Clinical trial NCT03350035
Conditions: Status Epilepticus Convulsive Status EPILEPTICUS Non Convulsive Status Epilepticus Epilepsy
Sponsor: Marinus Pharmaceuticals
Start date: 2018-02-19; Completion date: 2019-09-18
Enrollment: 17 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the effectiveness and safety of an investigational drug, IV ganaxolone, as adjunctive therapy to standard of care to treat subjects with status epilepticus.

Detailed description:
This is a double-blind, randomized, placebo-controlled study to evaluate the safety, tolerability, and efficacy of adjunctive IV ganaxolone in subjects with SE.

Study drug will be added to standard of care before IV anesthetic during the treatment of SE.

Subjects will be screened for inclusion/exclusion criteria prior to receiving study drug as adjunctive therapy by continuous IV. Subject's will be followed up for 3 weeks post-treatment.

Subjects who are known to be at risk for SE may be consented and/or assented prior to an SE event.

Arms: arm 1: Ganaxolone IV loading dose with continuous infusion (maintenance dose) for 2-4 days followed by an 18-hour taper. arm 2: Placebo IV loading dose with continuous infusion (maintenance dose) for 2-4 days followed by an 18-hour taper.
Interventions: intervention 1: IV Ganaxolone active intervention 2: IV Placebo, non-active
Intervention descriptions: intervention 1: IV intervention 2: IV

Protocol documents:
Prot_002.pdf: 
 
 
 
PROTOCOL: 1042-SE-2001 
TITLE: 
A double-blind randomized, placebo-controlled study to evaluate the 
safety, tolerability, efficacy, and pharmacokinetics of intravenous 
ganaxolone as adjunctive therapy to treat subjects with status epilepticus 
DRUG: 
Ganaxolone  
IND: 
129,433 
EUDRACT NO.: 
TBD 
SPONSOR: 
Marinus Pharmaceuticals, Inc. 
5 Radnor Corporate Center 
100 Matsonford Road, Suite 500  
Radnor, PA 19087 USA 
PROTOCOL 
HISTORY: 
Protocol Amendment 4: 07 August 2019, Version 5.0 
Protocol Amendment 3: 24 January 2019, Version 4.0 
Protocol Amendment 2:  10 May 2018, Version 3.0 
Protocol Amendment 1: 26 January 2018, Version 2.0 
Original Protocol: 29 September 2017, Version 1.0 
 
 
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. 


IND 129433 
Protocol t 042-SE-200 I 
PROTOCOL SIGNATURE PAGE 
Sponsor's (M 
Signature: 
pp 
M.D., Ph. 
Clinical Development 
Investigator's Acknowledgement 
I have read this protocol for Marinus Study 1042-SE-2001. 
Date: 
Marinus Pharmaceuticals, Inc. 
Version 5.0 
Title: A double-blind randomized, placebo-controlled study to evaluate the safety, tolerability, 
efficacy, and pharmacokinetics of intravenous ganaxolone as adjunctive therapy to treat subjects 
with status epilepticus. 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: ----------------
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SUMMARY OF CHANGES FROM PREVIOUS VERSION 
Protocol Amendments 
Summa1·y of Change(s) Since Last. Version of Approved Protocol 
Amendment Number 
Amendment Date 
Global/Country/Site Specific 
4 
07 August 2019 
Global 
Description of Change 
Section(s) Affected by Change 
Updated Marinus' office location and Marinus study team titles 
Front page, Emergency Contact Infonnation, 
Additional Contact Information 
Added abbreviations 
Abbreviations 
Updated the estimated enrollment numbers 
Synopsis and Section 3. I 
Changed all protocol references of ganaxolone to ganaxolone IV 
Synopsis and Sections 3.1, 5.2.1, 6.1, 6.3.1, 
solution; updated study drug fo1mulation from the 3 mg/mL vials 
6.3.2, 6.3.3, 8.2.1 
to 125 mL vials containing 100 mL of ganaxolone at a 
concentration of I mg/mL for the open-label group and study 
dtug details for tlte double-blind group 
Added qualifying text when referencing failure of first 2nd line IV 
Synopsis and Sections 2.2, 2.2.1, 3.1, 6.2.3, 
AED therapy 
7.1.2.1 
Added need for IV anesthetic dtugs as a secondaiy objective 
Synopsis and Section 2.2.2 
Added brivaracetam as a pe1mitted IV AED and clarified that 
Synopsis, Table I footnote h, and Sections 
administering fosphenytoin and/or phenytoin will be counted as 
4.1, 5.2.2, 7.2.3.5 
one (I) AED 
Updated study dtug infusion doses (mg/hour and mg/kg/hour) and 
Synopsis, Table I and Sections 3.1, 6.2.3, 
treatment duration (2 days which includes a 12-hour taper), and 
Table 2 & 3, 7.1.2.1, 7.1.2.2 
all references in the protocol that daily dose of ganaxolone is ~ 
830 mg/day, and that SE must be confumed immediately prior to 
study dtug bolus start 
Revised the dosing regimen under the increased Captisol level 
Synopsis and Section 6.2.3 
with the caveat that the dose may be further adjusted based on 
safety and efficacy findings for the open-label group and 
communicated through a future Protocol Adtninistrative Change 
Memo; deleted all references that "revisions will be inco1porated 
into the next amendtnent of the Protocol" 
Updated the nwnber of hours medical personnel must be present 
Synopsis and Section 6.2.3 
after sta1t of study dtug adtninistration 
Added guidance for introducing new IV AEDs 
Synopsis and Section 6.2.3 
Added 2 scenarios for stopping study dtug without a taper 
Synopsis and Sections 6.2.3, 7. 1.3 
Added guidance regarding dose adjustments and intenuptions and 
Synopsis and Section 6.2.3 
that the Mai·inus Medical Monitor must approve re-sta1t of 
infusion for intenuptions > 6 hours 
As there is no longer an option to extend the study dtug treatment 
Synopsis and Section 7.2.2.1 
for four days, removed reference to EEG seizure burden 
calculation 
Updated the required and variable collection timepoints for safety 
Synopsis, Table I, and Sections 7.2.2.1, 
and efficacy assessments/procedures; added Modified Ranking 
7.2.2.2, 7.2.2.3, 7.2.2.4, 7.2.2.5, 7.2.2.6, 
Scale (MRS), Full Outline ofUnResponsiveness (FOUR) Scale 
and Intubation Question; added 2 questions to the Seizw·e and SE 
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Questionnaire. Removed collection timepoints from specific 
assessment/procedure text in Section 7 
7.2.2.7, 7.2.3.3, 7.2.3.4, 7.2.3.6, 7.2.3.7, 
7.2.3.8 
Expanded collection requirements for Blood Gas  
Synopsis, Table 1 footnote n, and Section 
7.2.3.5 
Added guidance on the collection locations for the 
pharmacokinetic and neurosteroid samples 
Synopsis, Table 1 footnotes l and m, and 
Section 7.2.4.1, Table 4 and 5 
Added collection requirements for cerebral spinal fluid, if a 
lumbar puncture is performed per investigator’s discretion as part 
of their care, and if there is adequate volume for future analysis of 
ganaxolone   
Synopsis, Table 1 footnote o, and Section 
7.2.4.3.1, 9.9 
Listed examples of IV anesthetics including ketamine  
Synopsis, Table 1 footnote u, and Sections 
4.2,5.2, 5.2.2,7.1.3 
Added that “a 4th line treatment”, “a 4th line treatment e.g., 
immunosuppressants, magnesium” is prohibited  
Synopsis and Sections 5.2.2, 6.2.3, 7.1.3 
Modified when AEs and concomitant medications will be 
collected and added specific AEs that need to be recorded during 
the weekly follow-up visits. 
Synopsis, Table 1, and Sections 5.2, 8.1, 
Modified exclusion criterion #8 to exclude subjects who are 
currently on dialysis but allow subjects to start dialysis during the 
study 
Synopsis and Sections 4.2, 4.5.1 
Modified secondary endpoints for level of responsiveness to 
include the Four Score Scale and RASS; for clinical outcome the 
Modified Ranking Scale will be used; for hospital metrics 
including length of stay, need for and duration of intubation and 
mechanical ventilation.  
Synopsis and Sections 2.2, 9.7.2 
Table 1 Visit/Timepoint or Duration updated to support revised 
study design; footnotes updated to support revised required and 
variable collection timepoints 
Table 1 
Updated the Study Flow Diagram to reflect the revised dosing 
regimen. 
Figure 1 
Added clarity for subjects who discontinue by separating subjects 
who discontinue from study drug and subjects who withdrawal 
from the study   
Section 4.5 
Removed duplicate text describing prior concomitant treatment; 
revised collection requirements for concomitant treatment 
Section 5.1 
Expanded the guidance on administration of background oral 
AEDs if their administration is interrupted during the study 
Section 5.2.2 
Added statement that the Investigator’s Brochure has not been 
updated with the 1 mg/mL, ganaxolone IV solution formulation at 
this time but will be amended with the annual update 
Section 8.2.1 
Updated timeline for entering data into EDC 
Section 9.1 
Added exploratory endpoints to assess pressor administration and 
treatment of severe cardiovascular and respiratory events 
Section 9.7.3 
Added that APACHE or APACHE 2 score may be used as a 
prognostic tool in calculating mortality 
Section 9.8 


 
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Updated the Study Decision Tree 
Appendix 1 
Added Summary of Changes Table from Protocol Amendment 3 
Appendix 2 
Revisions made in the document to standardize text throughout 
the protocol such as: study drug initiation for dose initiation and 
dose start; study drug discontinuation for study drug stop; 24-hour 
post taper to in-patient follow-up day; subject for participant  
 
Additional grammatical, typographical errors and formatting 
revisions have been made in the document but are not identified 
here 
 
 


 
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EMERGENCY CONTACT INFORMATION 
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Marinus 
Serious Adverse Event form within 24 hours to the Marinus Safety Department or delegate. A 
copy of this form must also be sent to the contract research organization (CRO)/Marinus Medical 
Monitor by e-mail using the details below. 
Email: safetySE2001@marinuspharma.com 
Fax: +1 484-679-2151  
In addition, for protocol- or safety-related issues the investigator must contact the Marinus 
Medical Monitor: 
: 
, MD, PhD 
Email:
Office Telephone Number: 
 
Mobile Telephone Number:
(primary contact method via text or call to this 
number and followed by e-mail) 
 
If unavailable: 
 M.Ed. 
 Clinical Development Operations 
Marinus Pharmaceuticals, Inc. 
Email:
Office Telephone Number: 
 
Mobile Telephone Number: 
(primary contact method via text or call to this 
number followed by e-mail) 
 


 
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ADDITIONAL CONTACT INFORMATION 
In case of any other issues including non–safety-related issues or if the Medical Monitor is 
unable to be reached, the Investigator must contact the Marinus Program or Trial Manager:  
Marinus Program Manager: 
 M.Ed. 
 Clinical Development Operations 
Marinus Pharmaceuticals, Inc. 
Email: 
Office Telephone Number: 
Mobile Telephone Number: 
(primary contact method via text or call) 
 
Marinus Trial Manager: 
 BSN 
Marinus Pharmaceuticals, Inc. 
Email:
Office Telephone Number: 
Mobile Telephone Number:  
(primary contact method via text or call) 
 
 


 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................................2 
SUMMARY OF CHANGES FROM PREVIOUS VERSION ........................................................3 
EMERGENCY CONTACT INFORMATION ................................................................................6 
ADDITIONAL CONTACT INFORMATION ................................................................................7 
LIST OF TABLES .........................................................................................................................12 
LIST OF FIGURES .......................................................................................................................12 
LIST OF APPENDICES ................................................................................................................12 
ABBREVIATIONS .......................................................................................................................13 
1. 
BACKGROUND INFORMATION .......................................................................................36 
1.1 
Indication and Current Treatment Options ...............................................................36 
1.2 
Product Background and Clinical Information ........................................................37 
2. 
STUDY OBJECTIVES AND PURPOSE ..............................................................................40 
2.1 
Rationale for the Study .............................................................................................40 
2.2 
Study Objectives ......................................................................................................42 
2.2.1 Primary Objective ..................................................................................................42 
2.2.2 Secondary Objectives .............................................................................................42 
 
3. 
STUDY DESIGN ...................................................................................................................42 
3.1 
Study Design and Flow Chart ..................................................................................42 
3.2 
Duration and Study Completion Definition .............................................................44 
3.3 
Sites and Regions .....................................................................................................44 
4. 
STUDY POPULATION .........................................................................................................44 
4.1 
Inclusion Criteria ......................................................................................................45 
4.2 
Exclusion Criteria .....................................................................................................45 
4.3 
Restrictions ...............................................................................................................46 
4.4 
Reproductive Potential .............................................................................................46 
4.4.1 Female Contraception ............................................................................................46 
4.4.2 Male Contraception ................................................................................................47 
4.5 
Discontinuation of Subjects .....................................................................................47 
4.5.1 Subject Withdrawal Criteria ..................................................................................48 
4.5.2 Reasons for Discontinuation ..................................................................................49 
4.5.3 Subjects Lost to Follow-up Prior to Last Scheduled Visit .....................................49 
5. 
PRIOR AND CONCOMITANT TREATMENT ...................................................................49 
5.1 
Prior Treatment ........................................................................................................49 
5.2 
Concomitant Treatment ............................................................................................49 
5.2.1 Permitted Treatment ...............................................................................................50 
5.2.2 Prohibited Treatment .............................................................................................50 


 
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6. 
STUDY DRUG .......................................................................................................................51 
6.1 
Identity of Study drug ..............................................................................................51 
6.1.1 Blinding the Treatment Assignment ......................................................................52 
6.2 
Administration of Study drug(s) ..............................................................................52 
6.2.1 Interactive Response Technology for Study Drug Management ...........................52 
6.2.2 Allocation of Subjects to Treatment ......................................................................52 
6.2.3 Dosing ....................................................................................................................53 
6.2.4 Unblinding the Treatment Assignment ..................................................................58 
6.3 
Labeling, Packaging, Storage, and Handling ...........................................................58 
6.3.1 Labeling .................................................................................................................58 
6.3.2 Packaging ...............................................................................................................59 
6.3.3 Storage ...................................................................................................................60 
6.4 
Drug Accountability .................................................................................................60 
6.5 
Subject Compliance ..................................................................................................61 
7. 
STUDY PROCEDURES ........................................................................................................61 
7.1 
Study Schedule .........................................................................................................61 
7.1.1 Screening Period ....................................................................................................62 
7.1.1.1 
Screening ................................................................................................62 
7.1.2 Treatment Period ....................................................................................................62 
7.1.2.1 
Study Drug Initiation Through In-patient Follow-up Day (Day 1 to 
Day 3) .....................................................................................................62 
7.1.3 Follow-up Period ...................................................................................................62 
7.1.4 Additional Care of Subjects After the Study .........................................................63 
7.2 
Study Evaluations and Procedures ...........................................................................63 
7.2.1 Demographic and Other Baseline Characteristics .................................................63 
7.2.2 Efficacy ..................................................................................................................64 
7.2.2.1 
EEG ........................................................................................................64 
7.2.2.2 
Status Epilepticus Severity Score (STESS) ...........................................64 
7.2.2.3 
Glasgow Coma Scale (GCS) and Pediatric Glasgow Coma Scale 
(PGCS) ...................................................................................................64 
7.2.2.4 
Clinical Global Impression of Severity and Improvement (CGI-S 
and CGI-I, respectively) .........................................................................64 
7.2.2.5 
Richmond Agitation and Sedation Scale (RASS) ..................................64 
7.2.2.6 
Status Epilepticus and Seizure Questions ..............................................64 
7.2.2.7 
Intubation Question ................................................................................65 
7.2.3 Safety .....................................................................................................................65 
7.2.3.1 
Medical and Medication History ............................................................65 
7.2.3.2 
Physical and Neurologic Examination ...................................................65 
7.2.3.3 
Adverse Event Collection .......................................................................66 


 
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7.2.3.4 
Vital Signs ..............................................................................................66 
7.2.3.5 
Clinical Laboratory Evaluations .............................................................67 
7.2.3.6 
Electrocardiography ...............................................................................68 
7.2.3.7 
Modified Rankin Scale (MRS) ...............................................................68 
7.2.3.8 
Full Outline of UnResponsiveness (FOUR) Score ................................68 
7.2.4 Others .....................................................................................................................68 
7.2.4.1 
Clinical Pharmacology Blood Sample Collection and Handling 
Procedures ..............................................................................................68 
7.2.4.2 
Shipment of Plasma Pharmacokinetic Samples .....................................69 
7.2.4.3 
Plasma Drug Assay Methodology ..........................................................69 
7.2.4.3.1 
Cerebral Spinal Fluid (CSF) ...................................................................69 
7.2.4.4 
Neurosteroid Blood Sample Collection and Handling Procedures ........70 
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 Relationship Categorization ...................................................................................74 
8.1.3 Outcome Categorization ........................................................................................74 
8.1.4 Symptoms of the Disease Under Study .................................................................75 
8.1.5 Clinical Laboratory and Other Safety Evaluations ................................................75 
8.1.6 Pregnancy ...............................................................................................................75 
8.1.7 Abuse, Misuse, Overdose, and Medication Error ..................................................76 
8.2 
Serious Adverse Event Procedures ..........................................................................77 
8.2.1 Reference Safety Information ................................................................................77 
8.2.2 Reporting Procedures .............................................................................................77 
8.2.3 Serious Adverse Event Definition .........................................................................77 
8.2.4 Serious Adverse Event Collection Time Frame .....................................................78 
8.2.5 Serious Adverse Event Onset and Resolution Dates .............................................78 
8.2.6 Fatal Outcome ........................................................................................................78 
8.2.7 Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................79 
9. 
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................79 
9.1 
Data Collection .........................................................................................................79 
9.2 
Clinical Data Management .......................................................................................79 
9.3 
Statistical Analysis Process ......................................................................................79 
9.4 
Sample Size, Planned Interim Analysis, Adaptive Design, and Data 
Monitoring Committee .............................................................................................80 
9.5 
Sample Size Calculation and Power Considerations ................................................81 
9.6 
Study Population ......................................................................................................81 


 
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9.7 
Efficacy Analyses .....................................................................................................82 
9.7.1 Primary Efficacy Endpoint ....................................................................................82 
9.7.2 Secondary Endpoints .............................................................................................82 
 
9.8 
Safety Analyses ........................................................................................................83 
9.9 
Other Analyses .........................................................................................................83 
9.9.1 Pharmacokinetic Analyses .....................................................................................84 
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ...........................................84 
10.1 
Sponsor’s Responsibilities .......................................................................................84 
10.1.1 Good Clinical Practice (GCP) Compliance ...........................................................84 
10.1.2 Public Posting of Study Information ......................................................................85 
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees ...........................................85 
10.1.4 Study Suspension, Termination, and Completion..................................................85 
10.2 
Investigator’s Responsibilities .................................................................................85 
10.2.1 Good Clinical Practice Compliance .......................................................................85 
10.2.2 Protocol Adherence and Investigator Agreement ..................................................86 
10.2.3 Documentation and Retention of Records .............................................................86 
10.2.3.1 
Case Report Forms .................................................................................86 
10.2.3.2 
Recording, Access, and Retention of Source Data and Study 
Documents ..............................................................................................87 
10.2.3.3 
Audit/Inspection .....................................................................................87 
10.2.3.4 
Financial Disclosure ...............................................................................87 
10.3 
Ethical Considerations ..............................................................................................87 
10.3.1 Informed Consent...................................................................................................87 
10.3.2 Institutional Review Board or Ethics Committee ..................................................88 
10.4 
Privacy and Confidentiality ......................................................................................89 
10.5 
Study Results/Publication Policy .............................................................................89 
11. REFERENCES .......................................................................................................................91 
12. APPENDICES ........................................................................................................................94 
 


 
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LIST OF TABLES 
Table 1: 
Schedule of Assessments ...............................................................................29 
Table 2: 
Dosing for Subjects ≥ 40 kg (on an mg/hour basis) ......................................55 
Table 3: 
Dosing for Subjects < 40 kg (on an mg/kg/hour basis) .................................56 
Table 4: 
Volume of Blood to Be Drawn from Each Subject .......................................71 
Table 5: 
Volume of Blood to Be Drawn from Each Subject (Pediatric Hospital 
Sample Volumes) ..........................................................................................72 
Table 6: 
Interim Analysis Variables ............................................................................80 
Table 7:  
O’Brien-Fleming Power and Sample Size Power Calculation ......................81 
 
LIST OF FIGURES 
Figure 1: 
Study Design Flow Chart ..............................................................................44 
 
LIST OF APPENDICES 
Appendix 1: 
Study Decision Tree ......................................................................................94 
Appendix 2: 
Summary of Changes Table from Previous Protocol Amendments ..............95 
 


 
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ABBREVIATIONS 
AE 
adverse event 
AUC 
area under the curve 
ALT 
alanine Aminotransferase 
AST 
aspartate Aminotransferase 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
Cmax 
peak plasma concentration 
CRA 
clinical research associate 
CRO 
contract research organization 
CSE 
CSF 
convulsive status epilepticus 
cerebral spinal fluid 
DMC 
data monitoring committee 
EC 
ethics committee 
ECG 
electrocardiography 
eCRF 
electronic case report form 
EEG 
electroencephalography 
eGFR 
estimated glomerular filtration rate 
ESE 
established status epilepticus 
EU 
European Union 
FDA 
FOUR 
G 
Food and Drug Administration 
Full Outline of UnResponsiveness  
gram 
GABA   
gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
GCS 
Glasgow Coma Scale 
GCSE 
generalized convulsive status epilepticus  
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 


 
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ILAE 
International League Against Epilepsy  
IM 
intramuscular 
IRB 
Institutional Review Board 
IV 
intravenous  
LAR 
MG 
legally authorized representative 
milligram 
MMSE 
MRS 
Mini Mental State Exam 
Modified Rankin Scale 
NCSE 
Non-convulsive status epilepticus 
PGCS 
Pediatric Glasgow Coma Scale 
RASS  
Richmond Agitation and Sedation Scale  
PK 
Pharmacokinetic 
RSE 
refractory status epilepticus 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SE 
status epilepticus 
SRSE 
super-refractory status epilepticus 
 
 
 


 
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STUDY SYNOPSIS 
Protocol number: 1042-SE-2001 
Drug: ganaxolone 
Title of the study: A double-blind randomized, placebo-controlled study to evaluate the safety, 
tolerability, efficacy, and pharmacokinetics of intravenous ganaxolone as adjunctive therapy to treat 
subjects with status epilepticus 
Number of subjects (total and for each treatment arm): 
A total number of approximately 340 subjects will be screened to allow for up to approximately 
272 subjects to receive study drug.  
Open-label pharmacokinetic group: This open-label pharmacokinetic group will enroll up to 
approximately 30 males and females, at least 12 years of age to confirm that the dose selected will 
achieve an approximate targeted plasma concentration of ganaxolone in the status epilepticus (SE) 
population who are on concomitant medications, and to obtain a preliminary assessment of safety, 
efficacy and feasibility of ganaxolone administration. Enrolled subjects will receive ganaxolone IV 
solution as adjunctive therapy to their standard of care. Subjects who early terminate for reasons 
other than lack of efficacy or adverse events related to ganaxolone (e.g., pump failure and other 
operational issues) may be replaced. 
Double-blind group: This double-blind, placebo-controlled group will screen a sufficient number of 
subjects to randomize 242 males and females, at least 12 years of age with SE.  Randomized subjects 
will receive ganaxolone IV solution or placebo in a 1:1 ratio as adjunctive therapy to their standard of 
care. 
Investigator(s): Multicenter study 
Site(s) and Region:  
Multicenter study to be conducted globally at approximately 150 sites 
Study period (planned): June 2018 to May 2020  
Clinical phase:  2 
Objectives: 
Primary: 
 To establish that intravenous ganaxolone given concomitantly with 2nd line IV AED therapy is 
safe and effective in stopping status epilepticus that has already failed one 2nd line IV AED 
therapy that has been administered at an appropriate dose and duration to show efficacy and 
prevents escalation of treatment requiring an IV anesthetic drug (a 3rd line treatment) for 
seizure suppression 
 Secondary:  
 To assess other secondary efficacy endpoints such as mortality and seizure cessation in SE 
subjects 
 To assess the pharmacokinetics of adjunctive IV ganaxolone in SE subjects 
 To assess the need for IV anesthetic drugs for treatment of current SE event in SE subjects 


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Rationale: 
Status epilepticus (SE) is defined as a prolonged self-sustaining seizure or recmTent seizures without 
recove1y of consciousness between seizures. 1 The International League of Against Epilepsy fmi her 
defined SE as a condition resulting either from the failme of mechanisms responsible for seizme 
tennination or from the initiation of mechanisms, which lead to abno1mally, prolonged seizures 
(5 minutes for tonic-clonic SE and 10 minutes for focal SE with impaired consciousness) and which 
can have long-te1m consequences (after 30 minutes for tonic-clonic SE and >60 minutes for focal SE 
with impaired consciousness), including neuronal death and/or injmy, and alteration of nemonal 
networks, depending on the type and dmation of seizmes.1 SE is a neurological emergency that 
requires aggressive treatment to stop the seizmes and prevent pe1manent nemological damage. 3 
Mo1iality due to SE can range from 3% to 40% depending on etiology, age, SE type, and SE 
duration. 5 SE can be recognized clinically or using electroencephalograms (EEGs) by the presence 
of continuous ictal discharges.3 Studies have shown that SE can cause nemonal death via excitotoxic 
mechanisms as a result of excessive neuronal firing. 6 Fmihe1more, convulsive SE is associated with 
many complications, including cardiac anhythmias, rhabdomyolysis, pulmonaiy edema, electrolyte 
and glucose imbalance, and temperature distmbances. Approximately one third of subjects with 
refracto1y status epilepticus (RSE) and super refracto1y status epilepticus (SRSE) will die of their 
condition; one-third recover but with chronic neurologic or other deficits, and one third have been 
generally described as retmning to baseline. The prognosis worsens the longer subjects are kept in a 
medically-induced coma. The primaiy goal of SE treatment is to gain control of the seizmes rapidly 
and avoid complications, and treatment typically occurs in stages.2 In general, the treatment of SE is 
ve1y aggressive and paiiiculai·ly m gent for convulsive status epilepticus (CSE). 
The cunent therapies for SE have inherent risks, which must be balanced against the benefit of rapid 
seizme control. Benzodiazepines ai·e the agents of choice for first line treatment of SE but their use 
can cause respirato1y depression and hypotension, requiring the use of suppo1iive therapies.2 
Unfortunately, approximately 35-45% of patients are refracto1y to benzodiazepines. Second line 
therapy involves administration of an IV AED such as fosphenytoin, valproic acid, or levetiracetain 
for convulsive tonic-clonic status with the goal of stopping SE in patients who did not respond to first 
line treatment. 2 When a patient with SE fails to respond to a benzodiazepine and the initial 2nd line 
[AED] therapy they ai·e classified as having RSE. RSE develops in 31-44% of patients with SE, with 
a mo1iality of 16-39%.17.19 Additional therapeutic agents ai·e required immediately; typically, 
anesthetics via continuous infusion.2 CmTently, the recollllllended anesthetic diugs include 
midazolam, propofol, thiopental, and pentobarbital. Anesthetics are associated with risks, especially 
if adininistered for a long time - propofol infusion syndi·ome and hypotension are two recognized 
adverse events associated with anesthetics for SE treatment. In addition, the need for assisted 
ventilation and the management of hypotension and cardiopulmonaiy depression have their own 
risks.2 
Few therapies ai·e approved for the treatment of SE and the m gent need for more efficacious 
therapies remains. Only two-thirds of patients in SE respond to first-line treatment.3 Resistance to 
treatment has been aiiiall attributed to the internalization of ost-s na tic GABAA-rece tors and 
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externalization of glutamate receptors.3 As prolonged epileptiform bursting results in a reduction of 
GABAA-mediated synaptic inhibition, antiepileptic treatments which rely on enhancing intra-
synaptic GABAA neurotransmission become less effective the longer SE continues.  
Ganaxolone is a potent allosteric positive modulator of GABAA receptors in the brain at a site 
distinct from the site of action of benzodiazepine receptor agonists and barbiturates.  γ-aminobutyric 
acid (GABA) is recognized as the principal inhibitory neurotransmitter in the cerebral cortex, and a 
disturbance in GABA-mediated functions results in the occurrence of epileptic seizures.5 By 
enhancing the GABAA receptor function, ganaxolone provides an alternative mechanism in the 
treatment of seizures, and serves as effective therapy in the management of SE. Ganaxolone has been 
shown to stop SE in 2 distinct pre-clinical models of benzodiazepine-resistant SE.  
Ganaxolone for this study is a proprietary IV formulation solubilized by Captisol® (betadex 
sulfobutyl ether sodium). The study targets plasma concentrations of ganaxolone that mimic 
concentrations associated with anticonvulsant effects in preclinical animal models of SE and that are 
expected to demonstrate anticonvulsant properties in humans.  
The maximum level of Captisol® will not exceed 50 grams per day as agreed upon with the FDA. 
Study drug, Dose, and Mode of Administration:  
Once consent has been obtained, the study drug, ganaxolone IV solution for the open-label group and 
ganaxolone IV solution or placebo for the double-blind group, will be added to standard of care. The 
study drug will be added from the time that the first 2nd line IV AED, administered at an appropriate 
dose and duration to show efficacy, has failed and the second 2nd line IV AED is medically indicated.  
To reduce variability in the population being assessed, the concurrent 2nd line IV AED therapy will 
be limited to fosphenytoin/phenytoin, valproic acid, levetiracetam, lacosamide, or brivaracetam. 
Taking any of these drugs alone or in combination is acceptable. Administering fosphenytoin and/or 
phenytoin will be counted as one (1) AED. 
Ganaxolone IV solution for administration will be provided to the site as individual 125 mL vials 
containing 100 mL of 1 mg/mL of ganaxolone for the open-label group. Details of packaging, dose 
and administration of the ganaxolone IV solution and placebo for the double-blind group will be 
included in a future protocol amendment. 
Study drug should be administered, preferably, through a dedicated (peripheral or central) IV line.  
The infusion parameters result in daily doses of ganaxolone of ≤ 830 mg/day and Captisol of 
≤ 50 g/day as agreed upon with the FDA. Based on PK modeling, it is predicted that maximum 
concentrations of ganaxolone should remain within 1,000 ng/mL during infusion, but some 
variability is expected due to, for example, differences in subjects’ weight. Note, at any time the 
infusion rate of the ongoing administration may be decreased for safety reasons. 
Study drug will be administered as a 3-minute bolus, with a continuous infusion at the rate between 
20-80 mg/hour for 36 hours, and a 12-hour study drug taper. The presence of SE must be confirmed 
immediately prior to the study drug bolus. Once study drug administration is started it should be 
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Subjects weighing at least 40 kg: 
 A 30-mg bolus dose (over ~3 minutes) will be administered with a continuous infusion of 
80 mg/hour for 2 hours followed by a continuous infusion rate of 40 mg/hour for 10 hours, and 
then 20 mg/hour for the remaining 12 hours of Day 1.  
 On Day 2 (24-36 hours) the continuous infusion rate of 20 mg/hour will continue until the start of 
the study drug taper at 36 hours post study drug initiation. If needed, to manage seizure relapse or 
another medical reason, the infusion rate can be increased from 20 mg/hour up to a maximum 
rate of 45 mg/hour at any time during hours 24-36 of Day 2. 
 To taper the study drug, the infusion rate at the 36-hour post study drug initiation timepoint will 
be reduced by 33.3% every 4 hours until the infusion is stopped or if the infusion rate becomes 
too low to sustain the infusion line, at which point it will be stopped. The first taper will be 
33.3% from the current infusion rate, the second taper will be 33.3% from the first tapered 
infusion rate, and the final taper will be 33.3% from the previous tapered infusion rate. If, per the 
investigator’s judgment, the study drug taper needs to start at an earlier timepoint during the 
treatment period, the infusion rate at the start of the first taper will be decreased by 33.3% every 4 
hours as described.   
 At the time the study drug infusion is discontinued the subject will progress to the in-patient 
follow-up day assessments/procedures.  
Subjects weighing < 40 kg will be dosed on a per-kilogram basis: 
 A 0.43-mg/kg bolus dose (over ~3 minutes) will be administered with a continuous infusion at a 
dose of 1.14 mg/kg/hour for 2 hours followed by a continuous infusion dose of 0.57 mg/kg/hour 
for 10 hours, and 0.29 mg/kg/hour for the remaining 12 hours of Day 1. 
 On Day 2 (24-36 hours) the continuous infusion dose of 0.29 mg/kg/hour will continue until the 
start of the study drug taper at 36 hours post study drug initiation. If needed, to manage seizure 
relapse or for another medical reason, the infusion dose can be increased from 0.29 mg/kg/hour 
up to a maximum of 0.64 mg/kg/hour at any time during hours 24-36 of Day 2. 
 To taper the study drug, the infusion rate at the 36-hour post study drug initiation timepoint will 
be reduced by 33.3% every 4 hours until the infusion is stopped or if the infusion rate becomes 
too low to sustain the infusion line, at which point it will be stopped. The first taper will be 
33.3% from the current infusion rate, the second taper will be 33.3% from the first tapered 
infusion rate, and the final taper will be 33.3% from the previous tapered infusion rate. If, per the 
investigator’s judgment, the study drug taper needs to start at an earlier timepoint in the treatment 
period, the infusion rate at the start of the first taper will be decreased by 33.3% every 4 hours as 
described.   
 At the time the study drug infusion is discontinued the subject will progress to the in-patient 
follow-up day assessments/procedures.  
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 Medical personnel must be present at all times during at least the first 3 hours after the start of the 
study drug administration. Then close monitoring of the subject by the study staff will continue 
as medically needed throughout the study. 
 IV AED introduction: 
o For the first 10-hours of study drug administration, the decision to initiate new IV AEDs 
should be based on safety or efficacy and confirmed by relapsing clinical presentation or 
electrographic activity. Initiation of any new AEDs prophylactically (so called 
“transition/bridging”) is not recommended, unless medically indicated.  
o In the event of safety or efficacy presentation, i.e. seizure relapse, that would prompt the 
investigator to make a treatment intervention, introduction of a new IV AED is 
recommended over immediate progression to a 3rd line agent, however all treatment 
decisions are at the investigator’s discretion. 
o After the first 10-hours investigators are encouraged to initiate “transition/bridging” 
AEDs in anticipation of the study drug taper at 36-hours post study drug initiation on Day 
2.  
Study Drug Tapering: 
 The scenarios for stopping the study drug without a taper include: 
o For subjects who receive study drug for less than 2 hours and/or  
o Study drug infusion is discontinued or interrupted, and the decision is made to not restart 
the infusion and/or 
o If at any time during study drug administration the subject progresses to an IV anesthetic 
drug (a 3rd line and/or 4th line treatment) for seizure suppression or 
o It is no longer safe to continue drug administration per the investigator’s medical 
judgment. 
 During the open-label group, based on the safety, efficacy, and pharmacokinetic data from the 
ongoing study, the infusion parameters in subsequent subjects may be adjusted to maximize the 
safety and efficacy of study subjects. If the infusion parameters are amended, the new infusion 
parameters will not exceed the daily limit of 50 g/day Captisol (< 830 mg/day ganaxolone) as 
agreed upon with the FDA.  The revised infusion parameters will be communicated to Clinical 
Sites in a Protocol Administrative Change Memo and kept in the study and site files.   
 Note, the infusion rate cannot be rounded-up for any subject regardless of weight; ≥ 40 kg or < 40 
kg. 
 For study drug dosing instructions reference the Pharmacy Manual. 
Dose Adjustments and Interruptions: 
As a general rule, dose (infusion rate) decreases and interruptions of the continuous infusion are 
discouraged at any time during study drug treatment. However, if there is an urgent medical need 
(e.g., severe hypotension, acidosis, severe sedation) or a subject’s standard of care requires they 
undergo a procedure for which the infusion rate would need to be decreased or interrupted (e.g., an 


 
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MRI scan) it should be kept as short as possible but no longer than 6 hours. If > 6 hours the Marinus 
Medical Monitor must approve the re-start of the infusion.  
Note:  
 After the dose (infusion rate) decrease or infusion interruption, it will be per the investigator’s 
judgment and assessment of risk/benefit if the subject should continue in the study or early 
discontinue.  
 In cases when severe sedation is seen and early drug discontinuation is being considered, the 
Marinus Medical Monitor should be contacted prior to infusion termination, if feasible.  
 If the decision is made for the subject to continue in the study, the infusion should be re-
started at the rate matching the rate at the corresponding nominal time, counted from the start 
of the study drug infusion on Day 1. A study drug bolus or “catch-up” dose to deliver the 
study drug that was missed during the interruption should not be administered.  
 Dose (infusion rate) increases above those specified in the protocol (or based on a future 
Protocol Administrative Change Memo) are not allowed at any time during infusion. This is 
to ensure daily Captisol and ganaxolone limits are kept ≤ 50 g/day and ≤ 830 mg/day, 
respectively.  
Methodology: 
This is a double-blind, randomized, placebo-controlled study to evaluate the safety, tolerability, 
efficacy of adjunctive ganaxolone IV solution in subjects with SE. This study will start with a small 
open-label group to confirm that the dose selected will achieve a potentially therapeutic exposure 
(bolus plus continuous infusion) to stop SE. The dose selected for Day 2 is designed to provide a 
stable plasma concentration to maintain status cessation. If needed, doses in the open-label group 
portion of the study may be adjusted based on the dosing and pharmacokinetic/safety profile from the 
subject’s enrolled.  
As previously described, the study drug will be added to the standard of care from the time that the 
first 2nd line IV AED, administered at an appropriate dose and duration to show efficacy, has failed 
and the second 2nd line IV AED is medically indicated during the treatment of SE. Study drug must 
be administered with the 2nd line IV AED treatment and should be initiated as close to the initiation 
of the second 2nd line IV AED as possible.  
Potential subjects are anticipated to be identified in the emergency department and/or hospital in-
patient or intensive care units. 
Upon identification, subjects will be administered consent/assent and then screened for 
inclusion/exclusion criteria prior to receiving study drug as adjunctive therapy via continuous IV 
infusion, followed by a 12-hour study drug taper. As soon as the study drug administration is 
completed (with or without taper), subjects will have a 24-hour in-patient follow-up day and then 
follow-up visits/contacts at weeks 2, 3, and 4. For subjects who have the 12-hour study drug taper, 
the in-patient follow-up day starts as soon as the 12-hour study drug taper is complete. If the infusion 
rate becomes too low to sustain the infusion line, it can be discontinued at that point and the subject 
will progress into the in-patient follow-up day. For subjects where there is no study drug taper the in-
patient follow-up day starts as soon as the study drug administration is discontinued. These subjects 
will continue with the week 2, 3, and 4 follow-up visits.   
If the subject remains hospitalized, the week 2, 3, and 4 visits will be done in-person. If the subject 
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that discharged subjects return so at least one of these visits will be conducted in-person. In total, 
each subject will be followed for approximately 4 weeks after the initiation of study drug. 
Screening 
Procedures specific to this protocol will not be performed until written informed consent/assent from 
the subject/parent/guardian/legally authorized representative (LAR) has been appropriately obtained 
per the investigator’s hospital policy. As many of the subjects will not be able to provide 
consent/assent, the parent/guardian/LAR will provide consent on behalf of the subject to participate 
in the study. As soon as the subject is able, per the investigator’s hospitals guidelines, consent/assent 
will be administered to them for continued participation. Consent/assent for subjects who are known 
to be at risk for SE may be obtained prior to an SE event. 
Treatment and Follow-up 
Study Drug Dosing   
Up to approximately 30 subjects will be enrolled into the open-label group with ganaxolone and up 
to approximately 242 subjects will be randomized into the double-blind group. Subjects in the 
double-blind group will be randomized (1:1) to receive either ganaxolone IV solution or placebo with 
concurrent standard of care treatment. Study drug will be given as a bolus plus continuous infusion.  
After study drug initiation, the standard duration of treatment is 2 days which includes a 12-hour 
study drug taper.  
Safety and Assessments 
Study drug will be given in addition to standard of care for SE and medical or surgical interventions 
deemed appropriate by the investigator. In addition to the medically indicated treatment, safety and 
tolerability will be monitored by but not limited to the following: 
1. Physical examinations should be completed at: 
a. Pre-dose (screening) or, if not available, within 2 hours of study drug initiation, and at 
36-hours (+/- 1-hour), 
b. Time of study drug discontinuation, either at the end of the study drug taper or if the 
study drug is stopped without a taper and 
c. 24-hours (+/- 1-hour) after study drug discontinuation.  
d. If possible, for subjects who early terminate, collect at the time early termination is 
being considered and as close as possible to the end of the study drug administration.  
e. Any time, if medically indicated, per investigator’s judgment. 
2. Status Epilepticus Severity Score (STESS) should be collected pre-dose (screening). 
3. Vitals and the Glasgow Coma Scale (GCS) or Pediatric Glasgow Coma Scale (PGCS), 
Richmond Agitation and Sedation Scale (RASS), and the Full Outline of UnResponsiveness 
(FOUR) Score scales should be collected at: 
a. Pre-dose (screening), 60-minutes (+/- 15-min), 2- (+/- 15-min), 10-, 24-, and 36-hours 
(+/- 1 hour) after study drug initiation,  
b. Time of study drug discontinuation, either at the end of the study drug taper or if the 
study drug administration is stopped without a taper and 
c. 24-hours (+/- 1-hour) after study drug discontinuation. 
d. If possible, for subjects who early terminate from the study, collect at the time early 
termination is being considered and as close as possible to the end of the study drug 
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e. Any time, if medically indicated, per investigator’s judgment. 
Weight and height should be collected pre-dose (screening) for calculation of the BMI inclusion 
criterion, if feasible.  If not collected pre-dose (screening), collect prior to the end of the in-
patient follow-up day. 
4. Mini Mental State Examination (MMSE) should be performed at: 
a. The time consent/assent is administered to the subject for continued participation and 
then on the in-patient follow-up day.  
If the MMSE is not able to be assessed due to the subject’s state, this should be recorded. 
5. Electrocardiogram (ECG), the subject should have an ECG at: 
a. Pre-dose (screening), 2- (+/- 30-min) and 36-hours (+/- 1-hour) after study drug 
initiation,  
b. Time of study drug discontinuation; either at the end of the study drug taper or if the 
study drug administration is stopped without a taper and   
c. 24-hours (+/- 1-hour) after study drug discontinuation. 
d. If possible, for subjects who early terminate from the study, collect at the time early 
discontinuation is being considered and as close as possible to the end of the study 
drug administration.  
e. Any time, if medically indicated, per investigator’s judgment. 
6. Clinical laboratory measures, hematology, serum chemistry (including creatinine, blood urea 
nitrogen, and estimated glomerular filtration rate calculation), and concomitant AED levels 
(fosphenytoin/phenytoin, valproic acid, levetiracetam, lacosamide, or brivaracetam, if 
available), and Urinalysis (including urine protein, albumin and microscopic), should be 
collected at: 
a. Pre-dose (screening), if available, or within 2 hours of study drug initiation, at 24- and 
36-hours (+/- 1-hour) after study drug initiation, 
b. Time of study drug discontinuation, either at the end of the study drug taper or if the 
study drug administration is stopped without a taper and 
c. 24-hours (+/- 1-hour) after study drug discontinuation.  
d. One of the weekly follow-up visits (week 2, 3, or 4) for subjects in-house and if 
possible, for subjects who have been discharged. 
e. If possible, for subjects who early terminate from the study, collect at the time early 
termination is being considered and as close as possible to the end of the study drug 
administration.  
     Variable collections based on subject response: 
f. After the initial SE cessation, AED levels should be collected at time of first instance 
of seizure activity or SE relapse. 
     Between study drug initiation and the in-patient follow-up day, where possible, collect a 
     sample: 
i. If the decision is made to intubate the subject 
ii. At the time of a serious adverse event (related or not related)  
g. Any time, if medically indicated, per investigator’s judgment. 
7. Drugs of abuse (urine or serum), including alcohol testing and Pregnancy test (urine or 
serum) for women who are of childbearing potential, should be collected pre-dose 
(screening).  If not possible to collect pre-dose, collect as soon as possible after start of study 
drug infusion. Enrollment is not contingent upon results. However, if a subject has a positive 
test result, it will be at the investigator’s discretion to weigh the risks verses benefits for the 


 
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subject’s continued participation.  If the investigator decides to discontinue the study drug, 
refer to the study drug taper directions in the Study drug, Dose, and Mode of Administration 
section. 
8. EEG is required for confirmation of non-convulsive status epilepticus (NCSE) diagnosis. 
Ideally, continuous EEG monitoring should start before study drug initiation and continue 
through the in-patient follow-up day. If continuous EEG is not possible or needed to diagnose 
(for convulsive SE) it should be instituted at the earliest possible time after study drug 
initiation (if a pre-dose EEG was not performed for the diagnosis of convulsive SE).   
Several study sites may be offered the use of a rapid EEG device to assist with pre-screening 
of subjects with NCSE. It will be at the investigator’s discretion if they feel the device will 
benefit their site. More details can be found in Section 7.2.2. 
9. Blood sampling for pharmacokinetic analysis (venous or arterial) of ganaxolone will be 
collected at the following times:  
Required collections:  
a. After the start of the study drug infusion: 60-minutes, then 2-, 4-, 8-, 10-, 24- and 36-
hours, 
b. At the time of study drug discontinuation, either at the end of the study drug taper or if 
the study drug administration is stopped without a taper and  
c. 24-hours after study drug discontinuation. 
Variable collections based on subject response: 
d. After the initial SE cessation, collect a sample at the first instance of seizure activity 
or SE relapse and the subject does not progress to an IV anesthetic drug (a 3rd line 
treatment, e.g. midazolam, propofol, thiopental, pentobarbital, or ketamine) 
Between study drug initiation and the in-patient follow-up day, where possible, collect a 
sample: 
i. If the decision is made to intubate the subject  
ii. At the time of introduction of a new IV AED for safety/efficacy (not for AEDs 
given prophylactically for “transition/bridging”) 
iii. At the time of any serious adverse event (related or not related)  
If study drug is administered via central access, the PK sample must not be collected from 
any central access ports. If study drug is administered via venous access, the PK sample must 
be collected via the contra-lateral arm of the study drug arm. The location of study drug 
access and location of PK sample collection should be documented in the subject’s source. If 
the PK sample cannot be collected due to poor venous access and the study drug infusion site 
is the only viable option, the specimen should not be collected and the reason for non-
collection documented in the subject’s source.   
10. Blood sampling for neurosteroid levels (venous or arterial) will be collected pre-dose 
(screening) and at 24-hours (+/- 1-hour) of study drug initiation.  If study drug is discontinued 
during this 24 hours, the second sample should be collected prior to study drug 
discontinuation, if possible.  
The same collection rules as noted for pharmacokinetic sample collection apply for the 
neurosteroid sample collection. 
11. Blood gas including FiO2, PaO2, and arterial pH, if collected per the investigator’s discretion 
for subject’s care, from the time of SE diagnosis through the of the in-patient follow-up day 
and recorded in the eCRF.  If samples are not collected, a sample is not required.  


 
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However, if the decision is made to intubate the subject from study drug initiation through the 
end of the in-patient follow-up day, a blood gas sample should be collected. The sample 
should be collected immediately prior to or as close as possible to the time of intubation.  
During the study, it is expected that the total blood volume drawn from subjects for all safety, 
pharmacokinetic, and neurosteroid sampling at pediatric-only hospitals is approximately 62 to 
88 mL of blood and at all other hospitals approximately 192.6 to 278.3 mL of blood, 
regardless of sex.   
12. Cerebral Spinal fluid sample collection: If a subject has a lumbar puncture for the collection 
of cerebral spinal fluid (CSF) per investigator’s discretion as part of their care and there is 
adequate volume, a sample will be aliquoted for future analysis of ganaxolone. If multiple 
lumbar punctures are performed, a sample from each puncture is requested.  However, if not 
collected or not enough CSF is available to provide a sample for the study, a sample is not 
required. 
13. Clinical Global Impression of Severity and Improvement (CGI-S and CGI-I, respectively) 
CGI-S is collected at: 
a. Pre-dose (screening) and 36-hours (+/- 1-hour) after study drug initiation,  
b. Time of study drug discontinuation, either at the end of the study drug taper or if the 
study drug administration is stopped without a taper and 
c. 24-hours (+/- 1-hour) after study drug discontinuation. 
d. Week 2, 3, and 4 follow-up visits (in-person or via telephone call). 
e. If possible, for subjects who early terminate from the study, collect at the time early 
termination is being considered and as close as possible to the end of the study drug 
administration.  
f. Any time, if medically indicated, per investigator’s judgment. 
CGI-I is collected at:  
a. Within the first 2 hours of study drug initiation and 36-hours (+/- 1-hour) after study 
drug initiation, 
b. Time of study drug discontinuation, either at the end of the study drug taper or if the 
study drug administration is stopped without a taper and 
c. 24-hours (+/- 1-hour) after study drug discontinuation. 
d. Week 2, 3, and 4 follow-up visits (in-person or via telephone call).  
e. If possible, for subjects who early terminate from the study, collect at the time early 
termination is being considered and as close as possible to the end of the study drug 
administration.  
f. Any time, if medically indicated, per investigator’s judgment. 
14. Modified Rankin Scale (MRS) should be collected at:  
a. Time of study drug discontinuation, either at the end of the study drug taper or if the 
study drug administration is stopped without a taper and 
b. 24-hours (+/- 1-hour) after study drug discontinuation. 
c. Week 2, 3 and 4 follow-up visits (in-person or via telephone call). 
d. If possible, for subject’s who early terminate from the study, collect at the time early 
termination is being considered and as close as possible to the end of the study drug 
administration. 
e. Any time, if medically indicated, per investigator’s judgment. 
15. Status Epilepticus and Seizure Questions should be collected at:  


 
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a. 15-minutes (+/- 5-min), 30-, 60-minutes (+/- 15-min), 2- , 4-, 6-, 8-,10-, 12-, 18- (+/- 
30-min), and 24- and 36-hours (+/- 1 hour) after study drug initiation,  
b. Time of study drug discontinuation, either at the end of the study drug taper or if the 
study drug administration is stopped without a taper and 
c. 24-hours (+/- 1-hour) after study drug discontinuation. 
d. Week 2, 3, and 4 follow-up visits (in-person or via telephone call). 
e. If possible, for subjects who early terminate from the study, collect at the time early 
termination is being considered and as close as possible to the end of the study drug 
administration.  
Assessment questions:  
1. Is the subject in SE currently?  
2. Was the subject in SE since the previous assessment?   
(Note: N/A for the 15-minute timepoint) 
3. Is the subject having seizures currently?  
4. Did the subject have seizures since the previous assessment?   
(Note: N/A for the 15-minute timepoint) 
5. Have any new* AEDs been initiated since the last assessment? 
(Note: “New” refers to any AED that has not already been used to treat the current 
episode of SE) 
6. If a new AED was initiated, was it to treat the current seizure/SE episode or 
initiated prophylactically (e.g., for transition/bridging), or other reason?  
(Note: “Prophylactic” refers to any elective/transitional/bridging AED therapy that 
is not indicated to treat seizure/EEG abnormal activity at this time or since the last 
assessment) 
Record any new AEDS on the concomitant eCRF page. 
16. Intubation Question will be collected for subjects who are intubated either prior to study drug 
initiation or anytime through the end of the in-patient follow-up day: 
a. 18- (+/- 30-min), 24-, and 36-hours (+/- 1 hour) after study drug initiation, 
b. Time of study drug discontinuation, either at the end of the study drug taper or if the 
study drug administration is stopped without a taper and 
c. 24-hours (+/- 1-hour) after study drug discontinuation. 
Assessment point: 
1. Per your evaluation has the subject’s medical condition improved enough to 
warrant considering extubation? 
17. Adverse events (AEs) and Concomitant medications: AE’s will be collected throughout the 
study via non-direct questioning. Concomitant medications will be collected during the same 
time period however, the collection requirements will differ depending on the subject’s 
treatment progression as defined below. 
a. All adverse events and associated concomitant medications will be collected through 
the in-patient follow-up day.  
b. IV anesthetic agents (midazolam, propofol, thiopental, pentobarbital, or ketamine) 
administered during the study drug treatment period and the in-patient follow-up day 
should be followed through the week 4 visit/contact.   
c. During the weekly follow-up visits, only ongoing AEs and new AEs assessed by the 
investigator to be related to study drug will be recorded and the concomitant 
medications associated with these AEs.  


 
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d. In addition, during the weekly follow-up visits, AEs of urinary tract infection (UTI), 
hospital-acquired/ventilator-associated pneumonia, myocardial infarction (MI), sepsis 
from any source, critical illness myopathy/neuropathy, significant hypotension 
requiring support of vasopressors will be recorded regardless of relatedness. 
Associated concomitant medications for these AEs will not be recorded.  
e. All SAEs regardless of relationship to study drug and their associated concomitant 
medications will be recorded from the time of study drug initiation through the last 
follow-up visit/contact.  
f. For subjects who early terminate from the study, prior to discontinuation as much 
information as is available should be recorded for ongoing AEs/SAEs, new AEs/SAEs 
and their associated concomitant medications, especially those that may have led to 
the early termination.  
For some of the concomitant medications only the highest dose administered will be required in the 
eCRF. Reference the eCRF Completion Guidelines for guidance. 
Study Follow-up and Discontinuation: 
Subjects who discontinue study drug without a taper, e.g., takes study drug for less than 2 hours or 
progresses to an IV anesthetic drug (a 3rd line treatment) for seizure suppression or discontinues the 
study medication due to safety reasons will continue in the study and still have the in-patient follow-
up and the week 2, 3, and 4 follow-up visits/contacts. 
  
Subjects who early terminate from the study, e.g., due to consent withdrawn, should have the early 
termination procedures completed when early termination is being considered and as close as 
possible to the end of the study drug administration. 
All subjects, except those who are early terminated from the study, will have the in-patient follow-up 
day and the follow-up visits/contacts at Weeks 2, 3, and 4. If the subject remains hospitalized these 
visits will be done in person but if the subject has been discharged these contacts will be conducted via 
telephone call. Even if a subject has been discharged, efforts will be made to have the subject return so 
at least one of the visits will be conducted in-person. These visits will be conducted weekly, starting 
approximately 7 ± 3 days after the in-patient follow-up day. 
During these visits/calls, the site will follow-up on all serious adverse events (SAEs) and non-serious 
adverse events (AEs), AE resolution that occurs, and concomitant medications. In total, each subject 
will be followed for approximately 4 weeks. 
Inclusion and Exclusion Criteria:  
Inclusion Criteria:  
1. Subject, subject’s parent, guardian, or LAR must provide signature of informed consent, and, 
once capable (per the investigator’s hospital guidelines), there must be documentation of 
consent/assent by the subject indicating the subject is aware of the investigational nature of 
the study, is able and willing to participate in the study, and is aware of the required 
restrictions and procedures  
2. Male or female subjects 12 years of age and older at the time of the first dose of study drug 
3. Clinical and/or electrographic seizures defined as:  
o Documented clinical seizures (convulsive SE): greater than 5 minutes’ duration prior 
to treatment with study drug (per International League Against Epilepsy, ILAE) 
or 


 
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o Electrographic criteria (one must apply):  
 10 minutes of continuous seizure activity on EEG (per ILAE)  
 Intermittent EEG seizure activity for more than 50% of the previous 
60 minutes  
 If less than 60 minutes of EEG is available, then intermittent electrographic 
seizure activity must be present for greater than 50% of the available duration 
of the EEG AND the electrographic seizure activity must be at least 
10 minutes when taken in aggregate 
4. Subject on concurrent 2nd line IV AED therapy with fosphenytoin/phenytoin, valproic acid, 
levetiracetam, lacosamide, or brivaracetam for the management of the current episode of SE 
5. BMI < 40 or, if not able to be calculated at screening, assessed by investigator as not 
morbidly obese   
Exclusion Criteria:  
1. Life expectancy of less than 24 hours 
2. Anoxic brain injury as the primary cause of SE 
3. Recent (< 24 hour) traumatic brain injury as the primary cause of SE 
4. Administered anesthesia (3rd line treatment, e.g., midazolam, propofol, thiopental, 
pentobarbital, or ketamine) at adequate doses and duration for the treatment of the current 
episode of SE that required the subject to be hospitalized and 5 half-lives of the agent used 
has not elapsed    
5. Subjects who are intubated for the administration of an IV anesthetic drug (a 3rd line 
treatment; e.g., midazolam, propofol, thiopental, pentobarbital, or ketamine) to treat SE; 
subjects who are intubated for airway protection are not excluded 
6. Subjects known or suspected to be pregnant upon screening  
7. To the best knowledge of the investigator, has allergy to progesterone or allopregnanolone 
medications/supplements or has previously received ganaxolone or exogenous 
allopregnanolone 
8. If renal impairment is suspected (eGFR < 45 mL/min) or subject is currently on dialysis; if 
decision is made to start dialysis during study participation, subjects are not excluded 
9. To the best knowledge of the investigator, subject has hepatic insufficiency at screening, for 
example alanine transferase or aspartate transferase level more than 5 times the upper limit of 
normal (ULN), or total bilirubin more than 2 times ULN at the screening visit 
10. Subjects with a durable medical care agreement that would not allow hospital to administer 
their standard of care for treatment of SE 
11. Subjects on an investigational drug that is not recommended by treatment guidelines are 
required to have a reasonable expectation that the investigational study drug has been cleared 
from their system, that is, that five half-lives have elapsed 
12. Subjects who have a history or evidence of a medical condition that, in the investigator’s 
judgment, would expose subject to an undue risk of a significant adverse event or interfere 
with assessments of safety or efficacy during the course of the study 


 
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Maximum Duration of Subject Involvement in the Study: 
 Screening could be as short as a few minutes and as long as approximately 24 hours prior to the 
initiation of study drug. The screening period is from the time parent/guardian/LAR 
consent/assent is obtained to immediately prior to study drug initiation.  
 The planned duration of adjunctive treatment is 2 days which includes a 12-hour study drug 
taper.  
 There will be an in-patient follow-up period after the study drug administration is completed.   
The in-patient follow-up period starts at the time of study drug discontinuation; either at the end 
of the taper or if the study drug administration is stopped without a taper. The follow-up period 
consists of a 24 hour in-patient follow-up day and 3 weekly visits. These weekly visits can be 
performed as an in-person visit if the subject is still in the hospital, or as a telephone call if the 
subject has been discharged.  However, it is recommended that discharged subjects return so at 
least one of these visits will be conducted in-person. 
 In total, subjects will be followed for approximately 4 weeks. 
Endpoints and Statistical Analysis:   
Primary Endpoint:  
 The number of subjects who didn’t require an IV anesthetic drug (a 3rd line treatment) for SE 
treatment within the first 24 hours after study drug initiation 
Secondary Endpoints: 
 For subjects on concomitant second-line therapy: time to cessation of SE or next treatment 
decision (defined as the need for an IV anesthetic drug (a 3rd line treatment) when on 
ganaxolone)  
 Level of responsiveness as assessed by the GCS, Four Score Scale, and RASS at 24 hours 
post study drug initiation 
 The number of subjects who did not require additional 2nd line IV AED therapy for SE 
treatment in the 24-hours after study drug taper  
 Safety and tolerability of IV ganaxolone as adjunctive SE therapy as assessed by neurologic, 
EEG, physical examinations, clinical laboratory tests, ECGs, vital signs, and AEs 
 Number of subjects who maintained SE resolution 24 hours after study drug taper and at 
Week 4 
 Number of subjects with seizure(s) following the cessation of SE through the in-patient 
follow-up day 
 Seizure burden assessed as duration of electrographic seizure activity per hour of EEG 
recording collected 
 Clinical outcome as assessed by MRS at the in-patient follow-up day and Week 4 
 Characterization of the pharmacokinetic profile of ganaxolone IV solution in SE subjects 
 Length of stay in intensive care unit and hospital, mortality, morbidity, need for and duration 
of intubation and mechanical ventilation, and seizure freedom 


 
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STUDY SCHEDULE(S) 
Table 1: 
Schedule of Assessments 
Periods 
Screening a 
Treatment 
Follow-up b 
ET 
Visit/Timepoint 
or Duration 
Prior to 
study drug 
initiation  
Dosing 
Taper   
Study Drug 
Discontinuation 
without Taper  
 In-patient 
Follow-up 
Weekly follow-
up (Week 2, 3, 
& 4)  
Early 
Termination 
Day -1 to 
Day 1 
 
Pre-dose 
through 
screening 
 
 
Day 1 
Study Drug 
Initiation  
0 hours 
through 24 
hours post 
study drug 
initiation 
Day 2  
24 hours 
through  
36 hours 
post study 
drug 
initiation 
Day 2  
12-hours 
Starts at 
36-hours 
post study 
drug 
initiation 
 
Collected prior to 
or as close to 
study drug 
discontinuation as 
possible 
Day 3 Or 
Starts as soon as 
study drug 
administration 
ends, lasts 24 
hours 
7 ±3, 14 ±3, and 
21 ±3 days post 
last visit 
Collected prior 
to or as close to 
study drug 
discontinuation 
as possible 
Informed 
consent/assent 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion criteria 
 
 
 
 
 
 
 
 
Demography and 
medical/ 
medication  
history c 
 
 
 
 
 
 
 
 
Physical exam d 
 
 
 
 
 
 
 
 
Status Epilepticus 
Severity Score 
(STESS) 
 
 
 
 
 
 
 
 
Vital signs e  
 
 
 
 
 
 
 
 
Glasgow Coma 
Scale 
(GCS)/Pediatric 
GCS (PGCS) e 
 
 
 
 
 
 
 
 
Richmond 
Agitation and 
 
 
 
 
 
 
 
 


 
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Table 1: 
Schedule of Assessments 
Periods 
Screening a 
Treatment 
Follow-up b 
ET 
Visit/Timepoint 
or Duration 
Prior to 
study drug 
initiation  
Dosing 
Taper   
Study Drug 
Discontinuation 
without Taper  
 In-patient 
Follow-up 
Weekly follow-
up (Week 2, 3, 
& 4)  
Early 
Termination 
Day -1 to 
Day 1 
 
Pre-dose 
through 
screening 
 
 
Day 1 
Study Drug 
Initiation  
0 hours 
through 24 
hours post 
study drug 
initiation 
Day 2  
24 hours 
through  
36 hours 
post study 
drug 
initiation 
Day 2  
12-hours 
Starts at 
36-hours 
post study 
drug 
initiation 
 
Collected prior to 
or as close to 
study drug 
discontinuation as 
possible 
Day 3 Or 
Starts as soon as 
study drug 
administration 
ends, lasts 24 
hours 
7 ±3, 14 ±3, and 
21 ±3 days post 
last visit 
Collected prior 
to or as close to 
study drug 
discontinuation 
as possible 
Severity Scale 
(RASS) e 
Full Outline of 
UnResponsivenes 
(FOUR) Score e 
 
 
 
 
 
 
 
 
Mini mental state 
exam (MMSE) f 
 
 
 
 
 
 
  
 
12-lead ECG g 
 
 
 
 
 
 
 
 
Biochemistry, 
hematology, and 
antiepileptic drugs 
h 
 
 
 
 
 
 
 
 
Urinalysis h 
 
  
 
 
 
 
 
 
Drugs of abuse, 
including alcohol i 
 
 
 
 
 
 
 
 
Pregnancy test 
(WCBP only) i 
 
 
 
 
 
 
 
 
EEG j 
 
 
 
 
 
 
 
 


 
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Table 1: 
Schedule of Assessments 
Periods 
Screening a 
Treatment 
Follow-up b 
ET 
Visit/Timepoint 
or Duration 
Prior to 
study drug 
initiation  
Dosing 
Taper   
Study Drug 
Discontinuation 
without Taper  
 In-patient 
Follow-up 
Weekly follow-
up (Week 2, 3, 
& 4)  
Early 
Termination 
Day -1 to 
Day 1 
 
Pre-dose 
through 
screening 
 
 
Day 1 
Study Drug 
Initiation  
0 hours 
through 24 
hours post 
study drug 
initiation 
Day 2  
24 hours 
through  
36 hours 
post study 
drug 
initiation 
Day 2  
12-hours 
Starts at 
36-hours 
post study 
drug 
initiation 
 
Collected prior to 
or as close to 
study drug 
discontinuation as 
possible 
Day 3 Or 
Starts as soon as 
study drug 
administration 
ends, lasts 24 
hours 
7 ±3, 14 ±3, and 
21 ±3 days post 
last visit 
Collected prior 
to or as close to 
study drug 
discontinuation 
as possible 
Study Drug 
infusion k 
 
 
 
 
 
 
 
 
Pharmacokinetic 
blood sampling l 
 
 
 
 
 
 
 
 
 
Neurosteroid 
levels m 
 
 
 
 
 
 
 
 
Blood Gas n 
 
 
 
 
 
 
 
 
Cerebral Spinal 
Fluid o 
 
 
 
 
 
 
 
 
Clinical Global 
Impression of 
Severity (CGI-S) p 
  
 
 
 
 
 
 
 
Clinical Global 
Impression of 
Improvement 
(CGI-I) q 
 
 
 
 
 
 
 
 
 
SE & Seizure 
Questions r 
 
 
 
 
 
 
 
 
Intubation 
Question s 
 
 
 
 
 
 
 
 
Modified Rankin 
Scale (MRS) t 
 
 
 
 
 
 
 
 


 
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Table 1: 
Schedule of Assessments 
Periods 
Screening a 
Treatment 
Follow-up b 
ET 
Visit/Timepoint 
or Duration 
Prior to 
study drug 
initiation  
Dosing 
Taper   
Study Drug 
Discontinuation 
without Taper  
 In-patient 
Follow-up 
Weekly follow-
up (Week 2, 3, 
& 4)  
Early 
Termination 
Day -1 to 
Day 1 
 
Pre-dose 
through 
screening 
 
 
Day 1 
Study Drug 
Initiation  
0 hours 
through 24 
hours post 
study drug 
initiation 
Day 2  
24 hours 
through  
36 hours 
post study 
drug 
initiation 
Day 2  
12-hours 
Starts at 
36-hours 
post study 
drug 
initiation 
 
Collected prior to 
or as close to 
study drug 
discontinuation as 
possible 
Day 3 Or 
Starts as soon as 
study drug 
administration 
ends, lasts 24 
hours 
7 ±3, 14 ±3, and 
21 ±3 days post 
last visit 
Collected prior 
to or as close to 
study drug 
discontinuation 
as possible 
AEs/SAEs u 
 
 
 
 
 
 
 
 
Concomitant 
medication u 
 
 
 
 
 
 
 
 
ET, Early Termination; ECG, electrocardiogram; WCBP, women of childbearing potential; EEG, electroencephalograms; AE, adverse event; SAE, serious AE. 
a. The screening period is from the time parent/guardian/LAR consent is obtained to immediately prior to study drug initiation. 
b. The planned duration of follow-up will be 24 hours after study drug administration is stopped (called the in-patient follow-up day) and weekly for an additional 3 weeks. For 
Weeks 2, 3, and 4 the follow-up can be performed as an in-patient visit if the subject is still in the hospital or, if the subject has been discharged, as a telephone call. Attempts 
should be made to have discharged subjects return for one of the follow-up visits for clinical laboratory sample collection. The follow-up visit window is 7 ±3, 14 ±3, and 21 ±3 
days.  
c. Demography and medical history will ideally be collected prior to study drug initiation but can be collected whenever feasible before the end of study drug taper. 
d. Physical exam should be obtained from the subject’s chart or completed pre-dose (screening) or, if not available, collected within 2-hours of study drug initiation, and at 36-
hours (+/- 1-hour). Collect at the time of study drug discontinuation, either at the end of the study drug taper or if the study drug administration is stopped without a taper and 
24-hours (+/- 1-hour) after study drug discontinuation. If possible, for subjects who early terminate from the study, collect at the time of early termination is being considered 
and as close as possible to the end of the study drug administration. Collect any time, if medically indicated, per investigator’s judgment. 
e. Vital signs including blood pressure, pulse, respiratory rate, temperature, and oxygen saturation and the GCS/PGCS, RASS, and the FOUR scales should be collected pre-
dose (screening), 60-minutes (+/- 15-min) and 2- (+/- 15-min), 10- ,24-, and 36-hours (+/- 1-hour) after study drug initiation. Collect at the time of study drug discontinuation, 
either at the end of the study drug taper or if the study drug administration is stopped without a taper and 24-hours (+/- 1-hour) after study drug discontinuation. If possible, for 
subjects who early terminate from the study, collect at the time early termination is being considered and as close as possible to the end of the study drug administration.  
Collect any time, if medically indicated, per investigator’s judgment. Weight and height should be collected pre-dose (screening) for calculation of BMI inclusion criterion, if 
feasible. If not collected pre-dose (screening) collect prior to the end of the in-patient follow-up day. 
f. MMSE should be performed at the time consent/assent is administered to the subject for continued participation and then on the in-patient follow-up day. If the MMSE is not 
able to be assessed due to the subject’s state this should be recorded. 
g. ECG should be collected pre-dose (screening), 2- (+/- 30-min) and 36-hours (+/- 1-hour) after study drug initiation. Collect at the time of study drug discontinuation, either at 
the end of the study drug taper or if the study drug administration is stopped without a taper and 24-hours (+/- 1-hour) after study drug discontinuation. If possible, for subjects 


 
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Table 1: 
Schedule of Assessments 
Periods 
Screening a 
Treatment 
Follow-up b 
ET 
Visit/Timepoint 
or Duration 
Prior to 
study drug 
initiation  
Dosing 
Taper   
Study Drug 
Discontinuation 
without Taper  
 In-patient 
Follow-up 
Weekly follow-
up (Week 2, 3, 
& 4)  
Early 
Termination 
Day -1 to 
Day 1 
 
Pre-dose 
through 
screening 
 
 
Day 1 
Study Drug 
Initiation  
0 hours 
through 24 
hours post 
study drug 
initiation 
Day 2  
24 hours 
through  
36 hours 
post study 
drug 
initiation 
Day 2  
12-hours 
Starts at 
36-hours 
post study 
drug 
initiation 
 
Collected prior to 
or as close to 
study drug 
discontinuation as 
possible 
Day 3 Or 
Starts as soon as 
study drug 
administration 
ends, lasts 24 
hours 
7 ±3, 14 ±3, and 
21 ±3 days post 
last visit 
Collected prior 
to or as close to 
study drug 
discontinuation 
as possible 
who early terminate from the study, collect at the time early termination is being considered and as close as possible to the end of the study drug administration. Collect any 
time, if medically indicated, per investigator’s judgment. 
h. Clinical labs, hematology, serum chemistry (including creatinine, blood urea nitrogen, and estimated glomerular filtration rate calculation) and concomitant AED levels 
(fosphenytoin/phenytoin, valproic acid, levetiracetam, lacosamide, or brivaracetam, if available) and Urinalysis (including urine protein, albumin, and microscopic examination) 
should be collected pre-dose (screening), if available, or within 2 hours of study drug initiation, at 24- and 36- hours (+/- 1-hour) after study drug initiation. Collect at the time 
of study drug discontinuation, either at the end of the study drug taper or if the study drug administration is stopped without a taper and 24-hours (+/- 1-hour) after study drug 
discontinuation. Collect at one of the weekly follow-up visits (week 2, 3, or 4) for subjects in-house and if possible, for subjects who have been discharged. If possible, for 
subjects who early terminate from the study, collect at the time early termination is being considered and as close as possible to the end of the study drug administration.  After 
the initial SE cessation, AED levels should be collected at time of first instance of seizure activity or SE relapse. Between study drug initiation and the in-patient follow-up day, 
where possible, collect AED levels if the decision is made to intubate the subject and for any serious adverse event (related or not related). Collect clinical labs, AEDs and 
urinalysis any time, if medically indicated, per investigator’s judgment. 
i. Drugs of abuse (urine or serum), including alcohol testing, and pregnancy test (urine or serum) for women who are of childbearing potential, should be collected pre-dose 
(screening). If not possible to collect pre-dose, collect as soon as possible after start of study drug infusion. Enrollment is not contingent upon results. However, if a subject has 
a positive test result, it will be at the investigator’s discretion to weigh the risks verses benefits for the subject’s continued participation. If the investigator decides to discontinue 
the study drug, refer to the study drug taper directions in the Study drug, Dose and Mode of Administration section. 
j. EEG is required for confirmation of NCSE diagnosis. Continuous EEG recording ideally should start before study drug initiation and continue through the in-patient follow-
up day. If continuous EEG is not possible or needed to diagnose (for convulsive SE) it should be instituted at the earliest possible time after study drug initiation (if a pre-dose 
EEG was not performed for the diagnosis of convulsive SE). 
k. Subjects will receive a 30 mg bolus (over ~3 minutes) with a continuous infusion at a rate of 20-80 mg/hour for approximately 36 hours followed by 12-hour taper.   
l. Blood sample collection for pharmacokinetic analysis (venous or arterial) will occur at 60-minutes then at 2-,4-,8-,10-, 24- and 36-hours after the start of study drug infusion. 
Collect at the time of study drug discontinuation, either at the end of the study drug taper or if the study drug administration is stopped without a taper and 24-hours after study 
drug discontinuation. After the initial SE cessation, collect a sample at the first instance of seizure activity or SE relapse and the subject does not progress to an IV anesthetic.  
Between study drug initiation and the in-patient follow-up day, where possible, collect a sample if the decision is made to intubate the subject; collect at the time of introduction 
of a new IV AED for safety/efficacy (not for AEDs given prophylactically for “transition/bridging”), and at the time of any serious adverse event (related or not related). PK 
samples cannot be collected from the study drug infusion line. The location of study drug access and location of PK sample collection should be documented in the subject’s 
source.    


 
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Table 1: 
Schedule of Assessments 
Periods 
Screening a 
Treatment 
Follow-up b 
ET 
Visit/Timepoint 
or Duration 
Prior to 
study drug 
initiation  
Dosing 
Taper   
Study Drug 
Discontinuation 
without Taper  
 In-patient 
Follow-up 
Weekly follow-
up (Week 2, 3, 
& 4)  
Early 
Termination 
Day -1 to 
Day 1 
 
Pre-dose 
through 
screening 
 
 
Day 1 
Study Drug 
Initiation  
0 hours 
through 24 
hours post 
study drug 
initiation 
Day 2  
24 hours 
through  
36 hours 
post study 
drug 
initiation 
Day 2  
12-hours 
Starts at 
36-hours 
post study 
drug 
initiation 
 
Collected prior to 
or as close to 
study drug 
discontinuation as 
possible 
Day 3 Or 
Starts as soon as 
study drug 
administration 
ends, lasts 24 
hours 
7 ±3, 14 ±3, and 
21 ±3 days post 
last visit 
Collected prior 
to or as close to 
study drug 
discontinuation 
as possible 
m. Neurosteroid levels (venous or arterial) blood samples will be collected pre-dose (screening) and at 24-hours (+/- 1 hour) of study drug initiation. If study drug is 
discontinued during this 24 hours, the second sample should be collected prior to study drug discontinuation, if feasible. NS samples cannot be collected from the study drug 
infusion line. The location of study drug access and location of NS sample collection should be documented in the subject’s source. 
n. Blood gas including FiO2, PaO2, and Arterial pH, if collected per the investigator’s discretion for subject’s care, from the time of SE diagnosis through the in-patient follow-
up day. If no samples are collected, a sample is not required.  In addition, a blood gas sample should be collected when the decision is made to intubate the subject occurring 
after start of study drug infusion through the in-patient follow-up day. The sample should be collected immediately prior to or as close as possible to the time of intubation.    
o.  If a subject has a lumbar puncture for the collection of cerebral spinal fluid (CSF) per investigator’s discretion as part of their care and there is adequate volume, a sample 
will be aliquoted for future analysis of ganaxolone. If multiple lumbar punctures are performed, a sample from each puncture is requested. If not collected or not enough CSF is 
collected to provide a sample for the study, a sample is not required. 
p. CGI-S is collected pre-dose (screening) and 36-hours (+/- 1-hour) after study drug initiation. Collect at time of study drug discontinuation, either at the end of the study drug 
taper or if the study drug administration is stopped without a taper and 24-hours (+/- 1-hour) after study drug discontinuation. Collect at the week 2, 3, and 4 follow-up 
visits/contacts. If possible, for subjects who early terminate from the study, collect at the time early termination is being considered and as close as possible to the end of the 
study drug administration. Collect any time, if medically indicated, per investigator’s judgment. 
q. CGI-I is collected within 2 hours of study drug initiation and 36-hours (+/- 1-hour) after study drug initiation. Collect at time of study drug discontinuation, either at the end 
of the study drug taper or if the study drug administration is stopped without a taper and 24-hours (+/- 1-hour) after study drug discontinuation. Collect at the week 2, 3, and 4 
follow-up visits/contacts. If possible, for subjects who early terminate from the study, collect at the time early termination is being considered and as close as possible to the end 
of the study drug administration. Collect any time, if medically indicated, per investigator’s judgment. 
r. Status Epilepticus and Seizure Questions should be collected at 15-minutes (+/- 5-min), 30-, 60-minutes (+/- 15-min), 2-, 4-, 6-, 8-, 10- 12- 18- (+/- 30-minutes) and 24- and 
36- hours (+/- 1-hour) after study drug initiation. Collect at the time of study drug discontinuation, either at the end of the study drug taper or if the study drug is stopped 
without a taper and 24-hours (+/- 1-hour) after study drug discontinuation. Collect at the week 2, 3 and 4 follow-up visits/contacts. If possible, for subjects who early terminate 
from the study, collect at the time early termination is being considered and as close as possible to the end of the study drug administration. 
s. Intubation Question should be collected at 18- (+/- 30-min), 24- and 36-hours (+/- 1 hours) after study drug initiation. Collect at time of study drug discontinuation, either at 
the end of the study drug taper or if the study drug administration is stopped without a taper and 24-hours (+/- 1-hour) after study drug discontinuation. 
t. MRS is collected at the time of study drug discontinuation, either at the end of the study drug taper or if the study drug administration is stopped without a taper and 24-hours 
(+/- 1-hour) after study drug discontinuation. Collect at the week 2, 3, and 4 follow-up visits/contacts. If possible, for subjects who early terminate from the study, collect at the 


 
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Table 1: 
Schedule of Assessments 
Periods 
Screening a 
Treatment 
Follow-up b 
ET 
Visit/Timepoint 
or Duration 
Prior to 
study drug 
initiation  
Dosing 
Taper   
Study Drug 
Discontinuation 
without Taper  
 In-patient 
Follow-up 
Weekly follow-
up (Week 2, 3, 
& 4)  
Early 
Termination 
Day -1 to 
Day 1 
 
Pre-dose 
through 
screening 
 
 
Day 1 
Study Drug 
Initiation  
0 hours 
through 24 
hours post 
study drug 
initiation 
Day 2  
24 hours 
through  
36 hours 
post study 
drug 
initiation 
Day 2  
12-hours 
Starts at 
36-hours 
post study 
drug 
initiation 
 
Collected prior to 
or as close to 
study drug 
discontinuation as 
possible 
Day 3 Or 
Starts as soon as 
study drug 
administration 
ends, lasts 24 
hours 
7 ±3, 14 ±3, and 
21 ±3 days post 
last visit 
Collected prior 
to or as close to 
study drug 
discontinuation 
as possible 
time early termination is being considered and as close as possible to the end of the study drug administration. Collect any time if medically indicated, per investigator’s 
judgment. 
u. AEs and concomitant medications will be collected throughout the study; non-direct questioning will occur. The collection requirements will differ depending on the 
subject’s treatment progression as follows: 1. All adverse events and associated concomitant medications will be collected through the in-patient follow-up day. 2. IV anesthetic 
agents (midazolam, propofol, thiopental, pentobarbital, or ketamine) administered during the study drug treatment period and the in-patient follow-up day should be followed 
through the week 4 visit/contact. 3. During the weekly follow-up visits, only ongoing AEs and new AEs assessed by the investigator to be related to study drug will be recorded 
and the concomitant medications associated with these AEs. 4. In addition, during the weekly follow-up visits, AEs of urinary tract infection (UTI), hospital-acquired/ventilator-
associated pneumonia, myocardial infarction (MI), sepsis from any source, critical illness myopathy/neuropathy, significant hypotension requiring support of vasopressors will 
be recorded regardless of relatedness. Associated concomitant medications for these AEs will not be recorded. 5. All SAEs regardless of relationship to study drug and their 
associated concomitant medications will be recorded from the time of 1st dose through the last follow-up visit/contact. 6. For subjects who early terminate from the study, prior 
to discontinuation as much information as is available should be recorded for ongoing AEs/SAEs, new AEs/SAEs and their associated concomitant medications, especially 
those that may have led to the early termination. 
 
 


 
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1. 
BACKGROUND INFORMATION 
1.1 
Indication and Current Treatment Options  
Status epilepticus (SE) is a highly serious occurrence within the spectrum of epileptic disorders 
that is characterized by the manifestation of continuous or intermittent seizures lasting more than 
5 minutes in duration without full recovery of consciousness or 10 minutes of continuous seizure 
activity on EEG, or intermittent paroxysmal activity for more than 50% of an hour.1-4 
 
If SE is not treated immediately, prolonged seizure activity can result in permanent neuronal 
damage and contribute to the high morbidity and mortality associated with SE.2,4,5  Paroxysmal 
hypersynchronous electrical discharges occur when there is too much excitation or too little 
inhibition in the area of the brain where the abnormal discharge starts.6  Gamma-aminobutyric 
acid (GABA) is recognized as the principal inhibitory neurotransmitter in the cerebral cortex, 
and a disturbance in GABA-mediated functions results in the occurrence of epileptic seizures.6  
SE is often caused by pre-existing epilepsy, but it can also be caused by cerebral damage.2  In 
subjects with chronic epilepsy, low blood concentrations of antiepileptic drugs (AEDs) can lead 
to SE.1  Other recognized causes of SE include, but are not limited to, cerebrovascular accidents, 
anoxia or hypoxia, metabolic causes, and alcohol and drug withdrawal.1,2  
 
A growing body of evidence from research and clinical observation supports the concept that SE 
becomes more difficult to control as its duration increases, and prolonged SE and refractoriness 
to treatment are associated with poor prognosis.1  Resistance to treatment has been partially 
attributed to the internalization of postsynaptic GABAA receptors and externalization of 
glutamate receptors.5  It has also been postulated that resistance may occur because of a 
mechanistic shift from inadequate GABAergic inhibitory receptor–mediated transmission to 
excessive N-methyl-D-aspartic acid excitatory receptor–mediated transmission.7  Because 
prolonged epileptiform bursting results in a reduction of GABAA-mediated synaptic inhibition, 
antiepileptic treatments that rely on enhancing intrasynaptic GABAA neurotransmission become 
less effective the longer SE continues.   
 
SE can be classified into three subtypes: generalized convulsive SE (GCSE), non-convulsive SE 
(NCSE), and refractory SE (RSE).2,4  GCSE is characterized by convulsions that are associated 
with tonic-clonic movements of the extremities and mental status impairment, and may result in 
focal neurologic deficits lasting hours to days following an episode.4  NCSE is defined as seizure 
activity seen on electroencephalography (EEG) without clinical symptoms; however, acutely ill 
subjects may present with impaired mental status following an NCSE episode.4  RSE occurs in 
subjects who do not respond to the standard SE treatment regimen of a benzodiazepine and a 
secondary AED.4   
 
SE is a neurologic emergency that requires aggressive treatment to stop the seizures and prevent 
permanent neuronal damage.8  Mortality due to SE can range from 3% to 40% depending on 
etiology, age, status type, and status duration.9  Previous studies have shown that seizures cause 
neuronal death via excitotoxic mechanisms as a result of excessive neuronal firing.1  
Furthermore, GCSE is associated with many complications, including cardiac arrhythmias, 
rhabdomyolysis, pulmonary edema, electrolyte and glucose imbalance, and temperature 
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The prognosis worsens and the mortality increases for subjects whose SE develops into RSE or 
super-refractory SE (SRSE).11  Approximately one-third of subjects with RSE and SRSE will die 
of their condition; one-third recover but with chronic neurologic or other deficits, and one-third 
have been generally described as returning to baseline.12,13  The longer subjects are kept in a 
long-term medically-induced coma to stop the seizures, the worse the prognosis.14  
 
As SE is a medical emergency, the primary goal of treatment is to rapidly stop the seizures and 
avoid complications.  Treatment typically occurs in stages: emergent initial therapy (first-line), 
urgent control therapy (second-line), and refractory therapy (third-line).4  Therefore, continuous 
video-EEG monitoring is critical for monitoring sedation as well as SE outcome.20 
 
The first-line standard-of-care treatment for early and established SE (ESE) is parenteral 
benzodiazepines.7  A recent large-scale clinical study found that about 25% and 36% of subjects 
with SE did not respond to intramuscular (IM) midazolam and intravenous (IV) lorazepam, 
respectively.15  Only two-thirds of subjects with SE respond to the first treatment, and evidence 
shows prolonged seizures can result in permanent neuronal damage and contribute to the high 
morbidity and mortality associated with SE.6  Additionally, more than 20% of patients admitted 
for SE require intubation after benzodiazepine administration as first-line drug29, solely for the 
sake of airway protection.  
 
RSE is commonly defined as SE resistant to treatment with one first-line AED (benzodiazepines) 
and one second-line AED (phenytoin, phenobarbital, or valproate acid).16,17  Because SE tends to 
become more refractory to conventional treatment over time and with the number of 
pharmacologic agents used18 coma induction with an appropriate drug, such as barbiturates, 
propofol, or midazolam, is advocated after failure of second-line treatment.19  The use of 
third-line agents such as pentobarbital, midazolam, propofol, and phenobarbital usually results in 
iatrogenic coma, which necessitates protection of the airways by intubation and mechanical 
ventilation.  
 
As the goal of RSE treatment is to abolish all clinical and electrographic epileptic activity, 
continuous EEG monitoring is essential for this patient population. Without continuous EEG 
monitoring, the response to IV treatment could be difficult to interpret, because subclinical 
electrographic seizure activity can be detected in up to 48% of subjects after control of 
convulsive SE.21  Burst suppression is often required in the intensive care phase of SE treatment, 
since RSE is associated with substantial mortality. 
 
1.2 
Product Background and Clinical Information 
Ganaxolone is the 3β-methylated synthetic analogue of the neuroactive steroid allopregnanolone, 
but it is designed not to activate nuclear (classical) progesterone receptors. Ganaxolone differs 
from other GABA agents by interacting with both synaptic and extra-synaptic GABAA receptors 
and at binding sites distinct from benzodiazepines. Whereas benzodiazepines might lose their 
inhibitory action, ganaxolone does not because it selectively binds to GABAA receptors 
containing the α and δ subunits. By enhancing GABAA receptor function, ganaxolone provides 
an alternative mechanism in the treatment of seizures and could serve as effective therapy in the 
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The therapeutic strategy for SE is always aggressive, and subjects in this condition often present 
with many comorbidities. The introduction of another medication to control SE must be balanced 
with the potential risks it brings, and most commonly used AEDs are associated with significant 
toxicities.  Ganaxolone is an attractive potential therapy because of its current investigational 
safety profile, which is derived from a relatively large clinical database (> 1,500 subjects 
exposed) that contains both pediatric and adult populations. In clinical trials to date, it has shown 
anticonvulsant activity in subjects with seizure disorders.  Marinus is investigating the approach 
of dosing ganaxolone to a level required to successfully control SE in this patient population.   
 
Neuroactive steroids, which are positive allosteric modulators of both synaptic and extra-
synaptic GABAA receptors,22 have inhibitory properties to calm the overexcited brain (some 
have been used as anesthetics23) and might be effective in treating benzodiazepine-resistant SE. 
 
As of 10 October 2018, approximately 1,557 unique subjects have received treatment with 
ganaxolone in ongoing and completed company-sponsored clinical trials ranging in duration 
from 1 day to more than 2 years, using doses from 50 to 2,000 mg/day.24 
In addition, 175 subjects were enrolled in 2 post-partum depression studies and 41 subjects have 
been randomized in on-going phase 3 pediatric genetic epilepsy studies. 
In 20 completed Phase 1 studies, 319 healthy subjects received ganaxolone doses of 50 to 
2,000 mg/day for periods of up to 2 weeks.  
In the 20 completed Phase 2/3 clinical studies, 1238 unique subjects have received ganaxolone, 
including adult subjects with epilepsy, pediatric subjects with seizure disorders, pediatric 
subjects with fragile X syndrome, adult subjects with migraine, and subjects with post-traumatic 
stress disorder.  
The overall frequency of treatment-emergent adverse events (TEAE) in company-sponsored 
placebo-controlled studies was 61.7% (613/993 subjects) in subjects who received GNX 
and 51.8% (330/637 subjects) in subjects who received placebo.  The most frequently reported 
TEAEs in GNX-treated subjects were somnolence, dizziness, fatigue, and headache. All of these 
events, except for headache, occurred more frequently in GNX-treated subjects than placebo 
subjects. CNS-related evets appeared to be dose related, with the majority of these events 
occurring at doses ≥ 500 mg and were anticipated based on the mechanism of action of 
ganaxolone.  
The majority of TEAEs were anticipated based on the mechanism of action of GNX and were 
non-serious, mild to moderate in severity, and did not lead to discontinuation of treatment.   
In the ganaxolone development program overall, no clinically significant trends in 
electrocardiogram (ECG) intervals, vital signs, or physical or neurologic 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, 0.3% of subjects treated with ganaxolone and 0.5% of 


 
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subjects treated with placebo exhibited elevated liver function tests during the study (aspartate 
transaminase or alanine transaminase > 3 times the upper limit of normal [ULN]).  There have 
been no cases of Hy’s law considered to be related to ganaxolone in the ganaxolone development 
program. In controlled clinical trials of ganaxolone, 1.1% of subjects receiving placebo and 1.7% 
of subjects receiving ganaxolone reported an AE of rash suggesting there is no obvious 
imbalance between drug and placebo in terms of frequency of this AE. However, in placebo-
controlled studies rash led to discontinuation in GNX—treated subjects in 6 cases (0.6%) 
compared to no cases (0%) in placebo-treated subjects. Most rashes improved either while the 
drug was continued or following discontinuation. Two subjects participating in the Phase 2 study 
investigating ganaxolone in treatment of epilepsy developed an SAE of rash. Both events 
resolved after discontinuation of the study drug. 
Preclinical studies and a study in 36 healthy volunteers assessing safety, pharmacokinetics, and 
pharmacodynamics of IV ganaxolone have been completed. Preclinical toxicity studies showed 
IV ganaxolone to be generally safe and adverse events to be consistent with expected dose-
related sedation. In rats continuously dosed with IV ganaxolone for 14 days, no ganaxolone-
related changes were noted in clinical pathology parameters or histopathology examination. 
There was no evidence of local irritation when ganaxolone was given IV or perivenously in 
preclinical studies. Furthermore, IV ganaxolone did not cause hemolysis and was compatible 
with human plasma.  
The safety, pharmacokinetics, and pharmacodynamics of IV ganaxolone were investigated in 36 
healthy volunteers in study 1042-0405, in which ganaxolone was administered as a bolus dosing 
(Stage 1) or as a bolus dose followed by a continuous infusion (Stage 2). Ten of the 36 subjects 
enrolled were women.  
 Stage 1 enrolled and dosed subjects in four cohorts (A to D):  6 subjects in Cohort A 
(10 mg ganaxolone IV bolus in 3 subjects and 30 mg ganaxolone bolus in 3 subjects over 
5 minutes), 8 subjects in Cohort B (20 mg ganaxolone bolus over 2 minutes), 8 subjects 
in Cohort C (30 mg ganaxolone bolus over 1 hour), and 8 subjects in Cohort D (10 mg 
ganaxolone bolus over 1 hour).  Cohorts B, C, and D included 2 placebo subjects in each 
cohort.  
 Stage 2 of the study dosed a total of 6 subjects with a 6 mg bolus followed by a 4-hour 
infusion at 20 mg/hour.  
A total of 35 of the 36 subjects enrolled in Stages 1 and 2 completed the study as planned, while 
1 subject withdrew their consent after completion of dosing but failed to come back for follow-
up.  
Six subjects reported treatment-emergent AEs in Stage 1 and 2.  No single AE was seen twice.  
Only one event, headache, was considered by the investigator to be related to ganaxolone.  None 
of the treatment-emergent AEs was serious, and all were of mild intensity.  No clinically 
meaningful mean changes in laboratory test results, vital signs, or ECG parameters occurred in 
any cohort.  
Pharmacokinetic data from study 1042-0405 showed that a bolus infusion of 30 mg ganaxolone 
over 5 minutes led to transient peak concentration levels (Cmax) above 1,000 ng/mL with no 
safety concerns.  Infusion of 30 mg/hour for 1 hour and 20 mg/hour for 4 hours led to 


 
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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).   
It is not known if ganaxolone is excreted in breast milk.  After cessation of the infusion, plasma 
ganaxolone levels are expected to drop rapidly, but it is possible that low, subtherapeutic levels 
persist for several days as ganaxolone is slowly released from tissues.  Therefore, a washout 
period of 45 days is required following cessation of ganaxolone treatment before breastfeeding.  
Previous toxicology studies in animals focusing on prenatal and neonatal development have not 
demonstrated toxicities associated with ganaxolone.  Ganaxolone has been administered to 
infants with severe forms of epilepsy as early as 4 months of age.  
In clinical trials involving administration of ganaxolone over several weeks, the study drug has 
been tapered off over a 1- to 2-week period.  There have been no reports of withdrawal 
symptoms emerging after cessation of ganaxolone.  
Always refer to the latest version of the Ganaxolone Investigator’s Brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy, and safety of ganaxolone.  
2. 
STUDY OBJECTIVES AND PURPOSE 
2.1 
Rationale for the Study 
Status epilepticus (SE) is defined as a prolonged self-sustaining seizure or recurrent seizures 
without recovery of consciousness between seizures.1 The International League of Against 
Epilepsy further defined SE as a condition resulting either from the failure of mechanisms 
responsible for seizure termination or from the initiation of mechanisms, which lead to 
abnormally, prolonged seizures (5 minutes for tonic-clonic SE and 10 minutes for focal SE with 
impaired consciousness) and which can have long-term consequences (after 30 minutes for tonic-
clonic SE and > 60 minutes for focal SE with impaired consciousness), including neuronal death 
and/or injury, and alteration of neuronal networks, depending on the type and duration of 
seizures.1  SE is a neurological emergency that requires aggressive treatment to stop the seizures 
and prevent permanent neurological damage.3  Mortality due to SE can range from 3% to 40% 
depending on etiology, age, SE type, and SE duration.5  SE can be recognized clinically or using 
electroencephalograms (EEGs) by the presence of continuous ictal discharges.3 Studies have 
shown that SE can cause neuronal death via excitotoxic mechanisms as a result of excessive 
neuronal firing.6  Furthermore, convulsive SE is associated with many complications, including 
cardiac arrhythmias, rhabdomyolysis, pulmonary edema, electrolyte and glucose imbalance, and 
temperature disturbances. Approximately one third of subjects with refractory status epilepticus 
(RSE) and super refractory status epilepticus (SRSE) will die of their condition; one-third 
recover but with chronic neurologic or other deficits, and one third have been generally 
described as returning to baseline.  The prognosis worsens the longer subjects are kept in a 
medically-induced coma. The primary goal of SE treatment is to gain control of the seizures 
rapidly and avoid complications, and treatment typically occurs in stages.2 In general, the 


 
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treatment of SE is very aggressive and particularly urgent for convulsive status epilepticus 
(CSE).  
The current therapies for SE have inherent risks, which must be balanced against the benefit of 
rapid seizure control.  Benzodiazepines are the agents of choice for first line treatment of SE but 
their use can cause respiratory depression and hypotension, requiring the use of supportive 
therapies.2  Unfortunately, approximately 35-45% of patients are refractory to benzodiazepines.28 
Second line therapy involves administration of an IVAED such as fosphenytoin, valproic acid, or 
levetiracetam for convulsive tonic-clonic status with the goal of stopping SE in patients who did 
not respond to first line treatment.2 When a patient with SE fails to respond to a benzodiazepine 
and the initial 2nd line therapy they are classified as having RSE. RSE develops in 31-44% of 
patients with SE, with a mortality of 16-39%.29 Additional therapeutic agents are required 
immediately; typically, anesthetics via continuous infusion.2 Currently, the recommended 
anesthetic drugs include midazolam, propofol, thiopental, and pentobarbital. Anesthetics are 
associated with risks, especially if administered for a long time – propofol infusion syndrome 
and hypotension are two recognized adverse events associated with anesthetics for SE treatment. 
In addition, the need for assisted ventilation and the management of hypotension and 
cardiopulmonary depression have their own risks.2 
Few therapies are approved for the treatment of SE and the urgent need for more efficacious 
therapies remains.  Only two-thirds of patients in SE respond to first-line treatment.3 Resistance 
to treatment has been partially attributed to the internalization of post-synaptic GABAA-receptors 
and externalization of glutamate receptors.3 As prolonged epileptiform bursting results in a 
reduction of GABAA-mediated synaptic inhibition, antiepileptic treatments which rely on 
enhancing intra-synaptic GABAA neurotransmission become less effective the longer SE 
continues.  
Ganaxolone is a potent allosteric positive modulator of GABAA receptors in the brain at a site 
distinct from the site of action of benzodiazepine receptor agonists and barbiturates.  Γ-
aminobutyric acid (GABA) is recognized as the principal inhibitory neurotransmitter in the 
cerebral cortex, and a disturbance in GABA-mediated functions results in the occurrence of 
epileptic seizures.5 By enhancing the GABAA receptor function, ganaxolone provides an 
alternative mechanism in the treatment of seizures, and serves as effective therapy in the 
management of SE. Ganaxolone has been shown to stop SE in 2 distinct pre-clinical models of 
benzodiazepine-resistant SE.  
Ganaxolone for this study is a proprietary IV formulation solubilized by Captisol® (betadex 
sulfobutyl ether sodium). The study targets plasma concentrations of ganaxolone that mimic 
concentrations associated with anticonvulsant effects in preclinical animal models of SE and that 
are expected to demonstrate anticonvulsant properties in humans. On December 21, 2016 (Serial 
No. 0014), Marinus submitted a Request for FDA Feedback on the draft Phase 2 Study 1042-SE-
2001 protocol and provided specific questions.  One question was related to the proposed 
maximum daily dosing limit of Captisol exposure in this study of approximately 35 
grams/day.  On February 13, 2017, the FDA responded and indicated that the proposed 
maximum daily dosing limit of Captisol 35 grams/day, is acceptable in adults and pediatric 
patients > 12 years of age.  


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On November 15, 2018 (Serial No. 0034), Marinus submitted a Request for FDA Feedback with 
data from the cmTently emolled subjects to request an increase in the daily Captisol limit from 35 
g/day to 50 g/day. On December 13, 2018, the FDA provided their agreement citing, "Balancing 
the potential benefit of ganaxolone against the potential risk of a high Captisol exposme, we can 
allow you to exceed yow- cunent Captisol limit of 35 g/day but not to exceed 50 g/day in Study 
1042-SE-2001." Therefore, the maximum level of Captisol® in this study will not exceed 
50 g/day. 
The FDA indicated that if Marinus wanted to further increase the total daily dose of Captisol 
beyond 50 g/day, a new request for FDA feedback would need to be submitted based on a 
summa1y of the clinical experience from a sufficient number of subjects in Study 1042-SE-2001 
who achieved Captisol exposmes between 35 and 50 g/day. The FDA would review this data and 
respond accordingly. 
2.2 
Study Objectives 
2.2.1 
Primary Objective 
To establish that intravenous ganaxolone given concomitantly with 2nd line IV AED therapy is 
safe and effective in stopping status epilepticus that has already failed one 2nd line IV AED 
therapy administered at an appropriate dose and dmation to show efficacy and prevents 
escalation of treatment requiring an IV anesthetic drng (a 3rd line treatment) for seizme 
suppress10n. 
2.2.2 
Secondary Objectives 
To assess other secondaiy efficacy endpoints such as mortality and seizme cessation in SE 
subjects 
To assess the phan nacokinetics of adjunctive ganaxolone IV solution in SE subjects 
To assess the need for IV anesthetic diugs for treatment of cmTent SE event in SE subjects 
2.2.3 
Exploratory Objectives 
3. 
STUDY DESIGN 
3.1 
Study Design and Flow Chart 
This is double-blind, randomized, placebo-controlled study to evaluate the safety, tolerability, 
efficacy of adjunctive ganaxolone IV solution in subjects with SE. This study will staii with a 
small open-label group to confmn the dose selected will achieve an approximate tai·geted plasma 
concentration of ganaxolone in the SE population who ai·e on concomitant medications, and to 
obtain a preliminaiy assessment of safety, efficacy and feasibility of ganaxolone administration. 
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The dose selected for Day 2 is designed to provide a stable plasma concentration to maintain 
status cessation. If needed, doses in the open-label group may be adjusted based on the dosing 
and pharmacokinetic/safety profile from the subject’s enrolled.  
A total number of approximately 340 subjects will be screened to allow for up to approximately 
272 subjects to receive study drug in the open-label and the double-blind groups. Subjects who 
early terminate for reasons other than lack of efficacy or adverse events related to ganaxolone 
(e.g., pump failure and other operational issues) may be replaced. In the double-blind group, 
randomized subjects will receive ganaxolone IV solution or placebo in a 1:1 ratio.  
Study drug will be added to the standard of care at the time that the first 2nd line IV AED, 
administered at an appropriate dose and duration to show efficacy, has failed and the second 2nd 
line IV AED is medically indicated during the treatment of SE. Study drug must be administered 
with 2nd line IV AED as close to the dose initiation of the second 2nd line IV AED as possible.  
Potential subjects are anticipated to be identified in the emergency department and/or hospital in-
patient or intensive care units. 
Upon identification, subjects will be administered consent/assent and then screened for 
inclusion/exclusion criteria prior to receiving study drug as adjunctive therapy via continuous IV 
infusion, followed by a 12-hour study drug taper. As soon as the study drug administration is 
completed (with or without taper), subjects will have a 24-hour in-patient follow-up day and then 
follow-up visits/contacts at weeks 2, 3, and 4. For subjects who have the 12-hour study drug 
taper, the in-patient follow-up day starts as soon as the 12-hour study drug taper is complete. If 
the infusion rate becomes too low to sustain the infusion line, it can be discontinued at that point 
and the subject will progress into the in-patient follow-up day. For subjects where there is no 
study drug taper the in-patient follow-up day starts as soon as the study drug administration is 
discontinued. These subjects will continue with the week 2, 3, and 4 follow-up visits. 
If the subject remains hospitalized, the week 2, 3, and 4 visits will be done in-person.  If the 
subject has been discharged, these visits may be conducted via telephone call. However, it is 
recommended that discharged subjects return so at least one of these visits will be conducted in-
person.  


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Figure 1: Study Design Flow Chart 
s 
Treatment Period 
C 
Day l 
Day2 
r 
Hours 0-24 
e 
e 
n 
Bolus dose 
i 
n 
g 
Dose 
Initiation 
(Time 0) 
Continuous 
Hours 
-
Hours 36-48 
Continuous 
Infusion 
Infusion 
Taper 
_, ....... 
Infusion 
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Follow-up Period 
In-patient 
Weeks 2, 3, & 4 
Follow-up 
(3 week follow-up) 
Hours 48-72 
Adjunct treatment is planned to be 2-days (which includes a 12-hour taper). 
Hours 24-36 should start with an infusion rate of 20mg/hr with dose adjustments allowed up to 
45mg/hr. 
Total subject participation is expected to be approximately 4 weeks. 
3.2 
Duration and Study Completion Definition 
The subject's maximum duration of paiiicipation is expected to be approximately 4 weeks. It is 
anticipated the study will take 24 months to complete including approximately 18 months of 
subject emollment. 
The study completion date is defined as the date the final subject, across all sites, completes their 
final protocol-defined assessment. Please note that this includes the follow-up visit/contact, 
whichever is later. The study completion date is used to asce1iain timing for posting and 
repo1iing of study results. 
3.3 
Sites and Regions 
This multicenter study is to be conducted globally, with approximately 150 sites planned to 
paiiicipate. 
4. 
STUDY POPULATION 
Each subject/parent/guai·dian/legally authorized representative (LAR) must pa1iicipate in the 
info1med consent process and provide written info1med consent/assent before any procedures 
specified in the protocol ai·e perfo1med. Consent/assent will be administered per the hospital's 
IRB/EC policy and may vaiy across sites, i.e., some sites may be able to consent/assent over the 
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phone or other communication methods.  Consent/assent for subjects who are known to be at risk 
for SE may be obtained prior to a SE event. The period of time the pre-consent/assent is valid 
will be determined by each hospital’s IRB/EC. However, reconsenting will be needed should the 
consent/assent be updated at any point during the study. 
4.1 
 Inclusion Criteria 
The subject will not be considered eligible for the study without meeting all the criteria below. 
1. Subject, subject’s parent, guardian, or LAR must provide signature of informed consent, 
and, once capable (per the investigator’s hospital guidelines), there must be 
documentation of consent/assent by the subject indicating the subject is aware of the 
investigational nature of the study, is able and willing to participate in the study, and is 
aware of the required restrictions and procedures  
2. Male or female subjects 12 years of age and older at the time of the first dose of study 
drug 
3. Clinical and/or electrographic seizures defined as:  
o Documented clinical seizures (convulsive SE): greater than 5 minutes’ duration 
prior to treatment with study drug (per ILAE) 
or 
o Electrographic criteria (one must apply): 
 
10 minutes of continuous seizure activity on EEG (per ILAE) 
 
Intermittent electrographic seizure activity for more than 50% of the 
previous 60 minutes  
 
If less than 60 minutes of EEG is available, then intermittent 
electrographic seizure activity must be present for greater than 50% of the 
available duration of the EEG AND the electrographic seizure activity 
must be at least 10 minutes when taken in aggregate 
4. Subject on concurrent 2nd line IV AED therapy with fosphenytoin/phenytoin, valproic 
acid, levetiracetam, lacosamide, or brivaracetam for the management of the current 
episode of SE 
5. BMI < 40 or, if not able to be calculated at screening, assessed by investigator as not 
morbidly obese 
4.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following exclusion criteria are met.  
1. Life expectancy of less than 24 hours 
2. Anoxic brain injury as the primary cause of SE 
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4. Administered anesthesia (3rd line treatment; e.g., midazolam, propofol, thiopental, 
pentobarbital, or ketamine) at adequate doses and duration for the treatment of the current 
episode of SE that required the subject to be hospitalized and 5 half-lives of the agent 
used has not elapsed 
5. Subjects who are intubated for the administration of an IV anesthetic drug (a 3rd line 
treatment; e.g., midazolam, propofol, thiopental, pentobarbital, or ketamine) to treat SE; 
subjects who are intubated for airway protection are not excluded 
6. Subjects known or suspected to be pregnant upon screening 
7. To the best knowledge of the investigator, has allergy to progesterone or 
allopregnanolone medications/supplements or has previously received ganaxolone or 
exogenous allopregnanolone 
8. If renal impairment is suspected (eGFR < 45 mL/min) or subject is currently on dialysis; 
if decision is made to start dialysis during study participation, subject is not excluded.  
9. To the best knowledge of the investigator, subject has hepatic insufficiency at screening, 
for example alanine transferase or aspartate transferase level more than 5 times the upper 
limit of normal (ULN), or total bilirubin more than 2 times ULN at the screening visit 
10. Subjects with a durable medical care agreement that would not allow hospital to 
administer their standard of care for treatment of SE 
11. Subjects on an investigational drug that is not recommended by treatment guidelines are 
required to have a reasonable expectation that the investigational study drug has been 
cleared from their system, that is, that five half-lives have elapsed 
12. Subjects who have a history or evidence of a medical condition that, in the investigator’s 
judgment, would expose subject to an undue risk of a significant adverse event or 
interfere with assessments of safety or efficacy during the course of the study 
4.3 
Restrictions  
Subjects must abstain from the use of alcohol and from consuming grapefruit, Seville oranges, 
starfruit, or citrus-derived products until completion of the study. 
Females who are breastfeeding will be encouraged to “pump and dump” for the duration of study 
participation and for 45 days after the last dose of study drug.   
4.4 
Reproductive Potential 
4.4.1 
Female Contraception 
Sexually active females of childbearing potential should be using an acceptable form of 
contraception. Females of childbearing potential must be advised to use acceptable 
contraceptives throughout the study period and for 30 days after the last dose of study drug. If 
hormonal contraceptives are used, they should be administered per the package insert.  
Females of childbearing potential who are not currently sexually active must agree to use 
acceptable contraception, as defined below, if they become sexually active during the period of 
the study and 30 days after the last dose of study drug.  


 
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Female subjects should be: 
 Postmenopausal (12 consecutive months of spontaneous amenorrhea and  age 
51 years), or 
 Surgically sterile (having undergone one of the following surgical acts: 
hysterectomy, bilateral tubal ligation, bilateral oophorectomy, or bilateral 
salpingectomy) and at least 6 weeks post-sterilization, or 
 Should have specimens collected prior to study drug initiation. If not possible 
then, collected as soon as possible after study drug initiation. Enrollment is not 
contingent upon results. However, if a subject has a positive test result, it will be 
at the investigators discretion to weigh the risks verses benefits for the subjects 
continued participation.  
Acceptable methods of contraception are: 
 Intrauterine device plus condoms 
 Double-barrier methods (e.g., condoms and diaphragm with spermicidal gel or 
foam) 
 Hormonal contraceptives (oral, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the study participation, plus condoms. Note: If subject 
becomes sexually active during the study, they should use one of the other 
acceptable methods noted above in addition to the hormonal contraceptive until it 
has been stabilized for 30 days. 
4.4.2 
Male Contraception 
Male participants must agree to take all necessary measures to avoid causing pregnancy in their 
sexual partners during the study and for 3 months after the last dose of study drug. Medically 
acceptable contraceptives include surgical sterilization (such as a vasectomy) and a condom used 
with a spermicidal gel or foam. Contraceptive measures such as Plan BTM, sold for emergency 
use after unprotected sex, are not acceptable methods for routine use. 
Male subjects should not donate sperm during the study and for 30 days after the last dose of 
study drug. 
4.5 
Discontinuation of Subjects 
A subject may withdraw, or their parent, guardian, or LAR may withdraw the subject, from the 
study drug administration and/or the study at any time for any reason without prejudice to their 
future medical care by the physician or at the hospital. 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 study drug with the Medical Monitor when possible unless 
due to progression to an IV anesthetic drug (a 3rd line treatment) for seizure suppression. 


 
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Study drug discontinuation 
Subjects who discontinue study drug without a taper, e.g., takes study drug for less than 2 hours 
or progresses to an IV anesthetic (a 3rd line treatment) for seizure suppression or discontinues the 
study medication due to safety reasons will continue in the study and still have the in-patient 
follow-up day and the week 2, 3 and 4 follow-up visits/contacts. 
Study withdrawal 
Subjects who early terminate from the study, e.g. due to consent withdrawn, any outstanding 
screening procedures and the evaluations listed for the Early Termination Visit in Table 1 should 
be completed when early termination is being considered and as close as possible to the end of 
the study drug administration.   
4.5.1 
Subject Withdrawal Criteria 
All subjects reserve the right to withdraw from the clinical study at any time, as stated in the 
informed consent form.  The investigator may also discontinue subjects from the clinical study 
for any of the following reasons: 
1. The subject has persistent ventilatory depression that results in a SpO2 < 90% or ETCO2 > 
50 mmHg (measured using nasal cannula monitor) despite the use of airway maneuvers 
including assisted ventilation.  Standard airway maneuvers to treat sedation-induced upper 
airway obstruction (jaw thrust, chin lift, or supraglottic device such as a laryngeal mask 
airway) or hypoventilation (ventilation assisted with a mask or supraglottic device) would be 
instituted at the discretion of the physician monitoring the patient in order to maintain SpO2 
> 90% and ETCO2 < 51 mmHg.  If the subject does not respond to these methods, the 
subject would be discontinued 
2. ECG evidence of QT prolongation (QTcF > 500 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) 
3. Kidney function impairment such that eGFR ≤ 45 mL/min and subject is not starting dialysis  
4. Any other adverse event or safety issue (e.g., severe persistent hypotension/hypertension or 
tachycardia/bradycardia) that suggests it is not in the subject’s best interest to continue to 
receive study drug  
5. Rash that is clinically significant and considered to be related to the study drug (e.g., 
morbilliform, urticarial, papular) 
6. 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 prior to subject discontinuation unless due to the progression to an IV anesthetic drug (a 
3rd line treatment) for seizure suppression.  


 
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4.5.2 
Reasons for Discontinuation 
The reason for discontinuation must be determined by the investigator and recorded in the 
subject’s medical record and in the eCRF. If a subject is withdrawn for more than one reason, 
each reason should be documented in the source document and the most clinically relevant 
reason should be entered in the eCRF.  
Reasons for discontinuation include but are not limited to: 
 Adverse event 
 Protocol deviation 
 Consent withdrawal 
 Lost to follow-up 
 Lack of efficacy 
 Death 
 Physician decision 
 Other (must be specified in the subject source document and eCRF)  
 
4.5.3 
Subjects Lost to Follow-up Prior to Last Scheduled Visit 
A minimum of three documented attempts must be made to contact any subject lost to follow-up 
at any timepoint prior to the last scheduled contact (office visit or telephone contact). At least 
one of these documented attempts must include a written communication sent to the subject’s 
last known address via courier or mail (with an acknowledgment of receipt request) asking that 
they return to the site for final safety evaluations. If a contact is not made the subject should be 
classified as Lost to Follow-up in the eCRF. However, if contact is made but the subject refuses 
or is unable to come to the final safety evaluation, they should be classified as Other and the 
reason documented in the eCRF.  
5. 
PRIOR AND CONCOMITANT TREATMENT 
5.1 
Prior Treatment 
Prior treatment includes all non-study treatment received within 30 days prior to the first dose of 
study drug (or pharmacokinetic equivalent of five half-lives, whichever is longer). Treatments 
including but not limited to herbal treatments, vitamins, surgical implants (such as Vagus nerve 
stimulator), and prescribed medications, if available, must be recorded on the appropriate eCRF 
page. 
5.2 
Concomitant Treatment  
Concomitant treatment refers to all treatment taken between the date of the first dose of study 
drug and the end of the follow-up period, inclusive. However, the collection requirements will 
differ depending on the subject’s treatment progression as defined below.   


 
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 All concomitant medications will be collected through the in-patient follow-up day 
 During the weekly follow-up visits, only concomitant medications associated with 
ongoing AEs and new AEs assessed by the investigator to be related to study drug will be 
recorded 
 All concomitant medications associated with SAEs regardless of relationship to study 
drug will be recorded from the time of study drug initiation through the last follow-up 
visit/contact 
 In addition, for subjects who stop study drug administration without a taper but continue 
with the follow-up visits, any IV anesthetic agents (midazolam, propofol, thiopental, 
pentobarbital, or ketamine) that were started on the in-patient follow-up day should be 
followed through the last follow-up visit/contact  
 At the time that early termination from the study is being considered, prior to 
discontinuation as much information as is available should be recorded on the 
concomitant medications associated with ongoing AEs/SAEs and new AEs/SAEs, 
especially those that may have led to the early termination 
Concomitant treatment information must be recorded on the appropriate eCRF page. For some of 
the concomitant medications only the highest dose administered will be required in the eCRF. 
Reference the eCRF Completion Guidelines for guidance 
5.2.1 
Permitted Treatment 
Ganaxolone IV solution will be administered as adjunctive therapy to the hospital’s standard of 
care. Any medication classified by the hospital as per the standard of care will be acceptable. 
Anything outside of the standard of care should be discussed with the Medical Monitor. 
5.2.2 
Prohibited Treatment 
As per the exclusion criterion in Section 4.2, the only allowable concurrent 2nd line IV AED 
therapies to treat the current episode of SE are fosphenytoin/phenytoin, valproic acid, 
levetiracetam, lacosamide, or brivaracetam. Administering fosphenytoin and/or phenytoin will be 
counted as one (1) AED. These drugs can be used alone or in combination with each other. If the 
subject is receiving oral AED therapy to manage a subject’s chronic medical condition, for 
example, epilepsy, migraine, or neuropathic pain, that therapy is acceptable and should continue 
unchanged, if feasible and medically justified. This prophylactic treatment does not count 
towards the SE treatment failures required to qualify for this study. If any of these oral AED 
medications had to be interrupted around the time of the current SE episode, it is recommended 
that they would be re-started 10 hours after study drug initiation, if medically acceptable. Also, 
subjects who have been enrolled in another clinical study for SE are required to have a 
reasonable expectation that the other investigational drug has been cleared from their system, 
that is, that five half-lives have elapsed. Subjects on IV AEDs that are standard of care can be 
enrolled in the study. Subjects who have taken exogenous allopregnanolone or ganaxolone 
previously are not eligible for the study. 


 
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If a subject progresses at any time during the study to an IV anesthetic drug (a 3rd line treatment; 
e.g. midazolam, propofol, thiopental, pentobarbital, or ketamine and/or 4th line treatment; e.g., 
immunosuppressants, magnesium) for seizure suppression, study drug administration will be 
discontinued, however the subject will continue with the in-patient follow-up day and the week 
2, 3, and 4 follow-up visits.  
6. 
STUDY DRUG 
6.1 
Identity of Study drug 
The test product is ganaxolone IV solution, which will be provided in glass vials/bottles. 
For the Open-Label Group, ganaxolone IV solution, 1 mg/mL – 100 mL/vial is a sterile solution 
containing 1 mg of the active ingredient ganaxolone per 1 mL solution.  Ganaxolone IV 
Solution, 1 mg/mL – 100 mL/vial is packaged as a 100 mL dose in 125 mL glass vials. Details of 
packaging, dose and administration of the ganaxolone IV solution and placebo for the double-
blind group will be included in a future amendment. 
The formulation consists of a sterile solution of ganaxolone drug substance that has been 
solubilized by complexation with Captisol® (Betadex Sulfobutyl Ether Sodium).  In addition to 
Captisol, the formulation consists of water for injection (diluent), buffering agents (potassium 
phosphate, sodium phosphate) and sodium chloride (tonicity modifier).  The drug product is 
terminally heat sterilized.   
The composition of the Ganaxolone IV Solution, 1 mg/mL – 100 mL/vial is provided below. 
Quantitative Composition of Ganaxolone IV Solution, 1 mg/mL – 100 mL/Vial 
Component 
Reference to 
Standards 
Content per mL 
(mg/mL) 
Concentration 
(%w/w) 
Function 
Ganaxolone  
Marinus 
1.00 
0.097 
Active ingredient 
Betadex sulfobutyl ether sodium 
(Captisol) 
NF  
59.74 
5.817 
Solubilizing agent 
Potassium phosphate, monobasic 
(KH2PO4) 
NF 
2.46 
0.239 
Buffer agenta 
Sodium phosphate, dibasic 
heptahydrate (Na2HPO4.7H2O) 
USP 
2.78 
0.271 
Buffer agenta 
Sodium chloride 
USP 
2.00 
0.195 
Tonicity 
modifying agent 
Water for injection 
USP 
q.s. 1 mL 
93.381 
Diluent 
NF = National Formulary; USP = United States Pharmacopeia; w/w = weight by weight. 
a 
Formulation pH = 6.4 
 
Drug Product Name: Ganaxolone IV Solution, 1 mg/mL – 100 mL/vial 
Manufacturer: Alliance Contract Pharma, LLC., Harleysville, PA 19438 USA 
Strength for Open-Label Group: ready-to-infuse 1-mg/mL sterile solution in a glass vial 


 
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Packaging: Ganaxolone IV Solution, 1 mg/mL – 100 mL/vial will be provided to the site as 
individual vials containing 1 mg/mL of Ganaxolone.  
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor. 
Storage:  The investigator has the overall responsibility for ensuring that study drug is stored in 
a secure, limited-access location.  Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.  Study drugs are distributed 
by the pharmacy or by a nominated member of the study team.  
Ganaxolone IV solution, 1 mg/mL – 100 mL/vial has on-going stability and to date has been 
found stable if stored at 15°-25°C (59°-77°F) until use.  Excursions up to 30°C (86°C) that are 
experienced in pharmacies, hospitals, and warehouses, and during shipping are allowed. 
6.1.1 
Blinding the Treatment Assignment 
For the double-blind group, the site pharmacy personnel who dispenses the study drug is not 
required to be blinded and will not be involved in any study assessments.  All other participating 
staff involved in the evaluation and execution of the study will remain blinded to subject’s study 
drug treatment.  
6.2 
Administration of Study drug(s) 
6.2.1 
Interactive Response Technology for Study Drug Management 
For the double-blind group an Interactive Voice/Web Response System (IVRS/IWRS) will be 
utilized for the following study drug tasks: 
 
Randomization 
 
Supply management 
 
Inventory management and supply ordering 
 
Expiration date tracking 
 
Returns 
 
Emergency unblinding 
Details on the name and address of the system and use will be detailed in the Investigator files at 
each site. 
6.2.2 
Allocation of Subjects to Treatment  
This is a double-blind study with an initial open-label group. The actual treatment given to 
individual subjects in the double-blind group is determined by a randomization schedule. For 
both groups, subject identification numbers are assigned to all subjects prior to dosing. Within 
each site (numbered uniquely within a protocol), subject numbers are assigned per the sequence 
of subject presentation for study participation.  


 
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The randomization number represents a unique number corresponding to study drug allocated to 
the subject, once eligibility has been determined.  
Individual subject treatment for the double-blind is automatically assigned by the IVRS/IWRS. 
Subjects participating in the open-label portion of the study will be dispensed ganaxolone IV 
solution. The study drug will be identified as ganaxolone IV solution and any vial identified as 
such can be dispensed. Sites will be responsible for logging and tracking the open-label supplies 
via study accountability logs and entered into the eCRF. All open-label supplies will have a 
unique vial number for tracking purposes. 
6.2.3 
Dosing 
Total adjunctive ganaxolone IV solution therapy infusion treatment is planned to be 2 days 
which includes a 12-hour study drug taper. All subjects will have an ~3-minute bolus dose with a 
continuous infusion at the rate of 20-80 mg/hour, and a 12-hour study drug taper (see Table 2 
and 3 for details). Once study drug administration is started it should be delivered for 2 days (48 
hours) which includes a 12-hour taper.  
Study drug should be administered, ideally, through a dedicated (peripheral or central) IV line. 
These infusion parameters result in daily doses of ganaxolone of ≤ 830 mg/day and Captisol of ≤ 
50 g/day as agreed upon with the FDA. Based on PK modeling, it is predicted that maximum 
concentrations of ganaxolone should remain within 1,000 ng/mL during infusion, but some 
variability is expected due to, for example, differences in subjects’ weight. Note, at any time, the 
infusion rate of the ongoing administration may be decreased for safety reasons, see Dose 
Adjustments and Interruptions section below for more information. 
Note, pharmacokinetic data from study 1042-0405 in healthy volunteers showed that a bolus 
infusion of 30 mg ganaxolone over 5 minutes led to transient peak concentration levels (Cmax) 
above 1,000 ng/mL (maximal observed Cmax was 1,850 ng/mL) with no safety concerns. Infusion 
of 30 mg/hour for 1 hour and 20 mg/hour for 4 hours led to concentrations of 258 and 215 
ng/mL, respectively, again without any safety concerns (see Section 1.2 Product Background and 
Clinical Information). 
During the open-label group, based on the safety, efficacy, and pharmacokinetic data from the 
ongoing study, the infusion parameters in subsequent subjects may be adjusted to maximize the 
safety and efficacy of study subjects. If the infusion parameters are amended, the new infusion 
parameters will not exceed the daily limit of 50 g/day Captisol (< 830 mg/day ganaxolone) as 
agreed upon with the FDA. The revised infusion parameters will be communicated to Clinical 
Sites in a Protocol Administrative Change Memo and kept in the study and site files.    
Potential subjects must have failed one 2nd line IV AED therapy, administered at an appropriate 
dose and duration to show efficacy. Ganaxolone IV solution  (open-label group) or ganaxolone 
IV solution or placebo (double-blind group) will be administered in combination with standard 
of care at the time that the first 2nd line IV AED has failed and the second 2nd line AED is 
medically indicated during the treatment of SE. Study drug must be administered with 2nd line IV 
AED treatment and should be initiated as close to the dose initiation of the second 2nd line IV 
AED as possible. 


 
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Upon administration of study drug, subjects will be monitored for improvement or resolution of 
SE (clinical or EEG response).  
Note, the infusion rate cannot be rounded-up regardless whether dosing is in subjects ≥ 40 kg or 
< 40 kg. 
Subjects weighing at least 40 kg: 
 A 30-mg bolus dose (over ~3 minutes) will be administered with a continuous infusion of 
80 mg/hour for 2 hours followed by a continuous infusion rate of 40 mg/hour for 10 hours, 
and then 20 mg/hour for the remaining 12 hours of Day 1.  
 On Day 2 (24-36 hours) the continuous infusion rate of 20 mg/hour will continue until the 
start of the study drug taper at 36 hours post study drug initiation. If needed, to manage 
seizure relapse or another medical reason, the infusion rate can be increased from 20 mg/hour 
up to a maximum rate of 45 mg/hour at any time during hours 24-36 of Day 2. 
 To taper the study drug, the infusion rate at the 36-hour post study drug initiation timepoint 
will be reduced by 33.3% every 4 hours until the infusion is stopped or if the infusion rate 
becomes too low to sustain the infusion line, at which point it will be stopped. The first taper 
will be 33.3% from the current infusion rate, the second taper will be 33.3% from the first 
tapered infusion rate, and the final taper will be 33.3% from the previous tapered infusion 
rate. If, per the investigator’s judgment, the study drug taper needs to start at an earlier 
timepoint during the treatment period, the infusion rate at the start of the first taper will be 
decreased by 33.3% every 4 hours as described. 
 At the time the study drug infusion is discontinued the subject will progress to the in-patient 
follow-up day assessments/procedures.  
 
 


 
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a.  On Day 2 (24-36 hours), the continuous infusion rate can be increased from 20 mg/hour to a maximum rate of 45 mg/hour at 
any time, if needed, to manage seizure relapse or other medical reason.   
b. To taper the study drug, the infusion rate at the 36-hour post study drug initiation timepoint will be reduced by 33.3% every 4 
hours until the infusion rate is stopped or if the infusion rate becomes too low to sustain the infusion line, at which point it will be 
stopped. The first taper will be 33.3% from the current infusion rate, the second taper will be 33.3% from the first tapered 
infusion rate, and the final taper will be 33.3% from the previous tapered infusion rate. If, per the investigator’s judgment, the 
study drug taper needs to start at an earlier timepoint during the treatment period, the infusion rate at the start of the first taper 
will be decreased by 33.3% every 4 hours as described. 
 
Subjects weighing < 40 kg will be dosed on a per-kilogram basis: 
 A 0.43-mg/kg bolus dose (over ~3 minutes) will be administered with a continuous infusion 
at a dose of 1.14 mg/kg/hour for 2 hours followed by a continuous infusion rate of 0.57 
mg/kg/hour for 10 hours, and 0.29 mg/kg/hour for the remaining 12 hours of Day 1. 
 On Day 2 (24-36 hours) the continuous infusion dose of 0.29 mg/kg/hour will continue until 
the start of the study drug taper at 36 hours post study drug initiation. If needed, to manage 
seizure relapse or for another medical reason, the infusion dose can be increased from 0.29 
mg/kg/hour up to a maximum of 0.64 mg/kg/hour at any time during hours 24-36 of Day 2. 
 To taper the study drug, the infusion rate at the 36-hour post study drug initiation timepoint 
will be reduced by 33.3% every 4 hours until the infusion is stopped or if the infusion rate 
becomes too low to sustain the infusion line, at which point it will be stopped. The first taper 
Table 2: 
Dosing for Subjects ≥  0 kg (on an mg/hour basis) 
Days 
Start Time from Study Drug 
Initiation 
Study Drug 
Dose  
(mg/hour) 
Study Drug 
Infusion Rate 
(mL/hour) 
Duration 
Day 1 
0 hours: bolus dose via syringe 
or infusion pump 
30  
30 
3 minutes 
Day 1 
0 hours through 2 hours post 
study drug initiation: 
continuous infusion, started 
with bolus 
80  
80  
2 hours 
Day 1 
2 hours through 12 hours post 
study drug initiation 
40  
40 
10 hours 
Day 1 
12 hours through 24 hours post 
study drug initiation  
20  
20 
12 hours 
Day 2a 
24 hours through 36 hours post 
study drug initiation 
20 - 45  
20 - 45 
12 hours  
 
          Study Drug Taper 
Day 2b  
36 through 48 hours post study 
drug initiation (12-hour taper) 
13.34 - 30.02  
13.34 - 30.02 
4 hours 
8.90 - 20.02 
8.90 - 20.02 
4 hours 
5.93 - 13.35 
5.93 - 13.35 
4 hours 


 
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will be 33.3% from the current infusion rate, the second taper will be 33.3% from the first 
tapered infusion rate, and the final taper will be 33.3% from the previous tapered infusion 
rate. If, per the investigator’s judgment, the study drug taper needs to start at an earlier 
timepoint during the treatment period, the infusion rate at the start of the first taper will be 
decreased by 33.3% every 4 hours as described. 
 At the time the study drug infusion is discontinued the subject will progress to the in-patient 
follow-up day assessments/procedures.  
Table 3: 
Dosing for Subjects < 40 kg (on an mg/kg/hour basis) 
Days 
Start Time from Study 
Drug Initiation 
Study Drug 
Dose  
(mg/kg/hr) 
Study Drug 
Infusion Rate 
(mL/hr)a 
Duration 
Day 1 
0 hours: bolus dose via 
syringe or infusion pump 
0.43  
Variable 
depending on 
subject’s 
weight 
3 minutes 
Day 1 
0 hours through 2 hours 
post study drug initiation 
dose: continuous infusion, 
started with bolus 
1.14 
 
Variable 
2 hours 
Day 1 
2 hours through 12 hours 
post study drug initiation  
0.57 
Variable 
10 hours 
Day 1 
12 hours through 24 hours 
post study drug initiation 
0.29 
Variable 
12 hours 
Day 2b 
24 hours through 36 hours 
post study drug initiation   
0.29 - 0.64  
Variable 
12 hours 
 
             Study Drug Taper  
Day 2c  
 
36 through 48 hours post 
study drug initiation (12-
hour taper) 
0.19 - 0.43 
Variable 
4 hours 
0.13 - 0.29 
Variable 
4 hours 
    0.08 - 0.19     
Variable 
4 hours 
a.  Reference the Pharmacy Manual for study drug infusion rates based on mg/kg/hour dosing. 
b.  On Day 2 (24-36 hours), the continuous infusion dose can be increased from 0.29 mg/kg/hour to a maximum dose of   
0.64 mg/kg/hour at any time, if needed, to manage seizure relapse or other medical reason. 
c.  To taper the study drug, the infusion rate at the 36-hour post study drug initiation timepoint will be reduced by 33.3% every 4 
hours until the infusion rate becomes too low to sustain the infusion line, at which point it will be stopped. The first taper will be 
33.3% from the current infusion rate, the second taper will be 33.3% from the first tapered infusion rate, and the final taper will 
be 33.3% from the previous tapered infusion rate.  If, per the investigator’s judgment, the study drug taper needs to start at an 
earlier timepoint during the treatment period, the infusion rate at the start of the first taper will be decreased by 33.3% every 4 
hours as described. 
 


 
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Medical Oversight:  
Medical personnel must be present at all times during at least the first 3 hours after the start of 
the study drug infusion. Then close monitoring of the subject by the study staff will continue as 
medically needed throughout the study. 
New AED Introduction: 
 For the first 10-hours of study drug administration the decision to initiate new IV AEDs 
should be based on safety or efficacy and confirmed by relapsing clinical presentation or 
electrographic activity. Initiation of any new AEDs prophylactically (so called 
“transition/bridging”) is not recommended, unless medically indicated.  
 In the event of safety or efficacy presentation, i.e. seizure relapse that would prompt the 
investigator to make a treatment intervention, introduction of a new IV AED is recommended 
over immediate progression to a 3rd line agent, however all treatment decisions are at the 
investigator’s discretion. 
 After the first 10-hours investigators are encouraged to initiate prophylactic AEDs in 
anticipation of the study drug taper at 36 hours post study drug initiation on Day 2.  
Scenarios for stopping the study drug without a taper include: 
 For subjects who receive study drug for less than 2 hours and/or  
 Study drug infusion is discontinued or interrupted, and the decision is made to not restart the 
infusion and/or 
 If at any time during study drug administration the subject progresses to an IV anesthetic 
drug (a 3rd line and/or 4th line treatment) for seizure suppression or 
 It is no longer safe to continue drug administration per the investigator’s medical judgment. 
Dose Optimization: 
During the open-label group, based on the safety, efficacy, and pharmacokinetic data from the 
ongoing study, the infusion parameters in subsequent subjects may be adjusted to maximize the 
safety and efficacy of study subjects. If the infusion parameters are amended, the new infusion 
parameters will not exceed the daily limit of 50 g/day Captisol (< 830 mg/day ganaxolone) as 
agreed upon with the FDA.  The revised infusion parameters will be communicated to Clinical 
Sites in a Protocol Administrative Change Memo and kept in the study and site files. 
For study drug dosing instructions reference the Pharmacy Manual. 
 
Dose Adjustments and Interruptions: 
Dose (infusion rate) decreases and interruptions of the continuous infusion are discouraged at 
any time during study drug treatment. However, if there is an urgent medical need (e.g., severe 
hypotension, acidosis, severe sedation) or a subject’s standard of care requires they undergo a 


 
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procedure for which the infusion would need to be decreased or interrupted (e.g., an MRI scan) it 
should be kept as short as possible but no longer than 6 hours. If > 6 hours the Marinus Medical 
Monitor must approve the re-start of the infusion.  
Note:  
 After the dose (infusion rate) decrease or infusion interruption, it will be per the 
investigator’s judgment and assessment of risk/benefit if the subject should continue in 
the study or early discontinue.  
 In cases when severe sedation is seen and early drug discontinuation is being considered, 
the Marinus Medical Monitor should be contacted prior to infusion termination, if 
feasible.  
 If the decision is made for the subject to continue in the study, the infusion should be re-
started at the rate matching the rate at the corresponding nominal time, counted from the 
beginning of the study drug infusion on Day 1. A study drug bolus or “catch-up” dose to 
deliver the study drug that was missed during the interruption should not be administered.  
 Dose (infusion rate) increases above those specified in the protocol (or based on a future 
Protocol Administrative Change Memo) are not allowed at any time during infusion. This 
is to ensure daily Captisol and ganaxolone limits are kept ≤ 50 g/day and  
≤ 830 mg/day, respectively.  
 
6.2.4 
Unblinding the Treatment Assignment 
During the double-blind group, the treatment assignment must not be broken except in 
emergency situations in which the identification of the study drug is required for further 
treatment of the subject.  The investigator should contact the Medical Monitor before unblinding, 
if possible.  However, this should not delay unblinding in case of an emergency.  The 
investigator should contact the Medical Monitor as soon as possible after the investigator has un-
blinded the subject.  
In the event that the treatment assignment is broken, the date, the signature of the person who 
broke the code, and the reason for breaking the code are recorded in the source documents.  
Upon breaking the blind, the subject is withdrawn from the study, but should be followed up for 
safety purposes.  Any code-breaks that occur must be reported to the Contract Research 
Organization (CRO) and sponsor.  
6.3 
Labeling, Packaging, Storage, and Handling 
6.3.1 
Labeling 
Labels containing study information and vial identification are applied to the study drug 
containers.  
Each 125 mL vial contains 100 mL of ganaxolone at a concentration of 1 mg/mL (open-label 
group).  Details of packaging, dose and administration of the ganaxolone IV solution and placebo 
for the double-blind group will be added in a future amendment. A label is applied to each 
vial/bottle with information on strength, manufacturing batch or job number, expiry or 
manufacturing date, storage conditions, and name of the manufacturer, as well as a warning that 
the drug is intended for research only.  


 
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The study drug will be dispensed to qualified staff members who will administer the study drug 
to the subject. 
All study drug is labeled with a minimum of the following: protocol number, unique vial/bottle 
number, dosage form (including product name and quantity in pack), directions for use, storage 
conditions, batch number and/or packaging reference, the statements “For investigational use 
only” and/or “Caution: New Drug—Limited by Federal (or US) Law for Investigational Use” 
and “Keep out of reach of children,” and the sponsor’s name and address. No information should 
be visible, which could potentially unblind the study drug intended for the double-blind portion 
of the study. 
Additional labels (e.g., those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the study drug in order to satisfy local or hospital requirements, but must not: 
 Contradict the clinical study label 
 Obscure the clinical study label 
 Identify the study subject by name, without consultation with the sponsor (only 
applicable to the vial or bottle). Additional labels may not be added without the 
sponsor’s prior full agreement. 
Open-label Group: 
Ganaxolone IV Solution Vial Label (1 mg/mL): 
Protocol 1042-SE-2001 
 
 
 
Vial Number: XXX 
Contents: Ganaxolone IV Solution, 1mg/mL Quantity: 100 mL/vial 
                                                Fill volume: 100 mL 
Date of Manufacture: DDMMYYYY 
Dose according to Pharmacy Manual Instructions 
Store at 15°C to 25°C (59°F to 77°F) 
Intravenous use only. Keep out of reach of children. 
Caution: New Drug—Limited by Federal (US) Law to Investigational Use 
Manufactured by ACP, Harleysville, PA 19438 USA for Marinus Pharmaceuticals, Inc., Radnor, 
PA 19087 USA Telephone: (484) 801-4670 
Double-blind Group: 
Details of the label for Ganaxolone IV solution and placebo for the double-blind group will be 
added in a future amendment. 
 
6.3.2 
Packaging 
Ganaxolone IV solution for administration will be provided to the site as individual vials or 
bottles containing 1 mg/mL (open-label group) or 1 mg/mL or placebo (double-blind group). 
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor. 


 
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6.3.3 
Storage 
The investigator has overall responsibility for ensuring that study drug is stored in a secure, 
limited-access location. Limited responsibility may be delegated to the pharmacy or member of 
the study team, but this delegation must be documented. Study drugs are distributed by the 
pharmacy or by a nominated member of the study team. The 1 mg/mL ganaxolone IV solution 
vials should be stored at room temperature 15°C to 25°C (59°F to 77°F) until use. Excursions up 
to 30°C (86°F) that are experienced in pharmacies, hospitals, and warehouses, and during 
shipping are allowed.  Details on how to store the study drug can be found in the Pharmacy 
Manual. Prior to administration inspect the study drug for particulate matter, cloudiness, and 
discoloration. If any of these is present, do not use and notify the sponsor. 
Study drug must be stored in accordance with labeled storage conditions. Temperature 
monitoring of the study drug is required at the storage location to ensure that the study drug 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 by an in-house system, by 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. Such a device (i.e., certified min/max thermometer) would require 
manual resetting upon each recording. The sponsor 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 study drug 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 should be notified immediately if there are any changes to the storage area of the 
study drug that could affect the integrity of the product(s), such as fumigation of a storage room. 
6.4 
Drug Accountability 
Investigators will be provided sufficient amounts of the study drug to carry out this protocol for 
the agreed number of subjects. The investigator or designee will acknowledge receipt of the 
study drug, documenting shipment content and condition. Accurate records of all study drug 
dispensed, used, returned, and/or destroyed must be maintained as detailed further in this section. 
The investigator has the overall responsibility for administering/dispensing study drug. Where 
permissible, tasks may be delegated to a qualified designee (e.g., a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form. 
The investigator or their designee (as documented by the investigator in the applicable study 
delegation of authority form) will place the study drug administration orders and confirm that the 
study drug is only dispensed to subjects included in this study following the procedures set out in 
the study protocol. Each subject will be given only the study drug carrying their treatment 
assignment. All administered, and/or dispensed medication will be documented in the eCRFs 
and/or other study drug record.   


 
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No study drug stock or returned inventory from a Marinus-sponsored study may be removed 
from the site where originally shipped without prior knowledge and consent by the sponsor. If 
such transfer is authorized by the sponsor, all applicable local, state, and national laws must be 
adhered to for the transfer. 
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records. 
At the end of the study, or as instructed by the sponsor, all unused stock and 
subject-administered study drug is either to be sent to a nominated contractor on behalf of the 
sponsor for destruction or are to be destroyed by the site. Study drug being returned to the 
sponsor’s designated contractor must be counted and verified by clinical site personnel and the 
sponsor (or designated CRO). For unused supplies for which the original supplied tamper-
evident feature is verified as intact, the tamper-evident feature must not be broken and the 
labeled amount is to be documented in lieu of counting. Shipment return forms, when used, must 
be signed prior to shipment from the site. Returned study drug must be packed in a tamper-
evident manner to ensure product integrity. Contact the sponsor for authorization to return any 
study drug prior to shipment. Shipment of all returned study drug must comply with local, state, 
and national laws. 
With the written agreement of the sponsor, unused stock and subject-administered study drug 
may be destroyed at the site or a local facility. In this case, destruction records identifying what 
was destroyed, when, and how must be obtained with copies provided to the sponsor. 
Destruction of study drug must be in accordance with local, state, and national laws. 
Based on entries in the site’s drug accountability forms, it must be possible to reconcile study 
drug delivered with those used and returned. All study drug must be accounted for and all 
discrepancies investigated and documented to the sponsor’s satisfaction. 
6.5 
Subject Compliance 
The study drug will only be administered by appropriately trained site staff.  Drug accountability 
must be assessed at the container/packaging level for unused study drug that is contained within 
the original tamper-evident sealed container (e.g., vials, bottles) or at the individual count level 
for opened containers/packaging. The pharmacist/nominated person will record details on the 
drug accountability form. 
7. 
STUDY PROCEDURES 
7.1 
Study Schedule 
See Table 1 for details regarding scheduled assessments and procedures in this study.  
The following “priority order” will be in effect when more than one procedure or assessment is 
required at a timepoint: 
1. Spontaneous or solicited AE reporting 


 
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2. Vital signs 
3. Pharmacokinetic and Neurosteroid sample collection 
4. Clinical laboratory tests 
5. Physical examination 
NOTE:   Blood sampling for pharmacokinetic evaluation must be performed at the precise 
protocol scheduled time. Actual sampling time(s) must be accurately recorded in the source 
document and appropriate eCRF. 
7.1.1 
Screening Period  
7.1.1.1 Screening 
Potential subjects are anticipated to be identified in emergency departments and/or hospital in-
patient units. Upon identification, subjects will be screened for inclusion/exclusion criteria prior 
to receiving ganaxolone IV solution as adjunctive therapy.  
Procedures specific to this protocol and not otherwise considered standard of care, will not be 
performed until written informed consent from the subject/parent/guardian/LAR has been 
appropriately obtained. Consent for subjects who are at risk for SE may be obtained prior to an 
SE event, this is also referred to as pre-consenting. Additional details on consent can be found in 
Section 10.3.1. 
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
criteria and/or met at least one of the exclusion criteria and has not been administered the study 
drug. Subjects cannot be rescreened once they have been designated as a screen failure per 
incidence of SE. Subjects who fail the screening but are not treated with ganaxolone IV solution 
may be rescreened if they face a new SE event.  
7.1.2 
Treatment Period  
7.1.2.1 Study Drug Initiation Through In-patient Follow-up Day (Day 1 to Day 3) 
Eligible SE subjects receiving standard of care (potential subjects must have failed one 2nd line 
IV AED, administered at an appropriate dose and duration to show efficacy, will be given 
adjunctive ganaxolone IV solution. Ganaxolone IV solution will be given as an IV bolus with a 
continuous infusion at a rate of 20-80 mg/hour including a 12-hour study drug taper. The 
presence of SE must be confirmed immediately prior to the study drug bolus. Subjects will 
receive the ganaxolone IV solution as described in Section 6. 
7.1.3 
Follow-up Period  
The follow-up period for this protocol is approximately 4 weeks. 
Subjects will have an in-patient follow-up day after the study drug taper is completed as noted in 
the previous section.  The in-patient follow-up day starts as soon as the 12-hour study drug taper 
is completed. If the infusion rate becomes too low to sustain the infusion line, it can be 
discontinued at that point and the subject will progress into the in-patient follow-up assessments.  
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as the study drug administration is discontinued. These subjects will continue with the week 2, 3, 
and 4 follow-up visits. 
If, however, a subject takes study drug for less than 2 hours and/or progresses at any time during 
the study to an IV anesthetic drug (a 3rd line treatment and/or 4th line treatment e.g., 
immunosuppressants, magnesium) for seizure suppression they will be discontinued from the 
study drug without study drug taper. Any outstanding screening assessments should be 
completed, and Table 1 lists the assessments/procedures that should be collected when the 
decision to stop study drug administration is made and as close as possible to the end of the study 
drug administration. These subjects will progress to the in-patient follow-up day and the week 2, 
3, and 4 follow-up visits. 
Once dosing is completed, the planned duration of follow-up will be weekly for an additional 3 
weeks. These weekly visits can be performed as an in-patient visit if the subject is still in the 
hospital, or as a telephone call if the subject has been discharged. However, it is recommended 
that efforts be made to have discharged subjects return so at least one of these visits will be 
conducted in-person. The subject/parent/guardian/LAR, as appropriate, will receive a follow-up 
contact weekly approximately 7 ± 3, 14 ± 3, and 21 ± 3 days following the in-patient follow-up 
day.  
During these visits or calls, the site will follow-up on all SAEs and non-serious AEs, AE 
resolution that occurs, and concomitant medications. All AEs and SAEs that are not resolved at 
the time of this contact will be followed to closure (see Section 8.1). Table 1 lists the 
assessments that should be collected during the follow-up visits. 
A subject who discontinues or early terminates from the study (e.g., due to consent withdrawn) 
should have the early termination procedures completed when early termination is being 
considered and as close as possible to the end of the study drug administration. A list of early 
termination assessments can be found in Table 1.  
7.1.4 
Additional Care of Subjects After the Study 
No aftercare is planned for this study. Subjects should return to their physician’s care. 
7.2 
Study Evaluations and Procedures 
7.2.1 
Demographic and Other Baseline Characteristics 
The following demographic data will be recorded: 
 Date of birth 
 Sex 
 Ethnic origin (Hispanic or Latino or not Hispanic or Latino) 
 Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other, Pacific Islander, White, or Other)  
 


 
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7.2.2 
Efficacy  
Efficacy will be evaluated by collecting the following assessments as noted in Table 1.  
The name and address of each third-party vendor (e.g., central EEG reader) used in this study 
will be maintained in the investigator’s and sponsor’s files. 
7.2.2.1 EEG 
EEG is required for confirmation of NCSE diagnosis. Ideally, continuous EEG monitoring 
should start before study drug initiation to get a baseline assessment and continue through the in-
patient follow-up day. If continuous EEG is not possible or needed to diagnose (for convulsive 
SE) it should be instituted at the earliest possible time after study drug initiation (if a pre-dose 
EEG was not performed for the diagnosis of convulsive SE).   
Several study sites may be offered the use of a portable EEG device to assist with pre-screening 
of subjects with NCSE. All devices utilized in the study will have received FDA 510(k) 
clearance. It will be at the investigator’s discretion if they feel the device will benefit their site 
and if any institutional approvals are needed to utilize the device.  A copy of the device user 
manual and system specifications will be on file at any site utilizing the device.  
7.2.2.2 Status Epilepticus Severity Score (STESS)  
STESS is a prognostic score relying on four outcome predictors (age, history of seizures, seizure 
type and extent of consciousness impairment).  
7.2.2.3 Glasgow Coma Scale (GCS) and Pediatric Glasgow Coma Scale (PGCS) 
The GCS is a neurological scale which aims to give a reliable and objective way of recording the 
state of a person's consciousness for initial as well as subsequent assessments. The PGCS is the 
equivalent of the GCS and is used to assess the mental state of child patients.  For specific 
collection timepoints reference Table 1. 
7.2.2.4 Clinical Global Impression of Severity and Improvement (CGI-S and CGI-I, 
respectively) 
The CGI-S and CGI-I assess overall health and functional status of a subject. Subject and 
clinician rater versions indicate general worsening or improvement on a seven-point Likert-like 
scale. For specific collection timepoints reference Table 1. 
7.2.2.5 Richmond Agitation and Sedation Scale (RASS)  
The RASS is a medical scale used to measure the agitation or sedation level.  For specific 
collection timepoints reference Table 1. 
7.2.2.6 Status Epilepticus and Seizure Questions 
All subjects will be assessed for the presence of seizures and SE after the administration of the 
study drug.  For specific collection timepoints reference Table 1. 
 All assessment points:  


 
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1. Is the subject in SE currently? Yes or No 
2. Was the subject in SE since the previous assessment?  Yes or No  
(Note: N/A for the 15-minute timepoint) 
3. Is the subject having seizures currently? Yes or No 
4. Did the subject have seizures since the previous assessment Yes or No 
(Note: N/A for the 15-minute timepoint) 
5. Have any new AEDs been initiation since the last assessment? Yes or No 
(Note: “New” refers to any AED that has not already been used to treat the current 
episode of SE) 
6. If a new AED was initiated, was it to treat the current seizure/SE episode or initiated 
prophylactically (e.g., for transition/bridging), or other reason?  
(Note: “Prophylactic” refers to any elective/transitional/bridging AED therapy that is not 
indicated to treat seizure/EEG abnormal activity at this time or since the last assessment) 
Record any new AEDs on the concomitant eCRF page.  
 
7.2.2.7 Intubation Question 
All intubated subjects will be assessed for possible extubation based on medical improvement.  
For specific collection timepoints reference Table 1. 
Assessment Point: 
1. Per your evaluation has the subject’s medical condition improved enough to warrant 
considering extubation? Yes or No 
     
7.2.3 
Safety 
Safety will be evaluated by collecting the following assessments as noted in Table 1.  
If a third-party vendor is used for any safety analysis, then the name and address of each third-
party vendor will be maintained in the investigator’s and sponsor’s files. 
7.2.3.1 
Medical and Medication History 
Medical history will include the following: 
 Previous and concomitant illnesses, surgeries, and medications  
 Family history 
 History of drug and alcohol abuse 
 
History of seizures and/or SE events 
7.2.3.2 
Physical and Neurologic Examination  
A physical examination will be performed at the timepoints described in Table 1 by a qualified 
licensed physician, physician’s assistant, or nurse practitioner.   
The full physical examination will include a review of the following body systems:  
 General appearance 


 
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 Skin 
 Head, eyes, ears, nose and throat  
 Spine, neck, and thyroid 
 Musculoskeletal 
 Respiratory 
 Cardiovascular 
 Neurologic 
 Abdomen (including liver and kidneys) 
 
Other systems as appropriate 
 
Abnormalities identified at the first PE thought to be present prior to study drug initiation will be 
documented in the subject’s source documents and in the medical history eCRF. Conversely, 
abnormalities identified at this first PE that are thought to develop after study drug initiation 
should be recorded as AEs on the AE eCRF page, as deemed by the investigator. 
Changes after the first PE will be recorded as AEs on the AE eCRF page, as deemed by the 
investigator. 
Neurologic examinations should be performed at the time consent/assent is administered to the 
subject for continued participation and then on the in-patient follow-up day using the Mini 
Mental State Examination (MMSE) as stated in Table 1. 
7.2.3.3 Adverse Event Collection 
Subjects and their parent/guardian/LAR will be questioned in a general way to ascertain if AEs 
have occurred (e.g., “Have you had any health problems since your last visit?”). Adverse events 
are collected from the time of first dose of study drug through the last follow-up visit/contact.  
Refer to Section 8, Adverse and Serious Adverse Events Assessment. 
7.2.3.4 
Vital Signs 
Vital signs include blood pressure, pulse, respiration rate, oxygen saturation, and temperature. 
Ideally, noninvasive automated monitoring of vitals should be started at screening and continue 
until the in-patient follow-up day is completed. If not continuously monitored, vitals should be 
assessed as stated in Table 1 including collection for subjects who stop study drug without a 
taper or early terminate the study. 
Noninvasive blood pressure (systolic and diastolic) and pulse rate will be measured by an 
automated blood pressure device after the subject has been in a supine position for at least 5 
minutes. Ideally, the same arm should be used for all measurements.  
Any deviations from the screening vital signs that are deemed clinically significant in the opinion 
of the investigator are to be recorded as AEs. 
Weight and height should be collected at screening for calculation of the BMI inclusion criterion, 
if feasible. If not collected at screening they will need to be collected at any timepoint prior to 
the end of the in-patient follow-up day. 


 
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7.2.3.5 
Clinical Laboratory Evaluations 
All clinical laboratory assays will be performed per the hospitals laboratory’s normal procedures. 
The collection timepoints are detailed in Table 1. 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 pathologic changes. The investigator should assess out-of-range clinical laboratory 
values, indicating if the values are clinically significant or not clinically significant. Abnormal 
clinical laboratory values that 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. 
For drugs of abuse, including alcohol testing, enrollment is not contingent upon results. 
However, if a subject tests positive, it will be at the investigator’s discretion to weigh the risks 
verses benefits for the subject’s continued participation. If the investigator decides to discontinue 
the study drug, please refer to Section 4.5. 
The following clinical laboratory assessments will be performed as part of the protocol:  
Hematology & Coagulation 
Biochemistry 
Urinalysis 
Hemoglobin (Hb)  
Hematocrit  
Red blood cell count (RBC) 
White blood cell count; total and 
differential (WBC)  
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin 
concentration (MCHC) 
Mean corpuscular volume (MCV)  
Platelet count 
% Basophils 
% Eosinophils 
% Lymphocytes 
% Monocytes 
% Neutrophils 
Basophil count 
Eosinophil count 
Lymphocyte count 
Monocyte count 
Neutrophil count 
Fibrinogen 
Activated partial thromboplastin time 
(aPTT) 
Prothrombin time 
International normalized ratio (INR) 
Sodium 
Potassium 
Calcium 
Glucose  
Total protein 
Albumin 
Creatinine 
Blood urea nitrogen (BUN) 
Bilirubin 
Alkaline phosphatase (ALP)  
Aspartate transaminase (AST) 
Alanine transaminase (ALT)  
Gamma-glutamyl transferase 
(GGT) 
Total cholesterol 
Antiepileptic drug levels 
(AEDs): fosphenytoin/ 
phenytoin, valproic acid, 
levetiracetam, lacosamide, 
and/or brivaracetam  
pH 
Protein 
Blood 
Ketones 
Glucose 
Bilirubin 
Specific gravity 
Albumin 
 
If any abnormal value is observed on the 
urine dipstick test, the sample should be 
further analyzed with urine microscopy: 
WBC 
RBC 
Cellular casts 
Granular casts 
Hyaline casts 
 
Urine or Serum Drug Screen 
Phencyclidine 
Opiates metabolite 
THC methamphetamines/amphetamine 
Barbiturates 
Benzodiazepines 
Cocaine 
Methadone 
Oxycodone 
Alcohol 
 


 
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All blood gas samples, including FiO2, PaO2, and Arterial pH, if collected per the investigator’s 
discretion for subject’s care, from the time of SE diagnosis through the in-patient follow-up day, 
should be recorded in the eCRF. If no samples are collected, a sample will not be required.  
In addition, a blood gas sample should be collected when the decision is made to intubate the 
subject.  The sample should be collected immediately prior to or as close as possible to the time 
of intubation.     
Pregnancy Test  
As described in Table 1 and Section 4.4, a urine or serum pregnancy test should be collected for 
all females of childbearing potential prior to study drug initiation, and if pregnancy is suspected. 
If not possible to collect pre-dose, then collect as soon as possible after study drug initiation. It is 
at the sites’ discretion whether to perform a urine or serum pregnancy test. Enrollment is not 
contingent upon results. However, if a subject has a positive test result, it will be at the 
investigators discretion to weigh the risks verses benefits for the subjects continued participation.  
If the investigator decides to discontinue the study drug, please refer to Section 4.5.  
7.2.3.6 
Electrocardiography 
ECG should be collected after the subject has been in a supine position for at least 5 minutes. 
If abnormal results are observed, the investigator will assess clinical significance and determine 
whether the results should be recorded as an AE. 
ECGs should be collected at the timepoints noted in Table 1.  
7.2.3.7 Modified Rankin Scale (MRS) 
The MRS is a commonly used 6-point scale for measuring the degree of disability or dependence 
in the daily activities of people who have suffered a stroke or other causes of neurology 
disability. The MRS should be assessed at the timepoints noted in Table 1. 
7.2.3.8 Full Outline of UnResponsiveness (FOUR) Score 
The FOUR Score is a clinical grading scale in the assessment of patients with impaired level of 
consciousness.  The FOUR Score is a 17-point scale (with potential scores ranging from 0-16).  
Decreasing FOUR Score is associated with worsening levels of consciousness.  The FOUR Score 
assesses four domains of neurological function: eye responses, motor responses, brain stem 
reflexes, and breathing pattern.  The FOUR Score should be collected at the timepoints noted in 
Table 1. 
7.2.4 
Others  
7.2.4.1 
Clinical Pharmacology Blood Sample Collection and Handling Procedures 
Blood samples will be collected at the times specified in Table 1. The sponsor’s expectation is 
that the investigator will ensure that every effort is made to collect all pharmacokinetic blood 
samples at the precise protocol scheduled time. Pharmacokinetic blood collection must not 
deviate from the nominal collection time set forth in the protocol by more than 5 minutes from 
samples drawn within 4 hours post study drug initiation or by more than 60 minutes for samples 


 
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drawn beyond 4 hours post study drug initiation. Samples drawn outside these parameters will be 
considered a protocol deviation.  
Venous blood samples (2 mL) will be drawn from indwelling catheters or by direct venipuncture 
into K2EDTA Vacutainer® tubes (lavender top), capped, mixed by inversion (×10), and chilled 
immediately on crushed ice. If using indwelling catheters, they should be kept patent with 
isotonic saline and the saline should be withdrawn (1 mL) and discarded before the blood sample 
is taken. Use of topical anesthesia to reduce the pain of an indwelling catheter is permitted and, if 
used, must be documented as a concomitant medication. If venous blood sample collection is not 
possible an arterial sample may be collected. The type of sample will be recorded in the source 
documents and eCRF.   
If study drug is administered via central access, the PK sample cannot be collected from any 
central access ports.  If study drug is administered via venous access, the PK sample must be 
collected via the contra-lateral arm of the study drug arm. The location of study drug access and 
location of PK sample collection should be documented in the subject’s source.  If the PK 
sample cannot be collected due to poor venous access and the study drug infusion site is the only 
viable option, the specimen should not be collected and the reason for non-collection 
documented in the subject’s source.   
Details regarding sample collection, processing, storage, and shipment to the bioanalytical 
vendor are described in the Biospecimen Manual. The freezer temperature where these samples 
are stored must be controlled, monitored, and recorded during the storage period until the 
samples are shipped on dry ice to Quest Pharmaceutical Services for analysis. The study monitor 
must be notified of any temperature excursions. 
7.2.4.2 
Shipment of Plasma Pharmacokinetic Samples 
Unless agreed upon by the sponsor, within approximately 1 week after subjects complete the in-
patient follow-up day, the site will ship the primary plasma samples to QPS. Upon notification of 
receipt of the primary samples by QPS, the backup samples will be shipped to the bioanalytical 
laboratory. Refer to the Biospecimen Manual for details regarding specimen shipping.    
7.2.4.3 
Plasma Drug Assay Methodology 
Plasma concentrations will be measured using the most current validated liquid chromatography 
with tandem mass spectrometry (LC/MS/MS) method. Other metabolites may be monitored or 
quantitated as appropriate. Raw data will be stored in the archive of the designated bioanalytical 
laboratory.  
7.2.4.3.1 Cerebral Spinal Fluid (CSF) 
If a subject has a lumbar puncture for the collection of CSF per investigator’s discretion as part 
of their care and there is adequate volume, a sample will be aliquoted for future analysis of 
ganaxolone.  If multiple lumbar punctures are performed, a sample from each puncture is 
requested.  If not collected or not enough CSF is collected to provide a sample for the study, a 
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Details regarding sample collection, processing, storage, and shipment to Bioanalytical vendor 
are described in the Biospecimen Manual.  The freezer temperature where the samples are stored 
must be controlled, monitored, and recorded during the storage period until the samples are 
shipped on dry ice to Bioanalytical vendor for future analysis. The study monitor must be 
notified of any temperature excursions.  
7.2.4.4 Neurosteroid Blood Sample Collection and Handling Procedures 
Blood samples will be collected at the times specified in Table 1. Venous blood samples (2.5–6.0 
mL) will be drawn into K2EDTA Vacutainer® tubes (lavender top), capped, mixed by inversion 
(×10), and chilled immediately on crushed ice. If using indwelling catheters, they should be kept 
patent with isotonic saline and the saline should be withdrawn (1 mL) and discarded before the 
blood sample is taken. Use of topical anesthesia to reduce the pain of an indwelling catheter is 
permitted and, if used, must be documented as a concomitant medication.  
If study drug is administered via central access, the neurosteroid sample cannot be collected from 
any central access ports.  If study drug is administered via venous access, the neurosteroid 
sample must be collected via the contra-lateral arm of the study drug arm. The location of study 
drug access and location of neurosteroid sample collection should be documented in the subject’s 
source.  If the neurosteroid sample cannot be collected due to poor venous access and the study 
drug infusion site is the only viable option, the specimen should not be collected and the reason 
for non-collection documented in the subject’s source.   
If venous blood sample collection is not possible an arterial sample may be collected. The type 
of sample will be recorded in the source documents and eCRF. 
Details regarding sample processing, storage, and shipment to the bioanalytical 
storage/laboratory vendor are described in the Biospecimen Manual. The freezer temperature 
where the samples are stored must be controlled, monitored, and recorded during the storage 
period until the samples are shipped on dry ice to the bioanalysis storage/laboratory vendor. The 
study monitor must be notified of any temperature excursions.  
Specific collection times can be found in Table 1. 


 
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 Table 4: 
Volume of Blood to Be Drawn from Each Subject 
Assessment 
Sample 
Volume 
(mL) a 
Number of 
Required 
Collection 
Timepoint  
Samples 
Number of 
Variable 
Collection 
Timepoint 
Samples 
Total Volume (mL) 
Safety b 
Biochemistry 
(with indwelling 
catheter) 
8.5 
6 
2 
51-68 
 
Hematology  
4.0 
6 
2 
24-32 
 
Coagulation 
5.1 
6 
2 
30.6-40.8 
 
IV AEDs 
7.5 
6 
5 
45-82.5 
Pharmacokinetic samples 
(with indwelling catheter) c 
3.0 
9 
4 
27-39 
Neurosteroid samples (with 
indwelling catheter) c 
7.5 
2 
0 
15 
Arterial blood gas (for 
intubation only) b 
1.0 
0 
1 
1 
Total mL 
 
 
 
192.6-278.3 
a.   If a catheter is used, the first milliliter (mL) collected is to be discarded, then the required volume is collected into the 
appropriate tube for the assessment. This additional 1 mL has been added the biochemistry, pharmacokinetic, and neurosteroid 
collections noted in the table. This assumes the hematology, coagulation, and AED samples will be collected at the same times 
as the biochemistry samples. The collection volume for coagulation testing at sites ranged from 2.7mL to 7.5.0mL, as such the 
median volume of 5.1mL was used for the table calculation. 
b.   See Table 1 for a full sample collection list. There are required collection timepoints for all subjects and variable collection 
timepoints that only apply in specific situations. The two different types have been separated in the table to show the 
maximum and minimum number of sample collections for a subject. 
c.   Blood samples for pharmacokinetic and neurosteroid analysis will be collected as noted in Table 1. Venous or arterial 
samples are acceptable.  
 
 


 
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 Table 5: 
Volume of Blood to Be Drawn from Each Subject (Pediatric Hospital 
Sample Volumes) 
Assessment 
Sample 
Volume 
(mL) a 
Number of 
Required 
Collection 
Timepoint  
Samples 
Number of 
Variable 
Collection 
Timepoint 
Samples 
Total Volume (mL) 
Safety b 
Biochemistry 
(with indwelling 
catheter) 
2.0 
6 
2 
12-16 
 
Hematology  
1.0 
6 
2 
6-8 
 
Coagulation 
1.0 
6 
2 
6-8 
 
IV AEDs 
1.0 
6 
5 
6-11 
Pharmacokinetic samples 
(with indwelling catheter) c 
3.0 
9 
4 
27-39 
Neurosteroid samples (with 
indwelling catheter) c 
2.5 
2 
0 
5 
Arterial blood gas (for 
intubation only) b 
1.0 
0 
1 
1 
Total mL 
 
 
 
62–88 
a.  If a catheter is used, the first milliliter (mL) collected is to be discarded, then the required volume is collected into the 
appropriate tube for the assessment. This additional 1 mL has been added to the biochemistry, pharmacokinetic, and neurosteroid 
collections noted in the table. This assumes the hematology, coagulation, and AED samples will be collected at the same times as 
the biochemistry samples. 
b.  See Table 1 for a full sample collection list. There are required collection timepoints for all subjects and variable collection 
timepoints that only apply in specific situations. The two different types have been separated in the table to show the maximum 
and minimum number of sample collections for a subject. 
c.  Blood samples for pharmacokinetic and neurosteroid analysis will be collected as noted in Table 1. Venous or arterial samples 
are acceptable.  
 
During this study, it is expected that some sites (e.g., children’s hospitals) will collect smaller 
volumes of blood from subjects per their local laboratory standards.  The ranges in Table 4 and 
Table 5 reflect the possible range for adult and child verses a child-only hospital.  The total blood 
volume could be as low as approximately 62 mL for pediatric-only verses 192.6 mL for other 
hospitals and up to approximately 88 mL for pediatric-only and 278.3 mL for other hospitals.  
As noted in Table 1, several of the collection points are considered optional; however, to provide 
the most conservative estimate of the blood volume drawn, these option collections have been 
included in Table 4 and Table 5.  
Note: The amount of blood to be drawn for each assessment is an estimate.  The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than one blood assessment is to be done at a single 
timepoint/period, if they require the same type of tube, the assessments may be combined. 
 
 


 
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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 who has been 
administered a pharmaceutical product; it 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) 
product28.  
As this study allows for pre-consenting of subjects, all AEs will be collected from the time of 
first dose of study drug until the defined follow-up period stated in Section 7.1.3.  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 recorded on the 
appropriate AE pages in the eCRF and in source documents.  In addition to untoward AEs, 
unexpected benefits outside the study drug indication should also be recorded on the AE eCRF 
page. 
All AEs must be followed for the durations described below. For AEs followed to closure, this 
indicates that an outcome is reached, stabilization is 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. 
For subjects who: 
a. Have 2 days of treatment which includes a 12-hour study drug taper, all adverse events 
will be collected through the in-patient follow-up day. During the weekly follow-up visits 
only, ongoing AEs and new AEs assessed by the investigator to be related to study drug 
will be recorded. All SAEs regardless of relationship to study drug will be recorded from 
the time of 1st dose through the last follow-up visit/contact.  
b. Stop study drug administration without a study drug taper but continue with the follow-
up visits, all adverse events will be collected through the in-patient follow-up day. During 
the weekly follow-up visits, only ongoing AEs and new AEs assessed by the investigator 
to be related to study drug will be recorded. All SAEs regardless of relationship to study 
drug will be recorded from the time of 1st dose through the last follow-up visit/contact. 
Additionally, AEs of UTI, hospital-acquired/ventilator-associated pneumonia, MI, sepsis 
from any source, critical illness myopathy/neuropathy and significant hypotension 
requiring vasopressor support will be recorded as AEs regardless of relatedness. 
c. Early terminate from the study, prior to discontinuation as much information as is 
available should be recorded on any on-going AEs/SAEs and AEs/SAEs that may have 
led to the early termination. 
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.  An event that changes in severity should be recorded as a new 


 
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event.  Worsening of pretreatment events, after initiation of the study drug, must be recorded as 
new AEs on the appropriate eCRF page. 
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, that significantly 
affects clinical status, or that may require intensive therapeutic intervention. 
8.1.2 
Relationship Categorization 
A physician/investigator must make the assessment of relationship between the study drug and 
each AE.  The investigator should decide whether, in their medical judgment, there is a 
reasonable possibility that the event may have been caused by the study drug.  If there is no valid 
reason for suggesting a relationship, the AE should be classified as “not related.” Otherwise, if 
there is any valid reason, even if undetermined or untested, for suspecting a possible cause-and-
effect relationship between the study drug and the occurrence of the AE, the AE should be 
considered “related.” The causality assessment must be documented in the source document. 
The following additional guidance may be helpful: 
Term 
Relationship definition 
Related 
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident. 
 
 
Not related 
The event can be readily explained by other factors, such as the 
subject’s underlying medical condition, concomitant therapy, or 
accident, and no plausible temporal or biologic relationship exists 
between the investigational product and the event. 
  
8.1.3 
Outcome Categorization 
The outcome of AEs must be recorded during the course of the study in the eCRF.  Outcomes are 
as follows: 
 Fatal 


 
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 Not recovered/not resolved 
 Recovered/resolved 
 Recovered/resolved with sequelae  
 Recovering/resolving 
 Unknown 
8.1.4 
Symptoms of the Disease Under Study 
Symptoms of the disease under study 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. Specifically, SE signs and symptoms that were present at study 
entry and that varied in intensity over the duration of study treatment are not considered AEs 
unless in the investigator’s opinion there is an unexpected worsening of the events. However, if 
all seizure activity resolved and the subject returned to baseline status, but SE recurred, the event 
would then be recorded as an SAE. 
8.1.5 
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 significant or if, during treatment with the study drug, a shift of a 
parameter is observed from a normal value to an abnormal value, or 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 study drug), and the range of variation of the 
respective parameter within its reference range must be taken into consideration. 
For subjects who complete the study and don’t progress to an IV anesthetic drug (a 3rd line 
treatment) for seizure suppression, if, at the end of the treatment phase, there are abnormal 
clinical laboratory, vital sign, or ECG values that were not present in the pretreatment findings 
observed closest to the start of study drug initiation, 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. 
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 
Pregnancy 
As this study allows for pre-consenting of subjects, all pregnancies are to be reported from the 
time of first dose of study drug until the defined follow-up period stated in Section 7.1.3. 
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Marinus Safety Department or its delegate 


 
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using the Pregnancy Report Form.  A copy of the Pregnancy Report Form (and any applicable 
follow-up reports) must also be sent to the CRO/Marinus Medical Monitor using the details 
specified in the emergency contact information section at the beginning of the protocol.  If a 
subject has a positive test result, it will be at the investigator’s discretion to weigh the risks 
verses benefits for the subjects continued participation. 
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 after 
delivery.  
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported as outlined in Section 8.2 of the protocol using the 
Marinus SAE Fax Cover Letter.  Non-serious AEs are to be reported as per clinical electronic 
Case Report Form guidelines.  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 to the Marinus Safety Department or delegate as outlined in 
Section 8.2 of the protocol using the Marinus SAE Fax Cover Letter.  The test date of the first 
positive serum/urine -human chorionic gonadotropin test or ultrasound result will determine the 
pregnancy onset date. 
8.1.7 
Abuse, Misuse, Overdose, and Medication Error 
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
per the SAE reporting procedure whether or not it results in an AE/SAE as described in 
Section 8.2.  Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE.  
The categories below are not mutually exclusive; the event can meet more than one category. 
 Abuse: Persistent or sporadic intentional intake of a study drug for a nonmedical purpose 
(e.g., to alter one’s state of consciousness or get high) in a manner that may be 
detrimental to the individual and/or society. 
 Misuse: Intentional use of a study drug other than as directed or indicated at any dose.  
(Note: This includes a situation in which the study drug is not used as directed at the dose 
prescribed by the protocol.) 
 Overdose: Intentional or unintentional intake of a dose of a study drug exceeding a 
prespecified total daily dose of the product.  
 Medication error: An error made in prescribing, dispensing, administering, and/or use of 
a study drug.  For studies, medication errors are reportable to the sponsor only as defined 
below. 
Cases of subjects missing doses of the study drug are not considered reportable as medication 
errors. 


 
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Medication errors should be collected and reported for all products under investigation. 
The administration and/or use of an expired study drug should be considered as a reportable 
medication error. 
All study drug provided in this study will be administered by appropriate site staff. 
8.2 
Serious Adverse Event Procedures 
8.2.1 
Reference Safety Information 
The reference for safety information for this study is the Ganaxolone Investigator’s Brochure, 
which the sponsor has provided under separate cover to all investigators. However, the 
Investigator’s Brochure has not been updated with the details of the 1 mg/mL ganaxolone IV 
solution. The formulation details have been added to Section 6 and will be added to the 
Investigator’s Brochure at the annual update.   
8.2.2 
Reporting Procedures 
All initial and follow-up SAE reports must be reported by the investigator to the Marinus Safety 
Department or its delegate and the CRO/Marinus Medical Monitor within 24-hours of the first 
awareness of the event.  Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors (see Section 8.1.7) unless they result in 
an SAE.  
The investigator must complete, sign, and date the Marinus SAE Fax Cover Letter and verify the 
accuracy of the information recorded on the form with the corresponding source documents 
(Note: Source documents are not to be sent unless requested) and fax or e-mail the form to the 
Marinus Safety Department or its delegate. A copy of the Marinus SAE Fax Cover Letter (and 
any applicable follow-up reports) must also be sent to the CRO/Marinus Medical Monitor using 
the details specified in the emergency contact information section of the protocol. 
8.2.3 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence (whether considered to be related to study drug 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 were more severe. 
 Requires in-patient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
preexisting conditions that 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, a complication resulting from a 


 
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hospitalization for an elective or previously scheduled surgery that meets serious criteria 
must be reported as an SAE. 
 Results in persistent or significant disability or 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 SAEs when, 
based on appropriate medical judgment, they jeopardize the patient 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 in-patient hospitalization; or the development of drug dependency or drug abuse.  
8.2.4 
Serious Adverse Event Collection Time Frame 
As this study allows for pre-consenting of subjects, all SAEs (regardless of relationship to study) 
are collected from the time of first dose of study drug until the defined follow-up period stated in 
Section 7.1.3 and must be reported to the Marinus Safety Department and the CRO/Marinus 
Medical Monitor within 24-hours of the first awareness of the event.  
In addition, any SAE considered “related” to the study drug 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. 
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 
discharge dates are considered the onset and resolution dates, respectively. 
In addition, any signs or symptoms experienced by the subject after study drug initiation 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 study drug action was previously taken (e.g., the drug was interrupted, reduced, or 
withdrawn), the action taken with the study drug should be recorded as “dose not changed” or 
“not applicable” (if the subject never received the study drug). The study drug action of 
“withdrawn” should not be selected solely as a result of the subject’s death.  


 
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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 in the 
United States of related, unexpected SAEs. 
In addition, the sponsor or its delegate is responsible for notifying active sites and central IRBs 
of all related, unexpected SAEs occurring during all interventional studies across the Ganaxolone 
program.  
The investigator is responsible for notifying the local institutional review boards (IRBs), local 
ethics committee (EC), or the relevant local regulatory authority of all SAEs that occur at their 
site as required. 
9. 
DATA MANAGEMENT AND STATISTICAL METHODS 
9.1 
Data Collection 
The investigator’s authorized site personnel must enter the information required by the protocol 
in the eCRF. 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 in 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, the site should initiate data entry 
within 5 business days of study drug initiation with the goal of having all data entered within 4- 
weeks of study drug initiation. 
9.2 
Clinical Data Management 
Data are to be entered into a clinical database as specified in the CRO Data Management Plan 
and the eCRF Completion Guidelines. 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 Process 
The study will be analyzed by the sponsor or its agent.  
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information, such as subject disposition, demographics, and baseline 
characteristics, study drug exposure, and prior and concomitant medications. The SAP will also 
include a description of how missing, unused, and spurious data will be addressed. 


 
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To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock and the sponsor being unblinded to treatment assignments. 
All statistical analyses will be performed using SAS® (SAS Institute, Cary, NC 27513).  
R (R Foundation for Statistical Computing) may be used for the predictive probability 
calculations used in the interim analyses.  
9.4 
Sample Size, Planned Interim Analysis, Adaptive Design, and Data Monitoring 
Committee 
Data from the open-label group will be summarized using descriptive statistics and not included 
in double-blind efficacy analysis. 
In the double-blind group, the response rates in the treatment and control groups will be 
compared using a 1-sided hypothesis test. An O’Brien-Fleming error spending function will be 
used with two predefined interim analyses. The two interim analyses will occur after 
approximately 156 and 200 subjects have completed 24-hours of study drug administration.  
Prior to initiating these pre-planned analyses, the data for these subjects will have a minimum of 
their critical fields cleaned.  
Using a total one-sided Type I error of 2.5%, critical values for the two interim and one final 
analysis are noted in Table 6. 
Table 6: 
Interim Analysis Variables 
Analysis 
# Subjects who 
completed the 
study anytime 
within 24 hours of 
study drug 
administration  
One-sided 
Critical 
Value 
Error 
Spend 
Cumulative 
Error Spend 
Interim 1 
156 subjects 
0.0073 
0.0073 
0.0073 
Interim 2 
200 subjects 
0.0135 
0.0083 
0.0156 
Final 
242 subjects 
0.0200 
0.00935 
0.025 
 
In the double-blind group a Data Monitoring Committee (DMC) will be assembled to review the 
safety and efficacy data at various intervals of the study.  Only the unblinded DMC will be privy 
to these interim analyses and may recommend the trial stop for early success or safety findings. 
Likewise, at each interim analysis, Bayesian predictive probabilities for success at the maximum 
(N=242) sample size will be calculated.  If the predictive probability of success is < 5%, then the 
DMC may recommend the trial stops for futility.  These are non-binding futility analyses, e.g., 
the Type I error = 2.5% even without these futility analyses.  The Bayesian predictive 
probabilities will use non-informative Beta (1/2, 1/2) priors for both unknown response rates and 
be conducted using the methodology described in Saville et al., 2014 (Clinical Trials). 


 
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9.5 
Sample Size Calculation and Power Considerations 
The double-blind sample size was constructed to offer at least 85% power with a 20% effect. 
Table 7 shows the power for a control group response rates ranging from 30% to 70% and 
assuming a 20% improvement in the treatment group. 
Table 7:  O’Brien-Fleming Power and Sample Size Power Calculation 
Control 
Response % 
Treatment 
Response % 
Probability 
of 
Stopping 
at 156 
Subjects 
Probability 
of 
Stopping 
at 200 
Subjects 
Probability 
of 
Stopping 
at 242 
Subjects 
Total  
Power 
Expected 
N 
0.3 
0.5 
0.48 
0.19 
0.19 
0.86 
193 
0.4 
0.6 
0.44 
0.22 
0.19 
0.85 
195 
0.5 
0.7 
0.48 
0.19 
0.19 
0.86 
193 
0.6 
0.8 
0.56 
0.18 
0.16 
0.90 
187 
0.7 
0.9 
0.70 
0.16 
0.10 
0.97 
175 
 
Two-hundred and forty-two subjects with the described O’Brien-Fleming stopping rules ensures 
85% power in the scenario of 60% vs. 40% and increases for other scenarios with 20% effect 
sizes. 
Using the futility rules based upon predicted probabilities, when control and treatment group 
response rates are equal, the probability of early stopping is 88% and expected sample size is 
171. 
9.6 
Study Population 
The Screened Set will consist of all subjects who have signed an informed consent. 
The Safety Set will consist of all subjects who have received ganaxolone IV solution. 
The Modified Intent-to-Treat (mITT) Set includes all subjects who received at least one dose 
of the study drug and who provided any post study drug initiation seizure/status outcome data. 
The Per-Protocol Set will consist of all subjects in the mITT population without major protocol 
violations.  The Per Protocol population is for supportive efficacy analysis.  Major protocol 
violations will be defined prior to database lock. 
The Completer Set will consist of all subjects in the mITT who have completed the final 
scheduled primary assessment for the study. 
The Pharmacokinetic Set will consist of all subjects in the Safety Set for whom the primary 
pharmacokinetic data is considered sufficient and interpretable.  


 
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9.7 
Efficacy Analyses 
9.7.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the number of subjects who did not require an IV 
anesthetic drug (a 3rd line treatment) for SE treatment within the first 24 hours after study drug 
initiation. 
The primary efficacy analysis will be conducted over the mITT Set.  The primary efficacy 
analysis will be conducted by using a logistic model that includes treatment group as a factor 
along with factors controlling for age, GCS, and history of epilepsy.  One-sided tests will be 
performed and compared to the critical values shown in Section 9.4, thus ensuring overall 
1-sided Type I error  0.025. 
9.7.2 
Secondary Endpoints  
 For subjects on concomitant second-line therapy: time to cessation of SE or next 
treatment decision (defined as the need for an IV anesthetic drug (a 3rd line treatment) 
when on ganaxolone)  
 Level of responsiveness as assessed by the GCS, Four Score Scale, and RASS at 24 hours 
post study drug initiation 
  The number of subjects who did not require additional 2nd line IV AED therapy for SE 
treatment in the 24-hours after taper 
 Safety and tolerability of ganaxolone IV solution as adjunctive SE therapy as assessed by 
neurologic, EEG, and physical examinations, clinical laboratory tests, ECGs, vital signs, 
and spontaneously reported AEs 
 Number of subjects who maintained SE resolution 24 hours after study drug taper and at 
Week 4 
 Number of subjects with seizure(s) following cessation of SE through the in-patient 
follow-up day 
 Level of responsiveness as assessed by the GCS if SE is continuing, on the in-patient 
follow-up day 
 Seizure burden assessed as duration of electrographic seizure activity per hour of EEG 
recording collected 
 Clinical outcome as assessed by MRS at the in-patient follow-up day and Week 4 
 Characterization of the pharmacokinetic profile of ganaxolone IV solution in SE subjects 
 Length of stay in intensive care unit and hospital, mortality, morbidity, need for and 
duration of intubation and mechanical ventilation, and seizure freedom 




 
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Blood samples for neurosteroid levels will be analyzed by a bioanalytical laboratory.  Details of 
the data analysis and presentation will be detailed in the statistical analysis plan.  
Cerebral spinal fluid, if collected per the investigator’s discretion and adequate volume is 
available, will be stored for future analysis. 
9.9.1 
Pharmacokinetic Analyses 
The pharmacokinetic population includes all subjects who have received at least 1 dose of study 
drug and who have sufficiently complete concentration-time data (at least 5 data points with a 
quantifiable plasma ganaxolone concentration value). 
The following ganaxolone plasma pharmacokinetic parameters will be calculated as data allows 
and as appropriate using noncompartmental approaches.  Pharmacokinetic variables will be 
computed using WinNonlin Professional, version 5.2 or similar software.  Actual elapsed 
sampling times relative to ganaxolone administration will be used for the estimation of 
pharmacokinetic metrics.  The following pharmacokinetic parameters of ganaxolone in plasma 
will be calculated.  Additional parameters may be calculated on discretion of the 
pharmacokinicist, pending review of the data. 
 Maximum plasma concentration (Cmax) 
 Time of maximum concentration (Tmax) 
 Area under the concentration versus time curve from time 0 to t hours (AUC0-t) 
 Area under the concentration versus time curve from time 0 to infinity (AUCinf) 
 Clearance (CL).  Calculated as dose/AUCinfN 
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This study is conducted in accordance with current applicable regulations, International 
Conference on Harmonisation (ICH), European Union (EU) Directive 2001/20/EC and its 
updates, and local ethical and legal requirements.  
The name and address of each third-party vendor (e.g., CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate. 
10.1 
Sponsor’s Responsibilities 
10.1.1 
Good Clinical Practice (GCP) 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), and EU Directive 2001/20/EC, 
as well as all applicable national and local laws and regulations. 
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 


 
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(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 study 
drug for shipment to the site. 
10.1.2 
Public Posting of Study Information 
The sponsor, or their designee, is responsible for posting appropriate study information on 
applicable websites such as ClinicalTrials.gov. Information included in clinical study registries 
may include participating investigator’s names and contact information. 
10.1.3 
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees 
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the study 
completion date for pediatric studies and within 1 year for non-pediatric studies as per guidance.  
10.1.4 
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 that 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. 
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
personnel are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period. 
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study. 
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study. 


 
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A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995).  
10.2.2 
Protocol Adherence and Investigator Agreement 
The investigator and any sub-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 study drug, 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 
eCRFs 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 
observations and other data pertinent to the clinical investigation. eCRFs 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 into 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. 
Incorrect paper source entries must be crossed with a single line as to not obscure the original 
entry. Corrections must be made adjacent to the item to be altered, initialed, and dated by an 
authorized investigator or designee as stated in the site delegation log. Overwriting of this 
information or use of liquid correction fluid is not allowed. 


 
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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, the 
subject’s medical file and original clinical laboratory reports.  
All key data must be recorded in the subject’s medical records. 
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; 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 (and auditors, IRB/EC, or regulatory inspectors) may check the eCRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to allow the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC to have 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 Food and 
Drug Administration [FDA], European Medicines Agency [EMA], UK Medicines and 
Healthcare Products Regulatory Agency) 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 EMA, the UK 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, or retainer for 
ongoing consultation or honoraria; any proprietary interest in study drug; and any significant 
equity interest in the sponsor or subsidiaries as defined in 21 Code of Federal 
Regulations 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 and assent, where 
applicable, from all study subjects prior to any study-related procedures, including screening 


 
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assessments. As the disease under consideration is a life-threatening condition for which subjects 
presenting may not be capable of providing consent or assent for themselves, a 
parent/guardian/LAR will be required to sign upon identification of the subject for study 
participation. Consent /assent will be administered per the institutions IRB/EC policy and may 
vary across sites, i.e. some sites may be able to consent/assent over the phone or other 
communication methods. At the first opportunity, consent and assent should be obtained from 
the subject directly. Alternatively, consent and assent for subjects who are at risk for SE may be 
obtained prior to an SE event through a pre-consenting process. The period of time the pre-
consent/assent is valid will be determined by each hospitals IRB/EC.  However, reconsenting 
will be needed should the consent/assent be updated at any point during the study. 
All consent and assent documentation must be in accordance with applicable regulations and 
GCP.  Each subject, subject’s parent, guardian, or the LAR, as applicable, is requested to sign 
and date the subject’s informed consent form or a certified translation, if applicable, after the 
subject parent, guardian, or LAR has received and read (or been 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 and assent documentation (i.e, a complete set of 
subject information sheets and fully executed signature pages) must be given to the subject, 
subject’s parent, guardian, or the LAR, as applicable. 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. 
The principal investigator provides the sponsor with a copy of the consent form and assent 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 (abiding by 
regulatory guidelines and national provisions) prior to study start that another party (i.e., sponsor 
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. 
10.3.2 
Institutional Review Board or Ethics Committee 
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information, and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation. 
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. 
Study drug supplies will not be released until the sponsor or designee has received written 
IRB/EC approval of and copies of revised documents. 


 
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For sites outside the EU, 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.  This can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any SAEs and 
significant AEs. 
10.4 
Privacy and Confidentiality 
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with Health Insurance Portability and Accountability Act (HIPAA) of 1996.  
A site that is not a covered entity as defined by HIPAA must provide documentation of this fact 
to the CRO/sponsor. 
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After subjects, parent, guardian, or the LAR have consented to take part in the study, the sponsor 
and/or its representatives review the 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; third parties with whom the sponsor may 
develop, register, or market ganaxolone; national or local regulatory authorities; and the IRB/EC 
that 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 each 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 numbers, relevant medical records, 
and possibly initials and dates of birth will be recorded. They may be transferred to, and used in, 
other countries that may not afford the same level of protection that applies within the countries 
where this study is conducted. The purposes of any such transfer would include to support 
regulatory submissions, to conduct new data analyses to publish or present the study results, and 
to answer questions asked by regulatory or health authorities. 
10.5 
Study Results/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. Additionally, Marinus adheres to external guidelines 
(e.g., Good Publication Practices 2) when forming a publication steering committee, which may 
be done for large, multicenter Phase 2 to 4 and certain other studies as determined by Marinus. 
The purpose of the publication steering committee is to act as a noncommercial body that advises 
or decides on dissemination of scientific study data in accordance with the scope of this policy. 


 
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All publications relating to Marinus products or projects must undergo appropriate technical and 
intellectual property review, with Marinus agreement to publish prior to release of information.  
The review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, 
joint, or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications. 
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, invited lectures, opinion pieces, book chapters, electronic 
postings on medical/scientific websites, or other disclosure of the study results, in printed, 
electronic, oral, or other form. 
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results or necessary for other scholars to verify such study 
results.  Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Marinus, the hospital and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application. 
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results.  If such a multicenter publication is not submitted to 
a journal for publication by the sponsor within an 18-month period after conclusion, 
abandonment, or termination of the study at all sites, or after the sponsor confirms there shall be 
no multicenter study publication of the study results, an investigator may individually publish the 
study results from the specific site in accordance with this section. The investigator must, 
however, acknowledge in the publication the limitations of the single-site data being presented. 
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications. 
 


 
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11. REFERENCES 
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Lowenstein D, Alldredge B. Status Epilepticus. The New England Journal of Medicine, 
Vol 338, No 14 1998; 970-976. 
2. 
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W.E. Dodson, L. Garrity, A. Jagoda, D. Lowenstein, J. Pellock, J. Riviello, E. Sloan, D. 
Treiman Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in 
Children and Adults: Report of the Guideline Committee of the Epilepsy Society. 
Epilepsy Currents, Vol 16, No 1 (January/February) 2016; 48-61 American Epilepsy 
Society. 
3. 
Bhattacharjee A, Hirsch N. Management of status epilepticus. Anaesth Intens Care Med. 
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4. 
Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of 
status epilepticus. Neurocrit Care. 2012;17(1):3-23. 
5. 
Treiman DM. Status epilepticus. In: Aminoff MJ, Daroff RB, eds. Encyclopedia of the 
Neurological Sciences. 2nd ed. Oxford, UK: Academic Press; 2014:297-299. 
6. 
Treiman DM. GABAergic mechanisms in epilepsy. Epilepsia. 2001;42(suppl 3):8-12. 
7. 
Kapur J, Macdonald RL. Rapid seizure-induced reduction of benzodiazepine and Zn2+ 
sensitivity of hippocampal dentate granule cell GABAA receptors. J Neurosci. 
1997;17(19):7532-7540. 
8. 
Treiman DM. Importance of early recognition and treatment of generalised convulsive 
status epilepticus. Lancet Neurol. 2008;7(8):667-668. 
9. 
Knake S, Hamer HM, Rosenow F. Status epilepticus: a critical review. Epilepsy Behav. 
2009;15(1):10-14. 
10. 
Rossetti AO, Lowenstein DH. Management of refractory status epilepticus in adults: still 
more questions than answers. Lancet Neurol. 2011;10(10):922-930. 
11. 
Neligan A, Shorvon SD. Frequency and prognosis of convulsive status epilepticus of 
different causes: a systematic review. Arch Neurol. 2010;67(8):931-940. 
12. 
Hocker SE, Britton JW, Mandrekar JN, Wijdicks EF, Rabinstein AA. Predictors of 
outcome in refractory status epilepticus. JAMA Neurol. 2013;70(1):72-77. 
13. 
Sutter R, Marsch S, Fuhr P, Ruegg S. Mortality and recovery from refractory status 
epilepticus in the intensive care unit: a 7-year observational study. Epilepsia. 
2013;54(3):502-511. 


 
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14. 
Ferlisi M, Shorvon S. The outcome of therapies in refractory and super-refractory 
convulsive status epilepticus and recommendations for therapy. Brain. 2012;135(pt 
8):2314-2328. 
15. 
Rogawski MA, Loya CM, Reddy K, Zolkowska D, Lossin C. Neuroactive steroids for the 
treatment of status epilepticus. Epilepsia. 2013; 54(suppl 6):93-98. 
16. 
Rossetti AO, Logroscino G, Bromfield EB. Refractory status epilepticus: effect of 
treatment aggressiveness on prognosis. Arch Neurol. 2005;62: 1698-1702. 
17. 
Mayer SA, Claassen J, Lokin J, Mendelsohn F, Dennis LJ, Fitzsimmons BF. Refractory 
status epilepticus frequency, risk factors, and impact on outcome. Arch Neurol. 2002; 59: 
205-210. 
18. 
Treiman DM, Walton NY, Collins JF. Treatment of status epilepticus if first drug fails 
[abstract]. Epilepsia. 1999;40(suppl 7):243. 
19. 
Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med. 1998; 388: 970-976. 
20. 
Holtkamp M, Othman J, Buchheim K, Meierkord H. Predictors of refractory status 
epilepticus treated in a neurological intensive care unit. J Neurol Neurosurg Psychiatry. 
2005; 76: 534-539. 
21. 
Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus 
with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia. 
2002;43(2):146-153. 
22. 
Rogawski MA, Carlos ML, Kiran R, et al. Neuroactive steroids for the treatment of status 
epilepticus. Epilepsia. 2013; 54: 93-98. 
23. 
Bandyopadhyaya AK, Manion BD, Benz A, et al.  Neurosteroid analogues. 15. A 
comparative study of the anesthetic and GABAergic actions of alphaxalone, Δ16-
alphaxalone and their corresponding 17-carbonitrile analogues. Bioorg Med Chem Lett.  
2010;20(22):6680–6684. 
24. 
Ganaxolone [investigators brochure]. Radnor, PA: Marinus US Inc.; December 6, 2017. 
25. 
Bleck T, Cock H, Chamberlain J, et al. The established status epilepticus trial 2013. 
Epilepsia. 2013; 54(suppl 6):89-92. 
26. 
LexisNexis PxDx Medical Claims data 2015 
27. 
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. 
28. 
International Conference on Harmonisation (ICH) Guidance E2A March 1995. Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting. 


 
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29. 
Vohra, J.B. Miller, K.S. Nicholas, P.N. Varelas, D.M. Harsh, V. Durkalski, R. Silbergleit, 
H.E. Wang. Endotracheal Intubation in Patients Treated for Prehospital Status Epilepticus 
[Neurological Emergencies Treatment Trials (NETT) Investigators]. Neurocritical Care 
2015;23(1):33-43) 
 


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Protocol 1042-SE-2001 
12. APPENDICES 
Appendix 1: Study Decision Tree 
1st Line Therapy administered for Status Epilepticus 
SE Controlled? Note: ta kin a 1st line a ent is not re uired for stud indusion 
YES, SE Controlled 
Continue Standard of Care 
Treatment Not eligible for 
study. 
NO, SE persists 
Initiate 1st Second Line Therapy 
administration for Status Epilepticus 
SE Controlled? 
YES, SE Controlled 
Continue Standard of Care 
Treatment. Not Eligible for Study 
Seizures persist (1st Line Therapy failure) 
Possible subject for Marin us Study? 
• 
Pull Site Operations Manual 
• 
Check ind us ion criteria/ Any exclusionary 
criteria? 
• 
Pre-consent? Can we get consent? 
• 
Alert Pharmacy of possible subject? 
NO, SE Persists 
Eligible for the Mari nus Study? 
• 
Check Inclusion/ Exclusion 
• 
Consent• LAR/parenVguardian? 
• 
Order Study Drug & Deliver to bedside 
NO, Not Eligible & SE Persists 
Administer additional 2nd Line Therapies per Standard of Care (SOC) 
*Intubation: 1. NOT EXCLUDED if for airway protection. 
2. EXCLUDED if for anesthetic agents to achieve for Seizure Suppression 
YES, Eligible for Study 
• 
Enroll (Open-label) or Randomize Subject (Double-blind) 
• 
Administer additional 2
nd Line Therapies per SOC; Study Drug should be added to the SOC 
at the time the second IV AED is medically indicated 
• 
Perform Protocol Assessments as per Table 1 of the protocol 
• 
Subjects should be monitored and progress in their treatment per the SOC 
SE Controlled? 
YES, SE Improved/Controlled 
Continue Adjunctive Study Drug for a total 
NO, SE Persists 
of 36 hours (from start of study drug). 
Continue Adjunctive Study Drug as well as SOC. 
Assumes subject has not progressed to IV•---t~ On Day 2 (24-36hrs) Investigator can increase the 
Anesthetic for seizure suppression 
infusion rate per the protocol section 6.2.3. 
If IV Anesthetic started for Seizure Suppression, 
At 36 hours of Day 2 (36-48hrs) or if study 
drug is discontinued early (not due to an IV 
anesthetic agent), start 12hr study drug taper 
and continue with in-patient follow-up (Day 3, 
48-72hrs) and the weekly follow-up visits 
Discontinue Study Drug, no taper required then: 
• 
Complete any outstanding screening 
procedures, check Table 1 for procedures to 
be completed 
• 
Subject will progress directly to In-patient 
Follow-up Day and the weekly follow-up visits 
Note: Regardless of the Day the Study drug is discontinued (with or without taper), continue standard of care 
and study assessments/procedures through the in-patient follow-up visit. Follow-up contacVvisits will be 
conducted at Weeks 2, 3, and 4 
Note: For subjects who receive study drug for less than 2 hrs, have their infusion interrupted/ discontinued and 
not restarted, and/or if at any time during study drug administration the subject progresses to an IV anesthetic 
(a 3•• line treatment) for seizure suppression no study drug taper is required 
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Version 5.0 
Appendix 2: Summary of Changes Table from Previous Protocol Amendments 
Protocol Amendments 
Summa1-y of Change(s) Since Last Version of Approved Protocol 
Amendment Number 
Amendment Date 
Global/Country/Site Specific 
1 
26 Janua1-y 2018 
Global 
Description of Change 
Section(s) Affected by Change 
Clarified the total number of subjects expected to be screened and 
Synopsis, Section 3. 1 
enrolled in the study. 
In the Primary Objective, Prima1y Endpoint, and Secondary Endpoint, 
Synopsis, Sections 2.2.1, 9.7.1, and 
removed the wording " additional IV AEDs", "Additional 2nd line 
9.7.2 
therapy", and "subsequent AEDs" to simplify the study and target the 
key next medication (IV anesthetics) that physicians would see benefit in 
a.voiding. 
To provide consistency across sites, specified that the study dtug should 
Synopsis, Sections 3.1 and 6.2.3 
be added to the standard of care at the time that the second AED is 
medically indicated and ideally given via. its own dedicated line. 
Updated the two options for stopping study dtug. Added to the first 
Synopsis, Sections 6.2.3 and 7.1.3 
option that the 24hour taper is for subjects who have taken dtug for 
>2hours and do not progress to IV anesthetics for seizure suppression 
and the second option, immediately stopping study dtug without tapering 
is for subjects who have taken study dtug for less than 2 hours or who 
are progressing to an IV anesthetic dtug (a 3rd line treatment) for seizure 
suppression. In this second scenario no taper is needed as the subject 
will be receiving increasing doses of an anesthetic agent. 
Provided additional guidance that any subject who progresses to an IV 
Synopsis, Sections 4.5, 5.2.2, 6.2.3, 
anesthetic dtug (a. 3rd line treatment) for seizure suppression should 
and 7.1.3 
immediately have the study dtug stopped and be discontinued from the 
study. As possible, any outstanding screening procedures and early 
tennina.tion procedures should be completed. No additional procedures 
will be conducted other than following up on any ongoing AE/SAEs and 
the associated concomitant medications related to these AEISAEs. 
Added clarification that if the paitial seizure burden improvement is 
Synopsis, Sections 6.2.3 and 7.2.2 
betv.•een 33-50% the investigator can contact the Medical Monitor to 
discuss if study dtug treatment beyond the initial 2 days is medically 
indicated and that the seizure burden calculation should encompass the 
entire first 2 days of dosing. 
Added the collection of neurosteroids sainples, clarified that the 
Synopsis, Section 7.2.5 and 9.9 
pha1ma.cokinetic samples can be venous or a1terial, updated the sainple 
collection volumes, con-ected a. ma.th en-or in the total possible blood 
volume being collected, and removed the detailed vendor and 
pha1ma.cokinetic sample shipping information. 
Clarified the four blocks of time when seizure burden should be 
Synopsis and Section 7.2.2 
calculated. 
Clarified that if a. subject discontinues the study on the saine day that an 
Synopsis and Section 7.1.3 
assessment has already been collected, that the assessment doesn't need 
to be repeated for the early te1mination procedures unless there is a. 
change since the previous assessment collection. 
Pregnancy testing, added wording to confinn that it is at the sites 
Synopsis and Section 7.2.3.6 
discretion where to perform a urine or a. semm pregnancy test. 
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Version 5.0 
Added the Status Epilepticus and Seizure Questions should also be 
Synopsis and Section 7.2.2 
collected on the 24hour post-dose taper day. This would capture answers 
to the 2 questions for subjects who are discontinued from the study. 
Adverse Events and Concomitant Medications, added text to clarify the 
Synopsis and Section 7.1.3 
collection of information for subjects who discontinue the study. 
Inclusion criteria #4 has been revised to remove the "and" of the 
Synopsis and Section 4.1 
"and/or". New wording is as follows: "Subject on concun-ent 2nd line 
therapy with fosphenytoin/ phenytoin, valproic acid, levetiracetam, or 
lacosamide". 
Combined the Key Secondary and Secondaty Endpoints under the 
Synopsis and Section 9.7.2 
Secondary Endpoints header as this is a phase 2 study. 
Section 1.2 Product Background and Clinical Infonnation has been 
Sections 1.2 and 4.3 
updated to reflect the language in the most cun-ent Investigators 
Brochure and hannonize the language conceming breast feeding across 
the ganaxolone development program. 
Subject Withdrawal Criteria has been updated to clarify that subjects 
Section 4.5.1 
with impaired kidney function ( eGFR is 45 mL/min or below) can sta1t 
dialysis while on the study. 
Confirmed that the Medical Monitor does not need to be contacted if a 
Section 4.5.1 
subject is being discontinued because they are progressing to an IV 
anesthetic dmg (a 3rd line treatment) for seizure suppression. 
As the study allows for pre-consenting of subjects the wording was 
Sections 6.2.2, 7.2.3.3, 8.1, 8.1.6, 
updated to reflect that subject numbers will be assigned prior to dosing 
and 8.2.4 
instead of as they consent to take part in the study and that adverse 
events, serious adverse events and pregnancy will be collected from the 
time of study dmg initiation and not from the site of consent signature. 
Clarified that during the study dtug taper if the infusion rate becomes too 
Section 6.2.3 
low to sustain the infusion line that it can be discontinued at that point. 
Investigator's Brochure entty was updated to reflect the cun-ent version 
References 
infonnation. 
Study flow chrut was updated to reflect the dosing timepoint clarification 
Appendix 
and the oppo1tunity to consult the Medical Monitor if the seizure burden 
reduction is between 33-50%. 
Additional grrunmatical, typographical e11'0rs and fonnatting revisions 
have been made in the document but are not identified here. 
Protocol Amendments 
Summa1-y of Change(s) Since Last Version of Approved Protocol 
Amendment Number 
2 
Amendment Date 
10 May 2018 
Description of Change 
Updated the 
to-.,iD, PhD. 
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Global/Country/Site Specific 
Global 
Section(s) Affected by Change 
Protocol Signature Page and 
Emergency Contact 


 
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Increased the potential sample size of the open-label group and the study 
overall. Further defined the open-label group objectives and clarified that 
subjects who terminate early for reasons other than lack of efficacy or 
AEs related to ganaxolone can be replaced. 
Synopsis and Section 3.1 
Updated the open-label group dosing regimen including justification for 
the revision and correction that the daily dose of ganaxolone will not 
exceed 35 grams/day Captisol (approximately 500 mg/day ganaxolone) 
as agreed upon by the FDA.   
Synopsis and Sections 3.1 and 6.2.3 
To provide consistency across sites the wording describing when the 
study drug should be started with respect to the SE standard of care was 
expanded upon, “…study drug will be added to the standard of care from 
the time that the first 2nd line IV AED has failed and the second 2nd line 
IV AED is medically indicated during the treatment of SE. Study drug 
must be administered concomitantly with second 2nd line IV AED as 
close to the dose initiation of the second 2nd line IV AED as possible.”  
Synopsis and Sections 3.1 and 6.2.3 
The study drug is tapered over 18-hours. The length of the taper period 
has been updated from 24-hours to an 18-hour taper period to match. 
Also added language that the 24-hour post-taper follow-up day should 
start immediately upon the completion of the study drug taper.  
Synopsis including Table 1 and 
Sections 3.1, 6.2.3 including Table 2 
& 3, 7.1.3, and 7.2.5 
Clarified that the 24-hour in-patient follow-up period has been updated to 
“24-hour post-taper follow-up day”.  
Synopsis, Sections 3.1, and 7.1.3, 
Clarified the definition and calculation of seizure burden.  
Synopsis and Sections 6.2.3 and 
7.2.2 
Clarified that in addition to the pharmacokinetic samples already noted in 
the protocol, if subject terminates the study early or if a subject has SE 
relapse while the subject receives ganaxolone and is not being considered 
for early termination due to lack of efficacy, a pharmacokinetic sample 
should be collected.  
Two additional blood samples for pharmacokinetic analysis have been 
added to the total blood volume calculation. 
Synopsis and Section 7.2.5 Tables 4 
& 5 
The inclusion criteria were modified to add BMI and clarify the protocol 
required clinical and electrographic seizure criteria. 
Synopsis and Sections 4.1 and 
7.2.3.4 
The capture of EEG was clarified to explicitly state it is required for 
diagnosis of NCSE and continuous monitoring should begin as soon as 
possible.  
Synopsis and Section 7.2.2  
Clarified that if study drug is discontinued during this 24-hours, the 
second neurosteroid sample should be collected prior to study drug 
termination, if possible. 
Synopsis and Section 7.2.5 Tables 4 
& 5 
Clarified that the Status Epilepticus and Seizure Questions should be 
collected on the 24-hour post-taper follow-up day or at the time of early 
termination. 
Synopsis and Section 7.2.2 
Two exclusion criteria were added to further refine the possible patient 
population; the definition of traumatic brain injury was included and a 
general statement about the suitability of a subject based on their history 
and investigators judgment.  
Synopsis and Section 4.1 
Updated the enrollment numbers for the ongoing post-partum depression 
study and add the details of when the FDA confirmed the maximum dose 
of Captisol (35grams) allowed for this protocol.  
Section 1.2 
Updated the Study Flow Diagram to reflect the revised dosing regimen. 
Section 3.1, Figure 1 


IND 129433 
Marinus Phannaceuticals, Inc. 
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Version 5.0 
Added subject withdrawal criteria around respirato1y depression and 
Section 4.5.1 
other adverse events or safety issues. 
The reason for discontinuation was changed from Withdrawal by subject 
Section 4.5.2 
to Consent Withdrawn to align with the study population and that a 
subject or their parent, guardian, or LAR may withdraw the subject from 
the study. 
Specified that if a subject is receiving prophylactic oral AED therapy to 
Section 5.2.2 
manage a subject's chronic medical condition, for example, epilepsy, 
migraine, or neuropathic pain, that therapy is acceptable and should 
continue unchanged if feasible and medically justified. And that this 
prophylactic treatment does not count toward the SE treatment failures 
required to qualify for this study. 
As the study allows for pre-consenting of subjects the wording was 
Sections 7.2.3.3 and 8.2.5 
revised in Protocol Amendment 1 that adverse events, serious adverse 
events and pregnancy will be collected from the time of study dtug 
initiation and not from the site of consent signature. Two wording 
changes that were previously missed have been updated. 
Added detail on the data review the data monitoring committee will 
Sections 9.4 and 9.8 
perfonn during the double-blind group and that the study team will 
perfonn while the open-label group is on-going. 
Con-ect the Day 2 assessment of seizure burden percentages box in the 
Appendix 1 
Study Decision Tree where a call to the Medical Monitor is needed. 
Added Summa1y of Changes Table from Protocol Amendment 1. 
Appendix 2 
Additional grammatical, typographical e11'0rs and fonnatting revisions 
have been made in the document but are not identified here. 
Protocol Amendments 
Summa1-y of Change(s) Since Last Version of Approved Protocol 
Amendment Number 
Amendment Date 
Global/Country/Site Specific 
3 
24 Janua1-y 2019 
Global 
Description of Change 
Section(s) Affected by Change 
Updated the Marinus Emergency and Additional Contact Info1mation 
Emergency Contact and Additional 
Contact Infonnation 
Updated all protocol references to the maximum level of Captisol 
Synopsis and Sections 2.1 and 6.2.3 
allowed in the protocol to be 50 grams per day and 714 mg/day of 
Ganaxolone as agreed upon by the FDA on 13Dec2018. 
Revised the dosing regimen under the increased Captisol level with the 
Synopsis and Sections 3.1, 6.2.3 
caveat that the dose may be fwiher adjusted based on safety and efficacy 
(including Tables 2 and 3), 7.1.2.1 
findings for the open-label group and communicated through a Protocol 
Administrative Change Memo. However, the new infusion parameters 
will not exceed the daily limits of 50 grams/day Captisol (approximately 
714 mg/day ganaxolone) as agreed upon with the FDA. 
Removed reference to Loading and Maintenance Dosing. 
Refined the description of when study dtug tapering is not required. 
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Revised the follow-up visit criteria to require efforts be made to have at 
least one of the visits be in-person. During that in-patient visit clinical 
laboratory samples will be collected for safety assessment.   
Synopsis and Sections 3.1 and 7.1.3 
Revised that for at least the first 2 hours after the start of study drug 
administration medical personnel must be present at all times. 
Synopsis and Section 6.2.3 
Removed the Day 2 requirement for the investigator to contact the 
Medical Monitor to discuss if continued treatment beyond 2 days is 
medically indicated.  
Synopsis and Sections 6.2.3 and 
7.2.2 
Revised the procedures to be followed and assessment collected for 
subjects who discontinue study drug and continue to the follow-up visit 
as well as the procedures (either with 18-hour taper or without a taper) 
and assessment for subject who early terminate from the study e.g, due to 
withdraw of consent. This include the timeframe of when the in-patient 
follow-up visit (24-hour post-taper follow-up day) starts. 
Synopsis and Sections 3.1, 4.5, 5.2, 
5.2.2, 6.2.3, 7.1.3, 7.2.3.2, 7.2.3.3, 
7.2.3.4, 7.2.3.7 
Based on the new dosing regimen, one 10-hour post-dose initiation 
pharmacokinetic sample collection has been added. The total blood 
volume has been updated to include the additional pharmacokinetic 
sample as well as additional chemistry, AED, and hematology samples at 
the in-patient follow-up visit. 
Synopsis and Table 4 and 5 in 
Section 7.2.4.4 
Removed the brief physical exam and made all collections a full physical 
exam. 
Synopsis and Section 7.2.3.2 
Clarified that the Glasgow Coma Scale should be collected at any time 
there is a change in the subject’s state (both improvement and 
worsening) that the investigator thinks is clinically significant.  
Synopsis and Section 7.2.2 
Added language that several sites will be offered the use of a Rapid EEG 
machine for study pre-screening activities. 
Synopsis and Section 7.2.2 
Refine the exclusion criteria: 
Clarified that anesthesia administered for the treatment of the current 
episode of SE is exclusionary unless 5 half-lives have passed since its 
administration. 
Delete exclusion criterion #7 about pressor use as the exclusion of 
subject who have progressed to IV anesthetics makes this requirement 
obsolete  
Clarified that if a subject has previously received ganaxolone or 
exogenous allopregnanolone they are excluded 
Synopsis and Sections 4.2 and 5.2.2 
Table 1, Schedule of Assessments has been updated: 
Changed the Table header to be Visit/Time Point or Duration to better 
characterize the study days 
Combined the Dose Initiation and Day 1 columns as these are the same 
day.  
Changed the taper day to be Day 3 OR Day 5 and added the 18-hour 
duration. 
Specified that the Post-taper follow visit should start immediately after 
study drug administration is stopped i.e. 18-hour taper is completed or 
study drug is stopped without a taper. 
Added a Study Drug Discontinuation without Taper column and the 
associated assessments. 
Separated the 24-hour post-taper follow-up visit and the Early 
Termination visit into two columns.  
Synopsis 


 
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Added a biochemistry and hematology sample at one of the Week 2, 3, 
or 4 follow-up visits. 
Removed the check mark for AE/SAE collection prior to dose initiation. 
Updated the footnotes for the follow-up visit requirements, the 
assessments for subjects who stop study drug without a taper and those 
who early terminate the study, clinical laboratory sample collection, 
study drug dosing, and pharmacokinetic sample collection. 
Updated the enrollment numbers from the most recent Ganaxolone IB 
and for the ongoing Marinus studies.  
Section 1.2 
Added the communication details of when the FDA approved the 
Captisol daily limit increase (≤50g/day) allowed for this protocol. 
Section 2.1 
Updated the Study Flow Diagram to reflect the revised dosing regimen. 
Section 3.1, Figure 1 
Clarified the classification requirements for Lost to Follow-up subjects.  
Section 4.5.3 
Added language around dose adjustment and clarified the dose 
interruption restrictions. 
Section 6.2.3 
Removed the compounded study drug storage parameters and directed 
sites to refer to the Pharmacy Manual for details. 
Section 6.3.3 
Revised the text to specify that a PI/sub-I is ordering drug and specifying 
the administration orders in their system and appropriately trained site 
staff will administer the study drug.  
Sections 6.4 and 6.5 
Removed the pharmacokinetic and neurosteroid sample processing 
requirements and directed study staff to refer to the Biospecimen Manual 
for instructions.  
Sections 7.2.4.1 and 7.2.4.4 
Updated the blood volume table and footnotes to reflect the new 
pharmacokinetic sample, and the follow-up for subject who stop study 
drug without a taper and the early termination assessments. 
Revised the blood volumes to account for the chemistry, hematology, 
coagulation, and AED levels being drawn at the same timepoints so only 
one of the samples needs the extra 1mL of waste as well as the revised 
vacutainer tubing being used by some of the sites.  
Section 7.2.5, Table 4 and 5 
Updated the Study Decision Tree 
Appendix 1 
Added Summary of Changes Table from Protocol Amendment 2. 
Appendix 2 
Additional grammatical, typographical errors and formatting revisions 
have been made in the document but are not identified here.  
 
 

SAP_003.pdf: 
Study 1042-SE-2001 
Marinus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Version 1.0 Final 
 
CONFIDENTIAL 
Page 1 of 28 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol: 1042-SE-2001 
 
 
A double-blind randomized, placebo-controlled study to evaluate the safety, tolerability, 
efficacy, and pharmacokinetics of intravenous ganaxolone as adjunctive therapy to treat 
subjects with status epilepticus 
 
Sponsor: 
 
Marinus Pharmaceuticals, Inc. 
Version:  
 
Version 1.0 Final 
Issue Date: 
 
4 May 2020 
Status:   
 
Final Before Database Lock 
 
 
 
 
 
 
 
 
 
 
 


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Statistical Analysis Plan 
Version 1.0 Final 
 
CONFIDENTIAL 
Page 2 of 28 
STATISTICAL ANALYSIS PLAN APPROVAL 
 
Prepared by: 
 
 
 
 
____________________________ 
 
Date: ______________ 
 
 
 
 
 
Approved by: 
 
 
 
 
 
 
________________ 
 
Date: ______________ 
 
 
 
 
 Biostatistics 
 
 
Marinus Pharmaceuticals, Inc. 
 
 
 
 
________________ 
 
Date: ______________ 
 
 
 MD, MS.HP 
 
 
 
 
Marinus Pharmaceuticals, Inc. 
 
 
 
 
 


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Statistical Analysis Plan 
Version 1.0 Final 
 
CONFIDENTIAL 
Page 3 of 28 
 
TABLE OF CONTENTS 
1 
INTRODUCTION ........................................................................................ 5 
2 
STUDY OBJECTIVES ................................................................................ 6 
2.1 
Primary Objective .................................................................................... 6 
2.2 
Secondary Objectives............................................................................... 6 
 
 
3 
STUDY DESIGN ......................................................................................... 6 
3.1 
Study Design and Flow Chart .................................................................. 6 
3.2 
Duration and Study Completion Definition .............................................. 7 
3.3 
Sites and Regions ..................................................................................... 7 
3.4 
Study Population...................................................................................... 7 
3.5 
Study Evaluation...................................................................................... 7 
3.6 
Blinding and Treatment Assignment ........................................................ 8 
3.7 
Allocation of Subjects to Treatment ......................................................... 8 
3.8 
Sample Size and Power ............................................................................ 8 
4 
STATISTICAL METHODS ......................................................................... 8 
4.1 
Analysis Populations................................................................................ 8 
4.2 
Endpoints................................................................................................. 8 
4.2.1 
Primary Efficacy Endpoints ............................................................... 8 
4.2.2 
Secondary Endpoints .......................................................................... 8 
 
 
4.2.4 
Safety Endpoints ................................................................................ 9 
4.2.5 
Pharmacokinetic Endpoints ................................................................ 9 
4.3 
Planned Analyses and Analysis Population ............................................ 10 
4.4 
General Analysis and Reporting Convention .......................................... 10 
4.5 
Subject Disposition ................................................................................ 14 
4.6 
Demographic and Baseline Characteristics ............................................. 14 
4.7 
Protocol Violations ................................................................................ 14 
4.8 
Efficacy Analyses .................................................................................. 14 
4.8.1 
Status Epilepticus (SE) and Seizure .................................................. 15 
4.8.2 
Seizure Burden................................................................................. 15 
4.8.3 
Clinical Global Impression of Severity and Improvement (CGI-S and 
CGI-I) ............................................................................................. 15 
4.8.4 
Glasgow Coma Scale (GCS) of Pediatric Glasgow Coma Scale 
(PGCS) ........................................................................................... 15 
4.8.5 
Richmond Agitation and Sedation Scale (RASS).............................. 15 
4.8.6 
Mini-Mental State Examination (MMSE) ......................................... 15 
4.8.7 
Detailed Monitoring of EEG Data .................................................... 15 


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4.9 
Safety Analyses ..................................................................................... 15 
4.9.1 
Adverse Events ................................................................................ 16 
4.9.2 
Medical History ............................................................................... 16 
4.9.3 
Prior and Concomitant Treatments and Procedures........................... 16 
4.9.4 
Physical Examination ....................................................................... 17 
4.9.5 
Vital Signs ....................................................................................... 17 
4.9.6 
Laboratory Evaluations .................................................................... 17 
4.9.7 
Exposure to Investigation Product .................................................... 17 
4.9.8 
Electrocardiography ......................................................................... 17 
4.9.9 
Acute Physiology and Chronic Health Evaluation (APACHE) Score 18 
4.10 
Pharmacokinetic and Neurosteroid Analyses .......................................... 18 
4.11 
Interim Analysis .................................................................................... 18 
4.12 
Data Monitoring Committee (DMC) ...................................................... 18 
5 
CHANGES TO PLANNED ANALYSES................................................... 19 
5.1 
Changes from Protocol .......................................................................... 19 
6 
STATISTICAL SOFTWARE ..................................................................... 20 
7 
REFERENCES ........................................................................................... 21 
APPENDIX 1:  STUDY SCHEDULE ............................................................... 22 
 
 
 


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CONFIDENTIAL 
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1 INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide detailed descriptions of 
predefined methods to be used for efficacy and safety analyses for Protocol 1042-SE-
2001. The latest version of the protocol at the time of the writing of this statistical 
analysis plan is Final Protocol (Amendment 3, 24 January 2019, Version 4.0). 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA) and International Conference on 
Harmonization (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 international accepted guidelines published 
by the American Statistical Association2 for statistical practice. 
The following documents were also considered in preparation for writing this SAP: 
• International Conference on Harmonization (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  
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. 
The original protocol included  a double-blind phase which was planned after an open-
label lead-in to confirm the dose selected achieved an approximately targeted plasma 
concentration of ganaxolone in the target population and to collect safety, efficacy, and 
feasibility of ganaxolone administration  This SAP  supersedes the statistical 
considerations identified in the protocol; where considerations are substantially different.  
This SAP covers analysis of data collected from the open-label.  The double-blind phase 
will now be conducted as a separate phase 3 study.  Therefore, some of the analyses 
described in the study protocol will not be conducted.  Key efficacy, safety, and 
pharmacokinetic data are summarized, and no formal statistical tests are performed for 
inference. Subjects are categorized in to three cohorts based upon target dose of study 
medication.  Cohorts are: 
• Cohort 1: High (Target dose of 713 mg/day) 
• Cohort 2: Medium (Target dose of 650 mg/day) 
• Cohort 3: Low (Target dose of 500 mg/day) 


Study 1042-SE-2001 
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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
Marinus Phannaceuticals, Inc. 
Version 1.0 Final 
• 
To establish that intravenous ganaxolone given concomitantly with 2nd line IV AED 
therapy is safe and effective in stopping status epilepticus that has ah-eady failed one 
2nd line IV AED therapy and prevents escalation of treatment requiring an IV 
anesthetic chug (a 3rd line treatment) for seizure suppression. 
2.2 
Secondary Objectives 
• 
To assess other secondary efficacy endpoints such as mortality, seizure cessation in 
SE subjects 
• 
To assess the phannacokinetics of adjunctive IV ganaxolone in SE subjects 
2.3 
Exploratory Objectives 
I 
I 
3 
STUDY DESIGN 
For detail study design, as was originally planned, please refer to study protocol 
(Amendment 3, Version 4.0, 24 Janua1y 2019). 
3.1 
Study Design and Flow Chart 
This is double-blind, randomized, placebo-controlled study to evaluate the safety, 
tolerability, efficacy of adjunctive IV ganaxolone in subjects with SE. This study will 
start with a small open-label group to confinn the dose selected will achieve an 
approximate targeted plasma concentrntion of ganaxolone in the status epilepticus (SE) 
population who are on concomitant medications, and to obtain a preliminaiy assessment 
of safety, efficacy and feasibility of ganaxolone achninistration. 
As indicated in Section 1, the double-blind phase was not conducted as paii of this study. 
The double-blind phase will be conducted as a sepai·ate phase 3 study. 
Figure 1 below shows originally planned study design. 
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Study 1042-SE-2001 
Statistical Analysis Plan 
Figure 1: Study Design Flow Chart 
Screening 
Study Drug IV Infusion 
Day l 
(0-24hrs) 
Day 2 
(24-48hrs) 
or 
Day 2-4 
(24-96hrs) 
3 minute bolus dose 
D se 
Inif tion 
(I' e O) 
Continuous Infusion 
Infusion 
Taper 
(18hr 
taper) 
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Follow-up Period 
Post-taper 
Follow-up Day 
(24hr 
in-patient 
follow-up) 
Weeks 2, 3, & 4 
3 weeks follow-up 
Adjunct treatment is planned to be 3- or 5-days (including an 18-hour taper). 
Total subject pa1ticipation is expect to be approximately 4 weeks. 
3.2 
Duration and Study Completion Definition 
The original study was expected to be completed in 24 months. 
3.3 
Sites and Regions 
This study was originally planned to be conducted globally, with approximately 150 sites 
planned to paiiicipate. 
3.4 
Study Population 
Male or female subjects 12 yeai·s of age and older at the time of the first dose ai·e eligible 
to paiiicipate in this study. Potential subjects are anticipated to be identified in the 
emergency depai-tment and/or hospital inpatient or intensive care units. 
Each subject/pai·ent/guai·dian/legally authorized representative (LAR) must participate in 
the informed consent process and provide written informed consent/assent before any 
procedures specified in the protocol ai·e perfo1med. Consent/assent for subjects who are 
known to be at risk for SE may be gained prior to a SE event. 
3.5 
Study Evaluation 
The trial schedule of events is provided in Table 1 in Appendix 1. 
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3.6 
Blinding and Treatment Assignment 
Not applicable.  Only lead-in open-label phase was conducted in this study. 
3.7 
Allocation of Subjects to Treatment 
Not applicable.  Only lead-in open label phase was conducted hence there was no 
allocation of subjects to treatment. 
3.8 
Sample Size and Power 
Original sample size (completed subjects = 242) was computed to provide 85% power 
assuming a 20% effect size. Three-hundred and twenty-eight subjects were to be screened 
to enroll 262 subjects, to allow for drop-out. 
4 STATISTICAL METHODS  
4.1 
Analysis Populations 
The Study populations will be defined as follows: 
The Screened Population will consist of all subjects who have signed an informed 
consent. 
The Safety Population will consist of all subjects who have received at least one dose of 
IV ganaxolone. 
The Pharmacokinetic Population will consist of all subjects in the Safety Population 
for whom the primary pharmacokinetic data is available. 
4.2 
Endpoints 
4.2.1 
Primary Efficacy Endpoints 
The primary efficacy endpoint is defined as the number of subjects who did not require 
an IV anesthetic drug (a 3rd line treatment) for SE treatment within the first 24 hours after 
study drug initiation. 
4.2.2 
Secondary Endpoints 
The following are secondary endpoints: 
• For subjects on concomitant second-line therapy: time to cessation of SE or next 
treatment decision (defined as the need for an IV anesthetic drug (a 3rd line treatment) 
when on ganaxolone)  
• Level of responsiveness as assessed by the GCS within 24 hours of SE stopping  


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• 
The number of subjects who did not require additional 2nd line IV AED therapy for 
SE treatment in the 24-hours after study drng taper 
• 
Safety and tolerability of IV ganaxolone as adjunctive SE therapy as assessed by 
neurologic, EEG, and physical examinations, clinical laborato1y tests, ECGs, vital 
signs, and spontaneously reported AEs 
• 
Number of subjects who maintained SE resolution 24 hours after study drug taper and 
atWeek 4 
• 
Number of subjects with seizure( s) following cessation of SE through the 24-hour 
post-taper follow-up day 
• 
Level of responsiveness as assessed by the GCS if SE is continuing, on the 24-hour 
post-taper follow-up day 
• 
Seizure burden assessed as duration of electrographic seizure activity per hour of 
EEG recording collected 
• 
Clinical outcome at the 24-hour post-taper follow-up day and Week 4 
• 
Characterization of the phaimacokinetic profile ofIV ganaxolone in SE subjects 
• 
Length of stay in intensive cai·e unit and hospital, mortality, and seizure freedom 
4.2.3 
Exploratory Endpoints 
I 
I 
I 
4.2.4 
Safety Endpoints 
The following ai·e safety endpoints: 
• 
Adverse Events (AEs) 
• 
Clinical Laborat01y Tests 
• 
Vital Signs 
• 
ECG 
• 
Concomitant Medications 
4.2.5 
Pharmacokinetic Endpoints 
The following ai·e phaimacokinetic endpoints: 
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• Ganaxolone plasma concentration 
• Maximum plasma concentration (Cmax) 
• Time of maximum concentration (Tmax) 
• Area under the concentration versus time curve from time 0 to t hours (AUC0-t) 
• Area under the concentration versus time curve from time 0 to infinity (AUCinf) 
• Clearance (CL).  Calculated as dose/AUCinf 
4.3 
Planned Analyses and Analysis Population 
Planned Analysis 
Analysis Population 
Screened 
Population 
Safety 
Population 
Pharmacokinetic 
Population 
Comments 
Subject Disposition 
√ 
 
 
 
Demographic 
Characteristics 
 
√ 
 
 
Baseline Characteristics 
 
√ 
 
 
Prior and Concomitant 
Treatment 
 
√ 
 
 
Protocol Violation 
 
√ 
 
 
Efficacy Analyses 
 
√ 
 
 
Safety Analyses 
 
√ 
 
 
Pharmacokinetic 
Analyses 
 
 
√ 
 
 
4.4 
General Analysis and Reporting Convention 
Since data from only open-label phase are analyzed, there will be only one treatment 
group.  For efficacy and safety summaries, where applicable, subjects will be categorized 
into three cohorts (Cohort 1: High, Cohort 2: Medium, and Cohort 3: Low) based upon 
target dose of study medication.  An overall group will also be reported representing all 
subjects. 
General Convention: 
The following are general conventions for the analysis of study data.  If alternative 
methods are present in the specific evaluation sections of this SAP, those conventions 
will take precedence over these general conventions. 
• Continuous study measurements will be summarized by treatment group (Open-Label 
Group or Cohorts and Open-Label Group) and time point (as applicable) using 
descriptive statistics (n, mean, standard deviation, median, minimum, and maximum).  
Means and medians will be presented with one more decimal place than the precision 
of the data.  Standard deviations will be presented with two more decimal places than 
the precision of the data.  Minimums and maximums will be presented with the same 
precision as the original data. 


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• Categorical study assessments will be summarized by treatment group (Open-Label 
Group or Cohorts and Open-Label Group) and time point (as applicable) using 
frequency counts and percentages.  Unless stated otherwise, percentages are based on 
the number of subjects in the treatment group of the analysis set.  Percentages will be 
presented with one decimal place (xx.x), with the exception of 100%, which will be 
displayed without any decimal places.   
• Descriptive summaries based on the modified ITT (mITT) analysis set and per-
protocol (PP) analysis set will be displayed by randomized treatment. 
• Descriptive summaries based on the safety analysis set will be displayed by actual 
treatment received.   
• All listings will be listed by cohort, subject, and time point (if applicable).  
• Scheduled assessments will be included in summaries.  Unscheduled assessments will 
only be included in the display sections that report abnormal laboratory, vitals, or 
ECG values.  Data from all assessments (scheduled and unscheduled), will be 
included in listings. 
• All statistical tests will be performed at a significance level of 0.05 (two-tailed). 
Where applicable, two-sided 95% confidence intervals will be reported.  For tables. 
• p-values will be reported to 3 decimal places, with values less than 0.001 displayed as 
‘<0.001’.  Unless otherwise noted, no adjustments for multiple comparisons will be 
made. 
• No preliminary rounding will be performed; rounding should only occur after 
analysis. To round, consider the digit to the right of last significant digit:  if <5 then 
round down, if ≥5 then round up.  
• Unless stated otherwise, the baseline will be calculated as the last observed 
assessment (including scheduled and unscheduled assessments) before the initiation 
of dose.  Change from baseline values will be calculated as the post-baseline value 
minus the respective baseline value. 
• For the safety analysis set, prior medications are those that started and ended before 
the initiation of IV.  Concomitant medications are those that started before initiation 
of IV and continued into blinded treatment or those that started after the initiation of 
IV of blinded treatment. 
• Unless stated otherwise, available data from screen failures will be excluded from all 
tables and figures, but will be presented in any applicable data listings where data was 
collected for screen failure subjects.  
Safety and Other Rules: 
For adverse events with partially missing onset dates, an onset date is imputed as detailed 
in “Programming Specifications”. 
Missing or partially missing prior and/or concomitant start dates are imputed using the 
same rules for AE onset dates. If the stop date is missing the medication is considered to 
have been received during all periods after that determined by the start date (but see also 
rules for stop-date imputation). 
 


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Programming Specifications 
 
a) All output should have the following header at the upper left margin: 
Marinus Pharmaceuticals, Inc. 
Study 1042-SE-2001 
and the following header (right justified) at the upper right margin: 
    Page n of N 
ddMMMyyyy 
Tables/appendices/listings should be internally paginated (i.e., page numbers should 
appear sequentially within each table). All output should have SAS program name in the 
lower right, the data source(s) used to generate the output in the lower left. 
b) In general, data listings should be sorted by cohort, subject number and time 
point/start dates, unless specific instructions to do otherwise. 
c) The following algorithm should be used to estimate adverse event start dates and stop 
dates for which only partial information is known:  
• When the year is present and the month and day are missing: 
o If the year is same as the year of first day on IV, then the day and month of the 
start date of IV will be assigned to the missing fields. 
o If the year is prior to the year of first day on IV, then December 31 will be 
assigned to the missing fields. 
o If the year is after the year of first day on drug, then January 1 will be assigned 
to the missing fields. 
• When year and day are present and the month is missing: 
o If the year of AE start is same as the year of start of IV, then month will be set 
to the month of start of IV. 
o If the year is prior to the year of first day on IV, then month will be set to 
December. 
o If the year is after the year of first day on IV, then month will be set to January. 
• When year and month are present and day is missing: 
o If the year of AE start is same as year of initiation of IV and: 


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 
The month of AE start is same as month of initiation of IV, then the day 
will be set to the day of initiation of IV. 
 
The month of AE start is prior to the month of initiation of IV, then the day 
will be set to the last day of the month. 
 
The month of AE start is after the month of initiation of IV, then the day 
will be set to the 1st day of the month. 
o If the year of AE start is earlier than the year of initiation of IV, then the day 
will be set to the last day of the month. 
o If the year of AE start is after the year of initiation of IV, then the day will be 
set to the 1st day of the month. 
• If the AE stop date is complete and the imputed start date as above is after the stop 
date, the start date will be set to AE stop date. 
• Adverse events with partially missing stop dates will be imputed a stop date as 
follows:  
o year is missing - Date left missing. 
o month is missing - impute 'December'. 
o day is missing - impute 'last date of that month'. 
d) Prior and Concomitant Medication Date: If the start date (or end date) of a medication 
is completely missing or only the day is known, then the start date (or end date) will 
not be imputed.  Unless the end date is before the start date of IV, the medication is 
considered concomitant. 
• For a partial start date of medication, 
o If the year is present and the month and day are missing, then the month and 
day will be set to January 1. 
o If the year and day are present and the month is missing, then the month will 
be set to January. 
o If the year and the month are present and the day is missing, then the day will 
be set to the 1st day of month. 
o If the imputed start date of medication is after the non-imputed end date of 
medication, then the start date will be set to the end date of medication. 
• For a partial end date of medication, 
o If the year is present and the month and day are missing, then the month and 
day will be set to December 31. 


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o If the year and day are present and the month is missing, then the month will 
be set to December. 
o If the year and the month are present and the day is missing, then the day will 
be set to the last day of month. 
 
4.5 
Subject Disposition 
The number of subjects and the reasons for discontinuation (adverse events, protocol 
deviation, lost to follow-up, death, etc.) of study treatment and discontinuation from 
study will be listed and summarized by group (by cohort and overall) for the Enrolled 
Population.  
A data listing will be provided to define each cohort and identify subjects by cohort. 
Additionally, a listing of screen failures will be provided identifying reasons why they 
were not enrolled. 
4.6 
Demographic and Baseline Characteristics 
Descriptive summary statistics (n, mean, standard deviation, median, minimum, and 
maximum) and/or frequency distributions, as appropriate, will be provided by group (y 
cohort and overall) for the Safety Population.  Demographic characteristics summarized 
will include, age, sex, race, and ethnicity.  Baseline information summarized will include 
Status Epilepticus Severity Score (STESS), epileptic history, and status epilepticus (SE) 
history.  Demographic characteristics and baseline STESS and epileptic history will also 
be listed. 
Other than these characteristics, baseline values for safety and efficacy parameters will be 
summarized in respective tables.  
4.7 
Protocol Violations 
Protocol violations will be identified prior to database lock to measure adherence to key 
aspects of the protocol.  List of protocol deviations will be prepared before database lock.  
Specific data fields that will be examined to identify protocol violations include 
inclusion/exclusion criteria and prohibited prior and concomitant treatments as well as 
deviations identified by the investigator.  All protocol violations will be listed for the 
Safety Population. 
4.8 
Efficacy Analyses 
All efficacy analyses will be conducted for the Safety Population. 


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Considering that data from only open-label phase is available for analysis, efficacy 
assessments are only summarized and listed.  There will be no statistical inferential test 
of any efficacy endpoint. 
4.8.1 
Status Epilepticus (SE) and Seizure 
Status epilepticus and seizure questions will be listed and summarized by group (by 
cohort and overall) and time point.  Additionally, SE cessation time will be listed and 
summarized (by cohort and overall). 
4.8.2 
Seizure Burden 
Seizure burden will be listed and summarized by group (by cohort and overall) and time 
point. 
4.8.3 
Clinical Global Impression of Severity and Improvement (CGI-S and 
CGI-I) 
The CGI-S and CGI-I scores will be listed and summarized by group (by cohort and 
overall) and time point. 
4.8.4 
Glasgow Coma Scale (GCS) of Pediatric Glasgow Coma Scale (PGCS)  
The GCS or PGCS scores will be listed and summarized by group (by cohort and overall) 
and time point.  Both observed values and change from baseline will be listed and 
summarized. 
4.8.5 
Richmond Agitation and Sedation Scale (RASS) 
The RASS scores will be listed and summarized by group (by cohort and overall) and 
time point. 
4.8.6 
Mini-Mental State Examination (MMSE) 
The MMSE total scores will be listed by cohort, subject, and time point. 
4.8.7 
Detailed Monitoring of EEG Data 
Data collected from detailed monitoring of EEG activities will be listed and summarized. 
4.9 
Safety Analyses 
The comprehensive safety analysis is based on all subjects in the Safety Population, 
unless indicated in the individual safety endpoint analysis.  Safety data will be listed and 
summarized by group (by cohort and overall).  The following sections detail the analyses 
performed on the safety data. 


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4.9.1 
Adverse Events 
Adverse events are coded using the MedDRA dictionary, Version 20.1 or higher, and are 
categorized by system organ class (SOC) and preferred term (PT).  Only treatment 
emergent adverse events are included in the summary tabulations. All adverse events are 
included in the data listings.  
To allow differentiation as to which study period an Adverse Event occurred, two 
categories are defined based upon onset date. Adverse Events that had onset dates prior to 
the first dose of study medication are considered "prior”. Adverse events with onset dates 
on or after the first dose of study medication and up to end of follow-up period are 
considered "on-therapy" or equivalently “treatment emergent”.  Adverse events with an 
onset date prior to the first dose of study medication but worsens after treatment starts are 
considered a treatment emergent AE. 
 
Overall summary of Treatment-emergent adverse events (TEAE) will be provided.  The 
TEAEs will be summarized by MedDRA System Organ Class (SOC) and preferred term 
(PT), and by group (by cohort and overall). Treatment-emergent adverse events will 
further be summarized by severity and relationship to treatment medication.  Treatment-
emergent Serious Adverse Events (SAE) and AEs leading to discontinuation of study 
drug will also be summarized by SOC, PT, and group (by cohort and overall). 
Adverse events and serious adverse events will be listed. 
Deaths will be listed and summarized by group (by cohort and overall). 
4.9.2 
Medical History 
Medical history information recorded in eCRF will be listed for the Enrolled Population 
by cohort and subject. 
4.9.3 
Prior and Concomitant Treatments and Procedures 
Prior treatment includes all non-study treatment received within 30 days prior to the first 
dose of study medication.  Concomitant treatment refers to all treatment taken between 
the date of the first dose of study medication and the last follow-up visit/contact and are 
recorded in eCRF pages.  
Prior and concomitant medications (Non-AEDs) will be listed and summarized by group 
(by cohort and overall).  Antiepileptic drugs (AEDs) are also collected as part of prior 
and concomitant treatments.  A separate listing and summary table will be presented for 
AEDs. 
Additionally, Prior and concomitant Procedures and Anesthetics will be listed and 
summarized by group (by cohort and overall). 


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Medications are coded using the WHO Drug dictionary. 
4.9.4 
Physical Examination 
Physical examination results will be reported for the Safety Population.   
Physical examination abnormal findings at baseline will be listed for each subject.  Any 
changes in physical examination findings in subsequent time points from previous time 
point will also be listed. 
4.9.5 
Vital Signs 
Vital signs are listed and summarized by time point and group (by cohort and overall) for 
the Safety Population.  Systolic blood pressure, diastolic blood pressure, pulse, 
respiration rate, temperature, oxygen saturation, height, weight, and body mass index 
(BMI) will be summarized and listed.  Both observed values and change from baseline 
will be summarized. 
4.9.6 
Laboratory Evaluations 
Laboratory findings will be listed and summarized for the Safety Population. 
Chemistry, hematology, and urinalysis parameter results will be summarized using 
descriptive statistics by time point and group (by cohort and overall).  Both actual values 
and change from baseline will be summarized.  Similar table will be provided for AED 
laboratory results. 
Summary showing number and percent of subjects with abnormal laboratory test results 
will be provided by time point and group (by cohort and overall) for hematology, 
chemistry, and urinalysis parameters. 
Lab results, including AEDs, will be listed by cohort, subject, and time point. 
4.9.7 
Exposure to Investigation Product 
Investigational product administration to subjects will be listed and summarized (by 
cohort and overall) for the Safety Population.  Listing should include all doses 
administered to all subjects. 
4.9.8 
Electrocardiography 
ECG measurements will be listed and summarized by time point and group (by cohort 
and overall) for the Safety Population.  ECG parameters QT, QTcB, QTcF, PR, HR, and 
QRS will be presented. Summary of interpretation of ECG results will also be listed and 
summarized. 


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4.9.9 
Acute Physiology and Chronic Health Evaluation (APACHE) Score 
For all subjects both APACHE (if blood gas data is available) and APACHE II scores 
will be listed. 
4.10 Pharmacokinetic and Neurosteroid Analyses 
Ganaxolone plasma concentration data will be listed and summarized (by cohort and 
overall) for the Pharmacokinetic Population.  Plasma concentration time profile data will 
also be presented graphically.  Individual subject profile of plasma concentration will 
also be presented graphically. 
Additionally, neurosteroid concentration will also be listed. 
4.11 Interim Analysis 
No formal interim analysis was conducted. 
4.12 Data Monitoring Committee (DMC) 
A formal DMC to monitor safety data was not established in this study.  However, safety 
data were routinely monitored by investigators, study clinicians, and sponsor. 


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5 CHANGES TO PLANNED ANALYSES 
5.1 
Changes from Protocol 
The following analyses planned in this SAP deviates from original analyses proposed in protocol: 
Protocol Section 
Analyses Proposed in the Protocol 
Changes from Protocol 
Rationale for Change 
9.7.1 
A statistical comparison of primary 
efficacy endpoint between treatment 
groups using a logistic regression 
model. 
Data was only summarized. 
Study was closed before entering 
double-blind phase.  This analysis 
was not relevant. 
9.7.2 
Detailed statistical analysis of several 
secondary efficacy endpoints were 
proposed.   
Only a few secondary efficacy 
endpoints were summarized.  Please 
see Section 4.8 for details. 
Study was closed before entering 
double-blind phase.  This analysis 
was not relevant. 
9.7.3 
Three specific exploratory endpoints 
were identified to be evaluated.  
Exploratory analyses were not 
conducted. 
Study was closed before entering 
double-blind phase.  This analysis 
was not relevant. 
Section 9.9 
Detailed monitoring and analyses of 
EEG data. 
No such analysis was conducted. 
Study was closed before entering 
double-blind phase.  This analysis 
was not relevant. 
Section 9.9.1 
Besides ganaxolone plasma 
concentration data analysis, analysis 
of ganaxolone pharmacokinetic 
parameters was also proposed.  
Only plasma concentration data was 
analyzed.  
Considering lack of sufficient 
pharmacokinetic data profile, only 
plasma concentration data was 
analyzed. 
 


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6 STATISTICAL SOFTWARE 
All data summaries, statistical analyses, and listings will be performed using SAS 
Version 9.2 or later, under Microsoft Windows operating system. 


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7 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/EthicalGuidelines-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.  
 


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APPENDIX 1:  STUDY SCHEDULE 
 


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STUDY SCHEDULE(S) 
Table 1: 
Schedule of Assessments 
Periods 
Screening a 
Treatment 
Follow-up b 
ET 
Visit/Time Point or 
Duration 
Prior to dose 
initiation 
Dosing 
Taper 
Study Drug 
Discontinuation 
without Taper 
Post–taper 
(inpatient) Follow-
up 
Weekly 
follow-up 
(Week 2, 
3, & 4) 
Early 
Termination 
Day -1 to 
Day 1 
 
Pre-dose 
through 
screening 
Day 1 
 
Dose 
initiation (0 
hours) 
through 24 
hours post-
dose 
Day 2 to 
4 
 
Min 48 
– 
Max 96 
hours 
post-
dose 
Day 3 or 
5 
 
18 
hours 
Collected prior to or 
as close to study drug 
stopping as possible 
Day 4 or 6 
Or 
Starts as soon as 
study drug 
administration ends, 
lasts 24 hours 
7 ±3, 14 
±3, and 21 
±3 days 
post last 
visit 
Collected 
prior to or 
as close to 
study drug 
stopping as 
possible 
Informed 
consent/assent 
 
 
 
 
 
 
 
 
Inclusion/ exclusion 
criteria 
 
 
 
 
 
 
 
 
Demography and 
medical/ medication 
history c 
 
 
 
 
 
 
 
 
Physical exam d 
 
 
 
 
 
 
 
 
Status Epilepticus 
Severity Score 
(STESS) 
 
 
 
 
 
 
 
 
Glasgow Coma Scale 
(GCS)/Pediatric GCS 
(PGCS) e 
 
 
 
 
 
 
 
 
Mini mental state 
exam f 
 
 
 
 
 
 
 
 
Vital signs g 
 
 
 
 
 
 
 
 
12-lead ECG h 
 
 
 
 
 
 
 
 


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Marinus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Version 1.0 Final 
 
CONFIDENTIAL 
Page 24 of 28 
Table 1: 
Schedule of Assessments 
Periods 
Screening a 
Treatment 
Follow-up b 
ET 
Visit/Time Point or 
Duration 
Prior to dose 
initiation 
Dosing 
Taper 
Study Drug 
Discontinuation 
without Taper 
Post–taper 
(inpatient) Follow-
up 
Weekly 
follow-up 
(Week 2, 
3, & 4) 
Early 
Termination 
Day -1 to 
Day 1 
 
Pre-dose 
through 
screening 
Day 1 
 
Dose 
initiation (0 
hours) 
through 24 
hours post-
dose 
Day 2 to 
4 
 
Min 48 
– 
Max 96 
hours 
post-
dose 
Day 3 or 
5 
 
18 
hours 
Collected prior to or 
as close to study drug 
stopping as possible 
Day 4 or 6 
Or 
Starts as soon as 
study drug 
administration ends, 
lasts 24 hours 
7 ±3, 14 
±3, and 21 
±3 days 
post last 
visit 
Collected 
prior to or 
as close to 
study drug 
stopping as 
possible 
Biochemistry, 
hematology, and 
antiepileptic drugs i 
 
 
 
 
 
 
 
 
Urinalysis j 
 
 
 
 
 
 
 
 
Urine for drugs of 
abuse, including 
alcohol k  
 
 
 
 
 
 
 
 
 
Pregnancy test 
(WCBP only) urine or 
serum l 
 
 
 
 
 
 
 
 
EEG m 
 
 
 
 
 
 
 
 
Study Drug infusionn 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
blood sampling o 
 
 
 
 
 
 
 
 
Neurosteroid levels p 
 
 
 
 
 
 
 
 
Blood Gas q 
 
 
 
 
 
 
 
 
Clinical Global 
Impression of Severity 
(CGI-S) r 
 
 
 
 
 
 
 
 


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Marinus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Version 1.0 Final 
 
CONFIDENTIAL 
Page 25 of 28 
Table 1: 
Schedule of Assessments 
Periods 
Screening a 
Treatment 
Follow-up b 
ET 
Visit/Time Point or 
Duration 
Prior to dose 
initiation 
Dosing 
Taper 
Study Drug 
Discontinuation 
without Taper 
Post–taper 
(inpatient) Follow-
up 
Weekly 
follow-up 
(Week 2, 
3, & 4) 
Early 
Termination 
Day -1 to 
Day 1 
 
Pre-dose 
through 
screening 
Day 1 
 
Dose 
initiation (0 
hours) 
through 24 
hours post-
dose 
Day 2 to 
4 
 
Min 48 
– 
Max 96 
hours 
post-
dose 
Day 3 or 
5 
 
18 
hours 
Collected prior to or 
as close to study drug 
stopping as possible 
Day 4 or 6 
Or 
Starts as soon as 
study drug 
administration ends, 
lasts 24 hours 
7 ±3, 14 
±3, and 21 
±3 days 
post last 
visit 
Collected 
prior to or 
as close to 
study drug 
stopping as 
possible 
Clinical Global 
Impression of 
Improvement (CGI-I) s 
 
 
 
 
 
 
 
 
Richmond Agitation 
and Severity Scale 
(RASS) t 
 
 
 
 
 
 
 
 
SE & Seizure 
Questions u 
 
 
 
 
 
 
 
 
AEs/SAEs v 
 
 
 
 
 
 
 
 
Concomitant 
medication v 
 
 
 
 
 
 
 
 
ET, Early Termination; ECG, electrocardiogram; WCBP, women of childbearing potential; EEG, electroencephalograms; AE, adverse event; SAE, serious AE. 
a 
The screening period is from the time parent/guardian/LAR consent is obtained to immediately prior to study drug dose initiation. 
b 
The planned duration of follow-up will be 24 hours after study drug administration is stopped (called the 24-hour post-taper follow-up day) and weekly for 
an additional 3 weeks. For Weeks 2, 3, and 4 the follow-up can be performed as an inpatient visit if the subject is still in the hospital or, if the subject has 
been discharged, as a telephone call. Attempts should be made to have discharged subjects return for one of the follow-up visits for clinical laboratory 
sample collection. The follow-up visit window is 7 ±3, 14 ±3, and 21 ±3 days.  
c 
Demography and medical history will ideally be collected prior to dose initiation but can be collected whenever feasible before the end of study drug taper. 
d 
Physical exam should be obtained from the subject’s chart or completed at screening or, if not available, collected within 24 hours of dose initiation, prior to 
initiating the study drug taper, and at the  24-hour post-taper follow-up visit, at the time of study drug termination if there is no study drug taper and 
something has changed since the last PE was collected, and at the time of early termination, when the decision to stop study drug administration is made and 
as close as possible to the end of the study drug administration. 


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Marinus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Version 1.0 Final 
 
CONFIDENTIAL 
Page 26 of 28 
e 
GCS/PGCS is collected pre-dose, 60 minutes and 2 hours of dose initiation, once within each 24-hour period through the end of the 24-hour post-taper 
follow-up day, as well as any time there is a change in subject’s state that the investigator thinks is clinically significant. Also collect at the time of study 
drug termination if there is no taper and something has changed since the last GCS/PGCS was collected, and at the time of early termination, when the 
decision to stop study drug administration is made and as close as possible to the end of the study drug administration. 
f 
Mini Mental State Examination (MMSE) should be performed at the time consent/assent is administered to the subject for continued participation and then 
on the post–taper follow-up day. Also collect at the time of study drug termination if there is no taper and something has changed since the last MMSE was 
collected, and at the time of early termination, when the decision to stop study drug administration is made and as close as possible to the end of the study 
drug administration. If the MMSE is not able to be assessed due to the subject’s state this should be recorded. 
g 
Vital signs including blood pressure, pulse, respiratory rate, temperature, and oxygen saturation should be assessed at screening, once within the first 2 hours 
of dosing, 8 and 24 hours after study drug initiation, and then once within each 24-hour period through the 24- hour post-taper follow-up day. Also, at any 
time there is a change in the subject’s state that the investigator thinks is clinically significant. Also collect at the time of study drug termination if there is no 
study drug taper and at the time of early termination, when the decision to stop study drug administration is made and as close as possible to the end of the 
study drug administration. 
Weight and height should be collected at screening for calculation of BMI inclusion criterion, if feasible. If not collected at screening they need to be 
collected prior to the end of the 24-hour post-taper follow-up day. 
h 
ECG, if possible, should be collected pre-dose, 2-hours post- dose, and then once within each 24-hour period through the 24-hour post-taper follow-up day, 
plus any time there is a change in the subject’s state that the investigator thinks is clinically significant. Also collect at the time of study drug termination if 
there is no taper and something has changed since the last ECG was collected, and at the time of early termination, when the decision to stop study drug 
administration is made and as close as possible to the end of the study drug administration. 
i 
Clinical labs, hematology, serum chemistry (including creatinine, blood urea nitrogen, and estimated glomerular filtration rate calculation) and concomitant 
AED levels (fosphenytoin/phenytoin, valproic acid, levetiracetam, or lacosamide) should be collected at screening if available, or within 2 hours of dose 
initiation, once within each 24-hour period through the –24-hour post-taper follow-up day, as well as at any time there is a change in the subject’s state that 
the investigator thinks is clinically significant. Collect at the time of study drug termination if there is no study drug taper and at the time of early 
termination, when the decision to stop study drug administration is made and as close as possible to the end of the study drug administration. Also collect 
clinical labs (serum chemistry, AED, and hematology) at one of the weekly follow-up visits for subjects in-house and if possible, for subjects who have been 
discharged. 
j 
Urinalysis samples should be collected at screening if available or within 2 hours of dose initiation, 48 hours after dose initiation, on the 24-hour post-taper 
follow-up day, and for subjects stopping study drug without a taper or early terminating the study, when the decision to stop study drug administration is 
made and as close as possible to the end of the study drug administration. 
k 
Ideally, collect urine for drugs of abuse, including alcohol testing, prior to dose initiation but if not possible then, collect within the first 24 hours after dose 
initiation. Enrollment is not contingent upon results.  
l 
Urine or serum pregnancy test for women who are of potential childbearing age, should be collected prior to dose initiation. If not possible to collect pre-
dose then, collect as soon as possible after dose initiation. Enrollment is not contingent upon results. However, if a subject has a positive test result, it will be 
at the investigators discretion to weigh the risks verses benefits for the subjects continued participation. 
m 
EEG recording is required for confirmation of NCSE diagnosis. Continuous EEG recording ideally should start before dose initiation and continue through 
the 24-hour post-taper follow-up day. If continuous EEG is not possible or needed to diagnose (for convulsive SE) it should be instituted at the earliest 
possible time after study drug initiation (if a pre-dose EEG was not performed for the diagnosis of convulsive SE). 


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Statistical Analysis Plan 
Version 1.0 Final 
 
CONFIDENTIAL 
Page 27 of 28 
n 
Subjects will receive a 25 mg bolus (over ~3 minutes) with a continuous infusion at a rate of 18-80 mg/hour for approximately 48 to 96 hours followed by an 
18-hour taper.   
o 
Blood sample collection for pharmacokinetic analysis (venous or arterial) will occur at 60 minutes then at 2, 4, 8, 10, and 24 hours after the start of the 
infusion, at the time study drug administration is halted, e.g, at the end of the 18-hour study drug taper or, if study drug administration is halted without 
taper, and/or early termination, when the decision to stop study drug administration is made and as close as possible to the end of the study drug 
administration. In addition, if the SE relapses after initial SE cessation and the subject does not progress to an IV anesthetic drug (a 3rd line treatment), a 
pharmacokinetic sample should be collected. If there are multiple SE relapses, additional pharmacokinetic sample collection is not required. The collection 
windows for pharmacokinetics samples are ± 5 minutes for all collections through 4 hours’ post-dose initiation and ± 60 minutes for all other collection 
points. If an indwelling catheter is used, a 1-mL sample will be drawn and discarded prior to the pharmacokinetic sample collection.  
p 
Neurosteroid levels, one blood sample (venous or arterial) will be collected prior to study drug initiation and a second collected anytime within the 24 hours 
of study drug initiation. If study drug is discontinued during this 24-hour period, the second sample should be collected prior to study drug termination, if 
possible. 
q 
Blood gas including FiO2, PaO2, and Arterial pH, should be recorded if collected per the hospital’s standard of care. The sample collected closest to the time 
of SE diagnosis should be recorded. If no sample was collected at diagnosis, then the 1st blood gas sample after SE treatment initiation. Note, this may be 
prior to the start of study drug. If not collected per the hospital’s standard of care, this data will not be recorded.   
r 
CGI-S is collected pre-dose, once within each 24-hour period through the 24-hour post-taper follow-up day, and at the Week 4 follow-up visit (via phone if 
not in person), plus any time there is a change in the subject’s state that the investigator thinks is clinically significant. Also collect at the time of study drug 
termination if there is no taper and something has changed since the last CGI-S was collected, and at the time of early termination, when the decision to stop 
study drug administration is made and as close as possible to the end of the study drug administration. 
s 
CGI-I is collected within 2 hours of dose initiation, once within each 24-hour period through the 24-hour post-taper follow-up day, and at the Week 4 
follow-up visit (via phone if not in person), plus any time there is a change in the subject’s state that the investigator thinks is clinically significant. Also 
collect at the time of study drug termination if there is no taper and something has changed since the last CGI-I was collected, and at the time of early 
termination, when the decision to stop study drug administration is made and as close as possible to the end of the study drug administration. 
t 
RASS is collected pre-dose and within 2 hours of dose initiation, once within each 24-hour period through the end of the 24-hour post-taper follow-up day, 
as well as any time there is a change in subject’s state that the investigator thinks is clinically significant. Also collect at the time of study drug termination if 
there is no taper and something has changed since the last RASS was collected, and at the time of early termination, when the decision to stop study drug 
administration is made and as close as possible to the end of the study drug administration. 
u 
Status Epilepticus and Seizure Questions should be assessed at 60 minutes, 2 hours, 48 hours post-dose, and on the 24-hour post-taper follow-up day. and at 
weeks 2, 3, and 4. Also collect at the time of study drug termination if there is no taper and something has changed since the last collection timepoint, and at 
the time of early termination, when the decision to stop study drug administration is made and as close as possible to the end of the study drug 
administration. 
v 
AEs and concomitant medications will be collected throughout the study; non-direct questioning will occur. The collection requirements will differ 
depending on the subject’s treatment progression as defined here: 1. For subjects who have 2-4 days of treatment with an 18-hour study drug taper, all 
adverse events and associated concomitant medications will be collected though the 24-hour post-taper follow-up visit. During the weekly follow-up visits 
only, ongoing AEs and new AEs assessed by the investigator to be related to study will be captured along with their associated concomitant medications. 2. 
For subjects who stop study drug administration without a taper but continue with the follow-up visits, all adverse events will be collected though the 24-
hour post-taper follow-up visit, with their associated concomitant medications. During the weekly follow-up visits only, ongoing AEs and new AEs assessed 


Study 1042-SE-2001 
Marinus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Version 1.0 Final 
 
CONFIDENTIAL 
Page 28 of 28 
by the investigator to be related to study will be captured, with their associated concomitant medications. 3. For subjects who early terminate from the study, 
prior to discontinuation as much information as is available should be recorded on any on-going AEs/SAEs and AEs/SAEs with their associated concomitant 
medications, especially those that may have led to the early termination. 4. All SAEs regardless of relationship to study drug will be recorded from the time 
of 1st dose though the last follow-up visit, with their associated concomitant medications.