolone treatment has been completed, to monitor the disappearance of ganaxolone following cessation of 
treatment.  
Statistical Methods:  Data will be presented by study part (OL, DBPC), dosing or treatment group within study parts 
and if applicable, study visit.  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. 
Analysis Populations:  The Screened Set will consist of all subjects who have signed an informed consent.  The 
Randomized Set will consist of subjects randomized in the DBPC part of the trial.  The Safety Set will consist of all 
subjects who received investigational product (IP).  The modified Intent to Treat (mITT) Set will consist of all 
subjects in the DBPC part of the trial who received IP, and who have at least 1 post-baseline HAMD17 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. 
Efficacy Analysis:  Efficacy parameters will be summarized for both the OL and DBPC parts, but will be analyzed 
only for the DBPC part.  The primary time point of interest for all efficacy parameters will be Day 10 for the DBPC 
part and the visit at end of treatment (before initiation of taper) for the OL part.  The primary efficacy endpoint will 
be change from baseline in HAMD17 total score at Day 10 for the DBPC part and at the visit at end of treatment for 
the OL part.  The primary efficacy analysis will be done using the mITT set (DBPC group only), and the analytical 
method will be mixed model repeated measures (MMRM) with baseline HAMD17 total score as a covariate.  
Significance will be tested at a two-sided 0.05 level. 
Secondary efficacy endpoints will be change from baseline in HAMD17 total score other than at the primary endpoint 
time point, 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, and 
CGI-Improvement.  
 
  
 
 
 


IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
Confidential 
Page 18 of 131 
1 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.1  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.2  
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) receptor modulator, are 
known to increase throughout pregnancy and then precipitously drop after delivery.3, 4  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.5  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.6,5 
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 3-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.8  Ganaxolone has been studied in completed and ongoing clinical 
trials in healthy adults, adult subjects with epilepsy, adults with post-traumatic stress disorder 
(PTSD), adults with migraine, children with refractory epilepsy and seizure disorders including 
female pediatric subjects with protocadherin 19 (PCDH19) epilepsy, and children with Fragile X 
Syndrome.   


IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
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Page 19 of 131 
1.2.1 
Ganaxolone:  Oral Administration 
As of 
 approximately 1,588 unique subjects have received treatment with 
ganaxolone oral formulations in ongoing and completed clinical trials ranging in duration from 
1 day to more than 2 years, using doses from 50 to 2,000 mg/day.  Of these, 1,148 unique 
subjects have received ganaxolone oral formulation in completed studies.  In 19 completed 
Phase 1 studies, 289 healthy subjects received ganaxolone orally at doses of 50 to 2,000 mg/day 
for periods of up to 2 weeks.  Ganaxolone when given at doses 1,000 mg BID to healthy 
volunteers resulted in average Cmax and Cmin concentrations of 262 ng/ml and 57 ng/ml.  
In the 18 completed Phase 2 clinical studies, 859 unique subjects have received oral ganaxolone 
at doses up to 1,500 mg/day including 169 adult subjects with epilepsy, 135 pediatric subjects 
with seizure disorders, 59 pediatric subjects with Fragile X syndrome, 393 adult subjects with 
migraine, and 103 subjects with PTSD. 
In clinical trials of ganaxolone, adverse events (AEs) related to the GABAergic mechanism of 
action such as dizziness, sedation and sedation-related AEs (fatigue, somnolence), ataxia and 
diplopia, were reported more commonly in subjects receiving ganaxolone than placebo.  In 
general, the frequency of these events was dose related.  Most of these effects were reported as 
mild or moderate in severity and were reversible after dose decrease or drug discontinuation.  
In the largest clinical trial conducted so far, Study 1042-0603, a Phase 3 trial of ganaxolone in 
adults with drug-refractory partial onset seizures, the safety profile of ganaxolone was consistent 
with previously conducted studies.  In the double-blind portion of this study, 359 subjects were 
randomized to receive oral ganaxolone (900 mg twice a day) or placebo for 14 weeks.  Overall, 
ganaxolone was generally safe and well tolerated with no imbalance between the ganaxolone and 
placebo group in the number of subjects with serious adverse events (SAEs) (5% vs 5.1%).  The 
most common AEs (> 5%) reported at greater rates than placebo were somnolence (23.5% vs 
4.5%), dizziness (19.6% vs 4.5%), and fatigue (11.7% vs 6.8%).  Most of these AEs were rated 
as mild in severity.  There were 44 (25%) subjects treated with ganaxolone that discontinued the 
study compared with 26 (14%) subjects on placebo.  The most common reason for 
discontinuation was AE.  Nine subjects experienced SAEs in placebo and ganaxolone groups 
each.  
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.  Overall, there have been only a few clinically significant individual changes from 
baseline in clinical laboratory measurements in clinical trials of ganaxolone.  In the completed 
placebo-controlled Phase 1, 2 and 3 studies, 0.32% of subjects treated with ganaxolone and 
0.31% of subjects treated with placebo exhibited elevated liver function tests during the study 
(> 3 times the upper limit of normal [ULN] aspartate aminotransferase [AST] and/or alanine 
aminotransferase [ALT]).  There have been no cases of Hy’s Law in the ganaxolone 
development program.  In controlled clinical trials of ganaxolone, 1.1% of subjects receiving 
placebo and 2.0% of subjects receiving ganaxolone reported an AE of rash or papular rash.  Most 
rashes improved either while the drug was continued or following discontinuation.  Two subjects 


IND No. 135256 
Protocol 1042-PPD-2003 
Marinus Phrumaceuticals, Inc. 
Version 5.0 / 22 Oct 2018 
paiiicipating in the Phase 2 study investigating ganaxolone in treatment of epilepsy developed an 
SAE of rash. Both events resolved after discontinuation of the study diug. 
It is not known if ganaxolone is excreted in breast milk. After cessation of the infusion, plasma 
ganaxolone levels are expected to di·op 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 ti·eatment 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 orally to 
infants with severe fonns of epilepsy as early as 4 months of age. 
In clinical trials involving administi·ation of oral ganaxolone over several weeks, the study diug 
has been tapered off over a 1 to 2-week period. There have been no repo1is of withdrawal 
symptoms emerging after cessation of ganaxolone. 
1.2.2 
Ganaxolone: Intravenous Administration 
Preclinical studies and a study in 36 healthy volunteers assessing safety, phaim acokinetics (PK), 
and phan nacodynainics of inti·avenously (IV) administered ganaxolone have been completed. 
Preclinical toxicity studies showed IV anaxolone to be enerall safe and AEs consistent with 
ex ected dose-related sedation. 
There was no evidence of local initation when ganaxolone was given intra- or 
pen venous y in preclinical studies. Fmthennore, IV ganaxolone did not cause hemolysis and 
was compatible with human plasma. 
Six subjects repo1ied ti·eatment emergent AEs in Stage 1 and 2. No single AE was seen twice. 
Only 1 event (headache) was considered by the investigator to be related to ganaxolone. None of 
the ti·eatment emergent AEs were serious, and all were of mild intensity. No clinically 
meaningful mean changes in laborato1y test results, vital signs, or ECG parameters occw-red in 
any cohort. 
Confidential 
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IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
Confidential 
Page 21 of 131 
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.  
Infusion of 30 mg/h for 1 hour and 20 mg/h for 4 hours led to concentrations of 258 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).   


IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
Confidential 
Page 22 of 131 
2 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 is intended to explore the safety and efficacy of ganaxolone in women with 
PPD.  
2.2 
Study Objectives 
2.2.1 
Objectives of the Open-label Safety Part 
2.2.1.1 
Safety Objective 
To assess the safety and tolerability of ganaxolone in women with PPD 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.  
2.2.1.2 
Dosing Objective  
To develop an optimal dosing regimen for the double-blind placebo-controlled (DBPC) part of 
the study.  Adverse events and other safety data, including sedation and dosing changes, will be 
adjudicated by the Data Review Committee (DRC) before proceeding to the DBPC part of the 
study.   
2.2.1.3 
Efficacy Objective 
To assess the efficacy of ganaxolone using 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-Severity and 
Improvement (CGI-S and CGI-I) scales.  
2.2.1.4 
Pharmacokinetic Objective 
To collect samples of blood for pharmacokinetic (PK) analysis after administration of oral and 
IV ganaxolone to use in population-PK analyses, the results of which will be reported separately 
by the Sponsor. 
 


IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
Confidential 
Page 23 of 131 
2.2.2 
Objectives of the Double-blind Part  
2.2.3 
Efficacy Objective  
To assess the efficacy of ganaxolone vs placebo using the HAMD17, EPDS, STAI6, CGI-S and 
CGI-I scales.  
The primary efficacy variable in this study is change from baseline in the HAMD17 total score 
on Day 10 of the DBPC part between ganaxolone and placebo.  
2.2.4 
Safety Objective 
To assess the safety and tolerability of ganaxolone vs placebo in women with PPD as determined 
by AEs and changes from baseline in laboratory measures, vital signs, CSSRS, ECG, SSS, and 
physical examination.   
2.2.5 
Pharmacokinetic Objective  
To collect samples of blood for PK analysis after administration of oral doses of ganaxolone.  
Pharmacokinetics samples will be collected from the subjects participating in the open-label and 
DBPC parts of the study.  These data may be combined with data from other studies for 
population-PK analyses.  If such analyses are conducted, they will be reported separately by the 
Sponsor. 


IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
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Page 24 of 131 
3 STUDY DESIGN 
3.1 
Study Design and Study Population 
This is a Phase 2, multicenter study in women with PPD consisting of 2 dosing parts: an initial 
open-label safety part, and a DBPC part.   
The investigator has the flexibility to adjust the dose amount and/or timing of dosing if the 
subject experiences untoward effects during the open-label part, by reducing the dose first to a 
lower level and possibly increasing it later, if tolerance to the untoward effects develops. 
Enrollment and dosing will be completed in the open-label safety part before proceeding to the 
DBPC part.  The goal of the open-label part is to explore the safety of IV and oral ganaxolone in 
this population, and identify a dosing regimen for the DBPC part.   
Open-label Part 
For the open-label safety part, approximately 172 women aged 18 to 48 years with PPD will be 
screened to enroll approximately 88 subjects.    
In the first group with approximately 8 subjects, ganaxolone will be titrated to a daily dose of 
900 mg/day over 10 days, followed by a taper over 4 days.  This dosing group is called the 
open-label 3 times daily (OL TID) group.  
The second group with approximately 20 subjects will receive ganaxolone administered at 
bedtime (QHS).  For these subjects, ganaxolone will be titrated to a QHS dose of 675 mg over 
4 days, which is then maintained until Day 10, followed by a taper over 4 days.  This dosing 
group is called the OL QHS group.   
The third group with approximately 20 subjects will receive ganaxolone administered at a dose 
of 675 mg QHS for 28 days, followed by a taper over 4 days.  This dosing group is called the 
OL QHS 4-week dosing group. 
The fourth group with approximately 20 subjects will receive on the first 2 days, ganaxolone 
capsules 675 mg at dinner time and 675 mg at bedtime (for a total of 1,350 mg per day on the 
first 2 days), followed by 26 days of ganaxolone capsules 1,125 mg at dinner time (high fat diet), 
and a taper over 4 days.  This dosing group is called the OL 1,125 mg group.  
The fifth group with approximately 20 subjects will receive ganaxolone as IV 12 mg bolus over 
2 minutes at approximately 4 pm of the first day, followed by ganaxolone oral suspension 
750 mg at dinner time (high fat diet), and 750 mg at bedtime (with a high fat snack) for a total of 
1,512 mg on Day 1.  On Day 2, subjects will receive ganaxolone oral suspension 750 mg at 
dinner time and 750 mg at bedtime, for a total of 1,500 mg, followed by 26 days of ganaxolone 
oral suspension 1,000 mg at dinner time and a taper over 4 days. This dosing group is called the 
OL Bolus-oral group.   


IND No. 135256 
Protocol 1042-PPD-2003 
Double-blind Placebo-controlled Part 
Marinus Phrumaceuticals, Inc. 
Version 5.0 / 22 Oct 2018 
For the DBPC part, approximately 100 women with PPD aged 18 to 48 years will be screened to 
randomize 50 women in a 1: 1 ratio to receive ganaxolone or matching placebo for 14 days. 
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 
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.9 Ganaxolone may alleviate PPD by increasing 
neurosteroid activity. 
A previous study with IV allopregnanolone showed that allopregnanolone has the potential to 
produce a rapid and robust antidepressant activity.7 We hypothesize that a similar antidepressant 
activity may be obtained with IV and oral ganaxolone. 
Although ganaxolone has been administered to more than 1,500 subjects, there have been no 
previous studies exploring the safety or efficacy of ganaxolone in PPD or other mood disorders 
m women. 
Various dose amounts, fonnulations, dosing schemes and treatment durations will be evaluated 
in the Open-label pa1t to infonn the choice of the treatment scheme for the DBPC pa1t. 
Approximately 8 or 20 subjects, depending on the group, will receive open-label ganaxolone to 
evaluate safety, tolerability, kinetics and efficacy of the drng in women diagnosed with PPD. 
Assessments of AEs, laborato1y , ECG, and clinical ratings for safety and efficacy will be 
gathered to evaluate the possible differential effect of the various dosing schemes. 
A double-blind evaluation of safety and efficacy will follow the completion of the open-label 
pait. This study pait will utilize a randomized, parallel-group, placebo-controlled design in 
women diagnosed with PPD. Evaluations of safety and tolerability, as well as efficacy will 
utilize the same evaluation methods as in the open-label pait. The primaiy efficacy endpoint will 
be change from baseline in HAMD-17 of active vs placebo treatments. The concomitant use of 
antidepressants or no use of antidepressants will be stratified 1: 1 to emoll similar numbers of 
subjects in each strntum for both the ganaxolone and placebo treatment groups. 
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Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
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Page 26 of 131 
3.3 
Dose Selection  
Allopregnanolone levels increase gradually throughout pregnancy reaching peak mean 
concentrations at the end of pregnancy of about 15 to 60 ng/ml.  The levels then drop 
precipitously after delivery.3, 4, 10  We hypothesize that substitution of the low allopregnanolone 
levels with ganaxolone would alleviate or reverse the symptoms of PPD.  The target trough 
ganaxolone exposure level of approximately 50 ng/ml was chosen to achieve a level similar to 
that of allopregnanolone at the end of pregnancy.   
Open-label TID dosing group  
Ganaxolone doses are titrated for the OL TID dosing group from 225 mg on Day 1 to a daily 
dose of 900 mg starting on Day 7.  Previous studies have shown that the sedating effects of 
ganaxolone may be minimized via dose titration.  
With the proposed dosing regimen for the OL TID dosing group, the ganaxolone mean trough 
and peak plasma concentrations during the Days 8, 9, and 10 are predicted to fluctuate between 
40 ng/ml and 100 ng/ml respectively, based on PK modelling.  This dose range is considered to 
provide adequate ganaxolone plasma exposure from the point of view of testing whether the dose 
range of 50 to 60 ng/ml is necessary for alleviating the symptoms of PPD.  Based on the previous 
ganaxolone studies, plasma levels below 100 ng/ml have not been sedating in most subjects.  
The bedtime doses for the OL TID dosing group are selected to be higher than the daytime doses, 
and are expected to yield plasma mean peak concentrations up to 180 ng/ml during the night on 
Days 8, 9 and 10.  These levels may be sedating in some subjects.  Since disrupted sleep is a 
hallmark of depression, the potential sleep promoting effect of ganaxolone may in fact be 
beneficial.  
Approximately 8 subjects will be allocated for the OL TID group.   
Open-label QHS dosing group  
A QHS dosing group is included in the open-label part to explore whether QHS dosing only is 
well-tolerated and shows comparable therapeutic effect to the TID dosing.  In the QHS dosing 
group, the trough ganaxolone levels are expected to be below 40 ng/ml.  However, constant 
plasma exposures may not be necessary for antidepressant effect but the therapeutic efficacy 
under this dosing scenario could arise via other mechanisms, such as modulation of sleep 
architecture.  
Approximately 20 subjects will be allocated to the OL QHS group.  The enrollment for the OL 
QHS group will start after all subjects allocated to the OL TID group have started their dosing.  
Open-label QHS 4-week dosing group  
A QHS 4-week dosing group is included in the open-label part to explore whether administering 
ganaxolone at 675 mg QHS is well-tolerated and shows sustained therapeutic effect over 
4-weeks of dosing, and whether the therapeutic effects are maintained over a 3-month follow-up 
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Approximately 20 subjects will be allocated to the OL QHS 4-week dosing group.  The 
enrollment for the OL QHS 4-week group will start after all subjects allocated to the OL QHS 
group have started their dosing.  
Open-label 1,125 mg dosing group  
The OL 1,125 mg dosing group is included in the open-label part to explore whether 
administering ganaxolone orally at doses up to 1,125 mg per day over 4 weeks (including 
1,350 mg in the first 2 days) are safe and well-tolerated and show sustained effects, and whether 
the therapeutic effects are maintained over a 6-week follow-up period.  
The two evening 675 mg oral doses, within 3 hours of each other on Day 1 are expected to 
provide mean Cmax plasma concentrations of approximately 250-300 ng/mL, which may be 
mildly sedating.  Twin evening dosing on Day 2 is expected to lead to similar exposure.  In 
previous studies, ganaxolone has been given up to a daily dose of 2000 mg, and at single doses 
of 1000 mg.  Based on previous experience, this dose is expected to be safe.  
 
Approximately 20 subjects will be allocated to the OL 1,125 mg dosing group.  The enrollment 
for the OL 1,125 mg group will start after all subjects allocated to the OL QHS 4-week group 
have started their dosing.  
Open-label IV Bolus-oral dosing group  
The OL IV Bolus-oral dosing group is included in the open-label part to explore whether 
administering IV 12 mg ganaxolone bolus followed by oral suspension dosing of up to 1,000 mg 
per day (including up to 1,500 mg in the first 2 days) is safe and well-tolerated, and shows 
sustained therapeutic effect over 4 weeks of dosing, and whether the therapeutic effects are 
maintained over a 6-week follow-up period.  
This initial bolus infusion is targeted to provide a fast onset of antidepressant activity by delivery 
of rapid plasma exposures to ganaxolone.  Together with the two evening 750 mg oral doses 
within 3 hours of each other, Day 1 dosing is expected to provide mean Cmax plasma 
concentrations of approximately 250-300 ng/mL, which may be mildly sedating.  Twin evening 
dosing on Day 2 is expected to lead to similar exposure.  In previous studies, ganaxolone has 
been given up to a daily dose of 2,000 mg, and at single doses of 1,000 mg.  Based on previous 
experience, this dose is expected to be safe.   
 
Approximately 20 subjects will be allocated to the OL Bolus-oral dosing group.  The enrollment 
for the OL Bolus-oral group will start after all subjects allocated to the OL 1,125 mg group have 
started their dosing.  
Dose Justification in the Context of Previous Experience with IV Ganaxolone 
In Study 1042-0405, a completed Phase 1 study in healthy volunteers investigating the safety of 
IV ganaxolone, the highest bolus dose tested was 30 mg, which was infused over 5 minutes (the 
same rate [6 mg/min] as in the OL Bolus-oral group).  This dose led to peak concentration levels 
(Cmax) of > 1,000 ng/mL, with no safety concerns (except sedation).  This safety profile is 
consistent with findings from previous studies with the oral formulation of ganaxolone, where 


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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).  
Double-blind Placebo-controlled (DBPC) Part 
For the DBPC part of the study, the targeted ganaxolone plasma concentrations and the final 
dosing formulations will be determined based on the safety and efficacy results of the open-label 
safety data (Section 3.5).  Additional information for the dose-selection for the DBPC part may 
be obtained from the ongoing phase 2A study in PPD with the ganaxolone IV formulation 
(conducted under IND No. 106104).  
Blinding Scheme 
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).  
The placebo infusion and placebo capsules are identical to the ganaxolone infusion and 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 the DBPC part.  
Members of the DRC will be unblinded.  All other study personnel, including persons involved 
in the evaluation of the study subjects (e.g., investigators, sub-investigators, and 
physicians/nurses), with the exception of the study pharmacist, will remain blinded at all times, 
except in case of an emergency.  Subjects will be blinded.   
3.4 
Study Duration  
For both the open-label safety OL TID and OL QHS groups, and the DBPC part of the study, the 
screening period will be up to 2 weeks, followed by a 14-day outpatient treatment period and a 
14-day follow-up period.  For the OL QHS 4-week dosing group, the screening period will be up 
to 2 weeks, followed by a 28-day outpatient treatment period, a 4-day taper and a 3-month 
follow-up period.  For the OL 1,125 mg and OL Bolus-Oral dosing groups,the screening period 
of up to 2 weeks will be followed by a 28-day outpatient treatment period, a 4-day taper, and a 
6-week follow-up period (from Day 29). 
3.5 
Planned Analyses 
3.5.1 
Analysis After Completion of the Open Label Part  
At the completion of the open-label part, adverse events and other safety data, including sedation 
and dosing changes, will be adjudicated by the DRC before proceeding to the DBPC part of the 
study.  These data will be used to determine the dosing regimen for the DBPC part.   
3.5.2 
Analyses After Completion of the Double-blind Placebo-controlled Part 
After completion of the DBPC part, the data will be evaluated by an independent DRC.  Based 
on the analysis and recommendation by the DRC, the study may be closed at that point, or an 
additional approximately 50 women with PPD will be treated with ganaxolone or placebo under 


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a similar study design but using a different dosing regimen.  The daily dose may be lowered, 
increased, or the previous dosing may be repeated.   
3.6 
Definition of Completion   
A dosing group is considered complete when the final subject in the group has completed the 
final protocol-defined assessment, including follow-up visits for the group. 
 
The Study Completion Date is defined as the date the final subject, across all sites, completes her 
final protocol-defined assessments for the DBPC part, and includes all follow-up visits.  
3.7 
Sites and Regions 
The study will be conducted in the United States at approximately 30 investigational sites.  


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4 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 48 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 International Neuropsychiatric Interview (MINI) 7.0 interview  
5. Given birth in the last 12 months 
6. HAMD17 score of ≥ 20 at screening rated by a certified site rater 
7. HAMD17 ≥ 18 on Day 1 prior to study drug administration  
8. The diagnosis of PPD and severity of depression must be supported by the State versus trait; 
Assessability; Face validity; Ecological Validity; and Rule of 3 Ps (SAFER) interview 
9. Must agree to stop breastfeeding from start of study treatment until 45 days after receiving 
the last dose of the study drug 
10. Must agree to use acceptable contraceptive methods during the study period 
11. Must have a reliable family member, significant other or a trusted friend who can take a role 
as the primary childcare provider and support person at home (including during the night) 
while the subject is participating in the trial 
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 
4. Active suicidal ideation (e.g., answering “yes” to questions 4 or 5 in the CSSRS suicidal 
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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 alcohol or any substance use disorder, with the 
exception of tobacco or caffeine 
8. Positive drug screen for any illicit substances or prescription drugs at screening.  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 after 5 days 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 blood levels of 
∆9-tetrahydrocannabinol (THC), and its metabolites 11-hydroxy-THC and, 9-carboxy-THC.  
If THC is not detectable the subject is 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 QT interval Fridericia’s correction (QTcF) > 470 msec 
16. Unwillingness to withhold grapefruit, Seville oranges, star fruit, or concentrated citrus 
derived products from diet between screening and last on-treatment visit 
17. Receiving concomitant treatment with strong cytochrome P (CYP)3A4 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 
4.3.1 
Female Contraception 
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 (IUD) plus condoms (If the subject has a hormone-releasing 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 10 for OL TID and OL QHS groups or Day 29 for the OL QHS 4-week, OL 1,125 mg, and 
OL Bolus-oral groups are to be performed as completely as possible.  Whenever possible, all 
discontinued subjects should also undergo the protocol-specified follow-ups.  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 electronic case report form (eCRF) and 
source documents.  
4.4.1 
Subject Withdrawal Criteria 
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. Electrocardiogram 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 the principal 
investigator.  If feasible, the reason for discontinuation should be discussed with the medical 
monitor.  
4.4.2 
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) 
4.4.3 
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit 
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 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 PRIOR AND CONCOMITANT TREATMENT 
All non-study treatments (including herbal treatments and vitamins) 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 received from 
the time of the screening visit through the end of the follow-up period.  Concomitant 
psychological treatment information must be recorded on the concomitant psychological 
treatments eCRF page. 
5.3.1 
Permitted Treatment 
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.  Initiation of a new therapy (a new treatment modality or switching a therapist) 
is prohibited during the treatment period.  After the treatment period, psychotherapy should be 
continued using the same modality and at the same frequency as during the treatment period, 
provided that this is medically justified, in order to be able to determine whether there are 
sustained effects from the treatment the over the 30-, 42-, or 90-day follow-up periods.  Any 
changes must be recorded on the concomitant psychological treatments eCRF page.   
5.3.1.2 
Permitted Antidepressant Treatments  
The subject may continue their current SSRI, serotonin and norepinephrine reuptake inhibitors, 
bupropion, 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 


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change within 7 days of the screening visit.  The antidepressant medication must have been 
approved for treatment of major depressive 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 after 
discussion 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 doxepine 3 to 
5 mg for severe insomnia as needed.  Only 1 dose of 1 of the medications is allowed per night.  
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, and it is used in combination with an 
antidepressant), and the medication has been approved by the US Food and Drug Administration 
as an add-on therapy for major depression, she may continue this treatment throughout the study 
period provided that the medication is taken within the approved dose range.  Examples of such 
treatments would be quetiapine 50 mg at bedtime and aripiprazole 10 mg daily.  However, the 
antipsychotic medication must have been started at least 21 days before 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 completion of the 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.   
5.3.2 
Prohibited Treatments 
The following classes of medications and treatments are prohibited during the study.  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) 


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 Opioids  
 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. ) 
 Antipsychotic medications (unless the antipsychotic is used to augment antidepressant 
medication, is used in combination with an antidepressant, and is approved by the FDA as an 
add-on therapy for major depression)  


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6 INVESTIGATIONAL PRODUCTS 
6.1 
Identity of Investigational Products 
6.1.1 
Ganaxolone Immediate Release Oral Capsules (0.3 Micron Formulation)  
Ganaxolone capsules will be provided in size 00 white/opaque gelatin capsules packaged in 
high-density polyethylene (HDPE) bottles with a foil induction seal and child resistant closure.  
Each bottle will contain 28 or 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 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.  
All study medication will be labeled according to regional regulatory requirements.  At a 
minimum, labels will contain the study number; a blinded bottle number; contents including 
quantity; dose and form; route of administration; storage conditions; instructions for study drug 
administration; caution that this compound is an investigative drug intended for clinical trial use 
only; warning to keep out of reach of children; and the identity of manufacturer and Sponsor.  
For those regions that require it, a blinded lot number and an expiry date will also be listed. 
 
6.1.2 
Ganaxolone IV Infusion Solution  
 
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 
6.1.3 
Ganaxolone Oral Suspension 
 
Vehicle: The oral suspension contains ganaxolone (50 mg/mL), hydroxypropyl methylcellulose, 
polyvinyl alcohol, sodium lauryl sulfate, simethicone, methylparaben, propylparaben, sodium 
benzoate, citric acid, and sodium citrate at pH 3.8 to 4.2, and is sweetened with sucralose and 
flavored with artificial cherry. 
Formulation: Oral suspension 
Strength: 50 mg/mL oral suspension; 110 mL in 125 mL HDPE bottles 


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6.2 
Administration of Investigational Product(s) 
All study medication will be stored at the research pharmacy prior to dispensing, or in a locked 
cabinet accessible only to members of the investigational research team.  Ganaxolone capsules 
and ganaxolone oral suspension should be stored at room temperature 15°C to 25°C (59°F to 
77°F).  Ganaxolone stock solution investigational product for IV administration will be stored at 
refrigerated temperature 2ºC to 8ºC (36ºF to 46ºF).  Oral investigational product should be taken 
within ± 15 minutes of a fatty meal or snack (e.g., yogurt, nuts, avocado), and with 240 mL 
(8 oz) of water.   
For the IV bolus, ganaxolone 12 mg in 24 mL will be administered over 2 minutes via an 
indwelling catheter, or a butterfly inserted in a vein on the arm or hand.  The investigational 
product should be given as continuous infusion as instructed.  The catheter should be flushed 
with saline at the end of the bolus infusion.  For details, please see pharmacy manual.  
6.2.1 
Allocation of Subjects to Treatment 
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 by the 
Electronic Data Capture (EDC) system to subjects according to the sequence of presentation for 
study participation.  
In the open-label part, the first approximately 8 subjects will be assigned to OL TID dosing 
group.  After approximately 8 subjects have started dosing in the OL TID group, the dosing for 
the OL QHS group will commence.  Approximately 20 subjects will be dosed for the OL QHS 
group.  After approximately 20 subjects have started dosing in the OL QHS group, the 
enrollment into the OL QHS 4-week group will commence.  After approximately 20 subjects 
have started dosing in the OL QHS 4-week group, enrollment into the OL 1,125 mg group will 
commence.  Approximately 20 subjects will be dosed for the OL 1,125 mg group.  After 
approximately 20 subjects have started dosing in the OL 1,125 mg group, enrollment into the OL 
Bolus-oral group will commence.  Approximately 20 subjects will be dosed for the OL 
Bolus-oral group. 
In the DBPC part, subjects will be randomized to receive ganaxolone or matching placebo in a 
1:1 ratio.  Randomization will be stratified by the use of concomitant antidepressants so that the 
number of subjects who are treated with antidepressants and who are not treated with 
antidepressants will be similar in each treatment group. 
After being enrolled, a subject will be replaced only if she discontinues prior to receiving study 
treatment. 
6.2.2 
Dosing for the Open-label Treatment Part – OL TID Group 
Subjects start taking the study drug at bedtime (HS) on Day 1 (enrollment).  The first dose to be 
taken will be one 225 mg capsule.  The next evening (Day 2), the dose will be increased to 
450 mg (2 capsules) to be taken HS.  This dose is taken on Day 2 and Day 3.  


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There will be a study visit on Day 4, which should be scheduled to occur in the morning.  On 
Day 4, the dose is increased to 225 mg QAM (to be started after the study visit) and 450 mg 
QHS.  This dosing (225 mg QAM and 450 mg QHS) is continued on Day 5 and Day 6.   
There will be a study visit on Day 7 which should be scheduled to occur in the morning.  The 
morning dose of the study medication on Day 7 should be taken as scheduled before the study 
visit.  The dose will be increased on Day 7 to 225 mg QAM, 225 mg Q2PM and 450 mg QHS.  
This dose will be continued on Days 8 to 10.  The subject should take the new additional 
afternoon dose that day (Day 7). 
There will be a study visit on Day 10, which is the final visit before the taper is started.  The visit 
should occur in the morning of Day 10 before noon.  The morning dose of the study drug should 
be taken as scheduled before the visit.  
On Days 11-14, the study drug is tapered off following the schedule in Table 1.  The last dose is 
to be taken on Day 14 QHS.  
All doses taken must be recorded in the eCRF. 
The study visits are intended to allow evaluation of the subject by the principal investigator and 
making dose adjustments when necessary.  If there have been no adverse events, and the subject 
has not improved clinically, the investigator should follow the titration schedule and increase the 
dose.   


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Table 1. 
Study Drug Dosing Schedule – Open-Label TID Group 
                     V2 
     V3 
    V4 
     V5 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
QAM  
  
  
  
225 mg  
225 mg 
225 mg 
225 mg 
225 mg 
225 mg 
225 mg 
225 mg 
225 mg 
  
  
Q2PM 
  
225 mg 
225 mg 
225 mg 
225 mg 
QHS 
225 mg 
450 mg 
450 mg 
450 mg 
450 mg 
450 mg 
450 mg 
450 mg 
450 mg 
450 mg 
450 mg 
450 mg 
450 mg 
225 mg 
Total  
225 mg 
450 mg 
450 mg 
675 mg  
675 mg 
675 mg 
900 mg 
900 mg 
900 mg 
900 mg 
675 mg 
675 mg 
450 mg 
225 mg 
QAM = approximately 8 am, QHS = approximately 10 pm, or before going to bed for the night 
 


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6.2.3 
Dosing for the Open-Label Treatment Part – OL QHS Group 
Subjects start taking the study drug at bedtime (HS) on Day 1 (enrollment).  The first dose to be 
taken will be one 225 mg capsule.  The next evening (Day 2) the dose will be increased to 450 
mg (2 capsules) to be taken HS.  This dose is taken on Day 2 and Day 3.  
There will be a study visit on Day 4, which should be scheduled to occur in the morning.  On 
Day 4, the dose is increased to 675 mg QHS which is continued (through Day 7 visit) until Day 
10.  There is no planned dose adjustment at Day 7 visit.  
There will be a study visit on Day 10, which is the final visit before the taper is started.  The visit 
should occur in the morning of Day 10 before noon.   
On Days 11-14 the study drug is tapered off following the schedule in Table 2.  The last dose is 
to be taken on Day 14 QHS.  
All doses taken must be recorded in the eCRF. 
The study visits are intended to allow evaluation of the subject by the principal investigator and 
making dose adjustments when necessary.  If there have been no adverse events the investigator 
should follow the dosing schedule.   


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Table 2. 
Study Drug Dosing Schedule – Open-Label QHS Group 
                    V2 
    V3 
   V4 
    V5 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
QAM  
  
  
  
 
 
 
 
 
 
 
 
 
  
  
Q2PM 
  
 
 
 
 
 
 
 
 
 
QHS 
225 mg 
450 mg 
450 mg 
675 mg 
675 mg 
675mg 
675 mg 
675 mg 
675 mg 
675 mg 
450 mg 
450 mg 
225 mg 
225 mg 
Total  
225 mg 
450 mg 
450 mg 
675 mg  
675 mg 
675 mg 
675 mg 
675 mg 
675 mg 
675 mg 
450 mg 
450 mg 
225 mg 
225 mg 
QAM = approximately 8 am, QHS = approximately 10 pm, or before going to bed for the night 
 


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6.2.4 
Dosing for the Open-Label Treatment Part – OL QHS Group – 4 Week 
Subjects start taking the study drug at bedtime (QHS) on Day 1 (enrollment).  The first dose to 
be taken will be 675 mg (3 capsules), continuing through Day 28 at QHS.  
There will be a study visit on Day 2, Day 8, Day 15, and Day 22.  There is no planned dose 
adjustment at any of these visits.  
There will be a study visit on Day 29, which is the final visit before the taper is started. The visit 
should occur in the morning of Day 29 before noon. 
On Days 29 to 32 the study drug is tapered off following the schedule in Table 3. The last dose 
will be taken on Day 32 QHS.  
All doses taken must be recorded in the eCRF. 
The study visits are intended to allow evaluation of the subject by the principal investigator and 
making dose adjustments when necessary.  If there have been no adverse events the investigator 
should follow the dosing schedule.   


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Table 3. 
Study Drug Dosing Schedule – Open-Label QHS 4 Week Group 
 
V2 
V3 
V4 
V5 
V6 
V7 
 
 
 
Day 
1 
2 
8 
15 
22 
29 
30 
31 
32 
QHS 
675 mg 
675 mg 
675 mg 
675 mg 
675 mg 
450 mg 
450 mg 
225 mg  
225 mg 
Total  
675 mg 
675 mg 
675 mg 
675 mg 
675 mg 
450 mg 
450 mg 
225 mg 
225 mg 
 
There will be total of 11 study visits for the QHS 4-week dosing group: Screening, Day 1, Day 2, Day 8, Day 15, Day 22, Day 29 and 4 safety follow-up visits on 
Day 36, Day 59, Day 89, and Day 119. 
 


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6.2.5 
Dosing for the Open-Label Treatment Part – OL 1,125 mg Group 
Subjects will start taking ganaxolone capsules, 675 mg (3 capsules) at dinner time (7 pm) 
followed by 675 mg (3 capsules) at bedtime (HS) on Day 1 and Day 2 followed by 1,125 mg 
(5 capsules) at dinner time (7 pm) on the next 26 days (Day 3 through Day 28).  A 4-day taper 
will follow: 900 mg (4 capsules) on Day 29, 675 mg (3 capsules) on Day 30, 450 mg 
(2 capsules) on Day 31, and 225 mg (1 capsule) on Day 32 (Table 4) all at dinner time. 
In addition to screening, there will be study visits on days 1, 2, 8, 15, 22, 29, 36, 57, 71.  
Day 29 is the final visit before taper is started.  The visit should occur in the morning of Day 29 
before noon. 
All doses taken must be recorded in the eCRF.  
The study visits are intended to allow evaluation of the subject by the principal investigator and 
making dose and/or timing adjustments when necessary (see Section 6.2.7).  If there have been 
no adverse events the investigator should follow the dosing schedule.   
Oral ganaxolone should be taken within ± 15 minutes of a fatty meal or snack (e.g., yogurt, nuts, 
avocado) and with 240 mL (8 oz) of water.  
Table 4. 
Study Drug Dosing Schedule – Open-label 1,125 mg Group 
Visit 
V2 
V3 
 
V4 
V5 
V6 
V7 
 
 
 
Day 
1 
2 
3 
8 
15 
22 
29 
30 
31 
32 
Q7PM 
675 mg 
675 mg 
1,125 
mg 
1,125 mg 
1,125 mg 
1,125 mg 
900 mg 
675 mg 
450 
mg 
225 
mg 
QHS 
675 mg 
675 mg 
 
 
 
 
 
 
 
 
Total  
1,350 mg 
1,350 mg 
1,125 
mg 
1,125 mg 
1,125 mg 
1,125 mg 
900 mg 
675 mg 
450 
mg 
225 
mg 
 
There will be total of 10 study visits for the OL 1,125 mg dosing group: Screening, Day 1, Day 
2, Day 8, Day 15, Day 22, Day 29 and 3 safety follow-up visits on Day 36, Day 57, and Day 71. 
 
 
 


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6.2.6 
Dosing for the Open-Label Treatment Part – OL Bolus-Oral Group 
Dosing in the Bolus-Oral group will start with ganaxolone IV bolus 12 mg over 2 minutes at 
approximately 4 pm on Day 1.  Subjects will start taking ganaxolone 750 mg oral suspension 
(15 mL at 50 mg per mL) at dinner time (7 pm) followed by 750 mg oral suspension at bedtime 
(HS) on Day 1.  On Day 2 subjects will again take 750 mg oral suspension at dinner time (7 pm) 
followed by 750 mg at bedtime (HS).  For the following 26 days (Day 3 through Day 28) 
subjects will take ganaxolone 1,000 mg oral suspension (20 mL at 50 mg per mL) at dinner time 
(7 pm).  A 4-day taper will follow: 750 mg (15 mL) on Day 29, 500 mg (10 mL) on Day 30, 500 
mg (10 mL) on Day 31, and 250 mg (5 mL) on Day 32 (Table 5) all at dinner time.  
In addition to screening, there will be study visits on days 1, 2, 8, 15, 22, 29, 36, 57, 71.  
Day 29 is the final visit before taper is started.  The visit should occur in the morning of Day 29 
before noon. 
All doses taken must be recorded in the eCRF. 
The study visits are intended to allow evaluation of the subject by the principal investigator and 
making dose and/or timing adjustments when necessary (see Section 6.2.7).  If there have been 
no AEs, the investigator should follow the dosing schedule.   
Oral ganaxolone should be taken within ±15 minutes of a fatty meal or snack (e.g., yogurt, nuts, 
avocado) and with 240 mL (8 oz) of water.   
Table 5. 
Study Drug Dosing Schedule – Open-label Bolus-oral Group 
Visit 
V2 
V3 
 
V4 
V5 
V6 
V7 
 
 
 
Day 
1 
2 
3 
8 
15 
22 
29 
30 
31 
32 
4PM 
12 mg IV Bolus 
 
 
 
 
 
 
 
 
Q7PM 
750 mg 
750 mg 
1,000 
mg 
1,000 mg 
1,000 mg 
1,000 mg 
750 mg 
500 mg 
500 
mg 
250 
mg 
QHS 
750 mg 
750 mg 
 
 
 
 
 
 
 
 
Total  
1,512 mg 
1,500 mg 
1,000 
mg 
1,000 mg 
1,000 mg 
1,000 mg 
750 mg 
500 mg 
500 
mg 
250 
mg 
 
There will be total of 10 study visits for the OL Bolus-Oral dosing group: Screening, Day 1, 
Day 2, Day 8, Day 15, Day 22, Day 29 and 3 safety follow-up visits on Day 36, Day 57, and 
Day 71. 
 
 


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6.2.7 
Dose Adjustments During Open-label  
Adjusting doses for the OL TID dosing group 
During the study the investigator has the opportunity to de-escalate, skip dose escalation and 
re-escalate during the titration on Days 1 to 10 at the scheduled study visits if the subject is 
experiencing adverse events.  The dose adjustments done at the study visits should follow the 
schedule outlined in Table 1.  The investigator should de-escalate to a previous dosing schedule, 
repeat the current dosing schedule or re-escalate to dosing scheme outline in the table.  Other 
flexible adjustments are not allowed.  
Example 1:  
If the subject at Day 4 visit reports adverse effects (e.g., sedation) with the 450 mg QHS dose, 
the investigator may decrease the dose to 225 mg QHS (de-escalation) or continue the 450 mg 
QHS dose (skip dose escalation).  The investigator may then attempt to re-escalate the dose to 
the next dose level at the next visit (Day 7).  If the investigator opted to maintain the 450 mg 
QHS dose at the Day 4 visit, the investigator may then increase the dose to the next scheduled 
dose level (225 mg QAM and 450 mg QHS) at Day 7 visit provided that the subject has 
developed a tolerance to the sedative effects.  
Example 2:  
If the subject at study visit on Day 7 reports intolerable sedation after the morning dose, the 
investigator may choose to drop the dosing to 450 mg QHS or skip the escalation and maintain 
the current dosing (225 mg QAM and 450 mg QHS). 
Subjects who do not reach the 900 mg daily dose (225 mg QAM, 225 mg Q2PM and 450 mg 
QHS) will be tapered off the study medication by reducing the dose by about 225 mg per day or 
every other day over the Days 11 to 14.  The QHS dose should be the last dose before the drug is 
discontinued completely.  
The subjects who do not tolerate the first dose of 225 mg QHS should be considered for 
discontinuation.  
All doses taken must be recorded in the eCRF. 
If the study visit falls on the weekend, or if the subject is not able to come to the study scheduled 
study visit, each visit has a window + 3 days.  Under this scenario, the subject would continue at 
the prescribed dose level until the study visit.  
Adjusting doses for the OL QHS dosing group 
During the study the investigator has the opportunity to defer a dose escalation to 675 mg at 
Day 4 Visit if the subject reports adverse events (e.g., sedation in the morning) and attempt 
escalation at Day 7 Visit or continue the dosing at 450 mg QHS until Day 10 Visit.  


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Adjusting doses for the OL QHS 4 week dosing group 
The investigator has the flexibility to adjust treatment reducing the dose to one or two capsules, 
if the subject experiences sedation, dizziness or other untoward effects during the OL part.  
 
Adjusting dose and/or timings for the OL 1,125 mg dosing group 
The investigator has the flexibility to adjust dose by reducing the dose to 450 mg (2 capsules) at 
the second of Day 1 doses (at HS) and/or at either of Day 2 doses, and/or reduce to 900 mg, 
675 mg, or 450 mg on Day 3 through Day 28 (at dinner time) if subject experiences sedation, 
dizziness or other untoward effects during the OL part.  The investigator can also change the 
timing of the evening dose bringing it closer to bedtime and taking it with a fatty snack instead of 
dinner.  Any further adjustments as well as adjusted taper period doses should be discussed with 
the medical monitor.  The investigator may increase the dose back to default levels if tolerance 
develops to the untoward effects.  
Adjusting dose and/or timings for the OL Bolus-oral dosing group  
The investigator has the flexibility to adjust dose by reducing the dose to 500 mg (10 mL) for the 
second of Day 1 doses (at HS) and/or either of Day 2 doses, and/or reduce to 750 mg (15 mL), or 
500 mg (10 mL) at dinner time on Day 3 through Day 28 if subject experiences sedation, 
dizziness or other untoward effects during the OL part.  The investigator can also change the 
timing of the evening dose bringing it closer to bedtime and taking it with a fatty snack instead of 
dinner.  Any further adjustments as well as adjusted taper period doses should be discussed with 
the medical monitor.  The investigator may increase the dose back to default levels if tolerance 
develops to the untoward effects.  
6.2.8 
Blinding 
During the DBPC part, subjects randomized to placebo will receive placebo capsules which are 
identical to the active ganaxolone capsules.  
6.3 
Labeling, Packaging, and Storage 
6.3.1 
Labeling 
Bottles will be labeled before shipping to the sites.  In the DBPC part, the contents of each bottle 
will be blinded using labels.  The randomization schedule will match a subject number to a bottle 
number.  
6.3.2 
Packaging and Dispensing the Study Drug 
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.   


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The site pharmacy or delegated site staff will be responsible for dispensing the study treatment to 
the subject.  Sufficient amount of supplies will be provided to the subject until the next study 
visit and a minimum of 3 days’ overage to cover for weekends, study site closures and 
unexpected need for rescheduling the study visit.  
Detailed instructions on when to take the medication and a reminder to take oral study 
medication within ± 15 minutes of a fatty meal or snack (e.g., fatty yogurt, nuts, avocado) and 
with 240 mL (8 oz) of water will be provided to the subject. 
6.3.3 
Storage 
The investigator has overall responsibility for ensuring that investigational products are 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 for the IV administration will be stored at 
refrigerated temperature 2ºC to 8ºC (36ºF to 46ºF).   
The 0.3-micron ganaxolone capsules (225 mg), oral suspension, and matching placebos are 
stored in HDPE bottles with a foil induction seal and child resistant closure at room temperature 
(15oC to 25oC; 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 and supplies needed for each subject for the entire study will 
be supplied to the investigational site by the sponsor or a distributor on behalf of the sponsor.  
The pharmacist or delegated site staff 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 


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accurate records 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 study drug according to the dosing plan.  Upon 
receiving study drugs, 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 (SOP) 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 
Oral doses of the investigational product should be taken within ±15 minutes of a fatty meal or 
snack (e.g., fatty yogurt, nuts, avocado), and with 240 mL (8 oz) of water.   
For the IV bolus ganaxolone 12 mg in 24 mL will be administered over 2 minutes via an 
indwelling catheter or a butterfly, inserted in a vein on the arm or hand.  The investigational 
product should be given as continuous infusion as instructed.  The catheter should be flushed 
with saline at the end of the bolus infusion.  For details please see pharmacy manual.  
Subjects 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 subject 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, including for subjects who may stay 
overnight on the unit as part of the screening process and/or the PK subgroup. 


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7 STUDY PROCEDURES 
This is a Phase 2, multicenter study in women with postpartum depression (PPD) consisting of 
2 dosing parts: an initial open-label safety part and a DBPC part.   
For the open-label safety part, approximately 172 women 18 to 48 years of age with PPD will be 
screened to enroll approximately 88 subjects.  During this open-label safety part, for the first 
approximately 8 subjects, ganaxolone will be titrated to a daily dose of 900 mg/day over 10 days, 
followed by a taper over 4 days.  This dosing group is called OL TID group.  
For the next approximately 20 subjects, ganaxolone will be administered at QHS.  For these 
subjects, ganaxolone will be titrated to a QHS dose of 675 mg over 4 days which is then 
maintained until day 10, followed by a taper over 4 days. This dosing group is called OL QHS 
group. 
For the next approximately 20 subjects, ganaxolone will be administered at bedtime (QHS). For 
these subjects ganaxolone treatment will be a QHS dose of 675 mg over 28 days, followed by a 
taper over 4 days. This dosing group is called OL QHS 4-week group. 
The next approximately 20 subjects of the open-label safety part will receive on the first 2 days 
ganaxolone capsules 675 mg at dinner time and 675 mg at bedtime (for a total of 1,350 mg per 
day on the first 2 days) followed by 26 days of ganaxolone capsules 1,125 mg at dinner time, 
followed by a taper over 4 days.  This dosing group is called OL 1,125 mg group.  
For the next approximately 20 subjects of the open-label safety part, ganaxolone will be 
administered as IV bolus 12 mg over 2 minutes at approximately 4 pm on Day 1 followed by 
ganaxolone oral suspension 750 mg at dinner time and 750 mg at bedtime, for a total of 
1,512 mg on the first day. On Day 2 subjects will receive ganaxolone oral suspension 750 mg at 
dinner time and at 750 mg at bedtime, for a total of 1,500 mg, followed by 26 days of 
ganaxolone oral suspension 1000 mg at dinner time, followed by a taper over 4 days. This dosing 
group is called OL Bolus-Oral group. The investigator has the flexibility to adjust the dose 
and/or timing of the dose if the subject experiences sedation, dizziness or other untoward effects 
during the OL part (see Section 6.2.7).  
The open-label safety part will be enrolled, and dosing completed before proceeding to the 
DBPC part.  The goal of the open-label part is to explore safety of IV and oral ganaxolone in this 
population and identify a dosing regimen for the DBPC part. 
For the DBPC part, approximately 100 women with PPD 18 to 48 years of age will be screened 
to randomize 50 women in a 1:1 ratio to receive ganaxolone or matching placebo for 14 days.  
The dosing for the DBPC portion of the study will be decided based on the results of the 
open-label portion and recommendations of the DRC.  The DRC is comprised of Marinus’ Chief 
Medical Officer and 2 external physician experts.  The daily dose will not exceed 1,600 mg.  
Randomization will be stratified by the use of concomitant antidepressants so that the number of 
subjects who are treated with antidepressants and who are not treated with antidepressants will 
be similar in each treatment group. 


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7.1 
Screening Period (Day -14 to -1) for OL TID and OL QHS 
7.1.1 
Screening Visit (Visit 1) 
 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 7.0 (MINI 7.0)   
 Conduct HAMD17 interview (if a HAMD17 interview was conducted for Marinus PPD 
study 1042-PPD-2002 at the same investigative site within 2 weeks of the screening visit the 
screening HAMD17 interview does not have to be repeated).  
 Perform EPDS 
 Perform STAI6 
 Perform a physical examination  
 Collect vital signs (blood pressure [BP], pulse, temperature, respiratory rate [RR]) 
 Collect ECG 
 Collect urine for urinalysis, urine 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 investigational site must wait 
for the results of the SAFER interview before enrolling the subject into the treatment phase 
of the study (if a SAFER interview was conducted within 2 weeks for Marinus PPD study 
1042-PPD-2002 at the same investigative site the SAFER interview does not have to be 
repeated. In this instance the HAMD17 score from the SAFER interview can be used to 
qualify the subject for the study).  
 Screening period may be extended to 21 days with approval from the medical monitor (e.g., a 
laboratory sample was hemolyzed and had to be repeated causing a delay). 
7.2 
Treatment Period (Day 1 to Day 14; Visits 2 to 5) for OL TID and OL QHS 
7.2.1 
Start of the Open-label Safety Period (Day 1; Visit 2) 
 The subject arrives in the clinic to complete baseline assessments on Day 1.  
 Conduct HAMD17 interview 
 Perform EPDS 
 Perform STAI6 


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 Assess CGI-S 
 Review concomitant medications and therapies  
 Collect vital signs (BP, pulse, temperature, RR)  
 Measure weight  
 Collect ECG 
 Collect urine for urinalysis, urine drug screen and urine pregnancy test 
 Collect safety laboratory tests 
 Collect neurosteroid level 
 Collect SSS 
 Collect AEs 
 Conduct CSSRS interview  
 Review inclusion and exclusion criteria (including hematology, chemistry, urinalysis, urine 
drug screen and pregnancy tests from the screening visit); HAMD17 must be ≥ 18 for 
enrollment. 
 If the subject continues to meet the inclusion criteria and has not developed any exclusion 
criteria the subject will be enrolled in the study.  
 Dispense medication after enrollment to the open-label.  Provide the subject with dosing 
instructions.  
 The subject will be instructed to take the first dose of the study medication that night 
(225 mg)  
 If the subject is breastfeeding, she is encouraged to “pump and dump” during the study 
period and for 45 days after the last dose.  She should be provided with a breast pump if she 
does not have one.  Breast feeding is prohibited during the treatment phase and until 45 days 
following the last dose of the study drug.  
7.2.2 
Treatment Visits (Days 4, 7, 10) (+ 3 days) for OL TID and OL QHS 
 Conduct interviews for HAMD17  
 Conduct interviews for CGI-I  
 EPDS  
 STAI6  
 Collect AEs 
 Collect ECG (Day 7, Day 10) 
 Collect vital signs (BP, pulse, RR, temperature)  
 Collect SSS  
 Collect a PK sample  
 Record concomitant medications  
 Collect safety laboratory tests (Day 10 only) 
 Collect neurosteroid level (Day 10 only) 


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 Collect urine for urinalysis, urine drug screen and urine pregnancy test  
 Conduct CSSRS interview  
 Perform a physical examination and collect weight (Day 10 only) 
 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.  
 Start study drug taper on Day 11 
7.3 
Follow-up Visit 1 (Day 17 ± 2) and Follow-up Visit 2 (Day 38 ± 4) for OL TID 
and OL QHS 
 The Follow-up Visit 1 should occur about 1 week after D10 visit, and about 3 days after the 
subject has taken her last dose of the study medication.  The Follow-up Visit 2 should occur 
approximately 3 weeks after Follow-up Visit 1 (unless there is a medical need to see the 
subject sooner; an additional safety visit can be scheduled as per the investigator’s 
discretion).  
 Conduct interviews for HAMD17 and CGI-I  
 Perform EPDS 
 Perform STAI6 
 Review concomitant medications and therapies  
 Collect vital signs (BP, pulse, temperature, RR) 
 Collect safety laboratory tests (Follow-up Visit 1 only) 
 Collect neurosteroid level (Follow-up Visit 1 only)  
 Collect PK sample 
 Collect urine for urinalysis, urine drug screen, and urine pregnancy test  
 Measure weight  
 Conduct CSSRS interview 
 Collect SSS 
 Collect AEs  
 


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Table 6. 
Schedule of Assessments for the Open-label OL TID and OL QHS and Double-blind Groups 
VISIT 
Screening (V1) 
Day1  
(V2) 
Day4  
(V3) 
Day7  
(V4) 
D10  
(V5) 
Day17  
(V6, 1st FU)  
Day38  
(V7, 2nd FU) 
Informed consent 
X 
 
 
 
 
 
 
Demographics,  medical history 
X 
 
 
 
 
 
 
MINI neuropsychiatric interview 
X 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
Randomize patient (DB only) 
 
X 
 
 
 
 
 
Dispense medication 
 
X 
X 
X 
X 
 
 
Concomitant Medications and Prior Therapy 
Review 
X 
X 
X 
X 
X 
X 
X 
Physical examination  
X 
 
 
 
X 
 
 
SAFER Interview (during screening) 
X 
 
 
 
 
 
 
Vital signs (BP, Pulse, RR, temperature) 
X 
X 
X 
X 
X 
X 
X 
Height (screening only) and weight  
X 
X 
 
 
X 
X 
X 
ECGs 
X 
X 
 
X 
X 
 
 
Safety Laboratory Tests 
X 
X 
 
 
X 
X 
 
Neurosteroid sample collection 
 
X 
 
 
X 
X 
 
Urinalysis Drug Screen and Pregnancy Tests 
X 
X 
X 
X 
X 
X 
X 
Record AEs  
 
X 
X 
X 
X 
X 
X 
PK sample collection 
 
 
X 
X 
X 
X 
X 
HAMD17 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
X 
CGI-S 
X 
X 
 
 
 
 
 
EPDS 
X 
X 
X 
X 
X 
X 
X 
STAI6 
X 
X 
X 
X 
X 
X 
X 
CSSRS 
X 
X 
X 
X 
X 
X 
X 
SSS 
 
X 
X 
X 
X 
X 
X 
Start Taper 
 
 
 
 
X 
 
 
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 10) neurosteroid sample 11) PK sample 12) urinalysis, urine drug screen and pregnancy test 13) 
physical examination.  SAFER interview is scheduled if subject meets the eligibility criteria at the Screening visit.  The SAFER interview will be conducted 
during the screening period.  The investigational site must wait for the results of the SAFER interview before enrolling the subject into the treatment phase of the 
study. Screening period may be extended to 21 days with approval from the medical monitor. 
 
 


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7.4 
Screening Period (Day -14 to -1) for OL QHS 4 week 
7.4.1 
Screening Visit (Visit 1) 
 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 7.0 (MINI 7.0)   
 Conduct HAMD17 interview (if a HAMD17 interview was conducted for Marinus PPD 
study 1042-PPD-2002 at the same investigative site within 2 weeks of the screening visit the 
screening HAMD17 interview does not have to be repeated).  
 Perform EPDS 
 Perform STAI6 
 Perform a physical examination  
 Collect vital signs (blood pressure [BP], pulse, temperature, respiratory rate [RR]) 
 Collect ECG 
 Collect urine for urinalysis, urine 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 investigational site must wait 
for the results of the SAFER interview before enrolling the subject into the treatment phase 
of the study (if a SAFER interview was conducted within 2 weeks for Marinus PPD study 
1042-PPD-2002 at the same investigative site the SAFER interview does not have to be 
repeated. In this instance the HAMD17 score from the SAFER interview can be used to 
qualify the subject for the study).  
 Screening period may be extended to 21 days with approval from the medical monitor (e.g., a 
laboratory sample was hemolyzed and had to be repeated causing a delay). 
7.5 
Treatment Period (Day 1 to Day 28; Visits 2 to 7) for OL QHS 4 week 
7.5.1 
Start of the Open-label Safety Period (Enrollment Visit for the OL QHS 4 week) 
(Day 1) 
 The subject arrives in the clinic to complete baseline assessments on Day 1.  
 Conduct HAMD17 interview 
 Perform EPDS 
 Perform STAI6 


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 Assess CGI-S 
 Review concomitant medications and therapies  
 Collect vital signs (BP, pulse, temperature, RR)  
 Measure weight  
 Collect ECG 
 Collect urine for urinalysis, urine drug screen and urine pregnancy test 
 Collect safety laboratory tests 
 Collect neurosteroid level 
 Collect SSS 
 Collect AEs 
 Conduct CSSRS interview  
 Review inclusion and exclusion criteria (including hematology, chemistry, urinalysis, urine 
drug screen and pregnancy tests from the screening visit); HAMD17 must be ≥ 18 for 
enrollment. 
 If the subject continues to meet the inclusion criteria and has not developed any exclusion 
criteria the subject will be enrolled in the study  
 Dispense medication bottle after enrollment to the open-label    Provide the subject with 
dosing instructions and subject diary completion. 
 The subject will be instructed to take the first dose of the study medication that night 
(675 mg for the OL QHS 4 week group)  
 If the subject is breastfeeding, she is encouraged to “pump and dump” during the study 
period and for 45 days after the last dose.  She should be provided with a breast pump if she 
does not have one.  Breast feeding is prohibited during the treatment phase and until 45 days 
following the last dose of the study drug.  
7.5.2 
Treatment Visits (Days 2, 8, 15, 22, 29) for OL QHS 4 week 
 Conduct interviews for HAMD17  
 Conduct interviews for CGI-I  
 EPDS  
 STAI6  
 Collect AEs 
 Collect ECG (Day 7, Day 14) 
 Collect vital signs (BP, pulse, RR, temperature)  
 Collect SSS  
 Collect a PK sample  
 Record concomitant medications  
 Collect safety laboratory tests (Day 14 only) 
 Collect neurosteroid level (Day 14 only) 


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Protocol 1042-PPD-2003 
 
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 Collect urine for urinalysis, urine drug screen and urine pregnancy test  
 Conduct CSSRS interview  
 Perform a physical examination and collect weight (Day 14 only) 
 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.  
 Start study drug taper Day 29-32 
 
7.6 
Follow-up Visit 1 (Day 36 ± 2), Follow-up Visit 2 (Day 59 ± 2), Follow-up 
Visit 3 (Day 89 ± 4), and Follow-up Visit 4 (Day 119 ± 4) for the OL QHS 
4 week group 
 The Follow-up Visit 1 should occur about 1 week after D29 visit, and about 4 days after the 
subject has taken her last dose of the study medication.  The Follow-up Visit 2 should occur 
approximately 30 days after Follow-up Visit 1. The Follow-up Visit 3 should occur 
approximately 30 days after Follow-up Visit 2. The Follow-up Visit 4 should occur 
approximately 30 days after Follow-up Visit 3. (All Follow-up visits should be scheduled 
within visit window unless there is a medical need to see the subject sooner; an additional 
safety visit can be scheduled as per the investigator’s discretion) 
 Conduct interviews for HAMD17 and CGI-I  
 Perform EPDS 
 Perform STAI6 
 Review concomitant medications and therapies  
 Collect vital signs (BP, pulse, temperature, RR) 
 ECG (Follow-up Visit 1 only) 
 Collect safety laboratory tests (Follow-up Visit 1 and 2 only) 
 Collect neurosteroid level (Follow-up Visit 1 and 2 only)  
 Collect PK sample (Follow-up Visit 1 and 2 only) 
 Collect urine for urinalysis, urine drug screen and urine pregnancy test  
 Measure weight (Follow-up Visit 4 only) 
 Conduct CSSRS interview 
 Collect SSS 
 Collect AEs  
 Collect study medication bottle dispensed at Day 29 (Follow-up Visit 1 only).  Review 
subject dosing diary and complete drug accountability while subject is present.  
 
 


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Protocol 1042-PPD-2003 
 
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Table 7. 
Schedule of Assessments for the Open-label OL QHS 4 Week Group 
VISIT 
Screening 
(V1) 
Day1  
(V2) 
Day2  
(V3) 
Day8  
(V4) 
D15  
(V5) 
Day22  
(V6)  
Day29  
(V7) 
Day36 
(V8; 1st 
FU) 
Day59 
(V9; 2nd 
FU) 
Day89 
(V10; 3rd 
FU) 
Day 119 
(V11; 4th 
FU) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics,  medical history 
X 
 
 
 
 
 
 
 
 
 
 
MINI neuropsychiatric interview 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Dispense medication / Return 
Accountability 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Concomitant Medications and Prior 
Therapy Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination  
X 
 
 
 
 
 
X 
 
 
 
 
SAFER Interview (during screening) 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs (BP, Pulse, RR, 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height (screening only) and weight  
X 
X 
 
 
 
 
X 
 
 
 
X 
ECGs 
X 
 
 
 
X 
 
X 
X 
 
 
 
Safety Laboratory Tests 
X 
X 
 
 
X 
 
X 
X 
X 
 
 
PK sample collection 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
Neurosteroid sample collection 
 
X 
X 
X 
X 
 
X 
 X 
X 
 
 
Urinalysise Drug Screen and Pregnancy 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Record AEs  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAMD17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
 
 
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 
STAI6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CSSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SSS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Start Taper 
 
 
 
 
 
 
X 
 
 
 
 
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 10) neurosteroid sample 11) PK sample 12) urinalysis, urine drug screen and pregnancy test 13) 
physical examination.  SAFER interview is scheduled if subject meets the eligibility criteria at the Screening visit.  The SAFER interview will be conducted 
during the screening period.  The investigational site must wait for the results of the SAFER interview before enrolling the subject into the treatment phase of the 
study. Screening period may be extended to 21 days with approval from the medical monitor. 


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7.7 
Screening Period (Day -14 to -1) for OL 1,125 mg and OL Bolus-Oral groups 
7.7.1 
Screening Visit (Visit 1) 
 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 7.0 (MINI 7.0)   
 Conduct HAMD17 interview (if a HAMD17 interview was conducted for Marinus PPD 
study 1042-PPD-2002 at the same investigative site within 2 weeks of the screening visit the 
screening HAMD17 interview does not have to be repeated).  
 Perform EPDS 
 Perform STAI6 
 Perform a physical examination  
 Collect vital signs (blood pressure [BP], pulse, temperature, respiratory rate [RR]) 
 Collect ECG 
 Collect urine for urinalysis, urine 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 investigational site must wait 
for the results of the SAFER interview before enrolling the subject into the treatment phase 
of the study (if a SAFER interview was conducted within 2 weeks for Marinus PPD study 
1042-PPD-2002 at the same investigative site the SAFER interview does not have to be 
repeated. In this instance the HAMD17 score from the SAFER interview can be used to 
qualify the subject for the study).  
 Screening period may be extended to 21 days with approval from the medical monitor (e.g., a 
laboratory sample was hemolyzed and had to be repeated causing a delay). 
7.8 
Treatment Period (Day 1 to Day 29; Visits 2 to 7) for OL 1,125 mg and OL 
Bolus-Oral groups  
7.8.1 
Start of the Open-label Safety Period (Enrollment Visit for the OL 1,125 mg and 
OL Bolus-Oral groups) (Day 1) 
 The subject arrives in the clinic to complete baseline assessments on Day 1.  
 CTNI to conduct HAMD17 interview 
 Perform EPDS 


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 Perform STAI6 
 Assess CGI-S 
 Review concomitant medications and therapies  
 Collect vital signs (BP, pulse, temperature, RR)  
 Measure weight  
 Collect ECG 
 Collect urine for urinalysis, urine drug screen and urine pregnancy test 
 Collect safety laboratory tests 
 Collect neurosteroid level 
 Collect SSS 
 Collect AEs 
 Conduct CSSRS interview  
 Review inclusion and exclusion criteria (including hematology, chemistry, urinalysis, urine 
drug screen and pregnancy tests from the screening visit); HAMD17 (as determined by 
CTNI) must be ≥ 18 for enrollment. 
 If the subject continues to meet the inclusion criteria and has not developed any exclusion 
criteria the subject will be enrolled in the study  
 Dispense medication bottle after enrollment. Provide the subject with dosing instructions and 
subject diary completion. 
 For the OL 1,125 mg group: the subject will be instructed to take the first oral doses of the 
study medication that evening (675 mg [3 capsules] at dinner time [at 7 pm] and at bedtime 
[at 10 pm])  
 For the OL Bolus-Oral group: the subject will receive IV bolus 12 mg over 2 minutes at 
approximately 4 pm (preferably ±1 hour) while on the unit, be observed for development of 
sedation and/or other untoward effects for at least 1 hour post-bolus and then be discharged 
and instructed to take the first oral doses of the study medication that evening (750 mg [15 
mL oral suspension at 50 mg per mL] at dinner time [at 7 pm] and at bedtime [at 10 pm])  
 Oral IP should be taken within ±15 minutes of a fatty meal or snack (e.g., yogurt, nuts, 
avocado), and with 240 mL (8 oz) of water.   
 A sub-group of 6 subjects (to be called ‘PK sub-group’, Section 7.10.7) in each of the OL 
1,125 mg and OL Bolus-Oral groups will stay overnight on the unit between Day 1 and Day 
2 to undergo comprehensive PK assessment as follows: for the OL 1,125 mg group plasma 
samples for PK analysis will be drawn at the following times after the first oral dose on Day 
1 (i.e., the 675 mg oral capsules dose at 7 pm at dinner time; 0hr): +1hr, +2hr, +3hr (i.e., just 
prior to the 10 pm 675 mg dose), at +4hr, +5hr, +6hr, and at 8 am on Day 2. For the OL 
Bolus-Oral group plasma samples for PK analyses will be drawn at the following times after 
the IV bolus on Day 1 (e.g., the 12 mg IV bolus at 4 pm; 0hr): +1hr, +2hr, +3hr (i.e., just 
prior to the first oral dose of 750 mg oral suspension at dinner time), at +4hr, +5hr, +6hr (i.e., 
just prior to the second 750 mg oral suspension evening dose), at + 7hr, +8hr, and at 8 am on 
Day 2. 


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 If the subject is breastfeeding, she is encouraged to “pump and dump” during the study 
period and for 45 days after the last dose.  She should be provided with a breast pump if she 
does not have one.  Breast feeding is prohibited during the treatment phase and until 45 days 
following the last dose of the study drug.  
7.8.2 
Treatment Visits (Days 2, 8, 15, 22, 29 ± 3 days [except Day 2]) for OL 1,125 mg 
and OL Bolus-Oral groups 
 CTNI to conduct interview for HAMD17  
 Conduct interview for CGI-I  
 EPDS  
 STAI6  
 Collect AEs 
 Collect ECG (Day 2, Day 8, Day 15, Day 29) 
 Collect vital signs (BP, pulse, RR, temperature)  
 Measure weight (Day 15, Day 29) 
 Collect SSS  
 Collect a PK sample  
 Record concomitant medications  
 Collect safety laboratory tests (Day 15, Day 29) 
 Collect neurosteroid level (Day 2, Day 8, Day 15, Day 29) 
 Collect urine for urinalysis, urine drug screen and urine pregnancy test (Day 8, Day 15, Day 
22, Day 29) 
 Conduct CSSRS interview  
 Perform a physical examination (Day 29) 
 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.  
 For the OL 1,125 mg group: the subject will be instructed to take Day 2 oral doses of the 
study medication that evening (675 mg [3 capsules] at dinner time [at 7 pm] and 675 mg [3 
capsules] at bedtime [at 10 pm]) followed by 26 days of 1,125 mg (5 capsules) at dinner time 
 For the OL Bolus-Oral group: the subject will be instructed to take Day 2 oral doses of the 
study medication that evening (750 mg [15 mL oral suspension at 50 mg per mL] at dinner 
time [at 7 pm] and 750 mg [15 mL oral suspension at 50 mg per mL] at bedtime [at 10 pm]) 
followed by 26 days of 1,000 mg (20 mL oral suspension at 50 mg per mL) at dinner time 
 Oral IP should be taken within ±15 minutes of a fatty meal or snack (e.g., yogurt, nuts, 
avocado), and with 240 mL (8 oz) of water.   
 During Visit 7 (Day 29) start study drug taper (Day 29-32) (See Sections 6.2.5 and 6.2.6) 
 


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7.9 
Follow-up Visit 1 (Day 36 ± 3), Follow-up Visit 2 (Day 57 ± 3), and Follow-up 
Visit 3 (Day 71 ± 3) for the OL 1,125 mg and OL Bolus-Oral groups 
 The Follow-up Visit 1 should occur about 1 week after D29 visit, and about 4 days after the 
subject has taken her last dose of the study medication.  The Follow-up Visit 2 should occur 
approximately 21 days after Follow-up Visit 1. The Follow-up Visit 3 should occur 
approximately 14 days after Follow-up Visit 2 (All Follow-up visits should be scheduled 
within visit window unless there is a medical need to see the subject sooner; an additional 
safety visit can be scheduled as per the investigator’s discretion). 
 CTNI to conduct interview for HAMD17  
 Conduct interview for CGI-I  
 Perform EPDS 
 Perform STAI6 
 Review concomitant medications and therapies  
 Collect vital signs (BP, pulse, temperature, RR) 
 ECG (Follow-up Visit 1 only) 
 Collect safety laboratory tests (Follow-up Visit 1 and 3 only) 
 Collect neurosteroid level (Follow-up Visit 1 and 3 only)  
 Collect PK sample (Follow-up Visit 1 only) 
 Collect urine for urinalysis, urine drug screen and urine pregnancy test  
 Measure weight (Follow-up Visit 3 only) 
 Conduct CSSRS interview 
 Collect SSS 
 Collect AEs  
 Collect study medication bottle dispensed at Day 29 (Follow-up Visit 1 only).  Review 
subject dosing diary and complete drug accountability while subject is present.  
 
  


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Protocol 1042-PPD-2003 
 
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Table 8. 
Schedule of Assessments for the Open-label OL 1,125 mg and OL Bolus-oral Groups 
VISIT 
Screening 
(V1) 
Day1  
(V2) 
Day2  
(V3) 
Day8 ±3d 
(V4) 
D15 ±3d 
(V5) 
Day22 ±3d 
(V6)  
Day29 ±3d 
(V7) 
Day36 ±3d 
(V8; 1st FU) 
Day57 ±3d 
(V9; 2nd FU) 
Day71 ±3d 
(V10; 3rd FU) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics,  medical history 
X 
 
 
 
 
 
 
 
 
 
MINI neuropsychiatric interview 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Dispense medication / Return 
Accountability 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant Medications and Prior 
Therapy Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination  
X 
 
 
 
 
 
X 
 
 
 
SAFER Interview (during screening) 
X 
 
 
 
 
 
 
 
 
 
Vital signs (BP, Pulse, RR, 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height (screening only) and weight  
X 
X 
 
 
X 
 
X 
 
 
X 
ECGs 
X 
X 
X 
X 
X 
 
X 
X 
 
 
Safety Laboratory Tests 
X 
X 
 
 
X 
 
X 
X 
 
X 
b Bolus (OL Bolus-Oral group only) 
 
X 
 
 
 
 
 
 
 
 
PK sample collection 
 
 
X 
X 
X 
X 
X 
X 
 
 
PK subgroup sample collection 
 
c X 
 
 
 
 
 
 
 
 
Neurosteroid sample collection 
 
X 
X 
X 
X 
 
X 
 X 
 
X 
Urinalysis, Drug Screen and Pregnancy 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Record AEs  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a HAMD17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-S 
X 
X 
 
 
 
 
 
 
 
 
EPDS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
STAI6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CSSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SSS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Start Taper 
 
 
 
 
 
 
X 
 
 
 
 


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a CTNI will conduct all HAMD ratings except the one at screening 
b IV bolus is to be done at approximately 4 pm (preferably within ±1 hour) and allowing for at least 1-hour post-bolus follow-up at the site before discharge 
c A sub-group of 6 subjects (to be called ‘PK sub-group’) in each of the OL 1,125 mg and OL Bolus-Oral groups will stay overnight on the unit between Day 1 
and Day 2 to undergo comprehensive PK assessment as follows: for the OL 1,125 mg group plasma samples for PK analysis will be drawn at the following times 
after the first oral dose on Day 1 (e.g., the 675 mg oral capsules dose at 7 pm at dinner time; 0hr): +1hr, +2hr, +3hr (i.e., just prior to the 10 pm 675 mg dose), at 
+4hr, +5hr, +6hr, and at 8 am on Day 2. For the OL Bolus-Oral group plasma samples for PK analyses will be drawn at the following times after the IV bolus on 
Day 1 (e.g., the 12 mg IV bolus at 4 pm; 0hr): +1hr, +2hr, +3hr (i.e., just prior to the first oral dose of 750 mg oral suspension at dinner time), at +4hr, +5hr, +6hr 
(i.e., just prior to the second 750 mg oral suspension evening dose), at + 7hr, +8hr, and at 8 am on Day 2. 
 
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 10) neurosteroid sample 11) PK sample 12) urinalysis, urine drug screen and pregnancy test 13) 
physical examination.  SAFER interview is scheduled if subject meets the eligibility criteria at the Screening visit.  The SAFER interview will be conducted 
during the screening period.  The investigational site must wait for the results of the SAFER interview before enrolling the subject into the treatment phase of the 
study. Screening period may be extended to 21 days with approval from the medical monitor.


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7.10 Study Evaluations and Procedures 
7.10.1 
Demographics, Medical History, and Other Baseline Characteristics 
Demographics, medical history, and other baseline characteristics will be collected and recorded 
on the appropriate sections of the eCRF at the time of the screening visit.  
7.10.2 
Informed Consent 
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 this study will be discussed with the 
subject.  
7.10.3 
Eligibility Review 
An eligibility review will be conducted by the investigator at the visits specified in Table 8, 
using the subject inclusion and exclusion criteria as detailed in Section 4.  
7.10.4 
Prior Medication, Concomitant Medication and Concomitant Therapy Review 
At screening, prospective subjects will be asked about medications they have taken in the 
previous 60 days, including prescription medications, non-prescription medications, herbal 
medications, vitamins, and supplements.  At subsequent visits, the subjects will be asked about 
medications taken since the last visit.   
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 subject received from the time of screening through the 
last follow-up visit will be recorded on the Concomitant Psychological Treatment eCRF page.  
7.10.5 
Physical Examination 
A complete physical examination will be performed at screening and at Day 10 visit (Day 29 for 
OL QHS 4 week, OL 1,125 mg and OL Bolus-Oral groups).  
The physical examination will include a review of the following body systems: 
 General appearance 
 Skin 
 Head, eyes, ears, nose, mouth and throat 


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 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.  
7.10.5.1 
12-lead Electrocardiogram 
A 12-lead ECG will be conducted as outlined above.  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 
vendors’ 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) and documented on the appropriate AE eCRF page and, if an SAE, 
submitted to Marinus Safety Department on the SAE form.   
7.10.5.2 
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.  
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:  
Biochemistry  
Sodium, potassium, glucose, chloride, carbon dioxide, creatinine, total protein, blood urea 
nitrogen (BUN), albumin, total bilirubin (with reflex fractionation to direct and indirect bilirubin 
if total bilirubin is elevated and outside of the normal range), ALT, AST, alkaline phosphatase, 
thyroid stimulating hormone (with reflex to free T4 if thyroid stimulating hormone (TSH) is 


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outside of the normal range).  The investigator may determine serum β human chorionic 
gonadotropin (HCG) levels to confirm or exclude pregnancy.  
Hematology 
Hemoglobin, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, 
mean corpuscular hemoglobin concentration, platelet count, and white blood cell count with 
differential.  
Subjects are not required to be fasting prior to collection of the blood samples. 
Urinalysis 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.  
7.10.5.3 
Adverse Event Collection 
Please refer to Section 8, Adverse and Serious Adverse Events Assessment. 
7.10.5.4 
Vital Signs 
Vital signs including BP, pulse, respirations, and temperature (recorded in Celsius [°C]) 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 as outlined above. 
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.  
7.10.6 
Interviews, Questionnaires, and Scales 
The scales and assessments are listed in Appendix 2.  A separate file containing each 
scale/assessment will be provided to the site. 
7.10.6.1 
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.  


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7.10.6.2 
The Hamilton Depression Rating Scale  
The 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.  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.11  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).  
7.10.6.3 
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.   
7.10.6.4 
Clinical Global Impression-Improvement and Clinical Global 
Impression-Severity  
The 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 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. 
7.10.6.5 
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 (Obsessive 
Thoughts Questionnaire) 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 included in the calculation of the total EPDS score in the 
statistical analysis.  These 2 questions are rated on a 5-point scale.  
7.10.6.6 
Spielberg Trait-State Anxiety Inventory, 6 Item Version  
The STAI6 is a short questionnaire evaluating anxiety state.  The STAI6 has 6 questions, such as 
“I feel calm,” “I feel tense,” which the subject rates on a scale corresponding to “not at all,” 
“somewhat,” “moderately”, and “very much.”12  


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7.10.6.7 
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 enrollment to confirm 
validity of the diagnosis of PPD and eligibility for the study from depression perspective.  If the 
subject was screened by the SAFER team for Marinus study 1042-PPD-2002 and confirmed to 
have postpartum depression but the HAMD17 severity criteria were not met, the subject could be 
considered eligible for this study without repeating the SAFER interview provided that the 
original interview was done within 2 weeks of the screening visit for the current study. 
CTNI will also perform all HAMD ratings except the one done at screening. 
7.10.6.8 
Columbia Suicide Severity Rating Scale (CSSRS) 
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. 
7.10.7 
Pharmacokinetic Sampling 
Blood samples for pharmacokinetic analysis will be drawn at the times specified in Table 8 to 
allow determination of ganaxolone plasma levels.  
A sub-group of 6 subjects (to be called ‘PK sub-group’) in each of the OL 1,125 mg and OL 
Bolus-Oral groups will stay overnight on the unit between Day 1 and Day 2 to undergo 
comprehensive PK assessment as follows: for the OL 1,125 mg group plasma samples for PK 
analysis will be drawn at the following times after the first oral dose on Day 1 (i.e., the 675 mg 
oral capsules dose at 7 pm at dinner time; 0hr): +1hr, +2hr, +3hr (i.e., just prior to the 10 pm 675 
mg dose), at +4hr, +5hr, +6hr, and at 8 am on Day 2. For the OL Bolus-Oral group plasma 
samples for PK analyses will be drawn at the following times after the IV bolus on Day 1 (e.g., 
the 12 mg IV bolus at 4 pm; 0hr): +1hr, +2hr, +3hr (i.e., just prior to the first oral dose of 750 mg 
oral suspension at dinner time), at +4hr, +5hr, +6hr (i.e., just prior to the second 750 mg oral 
suspension evening dose), at + 7hr, +8hr, and at 8 am on Day 2. 
The first 6 consecutively enrolled subjects who are in units with overnight inpatient capabilities 
and who consent for inclusion in the PK subgroup will be included in the PK subgroup. 
 
7.10.8 
Neurosteroid Levels  
Blood samples for determination of neurosteroid levels (allopregnanolone and potentially other 
metabolites of progesterone) will be collected at time points specified in Table 8.  


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7.10.9 
Volume of Blood to Be Drawn from Each Subject 
Table 9. 
Volume of Blood to Be Drawn from Each Subject for the OL TID, OL QHS and 
Double-blind Groups 
Assessment 
Approximate Sample 
Volume (mL)a 
Number of 
Samples 
Approximate Total 
Volume (mL) 
Pharmacokinetic samples 
4 
5 
20 
Safety hematology  
3 
3 
9 
Safety chemistry 
7 
3 
21 
Neurosteroid level 
4 
2 
8 
Total mL 
 
 
58 
 
 
Table 10. Volume of Blood to Be Drawn from Each Subject for the OL QHS 4 Week, OL 
1,125 mg, and OL Bolus-oral groups 
Assessment 
Approximate Sample 
Volume (mL)a 
Number of 
Samples 
Approximate Total 
Volume (mL) 
Pharmacokinetic samples 
4 
6 
24 
Safety hematology  
3 
6 
18 
Safety chemistry 
7 
6 
42 
Neurosteroid level 
4 
7 
28 
Total mL 
 
 
112 
 
 
Table 11. Volume of Blood to Be Drawn from Each Subject for the PK Subgroup of OL 
1,125 mg Group 
Assessment 
Approximate Sample 
Volume (mL)a 
Number of 
Samples 
Approximate Total 
Volume (mL) 
Pharmacokinetic samples 
4 
12 
48 
Safety hematology  
3 
6 
18 
Safety chemistry 
7 
6 
42 
Neurosteroid level 
4 
7 
28 
Total mL 
 
 
136 
 
 
Table 12. Volume of Blood to Be Drawn from Each Subject for the PK Subgroup of OL 
Bolus-Oral Group 
Assessment 
Approximate Sample 
Volume (mL)a 
Number of 
Samples 
Approximate Total 
Volume (mL) 
Pharmacokinetic samples 
4 
14 
56 
Safety hematology  
3 
6 
18 
Safety chemistry 
7 
6 
42 
Neurosteroid level 
4 
7 
28 
Total mL 
 
 
144 
 


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During this study, approximately 58 mL of blood will be drawn from all subjects during the 
study for the OL TID, OL QHS and Double-blind groups.  Approximately 112 mL of blood will 
be drawn from all subjects during the study for the OL QHS 4 week, OL 1,125 mg, and OL 
Bolus-Oral groups. 
Subjects in the ‘PK subgroup’ of the OL 1,125 mg and OL Bolus-oral groups (6 subjects in each 
subgroup) will have additional 6 and 8 samples, respectively, at 4 mL each, for a total of 
approximately 136 mL and 144 mL of blood drawn, respectively.  
7.10.10 
Safety Plan for Medical Emergencies 
If the subject exhibits suicidal ideation during the study visit (for example answering “yes” to 
questions 4 and 5 in the suicidal ideation part of the CSSRS) she must be evaluated by a 
psychiatrist immediately.  Suicidality assessment and the decision regarding further evaluation 
and treatment may be done by a psychiatrist principal investigator (or a sub-investigator). If a 
psychiatrist is not available at the study site, the site must have a plan how to access psychiatric 
care immediately, for example at a local emergency room or other acute care facility.  
Each investigative study site must provide 24-hour medical coverage to address questions from 
the subjects and respond to medical emergencies, such as suicidal ideation and adverse events, 
including during the off-duty hours. Each subject will be provided with a wallet card and 
information how to contact the study site at all hours.  


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8 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 
(International Council on Harmonisation [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 period 
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. 
8.1.1 
Severity Categorization 
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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8.1.2 
Causality Categorization 
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?”  
8.1.3 
Variables 
The following variables will be collected for each AE: 
 AE  
 The date 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) 
 
8.1.4 
Symptoms of the Disease Under Study 
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. 
8.1.5 
Adverse Events Based on Clinical Laboratory and Other Safety Evaluations 
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 period, 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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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. 
8.1.6 
Adverse Events Based on Signs and Symptoms 
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. 
8.1.7 
Pregnancy 
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 -HCG test or ultrasound result will 
determine the pregnancy onset date. 
8.2 
Serious Adverse Event Procedures 
8.2.1 
Reference Safety Information 
The reference for safety information for this study is the Investigator’s Brochure (IB), which the 
sponsor has provided under separate cover to all investigators. 
8.2.2 
Reporting Procedures 
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:  safetyPPD2003@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.  
8.2.3 
Serious Adverse Event Definition 
An 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 
one 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.  
8.2.4 
Serious Adverse Event Collection Time Frame 
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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8.2.5 
Serious Adverse Event Onset and Resolution Dates 
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 
IV 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. 
8.2.6 
Fatal Outcome 
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.  
8.2.7 
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
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 
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9 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.   
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 
Statistical Analysis Plan 
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 data will be addressed.  
The SAP will be finalized prior to database lock and/or unblinding of any portion of the trial to 
preserve the integrity of the statistical analysis and study conclusions.  
9.3.1 
Data Review Committee (DRC) and Recommendations for Dosing  
Adverse events and other safety data, including sedation and dosing changes, will be adjudicated 
by the DRC before proceeding to the double-blind part of the study.  The dose recommendation 
will be made by a DRC comprised of the Marinus Chief Medical Officer and 2 external 
physicians and potentially other experts familiar with the clinical care of women with major 
depression or PPD and with experience in conducting clinical trials. The DRC may also consult 
other experts, such as a statistician and a pharmacokineticist.  A separate guidance document will 
outline the functions and membership of the DRC. 
After completion of the double-blind part, the data will be evaluated by an independent DRC.  
Based on the analysis and recommendation by the DRC, the study may be closed at that point, or 


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an additional approximately 50 women with PPD will be treated with ganaxolone or placebo 
under a similar study design but using a different dosing regimen.  The daily dose may be 
lowered, increased, or the previous dosing may be repeated.  However, the total daily dose will 
not exceed 1,200 mg and no single dose will be higher than 675 mg. 
Marinus may decide to stop the study, or make the data public at any time during the open-label 
portion of the trial or after completion of the double-blind part of the study. 
9.3.2 
Justification for Sample Size 
With a sample size of 50 subjects/group, the DBPC part of the trial will be able to detect a 
medium effect size (per Cohen’s d) with 93% power using a two-sided significance level of 0.05. 
9.3.3 
Study Population 
The Screened Set will consist of all subjects who have signed an informed consent. 
The Randomized Set will consist of subjects randomized in the DBPC part of the trial.  
The Safety Set will consist of all subjects who received IV IP.  
The modified Intent to Treat Set (mITT) will consist of all subjects in the DBPC part of the 
trial who received IP and who have at least 1 post-baseline HAMD17 assessment.  The mITT set 
will be the primary efficacy population for the DBPC part of the trial.  
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.  
9.4 
Analysis Methods 
Data will be presented by study part (OL, DBPC), dosing or treatment group within study part 
and, if applicable, study visit. 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. 
9.4.1 
Demographic and Baseline Characteristics 
Baseline characteristics will include a summary of the following: 
 Subject demographics 
 Pre-existing medical conditions 
 Prior therapies 
 Medical history 
 


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9.4.2 
Subject Disposition 
Frequencies and percentages of subjects who discontinued the study and reasons for 
discontinuation will be summarized. 
9.4.3 
Investigational Medicinal Product 
Overall exposure to investigational product, such as duration of exposure, as well as dose 
adjustments (i.e., deviations from the scheduled titration scheme) will be summarized. 
9.4.4 
Concomitant Medication 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD) and will be summarized by drug class and preferred drug name. 
9.4.5 
Safety Analyses 
Reported AEs terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The incidence of treatment emergent AEs (TEAEs), defined as AEs that started or 
worsened after first administration of IP, will be summarized by system organ class and 
preferred term. Separate summaries of TEAEs by severity and relatedness will be done.  SAEs 
and TEAEs leading to discontinuation of the study drug will also be summarized separately.  
The absolute values and change from baseline in laboratory tests, vital signs, SSS, ECG 
parameters, and CSSRS will be summarized.  
Results of physical examinations will be listed.  
9.4.6 
Efficacy Analyses 
Efficacy parameters will be summarized for both the open-label and DBPC parts but will be 
analyzed only for the DBPC part.  For the open-label part, referring to efficacy endpoints as 
“primary,” “secondary,” and “exploratory” is related to the degree of influence each type of 
endpoint is expected to have on decision-making rather than to considerations associated with 
inferential analysis (such as control of type 1 error). The primary time point of interest for all 
efficacy parameters will be Day 10 for the DBPC part and the visit at end of treatment (before 
initiation of taper) for the open-label part. 
9.4.6.1 
Primary Endpoint 
The primary efficacy endpoint will be HAMD17 total score change from baseline; this will be 
assessed at Day 10 for the DBPC part and at the visit at end of treatment for the open-label part. 
The primary efficacy analysis will be done using the mITT set (DBPC part only). The analytical 
method will be mixed model repeated measures (MMRM) with baseline HAMD17 total score as 
a covariate. Significance will be tested at a two-sided 0.05 level. Unstructured covariance will be 
specified although alternative covariance structures may be used, if appropriate, to achieve 
convergence or greater efficiency. Sensitivity analysis will be used to evaluate the assumption of 
data missing at random (MAR), if applicable. 


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9.4.6.2 
Secondary Endpoints 
Marinus Phrumaceuticals, Inc. 
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The ti·ial will also evaluate the following secondaiy endpoints at each post-baseline data 
collection time point to provide additional evidence of the efficacy of ganaxolone in ti-eating 
PPD: 
• 
Change from baseline in HAMD 17 total score other than at the primaiy endpoint time 
point 
• 
HAMDl 7 response defined as at least a 50% reduction from baseline in total score 
• 
HAMD 17 remission defined as total score <= 7 
• 
Change from baseline in EPDS total score 
• 
Change from baseline in ST AI6 
• 
CGI-I 
-
I 
I 
I 
I 
I 
I 
9.4.6.4 
Statistical Methods 
Efficacy pai·ameters will be sUilllnai·ized for open-label and DBPC paiis. Observed values and 
changes from baseline for HAMD 17, EPDS, and STAI6 total scores, subscales, and individual 
items will be smnmai·ized by visit. The categorical outcomes of HAMD 17 response, HAMD 17 
remission, and CGI-I will be sUilllnarized by visit. 
For the DBPC paii, the prefen ed approach for analyses of ti·eatinent group differences in 
secondaiy and explorato1y continuous efficacy vai·iables will be MMRM but other approaches 
such as t-tests, analysis of covai·iance, or non-parameti·ic methods may be used if necessa1y or 
more practical. Similarly, the prefen ed approach for analysis of secondaiy and explorato1y 
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categorical efficacy variables will be repeated measures (e.g., generalized estimating equations) 
but other approaches such as chi square or Fisher’s exact tests may be used. 
 
9.4.7 
Other Analyses 
No other analyses are planned in this study. 
9.4.8 
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. 
After completion of the study, a set of sensitivity analyses will be conducted to evaluate the 
impact of missing data on the results.  The methodologies for the addressing missing data will be 
specified in the Statistical Analysis Plan (SAP).   
9.4.9 
Pharmacokinetic Analyses 
Five samples of blood will be collected to determine ganaxolone plasma concentrations during 
the study.  Samples will be collected on 3 occasions during treatment with ganaxolone to 
determine trough concentrations in plasma.  An additional 2 samples of blood will be collected at 
follow up visits, after ganaxolone treatment has been completed, to monitor the disappearance of 
ganaxolone following cessation of treatment. 
 


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10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This study is conducted in accordance with current applicable regulations, 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., contract research organization [CRO]) 
used in this study will be maintained in the investigator’s and sponsor’s files, as appropriate. 
10.1 Sponsor’s Responsibilities 
10.1.1 
Good Clinical Practice Compliance 
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 Good Clinical Practice (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. 
10.1.2 
Public Posting of Study Information 
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.  
10.1.3 
Study Suspension, Termination, and Completion 
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. 
10.2 Investigator’s Responsibilities 
10.2.1 
Good Clinical Practice Compliance 
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. 


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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 primary diagnosis and eligibility for the trial are assessed by a qualified licensed physician 
investigator (or his/her delegate) at the study site. The physician at the study site will be 
accountable for clinical assessments, physical examinations, and medication administration 
(including deciding whether the dose is escalated or not). The remote SAFER interview will be 
conducted to confirm the diagnosis of PPD and eligibility for the trial from the depression 
severity point of view.  
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. 
10.2.2 
Protocol Adherence and Investigator Agreement 
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. 
10.2.3 
Documentation and Retention of Records 
10.2.3.1 
Case Report Forms 
Electronic 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.  Electronic case report forms 
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 
10.3.1 
Informed Consent 
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. 
10.3.2 
Institutional Review Board or Ethics Committee 
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. 


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10.4 Privacy and Confidentiality 
All sites and laboratories or entities providing support for this study, must, where applicable, 
comply with the Health Insurance Portability and Accountability Act (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. 
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 either the open-label part or double-blind part.  


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11 REFERENCES 
1. Gavin NI, Gaynes BN, Lohr KN, et al. Perinatal Depression. A Systematic Review of 
Prevalence and Incidence. Obstetrics and Gynecology. 2005;106:1071-83.  
2. Kaplan PS, Danko CM, Kalinka CJ, et al. A developmental decline in the learning-promoting 
effects of infant-directed speech for infants of mothers with chronically elevated symptoms 
of depression. Infant Behav Dev. 2012;35:369–79.  
3. 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.  
4. Gilbert Evans SE, Ross LE, Sellers EM, et al. 3a-reduced neuroactive steroids and their 
precursors during pregnancy and the postpartum period. Gynecological Endocrinology. 
2005;21:268-79.  
5. Hantsoo L, Ward-O’Brien D, Czarkowski KA, et al. A randomized, placebo-controlled, 
double-blind trial of sertraline for postpartum depression. Psychopharmacology. 
2014;231:939–48. 
6. 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. 
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. Carter RB, Wood PL, Wieland S, et al. Characterization of the anticonvulsant properties of 
ganaxolone (CCD 1042; 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a selective, 
high-affinity, steroid modulator of the gamma-aminobutyric acid(A) receptor. The Journal of 
Pharmacology and Experimental Therapeutics. 1997;280:1284–95 
9. Maguire J and Mody I. Steroid hormone fluctuations and GABAAR plasticity. 
Neuropsychoendocrinology. 2009;34:S84-S90. 
10. Turkmen S, Backstrom T, Wahlstrom G. Tolerance to allopregnanolone with focus on the 
GABAA receptor. British Journal of Pharmacology. 2011;162:311–27. 
11. 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. 
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. 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 
15. 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. 
16. 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 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) 
 
 
 
 


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Appendix 2.   Scales and Assessments 
The following scales/assessments will be utilized in this study: 
Full Title of Scale/Assessment 
Version  
Hamilton Depression Rating Scale (HAMD17)  
17-item version  
Spielberg Trait-State Anxiety Inventory 
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.  
 
 




IND No. 135256 
Protocol 1042-PPD-2003 
Amendment 4 Summary of Changes from version June 5, 2018 to 22 Oct, 2018 
Page 
13 
Section, Title, 
Para ra h, Line 
Title Page 
Study Synopsis Title 
01iginal Text 
TITLE: A Phase 2, Double-blind, Placebo-controlled, 
Multicenter Study to Evaluate Safety, Tolerability and 
Efficacy of Oral Administration ofGanaxolone in Women 
with Postpartum Depression 
Reason for Change: Addition of intravenous administration of Ganaxolone to study 
1 
Title Page 
Global/Count 
ry/Site 
Document 
Date 
Specific 
Original Protocol -
09 Jun 2017 
Global 
Version 1 
Amendment 1 -
15Aug2017 
Global 
Version 2 
Amendment 2 -
25 Jan 2018 
Global 
Version 3 
Amendment 3 -
05 Jun 2018 
Global 
Version 4 
Reason for Chan e: Administrative cha 
· 
2 
Protocol Signature Page 
Reason for Chan e: Chan°e to S nsor Medical Contact and Medical Monitor 
Confidential 
Marinus Phrumaceuticals, Inc. 
Version 5.0 / 22 Oct 2018 
Revised Text 
TITLE: A Phase 2, Double-blind, Placebo-controlled, 
Multicenter Study to Evaluate Safety, Tolerability and Efficacy 
of IV and Oral Adrninistration of Ganaxolone in Women with 
Postprutum Depression 
Global/Count 
1·y/Site 
Document 
Date 
Specific 
Original Protocol -
09 Jun 2017 
Global 
Version 1 
Amendment 1 - Version 
15 Aug 2017 
Global 
2 
Amendment 2 - Version 
25 Jan 2018 
Global 
3 
Amendment 3 - Version 
05 Jun 2018 
Global 
4 
Amendment 4 -
22 Oct 2018 
Global 
Version 5 
Page 93 of 131 


IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
Confidential 
Page 94 of 131 
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3 
Sponsor Contacts 
MD, PhD 
Telephone: 
Email:  
 
MD  
Marinus Pharmaceuticals Inc. 
Telephone:  : 
Email: 
Reason for Change:  Change to Sponsor Medical Contact and Medical Monitor 
13 
Study Synopsis 
Drug:  Ganaxolone oral capsule formulation 
Drug:  Ganaxolone IV, oral suspension, and oral capsule 
formulations 
Reason for Change:  Addition of intravenous administration of Ganaxolone to study and clarification of oral formulations 
13 
Study Synopsis 
 
Design:  
This is a Phase 2, multicenter study in women with 
postpartum depression (PPD) consisting of 2 parts:  Open 
Label Part: multiple ascending dose open-label focused on 
safety and tolerability in 5 groups that differ by total daily 
dosing and formulation of study drug; and Double-blind 
Part is a double-blind placebo-controlled (DBPC) focused on 
safety, tolerability and efficacy in one group.  The Double-
blind Part will begin after the Open Label Part dosing is 
completed. The dosing, treatment duration and timing of 
evaluations for the double-blind portion of the study will be 
decided based on the results of the Open Label Part and 
recommendations of the Data Review Committee (DRC).  
The DRC is comprised of Marinus’ Chief Medical Officer 
and 2 external physician experts.   
Figures 1A and 1B depict the design for each subject group 
in the Open Label and Double-blind Parts, respectively. 
Reason for Change:  Clarification of study design 
13 
Study Synopsis 
Number of subjects (total and for each treatment arm):   
This is a Phase 2, multicenter study in women with 
postpartum depression (PPD) consisting of 2 dosing groups:  
an initial open-label safety group and a double-blind 
placebo-controlled group.  The open-label safety group will 
Number of subjects and dose regimen for each treatment 
arm:  
For Open Label Part, approximately 176 women 18 to 48 
years of age with PPD will be screened to enroll 


IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
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Page 95 of 131 
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be enrolled and dosing completed before proceeding to the 
double-blind group.  The goal of the open-label group is to 
explore the safety of oral ganaxolone in this population and 
identify a dosing regimen for the double-blind phase.    
For the open-label safety group approximately 48 women 18 
to 48 years of age with PPD will be screened to enroll 
approximately 24 patients.  During this open-label safety 
phase, for the first approximately 8 patients, ganaxolone will 
be titrated to a daily dose of 900 mg/day over 10 days, 
followed by a taper over 4 days.  This dosing group is called 
open-label 3 times daily (OL TID) group. For the next 
approximately 8 patients, ganaxolone will be administered at 
bedtime (QHS). For these patients ganaxolone will be 
titrated to a dose of 675 mg QHS over 4 days, which is then 
maintained until day 10, followed by a taper over 4 days. 
This dosing group is called OL QHS group. For the next 
approximately 8 patients of the open-label safety group, 
ganaxolone will be administered at a dose 675 mg QHS for 
28 days, followed by a taper over 4 days. This dosing group 
is called OL QHS 4-week dosing group. 
The investigator has the flexibility to adjust the dose if the 
patient experiences sedation, dizziness or other untoward 
effects in each dosing group. 
For the double-blind group, approximately 100 women with 
PPD 18 to 48 years of age will be screened to randomize 50 
women in a 1:1 ratio to receive ganaxolone or matching 
placebo for 14 days.  The dosing for the double-blind portion 
of the study will be decided based on the results of the open-
label portion and recommendations of the Data Review 
Committee (DRC).  The DRC is comprised of Marinus’ 
Chief Medical Officer and 2 external physician experts.  The 
total daily dose will not exceed 1200 mg.  Randomization 
will be stratified by the use of concomitant antidepressants 
so that the number of patients who are treated with 
antidepressants and who are not treated with antidepressants 
approximately 88 subjects.   
The first group (called OL TID) of approximately 8 subjects 
will receive oral ganaxolone (capsules) titrated to a daily 
dose of 900 mg/day over 10 days, followed by a taper over 4 
days.   
The second group (called OL QHS) of approximately 20 
subjects will receive oral ganaxolone (capsules) at bedtime 
(QHS), titrated to a dose of 675 mg QHS over 4 days, which 
is then maintained until day 10, followed by a taper over 4 
days.  
The third group (called OL QHS 4-week) of approximately 
20 subjects, oral ganaxolone (capsules) will be administered 
at a dose of 675 mg QHS for 28 days, followed by a taper 
over 4 days.  
The fourth group (called OL 1,125 mg group) of 
approximately 20 subjects will receive, on the first 2 days, 
oral ganaxolone capsules at a dose of 675 mg at 
approximately 7 pm (with dinner) and 675 mg at 10 pm; 
followed, by 26 days of ganaxolone 1,125 mg at dinner time; 
followed by a taper over 4 days. Approximately 6 subjects 
will participate in PK collection that requires an overnight 
stay on Day 1. 
The fifth group (called OL Bolus-Oral) of approximately 20 
subjects will receive ganaxolone starting with a single IV 
bolus 12 mg over 2 minutes at approximately 4 pm of Day 1; 
followed by ganaxolone oral suspension 750 mg at 6pm (with 
a fatty meal) and 750 mg at 10pm. On Day 2 subjects will 
receive ganaxolone oral suspension 750 mg at dinner time 
and 750 mg at bedtime, followed by 26 days of ganaxolone 
oral suspension 1,000 mg at dinner time, Treatment will be 
tapered over 4 days. Approximately 6 subjects will 
participate in PK collection that requires an overnight stay 
on Day 1. 
 


IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
Confidential 
Page 96 of 131 
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will be similar in each treatment group.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FIGURE 1A: Design of Open-Label Part 
 
For the double-blind placebo-controlled (DBPC) part, 
approximately 100 women with PPD 18 to 48 years of age will 
be screened to randomize 50 women in a 1:1 ratio to receive 
ganaxolone or matching placebo for 14 days.  The dosing, 
treatment duration and timing of evaluations for the double-
blind portion of the study will be decided based on the results of 
the Open Label Part and recommendations of the Data Review 
Committee (DRC).  The total daily dose will not exceed 1,600 
mg.  Randomization will be stratified by the use of concomitant 
OlTID 
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IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
Confidential 
Page 97 of 131 
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antidepressants so that the number of subjects who are treated 
with antidepressants and who are not treated with 
antidepressants will be similar in each treatment group.   
 
FIGURE 1B: Design of the Double-Blind Placebo-Controlled 
Part 
 
 
 
 
 
 
 
 
 
The investigator has the flexibility to adjust the dose and/or 
timing of the dose if the subject experiences sedation, dizziness 
or other untoward effects in each dosing group, by reducing the 
dose first to a lower level and possibly increasing it back again 
later if tolerance develops to the untoward effects (see section 
6.2.7). 
Reason for change:  Clarification of number of subjects and dose regimen for each treatment arm 
15 
Study Synopsis 
Objectives:  
Open-label safety group:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Objectives:  
Open-label Part: Safety, dosing, efficacy and 
pharmacokinetics:  
3. To assess the efficacy of ganaxolone using 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-
Severity and Improvement (CGI-S and CGI-I) scales. 
4. To collect samples of blood for pharmacokinetic (PK) 
analysis after administration of oral and IV ganaxolone 
to use in population-pharmacokinetics analyses, the 
results of which will be reported separately by the 
Sponsor.  
 
Screening 
2 wks 
DB 
dosing  
2wk
GNX 
n=25 
PLA 
n=25 
30 Day  
Follow-up 
Taper 
4 days 


IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
Confidential 
Page 98 of 131 
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Double-blind phase:  
 
 
The primary efficacy variable in this study is change from 
baseline in the HAMD17 total score on Day 10 between 
ganaxolone and matching placebo.  
Double-Blind placebo controlled (DBPC) Part:  Safety, 
efficacy, and pharmacokinetics: 
The primary efficacy variable in this study is change from 
baseline in the HAMD17 total score on Day 10 of the DBPC 
part between ganaxolone and matching placebo.  
Reason for change:  Clarification of study objectives 
15 
Study synopsis 
Investigational product, dose, and mode of administration:  
Ganaxolone oral capsule (225 mg/capsule) formulations and 
matching placebo will be used.   
Investigational product, dose, and mode of administration:  
Ganaxolone IV, oral suspension, and oral capsule 
(225 mg/capsule) formulations and matching placebo will be 
used.   
Reason for Change:  Addition of intravenous administration of Ganaxolone to study and clarification of oral formulations 
15 
Study synopsis 
 
4.1 – Inclusion criteria 
6. HAMD17 score of ≥ 20 but < 26 at screening 
7. HAMD17 ≥ 18 at the time of randomization (Day 1) 
6. HAMD17 score of ≥ 20 at screening rated by a certified 
site rater 
7. HAMD17 ≥ 18 on Day 1 prior to study drug 
administration  
Reason for change:  Clarification of exclusion criteria 
16 
Study synopsis 
Maximum duration of subject involvement in the study:  
Approximately 7 weeks for the OL TID and OL QHS groups 
and the double-blind phase. The duration for the OL QHS 4 
week group is approximately 18 weeks. 
Maximum duration of subject involvement in the study:  
Approximately 7 weeks for the OL TID and OL QHS groups 
and the DBPC part.  The duration for the OL QHS 4-week 
group is approximately 18 weeks and the duration for the OL 
1,125 mg and OL Bolus-oral groups is approximately 
12 weeks. 
Reason for change:  Addition of 2 treatment groups 
16 
Study synopsis 
Key variables: 
Safety:  Adverse events, vital signs, CSSRS, ECG, SSS, and 
physical examination. 
Efficacy:  Hamilton Depression Rating Scale (HAMD17), 
Edinburgh Postnatal Depression Scale (EPDS), Spielberger 
State-Trait Anxiety Inventory 6 item version (STAI6) and 
Key variables: 
Safety:  Adverse events, laboratory measures, vital signs, 
CSSRS, ECG, SSS, and physical examination. 
Efficacy:  HAMD17, EPDS, STAI6, CGI-I and CGI-S scales. 
 


IND No. 135256 
Protocol 1042-PPD-2003 
Page 
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Clinical Global Impression-Improvement (CGI-1) scale. 
Statistical Methods: Approximately continuous endpoints 
will be analyzed using a mixed model repeated measures 
(MMRM) analysis of covariance (ANCOV A) with fixed 
factors of treatment, visit, the treatment-by-visit interaction, 
and baseline value of the endpoint. Ordered categorical 
endpoints will be analyzed at each visit by the Cochran-
Mantel-Haenszel (CMH) row mean scores test using rank 
scores. Dichotomous categorical endpoints will be analyzed 
at each visit by Fisher's exact test. 
Marinus Phrumaceuticals, Inc. 
Version 5.0 / 22 Oct 2018 
Revised Text 
Pharmacokinetics: For the OL TID and OL QHS groups, a total 
of 5 srunples of blood will be collected to dete1mine ganaxolone 
plasma concentrations during the study. Srunples will be 
collected on 3 occasions during treatment with ganaxolone to 
dete1mine trough concentrations in plasma. An additional 2 
samples of blood will be collected at follow up visits, after 
ganaxolone treatment has been completed, to monitor the 
disappearance of ganaxolone following cessation of treatment. 
For the OL QHS 4-week, OL 1,125 mg, and OL Bolus-oral 
groups, 6 samples of blood will be collected to determine 
ganaxolone plasma concentrations during the study. Samples 
will be collected on 4 occasions during treatment in the OL 
QHS 4 weeks group and on 5 occasions during treatment in the 
OL 1,125 mg and OL Bolus-oral groups to determine 
ganaxolone trough concentrations in plasma. Two additional 
samples of blood will be collected in the first 2 follow up visits 
in the OL QHS 4 weeks group and 1 additional sample will 
be collected in the OL 1,125 mg, and OL Bolus-oral groups 
at the first follow up visit after ganaxolone treatment has be.en 
completed, to monitor the disapperu·ance of ganaxolone 
following cessation of treatment. 
Statistical Methods: Data will be presented by study part 
(OL, DBPC), dosing 01· treatment group within study parts 
and if applicable, study visit. Continuous variables ,vill be 
summarized as numbers of obse1·vations, means, measures 
of variance (e.g., standard deviation), and percentiles (e.g., 
median, minimum, maximum). Categorical va1iables will be 
summarized as numbers of obse1·vations and percentages. 
Analysis Populations: The Screened Set will consist of all 
subjects who have signed an informed consent. The 
Randomized Set will consist of subjects randomized in the 
DBPC part of the ti·ial. The Safety Set will consist of all 
subjects who received investigational product. (IP). The 
modified Intent to Treat (mITT) Set ,vill consist of all 
sub·ects in the DBPC a11 of the trial who received IP, and 
Page 99 of 131 


IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
Confidential 
Page 100 of 131 
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who have at least 1 post-baseline HAMD17 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. 
Efficacy Analysis:  Efficacy parameters will be summarized 
for both the OL and DBPC parts, but will be analyzed only 
for the DBPC part.  The primary time point of interest for 
all efficacy parameters will be Day 10 for the DBPC part 
and the visit at end of treatment (before initiation of taper) 
for the OL part.  The primary efficacy endpoint will be 
change from baseline in HAMD17 total score at Day 10 for 
the DBPC part and at the visit at end of treatment for the 
OL part.  The primary efficacy analysis will be done using 
the mITT set (DBPC group only), and the analytical method 
will be mixed model repeated measures (MMRM) with baseline 
HAMD17 total score as a covariate.  Significance will be 
tested at a two-sided 0.05 level. 
Secondary efficacy endpoints will be change from baseline in 
HAMD17 total score other than at the primary endpoint 
time point, 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, and 
CGI-Improvement.  
Reason for change:  Clarification and addition of key study variables 
22 
2.2.1. Objectives of the 
Open-label Safety Part 
 
 
 
 
 
 
 
 
 
2.2.1.3   Efficacy Objective 
To assess the efficacy of ganaxolone using 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-Severity and Improvement 
(CGI-S and CGI-I) scales.  
 
2.2.1.4   Pharmacokinetic Objective 


IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
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To collect samples of blood for pharmacokinetic (PK) 
analysis after administration of oral and IV ganaxolone to 
use in population-pharmacokinetics analyses, the results of 
which will be reported separately by the Sponsor. 
Reason for Change: Addition of efficacy and pharmacokinetic objectives in the Open-label Safety Part 
24 
3.1.  Study Design and 
Study Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For the open-label safety group approximately 48 women 18 
to 48 years of age with PPD will be screened to enroll 
approximately 24 patients.  During this open-label safety 
phase, for the first approximately 8 patients, ganaxolone will 
be titrated to a daily dose of 900 mg/day over 10 days, 
followed by a taper over 4 days.  This dosing group is called 
OL TID group.  
For the next approximately 8 patients of the open-label 
safety group, ganaxolone will be administered at bedtime 
(QHS). For these patients ganaxolone will be titrated to a 
QHS dose of 675 mg over 4 days which is then maintained 
until day 10, followed by a taper over 4 days. This dosing 
group is called OL QHS group 
The investigator has the flexibility to adjust the dose amount 
and/or timing of dosing if the subject experiences untoward 
effects during the OL part, by reducing the dose first to a 
lower level and possibly increasing it back again later if 
tolerance to the untoward effects develops. 
 
The open-label safety part will be enrolled, and dosing 
completed before proceeding to the double-blind part.  The 
goal of the open-label part is to explore safety of IV and oral 
ganaxolone in this population and identify a dosing regimen 
for the double-blind part. 
 
Open-label Part 
For the open-label safety part, approximately 172 women 18 to 
48 years of age with PPD will be screened to enroll 
approximately 88 subjects.  
In the first group with approximately 8 subjects, ganaxolone 
will be titrated to a daily dose of 900 mg/day over 10 days, 
followed by a taper over 4 days.  This dosing group is called OL 
TID group.  
The second group with approximately 20 subjects will receive 
ganaxolone administered at bedtime (QHS). For these subjects, 
ganaxolone will be titrated to a QHS dose of 675 mg over 4 
days which is then maintained until day 10, followed by a taper 
over 4 days. This dosing group is called OL QHS group 
The third group with approximately 20 subjects will receive 
ganaxolone administered at a dose 675 mg QHS for 28 days, 
followed by a taper over 4 days. This dosing group is called OL 
QHS 4-week dosing group. 
The fourth group with approximately 20 subjects will 


IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
Confidential 
Page 102 of 131 
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For the next approximately 8 patients of the open-label 
safety group, ganaxolone will be administered at a dose 675 
mg QHS for 28 days, followed by a taper over 4 days. This 
dosing group is called OL QHS 4-week dosing group. 
The investigator has the flexibility to adjust the dose if the 
patient experiences sedation, dizziness or other untoward 
effects during the OL phase.  
The open-label safety group will be enrolled, and dosing 
completed before proceeding to the double-blind group.  The 
goal of the open-label group is to explore safety of oral 
ganaxolone in this population and identify a dosing regimen 
for the double-blind phase.  
receive on the first 2 days ganaxolone capsules 675 mg at 
dinner time and 675 mg at bedtime (for a total of 1,350 mg 
per day on the first 2 days) followed by 26 days of 
ganaxolone capsules 1,125 mg at dinner time, followed by a 
taper over 4 days. This dosing group is called OL 1,125 mg 
group.  
The fifth group with approximately 20 subjects will receive 
ganaxolone as IV bolus 12 mg over 2 minutes at 
approximately 4 pm of the first day followed by ganaxolone 
oral suspension 750 mg at dinner time and 750 mg at 
bedtime for a total of 1,512 mg on Day 1. On Day 2, subjects 
will receive ganaxolone oral suspension 750 mg at dinner 
time and 750 mg at bedtime, for a total of 1,500 mg, followed 
by 26 days of ganaxolone oral suspension 1,000 mg at dinner 
time, followed by a taper over 4 days. This dosing group is 
called OL Bolus-oral group  
Reason for Change:  Clarification of study design and addition of 2 treatment groups 
25 
3.2.  Rationale for Study 
Design 
This study is intended to test whether ganaxolone is 
efficacious and safe in treatment of PPD.  
Various dose amounts, formulations, dosing schemes and 
treatment durations will be evaluated in the Open Label 
Part to inform the choice of the treatment scheme for the 
DBPC Part.  
Approximately 8 or 20 subjects, depending of the group, will 
receive open label ganaxolone to evaluate safety, tolerability, 
kinetics and efficacy of the drug in women diagnosed with 
PPD. Assessments of adverse events, laboratory and ECG, 
and clinical ratings for safety and efficacy will be gathered 
to evaluate the possible differential effect of the various 
dosing schemes.  
A double-blind evaluation of safety and efficacy will follow 
the completion of the open label groups.  This study part will 
utilize a randomized, parallel-group, placebo-controlled 
design in women diagnosed with PPD. Evaluations of safety 
and tolerability, as well as efficacy will utilize the same 
evaluation methods as in the open label part. The primary 
efficacy endpoint will be change from baseline in HAMD-17 
of active vs placebo treatments. The concomitant use of 
antidepressants or no use of antidepressants will be 
stratified 1:1 to enroll similar numbers of subjects in each 


IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
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stratum for both ganaxolone and placebo treatment groups. 
Reason for Change:  Clarification of the rationale for the study design 
26 
3.3.  Dose Selection 
Open-label QHS dosing group 
Approximately 8 patients will be allocated to the OL QHS 
group.  The enrollment for the OL QHS group will start after 
all patients allocated to the OL TID group have started their 
dosing.  
 
Open-label QHS 4-week dosing group 
Approximately 8 patients will be allocated to the OL QHS 4-
week dosing group.  The enrollment for the OL QHS 4-week 
group will start after all patients allocated to the OL QHS 
group have started their dosing.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Open-label QHS dosing group 
Approximately 20 subjects will be allocated to the OL QHS 
group.  The enrollment for the OL QHS group will start after all 
subjects allocated to the OL TID group have started their 
dosing.  
 
Open-label QHS 4-week dosing group 
Approximately 20 subjects will be allocated to the OL QHS 4-
week dosing group.  The enrollment for the OL QHS 4-week 
group will start after all subjects allocated to the OL QHS group 
have started their dosing.  
 
Open-label 1,125 mg dosing group  
The OL 1,125 mg dosing group is included in the open-label 
part to explore whether administering ganaxolone orally at 
doses up to 1,125 mg per day over 4 weeks (including 1,350 
in the first 2 days) are safe and well-tolerated and show 
sustained effects, and whether the therapeutic effects are 
maintained over a 6-week follow-up period.  
The two evening 675 mg oral doses, within 3 hours of each 
other on Day 1 are expected to provide mean Cmax plasma 
concentrations of approximately 250-300 ng/mL, which may 
be mildly sedating. Day 2 twin evening dosing is expected to 
lead to similar exposure. 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.  
Approximately 20 subjects will be allocated to the OL 1,125 
mg dosing group.  The enrollment for the OL 1,125 mg 
group will start after all subjects allocated to the OL QHS 4-
week group have started their dosing.  
Open-label Bolus-Oral dosing group  


IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
Confidential 
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The OL Bolus-Oral dosing group will explore whether 
administering ganaxolone IV bolus 12 mg followed by oral 
suspension dosing of up to 1,000 mg per day (including up to 
1,500 mg in the first 2 days) is safe and well-tolerated and 
shows sustained therapeutic effect over 4-weeks of dosing, 
and whether the therapeutic effects are maintained over a 6-
week follow-up period.  
This initial bolus infusion is targeted to provide a fast onset 
of antidepressant activity by delivery of rapid plasma 
exposures to ganaxolone. Together with the two evening 750 
mg oral doses, within 3 hours of each other, Day 1 dosing is 
expected to provide mean Cmax plasma concentrations of 
approximately 250-300 ng/mL, which may be mildly 
sedating. Day 2 twin evening dosing is expected to lead to 
similar exposure. In previous studies ganaxolone has been 
given up to a daily dose of 2,000 mg, and at single doses of 
1,000 mg. Based on the previous experience this dose is 
expected to be safe.  
 
Approximately 20 subjects will be allocated to the OL Bolus-
Oral dosing group.  The enrollment for the OL Bolus-Oral 
group will start after all subjects allocated to the OL 1,125 
mg group have started their dosing.  
Dose justification in context of previous experience with IV 
ganaxolone 
In Study 1042-0405, which was a Phase 1 study in healthy 
volunteers investigating the safety of IV ganaxolone, the 
highest bolus dose tested was 30 mg, which was infused over 
5-minutes (the same rate, 6 mg/min., as in the OL Bolus-
Oral group). This dose led to peak concentration levels 
(Cmax) of > 1,000 ng/mL with no safety concerns (except 
sedation).  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).  
 
Double-blind Placebo-controlled (DBPC) Part 


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Double-blind phase 
 
 
 
Blinding Scheme 
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). The 
placebo infusion and placebo capsules are identical to the 
ganaxolone infusion and 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 the double-blind 
part. Members of the DRC will be unblinded. All other 
study personnel, including persons involved in the 
evaluation of the study subjects (e.g. investigators, 
sub-investigators, and physicians/nurses), with the exception 
of the study pharmacist, will remain blinded at all times, 
except in case of an emergency.  Subjects will be blinded.   
 
Reason for Change:  Clarification of dose selection, update to number of subjects per treatment group and addition of 2 treatment groups and blinding scheme 
28 
3.4.  Study Duration 
For both the open-label safety OL TID and OL QHS groups, 
and the double-blind phase of the study the screening period 
will be up to 2 weeks, followed by a 14-day outpatient 
treatment period and a 14-day follow-up period. For the OL 
QHS 4-week dosing group the screening period will be up to 
2 weeks, followed by a 28-day outpatient treatment period, a 
4-day taper and a 3 month follow-up period.  
For both the open-label safety OL TID and OL QHS groups, and 
the double-blind part of the study, the screening period will be 
up to 2 weeks, followed by a 14-day outpatient treatment period 
and a 14-day follow-up period. For the OL QHS 4-week dosing 
group, the screening period will be up to 2 weeks, followed by a 
28-day outpatient treatment period, a 4-day taper and a 3-month 
follow-up period.  For the OL 1,125 mg and OL Bolus-Oral 
dosing groups, a screening period of up to 2 weeks will be 
followed by a 28-day outpatient treatment period, a 4-day 
taper, and a 6-week follow-up period (from Day 29). 
Reason for Change:  Addition of study duration for additional treatment groups 


IND No. 135256 
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Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
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29 
3.6.  Definition of 
Completion 
 
A dosing group is considered complete when the final 
subject in the group has completed the final protocol-defined 
assessment, including follow-up visits, for the group. 
Reason for Change:  Addition of the definition of completion 
32 
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. 
 
 
 
If the investigational product is discontinued, regardless of 
the reason, the evaluations listed for Day 10 for OL TID and 
OL QHS groups or Day 28 for the OL QHS 4-week group 
are to be performed as completely as possible.  Whenever 
possible, all discontinued subjects should also undergo the 
protocol-specified follow-ups.  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 electronic 
case report form (eCRF) and source documents. 
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 10 for OL TID and OL 
QHS groups or Day 29 for the OL QHS 4-week, OL 1,125 mg, 
and OL Bolus-Oral groups are to be performed as completely 
as possible.  Whenever possible, all discontinued subjects 
should also undergo the protocol-specified follow-ups.  
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 electronic case report form (eCRF) and source 
documents.  
Reason for Change:  Clarification of study discontinuation procedure and addition of 2 treatment groups 
34 
5.3 - Concomitant 
Psychological Treatment 
Concomitant psychological treatment refers to all 
psychological care the subject 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 received from the time of the screening visit 
through the end of the follow-up period.  Concomitant 
psychological treatment information must be recorded on the 
concomitant psychological treatments eCRF page. 
Reason for Change:  Clarification of period of concomitant psychological treatment 


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Protocol 1042-PPD-2003 
Page 
34 
Section, Title, 
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5.3.1.1 - Peimitted 
O1iginal Text 
The subject may continue their cul1'ent fo1m of 
Psychological Treatments 
psychological treatment (e.g, cognitive behavioral therapy, 
psychodynamic psychotherapy, supportive psychotherapy) 
throughout the treatment period. Initiation of a new therapy 
(a new treatment modality or switching a therapist) is 
prohibited during the treatment period. After the treatment 
period, psychotherapy should be continued using the same 
modality and at the same frequency as during the treatment 
period, provided that this is medically justified, in order to 
be able to dete1mine whether there ru·e sustained effects from 
the treatment the over the 30-day follow-up period. Any 
changes must be recorded on the concomitant psychological 
treatments eCRF a.0 e. 
3 7 
6.1.2 - Gana.xolone IV 
Infusion Solution 
Reason for Change: Addition of identity of intra.venous Ganaxolone infusion solution 
37 
6.1.3 - Gana.xolone Oral 
Suspension 
Reason for Change: Addition of identity of Ganaxolone oral suspension 
Confidential 
Marinus Phrumaceuticals, Inc. 
Version 5.0 / 22 Oct 2018 
Revised Text 
The subject may continue their cwTent form of psychological 
treatment (e.g., cognitive behavioral therapy, psychodynrunic 
psychotherapy, supportive psychotherapy) throughout the 
treatment period. Initiation of a new therapy (a new treatment 
modality or switching a therapist) is prohibited during the 
treatment period. After the treatment period, psychotherapy 
should be continued using the same modality and at the srune 
frequency as during the treatment period, provided that this is 
medically justified, in order to be able to detennine whether 
there are sustained effects from the treatment the over the 30-, 
42-, or 90-day follow-up periods. Any changes must be 
recorded on the conco1nitant psychological treatments eCRF 
a _e. 
IV solution 
Fo1mulation: 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 phannacy 
manual. 
Route of administration: IV 
Ve 1cle: The oral suspension contains ganaxolone (50 mg/mL), 
hydroxypropyl methylcellulose, polyvinyl 
alcohol, sodium la.wyl sulfate, simethicone, methylparaben, 
propylparaben, sodium benzoate, citric acid, and sodium citrate 
at pH 3.8 to 4.2, and is swe.etened with sucra.lose and flavored 
with artificial cheny. 
Fo1mulation: Oral suspension 
Strength: 50 mg/mL oral suspension; 110 mL in 125 mL high-
densi 
ol eth lene bottles 
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Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
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38 
6.2 – Administration of 
Investigational Product(s) 
All study medication will be stored at the research pharmacy 
prior to dispensing, or in a locked cabinet accessible only to 
members of the investigational research team.  Study 
medication oral capsules) should be stored at room 
temperature 15°C to 25°C (59°F to 77°F).   
Ganaxolone will be administered orally with food (breakfast, 
lunch, dinner, or snack).  Ganaxolone should be taken just 
before or together with a meal or snack and with 240 mL (8 
oz) of water.   
 
All study medication will be stored at the research pharmacy 
prior to dispensing, or in a locked cabinet accessible only to 
members of the investigational research team.  Ganaxolone 
capsules and ganaxolone oral suspension should be stored at 
room temperature 15°C to 25°C (59°F to 77°F).  Ganaxolone 
stock solution investigational product for IV administration 
will be stored at refrigerated temperature 2ºC to 8ºC (36ºF 
to 46ºF).  Oral IP should be taken within ±15 minutes of a 
fatty meal or snack (e.g., yogurt, nuts, avocado), and with 
240 mL (8 oz) of water.   
For the IV bolus, ganaxolone 12 mg in 24 mL will be 
administered over 2 minutes via an indwelling catheter, or a 
butterfly, inserted in a vein on the arm or hand.  The IP 
should be given as continuous infusion as instructed.  The 
catheter should be flushed with saline at the end of the bolus 
infusion.  For details please see pharmacy manual.  
Reason for Change:  Clarification of storage of oral formulations and addition of storage and administration of intravenous ganaxolone 
38 
6.2.1 – Allocation of 
Subjects to Treatment 
In the open-label phase the first approximately 8 patients 
will be assigned to OL TID dosing group. After 
approximately 8 patients have started dosing in the OL TID 
group the dosing for the OL QHS group will commence. 
Approximately eight patients will be dosed for the OL QHS 
group. After approximately 8 patients have started dosing in 
the OL QHS group, the enrollment into the OL QHS 4-week 
group will commence.  
In the open-label part, the first approximately 8 subjects will be 
assigned to OL TID dosing group. After approximately 8 
subjects have started dosing in the OL TID group the dosing for 
the OL QHS group will commence. Approximately 20 subjects 
will be dosed for the OL QHS group. After approximately 20 
subjects have started dosing in the OL QHS group, the 
enrollment into the OL QHS 4-week group will commence.  
After approximately 20 subjects have started dosing in the 
OL QHS 4-week group, enrollment into the OL 1,125 mg 
group will commence.  Approximately 20 subjects will be 
dosed for the OL 1,125 mg group.  After approximately 20 
subjects have started dosing in the OL 1,125 mg group, 
enrollment into the OL Bolus-Oral group will commence.  
Approximately 20 subjects will be dosed for the OL Bolus-
Oral group. 
Reason for Change:  Update of subject numbers in treatment groups and addition of 2 treatment groups to study 


IND No. 135256 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
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45 
6.2.5 – Dosing for the 
Open-label Treatment 
Part – OL 1,125 mg 
Group 
 
Subjects will start taking ganaxolone capsules, 675 mg 
(3 capsules) at dinner time (7 pm) followed by 675 
mg (3 capsules) at bedtime (HS) on Day 1 and Day 2 
followed by 1,125 mg (5 capsules) at dinner time (7 
pm) on the next 26 days (Day 3 through Day 28). A 4-
day taper will follow: 900 mg (4 capsules) on Day 29, 675 mg 
(3 capsules) on Day 30, 450 mg (2 capsules) on Day 31, and 
225 mg (1 capsule) on Day 32 (Table 4) all at dinner time. 
In addition to screening, there will be study visits on days 1, 
2, 8, 15, 22, 29, 36, 57, 71.  
Day 29 is the final visit before taper is started. The visit 
should occur in the morning of Day 29 before noon. 
All doses taken must be recorded in the eCRF.  
The study visits are intended to allow evaluation of the 
subject by the principal investigator and making dose and/or 
timing adjustments when necessary (see Section 6.2.7).  If 
there have been no adverse events the investigator should 
follow the dosing schedule.   
Oral ganaxolone should be taken within ±15 minutes of a 
fatty meal or snack (e.g., yogurt, nuts, avocado) and with 
240 mL (8 oz) of water.  
 
Table 4.  Study Drug Dosing Schedule – Open-label 
1,125 mg Group 
Visit 
V
2 
V
3 
 
V
4 
V
5 
V6 
V7 
 
Day 
1 
2 
3 
8 
15 
22 
29 
30 
31 
32 
Q7P
M 
67
5 
m
g 
6
7
5 
m
g 
1,
12
5 
m
g 
1,
12
5 
m
g 
1,
12
5 
m
g 
1,1
25 
mg 
900 
mg 
67
5 
m
g 
45
0 
m
g 
225 
mg 
QHS 
67
5 
m
6
7
5 
 
 
 
 
 
 
 
 


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Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
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g 
m
g 
Total  
1,
35
0 
m
g 
1
,
3
5
0 
m
g 
1,
12
5 
m
g 
1,
12
5 
m
g 
1,
12
5 
m
g 
1,1
25 
mg 
900 
mg 
67
5 
m
g 
45
0 
m
g 
225 
mg 
 
There will be total of 10 study visits for the OL 1,125 mg 
dosing group: Screening, Day 1, Day 2, Day 8, Day 15, Day 
22, Day 29 and 3 safety follow-up visits on Day 36, Day 57, 
and Day 71. 
Reason for Change:  Addition of dosing information for OL 1,125 mg Group 
46 
6.2.6 – Dosing for the 
Open-label Treatment 
Part – OL Bolus-Oral mg 
Group 
 
Dosing in the Bolus-Oral group will start with ganaxolone IV 
bolus 12 mg over 2 minutes at approximately 4 pm on Day 1. 
Subjects will start taking ganaxolone 750 mg oral suspension 
(15 mL at 50 mg per mL) at dinner time (7 pm) followed by 750 
mg oral suspension at bedtime (HS) on Day 1.  On Day 2, 
subjects will again take 750 mg oral suspension at dinner time 
(7 pm) followed by 750 mg at bedtime (HS).  For the following 
26 days (Day 3 through Day 28), subjects will take ganaxolone 
1,000 mg oral suspension (20 mL at 50 mg per mL) at dinner 
time (7 pm). A 4-day taper will follow: 750 mg (15 mL) on Day 
29, 500 mg (10 mL) on Day 30, 500 mg (10 mL) on Day 31, and 
250 mg (5 mL) on Day 32 (Table 5) all at dinner time.  
In addition to screening, there will be study visits on days 1, 2, 
8, 15, 22, 29, 36, 57, 71.  
Day 29 is the final visit before taper is started. The visit should 
occur in the morning of Day 29 before noon. 
All doses taken must be recorded in the eCRF. 
The study visits are intended to allow evaluation of the subject 
by the principal investigator and making dose and/or timing 
adjustments when necessary (see Section 6.2.7).  If there have 


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Marinus Pharmaceuticals, Inc. 
Protocol 1042-PPD-2003 
 
Version 5.0 / 22 Oct 2018 
 
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been no adverse events the investigator should follow the dosing 
schedule.   
Oral ganaxolone should be taken within ±15 minutes of a fatty 
meal or snack (e.g., yogurt, nuts, avocado) and with 240 mL 
(8 oz) of water.   
Table 5. Study Drug Dosing Schedule – Open-label Bolus-oral 
Group 
Vi
sit 
V2 
V
3 
 
V
4 
V
5 
V
6 
V
7 
 
 
 
Da
y 
1 
2 
3 
8 
15 
22 
29 
30 
31 
32 
4P
M 
12 
mg 
IV 
Bo
lus 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Q7
P
M 
75
0 
mg 
75
0 
m
g 
1,
00
0 
m
g 
1,
00
0 
m
g 
1,
00
0 
m
g 
1,
00
0 
m
g 
75
0 
m
g 
500 
mg 
50
0 
m
g 
25
0 
m
g 
Q
H
S 
75
0 
mg 
75
0 
m
g 
 
 
 
 
 
 
 
 
To
tal  
1,5
12 
mg 
1,
50
0 
m
g 
1,
00
0 
m
g 
1,
00
0 
m
g 
1,
00
0 
m
g 
1,
00
0 
m
g 
75
0 
m
g 
500 
mg 
50
0 
m
g 
25
0 
m
g 
 
There will be a total of 10 study visits for the OL Bolus-Oral 


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Protocol 1042-PPD-2003 
 
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dosing group: Screening, Day 1, Day 2, Day 8, Day 15, Day 
22, Day 29 and 3 safety follow-up visits on Day 36, Day 57, 
and Day 71. 
Reason for Change:  Addition of dosing information for OL Bolus-oral Group 
47 
6.2.7 – Dose Adjustments 
During Open-label 
 
Adjusting dose and/or timings for the OL 1,125 mg dosing 
group 
The investigator has the flexibility to adjust dose by 
reducing the dose to 450 mg (2 capsules) at the second of 
Day 1 doses (at HS) and/or at either of Day 2 doses, and/or 
reduce to 900 mg, 675 mg, or 450 mg on Day 3 through Day 
28 (at dinner time) if subject experiences sedation, dizziness 
or other untoward effects during the OL part. The 
investigator can also change the timing of the evening dose 
bringing it closer to bedtime and taking it with a fatty snack 
instead of dinner. Any further adjustments as well as 
adjusted taper period doses should be discussed with the 
medical monitor. The investigator may increase the dose 
back to default levels if tolerance develops to the untoward 
effects.  
Adjusting dose and/or timings for the OL Bolus-Oral dosing 
group  
The investigator has the flexibility to adjust dose by 
reducing the dose to 500 mg (10 mL) for the second of Day 1 
doses (at HS) and/or either of Day 2 doses, and/or reduce to 
750 mg (15 mL), or 500 mg (10 mL) at dinner time on Day 3 
through Day 28 if subject experiences sedation, dizziness or 
other untoward effects during the OL part. The investigator 
can also change the timing of the evening dose bringing it 
closer to bedtime and taking it with a fatty snack instead of 
dinner. Any further adjustments as well as adjusted taper 
period doses should be discussed with the medical monitor. 
The investigator may increase the dose back to default levels 
if tolerance develops to the untoward effects.  


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Protocol 1042-PPD-2003 
 
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Reason for Change:  Addition of dose adjustment information for the 2 new treatment groups 
48 
6.3.2 – Packaging and 
Dispensing the Study 
Drug 
Detailed instructions when to take the medication and a 
reminder to take the study medication with food (just before 
or with a meal or snack) and with 240 mL (8 oz) of water 
will be provided to the patient. 
Detailed instructions on when to take the medication and a 
reminder to take oral study medication within ±15 minutes of a 
fatty meal or snack (e.g., fatty yogurt, nuts, avocado) and 
with 240 mL (8 oz) of water, will be provided to the subject. 
Reason for Change:  Clarification of instructions for taking the study drug 
49 
6.3.3 – Storage 
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 (15oC to 
25oC).  
The ganaxolone stock solution investigational product for 
the IV administration will be stored at refrigerated 
temperature 2ºC to 8ºC (36ºF to 46ºF).   
The 0.3-micron ganaxolone capsules (225 mg), oral 
suspension, and matching placebos are stored in HDPE bottles 
with a foil induction seal and child resistant closure at room 
temperature (15oC to 25oC; 60ºF to 75ºF).  
Reason for Change:  Addition of storage instructions for IV Ganaxolone 
50 
6.5 – Drug Administration 
Oral doses of ganaxolone should be taken with food just 
before or with a meal or snack and with 240 mL (8 oz) of 
water at home.   
 
 
 
 
 
 
 
 
 
 
The patient 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 patient is participating in 
the trial. 
Oral doses of the IP should be taken within ±15 minutes of a 
fatty meal or snack (e.g., fatty yogurt, nuts, avocado), and with 
240 mL (8 oz) of water.   
For the IV bolus, ganaxolone 12 mg in 24 mL will be 
administered over 2 minutes via an indwelling catheter, or a 
butterfly, inserted in a vein on the arm or hand.  The IP 
should be given as continuous infusion as instructed.  The 
catheter should be flushed with saline at the end of the bolus 
infusion. For details please see pharmacy manual.  
 
The subject 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, including for subjects who may stay overnight on the 
unit as part of the screening process and/or the PK 
subgroup. 
Reason for Change:  Addition of information for IV ganaxolone administration and clarification of subjects who require support during the trial 


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Protocol 1042-PPD-2003 
 
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 51 
7 – Study Procedures 
For the open-label safety group approximately 48 women 18 
to 48 years of age with PPD will be screened to enroll 
approximately 24 patients.  During this open-label safety 
phase, for the first approximately 8 subjects, ganaxolone will 
be titrated to a daily dose of 900 mg/day over 10 days, 
followed by a taper over 4 days.  This dosing group is called 
OL TID group.  
For the next approximately 8 subjects, ganaxolone will be 
administered at bedtime (QHS). For these subjects 
ganaxolone will be titrated to a QHS dose of 675 mg over 4 
days which is then maintained until day 10, followed by a 
taper over 4 days. This dosing group is called OL QHS 
group. 
For the next approximately 8 subjects, ganaxolone will be 
administered at bedtime (QHS). For these subjects 
ganaxolone treatment will be a QHS dose of 675 mg over 28 
days, followed by a taper over 4 days. This dosing group is 
called OL QHS 4-week group. 
The investigator has the flexibility to adjust the dose if the 
patient experiences sedation, dizziness or other untoward 
effects during the OL phase.  
 
 
 
 
 
 
 
 
 
 
For the open-label safety part approximately 172 women 18 to 
48 years of age with PPD will be screened to enroll 
approximately 88 subjects.  During this open-label safety part, 
for the first approximately 8 subjects, ganaxolone will be titrated 
to a daily dose of 900 mg/day over 10 days, followed by a taper 
over 4 days.  This dosing group is called OL TID group.  
For the next approximately 20 subjects, ganaxolone will be 
administered at bedtime (QHS). For these subjects ganaxolone 
will be titrated to a QHS dose of 675 mg over 4 days which is 
then maintained until day 10, followed by a taper over 4 days. 
This dosing group is called OL QHS group. 
For the next approximately 20 subjects, ganaxolone will be 
administered at bedtime (QHS). For these subjects ganaxolone 
treatment will be a QHS dose of 675 mg over 28 days, followed 
by a taper over 4 days. This dosing group is called OL QHS 4-
week group. 
The next approximately 20 subjects of the open-label safety 
part will receive on the first 2 days ganaxolone capsules 675 
mg at dinner time and 675 mg at bedtime (for a total of 
1,350 mg per day on the first 2 days) followed by 26 days of 
ganaxolone capsules 1,125 mg at dinner time, followed by a 
taper over 4 days. This dosing group is called OL 1,125 mg 
group.  
For the next approximately 20 subjects of the open-label 
safety part, ganaxolone will be administered as IV bolus 12 
mg over 2 minutes at approximately 4 pm on Day 1 followed 
by ganaxolone oral suspension 750 mg at dinner time and 
750 mg at bedtime, for a total of 1,512 mg on the first day. 
On Day 2 subjects will receive ganaxolone oral suspension 
750 mg at dinner time and at 750 mg at bedtime, for a total 
of 1,500 mg, followed by 26 days of ganaxolone oral 
suspension 1000 mg at dinner time, followed by a taper over 
4 days. This dosing group is called OL Bolus-Oral group. 
The investigator has the flexibility to adjust the dose and/or 
timing of the dose if the subject experiences sedation, 


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Protocol 1042-PPD-2003 
 
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The open-label safety group will be enrolled, and dosing 
completed before proceeding to the double-blind group.  The 
goal of the open-label group is to explore safety of oral 
ganaxolone in this population and identify a dosing regimen 
for the double-blind phase.  
For the double-blind group, approximately 100 women with 
PPD 18 to 48 years of age will be screened to randomize 50 
women in a 1:1 ratio to receive ganaxolone or matching 
placebo for 14 days.  The dosing for the double-blind portion 
of the study will be decided based on the results of the open-
label portion and recommendations of the DRC.  The DRC 
is comprised of Marinus’ Chief Medical Officer and 2 
external physician experts.  The daily dose will not exceed 
1200 mg.  Randomization will be stratified by the use of 
concomitant antidepressants so that the number of patients 
who are treated with antidepressants and who are not treated 
with antidepressants will be similar in each treatment group. 
dizziness or other untoward effects during the OL part (see 
Section 6.2.7).  
The open-label safety part will be enrolled, and dosing 
completed before proceeding to the double-blind part.  The goal 
of the open-label part is to explore safety of IV and oral 
ganaxolone in this population and identify a dosing regimen for 
the double-blind part. 
For the double-blind part, approximately 100 women with PPD 
18 to 48 years of age will be screened to randomize 50 women 
in a 1:1 ratio to receive ganaxolone or matching placebo for 
14 days.  The dosing for the double-blind portion of the study 
will be decided based on the results of the open-label portion 
and recommendations of the DRC.  The DRC is comprised of 
Marinus’ Chief Medical Officer and 2 external physician 
experts.  The daily dose will not exceed 1,600 mg.  
Randomization will be stratified by the use of concomitant 
antidepressants so that the number of subjects who are treated 
with antidepressants and who are not treated with 
antidepressants will be similar in each treatment group. 
Reason for Change:  Update to the number of subjects in each treatment group and maximum daily dose, and addition of 2 new treatment groups 
51 
7 – Study Procedures 
 
Collect urine drug screen and urine pregnancy test  
 
Collect urine for urinalysis, urine drug screen and urine 
pregnancy test  
Reason for Change:  Clarification of urinalysis procedure 


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60 
7.7 – Screening Period 
(Day -14 to -1) for OL 
1,125 mg and OL 
Bolus-oral Groups 
 
7.7  Screening Period (Day -14 to -1) for OL 1,125 mg and 
OL Bolus-oral Groups 
7.7.1  Screening Visit (Visit 1) 
 
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 
7.0 (MINI 7.0)   
 
Conduct HAMD17 interview (if a HAMD17 interview 
was conducted for Marinus PPD study 1042-PPD-2002 
at the same investigative site within 2 weeks of the 
screening visit the screening HAMD17 interview does 
not have to be repeated).  
 
Perform EPDS 
 
Perform STAI6 
 
Perform a physical examination  
 
Collect vital signs (blood pressure [BP], pulse, 
temperature, respiratory rate [RR]) 
 
Collect ECG 
 
Collect urine for urinalysis, urine 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 
investigational site must wait for the results of the 
SAFER interview before enrolling the subject into the 
treatment phase of the study (if a SAFER interview was 
conducted within 2 weeks for Marinus PPD study 1042-


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Protocol 1042-PPD-2003 
 
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PPD-2002 at the same investigative site the SAFER 
interview does not have to be repeated. In this instance 
the HAMD17 score from the SAFER interview can be 
used to qualify the subject for the study).  
 
Screening period may be extended to 21 days with 
approval from the medical monitor (e.g., a laboratory 
sample was hemolyzed and had to be repeated causing a 
delay). 
Reason for Change:  Addition of screening period information for new treatment groups 
60 
7.8 – Treatment Period 
(Day 1 to Day 29; Visits 2 
to 7) for OL 1,125 mg and 
OL Bolus-oral Groups 
 
7.8  Treatment Period (Day ! to Day 29; Visits 2 to 7) for OL 
1,125 mg and OL Bolus-oral Groups) 
7.8.1  Start of the Open-label Safety Period (Enrollment 
Visit for the OL 1,125 mg and OL Bolus-oral Groups) 
(Day 1) 
 
The subject arrives in the clinic to complete baseline 
assessments on Day 1.  
 
CTNI to conduct HAMD17 interview 
 
Perform EPDS 
 
Perform STAI6 
 
Assess CGI-S 
 
Review concomitant medications and therapies  
 
Collect vital signs (BP, pulse, temperature, RR)  
 
Measure weight  
 
Collect ECG 
 
Collect urine for urinalysis, urine drug screen and urine 
pregnancy test 
 
Collect safety laboratory tests 
 
Collect neurosteroid level 
 
Collect SSS 
 
Collect AEs 
 
Conduct CSSRS interview  
 
Review inclusion and exclusion criteria (including 
hematology, chemistry, urinalysis, urine drug screen 
and pregnancy tests from the screening visit); HAMD17 
(as determined by CTNI) must be ≥ 18 for enrollment. 
 
If the subject continues to meet the inclusion criteria 


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and has not developed any exclusion criteria the subject 
will be enrolled in the study  
 
Dispense medication bottle after enrollment. Provide the 
subject with dosing instructions and subject diary 
completion. 
 
For the OL 1,125 mg group: the subject will be 
instructed to take the first oral doses of the study 
medication that evening (675 mg [3 capsules] at dinner 
time [at 7 pm] and at bedtime [at 10 pm])  
 
For the OL Bolus-Oral group: the subject will receive 
IV bolus 12 mg over 2 minutes at approximately 4 pm 
(preferably ±1 hour) while on the unit, be observed for 
development of sedation and/or other untoward effects 
for at least 1 hour post-bolus and then be discharged 
and instructed to take the first oral doses of the study 
medication that evening (750 mg [15 mL oral suspension 
at 50 mg per mL] at dinner time [at 7 pm] and at 
bedtime [at 10 pm])  
 
Oral IP should be taken within ±15 minutes of a fatty 
meal or snack (e.g., yogurt, nuts, avocado), and with 240 
mL (8 oz) of water.   
 
A sub-group of 6 subjects (to be called ‘PK sub-group’, 
Section 7.10.7) in each of the OL 1,125 mg and OL 
Bolus-Oral groups will stay overnight on the unit 
between Day 1 and Day 2 to undergo comprehensive PK 
assessment as follows: for the OL 1,125 mg group 
plasma samples for PK analysis will be drawn at the 
following times after the first oral dose on Day 1 (i.e., the 
675 mg oral capsules dose at 7 pm at dinner time; 0hr): 
+1hr, +2hr, +3hr (i.e., just prior to the 10 pm 675 mg 
dose), at +4hr, +5hr, +6hr, and at 8 am on Day 2. For 
the OL Bolus-Oral group plasma samples for PK 
analyses will be drawn at the following times after the 
IV bolus on Day 1 (e.g., the 12 mg IV bolus at 4 pm; 
0hr): +1hr, +2hr, +3hr (i.e., just prior to the first oral 
dose of 750 mg oral suspension at dinner time), at +4hr, 
+5hr, +6hr (i.e., just prior to the second 750 mg oral 
suspension evening dose), at + 7hr, +8hr, and at 8 am on 


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Day 2. 
 
If the subject is breastfeeding, she is encouraged to 
“pump and dump” during the study period and for 45 
days after the last dose.  She should be provided with a 
breast pump if she does not have one.  Breast feeding is 
prohibited during the treatment phase and until 45 days 
following the last dose of the study drug.  
7.8.2  Treatment Visits (Days 2, 8, 15, 22, 29 ± 3 days [except 
Day 2]) for OL 1,125 mg and OL Bolus-oral Groups 
 
CTNI to conduct interview for HAMD17  
 
Conduct interview for CGI-I  
 
EPDS  
 
STAI6  
 
Collect AEs 
 
Collect ECG (Day 2, Day 8, Day 15, Day 29) 
 
Collect vital signs (BP, pulse, RR, temperature)  
 
Measure weight (Day 15, Day 29) 
 
Collect SSS  
 
Collect a PK sample  
 
Record concomitant medications  
 
Collect safety laboratory tests (Day 15, Day 29) 
 
Collect neurosteroid level (Day 2, Day 8, Day 15, Day 
29) 
 
Collect urine for urinalysis, urine drug screen and urine 
pregnancy test (Day 8, Day 15, Day 22, Day 29) 
 
Conduct CSSRS interview  
 
Perform a physical examination (Day 29) 
 
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.  
 
For the OL 1,125 mg group: the subject will be 
instructed to take Day 2 oral doses of the study 
medication that evening (675 mg [3 capsules] at dinner 
time [at 7 pm] and 675 mg [3 capsules] at bedtime [at 10 
pm]) followed by 26 days of 1,125 mg (5 capsules) at 
dinner time 


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 
For the OL Bolus-Oral group: the subject will be 
instructed to take Day 2 oral doses of the study 
medication that evening (750 mg [15 mL oral suspension 
at 50 mg per mL] at dinner time [at 7 pm] and 750 mg 
[15 mL oral suspension at 50 mg per mL] at bedtime [at 
10 pm]) followed by 26 days of 1,000 mg (20 mL oral 
suspension at 50 mg per mL) at dinner time 
 
Oral IP should be taken within ±15 minutes of a fatty 
meal or snack (e.g., yogurt, nuts, avocado), and with 240 
mL (8 oz) of water.   
 
During Visit 7 (Day 29) start study drug taper (Day 29-
32) (See Sections 6.2.5 and 6.2.6) 
Reason for Change:  Addition of treatment period information for new treatment groups 
63 
7.9 - Follow-up Visit 1 
(Day 36 ± 3), Follow-up 
Visit 2 (Day 57 ± 3), and 
Follow-up Visit 3 (Day 
71 ± 3) for the OL 1,125 
mg and OL Bolus-Oral 
groups 
 
7.9 – Follow-up Visit 1 (Day 36 ± 3), Follow-up Visit 2 (Day 
57 ± 3), and Follow-up Visit 3 (Day 71 ± 3) for the OL 
1,125 mg and OL Bolus-Oral Groups 
 
The Follow-up Visit 1 should occur about 1 week after D29 
visit, and about 4 days after the subject has taken her last 
dose of the study medication.  The Follow-up Visit 2 should 
occur approximately 21 days after Follow-up Visit 1. The 
Follow-up Visit 3 should occur approximately 14 days after 
Follow-up Visit 2 (All Follow-up visits should be scheduled 
within visit window unless there is a medical need to see 
the subject sooner; an additional safety visit can be 
scheduled as per the investigator’s discretion). 
 
CTNI to conduct interview for HAMD17  
 
Conduct interview for CGI-I  
 
Perform EPDS 
 
Perform STAI6 
 
Review concomitant medications and therapies  
 
Collect vital signs (BP, pulse, temperature, RR) 
 
ECG (Follow-up Visit 1 only) 
 
Collect safety laboratory tests (Follow-up Visit 1 and 3 
only) 
 
Collect neurosteroid level (Follow-up Visit 1 and 3 only)  
 
Collect PK sample (Follow-up Visit 1 only) 
 
Collect urine for urinalysis, urine drug screen and urine 


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Protocol 1042-PPD-2003 
 
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pregnancy test  
 
Measure weight (Follow-up Visit 3 only) 
 
Conduct CSSRS interview 
 
Collect SSS 
 
Collect AEs  
 
Collect study medication bottle dispensed at Day 29 
(Follow-up Visit 1 only).  Review subject dosing diary and 
complete drug accountability while subject is present.  
Table 8.  Schedule of Assessments for the Open-label OL 
1,125 mg and OL Bolusoral Groups 
VISIT 
Scr
een
ing 
(V1
) 
D
ay
1  
(V
2) 
D
ay
2  
(V
3) 
Day
8 
±3d 
(V4) 
D15 
±3d 
(V5
) 
Day
22 
±3d 
(V6
)  
Day
29 
±3d 
(V7
) 
Day3
6 ±3d 
(V8; 
1st 
FU) 
Day
57 
±3d 
(V9; 
2nd 
FU) 
Day7
1 
±3d 
(V10
; 3rd 
FU) 
Informed 
X 
 
 
 
 
 
 
 
 
 
Demographics,  X 
 
 
 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclu X X  
 
 
 
 
 
 
 
Dispense 
medication / 
 
X X X 
X 
X 
X 
X 
 
 
Concomitant 
Medications 
X X X X 
X 
X 
X 
X 
X 
X 
Physical 
X 
 
 
 
 
 
X 
 
 
 
SAFER 
X 
 
 
 
 
 
 
 
 
 
Vital signs 
X X X X 
X 
X 
X 
X 
X 
X 
Height 
X X  
 
X 
 
X 
 
 
X 
ECGs 
X X X X 
X 
 
X 
X 
 
 
Safety 
X X  
 
X 
 
X 
X 
 
X 
b Bolus (OL 
 
X  
 
 
 
 
 
 
 
PK sample 
 
 X X 
X 
X 
X 
X 
 
 
PK subgroup 
sample 
collection 
 
c X  
 
 
 
 
 
 
 


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Neurosteroid 
 
X X X 
X 
 
X 
 X 
 
X 
Urinalysis, 
X X  
X 
X 
X 
X 
X 
X 
X 
Record AEs  
 
X X X 
X 
X 
X 
X 
X 
X 
a HAMD17 
X X X X 
X 
X 
X 
X 
X 
X 
CGI-I 
 
 X X 
X 
X 
X 
X 
X 
X 
CGI-S 
X X  
 
 
 
 
 
 
 
EPDS 
X X X X 
X 
X 
X 
X 
X 
X 
STAI6 
X X X X 
X 
X 
X 
X 
X 
X 
CSSRS 
X X X X 
X 
X 
X 
X 
X 
X 
SSS 
 
X X X 
X 
X 
X 
X 
X 
X 
Start Taper 
 
 
 
 
 
 
X 
 
 
 
a CTNI will conduct all HAMD ratings except the one at screening 
b IV bolus is to be done at approximately 4 pm (preferably within ±1 hour) and 
allowing for at least 1-hour post-bolus follow-up at the site before discharge 
c A sub-group of 6 subjects (to be called ‘PK sub-group’) in each of the OL 
1,125 mg and OL Bolus-Oral groups will stay overnight on the unit between 
Day 1 and Day 2 to undergo comprehensive PK assessment as follows: for the 
OL 1,125 mg group plasma samples for PK analysis will be drawn at the 
following times after the first oral dose on Day 1 (e.g., the 675 mg oral 
capsules dose at 7 pm at dinner time; 0hr): +1hr, +2hr, +3hr (i.e., just prior to 
the 10 pm 675 mg dose), at +4hr, +5hr, +6hr, and at 8 am on Day 2. For the 
OL Bolus-Oral group plasma samples for PK analyses will be drawn at the 
following times after the IV bolus on Day 1 (e.g., the 12 mg IV bolus at 4 pm; 
0hr): +1hr, +2hr, +3hr (i.e., just prior to the first oral dose of 750 mg oral 
suspension at dinner time), at +4hr, +5hr, +6hr (i.e., just prior to the second 
750 mg oral suspension evening dose), at + 7hr, +8hr, and at 8 am on Day 2. 
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 10) 
neurosteroid sample 11) PK sample 12) urinalysis, urine drug screen and 
pregnancy test 13) physical examination.  SAFER interview is scheduled if 
subject meets the eligibility criteria at the Screening visit.  The SAFER 
interview will be conducted during the screening period.  The investigational 
site must wait for the results of the SAFER interview before enrolling the 
subject into the treatment phase of the study. Screening period may be 
extended to 21 days with approval from the medical monitor.   
 
 
 
 
 


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Reason for Change:  Addition of follow-up period information for new treatment groups 
66 
7.10.4 – Prior Medication, 
Concomitant Medication 
and Concomitant Therapy 
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 mediations taken 
since the last visit.   
The type of psychological counseling the subject is receiving 
at the time of screening will be recorded on the Concomitant 
Psychological Treatment eCRF page.  
At screening, prospective subjects will be asked about 
medications they have taken in the previous 60 days, including 
prescription medications, non-prescription medications, herbal 
medications, vitamins, and supplements.  At subsequent visits, 
the subjects will be asked about medications taken since the last 
visit.   
The type of psychological counseling the subject received from 
the time of screening through the last follow-up visit will be 
recorded on the Concomitant Psychological Treatment eCRF 
page.  
Reason for Change:  Clarification of concomitant medications and time period for follow-up 
66 
7.10.5 - Physical 
Examination 
A complete physical examination will be performed at 
screening and at Day 10 visit (Day 29 for OL QHS 4 week 
group).  
A complete physical examination will be performed at screening 
and at Day 10 visit (Day 29 for OL QHS 4 week, OL 1,125 mg 
and OL Bolus-Oral groups).  
Reason for Change:  Addition of 2 new treatment groups 
70 
7.10.6.7 – SAFER 
Interview 
 
CTNI will also perform all HAMD ratings except the one 
done at screening. 
Reason for Change:  Clarification of SAFER interview for study 
70 
7.10.7 – Pharmacokinetic 
Sampling 
 
A sub-group of 6 subjects (to be called ‘PK sub-group’) in 
each of the OL 1,125 mg and OL Bolus-Oral groups will stay 
overnight on the unit between Day 1 and Day 2 to undergo 
comprehensive PK assessment as follows: for the OL 1,125 
mg group plasma samples for PK analysis will be drawn at 
the following times after the first oral dose on Day 1 (i.e., the 
675 mg oral capsules dose at 7 pm at dinner time; 0hr): 
+1hr, +2hr, +3hr (i.e., just prior to the 10 pm 675 mg dose), 
at +4hr, +5hr, +6hr, and at 8 am on Day 2. For the OL 
Bolus-Oral group plasma samples for PK analyses will be 
drawn at the following times after the IV bolus on Day 1 
(e.g., the 12 mg IV bolus at 4 pm; 0hr): +1hr, +2hr, +3hr 
(i.e., just prior to the first oral dose of 750 mg oral 
suspension at dinner time), at +4hr, +5hr, +6hr (i.e., just 
prior to the second 750 mg oral suspension evening dose), at 
+ 7hr, +8hr, and at 8 am on Day 2. 


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Protocol 1042-PPD-2003 
 
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The first 6 consecutively enrolled subjects who are in units 
with overnight inpatient capabilities and who consent for 
inclusion in the PK subgroup will be included in the PK 
subgroup. 
Reason for Change:  Addition of PK sub-group from the additional treatment groups 
71 
7.10.9 – Volume of Blood 
to be Drawn from Each 
Subject 
Table 7. Volume of Blood to Be Drawn from Each Subject 
for the OL QHS  4 Week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 10. 
Volume of Blood to Be Drawn from Each 
Subject for the OL QHS  4 Week, OL 1,125 mg, and OL 
Bolus-Oral groups 
 
Table 11.  
Volume of Blood to be Drawn from Each 
Subject for the PK Subgroup of OL 1,125 mg Group 
Assessment 
Approxima
te Sample 
Volume 
(mL)a 
Number of 
Samples 
Approxima
te Total 
Volume 
(mL) 
Pharmacoki
netic 
samples 
4 
12 
48 
Safety 
hematology  
3 
6 
18 
Safety 
chemistry 
7 
6 
42 
Neurosteroi
d level 
4 
7 
28 
Total mL 
 
 
136 
 
Table 12.  
Volume of Blood to be Drawn from Each 
Subject for the PK Subgroup of OL Bolus-oral Group 
Assessment 
Approxima
te Sample 
Volume 
(mL)a 
Number of 
Samples 
Approxima
te Total 
Volume 
(mL) 
Pharmacoki
netic 
samples 
4 
14 
56 


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During this study, approximately 58 mL of blood will be 
drawn from all subjects during the study for the OL TID,OL 
QHS and Double-blind groups. Approximately 112 mL of 
blood will be drawn from all subjects during the study for 
the OL QHS 4 week group. 
 
 
 
 
 
 
 
Safety 
hematology  
3 
6 
18 
Safety 
chemistry 
7 
6 
42 
Neurosteroi
d level 
4 
7 
28 
Total mL 
 
 
144 
 
During this study, approximately 58 mL of blood will be drawn 
from all subjects during the study for the OL TID, OL QHS and 
Double-blind groups. Approximately 112 mL of blood will be 
drawn from all subjects during the study for the OL QHS 4 
week, OL 1,125 mg, and OL Bolus-Oral groups. 
Subjects in the ‘PK subgroup’ of the OL 1,125 mg and OL 
Bolus-Oral groups (6 subjects in each subgroup) will have 
additional 6 and 8 samples, respectively, at 4 mL each, for a 
total of approximately 136 mL and 144 mL of blood drawn, 
respectively.  
Reason for Change:  Addition of 2 treatment groups 


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78 
9.3 -  Statistical Analysis 
Plan 
The SAP will be finalized prior to completion of the double-
blind phase to preserve the integrity of the statistical analysis 
and study conclusions.  
The SAP will be finalized prior to database lock and/or 
unblinding of any portion of the trial to preserve the integrity 
of the statistical analysis and study conclusions.  
Reason for Change:  Clarification of SAP finalization 
78 
9.3.1 – Data Review 
Committee (DRC) and 
Recommendations for 
Dosing 
Marinus may decide to stop the study, or make the data 
public, after completion of the open-label group or the 
double-blind phase of the study. 
Marinus may decide to stop the study, or make the data public 
at any time during the open-label portion of the trial or after 
completion of the double-blind part of the study. 
Reason for Change:  Clarification of study stopping procedures 
79 
9.3.2 – Justification for 
Sample Size 
A sample size of 20 patients per group would be needed to 
detect a 3.5 point difference on the HAMD17 scale assuming 
standard deviation of 3.5 with power=86%, alpha=0.05, and 
2-sided t-test.  A sample size of 20 patients per group would 
be needed to detect a 5 point difference on the HAMD17 
scale assuming standard deviation of 3.5 with power=99%, 
alpha=0.05, and 2-sided t-test.  In a recent study by Hantsoo 
et al., (2014) sertraline was shown to be effective in 
treatment of PPD over 6 weeks of treatment (n=27; subset of 
women with strictly defined PPD).  The separation between 
sertraline and placebo was 7.8 points at the study end-point.  
Standard deviations were 2.8 and 3.9 for the placebo and 
sertraline groups, respectively. 
With a sample size of 50 subjects/group, the DBPC part of 
the trial will be able to detect a medium effect size (per 
Cohen’s d) with 93% power using a two-sided significance 
level of 0.05.   
Reason for Change:  Clarification of justification for sample size 
79 
9.3.3 – Study Population 
 
 
 
The modified Intent to Treat Set (mITT) will consist of all 
subjects in the Safety Set who have at least 1 post-
enrollment HAMD17 assessment.  The mITT set will be 
used for all efficacy assessments.  
The Randomized Set will consist of subjects randomized in the 
DBPC part of the trial. 
The modified Intent to Treat Set (mITT) will consist of all 
subjects in the DBPC part of the trial who received IP and 
who have at least 1 post-baseline HAMD17 assessment.  The 
mITT set will be the primary efficacy population for the 
DBPC part of the trial.  
Reason for Change:  Addition of definition of randomized set and clarification of mITT set 


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Protocol 1042-PPD-2003 
 
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79 
9.4 – Analysis Methods 
 
Data will be presented by study part (OL, DBPC), dosing or 
treatment group within study part and, if applicable, study visit. 
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. 
Reason for Change:  Addition of analysis  methods 
79 
9.4.1 – Demographic and 
Baseline Characteristics 
Descriptive summaries of demographic and baseline 
characteristics as well as subject disposition will be 
presented by study phase (open-label safety group, double-
blind phase) and by treatment within the double-blind phase. 
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. 
Baseline characteristics will include a summary of the 
following: 
 
Subject demographics 
 
Pre-existing medical conditions 
 
Prior therapies 
 
Medical history 
Reason for Change:  Clarification of analysis method 
80 
9.4.2 – Subject 
Disposition 
 
Frequencies and percentages of subjects who discontinued 
the study and reasons for discontinuation will be 
summarized. 
Reason for Change:  Clarification of analysis method 
80 
9.4.3 – Investigational 
Medicinal Product 
Summary statistics for the duration of exposure to 
investigational medicinal product, will be presented by study 
phase and by treatment group. 
Overall exposure to IP, such as duration of exposure, as well 
as dose adjustments (i.e, deviations from the scheduled 
titration scheme) will be summarized. 
Reason for Change:  Clarification of analysis method 


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Protocol 1042-PPD-2003 
 
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80 
9.4.4 – Concomitant 
Medication 
Concomitant medications will be listed and summarized by 
preferred drug name by study phase and treatment group. 
Concomitant medications will be coded using the World 
Health Organization Drug Dictionary (WHO-DD) and will 
be summarized by drug class and preferred drug name. 
Reason for Change:  Clarification of analysis method 
80 
9.4.5 – 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 relatedness for the open-label 
safety group and double-blind phase.  SAEs and AEs leading 
to discontinuation of the study drug will be summarized by 
study phase (open-label safety group and double-blind 
phase) and treatment group.  
The absolute values and change from baseline in laboratory 
tests, vital signs, SSS, ECGs, and CSSRS will be 
summarized by study phase (open-label safety group and 
double-blind phase) and treatment group.  
Dose adjustments (i.e, deviations from the scheduled 
titration scheme) will be summarized.  
Potentially clinically important findings will be summarized 
or listed. 
Results of the physical examination will be listed.  
Reported AEs terms will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA).  The incidence of 
treatment emergent AEs (TEAEs), defined as AEs that started 
or worsened after first administration of IP, will be 
summarized by system organ class and preferred term.  
Separate summaries of TEAEs by severity and relatedness 
will be done.  SAEs and TEAEs leading to discontinuation of 
the study drug will also be summarized separately.  
The absolute values and change from baseline in laboratory 
tests, vital signs, SSS, ECG parameters, and CSSRS will be 
summarized.  
Results of physical examinations will be listed.  
Reason for Change:  Clarification of safety analyses 
80 
9.4.6 – Efficacy Analyses 
Approximately continuous endpoints (e.g, HAMD17, 
HAMD6, STAI6, and EPDS) will be analyzed by mixed 
model repeated measures (MMRM) analysis of covariance 
(ANCOVA) including all post-baseline treatment visits (but 
not the follow-up visits).  The model will include fixed 
effects of treatment, visit, treatment-by-visit interaction, and 
baseline value of the endpoint.  If at least 8 subjects are 
taking concomitant antidepressants during the study, it will 
also be included as a fixed effect.  An unstructured residual 
covariance matrix will be used; however alternate structures, 
Efficacy parameters will be summarized for both the OL 
and DBPC parts but will be analyzed only for the DBPC 
part.  For the OL part, referring to efficacy endpoints as 
“primary,” “secondary,” and “exploratory” is related to the 
degree of influence each type of endpoint is expected to have 
on decision-making rather than to considerations associated 
with inferential analysis (such as control of type 1 error).  
The primary time point of interest for all efficacy 
parameters will be Day 10 for the DBPC part and the visit at 


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Protocol 1042-PPD-2003 
 
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to be specified in the SAP, will be used in the event of 
convergence issues.  Differences between the treatments 
overall and at each visit will be tested for statistical 
significance. 
Ordered categorical endpoints (CGI-I, EPDS obsessive 
thoughts - time occupied, EPDS obsessive thoughts – 
distress) will be analyzed at each visit by the Cochran-
Mantel-Haenszel (CMH) row mean scores test using rank 
scores.  Dichotomous categorical endpoints will be analyzed 
at each visit by Fisher's exact test [HAMD17 response (≥ 
50% decrease from Baseline), HAMD6 response (≥ 50% 
decrease from Baseline), HAMD17 remission (HAMD17 
total score ≤ 7].  However, if concomitant antidepressants 
are included in the model of approximately continuous 
endpoints, then the CMH row means scores test will control 
for their use, and the Fisher's exact test will be replaced with 
the CMH general association test, controlling for their use. 
Items related to sleep and anxiety within the HAMD17 and 
EPDS scales may be tabulated separately.   
After the completion of the double-blind phase and analysis 
of the data by the DRC Marinus may decide to enroll 
another group of subjects who are randomized to receive 
ganaxolone or placebo.  Since this is a Phase 2 study, no 
adjustments to the Type I error protections are considered 
necessary.  
Efficacy data for the open-label safety group will be 
summarized descriptively. 
end of treatment (before initiation of taper) for the OL part. 
Reason for Change:  Clarification of efficacy analyses 
80 
9.4.6.1 – Primary 
Endpoint 
 
The primary efficacy endpoint will be HAMD17 total score 
change from baseline; this will be assessed at Day 10 for the 
DBPC part and at the visit at end of treatment for the OL 
part. The primary efficacy analysis will be done using the 
mITT set (DBPC part only). The analytical method will be 
mixed model repeated measures (MMRM) with baseline 
HAMD17 total score as a covariate. Significance will be 


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tested at a two-sided 0.05 level. Unstructured covariance will 
be specified although alternative covariance structures may 
be used, if appropriate, to achieve convergence or greater 
efficiency. Sensitivity analysis will be used to evaluate the 
assumption of data missing at random (MAR), if applicable. 
Reason for Change:  Addition of analysis method 
81 
9.4.6.2 – 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 ganaxolone in 
treating PPD: 
• 
Change from baseline in HAMD17 total score other 
than at the primary endpoint time point 
• 
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 
Reason for Change:  Addition of analysis method 
81 
9.4.6.3 – Exploratory 
Endpoints 
 


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Reason for Change:  Addition of analysis method 
81 
9.4.6.4 – Statistical 
Methods 
 
Efficacy parameters will be summarized for OL and DBPC 
parts. Observed values and changes from baseline for 
HAMD17, EPDS, and STAI6 total scores, subscales, and 
individual items will be summarized by visit.  The 
categorical outcomes of HAMD17 response, HAMD17 
remission, and CGI-I will be summarized by visit. 
For the DBPC part, the preferred approach for analyses of 
treatment group differences in secondary and exploratory 
continuous efficacy variables will be MMRM but other 
approaches such as t-tests, analysis of covariance, or non-
parametric methods may be used if necessary or more 
practical. Similarly, the preferred approach for analysis of 
secondary and exploratory categorical efficacy variables will 
be repeated measures (e.g., generalized estimating 
equations) but other approaches such as chi square or 
Fisher’s exact tests may be used. 
Reason for Change:  Addition of statistical methods for each part of the study 
 

SAP_003.pdf: 
 
 
 
Page 1 of 40 
 
IND No. 135256 
Protocol 1042-PPD-2003 
  
Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Protocol Title: 
A Phase 2, Double-blind, Placebo-controlled, Multicenter Study to 
 
Evaluate Safety, Tolerability and Efficacy of Oral Administration of 
Ganaxolone in Women with Postpartum Depression  
 
Protocol Version: 
Amendment 4, Version 5, October 22, 2018 
Protocol Number: 
1042-PPD-2003 
 
Statistical Analysis 
Plan Author: 
PhD 
Version: 
Version 1.0 
Release Date: 
November 15, 2018 
 
Study Name: 
Amaryllis 
Study Phase: 
Phase 2 
Product: 
Ganaxolone (CCD 1042:3α-hydroxy-3β-methyl-5α-pregnan-20-one) 
Indication: 
Postpartum Depression  
 
Sponsor: 
 
Marinus Pharmaceuticals, Inc.  
170 N. Radnor Chester Road 
Suite 250 
Radnor, PA 19087 
USA 
 
 
 
 
 
 


 
 
 
Page 2 of 40 
 
IND No. 135256 
Protocol 1042-PPD-2003 
  
Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
CONFIDENTIALITY STATEMENT 
 
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. 
 
 


lND No. 135256 
Protocol 1042-PPD-2003 
APPROVALS 
PhD 
PPD 
Consultant to Marinus Pharmaceuticals, Inc. 
Mari.nus Phaanaceuticals, Inc. 
Marinus Pharmaceuticals; Inc. 
Page 3 of 40 
Date 
Date 
Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version l.6. November 15, 2.018 


 
 
 
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IND No. 135256 
Protocol 1042-PPD-2003 
  
Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
REVISION HISTORY 
 
Version 
Date 
Author(s) 
Summary of Revision(s) 
1.0 
New document 
 
 
 
 
 


 
 
 
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IND No. 135256 
Protocol 1042-PPD-2003 
  
Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
TABLE OF CONTENTS 
APPROVALS .................................................................................................................................3 
REVISION HISTORY ..................................................................................................................4 
LIST OF ABBREVIATIONS .......................................................................................................8 
PREFACE .....................................................................................................................................10 
1. 
BACKGROUND ..............................................................................................................11 
2. 
STUDY OBJECTIVES ....................................................................................................11 
2.1 
Objectives of the OL Safety Part .......................................................................................11 
2.2 
Objectives of the DBPC Part .............................................................................................11 
3. 
STUDY DESIGN ..............................................................................................................12 
3.1 
OL Safety Part....................................................................................................................12 
3.2 
DBPC Part ..........................................................................................................................12 
4. 
TREATMENT GROUPS AND STUDY ENDPOINTS ...............................................13 
4.1 
Treatment Group Comparisons ..........................................................................................13 
4.2 
Study Endpoints .................................................................................................................13 
4.2.1 
Primary Efficacy Endpoint ...................................................................................13 
4.2.2 
Secondary Efficacy Endpoints .............................................................................13 
 
 
4.2.4 
Safety Endpoints ...................................................................................................14 
4.2.5 
PK Parameters ......................................................................................................15 
5. 
SAMPLE SIZE .................................................................................................................15 
6. 
TREATMENT ASSIGNMENT, BLINDING, AND UNBLINDING ..........................15 
6.1 
Treatment Assignment .......................................................................................................15 
6.2 
Blinding..............................................................................................................................15 
6.3 
Unblinding .........................................................................................................................15 
7. 
ANALYSIS POPULATIONS .........................................................................................15 
8. 
REPORTING AND ANALYSIS CONVENTIONS ......................................................16 
8.1 
Programming Environment ................................................................................................16 
8.2 
Reporting Conventions ......................................................................................................16 
8.3 
General Analysis Conventions ...........................................................................................17 
8.4 
Subgroups ..........................................................................................................................17 
8.5 
Missing Data ......................................................................................................................18 
8.6 
Study Period and Time Point Definitions ..........................................................................18 
8.7 
Visit Windows ...................................................................................................................18 
8.7.1 
OL TID, OL QHS, and DBPC Windows .............................................................19 


 
 
 
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Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
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8.7.2 
OL QHS 4-Week Windows ..................................................................................19 
8.7.3 
OL 1125 mg and OL Bolus-Oral Windows .........................................................19 
9. 
STUDY POPULATION ..................................................................................................20 
9.1 
Analysis Populations ..........................................................................................................20 
9.2 
Eligibility and Informed Consent.......................................................................................20 
9.3 
Baseline Characteristics .....................................................................................................20 
9.4 
Medical History .................................................................................................................20 
9.5 
Mini Neuropsychiatric Interview v7.0 (MINI) ..................................................................20 
9.6 
State versus trait; Assessability; Face Validity; Ecological Validity; and Rule of 3 Ps 
(SAFER) Interview ........................................................................................................................21 
9.7 
Clinical Global Impression – Severity (CGI-S) Scale .......................................................21 
9.8 
Subject Study Progress ......................................................................................................21 
9.9 
Subject Disposition ............................................................................................................21 
10. 
TREATMENTS................................................................................................................21 
10.1.1  IP Exposure ..........................................................................................................21 
10.1.2  Other Medications and Psychological Treatments ...............................................22 
11. 
EFFICACY ANALYSIS ..................................................................................................22 
11.1 
Efficacy Parameters ...........................................................................................................23 
11.1.1  HAMD17 ..............................................................................................................23 
11.1.2  EPDS ....................................................................................................................23 
11.1.3  STAI6 ...................................................................................................................23 
11.1.4  CGI-I ....................................................................................................................23 
11.2 
Statistical Methods .............................................................................................................23 
11.2.1  Primary Efficacy Endpoint ...................................................................................23 
11.2.2  Secondary Efficacy Endpoints .............................................................................24 
 
11.2.4  Method of Analysis for Longitudinal Continuous Endpoints ..............................25 
11.2.5  Method of Analysis for Longitudinal Ordinal Endpoints ....................................25 
11.2.6  Missing Observations ...........................................................................................26 
11.2.7  Multiplicity ...........................................................................................................26 
12. 
SAFETY PARAMETERS ...............................................................................................26 
12.1 
AEs .....................................................................................................................................26 
12.2 
Safety Laboratory Measurements ......................................................................................27 
12.3 
Vital Signs, Height, Weight, and Body Mass Index (BMI) ...............................................27 
12.4 
CSSRS................................................................................................................................27 
12.5 
12-Lead ECG .....................................................................................................................28 
12.6 
SSS .....................................................................................................................................28 


 
 
 
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IND No. 135256 
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Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
12.7 
Physical Examination.........................................................................................................28 
13. 
OTHER DATA COLLECTED .......................................................................................28 
13.1 
Neurosteroid Levels ...........................................................................................................28 
13.2 
Laboratory Sample Collection ...........................................................................................28 
13.3 
Protocol Deviations ............................................................................................................29 
14. 
SEQUENCE OF PLANNED ANALYSES ....................................................................29 
14.1 
Safety Reviews...................................................................................................................29 
14.2 
Administrative Interim Analyses .......................................................................................29 
14.3 
Final Analysis of the OL Safety Part .................................................................................29 
14.4 
Final Analysis of the DBPC Part .......................................................................................29 
15. 
DRC ...................................................................................................................................30 
16. 
DEVIATIONS FROM STATISTICAL METHODS IN THE PROTOCOL .............30 
REFERENCES .............................................................................................................................31 
APPENDIX A:  SCHEDULES OF ASSESSMENTS ...............................................................32 
APPENDIX B: TABLES OF CONTENTS FOR TABLES, FIGURES, AND LISTINGS ...36 
 


 
 
 
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IND No. 135256 
Protocol 1042-PPD-2003 
  
Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION
ΔG 
ganaxolone mean change from baseline 
ΔP 
placebo mean change from baseline 
AE 
adverse event 
AIC 
Akaike’s Information Criterion 
ANCOVA 
analysis of covariance 
BMI 
body mass index 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
CMH 
Cochran-Mantel-Haenszel 
CSR 
Clinical Study Report 
CSSRS 
Columbia Suicide Severity Rating Scale 
DBPC 
double-blind placebo-controlled 
DRC 
Data Review Committee 
ECG 
electrocardiogram 
EOS 
end of study 
EPDS 
Edinburgh Postnatal Depression Scale 
FCS 
fully conditional specification 
GABA 
gamma-aminobutyric acid 
GEE 
generalized estimating equations 
HA 
alternative hypothesis 
Ho 
null hypothesis 
HAMD17 
Hamilton Depression Rating Scale 17-item version 
ICH 
International Conference on Harmonisation 
IP 
investigational product 
IV 
intravenous 
IxRS 
Interactive Voice and/or Web Response System 
LS 
least squares 
MAR 
missing at random 
MCAR 
missing completely at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini Neuropsychiatric Interview 
mITT 
modified intent-to-treat 
MMRM 
“mixed model” for repeated measures 
MNAR 
missing not at random 
OL 
open label 
PK 
pharmacokinetic 
PPD 
postpartum depression 
PT 
Preferred Term 


 
 
 
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IND No. 135256 
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Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
QHS 
every night at bedtime 
QIC 
Quasilikelihood under the Independence model Criterion 
SAE 
serious adverse event 
SAFER 
State versus trait; Assessability; Face Validity; Ecological 
Validity; and Rule of 3 Ps 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SSS 
Stanford Sleepiness Scale 
STAI6 
Spielberger State-Trait Anxiety Inventory 6-item version 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
TID 
3 times daily 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
 
 
 


 
 
 
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IND No. 135256 
Protocol 1042-PPD-2003 
  
Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
PREFACE 
The purpose of this statistical analysis plan (SAP) is to outline the planned analyses and 
reporting to be completed to support the completion of the Clinical Study Report (CSR) for 
Marinus Protocol 1042-PPD-2003 (Amaryllis). The planned analyses identified in this SAP will 
be included in regulatory submissions and/or future manuscripts. Also, exploratory analyses not 
necessarily identified in this SAP may be performed to support the clinical development 
program. Any post-hoc, or unplanned, analyses not identified in this SAP performed will be 
clearly identified in the respective CSR. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the FDA and International Conference on Harmonisation (ICH) of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH): Guidance on Statistical 
Principles in Clinical Trials.1 All work planned and reported for this SAP will follow 
internationally accepted guidelines published by the American Statistical Association2 for 
statistical practice. 
The following documents were also considered in preparation for writing this SAP:  
 
 Clinical Research Protocol 1042-PPD-2003, Amendment 4, Version 5, October 22, 2018 
 International Conference on Harmonisation (ICH) E3 Guideline: Structure and Content of 
Clinical Study Reports3 
 ICH E6 Guideline on Good Clinical Practice4 
 ICH E8 General Considerations for Clinical Trials5 
 ICH E9 Statistical Principles for Clinical Trials6 
 Statistical Analysis Plans: Principles and Practice7 
The SAP is a supplement to the study protocol, which should be referred to for additional details 
on study design, study conduct, and other operational aspects of the study. 
 
 
 
 
 
 


 
 
 
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IND No. 135256 
Protocol 1042-PPD-2003 
  
Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
1. 
BACKGROUND 
Postpartum depression (PPD) is a mood disorder that occurs in women following 
the birth of a child. Rapid changes in the levels of endogenous neurosteroids during pregnancy 
are thought to be related to the development of PPD in women who are vulnerable to developing 
this condition. Plasma levels of allopregnanolone, which is a metabolite of progesterone and an 
endogenous gamma-aminobutyric acid (GABA) receptor modulator, are known to increase 
throughout pregnancy and then precipitously drop after delivery. Recently published data 
demonstrated that a continuous infusion of allopregnanolone rapidly alleviates symptoms of 
depression in women with PPD. The rationale for this trial is to evaluate whether ganaxolone, a 
synthetic analog of allopregnanolone, may provide benefit to women with PPD. 
2. 
STUDY OBJECTIVES  
The study will consist of two parts: an initial open-label (OL) safety part and a 
double-blind placebo-controlled (DBPC) part.  
2.1 
Objectives of the OL Safety Part 
The safety objective of the OL safety part is to assess the safety and tolerability of ganaxolone in 
women with PPD as determined by adverse events (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.  
 
The dosing objective of the OL safety part is to develop an optimal dosing regimen for the 
DBPC part of the trial. 
The efficacy objective of the OL safety part is to assess the efficacy of ganaxolone using 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) scales. 
The pharmacokinetic (PK) objective of the OL safety part is to collect samples of blood for PK 
analysis after administration of oral and intravenous (IV) ganaxolone to use in population-PK 
analyses, the results of which will be reported separately by the Sponsor. 
2.2 
Objectives of the DBPC Part 
The efficacy objective of the DBPC part is to assess the efficacy of ganaxolone vs. placebo using 
the HAMD17, EPDS, STAI6, and CGI-I scales. 
To safety objective of the DBPC part is to assess the safety and tolerability of ganaxolone vs. 
placebo in women with PPD as determined by AEs and changes from baseline in laboratory 
measures, vital signs, CSSRS, ECG, SSS, and physical examination. 
 
The PK objective of the DBPC part is to collect samples of blood for PK analysis after 
administration of oral doses of ganaxolone to use in population-PK analyses, the results of which 
will be reported separately by the Sponsor. 


 
 
 
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Protocol 1042-PPD-2003 
  
Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
3. 
STUDY DESIGN 
This is a Phase 2, multicenter study in women with PPD and will consist of two dosing parts: an 
initial OL safety part followed by a DBPC part. Dosing will be completed for the OL safety part 
before proceeding to the DBPC part. Schedules of assessments are in Appendix A. 
3.1 
OL Safety Part 
Approximately 172 women with PPD, 18 to 48 years of age, will be screened to enroll 
approximately 88 subjects into one of three groups, enrolled sequentially: 
 
Group 1: OL TID. The first group of approximately 8 subjects will receive ganaxolone 3 times 
daily, titrated from 225 mg/day to 900 mg/day over 10 days, followed by a taper over 4 days and 
a 14-day follow-up period. 
Group 2: OL QHS. The second group of approximately 20 subjects will receive ganaxolone at 
bedtime (QHS) titrated to a dose of 675 mg over 4 days which is then maintained until day 10, 
followed by a taper over 4 days and a 14-day follow-up period.  
Group 3: OL QHS 4-week. The third group of approximately 20 subjects will receive 
ganaxolone at a dose of 675 mg QHS for 28 days, followed by a taper over 4 days and a 3-month 
follow-up period.  
Group 4: OL 1125 mg. The fourth group of approximately 20 subjects will receive ganaxolone 
capsules 675 mg at dinner time and 675 mg at bedtime (for a total of 1,350 mg per day) on the first 2 
days, followed by 26 days of ganaxolone capsules 1,125 mg at dinner time and a taper over 4 days. 
Group 5: OL Bolus-Oral. The fifth group of approximately 20 subjects will receive ganaxolone 
as IV 12 mg bolus over 2 minutes at approximately 4 pm of the first day, followed by 
ganaxolone oral suspension 750 mg at dinner time and 750 mg at bedtime for a total of 1,512 mg 
on Day 1. On Day 2, subjects will receive ganaxolone oral suspension 750 mg at dinner time and 
750 mg at bedtime for a total of 1,500 mg, followed by 26 days of ganaxolone oral suspension 
1,000 mg at dinner time and a taper over 4 days.  
For all OL groups, if the subject experiences untoward effects the investigator has the flexibility 
to adjust the dose amount and/or timing of dosing by reducing the dose to a lower level and then 
possibly increasing it later if tolerance to the untoward effects develops. 
3.2 
DBPC Part 
Group 1: Approximately 100 women with PPD, 18 to 48 years of age, will be screened to 
randomize 50 subjects in a 1:1 ratio to receive ganaxolone or matching placebo for 14 days 
followed by a 14-day follow-up period. The targeted ganaxolone plasma concentrations and the 
final dosing formulations for the DBPC part will be decided upon based on safety and efficacy 
results from the OL safety part and on recommendations by the DRC. Additional information for 
the dose selection for the DBPC part may be obtained from the ongoing phase 2A study of the 
ganaxolone IV formulation for PPD (conducted under IND No. 106104). The total daily dose 
will not exceed 1600 mg. 


IND No. 135256 
Protocol 1042-PPD-2003 
Marinus Phannaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018 
Optional Group 2: After evaluation of the Group 1 DBPC data by a Data Review Committee 
(DRC), an additional approximately 50 women with PPD may be randomized 1: 1 to be ti·eated 
with ganaxolone or placebo for 14 days followed by a 14-day follow-up period. The daily dose 
may be lower, higher, or the same as in Group 1. However, the total daily dose will not exceed 
1600 mg and no single dose will be higher than 675 mg. 
In both groups, randomization will be sti·atified by the use of concomitant antidepressants. 
4-
TREATMENT GROUPS AND STUDY ENDPOINTS 
4-1 
Treatment Group Comparisons 
For the OL safety paii of the u-ial, info1mal descriptive compai·isons will be made across dosing 
groups. For the DBPC pait, ganaxolone and placebo will be statistically compai·ed within groups. 
4-2 
Study Endpoints 
4.2.1 
Primary Efficacy Endpoint 
The prima1y efficacy endpoint is change from baseline in HAMD 17 total score, assessed at Day 
10 for the DBPC paii and at the visit at end of ti·eatment for the OL paii of the ti·ial. 
4.2.2 Secondary Efficacy Endpoints 
The ti·ial will also evaluate the following secondaiy endpoints at each post-baseline data 
collection time point to provide additional evidence of the efficacy of ganaxolone in ti-eating 
PPD: 
• 
Change from baseline in HAMD 17 total score other than at the primaiy endpoint time point 
• 
HAMDl 7 response defined as at least a 50% reduction from baseline in total score 
• 
HAMDl 7 remission defined as total score <= 7 
• 
Change from baseline in EPDS total score 
• 
Change from baseline in STAI6 total score 
• 
CGI-I scale 
I 
I 
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IND No. 135256 
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Marinus Phannaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018 
I 
D 
I 
I 
I 
4.2.4 Safety Endpoints 
Safety endpoints for the OL TID, OL QHS, and DBPC groups will be: 
• 
Incidence, relationship to investigational product (IP), severity, and seriousness of AEs 
throughout the trial 
• 
Changes from baseline to Day 10 and 17 in laborato1y measurements 
• 
Changes from baseline to Day 4, 7, 10, 17, and 38 in vital signs 
• 
Changes from baseline to Day 10, 17, and 38 in weight and body mass index (BMI) 
• 
Change from baseline to Day 4, 7, 10, 17, and 38 in CSSRS 
• 
Change from baseline to Day 7 and 10 in ECG parameters 
• 
Change from baseline to Day 4, 7, 10, 17, and 38 in SSS 
• 
Changes from baseline to Day 10 in physical examination evaluations 
Safety assessments for the OL QHS 4-week group will be: 
• 
Incidence, relationship to IP, severity, and seriousness of AEs throughout the trial 
• 
Changes from baseline to Day 15, 29, 36, and 59 in laborato1y measurements 
• 
Changes from baseline to Day 2, 8, 15, 22, 29, 36, 59, 89, and 119 in vital signs 
• 
Changes from baseline to Day 29 and 119 in weight and BMI 
• 
Change from baseline to Day 2, 8, 15, 22, 29, 36, 59, 89, and 119 in CSSRS 
• 
Changes from baseline to Day 15, 29, and 36 in ECG parameters 
• 
Change from baseline to Day 2, 8, 15, 22, 29, 36, 59, 89, and 119 in SSS 
• 
Changes from baseline to Day 29 in physical examination evaluations 
Safety assessments for the OL 1125 mg and OL Bolus-Oral groups will be: 
• 
Incidence, relationship to IP, severity, and seriousness of AEs throughout the trial 
• 
Changes from baseline to Day 15, 29, 36, and 71 in laborato1y measurements 
• 
Changes from baseline to Day 2, 8, 15, 22, 29, 36, 57, and 71 in vital signs 
• 
Changes from baseline to Day 15, 29 and 71 in weight and BMI 
• 
Change from baseline to Day 2, 8, 15, 22, 29, 36, 57, and 71 in CSSRS 
• 
Changes from baseline to Day 2, 8, 15, 29, and 36 in ECG parameters 
• 
Change from baseline to Day 2, 8, 15, 22, 29, 36, 57, and 71 in SSS 
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 Changes from baseline to Day 29 in physical examination evaluations 
4.2.5 PK Parameters 
PK parameters will be detailed in a separate SAP if PK analyses are to be done. 
5. 
SAMPLE SIZE  
With a sample size of 50 subjects per treatment group, the DBPC part of the trial will be able to 
detect a medium effect size (Cohen’s d) with 93% power using a two-sided significance level of 
0.05. 
6. 
TREATMENT ASSIGNMENT, BLINDING, AND UNBLINDING 
6.1 
Treatment Assignment 
Eligible subjects for the OL safety part of the trial will be sequentially assigned to dosing groups 
as they are enrolled into the study. 
Eligible subjects for the DBPC part will be randomized in a 1:1 ratio to receive either 
ganaxolone or placebo.  Randomization will be stratified by use of concomitant antidepressant 
medication. The randomization scheme will be executed 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). 
6.2 
Blinding 
The placebo infusion and placebo capsules are identical to the ganaxolone infusion and 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 the DBPC part of the trial. 
Members of the DRC will be unblinded. 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. 
6.3 
Unblinding 
In the event of a medical emergency in an individual subject for which knowledge of the IP is 
critical to the subject’s management, the blind for that subject may be broken by the treating 
physician. Unblinding will be managed via the IxRS.  
Before breaking the blind of an individual subject’s treatment, the investigator should determine 
that the information is necessary; i.e., that it will alter the subject’s immediate management. In 
many cases, particularly when the emergency is clearly not related to the IP, the problem may be 
properly managed without unblinding, by assuming that the subject is receiving active product. 
7. 
ANALYSIS POPULATIONS 
The following analysis populations are defined for the trial: 
Screened set: Subjects who signed an informed consent. 


 
 
 
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Randomized set: Subjects who were randomized into the DBPC part of the trial. 
Safety set: Subjects who were dispensed IP or who received an IV bolus of IP. For the DBPC 
part of the trial, subjects will be summarized and analyzed per treatment actually dispensed (or 
received), regardless of their randomization assignment.  
Modified Intent-to-Treat (mITT) set: Subjects in the DBPC part of the trial who are in the safety 
set and who have at least one post-baseline observation for HAMD17 total score. Subjects will 
be summarized and analyzed per their randomization assignment, regardless of the treatment 
actually received. 
Per protocol set: Subjects in the mITT set who do not have protocol deviations that could affect 
treatment group comparisons on key efficacy endpoints. A list of subjects with protocol 
deviations that preclude them from being in the per protocol population will be compiled prior to 
database lock.  
8. 
REPORTING AND ANALYSIS CONVENTIONS  
8.1 
Programming Environment 
SAS® version 9.3 or higher (SAS Institute, Cary, North Carolina) will be used for statistical 
analyses and the production of tables, figures, and listings (TFLs).  
8.2 
Reporting Conventions 
Tables of contents for TFLs to be produced are shown in Appendix B. Separate sets of TFLs will 
be produced for the OL safety and DBPC parts of the trial. Separate tables and figures may be 
produced within parts of the trial for visit-based assessments where visit schedules differ; e.g., 
the OL QHS 4-week dosing group has a different visit schedule than the OL TID and OL QHS 
dosing groups and may therefore be presented in a separate set of tables and figures. TFLs will 
be appended to the final CSR. 
TFLs will be displayed in landscape orientation unless the presentation is easier to interpret in 
portrait mode. TFLs displayed in-text in the CSR will be in portrait mode. 
Fonts are to be Times New Roman or Arial only. Font size is to be no smaller than 9pt. 
Titles and footnotes must appear on every page of the TFL. Titles on pages other than the first 
page must indicate that the TFL is a continuation of the first page (e.g., “(cont’d)” at the end of 
the first title line). Titles should be as short as possible, ideally 126 characters or less. Footnotes 
should be used sparingly and must add value to the TFL. If more than four footnote lines are 
planned then a cover page may be used to display footnotes. Superscripts are not to be used in 
TFL titles. 
Cells with missing values for either numeric or character variables will be populated with an 
indicator for missingness (e.g., “—“). 
All date values will be presented as DDMMMYYYY (e.g., 29AUG2001) format. A four-digit 
year is preferred for all dates. All observed time values will be presented using a 24-hour clock 
HH:MM:SS format (e.g., 01:35:45 or 11:26). Seconds should only be reported if they were 
measured as part of the study. 


 
 
 
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TFLs will have the name of the program, the data source, and a date/time stamp on the bottom of 
each page. There will be a 1:1 relationship between programs and TFLs; i.e., each program will 
output one and only one TFL. 
Tables and figures will present data summaries and/or analyses for the appropriate study 
population; e.g., summaries of safety parameters will be shown for the safety set only. Treatment 
group order in tables and figures for the OL safety part of the trial will be OL TID, OL QHS, OL 
QHS 4-week; some tables and figures may also display “All Subjects.” Treatment group order in 
tables and figures for the DBPC part will be Ganaxolone, Placebo; some tables and figures may 
also display “All Subjects.” Tables and figures will present summaries/analyses by study visit or 
analysis visit window, as appropriate. Table column headers and figure legends will include 
subgroup sample sizes (“N = xx”). Sample sizes reported as part of descriptive statistics (“n”) 
will be the number of non-missing observations. 
Listings will present all data collected for the OL safety set and for the randomized set, unless 
otherwise noted below. Listings will be ordered by unique subject identifier, date, data collection 
time if applicable, nominal study visit, and analysis visit window if applicable (see Section 8.7). 
8.3 
General Analysis Conventions 
Categorical variables will be summarized using frequencies and percentages in each category for 
which there was at least one response.  Percentages will be reported to one decimal place. Unless 
otherwise noted in Section 11, categorical variables will be analyzed using chi square tests of 
association or, if any contingency table cell has less than 5 subjects, Fisher’s exact test. 
Continuous variables will be summarized using descriptive statistics (e.g., n, mean, standard 
deviation, least-squares mean with standard error, distribution percentiles). The number of 
decimal places for minimums and maximums will be the same as the original data. The number 
of decimal places for means, medians, and interquartile ranges will be the same as the original 
data plus one. The number of decimal places for measures of variance will be the same as the 
original data plus two. Unless otherwise noted in Section 11, continuous variables will be 
analyzed using t-tests or, if appropriate, analysis of covariance with baseline as a covariate. Non-
parametric tests and data transformations will be considered for variables with distributions that 
violate parametric assumptions. 
Data with qualifiers (e.g., “<”) will be listed with but summarized without the qualifier. 
P-values will be presented in summary tables to two decimal places if > 0.01, to three places if < 
0.01 but > 0.001, and to four places if < 0.001 but > 0.0001. However, p-values > 0.045 but < 
0.055 will also be presented to three decimal places. P-values < 0.0001 will be presented as “< 
0.0001.” 
Statistical tests will be two-sided and tested at the 0.05 significance level unless otherwise noted 
in Section 11. 
8.4 
Subgroups 
There are no planned analyses by subgroups. 


 
 
 
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8.5 
Missing Data 
Listings will present data as reported. Missing or partially missing dates that are required for 
date-dependent definitions (e.g., treatment-emergent AEs, concomitant medications) will be 
assumed to be the most conservative date possible. For example, an AE with a completely 
missing start date will be considered treatment-emergent; similarly, an AE that started the same 
month and year as date of first dose of IP but with missing start day will be considered treatment-
emergent. Handling of missing observations for the primary efficacy endpoint is described in 
Section 11.2.6. 
8.6 
Study Period and Time Point Definitions 
The following study periods and time points are defined: 
 
Screening Period: the 1- to 14-day time period before day of enrollment for the OL safety part of 
the trial or day of randomization for the DBPC part. 
 
Baseline Observation: for a given parameter for a given subject, the last observation before the 
first dose of IP or planned first dose of IP if not dosed. 
 
Study Day 1: for a given enrolled subject, the day of actual first dose of IP or planned first dose 
of IP if not dosed. 
 
(Nominal Visit) Analysis Time Point: analysis based on data collected at the (nominal visit) time 
point, where nominal visits are as shown below in Section 8.7. 
 
End of Study (EOS), Subject Level: the date of completion of the last planned study visit or date 
of discontinuation for any reason. 
 
EOS, Study-Level: the date when all enrolled subjects in the OL safety part of the trial and all 
randomized subjects in the DBPC part have reached subject-level EOS. 
8.7 
Visit Windows 
Visit windows will be based on study day of the observation and Study Day 1; specifically: 
 On or after Study Day 1: study day = date of observation – Study Day 1 date + 1 
 Before Study Day 1: study day = date of observation – Study Day 1 date 
For subjects in the screened set who were not enrolled or for subjects who otherwise did not have 
a planned date of first dose, all observations belong to the screening visit analysis window. 
If multiple valid, non-missing observations exist within a given window, the observation to be 
used will be: 
1. the observation closest to the nominal visit day in question, or 
2. the latest observation if the multiple observations are equidistant from the nominal visit 
day, or 


 
 
 
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3. the average (arithmetic or geometric, as appropriate) of the observations if the multiple 
observations have the same actual time point. In instances of multiple observations with 
the same time point from different laboratories, only observations from the central 
laboratory will be used. 
For PK analyses, actual dates and times will be used. 
8.7.1 OL TID, OL QHS, and DBPC Windows 
Visit windows per protocol and to be used in listings, summaries and analyses for the OL TID, 
OL QHS, and DBPC groups are as follows: 
Nominal Visit 
Nominal 
Day 
Min Day Per 
Protocol 
Max Day Per 
Protocol 
Min Day for 
Analyses 
Max Day for 
Analyses 
Screening 
-- 
-14
-1
-14
-1
Day 1 
1 
1
1
1
1
Day 4 
4 
4
6
2
6
Day 7 
7 
7
9
7
9
Day 10 
10 
10
13
10
13
Day 17 
17 
15
19
14
27
Day 38 
38 
34
42
28
48
8.7.2 OL QHS 4-Week Windows 
Visit windows per protocol and to be used in listings, summaries and analyses for the OL QHS 
4-week group are as follows: 
Nominal Visit 
Nominal 
Day 
Min Day Per 
Protocol 
Max Day Per 
Protocol 
Min Day for 
Analyses 
Max Day for 
Analyses 
Screening 
-- 
-14
-1
-14
-1
Day 1 
1 
1
1
1
1
Day 2 
2 
2
2
2
5
Day 8 
8 
8
8
6
11
Day 15 
15 
15
15
12
18
Day 22 
17 
15
19
19
23
Day 29 
29 
29
29
24
32
Day 36 
36 
34
38
33
47
Day 59 
59 
57
61
48
74
Day 89 
89 
85
93
75
104
Day 119 
119 
115
123
105
133
8.7.3 OL 1125 mg and OL Bolus-Oral Windows 
Visit windows per protocol and to be used in listings, summaries and analyses for the OL 1125 
mg and OL Bolus-Oral groups are as follows: 
Nominal Visit 
Nominal 
Day 
Min Day Per 
Protocol 
Max Day Per 
Protocol 
Min Day for 
Analyses 
Max Day for 
Analyses 
Screening 
-- 
-14
-1
-14
-1
Day 1 
1 
1
1
1
1
Day 2 
2 
2
4
2
4


 
 
 
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Day 8 
8 
5
11
5
11
Day 15 
15 
12
18
12
18
Day 22 
17 
19
25
19
25
Day 29 
29 
26
32
26
32
Day 36 
36 
33
39
33
47
Day 57 
59 
54
60
48
64
Day 71 
89 
68
74
65
77
9. 
STUDY POPULATION 
Summaries of study population parameters will be done for the safety set unless otherwise noted. 
The study population will be described by the parameters below. 
9.1 
Analysis Populations 
The analysis populations defined in Section 7 will be described in terms of the identification of 
subjects in each population and the frequency distribution of each population. Summaries will be 
done for the OL safety set (OL safety part) and for the randomized set (DBPC part). 
9.2 
Eligibility and Informed Consent 
Eligibility and informed consent parameters will be listed and will include protocol version 
(date), date of informed consent, inclusion and/or exclusion criteria that were not met, whether or 
not the subject was a previous screen failure and, if so, date of previous screen and previous 
subject number. Satisfaction of inclusion/exclusion criteria will be summarized. 
9.3 
Baseline Characteristics 
Demographic and other baseline characteristics will be listed and summarized and will include 
study site, age, race, and ethnicity. Age will be computed in SAS as follows: 
AGE = floor((intck('MONTH', bdt, rdt) - (day(rdt) < day(bdt))) / 12) 
where bdt = birth date in SAS date format and rdt = Study Day 1 date in SAS date format. For 
the DBPC group, data will be summarized for both the safety set and the mITT set. 
9.4 
Medical History 
Medical history will be listed and summarized. Reported medical conditions will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA), version 19.1, to a System Organ 
Class (SOC) and Preferred Term (PT). A summary will be produced showing number and 
percentage of subjects with each PT within SOCs. 
9.5 
Mini Neuropsychiatric Interview v7.0 (MINI) 
MINI results will be listed; namely, whether or not the assessment was performed, date and time 
of the assessment, whether or not the subject met the inclusion criterion for major depressive 
episode per the MINI, and other psychiatric diagnosis per the MINI. 


 
 
 
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9.6 
State versus trait; Assessability; Face Validity; Ecological Validity; and 
Rule of 3 Ps (SAFER) Interview 
SAFER results will be listed; namely, whether or not the assessment was performed, date and 
time of the assessment, and whether or not the subject met the inclusion criteria for diagnosis of 
PPD and severity of depression per the SAFER. 
9.7 
Clinical Global Impression – Severity (CGI-S) Scale 
The CGI-S is a clinician-rated 7-point scale to assess severity of a subject's depression relative to 
the clinician's past experience with subjects who have the same diagnosis. CGI-S will be done 
only at screening and on Day 1. Possible responses are: 1 = normal, not at all ill; 2 = borderline 
mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7= extremely ill. 
Observed values will be listed, and frequencies and percentages of subjects at each response 
level will be summarized. 
9.8 
Subject Study Progress 
A listing of subject study progress will show dates of screening, informed consent, study visits, 
and EOS. Number of subjects who completed each milestone and visit will be summarized. 
9.9 
Subject Disposition 
A listing of subject disposition will include dates of randomization (DBPC part only), first dose 
of IP, last dose of IP, and EOS; and reasons for IP and/or study discontinuation (if applicable). 
Frequencies and percentages of subjects who discontinued the IP and/or study will be 
summarized. Reasons for discontinuation will also be summarized. 
10. 
TREATMENTS 
Treatment parameters will be listed and summarized for the safety set.  Some or all summaries 
may also be done for other analysis populations defined in Section 7. Treatment parameters are 
described below. 
10.1.1 IP Exposure 
A listing of IP exposure will include IV bolus infusion start/stop date/times and infusion rate (OL 
Bolus-to-Oral group only), number of capsules dispensed, number of capsules returned, mean 
daily dose (mg), duration of exposure, and percent compliance. Duration of exposure will be 
calculated as: 
 
days of exposure = date of last dose – date of first dose + 1. 
 
Percent compliance at a given visit will be calculated as: 
 
percent compliance = (number of capsules ingested) / (number of expected capsules ingested) x 100 
 


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where number of capsules ingested will be calculated as the number of capsules dispensed at the 
prior visit minus the number of capsules returned at the given visit. 
Mean daily dose, dmation of exposme, and percent compliance will be listed and summarized 
for each post-baseline visit as well as cumulatively over the total dosing period. A listing will 
also be provided of subjects who has dose adjustments (i.e., deviations from the scheduled 
titrntion scheme), and dose adjustments will be summarized. 
11-
EFFICACY ANALYSIS 
Summaries of efficacy parameters will be done for the safety set from the OL safety pa1t of the 
trial and for the mITT set. Statistical analyses will primarily be done for the mITT set. Some or 
all summaries and/or analyses may also be done for other analysis populations defined in Section 
1. 
For the OL safety pali of the trial, refeITing to efficacy endpoints as "primaiy," "secondaiy," and 
"explorato1y" is related to the degree of influence each type of endpoint is expected to have on 
decision-making rather than to considerations associated with inferential analysis (such as 
control of type 1 eITor). The primaiy time point of interest for all efficacy pai·ameters will be Day 
10 for the DBPC pait of ti·ial and the visit at end of ti·eatment (before initiation of taper) for the 
OL safety pait. 
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11.1 Efficacy Parameters 
11.1.1 HAMD17 
The HAMD17 is a 17-item clinician-rated instrument used to assess the range of symptoms 
associated with major depression and will be done at every study visit. Items are scored either 
from 0 to 2 or 0 to 4, depending on the item, and a total score is derived by summing over all 17 
items. Observed values, changes from baseline, “response,” and “remission” based on the total 
score will be listed and summarized. “Response” is defined as > 50% decrease from baseline. 
“Remission” is defined as an observed total score of 0 to 7 (note: HAMD17 total score must be > 
18 at randomization). The listing will also include observed values and changes from baseline for 
each of the 17 items. Improvement is indicated by negative change scores and this will be 
footnoted in TFLs.  
11.1.2 EPDS 
The EPDS is a 10-question self-rated instrument used to assess symptoms of PPD and will be 
administered at every study visit. Items are scored from 0 to 3 with a total score derived by 
summing over all 10 items. Observed values and changes from baseline based on the total score 
will be listed and summarized. The listing will also include observed values and changes from 
baseline for each of the 10 items. Improvement is indicated by negative change scores and this 
will be footnoted in TFLs. 
An Obsessive Thoughts questionnaire, comprised of two questions scored from 0 to 4, is an add-
on to the EPDS but will not be included in the EPDS total score for analysis. A listing and 
summary table will be provided. 
11.1.3 STAI6 
The STAI6 is a 6-question self-rated instrument used to assess anxiety state and will be 
administered at every study visit. Items are scored from 1 to 4 with a total score derived by 
summing over all 6 items and multiplying by 20/6. Observed values and changes from baseline 
based on the total score will be listed and summarized. The listing will also include observed 
values and changes from baseline for each of the 6 items. Improvement is indicated by negative 
change scores and this will be footnoted in TFLs.  
11.1.4 CGI-I 
The CGI-I is a clinician-rated 7-point scale to assess degree of improvement from baseline and 
will be done at every post-baseline study visit. Possible responses are: 1 = very much improved 2 
= much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much 
worse, 7 = very much worse. Observed values will be listed, and frequencies and percentages of 
subjects at each response level will be summarized. Both original scores as well as scores 
dichotomized as “very much or much improved” (response = 1 or 2) vs. all other responses (3-7) 
will be analyzed.  
11.2 Statistical Methods 
11.2.1 Primary Efficacy Endpoint 


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The prirmuy efficacy endpoint will be HAMD 17 total score change from baseline, assessed at 
Day 10 for the DBPC paii and at the visit at end of treatment for the OL safety paii of the trial. 
The null (Ho) and alternative (HA) hypotheses will be: 
where .6.G and ,6.p ai·e mean change from baseline to Day 10 in HAMD 17 total score in 
ganaxolone and placebo groups, respectively. Rejection of Ho at a 0.05 significance level will be 
considered successful demonstrntion of efficacy. Analysis will be done using a "mixed model" 
for repeated measures (MMRM) as described below. For the effect of interaction between 
treatment and day, the estimated ti·eatment group difference in least squares (LS) means at Day = 
10, along with the associated p-value, will be repo1ied. 
11.2.2 Secondary Efficacy Endpoints 
The ti·ial will also evaluate the following secondaiy endpoints at each post-baseline data 
collection time point to provide additional evidence of the efficacy of ganaxolone in ti·eating 
PPD: 
• 
Change from baseline in HAMD 17 total score other than at the primaiy endpoint time point 
• 
HAMDl 7 response defined as at least a 50% reduction from baseline in total score 
• 
HAMDl 7 remission defined as total score <= 7 
• 
Change from baseline in EPDS total score 
• 
Change from baseline in STAI6 total score 
• 
CGI-I 
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11.2.4 Method of Analysis for Longitudinal Continuous Endpoints 
Treatment group comparisons on endpoints that are continuous variables assessed longitudinally 
will be done using MMRM with change from baseline as the dependent variable; nominal visit 
(day), treatment group, and treatment-by-day interaction as fixed effects; baseline observation as 
a fixed-effect covariate; and coITelated eITors within subject. Use of concomitant antidepressants 
will also be considered as a fixed-effect covariate since it is a randomization strntification factor. 
Covariance estimation will be done using restricted maximum likelihood. 
Enor degrees of freedom will be calculated using the Kenward-Rogers approximation. Unstrnctured 
covariance for the residuals (R matrix) will initially be specified but other covariance strnctures 
may be explored by examining the R matrix and using goodness-of-fit measures (e.g., Akaike's 
Info1mation Criterion (AIC)). If a strnctured covariance is used, the sandwich estimator will be 
used for standard eITors and eITor degrees of freedom will be calculated using the between-within 
method. Model-based LS means will be reported for each treatment group, along with p-values 
for treatment group comparisons, for each nominal visit. A p-value for treatment group 
comparison over all visits will only be repo1ied ifthere does not appear to be a treatment-by-day 
interaction, either based on the interaction p-value or by a descriptive exarnination of the data, 
and the term for treatment-by-day interaction will not be included in the model. 
Model assumptions will be evaluated using diagnostic tools such as Q-Q and scatter plots of 
residuals, and sensitivity analyses using alternative methods (e.g., rank-based, analysis of 
covariance (ANCOV A) at individual time points) will be considered if there appear to be 
substantial deviations from model assumptions. Outlier assessment will be done using visual 
inspection (e.g., box-and-whisker plots) and potential outliers will be investigated for data entiy 
accuracy and biological consistency. If unexplainable outliers are present for the primary 
efficacy endpoint, a sensitivity analysis will be done excluding the outliers to assess their effect 
on the efficacy conclusion. 
11.2.5 Method of Analysis for Longitudinal Ordinal Endpoints 
Treatment group comparisons on ordinal (including binaiy) endpoints assessed longitudinally 
will be done using generalized estimating equations (GEE) with nominal visit (day) and 
ti·eatment group as main effects, treatment-by-day as an interaction term, an appropriate baseline 
value as a covai·iate, where applicable; and coITelated eITors within subject. Use of concomitant 
antidepressants will also be considered as a covariate. 
The working coITelation sti11cture will initially be specified as unstiuctured but other stiuctures 
may be explored by exarnining the covai·iance mati·ix and using goodness-of-fit measures (e.g., 
Quasilikelihood under the Independence model Criterion (QIC)). P-values for ti·eatment group 
compai·isons will be repo1ied for each n01ninal visit. A p-value for ti·eatment group compai·ison 
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over all visits will only be reported if there does not appear to be a treatment-by-day interaction, 
either based on the interaction p-value or by a descriptive examination of the data, and the term 
for treatment-by-day interaction will not be included in the model. 
Alternative approaches for the analysis of ordinal endpoints may be considered and will include 
the Cochran-Mantel-Haenszel (CMH) row mean scores test using rank scores, chi square tests of 
association, and Fisher’s exact test. 
11.2.6 Missing Observations 
One of the assumptions of MMRM for longitudinal continuous variables is that missing 
observations are missing at random (MAR), i.e., missingness is unrelated to the missing variable 
but can be related to another variable on which data have been collected. Because this 
assumption is not testable, and because it seems possible that subjects with poorer outcomes may 
be more likely to miss trial assessments, a sensitivity analysis under a missing-not-at-random 
(MNAR) assumption may be done for any endpoint but will be done for the primary efficacy 
endpoint if change-from-baseline observations for HAMD17 total score are missing at any time 
point for at least 10% of subjects. For the MNAR model, the imputation will be based only on 
subjects randomized to placebo. The imputation method will be fully conditional specification 
(FCS) regression with 25 imputations. The imputer’s model will include observed values at each 
time point included in the MMRM analysis, including baseline. 
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 using FCS logistic regression as 
the imputation method. 
11.2.7 Multiplicity 
There will be no adjustments for type 1 error inflation due to multiplicity. 
12. 
SAFETY PARAMETERS 
Listings and summaries of safety parameters will be done for the safety set.  Some or all 
summaries may also be done for other analysis populations defined in Section 7.  
12.1 AEs 
AEs reported from screening through EOS will be coded according to MedDRA® version 19.1 or 
greater. Each reported AE will be mapped to a PT and 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 
interruption or discontinuation (excluding deaths), or dose reduction. Listings will include 
reported term, PT, and SOC; start and stop date; outcome; whether or not the AE was serious; 


 
 
 
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Protocol 1042-PPD-2003 
  
Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
severity; whether or not the AE was related to IP; whether or not the AE caused the subject to 
discontinue from the study; and action taken. 
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 relationship will be 
considered related and missing severity will be considered severe. 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. 
12.2 Safety Laboratory Measurements 
Specific laboratory measurements to be obtained are detailed in Section 7 of the protocol.  
Collection will be done at select visits (see Appendix A). Listings of safety laboratory 
measurements will include normal ranges, observed values with out-of-range values flagged, and 
changes from baseline.  
Observed values and changes from baseline will be summarized. A separate series of summaries 
will show incidence of out-of-range observations. Shift tables will summarize shifts from one 
out-of-range category at baseline to another out-of-range category at each subsequent study visit. 
Listings and summaries will be done separately for each of the following groups of laboratory 
measurements: 
 Biochemistry  
 Hematology 
 Urinalysis 
 Urine pregnancy test 
 Urine drug screen 
12.3 Vital Signs, Height, Weight, and Body Mass Index (BMI) 
Vital signs will include systolic and diastolic blood pressure, pulse rate, respiration rate, and 
body temperature and will be measured at every study visit. Any abnormal screening vital sign 
results considered to be clinically significant should be repeated to confirm the finding. Height 
will be measured at the screening visit. Weight will be collected at select visits (see Appendix 
A). Listings of vital signs, height, weight, and BMI will include observed values and changes 
from baseline. BMI will be calculated as:  
 
12.4 CSSRS 
The CSSRS is a clinician-rated assessment of suicidality and will be done at every study visit. 
The CSSRS consists of three sections: Suicide Ideation, Intensity of Ideation, and Suicide 
Behavior. The Suicide Ideation section consists of 5 questions and proceeds as follows: 


 
 
 
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IND No. 135256 
Protocol 1042-PPD-2003 
  
Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
 
1. Ask Questions 1 and 2. 
2. If Question 1 and 2 are negative, proceed to the Suicide Behavior section. 
3. If the answer to Question 1 and/or 2 is “yes,” complete the Intensity of Ideation section. 
4. If the answer to Question 2 is “yes,” ask Questions 3-5, then proceed to the Suicide Behavior 
section. 
5. If the answer to Question 2 is “no,” proceed to the Suicide Behavior section. 
 
CSSRS responses will be listed and summarized.   
12.5 12-Lead ECG  
12-lead ECG will be performed at select visits (see Appendix A). The ECG vendor will provide 
an external database. Observed values and changes from baseline for continuous ECG 
parameters (e.g., heart rate, PR interval, QRS complex, QTcF) will be listed and summarized. 
Interpretation (normal, abnormal not clinically significant, or abnormal clinically significant) and 
specification of abnormalities will also be listed and summarized.   
12.6 SSS 
The SSS is an 8-item self-rated scale designed to measure level of sleepiness and will be 
administered at every study visit except screening. Possible responses range from 1 (“Feeling 
active, vital, alert, or wide awake”) to 8 (“asleep”). Observed values will be listed and 
summarized. 
12.7 Physical Examination 
Physical examinations will be conducted at screening and at Day 10 (OL TID, OL QHS, and 
DBPC groups) or at Day 29 (OL QHS 4-week, OL 1125 mg, and OL Bolus-Oral groups). The 
listing will include the overall assessment of the examination (normal or abnormal) and 
abnormalities, if any, for each body system. Findings will be summarized either as frequencies of 
normal/abnormal indicators or, if appropriate (i.e., if data are not too sparse), as shifts from 
baseline in normal/abnormal indicators for each body system.  
13. 
OTHER DATA COLLECTED 
13.1 Neurosteroid Levels 
Blood samples for determination of neurosteroid levels (allopregnanolone and potentially other 
metabolites of progesterone) will be collected at select visits (see Appendix A). Data will be 
listed, summarized, and/or analyzed by a third-party vendor. 
13.2 Laboratory Sample Collection 
A listing of laboratory sample collection dates, times, and accession numbers will be provided 
and will include PK collection data as well. 


 
 
 
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Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
13.3 Protocol Deviations 
In addition to the listing of eligibility detailed in Section 9.2, a separate listing will show all other 
protocol deviations and will include protocol version, the category of the deviation (to be 
determined), and an indicator for per protocol exclusion (DBPC part only), to be determined on a 
case-by-case basis before database lock. Frequency and percentage of subjects in each deviation 
category and excluded from the per protocol population will be summarized.  
14. 
SEQUENCE OF PLANNED ANALYSES 
14.1 Safety Reviews 
During the OL safety part of the trial, the sponsor will review safety data after completion of 
each dosing group and before beginning randomization for the DBPC part. The DRC will review 
safety data from Group 1 of the DBPC part before beginning randomization for Group 2 (if 
applicable). 
14.2 Administrative Interim Analyses 
The sponsor may perform administrative interim analyses, including public release of top line 
results, at any time during the OL safety part of the trial, for the purpose of planning subsequent 
clinical trials.   
14.3 Final Analysis of the OL Safety Part 
Final analysis of the OL safety part will occur when all OL subjects have reached EOS, 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 have been identified, and the database for the OL safety part has 
been locked. 
The sponsor may decide to stop the study, or make the data public, after completion of the OL 
safety part. 
14.4 Final Analysis of the DBPC Part 
Final analysis of Group 1 of the DBPC part will occur when all DBPC subjects from Group 1 
have reached EOS, 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 population have been 
identified, and the database for Group 1 has been locked. 
Final analysis of Group 2 of the DBPC part (if applicable) will occur when all DBPC subjects 
from Group 2 have reached EOS, 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 
population have been identified, and the database for Group 2 has been locked. 
The sponsor may decide to stop the study, or make the data public, after completion of Group 1 
of the DBPC part. 


 
 
 
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Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
15. 
DRC 
After completion of Group 1 of the DBPC part, the data will be evaluated by an independent 
DRC. Based on the analysis and recommendation by the DRC, at that point the study may be 
closed or may proceed to randomize Group 2 of the DBPC part. A separate guidance document 
will outline the functions and membership of the DRC. 
 
Data on the following, in the form of TFLs and/or narratives, will be provided to the DRC for 
review: 
 
 Subject disposition 
 Demographic and other baseline characteristics 
 Ganaxolone exposure 
 Treatment-emergent AEs and SAEs 
 Safety laboratory evaluations 
 Vital signs 
 HAMD17 
 EPDS 
 STAI6 
16. 
DEVIATIONS FROM THE PROTOCOL 
 
Protocol 
Deviation 
CGI-S mentioned in efficacy objective 
CGI-S is not an efficacy endpoint (it is not 
assessed post-baseline)
Safety set: all subjects who received IV IP. 
Safety set: Subjects who were dispensed IP or 
who received an IV bolus of IP.  
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 Per-Protocol Set will consist of all 
subjects in the mITT set who do not have 
protocol deviations that may affect key 
efficacy endpoints. 
mITT set: all subjects in the DBPC part of the 
trial who received IP and who have at least 1 
post-baseline HAMD17 assessment. 
mITT set: Subjects in the DBPC part of the 
trial who are in the safety set and who have at 
least one post-baseline observation for 
HAMD17 total score.  
The dosing, treatment duration and timing of 
evaluations for the double-blind portion of the 
study will be decided based on the results of 
the Open Label Part and recommendations of 
the Data Review Committee (DRC). 
An independent DRC will be in place for the 
DBPC part only. 
 
 


 
 
 
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IND No. 135256 
Protocol 1042-PPD-2003 
  
Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
REFERENCES 
1. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), September 1998. 
2. ASA. (2018) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April, 2018. http://www.amstat.org/ASA/Your-Career/Ethical-
Guidelines-for-Statistical-Practice.aspx. 
3. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), November 1995. 
4. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Good Clinical 
Practice (E6), April 1996. 
5. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, General 
Considerations for Clinical Trials (E8), July 1997. 
6. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), September 1998. 
7. Johnson JR, Fitts D. Statistical Analysis Plans: Principles and Practice. Workshop Number 8. 
Presented at the Society for Clinical Trials 2007 Annual Meeting Montreal, Canada Sunday 
May 20, 2007. http://docshare01.docshare.tips/files/9381/93818340.pdf. 
   


IND No. 135256 
Protocol 1042-PPD-2003 
APPENDIX A: SCHEDULES OF ASSESSMENTS 
OL TID, OL QHS, and DBPC 
VISIT 
Sr1·eening (YI) 
Day! 
(Y2) 
Informed consent 
X 
Demoimt0hics, medical historv 
X 
MINI neuropsychiatric interview 
X 
Inclusion/Exclusion criteria 
X 
X 
Randomize patient (DB only) 
X 
Disuense medication 
X 
Concoruit-ant Medications and Prior TI1erapy 
X 
X 
Review 
Physical examination 
X 
SAFER Interview (during screening) 
X 
Vital si"rn; ffiP, Pulse. RR, temnerature) 
X 
X 
Height (screening onlv) and weight 
X 
X 
ECGs 
X 
X 
Safety Laboratorv Tests 
X 
X 
Neurosteroid sample collection 
X 
Urine Drug Screen and Pre-smancy Tests 
X 
X 
Record AEs 
X 
PK sample collection 
HAMD17 
X 
X 
CGI-1 
CGI-S 
X 
X 
EPDS 
X 
X 
STAI6 
X 
X 
CSSRS 
X 
X 
sss 
X 
Start Taper 
Day4 
Day7 
DIO 
(Y3) 
(Y4) 
(\'5) 
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 
Marinus Phrumaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018 
Dayl 7 
DaY38 
(\-6, 1st FU) 
(\-7, 2•d Fl.J 
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 
The following priority order will be in effect when more than 1 assessment is required at a particular time point: 1) HAMDl 7 2) CGI-I/CGI-S 3) EPDS 
4) STAI6 5) SSS 6) CSSRS 7) vital signs 8) ECG 9) safety labs 10) neurosteroid sample 11) PK sample 12) urine drug screen and pregnancy test 13) physical 
examination. SAFER interview is scheduled if subject meets the eligibility criteria at the Screening visit. The SAFER interview will be conducted during the 
screening period. The investigational site mw;t wait for the results of the SAFER interview before enrolling the subject into the treabuent phase of the study. 
Screening period may be extended to 21 days with approval from the medical monitor. 


 
 
  
 
 
 
 
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Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
IND No. 135256 
Protocol 1042-PPD-2003 
  
OL QHS 4-Week 
VISIT 
Screening 
Dayl 
Day2 
Day8 
D15 
Day22 
Day29 
Day36 
DaY59 
DayS9 
Day 119 
{VI ) 
(V2) 
(' 3) 
(V4) 
(VS) 
('T6) 
(V7) 
(' 8; l st 
{V9~ 2nd 
(VlO; 3n1 ('TU; 4111 
FU) 
FU) 
FU) 
FU) 
Informed consent 
X 
Demographics. medical hi.story 
X 
IMI1'H neuroosvchiatric interview 
X 
Inclusion.lExdusion criteria 
X 
X 
Randomize patient (DB only) 
X 
Dispense medication / Return 
X 
X 
X 
X 
X 
X 
X 
!Accountability 
Concomitant Medications and Prior 
Therapy Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
SAFER Interviev,r (during screening) 
X 
Vital signs IBP, Pulse, RR, 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height (screening only) and weight 
X 
X 
X 
X 
ECGs 
X 
X 
X 
X 
Safety Laboratory Tests 
X 
X 
X 
X 
X 
X 
PK sample collection 
X 
X 
X 
X 
X 
X 
Neurosteroid sample collection 
X 
X 
X 
X 
X 
X 
X 
Urine Drug Screen and Pregnancy Tests 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HA!YID17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
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 
STA.16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CSSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
sss 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Start Tao-er 
X 
The follO\ving priority order will be in effect when more than 1 assessment is required at a particular time point: 1) HAMDl 7 2) CGI-I/CGI-S 3) EPDS 
4) STA.16 5) SSS 6) CSSRS 7) vital signs 8) ECG 9) safety fabs 10) neurnsteroid sample 11) PK sample 12) urine drug scree-n and pregnancy test 13) physical 
examination. SAFER interview is scheduled if subject meets the eligibility criteria at the Screening visit. The SAFER interview will be conducted during the 
screening period. TI1e investigational site must wait for the results of the SAFER interview before enrolling the subject into the treatment phase -of the study. 
Screening period may be extended to 21 days with approval from the medical monitor. 


 
 
  
 
 
 
 
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Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
IND No. 135256 
Protocol 1042-PPD-2003 
  
OL 1125 mg and OL Bolus-Oral 
 
\-'ISIT 
Se1·eening Dayl 
Day2 Day8 ±3d Dl5±3d Day22 ±3d Day29±3d Day36 ±3d 
Day57 ±3d Day I ±3d 
(VI) 
(V2) 
(V3) 
(V4) 
(VS) 
(\ 6) 
(\"7) 
(V8; 1st FU) (\'9; 2nd FU) (\· 10; 3 n1 FU) 
Infonned consent 
X 
Demo,graphics, medical history 
X 
MINI neuropsychiatric interviev,r 
X 
Indusion/Exdusion criteria 
X 
X 
Dispense medication / Return 
X 
X 
X 
X 
X 
X 
X 
Accountability 
Concomitant Medications and Prior 
Therapy Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phvsical examination 
X 
X 
SAFER Interview ( during scree.ning) 
X 
Vital sil!l.1s ffiP, Pulse, RR. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height (screening only) and weight 
X 
X 
X 
X 
X 
ECGs 
X 
X 
X 
X 
X 
X 
X 
Safety Laboratory Tests 
X 
X 
X 
X 
X 
X 
0 Bolus (OL Bolus-Ornl 2:rnup only) 
X 
PK sample colle.ction 
X 
X 
X 
X 
X 
X 
PK subgroup sample collection 
' X 
N eurosteroid sample collection 
X 
X 
X 
X 
X 
X 
X 
Urinalysis, Drug Screen and Pregnancy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record AE.5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
3 HAMD1 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-1 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-S 
X 
X 
EPDS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
STAI6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CSSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
sss 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Start Taper 
X 


 
 
  
 
 
 
 
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Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
IND No. 135256 
Protocol 1042-PPD-2003 
  
 
• CTNI will conduct all HA1vID ratings except the one a-t scree0ning 
b IV bolus is to be done at approximately 4 pm (preferably \Vithin ±1 hour) and allowing for at least I -hour post-bolus follo,v-up at the site before discharge 
< A sub-group of 6 subjects. (to be called ·pK sub-group') in each of the OL 1,125 mg and OL Bolus-Oral groups will stay overnight on the unit between Day 1 
and Day 2 to undergo comprehensive PK assessment as follows: for the OL I, 125 mg group plasma samples for PK analysis ,vill be drawn at the following tLmes 
after the first oral dose on Day 1 (e.g. the 675 mg oral capsules dose at 7 pm at dinner time; Ohr) +lhr, +2hr, +3hr (i.e , just prior to the 10 pm 675 mg dose), at 
+4hr, +Shr, +6hr, and at 8 am on Day ._ For the OL Bolus-Oral grot1p plasma. samples for PK analyses will be drawn at the following times after t11e IV bolus on 
Day 1 (e.g., the 12 mg IV bolus at 4 pm; Ohr): 1hr, +2hr, +3hr (i.e., just prior to the first oral dos,e of 750 mg oral suspension at dinner time), at 4hr, +5hr, +6hr 
(i.e., just prior to the secood 750 mg oral suspension evening dose), at+ 7hr, 8hr, and at 8 am on Day 2. 
The follmving priority order will be in effect when more than 1 assessment is i,equired at. a particular time point: 1) HAMD 17 2) CGI- CGI-S 3) EPDS 
4) STAI6 5) SSS 6) CSSRS 7) vital signs 8) ECG 9) safety fabs 10) neurosteroid sample 11) PK sample 12) urinalysis, urine drug screen and pregnancy te.st 13) 
physical examination. SAFER interview is scheduled if subject meets the eligibility criteria at ilie Screening visit. The AFER interview will be conducted 
during the screening period. The investigational site must wait for the results of the SAFER intenrie\v before enrolling the subject into the treatment phase of the 
study. Screening period may be extended to 21 days with approval from the medical monitor. 


 
 
  
 
 
 
 
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Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
IND No. 135256 
Protocol 1042-PPD-2003 
  
APPENDIX B: TABLES OF CONTENTS FOR TABLES, FIGURES, AND LISTINGS 
 
TABLES 
STUDY POPULATION 
14.1.1 
Number of Subjects by Study Visit 
14.1.2 
Subject Disposition 
14.1.3.1 
Inclusion/Exclusion Criteria Not Met 
14.1.3.2 
Protocol Deviations 
14.1.4 
Analysis Populations 
14.1.5.1 
Demographics 
14.1.5.2 
Medical History 
14.1.5.3 
MINI 
14.1.5.4 
SAFER 
14.1.5.5 
CGI‐S 
14.1.5.6.1 
Pre‐Treatment AEs 
14.1.5.6.2 
Pre‐Treatment SAEs 
14.1.5.6.1 
Baseline General Medications 
14.1.5.6.2 
Baseline Psychological Medications 
14.1.5.6.3 
Baseline Psychological Treatments 
14.1.6.1 
Investigational Product Exposure 
14.1.6.2 
Investigational Product Accountability & Compliance 
 
 
EFFICACY 
 
14.2.1.1.1.1 
HAMD17 Total Score  
14.2.1.1.2.1 
HAMD17 Bech Subscale (HAMD6) 
14.2.1.1.3.1 
HAMD17 Anxiety Subscale   
14.2.1.1.4.1 
HAMD17 Gibbons Subscale   
14.2.1.2.1.1 
HAMD17 Responder Analysis 
14.2.1.3.1.1 
HAMD17 Remission Analysis 
14.2.2.1.1.1 
EPDS Total Score   
14.2.2.1.2.1 
EPDS Anxiety Subscale 
14.2.3.1.1.1 
STAI6 Total Score   
14.2.4.1.1 
CGI‐I 
 
 
SAFETY 
 
14.3.2.1 
Overall Summary of AEs 
14.3.2.1.2 
Treatment‐Emergent Adverse Events with Max Severity Annotated 
14.3.2.1.3 
Treatment‐Emergent Adverse Events Related to IP with Max Severity Annotated 


 
 
  
 
 
 
 
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Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
IND No. 135256 
Protocol 1042-PPD-2003 
  
14.3.2.1.4 
Treatment Emergent Adverse Events Leading to Study Medication Discontinuation 
14.3.2.1.5 
Treatment Emergent Adverse Events Leading to Dose Reduced or Interrupted 
14.3.2.1.6 
TEAEs by Preferred Term (descending order among all subjects combined) 
14.3.2.2.2 
Treatment‐Emergent SAEs with Max Severity Annotated 
14.3.2.2.3 
Treatment‐Emergent SAEs Related to IP with Max Severity Annotated 
14.3.2.2.4 
Treatment Emergent SAEs Leading to Study or Study Medication Discontinuation 
14.3.2.2.5 
Treatment Emergent SAEs Leading to Dose Reduced or Interrupted 
14.3.2.2.6 
Treatment‐Emergent SAEs by Preferred Term (descending order) 
14.3.5.1.1 
Biochemistry 
14.3.5.1.2 
Biochemistry Out of Range 
14.3.5.1.3 
Biochemistry Shifts From Baseline 
14.3.5.2.1 
Hematology 
14.3.5.2.2 
Hematology Out of Range 
14.3.5.2.3 
Hematology Shifts From Baseline 
14.3.5.3.1 
Urinalysis (continuous) 
14.3.5.3.2 
Urinalysis (categorical) 
14.3.5.3.3 
Urinalysis Out of Range 
14.3.5.3.4 
Urinalysis Shifts From Baseline 
14.3.5.4 
Urine Pregnancy 
14.3.5.5 
Urine Drug Test 
14.3.6.1.1 
Concomitant Medications 
14.3.6.1.2 
Concomitant Psychological Medications 
14.3.6.1.3 
Concomitant Psychological Treatments
14.3.6.2 
Vital Signs 
14.3.6.3 
Weight, Height, Body Mass Index 
14.3.6.4 
Physical Examination 
14.3.6.5.1 
12‐Lead Electrocardiogram (continuous variables) 
14.3.6.5.2 
12‐Lead Electrocardiogram (categorical variables) 
14.3.6.6 
Columbia Suicide Severity Rating Scale (CSSRS) 
14.3.6.7 
Stanford Sleepiness Scale (SSS) 
 
 
 


 
 
  
 
 
 
 
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Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
IND No. 135256 
Protocol 1042-PPD-2003 
  
FIGURES 
EFFICACY 
 
14.2.1.1.1.1.1 
HAMD17 Total Score Dynamite Plot   
14.2.1.1.1.3.1 
HAMD17 Total Score Line Plot   
14.2.1.1.2.1.1 
HAMD17 Bech Subscale (HAMD6) Dynamite  Plot 
14.2.1.1.2.3.1 
HAMD17 Bech Subscale (HAMD6) Line Plot 
14.2.1.1.3.1.1 
HAMD17 Anxiety Subscale Dynamite Plot 
14.2.1.1.3.3.1 
HAMD17 Anxiety Subscale Line Plot   
14.2.1.1.4.1.1 
HAMD17 Gibbons Subscale Dynamite Plot   
14.2.1.1.4.3.1 
HAMD17 Gibbons Subscale Line Plot   
14.2.1.1.6.4.1 
HAMD17 Individual Items Matrix Plot 
14.2.1.2.1.1 
HAMD17 Response 
14.2.1.3.1.1 
HAMD17 Remission 
14.2.2.1.1.1.1 
EPDS Total Score Dynamite Plot   
14.2.2.1.1.3.1 
EPDS Total Score Line Plot   
14.2.2.1.2.1.1 
EPDS Anxiety Subscale Dynamite Plot   
14.2.2.1.2.3.1 
EPDS Anxiety Subscale Line Plot   
14.2.1.1.3.4.1 
EPDS Individual Items Matrix Plot 
14.2.3.1.1.1.1 
STAI6 Total Score Dynamite Plot   
14.2.3.1.1.3.1 
STAI6 Total Score Line Plot   
14.2.3.1.2.4.1 
STAI6 Individual Items Matrix Plot 
14.2.4.1.1.1 
CGI‐I Improved vs Not 
14.2.4.2.3.1 
CGI‐I Score Line Plot   
 
 
SAFETY 
 
14.3.6.7.1.3.1 
SSS Line Plot  
 
 
 


 
 
  
 
 
 
 
Page 39 of 40 
 
Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
IND No. 135256 
Protocol 1042-PPD-2003 
  
LISTINGS 
 
STUDY POPULATION 
16.2.1.1 
Critical Dates and Scheduled Visits 
16.2.1.2 
Subject Study Visits 
16.2.1.3 
Subject Disposition 
16.2.2.1 
Informed Consent 
16.2.2.2 
Eligibility & Randomization 
16.2.2.3 
Protocol Deviations 
16.2.3 
Analysis Populations 
16.2.4.1 
Demographics 
16.2.4.2 
Medical History 
16.2.4.3.1 
MINI 
16.2.4.3.2 
SAFER 
16.2.4.3.3 
CGI‐S 
16.2.4.4.1 
Pre‐Treatment AEs 
16.2.4.4.2 
Pre‐Treatment SAEs 
16.2.4.5.1 
Baseline General Medications 
16.2.4.5.2 
Baseline Psychological Medications 
16.2.4.5.3 
Baseline Psychological Treatments 
16.2.5.1 
Investigational Product Exposure 
16.2.5.2 
Investigational Product Accountability & Compliance 
 
 
EFFICACY 
 
16.2.6.1 
Hamilton Depression Rating Scale (HAMD) 
16.2.6.2 
Edinburgh Postnatal Depression Scale (EPDS) 
16.2.6.3 
Spielberger Trait‐State Anxiety Inventory (STAI6) 
16.2.6.4 
Clinical Global Impression ‐ Improvement (CGI‐I) 
16.2.6.5 
Obsessive Thoughts 
 
 
SAFETY 
 
16.2.7.1 
Treatment‐Emergent Adverse Events (TEAEs) 
16.2.7.2 
Treatment‐Emergent Serious Adverse Events (TESAEs) 
16.2.7.3 
TEAEs Resulting in IP Discontinuation 
16.2.7.4 
TEAEs Resulting in Dose Reduction or Interruption 
16.2.7.5 
TEAEs Resulting in Death 
16.2.8.1 
Biochemistry 
16.2.8.2 
Hematology 
16.2.8.3 
Urinalysis 
16.2.8.4 
Urine Pregnancy 
16.2.8.5 
Urine Drug Test 
16.2.8.6 
Lab Sample Collection 


 
 
  
 
 
 
 
Page 40 of 40 
 
Marinus Pharmaceuticals, Inc 
Statistical Analysis Plan. 
Version 1.0, November 15, 2018   
IND No. 135256 
Protocol 1042-PPD-2003 
  
16.2.9.1.1 
Concomitant Medications 
16.2.9.1.2 
Concomitant Psychological Medications 
16.2.9.1.3 
Concomitant Psychological Treatments 
16.2.9.2 
Vital Signs 
16.2.9.3 
Weight, Height, Body Mass Index 
16.2.9.4 
Physical Examination 
16.2.9.5 
12‐Lead Electrocardiogram 
16.2.9.6 
Columbia Suicide Severity Rating Scale (CSSRS) 
16.2.9.7 
Stanford Sleepiness Scale (SSS)