Clinical trial NCT04391569
Conditions: Status Epilepticus
Keywords: Seizure Status Epilepticus Convulsive Status Epilepticus Non-Convulsive Status Epilepticus Epilepsy
Sponsor: Marinus Pharmaceuticals
Start date: 2020-12-09; Completion date: 2024-04-28
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluated the effectiveness and safety of an investigational product (IP), intravenous (IV) ganaxolone, to treat participants with status epilepticus (SE).

Detailed description:
This is a double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of IV ganaxolone in status epilepticus. Investigational product was added to standard of care following failure of any two or more antiseizure medications (benzodiazepine and one IV antiepileptic drug (AED) or two IV AEDs. Participants were screened for inclusion/exclusion criteria prior to receiving investigational product by continuous IV infusion. Participants were followed for approximately 4 weeks. Participants who are known to be at risk for SE were consented or assented prior to an SE event.

Arms: arm 1: Placebo bolus dose followed by continuous infusion for 36 hours, followed by 12 hour taper arm 2: Ganaxolone bolus dose followed by continuous infusion for 36 hours, followed by 12 hour taper
Interventions: intervention 1: Ganaxolone intervention 2: Placebo
Intervention descriptions: intervention 1: Ganaxolone will be administered. intervention 2: Placebo will be administered.

Protocol documents:
Prot_000.pdf: 
 
 
 
PROTOCOL: 1042-SE-3003 
TITLE: 
A double-blind, randomized, placebo-controlled study to evaluate the 
efficacy and safety of intravenous ganaxolone in status epilepticus 
DRUG: 
Ganaxolone  
IND: 
129433 
EUDRACT NO.: 
TBD 
SPONSOR: 
Marinus Pharmaceuticals, Inc. 
5 Radnor Corporate Center 
100 Matsonford Road, Suite 500 
Radnor, PA 19087 USA 
PROTOCOL 
HISTORY: 
Amendment 5:  06May2024, Version 6.0 
Amendment 4: 13Oct2023, Version 5.0 
Amendment 3: 10June2022, Version 4.0 
Amendment 2: 19November2021, Version 3.0 
Amendment 1: 14July2020, Version 2.0  
Original Protocol: 13April2020, 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. 
 






 
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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 Drug Safety vendor. A copy of this 
form must also be sent to the contract research organization (CRO)/Medical Monitor by e-mail 
using the details below. 
Email: 
 
Fax: 
In addition, for protocol or safety related issues the investigator must contact the Medical 
Monitor: 
Medical Monitor: 
, MD, PhD 
, Clinical Development 
Marinus Pharmaceuticals, Inc. 
Email: 
 
Mobile Telephone Number: 
 (primary contact method via text or call to this 
number and followed by e-mail) 
If unavailable: 
, MD 
, Clinical Development 
Marinus Pharmaceuticals, Inc. 
Email: 
 
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 Clinical Trial Manager:  
Marinus Trial Manager: 
 
 
Marinus Pharmaceuticals, Inc. 
Email: 
 
Mobile Telephone Number: 
(primary contact method via text or call) 
 
Marinus Program Manager: 
, PharmD 
, Clinical Development Operations 
Marinus Pharmaceuticals, Inc. 
Email: 
 
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 ................................................................................4 
ADDITIONAL CONTACT INFORMATION ................................................................................5 
LIST OF TABLES .........................................................................................................................11 
LIST OF FIGURES .......................................................................................................................11 
ABBREVIATIONS .......................................................................................................................12 
STUDY SYNOPSIS ......................................................................................................................14 
STUDY SCHEDULE(S) ...............................................................................................................27 
1 
BACKGROUND INFORMATION .......................................................................................33 
1.1 
Indication and Current Treatment Options ........................................................................33 
1.2 
Product Background and Clinical Information ..................................................................34 
2 
STUDY OBJECTIVES AND PURPOSE ..............................................................................37 
2.1 
Rationale for the study .......................................................................................................37 
2.2 
Study Objectives ................................................................................................................39 
2.2.1 
Primary Objective ........................................................................................................39 
2.2.2 
Secondary Objectives ...................................................................................................39 
2.2.3 
Exploratory Objectives ................................................................................................39 
3 
STUDY DESIGN ...................................................................................................................39 
3.1 
Study Design and Flow Chart ............................................................................................39 
3.1.1 
Double-blind Phase ......................................................................................................39 
3.1.2 
Open-label Phase .........................................................................................................40 
3.2 
Interim Analysis .................................................................................................................41 
3.3 
Duration and Study Completion Definition .......................................................................41 
3.4 
Sites and Regions ...............................................................................................................41 
4 
STUDY POPULATION .........................................................................................................41 
4.1 
Inclusion Criteria ...............................................................................................................41 
4.2 
Exclusion Criteria ..............................................................................................................42 
4.3 
Restrictions ........................................................................................................................43 
4.4 
Reproductive Potential .......................................................................................................43 
4.4.1 
Female Contraception ..................................................................................................43 
4.4.2 
Male Contraception ......................................................................................................44 
4.5 
Discontinuation of Participants ..........................................................................................44 
4.5.1 
Investigational product discontinuation .......................................................................44 
4.5.1.1 
Reasons for IP discontinuation include, but are not limited to, the 
following: ...............................................................................................................45 
4.5.1.2 
Study Withdrawal ..................................................................................................45 
4.5.2 
Participant Withdrawal Criteria ...................................................................................45 
4.5.3 
Reasons for Study Discontinuation ..............................................................................46 
4.5.4 
Participants Lost to Follow-up Prior to Last Scheduled Visit .....................................46 


 
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PRIOR AND CONCOMITANT TREATMENT ...................................................................46 
5.1 
Prior Treatment ..................................................................................................................46 
5.2 
Concomitant Treatment .....................................................................................................47 
5.2.1 
Permitted Treatment .....................................................................................................48 
5.2.2 
Prohibited Treatment ...................................................................................................48 
6 
INVESTIGATIONAL PRODUCT ........................................................................................48 
6.1 
Identity of Investigational Product .....................................................................................48 
6.1.1 
Blinding the Treatment Assignment ............................................................................49 
6.1.2 
Double-Blind Phase .....................................................................................................49 
6.1.3 
Open-Label Phase ........................................................................................................49 
6.2 
Administration of Investigational Product(s) .....................................................................49 
6.2.1 
Interactive Response Technology for Investigational Product Management ..............49 
6.2.2 
Allocation of Participants to Treatment .......................................................................49 
6.2.2.1 
Double-Blind Phase ...............................................................................................49 
6.2.2.2 
Open-Label Phase ..................................................................................................49 
6.2.3 
Dosing ..........................................................................................................................50 
6.2.3.1 
Participants weighing at least 40 kg: .....................................................................51 
6.2.3.2 
Participants weighing <40 kg will be dosed on a per kilogram basis: ...................52 
6.2.4 
Investigational Product Infusion Precautions ..............................................................53 
6.2.5 
Medical Oversight ........................................................................................................54 
6.2.6 
Investigational Product Tapering (One or More May Apply) .....................................54 
6.2.7 
Dose Adjustments and Interruptions ............................................................................54 
6.2.8 
Unblinding the Treatment Assignment ........................................................................55 
6.2.8.1 
Double-Blind Phase ...............................................................................................55 
6.3 
Labeling, Packaging, Storage, and Handling .....................................................................55 
6.3.1 
Labeling .......................................................................................................................55 
6.3.2 
Packaging .....................................................................................................................56 
6.3.3 
Storage .........................................................................................................................56 
6.4 
Investigational Product Accountability ..............................................................................56 
6.5 
Participant Compliance ......................................................................................................57 
7 
STUDY PROCEDURES ........................................................................................................58 
7.1 
Study Schedule...................................................................................................................58 
7.1.1 
Screening Period ..........................................................................................................58 
7.1.1.1 
Screening................................................................................................................58 
7.1.1.2 
Screen Failures .......................................................................................................58 
7.1.2 
Treatment Period ..........................................................................................................59 
7.1.2.1 
Investigational Product Initiation Through Taper (Day 1 to Day 2) .....................59 
7.1.3 
Follow-up Period (starting at IP discontinuation through Week 4) .............................59 
7.1.4 
Additional Care of Participants After the Study ..........................................................59 
7.2 
Study Evaluations and Procedures .....................................................................................60 
7.2.1 
Demographic and Other Baseline Characteristics .......................................................60 


 
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7.2.2 
Efficacy ........................................................................................................................60 
7.2.2.1 
Electroencephalogram (EEG) ................................................................................60 
7.2.2.2 
Status Epilepticus Severity Score (STESS) ...........................................................60 
7.2.2.3 
Clinical Global Impression of Severity and Improvement (CGI-S and 
CGI-I, respectively) ...............................................................................................61 
7.2.2.4 
Richmond Agitation and Sedation Scale (RASS) ..................................................61 
7.2.2.5 
The Full Outline of UnResponsiveness (FOUR) Score .........................................61 
7.2.2.6 
Seizure Description Questionnaire ........................................................................61 
7.2.2.7 
Status Epilepticus Cessation Questionnaire ...........................................................61 
7.2.2.8 
Super Refractory Status Epilepticus Questionnaire ...............................................61 
7.2.2.9 
Modified Rankin Scale (mRS) ...............................................................................61 
7.2.2.10 
EuroQol (EQ-5D-5L) .............................................................................................62 
7.2.3 
Safety ...........................................................................................................................62 
7.2.3.1 
Medical, Seizure or SE, and Medication History ..................................................62 
7.2.3.2 
Physical Examination.............................................................................................62 
7.2.3.3 
Adverse Event Collection ......................................................................................63 
7.2.3.4 
Vital Signs ..............................................................................................................63 
7.2.3.5 
Electrocardiography (ECG) ...................................................................................63 
7.2.3.6 
Cardiodynamic 12-Lead Electrocardiography (ECG) Monitoring ........................63 
7.2.3.7 
Clinical Laboratory Evaluations ............................................................................64 
7.2.4 
Others ...........................................................................................................................66 
7.2.4.1 
Clinical Pharmacology Blood Sample Collection and Handling Procedures ........66 
7.2.4.2 
Shipment of Plasma Pharmacokinetic Samples .....................................................66 
7.2.4.3 
Plasma Drug Assay Methodology .........................................................................66 
7.3 
Healthcare Utilization Questionnaires ...............................................................................68 
8 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................69 
8.1 
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events ..............................................................................................................................69 
8.1.1 
Severity Categorization ................................................................................................69 
8.1.2 
Relationship Categorization .........................................................................................70 
8.1.3 
Outcome Categorization ..............................................................................................70 
8.1.4 
Symptoms of the Disease Under Study .......................................................................70 
8.1.5 
Clinical Laboratory and Other Safety Evaluations ......................................................71 
8.1.6 
Pregnancy .....................................................................................................................71 
8.1.7 
Medication Errors and Other Reportable Information .................................................72 
8.2 
Serious Adverse Event Procedures ....................................................................................72 
8.2.1 
Reference Safety Information ......................................................................................72 
8.2.2 
Reporting Procedures ...................................................................................................72 
8.2.3 
Serious Adverse Event Definition ...............................................................................73 
8.2.4 
Serious Adverse Event Collection Time Frame ...........................................................73 
8.2.5 
Serious Adverse Event Onset and Resolution Dates ...................................................73 


 
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8.2.6 
Fatal Outcome ..............................................................................................................74 
8.2.7 
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting ....................................................................................................................74 
9 
DATA MANAGEMENT .......................................................................................................75 
9.1 
Data Collection ..................................................................................................................75 
9.2 
Clinical Data Management ................................................................................................75 
9.3 
Data Monitoring Committee (DMC) .................................................................................75 
10 STATISTICAL CONSIDERATIONS ...................................................................................75 
10.1 
Statistical Analysis Process ................................................................................................75 
10.2 
Sample Size Determination ................................................................................................76 
10.3 
Analysis Populations ..........................................................................................................76 
10.4 
Statistical Analyses ............................................................................................................76 
10.4.1 
Primary Endpoints (Double-Blind Phase) ...................................................................76 
10.4.2 
Key Secondary Endpoints (Double-Blind Phase) ........................................................77 
10.4.3 
Other Secondary Endpoints .........................................................................................77 
10.4.4 
Healthcare Utilization Endpoints .................................................................................78 
10.4.5 
Open-Label Endpoints .................................................................................................78 
10.5 
Safety Analyses ..................................................................................................................78 
10.6 
Pharmacokinetic Analyses .................................................................................................79 
10.7 
Interim Analyses ................................................................................................................79 
11 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ...........................................79 
11.1 
Sponsor’s Responsibilities .................................................................................................80 
11.1.1 
Good Clinical Practice (GCP) Compliance .................................................................80 
11.1.2 
Public Posting of Study Information ............................................................................80 
11.1.3 
Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees ....................................................80 
11.1.4 
Study Suspension, Termination, and Completion........................................................80 
11.2 
Investigator’s Responsibilities ...........................................................................................81 
11.2.1 
Good Clinical Practice Compliance .............................................................................81 
11.2.2 
Protocol Adherence and Investigator Agreement ........................................................81 
11.2.3 
Documentation and Retention of Records ...................................................................82 
11.2.3.1 
Case Report Forms .................................................................................................82 
11.2.3.2 
Recording, Access, and Retention of Source Data and Study Documents ............82 
11.2.3.3 
Audit/Inspection .....................................................................................................83 
11.2.3.4 
Financial Disclosure ...............................................................................................83 
11.3 
Ethical Considerations .......................................................................................................83 
11.3.1 
Informed Consent.........................................................................................................83 
11.3.2 
Institutional Review Board or Ethics Committee ........................................................84 
11.4 
Privacy and Confidentiality ...............................................................................................84 
11.5 
Study Results/Publication Policy .......................................................................................85 
12 REFERENCES .......................................................................................................................87 


 
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13 APPENDICES ........................................................................................................................91 
 
 
 


 
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LIST OF TABLES 
Table 1. 
Schedule of Assessments (Double Blind and Open-Label Phases) .......................27 
Table 2. 
Investigational Product Infusion and Pharmacokinetic Sample Collection (Double 
Blind and Open-Label Phases)...............................................................................32 
Table 3. 
Enrollment in Study 1042-SE-2001 Dose Level Cohorts ......................................38 
Table 4. 
Dosing for Participants ≥40 kg (on a mg/hour basis) ............................................52 
Table 5. 
Dosing for Participants <40 kg (on a mg/kg/hour basis) .......................................53 
Table 6. 
Clinical Laboratory Tests .......................................................................................65 
Table 7. 
Volume of Blood to Be Drawn from Each Participant ..........................................67 
Table 8. 
Volume of Blood to Be Drawn from Each Participant (Pediatric Institution 
Sample Volumes) ...................................................................................................67 
 
LIST OF FIGURES 
Figure 1. 
Study Design Flow Chart .......................................................................................40 
 


 
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ABBREVIATIONS 
AE 
adverse event 
AED 
antiepileptic drug 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
twice daily 
BMI 
body mass index 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
CRA 
clinical research associate 
CRO 
contract research organization 
CSE 
convulsive status epilepticus 
DMC 
data monitoring committee 
EC 
Ethics Committee 
ECG 
electrocardiography 
eCRF 
electronic case report form 
EEG 
electroencephalography 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
ESE 
established status epilepticus 
ESETT 
Established Status Epilepticus Treatment Trial 
EU 
European Union 
Euro QOL 
Euro Quality of Life 
FCBP 
Females of childbearing potential 
FDA 
United States Food and Drug Administration 
FOUR Score 
Full Outline of UnResponsiveness Score 
GABA 
gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
GCSE 
generalized convulsive status epilepticus  
GNX 
ganaxolone 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICU 
Intensive Care Unit 
ILAE 
International League Against Epilepsy 
IV 
intravenous 
IM 
intramuscular 
IP 
investigational product 
IRB 
Institutional Review Board 
ITT 
Intent to treat 
LAR 
legal authorized representative 
MRI 
Magnetic Resonance Imaging 
mRS 
Modified Rankin Scale 
NCSE 
non-convulsive status epilepticus 


 
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NLT 
not less than 
PND 
Postnatal Day 
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 
STESS 
Status Epilepticus Severity Scale 
ULN 
upper limit of normal 


 
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STUDY SYNOPSIS 
Protocol number: 1042-SE-3003 
Drug: GGGanaxolone 
Title of the study: A double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of 
intravenous ganaxolone in status epilepticus 
Number of participants (total and for each treatment arm): 
The term “participant” will be used in place of “subject” in accordance with the Food and Drug Administration 
(FDA) glossary, which states these may be used interchangeably. The double-blind phase of the study plans to 
screen approximately 160 patients aged 12 years of age and older with status epilepticus (SE) to randomize 
approximately 124 participants. Participants will be randomized in a 1:1 ratio to receive ganaxolone IV solution 
or placebo added to SE standard of care. Should the interim analysis result in demonstration of efficacy, the study 
will transition to an open-label treatment with all participants receiving ganaxolone IV solution added to SE 
standard of care. 
Investigator(s): Multicenter study 
Site(s) and Region(s):  
Multicenter study to be conducted in the United States, Canada, and Australia at approximately 100 sites 
Study period (planned): August 2020 to December 2024 
Clinical phase: 3 
Objectives: 
Primary: 
• 
To evaluate the efficacy and safety of ganaxolone IV for the treatment of SE after failure of two or more 
antiseizure medications. 
Secondary:  
• 
To assess the time to SE cessation following ganaxolone administration. 
• 
To evaluate the sustained efficacy of ganaxolone IV beyond the 48-hour treatment period as assessed by 
prevention of progression to IV anesthesia for the treatment of SE.  
Exploratory:  
• 
To determine the effect of ganaxolone on healthcare resource utilization. 
• 
To assess the effect of ganaxolone on doses of other antiseizure treatments and changes in seizure burden. 
• 
To evaluate the effect of ganaxolone on quality of life, functional status, and level of responsiveness. 
Rationale: 
Status epilepticus is defined as a prolonged, self-sustaining seizure or recurrent seizures without intervening 
recovery of consciousness.1 The International League Against Epilepsy (ILAE) further defined SE as a condition 
resulting either from the failure of mechanisms responsible for seizure termination or from the initiation of 
mechanisms leading to prolonged seizures.2 SE duration is typically defined as 5 minutes for convulsive (CSE) 
and 10 minutes for nonconvulsive (NCSE).3 The ILAE has proposed definitions that encompass the time at which 
seizures become self-sustaining (t1) and a time when neurologic damage results (t2).2 For generalized convulsive 
status epilepticus (GCSE), these are 5 and 30 minutes, respectively; for NCSE, they are 10 and 60 minutes. 
Status epilepticus is a neurological emergency that requires urgent treatment to stop seizures and avoid 
neurologic sequelae.4 Mortality can range from 3% to 40% depending on etiology, age, SE type, and duration.5,6,7 
Convulsive SE is associated with complications that include cardiac arrhythmias, rhabdomyolysis, pulmonary 
edema, electrolyte and glucose imbalances and body temperature disturbances. Approximately one third of 
patients with refractory status epilepticus (RSE) and super refractory SE (SRSE) will die and one-third will 
recover with chronic neurologic sequelae. 


 
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Benzodiazepines are the agents of choice for first-line treatment of SE, but may cause respiratory depression and 
hypotension, requiring the use of supportive therapies.8 Approximately 35% to 45% of patients fail first-line 
treatment with benzodiazepines and are then considered to have established status epilepticus (ESE). The recently 
published findings from the Established Status Epilepticus Treatment Trial (ESETT), comparing the efficacy and 
safety of three commonly administered second-line IV antiepileptic drug (AEDs; fosphenytoin, levetiracetam and 
valproic acid) found that SE was not controlled in over 50% of ESE patients and that none of the medications 
tested was superior to the others.9 
When a patient fails to respond to a benzodiazepine and the initial second-line IV AED, they are classified as 
having refractory SE (RSE). Refractory SE develops in 31% to 50% of patients with SE and has a mortality of 16 
to 39%.1,10,11 Because SE tends to become more refractory as it progresses, patients who fail second-line IV 
AEDs may require treatment with an IV anesthetic.12,13 Third-line agents such as pentobarbital, midazolam and 
propofol are administered at anesthetic doses to induce coma that is maintained for 24 hours or longer, after 
which the dose of anesthetic agent is reduced to determine whether seizure activity has been aborted. IV 
anesthesia is an independent risk factor for increased morbidity and mortality in SE, with longer duration of 
anesthesia associated with a worse prognosis.14,15,16 
Few drugs are approved for the treatment of SE and there is a need for more evidence-based, efficacious 
therapies. Treatment resistance in SE has been partially attributed to the internalization of post-synaptic γ-
aminobutyric acid (GABA)A receptors and externalization of glutamate receptors.10,12 With the down-regulation 
of GABAA-mediated synaptic inhibition that occurs in SE, antiepileptic treatments relying on enhancement of 
synaptic GABAA neurotransmission become less effective. 
Ganaxolone is a potent positive allosteric modulator of GABAA receptors that binds at a site distinct from that 
responsible for the action of benzodiazepines and barbiturates.17 Unlike benzodiazepines, neuroactive steroids 
such as ganaxolone bind to both synaptic and extrasynaptic GABAA receptors.18 By enhancing GABAA receptor 
function, especially through its action at extrasynaptic GABAA receptors, ganaxolone provides an alternative 
mechanism in the treatment of seizures. Thus, ganaxolone may serve as a novel and effective therapy in the 
management of SE. 
The ganaxolone to be used for this study is a proprietary IV formulation solubilized by Captisol® (betadex 
sulfobutyl ether sodium). Dosing targets plasma concentrations of ganaxolone that mimic those associated with 
anticonvulsant effects in preclinical animal models of SE and that are expected to demonstrate anticonvulsant 
properties in humans. The dose of Captisol® will not exceed 50 g/day (1.25 g/kg/day in participants weighing 
<40 kg) which corresponds to a maximum ganaxolone dose of 833 mg/day (20.825 mg/kg/day in participants 
weighing <40 kg). 
Investigational Product, Dose, and Mode of Administration: 
Once consent/assent has been obtained or deferred where allowed by law, ganaxolone IV solution or placebo, 
referred to as investigational product (IP) throughout this document, will be added to standard of care.  
Participants must have received any two or more of the following agents for treatment of the current episode of 
SE, administered at an adequate dose and for a sufficient duration, in the judgment of the investigator, to 
demonstrate efficacy:  
• 
Benzodiazepines, 
• 
IV Fosphenytoin/phenytoin, 
• 
IV Valproic acid, 
• 
IV Levetiracetam, 
• 
IV Lacosamide,  
• 
IV Brivaracetam, or 
• 
IV Phenobarbital. 
Fosphenytoin and phenytoin will be counted as 1 AED. Levetiracetam and brivaracetam will be counted as 
2 AEDs. 
Investigational product for administration will be provided to the site as individual 500 mL bottles of 1 mg/mL of 
ganaxolone, or placebo. Each bottle contains not less than (NLT) 425 mL of IP. 


 
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Investigational product should be administered through a dedicated peripheral or central IV line or a dedicated 
lumen of a multi-lumen catheter. Note: At any time, the infusion rate of IP may be temporarily decreased or 
permanently stopped for safety reasons. 
The total time of IP administration will be 48 hours (36 hours IP administration and 12 hours of IP taper). The 
investigator will confirm that the participant meets clinical and electroencephalographic (EEG) criteria for SE 
during the 60-minute period prior to IP initiation and will reconfirm that ongoing ictal activity is present within 
30 minutes immediately prior to IP initiation. The dosing of IP will be as follows: 
Participants 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 (time 0 to 24 hours).  
• 
On Day 2, from 24 to 36 hours following IP initiation, the continuous infusion rate of 20 mg/hour can be 
increased up to a maximum rate of 45 mg/hour until the start of the taper at 36 hours. The infusion rate will 
be determined by the investigator to best manage seizure relapse and cannot exceed a rate of 45 mg/hour 
between 24 and 36 hours following IP initiation. 
• 
To taper IP, beginning 36 hours following IP initiation, the infusion rate will be reduced by 33.3% every 
4 hours until the infusion is stopped or until the infusion rate becomes too low to sustain the IV line. 
Note: If, according to the investigator’s clinical judgment, IP taper needs to start sooner than 36 hours after 
initiation, the infusion rate will be decreased by 33.3% of the rate at the beginning of the IP taper every 
4 hours. 
• 
At the time the IP infusion is discontinued, the participant will progress to the follow-up period 
assessments/procedures.  
Participants weighing <40 kg will be dosed on a per-kilogram basis: 
• 
A 0.75 mg/kg bolus dose (over ~3 minutes) will be administered with a continuous infusion at a dose of 
2 mg/kg/hour for 2 hours followed by a continuous infusion dose of 1 mg/kg/hour for 10 hours, and 
0.5 mg/kg/hour for the remaining 12 hours of Day 1 (time 0 to 24 hours). 
• 
On Day 2, 24 to 36 hours following IP initiation, the continuous infusion rate of 0.5 mg/kg/hour can be 
increased up to a maximum of 1.125mg/kg/hour until the start of IP taper at 36 hours. The infusion rate will 
be determined by the investigator to best manage seizure relapse and cannot exceed a rate of 1.125 
mg/kg/hour during hours 24 to 36 of Day 2. 
• 
To taper IP, beginning 36 hours following IP initiation, the infusion rate will be reduced by 33.3% every 
4 hours until the infusion is stopped or until the infusion rate becomes too low to sustain the IV line.  
Note: If, according to the investigator’s clinical judgment, IP taper needs to start sooner than 36 hours after 
initiation, the infusion rate will be decreased by 33.3% of the rate at the beginning of the IP taper every 
4 hours.  
• 
At the time the IP infusion is discontinued, the participant will progress to the follow-up period 
assessments/procedures.  
Investigational product infusion precautions: 
Throughout the study, heart rate and rhythm, blood pressure, and oxygen saturation will be monitored. 
Investigational product may be temporarily or permanently discontinued, if clinically indicated, for treatment of 
persistent hypotension (sustained systolic blood pressure 90 mmHg), cardiac arrhythmia or oxygen desaturation. 
Investigational product may also be terminated for any serious adverse event during infusion that the treating 
physician believes is IP related and necessary for participant safety. Investigational product discontinuation does 
not affect continued participation in the study. All participants should be followed, regardless of early 
discontinuation of IP, until the final study follow-up visit/contact unless consent is withdrawn. 
Medical oversight: 
Participants will require close medical monitoring as defined by local institutional practice guidelines for the 
treatment of patients with the diagnosis of seizures and/or status epilepticus. 
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Telemedicine is an acceptable practice for conducting protocol-driven assessments/procedures as defined by local 
institutional practice guidelines. 
Investigational product discontinuation (one or more may apply): 
• 
Scenarios for stopping IP without a taper may include: 
o Participants who receive IP for less than 2 hours. 
o Investigational product infusion is discontinued or interrupted (e.g., for safety concerns related or 
not related to IP or due to planned medical procedures), and a decision is made not to restart the 
infusion. 
o If at any time during IP administration the participant progresses to an anesthetic with the primary 
intent specifically to treat seizures or achieve burst suppression. 
o For other safety reasons based on the investigator’s clinical judgment. 
Dose adjustments and interruptions: 
Investigational product dose (infusion rate) decreases, and interruptions are discouraged during treatment. 
However, if there is an urgent medical need (e.g., severe hypotension, severe sedation) or standard of care 
requires a procedure for which the infusion rate would need to be temporarily decreased or interrupted (e.g., 
MRI) it should be kept as short as possible and should not exceed 2 hours. If the interruption is >2 hours, the 
Medical Monitor should be consulted before restarting the infusion.  
Note:  
• 
After a dose (infusion rate) decrease or interruption, the investigator’s clinical judgment of risk/benefit will 
determine IP administration or discontinuation.  
• 
Investigational product discontinuation does not affect continued participation in the study. All participants 
should be followed, regardless of early discontinuation of IP, until they reach the final study follow-up 
visit/contact unless consent is withdrawn. 
• 
In cases when IP discontinuation is being considered (e.g., severe sedation), when possible, the Medical 
Monitor should be contacted prior to infusion termination.  
• 
If the decision is made to restart IP, the infusion should be restarted at the rate matching the rate at the 
corresponding nominal time, counted from the start of the IP infusion on Day 1. Investigational product 
bolus or “catch-up” dose to deliver the IP that was missed during the interruption should not be administered.  
Dose (infusion rate) increases above those specified in the protocol are not allowed at any time during infusion. 
This is to ensure daily Captisol® and ganaxolone limits are maintained at ≤50 g/day (1.25 g/kg/day in participants 
weighing <40 kg) and ≤833 mg/day (20.825 mg/kg/day in participants weighing <40 kg), respectively. 
Methodology: 
This is a double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of ganaxolone IV 
solution in SE, with the option to transition the study to an open-label phase to obtain additional safety data. 
Screening, duration of the treatment, and follow-up periods, as well as the study schedule, remain the same for 
participants enrolled under either the double-blind or open-label phases.  
As previously described, IP will be added to standard of care after failure of two or more antiseizure treatments 
(benzodiazepine and one IV AED or two IV AEDs).  
Potential participants may be identified in the emergency department, ICU, or other units in the hospital, and will 
be consented/assented and then screened for inclusion/exclusion criteria prior to being randomized to start IP 
treatment. Investigational product will be administered as a 3-minute bolus that will be started with a continuous 
IV infusion of IP lasting for 36 hours and followed by a 12- hour taper. After the IP has been discontinued, the 
follow-up period assessments/procedures will be collected every 24 hours through 120 hours (or until hospital 
discharge) and at the time of hospital discharge followed by weekly follow-up visits/contacts at Week 1, 2, 3 and 
4.  
Weeks 1, 2, 3, and 4 visits can be conducted as inpatient visits, if the participant is still in the hospital or as a 
telephone contact if the participant has been discharged. Attempts should be made to have discharged participants 
return for one of these visits to be in person. In total, each participant will be followed for approximately 4 weeks 
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An interim analysis will be conducted when approximately two-thirds of the ITT population have completed 
72 hours of efficacy assessments (approximately 41 participants per arm). Enrollment in the double-blind phase 
will continue until the DMC provides a recommendation regarding study continuation. Based upon the interim 
analysis results, recommendation from the DMC, and agreement from the Sponsor, the double-blind study will 
either continue without modification or will transition to enrollment in an open-label phase. All participants 
enrolled subsequently will receive open--label ganaxolone IV solution added to SE standard of care. 
Approximately 60 to 100 study participants will receive ganaxolone IV in the double-blind and open-label phases 
combined.  
Screening 
Procedures specific to this protocol will not be performed until written informed consent/assent from the 
prospective participant/participant’s parent/guardian/legally authorized representative (LAR) has been 
appropriately obtained according to institution policy. As many of the participants will not be able to provide 
consent/assent, a parent/guardian/LAR may provide consent on behalf of the participant. Where allowed by law, 
if the patient lacks the capacity to make informed decisions regarding his/her medical treatment options, the 
treating clinician may follow their deferred consenting practices. As soon as the participant is able, according to 
institution guidelines, consent/assent will be obtained. Consent/assent for participants who are known to be at risk 
for SE may be obtained prior to the occurrence of SE.  
Standard of care assessments conducted prior to obtaining informed consent, that the investigator judges to be 
clinically relevant to the participant’s current condition, can be utilized in the study and do not need to be 
repeated. For medically unstable participants, screening activities (e.g., labs or vital signs) should be collected as 
close to IP initiation as possible. 
Treatment and Follow-up 
Investigational Product Dosing 
Approximately 160 participants will be enrolled in the double-blind phase of the study. For the double-blind 
phase, participants will be randomized (1:1) to receive either ganaxolone IV solution or placebo added to SE 
standard of care. In the open-label phase, all enrolled participants will receive ganaxolone IV solution added to 
SE standard of care. Investigational product will be given as a bolus plus continuous infusion. Following IP 
initiation, the standard duration of treatment is 2 days (48 hours) which includes a 12-hour taper.  
Safety and Assessments 
Investigational product will be given in addition to standard of care for SE and other medical or surgical 
interventions deemed appropriate by the investigator. Safety and tolerability will be monitored including but not 
limited to the following: 
1. Physical examination should be completed: 
a. 
Predose (screening) or, if unable to perform predose, conduct within 2 hours following IP initiation, 
and at 36 hours, if clinically indicated, following IP initiation, 
b. At the time of IP discontinuation (+/- 1 hour), either at the end of the taper or if the IP 
administration is stopped without a taper,  
c. 
24 hours (+/- 1 hour) following IP discontinuation, and 
d. At the time of hospital discharge. 
e. 
For participants who terminate early from the study, at the time of early termination (whenever 
possible).  
f. 
At any other time based on the clinical judgment of the investigator. 
2. Status Epilepticus Severity Score (STESS) should be collected predose (screening). 
3. Vital signs should be collected: 
a. 
Predose (screening), 60 minutes (+/- 15 min), 2 (+/- 15 min), 6, 10, 24, and 36 hours (+/- 2 hour) 
following IP initiation,  
b. At the time of IP discontinuation (+/- 1 hour), either at the end of the taper or if the IP 
administration is stopped without a taper,  
c. 
24 hours (+/- 2 hour) following IP discontinuation, and 
d. At the time of hospital discharge. 


 
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e. 
For participants who terminate early from the study, at the time of early termination (whenever 
possible). 
f. 
At any other time based on the clinical judgment of the investigator. 
4. Weight and height should be collected predose (screening) for calculation of the BMI inclusion criterion, 
if feasible. If unable to collect predose, collect prior to the end of the first 24 hours of the follow-up 
period. 
5. Richmond Agitation and Sedation Scale (RASS) and the Full Outline of UnResponsiveness (FOUR) 
Score Scale should be collected: 
a. 
Predose (screening), 
b. 60 minutes (+/- 15 min), 2, 6, 10 (+/- 30 min), 24 and 36 hours (+/- 1 hour) following IP initiation, 
c. 
At the time of IP discontinuation (+/- 1 hour), either at the end of the taper or if the IP 
administration is stopped without a taper, 
d. 24 (+/- 1 hour), 48, 72, 96, and 120 hours (+/- 2 hours) following IP discontinuation, and 
e. 
At the time of hospital discharge. 
f. 
At the weekly follow-up visits (Week 1, 2, 3, or 4) for hospitalized participants and for participants 
who have been discharged (whenever possible). 
g. For participants who terminate early from the study, at the time of early termination (whenever 
possible).  
6. Electrocardiogram (ECG), the participant should have a safety 12 lead ECG: 
a. 
Predose (screening), 2 (+/- 30 min) following IP initiation,  
b. At the time of IP discontinuation (+/- 1 hour), either at the end of the taper or if the IP 
administration is stopped without a taper, 
c. 
24 hours (+/- 1 hour) following IP discontinuation, and 
d. At the time of hospital discharge. 
e. 
For participants who terminate early from the study, at the time of early termination (whenever 
possible). 
f. 
At any other time based on the clinical judgment of the investigator. 
7. Cardiodynamic 12 lead ECG monitoring: Select sites will participate in a sub study using a continuous 
12 lead ECG recorder which should begin approximately 60 minutes prior to the initiation of IP and 
continue for 36 hours following IP initiation. 
8. Clinical laboratory measures, hematology, serum chemistry (including creatinine, blood urea nitrogen 
[BUN], estimated glomerular filtration rate [eGFR] calculation (if available), creatinine clearance 
calculation (if available), and concomitant AED levels (fosphenytoin/phenytoin, valproic acid, 
levetiracetam, lacosamide, phenobarbital, or brivaracetam, if collected per standard of care), and  
Urinalysis (including urine protein and microscopic, if any abnormal value is observed on the urine 
dipstick test), should be collected: 
a. 
Predose (screening), if unable to collect predose, collect within 2 hours following IP initiation,  
b. At the time of IP discontinuation (+/- 1 hour); either at the end of the taper or if the IP 
administration is stopped without a taper,  
c. 
24 hours (+/- 1 hour) following IP discontinuation, and  
d. At the time of hospital discharge. 
e. 
At the weekly follow-up visits (Week 1, 2, 3, or 4) for hospitalized participants and for participants 
who have been discharged (whenever possible). 
f. 
For participants who terminate early from the study, at the time of early termination (whenever 
possible).  
g. In the event of an SAE. 
h. At any other time based on the clinical judgment of the investigator. 
Urine chemistry samples for N-acetyl-β-D-glucosaminidase [NAG], β2-microglobulin, and creatinine 
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a. 
Predose (screening), if unable to collect predose, collect within 2 hours following IP initiation, 
b. 24 hours (+/- 1 hour) following IP discontinuation, and 
c. 
At the time of hospital discharge. 
d. At the weekly follow-up visits (Week 1, 2, 3, or 4) for hospitalized participants and for participants 
who have been discharged (whenever possible). 
e. 
For participants who terminate early from the study, at the time of early termination (whenever 
possible). 
Urine samples will be stored frozen unless otherwise dictated or revised in the Biospecimen Manual. 
Coagulation (including fibrinogen, activated partial prothrombin time [APTT], prothrombin time [PT] 
and international normalized ratio [INR]) samples should be collected: 
a. 
Predose (screening), if unable to collect predose, collect within 2 hours following IP initiation,  
b. 24 hours (+/- 1 hour) following IP discontinuation, and  
c. 
At the time of hospital discharge. 
d. For participants who terminate early from the study, at the time of early termination (whenever 
possible). 
e. 
At any other time based on the clinical judgment of the investigator. 
9. Drugs of abuse testing should be collected predose (screening) per institution standard of care. Alcohol 
testing should be collected if medically indicated. Samples can be urine or serum. If unable to collect 
predose, collect as soon as possible following IP initiation. Enrollment is not contingent upon results. 
However, if a participant has a positive test result, it will be at the investigator’s discretion to weigh the 
risks versus benefits for enrollment or continued participation. 
10. Pregnancy test for females of childbearing potential, should be collected predose (screening). Samples 
can be urine or serum. If unable to collect predose, collect as soon as possible following IP initiation. 
Enrollment is not contingent upon results. However, if a participant has a positive test result, it will be at 
the investigator’s discretion to weigh the risks versus benefits for enrollment or continued participation. 
If the institution requires the pregnancy test results to be obtained prior to IP initiation, the institution’s 
guidelines will be followed.  
11.  Electroencephalogram is required for confirmation of CSE and NCSE diagnosis. Ideally, continuous 
EEG monitoring should start at least 60 minutes before IP initiation and continue through the end of the 
first 24 hours of the follow-up period.  
Sites will be offered the use of a rapid EEG device to assist with screening of participants with NCSE. It 
is preferred that a conventional EEG is used for the purposes of confirming inclusion criterion #3 and 
EEG monitoring during IP administration. In situations when a conventional EEG is not immediately 
available, the rapid EEG may be used to confirm inclusion criterion #3. Since the rapid EEG has a 
limited battery life, it should be switched to a conventional EEG within several hours but not earlier than 
90 minutes after IP initiation to allow uninterrupted collection of EEG for the 30-minute SE cessation 
co-primary endpoint. It will be at the investigator’s discretion if the use of the rapid EEG will benefit 
their site. The device should be used according to institution standard practices.  
12. Blood sampling (venous or arterial) for pharmacokinetic (PK) analysis of ganaxolone and Captisol® will 
be collected at the following times:  
Required collections:  
a. 
After the start of the IP infusion: 60 minutes (+/- 5 min), then 2, 6 (+/- 5 min), 10, 24 and 
36 hours (+/- 2 hour) following IP initiation, 
b. At the time of IP discontinuation (+/- 1 hour), either at the end of the taper or if the IP 
administration is stopped without a taper (e.g., when the participant progresses to IV anesthesia 
for seizure/SE treatment), and  
c. 
24 hours (+/- 1 hour) following IP discontinuation. 
Variable PK collection times based on participant response: 
Between IP initiation and at the end of the first 24 hours of the follow-up period, where possible, collect 
a PK sample: 
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Pharmacokinetic samples should be collected from the contralateral peripheral access or the arterial line 
and avoid collecting samples downstream of the IP infusion. The location of IP access and location of 
PK sample collection should be documented in the participant’s source. If the PK sample cannot be 
collected due to poor venous or arterial access and the IP infusion site is the only viable option, the 
sample should not be collected and the reason for non-collection documented in the participant’s source. 
Pharmacokinetic samples will be stored frozen as per the Biospecimen Manual.  
13. Blood gas samples, arterial or venous, if collected to manage the participant’s care from the time of SE 
diagnosis through the end of the first 24 hours of the follow-up period, the electronic case report form 
(eCRF) should be completed. If samples are not collected, a sample is not required.  
If a decision is made to intubate the participant between IP initiation through the end of the first 24 hours 
of the follow-up period, 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. 
14. Clinical Global Impression of Severity and Improvement (CGI-S and CGI-I, respectively) 
CGI-S should be collected: 
a. 
Predose (screening)  
CGI-I should be collected:  
a. 
10 and 24 hours (+/- 1 hour) following IP initiation, 
b. The time of IP discontinuation (+/- 1 hour), either at the end of the taper or if the IP 
administration is stopped without a taper,  
c. 
24 (+/- 1 hour), 48, 72, 96, and 120 hours (+/- 2 hours) following IP discontinuation, and 
d. At the time of hospital discharge. 
e. 
Week 1, 2, 3, and 4 follow-up visits (in person or via telephone contact).  
f. 
For participants who terminate early from the study, collect at the time of early termination 
(whenever possible).  
15. EuroQoL (EQ-5D-5L) questionnaire should be collected: 
a. 
120 hours (+/- 2 hour) following IP discontinuation and 
b. At the time of hospital discharge. 
c. 
Week 2, 3, and 4 follow-up visits (in person or via telephone contact). 
d. For participants who terminate early from the study, collect at the time of early termination 
(whenever possible). 
16. Modified Rankin Scale (mRS) should be collected:  
a. 
24 (+/- 1 hour), 48, 72, 96, and 120 hours (+/- 2 hours) following IP discontinuation, and 
b. At the time of hospital discharge. 
c. 
Week 2, 3 and 4 follow-up visits (in person or via telephone contact). 
d. For participants who terminate from the study, collect at the time of early termination (whenever 
possible). 
17. Etiology of Status Epilepticus Questionnaire should be collected predose (screening). 
18. Seizure Description Questionnaire should be collected predose (screening) and as close as possible to IP 
initiation. 
19. Status Epilepticus Cessation Questionnaire should be collected as close as possible to 24 and 72 hours 
following IP initiation.  
20. Super Refractory Status Epilepticus Questionnaire should be collected as close as possible to the 
diagnosis of SRSE and no later than the final study follow-up visit/contact. 
21. Adverse events (AEs) and Concomitant medications: AEs will be collected from the time of IP initiation 
until the final study follow-up visit/contact via non-direct questioning. Concomitant medications will be 
collected during the same time period.  
a. 
All adverse events and associated concomitant medications will be collected through the final study 
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b. For participants who terminate early from the study, prior to discontinuation, as much information 
as is available should be recorded for AEs/SAEs and their associated concomitant medications, 
especially those that may have led to the early termination.  
c. 
AEDs administered within 14 days of IP initiation will be recorded along with the reason for 
administration.  
Instructions for collecting benzodiazepines, AEDs, anesthesia, and vasopressor medications prior to and 
post IP initiation is referenced in Sections 5.1 and 5.2. Some concomitant medications only require 
eCRF entries to support the highest dose administered, please reference the eCRF Completion 
Guidelines for details. 
22. Healthcare Utilization Questionnaires include the Hospitalization Questionnaire and the Positive Pressure 
Ventilation (PPV) and Intubation Questionnaire. The Hospitalization Questionnaire should be collected 
at hospital discharge or at final study visit/contact.  
The need for non-invasive or invasive ventilatory support within 24 hours prior to IP initiation and 
following IP initiation and within 48 hours following IP discontinuation should be collected as close as 
possible to the event.  
Study follow-up and discontinuation: 
Participants who terminate early from the study, e.g., due to withdrawal of consent, should have early termination 
procedures completed when early termination is being considered, wherever possible. 
Participants who discontinue IP with or without a taper (e.g., were administered IP for less than 2 hours, progress 
to anesthesia for seizure suppression or discontinue IP due to safety or any other reason except due to withdrawal 
of consent) will continue in the study. The follow-up period assessments/procedures will be collected every 
24 hours through 120 hours (or until hospital discharge) and at the time of hospital discharge, followed by weekly 
follow-up visits/contacts at Week 1, 2, 3, and 4. 
All participants who discontinue IP, except those who are terminated early from the study, will have the follow-
up period assessments/procedures, and the follow-up visits/contacts at Week 1, 2, 3, and 4. Weeks 1, 2, 3 and 4 
visits can be conducted as an inpatient visit, if the participant is still in the hospital or as a telephone contact, if 
the participant has been discharged. Attempts should be made to have discharged participants return for one of 
these visits to be in person. 
During these visits/contacts, the site will follow-up on all SAEs and AEs, and medications administered. Each 
participant will be followed for approximately 4 weeks. 
During the study, it is expected that the total blood volume drawn from pediatric participants for all safety and 
pharmacokinetic sampling will be approximately 36 mL and will not exceed 40 mL of blood. The total blood 
drawn from adult participants will be approximately 140.3 mL and will not exceed 190.4 mL. 
Inclusion and Exclusion Criteria:  
Inclusion Criteria:  
1. Participant, participant’s parent, guardian, or LAR must provide signed informed consent/assent, 
and once capable (per institutional guidelines), there must be documentation of consent/assent by 
the participant demonstrating they are willing and aware of the investigational nature of the study 
and related procedures. Where allowed by law, if the patient lacks the capacity to make informed 
decisions regarding his/her medical treatment options, the treating clinician may follow their 
deferred consenting practices. The clinician will make the final decision based on the best 
interests of the patient. 
2. 
Male or females 12 years of age and older at the time of the first dose of IP. 
3. 
SE meeting the following criteria:  
a. 
A diagnosis of SE with or without prominent motor features based on clinical and EEG findings 
according to the investigator’s judgment, based on the following: 
i. 
For SE with prominent motor features: Clinical and EEG seizure activity indicative of 
convulsive, myoclonic or focal motor SE 
ii. For SE without prominent motor features (nonconvulsive SE): Appropriate clinical features and 
an EEG indicative of NCSE (see modified Salzburg criteria19 in Appendix 3). 
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• Approximately 6 minutes of cumulative seizure activity over a 30-minute period within the 
hour before IP initiation, AND 
• Seizure activity during the 30 minutes immediately prior to IP initiation. 
b. The treating clinician(s) anticipate that IV anesthesia is likely to be the next treatment for SE that 
persists following initiation of IP. 
4. Participants must have received any two or more of the following agents for treatment of the 
current episode of SE administered at an adequate dose and for a sufficient duration, in the 
judgment of the investigator, to demonstrate efficacy (guidelines for adequate doses are provided 
in Appendix 2): 
o 
Benzodiazepines, 
o 
IV Fosphenytoin/phenytoin, 
o 
IV Valproic acid, 
o 
IV Levetiracetam, 
o 
IV Lacosamide, 
o 
IV Brivaracetam, or 
o 
IV Phenobarbital 
5 
BMI <40 or, if BMI is not able to be calculated at screening, participant is assessed by investigator as 
not morbidly obese. 
Exclusion Criteria:  
1. Life expectancy of less than 24 hours. 
2. Anoxic brain injury or an uncorrected, rapidly reversable metabolic condition as the primary cause of SE 
(e.g., hypoglycemia <50 mg/dL or hyperglycemia >400 mg/dL). 
3. Participants who have received high-dose IV anesthetics (e.g., midazolam, propofol, thiopental, or 
pentobarbital) during the current episode of SE for more than 18 hours, or who continue to have clinical 
or electrographic evidence of persistent seizures while receiving high-dose IV anesthetics.  
4. Clinical condition or advance directive that would NOT permit use of IV anesthesia. 
5. Participants known or suspected to be pregnant. 
6. Participants with known allergy or sensitivity to progesterone or allopregnanolone 
medications/supplements. 
7. Receiving a concomitant IV product containing Captisol® (marketed products listed in Appendix 4). 
8. Known or suspected hepatic insufficiency or hepatic failure leading to impaired synthetic liver function.  
9. Known or suspected stage 3B (moderate to severe; eGFR 44-30 mL/min/1.73m2), stage 4 (severe; 
eGFR 29-15 mL/min/1.73m2), or stage 5 (kidney failure; eGFR <15 mL/min/1.73m2 or dialysis) 
kidney disease. 
10. Use of an investigational product for which less than 30 days or 5 half-lives have elapsed from the final 
product administration. Participation in a non-interventional clinical study does not exclude eligibility. 
11. Known or suspected history or evidence of a medical condition that, in the investigator’s judgment, 
would expose participant to an undue risk of a significant adverse event or would interfere with 
assessments of safety or efficacy during the study. 
Maximum Duration of Participant Involvement in the Study: 
• 
The screening period is from the time consent/assent is obtained (or deferred, if allowed by law) to 
immediately prior to IP initiation (excluding pre-consent). However, assessments collected prior to this 
timeframe that the investigator judges to be clinically relevant to the participant’s current state can be 
utilized in the study and do not need to be repeated. For medically unstable participants, screening 
activities (e.g., labs or vital signs) should be collected as close to IP initiation as possible. 
• 
The planned duration of treatment is 2 days which includes a 12-hour taper.  


 
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• 
The planned duration for the follow-up period following IP discontinuation with or without a taper is 
approximately 4 weeks. The follow-up period study assessments/procedures will be collected every 24 
hours through 120 hours (or until hospital discharge) and at hospital discharge with weekly 
visits/contacts at Week 1, 2, 3, and 4. Weeks 1,2, 3, and 4 visits can be conducted as inpatient visits, if 
the participant is still in the hospital, or as telephone visits, if the participant has been discharged. 
Attempts should be made to have discharged participants return for one of these visits in person. 
Endpoints: 
Primary Endpoints:  
• 
Proportion of participants with SE cessation within 30 minutes of IP initiation without medications for 
the acute treatment of SE* 
• 
Proportion of participants with no progression to IV anesthesia for 36 hours following IP initiation 
SE cessation will be assessed by the investigator based on clinical and EEG features. Training will be provided to 
guide and help standardize decisions across clinical sites. In addition, a central reader blinded to treatment 
assignment will review EEG recordings retrospectively and corroborate the accuracy of interpretation. 
*Medications for the acute treatment of SE are defined as AEDs administered to abort ongoing SE or prevent 
imminent recurrence of SE based on clinical or EEG evidence. This definition excludes maintenance doses of 
AEDs or medications with anticonvulsant properties used for other reasons, such as procedural sedation. 
Key Secondary Endpoints: 
• 
Time to SE cessation following IP initiation  
• 
Proportion of participants with no progression to IV anesthesia for 72 hours following IP initiation 
Other Secondary Endpoints: 
• 
Proportion of participants with any escalation of treatment in the first 24 hours following IP initiation, 
i.e., any medication other than IP administered for the acute treatment of SE in the first 24 hours 
• 
Time to treatment escalation following IP initiation (any other medication used for acute treatment of 
SE) 
• 
Time to initiation of anesthesia for SE treatment through the final study follow-up visit/contact 
• 
Proportion of participants who develop SRSE through the final study follow-up visit/contact 
• 
Seizure burden through 72 hours following IP initiation 
• 
Level of responsiveness as assessed by the FOUR Score Scale 
• 
Level of sedation/agitation as assessed by the RASS  
• 
Clinician Global Impression-Improvement (CGI-I)  
• 
Level of functioning as assessed by the mRS  
• 
Level of functioning as assessed by the EuroQoL (EQ-5D-5L) 
• 
Proportion of participants with mRS >3 at the time of hospital discharge 
• 
Proportion of participants whose treatment does not progress to IV anesthesia during the follow-up 
period  
 
Healthcare Utilization Endpoints: 
• 
Time on positive pressure ventilation after IP initiation  
• 
Proportion of participants requiring positive pressure ventilation initiated during IP infusion 
• 
Length of stay in the intensive care unit and in-hospital after IP initiation 
• 
Discharge destination (location where the participant resides at the last follow-up visit assessment) 
• 
Proportion of participants requiring artificial ventilation 
 
Open-Label Phase Endpoints 
If the study transitions to an open-label phase, all endpoint assessments as described for the double-blind phase 
will be summarized using descriptive statistics and no formal hypothesis testing will be performed.  
 
Safety Endpoints: 
Safety and tolerability will be assessed by physical examinations, clinical laboratory tests, ECGs, vital signs, use 
of concomitant medications, and occurrence of AEs 


 
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Statistical Methods: 
The statistical analysis plan (SAP) will provide the complete details for the analysis and reporting of the data 
from the study.  
 
Analysis of Primary Endpoint (Double-Blind Phase) 
The primary efficacy objective of this study is to assess the efficacy of ganaxolone plus standard of care versus 
placebo plus standard of care in producing rapid and durable SE cessation without the need for treatment 
escalation to IV anesthesia for at least 36 hours following IP initiation. 
Since the primary objective is a composite objective, in order to establish effectiveness of ganaxolone, the 
superiority of ganaxolone versus placebo added to standard of care would need to be established for the following 
co-primary endpoints: 
1. Proportion of participants with SE cessation as determined by the investigator within 30 minutes of IP 
initiation without medications for the acute treatment of SE 
2. Proportion of participants with no progression to IV anesthesia for 36 hours following IP initiation 
Analysis of the response rates observed for each co-primary efficacy endpoint will be conducted using logistic 
regression methods. The model will include terms for treatment group and baseline STESS as a covariate. The 
analysis will be based on the intent to treat (ITT) population. Model-based point estimates (i.e., odds ratio), 95% 
confidence intervals and p-values will be reported. In addition, the point estimate of difference of the proportions 
of participants achieving either and both co-primary endpoints between two treatment arms will be provided. The 
95% confidence interval will be provided using Clopper-Pearson method. 
 
Analysis of Key Secondary Endpoints (Double-Blind Phase) 
The following key secondary endpoints will be analyzed: 
1. Time to SE cessation following IP initiation 
2. Proportion of participants with no progression to IV anesthesia for 72 hours following IP initiation 
If the primary endpoints are statistically significant, the analysis of key secondary efficacy endpoints will be 
performed sequentially in the order listed above.  
The time to SE cessation will be analyzed using the Kaplan-Meier method.20 The comparison of the survival 
curves between treatment groups will be conducted by a log-rank test. The second key secondary endpoint will be 
analyzed using the same statistical model as pre-specified for the co-primary endpoints.  
Further details will be provided in the SAP. 
 
Data Monitoring Committee 
Emerging study data will be reviewed on a regular basis by an independent Data Monitoring Committee (DMC). 
The mission of the DMC is to safeguard the interests of study participants and to ensure the integrity and 
credibility of the trial. To enable the DMC to achieve its mission, it will have ongoing access to efficacy and 
safety data and information regarding quality of trial conduct and will ensure that the confidentiality of these data 
is protected. A DMC charter will provide the principles and guidelines for the DMC process. 
 
Sample Size 
The planned sample size for the study was 124 participants randomized in a 1:1 ratio. This sample size assumed 
at least a 75% response rate with ganaxolone treatment for each of the co-primary endpoints and no more than a 
45% response rate with placebo. With 62 participants randomized to each treatment arm, there would be at least 
90% power for each co-primary endpoint to achieve statistical significance at a 2-sided 5% level of significance. 


 
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Interim Analysis 
An interim analysis was planned when two-thirds of the ITT population have completed 72 hours of efficacy 
assessments on the co-primary and key secondary endpoints (approximately 41 participants per arm). The overall 
type I error rate (i.e., alpha=0.05, 2-sided) will be controlled using a power family alpha spending function, with a 
2-sided nominal alpha level of 0.0293 at the interim analysis. The interim analysis will be performed by an 
independent statistician who is not involved in study operation or study conduct. 
The interim analysis was performed by an independent statistician who was not involved in study operation or 
study conduct and was based on 83 participants who had completed the primary and key secondary efficacy 
assessments. The DMC recommended may continue without modification. 
Further details will be provided in the SAP. 


 
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STUDY SCHEDULE(S) 
Table 1. 
Schedule of Assessments (Double-Blind and Open-Label Phases) 
Periods/Day/ 
Duration 
Screening 
a 
Day -1 to 
Day 1 
Predose 
through 
screening 
Dosing 
Day 1 
IP initiation 
0 through 24 hours 
following IP initiation 
Dosing 
Day 2 
24 hours 
through 36 
hours 
following IP 
initiation 
Taper 
Day 2 
(12 hours) 
Starts at 36 hours 
following IP 
initiation 
IP 
Discontinuation 
IP Discontinuation 
Follow-up b 
Early 
Termination 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 – 14 
98 
Timepoint 
 
Minutes (m) /Hours (h) following IP initiation 
  
With or without 
Taper  
Hours following IP 
Discontinuation 
 
 
Hospital 
Discharge 
Weekly 
follow-
up 
(Week 1, 
2, 3, & 4) 
ET 
-0 
60 
m 
2 
h 
6 
h 
10 
h 
24 
h 
36 
h 
48 
h 
Collected prior 
to or as close to 
IP 
discontinuation 
as possible 
24 
48  
72 
96 
120 
 
6 ± 3 
14 ± 3, 
21 ± 3, 
and 28 ± 
3 days 
following 
IP discon 
 
Informed consent/assent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography and medical, 
including seizures or SE 
etiology and medication  
historyc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STESS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signse  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RASSf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FOUR Scoref 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 12 lead ECGg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiodynamic 12 lead 
ECG monitoring (sub study 
only)h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biochemistry, hematology, 
and AEDsi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table 1. 
Schedule of Assessments (Double-Blind and Open-Label Phases) 
Periods/Day/ 
Duration 
Screening 
a 
Day -1 to 
Day 1 
Predose 
through 
screening 
Dosing 
Day 1 
IP initiation 
0 through 24 hours 
following IP initiation 
Dosing 
Day 2 
24 hours 
through 36 
hours 
following IP 
initiation 
Taper 
Day 2 
(12 hours) 
Starts at 36 hours 
following IP 
initiation 
IP 
Discontinuation 
IP Discontinuation 
Follow-up b 
Early 
Termination 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 – 14 
98 
Timepoint 
 
Minutes (m) /Hours (h) following IP initiation 
  
With or without 
Taper  
Hours following IP 
Discontinuation 
 
 
Hospital 
Discharge 
Weekly 
follow-
up 
(Week 1, 
2, 3, & 4) 
ET 
-0 
60 
m 
2 
h 
6 
h 
10 
h 
24 
h 
36 
h 
48 
h 
Collected prior 
to or as close to 
IP 
discontinuation 
as possible 
24 
48  
72 
96 
120 
 
6 ± 3 
14 ± 3, 
21 ± 3, 
and 28 ± 
3 days 
following 
IP discon 
 
Urine chemistry (N-acetyl-
β-D-glucosaminidase 
(NAG), β2-microglobulin, 
and Creatinine)k 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulationk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Routine Urinalysisi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drugs of abuse, including 
alcoholl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (FCBP only)l 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EEGm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Gasn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGI-S 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGI-Io 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Seizure Description 
Questionnaire-predosep 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Status Epilepticus Cessation 
Questionnaireq 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Super Refractory Status 
Epilepticus Questionnaire 
(SRSE)r 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EuroQol (EQ-5D-5L)s 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
mRS  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEsu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table 1. 
Schedule of Assessments (Double-Blind and Open-Label Phases) 
Periods/Day/ 
Duration 
Screening 
a 
Day -1 to 
Day 1 
Predose 
through 
screening 
Dosing 
Day 1 
IP initiation 
0 through 24 hours 
following IP initiation 
Dosing 
Day 2 
24 hours 
through 36 
hours 
following IP 
initiation 
Taper 
Day 2 
(12 hours) 
Starts at 36 hours 
following IP 
initiation 
IP 
Discontinuation 
IP Discontinuation 
Follow-up b 
Early 
Termination 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 – 14 
98 
Timepoint 
 
Minutes (m) /Hours (h) following IP initiation 
  
With or without 
Taper  
Hours following IP 
Discontinuation 
 
 
Hospital 
Discharge 
Weekly 
follow-
up 
(Week 1, 
2, 3, & 4) 
ET 
-0 
60 
m 
2 
h 
6 
h 
10 
h 
24 
h 
36 
h 
48 
h 
Collected prior 
to or as close to 
IP 
discontinuation 
as possible 
24 
48  
72 
96 
120 
 
6 ± 3 
14 ± 3, 
21 ± 3, 
and 28 ± 
3 days 
following 
IP discon 
 
Concomitant medicationu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Healthcare Utilization 
Questionnairesv 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Discon = discontinuation; ET = Early Termination; ECG = electrocardiogram; IP = investigational product;; FCBP = females of childbearing potential; EEG = electroencephalograms; AE = adverse event; SAE = 
serious AE; STESS = Status Epilepticus Severity Score; RASS = Richmond Agitation and Sedation Scale; FOUR Score = Full Outline of UnResponsiveness Score; AED = antiepileptic drug; CGI-S = Clinical 
Global Impression of Severity; CGI-I = Clinical Global Impression of Improvement; mRS = modified Rankin Scale  
a. 
The screening period is from the time participant/participant’s parent/guardian/LAR consent is obtained (or deferred, if allowed by law) to immediately prior to IP initiation However, assessments collected 
prior to this timeframe that the investigator judges to be clinically relevant to the participant’s current state can be utilized in the study and do not need to be repeated. For medically unstable participants, 
screening activities (e.g., labs or vital signs) should be collected as close to IP initiation as possible. 
b. The planned duration for the follow-up period after IP is discontinued is approximately 4 weeks. Study assessments/procedures will be collected every 24 hours through 120 hours (or until hospital discharge) 
and at the time of hospital discharge followed by weekly follow-up visits at Week 1, 2, 3 and 4. Weeks 1, 2, 3 and 4 visits can be conducted as an inpatient visit, if the participant is still in the hospital, or as a 
telephone contact, if the participant has been discharged. Attempts should be made to have discharged participants return for one of these visits to be in person for clinical laboratory sample collection and 
RASS & FOUR Score assessments which can only be performed in person. 
c. 
Demography, medical history, including seizures or SE etiology, and medication history will be collected prior to IP initiation but can be collected whenever feasible before the end of the taper.  
d. Physical exam should be obtained from the participant’s chart or completed predose (screening) or, if not available, collect within 2 hours following IP initiation, and at 36 hours, if clinically indicated, 
following IP initiation. Collect at the time of IP discontinuation (+/- 1 hour), either at the end of the taper or if the IP administration is stopped without a taper and 24 hours (+/- 1 hour) following IP 
discontinuation and at the time of hospital discharge. For participants who terminate early from the study, collect at the time of early termination (whenever possible). The investigator may conduct at any 
other time based on clinical judgment. 
e. 
Vital signs including blood pressure, pulse, respiratory rate, temperature, and oxygen saturation should be collected predose (screening), 60 minutes (+/- 15 min), 2 (+/- 15 min), 6, 10, 24, and 36 hours 
(+/- 2 hour) following IP initiation. Collect at the time of IP discontinuation (+/- 1 hour), either at the end of the taper or if the IP administration is stopped without a taper and 24 hours (+/- 2 hours) following 
IP discontinuation, and at the time of hospital discharge. For participants who terminate early from the study, collect at the time of early termination (whenever possible). The investigator may collect at any 
other time based on clinical judgment. Weight and height should be collected predose (screening) for calculation of BMI inclusion criterion, if feasible. If not collected predose (screening), collect prior to the 
end of the first 24 hours of the follow-up period. 
f. 
RASS and FOUR score scales should be collected predose (screening),60 minutes (+/- 15-min), 2, 6, 10 (+/- 30 minutes), 24 and 36 hours (+/- 1 hour) following IP initiation. Collect at the time of IP 
discontinuation (+/- 1 hour), either at the end of the taper or if the IP administration is stopped without a taper. Collect 24 (+/- 1 hour), 48, 72, 96, and 120 hours (+/- 2 hours) following IP discontinuation and 
at the time of hospital discharge. Collect at the weekly follow-up visits (Week 1, 2, 3, or 4) for hospitalized participants and for participants who have been discharged (whenever possible). For participants 
who terminate early from the study (whenever possible), collect at the time of early termination. 
g. ECG should be collected predose (screening) and 2 hours (+/- 30 min) following IP initiation. Collect at the time of IP discontinuation (+/- 1 hour), either at the end of the taper or if the IP administration is 
stopped without a taper and 24 hours (+/- 1 hour) following IP discontinuation and at the time of hospital discharge. For participants who terminate early from the study, collect at the time of early termination 
(whenever possible). The investigator may collect any other time based on clinical judgment. 
h. Cardiodynamic 12 lead ECG monitoring. Select sites will participate in a sub study using a continuous 12 lead ECG recorder which should be started approximately 60 minutes prior to IP initiation and 
should continue for 36 hours following IP initiation. For more details refer to Appendix 5. 
i. 
Clinical labs, hematology, serum chemistry (including creatinine, blood urea nitrogen, creatinine clearance calculation [if available], estimated glomerular filtration rate [eGFR] calculation [if available]), and 
concomitant AED levels (fosphenytoin/phenytoin, valproic acid, levetiracetam, lacosamide, phenobarbital, or brivaracetam, if collected per standard of care) and Routine Urinalysis (including urine protein, 
and microscopic examination, if any abnormal value is observed on the urine dipstick test) should be collected predose (screening), if unable to collect predose, collect within 2 hours following IP initiation.  
Collect at the time of IP discontinuation (+/- 1 hour), either at the end of the taper or if the IP administration is stopped without a taper and 24 hours (+/- 1 hour) following IP discontinuation and at the time of 
hospital discharge. Collect at the weekly follow-up visits (Week 1, 2, 3, or 4) for hospitalized participants and for participants who have been discharged (whenever possible). For participants who terminate 
early from the study, collect at the time of early termination (whenever possible). Collect in the event of an SAE. The investigator may collect at any other time based on clinical judgment.  
j. 
Urine chemistry sample for N-acetyl-β-D-glucosaminidase (NAG),β2-microglobulin, and creatinine should be collected predose (screening), if unable to collect predose, collect within 2 hours following IP 
initiation, 24 hours (+/- 1 hour) following IP discontinuation and at the time of hospital discharge. Collect at one of the weekly follow-up visits (Week 1, 2, 3, or 4) for hospitalized participants and when 
possible, for participants who have been discharged. For participants who terminate early from the study, collect at the time of early termination (whenever possible). Urine samples will be stored frozen 
unless otherwise dictated or revised in the Biospecimen Manual. 
k. Clinical coagulation (including fibrinogen, activated partial thromboplastin time [APTT], prothrombin time [PT] and international normalize ratio [INR]) should be collected predose (screening), if unable to 
collect predose, collect within 2 hours following IP initiation, 24 hours (+/- 1 hour) following IP discontinuation and at the time of hospital discharge. For participants who terminate early from the study, 
collect at the time of early termination (whenever possible). The investigator may collect at any other time based on clinical judgment. 
l. 
A urine or serum sample for drugs of abuse testing should be collected predose per the institution standard of care. A urine or serum sample for alcohol testing should be collected, if medically indicated. A 
urine or serum sample for pregnancy testing for females who are of childbearing potential, should be collected predose (screening). If unable to collect sample(s) at predose, collect as soon as possible 
following IP initiation. Enrollment is not contingent upon results. However, if a participant has a positive test result, it will be at the investigator’s discretion to weigh the risks versus benefits for enrollment or 
continued participation. If the investigator decides to discontinue the IP, refer to the taper directions in the Investigational Product, Dose and Mode of Administration section. If the institution requires the 
pregnancy test results be obtained prior to IP initiation, the institution guidelines will be followed. The investigator may collect at any other time based on clinical judgment. 
m. EEG is required for confirmation of CSE and NCSE diagnosis. Continuous EEG recording should be utilized for all participants and should start at least 60 minutes before IP initiation and continue through 
the end of the first 24 hours of the follow-up period.  


 
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n. Blood gas, arterial or venous, if collected to manage the participant’s care from the time of SE diagnosis through the first end of the first 24 hours of the follow-up period, the eCRF should be completed. If 
samples are not collected, a sample is not required. If a decision is made to intubate the participant between IP initiation through the end of the first 24 hours of the follow-up period, 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.  
o. CGI-I should be collected 10 and 24 hours (+/- 1 hour) following IP initiation. Collect at time of IP discontinuation (+/- 1 hour), either at the end of the taper or if the IP administration is stopped without a 
taper. Collect 24 (+/- 1 hour), 48, 72, 96, and 120 hours (+/- 2 hours) following IP discontinuation and at the time of hospital discharge. Collect at Week 1, 2, 3, and 4 follow-up visits/contacts. For 
participants who terminate early from the study, collect at the time of early termination (whenever possible). 
p. Seizure Description Questionnaire should be collected predose (screening) as close as possible prior to IP initiation. 
q. Status Epilepticus Cessation Questionnaire should be collected as close as possible to 24 and 72 hours following IP initiation. 
r. 
Super Refractory Status Epilepticus (SRSE) Questionnaire should be collected as close as possible to the diagnosis of SRSE and no later than the final study follow-up visit/contact. 
s. 
EuroQoL (EQ-5D-5L) should be collected at 120 hours (+/- 2 hours) following IP discontinuation and at the time of hospital discharge. Collect at Week 2, 3, and 4 follow-up visit/contacts. For participants 
who terminate early from the study, collect at the time of early termination (whenever possible).  
t. 
mRS should be collected 24 (+/- 1 hour), 48, 72, 96, and 120 hours (+/- 2 hours) following IP discontinuation and at the time of hospital discharge. Collect at Week 2, 3, and 4 follow-up visits/contacts. For 
participants who terminate early from the study, collect at the time of early termination (whenever possible). 
u. AEs will be collected from the time of IP initiation until the final study follow-up visit/contact via non-direct questioning. Concomitant medications will be collected during the same time period. All AEs and 
associated concomitant medications will be collected through the final study follow-up visit/contact. For participants who terminate early 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. Each AED administered within 
14 days of IP initiation will be recorded and the reason for administration through the final study follow-up visit/contact. 
v. Healthcare Utilization Questionnaires include the Hospitalization Questionnaire and the Positive Pressure Ventilation (PPV) and Intubation Questionnaire. The Hospitalization Questionnaire should be 
collected at hospital discharge or at final study visit/contact. The need for non-invasive or invasive ventilatory support within 24 hours prior to IP initiation and following IP initiation and within 48 hours 
following IP discontinuation should be collected as close as possible to the event.  
 
 


 
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Table 2. 
Investigational Product Infusion and Pharmacokinetic Sample Collection (Double-Blind and Open-Label Phases) 
Periods/Day/ 
Duration 
Screening  
Day -1 to 
Day 1 
Predose 
through 
screening 
Dosing 
Day 1 
IP initiation 
0 through 24 hours following IP 
initiation 
Dosing 
Day 2 
24 hours through 36 hours 
following IP initiation 
Taper 
Day 2 
(12 hours) 
Starts at 36 hours  
following IP initiation 
IP  
Discontinuation 
With or without 
Taper 
IP 
Discontinuation 
Follow-up 
Visit 
1 
2 
3 
3 
4 
5 
IP infusiona 
 
 
 
 
 
 
Timepoint 
 
Minutes (m) /Hours (h) following IP initiation 
 
 
Hours following 
IP 
Discontinuation 
-0 
60 
m 
2 
h 
6 
h 
10 
h 
 
24 
h 
36 
h 
 
 
24 
h 
Pharmacokinetic 
blood sample 
collectionb 
 
 
 
 
 
 
 
 
 
 
 
IP = investigational product 
a. 
Investigational product will be administered as a 48-hour continuous infusion, which includes an initial 3-minute bolus and ends with a 12-hour taper. 
b. 
Blood sample collection (venous or arterial) for pharmacokinetic analysis (ganaxolone and Captisol®) will occur at 60 minutes (± 5 min), then at 2, 6 (± 5 min), 10, 24 and 36 hours 
(± 2 hours) following IP initiation. Collect at the time of IP discontinuation (± 1 hour), either at the end of the taper or if the IP administration is stopped without a taper (e.g., when the 
participant progresses to IV anesthesia for seizure/SE treatment), and 24 hours (± 2 hour) following IP discontinuation. Variable PK collection time between IP initiation and the end 
of the first 24 hours in the follow-up period, where possible, collect a PK sample at the time of an SAE (related or not related); Pharmacokinetic samples should be collected from the 
contralateral peripheral access or the arterial line and avoid collecting samples downstream of the IP infusion. The location of IP access and location of PK sample collection should be 
documented in the participant’s chart. If the PK sample cannot be collected due to poor venous or arterial access and the IP infusion site is the only viable option, the sample should not 
be collected and the reason for non-collection documented in the participant’s source. Pharmacokinetic samples will be stored frozen as per the Biospecimen Manual. 
 
 
 
 
 


 
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1 BACKGROUND INFORMATION 
1.1 
Indication and Current Treatment Options 
Status epilepticus (SE) is defined as a prolonged, self-sustaining seizure or recurrent seizures 
without intervening recovery of consciousness.1 The International League Against Epilepsy 
(ILAE) has 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 prolonged 
seizures.2 The minimum duration of seizures constituting SE is typically defined as 5 minutes for 
convulsive SE (CSE) and 10 minutes for non-convulsive SE (NCSE).3 The ILAE has proposed 
definitions that encompass the time at which seizures become self-sustaining (t1) and a time 
when neurologic damage results (t2). For GCSE, these are 5 and 30 minutes, respectively; for 
nonconvulsive SE (NCSE), they are 10 and 60 minutes.2  
In general, SE incidence varies from 9.9 to 41/100,000 per year with a bimodal age distribution. 
The youngest and oldest patients suffer from SE most often, specifically those in the first decade 
of life (14.3/100,000) and those over 60 years of age (28.4/100,000).21 While the etiologies tend 
to be unique to specific age groups, the basic approach to treatment is similar across all ages and 
etiologies.22,23 Treatment is largely focused on rapid SE cessation, including initiation of drugs to 
terminate seizures and reversal of conditions that may lower seizure threshold. Potentiating 
GABAergic inhibition is a key mechanism to achieve rapid seizure cessation in both adults and 
children. 
If not treated immediately, prolonged seizure activity can result in permanent neuronal damage 
and contribute to the high morbidity and mortality associated with SE.8,24,25 Mortality due to SE 
can range from 3% to 40% depending on etiology, age, type of SE and its duration.26 Previous 
studies have shown that seizures cause neuronal death via excitotoxic mechanisms as a result of 
excessive neuronal activity.1 Furthermore, CSE is associated with many complications, including 
cardiac arrhythmias, rhabdomyolysis, pulmonary edema, electrolyte and glucose imbalance, and 
temperature disturbances.27 
Status epilepticus often occurs in the setting of pre-existing epilepsy, but it can also be caused by 
cerebral injury in individuals with no prior history of seizures.8 In patients with chronic epilepsy, 
low blood concentration of antiepileptic drugs (AEDs) is a common cause of SE.1 Other 
recognized causes of SE include, but are not limited to, stroke, anoxia or hypoxia, metabolic 
causes, and alcohol or drug withdrawal.1,8  
Status epilepticus can be classified into 2 subtypes: Convulsive SE and NCSE.8,24 Convulsive SE 
is characterized by continuous or repetitive tonic-clonic seizures without interictal recovery of 
full consciousness. Nonconvulsive SE is defined as prolonged continuous electrographic seizure 
activity without convulsive clinical symptoms or a series of nonconvulsive seizures without 
complete interictal clinical recovery. If CSE is prolonged, clinical manifestations may evolve to 
those of NSCE, a stage sometimes referred to as “subtle convulsive status epilepticus”.28,6 
Additionally, SE can be categorized based on its refractoriness to treatment. The first-line 
standard of care medications for SE are benzodiazepines which, depending on the agent used, 
may be administered intravenously, intramuscularly or via the buccal route.13 While these agents 


 
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have demonstrated efficacy in early SE, a recent study found that 25% and 36% of subjects with 
SE did not respond to intramuscular (IM) midazolam or intravenous (IV) lorazepam, 
respectively.29 Early SE that is refractory to first line treatment is termed established SE (ESE). 
Only two-thirds of subjects with SE respond to the first treatment, and evidence shows that 
prolonged seizures can result in permanent neuronal damage and contribute to the high morbidity 
and mortality associated with SE.30 
Refractory SE (RSE) is defined as SE resistant to treatment with one first-line AED 
(benzodiazepines) and one second-line AED such as IV fosphenytoin/phenytoin, valproic acid or 
levetiracetam.11,31 The prognosis worsens with progression to RSE, with mortality in 
approximately one-third of patients and another one-third suffering from chronic neurologic 
sequalae.14,32,33 
If second-line IV AEDs fail, IV anesthetic agents must be used to induce therapeutic coma to 
attempt control of SE.1 Midazolam, propofol, pentobarbital or other anesthetics are administered, 
and coma is maintained for 24 hours or longer, after which the dose of the anesthetic agent is 
reduced to determine whether seizure activity has been aborted. Repeated courses of IV 
anesthesia may be attempted to control SE, with longer duration of IV anesthesia associated with 
a worse prognosis.15 SE that fails treatment with a course of IV anesthesia is classified as super-
refractory SE (SRSE), which is associated with increased length of hospitalization and higher 
costs of care.34 SRSE represents only 13% of hospital admissions for SE but is responsible for 
56% of costs. Mortality in SRSE is 40%, compared to 15% for RSE and 10% for non-refractory 
SE.  
A recently completed study assessed the neurosteroid, brexanolone (allopregnanolone), 
compared to placebo in the treatment of SRSE (ClinicalTrial.gov NCT02477618). The study 
failed to meet its primary endpoint, the proportion of patients successfully weaned from IV 
anesthetics (43.9% vs. 42.4% for brexanolone and placebo, respectively, p=0.8775). The failure 
of brexanolone to treat SRSE may have been due to the severity or stage of progression of SE or 
to other factors. There has not been a controlled clinical trial of an AED for RSE.  
An important aspect of SE diagnosis and treatment is the use of electroencephalographic (EEG) 
monitoring. EEG is necessary to determine the adequacy of SE therapy, particularly in NCSE, 
which often has no clinical manifestations to guide treatment. After control of CSE, subclinical 
electrographic seizure activity can be detected in up to 48% of patients.35 If IV anesthesia is 
required, the EEG is used to assess whether depth of sedation is sufficient. The presence of a 
burst-suppression pattern on EEG is indicative of adequate levels of anesthesia for control of SE.  
1.2 
Product Background and Clinical Information  
Nonclinical Data 
The biological effects of ganaxolone (GNX) have been assessed in numerous in vitro and in vivo 
models and non-clinical pharmacodynamics (PD), pharmacokinetics (PK), and toxicology 
studies conducted in mice, rats, rabbits, monkeys, and dogs.36 


 
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The most common effect following treatment with GNX in toxicology studies was dose-related 
sedation, an expected pharmacological effect of a positive modulator of GABAA receptors. In 
both the oral (PO) and IV programs, there was little evidence of target organ or systemic toxicity 
associated with either single- or multiple-dose treatment with GNX. No functional or anatomic 
changes within hematopoietic tissue or any specific organ such as liver, kidney or 
gastrointestinal (GI) systems were seen in the repeat-dose studies.  
Ganaxolone was not teratogenic in rats or mice and did not significantly affect the development 
of offspring. Ganaxolone had no effects on fertility and early embryonic development in rats. No 
potential for genotoxicity was detected. Treatment of neonatal rats with GNX produced expected 
signs of sedation but did not affect development or demonstrate any postmortem changes. 
In rats continuously dosed with IV GNX for 14 days, no GNX-related changes were noted in 
clinical pathology parameters or histopathology examination. There was no evidence of local 
irritation when GNX was given IV or peri-venously in preclinical studies. Furthermore, IV GNX 
did not cause hemolysis and was compatible with human plasma. 
The anticonvulsant activity of GNX was established in multiple in vivo models of seizure 
activity in rats and mice. The results from these studies show that GNX blocks seizure 
propagation, elevates seizure threshold, and can reverse seizures with delayed administration. 
Ganaxolone, administered IV, was also evaluated and shown to be effective in models of SE.37 
These evaluations were conducted in rats and SE was induced by lithium pilocarpine 
administration. Seizure response was measured by EEG activity, behavioral convulsions, and 
seizure related mortality. In these studies, the administration of GNX was delayed up to 
60 minutes after SE onset. Seizures at this time point after SE onset are resistant to 
benzodiazepine treatment and are considered to represent a treatment resistant version of SE. 
Ganaxolone, administered IV, produced a long-lasting reduction in EEG seizure response, 
behavioral convulsions, and also decreased seizure related mortality. In a study in which a 
subtherapeutic dose of GNX was co-administered with a subtherapeutic dose of diazepam, a 
synergistic effect on reduction of EEG seizure was observed. In comparison to IV administered 
allopregnanolone, GNX produced a longer lasting reduction in seizure activity. These preclinical 
data provide the support for the clinical evaluation of GNX in SE subjects. 
Ganaxolone administered IV was also evaluated for effects on EEG patterns in otherwise normal 
(non-epileptic) rats. In one study, GNX was administered at a dose of 3 mg/kg every 30 minutes 
for 5 doses (total: 15 mg/kg). Under this dosing paradigm, GNX produced a complex EEG 
profile. Shortly after dosing, brief (~1 sec) periods of intense EEG activity with a peak frequency 
of around 10 Hz were observed. EEG power was increased in the GNX compared to the vehicle 
group from 0–50 Hz and reduced from 50–96 Hz. This EEG is consistent with a sedation EEG 
pattern. Rats still responded to painful stimuli. Thus, GNX did not produce an anesthetic 
response. In the second study, GNX was administered IV at 3 mg/kg every 3 minutes. Under this 
dosing paradigm, GNX produced a burst suppression-like EEG pattern after 4 doses (12 mg/kg). 
Rats were sedated, but still responded to tail pinch stimuli indicating that GNX did not cause a 
full anesthetic response. 
The toxicity of Captisol® was evaluated in juvenile male and female Sprague Dawley rats dosed 
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Day (PND) 14 through PND 35 (Study 00398517). Endpoints included mortality, clinical signs, 
body weights, body weight gains, food consumption, organ weights, and macroscopic and 
microscopic examinations. All males and females survived to the scheduled necropsies. No 
remarkable clinical observations were noted during the detailed clinical observations or 1–2 
hours following the first daily dose at any dose level. Nonadverse lower mean weight gain and 
corresponding food consumption was noted in the 5000 mg/kg/day group males and nonadverse 
microscopic findings in the kidneys, adrenal glands, axillary lymph node, and injection sites 
were observed in the 1000, 2500, and 5000 mg/kg/day group males and females. The epithelial 
cell vacuolation in the kidneys was not considered severe and histiocytic vacuolation in the 
adrenal gland, axillary lymph node, and injection sites were due to a biologic response to the 
presence of foreign material at the injection sites. At the recovery necropsy, microscopic findings 
persisted in the kidneys, adrenal glands, axillary lymph node, and injection sites, but with a 
general decrease in severity, suggesting partial recovery. 
Based on the lack of adverse effects in males and females at all dose levels tested, a dose level of 
5000 mg/kg/day (2500 mg/kg/dose BID) was considered to be the no-observed-adverse-effect 
level (NOAEL) for juvenile toxicity of Captisol® in rats. 
Clinical Data 
In 20 completed Phase 1 studies, 319 healthy volunteers received GNX doses of 50 to 
2,000 mg/day for periods of up to 2 weeks. 
In the 20 completed Phase 2/3 clinical studies, 1,238 study participants have received GNX, 
including adults with epilepsy, migraine and post-traumatic stress disorder, and children with 
epilepsy and Fragile X syndrome. There are 109 pediatric study participants currently enrolled in 
2 ongoing epilepsy trials (CDKL5-deficiency disorder and PCDH19-related epilepsy).  
The overall frequency of treatment-emergent adverse events (TEAE) in company-sponsored 
placebo-controlled studies was 61.7% (613/993) in study participants who received GNX 
and 51.8% (330/637) in those who received placebo. The most frequently reported 
TEAEs in GNX-treated participants were somnolence, dizziness, fatigue, and headache. All of 
these events, except for headache, which occurred more frequently in GNX- than placebo-treated 
study participants. CNS-related adverse events were dose-related, with the majority occurring at 
doses ≥500 mg/day. The majority of TEAEs were not unexpected 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.  
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 laboratory measurements in GNX trials. In the completed, 
placebo-controlled Phase 1, 2, and 3 studies, 0.3% of subjects treated with GNX and 0.5% of 
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 attributed to GNX fulfilling criteria for Hy’s law.  


 
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In controlled clinical trials of GNX, 1.1% of subjects receiving placebo and 1.7% of subjects 
receiving GNX reported an AE of rash. However, rash led to discontinuation in GNX-treated 
subjects in 6 cases (0.6%) compared to no cases (0%) in placebo-treated subjects. Two subjects 
participating in a Phase 2 study investigating GNX in treatment of epilepsy developed an SAE of 
rash. Both events resolved after discontinuation of the IP. 
Ganaxolone is rapidly absorbed into plasma and readily moved into breast milk. The effects of 
GNX on milk production and the breastfed infant are unknown. After cessation of the infusion, 
plasma GNX levels are expected to drop rapidly, but it is possible that low, subtherapeutic levels 
persist for several days as GNX is slowly released from tissues. Therefore, a washout period of 
45 days is required following cessation of GNX treatment before breastfeeding. Previous 
toxicology studies in animals focusing on prenatal and neonatal development have not 
demonstrated toxicities associated with GNX. Ganaxolone has been administered to infants with 
severe forms of epilepsy as early as 4 months of age.  
In clinical trials involving administration of GNX over several weeks, the IP has been tapered off 
over a 1- to 2- week period. There have been no reports of withdrawal symptoms emerging after 
cessation of GNX.  
Always refer to the latest version of the GNX Investigator’s Brochure (IB) for the overall 
risk/benefit assessment and the most accurate and current information regarding metabolism, 
pharmacokinetics, efficacy, and safety of GNX.  
2 STUDY OBJECTIVES AND PURPOSE 
2.1 
Rationale for the study 
Few drugs are approved for the treatment of SE and an urgent need for evidence-based, 
efficacious therapies remains, particularly for patients with RSE who have failed treatment with 
benzodiazepines and one or more second-line AEDs.13 There is no evidence from randomized, 
controlled trials to support the use of one AED over another in any but the earliest stage of SE, in 
which benzodiazepines such as IV lorazepam or IM midazolam have been demonstrated to be 
effective.29 The Established Status Epilepticus Treatment Trial (ESETT) demonstrated that three 
commonly used AEDs were ineffective in over half of patients with established status epilepticus 
(ESE), and none were superior to the others in stopping seizures.9 There is limited evidence from 
retrospective case series suggesting potential utility for IV levetiracetam or lacosamide in 
RSE38,39 though interpretability is limited by the retrospective nature of the data, lack of control 
groups and potential confounding by use of concomitant treatments. 
Ganaxolone is the 3β-methylated synthetic analogue of the neuroactive steroid allopregnanolone. 
It differs from other GABAergic agents in that it binds to both synaptic and extrasynaptic 
GABAA receptors at a binding site distinct from benzodiazepines or barbiturates.17 Resistance to 
treatment in SE has been attributed to the internalization of postsynaptic GABAA receptors and 
increase in synaptic density of glutamate receptors.12 This alteration of receptor trafficking may 
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Because prolonged seizures result in a reduction of GABAA-mediated synaptic inhibition, 
antiepileptic treatments that rely on enhancing intrasynaptic GABAA neurotransmission become 
less effective the longer SE continues. Because of its action at extrasynaptic GABAA receptors, 
which are not downregulated with progression of SE, ganaxolone has the potential for 
therapeutic benefit when benzodiazepines and barbiturates are likely to be ineffective. Because 
of its mode of action, as well as its extensive safety record, ganaxolone represents a promising 
alternative to current treatments for SE. 
The potential utility of ganaxolone for treatment of SE is also supported by the results of a 
phase 2, open-label study in 17 patients with RSE (Study 1042-SE-2001). Ganaxolone was 
administered IV via a bolus dose and concurrent initiation of a 48 to 96-hour infusion according 
to one of three dosing regimens as outlined in Table 3. 
Table 3. 
Enrollment in Study 1042-SE-2001 Dose Level Cohorts 
Cohort 
Dose of GNX/day 
Duration at target level 
≥500 ng/mL (hours) 
Number of patients per 
cohort 
Low 
500 mg/day 
4 
5 
Medium  
650 mg/day 
0 
4 
High 
713 mg/day 
8 
8 
GNX = ganaxolone. 
The median age of enrolled patients was 56.9 years (range 23 to 88 years) and 53% were female. 
Causes of SE included vascular disease (stroke or intracranial hemorrhage, N = 7), brain tumors 
(N = 4), alcohol withdrawal or drug overdose (N = 2), metabolic disturbances (N = 2) or 
autoimmune causes (N = 2). In two patients, the etiology of SE was unknown.  
The majority of patients (N = 12) had NCSE, one of whom had converted from convulsive to 
non-convulsive SE. Study participants had failed a mean of 2.9 IV AEDs, including first-line 
treatment with benzodiazepines. The mean number of second-line IV AEDs was 2.1, including 
phenytoin, fosphenytoin, valproate, lacosamide and levetiracetam. All of the patients had 
received either lacosamide or levetiracetam, or both.  
None of the 17 enrolled patients required treatment with IV anesthetics through 24 hours 
following initiation of ganaxolone, the primary efficacy endpoint of the study. The median time 
to SE cessation was 5 minutes from initiation of ganaxolone (N = 15 evaluable patients); 14/15 
achieved SE cessation within 30 minutes and one achieved SE cessation at approximately 
4 hours. Post hoc analysis of EEG monitoring data indicated that maintenance of an infusion rate 
producing a blood ganaxolone concentration of 500 ng/mL for 8 hours, and not 4 hours, resulted 
in sustained suppression of epileptiform activity. The dosing regimen in the present study is 
designed to maintain a ganaxolone concentration ≥500 ng/mL for the first 12 hours of IP 
infusion. It will also achieve plasma concentrations that replicate those associated with 
anticonvulsant effects in preclinical SE models and that are therefore expected to demonstrate 
anticonvulsant properties in humans.  
The ganaxolone IV to be used in this study is a proprietary formulation that is solubilized with 
Captisol® (betadex sulfobutyl ether sodium), with the dose of Captisol® not exceeding 50 grams 
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Among the 17 enrolled subjects who received GNX, the most common TEAE were somnolence 
(5 subjects, 29.4%), hypotension (4 subjects, 23.5%), and hypokalemia (3 subjects, 17.6%). 
Severe TEAEs were reported in 6 subjects (35.3%). The most frequently (reported in 2 or more 
subjects [i.e., ≥10%]) reported severe TEAEs by system organ class were Nervous System 
Disorders, reported in 4 subjects (23.5%). Refer to the GNX IB for detailed safety information. 
2.2 
Study Objectives 
2.2.1 
Primary Objective 
• 
To evaluate the efficacy and safety of ganaxolone IV for the treatment of SE after failure of 
two or more antiseizure medications.  
2.2.2 
Secondary Objectives 
• 
To assess the time to SE cessation following ganaxolone administration. 
• 
To evaluate the sustained efficacy of ganaxolone IV beyond the 48-hour treatment period as 
assessed by prevention of progression to IV anesthesia for the treatment of SE. 
2.2.3 
Exploratory Objectives 
• 
To determine the effect of ganaxolone on healthcare utilization.  
• 
To assess the effect of ganaxolone on doses of other antiseizure treatments and changes in 
seizure burden. 
• 
To evaluate the effect of ganaxolone on quality of life, functional status, and level of 
responsiveness. 
3 STUDY DESIGN 
3.1 
Study Design and Flow Chart 
This is a double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety 
of ganaxolone IV solution in SE, with an option to transition to open-label treatment to obtain 
additional safety data following a demonstration of efficacy at the interim analysis, data 
monitoring committee (DMC) recommendation, and Sponsor agreement. The term “participant” 
will be used in place of “subject” in accordance with the FDA glossary which states these terms 
may be used interchangeably. 
3.1.1 
Double-blind Phase 
Approximately 160 participants were planned to be screened to randomize approximately 124 
study participants at least 12 years of age with SE. Randomization stopped at 100 patients for 
business reasons. Randomized participants will receive ganaxolone IV solution or placebo, 
referred to as investigational product (IP), in a 1:1 ratio added to SE standard of care.  
Potential participants may be identified in the emergency department, ICU or other units in the 
hospital and will be consented/assented or deferred, where allowed by law and then screened for 
inclusion/exclusion criteria prior to being randomized to start IP treatment. 




 
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Approximately 60 to 100 study participants will receive ganaxolone IV in the double-blind and 
open-label phases combined.  
 
3.2 
Interim Analysis 
As described in Section 10.7, an interim analysis will be conducted when two-thirds of the ITT 
population have completed 72 hours of efficacy assessments (approximately 41 participants per 
arm). Based upon the interim analysis results, recommendation from the DMC, and agreement 
from the Sponsor, the study will either continue without modification or will transition to 
enrollment in an open-label phase. All participants enrolled in the open-label phase will receive 
open-label ganaxolone IV solution added to SE standard of care. The screening, duration of the 
treatment, and follow-up periods, as well as the study schedule, would remain the same for 
participants enrolled under either the double-blind or open-label phases as described above and 
in Figure 1. Approximately 60 to 100 study participants are planned to receive ganaxolone IV in 
the double-blind and open-label phases combined.  
3.3 
Duration and Study Completion Definition 
The maximum duration of study participation is expected to be approximately 4 weeks.  
The study completion date is defined as the date the final participant, across all sites, completes 
their final study assessment/procedure; this includes the follow-up visit/contact, whichever is 
later. The study completion date is used to ascertain timing for posting and reporting of study 
results. 
3.4 
Sites and Regions 
This multicenter study is to be conducted in the United States, Canada, and Australia, with 
approximately 100 sites planned to participate.  
4 STUDY POPULATION 
Each participant/participant’s parent/guardian/legally authorized representative (LAR) must 
participate in the informed consent process and provide written informed consent/assent, 
unless allowed by law, e.g., deferred consent, before any procedures specified in the 
protocol are performed. Consent/assent will be administered per institution 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. Informed consent/assent for participants who are known to 
be at risk for SE may be obtained prior to a SE event. The period the pre-consent/assent is 
valid will be determined by institution IRB/EC. However, reconsenting will be needed 
should the consent/assent be updated at any point during the study.  
4.1 
Inclusion Criteria 
The participant will not be considered eligible for the study without meeting all the criteria 
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1. Participant, participant’s parent, guardian, or LAR must provide signed informed 
consent/assent, and once capable (per institution guidelines), there must be 
documentation of consent/assent by the participant demonstrating they are willing 
and aware of the investigational nature of the study and related procedures. Where 
allowed by law, where the patient lacks the capacity to make informed decisions 
regarding his/her medical treatment options, the treating clinician may follow their 
deferred consenting practices. The clinician will make the final decision based on the 
best interests of the patient. 
2. Male or females 12 years of age and older at the time of the first dose of IP. 
3. SE meeting the following criteria:  
a. A diagnosis of SE with or without prominent motor features based on clinical 
and EEG findings according to the investigator’s judgement, based on the 
following: 
i. For SE with prominent motor features: Clinical and EEG seizure activity 
indicative of convulsive, myoclonic or focal motor SE 
ii. For SE without prominent motor features (nonconvulsive SE): 
Appropriate clinical features and an EEG indicative of NCSE (see 
modified Salzburg criteria19 in Appendix 3). 
iii. For any type of SE: 
• Approximately 6 minutes of cumulative seizure activity over a 
30-minute period within the hour before IP initiation, AND 
• Seizure activity during the 30 minutes immediately prior to IP 
initiation. 
b. The treating clinician(s) anticipate that IV anesthesia is likely to be the next 
treatment for SE that persists following initiation of IP. 
4. Participants must have received any two or more of the following agents for treatment of 
the current episode of SE administered at an adequate dose and for a sufficient duration, 
in the judgment of the investigator, to demonstrate efficacy (guidelines for adequate 
doses are provided in Appendix 2): 
o 
Benzodiazepines, 
o 
IV Fosphenytoin/phenytoin, 
o 
IV Valproic acid, 
o 
IV Levetiracetam, 
o 
IV Lacosamide, 
o 
IV Brivaracetam, or 
o 
IV Phenobarbital 
5. BMI <40 or, if BMI is not able to be calculated at screening, participant is assessed by 
investigator as not morbidly obese. 
 
4.2 
Exclusion Criteria 
Participants are excluded from the study if any of the following exclusion criteria are met.  


 
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1. Life expectancy of less than 24 hours.  
2. Anoxic brain injury or an uncorrected rapidly reversable metabolic condition as the primary 
cause of SE (e.g., hypoglycemia <50 mg/dL or hyperglycemia >400 mg/dL). 
3. Participants who have received high-dose IV anesthetics (e.g., midazolam, propofol, 
thiopental, or pentobarbital) during the current episode of SE for more than 18 hours, or who 
continue to have clinical or electrographic evidence of persistent seizures while receiving 
high-dose IV anesthetics. 
4. Clinical condition or advance directive that would NOT permit use of IV anesthesia. 
5. Participants known or suspected to be pregnant. 
6. Participants with known allergy or sensitivity to progesterone or allopregnanolone 
medications/supplements. 
7. Receiving a concomitant IV product containing Captisol® (marketed products listed in 
Appendix 4). 
8. Known or suspected hepatic insufficiency or hepatic failure leading to impaired synthetic 
liver function. 
9. Known or suspected stage 3B (moderate to severe; eGFR 44-30 mL/min/1.73m2), stage 4 
(severe; eGFR 29-15 mL/min/1.73m2), or stage 5 (kidney failure; eGFR <15 mL/min/1.73m2 
or dialysis) kidney disease.  
10. Use of an investigational product for which less than 30 days or 5 half-lives have elapsed 
from the final product administration. Participation in a non-interventional clinical study does 
not exclude eligibility. 
11. Known or suspected history or evidence of a medical condition that, in the investigator’s 
judgment, would expose participant to an undue risk of a significant adverse event or would 
interfere with assessments of safety or efficacy during the study. 
4.3 
Restrictions  
Participants must abstain from the use of alcohol until the end of the 24-hour IP discontinuation 
follow-up period. 
Females are prohibited from breastfeeding for 45 days after the last dose of IP. 
4.4 
Reproductive Potential 
4.4.1 
Female Contraception 
Sexually active females of childbearing potential should be using an acceptable form of 
contraception and must be advised to use acceptable contraceptives throughout the study period 
and for 30 days after the last dose of IP. If hormonal contraceptives are used, they should be 
administered according to 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 IP.  
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• 
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 a urine or serum sample collected for pregnancy testing prior to IP initiation. 
If not possible, collect as soon as possible following IP initiation. Enrollment is not 
contingent upon results. However, if a participant has a positive test result, it will be at the 
investigators’ discretion to weigh the risks versus benefit for continued participation. If 
the institution requires the pregnancy test results be obtained prior to IP initiation, the 
institution guidelines will be followed. 
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 participant 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. 
Contraceptive measures such as Plan BTM, sold for emergency use after unprotected sex, are not 
acceptable methods for routine use. 
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 30 days after the last dose of IP. Medically acceptable 
contraceptives include surgical sterilization (such as a vasectomy) and a condom used with a 
spermicidal gel or foam. 
Male participants should not donate sperm during the study and for 30 days after the last dose of 
IP. 
4.5 
Discontinuation of Participants 
A participant may withdraw, or their parent, guardian, or LAR may withdraw the participant 
from the IP administration and/or the study at any time for any reason without prejudice to their 
future medical care by the physician or the institution. The investigator or Sponsor may 
withdraw the participant at any time (e.g., in the interest of participant safety). The investigator is 
encouraged to discuss withdrawal of a participant from IP with the Medical Monitor, when 
possible, unless due to progression to an IV anesthetic for seizure suppression. 
4.5.1 
Investigational product discontinuation 
Participants who discontinue IP without a taper (e.g., were administered IP for less than 2 hours, 
progress to anesthesia for seizure suppression or discontinue IP due to safety or any other reason, 
except due to withdrawal of consent) will have the follow-up assessments/procedures collected 


 
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every 24 hours through 120 hours (or until hospital discharge) and at the time of hospital 
discharge, followed by weekly follow-up visits/contacts at Week 1, 2, 3 and 4.  
4.5.1.1 
Reasons for IP discontinuation include, but are not limited to, the following: 
• Adverse event or imminent safety concern 
• Medical procedure 
• Lack of efficacy with progression to high dose IV anesthesia for seizure/SE control 
• Lack of efficacy without progression to high dose IV anesthesia for seizure/SE control 
• Progression to high dose IV anesthesia for reason not related to seizure/SE 
• Death 
• Consent withdrawal 
• Physician decision (must be specified in the participant’s source documents and 
electronic case report form [eCRF]) 
• Other (must be specified in the participant’s source documents and eCRF). 
4.5.1.2 
Study Withdrawal 
All participants reserve the right to withdraw from the clinical study at any time, as stated in the 
informed consent/assent form.  
Participants who terminate early from the study (e.g., due to consent withdrawn), any 
outstanding procedures and the evaluations listed for the Early Termination Visit in Table 1 
should be completed when early termination is being considered. 
4.5.2 
Participant Withdrawal Criteria 
The Sponsor is not providing formal thresholds to discontinue a participant from the study. The 
Sponsor encourages the investigator to continuously assess any potential risks and benefits of 
participation during the entire study. The investigator should not hesitate to discontinue a 
participant from the clinical study if, according to the investigator’s clinical judgment, the risks 
exceed any potential benefits. Reference examples below. 
1. If the participant experiences worsening and persistent ventilatory depression despite routine 
clinical interventions (e.g., jaw thrust, chin lift or oxygen supplementation) that, in the 
judgment of the investigator, can be improved upon by discontinuation of the IP, the 
investigator may choose to discontinue such participant from the study. If positive ventilatory 
support is initiated and the participant is stable as per the investigator’s clinical judgment, IP 
may be continued. 
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 ≤44 mL/min/1.73m2 and participant is not 
starting dialysis. 


 
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4. Any other adverse event or safety issue (e.g., severe persistent hypotension/hypertension or 
tachycardia/bradycardia) that suggests it is not in the participant’s best interest to continue to 
receive IP. 
5. Rash that is clinically significant and considered to be related to the IP (e.g., morbilliform, 
urticarial, papular). 
6. Participant experiences an SAE considered to be related to the IP. 
Decisions to discontinue from the study will be made by the investigator. If feasible, the reason 
for discontinuation should be discussed with the Medical Monitor prior to the participant’s 
discontinuation unless due to the progression to anesthesia for seizure suppression.  
4.5.3 
Reasons for Study Discontinuation 
The reason for study discontinuation must be determined by the investigator and recorded in the 
participant’s medical record and in the eCRF. If a participant 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, the following: 
• Adverse event 
• Protocol deviation 
• Consent withdrawal 
• Lost to follow-up 
• Lack of efficacy 
• Death 
• Physician decision (must be specified in the participant’s source documents and eCRF) 
• Other (must be specified in the participant’s source documents and eCRF)  
4.5.4 
Participants Lost to Follow-up Prior to Last Scheduled Visit 
A minimum of three documented attempts must be made to contact any participant 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 
participant’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 
participant should be classified as Lost to Follow-up in the eCRF. However, if contact is made 
but the participant 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 (including AEDs) administered within 14 days 
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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. 
Benzodiazepines, AEDs and Anesthesia Medications 
• Prior to IP initiation (not experiencing a seizure event) 
o Medications administered during this timeframe will be collected per the medication 
order 
• Prior to IP initiation (for the current SE event) 
o Medications administered during this timeframe will be collected separately (i.e., 
each dose administered will be collected separately) 
Vasopressors 
• The administration of a continuous IV vasopressor infusion in the 24-hours prior to IP 
initiation will be collected in the Prior and Concomitant Medication eCRF 
5.2 
Concomitant Treatment  
Concomitant treatment refers to all treatment taken between the date of the first dose of IP and 
the final study follow-up visit/contact. 
Concomitant treatment information must be recorded on the appropriate eCRF page. 
Benzodiazepines, AEDs and Anesthesia Medications 
• During IP administration and for 120 hours of the follow-up period 
o Medications administered during this timeframe will be collected separately (i.e., 
each dose administered will be collected separately) 
• Follow-up period (starts 120 hours following IP discontinuation) 
o Medications administered during this timeframe will be collected per the medication 
order 
Vasopressors 
• Administration of a continuous IV vasopressor infusion during IP administration or within 24 
hours following IP discontinuation will be collected in the Prior and Concomitant Medication 
eCRF. 
For some of the concomitant medications only the highest dose administered will be required in 
the eCRF. Reference the eCRF Completion Guidelines for guidance. 


 
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5.2.1 
Permitted Treatment 
To qualify for inclusion (Section 4.1), the participant must have received an acute treatment with 
any two or more of the following agents for treatment of the current episode of SE: 
benzodiazepines, IV fosphenytoin/phenytoin, IV valproic acid, IV levetiracetam, IV lacosamide, 
IV phenobarbital, IV brivaracetam, or IV phenobarbital. Taking any of these drugs alone or in 
combination is acceptable. Fosphenytoin/phenytoin will be counted as one (1) IV AED. 
Levetiracetam and brivaracetam will be counted as two (2) IV AEDs.  
If the participant is receiving an oral AED to manage a chronic medical condition, (e.g., epilepsy, 
migraine, or neuropathic pain), the AED is acceptable and may continue unchanged. This 
maintenance treatment does not count towards the SE treatment failures required to qualify for 
this study. 
The site will record the reason for each AED dose during IP administration in the appropriate 
CRF page. 
5.2.2 
Prohibited Treatment 
If a participant progresses at any time during the study to an IV anesthetic (e.g., midazolam, 
propofol, thiopental, or pentobarbital) given with the primary intent specifically to treat seizures 
or achieve burst suppression IP administration will be discontinued without taper but the 
participant will continue in the study. Additional details can be found in Section 4.5. 
Concomitant use of IV products containing Captisol® during IP administration is prohibited (see 
exclusion criterion #7 and Appendix 4). 
6 INVESTIGATIONAL PRODUCT 
6.1 
Identity of Investigational Product 
The IP is ganaxolone IV solution, 1 mg/mL, or placebo which will be provided in 500 mL glass 
bottles with a grey stopper, purple flip-off cap and aluminum overseal. Each 500 mL bottle 
contains 425 mL of a sterile solution. The IP is provided as a unit dose bottle. Placebo will only 
be used for the double-blind phase of the study. Should the study transition to open-label, the 
ganaxolone IV solution administered as IP will be identical to the ganaxolone IV solution 
administered during the double-blind phase.  
The active formulation consists of a sterile solution of ganaxolone drug substance that has been 
solubilized by complexation with Captisol® (Betadex Sulfobutyl Ether Sodium). The drug 
product is terminally heat-sterilized.  
On 01 June 2022 the Drug Enforcement Administration (DEA) issued its interim final rule 
placing ganaxolone, including its salts, in schedule V of the Controlled Substances Act. The 
DEA drug code for Ganaxolone (commercial name, Ztalmy) is 2401. 
For more details on the composition of the ganaxolone IV solution, 1 mg/mL refer to the 
Pharmacy Manual. 


 
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6.1.1 
Blinding the Treatment Assignment 
6.1.2 
Double-Blind Phase 
During the double-blind phase of the study, all participating staff involved in the evaluation and 
execution of the study will remain blinded to the participant’s treatment assignment.  
6.1.3 
Open-Label Phase 
If the study transitions to an open-label phase (refer to Section 10.7), blinding will not be 
applicable for new participants enrolled in the open-label phase of the study.  
6.2 
Administration of Investigational Product(s) 
6.2.1 
Interactive Response Technology for Investigational Product Management 
Interactive Response Technology (IRT) will be utilized for the following tasks: 
• 
IP allocation (double-blind phase only) 
• 
Randomization (double-blind phase only) 
• 
Supply management 
• 
Inventory management and supply ordering 
• 
Expiration date tracking 
• 
Returns 
• 
Emergency unblinding (double-blind phase only) 
Details of the system and a system user manual will be provided for the investigator files at each 
site. 
6.2.2 
Allocation of Participants to Treatment 
6.2.2.1 
Double-Blind Phase 
The actual treatment given to individual participants is determined by a randomization schedule. 
Participant identification numbers are assigned prior to dosing. Within each site (numbered 
uniquely within a protocol), participant numbers are assigned in the sequence of participant 
presentation for study participation. To allow for timely delivery of IP to the hospital unit, the IP 
bottles may be allocated for use in the IRT prior to the participant meeting all eligibility criteria 
to avoid impact to standard of care. Investigational product will not be administered until 
eligibility has been determined. Enrollment is defined as the initiation of IP infusion.  
6.2.2.2 
Open-Label Phase 
All eligible participants enrolled under the open-label phase of the study will receive ganaxolone 
IV solution added to SE standard of care. No randomization will occur.  
As per the double-blind phase, within each site, participant numbers will be assigned in the 
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administered until eligibility has been determined. Enrollment is defined as the initiation of IP 
infusion. 
6.2.3 
Dosing 
Once consent/assent has been obtained or deferred, where allowed by law and if the participant 
meets protocol entry criteria, IP will be added to standard of care.  
Participants must have received any two or more of the following agents for the treatment of the 
current episode of SE (benzodiazepine and one IV AED or two IV AEDs), administered at an 
adequate dose and for a sufficient duration, in the judgment of the investigator, to demonstrate 
efficacy (guidelines for adequate doses are provided in Appendix 2):  
• Benzodiazepines, 
• IV Fosphenytoin/phenytoin, 
• IV Valproic acid, 
• IV Levetiracetam, 
• IV Lacosamide, 
• IV Brivaracetam, or  
• IV Phenobarbital 
Administering fosphenytoin/phenytoin will be counted as one (1) AED. Administering 
levetiracetam and brivaracetam will be counted as two (2) AEDs. 
Investigational product will be administered as a 48-hour continuous infusion, which includes an 
initial 3-minute bolus and ends with a 12-hour taper. 
The investigator will confirm that the participant meets clinical and EEG criteria for SE during 
the 60-minute period prior to IP initiation and will reconfirm that ongoing ictal activity is present 
within 30 minutes immediately prior to IP initiation.  
Investigational product should be administered through a dedicated peripheral or central IV line 
or a dedicated lumen of a multi-lumen catheter. Infusion lines should be changed according to 
institution standard practices. The maximum time an IP bottle can be hung at the participant’s 
bedside for administration is 24 hours.  
Note: At any time, the infusion rate of IP may be temporarily decreased or permanently stopped 
for safety reasons. 
Status epilepticus cessation will be assessed by the investigator based on clinical and EEG 
features. Training will be provided to guide and help standardize decisions across clinical sites. 
In addition, during the double-blind phase, a central reader blinded to treatment assignment will 
review EEG recordings retrospectively and corroborate accuracy of interpretation. If the study 
transitions to open-label treatment after a demonstration of efficacy at the interim analysis, a 
central reader will still review the EEG recordings retrospectively and corroborate accuracy of 
interpretation but will not be blinded to treatment assignment given that all participants will be 
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6.2.3.1 
Participants 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, from 24 to 36 hours following IP initiation, the continuous infusion rate of 20 
mg/hour can be increased up to a maximum rate of 45 mg/hour until the start of the taper at 
36 hours. The infusion rate will be determined by the investigator to best manage seizure 
relapse and cannot exceed the rate of 45 mg/hour between 24- and 36- hours following IP 
initiation. 
• 
To taper IP, beginning 36 hours following IP initiation, the infusion rate will be reduced by 
33.3% every 4 hours until the infusion is stopped or until the infusion rate becomes too low 
to sustain the IV line. 
• 
Note: If, according to the investigator’s clinical judgment, IP taper needs to start sooner than 
36 hours after initiation, the infusion rate will be decreased by 33.3% of the rate at the 
beginning of the IP taper every 4 hours. 
• 
At the time the IP infusion is discontinued, the participant will progress to the follow-up 
period assessments/procedures.  


 
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6.2.3.2 
Participants weighing <40 kg will be dosed on a per kilogram basis: 
• 
A 0.75 mg/kg bolus dose (over ~3 minutes) will be administered with a continuous infusion 
at a dose of 2.0 mg/kg/hour for 2 hours followed by a continuous infusion dose of 
1.0 mg/kg/hour for 10 hours, and 0.5 mg/kg/hour for the remaining 12 hours of Day 1. 
• 
On Day 2, 24 to 36 hours following IP initiation, the continuous infusion rate of 
0.5 mg/kg/hour can be increased up to a maximum of 1.125 mg/kg/hour until the start of IP 
taper at 36 hours. The infusion rate will be determined by the investigator to best manage 
seizure relapse and cannot exceed the rate of 1.125 mg/kg/hour during hours 24 to 36 of 
Day 2 at any time. 
• 
To taper IP, beginning 36 hours following IP initiation, the infusion rate will be reduced by 
33.3% every 4 hours until the infusion is stopped or until the infusion rate becomes too low 
to sustain the IV line.  
Note: If, according to the investigator’s clinical judgment, IP taper needs to start sooner than 
36 hours after initiation, the infusion rate will be decreased by 33.3% of the rate at the 
beginning of the IP taper every 4 hours.  
Table 4. 
Dosing for Participants ≥40 kg (on a mg/hour basis) 
Days 
Start Time from IP Initiation 
IP Dose 
 
IP Infusion Rate 
(mL/hour) 
Duration 
Day 1 
0 hours: bolus dose via syringe or 
infusion pump 
30 mga 
N/A 
3 minutes 
(0.05 hours) 
Day 1 
0 hours through 2 hours following IP 
initiation: continuous infusion, started 
with bolus 
80 mg/hr 
80  
2 hours 
Day 1 
2 hours through 12 hours following 
IP initiation 
40 mg/hr 
40 
10 hours 
Day 1 
12 hours through 24 hours following 
IP initiation  
20 mg/hr 
20 
12 hours 
Day 2b 
24 hours through 36 hours following 
IP initiation 
20 - 45 mg/hr 
20 - 45 
12 hours  
 
Taper 
Day 2c 
36 through 48 hours following IP 
initiation (12-hour taper) 
13 - 30 mg/hr  
13 - 30 
4 hours 
9 - 20 mg/hr 
9 - 20 
4 hours 
6 - 13 mg/hr 
6 - 13 
4 hours 
IP = investigational product. 
a. 
The 30 mg bolus is administered over ~3 minutes. 
b. On Day 2 (24 through 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. 
c. 
To taper the IP, the infusion rate at the 36-hour following IP 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 (e.g., if the 
current infusion rate is 20 mg/hr, the first taper will be 13 mg/hr) the second taper will be 33.3% from the first 
tapered infusion rate (e.g., if the current infusion rate is 20 mg/hr, the second taper will be 9 mg/hr), and the 
final taper will be 33.3% from the previous tapered infusion rate (e.g., if the current infusion rate is 20 mg/hr, 
the final taper will be 6 mg/hr). If, in the investigator’s judgment, the 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 
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• 
At the time the IP infusion is discontinued the participant will progress to the follow-up 
period assessments/procedures.  
Table 5. 
Dosing for Participants <40 kg (on a mg/kg/hour basis) 
Days 
Start Time from IP Initiation 
IP Dose 
IP Infusion Rate 
(mL/kg/hour)a 
Duration 
Day 1 
0 hours: bolus dose via syringe or 
infusion pump 
0.75 mg/kgb 
N/A 
3 minutes 
Day 1 
0 hours through 2 hours following IP 
initiation continuous infusion, started 
with bolus 
2.0 mg/kg/hr 
2.0 
2 hours 
Day 1 
2 hours through 12 hours following IP 
initiation  
1.0 mg/kg/hr 
1.0 
10 hours 
Day 1 
12 hours through 24 hours following 
IP initiation 
0.50 mg/kg/hr 
0.50 
12 hours 
Day 2c 
24 hours through 36 hours following 
IP initiation 
0.50 – 1.125 
mg/kg/hr  
0.50 - 1.125 
12 hours 
 
Taper  
Day 2d  
36 through 48 hours following IP 
initiation (12-hour taper) 
0.34 – 0.75mg/kg/hr 
0.34 - 0.75 
4 hours 
0.22 – 0.51mg/kg/hr 
0.22 - 0.51 
4 hours 
0.15 – 0.34mg/kg/hr 
0.15 - 0.34 
4 hours 
IP = investigational product. 
a. 
Reference the Pharmacy Manual for IP infusion rates based on mg/kg/hour dosing. 
b. The 0.75 mg/kg bolus is administered over ~ 3 minutes. 
c. 
On Day 2 (24 through 36 hours), the continuous infusion dose can be increased from 0.5 mg/kg/hour to a 
maximum dose of 1.125 mg/kg/hour at any time, if needed, to manage seizure relapse or other medical 
reason. 
d. To taper the IP, the infusion rate at the 36-hour following IP 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 (e.g., if the current infusion rate is 0.50 
mg/kg/hr, the first taper will be 0.34 mg/kg/hr), the second taper will be 33.3% from the first tapered infusion 
rate (e.g., if the current infusion rate is 0.50 mg/kg/hr, the second taper will be 0.22 mg/kg/hr), and the final 
taper will be 33.3% from the previous tapered infusion rate (e.g., if the current infusion rate is 0.5 mg/kg/hr, 
the final taper will be 0.15 mg/kg/hr). If, in the investigator’s judgment, the 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. 
 
6.2.4 
Investigational Product Infusion Precautions 
Throughout the study, heart rate and rhythm, blood pressure, and oxygen saturation are 
monitored. Investigational product may be temporarily or permanently discontinued, if clinically 
indicated, for treatment of persistent hypotension (sustained systolic blood pressure <90 mmHg), 
cardiac arrhythmia or oxygen desaturation. 
Due to Captisol® presence in the IV formulation of the IP, renal function will be monitored 
throughout the study. In addition to standard and accepted biomarkers of renal function (i.e., 
creatinine clearance and estimated glomerular filtration ratio [eGFR]), urinary exploratory 
biomarkers of renal function (N-acetyl-β-D-glucosaminidase [NAG], β2-microglobulin, and 
creatinine) will be monitored throughout the study and reviewed by the DMC. 


 
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6.2.5 
Medical Oversight  
Participants will require close medical monitoring as defined by local institutional practice 
guidelines for the treatment of patients with the diagnosis of seizures or status epilepticus. 
Telemedicine 
Telemedicine is an acceptable practice for conducting protocol-driven assessments/procedures as 
defined by local institutional practice guidelines. 
6.2.6 
Investigational Product Tapering (One or More May Apply) 
Scenarios for stopping IP without a taper may include: 
o Participants who receive IP for less than 2 hours  
o Investigational product infusion is discontinued or interrupted (e.g., for safety concerns 
related or not related to IP or due to planned medical procedures), and a decision is made 
not to restart the infusion  
o If at any time during IP administration the participant progresses to an anesthetic with the 
primary intent specifically to treat seizures or achieve burst suppression  
o For other safety reasons based on the investigator’s clinical judgment 
6.2.7 
Dose Adjustments and Interruptions 
Investigational product dose (infusion rate) decreases, and interruptions are discouraged during 
treatment. However, if there is an urgent medical need (e.g., severe hypotension, severe sedation) 
or standard of care requires a procedure for which the infusion rate would need to be temporarily 
decreased or interrupted (e.g., MRI) it should be kept as short as possible and should not exceed 
2 hours. If the interruption is >2 hours, the Medical Monitor should be consulted before 
restarting the infusion.  
Note:  
• After a dose (infusion rate) decrease or interruption, the investigator’s clinical judgment 
of risk/benefit will determine IP administration or discontinuation.  
• Investigational product discontinuation does not affect participation in the study. All 
participants should be followed until they reach the final study follow-up visit/contact or 
consent is withdrawn. 
• In cases when IP discontinuation is considered (e.g., severe sedation), when possible, the 
Medical Monitor should be contacted prior to IP discontinuation.  
• If the decision is made to restart IP, the infusion should be restarted at the rate matching 
the rate at the corresponding nominal time, counted from the start of the IP infusion on 
Day 1 (Time 0). Investigational product bolus or “catch-up” dose to deliver the IP that 
was missed during the interruption should not be administered.  
• Infusion rate increases above those specified in the protocol are not allowed at any time 
during infusion. This is to ensure daily Captisol® and ganaxolone limits are maintained at 
≤50 g/day or 1.25 g/kg/day (in participants weighing <40 kg) and ≤833 mg/day or 
20.825 mg/kg/day (in participants weighing <40 kg), respectively. 


 
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6.2.8 
Unblinding the Treatment Assignment 
6.2.8.1 
Double-Blind Phase 
During the study, the treatment assignment must not be broken except in emergency situations in 
which the identification of the IP is required for further treatment of the participant. If possible, 
the investigator should contact the Medical Monitor before unblinding. 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 unblinded the participant.  
If 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 participant will have the follow-up period assessments/procedures, and the follow-up 
visits/contacts at Weeks 1, 2, 3, and 4. The IRT will record all unblinding events. 
6.3 
Labeling, Packaging, Storage, and Handling 
6.3.1 
Labeling 
Labels containing study information and bottle identification are applied to the IP containers.  
Each 500 mL bottle contains no less than (NLT) 425 mL of IP at a ganaxolone concentration of 
1 mg/mL or placebo. (Note: placebo is only applicable for the double-blind phase). A label is 
applied to each bottle with information on strength, manufacturing batch numbers or job number, 
storage conditions, and name of the manufacturer, as well as a warning that the drug is intended 
for research only.  
The IP will be dispensed to qualified staff members who will administer the IP to the participant. 
All IP is labeled with a minimum of the following: protocol number, unique bottle number, 
dosage form (including product name and quantity in pack), directions for use, storage 
conditions, batch number and/or packaging reference, the statements “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 IP (only applicable for the double-blind phase). The label may be updated per local 
requirements. 
Additional labels (e.g., those used when dispensing marketed product) may be applied to the IP 
bottle to satisfy local or institution requirements, but must not: 
• Contradict the clinical study label. 
• Obscure the clinical study label. 
Sponsor approval is not required to make this change. 


 
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6.3.2 
Packaging 
IP solution for administration will be provided to the site as individual bottles containing 
ganaxolone IV solution 1 mg/mL, or placebo. (Note: placebo is only applicable to the 
double-blind phase). 
Changes to Sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the Sponsor. 
6.3.3 
Storage 
The investigator has overall responsibility for ensuring that IP is stored in a secure, limited 
access location in accordance with applicable requirements under the Controlled Substance Act 
(CSA) and Drug Enforcement Administration (DEA) regulations. Limited responsibility may be 
delegated to the pharmacy or member of the study team, but this delegation must be documented. 
Investigational products are distributed by the pharmacy or by a nominated member of the study 
team. Details on how to store the IP can be found in the Pharmacy Manual. Prior to 
administration inspect the IP for particulate matter, cloudiness, and discoloration. If any of these 
is present, do not use and notify the Sponsor. 
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring of the IP is required at the storage location to ensure that the IP 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 IP and will provide supportive documentation, as necessary. Under no 
circumstances should the product be dispensed to participants 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 IP 
that could affect the integrity of the product(s), such as fumigation of a storage room. 
6.4 
Investigational Product Accountability 
Investigators will be provided ample amounts of the IP to carry out this protocol for the agreed 
number of participants. The investigator or designee will acknowledge receipt of the IP, 
documenting shipment content and condition. Accurate records of all IP dispensed, used, 
returned, and/or destroyed must be maintained as detailed further in this section. 
The investigator has the overall responsibility for dispensing/administering IP. Where 
permissible, tasks may be delegated to a qualified designee (e.g., pharmacist) who is adequately 


 
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trained in the protocol and who works under the 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 IP administration orders and confirm that the IP is 
only administered to participants included in this study following the procedures set out in the 
study protocol. Each participant will be given only the IP carrying their treatment assignment. 
All dispensed medication will be documented in the eCRFs and/or other IP record.  
No IP 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 will be sent to a 
nominated contractor on behalf of the Sponsor for destruction or will be destroyed by the site. 
Investigational product 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 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 IP must be packed in 
a tamper evident manner to ensure product integrity. Contact the Sponsor for authorization to 
return any IP prior to shipment. Shipment of all returned IP must comply with local, state, and 
national laws. 
Investigational product administered to the participant will be destroyed upon completion of the 
individual bottle administration according to institution standard procedures. 
With the written agreement of the Sponsor, unused stock 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 IP must be in accordance with 
local, state, and national laws. 
Based on entries in the IP accountability forms, it must be possible to reconcile IP delivered with 
those used and returned. All IP must be accounted for, and all discrepancies investigated and 
documented to the Sponsor’s satisfaction. 
6.5 
Participant Compliance 
The IP will only be administered by appropriately trained site staff. Investigational product 
accountability must be assessed at the container/packaging level for unused IP that is contained 
within the original tamper evident sealed container (e.g., bottles) or at the individual count level 
for opened containers/packaging. The pharmacist/nominated person will record details on the IP 
accountability form. 


 
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7 STUDY PROCEDURES 
7.1 
Study Schedule 
The study schedule will remain the same under both the double-blind and open-label phases. See 
Table 1 and Table 2 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 
2. Vital signs 
3. Pharmacokinetic sample collection 
4. Clinical laboratory tests 
5. Physical examination 
NOTE: Blood sampling for pharmacokinetic evaluation should 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 participants may be identified in the emergency department, ICU, or other units in the 
hospital, and will be consented/assented and then screened for inclusion/exclusion criteria prior 
to being enrolled to start IP treatment.  
Procedures specific to this protocol and not otherwise considered standard of care, will not be 
performed until written informed consent/assent from the participant/participant’s 
parent/guardian/LAR has been appropriately obtained or deferred, where allowed by law. 
Consent for participants who are at risk for SE may be obtained prior to occurrence of SE, this is 
also referred to as pre-consenting. Additional details on consent/assent can be found in Section 
11.3.1. 
7.1.1.2 
Screen Failures 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened once they have been designated as a screen failure during the same episode of SE. 
Participants who have failed screening in a prior episode of SE may be rescreened if they 
experience a new SE event.  


 
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7.1.2 
Treatment Period  
7.1.2.1 
Investigational Product Initiation Through Taper (Day 1 to Day 2) 
Eligible SE participants will be enrolled to receive either ganaxolone IV solution or placebo 
(double-blind phase) or ganaxolone IV solution (open-label phase) added to SE standard of care. 
Investigational product will be administered as a 48-hour continuous infusion, which includes an 
initial 3-minute bolus and ends with a 12-hour taper. 
The investigator will confirm that the participant meets clinical and EEG criteria for SE during 
the 60-minute period prior to IP initiation and will reconfirm that ongoing ictal activity is present 
within 30 minutes immediately prior to IP initiation. Following IP initiation, the standard 
duration of treatment is 2 days (48 hours) which includes a 12-hour taper as described in 
Section 6. 
7.1.3 
Follow-up Period (starting at IP discontinuation through Week 4) 
Participants will have the follow-up period assessments/procedures collected following IP 
discontinuation (with or without taper) as noted in Section 3. Assessments/procedures will be 
collected every 24 hours through 120 hours (or until hospital discharge) and at the time of 
hospital discharge, followed by weekly follow-up visits/contacts at Week 1, 2, 3 and 4. 
Participants who discontinue IP without a taper, e.g., were administered IP for less than 2 hours, 
progress to anesthesia for seizure suppression or discontinue IP due to safety or any other reason, 
except due to withdrawal of consent, will have the follow-up assessments/procedures collected 
every 24 hours through 120 hours (or until hospital discharge) and at the time of hospital 
discharge, followed by weekly follow-up visits/contacts at Week 1, 2, 3 and 4.  
The follow-up period for this protocol is approximately 4 weeks. Week 1, 2, 3, and 4 visits may 
be conducted as an inpatient visit, if the participant is still in the hospital, or as a telephone 
contact, if the participant has been discharged. Attempts should be made to have discharged 
participants return for one of these visits to be in person. The participant/participant’s 
parent/guardian/LAR, as appropriate, will receive a follow-up contact weekly approximately 7 ± 
3, 14 ± 3, 21 ± 3, and 28 ± 3 days following the IP discontinuation date. If the hospital discharge 
visit corresponds to the Week 1, 2, 3, or 4 (± 3 days) visits, it can take the place of the weekly 
visit.  
During these follow-up period visits/contacts, the site will follow-up on all SAEs and non-
serious AEs, AE resolution that occurs, and concomitant medications. Adverse events and SAEs 
that are not resolved at the time of contact will be followed to closure (see Section 8.1). Table 1 
lists the assessments that should be collected during the follow-up visits/contacts. 
7.1.4 
Additional Care of Participants After the Study 
No aftercare is planned for this study. Participants should follow their physician’s care plan and 
referral guidance. 


 
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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)  
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 
Electroencephalogram (EEG) 
An EEG is required for confirmation of CSE and NCSE diagnosis. Continuous EEG monitoring 
should be used for all study participants and should start before IP initiation to obtain a baseline 
assessment and should continue through the end of the first 24 hours of the follow-up period 
(i.e., 24 hours following IP discontinuation).  
Sites will be offered the use of a rapid EEG device to assist with screening and enrollment of 
participants with NCSE. It is preferred that a conventional EEG is used for the purpose of 
confirming inclusion criterion #3 and EEG monitoring during IP administration.  
In situations when a conventional EEG is not immediately available, the rapid EEG may be used 
to confirm inclusion criterion #3 and enroll the participant. Since the rapid EEG has a limited 
battery life, it should be switched to a conventional EEG within several hours but not earlier than 
90 minutes after IP initiation to allow uninterrupted collection of EEG for the 30-minute SE 
cessation co-primary endpoint. It will be at the investigator’s discretion if the use of the rapid 
EEG will benefit their site. The device should be used according to institution standard practices. 
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) 
The STESS is a prognostic score relying on 4 outcome predictors (age, history of seizures, 
seizure type and extent of consciousness impairment).  


 
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7.2.2.3 
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 participant. Participant and 
clinician rater versions indicate general worsening or improvement on a seven-point Likert-like 
scale. For specific collection timepoints reference Table 1. 
7.2.2.4 
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. 
7.2.2.5 
The Full Outline of UnResponsiveness (FOUR) Score 
The FOUR Score is a tool designed to assess patients with impaired level of consciousness. 
There are four parameters evaluated in order to cover domains of neurological function: eye 
response, motor response, brainstem reflex and respiration. For specific collection timepoints 
reference Table 1. 
7.2.2.6 
Seizure Description Questionnaire  
The Seizure Description Questionnaire is a descriptive questionnaire that captures the clinical 
features of SE prior to IP initiation using ILAE 2015 classification. This questionnaire should be 
collected as close as possible to IP initiation. Reference Table 1. 
7.2.2.7 
Status Epilepticus Cessation Questionnaire 
For this study, SE Cessation is defined as the beginning of the first 30-minute epoch following IP 
initiation in which SE burden is no longer fulfilled (<20% ictal burden and is at least 50% less 
during the 30 minutes prior to IP initiation). This questionnaire should be collected as close as 
possible to 24 and 72 hours following IP initiation. Reference Table 1. 
7.2.2.8 
Super Refractory Status Epilepticus Questionnaire 
The definition of SRSE is SE that is continuous or recurs during or after the SE treatment with 
IV anesthesia for 24 hours or longer. This questionnaire should be collected as close as possible 
to the diagnosis of SRSE and no later than the final study follow-up visit/contact. Reference 
Table 1. 
7.2.2.9 
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.  


 
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7.2.2.10 
EuroQol (EQ-5D-5L) 
The EQ-5D-5L is a descriptive system of health-related quality of life states consisting of 5 
dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For 
specific collection timepoints reference Table 1.  
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, Seizure or SE, and Medication History 
Medical history will include the following: 
• Previous and concomitant illnesses, surgeries, and medications  
• Family history 
• History of drug and alcohol abuse 
• Seizure or SE etiology  
7.2.3.2 
Physical 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 physical examination will include a review of the following body systems:  
• General appearance 
• 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 IP initiation will be 
documented in the participant’s source documents and in the medical history eCRF. Conversely, 
abnormalities identified at the first PE that are thought to develop following IP initiation should 
be recorded as AEs on the AE eCRF page, as deemed by the investigator. 


 
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Changes after the first PE will be recorded as AEs on the AE eCRF page, as deemed by the 
investigator. 
7.2.3.3 
Adverse Event Collection 
Participants 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 will be collected from the time of IP initiation through the final study 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 
through the end of the first 24 hours of the follow-up period. If not continuously monitored, 
vitals should be assessed as stated in Table 1 including collection for participants who stop IP 
without a taper or terminate early from the study. 
Noninvasive blood pressure (systolic and diastolic) and pulse rate will be measured by an 
automated blood pressure device after the participant 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 predose (screening) vital signs that are deemed clinically significant 
based on investigator judgment should be recorded as AEs. 
Weight and height should be collected predose (screening) for calculation of the BMI inclusion 
criterion, if feasible. If not collected at screening, they will need to be collected prior to the end 
of the first 24 hours of the follow-up period. 
7.2.3.5 
Electrocardiography (ECG) 
A 12 lead ECG should be collected after the participant 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. 
The timepoints for ECG collection is noted in Table 1. 
7.2.3.6 
Cardiodynamic 12-Lead Electrocardiography (ECG) Monitoring 
Select sites will participate in a sub study using a continuous 12 lead ECG recorder. For more 
details refer to Appendix 5.  


 
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7.2.3.7 
Clinical Laboratory Evaluations 
All clinical laboratory assays will be performed according to the institution’s laboratory normal 
procedures. If there are laboratory collections that are not done by the institution’s laboratory, the 
institution should follow their standard procedures for sending samples to their reference 
laboratories for analysis (e.g., AEDs). 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 participant’s clinical condition may, at the discretion of the investigator 
or Sponsor, be repeated as soon as possible until confirmed, explained, or resolved. 
Urine Chemistry 
Urine samples for N-acetyl-β-D-glucosaminidase (NAG), β2-microglobulin, and creatinine will 
be collected at the times specified in Table 1. Urine samples will be stored frozen. Details 
regarding sample collection, processing, storage, and shipment to the bioanalytical vendor are 
described in the Biospecimen Manual.  
Drugs of Abuse Testing 
A urine or serum sample for drugs of abuse testing should be collected per the institution 
standard of care and prior to IP initiation. A urine or serum sample for alcohol testing should be 
collected if medically indicated. If medically indicated, the investigator may expand testing for 
additional drugs of abuse above the institution’s standard of care. If unable to collect predose, 
collect as soon as possible following IP initiation. However, if a participant tests positive, it will 
be at the investigator’s discretion to weigh the risks versus benefits for enrollment or continued 
participation. If the investigator decides to discontinue the IP, refer to Section 4.5. 
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 IP initiation, and if pregnancy is suspected. If 
unable to collect predose, collect as soon as possible following IP initiation. Enrollment is not 
contingent upon results. However, if a participant has a positive test result, it will be at the 
investigator’s discretion to weigh the risks versus benefits for continued participation. If the 
investigator decides to discontinue the IP, please refer to Section 4.5. If the institution requires 
the pregnancy test results be obtained prior to IP initiation, the institution guidelines will be 
followed.  
Blood Gas 
All blood gas samples arterial or venous, if collected, will be at the investigator’s discretion to 
manage care. If collected from the time of SE diagnosis through the end of the first 24 hours of 
the follow-up period, the eCRF should be completed. If samples are not collected, a sample will 
not be required.  


 
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If a decision is made to intubate the participant between IP initiation through the end of the first 
24 hours of the follow-up period, a blood sample should be collected. The sample should be 
collected immediately prior to or as close as possible to the time of intubation. 
The clinical laboratory tests performed as part of the protocol are listed in Table 6. 
Table 6. 
Clinical Laboratory Tests 
Hematology  
Coagulation 
Biochemistry 
Urinalysis 
Hemoglobin  
(Hb)  
Hematocrit  
(Hct)  
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 
WBC Differential 
% Basophils 
% Eosinophils 
% Lymphocytes 
% Monocytes 
% Neutrophils 
Basophil count 
Eosinophil count 
Lymphocyte count 
Monocyte count 
Neutrophil count 
Fibrinogen 
Activated partial 
thromboplastin time 
(aPTT) 
Prothrombin time 
(PT) 
International 
normalized ratio 
(INR) 
Sodium 
Potassium 
Calcium 
Glucose  
Total protein 
Albumin 
Creatinine 
Blood urea nitrogen  
(BUN) 
Total Bilirubin 
Alkaline phosphatase  
(ALP)  
Aspartate transaminase (AST) 
Alanine transaminase  
(ALT)  
Total cholesterol1 
Estimated Glomerular 
Filtration Rate (eGFR), if 
available 
Creatinine Clearance 
calculation, if available 
 
Urine Chemistry 
N-acetyl-β-D-glucosaminidase 
[NAG]  
Β2-microglobulin 
Creatinine  
 
Antiepileptic drug levels 
(AEDs; per institution 
standard of care) 
fosphenytoin/ phenytoin,  
valproic acid,  
levetiracetam, 
 lacosamide, phenobarbital or 
brivaracetam  
pH 
Protein 
Blood 
Ketones 
Glucose 
Bilirubin 
Specific gravity 
 
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 Drugs of 
Abuse Testing  
(per institution standard of 
care) 
Phencyclidine 
Opioids2  
Cannabinoids3  
Methamphetamine/Ampheta
mine 
Cocaine 
Barbiturates 
Benzodiazepines 
Alcohol, if medically 
indicated 
 
Urine or Serum Pregnancy 
1. Total cholesterol level, if collected per standard of care, should be collected predose (screening). 
2. May be limited to drug class or list specific drug such as oxycodone, methadone, heroin. 
3. May be limited to drug class or list specific substance such as THC. 


 
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7.2.4 
Others  
7.2.4.1 
Clinical Pharmacology Blood Sample Collection and Handling Procedures 
Blood samples for pharmacokinetic analysis (PK) will be collected at the times specified in 
Table 2. The Sponsor’s expectation is that the investigator will ensure that every effort is made 
to collect all PK 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 for samples drawn within 6 hours following IP initiation or by more than ± 
2 hours for samples drawn beyond 36 hours following IP 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, should 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.  
Pharmacokinetic samples should be collected from the contralateral peripheral access or the 
arterial line and avoid collecting samples downstream of the IP infusion. The location of IP 
access and location of PK sample collection should be documented in the participant’s source. If 
the PK sample cannot be collected due to poor venous access and the IP infusion site is the only 
viable option, the sample should not be collected and the reason for non-collection documented 
in the participant’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 the bioanalytical vendor for analysis. The Sponsor 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 participants complete the 
first 24 hours of the follow-up period, the site will ship the primary plasma samples to the 
bioanalytical vendor. Upon notification of receipt of the primary samples by the bioanalytical 
vendor, the backup samples will be shipped to the bioanalytical laboratory. Refer to the 
Biospecimen Manual for details regarding sample 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.  


 
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Table 7. 
Volume of Blood to Be Drawn from Each Participant 
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 
5 
3 
42.5 to 68 
 
Hematology  
4.0 
5 
3 
20 to 32 
 
Coagulation 
5.1 
3 
1 
15.3 to 20.4 
Pharmacokinetic samples 
(with indwelling catheter) c 
3.0 
8 
0 
24  
Blood gas (for intubation 
only) b 
1.0 
0 
1 
1 
Total mL 
140.3 to 190.4 
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 and 
pharmacokinetic 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 sample collection timepoints. There are required collection timepoints for all participants 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 participant. 
c. 
Blood samples for pharmacokinetic analysis will be collected as noted in Table 2. 
d. Venous or arterial samples are acceptable. 
 
Table 8. 
Volume of Blood to Be Drawn from Each Participant (Pediatric Institution 
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 
5 
3 
10 to 16 
 
Hematology  
1.0 
5 
3 
5 to 8 
 
Coagulation 
1.0 
3 
1 
3 to 4 
Pharmacokinetic samples 
(with indwelling catheter) c 
3.0 
8 
0 
24  
Blood gas (for intubation 
only) b 
1.0 
0 
1 
1 
Total mL 
36 to 40 
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 and 
pharmacokinetic 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 sample collection timepoints. There are required collection timepoints for all participants 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 participant. 


 
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c. 
Blood samples for pharmacokinetic analysis will be collected as noted in Table 2. Venous or arterial samples 
are acceptable.  
  
During the study, it is expected that some sites (e.g., pediatric institutions) will collect smaller 
volumes of blood from participants per local laboratory standards. The ranges in Table 7 and 
Table 8 reflect the possible range for adult and child versus a pediatric only institution. The total 
blood volume drawn from pediatric participants for all safety and pharmacokinetic sampling will 
be approximately 36 mL and will not exceed 40 mL. The total blood drawn from adult 
participants will be approximately 140.3 mL and will not exceed 190.4 mL. 
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 optional collections have been 
included in Table 7 and Table 8.  
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 collection tube, the assessments may be 
combined. 
7.3 
Healthcare Utilization Questionnaires 
The Healthcare Utilization Questionnaires include the Hospitalization Questionnaire and the 
Positive Pressure Ventilation (PPV) and Intubation Questionnaire. The Hospitalization 
Questionnaire should be collected at hospital discharge or at final study visit/contact. The need 
for non-invasive or invasive ventilatory support within 24 hours prior to IP initiation and 
following IP initiation and within 48 hours following IP discontinuation should be collected as 
close as possible to the event. 
 


 
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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 participant 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 an IP 
product, whether or not related to the IP.40  
As this study allows for pre-consenting of participants, all AEs will be collected from the time of 
IP initiation until the final study follow-up visit/contact stated in Section 7.1. 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 AE eCRF 
page and in source documents. In addition to untoward AEs, unexpected benefits outside the IP 
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 participants who terminate early from the study, prior to discontinuation as much 
information as possible as is available should be recorded for AEs/SAEs and their associated 
concomitant medication, especially those 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 
event. Worsening of pretreatment events, after initiation of the IP, 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 participant. 
Severe: 
A type of AE that interrupts usual activities of daily living, that significantly affects 
clinical status, or that may require intensive therapeutic intervention. 


 
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8.1.2 
Relationship Categorization 
A physician/investigator must make the assessment of the relationship between the IP 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 IP. 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 IP 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 participant’s medical condition, other therapies, or 
accident. 
Not related 
The event can be readily explained by other factors, such as the 
participant’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 study in the eCRF. Outcomes are as follows: 
• 
Fatal 
• 
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 participant returned to baseline status, but SE recurred, the 
event would then be recorded as an SAE. 


 
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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 IP, 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 following IP 
discontinuation), and the range of variation of the respective parameter within its reference range 
must be taken into consideration. 
At the end of the treatment phase, for participants who complete the study and do not progress to 
an IV anesthetic for seizure suppression, if there are abnormal clinical laboratory, vital sign, or 
ECG values that were not present in the pretreatment assessments closest to the start of IP 
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 
participant, 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 participants, all pregnancies are to be reported from 
the time of IP initiation until the defined follow-up period stated in Section 7.1. 
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 Drug Safety vendor using the 
Pregnancy Report Form. If a participant has a positive test result, it will be at the investigator’s 
discretion to weigh the risks versus benefits for 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 eCRF 
Completion 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 Drug Safety vendor 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 β-human chorionic gonadotropin test or ultrasound result will determine the 
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8.1.7 
Medication Errors and Other Reportable Information 
Medication errors made in prescribing, dispensing, administering, or use of an IP must be 
reported as protocol deviations. An overdose is a medication error and is defined as 
administration of IP exceeding the prespecified total daily dose of the IP which for this study is 
set by a 50 g/day (1.25 g/kg/day in participants weighing <40 kg) Captisol® limit which 
corresponds to a maximum of 833 mg/day (20.825 mg/kg/day in participants weighing <40 kg) 
ganaxolone.  
If a medication error results in a Captisol®/ganaxolone overdose, this is a protocol deviation that 
may have the potential to affect the safety of the affected participant. The administration of lower 
doses of the IP as a result of an IP rate decrease or as part of IP discontinuation are not 
considered medication errors and are permitted by protocol. 
In addition to medication errors the following events are considered other reportable information 
and are reportable to the Marinus Drug Safety vendor within 15 days of awareness of the event 
using the Medication Errors and Other Reportable Information Report Form. A copy of the 
Report Form (and any applicable follow-up reports) must also be sent to the Medical Monitor 
using the details specified in the emergency contact information section at the beginning of the 
protocol: 
• Accidental exposure 
• Lactation exposure 
• Product Misuse 
All IP 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 Safety Information for this study is the Ganaxolone IB, which the Sponsor has 
provided under separate cover to all investigators.  
8.2.2 
Reporting Procedures 
All initial and follow-up SAE reports must be reported by the investigator to the Marinus Drug 
Safety vendor within 24 hours of the first awareness of the event. Note: The 24-hour reporting 
requirement for SAEs does not apply to reports of medication errors and other reportable 
information (see Section 8.1.7) unless the event results 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 email the form to the 
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follow-up reports) must also be sent to the 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 IP 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 participant 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 inpatient 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 
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 SAE 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 that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.  
8.2.4 
Serious Adverse Event Collection Time Frame 
As this study allows for pre-consenting of participants, all SAEs (regardless of relationship to 
study) are collected from the time of IP initiation until the final study follow-up visit/contact 
stated in Section 7.1 and must be reported to the Marinus Drug Safety vendor within 24 hours of 
the first awareness of the event.  
In addition, any SAE considered “related” to the IP and discovered by the investigator at any 
interval after the study has completed must be reported to the Marinus Drug Safety vendor 
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 
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In addition, any signs or symptoms experienced by the participant following IP 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 participant’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 participant’s 
death, the outcome should be considered not resolved, without a resolution date recorded. 
For any SAE that results in the participant’s death or any ongoing events at the time of death, 
unless another IP action was previously taken (e.g., the IP was interrupted, reduced, or 
withdrawn), the action taken with the IP should be recorded as “dose not changed” or “not 
applicable” (if the participant never received the IP). The IP action of “withdrawn” should not be 
selected solely as a result of the participant’s death.  
8.2.7 
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor or its delegate is responsible for notifying the relevant regulatory authorities in the 
US of related, unexpected SAEs. For ex-US countries, the Sponsor will comply with local laws 
and requirements with regard to SAE reporting. 
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 IRBs, local EC, or the relevant local 
regulatory authority of all SAEs that occur at their site as required. 
 
 


 
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9 DATA MANAGEMENT  
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 prior to enrollment (e.g., 
site initiation or other type of visit, investigator meeting, or other planned training). Once a 
participant is enrolled, the site should initiate data entry within 5 days of enrollment with the 
goal of having all protocol required data entered within 5 days of the participant’s last follow-up 
visit/contact.  
9.2 
Clinical Data Management 
Data are to be entered into a clinical database as specified in 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 
Data Monitoring Committee (DMC) 
The emerging study data will be reviewed on a regular basis by an independent DMC. The 
mission of the DMC will be to safeguard the interests of study participants and to enhance the 
integrity of the trial. To enable the DMC to achieve its mission, it will have ongoing access to 
efficacy and safety data and information regarding quality of trial conduct and will ensure that 
the confidentiality of these data are protected. A DMC charter will provide the principles and 
guidelines for the DMC process. 
10 STATISTICAL CONSIDERATIONS 
10.1 Statistical Analysis Process 
The statistical analysis plan (SAP) will provide the complete details for the analysis and 
reporting of the data from the study.  
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized and approved prior to database lock for the interim analysis and prior to the Sponsor 
being unblinded to treatment assignments. All deviations from or changes to the SAP following 
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10.2 Sample Size Determination 
Approximately 124 participants will be randomized and qualified for the study. The sample size 
is based on the assumption of at least 75% response rate to ganaxolone treatment for each of the 
co-primary endpoints and no more than 45% response rate to placebo treatment and 1:1 
randomization ratio.  
With 62 participants randomized to each treatment arm, there would be at least 90% power for 
each co-primary endpoint to achieve statistical significance at 2-sided 5% level of significance. 
10.3 Analysis Populations 
The following population are defined: 
Population 
Description 
Safety 
All participants who received IP. 
Intent to Treat (ITT) 
All randomized participants in the double-blind phase of the study who 
received IP and had at least one non-missing efficacy assessment. 
Per Protocol (PP) 
All participants in the ITT population without major protocol deviations 
related to co-primary endpoint efficacy assessments. 
Open-Label (if applicable) 
All enrolled participants who received open-label IP (should the study 
transition to open-label). 
 
10.4 Statistical Analyses 
The SAP will be finalized prior to database lock (DBL) and it will include a more technical and 
detailed description of the statistical analyses described in this section. This section is a summary 
of the planned statistical analyses of the most important endpoints including primary and key 
secondary endpoints. 
10.4.1 
Primary Endpoints (Double-Blind Phase) 
The primary efficacy objective of this study is to assess the efficacy of ganaxolone plus standard 
of care versus placebo plus standard of care in producing rapid and durable SE cessation without 
the need for treatment escalation to IV anesthesia for at least 36 hours following IP initiation. 
Since the primary efficacy objective is a composite objective, in order to establish effectiveness 
of ganaxolone and support approval, the superiority of ganaxolone vs placebo added to standard 
of care would need to be established for the following co-primary endpoints: 
1. Proportion of participants with SE cessation within 30 minutes of IP initiation without 
medications for the acute treatment of SE 
2. Proportion of participants with no progression to IV anesthesia for 36 hours following IP 
initiation 
SE cessation will be determined by the investigator based on clinical and EEG features (see 
Appendix 1 for SE cessation guide). Training will be provided to guide and help standardize 
decisions across clinical sites. In addition, a retrospective, confirmatory analysis of time of SE 
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Medications for the acute treatment of SE are defined as AEDs administered to abort ongoing SE 
or prevent imminent recurrence of SE based on clinical or EEG evidence. This definition 
excludes maintenance doses of AEDs or medications with anticonvulsant properties used for 
other reasons, such as procedural sedation. 
Both co-primary efficacy endpoints must be statistically significant to claim the study being 
positive. No ordering is involved in the hypothesis testing of the two co-primary endpoints. 
The efficacy analysis of the response rates observed for each co-primary endpoint will be 
conducted by using logistic regression methods. The model will include terms for treatment 
group and baseline STESS as a covariate. The analysis will be based on the ITT population. 
Model-based point estimates (i.e., odds ratio), 95% confidence intervals and p-values will be 
reported. In addition, the point estimate of difference of the proportions of participants achieving 
either and both co-primary endpoints between two treatment arms will be provided. The 95% 
confidence interval will be provided using Clopper-Pearson method.41 
Due to the nature of the disease and short observational period, occurrence of intercurrent events 
is expected to be low, and thus a treatment policy approach is planned for the co-primary 
analyses. 
10.4.2 
Key Secondary Endpoints (Double-Blind Phase) 
The following key secondary endpoints will be analyzed: 
1. Time to SE cessation following IP initiation  
2. Proportion of participants with no progression to IV anesthesia for 72 hours following IP 
initiation 
If the primary endpoints are statistically significant, the key secondary endpoints will be 
compared between ganaxolone and placebo treatment groups based on the ITT population with a 
hierarchical testing progress at the same alpha level of the primary endpoints. Each key 
secondary endpoint will only be tested if the prior endpoint is statistically significant.  
The time to SE cessation endpoint will be analyzed using the Kaplan-Meier method.20 The 
comparison of the survival curves between treatment groups will be conducted by a log-rank test. 
The second key secondary endpoint will be analyzed using the same statistical model as 
pre-specified for the co-primary endpoints. 
10.4.3 
Other Secondary Endpoints  
The following secondary endpoints will be analyzed: 
• 
Proportion of participants with any escalation of treatment in the first 24 hours following IP 
initiation, i.e., any medication other than IP for the acute treatment of SE in the first 24 hours 
• 
Time to treatment escalation following IP initiation (any other mediation used for acute 
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• 
Time to initiation of anesthesia for SE treatment through the final study follow-up 
visit/contact 
• 
Proportion of participants who develop SRSE through the final study follow-up visit/contact 
• 
Seizure burden through 72 hours following IP initiation 
• 
Level of responsiveness as assessed by the FOUR Score Scale 
• 
Level of sedation/agitation as assessed by the RASS  
• 
Clinician Global Impression-Improvement (CGI-I)  
• 
Level of functioning as assessed by the mRS  
• 
Level of functioning as assessed by the EuroQoL (EQ-5D-5L) 
• 
Proportion of participants with mRS ≥3 at the time of hospital discharge 
• 
Proportion of participants whose treatment does not progress to IV anesthesia for 4 weeks 
following IP initiation 
10.4.4 
Healthcare Utilization Endpoints 
If the key secondary endpoints are statistically significant, analysis of the first healthcare 
utilization endpoint, time on positive pressure ventilation, will be performed. The time on 
positive pressure ventilation endpoint will be analyzed using the Kaplan-Meier method. The 
comparison of the survival curves between treatment groups will be conducted by a log-rank test. 
• 
Time on positive pressure ventilation after IP initiation. 
• 
Proportion of participants requiring positive pressure ventilation initiated during IP infusion. 
• 
Length of stay in the intensive care unit and in hospital after IP initiation. 
• 
Discharge destination (location where the participant is living at the last follow-up 
assessment). 
The other healthcare utilization endpoints will be summarized descriptively. 
Further details are provided in the SAP. 
10.4.5 
Open-Label Endpoints 
If the study transitions to the open-label phase, all endpoint assessments as described for the 
double-blind phase will be summarized using descriptive statistics and no formal hypothesis 
testing will be performed. Efficacy analyses performed for the open-label phase of this study will 
be based on the Open-Label (OL) population. 
10.5 Safety Analyses 
Adverse Events will be coded using the Medical Dictionary for Regulatory Activities. The 
number of events, incidence, and percentage of treatment-emergent AEs will be calculated 
overall, by system organ class, by preferred term, and by treatment group in the double-blind 
phase, and summarized overall if the study transitions to open-label. Treatment emergent AEs 
will be further summarized by severity and relationship to IP. Adverse events related to IP, AEs 
leading to withdrawal, SAEs, and deaths will be similarly summarized and listed. 


 
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Physical examinations, clinical laboratory tests, vital signs, ECG findings, use of concomitant 
medications will be summarized by treatment group in the double-blind phase, and summarized 
overall if the study transitions to open-label.  
10.6 Pharmacokinetic Analyses 
The PK population will include all participants who have received at least 1 dose of IP and who 
have had at least 1 sample collected and a valid bioanalytical result obtained. The following 
plasma pharmacokinetic parameters for ganaxolone and Captisol will be calculated as data 
allows and as appropriate using noncompartmental approaches:  
• 
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. 
Pharmacokinetic variables will be computed using WinNonlin Professional, version 5.2 or 
similar software. Actual elapsed sampling times relative to IP administration will be used for the 
estimation of pharmacokinetic metrics. Additional parameters may be calculated on discretion of 
the pharmacokineticist, pending review of the data.  
10.7 Interim Analyses 
An interim analysis was planned when two-thirds of the ITT population have completed 72 hours 
of efficacy assessments on the co-primary and key secondary endpoints (approximately 41 
participants per arm). The overall type I error rate (i.e., alpha=0.05, 2-sided) will be controlled 
using a power family alpha spending function, with a 2-sided nominal alpha level of 0.0293 at 
the interim analysis. The interim analysis will be performed by an independent statistician who is 
not involved in study operation or study conduct. 
The interim analysis was performed by an independent statistician who was not involved in study 
operation or study conduct and was based on 83 participants who had completed the primary and 
key secondary efficacy assessments. The DMC recommended that the study may continue 
without modification. 
To control the overall type I error rate (i.e., a two-sided alpha level of 0.05), the alpha value for 
the final analysis will be adjusted by the final sample size.  For example, if the final analysis 
sample size is 100, the two-sided alpha level for the final analysis is 0.0410. 
Further details will be provided in the SAP. 
11 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This study is conducted in accordance with current applicable regulations, International Council 
for Harmonisation (ICH), European Union (EU) Directives and its updates, and local ethical and 
legal requirements.  


 
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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. 
11.1 Sponsor’s Responsibilities 
11.1.1 
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 
current, applicable industry regulations, ICH GCP Guidelines, and EU Directives, 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, participants’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities. 
The Sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The Sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of IP for 
shipment to the site. 
11.1.2 
Public Posting of Study Information 
The Sponsor, or their designee, is responsible for posting appropriate study information on 
applicable websites such as ClinicalTrials.gov and Europe’s website - Eudract.ema.europa.eu. 
Information included in clinical study registries may include participating investigator’s names 
and contact information. 
11.1.3 
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.  
11.1.4 
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 
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11.2 Investigator’s Responsibilities 
11.2.1 
Good Clinical Practice Compliance 
The investigator must undertake to perform the study in accordance with current ICH GCP 
Guidelines, EU Directives, 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 the potential for recruiting the 
required number of suitable participants 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 participant has a primary care physician, the investigator should, with the 
participant’s consent, inform them of the participant’s participation in the study. 
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).  
11.2.2 
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 participants 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 or destroy all IP, containers, and other study materials in accordance 
with the Sponsor instructions. 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. 


 
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11.2.3 
Documentation and Retention of Records 
11.2.3.1 
Case Report Forms 
Electronic CRFs are supplied by the Data Management vendor detailed in the investigator’s and 
Sponsor’s files, as applicable, and should be handled in accordance with the 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. Electronic CRFs must be 
completed by the investigator or designee as stated in the site delegation log. 
All data will have separate source documentation; no data will be recorded directly 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 according to 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. 
11.2.3.2 
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 
participant’s medical file and original clinical laboratory reports.  
All key data must be recorded in the participant’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 
participant 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., participant’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 applicable regulatory authority or an 
auditor. 


 
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Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the Sponsor. 
11.2.3.3 
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 FDA, other regulatory 
authorities, the Sponsor or its representatives, and the IRB/EC for each site. 
11.2.3.4 
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 IP; and any significant equity 
interest in the Sponsor or subsidiaries as defined in 21 Code of Federal Regulations 54 2(b) 
(1998). 
11.3 Ethical Considerations 
11.3.1 
Informed Consent 
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable, from all study participants prior to any study related procedures, including screening 
assessments. As the disease under consideration is a life-threatening condition for which 
participants 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 participant for study 
participation. Consent/assent will be administered according to institution 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 participant directly. Alternatively, consent and assent for participants 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 institutions IRB/EC. However, 
reconsenting will be required 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 participant, participant’s parent, guardian, or the LAR, as applicable, is requested to 
sign and date the participant’s informed consent form/assent or a certified translation, if 
applicable, after the participant, participant’s parent, guardian, or LAR has received and read (or 
been read) the written participant information and received an explanation of what the study 
involves, including but not limited to the objectives, potential benefits and risk, inconveniences, 
and the participant’s rights and responsibilities. A copy of the informed consent and assent 
documentation (i.e., a complete set of participant information sheets and fully executed signature 
pages) must be given to the participant, participant’s parent, guardian, or the LAR, as applicable. 


 
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This document may require translation into the local language. Signed consent forms must 
remain in each participant’s study file and must be available for verification at any time. 
The 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 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample participant information and consent document provided by the Sponsor, the 
documentation supporting this requirement must be provided to the Sponsor. 
11.3.2 
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 and assent documents (approved by the Sponsor or their designee), relevant 
supporting information, and all types of participant 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/assent documents and amendments to the protocol unless there 
is a participant safety issue. 
Investigational product supplies will not be released until the Sponsor or designee has received 
written IRB/EC approval of and copies of revised documents. 
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. 
11.4 Privacy and Confidentiality 
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA). A 
site that is not a covered entity as defined by HIPAA must provide documentation of this fact to 
the CRO/Sponsor. All sites, laboratories, or entities providing support for this study, must, where 
applicable, comply with General Data Protection Regulation (GDPR) for purposes of data 
protection and privacy. 
The confidentiality of records that may be able to identify participants will be protected in 
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After participant, participant’s 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 participants’ 
identities. 
Participants 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 participant).  
The results of studies containing participants’ 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. 
11.5 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. 
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, 
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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 institution 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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12 REFERENCES 
1. 
Lowenstein, D. and Alldredge, B. (1998). Status epilepticus. New England Journal of 
Medicine, 338: 970-76. 
2. 
Trinka, E., Cock, H., Hesdorffer, D., Rossetti, A., Scheffer, I., Shinnar, S., Shorvon, S. 
and Lowenstein, D. (2015). A definition and classification of status epilepticus-Report of 
the ILAE Task Force on Classification of Status Epilepticus. Epilepsia, 56: 1515-23. 
3. 
Falco-Walter, J. and Bleck, T. (2016). Treatment of established status epilepticus. 
Journal of Clinical Medicine, 5 (5): 49. 
4. 
Bhattacharjee, A. and Hirsch, N. (2015). Management of status epilepticus. Anaesthesia 
& Intensive Care Medicine, 16: 159-60. 
5. 
Treiman, D. (2014). Status epilepticus. Daroff, R. and Aminoff, M. (editors). 
Encyclopedia of the Neurological Sciences (Academic Press: Oxford, UK). 
6. 
Treiman, D. (2007). Treatment of convulsive status epilepticus. International Review of 
Neurobiology, 81: 273-85. 
7. 
Koubeissi M, Alshekhlee A. (2007). In-hospital mortality of generalized convulsive 
status epilepticus: a large scale US sample. Neurology, 69: 886-893. 
8. 
Glauser, T., Shinnar, S., Gloss, D., Alldredge, B., Arya, R., Bainbridge, J., Bare, M., 
Bleck, T., Dodson, W.E., and Garrity, L. (2016). Evidence-based guideline: treatment of 
convulsive status epilepticus in children and adults: report of the Guideline Committee of 
the American Epilepsy Society. Epilepsy Currents, 16: 48-61. 
9. 
Kapur, J., Elm, J., Chamberlain, J., Barsan, W., Cloyd, J., Lowenstein, D., Shinnar, S., 
Conwit, R., Meinzer, C., Cock, H., Fountain, N., Connor, J., Silbergleit, R., Nett and 
Pecarn Investigators. (2019). Randomized trial of three anticonvulsant medications for 
status epilepticus. New England of Journal Medicine, 381: 2103-13. 
10. 
Kapur, J. and Macdonald, R. (1997). Rapid seizure-induced reduction of benzodiazepine 
and Zn2+ sensitivity of hippocampal dentate granule cell GABAA receptors. Journal of 
Neuroscience, 17: 7532-40. 
11. 
Mayer, S., Claassen, J., Lokin, J., Mendelsohn, F., Dennis, L. and Fitzsimmons, B.F. 
(2002). Refractory status epilepticus: frequency, risk factors, and impact on outcome. 
Archives of Neurology, 59: 205-10. 
12. 
Niquet, J., Baldwin, R., Suchomelova, L., Lumley, L., Naylor, D., Eavey, R. and 
Wasterlain, C. (2016). Benzodiazepine-refractory status epilepticus: pathophysiology and 
principles of treatment. Annals of the New York Academy of Sciences, 1378: 166-73. 
13. 
Trinka, E., Höfler, J., Leitinger, M. and Brigo, F. (2015). Pharmacotherapy for status 
epilepticus. Drugs, 75: 1499-521. 


 
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14. 
Hocker, S., Britton, J., Mandrekar, J., Wijdicks, E. and Rabinstein, A. (2013). Predictors 
of outcome in refractory status epilepticus. JAMA Neurology, 70: 72-77. 
15. 
Shorvon, S. and Ferlisi, M. (2012). The outcome of therapies in refractory and super-
refractory convulsive status epilepticus and recommendations for therapy. Brain, 135: 
2314-28. 
16. 
Sutter, R., Marsch, S., Fuhr, P., Kaplan, P. and Rüegg, S. (2014). Anesthetic drugs in 
status epilepticus: risk or rescue?: a 6-year cohort study. Neurology, 82: 656-64. 
17. 
Nohria, V. and Giller, E. (2007). Ganaxolone. Neurotherapeutics, 4: 102-05. 
18. 
Rogawski, M., Loya, C., Reddy, K., Zolkowska, D. and Lossin, C. (2013). Neuroactive 
steroids for the treatment of status epilepticus. Epilepsia, 54(suppl 6): 93-98. 
19. 
Leitinger, M., Trinka, E., Gardella, E., Rohracher, A., Kalss, G., Qerema, E., Höfler, J., 
Hess, A., Zimmermann, G., Kuchukhidze, G., Dobesberger, J., Langthaler, P., Beniczky, 
S. (2016). Diagnostic accuracy of the Salzburg EEG criteria for non-convulsive status 
epilepticus: a restrospective study. The Lancet Neurology, 15:1054-62. 
20. 
Kaplan, E. and Meier, P. (1958). Nonparametric estimation from incomplete 
observations. Journal of the American Statistical Association; 53: 457-481.  
21. 
Jędrzejczak J, Mazurkiewicz-Bełdzińska M, Szmuda M, et al. Convulsive status 
epilepticus management in adults and children: Report of the Working Group of the 
Polish Society of Epileptology. Neurol Neurochir Pol. 2018;52(4):419-426. 
22. 
Chiarello D, Duranti F, Lividini A, et al. Clinical characterization of status epilepticus in 
childhood: a retrospective study in 124 patients. Seizure. 2020;78:127-133. 
23. 
Marawar R, Basha M, Mahulikar A, et al. Updates in Refractory Status Epilepticus. Crit 
Care Res Pract. 2018;2018:9768949. 
24. 
Brophy, G., Bell, R., Claassen, J., Alldredge, B., Bleck, T., Glauser, T., Laroche, S., 
Riviello, Jr., J., Shutter, L., Sperling, M., Treiman, D., Vespa, P. and Committee 
Neurocritical Care Society Status Epilepticus Guideline Writing. (2012). Guidelines for 
the evaluation and management of status epilepticus. Neurocrit Care, 17: 3-23. 
25. 
Treiman, D. (2008). Importance of early recognition and treatment of generalized 
convulsive status epilepticus. The Lancet Neurology, 7: 667-68. 
26. 
Knake, S., Hamer, H. and Rosenow, F. (2009). Status epilepticus: a critical review. 
Epilepsy and Behavior, 15: 10-4. 
27. 
Rossetti, A. and Lowenstein, D. (2011). Management of refractory status epilepticus in 
adults: still more questions than answers. The Lancet Neurology, 10: 922-30. 


 
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28. 
DeLorenzo, R., Waterhouse, E., Towne, A., Boggs, J., Ko, D., DeLorenzo, G., Brown, A. 
and Garnett, L. (1998). Persistent nonconvulsive status epilepticus after the control of 
convulsive status epilepticus. Epilepsia, 39: 833-40. 
29. 
Silbergleit, R., Durkalski, V., Lowenstein, D., Conwit, R., Pancioli, A., Palesch, Y. and 
Barsan, W. (2012). Intramuscular versus intravenous therapy for prehospital status 
epilepticus. New England Journal of Medicine, 366: 591-600. 
30. 
Treiman, D. (2001). GABAergic mechanisms in epilepsy. Epilepsia, 42(Suppl. 3): 8-12. 
31. 
Rossetti, A., Logroscino, G. and Bromfield, E. (2005). Refractory status epilepticus: 
effect of treatment aggressiveness on prognosis. Archives of Neurology, 62: 1698-702. 
32. 
Neligan, A. and Shorvon, S. (2010). Frequency and prognosis of convulsive status 
epilepticus of different causes: a systematic review. Archives of Neurology, 67: 931-40. 
33. 
Sutter, R., Kaplan, P. and Rüegg, S. (2013). Outcome predictors for status epilepticus-
what really counts. Nature Reviews Neurology, 9: 525-34. 
34. 
Strzelczyk, A., Ansorge, S., Hapfelmeier, J., Bonthapally, V., Erder, M. and Rosenow, F. 
(2017). Costs, length of stay, and mortality of super-refractory status epilepticus: A 
population-based study from Germany. Epilepsia, 58: 1533-41. 
35. 
Claassen, J., Hirsch, L., Emerson, R. and Mayer, S. (2002). Treatment of refractory status 
epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia, 
43: 146-53. 
36. 
Ganaxolone Investigator’s Brochure. (December 2021). Radnor, PA: Marinus 
Pharmaceuticals, Inc. 
37. 
Saporito, M., Gruner, J., DiCamillo, A., Hinchliffe, R., Barker-Haliski, M., White, H. 
(2019). Intravenously administered ganaxolone diazepam-resistant lithium-pilocarpine-
induced status epilepticus in rats: comparison with allopregnanolone. Journal of 
Pharmacology and Experimental Therapeutics, 368: 326-337. 
38. 
Albers, J., Moddel, G., Dittrich, R., Steidl, C., Suntrup, S., Ringelstein, E. and Dziewas, 
R. (2011). Intravenous lacosamide-an effective add-on treatment of refractory status 
epilepticus. Seizure, 20: 428-30. 
39. 
Moddel, G., Bunten, S., Dobis, C., Kovac, S., Dogan, M., Fischera, M., Dziewas, R., 
Schabitz, W., Evers, S. and Happe, S. (2009). Intravenous levetiracetam: a new treatment 
alternative for refractory status epilepticus. Journal of Neurology, Neurosurgery and 
Psychiatry, 80: 689-92. 
40. 
International Conference on Harmonisation (ICH) Guidance E2A March 1995. Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting. 


 
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41. 
Clopper, C., Pearson, E.S. (1934). The use of confidence or fiducial limits illustrated in 
the case of the binomial. Biometrika, 26 (4): 404-413. 
 
 


 
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13 APPENDICES 
 
 


 
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APPENDIX 1 STATUS EPILEPTICUS CESSATION GUIDE 
Status epilepticus cessation will be based on investigator judgment, guided by the following 
clinical and electrographic features: 
1. The first 30-minute SE free period after IP initiation denotes the onset of SE cessation 
2. Electrographically SE cessation should coincide with the beginning of the first 30-
minute epoch of EEG which demonstrates seizure burden <20% and at least 50% less 
than during the 30 minutes prior to IP initiation 
3. For the first co-primary endpoint only, SE cessation observed without administration 
of medications for the acute treatment of SE* from the time of IP initiation through 
30 minutes following the onset of SE cessation 
*Medications for the acute treatment of SE are defined as AEDs administered to abort ongoing 
SE or prevent imminent recurrence of SE based on clinical or EEG evidence. This definition 
excludes maintenance doses of AEDs or medications with anticonvulsant properties used for 
other reasons, such as procedural sedation. 
 
 


 
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APPENDIX 2 THERAPEUTIC DOSES OF BENZODIAZEPINES AND 2ND 
LINE IV AEDS 
Benzodiazepines 
Drug Name 
Dose 
Diazepam 
• 
0.15-0.2 mg/kg IV up to 10 mg per dose 
• 
may repeat in 5 minutes 
Diazepam (rectal) 
• 
0.2-0.5 mg/kg, maximum 20 mg/dose 
Lorazepam 
• 
0.1 mg/kg IV up to 4 mg/dose 
• 
may repeat in 5-10 minutes 
Midazolam 
• 
0.2 mg/kg IM, maximum 10 mg/dose  
 
 
2nd line IV AEDs 
Drug Name 
Dose 
Phenytoin (PHT)/ 
fos-phenytoin (fPHT) 
• 
PHT loading dose: 15-20 mg/kg IV given once, which can be 
followed by additional 10 mg/kg IV after 20 minutes if there 
is no response to the initial dose 
• 
PHT maintenance dose: 100 mg IV q6-8 hours (adjusted based 
on treatment response or blood levels) 
• 
fPHT loading dose: 18-20 mg PE/kg with a maximum 
infusion rate of 150 mg PE/min IV 
• 
Maintenance dose should begin 12 hours after loading dose 
• 
fPHT, maintenance dose: 5 mg PE/kg/day IM/IV divided daily 
TID 
Valproic acid (VPA) 
• 
Loading dose: 20-40 mg/kg IV at an infusion rate of 
6 mg/kg/min 
• 
Maintenance dose: 10-20 mg/kg/day divided in BID-TID 
dosing 
Levetiracetam (LEV) 
• 
Loading dose: 20-60 mg/kg 
• 
Maintenance dose: 1000-3000 mg/day or  
20 mg/kg/day 
Brivaracetam (BRI) 
• 
Loading dose: 2-4 mg/kg 
Lacosamide (LAC) 
• 
Loading dose: 400-600 mg IV 
• 
Maintenance dose: 20-300 mg BID 
Phenobarbital (PHEN) 
• 
Loading dose: 15-20 mg/kg IV 
• 
Maintenance dose: 1-4 mg/kg/day 
The doses cited above are based on the published literature and should serve as guidance only.  
 
References: 
Aicua-Rapun, I., Andre, P., Rossetti, A.O., Decosterd, L.A., Buclin, T. & Novy, J. (2019) Intravenous brivaracetam in status 
epilepticus: Correlation between loading dose, plasma levels and clinical response. Epilepsy Res, 149, 88-91. 
 
Brophy, G.M., Bell, R., Claassen, J., Alldredge, B., Bleck, T.P., Glauser, T., Laroche, S.M., Riviello, J.J., Jr., Shutter, L., 
Sperling, M.R., Treiman, D.M., Vespa, P.M. & Neurocritical Care Society Status Epilepticus Guidelines Writing, C. (2012). 
Guidelines for the evaluation and management of status epilepticus. Neurocrit Care, 17, 2-23. 
 
Glauser, T., Shinnar, S, Gloss, D., Alldredge, B., Arya, R., Bainbridge, J., Bare, M., Bleck, T., Dodson, W.E., Garrity, L., Jagoda, 
A., Lowenstein, D., Pellock, J., Riviello, J., Sload, E. & Treiman, D.M. (2016) Evidence-Based Guideline: Treatment of 
Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society.  
Epilepsy Curr, 16, 48-61. 


 
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Wasim, M. & Husain, A.M. (2015 Nonconvulsive seizure control in the intensive care unit. Curr Treat Options Neurol, 17, 340. 


 
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APPENDIX 3 SALZBURG EEG CRITERIA FOR NCSE 
Patients with known epileptic encephalopathy should have an increase in prominence or 
frequency of the features above when compared to baseline and observable change in clinical 
state.  
Participants in RED box are eligible for enrollment.  
 
Beniczky S et al. Epilepsia 2013;54 (suppl 6): 28-29; Leitinger M et al. Lancet Neurol 2016;15:1054-62. Image reproduced with 
permission from publisher. 
 
 


 
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APPENDIX 4 GLOBAL-MARKETED PRODUCTS CONTAINING 
CAPTISOL® 
The following table lists the commonly found but not exhaustive list of products containing 
Captisol® 
Product 
Active/Dosage Form 
 
VFEND IV 
voriconazole for injection 
 
GEODON/ZELDOX IM 
ziprasidone mesylate for injection 
 
ABILIFY IM 
aripiprazole injection 
 
NEXTERONE 
amiodarone injection 
 
KYPROLIS 
carfilzomib for injection 
 
NOXAFIL injection 
posaconazole injection 
 
EVOMELA 
melphalan for injection 
 
CARNEXIV 
carbamazepine injection 
 
BAXDELA intravenous 
delafloxacin meglumine for injection 
 
ZULRESSO CIV 
brexanolone injection 
 
Generic ‘VFEND IV’ 
voriconazole for injection 
 
REMIVIR, VEKLURY 
Remdesivir 
 






 
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IP initiation from 15 minutes to 6 minutes; and revised Convulsive SE 
criteria to include EEG seizure activity. 
Exclusion criteria #4: revised wording to ‘Seizure burden or clinical state 
would NOT warrant IV anesthesia for seizure control over the next 24 
hours’ 
Synopsis, Section 4.2 
Defined medications for the acute treatment of SE 
Synopsis, Section 104.1 
Primary Endpoint: Revised the seizure burden to <20% and that the 
seizure burden is at least 50% less than during the 30 minutes prior to IP 
initiation 
Synopsis, Section 10.4.1 
Other Secondary Endpoints added clarifying text for Proportion of 
participants with any escalation of treatment in the first 24 hours 
following IP initiation 
Section 10.4.3 
Deleted all references of the Intent to Treat (ITT) population as per FDA 
comment to use mITT instead. Revised the description of the mITT 
population. Removed all references to Full Analysis Set (FAS) 
Synopsis, Sections 10.3, 10.4.1 
Added sentence that the reason for each AED dose during IP 
administration will be recorded in the appropriate CRF 
Section 5.2.1 
Appendix 3: Remdesivir added to the list of US-marketed products 
containing Captisol® 
Section 13, Appendix 3 
Additional grammatical, typographical errors and formatting revisions 
have been made in the document but are not identified here 
 
 
 




 
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Added “if available” for estimated glomerular filtration rate (eGRF) 
and calculated creatinine clearance and removed albumin as this 
analyte is not tested in a routine urinalysis; added phenobarbital to 
the list of AED level collection 
Synopsis (Methodology); Table 1 
footnote i; Table 6 
Added “if available” for estimated glomerular filtration rate (eGRF) 
and calculated creatinine clearance and removed albumin as this 
analyte is not tested in a routine urinalysis; added phenobarbital to 
the list of AED level collection 
Synopsis (Methodology); Table 1 
footnote i; Table 6 
Revised Drugs of Abuse testing and clarified that alcohol testing 
should be collected, if medically indicated to align with the 
institution SOC; T. Chol footnote 1 revised and footnote 2 and 3 
added 
Synopsis (Methodology); Table 1 
footnote l; Table 6 
Clarified that institution guidelines will be followed for pregnancy 
test results prior to IP initiation 
 Synopsis (Methodology); Table 1 
footnote l; Sections 4.4.1; 7.2.3.7 
Clarified that Electroencephalogram (EEG) is required for 
confirmation of CSE diagnosis; removed “If continuous EEG is not 
possible or needed to diagnose (for convulsive SE) it should be 
instituted at the earliest possible time following IP initiation (if a 
predose EEG was not performed for the diagnosis of convulsive SE) 
as this statement no longer applies 
Added “Sites will be offered the use of a rapid EEG device to 
assist with screening of participants with NCSE. It is preferred 
that a conventional EEG is used for the purpose of confirming 
inclusion criterion #3 and EEG monitoring during IP 
administration. In situations when a conventional EEG is not 
immediately available, the rapid EEG may be used to confirm 
inclusion criterion #3. Since the rapid EEG has a limited battery 
life, it should be switched to a conventional EEG within several 
hours but not earlier than 90 minutes after IP initiation to allow 
uninterrupted collection of EEG for the 30-minute SE cessation 
co-primary endpoint. It will be at the investigator’s discretion if 
the use of the rapid EEG will benefit their site. The device should 
be used according to institution standard practices.” This change 
will allow screening and enrollment based on a portable EEG device, 
Ceribell, (approved by the FDA), in situations when conventional 
EEG is not immediately available (e.g., during night hours). 
Synopsis (Methodology), Table 1 
footnote m; Section 7.2.2.1 
Clarified where pharmacokinetic samples should be collected in 
relation to IP infusion site. 
Synopsis (Methodology); Table 2 
footnote b, Section 7.2.4.1 
Seizure Description Questionnaire should be collected predose only 
and as close as possible to IP initiation; all timepoints following IP 
initiation have been removed to reduce the burden of assessments 
throughout the study and to decrease the amount of redundant 
information collected. 
Synopsis (Methodology); Table 1 
footnote p; Section 7.2.2.6 
Status Cessation and Super Refractory Status Epilepticus 
Questionnaires and Sections 7.2.2.7 and 7.2.2.8, respectively added 
Synopsis (Methodology); Table 1; 
footnote q & r, respectively 
Health Utilization Questionnaires and Section 7.2.2.8 added to align 
with statistical endpoints  
Synopsis (Methodology); Table 1; 
footnote v 
The following inclusion criteria revised:  
#3. Removed “…without a pattern of improvement and at least 6 
minutes of continuous or cumulative, intermittent seizure activity in 
the 30-minute period immediately prior to IP initiation, and either” 
replaced with “…with seizure burden warranting imminent 
Synopsis (Inclusion/Exclusion Criteria); 
Section 4.1 
 
 


 
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progression to IV anesthesia for seizure control. Ictal patterns 
and burden defined below.” Added “Ictal burden of 
approximately 6 minutes or more within 30-minutes immediately 
prior to IP initiation is targeted” 
These changes in inclusion criterion #3 were made to better align 
with practical aspects of assessment of seizure burden at the bedside 
and with the second co-primary efficacy endpoint (progression to IV 
anesthesia within 36 hours). 
#4. Added phenobarbital to the list of acceptable second-line IV 
AEDs to align with SOC in the pediatric population 
#5. Revised BMI from <35 to <40 
The BMI cut-off was increased to allow enrollment of patients who 
are severely obese but not yet considered morbidly obese. BMI >40 is 
generally considered for the designation of “morbidly obese”. 
 
 
 
 
 
The following exclusion criteria revised: 
#2. Replaced “uncontrolled” with “rapidly reversible” when 
describing a metabolic cause of SE, e.g., hypoglycemia as this better 
describes the condition like severe hypoglycemia 
#3.Removed “phenobarbital or ketamine” from the list of anesthetic 
agents and added “with the primary intent specifically to treat 
seizures or achieve burst suppression” as phenobarbital has been 
added as an approved 2nd line IV AED counted for failure (inclusion 
criterion #4) and ketamine is generally not considered an IV 
anesthetic that can produce burst suppression or indicate SRSE if 
fails to control seizures 
#5. Added (e.g., directive Do Not Intubate) at the end of the 
criterion 
#10. Added reporting unit for eGFR 
#11. Removed “whichever is greater” when describing the use of an 
investigational product; added “Participation in a non-
interventional clinical study does not exclude eligibility” 
Synopsis (Inclusion/Exclusion Criteria); 
Section 4.2 
 
Synopsis (Investigational Product, Dose, 
and Mode of Administration);  
Sections 5.2.2; 6.2.6 
 
Revised timeframe for recording prior medications, including AEDs, 
administered from 30 for prior medications (7 for AEDs) to 14 days 
to reduce the amount of data collected for this acute indication and 
focus only on the medications that are expected to be relevant to 
acute events 
Synopsis (Methodology); Table 1 
footnote u; Section 5.1 
Revised the definition for medications for the acute treatment of SE 
with the addition of “…or prevent imminent recurrence of SE based 
on clinical or EEG evidence” 
Synopsis (Endpoints); Section 10.4.1 
Healthcare Utilization Endpoints - removed list of discharge locations 
as they were not aligned with the case report form  
Synopsis (Endpoints); Section 10.4.4 
Safety Endpoints – Removed “neurological” as this assessment is 
included in the physical examination; added “use of concomitant 
medications, and occurrence of AEs” to the safety analyses  
Synopsis (Endpoints); Section 10.5 
Removed “and status strata (CSE or NCSE) as fixed effects” from 
logistic regression model to avoid unstable estimation of the 
regression coefficient of status strata as the majority of the 
participants will be NCSE 
Added “In addition, the point estimate of difference of the 
proportions of participants achieving either and both of the co-
primary endpoints between two treatment arms will be provided. 
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The 95% confidence interval will be provided using Clopper-
Pearson method” to facilitate interpretation of the treatment effect 
Clinical Data 
Added findings from May 2021 breastfeeding study that have 
become available after the initial date of this protocol. 
Section 1.2 
Added paragraph that describes the most common treatment 
emergent adverse events reported in the 1042-SE-2001 study 
Section 2.1 
Added Exploratory Objectives to align with the Synopsis 
Section 2.2.3 
Restrictions 
Removed “from consuming grapefruit, Seville oranges, starfruit or 
citrus derived products” based on current DDI data; revised the 
restriction period for use of alcohol until the “end of the 24 hour IP 
discontinuation follow-up period” based on the relatively short 
half-life of ganaxolone that is expected to be cleared from the body 
within 24 hours post discontinuation 
Clarified that breastfeeding is prohibited for 45 days after the last 
dose of IP 
Section 4.3 
Revised duration for males to avoid causing pregnancy in their sexual 
partner during the study and for 30 days after the last dose of IP 
Section 4.4.2 
Added Section 4.5.1.1 Reason for IP Discontinuation  
 
Clarified that investigator clinical judgment should be used to 
determine if a participant should be discontinued from the study 
Revised participant withdrawal criteria related to ventilatory 
depression 
Section 4.5.2 
Revised Section header to Reason for Study Discontinuation 
4.5.3 
Added details for collecting benzodiazepines, AEDs, anesthesia, and 
vasopressors data for prior to and concomitant treatment 
Sections 5.1, 5.2 
Allocation of Participants to Treatment – clarified that randomization 
is defined as the initiation of IP infusion; provides flexibility for 
timing of randomization to avoid impact to SOC; emphasizes that IP 
administration cannot occur until eligibility criteria has been met 
Section 6.2.2 
Clarified that IWRS will record all unblinding events and removed 
instruction that “code breaks must be reported to the Clinical 
Research Organization (CR) and Sponsor” 
Section 6.2.8 
The protocol allows for additional labels to be applied to the IP to 
satisfy local or institution requirements; therefore, “on a case by case 
basis” was removed 
Removed the following paragraph “Identify the study participant by 
name…” and replaced with “Sponsor approval is not needed to make 
this change” 
Section 6.3.1 
Section header revised to “Follow-up Period (24 hours following IP 
to Week 4) for clarification purposes 
Section 7.1.3 
Section header revised to “Medical, Seizure or SE, and Medication 
History and added bullet “Seizure or SE Etiology” to be aligned with 
the data being collected 
Section 7.2.3.1 
Removed “A neurological examination should be performed at the 
time of assent/consent is administered to the participant for continued 
participation…” as a neurological assessment is part of the physical 
examination and, therefore, no need to specify each system 
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Section header revised to “Medication Errors” and section content 
updated to align with events that may occur when administering the 
IV formulation; removed references of “abuse, misuse or overdose”; 
added Other Reportable Information; clarified that reports of 
Medication Errors and Other Reportable Information are subject to 
the 24-hour reporting requirement 
Sections 8.1.7; 8.2.2 
Removed paragraph that states that the IB has not been updated to 
include the 1 mg/mL ganaxolone IV formulation as the current IB 
includes this information 
Section 8.2.1 
Revised guidance for data entry of participant data in the electronic 
data capture system; removed reference to Data Management Plan 
(DMP) as this is an internal document 
Sections 9.1 and 9.2 
Revised the Analysis Population descriptions for Enrolled, Safety, 
Modified Intent to Treat (mITT) and Per Protocol (PP); added 
Randomized 
Section 10.2 
Removed “During the study, participants will receive usual SOC …” 
through “The comparison for statistical significance….”;  
Added “Both co-primary efficacy endpoints must be statistically 
significant at 2-sided 5%...”  
Added “In addition, the point estimate of difference…to align with 
statistical principles 
Section 10.4 
Clarified which data are included in the Safety Analyses 
Section 10.5 
Clarified that there is no formal interim analysis planned for this 
study and that the DMC is chartered to review the study data 
periodically without any hypothesis testing 
Section 10.7 
Reference 37 and 38 added 
References 
Salzburg Criteria: Illustration revised to clarify patient eligibility 
Appendix 2 
Clarified that the table listing the US-Marketed Products containing 
Captisol® is not an exhaustive list 
Appendix 3 
Added recording window for extraction of the 3 timepoints 
Appendix 4 
Added Appendix 5 Summary of changes from Protocol Amendment 
1  
 
Additional grammatical, typographical errors and formatting 
revisions have been made in the document but are not identified here 
 
 
 




 
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To align with the revised inclusion criteria all references to the text in the bullets below has 
been removed or revised to align with the updated inclusion criteria:  
• 
“following initial benzodiazepine treatment and administration of two or more 
second-line IV AEDs.”  
• 
“after initial treatment with benzodiazepines and” 
• 
“Investigators should determine that doses of administered second-line AEDs 
were sufficient for treatment of SE.”  
• 
“Antiepileptic drug doses utilized in the treatment of SE are provided in 
Appendix 1.” 
In addition, the following have been updated throughout the protocol to align with the 
update inclusion criteria: 
• 
References to the participants receiving any two or more of the following agents 
for the treatment of the current episode of SE, administered at an adequate dose 
and for a sufficient duration, in the judgment of the investigator, based on 
investigator judgment, at an adequate dose and for a sufficient duration to 
have demonstrated efficacy: As previously described, IP will be added to SOC 
after “initial treatment with benzodiazepines and” failure of any two or more 
“second-line IV AEDs” antiseizure treatments (benzodiazepine and one IV 
AED or two IV AEDs). 
And Benzodiazepine has been added to the list of possible treatments a participant may fail 
prior to IP initiation and IV has been added to all the 2nd line IV AEDs 
Synopsis 
(Investigational 
Product, Dose, and 
Mode of 
Administration), 
(Methodology), 
Sections 3.1, 5.2.1, 
6.2.3 
 
 
To align with the inclusion criteria, the original wording, “After meeting the criteria for SE 
(clinical and EEG) within 60 minutes prior to IP initiation, the presence of ictal activity SE 
(clinical and EEG) should be confirmed during the 30 minutes immediately prior to IP 
initiation (bolus dose). Has been updated to the following:  
The investigator will confirm that the participant meets clinical and EEG criteria for 
SE during the 60-minute period prior to IP initiation and will reconfirm that ongoing 
ictal activity is present within 30 minutes immediately prior to IP initiation.  
Synopsis 
(Investigational 
Product, Dose, and 
Mode of 
Administration), 
Sections 6.2.3 and 
7.1.2.1 
 
Moved, “Status epilepticus cessation will be assessed by the investigator based on clinical 
and EEG features. Training will be provided to guide and help standardize decisions across 
clinical sites. In addition, a retrospective confirmatory analysis of EEGs will be performed 
by a central reader who is blinded to treatment assignment" from the Methodology section 
to the Endpoints section as, “SE cessation will be assessed by the investigator based on 
clinical and EEG features (see Appendix 1 for seizure cessation guide). Training will be 
provided to guide and help standardize decisions across clinical sites. In addition, a central 
reader blinded to treatment assignment will review EEG recordings retrospectively and 
corroborate accuracy of interpretation.” And moved to Appendix 1, “*SE cessation will 
be determined by the investigator based on clinical and EEG findings. The criterion for 
time of electrographic seizure cessation will be the beginning of the first 30-minute epoch 
of EEG in which  
The seizure burden (percent of time during which there is electrographic seizure activity) is 
<20%”  
and 
“The seizure burden is at least 50% less than during the 30 minutes prior to IP initiation”  
to align the Endpoint section of the synopsis to align the Endpoints. 
Synopsis 
(Methodology), 
(Endpoints), Section 
6.3 2, Section 10.4.1 
Expanded the Vital signs collection window from (+/- 1 hour) to (+/- 2 hour) for 24 hours 
(+/- 1 hour) following IP discontinuation timepoint.  
Removed the 12-hour and added a 10-hour collection timepoint to better align with the 
RASS, FOUR Score, CGI-I, and PK collections. 
Synopsis 
(Methodology), Table 
1 footnote e 


 
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Removed the 12-hour and added a 10-hour collection timepoint for the RASS and FOUR 
Score to better align with the Vital Sign, CGI-I, and PK collections. 
Synopsis 
(Methodology), Table 
1 footnote f 
Removed the 36 hours (+/- 1 hour) following IP initiation for the 12 lead 
Electrocardiogram (ECG). 
Synopsis 
(Methodology), Table 
1 footnote g 
Added clarification, concomitant AED levels only need to be collected if required per the 
standard of care.  
Removed all requirements for variable AED collections: 
Variable AED collection times based on participant response: 
Between IP initiation and at the end of the first 24 hours of the follow-up period, 
where possible, collect sample for AED level(s):  
I. 
If a decision is made to intubate 
II. 
After initial SE cessation, AED levels should be collected at time of 
first recurrence of seizure activity or SE 
Synopsis 
(Methodology), Table 
1 footnote i 
Removed the weekly follow up visit Coagulation sample collection  
At the weekly follow-up visits (Week 1, 2, 3, or 4) for hospitalized participants and for 
participants who have been discharged (whenever possible). 
Synopsis 
(Methodology), Table 
1 footnote k 
Removed the 4, 8, and 12-hour PK collections and added a 6 and 10 hour collections to 
make the sample collections not intersect with an infusion change.  
Increased the collection window for 10, 24, and 36 hour samples to (+/- 2 hour) 
Removed requirements I, II, and IV for variable PK collections: 
Variable PK collection times based on participant response: 
Between IP initiation and at the end of the first 24 hours of the follow-up period, 
where possible, collect a PK sample: 
I. If a decision is made to intubate 
II. At the time of introduction of a new AED for safety/efficacy (not for AEDs 
given prophylactically for “transition/bridging”) 
IV. After the initial SE cessation, collect a sample at the first instance of seizure activity or 
SE relapse and does not progress to anesthesia (e.g., midazolam, propofol, thiopental, or 
pentobarbital) 
Synopsis 
(Methodology), Table 
2 footnote b 
Removed the 12-hour and added a 10-hour collection timepoint for the CGI-I to better 
align with the Vital Sign, RASS, FOUR Score, and PK collections. 
Synopsis 
(Methodology); Table 
1 footnote o 
Unified all references to mechanical or artificial ventilation to be positive pressure 
ventilation (PPV) 
Synopsis 
(Methodology), 
(Endpoints), Sections 
7.3, 10.4.2, and 
10.4.4 
The following inclusion criteria revised:  
As the study is expanding globally #1 was updated to allow for deferred consent to be 
obtained where allowed by law.  
1. Participant, participant’s parent, guardian, or LAR must provide signed 
informed consent/assent, and once capable (per institutional guidelines), 
there must be documentation of consent/assent by the participant 
demonstrating they are willing and aware of the investigational nature of the 
study and related procedures. Where allowed by law, if the patient lacks 
the capacity to make informed decisions regarding his/her medical 
treatment options, the treating clinician may follow their deferred 
Synopsis 
(Inclusion/Exclusion 
Criteria), Section 4.1 
 
 
 
 
 
 


 
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consenting practices. The clinician will make the final decision based on 
the best interests  
of the patient. 
#3 was completely deleted, and new wording added to clarify the requirement and better 
align with clinical practice of SE diagnosis 
3. SE meeting the following criteria:  
a. A diagnosis of SE with or without prominent motor features based 
on clinical and EEG findings: 
i. Diagnosis is established by: 
• 
For SE with prominent motor features: Clinical and EEG 
seizure activity indicative of convulsive, myoclonic or focal 
motor SE 
• 
For SE without prominent motor features (nonconvulsive 
SE): Appropriate clinical features and an EEG indicative 
of NCSE (see modified Salzburg criteria19 in Appendix 3) 
ii. For any type of SE: 
• 
At least 6 minutes of cumulative seizure activity over a 30-
minute period within the hour before IP initiation, AND 
• 
Seizure activity during the 30 minutes immediately prior 
to IP initiation 
b. The treating clinician(s) anticipate that IV anesthesia is likely to be 
the next treatment for SE that persists following initiation of IP 
#4 Revised to clarify the requirement and better align with clinical current practice that 
some patients may not be receiving benzodiazepines and would be started on second-line 
agents directly. “Participants must have received a benzodiazepine and two or more of the 
following second-line IV AEDs for treatment of the current episode of SE” was revised to 
“Participants must have received any two or more of the following agents for treatment 
of the current episode of SE” 
Benzodiazepine was added to the bulleted list of medications and IV was added to all 
the bulleted second-line IV AEDs: 
o 
Benzodiazepines, 
o 
IV Fosphenytoin/phenytoin, 
o 
IV Valproic acid, 
o 
IV Levetiracetam, 
o 
IV Lacosamide, 
o 
IV Brivaracetam, or 
o 
IV Phenobarbital 
 
The following exclusion criteria 2, 3, 4, 8, 11 revised 
#2 added “an uncorrected”, to Anoxic brain injury or an uncorrected rapidly reversable 
metabolic condition as the primary cause of SE (e.g., hypoglycemia <50 mg/dL or 
hyperglycemia >400 mg/dL). 
#3 deleted the text, “with the primary intent to treat seizures or achieve burst suppression” 
and added the bolded text below 
Participants who have received high-dose IV anesthetics (e.g., midazolam, 
propofol, thiopental, or pentobarbital) during the current episode of SE for 
more than 18 hours, or who continue to have clinical or electrographic 
evidence of persistent seizures while receiving high-dose IV anesthetics. 
Synopsis 
(Inclusion/Exclusion 
Criteria); Section 4.2 
 
 


 
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#4 and #5 were deleted and a new exclusion added:  
Clinical condition or advance directive that would NOT permit use of IV anesthesia 
The changes to exclusion #3, 4, and 5 were all made to simplify the protocol requirements 
around IV anesthetic use in this patient population.  
 
Due to the combining of exclusion #4 and 5, the remaining criteria have been renumbered. 
#7 “US-” was removed as the appendix now reflects the global marketed products 
containing Captisol® 
#8 leading to impaired synthetic liver function was added to hepatic restrictions to better 
define the medical condition and guide the investigators 
Clarified that while the screening period is from the time consent/assent is obtained (or 
deferred, if allowed by law) to immediately prior to IP initiation (excluding pre-consent). 
Assessments collected prior to this timeframe that the investigator judges to be clinically 
relevant to the participant’s current state can be utilized in the study and do not need to be 
repeated. For medically unstable participants, screening activities (e.g., labs or vital signs) 
should be collected as close to IP initiation as possible. 
Synopsis (Maximum 
Duration of 
Participant 
Involvement in the 
Study), Table 1 
footnote a 
Other Secondary Endpoint, Level of sedation has added agitation to better define the 
assessment collection. 
Synopsis (Endpoints), 
Section 10.4.3 
Added Time on positive pressure ventilation to the Healthcare Utilization Endpoints 
and moved Proportion of participants requiring positive pressure ventilation to the second 
bullet based on key opinion leader feedback of the rank of meaningful clinical response. 
Synopsis (Endpoints), 
Section 10.4.4 
 
Removed “Status epilepticus cessation will be based on investigator judgment, according to 
the following criteria:  
a. 
SE cessation of at least 30 minutes duration, and  
b. Without administration of medications for the acute treatment of SE from the 
time of IP initiation through 30 minutes following the onset of SE cessation” 
Removed “Key secondary endpoints will be compared between ganaxolone- and placebo-
treated participants in the mITT population with a hierarchical testing process at the 5% 
level of significance. The analysis of secondary efficacy endpoints will use the order of 
endpoints listed above. Assuming that a statistically significant difference between groups 
was observed on both co-primary endpoints, the first key secondary endpoint will be 
compared between groups. If statistical significance is established on the first key 
secondary endpoint, then the testing process will proceed to the second key secondary 
endpoint.” And replaced it with, If the primary endpoints are statistically significant, 
the analysis of key secondary efficacy endpoints will be performed sequentially in the 
order as listed above. If the key secondary endpoints are statistically significant, 
analysis of the first healthcare utilization endpoint, time on positive pressure 
ventilation, will be performed.  
 
Added that the time on positive pressure ventilation endpoints will be analyzed using the 
Kaplan-Meier method. 
 
Added an Interim Analysis section to the Synopsis:  
Synopsis (Statistical 
Methods), Section 
10.4.2 and 10.7 
 


 
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We plan to conduct an interim analysis when two-thirds of the subjects have 
completed the study (41 participants per arm). The overall type I error rate (i.e., 
alpha=0.05, two-sided) will be controlled using a power family alpha spending 
function, with a two-sided nominal alpha level of 0.0293 at the interim analysis. If one 
or both primary efficacy endpoints fail to reach statistical significance at the interim 
analysis, the same testing process will be repeated at the final analysis at the nominal 
alpha level of 0.0343. The interim analysis will be performed by an independent 
statistician who is not involved in study operation and conduct. 
If study enrollment is proceeding at a rate that the study would be complete or nearly 
complete by the time an interim analysis is accomplished, the Sponsor may elect not to 
conduct it. 
Further details will be provided in the SAP. 
Updated the exclusion criterion reference from #8 to #7 to match the renumbering. 
Section 5.2.2  
Removed reference to the IP formulation and storage requirements as this information will 
be detailed in the pharmacy manual, “In addition to Captisol®, the formulation consists of 
water for injection (diluent), buffering agents (potassium phosphate, sodium phosphate) 
and sodium chloride (tonicity modifier).”  
 
To simplify the protocol and refer the reader to the Pharmacy Manual. 
 
Added, “On 01 June 2022 the Drug Enforcement Administration (DEA) issued its 
interim final rule placing ganaxolone, including its salts, in schedule V of the 
Controlled Substances Act. The DEA drug code for Ganaxolone (commercial name, 
Ztalmy) is 2401.” 
Also removed the storage requirements as the information is detailed in Section 6.3.3 
(Storage) 
Section 6.1 
The Interactive Response Technology (IRT) features are being updated, and as a result, IP 
allocation has been added to the list of available tasks.  
The following has been deleted:  
Randomization consists of two steps. The participant will first be assigned a randomization 
number and assignment of IP bottles by the IRT followed by the initiation of IP. This 
second step of initiation of the IP means the patient is randomized.  
The randomization number represents a unique number corresponding to IP allocated to the 
participant. 
Section 6.2.1, 6.2.2 


 
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Individual participant treatment is automatically assigned by the IRT 
To allow for timely delivery of IP to the hospital unit, the IP bottles may be allocated for 
use in the IRT prior to the participant meeting all eligibility criteria to avoid impact to 
SOC. Investigational product will not be administered until eligibility has been determined. 
Enrollment is defined as the initiation of IP infusion. 
Added a reminder that the investigator is responsible for complying with the DEA and CSA 
regulations now that ganaxolone is a scheduled drug, “The investigator has overall 
responsibility for ensuring that IP is stored in a secure, limited access location in 
accordance with applicable requirements under the Controlled Substance Act (CSA) 
and Drug Enforcement Administration (DEA) regulations.” 
Removed the temperature ranges, “The 1 mg/mL ganaxolone IV solution and placebo 
bottles 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 less than or equal to 72 hours are allowed” and 
referred the site staff to the pharmacy manual for the storage requirements.  
Section 6.3.3 
To clarify the collection requirements if a weekly follow-up visit is close to the discharge 
visit the bold sentence has been added: The follow-up period for this protocol is 
approximately 4 weeks. Week 1, 2, 3, and 4 visits may be conducted as an inpatient visit, if 
the participant is still in the hospital, or as a telephone contact, if the participant has been 
discharged. Attempts should be made to have discharged participants return for one of 
these visits to be in person. The participant/participant’s parent/guardian/LAR, as 
appropriate, will receive a follow-up contact weekly approximately 7 ± 3, 14 ± 3, 21 ± 3, 
and 28 ± 3 days following the IP discontinuation date. If the hospital discharge visit 
corresponds to the Week 1, 2, 3, or 4 (± 3 days) visits it can take the place of the 
weekly visit.  
Section 7.1.3 
Clarified that rapid EEG can be utilized to screen and enroll participations where a 
conventional EEG may not be available.  
Section 7.2.2.1 
Updated blood collection volumes to 48 to 59 mL for pediatric institutions and 140.3 to 
190.4 mL for adult participants, based on the revisions to Table 1 and Table 2. 
Section 7.2.4.3 
(Tables 7 and 8) 
The following text was added to the protocol to cover the expansion of the study to 
countries outside of the USA 
• 
For ex-US countries, the Sponsor will comply with local laws and 
requirements with regard to SAE reporting  
• 
European Public posting site, Europe’s website - Eudract.ema.europa.eu 
• 
All EU and UK based sites, laboratories, or entities providing support for this 
study, must, where applicable, comply with General Data Protection 
Regulation (GDPR) 2016/679 for the purposes of data protection and privacy. 
Sections 8.2.7, 11.1.2, 
and 11.4  
Simplified the population definitions by removing the Enrolled and Randomized population 
definitions. Additional population data can be found in the SAP. 
Enrolled: All participants who signed the ICF and received a participant number.  
Randomized: All enrolled participants who received a randomization number and met all 
inclusion criteria and none of the exclusion criteria or received IP. 
Section 10.3 
Updated Reference 32 to the latest version of the investigator brochure  
References 
Updated the US-Marketed Products containing Captisol® to be the Global list of marketed 
products and removed the Sponsor 
Appendix 4 
Added Appendix 6 Summary of changes from Protocol Amendment 2  
Appendix 6 
Additional grammatical, typographical errors and formatting revisions have been made in 
the document but are not identified here 
 
 
 
 




 
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largely focused on rapid SE cessation, including initiation of drugs to terminate 
seizures and reversal of conditions that may lower seizure threshold. Potentiating 
GABAergic inhibition is a key mechanism to achieve rapid seizure cessation in both 
adults and children. 
Summary of nonclinical Captisol® data in rats added. 
Section 1.2 
Language for secondary objective updated to “To evaluate the sustained efficacy of 
ganaxolone IV beyond the 48-hour treatment period as assessed by prevention of 
progression to IV anesthesia for the treatment of SE” for clarity. 
Secondary objective “Determine the effect of ganaxolone on healthcare utilization” 
changed to an exploratory objective.  
Synopsis (Objectives) 
Section 2.2 
Expanded regions/sites to United States, Canada and Australia. 
Synopsis (Site(s) and Region(s)) and 
Section 3.3  
Inclusion criterion #3 updated to “approximately 6 minutes” for SE diagnosis as precise 
and prospective calculation of ictal burden by providers caring for patients at the bedside 
may result in delay of standard of care. 
Synopsis (Inclusion and Exclusion 
Criteria) 
Section 4.1 
The following exclusion criteria has been reinserted into Section 4.2 to align with the 
synopsis. 
11. 
Known or suspected history or evidence of a medical condition that, in the 
investigator’s judgment, would expose participant to an undue risk of a significant 
adverse event or would interfere with assessments of safety or efficacy during the 
study. 
Section 4.2 
Inclusion of creatinine collection for urine chemistry evaluations alongside N-acetyl-β-D-
glucosaminidase [NAG] and β2-microglobulin. 
Synopsis (Safety and Assessments), 
Section 6.2.4, Section 7.2.3.7 
(including Table 6) 
The maximum dosing for Captisol® was clarified as 50 g/day (1.25 g/kg/day in 
participants weighing <40 kg) which corresponds to a maximum ganaxolone dose of 
833 mg/day (20.825 mg/kg/day in participants weighing <40 kg). 
Synopsis (Rationale, Dose 
adjustments and interruptions), 
Section 6.2.7 
Section 8.1.7 
Pharmacokinetic blood collection time window updated for consistency within protocol 
and ganaxolone and Capitsol specified to be collected. 
Synopsis (Safety and Assessments) 
Section 7.2.4.1 
Total blood volume values corrected and assessment for IV AEDs row removed as no 
longer required per protocol. 
Synopsis (Safety and Assessments) 
Section 7.2.4.3 and Table 8 
Updated “Marinus Safety Department or its delegate” to Marinus Drug Safety vendor. 
EMERGENCY CONTACT 
INFORMATION  
Sections 8.1.6, 8.1.7, 8.2.2, 8.2.4 
Removed “A copy of the Pregnancy Report Form (and any applicable follow-up reports) 
must also be sent to the Medical Monitor using the details specified in the emergency 
contact information section at the beginning of the protocol.” 
Section 8.1.6 
Time to SE cessation following IP initiation designated as first key secondary endpoint. 
Secondary endpoint language expanded for consistency with primary endpoint to 
“Proportion of participants with no progression to IV anesthesia for 72 hours following 
IP initiation” and other secondary endpoint clarified as “Proportion of participants 
whose treatment does not progress to IV anesthesia for 4 weeks following IP initiation”. 
Synopsis (Endpoints, Statistical 
Methods) 
Section 10.4 
Clarification added on the timing of the Healthcare Utilization endpoints as follows: 
• 
Time on positive pressure ventilation after IP initiation  
Synopsis (Healthcare Utilization 
Endpoints) 
Section 10.4.4 


 
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IND 129433 
 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-SE-3003 
 
Version 6.0 
• 
Proportion of participants requiring positive pressure ventilation initiated during 
IP infusion 
• 
Length of stay in intensive care unit and in hospital after IP initiation. 
Details for the pharmacokinetic analyses added to replace cross-reference to separate 
analysis plan. 
Section 10.6 
Additional grammatical, typographical errors and formatting revisions have been made in 
the document but are not identified here. 
Throughout the document 
 

SAP_001.pdf: 
 
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Marinus Pharmaceuticals, Inc. 
 
                       Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
Version 4.0, Amendment 3 
 
Statistical Analysis Plan 
 
 
 
 
1042-SE-3003 
 
A double-blind, randomized, placebo-controlled study to evaluate the 
efficacy and safety of intravenous ganaxolone in status epilepticus 
 
 
Investigational Product: 
Ganaxolone  
Reference Product: 
Placebo 
Indication: 
Status Epilepticus (SE) 
Phase： 
3 
Final： 
Version 4.0, Amendment 3 
Date: 
June 4, 2024 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document is privileged and confidential.  Do not copy, 
circulate, or otherwise distribute without written authorization from  
Marinus Pharmaceuticals, Inc. 
 
 


 
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Marinus Pharmaceuticals, Inc. 
 
                       Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
Version 4.0, Amendment 3 
Statistical Analysis Plan Approval 
 
 
 
 
Author:   
  
_______________________ 
 
________________ 
, Ph.D. 
 
 
 
 
Date (dd/mmm/yyyy) 
Biostatistics 
Marinus Pharmaceuticals, Inc. 
 
Review:         
___________________ 
 
________________ 
, M.D.  
 
 
            Date (dd/mmmyyyy) 
Marinus Pharmaceuticals, Inc. 
 
 
Approval: 
 
________________________ 
 
________________ 
, Ph.D. 
 
 
                        Date (dd/mmmyyyy) 
 Biometrics 
Marinus Pharmaceuticals, Inc. 
 
 


 
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                       Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
Version 4.0, Amendment 3 
 
TABLE OF CONTENTS 
 
ABBREVIATIONS ..................................................................................................................................... 6 
SUMMARY OF MAJOR CHANGES FROM PREVIOUS VERSION ...................................................................... 8 
1. 
INTRODUCTION ................................................................................................................................ 9 
1.1 
Study Objectives ........................................................................................................................... 9 
1.1.1     Primary Objective ..................................................................................................................... 9 
1.1.2     Secondary Objectives ............................................................................................................... 9 
1.1.3     Exploratory Objectives ............................................................................................................. 9 
1.2 
Study Endpoints .......................................................................................................................... 10 
1.2.1     Primary Endpoints .................................................................................................................. 10 
1.2.2     Key Secondary Endpoints ....................................................................................................... 10 
1.2.3     Other Secondary Endpoints.................................................................................................... 10 
1.2.4    Healthcare Utilization Endpoints ............................................................................................ 11 
1.2.5    Safety Endpoints ...................................................................................................................... 11 
1.2.7 Pharmacokinetic Endpoints ....................................................................................................... 11 
1.3 
Study Design and Flow Chart ..................................................................................................... 12 
1.3.1    General Study Design and Plan ............................................................................................... 12 
1.3.2     Sample Size and Power .......................................................................................................... 13 
1.3.3     Randomization ....................................................................................................................... 14 
1.3.4    Blinding and Treatment Assignment ....................................................................................... 14 
1.3.5     Unblinding the Treatment Assignment .................................................................................. 14 
2. 
STATISTICAL CONSIDERATIONS ................................................................................................ 14 
2.1 
General Considerations ............................................................................................................... 14 
2.2 
Analysis Populations ................................................................................................................... 15 
2.2.1     Safety Population ................................................................................................................... 15 
2.2.2     Intent to Treat (ITT) Population.............................................................................................. 15 
2.2.3     Per Protocol Population (PP) .................................................................................................. 16 
2.2.4     Open-Label Population ........................................................................................................... 16 
2.2.5     Planned Analyses by Study Population .................................................................................. 16 
2.3 
Time Windows for Analyses ....................................................................................................... 17 
2.4 
Pooling of Centers ....................................................................................................................... 17 


 
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                       Statistical Analysis Plan 
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Version 4.0, Amendment 3 
2.5 
Handling of Missing Data ........................................................................................................... 17 
2.6 
Analysis Software ....................................................................................................................... 19 
2.7 
Handling of Data after Interim Analysis ..................................................................................... 19 
3. 
STATISTICAL ANALYSIS .............................................................................................................. 20 
3.1 
Participant Information ............................................................................................................... 20 
3.1.1     Disposition of Study Participants ........................................................................................... 20 
3.1.2     Protocol Deviations ................................................................................................................ 20 
3.1.3     Demographics and Baseline Characteristics ........................................................................... 20 
3.1.4     Medical History ...................................................................................................................... 21 
3.1.5     Prior and Concomitant Medications ...................................................................................... 21 
3.1.6     Investigational Product Infusion Summary ............................................................................ 22 
3.2 
Efficacy Analysis ........................................................................................................................ 24 
3.2.1.1      Primary Analysis ............................................................................................................ 25 
3.2.1.2      Sensitivity Analysis ........................................................................................................ 26 
3.2.1.3      Subgroup Analysis ......................................................................................................... 27 
3.2.2     Key Secondary Efficacy Endpoints .......................................................................................... 27 
3.2.2.1      Primary Analysis ............................................................................................................ 27 
3.2.2.2      Sensitivity Analysis ........................................................................................................ 27 
3.2.2.3      Subgroup Analysis ......................................................................................................... 28 
3.2.3     Other Secondary Efficacy Endpoints ...................................................................................... 28 
3.2.3.1      Proportion of Participants With Any Escalation of Treatment in the First 24 Hours 
Following IP Initiation .................................................................................................................... 28 
3.2.3.2      Time to Treatment Escalation Following IP Initiation................................................... 28 
3.2.3.3      Time to Initiation of Anesthesia for SE Treatment Through the Final Study Follow-up 
Visit/Contact ................................................................................................................................... 28 
3.2.3.4      Proportion of Participants Who Develop Super Refractory SE (SRSE) Through the 
Final Study Follow-up Visit/Contact .............................................................................................. 29 
3.2.3.5      Seizure Burden Through 72 Hours Following IP Initiation ........................................... 29 
3.2.3.6      Level of Responsiveness as Assessed by the Full Outline of UnResponsiveness (FOUR) 
Score Scale ...................................................................................................................................... 29 
3.2.3.7      Level of Sedation as Assessed by the Richmond Agitation and Sedation Scale (RASS)
 ........................................................................................................................................................ 29 
3.2.3.8      Clinician Global Impression-Improvement (CGI-I) ...................................................... 29 
3.2.3.9      Level of Functioning as Assessed by the Modified Rankin Scale (mRS) ...................... 30 
3.2.3.10     Level of Functioning as Assessed by the EuroQoL (EQ-5D-5L) ................................. 30 


 
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3.2.3.11     Proportion of Participants with mRS ≥ 3 at the Time of Hospital Discharge ............... 30 
3.2.3.12     Proportion of Participants With No Progression to IV Anesthesia for 4 Weeks 
Following IP Initiation .................................................................................................................... 30 
3.2.4 
    Healthcare Utilization Endpoints ....................................................................................... 31 
3.2.4.1     Time on Positive Pressure Ventilation After IP Initiation .............................................. 31 
3.2.4.2     Proportion of Participants Requiring Positive Pressure Ventilation Initiated During IP 
Infusion ........................................................................................................................................... 31 
3.2.4.3     Length of Stay in ICU and in Hospital ............................................................................ 31 
3.2.4.4     Discharge Destination ..................................................................................................... 31 
Count and percentage of each discharge destination will be summarized by treatment group. .............. 31 
3.2.5 Open-label Phase Efficacy Summary .......................................................................................... 32 
3.3 
Safety Analysis ........................................................................................................................... 32 
3.3.1     Adverse Events ....................................................................................................................... 32 
3.3.2     Vital Signs ............................................................................................................................... 33 
3.3.3     Laboratory Evaluations ........................................................................................................... 33 
3.3.4     Electrocardiogram .................................................................................................................. 34 
3.3.5     Physical Examination .............................................................................................................. 34 
3.4 
Pharmacokinetic Analysis ........................................................................................................... 35 
3.5 
Interim Analysis .......................................................................................................................... 35 
4. CHANGE TO ANALYSES SPECIFIED IN PROTOCOL .................................................................... 37 
5. PROGRAMMING SPECIFICATIONS ................................................................................................. 37 
6. TABLES/LISTINGS/FIGURES TEMPLATES ..................................................................................... 37 
7. REFERENCES ....................................................................................................................................... 37 
8. APPENDICES ........................................................................................................................................ 38 
8.1 
Schedule of Assessments ............................................................................................................ 38 
 
 
 
 


 
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                       Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
Version 4.0, Amendment 3 
ABBREVIATIONS 
AE 
Adverse Event 
AED 
Antiepileptic Drug 
ATC 
Anatomical-Therapeutic-Chemical 
BMI 
Body Mass Index 
CGI-I 
Clinical Global Impression of Improvement  
CGI-S 
Clinical Global Impression of Severity 
CI 
Confidence Interval 
CRF 
Case Report Form  
CSE 
Convulsive Status Epilepticus 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FOUR 
Full Outline of UnResponsiveness Score 
GCP 
Good Clinical Practice 
GNX 
Ganaxolone 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
ICU 
Intensive Care Unit 
IP 
Investigational Product 
IV 
Intravenous 
IVRS 
Interactive Voice Response System  
IWRS 
Interactive Web Response System 
LAR 
Legally Authorized Representative 
MedDRA    
 
Medical Dictionary for Regulatory Activities 
ITT 
Intent-to-Treat  
mRS 
Modified Rankin Scale 
NCSE 
Non-convulsive Status Epilepticus 
PT 
Preferred Term  
PP 
Per Protocol 


 
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                       Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
Version 4.0, Amendment 3 
RASS 
Richmond Agitation and Sedation Scale 
RSE 
Refractory Status Epilepticus 
SAE 
Serious Adverse Events  
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Status Epilepticus 
SOC 
System Organ Class 
SRSE 
Super Refractory Status Epilepticus 
STESS 
Status Epilepticus Severity Score 
TEAE 
Treatment-Emergent Adverse Event 
WHO 
World Health Organization 
 
 


 
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                       Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
Version 4.0, Amendment 3 
SUMMARY OF MAJOR CHANGES FROM PREVIOUS VERSION 
SAP version 4.0 as an Amendment to SAP version 3.0 
Change 
Rationale 
Updated testing procedure 
Requested by FDA 
 
 


 
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                       Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
Version 4.0, Amendment 3 
1. INTRODUCTION 
 
The purpose of this Statistical Analysis Plan (SAP) is to provide detailed descriptions and 
methods to be used for efficacy and safety analyses for Protocol 1042-SE-3003. This SAP is 
based on the Protocol 1042-SE-3003 amendment 5 (06May2024). 
 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA) and International Council for 
Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use 
(ICH): Guidance on Statistical Principles in Clinical Trials.1 All work planned and reported for 
this SAP will follow internationally accepted guidelines for statistical practice published by the 
American Statistical Association.2  
 
This is a double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety 
of ganaxolone IV solution in status epilepticus (SE), with the option to transition the study to an 
open-label phase to obtain additional safety data. Unless stated otherwise, the analyses covered 
in this SAP apply to the double-blind phase of the study. The protocol contains additional details 
on study design, study conduct, and other operational aspects.  
 
1.1 
Study Objectives 
 
1.1.1     Primary Objective 
 
The primary objective of the study is to evaluate the efficacy and safety of intravenous (IV) 
ganaxolone (GNX) for the treatment of SE after failure of two or more antiseizure medications. 
 
1.1.2     Secondary Objectives 
 
The secondary objectives of the study are the following: 
• Assess time to SE cessation following ganaxolone administration.  
• Evaluate sustained efficacy of IV ganaxolone beyond the 48-hour treatment period as 
assessed by prevention of progression to IV anesthesia for the treatment of SE. 
 
1.1.3     Exploratory Objectives 
 
The exploratory objectives of the study are the following: 
 
• Determine the effect of ganaxolone on healthcare resource utilization. 
• Assess the effect of ganaxolone on doses of other antiseizure treatments and changes in 
seizure burden. 


 
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Protocol 1042-SE-3003 
 
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• Evaluate the effect of ganaxolone on quality of life, functional status, and level of 
responsiveness. 
 
1.2 
Study Endpoints 
 
1.2.1     Primary Endpoints 
 
The following co-primary endpoints are established to support the primary objective of the study:  
• Proportion of participants with SE cessation within 30 minutes of investigational product 
(IP) initiation without medications for the acute treatment of SE. 
• Proportion of participants with no progression to IV anesthesia for 36 hours following 
IP initiation. 
 
1.2.2     Key Secondary Endpoints 
 
The following key secondary endpoints will be analyzed: 
• Time to SE cessation following IP initiation. 
• Proportion of participants with no progression to IV anesthesia for 72 hours following IP 
initiation. 
 
1.2.3     Other Secondary Endpoints 
 
The following additional secondary endpoints will be analyzed: 
• 
Proportion of participants with any escalation of treatment in the first 24 hours following 
IP initiation, i.e., any medication other than IP for the acute treatment of SE in the first 24 
hours. 
• 
Time to treatment escalation following IP initiation (any other medication used for acute 
treatment of SE). 
• 
Time to initiation of anesthesia for SE treatment through the final study follow-up 
visit/contact. 
• 
Proportion of participants who develop Super Refractory SE (SRSE) through the final 
study follow-up visit/contact. 
• 
Seizure burden through 72 hours following IP initiation. 
• 
Level of responsiveness as assessed by the Full Outline of UnResponsiveness (FOUR) 
Score Scale. 
• 
Level of sedation/agitation as assessed by the Richmond Agitation and Sedation Scale 
(RASS). 
• 
Clinician Global Impression-Improvement (CGI-I).  
• 
Level of functioning as assessed by the modified Rankin Scale (mRS).  


 
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Protocol 1042-SE-3003 
 
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• 
Level of functioning as assessed by the EuroQoL (EQ-5D-5L). 
• 
Proportion of participants with mRS ≥ 3 at the time of hospital discharge. 
• 
Proportion of participants whose treatment does not progress to IV anesthesia for 4 weeks 
following IP initiation. 
 
1.2.4    Healthcare Utilization Endpoints 
 
The following healthcare utilization endpoints will be analyzed: 
 
• Time on positive pressure ventilation after IP initiation.  
• Proportion of participants requiring positive pressure ventilation initiated during IP 
infusion. 
• Length of stay in intensive care unit (ICU) and in hospital after IP initiation. 
• Discharge destination (location where the participant is residing at the last follow-up 
[FU] assessment).   
 
1.2.5    Safety Endpoints 
 
• Vital signs (height, weight, blood pressure [BP], pulse, respiratory rate [RR], body 
temperature, oxygen saturation). 
• Electrocardiogram (ECGs). 
• Clinical laboratory tests (hematology, chemistry and urinalysis, pregnancy and drug test). 
• Physical exam findings. 
• Use of concomitant medications. 
Adverse events.   
 
1.2.6    Open-label Phase Endpoints 
If the study transitions to open label, all endpoint assessments as described for the double-blind 
phase will be summarized using descriptive statistics and no formal hypothesis testing will be 
performed. 
 
1.2.7 Pharmacokinetic Endpoints 
 
• 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). 


 
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                       Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
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• 
Clearance (CL). Calculated as dose/AUCinf. 
 
1.3 
Study Design and Flow Chart 
 
1.3.1    General Study Design and Plan 
 
This is a double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of 
ganaxolone IV solution in SE, with the option to transition the study to an open-label phase to 
obtain additional safety data. Open-label enrollment would commence if there were a finding of 
efficacy from the double-blind phase at the interim analysis. Approximately 160 patients 12 years 
and older with SE will be screened to randomize approximately 124 participants.  Randomized 
participants will receive ganaxolone IV solution or placebo, referred to as investigational product 
(IP), in a 1:1 ratio added to standard of care treatment.  
 
After the IP has been discontinued, participants will enter the follow-up period where 
assessments/procedures will be collected every 24 hours through 120 hours (or until hospital 
discharge) and at the time of hospital discharge, followed by weekly visits/contacts at Week 1, 2, 
3, and 4 following IP initiation. 
 
The Week 1, 2, 3, and 4 visits can be conducted as inpatient visits if the participant is still in the 
hospital, or as telephone visits if the participant has been discharged. Attempts should be made to 
have discharged participants return for one of these visits in person.  Each participant will be 
followed for approximately 4 weeks following IP initiation (Figure 1). 
 
 




 
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                       Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
Version 4.0, Amendment 3 
After receiving the DMC recommendation that the study may continue after the interim analysis, 
the sponsor made the decision to stop enrollment of the study, at which point about 100 
participants have been randomized. 
 
1.3.3     Randomization  
 
The double-blind treatment for each participant will be determined by a predetermined 
randomization schedule.  Participant identification numbers are assigned prior to dosing.  Within 
each site (numbered uniquely within a protocol), participant identification numbers are assigned 
according to their sequence of presentation for study participation. Individual participant treatment 
is automatically assigned by the Interactive Voice Response System (IVRS)/Interactive Web 
Response System (IWRS). 
 
1.3.4    Blinding and Treatment Assignment 
 
The site pharmacy personnel who dispense are not required to be blinded and will not be involved 
in any study assessment. All participating staff involved in the evaluation and execution of the 
study will remain blinded to the participant’s treatment assignment. 
 
1.3.5     Unblinding the Treatment Assignment 
 
During the study, the treatment assignment must not be broken except in emergency situations in 
which the identification of the IP is required for further treatment of the participant.  If possible, 
the investigator should contact the Medical Monitor before unblinding.  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 unblinded the participant.  
 
If 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 
blinding, the participant will have the follow-up period assessments/procedures, and the follow-
up visits/contacts at Week 1, 2, 3, and 4.  The IRT (Interactive Response Technology) will record 
all unblinding events. 
 
2. STATISTICAL CONSIDERATIONS 
 
2.1 
General Considerations  
• The treatment groups will be coded as “Ganaxolone” and “Placebo,” and all summary 
tables will be provided by treatment group and overall. When applicable, treatment in open-
label phase will be coded as “Openlabel Ganaxolone”. 
• In general, descriptive statistics (n, mean standard deviation [SD], median, 25th and 75th 
percentiles, minimum, and maximum) will be summarized by treatment group for 
continuous variables. 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 


 
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Protocol 1042-SE-3003 
 
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places than the precision of the data. Minimums and maximums will be presented with the 
same precision as the original data. 
• Count and percentage of participants in each category will be provided for categorical 
variables. Unless stated otherwise, percentages are based on the number of participants 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, and the exception of 0%, which will not be displayed.  
• All listings will be listed by treatment group, participant, test parameter, 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 results, vital signs, or 
ECG values. Data from all assessments (scheduled or unscheduled), will be included in the 
listings.  
• Unless stated otherwise, baseline is defined as the last non-missing value prior to the first 
dose of study drug administration. 
• P-values will be reported to 3 decimal places, with values less than 0.001 displayed as 
“<0.001.”  
• All outputs should have the following header at the upper left margin: 
 
Marinus Pharmaceuticals, Inc.  
Study 1042-SE-3003 
 
And the following header (right justified) at the upper right margin: 
 
Page n of N 
 
Tables/appendices/listing should be internally paginated (i.e., page numbers should appear 
sequentially within each table). All outputs should have SAS program name, source listing, 
and execution date and time included in the footnotes.  
 
2.2 
Analysis Populations 
    
2.2.1     Safety Population 
 
The Safety Population comprises all participants who received IP. Participants will be analyzed 
according to the intervention they received. 
 
2.2.2     Intent to Treat (ITT) Population 
 
The ITT Population comprises all randomized participants in the double-blind phase of the study 
who received IP and had at least one non-missing efficacy assessment. Participants will be 
analyzed according to the intervention to which they were randomized. 
 


 
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Protocol 1042-SE-3003 
 
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2.2.3     Per Protocol Population (PP) 
 
The PP Population comprises of all participants in the ITT population without major protocol 
violations or deviations related to co-primary endpoint efficacy assessments. Participants will be 
analyzed according to the intervention they received. 
2.2.4     Open-Label Population  
 
All enrolled participants who receive open-label IP (should the study transition to open label). 
 
2.2.5     Planned Analyses by Study Population 
 
The planned analyses by population are listed in Table 1.   
 
 
 


 
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                       Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
Version 4.0, Amendment 3 
Table 1. Planned Analyses by Study Population 
Planned Analysis 
Analysis Population 
Safety 
ITT 
PP 
Open-Label 
Demographic and 
Baseline Characteristics 
√ 
 
 
√ 
Medical History 
√ 
 
 
√ 
Prior and Concomitant 
Treatment 
√ 
 
 
√ 
Protocol Deviation 
√ 
 
 
√ 
IP Infusion Summary 
√ 
 
 
√ 
Primary Efficacy 
 
√ 
√ 
 
descriptive 
Key Secondary 
Efficacy Analysis 
 
√ 
√ 
 
descriptive 
Other Secondary 
Efficacy Analysis 
 
√ 
 
descriptive 
Healthcare Utilization 
Endpoints 
 
√ 
 
descriptive 
Safety Analyses 
√ 
 
 
√ 
 
2.3 
Time Windows for Analyses 
 
For by-visit safety or efficacy summaries, only scheduled visits will be analyzed. Data collected 
at unscheduled visits will be provided in listings. 
 
2.4 
Pooling of Centers 
 
This multicenter study is to be conducted at approximately 100 sites in the United States, Canada, 
and Australia. Data from all centers will be pooled for analysis. 
 
2.5 
Handling of Missing Data  
 
Unless stated otherwise, there will be no imputation of incomplete or missing data other than 
the dates mentioned below. Missing efficacy data will be imputed in a sensitivity analysis as 
described in Section 3.2.1.1.   


 
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Protocol 1042-SE-3003 
 
Version 4.0, Amendment 3 
 
The handling of partial start and stop dates for AEs are described in Table 2 below. Similar 
algorithms for handling missing and partial dates of concomitant medication usage are described 
in Table 3. In both cases, if a stop date is complete and an imputed start date is after the stop date, 
the start date will be set to the stop date. 
Table 2:  
Adverse Event Start/Stop Date Imputation 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date for 
AEs 
 
D 
M and Y same as M and Y of initiation of IP 
infusion 
Date of initiation of IP infusion 
Y same but M prior to month of initiation of 
IP 
Last day of month 
Y same but M after month of initiation of IP 
infusion 
First day of month 
Y is prior to year of initiation of IP infusion 
Last day of month 
Y is after year of initiation of IP infusion 
First day of month 
M 
Y is same as Y of initiation of IP infusion 
Month of initiation of IP infusion 
Y is prior to year of initiation of IP infusion 
M = December 
Y is after Y of initiation of IP infusion 
M = January 
D and M 
Y same as Y of initiation of IP infusion 
Date of initiation of IP infusion 
Y prior to Y of initiation of IP infusion 
M and D will be December 31 
Y after Y of initiation of IP infusion 
M and D will be January 1 
Y, or M, D, 
Y 
Y and/or start date missing 
Date of initiation of IP infusion 
Stop date for 
AEs 
 
D 
M and Y not missing 
Use last day of month (i.e., D may 
take on values of 28, 29, 30, or 31, 
depending on month) 
M 
Y not missing; if D also missing, impute D as 
described above 
M = December 
 
Y, or M, D, 
Y 
Y and/or stop date missing. 
No imputation. Date left missing. 
D=day, M=month, Y=year 
Note:   In all cases, if an estimated start date is after a complete stop date, the start date will be set to the AE stop 
date. Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of the 
start day month. 
 
 


 
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Table 3: 
Imputation for Prior/Concomitant Medication Missing and Partial Dates 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date for 
con meds  
D only 
M and Y are not missing or imputed. 
Use 1st day of M. 
M only 
D and Y are not missing or imputed. 
M = January 
M and D 
Y is not missing or imputed. 
Use Jan 01 of Y 
M, D, and Y 
None - date completely missing 
No imputation but considered 
concomitant unless stop date is 
prior to first dose of IP. 
Stop date for 
con meds  
D only 
M and Y are not missing or imputed.  
Last day of month 
M only 
D and Y are not missing or imputed. 
M = December 
M and D 
Y is not missing or imputed 
Use Dec 31 of Y 
M, D, and Y 
None - date completely missing and NOT 
ongoing 
No imputation 
Note:  In all cases, if an estimated start date is after a complete stop date, the start date will be set to the end date of   
     medication. 
 
2.6 
Analysis Software 
 
All summaries and statistical analyses will be generated using SAS® version 9.4 or later. 
 
2.7 
Handling of Data after Interim Analysis 
 
The interim analysis will be conducted based on data from approximately the first 82 participants 
in the ITT population who have completed assessments for the co-primary and key secondary 
endpoints. It is anticipated that data cleaning, data analysis, preparation of data and its review by 
the DMC will require approximately 8-12 weeks. During this time, double-blind randomization 
will continue.  
 
If the decision is made based on the interim analysis results to discontinue the double-blind phase 
due to demonstration of efficacy, the analysis set for the primary and key secondary endpoints will 
consist of data provided to the DMC for review, i.e., approximately 82 participants in the ITT 
population. Co-primary and key secondary endpoint data for additional double-blind participants 
enrolled after the interim analysis data cutoff will be summarized in combination with data from 
the interim analysis using descriptive statistics.  Interim efficacy analyses will only be performed 
for the primary and key secondary endpoints; the analyses of other efficacy endpoints will be 
performed in the full ITT population in the double-blind phase. Additionally, efficacy endpoint 
data from the open-label phase will be summarized using descriptive statistics.   


 
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If the decision is made at the interim analysis to continue the double-blind phase, safety and 
efficacy data collected after the interim analysis will be integrated with the interim data and will 
be included in the final analysis. Safety data from the double-blind and open-label phases will be 
summarized separately and in combination.  
 
The interim analysis was conducted on the first 83 participants in the ITT population who have 
completed assessments for the co-primary and key secondary endpoints. The DMC recommended 
the study may continue without modification. 
 
3. STATISTICAL ANALYSIS 
 
3.1 
Participant Information 
 
3.1.1     Disposition of Study Participants 
 
The number of participants screened for this study, the number of screen failures and the number 
of participants who received at least one dose of IP will be summarized using the Enrolled 
Population. Reasons for screen failure will be provided in the data listing. 
 
Study completion and withdrawal from the double-blind phase will be summarized by treatment 
group for all enrolled participants. The summary table will include the numbers of participants 
included in each analysis set and those who completed or did not complete the study, along with 
the reasons for discontinuation (adverse events, protocol deviation, lost to follow-up, death, etc.) 
of study treatment and discontinuation from study will be summarized. 
 
Reason for discontinuation from study will be provided in the data listing.  
 
In addition, a summary of the number of participants included in each analysis set will be presented.  
 
3.1.2     Protocol Deviations 
 
Protocol deviations will be identified to measure adherence to key aspects of the protocol before 
the database freeze/lock for the relevant analysis. Specific data fields that will be examined to 
identify protocol deviation or violations include inclusion/exclusion criteria and deviations 
identified by the investigator. The protocol deviations will be summarized by deviation category 
based on the Safety Population. A data listing will also be provided. 
 
3.1.3     Demographics and Baseline Characteristics 
 


 
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Descriptive summary statistics (n, mean, standard deviation, median, 25th and 75th percentiles, 
minimum, and maximum) and/or frequency distributions (count and percentage), as appropriate, 
will be provided by treatment group for the Safety Population.  
Demographic characteristics summarized will include:  
• Age  
• Age group (12 to < 18 yrs, ≥18 yrs) 
• Sex (male, female) 
• Race/ethinicity 
• Height (cm) 
• Weight (kg) 
• Weight group (<40 kg, ≥40 kg) 
• Body Mass Index (BMI; kg/m2) 
Baseline characteristics summarized will include: 
• Etiology of SE (Cerebrovascular accidents, Anoxia or hypoxia, etc.) 
• Pre-infusion duration of SE 
• Number of failed AEDs 
• Previous epilepsy history 
• Status Epilepticus Severity Score (STESS) 
• Richmond Agitation and Sedation Scale (RASS) 
• Full Outline of UnResponsiveness (FOUR) Score  
• 
Clinical Global Impression of Severity (CGI-S) 
 
3.1.4     Medical History 
 
Medical history will be coded with the Medical Dictionary for Regulatory Activities (MedDRA) 
Terminology version 22.0 or higher. The number and percentage of participants with medical 
history will be summarized by System Organ Class (SOC) and Preferred Term (PT) based on the 
Safety Population. 
 
3.1.5     Prior and Concomitant Medications 
 
Prior medications are defined as medications that started prior to the initiation of IP. 
Concomitant medications are defined as medications that started after the initiation of IP or 
started before the administration of the study drug and ongoing after the IP initiation.  
 
All investigator terms for prior and concomitant medications recorded on the Case Report Form 
(CRF) will be coded using the World Health Organization (WHO) Anatomical Therapeutic 
Chemical (ATC) drug dictionary (WHO Drug Dictionary, March 1, 2021). 
 


 
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The number and percentage of participants with prior and concomitant medications will be 
summarized by ATC level 2 and PT based on the Safety Population, by treatment group and 
overall. Listings will also be provided for all prior and concomitant medications.  Listing will 
identify treatments as either prior (before the initiation of IP) or concomitant (from initiation of 
IP to end of follow-up visit/contact). 
 
In addition, benzodiazepines, AEDs, and anesthesia medications, as collected in a separated 
CRF, will be summarized in a similar fashion. A separate listing and summary table will be 
presented for Benzodiazepines, AEDs, and IV anesthesia. 
 
3.1.6     Investigational Product Infusion Summary 
 
Investigational product will be administered as a 48-hour continuous infusion, which includes 
an initial 3-minute bolus and ends with a 12-hour taper based on Table 4 and Table 5. The total 
administered dose (mg) for IP infusion and duration of IP infusion will be summarized based 
on the Safety Population.  
 
 
 


 
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Table 4. Dosing for Participants ≥ 40 kg (on a mg/hour basis) 
 
 
Days 
Start Time from IP Initiation 
IP Dose 
 
IP Infusion Rate 
(mL/hour) 
Duration 
Day 1 
0 hours: bolus dose via syringe or 
infusion pump 
30 mga 
N/A 
3 minutes 
(0.05 hours) 
Day 1 
0 hours through 2 hours following IP 
initiation: continuous infusion, started 
with bolus 
80 mg/hr 
80  
2 hours 
Day 1 
2 hours through 12 hours following IP 
initiation 
40 mg/hr 
40 
10 hours 
Day 1 
12 hours through 24 hours following 
IP initiation  
20 mg/hr 
20 
12 hours 
Day 2b 
24 hours through 36 hours following 
IP initiation 
20 - 45 mg/hr 
20 - 45 
12 hours  
 
Taper 
Day 2c 
36 through 48 hours following IP 
initiation (12-hour taper) 
13 - 30 mg/hr  
13 - 30 
4 hours 
9 - 20 mg/hr 
9 - 20 
4 hours 
6 - 13 mg/hr 
6 - 13 
4 hours 
IP = investigational product. 
a. 
The 30 mg bolus is administered over ~3 minutes. 
b. On Day 2 (24 through 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.   
c. 
To taper the IP, the infusion rate at the 36-hour following IP 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 (e.g., if the current 
infusion rate is 20 mg/hr, the first taper will be 13 mg/hr) the second taper will be 33.3% from the first tapered 
infusion rate (e.g., if the current infusion rate is 20 mg/hr, the second taper will be 9 mg/hr), and the final taper 
will be 33.3% from the previous tapered infusion rate (e.g., if the current infusion rate is 20 mg/hr, the final taper 
will be 6 mg/hr).  If, in the investigator’s judgment, the 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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Table 5. Dosing for Participants < 40 kg (on a mg/kg/hour basis) 
Days 
Start Time from IP Initiation 
IP Dose 
IP Infusion Rate 
(mL/kg/hour)a 
Duration 
Day 1 
0 hours: bolus dose via syringe or 
infusion pump 
0.75 mg/kgb 
N/A 
3 minutes 
Day 1 
0 
hours 
through 
2 
hours 
following 
IP 
initiation 
continuous infusion, started with 
bolus 
2.0 mg/kg/hr 
 
2 hours 
Day 1 
2 
hours 
through 
12 
hours 
following IP initiation  
1.0 mg/kg/hr 
 
10 hours 
Day 1 
12 hours through 24 hours 
following IP initiation 
0.50 mg/kg/hr 
 
12 hours 
Day 2c 
24 hours through 36 hours 
following IP initiation   
0.50 – 1.125 
mg/kg/hr 
 
12 hours 
 
Taper 
Day 2d  
 
36 through 48 hours following IP 
initiation (12-hour taper) 
0.34 – 0.75 
mg/kg/hr 
 
4 hours 
0.22 – 0.51 
mg/kg/hr 
 
4 hours 
0.15 – 0.34 
mg/kg/hr 
 
4 hours 
IP = investigational product. 
a. 
Reference the Pharmacy Manual for IP infusion rates based on mg/kg/hour dosing. 
b. The 0.75 mg/kg bolus is administered over ~ 3 minutes. 
c. 
On Day 2 (24 through 36 hours), the continuous infusion dose can be increased from 0.5 mg/kg/hour to a 
maximum dose of 1.125 mg/kg/hour at any time, if needed, to manage seizure relapse or other medical reason. 
d. To taper the IP, the infusion rate at the 36-hour following IP 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 (e.g., if the current infusion rate is 0.50 
mg/kg/hr, the first taper will be 0.34 mg/kg/hr), the second taper will be 33.3% from the first tapered infusion 
rate (e.g., if the current infusion rate is 0.50 mg/kg/hr, the second taper will be 0.22 mg/kg/hr), and the final 
taper will be 33.3% from the previous tapered infusion rate (e.g., if the current infusion rate is 0.5 mg/kg/hr, 
the final taper will be 0.15 mg/kg/hr).  If, in the investigator’s judgment, the 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. 
 
3.2 
Efficacy Analysis 
 
Statistical hypotheses testing will be performed for the co-primary and key secondary endpoints 
for the double-blind phase.  To control the family wise type I error, the testing will be performed 
sequentially (the coprimary endpoints will be tested simultaneously), in the order as listed.  
Subsequent testing will only be performed if the prior tests are significant.  
 
3.2.1     Primary Efficacy Endpoints  


 
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3.2.1.1      Primary Analysis 
 
The co-primary efficacy endpoints are: 
1. Proportion of participants with SE cessation within 30 minutes of IP initiation without 
medications for the acute treatment of SE.* 
2. Proportion of participants with no progression to IV anesthesia for 36 hours following IP 
initiation. 
*SE cessation will be determined by the investigator based on clinical and EEG features (details in the protocol).   
Medications for the acute treatment of SE are defined as AEDs administered to abort 
ongoing SE or prevent imminent recurrence of SE based on clinical or EEG evidence. This 
definition excludes maintenance doses of AEDs or medications with anticonvulsant 
properties used for other reasons, such as procedural sedation. 
 
The proportion of participants with SE cessation within 30 minutes and the proportion of 
participants with no progression to IV anesthesia for 36 hours following IP initiation will be 
summarized based on the ITT population. Descriptive statistics, count and percentage of 
participants will be summarized by treatment group. 
 
An interim analysis will be performed when two thirds of the planned participants have 
completed assessment of the co-primary and key secondary efficacy endpoints. The overall type 
I error rate (i.e., alpha=0.05, two-sided) will be controlled using a power family alpha spending 
function 0.05tlog(2.5)/log(2), where an alpha of 0.0293 will be spent at the interim and the remaining 
alpha will be reserved for the final analysis. The statistical hypotheses will be tested for both co-
primary endpoints at the same respective alpha level at interim or final analysis. The interim 
analysis was conducted on the first 83 participants in the ITT population who have completed 
assessments for the co-primary and key secondary endpoints. The study enrollment was stopped 
due to business reasons.  More details can be found in Section 3.5. The final analysis will be 
conducted using the fixed weight combination test. The weights are based on the original amount 
of information before and after the interim analysis (i.e., 2/3 and 1/3) and the test is conducted 
using the original calculated final 2-sided alpha of 0.0343. 
 
The interim analysis will be performed using the logistic regression method described below. Due 
to the limited amount of data, the data after the interim analysis will be analyzed using the 
Boschloo test.  If the p-value (one-sided) of the interim analysis is p1 and the p-value (one-sided) 
from after the interim analysis is p2, and let Ф−1 be the inverse Normal function, a final Z score is 
calculated as  
 
𝑍𝑍= ඨ2
3 Ф−1(1 −𝑝𝑝1) + ඨ1
3 Ф−1(1 −𝑝𝑝2) 
 
The Z-test using the above Z score will be used as the final test. 


 
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The efficacy analysis of the response rates observed for each co-primary endpoint will be 
conducted by using logistic regression methods.  The model will include terms for treatment group 
and baseline STESS as a covariate.  The analysis will be based on the ITT population.  Model-
based point estimates (i.e., odds ratio), 95% confidence intervals and p-values will be reported. In 
addition, the point estimate of difference of the proportions of participants achieving either and 
both co-primary endpoints between two treatment arms will be provided. The 95% confidence 
interval will be provided using Clopper-Pearson method.   
 
The concerned estimand is defined by its attributes below:  
• Population: the target study population comprises participants with status epilepticus who 
also meet the inclusion and exclusion criteria as specified in the study protocol. The analysis 
population is the Intent-to-Treat (ITT) population as defined in Section 2.  
• Variable for the first co-primary: a binary response variable indicating a successful response 
which is defined as SE termination beginning within 30 minutes of IP initiation without use 
of medications for the acute treatment of SE.  
• Variable for the second co-primary: a binary response variable indicating absence of IV 
anesthesia for 36 hours following IP initiation.  
• Intercurrent events: 
o Discontinuation of study treatment due to any reason 
o Death 
• Population-level summary: odds ratio between treatment groups.  
 
The participants with any of the listed intercurrent events will be considered as a treatment non-
responder. To deal with other intercurrent events, a treatment policy approach will be adopted. 
Due to the nature of the disease and short observational period, occurrence of intercurrent events 
is expected to be low. 
 
3.2.1.2      Sensitivity Analysis 
 
The primary efficacy analysis will be repeated in the PP population. 
In addition to logistic regression, response rates for both primary endpoints will also be analyzed 
using the Boschloo test.   
If missing data on the first or second co-primary endpoint exceeds 5%, a tipping point analysis 
will be performed for that endpoint. Assuming Nc participants have missing primary outcome 
data in the control group and Nt participants have missing primary outcome data in the treatment 
group, the primary analysis will be performed to assume 0 to Nc control participants achieved the 
primary outcome and 0 to Nt treatment group participants achieved the primary outcome. All 
(Nc+1)(Nt+1) outcomes will be enumerated in a grid that shows the treatment effect and p-value 
and the ‘tipping point’ when the result would cease to be statistically significant. Model 
averaging will be used to account for multiple possible scenarios contributing to the same number 
of missing data values. 
 


 
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3.2.1.3      Subgroup Analysis 
 
The primary efficacy analysis will be repeated for subgroups defined by the following baseline 
variables: 
• Age group (12-18 yrs, ≥18 yrs) 
• Sex (male, female) 
• Weight group (<40, ≥ 40kg) 
 
Subgroups could be collapsed if the number of participants in some subgroups is too small. 
3.2.2     Key Secondary Efficacy Endpoints 
 
3.2.2.1      Primary Analysis  
The key secondary efficacy endpoints are: 
1. Time to SE cessation following IP initiation 
2. Proportion of participants with no progression to IV anesthesia for 72 hours following IP 
initiation 
Time to SE cessation will be assessed for the first 72 hours following IP initiation. Observations 
for cessation of SE that occurs at a time greater than 72 hours will be censored at 72 hours. Key 
secondary endpoints will be compared between GNX and placebo groups in the ITT population. 
The hypotheses for the key secondary endpoints will be tested only if both co-primary endpoints 
are statistically significant. The key secondary endpoints will be tested in the order listed, at the 
same alpha level of significance as the primary endpoints. More details can be found in Section 
3.5.   
For time to SE cessation following IP initiation, the comparison of the survival curves of time to 
SE cessation between treatment groups will be conducted by a log-rank test. The quartiles (1st 
[25% percentile], 2nd [median], 3rd [75% percentile]) and the associated 95% CI will be provided 
based on the Kaplan-Meier estimate of the survival curves. participants without SE cessation 
before 72 hours post dose initiation or at the time of discontinuation will be censored at 72 hours 
or the time of discontinuation, whichever is earlier; death before SE cessation will be censored at 
72 hours.  
 
The proportion of participants with no progression to IV anesthesia for 72 hours following IP 
initiation will be summarized based on the ITT population. Descriptive statistics, count and 
percentage of participants will be summarized. This key secondary efficacy endpoint will be 
analyzed using logistic regression, the same analysis method as for the co-primary endpoints.  
 
3.2.2.2      Sensitivity Analysis 
 
The Primary analysis method will be repeated in the PP population. 


 
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3.2.2.3      Subgroup Analysis 
 
The primary analyses of the key secondary endpoints will be repeated for subgroups defined by 
the following baseline variables: 
• Age group (12-18 yrs, ≥18 yrs) 
• Sex (male, female) 
• Weight group (<40, ≥ 40kg) 
 
Subgroups could be collapsed if the number of participants in some subgroups is too small. 
 
3.2.3     Other Secondary Efficacy Endpoints 
 
All the other secondary endpoints analysis will be done in the ITT population. The secondary 
endpoints will be analyzed descriptively. No formal statistical comparisons are planned for these 
endpoints. 
 
3.2.3.1      Proportion of Participants With Any Escalation of Treatment in the First 24 Hours 
Following IP Initiation 
 
Proportion of participants with any escalation of treatment in the first 24 hours following IP 
initiation, i.e. any medication other than IP administered for the acute treatment of SE in the first 
24 hours following IP initiation will be summarized by count and percentage of participants by 
treatment group. The 95% CIs will be also calcualted using Clopper Pearson method.  
 
3.2.3.2      Time to Treatment Escalation Following IP Initiation 
 
For time to treatment escalation following IP initiation (any mediation used for acute treatment 
of SE), the quartiles (1st [25% percentile], 2nd [median], 3rd [75% percentile]) and the associated 
95% CI will be provided based on the Kaplan-Meier estimate of the survival curves. For 
participants without treatment escalation, the time to treatment escalation will be censored at IP 
completion, or discontinuation from the study or death, whichever occurs earlier. 
 
3.2.3.3      Time to Initiation of Anesthesia for SE Treatment Through the Final Study Follow-up 
Visit/Contact 
 
For time to initiation of anesthesia for SE treatment through the final study follow-up 
visit/contact, the quartiles (1st [25% percentile], 2nd [median], 3rd [75% percentile]) and the 
associated 95% CI will be provided based on the Kaplan-Meier estimate of the survival curves. 
For participants without initiation of anesthesia for SE treatment, the time to initiation of 
anesthesia will be censored at IP completion, discontinuation from the study or death, whichever 
occurs first. 
 


 
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3.2.3.4      Proportion of Participants Who Develop Super Refractory SE (SRSE) Through the Final 
Study Follow-up Visit/Contact 
 
Count and percentage of participants who develop SRSE through the final study follow-up 
visit/contact will be provided for each treatment group.  
 
3.2.3.5      Seizure Burden Through 72 Hours Following IP Initiation 
 
The seizure burden through 72 hours following IP initiation is described as the percent of time 
during which there is electrographic seizure activity from IP initiation to 72 hours. Descriptive 
summary statistics (n, mean, standard deviation, median, 25th and 75th percentiles, minimum, 
and maximum) of seizure burden will be provided by treatment group. The change from baseline 
of seizure burden will also be summarized using descriptive statistics by treatment group. The 
baseline seizure burden is defined for 30 minutes prior to IP initiation. 
The number and percentage in each category of seizure burden (<20%, 20-50%, and >50%) will 
be also summarized by treatment group.  
 
3.2.3.6      Level of Responsiveness as Assessed by the Full Outline of UnResponsiveness (FOUR) 
Score Scale 
 
The FOUR Score is a tool designed to assess participants with impaired level of consciousness. 
It has a 17-point scale (with potential scores ranging from 0 to 16). The FOUR Score assesses 
four domains of neurological function: eye responses, motor responses, brainstem reflexes, and 
respiration. Each component is a 5-point scale, ranging from 0 to 4. 
 
Descriptive summary statistics (n, mean, standard deviation, median, 25th and 75th percentiles, 
minimum, and maximum) will be provided by treatment group and by scheduled visit for total 
FOUR Score.  
 
Count and percentage of each scale for each component will also be provided by treatment group 
and by visit. 
 
3.2.3.7      Level of Sedation as Assessed by the Richmond Agitation and Sedation Scale (RASS) 
 
The RASS is a medical scale used to measure the agitation or sedation level. It is a 10-point scale, 
with four levels of anxiety or agitation (+1 [restless] to +4 [combative]), one level to denote a calm 
and alert state (0), and 5 levels of sedation (−1 [drowsy] to −5 [unarousable]).   
 
Count and percentage of each scale for each component will be provided by treatment group and 
by visit. 
 
3.2.3.8      Clinician Global Impression-Improvement (CGI-I) 
 
The CGI-S and CGI-I assess overall health and functional status of a participant. Participant and 


 
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clinician rater versions indicate general worsening or improvement on a seven-point Likert-like 
scale.  
 
The CGI-S contains a 7-point Likert scales for baseline overall severity of the participant’s 
presentation (ranging from 1 = normal to 7 = very severe problem) and the CGI-I contains a 7-
point Likert scale for overall global impression of change relative to baseline (ranging from 1 = 
very much improved to 7 = very much worse). 
 
Descriptive summary statistics (n, mean, standard deviation, 25th and 75th percentiles, median, 
minimum, and maximum) will be provided for CGI-I score by treatment group and by schedule 
visit. Count and percentage of each scale for CGI-S and CGI-I will be summarized by treatment 
group and by visit. 
 
3.2.3.9      Level of Functioning as Assessed by the Modified Rankin Scale (mRS) 
 
The Modified Rankin Score (mRS) is a 6-point disability scale with possible scores ranging 
from 0 (no symptom at all) to 5 (severe disability). A separate category of 6 is usually added for 
participants who expire. 
 
Descriptive summary statistics (n, mean, standard deviation, 25th and 75th percentiles, median, 
minimum, and maximum) will be provided for mRS score by treatment group and by schedule 
visit. Count and percentage of each scale will be summarized by treatment group and by visit. 
 
3.2.3.10     Level of Functioning as Assessed by the EuroQoL (EQ-5D-5L) 
 
The EuroQoL (EQ-5D-5L) is a standardized measure of health-related quality of life which 
comprises five dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate 
problems, severe problems, and extreme problems.  
 
Descriptive summary statistics (n, mean, standard deviation, 25th and 75th percentiles, median, 
minimum, and maximum) will be provided for EQ-5D-5L index score by treatment group and 
by schedule visit. Count and percentage of each level for each dimension will be summarized 
by treatment group and by visit. 
 
3.2.3.11     Proportion of Participants with mRS ≥ 3 at the Time of Hospital Discharge 
 
Count and percentage of participants with mRS ≥ 3 at the time of hospital discharge will be 
provided for each treatment group.  
 
3.2.3.12     Proportion of Participants With No Progression to IV Anesthesia for 4 Weeks Following 
IP Initiation 
 
The number and percentage of participants with no progression to IV anesthesia for 4 weeks 


 
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following IP initiation will be summarized by treatment group.  
 
3.2.4     Healthcare Utilization Endpoints 
 
All the healthcare utilization endpoints analysis will be conducted in the ITT population. 
Healthcare utilization endpoints will be summarized descriptively by treatment group. No formal 
statistical comparisons are planned for these endpoints. 
 
3.2.4.1     Time on Positive Pressure Ventilation After IP Initiation 
 
Time on positive pressure ventilation will be analyzed by a stratified log-rank test, where the time 
to event for each participant is defined as time from treatment initiation (or positive pressure 
ventilation initiation if the participant was not on ventilation at the start of treatment) to positive 
pressure ventilation being off, whether the participant was on ventilation at the start of treatment 
is used as the stratification factor. Participants who never needed positive pressure ventilation are 
defined to have 0 amount of time on positive pressure ventilation. Participants who died before 
getting off positive pressure ventilation will be censored at the latest possible assessment time. 
Participants who never got off positive pressure ventilation while on study will be censored at the 
last assessment time. The quartiles (1st [25% percentile], 2nd [median], 3rd [75% percentile]) and 
the associated 95% CI will be provided based on the Kaplan-Meier estimate of the survival curves. 
   
3.2.4.2     Proportion of Participants Requiring Positive Pressure Ventilation Initiated During IP 
Infusion 
 
Proportion of participants requiring positive pressure ventilation initiated during IP infusion will 
be summarized by count and percentage by treatment group. The summary will be based on 
participants who were not on positive pressure ventilation at baseline. 
    
3.2.4.3     Length of Stay in ICU and in Hospital 
 
Post IP initiation Length of stay (hours) in ICU = Time of discharge from ICU – IP initiation time  
Length of stay (hours) in hospital = Time of discharge from hospital – IP initiation time 
Length of stay will be summarized with descriptive statistics (n, mean, standard deviation, 
median, 25th and 75th percentile, min and max) by treatment group.  
 
3.2.4.4     Discharge Destination 
 
Discharge destination is the location where the participant is living at the last follow-up 
assessment.  
 
Count and percentage of each discharge destination will be summarized by treatment group. 
 


 
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                       Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
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3.2.5 Open-label Phase Efficacy Summary 
 
Efficacy assessments for the open-label phase will be summarized using descriptive statistics. 
 
3.3 
Safety Analysis 
 
All the safety summaries are based on the Safety Population. Baseline is defined as the last non-
missing value prior to the first dose of study drug administration.  
 
3.3.1     Adverse Events 
 
Adverse events (AEs) will be coded by MedDRA® version 22.0 or higher and grouped by SOC 
and PT. The verbatim term will be included in the AE listings. Except where indicated, the 
summary tables will include only TEAEs. All AEs, treatment-emergent or otherwise, will be 
presented in participant data listings. 
 
A treatment-emergent adverse event (TEAE) is defined as an AE that occurred or worsened at the 
time of or following IP initiation. To allow differentiation between the study period in which an 
AE occurred, two categories are defined based upon onset date. Adverse events that had onset 
dates prior to the IP initiation are considered “prior.” Adverse events with onset dates on or after 
IP initiation and up to the end of the follow-up period are considered "on-therapy" or equivalently 
“treatment emergent”. Adverse events with onset dates prior to the IP initiation but that worsen 
after IP starts will be considered treatment emergent.  
 
An overview table, including number and percentage of participants with AEs, TEAEs, TEAEs by 
highest severity, serious TEAEs, study drug related TEAEs, TEAEs leading to IP discontinuation, 
and TEAEs leading to death will be provided.  
 
In addition, the following summary tables will be provided: 
• TEAE by SOC and PT 
• TEAEs by PT  
• TEAE by SOC, PT, and severity 
• Study drug related TEAE by SOC and PT 
• Serious TEAE by SOC and PT 
• Serious and drug-related TEAE by SOC and PT 
• TEAEs leading to study drug discontinuation by SOC and PT 
• TEAEs leading to withdrawal 


 
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                       Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
Version 4.0, Amendment 3 
 
All AE tables will be sorted by SOC and PT in decreasing frequency of the number of participants 
in the GNX-treated group. If frequency ties, the sorting will be alphabetic. 
 
A participant having the same AE more than once will be counted only once in the number and 
percentage of participants' calculation for that AE. Similarly, if a participant had more than one AE 
in a SOC, the participant will be counted only once in the number of participants with an AE for 
that SOC. If a participant has the same AE on multiple occasions, the highest severity (severe > 
moderate > mild) recorded for the event will be presented in the AEs by severity table.  
 
Adverse event listing will be provided for all TEAE, serious TEAEs, TEAE related to IP, TEAE 
leading to study drug discontinuation, AEs leading to withdrawal, and participants who died during 
the study. 
 
3.3.2     Vital Signs 
 
Vital signs include weight (kg), height (cm), temperature (°C), systolic blood pressure (mmHg), 
diastolic blood pressure (mmHg), pulse rate (bpm), respiration rate (breaths per minute), and 
oxygen saturation (%). Descriptive statistics for vital signs and changes from baseline values at 
each time point will be provided for each parameter. 
 
All vital signs data will be presented in the participant data listings. 
 
3.3.3     Laboratory Evaluations 
 
All laboratory parameters will be presented in Standard International (SI) units. Only scheduled 
lab parameters will be included in the lab summaries.  
 
Laboratory data collected in this study include serum chemistry and hematology values, urinalysis 
results, pregnancy results, and drug of abuse results. The baseline laboratory value is defined as 
the last value observed prior to IP initiation. Any values collected after IP initiation are regarded 
as post-baseline. Change from baseline will be calculated as the post-baseline value minus the 
baseline value. Only the numeric part in laboratory values that contain non-numeric qualifiers, 
such as less than (<) a certain value or greater than (>) a certain value, will be used in the summary 
statistics. 
 
Quantitative results (including actual value and change from baseline) will be summarized using 
descriptive statistics by baseline and post-baseline visit for each laboratory test based on the Safety 
Population. Shift tables cross-tabulating the baseline and post-baseline classifications (below [L], 
Normal [N], or above [H] the reference range), by visit, will be provided. 
 


 
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                       Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
Version 4.0, Amendment 3 
All laboratory data will be included in the listing, including whether the value was below (L), 
within (N), or above (H) the normal reference range (some urinalysis labs are assigned only normal 
and abnormal classifications).  
 
Pregnancy results performed on selected participants will be listed.  
 
Screening results for drugs of abuse, including alcohol, will be listed separately.  
 
All blood gas results, including FiO2, PaQ2, and arterial pH, if available will be listed. 
 
3.3.4     Electrocardiogram 
 
Descriptive statistics for ECG parameters (PR interval, RR interval, QRS interval, QT interval, 
QTcF [QT interval corrected using Fridericia's method], QTcB [QT interval corrected using 
Bazett’s method], heart rate) and changes from baseline values at each time point will be provided.  
 
In addition, the number and percentage of participants in each category of the interpretation 
(normal, abnormal not clinically significant, abnormal clinically significant) will be summarized. 
 
Select sites will participate in a substudy using a continuous 12 lead ECG recorder which should 
start approximately 60 minutes prior to IP initiation and should continue for 36 hours following IP 
initiation. The data from the substudy of cardiodynamic 12 Lead Electrographic (ECG) monitoring 
will be summarized in separate tables using the same approach as for the main study if the data is 
ready by the primary analysis. 
 
All ECG data will be presented in the data listing. 
 
3.3.5     Physical Examination 
 
The physical examination will include a review of the following body systems:  
• General appearance  
• Skin  
• Head, eyes, ears, nose, and throat  
• Spine, neck, and thyroid  
• Musculoskeletal  
• Respiratory  
• Cardiovascular  
• Neurologic  
• Abdomen (including liver and kidneys)  
• Other systems as appropriate  


 
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                       Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
Version 4.0, Amendment 3 
 
Physical examination results for each body system are interpreted as normal and abnormal. The 
number and percentage of participants in each category (normal, abnormal) and change from 
baseline (normal to abnormal or abnormal to abnormal) will be summarized for each body system 
by treatment group and by visit.  
 
Listings for all the physical examinations will be provided. 
 
3.4 
Pharmacokinetic Analysis 
 
The PK analyses will include all participants who have received at least 1 dose of IP and who have 
had at least 1 sample collected and a valid bioanalytical result obtained. The following plasma 
pharmacokinetic parameters for ganaxolone and Captisol will be calculated as data allows and as 
appropriate using noncompartmental approaches:  
• 
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 
Pharmacokinetic variables will be computed using WinNonlin Professional, version 5.2 or similar 
software. Actual elapsed sampling times relative to IP administration will be used for the 
estimation of pharmacokinetic metrics. Additional parameters may be calculated on discretion of 
the pharmacokineticist, pending review of the data. 
 
3.5 
Interim Analysis 
 
An interim analysis is planned when two thirds of the ITT population have completed assessments 
for the primary and key secondary efficacy endpoints. If study enrollment is proceeding at a rate 
that the study would be nearly complete by the time an interim analysis is accomplished, the 
Sponsor may elect not to conduct it. If the interim analysis is conducted, an alpha of 0.0293 (details 
below) will be spent at the interim; if the interim is not conducted, no alpha will be spent. The 
interim analysis will be performed by an independent statistical organization and reviewed by an 
independent Data Monitoring Committee (DMC) who are not involved in the regular study 
operation and conduct.  
 
The overall type I error rate (i.e., alpha=0.05, two-sided) will be controlled using a power family 
alpha spending function 0.05tlog(2.5)/log(2), with two-sided nominal alpha levels of 0.0293 and 0.0343 
(with adjustment as needed) at the interim and the final analyses, respectively. At the interim 
analysis, the two co-primary endpoints will be tested first, both at the same nominal alpha level of 
0.0293. If both endpoints are statistically significant, the key secondary endpoints will be tested 
sequentially (a test will only be performed if all the prior ones are significant) in the order as listed, 


 
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                       Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
Version 4.0, Amendment 3 
at the same nominal alpha level of 0.0293 as for the primary endpoints. If one or both primary 
efficacy endpoints fail to reach statistical significance at the interim analysis, the same testing 
process will be repeated at the final analysis at the nominal alpha level of 0.0343. The operational 
details of the interim analysis will be described in the Interim Analysis Plan. 
 
An interim analysis was performed with 83 participants spending a two-sided alpha of 0.0293 as 
planned.  The independent DMC recommended that the study could continue without 
modification. However, the sponsor made the decision to stop enrollment when 100 participants 
were randomized. The final analysis will be conducted using the fixed weight combination test. 
The weights are based on the amount of information that would have originally been available 
before and after the interim analysis (i.e., 2/3 and 1/3) and the test will be conducted using the 
original calculated final 2-sided alpha of 0.0343. 
 
 


 
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                       Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
Version 4.0, Amendment 3 
4. CHANGE TO ANALYSES SPECIFIED IN PROTOCOL 
 
No changes.  
 
5. PROGRAMMING SPECIFICATIONS  
 
Detailed programming specifications will be documented and filed in the study file. 
 
6. TABLES/LISTINGS/FIGURES TEMPLATES  
 
Templates for planned tables, listings, and figures will be documented and filed in the study file.  
 
7. REFERENCES  
 
1. International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9).  
2. American Statistical Association (ASA) Ethical Guidelines for Statistical Practice. Prepared 
by the Committee on Professional Ethics.  
 
 
 


 
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Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
Version 4.0, Amendment 3 
8. APPENDICES 
 
8.1 
Schedule of Assessments 
 
Details of schedule of assessment can be found in the protocol and protocol clarification memos 
Periods/Day/ 
Duration 
Screeninga 
Day -1 to 
Day 1 
Predose 
through 
screening 
Dosing 
Day 1 
IP initiation 
0 through 24 hours 
following IP initiation 
Dosing 
Day 2 
24 
hours 
through 
36 
hours 
following 
IP 
initiation 
Taper 
Day 2 
(12 hours) 
Starts at 36 hours 
following 
IP 
initiation 
IP 
Discontinuation 
IP Discontinuation 
Follow-up b 
Early 
Termin
ation 
Visit 
1 
 2   
3 
4 
5 
6 
7 
8 
9 
10 
11 - 14 
98 
Timepoint 
 
Minutes (m) /Hours (h) following IP initiation 
  
With or without 
Taper  
Hours following IP 
Discontinuation 
 
 
Hospital 
Discharge 
Weekly 
follow-
up 
(Week 
1, 2, 3, 
& 4) 
ET 
-0 
60 
m 
2 
h 
6 
h 
10 
h 
24 
h 
36 
h 
48 
h 
Collected prior to 
or as close to IP 
discontinuation 
as possible 
24 
48  
72 
96 
120 
 
6 ± 3,  
14 ± 3, 
21 ± 3, 
and 28 ± 
3 
days 
followin
g 
IP 
discon 
 
Informed consent/assent 
a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ exclusion criteria 
a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography and medical, 
including seizures or SE 
etiology and medication  
historyc 
a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examd 
a 
 
 
 
 
 
a 
 
a 
a 
 
 
 
 
a 
 
a 
STESS 
a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signse  
a 
a 
a 
a 
a 
a 
a 
 
a 
a 
 
 
 
 
a 
 
a 
RASSf 
a 
a 
a 
a 
a 
a 
a 
 
a 
a 
a 
a 
a 
a 
a 
a 
a 
FOUR Scoref 
a 
a 
a 
a 
a 
a 
a 
 
a 
a 
a 
a 
a 
a 
a 
a 
a 
Safety 12 lead ECGg 
a 
 
a 
 
 
 
a 
 
a 
a 
 
 
 
 
a 
 
a 


 
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Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
Version 4.0, Amendment 3 
Details of schedule of assessment can be found in the protocol and protocol clarification memos 
Periods/Day/ 
Duration 
Screeninga 
Day -1 to 
Day 1 
Predose 
through 
screening 
Dosing 
Day 1 
IP initiation 
0 through 24 hours 
following IP initiation 
Dosing 
Day 2 
24 
hours 
through 
36 
hours 
following 
IP 
initiation 
Taper 
Day 2 
(12 hours) 
Starts at 36 hours 
following 
IP 
initiation 
IP 
Discontinuation 
IP Discontinuation 
Follow-up b 
Early 
Termin
ation 
Visit 
1 
 2   
3 
4 
5 
6 
7 
8 
9 
10 
11 - 14 
98 
Timepoint 
 
Minutes (m) /Hours (h) following IP initiation 
  
With or without 
Taper  
Hours following IP 
Discontinuation 
 
 
Hospital 
Discharge 
Weekly 
follow-
up 
(Week 
1, 2, 3, 
& 4) 
ET 
-0 
60 
m 
2 
h 
6 
h 
10 
h 
24 
h 
36 
h 
48 
h 
Collected prior to 
or as close to IP 
discontinuation 
as possible 
24 
48  
72 
96 
120 
 
6 ± 3,  
14 ± 3, 
21 ± 3, 
and 28 ± 
3 
days 
followin
g 
IP 
discon 
 
Cardiodynamic 12 lead ECG 
monitoring (sub study only)h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biochemistry, hematology, 
and AEDsi 
a 
 
 
 
 
 
 
 
a 
a 
 
 
 
 
a 
a 
a 
Urine chemistry (N-acetyl-
β-D-glucosaminidase 
(NAG) 
and 
β2-
microglobulin)j 
a 
 
 
 
 
 
 
 
 
a 
 
 
 
 
a 
a 
a 
Coagulationk 
a 
 
 
 
 
 
 
 
 
a 
 
 
 
 
a 
 
a 
Routine Urinalysisi 
a 
 
 
 
 
 
 
 
a 
a 
 
 
 
 
a 
a 
a 
Drugs of abuse, including 
alcoholl 
a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (FCBP only)l 
a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EEGm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Gasn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGI-S 
a  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGI-Io 
 
 
 
 
a 
a 
 
 
a 
a 
a 
a 
a 
a 
a 
a 
a 
Seizure 
Description 
Questionnaire-predosep 
a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
Version 4.0, Amendment 3 
Details of schedule of assessment can be found in the protocol and protocol clarification memos 
Periods/Day/ 
Duration 
Screeninga 
Day -1 to 
Day 1 
Predose 
through 
screening 
Dosing 
Day 1 
IP initiation 
0 through 24 hours 
following IP initiation 
Dosing 
Day 2 
24 
hours 
through 
36 
hours 
following 
IP 
initiation 
Taper 
Day 2 
(12 hours) 
Starts at 36 hours 
following 
IP 
initiation 
IP 
Discontinuation 
IP Discontinuation 
Follow-up b 
Early 
Termin
ation 
Visit 
1 
 2   
3 
4 
5 
6 
7 
8 
9 
10 
11 - 14 
98 
Timepoint 
 
Minutes (m) /Hours (h) following IP initiation 
  
With or without 
Taper  
Hours following IP 
Discontinuation 
 
 
Hospital 
Discharge 
Weekly 
follow-
up 
(Week 
1, 2, 3, 
& 4) 
ET 
-0 
60 
m 
2 
h 
6 
h 
10 
h 
24 
h 
36 
h 
48 
h 
Collected prior to 
or as close to IP 
discontinuation 
as possible 
24 
48  
72 
96 
120 
 
6 ± 3,  
14 ± 3, 
21 ± 3, 
and 28 ± 
3 
days 
followin
g 
IP 
discon 
 
Status Epilepticus Cessation 
Questionnaireq 
 
 
 
 
 
 
 
 
 
 
 
a 
 
 
 
 
 
Super 
Refractory 
Status 
Epilepticus 
Questionnaire 
(SRSE)r 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 
 
EuroQol (EQ-5D-5L)s 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 
a 
a 
a 
mRSt 
 
 
 
 
 
 
 
 
 
a 
a 
a 
a 
a 
a 
a 
a 
AEs/SAEsu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medicationu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Healthcare 
Utilization 
Questionnairesv 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discon = discontinuation; ET = Early Termination; ECG = electrocardiogram; IP = investigational product;; FCBP = females of childbearing potential; EEG = electroencephalograms; AE = adverse event; 
SAE = serious AE; STESS = Status Epilepticus Severity Score; RASS = Richmond Agitation and Sedation Scale; FOUR Score = Full Outline of UnResponsiveness Score; AED = antiepileptic drug; CGI-
S = Clinical Global Impression of Severity; CGI-I = Clinical Global Impression of Improvement; mRS = modified Rankin Scale  
a. 
The screening period is from the time participant/participant’s parent/guardian/LAR consent is obtained (or deferred, if allowed by law) to immediately prior to IP initiation However, assessments 
collected prior to this timeframe that the investigator judges to be clinically relevant to the participant’s current state can be utilized in the study and do not need to be repeated. For medically unstable 
participants, screening activities (e.g., labs or vital signs) should be collected as close to IP initiation as possible. 
b. The planned duration for the follow-up period after IP is discontinued is approximately 4 weeks. Study assessments/procedures will be collected every 24 hours through 120 hours (or until hospital 
discharge) and at the time of hospital discharge followed by weekly follow-up visits at Week 1, 2, 3 and 4.  Weeks 1, 2, 3 and 4 visits can be conducted as an inparticipant visit, if the participant is 


 
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Statistical Analysis Plan 
Protocol 1042-SE-3003 
 
Version 4.0, Amendment 3 
still in the hospital, or as a telephone contact, if the participant has been discharged. Attempts should be made to have discharged participants return for one of these visits to be in person for clinical 
laboratory sample collection and RASS & FOUR Score assessments which can only be performed in person. 
c. 
Demography, medical history, including seizures or SE etiology, and medication history will be collected prior to IP initiation but can be collected whenever feasible before the end of the taper.  
d. Physical exam should be obtained from the participant’s chart or completed predose (screening) or, if not available, collect within 2 hours following IP initiation, and at 36 hours, if clinically indicated, 
following IP initiation. Collect at the time of IP discontinuation (+/- 1 hour), either at the end of the taper or if the IP administration is stopped without a taper and 24 hours (+/- 1 hour) following IP 
discontinuation and at the time of hospital discharge. For participants who terminate early from the study, collect at the time of early termination (whenever possible).  The investigator may conduct 
at any other time based on clinical judgment. 
e. 
Vital signs including blood pressure, pulse, respiratory rate, temperature, and oxygen saturation should be collected predose (screening), 60 minutes (+/- 15 min), 2 (+/- 15 min), 6, 10, 24, and 36 
hours (+/- 2 hour) following IP initiation. Collect at the time of IP discontinuation (+/- 1 hour), either at the end of the taper or if the IP administration is stopped without a taper and 24 hours (+/- 
2hour) following IP discontinuation, and at the time of hospital discharge. For participants who terminate early from the study, collect at the time of early termination (whenever possible).  The 
investigator may collect at any other time based on clinical judgment. Weight and height should be collected predose (screening) for calculation of BMI inclusion criterion, if feasible. If not collected 
predose (screening), collect prior to the end of the first 24 hours of the follow-up period. 
f. 
RASS and FOUR score scales should be collected predose (screening),60 minutes (+/- 15-min), 2, 6, 10 (+/- 30 minutes), 24 and 36 hours (+/- 1 hour) following IP initiation. Collect at the time of IP 
discontinuation (+/- 1 hour), either at the end of the taper or if the IP administration is stopped without a taper. Collect 24 (+/- 1 hour), 48, 72, 96, and 120 hours (+/- 2 hours) following IP discontinuation 
and at the time of hospital discharge. Collect at the weekly follow-up visits (Week 1, 2, 3, or 4) for hospitalized participants and for participants who have been discharged (whenever possible). For 
participants who terminate early from the study (whenever possible), collect at the time of early termination. 
g. ECG should be collected predose (screening) and 2 (+/- 30 min) following IP initiation. Collect at the time of IP discontinuation (+/- 1 hour), either at the end of the taper or if the IP administration is 
stopped without a taper and 24 hours (+/- 1 hour) following IP discontinuation and at the time of hospital discharge. For participants who terminate early from the study, collect at the time of early 
termination (whenever possible). The investigator may collect any other time based on clinical judgment. 
h. Cardiodynamic 12 lead ECG monitoring. Select sites will participate in a sub study using a continuous 12 lead ECG recorder which should be started approximately 60 minutes prior to IP initiation 
and should continue for 36 hours following IP initiation. For more details refer to Appendix 5. 
i. 
Clinical labs, hematology, serum chemistry (including creatinine, blood urea nitrogen, creatinine clearance calculation [if available], estimated glomerular filtration rate [eGFR] calculation [if 
available]), and concomitant AED levels (fosphenytoin/phenytoin, valproic acid, levetiracetam, lacosamide, phenobarbital, or brivaracetam, if collected per standard of care) and Routine Urinalysis 
(including urine protein, and microscopic examination, if any abnormal value is observed on the urine dipstick test) should be collected predose (screening), if unable to collect predose, collect within 
2 hours following IP initiation.  Collect at the time of IP discontinuation (+/- 1 hour), either at the end of the taper or if the IP administration is stopped without a taper and 24 hours (+/- 1 hour) 
following IP discontinuation and at the time of hospital discharge. Collect at the weekly follow-up visits (Week 1, 2, 3, or 4) for hospitalized participants and for participants who have been discharged 
(whenever possible).  For participants who terminate early from the study, collect at the time of early termination (whenever possible). Collect in the event of an SAE. The investigator may collect at 
any other time based on clinical judgment.  
j. 
Urine chemistry sample for N-acetyl-β-D-glucosaminidase (NAG) and β2-microglobulin should be collected predose (screening), if unable to collect predose, collect within 2 hours following IP 
initiation, 24 hours (+/- 1 hour) following IP discontinuation and at the time of hospital discharge. Collect at one of the weekly follow-up visits (Week 1, 2, 3, or 4) for hospitalized participants and 
when possible, for participants who have been discharged. For participants who terminate early from the study, collect at the time of early termination (whenever possible). Urine samples will be 
stored frozen unless otherwise dictated or revised in the Biospecimen Manual. 
k. Clinical coagulation (including fibrinogen, activated partial thromboplastin time [APTT], prothrombin time [PT] and international normalize ratio [INR]) should be collected predose (screening), if 
unable to collect predose, collect within 2 hours following IP initiation, 24 hours (+/- 1 hour) following IP discontinuation and at the time of hospital discharge. For participants who terminate early 
from the study, collect at the time of early termination (whenever possible). The investigator may collect at any other time based on clinical judgment. 
l. 
A urine or serum sample for drugs of abuse testing should be collected predose per the institution standard of care. A urine or serum sample for alcohol testing should be collected, if medically 
indicated. A urine or serum sample for pregnancy testing for females who are of childbearing potential, should be collected predose (screening).  If unable to collect sample(s) at predose, collect as 
soon as possible following IP initiation. Enrollment is not contingent upon results. However, if a participant has a positive test result, it will be at the investigator’s discretion to weigh the risks versus 


 
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Protocol 1042-SE-3003 
 
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benefits for enrollment or continued participation. If the investigator decides to discontinue the IP, refer to the taper directions in the Investigational Product, Dose and Mode of Administration section. 
If the institution requires the pregnancy test results be obtained prior to IP initiation, the institution guidelines will be followed. The investigator may collect at any other time based on clinical judgment. 
m. EEG is required for confirmation of CSE and NCSE diagnosis. Continuous EEG recording should be utilized for all participants and should start at least 60 minutes before IP initiation and continue 
through the end of the first 24 hours of the follow-up period.  
n. Blood gas, arterial or venous, if collected to manage the participant’s care from the time of SE diagnosis through the first end of the first 24 hours of the follow-up period, the eCRF should be completed. 
If samples are not collected, a sample is not required. If a decision is made to intubate the participant between IP initiation through the end of the first 24 hours of the follow-up period, 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.  
o. CGI-I should be collected 10 and 24 hours (+/- 1 hour) following IP initiation. Collect at time of IP discontinuation (+/- 1 hour), either at the end of the taper or if the IP administration is stopped 
without a taper. Collect 24 (+/- 1 hour), 48, 72, 96, and 120 hours (+/- 2 hours) following IP discontinuation and at the time of hospital discharge. Collect at Week 1, 2, 3, and 4 follow-up visits/contacts. 
For participants who terminate early from the study, collect at the time of early termination (whenever possible). 
p. Seizure Description Questionnaire should be collected predose (screening) as close as possible prior to IP initiation. 
q. Status Epilepticus Cessation Questionnaire should be collected as close as possible to 72 hours following IP initiation. 
r. 
Super Refractory Status Epilepticus (SRSE) Questionnaire should be collected as close as possible to the diagnosis of SRSE and no later than the final study follow-up visit/contact. 
s. 
EuroQoL (EQ-5D-5L) should be collected at 120 hours (+/- 2 hours) following IP discontinuation and at the time of hospital discharge. Collect at Week 2, 3, and 4 follow-up visit/contacts.  For 
participants who terminate early from the study, collect at the time of early termination (whenever possible).  
t. 
mRS should be collected 24 (+/- 1 hour), 48, 72, 96, and 120 hours (+/- 2 hours) following IP discontinuation and at the time of hospital discharge. Collect at Week 2, 3, and 4 follow-up visits/contacts. 
For participants who terminate early from the study, collect at the time of early termination (whenever possible). 
u. AEs will be collected from the time of IP initiation until the final study follow-up visit/contact via non-direct questioning. Concomitant medications will be collected during the same time period. All 
AEs and associated concomitant medications will be collected through the final study follow-up visit/contact.  For participants who terminate early 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. Each 
AED administered within 14 of IP initiation will be recorded and the reason for administration through the final study follow-up visit/contact. 
v. Healthcare Utilization Questionnaires include the Hospitalization Questionnaire and the Positive Pressure Ventilation (PPV) and Intubation Questionnaire. The Hospitalization Questionnaire should 
be collected at hospital discharge or at final study visit/contact. The need for non-invasive or invasive ventilatory support within 24 hours prior to IP initiation and following IP initiation and within 
48 hours following IP discontinuation should be collected as close as possible to the event.