Clinical trial NCT02519439
Conditions: Drug Resistant Partial Onset Seizure
Keywords: Partial Onset Seizures complex partial seizures simple partial seizures anticonvulsant ganaxolone neurosteroid Marinus epilepsy
Sponsor: Marinus Pharmaceuticals
Start date: 2015-02-01; Completion date: 2016-12-01
Enrollment: 26 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A follow-on, two-year open-label extension study of ganaxolone as add-on therapy in adult patients with drug-resistant partial-onset seizures

Detailed description:
This study is a 2-year, open-label continuation for those patients benefiting from ganaxolone treatment after completing Protocol 1042-0603.

Arms: arm 1: Up to a maximum of 1800 mg/day
Interventions: intervention 1: ganaxolone
Intervention descriptions: intervention 1: 225 mg capsules 450 mg to 900 mg 2x/day

Protocol documents:
Prot_002.pdf: 
Clinical Study Report 
 
Study 1042-0604 
Marinus Pharmaceuticals, Inc. 
 
 
 
16.1 
STUDY INFORMATION 
16.1.1 
Protocol 


 
CONFIDENTIAL INFORMATION 
 
 
CLINICAL STUDY PROTOCOL 
 
STUDY TITLE: A follow-on, two-year open-label extension study of ganaxolone as 
add-on therapy in adult patients with drug-resistant partial-onset seizures  
 
SHORT TITLE:  Ganaxolone Two-year Open-label Extension Study 
 
PROTOCOL NUMBER: 1042-0604 
STUDY PHASE: III 
STUDY DRUG(S): Ganaxolone (CCD 1042:3α-hydroxy-3β-methyl-5α-pregnan-20-one)  
IND NUMBER:  44,020 
INDICATION:  Epilepsy with drug-resistant partial-onset seizures 
 
SPONSOR: 
Marinus Pharmaceuticals, Inc. 
Three Radnor Corporate Center 
100 Matsonford Road, Suite 304 
Radnor, PA 19087 
 
SPONSOR CONTACT:    
 
Sr. Director, Clinical Operations 
Telephone:
Email: 
 
 
SPONSOR’S MEDICAL 
REPRESENTATIVE:  
, MD, PhD 
 
Vice President, Clinical Development 
 
Office Phone: 
Mobile Phone:
 
 
Email: 
  
 
INITIAL VERSION:  
January 15, 2015 
 
AMENDMENT 1:    
February 29, 2016




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CONFIDENTIAL INFORMATION 
2. 
SYNOPSIS 
Name of Sponsor/Company: Marinus Pharmaceuticals, Inc. 
 
Protocol Number: 1042-0604 
 
Phase of Development: III 
 
Title of the Protocol: A follow-on,  two-year open-label extension study of ganaxolone as add-on 
therapy in adult subjects with drug-resistant partial-onset seizures  
 
Primary Objectives: To assess the safety and tolerability of adjunctive ganaxolone during a two-year 
open-label treatment in adult subjects with drug-resistant partial-onset seizures 
 
Secondary Objectives: To assess efficacy of adjunctive ganaxolone during a two-year open-label 
treatment in adult subjects with drug-resistant partial-onset seizures 
 
Study Design and Methodology: Subjects who successfully completed Study 1042-0603 and meet 
inclusion/exclusion criteria are eligible to enter Study 1042-0604 and continue open-label adjunctive 
treatment with ganaxolone capsules in the dose range of 900 - 1800 mg daily. 
 
Study Population and Main Criteria for Inclusion/Exclusion: Adults with drug-resistant partial onset 
seizures currently taking 1-3 prescribed AEDs who completed all scheduled clinical study visits in Study 
1042-0603, were compliant, derived benefit from open-label ganaxolone and did not experience any 
serious or medically important adverse event judged probably or definitely due to ganaxolone. 
 
Number of Subjects: A maximum of approximately 350 subjects may enter this protocol, after 
satisfactorily completing Study 1042-0603.   
 
Test Product, Dose and Mode of Administration: Ganaxolone 225 mg capsules administered in BID 
in the dose range of 900 to 1800 mg/day. 
 
Duration of Treatment: Up to 104 weeks treatment on the maintenance dose with an additional 2 
weeks of dose de-escalation. 
 
Reference Therapy, Dose and Mode of Administration:  None 
 
Safety Criteria for Evaluation: 
Adverse Events, vital signs, safety laboratory assessments, ECGs 
 




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CONFIDENTIAL INFORMATION 
TABLE OF CONTENTS 
1. 
SIGNATURE PAGE ..........................................................................................2 
2. 
SYNOPSIS ..........................................................................................................3 
2.1 ........... Table 1:  Schedule of Events ................................................................4 
3. 
LIST OF ACRONYMS, ABBREVIATIONS, AND DEFINITIONS 
OF TERMS .........................................................................................................7 
4. 
ETHICS ...............................................................................................................9 
4.1 ........... Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ..........................................................................................9 
4.2 ........... Ethical Conduct of Study ....................................................................9 
4.3 ........... Subject Information and Consent ......................................................9 
5. 
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE ...................................................................................................10 
6. 
INTRODUCTION ............................................................................................11 
7. 
STUDY OBJECTIVES ....................................................................................14 
7.1 ........... Primary ...............................................................................................14 
7.2 ........... Secondary............................................................................................14 
8. 
INVESTIGATIONAL PLAN ..........................................................................15 
8.1 ........... Overall Study Design and Plan .........................................................15 
8.2 ........... Discussion of Study Design ................................................................15 
8.3 ........... Selection of Study Population ...........................................................16 
8.3.1 
Number of Subjects: ..........................................................16 
8.3.2 
Inclusion Criteria ...............................................................16 
8.3.3 
Exclusion Criteria ..............................................................17 
8.3.4 
Removal of Subjects from Therapy or Assessments ..........18 
8.3.4.1 
Criteria for withdrawal..................................18 
8.3.4.2 
Early Termination Procedures.......................20 
8.3.4.3 
Consequences of Early Termination .............20 
8.4 ........... TREATMENTS ..................................................................................20 
8.4.1 
Identity of Investigational Product(s) ................................20 
8.4.2 
Treatment Groups ..............................................................21 
8.4.3 
Subject Numbering ............................................................21 
8.4.4 
Selection of Doses in the Study .........................................21 
Table 2. Dosing Schedule for De-Escalation Period ......................................22 
8.4.5 
Dose Administration ..........................................................22 
8.4.6 
Missing a Dose ...................................................................22 
8.4.7 
Blinding..............................................................................23 
8.4.8 
Excluded, Prior and Concomitant Medications .................23 
8.4.9 
Excluded Concomitant Medications ..................................23 
8.4.10 
Treatment Compliance .......................................................25 
8.5 ........... Efficacy and Safety Variables ...........................................................25 


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CONFIDENTIAL INFORMATION 
8.5.1 
Efficacy Measurements, Safety Assessments and 
Schedule of Study Procedures ...........................................25 
8.5.1.1 
Efficacy Measurements .................................25 
8.5.1.2 
Safety Assessments .......................................25 
8.5.1.3 
Schedule of Study Procedures ......................26 
8.6 ........... Data Quality Assurance .....................................................................28 
8.7 ........... Statistical Methods Planned and Determination of Sample Size...28 
8.7.1 
Statistical and Analytical Plans ..........................................28 
8.7.1.1 
Randomization ..............................................28 
8.7.1.2 
Analysis Populations.....................................28 
8.7.1.3 
Analysis of Efficacy Variables ......................28 
8.7.1.4 
Analysis of Safety Variables .........................29 
8.7.2 
Determination of Sample Size ...........................................29 
9. 
INVESTIGATOR REQUIREMENTS ...........................................................30 
9.1 ........... Study Initiation...................................................................................30 
9.2 ........... Study Completion...............................................................................30 
9.3 ........... Study Discontinuation .......................................................................31 
9.4 ........... Informed Consent ..............................................................................31 
9.5 ........... Adverse Events ...................................................................................31 
9.5.1 
Definitions..........................................................................32 
9.5.2 
Evaluating and Recording of Adverse Events ...................33 
9.5.3 
Reporting of Adverse Events .............................................34 
9.5.3.1 
Serious Adverse Events ................................34 
9.5.3.2 
Medical Inquiries ..........................................36 
9.5.3.3 
Pregnancy......................................................37 
9.6 ........... Study Monitoring and Audit Requirements ....................................37 
9.7 ........... Case Report Forms (CRFs) ...............................................................38 
9.8 ........... Study Drug Accountability ................................................................38 
9.9 ........... Confidentiality of Data ......................................................................38 
9.10 ........ Retention of Records..........................................................................38 
9.11 ......... Protocol Adherence ............................................................................39 
10. 
PUBLICATION PLAN ....................................................................................40 
11. 
REFERENCES .................................................................................................41 
12. 
APPENDICES ..................................................................................................42 
12.1 ........ Appendix 1: Clinical Laboratory Tests ............................................42 
12.2 ........ Appendix 2: Strong and Moderate Cytochrome P450 CYP 3A4, 
5, 7 Inducers and Inhibitors Prohibited During Study 1042-0603 43 
12.3 ........ Appendix 3: Dosing Instructions for Subjects .................................44 
12.4 ........ Appendix 4:  Subject Seizure Calendar ...........................................47 
12.5 ........ Appendix 5:  Clinical Global Impression – Improvement 
(Patient/Caregiver) ............................................................................52 
12.6 ........ Appendix 6:  Columbia Suicide Severity Rating Scale (C-SSRS) 
Since Last Visit ...................................................................................54 
12.7 ........ Appendix 7:  Protocol History ..........................................................58 


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CONFIDENTIAL INFORMATION 
3. 
 LIST OF ACRONYMS, ABBREVIATIONS, AND DEFINITIONS OF 
TERMS 
Term 
Definition 
3α,5α-P 
3α-hydroxy-5α-pregnan-20-one; allopregnanolone 
AE 
adverse event 
AE CRF 
adverse event case report form 
AED 
antiepileptic drug 
ALT 
alanine transferase (SGPT) 
ARS 
acute repetitive seizures 
AST 
aspartate transferase (SGOT) 
ANCOVA 
analysis of covariance 
BID 
bis in die; two times per day 
CFR 
Code of Federal Regulations 
°C 
degrees centigrade 
CGI-I 
Clinician’s Global Impression of Improvement 
CNS 
central nervous system 
CPS 
complex partial seizures 
CRF 
case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
computed tomography 
DB 
double-blind 
DDI 
drug-drug interaction 
ECG, EKG 
electrocardiogram 
EEG 
electroencephalogram 
ET 
Early Termination 
°F 
degrees Fahrenheit 
FAP 
full analysis population 
FDA 
Food and Drug Administration 
POS 
Partial-onset seizure 
FS 
Focal seizure 
FPFV 
first patient, first visit 
GABAA 
γ-aminobutyric acidA 
GCP 
Good Clinical Practice 
GTCS 
generalized tonic-clonic seizure 
Hz 
Hertz 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
ILAE 
International League Against Epilepsy 
IPIN 
Investigational Product Identification Number 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
kg 
kilogram 
LOCF 
last observation carried forward 
LPLV 
last patient, last visit 
m 
meter 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 


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CONFIDENTIAL INFORMATION 
Term 
Definition 
mg/d 
milligram per day 
min 
minutes 
mL 
millilitre 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
n 
number of subjects 
OL 
open-label 
OLE 
open-label extension 
oz 
ounces 
PCGI-I 
Patient/Caregiver Global Impression of Improvement 
PK 
pharmacokinetics 
POS 
partial-onset seizure 
PTZ 
pentylenetetrazol 
PP 
per-protocol 
SAE 
serious adverse event 
SAE CRF 
serious adverse event case report form 
SOC 
system organ class 
SP 
safety population 
SPS 
simple partial seizure 
t.i.d. 
three times daily 
Tmax  
time to maximum concentration  
ULN 
upper limits of normal 
USA 
United States of America 
VNS 
vagal nerve stimulator 
WCBP 
women of child bearing potential 
 
 


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CONFIDENTIAL INFORMATION 
4. 
ETHICS 
4.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
This study will be conducted in compliance with current Good Clinical Practices (GCP) 
and Title 21 Part 56 of the United States of America (USA) Code of Federal Regulations 
(CFR) relating to IRBs and the International Conference on Harmonisation (ICH) E6 
guidelines for Good Clinical Practice.  
4.2 
Ethical Conduct of Study 
The study will be conducted in accordance with GCP as described in the USA Food and 
Drug Administration (FDA) CFR (21 CFR § 50, 56, 312), and the International 
Conference on Harmonisation (ICH) and the ethical principles of the Declaration of 
Helsinki. 
4.3 
Subject Information and Consent 
This study will be conducted in compliance with Title 21 Part 50 of the USA CFR and 
ICH E6(RI) (Section 4.8) pertaining to informed consent.  At the first visit, prior to 
initiation of any study-related procedures, subject will give their written consent to the 
study after having been informed about the nature and purpose of the study, conditions 
for study participation/termination, and potential risks and benefits. 


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CONFIDENTIAL INFORMATION 
5. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
This will be a multi-center study with approximately 58 investigational sites in the USA, 
the Russian Federation (Russia), Australia, Bulgaria, Germany and Poland with 
approximately 6 subjects enrolled at each site.  Duration of subject participation is 106 
weeks. 
 
 


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CONFIDENTIAL INFORMATION 
6. 
INTRODUCTION 
Approximately 2 million people in the United States of America (USA) have epilepsy.  
As many as 30% of epilepsy subjects may not be well controlled on treatment with a 
single or multiple existing antiepileptic drugs (AEDs; French et al., 2004).  The approach 
of adding on an experimental AED to an existing non-optimal therapeutic regimen has 
proven to be a useful technique for demonstrating efficacy of novel compounds.  The 
present study will evaluate the safety, tolerability and efficacy in a second year of open-
label treatment with ganaxolone when used as an add-on therapy in adult subjects with 
drug-resistant partial-onset (focal) seizures. 
Ganaxolone is the 3β-methylated synthetic analog of allopregnanolone, which is 
synthesized in vivo when progesterone undergoes 5α-reduction and loses all 
progestational activity.  Ganaxolone is a positive allosteric modulator of γ-aminobutyric 
acid A (GABAA) receptors with potency and efficacy comparable to its endogenous 
analog allopregnanolone (Carter et al., 1997).  As with allopregnanolone, ganaxolone 
potentiation of the GABAA receptor occurs at a site distinct from the benzodiazepine site.  
Ganaxolone has protective activity in diverse rodent seizure models, including clonic 
seizures induced by pentylenetetrazol (PTZ) and bicuculline, limbic seizures in the 6 Hz 
model, and amygdala kindled seizures (Carter et al., 1997; Kaminski et al., 2004; Reddy 
et al., 2004). Unlike allopregnanolone, ganaxolone cannot be converted to an active 
steroid; it is currently under study for treatment of chronic neurologic and psychiatric 
conditions such as adult and pediatric epilepsy, Posttraumatic Stress Disorder and 
behaviors in Fragile X Syndrome.  Human trials indicate that ganaxolone is well tolerated 
and that it may be efficacious in the treatment of diverse forms of epilepsy in children 
and adults (Bialer et al. 2010). 
As of May 31, 2013, 986 subjects have received and completed treatment with 
ganaxolone in 35 studies, ranging in duration from 1 day to more than 2 years. Two 
hundred and eighty-nine subjects received ganaxolone in Phase 1 studies, including 22 
subjects in Study 1042-0404 which was an open-label, ascending multiple-dose safety 
and tolerability study of 1200, 1600 and 2000 mg/day.   


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Subjects in Study 1042-0404 were maintained at each dose level for 3-5 days; the doses 
were safe and generally well-tolerated. Pharmacokinetics were assessed at steady state 
after each dose level.  Results showed that both Cmax and levels increased with 
increasing dose over the range of 600 to 1000 mg BID under fed conditions, though not 
in proportion to increases in dose. The incidence of adverse events (AEs) was dose-
related and most AEs were classified as mild and possibly related to study drug. The most 
common AEs affecting more than 20% of subjects (n, %) were somnolence (19, 86%), 
euphoric mood (13, 59%), nausea (8, 36%), headache (6, 27%), and tremor, flatulence 
and muscle spasms (each 5, 23%).   There were no clinically significant findings for 
laboratory safety values, vital signs or ECG data. There were no positive findings on the 
Columbia-Suicide Severity Rating Scale (C-SSRS) during the study. 
In Phase 2 adult trials in the ganaxolone program, 697 adults received ganaxolone in 9 
studies, 6 of which were in epilepsy. To date, the largest placebo-controlled completed 
study (N=147) of ganaxolone in epilepsy was 10-week, double-blind Study 1042-0600 
followed by an open-label extension of up to two years duration. Study 1042-0600 
showed ganaxolone (500 mg tid) adjunctive therapy significantly reduced partial onset 
seizures, with or without secondary generalizations, compared to placebo (p= 0.014). 
Ganaxolone-treated subjects experienced a median decrease of 26% (17.6% mean) 
compared to a 10.2% (+2.0% mean) decrease in placebo.  
Most of the adverse events reported in the clinical development program were mild or 
moderate in severity, dose-related, and resolved upon treatment discontinuation. Adult 
and pediatric subjects in open label extension studies to the epilepsy trials have been 
dosed with ganaxolone for >2 years with no new adverse events reported as compared to 
the controlled trials.  Three deaths have been reported in the program, none related to 
ganaxolone. 
Adverse events reported from Study 1042-0600 in at least 5% of subjects and >1.5 times 
more frequent in the ganaxolone group than the placebo group were dizziness (16.3 v. 
8.3%), fatigue (16.3 v. 8.3%) and somnolence (13.3 v. 2.0%). The discontinuation rates 
due to adverse events between the ganaxolone and placebo groups in Study 1042-0600 
were comparable, 7.1% and 6.1% respectively.  


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In Study 1042-0600 and in the ganaxolone development program overall, no clinically 
significant trends in changes from baseline electrocardiogram (ECG) recordings, vital 
signs, or physical or neurological examinations have been noted in the clinical studies, 
and no mean changes from baseline in clinical labs have been identified. Transient 
increases in LFTs (>3xULN) have been noted in less than 1% of subjects treated with 
ganaxolone. Serious adverse events (SAEs) reported in the ganaxolone epilepsy trials 
were considered by a Scientific Advisory Board to be usual for the population without 
any pattern attributable to ganaxolone.  Profiles of the most frequently reported AEs have 
been consistent with the predicted pharmacology of the drug.  
Due to the favorable tolerability profile of ganaxolone in Study 1042-0600 and its open-
label extension, the current study is designed to further examine the safety, tolerability 
and efficacy in a second year of open-label treatment with ganaxolone when used as an 
add-on therapy in adult subjects with drug-resistant partial-onset (focal) seizures. 
 


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CONFIDENTIAL INFORMATION 
7. 
STUDY OBJECTIVES 
7.1 
Primary 
To assess the safety and tolerability of adjunctive ganaxolone during two-year open-
label treatment in adult subjects with drug-resistant partial-onset seizures. 
7.2 
Secondary 
To assess efficacy of adjunctive ganaxolone during a two-year open-label treatment in 
adult subjects with drug-resistant partial-onset seizures. 
 


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8. 
INVESTIGATIONAL PLAN 
8.1 
Overall Study Design and Plan 
Study 1042-0604 is an open-label extension of Study 1042-0603, providing a two-year 
adjunctive ganaxolone treatment (900-1800 mg/d) to adult subjects with epilepsy 
consisting of partial-onset seizure (POS).  Subjects will enter the study at their current 
dose of ganaxolone from study 1042-0603.  The dose of ganaxolone may be adjusted for 
tolerability and response.  
8.2 
Discussion of Study Design 
This open-label protocol is designed to provide ganaxolone to adult subjects with 
epilepsy consisting of uncontrolled POS who are deriving significant benefit from current 
ganaxolone adjunctive therapy. Subjects who have completed all scheduled clinical study 
visits in the previous protocol 1042-0603 and have shown a minimum 35% improvement 
in mean seizure frequency per 28-days vs. baseline over the three 28-day periods 
preceding study entry, and acceptable tolerability, are eligible to participate. Safety and 
tolerability will be assessed by diary record and at clinic visits approximately every four 
months.  During the study if the patient fails to continue to meet the minimum 
improvement criteria (mean 28-day seizure frequency over the past three 28-day periods 
before the study visit showing 35% improvement over baseline) at any study visit the 
investigator should consider discontinuing the patient from the study. Efficacy will 
primarily be assessed based on daily seizure calendar entries.  Baseline for evaluation of 
seizure frequency will be each subject's baseline from Study 1042-0603, though other 
calculations may also be performed. 
Adjunctive therapies (1-3 background AED medications, with or without implanted 
VNS) should be stable for the one month prior to study entry but may be adjusted as 
clinically warranted at other times during the study.  The dose of ganaxolone may be 
adjusted as minimum 3 day intervals as warranted for tolerability and efficacy, up to a 
maximum of 1800 mg/d. 


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8.3 
Selection of Study Population 
8.3.1 
Number of Subjects:   
This study may treat up to approximately 350 subjects depending upon the number of 
subjects continuing from the previous Study 1042-0603. 
8.3.2 
Inclusion Criteria 
1. Subjects who have completed all scheduled clinical study visits in the previous 
protocol 1042-0603 and have shown a minimum 35% improvement in mean 28-
day seizure frequency over the last three 28-day periods in study 1042-603 as 
compared to the baseline of study 1042-0603. 
 
2. Subjects whose daily study drug compliance in Study 1042-0603 was 90% or 
greater, and for whom the investigator feels that the subject was compliant with 
the full dose as prescribed. 
 
3. Able to give informed consent in writing, or have a legally authorized 
representative able to do so, after being properly informed of the nature and risks 
of the study and prior to engaging in any study-related procedures. 
 
4. Currently being treated and maintained with a stable regimen of 1, 2, or 3 AEDs 
at a consistent dose for one month prior to study entry.  See Section 8.4.8 for 
restrictions on certain AEDs. 
 
5. Implanted VNS (Vagus Nerve Stimulator) is permitted and will not count towards 
the number of concomitant AEDs.   
6. Able and willing to maintain an accurate and complete daily written seizure 
calendar or has a caregiver who is able and willing to maintain an accurate and 
complete daily written seizure calendar. 
7. Able and willing to take drug with food twice daily. Ganaxolone must be 
administered with food. 
8. Sexually active women of childbearing potential (WCBP) must be using a 
medically acceptable method of birth control and have a negative pregnancy test 
at Visit 1 and at subsequent visits.  A woman of childbearing potential is defined 
as a female who is biologically capable of becoming pregnant.  A medically 
acceptable method of birth control includes intrauterine devices in place for at 
least 3 months, surgical sterilization, or adequate barrier methods (e.g., diaphragm 
and foam).  An oral contraceptive alone is not considered adequate for the 
purpose of this study.  Use of oral contraceptives in combination with another 
method (e.g., a spermicidal cream) is acceptable. In subjects who are not sexually 
active, abstinence is an acceptable form of birth control. Birth control should be 
continued for a minimum of 3 days after the last dose of study drug. 
 


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8.3.3 
Exclusion Criteria 
1. Have any medical condition that, in the investigator's judgment, is considered to 
be clinically significant and could potentially affect subject safety or study 
outcome, including but not limited to: clinically significant cardiac, renal, 
pulmonary, gastrointestinal, hematologic or hepatic conditions; or a condition that 
affects the absorption, distribution, metabolism or excretion of drugs.  
 
2. Experienced a Serious Adverse Event or a moderate or severe medically 
important adverse event judged probably or definitely related to open-label 
ganaxolone in the previous study, 1042-0603. 
 
3. Have Alanine transferase (ALT; SGPT) or Aspartate transferase (AST; SGOT) 
levels >3 times upper limits of normal (ULN), or total bilirubin >1.5 times ULN 
during Study 1042-0603.  (Since Study 1042-0603 Visit 10 safety laboratory 
results will not be available at the time of inclusion in Study 1042-0604, these 
results will be assessed against Section 8.3.4.Criteral for withdrawal #11.) 
 
4. Have a history of malignancy within the past 2 years, with the exception of basal 
cell carcinoma. 
 
5. Seizures secondary to illicit drug or alcohol use, infection, neoplasm, 
demyelinating disease, degenerative neurological disease, or central nervous 
system (CNS) disease deemed progressive, metabolic illness, or progressive 
degenerative disease. 
 
6. Have active suicidal plan/intent, or have had active suicidal thoughts in the past 6 
months.  Have a history of an actual suicide attempt in the last 5 years or more 
than 1 lifetime actual suicide attempt as classified by the Columbia-Suicide 
Severity Rating Scale (C-SSRS).  
 
7. Have a history of drug or alcohol abuse within the past 5 years. As with other 
AEDs, the use of alcohol is not advised.  
 
8. Are currently following or planning to follow a ketogenic diet. 
  
9. Current use of vigabatrin or ezogabine (retigabine; Potiga; Trobalt) is not 
permitted. 
 
10. Females who are pregnant, currently breastfeeding or planning to become 
pregnant during the study. 
 
11. Inability/unwillingness to withhold grapefruit and grapefruit juice from diet 
during the entire clinical trial. 
 
 
Subjects meeting all inclusion and exclusion criteria will be allowed to enroll into this 


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CONFIDENTIAL INFORMATION 
study at the Investigator’s discretion.   
 
8.3.4 
Removal of Subjects from Therapy or Assessments 
8.3.4.1 
Criteria for withdrawal 
All subjects reserve the right to withdraw from the clinical study at any time, as 
stated in the informed consent form (ICF).  The Investigator may discontinue 
subjects from the clinical study for any of the following reasons: 
1. QTc interval >500 msec or uncorrected QT interval >600 msec; for subjects 
with bundle branch block, QTc >530 msec based on average QTc value of 
triplicate ECGs. A subject with an increase in QTc of >60 msec from Visit 1 
must also be withdrawn. 
a. If an ECG indicates a QTc interval outside of these limits, then 2 
additional ECGs should be collected and the average QTc value of these 
3 ECGs will be used. If the average values of the triplicate ECGs exceed 
the stated limits, the subject must be withdrawn. 
2. Subject is found to have entered the clinical investigation in violation of the 
protocol; 
3. Subject requires the use of an unacceptable or contraindicated concomitant 
medication. Should a prohibited CYP 3A 4, 5, 7 inhibitor or inducer be 
required for short term treatment, the subject may be permitted to remain in 
the study with permission from the Sponsor's Medical Monitor. 
4. Use of benzodiazepines as rescue for innumerable seizure clusters more than 
three times in a 28-day period must be reviewed with Sponsor's Medical 
Monitor to assess suitability for continuation.  
5. Subject’s condition changes after entering the clinical investigation so that 
the subject no longer meets the inclusion criteria or develops any of the 
exclusion criteria; 
6. Subject is noncompliant with procedures set forth in the protocol in an 
ongoing or repeated manner; 
7. Subject experiences an adverse event (AE) that warrants withdrawal from 
the clinical investigation; 
8. Patient’s mean 28-day seizure rate over the past three 28-day periods before 
the study visit shows less than 35% improvement in comparison to the 
patient’s baseline in the 1042-603 study; 
9. It is the Investigator’s opinion that it is not in the subject’s best interest to 
continue in the study; 


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10. Any subject who exhibits any of the following will be immediately 
withdrawn from the clinical investigation: 
a. Clinically significant worsening of seizures as judged by Investigator 
or subject such that treatment outside of the protocol is assumed to 
be in the subject’s best interest. 
b. Two episodes of generalized tonic-clonic seizures (GTCS) if not 
present in medical history. 
c. Status epilepticus at any time during the clinical investigation. 
d. Any Suicidal Behavior as classified by the Columbia Suicide 
Severity Rating Scale (C-SSRS) or a “yes” answer to questions 4 and 
5 in the Suicidal Ideation section of the C-SSRS. These patients 
should be referred to psychiatric evaluation immediately.  
 
11. Any subject who has the following liver enzyme findings should be 
immediately contacted and instructed to stop the study drug or start 
immediate down titration of the study drug 
 
a. ALT or AST > 8 x ULN 
b. ALT or AST > 5 x ULN for more than 2 weeks 
c. ALT or AST > 3 x ULN and total bilirubin > 2 x ULN 
d. ALT or AST > 3 ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash or 
eosinophilia 
 
Patients with ALT or AST > 3 x ULN but < 8 x ULN and no clinical signs 
or symptoms indicating liver dysfunction can, at the discretion of the 
investigator, continue the intake of study drug with close monitoring.  
 
All patients who fall into either category (patients who must discontinue 
the study drug [a, b, c, and d] and who may continue the study drug with 
close monitoring) must be brought back to the study center without any 
delay, the next day if possible, but no later than 72 hours after the study 
results have been received, for evaluation of the underlying cause and 
confirmatory laboratory testing.  More frequent monitoring of the liver 
tests should be initiated.  
Discontinuation decisions will be made at each participating site by the Site Principal 
Investigator.  If feasible, the process of discontinuation should be discussed with the 
Medical Monitor. The decisions regarding the discontinuation of the investigational 
therapy, whether the study medication should be stopped immediately or tapered should 
be discussed with the Medical Monitor, but final decisions about the process will remain 
at the discretion of the Site Principal Investigator.  


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8.3.4.2 
Early Termination Procedures 
Any subject who informs the site of an intention to withdraw from the study, or any 
subjects who are discontinued prior to the end of the study, will be asked to 
complete the procedures for Visit 7 (Study Completion/Early Term) which include: 
concomitant AED review, vital signs, physical and neurological exams, laboratory 
assessments, ECG, pregnancy test, C-SSRS, collection of adverse events, CGI-I, 
PCGI-I and seizure calendar review.  The study drug will then be continuously 
tapered over one to two weeks, if possible, based on the dose and duration of 
treatment.  A post-taper safety follow-up visit would then be completed.  Subjects 
who are discontinued from the clinical investigation should return to their 
physician’s care and continue appropriate medical treatment.  Any AEs that have 
not resolved as of discontinuation will be followed until resolution. An end-of-study 
letter will be provided, if requested.  Any follow-up information that is available 
will be added to the case report form up until the time that the database is locked. 
8.3.4.3 
Consequences of Early Termination 
The protocol specifies dose de-escalation of study medication over one to two 
weeks depending upon dose and duration of treatment. This recommendation is 
based on cumulative evidence from various classes of CNS drugs that slow taper is 
beneficial. It is possible that abrupt cessation of the drug might cause 
discontinuation symptoms.  Every effort will be made to ensure implementation of 
the dose de-escalation.   
8.4 
TREATMENTS 
8.4.1 
Identity of Investigational Product(s) 
Ganaxolone will be provided in size 00 white/opaque gelatin capsules packaged in HDPE 
bottles with a foil induction seal and child resistant closure.  Each bottle will contain 70 
capsules.  Each capsule contains 225 mg ganaxolone (3α-hydroxy-3β-methyl-5α-
pregnan-20-one), and hydroxypropyl methylcellulose, sucrose, polyethylene glycol 3350, 
polyethylene glycol 400, sodium lauryl sulfate, sodium benzoate, citric acid anhydrous, 
sodium methyl paraben, microcrystalline cellulose, 30% Simethicone Emulsion, gelatin 
capsules, polysorbate 80, and sodium chloride.  


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All study medication will be stored at the research pharmacy prior to dispensing, or in a 
locked cabinet accessible only to members of the investigative research team after the 
completion of each study visit. Study medication should be stored at room temperature 
15°C to 25°C (59°F to 77°F). 
8.4.2 
Treatment Groups 
Starting at Visit 1, all subjects will take ganaxolone beginning with the dose currently 
being taken in the 1042-0603 study, between 900 - 1800 mg/d. 
8.4.3 
Subject Numbering 
Subjects will retain the 6-digit subject number assigned by each site’s study staff for 
preceding protocol 1042-0603. The subject’s number and initials (first/middle/last, in 
regions where permitted) are required to be entered on all clinical investigation 
documentation (i.e., CRFs, labeling of clinical materials and samples containers, drug 
accountability logs, etc.). 
8.4.4 
Selection of Doses in the Study 
In meeting efficacy and tolerability criteria to participate in the study, it is expected that 
the subject will continue with the dose of ganaxolone (between 900-1800 mg/d) last 
prescribed in Study 1042-0603. Changes at V1 can be addressed with the Sponsor's 
Medical Monitor.  During the study, the dose of ganaxolone may be adjusted at the 
Investigator’s discretion based on tolerability and efficacy between 900 and 1800 mg/d, 
typically on the MTD of ganaxolone that provides adequate seizure control.  Doses may 
be adjusted upward or downward in 225 mg/d increments every 3 days to reach an 
optimal dose level over the duration of the 52-week treatment period.  Dose adjustments 
should be made with the investigator’s agreement. Frequency of dosing changes may not 
be less than 3 days unless required for safety.  
De-escalation Period:  The study drug will be decreased in increments of 450mg/d in 4-
day intervals over 12 days for 1800 mg.  Decreases from doses less than 1800 mg will be 
adjusted accordingly (See Table 2).  The subject will return for final post-taper safety 
assessment visit. 
Details of the de-escalation regimen are provided in the table below.  


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Table 2. Dosing Schedule for De-Escalation Period 
De-Escalation, Study Completion or Early Termination (ET) 
 
Visit 
 Taper 
Day 
Dose (mg)/day 
225 mg cap/day 
Visit 7  
(Study Comple- 
tion/Early Term) 
Last full 
dose 
 
1800 
 
8 
 
1 
1350 
6 
 
2 
1350 
6 
 
3 
1350 
6 
 
4 
1350 
6 
 
5 
900 
4 
 
6 
900 
4 
 
7 
900 
4 
 
8 
900 
4 
 
9 
450 
2 
 
10 
450 
2 
 
11 
450 
2 
 
12 
450 
2 
 
13 
0 
0 
 
14 
0 
0 
 
8.4.5 
Dose Administration 
Ganaxolone will be administered BID, 12 hours apart with food, i.e. 8:00 AM with 
breakfast and 8:00 PM after the evening meal.  A missed dose of study medication may 
be taken later up to 8 hours before the next scheduled dose, otherwise the missed dose 
should not be given (See Section 8.4.6 Missing a Dose).  It is important that ganaxolone 
be dosed with food. 
The dose of ganaxolone may be adjusted based upon tolerability or efficacy. Subjects 
experiencing intolerable AEs at any dose level may have the dose reduced per 
Investigator direction to attempt to alleviate the event.  See section 8.4.4 for dosage 
adjustments and de-escalation procedures. 
8.4.6 
Missing a Dose 
A missed dose of study medication may be taken up to 8 hours before the next scheduled 
dose; otherwise, the missed dose should not be given. For example, if a subject usually 
takes their doses at 7:00 AM and 7:00 PM and forgets to take a 7:00 PM dose at 


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dinnertime, that dose may be taken up to 9:00 PM at night (2 hrs after the evening meal, 
more than 8 hours until the next 7:00 AM dose).  Alternatively, that dose could be taken 
until 11:00 PM at night with a small snack.   
Subjects should be instructed that if s/he misses 4 doses in a row or more, the site should 
be contacted to determine whether any adjustment in study medication is needed. 
8.4.7 
Blinding 
This study is not blinded so all subjects will receive active drug. All bottles will be 
labeled with a unique 6-digit number to help track study drug accountability, lot number, 
expiry date, and ganaxolone 225 mg capsules. 
8.4.8 
Excluded, Prior and Concomitant Medications 
Subjects participating in the study are to be taking 1-3 AEDs in addition to the 
investigational medication.  AEDs may be adjusted during the course of the study, but 
subjects must continue on at least on AED.  Marketed medications indicated for the 
treatment of partial seizures are acceptable with the exceptions noted below: 
Vigabatrin: Current use of vigabatrin (Sabril) is not permitted.  
Ezogabine (retigabine; Potiga; Trobalt): Current use of ezogabine (retigabine) is not 
permitted.  
Perampanel (Fycompa): Perampanel is permitted as a concomitant medication only if 
the subject has been on a stable dose for at least 3 months prior to Visit 1 and has not 
experienced any serious psychiatric and behavioral reactions and is expected to remain on 
a constant dose throughout the study. 
Felbamate: Felbamate (Felbatol) is permitted as a concomitant medication only if the 
subject has been on felbamate for at least 18 months and has stable AST/ALTs and 
hematology laboratory tests and is expected to remain constant throughout the study. 
Benzodiazepines: If a subject is taking a benzodiazepine chronically for epilepsy and/or 
non-epilepsy conditions, it will be counted as 1 of the 3 AEDs. 
Vagal Nerve Stimulator: Subjects receiving treatment with a VNS may be included.  
VNS will not be counted as one of the 3 concomitant AEDs. 
8.4.9 
Excluded Concomitant Medications 
A list of medications that are inducers or inhibitors of CYP 3A4/5/7 and are not 
permitted during the study are in Appendix 2. Consult with your in-country Medical 


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Monitor if you have any questions. Note that phenytoin, carbamazepine and 
phenobarbital are permitted as background AEDs though they are moderate CYP 3A4 
inducers. Treatment with the 5-α-reductase inhibitor finasteride is not permitted during 
the study. 
Generally, concomitant medications including non-prescription medication can be used if 
medically necessary for indications that are not exclusionary in the protocol, and if the 
medication is not expected to interact with study medication nor to adversely impact the 
subject’s ability to comply with protocol requirements (such as keeping seizure calendar 
and clinic appointments.) The Investigator must make the decision to authorize the use of 
such a medication only after consideration of the clinical situation, the potential for 
masking symptoms of a more significant underlying event, and whether the use of the 
medication will compromise the outcome or validity of the clinical investigation. The 
Medical Monitor may be consulted for additional input.  If medication is required, the 
name, strength, frequency, and reason for use will be recorded in source documents and 
name and reason entered in the case report form (CRF). 
Benzodiazepines may be used intermittently (i.e., 1 to 2 doses over a 24-hour period) as 
rescue for the control of seizures. For subjects requiring benzodiazepine rescue more than 
once per 28-day period, the investigator will determine and document the benefit to the 
subject for remaining in the trial.  If a subject requires use of rescue benzodiazepines 3 
times or more during a 28-day period, the Sponsor's Medical Monitor should be 
consulted regarding the subject's continued participation. 
Use of dietary supplements or herbal preparations are permitted if subject has been using 
them consistently for more than 6 months prior to Visit 1, and does not plan changing the 
regimen for the duration of the study.  Changes may be made during the study at the 
discretion of the Principal Investigator.  Use of St. John’s Wort is not permitted (see 
Appendix 2 for prohibited medications). 
As with other AEDs, the concomitant use of ganaxolone and alcohol during the course of 
the study is not advised. The effects of ganaxolone in combination with alcohol are not 
known. 


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Grapefruit and grapefruit juice are strictly prohibited during the clinical trial.   
8.4.10 
Treatment Compliance 
A record of all investigational products dispensed and returned will be maintained at each 
clinical site.  This record will include the date the investigational product is dispensed to 
a subject, initials of the individual dispensing investigational product, quantity dispensed 
(by unit), the date investigational product containers are returned from the subject, and 
the quantity returned. Investigational product and associated accountability forms that are 
maintained at the clinical site will be present for review by Clinical Investigation 
Monitors at each monitoring visit. 
At each visit all subjects will receive monthly Subject Seizure Calendars.  Subjects are to 
record administration of study drug and background AEDs on the Seizure Calendar.  
Compliance with study drug treatment will be assessed by inspecting the Subjects’ 
Seizure Calendars and returned supplies with queries as necessary.  If the subject is 
suspected to be non-compliant with study medication or seizure calendar recording, 
he/she may be discontinued from the study. 
8.5 
Efficacy and Safety Variables 
8.5.1 
Efficacy Measurements, Safety Assessments and Schedule of Study 
Procedures 
8.5.1.1 
Efficacy Measurements 
Efficacy will be assessed using the daily seizure calendar, the Clinician's Global 
Impression of Improvement, and the Patient/Caregiver Global Impression of 
Improvement. 
8.5.1.2 
Safety Assessments 
Planned safety assessments include: 
• Neurological and physical examinations 
• Clinical laboratory tests 
• 12-lead ECG 
• Vital signs including temperature, blood pressure, pulse rate, respiration rate, 
height, weight and BMI 
• AE monitoring: frequency, severity, duration, causality, outcome 
 


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Safety laboratories, vitals and ECG measurements may be repeated if needed to 
corroborate or refute abnormal findings. Both the original and replicate assessments 
should be recorded in the CRF. 
See Schedule of Events for timing of Safety Assessments. 
8.5.1.3 
Schedule of Study Procedures 
8.5.1.3.1 
Visit 1 (same as Study1042-0603 Visit 10/Open Label Month 12)  
1042-0603 Visit 10/Last Visit procedures: physical and neurological examination, 
12-lead ECG, vital signs, blood and urine samples for safety laboratory tests and 
urine pregnancy test for WCBP, trough concomitant AED levels, subject diaries, C-
SSRS, CGI-I, PCGI-I , AEs reviewed, medication compliance checked and study 
medication returned;  
Additional 1042-0604 procedures: informed consent reviewed and signed; 
inclusion/exclusion and demographics/medical history reviewed; and 1042-0604 
seizure calendars and study medication dispensed. Any Adverse Event that occurred 
in study 1042-0603 which is not resolved at the time of enrollment into 1042-0604 
or is deemed significant by the Principal Investigator is to be captured in the 
subject’s 1042-0604 medical history. If the frequency, severity or duration of this 
event changes in any way then it is to be captured as an Adverse Event in 1042-
0604.  
8.5.1.3.2 
 Visit 2 (Week 17) 
Concomitant AEDs reviewed, brief physical and neurological exams, vital signs, 
safety laboratory tests, urine pregnancy test, C-SSRS, review safety and record 
AEs, subject calendar review, study medication return and compliance check and 
dispense study medication.  
8.5.1.3.3 
Visit 3 (Week 34)  
Concomitant AEDs reviewed, brief physical and neurological exams, vital signs, 
safety laboratory tests, urine pregnancy test, C-SSRS, review safety and record 
AEs, subject calendar review, study medication return and compliance check and 
dispense study medication.  


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8.5.1.3.4 
Visit 4 (Week 52) 
Concomitant AEDs reviewed, physical and neurological exams, vital signs,  local 
ECG, safety laboratory tests, urine pregnancy test, C-SSRS, review safety and 
record AEs, subject calendar review, CGI-I, PCGI-I, study medication return and 
compliance check and dispense study medication.  
8.5.1.3.5 
Visit 5 (Week 69)  
Concomitant AEDs reviewed, brief physical and neurological exams, vital signs, 
safety laboratory tests, urine pregnancy test, C-SSRS, review safety and record 
AEs, subject calendar review, study medication return and compliance check and 
dispense study medication.  
8.5.1.3.6 
Visit 6 (Week 86)  
Concomitant AEDs reviewed, brief physical and neurological exams, vital signs, 
safety laboratory tests, urine pregnancy test, C-SSRS, review safety and record 
AEs, subject calendar review, study medication return and compliance check and 
dispense study medication.  
8.5.1.3.7 
Visit 7/Early Term Visit (Week 104; start of dose de-escalation period) 
Concomitant AEDs reviewed, physical and neurological exams, vital signs, local 
ECG, safety laboratory tests, urine pregnancy test, C-SSRS, review safety and 
record AEs, subject calendar review, CGI-I, PCGI-I, study medication return and 
compliance check and dispense study medication.; dose de-escalation instructions 
given.  
8.5.1.3.8 
Visit 8 Safety Follow-up (Week 106; follow-up for end of dose de-
escalation period)  
Concomitant AEDs reviewed, brief physical and neurological exams, vital signs, 
safety laboratory tests, urine pregnancy test, C-SSRS, review safety and record 
AEs, subject calendar review and study medication return and compliance check. 


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8.5.1.3.9 
Unscheduled Visit  
Activities to be determined by the nature of the visit, are at the Investigator’s 
discretion.  In most cases basic safety procedures (vital signs, review of adverse 
events) should be completed.  
8.6 
Data Quality Assurance 
Steps to be taken to assure the accuracy and reliability of safety data include the selection 
of qualified Investigators and appropriate study centers, review of protocol procedures 
with the Investigator and associated personnel prior to the study, and periodic monitoring 
by a Sponsor representative. Case report forms will be reviewed for accuracy and 
completeness by a Sponsor representative during on-site monitoring visits and after their 
return to the Sponsor, and any discrepancies will be resolved with the Investigator or 
designees, as appropriate.  The data will be entered into the clinical trial database and 
verified for accuracy.   
8.7 
Statistical Methods Planned and Determination of Sample Size 
8.7.1 
Statistical and Analytical Plans 
8.7.1.1 
Randomization 
This is an open-label extension study and no randomization will occur.     
8.7.1.2 
Analysis Populations 
All subjects who sign informed consent and take one dose of study medication in 
this study will be included in the ITT Safety Population.  Subjects who return at 
least 25 days of seizure calendar data will be included in the Full Analysis 
Population. 
8.7.1.3 
Analysis of Efficacy Variables 
The primary outcome measure is the percentage change in seizure (POS with or 
without secondary generalization) frequency per 28-days relative to baseline in 
study 1042-0603.  Results will be expressed in mean and median change.  
Secondary efficacy outcome measures include proportion of subjects experiencing a 
≥ 50% reduction at the end of the study compared with Study 1042-0603 baseline 


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(proportion of Responders), seizure free intervals and seizure free days.  The CGI-I 
and PCGI-I are also secondary efficacy assessments. 
8.7.1.4 
Analysis of Safety Variables 
Adverse events (AEs) will be tabulated by overall, system organ class (SOC), and 
Preferred Term using the MedDRA v.16.0 coding system. Incidence and percentage 
of adverse events, by dose and overall. Additional tables, with AEs subset by 
severity and by relationship to drug as assessed by the investigator will be 
presented. Subset listings will be produced for adverse events that cause withdrawal 
and for SAEs. 
Laboratory data, vital signs and ECGs will be summarized using descriptive 
statistics. Important changes in laboratory, ECG values and vital signs will be 
flagged in data listings. Listings of most abnormal changes will be provided. 
8.7.2 
Determination of Sample Size 
This is an open-label, long-term continuation study. Sample size will be determined 
by those eligible after successful completion of Study 1042-0603. 


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9. 
INVESTIGATOR REQUIREMENTS 
9.1 
Study Initiation 
The following documentation must be received by the Sponsor or their representative 
prior to initiation of the trial: 
1. Completed FDA Form 1572, signed by Principal Investigator. Investigators must 
also complete all regulatory documentation as required by the ICH GCP and local 
or national regulations. 
2. Current curricula vitae of the Principal Investigator, all sub-investigators and key 
research personnel. 
3. Institutional Review Board (IRB) or Ethics Committee (EC) membership list 
and/or Department of Health and Human Services number. 
4. The ICF must be reviewed and approved by the Sponsor or their designee. 
5. Written documentation of IRB/EC approval of protocol (identified by protocol 
number or title and date of approval) and ICF (identified by protocol number or 
title and date of approval). A copy of the approved ICF must be supplied. 
6. Current laboratory certification of any laboratories performing the analysis 
(issuing agency and expiration date), as well as current normal laboratory ranges 
for all laboratory tests. 
7. A signed Clinical Research (Protocol) Agreement. 
8. Certified translations of IRB/EC approval letters, pertinent correspondence, and 
approved ICF (when applicable). 
9. Financial disclosure form for Principal Investigator and all sub-investigators. 
9.2 
Study Completion 
The following data and materials are required by the Sponsor or their designee before the 
study can be considered complete or terminated: 
1. All test results from Visit 1 through the end of the study (e.g., clinical data, all 
special test results). 
2. Information properly recorded in the CRFs by appropriate study personnel and 
signed and dated by the Investigator. 
3. Completed drug accountability records. 
4. Copies of protocol or ICF amendments and IRB/EC approval/notification, if 
appropriate. 
5. Copies of IRB/EC notification or approval for safety updates. 
6. A summary of the study prepared by the Principal Investigator (an IRB/EC 
summary close letter is acceptable). 


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9.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating the 
study may include the following: 
• Identification of new safety risk(s) or a change in the incidence or severity of 
known risk(s) of ganaxolone that indicates a potential health hazard to subjects. 
• Subject enrollment is unsatisfactory. 
• Data recording is inaccurate or incomplete. 
9.4 
Informed Consent 
Template ICFs will be provided to the site.  No major deviations should be made; all 
changes must be approved by the Sponsor. It is recommended that the Sponsor or its 
Designee review changes to the ICF template prior to IRB or EC submission. The final 
IRB-approved document must be provided to Sponsor or their designee for their records. 
Each subject or the subject’s legally authorized representative must be presented with the 
ICF, given an opportunity to ask questions, and must sign the ICF before the subject may 
participate in any study-related procedures or activities.  The consent process should be 
documented in the subject’s medical record. A signed copy of the ICF must be provided 
to the subject or the subject’s legally authorized representative.  When applicable, it will 
be provided in a certified translation of the local language. 
Signed consent forms must remain in each subject’s study file and must be available for 
verification by study monitors at any time. 
9.5 
Adverse Events 
The AE definitions and reporting procedures provided in this protocol comply with 
current CFR 21 Part 312.  The Medical Monitor assigned by the Sponsor must promptly 
review all information relevant to the safety of an investigational new product received 
from any source.  The Investigator will carefully monitor each subject throughout the 
study for possible AEs.  All AEs will be documented on CRFs designed specifically for 
this purpose, and will be followed until either completely resolved or until a stable 
chronic outcome is determined by the Investigator.  It is also important to report all AEs 
that result in permanent discontinuation of the investigational drug, whether serious or 
non-serious. 


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9.5.1 
Definitions 
Adverse event means any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug related. An AE can therefore be any 
unfavorable and unintended sign (including a clinically significant abnormal laboratory 
finding), symptom or disease temporally associated with the use of an investigational 
product, whether or not considered related to the investigational product.  Any worsening 
of a preexisting condition (i.e., any clinically significant adverse change in frequency 
and/or intensity) which is temporally associated with the use of the investigational 
product, is also an adverse event. 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose 
(including overdose) that meets one or more of the following criteria: 
• Is fatal, as a direct outcome of the AE 
• Is life threatening 
This serious criterion applies if the subject, in the view of the Investigator, is at 
substantial risk of dying from the AE as it occurs.  It does not apply if an AE 
hypothetically might have caused death if it were more severe. 
• Requires or prolongs inpatient hospitalization 
This serious criterion applies if the reported AE necessitates an inpatient admission 
(in the US) or a minimum 24-hour inpatient hospitalization (outside US) or, if in the 
opinion of the Investigator, prolongs an existing hospitalization.  A hospitalization for 
an elective procedure, a routinely scheduled treatment or a social admission is not an 
SAE. 
• Results in permanent or significant disability/incapacity 
This serious criterion applies if the “disability” caused by the reported AE results in a 
substantial disruption of the subject’s ability to carry out normal life functions. 
• Results in a congenital anomaly/birth defect 
This serious criterion applies if a subject exposed to the investigational product gives 
birth to a child with congenital anomaly or birth defect. 
Important medical events that do not meet any of the criteria above may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 


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that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse.  
9.5.2 
Evaluating and Recording of Adverse Events 
At each visit all adverse events that are observed, elicited by the Investigator, or reported 
by the subject, will be recorded in the appropriate section of the AE CRF and evaluated 
by the Investigator. 
Minimum information required for each AE includes type of event, duration (start and 
end dates), severity, seriousness, causality to study drug, action taken, and outcome. 
Severity of AEs will be graded by the Investigator using the following criteria as 
guidelines: 
1.  Mild: 
Nuisance, barely noticeable. 
2.  Moderate: 
Uncomfortable, troublesome symptoms not significantly 
interfering with daily activities or sleep. 
3.  Severe: 
Symptoms significantly interfere with daily activities or sleep. 
 
The relationship of the AE to the study drug should be specified by the Investigator, 
using the following definitions: 
1.  Not Related: 
Concomitant illness, accident or event with no reasonable 
association with study drug. 
2.  Unlikely Related: 
The event has little or no temporal sequence from administration 
of the study drug, and/or a more likely alternative etiology exists. 
3.  Possibly Related: 
The event follows a reasonable temporal sequence from 
administration of study drug but which could also be explained 
by concurrent disease or other factors or medications. 
4.  Probably Related: 
The event follows a reasonable temporal sequence from 
administration of study drug, but is unlikely to be attributed 
to concurrent disease or other factors or medications. A clinically 
reasonable response may be observed if the study drug is 
withdrawn or dose reduced. 
5.  Definitely Related: the event follows a reasonable temporal sequence from 
administration of study drug and is definitive 
pharmacologically; cannot to be attributed to concurrent disease 
or other factors or medications. A clinically reasonable response 


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should be observed if the study drug is withdrawn or dose 
reduced. 
 
If discernible at the time of completing an AE CRF, a specific disease or syndrome rather 
than individual associated signs and symptoms should be recorded on the AE CRF.  
However, if an observed or reported sign, symptom, or clinically significant laboratory 
anomaly is not considered by the Investigator to be a component of a specific disease or 
syndrome, then it should be recorded as a separate AE on the AE CRF (clinically 
significant laboratory abnormalities are those that are identified as such by the 
Investigator and/or those that require intervention). 
9.5.3 
Reporting of Adverse Events 
9.5.3.1 
Serious Adverse Events 
Any SAEs, including death due to any cause, which occurs to any subject who has signed 
Informed Consent (personally or by legally authorized representative) in this study or 
within 30 days following cessation of the last dose of treatment with the study drug, 
whether or not considered related to the investigational product, must be reported within 
24 hours to the Sponsor or their designee.  SAEs that occur more than 30 days after the 
last dose of study drug and are suspected to be related to study treatment should also be 
reported. All subjects with SAEs must be followed up for outcome. 
SAEs can be reported by faxing a completed SAE Fax Cover Sheet and serious adverse 
event CRF (SAE CRF) or by direct telephone communication to the SAE telephone 
reporting numbers below.  A completed SAE Fax Cover Sheet and SAE CRF should 
follow all telephone reports within 24 hours.   
 
SAE REPORTING 
If a fatal or imminently life-threatening SAE or a medical emergency occurs you may 
contact your local medical monitor or local team leader.  If they are not available contact 
the Global Study Leader or Study Team Physician noted below. 
 


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Role in the study 
Name 
Address & telephone number 
Global Study Leader 
 
O: 
M: 
Study Team Physician 
, 
MD, PhD 
O: 
M: 
 
Chief Medical Officer 
, MD 
O: 
M: 
SAE reporting for US Sites: 
Telephone number (Mon.-Fri.; 9am-4pm EST): 1 800-265-1542 
Fax Number (24 hours; 7 days/week): 1 877-464-7787 
SAE reporting for Russian Sites: 
Telephone number (Mon-Fri.; 10am-7pm MSK): +7 812 703-00-08 
GCT FAX Number: (24 hours; 7 days/week): +7 812 703-00-09 
GCT email: SAE-study604-Russia@gctrials.com 
SAE reporting for Bulgarian Sites: 
Telephone number (Mon.-Fri.; 9am-6pm SOF): +359 2 983 53 58 
GCT FAX Number: (24 hours; 7 days/week): +359 2 998 30 05 
GCT email: SAE-study604-Bulgaria@gctrials.com  
SAE reporting for German & Polish Sites: 
Telephone number (Mon.-Fri.; 9am-6pm CET): +49 2173-10947-17 
Prisma FAX Number: (24 hours; 7 days/week): +49 2173-10947-20 
Prisma email: safety@prisma-cro.com  
 
 


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SAE reporting for Australian Sites: 
Fax SAE reports to INC Global Fax Number (24hours; 7 days/week; 365 days; can be 
used during holiday period): 8-10-8002-8631012 
9.5.3.2 
Medical Inquiries 
For medical inquiries related to inclusion/exclusion criteria, concomitant medications and 
other medical inquires not related to SAEs, please call or email the following: 
For US Sites & Australian Sites outside of business 
hours: 
, MD, PhD 
Marinus Pharmaceuticals 
Office Telephone:
Mobile phone: 
  
Email:  
   
 
For Bulgarian sites: 
, M.D. 
Global Clinical Trials (BCT Global) 
Telephone: 
 
Email: 
 
 
For Russian sites: 
, M.D. 
Global Clinical Trials (RCT Global) 
Telephone: 
 
Email: 
 
 
For German and Polish Sites: 
, M.D. 
Prisma – CRO GmbH 


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Telephone: 
 
Email: 
 
 
For Australian Sites (during business hours): 
Prof. 
, M.D. 
The Royal Melbourne Hospital 
Telephone:  
 
Email:  
 
 
9.5.3.3 
Pregnancy 
Although not considered an AE, it is the responsibility of the Investigator or their 
designees to report and record any pregnancy in a subject (whether spontaneously 
reported or identified via testing) that occurs during the study or within 14 days of 
completing the study.  Pregnancy will be documented in the AE CRF for purposes of 
reporting.  All subjects who become pregnant should be discontinued from the study and 
must be followed to the completion or termination of the pregnancy.  Efforts will be 
made to follow the newborn for at least 8 weeks post-delivery. The decision whether to 
taper the study medication is up to the discretion of the Investigator, taking into account 
the dose, duration of treatment, and other relevant factors. If the pregnancy continues to 
term, the outcome (health of infant) must also be reported to the Sponsor or their 
designee. 
9.6 
Study Monitoring and Audit Requirements 
Site visits will be conducted by the Sponsor or their representative to inspect all study 
related documentation and records including study data, subject’s medical records, CRFs, 
etc. 
The Principal Investigator will permit the Sponsor, their authorized representative 
including quality assurance groups, the USA FDA, EC/IRB, and the respective national 
and local authorities to inspect facilities and records relevant to this study. The 
investigator will ensure the capability for inspections of applicable study-related facilities 
(e.g., pharmacy, diagnostic laboratory, etc.). 


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9.7 
Case Report Forms (CRFs) 
CRFs will be used to store subject information.  The CRFs will be provided by the 
Sponsor and should be handled in accordance with the instructions provided.  CRFs must 
be completed as soon as possible after any subject evaluation or communication.  CRFs 
should be completed by examining personnel or the study coordinator and must be 
reviewed, and signed and dated by the Investigator.  CRFs must be accessible to study 
monitors and other regulatory auditors. 
9.8 
Study Drug Accountability 
All study drug required for completion of this study will be provided by the Sponsor or 
their designee.  The recipient will acknowledge receipt of the drug indicating shipment 
content and condition.  Damaged supplies will be replaced. 
Accurate records of all study drug dispensed from and returned to the study site should be 
maintained. 
All partially used, empty, expired and/or assigned, unused bottles of study drug will be 
reconciled by the Clinical Monitor and returned for disposal as directed by the Sponsor.  
9.9 
Confidentiality of Data 
Subject medical information obtained by this study is confidential, and disclosure to third 
parties other than those noted below is prohibited. 
With the subject’s permission, medical information may be given to his or her personal 
physician or other appropriate medical personnel responsible for his or her welfare. 
Data generated by this study must be available for inspection by representatives of the 
USA FDA, national and local health authorities, the Sponsor or their designee, and the 
IRB/EC. 
9.10 
Retention of Records 
USA FDA regulations (21 CFR 312.62[c]) require that records and documents pertaining 
to the conduct of this study and the distribution of investigational drug, including CRFs, 
consent forms, laboratory test results, and medical inventory records, must be retained by 
the Principal Investigator for 2 years after marketing application approval. If no 


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application is filed, these records must be kept 2 years after the investigation is 
discontinued and the USA FDA and the applicable national and local health authorities 
are notified. The Sponsor or their designee will notify the Principal Investigator of these 
events.   
For German and Polish sites all records and documents pertaining to the conduct of this 
study must be retained for 15 years after the completion of the study unless a longer 
period is required by applicable laws or regulations.     
9.11 
Protocol Adherence 
Each Investigator must adhere to the protocol as detailed in this document and agrees that 
any changes to the protocol must be approved by the Sponsor or their designee prior to 
seeking approval from the IRB/EC.  Each Investigator will be responsible for enrolling 
only those subjects who have met protocol eligibility criteria. 


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10. 
PUBLICATION PLAN 
The study will be listed in the ClinicalTrials.gov registry.  Study results will be made 
public and disseminated to individual research sites in a timely manner, and no later than 
one year after study completion. 
 


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11. 
REFERENCES 
Bialer, M., et al. (2010) Progress report on new antiepileptic drugs: A summary of the 
Tenth Eilat Conference (EILAT X). Epilepsy Res 92:89-124. 
Carter RB, Wood PL, Wieland S, Hawkinson JE, Belelli D, Lambert JJ, White HS, Wolf 
HH, Mirsadeghi S, Tahir SH, Bolger MB, Lan NC, Gee KW (1997) 
Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 
3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a selective, high-affinity, 
steroid modulator of the gamma-aminobutyric acid(A) receptor. J Pharmacol Exp 
Ther 280:1284-1295. 
French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, Theodore 
WH, Bazil C, Stern J, Schachter SC, Bergen D, Hirtz D, Montouris GD, Nespeca 
M, Gidal B, Marks WJ, Jr., Turk WR, Fischer JH, Bourgeois B, Wilner A, Faught 
RE, Jr., Sachdeo RC, Beydoun A, Glauser TA (2004) Efficacy and tolerability of 
the new antiepileptic drugs II: treatment of refractory epilepsy: report of the 
Therapeutics and Technology Assessment Subcommittee and Quality Standards 
Subcommittee of the American Academy of Neurology and the American 
Epilepsy Society. Neurology 62:1261-1273. 
Kaminski RM, Livingood MR, Rogawski MA (2004) Allopregnanolone analogs that 
positively modulate GABA receptors protect against partial seizures induced by 
6-Hz electrical stimulation in mice. Epilepsia 45:864-867. 
Reddy DS, Castaneda DC, O'Malley BW, Rogawski MA (2004) Anticonvulsant activity 
of progesterone and neurosteroids in progesterone receptor knockout mice. J 
Pharmacol Exp Ther 310:230-239. 


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12. 
APPENDICES 
12.1 
Appendix 1: Clinical Laboratory Tests 
 
 
Clinical Chemistry 
 
Hematology 
Urinalysis 
Total Bilirubin 
Hemoglobin 
pH 
AST (SGOT) 
Hematocrit 
Color 
ALT (SGPT) 
Erythrocytes 
Transparency 
BUN 
Leukocytes + differential 
Specific Gravity 
Glucose 
Thrombocytes (platelet count) 
Urobilinogen 
Potassium 
 
Ketones 
Sodium 
 
Protein 
Calcium 
 
Glucose 
Alkaline Phosphatase 
 
Hemoglobin 
Chloride 
 
 
Creatinine 
 
 
CO2 
 
 
Total Protein 
 
 
Serum Albumin 
 
 
 
ALT = alanine transferase; AST = aspartate transferase; BUN = blood urea nitrogen 
 


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12.2 
Appendix 2: Strong and Moderate Cytochrome P450 CYP 3A4, 5, 7 
Inducers and Inhibitors Prohibited During Study 1042-0603 
 
Prohibited Strong and 
Moderate CYP 3A4 Inhibitors 
Prohibited Strong and Moderate 
CYP 3A4 Inducers* 
amprenavir 
aprepitant 
atazanavir  
boceprevir  
ciprofloxacin  
clarithromycin 
conivaptan (not sold in Germany, 
Poland) 
diltiazem 
erythromycin 
fluconazole  
fluvoxamine 
fosamprenavir 
grapefruit juice 
imatinib 
indinavir 
itraconazole 
ketoconazole 
mibefradil (not sold in US, 
Russia, Poland, Germany) 
nefazodone (not sold in US, 
Russia, Poland, Germany) 
nelfinavir (not sold in Germany, 
Poland) 
posaconazole  
ritonavir 
saquinavir 
telaprevir  
telithromycin 
troleandomycin (not sold in US, 
Russia, Poland, Germany) 
verapamil 
voriconazole 
avasimibe (not sold in Germany, 
Poland)  
bosentan 
efavirenz 
etravirine 
modafinil 
nafcillin (not sold in Germany, Poland) 
rifabutin (not sold in Germany, 
Poland) 
rifampin 
St. John's wort 
troglitazone (not sold in US, Russia, 
Poland, Germany) 
 
*Carbamazepine, phenytoin and phenobarbital are moderate CYP 3A4 inducers but are permitted 
as background AEDs during the study.  
Note: This list is not exhaustive so please consult with your in-country Medical Monitor. 
Data 
from http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter
actionsLabeling/ucm080499.htm and 
http://medicine.iupui.edu/clinpharm/ddis/ClinicalTable.aspx; accessed 12June13 


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12.3 
Appendix 3: Dosing Instructions for Subjects 
Translations in Bulgarian, German, Polish and Russian are available upon request. 
 
 


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12.4 
Appendix 4:  Subject Seizure Calendar 
Translations in Bulgarian, German, Polish and Russian are available upon request. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12.5 
Appendix 5:  Clinical Global Impression – Improvement (Patient/Caregiver) 
Translations in Bulgarian, German, Polish and Russian are available upon request. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12.6 
Appendix 6:  Columbia Suicide Severity Rating Scale (C-SSRS) Since Last Visit 
Translations in Bulgarian, German, Polish and Russian are available upon request. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12.7 
Appendix 7:  Protocol History 
Amendment 1 Summary of Changes from January 15, 2015 
Page 
Section, Title, 
Paragraph, Line 
Original Text 
Revised Text 
1 
Study Title 
A follow-on, second year open-label 
extension study of ganaxolone as add-
on therapy in adult patients with drug-
resistant partial-onset seizures 
A follow-on, two-year open-label 
extension study of ganaxolone as add-on 
therapy in adult patients with drug-
resistant partial-onset seizures 
1  
Short Title 
Ganaxolone Second Year Extension 
Study 
Ganaxolone Two-year Open-label 
Extension Study 
Reason for Change:  Updated to increase the study duration from one to two years 
1 
Sponsor  Contact 
, Ph.D. 
Sr. Director, Clinical Development 
Telephone: 
 
Email:  
 
 
Sr. Director, Clinical Operations 
Telephone:
Email:
1 
Sponsor’s Medical 
Representative 
, M.D., MBA 
Chief Medical Officer 
Office Phone: 
Mobile phone:
Email: 
 
, MD, PhD 
Vice President, Clinical Development 
Office Phone: 
Mobile Phone:
Email: 
 
 
 Reason for Change: Administrative change - contact information 
3 
Synopsis-Title of 
the Protocol 
A follow-on, second year open-label 
extension study of ganaxolone as add-
on therapy in adult subjects with drug-
resistant partial-onset seizures 
A follow-on, two-year open-label 
extension study of ganaxolone as add-on 
therapy in adult subjects with drug-
resistant partial-onset seizures 
3 
Synopsis-Primary 
Objectives 
To assess the safety and tolerability of 
adjunctive ganaxolone during a second 
year of open-label treatment in adult 
subjects with drug-resistant partial-
onset seizures 
To assess the safety and tolerability of 
adjunctive ganaxolone during a two-year 
open-label treatment in adult subjects 
with drug-resistant partial-onset seizures 
3 
Synopsis- 
Secondary 
Objectives 
To assess efficacy of adjunctive 
ganaxolone during a second year of 
open-label treatment in adult subjects 
with drug-resistant partial-onset 
seizures 
To assess efficacy of adjunctive 
ganaxolone during a two-year open-label 
treatment in adult subjects with drug-
resistant partial-onset seizures 
3 
Synopsis-Duration 
of Treatment 
Up to 52 weeks treatment on the 
maintenance dose with an additional 2 
weeks of dose de-escalation. 
Up to 104 weeks treatment on the 
maintenance dose with an additional 2 
weeks of dose de-escalation. 
Reason for Change:  Updated to increase the study duration from one to two years 


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4 
2.1 Table 1: 
Schedule of Events 
 
Week 52/Early Term –V4 
Week 54 – V5 
 
 
 
 
 
 
 
ECG (12 lead, 2-3 hours after dosing) 
 
The Schedule of Events was revised to 
incorporate the changes to the protocol. 
Week 52 – V4 
Week 69 – V5 
Added:  Week 86 – V6 
Added:  Week 104 (Study completion/ET 
– V7 
Added:  Week 106 (Post-Taper Safety 
Follow-Up) – V8 
ECG (12 lead) 
Added:  Footnotes 1, 3 and 5  
Reason for Change:  Clarification of the visit labels/schedule for the additional year 
10 
5. Investigators and 
Study 
Administrative 
Structure 
Duration of subject participation is 54 
weeks. 
Duration of subject participation is 106 
weeks. 
Reason for Change: Updated to increase the study duration from one to two years 
14 
7.1 Primary 
Objectives 
 
To assess the safety and tolerability of 
adjunctive ganaxolone during a second 
year of open-label treatment in adult 
subjects with drug-resistant partial on-
set seizures. 
To assess the safety and tolerability of 
adjunctive ganaxolone during two-year 
open-label treatment in adult subjects 
with drug-resistant partial on-set seizures. 
14 
7.2 Secondary 
Objectives 
To assess the efficacy of adjunctive 
ganaxolone during a second year of 
open-label treatment in adult subjects 
with drug-resistant partial on-set 
seizures. 
To assess the efficacy of adjunctive 
ganaxolone during two-year open-label 
treatment in adult subjects with drug-
resistant partial on-set seizures. 
Reason for Change: Updated to increase the study duration from one to two years 
15 
8.1 Overall Study 
Design and Plan, 
Line 1 
Study 1042-0604 is an open-label 
extension of Study 1042-0603, 
providing a second year of adjunctive 
ganaxolone treatment (900-1800 mg/d) 
to adult subjects with epilepsy 
consisting of partial-onset seizure 
(POS).   
Study 1042-0604 is an open-label 
extension of Study 1042-0603, providing 
a two-year adjunctive ganaxolone 
treatment (900-1800 mg/d) to adult 
subjects with epilepsy consisting of 
partial-onset seizure (POS).   
Reason for Change:  Updated to increase the study duration from one to two years 
16 
8.2 Discussion of 
Study Design, 
Paragraph 1, Line 8 
 
Added:  During the study if the patient 
fails to continue to meet the minimum 
improvement criteria (mean 28-day 
seizure frequency over the past three 28 
day periods before the study visit 
showing 35% improvement over 
baseline) at any study visit the 
investigator should consider 
discontinuing the patient from the study. 


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Reason for Change:  Clarification of criteria for discontinuation. This criteria is intended to ensure that the 
patients are periodically assessed for benefits and risks of ganaxolone, and that the patients who no longer derive 
significant benefit from ganaxolone are considered for exclusion.   
16 
8.3.2 Inclusion 
Criteria 
1. Subjects who have completed all 
scheduled clinical study visits in the 
previous protocol 1042-0603 and have 
shown a minimum 35% improvement 
in mean seizure frequency per 28 days 
vs. baseline over the three 28 day 
periods preceding study entry. 
1. Subjects who have completed all 
scheduled clinical study visits in the 
previous protocol 1042-0603 and have 
shown a minimum 35% improvement in 
mean 28-day seizure frequency over the 
last three 28 day periods in study 1042-
603 as compared to the baseline of study 
1042-603. 
16 
8.3.2 Inclusion 
Criteria 
4. Currently being treated and 
maintained with a stable regimen of 1, 
2, or 3 AEDs at a consistent dose for 
one month prior to study entry. 
a.Felbamate: The use of felbamate is 
allowed provided that the subject has 
been maintained on a stable dose of 
felbamate for >18 months, and has had 
stable liver function (AST/ALT) and 
hematology during the course of 
treatment, and is expected to remain 
constant throughout the study. 
b.Perampanel: The use of perampanel 
is allowed provided that the subject has 
been maintained on a stable dose of 
perampanel for >3 months and has not 
experienced any serious psychiatric and 
behavioral reactions such as hostility- 
and aggression- related adverse reac 
4. Currently being treated and maintained 
with a stable regimen of 1, 2, or 3 AEDs 
at a consistent dose for one month prior 
to study entry. See Section 8.4.8 for 
restriction on certain AEDs. 
Deleted: a. & b. 
Reason for Change: This section was redundant with section 8.4.8 of the protocol. The criteria for using 
concomitant AEDs, including Felbamate and Perampanel, is explained in section 8.4.8.  
17 
8.3.3 Exclusion 
Criteria 
3. Have Alanine transferase (ALT; 
SGPT) or Aspartate transferase (AST; 
SGOT) levels > 3 times upper limits of 
normal (ULN), or total bilirubin >1.5 
time ULN during Study 1042-0603.  
Added:  (Since Study 1042-0603 Visit 10 
safety laboratory results will not be 
available at the time of inclusion in Study 
1042-0604, these results will be assessed 
against Section 8.3.4.1 Criteria for 
withdrawal #11.) 
Reason for Change: Clarification for assessing subject eligibility post Visit 1. 
18 
8.3.4.1 
Investigator-
initiated 
withdrawal of a 
subject 
8.3.4.1 Investigator-initiated 
withdrawal of a subject 
8.3.4.1 Criteria for withdrawal 
18 
8.3.4.1 
Investigator-
initiated 
1. Post-treatment QTc interval 
>500 msec or uncorrected QT interval 
>600 msec; for subjects with bundle 
1. QTc interval >500 msec or uncorrected 
QT interval >600 msec; for subjects with 
bundle branch block, QTc >530 msec 


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withdrawal of a 
subject 
branch block, post-treatment QTc 
>530 msec based on average QTc value 
of triplicate ECGs. A subject with a 
post-treatment increase in QTc of 
>60 msec from Visit 1 must also be 
withdrawn. 
a. If the initial ECG indicates a QTc 
interval outside of these limits, then 2 
additional ECGs should be collected 
and the average QTc value of these 3 
ECGs will be used. If the average 
values of the triplicate ECGs exceed 
the stated limits, the subject must be 
withdrawn. 
based on average QTc value of triplicate 
ECGs. A subject with an increase in QTc 
of >60 msec from Visit 1 must also be 
withdrawn. 
a. If an ECG indicates a QTc interval 
outside of these limits, then 2 additional 
ECGs should be collected and the 
average QTc value of these 3 ECGs will 
be used. If the average values of the 
triplicate ECGs exceed the stated limits, 
the subject must be withdrawn. 
18 
8.3.4.1 
Investigator-
initiated 
withdrawal of a 
subject 
 
Added:  8. Patient’s mean 28-day seizure 
rate over the past three 28-day periods 
before the study visit shows less than 
35% improvement in comparison to the 
patient’s baseline in the 1042-603 study. 
18 
8.3.4.1 
Investigator-
initiated 
withdrawal of a 
subject 
9. Any subject who exhibits any of the 
following will be immediately 
withdrawn from the clinical 
investigation: 
a. Clinically significant worsening of 
seizures as judged by Investigator or 
subject such that treatment outside of 
the protocol is assumed to be in the 
subject’s best interest. 
b. Two episodes of generalized tonic-
clonic seizures (GTCS) if not present in 
medical history. 
c. Status epilepticus at any time during 
the clinical investigation. 
d. An “actual suicide attempt” as 
classified by the Columbia-Suicide 
Severity Rating Scale (C-SSRS). 
 
10. Any subject who exhibits any of the 
following will be immediately withdrawn 
from the clinical investigation: 
a. Clinically significant worsening of 
seizures as judged by Investigator or 
subject such that treatment outside of the 
protocol is assumed to be in the subject’s 
best interest. 
b. Two episodes of generalized tonic-
clonic seizures (GTCS) if not present in 
medical history. 
c. Status epilepticus at any time during 
the clinical investigation. 
d. Any Suicidal Behavior as classified by 
the Columbia Suicide Severity Scale (C-
SSRS) or a “yes” answer to questions 4 
and 5 in the Suicidal Ideation section of 
the C-SSRS.  These patients should be 
referred to psychiatric evaluation 
immediately. 
18 
8.3.4.1 
Investigator-
initiated 
withdrawal of a 
subject 
 
Added: 11. Any subject who has the 
following liver enzyme findings should 
be immediately contacted and instructed 
to stop the study or start immediate down 
titration of the study drug: 
a. ALT or AST >8xULN 
b. ALT or AST >5xULN for more than 2 
weeks 
c. ALT or AST >3xULN with the 


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appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, 
fever, rash or eosinophilia 
Patients with ALT or AST .3xULN but 
<8xULN and no clinical signs or 
symptoms indicating liver dysfunction 
can, at the discretion of the investigator, 
continue the intake of study drug with 
close monitoring. 
All patients who fall into either category 
(patients who must discontinue the study 
drug [a, b c, and d] and who may 
continue the study with close monitoring) 
must be brought back to the study center 
without any delay, the next day if 
possible, but no later than 72 hours after 
the study results have been received, for 
evaluation of the underlying cause and 
confirmatory laboratory testing. More 
frequent monitoring of the liver tests 
should be initiated. 
 
Reason for Change: Subjects with <35% improvement in seizure frequency as compared to baseline: This 
criteria is intended to ensure that patients are periodically assessed for benefits and risks of ganaxolone, and that 
the patients who no longer derive significant benefit from ganaxolone are considered for exclusion.   C-SSRS: 
More specific guidance how to utilize the C-SSRS instrument in assessing risk for suicide is provided. 
Specifically, patients with any suicidal behavior and/or suicidal ideation with intent or plan (ideation questions 4 
and 5 in the C-SSRS) should be discontinued from the study and referred to psychiatric evaluation. Managing 
elevated LFTs: These stopping rules are intended to guide the investigator how to manage patients with elevated 
liver enzymes during the study. These stopping rules are in line with FDA’s recommendation on managing 
patients with elevated liver enzymes during clinical trials (Guidance for Industry: Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation) 
20 
8.3.4.2 Early 
Termination 
Procedures, Line 3 
Any subject who informs the site of an 
intention to withdraw from the study, or 
any subjects who are discontinued prior 
to the end of the study (early 
termination; ET), will be asked to 
complete the procedures for Visit 4 (52 
weeks/pre-taper/ET) which include: 
concomitant AED review, vital signs, 
physical and neurological exams, 
laboratory assessments, ECG, 
pregnancy test, C-SSRS, collection of 
adverse events, CGI-I, PCGI-I and 
seizure calendar review.   
Any subject who informs the site of an 
intention to withdraw from the study, or 
any subjects who are discontinued prior 
to the end of the study will be asked to 
complete the procedures for Visit 7 
(Study Completion/Early Term) which 
include: concomitant AED review, vital 
signs, physical and neurological exams, 
laboratory assessments, ECG, pregnancy 
test, C-SSRS, collection of adverse 
events, CGI-I, PCGI-I and seizure 
calendar review.   
Reason for Change:  Clarification of the visit label/schedule  
20 
8.3.4.3 
Consequences of 
Early Termination, 
Line 5 
Every effort will be made to ensure 
implementation of the de-escalation.   
Every effort will be made to ensure 
implementation of the dose de-escalation.   


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Protocol 1042-0604 Amendment 1 V1.0 
29 February 2016 
 
CONFIDENTIAL INFORMATION 
21 
8.4.4 Selection of 
Doses in the Study, 
Paragraph 2 
 
De-escalation Period:  The study drug 
will be decreased in increments of 
450mg/d in 3-day intervals over 12 
days for 1800 mg.  Decreases from 
doses less than 1800 mg will be 
adjusted accordingly (See Table 1).  
The subject will return for final post-
taper safety assessment visit. 
De-escalation Period:  The study drug 
will be decreased in increments of 
450mg/d in 4-day intervals over 12 days 
for 1800 mg.  Decreases from doses less 
than 1800 mg will be adjusted 
accordingly (See Table 2).  The subject 
will return for final post-taper safety 
assessment visit. 
Reason for Change: Text in section 8.4.4. has been corrected to reflect the dose de-escalation schedule presented 
in Table 2. According to Table 2, which presents the correct de-escalation schedule, ganaxolone dose is decreased 
every 4 days.  
22 
Table 2. Dosing 
Schedule for De-
Escalation Period 
De-Escalation, Study Completion or 
Early Termination 
Visit 
Visit 4/ 
Taper Visit/ 
De-Escalation, Study Completion or 
Early Termination (ET) 
Visit 
Visit 7 
(Study Completion/ 
Early Term) 
 
Reason for Change:  Clarification of the visit label/schedule  
23 
8.4.8 Excluded, 
Prior and 
Concomitant 
Medications, 
Paragraph 1 
Subjects participating in the study are 
to be taking 1-3 AEDs in addition to 
the investigational medication.  
Marketed medications indicated for the 
treatment of partial seizures are 
acceptable with the exceptions noted 
below: 
 
Subjects participating in the study are to 
be taking 1-3 AEDs in addition to the 
investigational medication.  AEDs may 
be adjusted during the course of the 
study, but subjects must continue on at 
least one AED.  Marketed medications 
indicated for the treatment of partial 
seizures are acceptable with the 
exceptions noted below: 
Reason for Change:  Provides clarification that the investigators may adjust the concomitant medications during 
this trial.  
23 
8.4.9 Excluded 
Concomitant 
Medications, 
Paragraph 1, Line 3 
Note that phenytoin and 
carbamazepine are permitted as 
background AEDs though they are 
moderate CYP 3A4 inducers. 
Note that phenytoin, carbamazepine 
and phenobarbital are permitted as 
background AEDs though they are 
moderate CYP 3A4 inducers. 
23 
8.4.9 Excluded 
Concomitant 
Medications, 
Paragraph 4 
Use of dietary supplements or herbal 
preparations are permitted if subject has 
been using them consistently for more 
than 6 months prior to Visit 1, and does 
not plan changing the regimen for the 
duration of the study.  Use of St. John’s 
Wort is not permitted (see Appendix 2). 
Use of dietary supplements or herbal 
preparations are permitted if subject has 
been using them consistently for more 
than 6 months prior to Visit 1, and does 
not plan changing the regimen for the 
duration of the study.  Any changes 
during the study should be approved by 
the medical monitor. Use of St. John’s 
Wort is not permitted (see Appendix 2) 
Reason for Change:  Clarification of permitted medication and process. Phenobarbital is an AED and CYP3A4 
inducer akin to phenytoin and carbamazepine, and may be permitted as a concomitant AED.   


Marinus Pharmaceuticals, Inc. 
 
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Protocol 1042-0604 Amendment 1 V1.0 
29 February 2016 
 
CONFIDENTIAL INFORMATION 
26 
8.5.1.3.1 Visit 1 
(same as Study 
1042-0603 Visit 
10/Open Label 
Month 12), 
Paragraph 2 
Additional 1042-0604 procedures: 
informed consent reviewed and signed; 
inclusion/exclusion and 
demographics/medical history 
reviewed; and 1042-0604 seizure 
calendars and study medication 
dispensed.  
 
Added:  Any Adverse Event that 
occurred in study 1042-0603 which is not 
resolved at the time of enrollment into 
1042-0604 or is deemed significant by 
the Principal Investigator is to be 
captured in the subject’s 1042-0604 
medical history.  If the frequency, 
severity or duration of this event changes 
in any way then it is to be captured as an 
Adverse Event in 1042-0604. 
 
27 
8.5.1.3.4 Visit 4, 
Line 1 and 4 
Visit 4/Early Term (Week 52; start of 
dose de-escalation period) 
Concomitant AEDs reviewed, physical 
and neurological exams, vital signs, 
ECG, safety laboratory tests, urine 
pregnancy test, C-SSRS, review safety 
and record AEs, subject calendar 
review, CGI-I, PCGI-I, study 
medication return and compliance 
check and dispense study medication.; 
dose de-escalation instructions given.  
Visit 4 (Week 52) 
Added:  local ECG 
Deleted: …dose de-escalation 
instructions given. 
27 
8.5.1.3.5 Visit 5 
Visit 5 (Week 54; follow-up for end of 
dose de-escalation period) 
Concomitant AEDs reviewed, brief 
physical and neurological exams, vital 
signs, safety laboratory tests, urine 
pregnancy test, C-SSRS, review safety 
and record AEs, subject calendar 
review and study medication return and 
compliance check. 
 
Visit 5 (Week 69) 
Concomitant AEDs reviewed, brief 
physical and neurological exams, vital 
signs, safety laboratory tests, urine 
pregnancy test, C-SSRS, review safety 
and record AEs, subject calendar review 
and study medication return and 
compliance check and dispense study 
medication. 
27 
8.5.1.3.6 Visit 6 
Unscheduled Visit 
Activities to be determined by the 
nature of the visit, are at the 
Investigator’s discretion.  In most cases 
basic safety procedures (vital signs, 
review of adverse events) should be 
completed.  
Visit 6 (Week 86) 
Concomitant AEDs reviewed, brief 
physical and neurological exams, vital 
signs, safety laboratory tests, urine 
pregnancy test, C-SSRS, review safety 
and record AEs, subject calendar review, 
study medication review and compliance 
check and dispense study medication. 
27 
8.5.1.3.7  
 
Section Added: Visit 7/Early Term Visit  
(Week 104; start of dose-escalation 
period) 
Concomitant AEDs reviewed, physical 
and neurological exams, vital signs, local 
ECG, safety laboratory tests, urine 
pregnancy tests, C-SSRS, review safety 
and record AEs, subject calendar review, 
CGI-I, PCGI-I, study medication return 




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Protocol 1042-0604 Amendment 1 V1.0 
29 February 2016 
 
CONFIDENTIAL INFORMATION 
, M.D. (
) in 
addition to faxing the SAE report. 
Reason for Change: Administrative change – Contact information 
36 
9.5.3.2 Medical 
Inquiries 
For US & Australian Sites: 
, M.D. 
Marinus Pharmaceuticals 
Office Telephone:
Mobile phone: 
Email: 
 
 
 
 
For US & Australian Sites outside of 
business hours: 
, MD, PhD 
Marinus Pharmaceuticals 
Office Telephone:
Mobile phone:
 
Email:  
 
 
Added:  For Australian Sites (during 
business hours) 
Prof. 
, M.D. 
The Royal Melbourne Hospital 
Telephone: 
 
Email:
Reason for Change:  Administrative change – Contact information 
43 
12.2 Appendix 2, 
Line 1 below table 
*Carbamazepine and phenytoin are 
both moderate CYP 3A4 inducers but 
are permitted as background AEDs 
during the study.  
*Carbamazepine, phenytoin and 
phenobarbital are moderate CYP 3A4 
inducers but are permitted as background 
AEDs during the study.  
58 
12.7 Appendix 7: 
Protocol History 
 
Added 
 
 
 

SAP_001.pdf: 
Clinical Study Report 
 
Study 1042-0604 
Marinus Pharmaceuticals, Inc. 
 
 
 
16.1.9 
Documentation of Statistical Methods 
 


Sponsor: Marinus Pharmaceuticals, Inc. 
 
Protocol No: 1042-0604 Amendment 1 V1.0 
Statistical Analysis Plan
 
 
Version: 1.0  
Confidential 
Page 1 of 18 
 
 
 
Statistical Analysis Plan 
 
Protocol No.: 1042-0604  
 
A follow-on, two-year open-label extension study of ganaxolone as 
add-on therapy in adult patients with drug-resistant partial-onset 
seizures 
 
 
 
 
 
 
 
Sponsor: 
 
Marinus Pharmaceuticals, Inc. 
 
Version: 
 
Final, Version 1.0 
 
Issue Date: 
05 December, 2016 
 
 
 
 
 


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Page 2 of 18 
 
STATISTICAL ANALYSIS PLAN APPROVAL 
 
Author: 
 
 
_________________________________________ 
 
Date:  _____/_____/_________ 
, PhD 
Biostatistics, FMD K&L Inc. 
 
Reviewed and approved by: 
 
_________________________________________ 
 
Date:  _____/_____/_________ 
, PhD 
Biostatistics, FMD K&L Inc. 
 
 
Sponsor Review: 
 
_________________________________________ 
 
Date:  _____/_____/_________ 
, MD, PhD 
Clinical Development,  
Marinus Pharmaceuticals, INC. 
 
 


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TABLE OF CONTENTS 
ABBREVIATIONS 
5 
1. 
INTRODUCTION 
7 
1.1 
STUDY OBJECTIVES 
7 
1.1.1 Primary Objective 
7 
1.1.2 Secondary Objective 
7 
1.2 
STUDY ENDPOINTS 
7 
1.2.1 Safety Endpoints 
7 
1.2.2 Main Efficacy Endpoint 
7 
1.2.3 Other Efficacy Endpoints 
7 
1.3 
SUMMARY OF THE STUDY DESIGN 
8 
1.3.1 General Study Design and Plan 
8 
1.3.2 Randomization and Blinding 
10 
1.3.3 Sample Size and Statistical Power Considerations 
10 
2. 
STATISTICAL METHODS 
10 
2.1 
GENERAL CONSIDERATIONS 
10 
2.1.1 Reporting Precision 
10 
2.2 
DEFINITIONS OF ANALYSIS POPULATIONS (ANALYSIS SETS) 
11 
2.2.1   Safety Population 
11 
2.2.2   Full Analysis Population (FAP) 
11 
2.3 
TIME WINDOWS FOR ANALYSIS 
11 
2.4 
POOLING OF CENTERS 
11 
2.5 
HANDLING OF MISSING DATA 
11 
2.6 
ANALYSIS SOFTWARE 
11 
3. 
STUDY SUBJECTS 
11 
3.1 
DISPOSITION OF SUBJECTS 
11 
3.2 
PROTOCOL DEVIATIONS 
12 
4. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
12 
4.1 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
12 
4.2 
MEDICAL HISTORY 
12 
5. 
STUDY DRUG AND EXPOSURE 
13 
5.1 
EXTENT OF EXPOSURE 
13 
5.2 
PRIOR AND CONCOMITANT THERAPY 
13 
6. 
EFFICACY ANALYSES 
14 
6.1 
MAIN EFFICACY ANALYSIS 
14 
6.2 
OTHER EFFICACY ANALYSIS 
14 
6.2.1 Responder rate, Proportion of subjects with >=50% 
reduction in 28-day seizure frequency compared with baseline. 
14 


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6.3 
SUBGROUP ANALYSIS 
14 
7. 
SAFETY ANALYSIS 
15 
7.1 
ADVERSE EVENTS 
15 
7.1.1 Deaths, Serious and Other Significant Adverse Events 
16 
7.2 
CLINICAL LABORATORY PARAMETERS 
16 
7.3 
VITAL SIGNS, 12-LEAD ECG, PHYSICAL AND NEUROLOGICAL 
EXAMINATIONS, AND C-SSRS 
17 
7.3.1 Vital Signs 
17 
7.3.2 12-Lead ECG 
17 
7.3.3 Physical and Neurological Examinations 
17 
7.3.4 C-SSRS 
17 
8. 
INTERIM ANALYSES AND DATA AND SAFETY MONITORING 
BOARD (DSMB) 
18 
8.1 
INTERIM ANALYSES 
18 
8.2 
DATA AND SAFETY MONITORING BOARD (DSMB) 
18 
9. 
SUMMARY OF MAJOR CHANGES IN THE PLANNED 
ANALYSES 
18 
 
 
 
 
 
 
 
 
 
 
 
 


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ABBREVIATIONS 
Abbreviation 
Term 
AEs 
Adverse Events 
AEDs 
Anti-Epilepsy Drugs 
ALT 
Alanine Aminotransferase  
AST 
Aspartate Aminotransferase  
ATC 
Anatomical Therapeutic Chemical  
BID 
Two Times Daily  
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
cm 
Centimeter 
CO2 
Carbon Dioxide  
CRF 
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
eCRF 
Electronic Case Report Form 
CPS 
Complex Partial Seizures 
°C 
Degrees Centigrade 
°F 
Degrees Fahrenheit 
ECG 
Electrocardiography 
FAP 
Full Analysis Population 
FDA 
Food And Drug Administration 
kg 
Kilogram 
kg/m2 
Kilogram Per Square Meter 
lb 
Pound 
m 
Meter 
MedDRA 
Medical Dictionary For Regulatory Activities 
POS 
Partial-Onset Seizure 
PT 
Preferred Term 
SAEs 
Serious Adverse Events 
SAP 
Statistical Analysis Plan  
SD 
Standard Deviation 
SI 
Système International 
SOC 
System Organ Class 
SPS-motor 
Simple Partial Seizure with Motor/Observable Component 


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Abbreviation 
Term 
SGTC 
Secondarily Generalized Tonic-Clonic (seizures) 
TEAE 
Treatment-Emergent Adverse Event  
WHO 
World Health Organization  
 


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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for Protocol 1042-0604 (Amendment 1 
V1.0, 29 February, 2016). 
1.1 
STUDY OBJECTIVES 
1.1.1 
Primary Objective 
To assess the safety and tolerability of adjunctive ganaxolone during two-year open label 
treatment in adult subjects with drug-resistant partial-onset seizures. 
1.1.2 
Secondary Objective 
To assess efficacy of adjunctive ganaxolone during a two-year open-label treatment in adult 
subjects with drug-resistant partial-onset seizures. 
 
1.2 
STUDY ENDPOINTS 
1.2.1 
Safety Endpoints 
Safety endpoints include: 
• Adverse events (AEs) 
• Clinical laboratory tests  
• Vital signs  
• 12-lead ECG 
• Physical and neurological examinations 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
1.2.2 
Main Efficacy Endpoint 
Percentage change in seizure (partial-onset seizure (POS) with or without secondary 
generalization) frequency per 28-days relative to baseline in study 1042-0603. POS seizures only 
includes three seizure subtypes which are simple partial seizure with motor/observable 
component (SPS-motor), complex partial seizures (CPS) and secondarily generalized tonic-
clonic seizures (SGTC).  
 
1.2.3 
Other Efficacy Endpoints 
Responder rate (experiencing a ≥ 50% reduction at the end of the study compared with Study 
1042-0603 baseline  


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1.3 
SUMMARY OF THE STUDY DESIGN  
1.3.1 
General Study Design and Plan 
Study 1042-0604 is an open-label extension of Study 1042-0603, providing a two-year 
adjunctive ganaxolone treatment (900-1800 mg/d) to adult subjects with epilepsy consisting of 
partial-onset seizure (POS). Subjects who have completed all scheduled clinical study visits in 
the previous protocol 1042-0603 and have shown a minimum 35% improvement in mean seizure 
frequency per 28-days vs. baseline over the three 28-day periods preceding study entry, and 
acceptable tolerability, are eligible to participate.  
 
Subjects will enter the study at their current dose of ganaxolone from study 1042-0603. The dose 
of ganaxolone may be adjusted for tolerability and response.  Safety and tolerability will be 
assessed by diary record and at clinic visits approximately every four months. During the study if 
the patient fails to continue to meet the minimum improvement criteria (mean 28-day seizure 
frequency over the past three 28-day periods before the study visit showing 35% improvement 
over baseline) at any study visit the investigator should consider discontinuing the patient from 
the study. Efficacy will primarily be assessed based on daily seizure calendar entries.  
 
Baseline for safety and efficacy evaluations will be each subject's baseline from Study 1042-
0603.  
 
The Schedule of Events is presented in Table 1.  
 
 
 
 




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1.3.2 
Randomization and Blinding 
This is an open-label extension study and no randomization was planned. 
 
1.3.3 
Sample Size and Statistical Power Considerations 
This is an open-label, long-term continuation study. Sample size will be determined by those 
eligible after successful completion of Study 1042-0603. 
 
2. 
STATISTICAL METHODS 
2.1 
GENERAL CONSIDERATIONS 
In general, continuous variables will be summarized by number of subjects, mean, standard 
deviation (SD), median, minimum, and maximum values. Categorical variables will be 
summarized by counts and percentage of subjects in each category. If data is sparse, no summary 
table will be presented. Summary tables will present data by treatment received during the this 
study, i.e. Ganaxolone. Source data for the summary tables and statistical analyses will be 
presented as subject data listings, which include data collected on the electronic case report 
forms (eCRFs) as well as any derived variables for all enrolled subjects. 
Baseline seizure activity will be determined by 8 weeks of retrospective recording in subject 
daily seizure calendars in Study 1042-0603. 
 
Baselines for safety assessments are defined as the last non-missing value of the assessment 
before the first dose of treatment in Study 1042-0603.  
 
2.1.1 Reporting Precision 
Summary statistics will be presented to the following degree of precision, unless otherwise 
specified: 
Statistics 
Degree of Precision 
Mean, Geometric mean, Median, 
Quartiles, Confidence limit boundaries 
One decimal place more than the raw data. 
Standard deviation, Standard error 
Two decimal places more than the raw data. 
Minimum, Maximum 
The same as the raw data. 
p-value 
Rounded to 4 decimal places and therefore 
presented as 0.xxxx; p-values smaller than 0.0001 
as ‘<0.0001’; p-values greater than 0.9999 as 


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‘>0.9999’. 
Percentage 
One decimal place. A percentage of 100% will be 
reported as 100%. Percentages of zero will be 
reported as 0. 
For weight and height, one decimal place will be used for summary statistics. Fractional numeric 
values will be presented with a zero to the left of the decimal point (for example, 0.12 – 0.30). 
2.2 
DEFINITIONS OF ANALYSIS POPULATIONS (ANALYSIS SETS) 
2.2.1   Safety Population 
All subjects who signed informed consent and took one dose of study medication in this study.  
In protocol, it is termed ITT Safety population.  
2.2.2   Full Analysis Population (FAP) 
Subjects who returned at least 25 days of seizure calendar data. 
 
2.3 
TIME WINDOWS FOR ANALYSIS 
No visit window will be constructed for the analysis.  Summary table will present data of 
scheduled visits. Data of unscheduled visits will only be reported in listings.  
 
2.4 
POOLING OF CENTERS  
Data of all sites will be pooled together for analysis. 
 
2.5 
HANDLING OF MISSING DATA 
Unless otherwise specified, missing data will not be imputed. All analyses will be based on 
available data. 
 
2.6 
ANALYSIS SOFTWARE 
All summaries and statistical analyses will be generated using SAS® version 9.2 or later. 
 
3. 
STUDY SUBJECTS 
3.1 
DISPOSITION OF SUBJECTS 
Disposition will be summarized by treatment, i.e. Ganaxolone, in all enrolled subjects to this 
study. 


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The disposition will include the following: 
• Subjects enrolled to Study 1042-0604 
• Subjects in the Safety Population 
• Subjects in the FAP 
• Subjects completed study 
• Subjects discontinued study  
• Reasons for discontinuation  
A listing of dispositions will be provided for all subjects. 
3.2 
PROTOCOL DEVIATIONS 
The clinical team will identify deviations and the deviations will be recorded into the database.  
 
A subject data listing will be provided. 
 
4. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
4.1 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographic data (age, gender, race, and ethnicity) and baseline characteristics (including 
height, weight and body mass index (BMI)) collected at study screening will be summarized 
using descriptive statistics by treatment, i.e. Ganaxolone, in the safety population and FAP, 
separately.  
Height (in cm) = Height (in inches) * 2.54 
Weight (in kg) = Weight (in lbs) * 0.4536 
BMI (kg/m2) = Weight (kg)/[Height(m)2] 
 
A subject data listing of demographics and baseline characteristics will be provided. 
4.2 
MEDICAL HISTORY 
Medical history will be coded with the Medical Dictionary for Regulatory Activities (MedDRA) 
Terminology version 16.0. The number and percent of subjects with clinically significant 
medical history at screening will be summarized by system organ class (SOC) and preferred term 
(PT) by treatment, i.e. Ganaxolone, in safety population. 
 


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5. 
STUDY DRUG AND EXPOSURE 
5.1 
EXTENT OF EXPOSURE 
Exposure to study medication will be summarized as a continuous variable, via the number of 
days of drug taken. Ganaxolone will be administered BID following the morning and evening 
meals. A missed dose of study medication may be taken later up to 8 hours before the next 
scheduled dose; otherwise, the missed dose should not be given. Treatment exposure and 
treatment compliance will be summarized using the Safety population. 
• Treatment Exposure = the number of days of drug taken = drug stop date – start date + 1 
• Treatment Compliance %= [(drug stop date – start date) + 1 – number of days drug not 
taken] / [(drug stop date – start date) +1] x 100%. 
A subject data listing will be provided for study drug dispense and return. 
5.2 
PRIOR AND CONCOMITANT THERAPY 
Prior medications are defined as medications that started prior to the first dose of study drug in 
study 1042-0604. Concomitant medications are defined as medications (other than the study 
drug) taken on or after the first does of the study drug during the study. Medications started 
before the first dose of study drug and continuing at the time of the first dose of study drug are 
considered both prior medication and concomitant medication. Medications with complete 
missing start/end date are considered both prior and concomitant medications. 
All investigator terms for medications recorded on the CRF will be coded using the World Health 
Organization (WHO) Anatomical Therapeutic Chemical (ATC) drug dictionary (Version WHO 
Drug Dictionary, March 2014).  The number (percentage) of subjects who took prior and 
concomitant medications will be summarized by treatment, i.e. Ganaxolone, in safety population, 
by ATC Classification and WHO Drug PT.  
A subject data listing of prior and concomitant therapy will be provided. 
To define prior or concomitant medication, the following table describes how missing date 
information will be handled 
Partial Missing Start or 
Stop Date 
Imputed Start Date 
Imputed Stop Date 
Missing month and day, 
and the year  is present 
 
January 1 of that year or first dose 
date if the year is the same as the 
year of  first dose date 
December 31 of that 
year 
Missing day, but year and 
month are present 
 
First day of that month or first 
dose date if the year and month 
are the same as the year and 
month of first dose date 
Last day of that month 
Missing month, but year 
and day are present 
Missing 
month 
imputed 
as 
January 
Missing month imputed 
as December 
 


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6. 
EFFICACY ANALYSES 
All efficacy analyses will be performed for partial-onset seizure (POS) with or without secondary 
generalization only. POS seizures includes three seizure subtypes which are SPS-motor, CPS and 
SGTC.  
All efficacy data will be summarized by treatment, i.e. Ganaxolone, in FAP. 
 
6.1 
MAIN EFFICACY ANALYSIS 
The primary efficacy endpoint is the percentage change in POS seizure frequency per 28-days 
relative to baseline in study 1042-0603. Post-baseline 28-day seizure frequency will be 
calculated as the total number of seizures in this open-label extension study (Study 1042-0604) 
divided by the number of days with available seizure data in the post-baseline period, multiplied 
by 28. Baseline 28-day seizure frequency will be calculated as the total number of seizures in the 
baseline period of Study 1042-0603 (≤ 56 days) divided by the number of days with available 
seizure data in the baseline period, multiplied by 28. The calculation for percent change from 
baseline in 28-day seizure frequency will be done as follows for each subject: 
 
 
The baseline, post-baseline, and percent change from baseline in 28-day seizure frequency will 
be summarized by treatment, i.e. Ganaxolone, in FAP. 
 
A subject data listing will be provided. 
 
6.2 
OTHER EFFICACY ANALYSIS 
 
6.2.1 
Responder rate, Proportion of subjects with >=50% reduction in 28-day seizure 
frequency compared with baseline.  
A 50% responder is an individual whose reduction of percent change from baseline to the end of 
the open label extension period in 28-day POS seizure frequency is greater than or equal to 50%. 
The number and percentage of responders will be summarized.  
 
A subject data listing will be provided. 
6.3 
SUBGROUP ANALYSIS 
No subgroup analysis planned.  


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7. 
SAFETY ANALYSIS 
All safety analyses will be performed by treatment, i.e. Ganaxolone, in the Safety Population.  
Safety assessments include: 
• AE  
• Clinical laboratory tests  
• Vital signs including temperature, blood pressure, pulse rate, and weight 
• 12-lead ECG 
• Physical and neurological  examinations 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Baseline is defined as the last non-missing value obtained before the first treatment in the 
preceding Study 1042-0603.  
 
7.1 
ADVERSE EVENTS 
Adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA®, version 16.0/AECODE). 
The verbatim term will be included in the AE listings. 
A treatment-emergent adverse event (TEAE) is defined as an AE that occur or worsen on or after 
the first dose of study drug in Study 1042-0604 and before the end of the  study (including the 
safety follow-up period). Only TEAEs will be included in summary tables. All AEs, treatment 
emergent or otherwise, will be presented in subject data listings. 
The TEAEs will be summarized as the number (percentage) of subjects with TEAEs within SOC 
and PT.  Subjects who report the same PT on multiple occasions will be counted once for the PT: 
under the highest severity (severe > moderate > mild) when summarized by severity and under 
the closest relationship (related > probably related > possibly related > unlikely related > Not 
related) to study drug when summarized by relationship. If a subject reports multiple PT for a 
SOC, the subject will be counted only once for that SOC. Treatment related AEs are defined as 
those events recorded on the CRF as ‘Related’, ‘Probably Related’ or ‘Possibly Related’, others 
will not be related AEs. 
TEAEs will be summarized as below.  
• An overview table, including number of subjects with  
o TEAEs 
o serious AEs (SAEs) 
o study drug related TEAEs 
o TEAEs by severity  


Sponsor: Marinus Pharmaceuticals, Inc. 
 
Protocol No: 1042-0604 Amendment 1 V1.0 
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Version: 1.0  
Confidential 
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o TEAEs leading to study discontinuation 
o TEAEs leading to death 
• TEAE by SOC and PT 
• TEAE by SOC, PT, and Severity 
• TEAE by PT 
• TEAEs by SOC, PT, and Relationship to Study Drug 
All AE tables will be sorted by SOC and PT in decreasing frequency of the number and 
percentage of subjects.   
Missing date will be imputed followed table describes how missing date information will be 
handled: 
 
Partial Missing Start or 
Stop Date 
Imputed Start Date 
Imputed Stop Date 
Missing month and day, 
and the year  is present 
 
January 1 of that year or first dose 
date if the year is the same as the 
year of  first dose date 
December 31 of that 
year 
Missing day, but year and 
month are present 
 
First day of that month or first 
dose date if the year and month 
are the same as the year and 
month of first dose date 
Last day of that month 
Missing month, but year 
and day are present 
Missing 
month 
imputed 
as 
January 
Missing month imputed 
as December 
 
7.1.1 
Deaths, Serious and Other Significant Adverse Events  
The listings of serious AEs, AE leading to study discontinuation, and subjects who died during 
the study will be provided.  
7.2 
CLINICAL LABORATORY PARAMETERS 
Laboratory assessments include hematology, clinical chemistry, and urinalysis as in Table 2: 
 
Table 2: Clinical laboratory parameters: 
 
Clinical Chemistry 
Hematology 
Urinalysis 
Total Bilirubin 
Hemoglobin 
pH 
AST (SGOT) 
Hematocrit 
Color 
ALT (SGPT) 
Erythrocytes 
Transparency 


Sponsor: Marinus Pharmaceuticals, Inc. 
 
Protocol No: 1042-0604 Amendment 1 V1.0 
Statistical Analysis Plan
 
 
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BUN 
Leukocytes + differential 
Specific Gravity 
Glucose 
Thrombocytes (platelet count) 
Urobilinogen 
Potassium 
Ketones 
Sodium 
Protein 
Calcium 
Glucose 
Alkaline Phosphatase 
Hemoglobin 
Chloride 
Creatinine 
CO2 
Total Protein 
Serum Albumin 
 
ALT = alanine transferase; AST = aspartate transferase; BUN = blood urea nitrogen 
All laboratory parameters will be presented in Système International (SI) units. Quantitative 
results (including actual value, and change from baseline) for hematology and chemistry will be 
summarized using descriptive statistics by visit. The number (and percentage) of subjects with 
urine abnormalities will be summarized by visit. 
All laboratory data will be included in the listings. A pregnancy listing will be provided 
separately.  
7.3 
VITAL SIGNS, 12-LEAD ECG, PHYSICAL AND NEUROLOGICAL EXAMINATIONS, AND C-
SSRS 
7.3.1 
Vital Signs 
Vital signs include temperature, blood pressure, pulse rate, respiration rate, height, weight and 
BMI. 
All vital signs will be presented in Système International (SI) units. Quantitative results 
(including actual value, and change from baseline to each post-baseline visit) will be summarized 
using descriptive statistics by post-baseline time point for each parameter.  
Listings of vital signs with abnormal flags will be provided.  
7.3.2 
12-Lead ECG 
12-lead ECG data will be reported in listing. 
  
7.3.3 
Physical and Neurological Examinations 
Physical examination data will be summarized using descriptive statistics by post-baseline visit, 
for each component. Listings for physical examination will be provided.  
 
Neurological examination data will be reported in listing. 
7.3.4 
C-SSRS 
C-SSRS data will be summarized and listed for each question by visit. 


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8. 
INTERIM ANALYSES AND DATA AND SAFETY MONITORING BOARD 
(DSMB)  
8.1 
INTERIM ANALYSES 
No formal interim analyses are planned. 
8.2 
DATA AND SAFETY MONITORING BOARD (DSMB)  
DSMB is N/A. 
 
9. 
SUMMARY OF MAJOR CHANGES IN THE PLANNED ANALYSES 
Below changes from protocol have been made in the SAP. 
 
Safety Endpoints: 
Due to early termination of the study and low patient numbers 12-lead ECG and Neurological 
Examination results will only be reported in listings. C-SSRS data were collected in eCRF and 
will be reported as one of the safety endpoints.  
 
Efficacy Endpoints: 
Due to early termination of the study and low patient numbers seizure free intervals and seizure 
free days will not be derived and the Clinician's Global Impression of Improvement, and the 
Patient/Caregiver Global Impression of Improvement results will only be reported in listings 
 
To avoid confusion, protocol defined primary and secondary efficacy endpoints are re-named as 
main and other efficacy endpoints, respectively, to clarify that the primary objective of the study 
is to assess the safety and tolerability of adjunctive ganaxolone during two-year open-label 
treatment in adult subjects with drug-resistant partial-onset seizures.