Conditions: Drug Resistant Partial Onset Seizure
Keywords: partial onset seizures complex partial seizures simple partial seizures anticonvulsant ganaxolone neurosteroid Marinus epilepsy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 405
Healthy volunteers: no

Brief summary:
The study will evaluate the effectiveness and safety of an investigational drug-ganaxolone - on partial seizure frequency in adults with epilepsy taking a maximum of 3 antiepileptic medications (AEDs).

Detailed description:
This is a 2-cohort study comprised of 2 phases in each cohort. Phase 1 is a double-blind (DB) phase followed by Phase 2, an open-label phase. Cohort 1 will provide tolerability, safety, and PK information for ganaxolone 1200 milligram per day (mg/day), 1800 mg/day and placebo. Cohort 2 will investigate the efficacy, tolerability and safety of ganaxolone 1800 mg/day compared to placebo. Cohort 1 (N= approximately 50) will enroll into a 67-week study comprised of a 4-week prospective baseline period plus 4 week retrospective baseline followed by two treatment phases: a 9-week randomized DB placebo-controlled treatment phase followed by a 52-week open label treatment phase. Cohort 2 (N=150) will enroll into a 72-week study comprised of a 8-week prospective baseline period followed by two treatment phases: a 14-week randomized DB placebo-controlled treatment phase followed by a 52-week open label treatment phase.

Arms:
arm 1: 1200 mg/day and 1800 mg/day + AED arm 2: Placebo + AED arm 3: 1800 mg/day + AED arm 4: 1800 mg/day + AED arm 5: Placebo +AED arm 6: 1800 mg/day + AED

Interventions: intervention 1: ganaxolone intervention 2: Placebo
Intervention descriptions: intervention 1: 200 mg and 225 mg capsules; target dose 1800 mg/day dosed 900mg 2x/day intervention 2: placebo

Protocol document:
Prot_000.pdf: 
Clinical Study Report 
 
Study 1042-0603 
Marinus Pharmaceuticals, Inc. 
 
 
 
16.1 
STUDY INFORMATION 
16.1.1 
Protocol 




 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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2. 
SYNOPSIS  
 
Name of Sponsor/Company: Marinus Pharmaceuticals, Inc. 
Protocol Number: 1042-0603 
Phase of Development: 3 
Title of Protocol: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial 
to Determine the Efficacy and Safety of Ganaxolone as Adjunctive Therapy for Adults 
with Drug-Resistant Partial-Onset Seizures Followed by Long-term Open-Label 
Treatment 
Primary Objectives: To evaluate efficacy of ganaxolone compared to placebo as 
adjunctive therapy in adults with partial-onset seizures (POS), with or without 
secondary generalizations. 
Secondary Objectives:  
 To evaluate the safety and tolerability of ganaxolone compared to placebo as 
adjunctive therapy in adults with POS  
 To evaluate serum levels of ganaxolone at 1200 mg/d and 1800 mg/d after 
chronic dosing 
 To evaluate the safety and tolerability of ganaxolone when administered as 
adjunctive therapy in adults with POS over a 12-month period. 
Study Design and Methodology: This is a 2-cohort study comprised of 2 phases in 
each cohort. Phase 1 is a double-blind phase followed by Phase 2, an open-label phase. 
Cohort 1 will provide tolerability, safety, and PK information for ganaxolone 1200 
mg/d, 1800 mg/d and placebo. Cohort 2 will investigate the efficacy, tolerability and 
safety of ganaxolone 1800 mg/d compared to placebo. Cohort 1 (N=approximately 46) 
will enroll into a 67-week study comprised of a 4-week prospective baseline period 
plus 4 week retrospective baseline followed by two treatment phases: a 9-week 
randomized double-blind (DB) placebo-controlled treatment phase followed by a 52-
week open-label (OL) treatment phase. Cohort 2 (approximately N=359) will enroll 
into a 76-week study comprised of an 8-week prospective baseline period followed by 
two treatment phases: a 14-week randomized DB placebo-controlled treatment phase 
followed by a 52-week open-label (OL) treatment phase. A final safety assessment will 
be conducted two weeks following the end of each OL treatment phase. The Schedule 
of Events is contained in Appendix 1. 
Study Population and Main Criteria for Inclusion/Exclusion: Male and female 
subjects 18 years of age and older able to provide written informed consent with a 
confident diagnosis of epilepsy with POS with or without secondary generalization 
with a POS frequency rate of 3 POS per 28-day who are currently treated on a stable 
regimen of AEDs. 
Subjects must not have previous exposure to ganaxolone, generalized epilepsy, have 
less than 3 POS seizures per 28-day period or 21 seizure-free days. Subject should 
not have innumerable seizures, more than 100 POS total per each 4-week baseline 
period. No subjects will be admitted who have an active central nervous system (CNS) 
infection, demyelinating disease, degenerative neurological disease, CNS disease 


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CONFIDENTIAL INFORMATION 
deemed progressive, clinically unstable psychiatric disorder, suicide attempt within the 
last 5 years, or current significant suicidal ideation.  
Number of Subjects: Approximately 525 subjects will be screened to randomize 
approximately 46 subjects into Cohort 1 and 359 subjects into Cohort 2 at 1:1 
ganaxolone or placebo. 
Test Product, Dose and Mode of Administration: Ganaxolone 200 mg or 225 mg 
capsules or matching placebo, administered in BID up to a total of 1800 mg/day.  
Duration of Treatment: Cohort 1: Four weeks prospective baseline plus 63 weeks 
treatment: 1 week titration, 4 weeks at 1200 mg/day, 4 weeks at 1800 mg/day for 
double-blind phase, 1 week transition to OL, 51 weeks at 1800 mg/day for open-label 
phase. Cohort 2: Eight weeks prospective baseline plus 68 weeks treatment: 2 week 
titration, 12 weeks at 1800 mg/day for double-blind phase, 2 week transition to OL, 50 
weeks at 1800 mg/day for open-label phase. Subjects will de-escalate treatment over 2 
weeks at end of the OL phase or at discontinuation. 
Reference Therapy, Dose and Mode of Administration: Orally-administered 
placebo capsules administered BID. 
Criteria for Efficacy Evaluation:  The primary efficacy endpoint for US Food and 
Drug Administration registration is the percent change in the 28-day seizure frequency 
(POS with or without secondary generalization) from baseline to the DB phase for 
Cohort 2. The primary endpoint analysis will consist of rank analysis of covariance 
(ANCOVA) conducted on the percent change data, with treatment and pooled countries 
as factors and the rank baseline seizure frequency per 28 days as a covariate  
 
The primary efficacy endpoint for European registration is 50% responder rate during 
the maintenance treatment phase of the double-blind phase for Cohort 2. A 50% 
responder is an individual who experiences at least a 50% decrease in seizure 
frequency compared to baseline. 
 
Key secondary end-points 
 
The three key secondary endpoints will be tested using a fixed sequence procedure to 
protect the familywise error rate at 0.05. If the primary outcome measure is statistically 
significant, the p-values of the secondary measures will be examined in the order listed 
below. The process stops at the first p-value above 0.05.  
 Responder rate (experiencing a ≥ 50% reduction) during the titration + 
maintenance treatment periods of the DB phase for Cohort 2 
 Change in the number of seizure free days per 28-day period from baseline 
during the titration + maintenance treatment periods of the DB phase for Cohort 
2  
 Clinical Global Impression of Change – Improvement (CGI-I; Investigator) at 
Week 14 of the double  blind treatment phase relative to the baseline for Cohort 
2 


 
 
 
 
   
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 


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d) Ganaxolone Maintenance 1800 mg/d vs placebo (Cohort 1: Weeks 6-9). 
e) Ganaxolone maintenance 1200 mg/d vs placebo (Cohort 1: Weeks 2-5). 
f) OL (Cohort 1: Weeks 10-61; Cohort 2: Weeks 16-66). 
Safety: Neurological and physical examinations, clinical laboratory tests, Columbia 
Suicide Severity Rating Scale (C-SSRS), seizure severity, electrocardiogram (ECG), 
vital signs, and spontaneously reported adverse events (AEs). 
Pharmacokinetic Data: Blood samples for concomitant AEDs will be drawn at Visits 
1, 2, 3, 4, 5, 7, 8, 9 and 10. Blood samples for ganaxolone will be drawn at Visits 4, 5, 
7, 8, 9 and 10.  
Pharmacokinetic evaluation will be conducted if needed and reported separately. 
Levels of ganaxolone and of concomitant AEDs are not considered a safety assessment 
within this protocol. 
Statistical Methods: The primary endpoint analysis will consist of rank analysis of 
covariance (ANCOVA) conducted on the percent change data, with treatment and 
pooled countries as factors and the rank baseline seizure frequency per 28 days as a 
covariate.  
The responder rates and seizure-free rates between ganaxolone and placebo will be 
compared using a logistic regression analysis.  To take into account the ordinal nature 
of the response to Clinical Global Impression of Change and Patient Global Impression 
of Change scales (CGI-I, PGI-I), the Row Mean Score Difference, and the p-value 
based on Cochran-Mantel-Haenszel test adjusting for pooled center (either US or 
ROW), will be used to test if there is a treatment effect.  
Adverse events (AEs) will be tabulated by Overall, system organ class (SOC), and 
Preferred Term using the MedDRA v.16.1 coding system.  Frequency and percentage 
of subjects with adverse events will be calculated for each cohort in each phase of the 
study, by treatment and overall, and in Cohort 1 double blind phase, by dose level 
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 
by treatment including changes from baseline.  Critically significant changes in 
laboratory and ECG values and vital signs will be flagged in data listings. Listings of 
most abnormal changes will be provided. 


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3. 
TABLE OF CONTENTS 
1. 
SIGNATURE PAGE ..........................................................................................2 
2. 
SYNOPSIS ..........................................................................................................3 
3. 
TABLE OF CONTENTS ...................................................................................7 
4. 
LIST OF ACRONYMS, ABBREVIATIONS AND DEFINITIONS 
OF TERMS .......................................................................................................11 
5. 
ETHICS .............................................................................................................13 
5.1 
Independent Ethics Committee (IEC) or Institutional 
Review Board (IRB) ...........................................................................13 
5.2 
Ethical Conduct of Study ..................................................................13 
5.3 
Subject Information and Consent ....................................................13 
6. 
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE ...................................................................................................14 
7. 
INTRODUCTION ............................................................................................15 
8. 
STUDY OBJECTIVES ....................................................................................18 
8.1 
Primary Objectives ............................................................................18 
8.2 
Secondary Objectives.........................................................................18 
9. 
INVESTIGATION PLAN ...............................................................................19 
9.1 
Overall Study Design and Plan .........................................................19 
9.2 
Discussion of Study Design, including the Choice of Control 
Group ..................................................................................................21 
9.3 
Selection of study population ............................................................22 
9.3.1 
Number of Subjects............................................................22 
9.3.2 
Inclusion Criteria ...............................................................22 
9.3.3 
Exclusion Criteria ..............................................................25 
9.3.4 
Removal of Subjects from the Study .................................28 
9.3.4.1 
Criteria for Withdrawal .................................28 
9.3.4.2 
Early Termination Procedures.......................30 
9.3.4.3 
Consequences of Early Termination .............31 
9.4 
Treatments ..........................................................................................31 
9.4.1 
Treatments Administered ...................................................31 
9.4.2 
Identity of Investigational Products ...................................31 
9.4.3 
Method of Assigning Subjects to Treatment Groups .........32 
9.4.4 
Subject Numbering ............................................................33 
9.4.5 
Study Dosing and Dosage Adjustments .............................33 
9.4.6 
Dose Administration ..........................................................38 
9.4.7 
Missing a Dose ...................................................................39 
9.4.8 
Blinding..............................................................................39 
9.4.9 
Un-blinding ........................................................................40 
9.4.10 
Background AED Medication: ...........................................42 
9.4.11 
Excluded, Prior, and Concomitant Medications ................43 
9.4.12 
Treatment Compliance .......................................................44 


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9.5 
Efficacy and Safety Variables ...........................................................45 
9.5.1 
Calculation of Baseline ......................................................45 
9.5.2 
Efficacy Assessments .........................................................45 
9.5.3 
Safety Assessments ............................................................46 
9.5.4 
Other Assessments .............................................................48 
9.5.5 
Schedule of Study Procedures ...........................................48 
9.5.5.1 
Visit 1 (Screening Visit) ................................48 
9.5.5.2 
Visit 2 (Randomization; Week 0) ..................49 
9.5.5.3 
Visit 3 (Up-Titration; Cohort 1: Week 
1; Cohort 2: Week 2) .....................................49 
9.5.5.4 
Telephone Follow Up (Cohort 2: Week 
5) ...................................................................49 
9.5.5.5 
Visit 4 (Evaluation; Cohort 1: Week 5; 
Cohort 2: Week 8) .........................................49 
9.5.5.6 
Telephone Follow Up (Cohort 2: Week 
11) .................................................................50 
9.5.5.7 
Visit 5 (Final DB Evaluation; Cohort 
1: Week 9; Cohort 2: Week 14) .....................50 
9.5.5.8 
Visit 6 (DB Conversion; Cohort 1: 
Week 10; Cohort 2: Week 16) .......................50 
9.5.5.9 
Visit 7 (Cohort 1: Week 14; Cohort 2: 
Week 20) .......................................................50 
9.5.5.10 
Visit 8 (Cohort 1: Week 22; Cohort 2: 
Week 28) .......................................................50 
9.5.5.11 
Telephone Follow Up (Cohort 1: Week 
32; Cohort 2: Week 36) .................................51 
9.5.5.12 
Visit 9 (Cohort 1:  Week 42; Cohort 2:  
Week 44) .......................................................51 
9.5.5.13 
Telephone Follow Up (Cohort 1: Week 
52; Cohort 2:  Week 52) ................................51 
9.5.5.14 
Visit 10 Pre-Taper/ET Visit (Cohort 1: 
Week 61; Cohort 2: Week 66) .......................51 
9.5.5.15 
Visit 11 Post-Taper Safety Follow-up 
Visit (Cohort 1: Week 63; Cohort 2: 
Week 68) .......................................................51 
9.5.6 
Appropriateness of Measurements .....................................52 
9.6 
Data Quality Assurance .....................................................................52 
9.7 
Statistical Methods Planned and Determination of Sample 
Size .......................................................................................................52 
9.7.1 
Randomization ...................................................................52 
9.7.2 
Analysis Populations ..........................................................52 
9.7.3 
Missing Data ......................................................................53 
9.7.4 
Baseline and Demographic Characteristics .......................53 
9.7.5 
Analysis of the Primary Efficacy Variable .........................53 
9.7.6 
Analysis of Secondary Efficacy Variables .........................54 
9.7.7 
Analysis of Safety Variables ..............................................57 
9.7.8 
PK Analysis ........................................................................57 


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9.7.9 
Determination of Sample Size ...........................................57 
10. 
INVESTIGATOR REQUIREMENTS ...........................................................59 
10.1 
Prior to Study Initiation ....................................................................59 
10.2 
Prior to Study Completion ................................................................59 
10.3 
Study Discontinuation .......................................................................60 
10.4 
Informed Consent ..............................................................................60 
10.5 
Adverse Events ...................................................................................61 
10.5.1 
Definitions..........................................................................61 
10.5.2 
Evaluating and Recording of Adverse Events ...................62 
10.5.3 
Reporting of Adverse Events .............................................64 
10.5.3.1 
Serious Adverse Events ................................64 
10.5.3.2 
Medical Inquiries ..........................................66 
10.5.3.3 
Pregnancy......................................................67 
10.6 
Study Monitoring and Audit Requirements ....................................68 
10.7 
Electronic Case Report Forms ..........................................................68 
10.8 
Study Drug Accountability ................................................................68 
10.9 
Confidentiality of Data ......................................................................69 
10.10 
Retention of Records..........................................................................69 
10.11 
Protocol Adherence ............................................................................69 
11. 
PUBLICATION PLAN ....................................................................................70 
12. 
REFERENCES .................................................................................................71 
APPENDICES ..................................................................................................................72 
12.1 
Appendix 1: Schedule of Events .......................................................72 
12.2 
Appendix 2: Clinical Laboratory Tests ............................................80 
12.3 
Appendix 3: Strong and Moderate Cytochrome P450 CYP 
3A4, 5, 7 Inducers and Inhibitors Prohibited During Study 
1042-0603 ............................................................................................81 
12.4 
Appendix 4: Titration Dosing Instructions for Subjects ................82 
12.5 
Appendix 5:  Subject Seizure Calendar ...........................................87 
 
88 
12.6 
Appendix 6: Clinical Global Impression- Improvement 
(Patient/Caregiver) ............................................................................96 
12.7 
Appendix 7: Columbia Suicide Severity Rating Scale (C-
SSRS) Baseline/Screen .......................................................................99 
Appendix 7 Continued: Columbia Suicide Severity Rating Scale (C-
SSRS)-Since Last Visit .....................................................................106 
12.8 
Appendix 8:  Protocol History ........................................................ 113 
 
 
 


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LIST OF WITHIN TEXT FIGURES AND TABLES 
PAGE 
 
Figure 1.  Cohort 1 Trial Design .....................................................................................21 
Figure 2. Cohort 2 Trial Design ......................................................................................21 
Table  1. Dosing Schedule for Cohort 1 Double-blind Phase, Open-Label 
Phase, and De-Escalation Period ....................................................................................35 
Table  2. Dosing Schedule for Cohort 2 Double-blind Phase, Open-Label 
Phase, and De-Escalation Period ....................................................................................37 
 
 
 


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4. 
LIST OF ACRONYMS, ABBREVIATIONS AND DEFINITIONS OF 
TERMS 
Term 
Definition 
3,5-P 
3-hydroxy-5-pregnan-20-one; allopregnanolone 
AE 
adverse event 
AE eCRF 
adverse event electronic 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 
β-HCG 
β-human chorionic growth hormone  
°C 
degrees centigrade 
CNS 
central nervous system 
CPS 
complex partial seizures 
eCRF 
electronic case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
computed tomography 
DB 
double-blind 
DDI 
drug-drug interaction 
ECG 
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 
-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 
mg/d 
milligram per day 


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Term 
Definition 
Min 
mITT 
minutes 
modified intent to treat 
mL 
millilitre 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
n 
number of subjects 
OL 
open-label 
OLE 
open-label extension 
oz 
ounces 
PK 
pharmacokinetics 
POS 
partial-onset seizure 
PTZ 
pentylenetetrazol 
POP-PK 
population pharmacokinetics 
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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5. 
ETHICS 
5.1 
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.  
5.2 
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. 
5.3 
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, will give their written consent to in 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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6. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
This will be a multi-center study with approximately 55 investigational sites in the USA, 
the Russian Federation (Russia), Australia, Bulgaria, Germany and Poland with 
approximately 6 subjects enrolled at each site.  Study enrollment is planned for 26 
months from the time of first subject visit.  Duration of subject participation in Cohort 1 
is up to 67 weeks: 4 weeks prospective seizure recording, 1 week titration, 8 weeks 
double-blind maintenance (total 9 weeks of double-blind [DB] treatment), 52 weeks of 
additional open-label (OL) treatment ± 2 weeks of dose de-escalation at study end. 
Duration of subject participation in Cohort 2 is up to 76 weeks: 8 weeks prospective 
seizure recording, 2 week titration, 12 weeks double-blind maintenance (total 14 weeks 
of double-blind [DB] treatment), 52 weeks of additional open-label (OL) treatment ± 2 
weeks of dose de-escalation at study end. 
 


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7. 
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 is designed to evaluate the safety, tolerability and efficacy of ganaxolone 
when used as an add-on therapy in adult subjects with epilepsy consisting of partial-onset 
(focal) seizures that are uncontrolled on their present AED regimen. 
Ganaxolone is the 3-methylated synthetic analog of allopregnanolone, which is 
synthesized in vivo when progesterone undergoes 5-reduction and loses all 
progestational activity.  Ganaxolone is a positive allosteric modulator of -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 neuropsychiatric conditions 
such as 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.  Subjects 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 


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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 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 t.i.d.) 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.  
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, 


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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 of ganaxolone as adjunctive treatment of POS when administered BID at 
doses up to 1800 mg/day in a capsule formulation. 


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8. 
STUDY OBJECTIVES 
8.1 
Primary Objectives  
1. To evaluate efficacy of ganaxolone compared to placebo as adjunctive 
therapy in adults with partial-onset seizures (POS), with or without 
secondary generalizations.  
 
8.2 
Secondary Objectives 
1. To evaluate the safety and tolerability of ganaxolone compared to placebo 
as adjunctive therapy in adults with POS.  
2. To evaluate serum levels of ganaxolone at 1200 mg/d and 1800 mg/d after 
chronic dosing. 
3. To evaluate the safety and tolerability of ganaxolone when administered as 
adjunctive therapy in adults with POS over a 12-month period. 
 


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9. 
INVESTIGATION PLAN 
9.1 
Overall Study Design and Plan 
This is a 2-cohort study with each cohort comprised of 2 treatment phases. Phase 1 is a 
double-blind phase followed by Phase 2, an open-label phase. Cohort 1 will provide 
tolerability, safety, and PK information for ganaxolone 1200 mg/d, 1800 mg/d and 
placebo.  Cohort 2 will investigate the efficacy, tolerability and safety of ganaxolone 
1800 mg/d compared to placebo. Cohort 1 (N=approximately 46) will enroll into a 67-
week protocol comprising a 4-week prospective baseline period and two treatment 
phases: a 9-week double-blind treatment phase followed by a 52-week open label 
treatment phase. Cohort 2 (N=359) will enroll into a 76-week study comprising an 8-
week baseline phase and two treatment phases: a 14-week double-blind treatment phase 
followed by a 52-week open label treatment phase.  A final safety assessment will be 
conducted two weeks following the end of each OL treatment phase.   
Baseline seizure activity will be determined by 8 weeks of recording in a daily seizure 
calendar.  After completing the 8-week baseline period, eligible subjects will be 
randomized to receive either ganaxolone or placebo.   
Cohort 1, Phase 1 of treatment includes a 9-week double-blind placebo-controlled 
treatment period to evaluate oral study medication as add-on therapy in adults with 
epilepsy consisting of uncontrolled partial-onset seizures (POS) with or without 
secondary generalizations. Study subjects will be randomized to one of the two study 
treatment arms: ganaxolone at 1200 mg/day (mg/d) and 1800 mg/d, or placebo. Phase 1 is 
comprised of 3 periods: Baseline (4 weeks), Titration (1 week, step titration up to 1200 
mg/d) and Maintenance (8 weeks; 4 weeks on 1200 mg/d followed by 4 weeks on 1800 
mg/d).  Subjects in Cohort 1 are to provide 4 weeks of retrospective seizure calendar data 
to be used for baseline assessment. 
Cohort 1, Phase 2 is the open-label treatment period consisting 3 periods: Transition (1 
week, step titration for placebo subjects from 900 mg/d to 1800 mg/d while ganaxolone 
subjects are maintained on their current dose), Flexible Dosing (51-week flexible dosing 
during which time the dose may be adjusted based on efficacy and tolerability 
guidelines), and De-escalation (2 weeks, at study termination). Subjects discontinued 


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during study will be de-escalated over 1-2 weeks based on dose, duration, and tolerability 
in the opinion of the investigator. 
Cohort 2, Phase 1 of treatment includes a 14-week double-blind placebo-controlled 
treatment period to evaluate oral study medication as add-on therapy in adults with 
epilepsy consisting of uncontrolled POS with or without secondary generalizations.  
Study subjects will be randomized to one of the two study treatment arms: ganaxolone at 
1800 mg/d or placebo. Phase 1 is comprised of 3 periods: Baseline (8 weeks), Titration (2 
weeks up to 1800 mg/d) and Maintenance (12 weeks on 1800 mg/d). Subjects entered 
into Cohort 2, under Protocol Amendment 2, collected 4 weeks retrospective and 4 weeks 
prospective baseline data. 
Cohort 2, Phase 2 is the open-label treatment period consisting 3 periods: Transition (2 
week, step titration for placebo subjects from 900 mg/d to 1800 mg/d while ganaxolone 
subjects are maintained on their current dose), Flexible Dosing (50-week flexible dosing 
during which time the dose may be adjusted based on efficacy and tolerability 
guidelines), and De-escalation (2 weeks, at study termination). Subjects discontinued 
during study will be de-escalated over 1-2 weeks based on dose, duration, and tolerability 
in the opinion of the investigator. 
At all dose levels ganaxolone capsules or matching placebo will be administered BID in 
divided doses. Subjects will maintain seizure calendars to record the number and type of 
seizures throughout the entire study. Subjects will also record concomitant medications 
and any errors in study medication dosing in their seizure calendars. 
A graphic representation of the design of this study is provided in Figure 1.  The 
complete list of tasks per visit is described in Section 9.5.5 Schedule of Study Procedures 
and the visit schedule may be found in Appendix 1 Schedule of Events.  
 
 
 


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Figure 1.  Cohort 1 Trial Design   
 
 
 
 
Figure 2. Cohort 2 Trial Design 
 
9.2 
Discussion of Study Design, including the Choice of Control Group 
The study is designed to investigate the efficacy, safety, and tolerability of a capsule 
formulation of ganaxolone administered as 1800 mg per day in divided (BID) doses in 


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the adult epilepsy population with drug-resistant epilepsy consisting of POS, compared to 
placebo. A secondary goal is to evaluate blood levels, efficacy and tolerability of 
ganaxolone 1200 mg/d and 1800 mg/d in a separate cohort of subjects. Completers in 
both cohorts are eligible to enter into a one year, open-label, flexible dose continuation 
phase.   
The two-cohort design permits evaluation of the relative blood levels of 1200 mg/d and 
1800 mg/d doses of ganaxolone in Cohort 1, and while Cohort 2, evaluates efficacy, 
tolerability and safety of the 1800 mg/d dose in an appropriately powered sample size for 
a 12 week duration that is consistent with regulatory standards for registration studies.   
Administration of study drug as adjunctive therapy to background AEDs permits 
comparison with placebo while maintaining the subjects on prior anticonvulsant therapy. 
 
9.3 
Selection of study population 
9.3.1 
Number of Subjects 
Approximately 525 subjects will be screened to randomize approximately 46 subjects 
into Cohort 1 and approximately 359 subjects into Cohort 2 at a 1:1 ratio of ganaxolone 
to placebo, assuming a screen-failure rate of 15%.  It is estimated that approximately 320 
subjects will complete the 14-week double-blind phase of Cohort 2, which assumes 
approximately 10% discontinuation rate. 
9.3.2 
Inclusion Criteria 
Subjects must meet all inclusion criteria to be eligible for entry in the study.  The option 
for re-screening of subjects who do not meet all criteria must be discussed with the 
Medical Monitor. 
1. Able to give informed consent in writing, or have a legally authorized 
representative able to do so (if permitted in your country/region), after being 
properly informed of the nature and risks of the study and prior to engaging in any 
study-related procedures.  
 


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2. Willing to enter and participate for the full term of 9 or 14-week double-blind 
phase and willing to enter into the open-label phase. 
 
3. Male or female outpatients >18 years of age at time of consent. 
 
4. Have a confident diagnosis of drug-resistant epilepsy with POS with or without 
secondary generalization (classified according to International League Against 
Epilepsy Guidelines [Guy, 1981] and as determined by secondary review by the 
Epilepsy Consortium) for 2 years and is having POS despite having been treated 
in the past with 2 approved anti-epilepsy drugs (AEDs) either alone or in 
combination at adequate doses for a sufficient length of time in the opinion of the 
investigator.  Diagnosis should have been established by clinical history, 
electroencephalogram (EEG) or video EEG with results consistent with partial-
onset epilepsy, and computerized tomography (CT) or magnetic resonance 
imaging (MRI) of the brain to rule out progressive structural lesions within the 
last 10 years.  For Poland, a CT or MRI of the brain to rule out progressive 
structural lesions should be performed within 2 years prior to screening visit. 
 
5. Based on documented history of POS, the investigator judges that the subject is 
likely to have 3 or more POS* during any 4-week period prior to study treatment, 
i.e., rarely falls below that threshold with usual fluctuations.  Further, the pattern 
of seizures makes it unlikely the subject will have 21 seizure-free days in any 4-
week period prior to study treatment.  
 
* POS includes complex partial seizures [CPS], and simple partial seizures [SPS] 
with motor expression. Partial seizures may be seizures secondarily generalized 
[SGTC].  Subjects who only have simple partial seizures without any observable 
motor component will NOT be eligible to participate in this study. 
 
6. Currently being treated and maintained with a stable regimen of 1, 2, or 3 AEDs 
for 1 month prior to the screening visit, without a foreseeable change in dosing 


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for the duration of the double-blind phase of the study (AEDs may be adjusted 
during the open-label phase of the study).  
a. Barbituates: If the subject is taking barbiturates (e.g., phenobarbital), the 
dose of the barbiturate must have been stable for 3 months prior to the 
screening visit. 
b. Vagus Nerve Stimulator (VNS): VNS will not be counted towards the 
number of concomitant AEDs. Subjects with surgically implanted VNS 
will be allowed to enter the study provided that all of the following 
conditions are met: 
i. The VNS has been in place for 1 year prior to the screening visit 
ii. The settings must have remained constant for 3 months prior to 
the screening visit and remain constant throughout the study 
iii. The battery is expected to last for the duration of DB Phase I (9 or 
14 weeks) of the study 
c. Benzodiazepines: The chronic use of a benzodiazepine as a concurrent 
AED is permitted as long as the dose has been stable for 1 month prior to 
the screening visit and remains constant throughout the study.  See Section 
9.4.10 for use of benzodiazepines for seizure rescue or for other 
indications. 
d. 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. 
e. 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 reactions. 
 
7. 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. 


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8. Able and willing to take drug with food twice daily. Ganaxolone must be 
administered with food. 
 
9. Sexually active women of childbearing potential (WCBP) must be using a 
medically acceptable method of birth control and have a negative qualitative 
serum -human chorionic growth hormone (-HCG) pregnancy test from a blood 
sample collected at the screening visit and negative urine pregnancy tests at 
baseline line and 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 and β-HCG will be tested per 
protocol. Birth control should be continued for a minimum of 3 days after the last 
dose of study drug. 
 
9.3.3 
Exclusion Criteria 
1. Have had previous exposure to ganaxolone.  
 
2. Known sensitivity or allergy to any component in the study drug, progesterone, or 
other related steroid compounds. 
 
3. Exposure to any investigational drug or device <30 days prior to screening, or 
plans to take another investigational drug at any time during the study. 
 
4. Time of onset of epilepsy treatment <2 years prior to enrollment 
 
5. Have generalized epilepsy, such as Lennox-Gastaut syndrome, juvenile myoclonic 


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epilepsy, absence epilepsy, or non-epileptic seizures within the last 12- month 
period prior to study entry. 
 
6. Have less than 3 POS seizures in a 28-day period or more than 21 consecutive 
seizure-free days during the 8-week baseline period. 
 
7. Have only simple partial seizures without any observable motor component. 
 
8. Have innumerable seizures or status epilepticus within the last 12-months prior to 
screening.  
 
9. Have more than 100 POS total (complex partial seizures [CPS] only + simple 
partial seizures [SPS] with motor (both types with or without secondary 
generalized tonic-clonic seizures [SGTC]) per each 4-week baseline period. 
 
10. 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. 
 
11. Current use of vigabatrin is not permitted, as well as prior use of vigabatrin 
without stable visual fields tested prior to screening.  If used during the last 12 
months two visual fields tests are required. 
 
12. Current use of ezogabine (retigabine; Potiga; Trobalt) is not permitted. Subjects 
who may have used this agent in the past should have been off this medication for 
at least 3 months prior to screening and should have had a documented normal 
fundoscopic exam by an ophthalmologist. 
 
13. Are planning surgery, or to be evaluated for surgery, during the 9 or 14-week 
double-blind phase to control seizures including those subjects who are 
considering implantation of a VNS device.  


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14. Are suffering from acute or progressive neurological disease, moderate or severe 
psychiatric disease, or severe mental abnormalities that are likely to require 
changes in pharmacotherapy during the 9 or 14-week double-blind portion of the 
study or interfere with the objectives of the study or the ability to adhere to the 
protocol requirements. 
 
15. Have active suicidal plan/intent, or have had active suicidal thoughts in the past 
6 months. 
 
16. 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). 
 
17. Have a positive urine drug screen at Screening or meet criteria for current or 
historical Substance Use Disorder (DSM-V criteria) within the past 5 years.  As 
with other AEDs, the use of alcohol is not advised.  
 
18. 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. 
 
19. 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 at 
the screening and baseline visits. 
 
20. Have a history of malignancy within the past 2 years, with the exception of basal 
cell carcinoma. 
 
21. Are currently following or planning to follow a ketogenic diet. 


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22. Use of dietary supplements or herbal preparations are not permitted if subject has 
been using them consistently for less than 6 months prior to screening, or does not 
plan on remaining on stable doses for the duration of the double-blind phase.  Use 
of St. John’s Wort is not permitted (See Section 9.4.10: Excluded, Prior, and 
Concomitant Medications). 
 
23. Females who are pregnant, currently breastfeeding or planning to become 
pregnant during the duration of the study. 
 
24. A history of chronic noncompliance with drug regimens. 
 
25.  Inability to withhold grapefruit and grapefruit juice from diet during the entire 
clinical trial (See Section 9.4.11: Excluded, Prior, and Concomitant Medications). 
 
9.3.4 
Removal of Subjects from the Study 
9.3.4.1 
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. Post-treatment QTc interval >500 msec or uncorrected QT interval >600 msec; 
for subjects with bundle 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 Baseline must also be withdrawn. 
a. If the initial electrocardiogram (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; 


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3. Subject requires the use of an unacceptable or contraindicated concomitant 
medication; 
4. Use of benzodiazepines as rescue for innumerable seizure clusters more than two 
times during 9 or 14-week DB phase, or more than once in a 28-day period must 
be discontinued;  
5. Use of benzodiazepines as rescue for innumerable seizure clusters more once in a 
28-day period during the Open-Label Phase, Investigator should consider 
discontinuation; 
6. 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; 
7. Subject is noncompliant with procedures set forth in the protocol in an ongoing or 
repeated manner; 
8. Subject experiences an adverse event (AE) that warrants withdrawal from the 
clinical investigation; 
9. It is the Investigator’s opinion that it is not in the subject’s best interest to 
continue in the study; 
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 at 
baseline. 
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 question 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 down titration of the study 
drug 


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a.    ALT or AST > 8 x ULN 
b. ALT or AST >5 x ULN for more than 2 weeks 
c. ALT or AST > 5 x ULN and total bilirubin >2 x ULN 
d. ALT or AST >3 x 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 and 
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.  
Subjects who are discontinued from the clinical investigation for any reason will not be 
replaced. 
9.3.4.2 
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 (early termination; ET), will 
be asked to complete the procedures for Visit 10 (pre-taper/ET) which include: physical 
and neurological exams, labs, ECG, pregnancy test, C-SSRS, collection of adverse events 
and seizure calendar review.  The study drug will then be continuously tapered over one 


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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. 
9.3.4.3 
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 de-escalation.   
9.4 
Treatments 
9.4.1 
Treatments Administered 
All study medication will be provided as identically appearing white/opaque gelatin 
capsules.  Study drug will be packaged in bottles.  Ganaxolone or placebo capsules will 
be administered two times daily (BID), following the morning and evening meals. No 
study-related tests or treatments, including screening, will be conducted before the 
subject has signed the ICF.   
9.4.2 
Identity of Investigational Products 
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 either 200 mg or 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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Placebo formulation is comprised of sucrose spheres of comparable size to the 
ganaxolone spray layered spheres encapsulated in a size 00 white/opaque gelatin capsule. 
The weights of placebo capsules are matched to ganaxolone capsules. 
All study medication will be labeled according to regional regulatory requirements. At 
minimum labels will contain the study number; a blinded bottle number; contents 
including quantity; dose and form; route of administration; storage conditions; 
instructions for study drug administration; caution that this compound is an investigative 
drug intended for clinical trial use only; warning to keep out of reach of children; and the 
identity of manufacturer and Sponsor. For those regions that require it, a blinded lot 
number and an expiry date will also be listed. 
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 30°C (59°F to 86°F). 
9.4.3 
Method of Assigning Subjects to Treatment Groups 
No study related tests or treatments, including screening, will be conducted until the 
subject has signed the ICF. 
Subjects will be randomized (Visit 2, Week 0, before dosing) to receive investigational 
product in an active:placebo ratio of 1:1, with stratification by country. The interactive 
web response system (IWRS) will centrally randomize subjects.  The randomization 
schedule will be generated using a standard, validated method and maintained by the 
investigational product supplier and IWRS vendor.  The Investigator will be told which 
numbered bottle to use to dose a subject by the IWRS.  The Investigator and research 
staff will be aware of the ascending dose design of the clinical investigation; however, the 
Investigator, the research staff, and the subjects will be blinded with respect to who is 
receiving active drug versus placebo.  The maximum placebo period is 9 weeks for 
Cohort 1 and 14 weeks for Cohort 2. 
The contents of each bottle will be blinded using labels.  The randomization schedule will 
match a subject number to a bottle number.  Upon completion of baseline evaluations for 
each subject, the Investigator or appropriate designee will log into the IWRS to receive a 


 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
  
 
  
   
 
 
 
  
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
  


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Both titration schedules are consistent with acceptable starting doses and MTDs from 
previous ganaxolone studies. 
Open-Label Phase:  Following the completion of the double-blind (DB) phase in either 
cohort, subjects randomized to placebo will transition to ganaxolone while subjects 
randomized to ganaxolone will stay on 1800 mg/d. Cohort 1 placebo subjects will begin 
the 1-week dose titration to 1800 mg/d after completing their Visit 5. Subjects will 
receive ganaxolone 900 mg/d in divided doses BID for 2 days and step up to 1350 mg for 
3 days and then increase to 1800 mg in divided doses BID for 2 days until their Visit 6 
(Table 1).  Titration for Cohort 2 placebo subjects will mirror the DB phase. Subjects will 
begin the 2-week dose titration to 1800 mg/d after completing their Visit 5. Subjects will 
start with 450 mg/d in divided doses BID for 3 days, 900 mg/d in divided doses BID for 3 
days, 1350 mg/d in divided doses BID for 4 days, and 1800 mg/d in divided doses BID 
for 4 days until their Visit 6 (Table 2). At Visit 6, all subjects in both cohorts will be 
evaluated for tolerability and the investigator will make the determination to maintain the 
subject on 1800 mg/d or adjust their dose. If the patient experiences any tolerability 
issues during the transition to OL, such as sedation or dizziness, changes to the titration 
schedule (e.g., conducting the titration over 3 weeks vs. 2 weeks) may be approved after 
discussion with the medical monitor. Subjects may be maintained on the MTD of 
ganaxolone that provides adequate seizure control that is not less than 900 mg/d and not 
more than 1800 mg/d.  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 
OL phase.  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 1 & 2).  The subject will return for final post-taper safety 
assessment visit. 
Details of the dosing regimen are provided in the table below.  
 
 


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Table  1. Dosing Schedule for Cohort 1 Double-blind Phase, Open-Label Phase, and 
De-Escalation Period 
Cohort 1, Phase 1- Double-blind  
Visit 
Study 
Day 
Dose (mg)/day 
200 mg cap/day 
or matching 
placebo 
225 mg cap/day 
or matching 
placebo 
Titration to 1200 mg/d 
(Visit 2) 
1 
400 
2 
0 
 
2 
400 
2 
0 
 
3 
800 
4 
0 
 
4 
800 
4 
0 
 
5 
1200 
6 
0 
 
6 
1200 
6 
0 
 
7 
1200 
6 
0 
1200 mg/d 
Maintenance (Visit 3) 
8- 35 
1200 
6 
0 
Step Titration to 1800 
mg (Visit 4) 
36 
1800 
0 
8 
1800 mg/d 
Maintenance 
 
37-63 
1800 
0 
8 
 
Cohort 1, Phase 2- Open-label 
DB Transition to Open-Label 
Visit 
 Study Day 
Dose (mg)/day 
Bottle A 225 
mg or PBO 
cap/day 
Bottle B 225 
mg or PBO 
cap/day  
GNX: 225 mg 
GNX: 225 mg 
GNX/GNX 
PBO/PBO 
PBO: 225 mg 
PBO: PBO 
Visit 5 
64  
1800 
900 
4 
4 
 
65 
1800 
900 
4 
4 
 
66 
1800 
1350 
6 
2 
 
67 
1800 
1350 
6 
2 
 
68 
1800 
1350 
6 
2 
 
69 
1800 
1800 
8 
0 
 
70 
1800 
1800 
8 
0 
 
 


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Cohort 1, Phase 2- Open-label 
All Subjects 
 
Visit 
Study Day 
Dose (mg)/day 
225 mg cap/day 
 
1800 mg/d  
Maintenance 
Visit 6 
 71 
1800 
 
8 
OL Flex 
Dosing 
Visit 6-10 
72-427 
1800 or MTD 
 
8 
Cohort 1, De-Escalation Study Completion or Early Termination 
 
Visit 
 Study Day 
Dose (mg)/day 
225 mg cap/day 
Visit10 / 
Taper Visit/ 
Last full dose 
427 
1800 
 
8 
 
428 
1350 
6 
 
429 
1350 
6 
 
430 
1350 
6 
 
431 
1350 
6 
 
432 
900 
4 
 
433 
900 
4 
 
434 
900 
4 
 
435 
900 
4 
 
436 
450 
2 
 
437 
450 
2 
 
438 
450 
2 
 
439 
450 
2 
 
440 
0 
0 
 
441 
0 
0 
 
 
 


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Table  2. Dosing Schedule for Cohort 2 Double-blind Phase, Open-Label Phase, and 
De-Escalation Period 
Cohort 2, Phase 1- Double-blind  
Visit 
Study 
Day 
Dose 
(mg)/day 
225 mg cap/day or 
matching placebo 
Titration to 1800 mg/d (Visit 2) 
1 
450 
2 
 
2 
450 
2 
 
3 
450 
2 
 
4 
900 
4 
 
5 
900 
4 
 
6 
900 
4 
 
7 
1350 
6 
 
8 
1350 
6 
 
9 
1350 
6 
 
10 
1350 
6 
 
11 
1800 
8 
 
12 
1800 
8 
 
13 
1800 
8 
 
14 
1800 
8 
1800 mg/d Maintenance (Visit 3) 
15-56 
1800 
8 
1800 mg/d Maintenance (Visit 4) 
57-98 
1800 
8 
 
Cohort 2, Phase 2- Open-Label 
DB Transition to Open-Label 
Visit 
 Study 
Day 
Dose (mg)/day 
Bottle A 225 mg or 
PBO cap/day 
Bottle B 225 mg or 
PBO cap/day  
GNX: 225 mg 
GNX: 225 mg 
GNX/GNX 
PBO/PBO 
PBO: 225 mg 
PBO: PBO 
Visit 5 
99  
1800 
450 
2 
6 
 
100 
1800 
450 
2 
6 
 
101 
1800 
450 
2 
6 
 
102 
1800 
900 
4 
4 
 
103 
1800 
900 
4 
4 
 
104 
1800 
900 
4 
4 
 
105 
1800 
1350 
6 
2 
 
106 
1800 
1350 
6 
2 
 
107 
1800 
1350 
6 
2 
 
108 
1800 
1350 
6 
2 
 
109 
1800 
1800 
8 
0 
 
110 
1800 
1800 
8 
0 
 
111 
1800 
1800 
8 
0 
 
112 
1800 
1800 
8 
0 
 
 


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Cohort 2, Phase 2- Open-Label 
All Subjects 
 
Visit 
Study Day 
Dose (mg)/day 
225 mg cap/day 
 
1800 mg/d  
Maintenance 
Visit 6 
 113 
1800 
 
8 
OL Flex 
Dosing 
Visit 6-10 
114-477 
1800 or MTD 
 
8 
Cohort 2, De-Escalation Study Completion or Early Termination 
 
Visit 
 Study Day 
Dose (mg)/day 
225 mg cap/day 
Visit10 / 
Taper Visit/ 
Last full dose 
478 
1800 
 
8 
 
479 
1350 
6 
 
480 
1350 
6 
 
481 
1350 
6 
 
482 
1350 
6 
 
483 
900 
4 
 
484 
900 
4 
 
485 
900 
4 
 
486 
900 
4 
 
487 
450 
2 
 
488 
450 
2 
 
489 
450 
2 
 
490 
450 
2 
 
491 
0 
0 
 
492 
0 
0 
 
9.4.6 
Dose Administration 
Ganaxolone will be administered BID following the morning and evening meals, i.e., 
1200 mg is dosed 600 mg am and 600 mg pm.  Doses should be taken just before or up to 
2 hours after a meal or snack, with 240 mL (8 oz) of water.  Each dose should be 
separated by a minimum of 8 hours and a maximum of 12 hours.  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 9.4.7 Missing a Dose).  


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Subjects will be informed about possible side effects from the study medication and 
cautioned to avoid quick postural changes, at least until they know how the study drug 
affects them. Subjects will be advised not to drive, operate heavy machinery, or 
participate in any potentially hazardous activity that requires full mental alertness until 
they are sure the medication is not affecting alertness. Subjects will be reminded that the 
dose of study medication could change after each study visit. They will also be cautioned 
that non-adherence to the dosing instructions (e.g., increasing the dose, taking the study 
medication doses too close together, or using alcohol) could produce side effects.   
 
Patients will be instructed to take the first dose of study drug in the morning with 
breakfast or a snack and 8 ounces of water. Subjects who are randomized at a morning 
clinic visit may take their first dose on the same day if they have a minimum of 8 hours 
until the evening dose. Subjects randomized later in the day will be instructed to take 
their first dose the following morning.   
9.4.7 
Missing a Dose 
Each dose should be separated by a minimum of 8 hours and a maximum of 12 hours. 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 dose at 7am and 7pm and forgets to take a 7pm dose at dinnertime, that dose 
may be taken up to 9pm at night (2 hours after the evening meal, more than 8 hours until 
the next 7am dose).  Alternatively, that dose could be taken until 11pm 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.  
9.4.8 
Blinding 
All study medication will be provided as identically appearing gelatin capsules.  
The contents of each bottle will be blinded using labels that contain a unique bottle 
number and a code for manufacturing lot. The randomization schedule will match a 
subject number to a bottle number. Upon completion of baseline (retrospective and 
prospective) evaluations for each subject, the Investigator or appropriate designee will 
log into the IWRS to randomize the subject to study drug assignment and receive bottle 




 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 


 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
  
 
 
  
  
 
  
 
 
 
 
 
 
  
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
   
 
 
  
 
 
 
 
  
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
   
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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hematology laboratory tests and is expected to remain constant through the double-blind 
phase of 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 and the dose cannot be 
changed during the double-blind phase of the study. 
Vagal Nerve Stimulator: Subjects receiving treatment with a VNS may be included as 
long as the VNS has been in place for at least 1 year prior to entry into the study, the VNS 
battery is not due for replacement during the double-blind phase (Cohort 1 weeks 1-9 and 
Cohort 2 weeks 1-14), and stimulation parameters have been kept constant for 3 months 
prior to screening.  VNS will not be counted as one of the 3 concomitant AEDs. 
9.4.11 
Excluded, Prior, and Concomitant Medications 
A list of medications that are inducers or inhibitors of CYP 3A4/5 and are not permitted 
during the study are in Appendix 3. This list is not exhaustive so please consult with your 
in-country Medical Monitor if you have any questions. Note that phenytoin and 
carbamazepine are permitted as background AEDs though they are moderate CYP 3A4 
inducers. Treatment with the 5--reductase inhibitor finasteride may not be initiated 
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 electronic case report form (eCRF). 
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 


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than once per 28-day period, the investigator will determine and document the benefit to 
the subject for remaining in the trial. 
Use of dietary supplements or herbal preparations are permitted if subject has been using 
them consistently for more than 6 months prior to screening, and does not plan changing 
the regimen for the duration of the double-blind phase.  Use of St. John’s Wort is not 
permitted (see Appendix 3). 
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. 
Grapefruit and grapefruit juice are strictly prohibited during the clinical trial.   
9.4.12 
Treatment Compliance 
A record of all investigational products used 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 and 
strength), the date unused investigational product and empty investigational product 
containers are returned from the subject, and the quantity returned during 
Visits 3 through 10 and final post-taper safety assessment.  Investigational product and 
associated accountability forms that are maintained at the clinical site will be present for 
review by Clinical Research 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.  Subjects that fall 
below 80% compliance at 2 consecutive visits during the double-blind phase should be 
withdrawn from the study. 


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9.5 
Efficacy and Safety Variables 
This is a 2-cohort study comprised of two phases: a double-blind, placebo-controlled 
(Phase 1) and a 52-week open-label (Phase 2). A 2-week de-escalation period prior to 
final safety assessment will be implemented at the end of study or at discontinuation. 
9.5.1 
Calculation of Baseline 
For subjects enrolled under and prior to Amendment 2, baseline will be calculated based 
upon a combination of 4 weeks of prospective recording in a daily seizure calendar 
contiguous with 4 weeks of retrospective seizure history (seizure diary) which will be 
collected after obtaining informed consent. Acceptable retrospective daily seizure data 
include a diary record of the frequency and type of seizures by day. After completing the 
4-week prospective baseline period, eligible subjects will be randomized to receive either 
ganaxolone or placebo.   
For subjects enrolled under Amendment 3, baseline will be calculated based upon the 8 
weeks prospective recording in a daily seizure calendar, which will be collected after 
obtaining informed consent. 
9.5.2 
Efficacy Assessments 
Subjects will record the type and number of seizures daily in the Subject Seizure 
Calendars that will be used for the primary analysis of efficacy.  Cohort 1 subjects will be 
required to visit the clinic at screening and on Weeks -4, 0, 1, 5, and 9 (end of double-
blind phase) and at Weeks 10, 14, 22, 42, and 61/ pre-taper during OL phase. Two 
telephone safety calls will also be conducted at Weeks 32 and 52 in Cohort 1. Cohort 2 
subjects entered under Amendment 3 of the protocol will be required to visit the clinic at 
screening and on Weeks -8, 0, 2, 8, and 14 (end of double-blind phase) and at Weeks 16, 
20, 28, 44, and 66/ pre-taper during OL phase. Four telephone safety calls will also be 
conducted in Cohort 2, two during double-blind Weeks 5 and 11 and two during OL 
Weeks 36 and 56. A final post-taper safety visit will be conducted at the end of de-
escalation phase after study completion or early termination. At each visit, study 
coordinators will review each Subject’s Seizure Calendars, classify seizure types, and 
calculate frequencies of seizures, and enter the information in the eCRF.   


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The primary outcome measure is the percentage change in seizure (POS with or without 
secondary generalization) frequency per 28 days in the Cohort 2 double-blind period 
relative to baseline. Please refer to Section 9.7 and the Statistical Analysis Plan (SAP) for 
further details regarding the statistical methods and derivation of key secondary and 
secondary end-points. Clinical Global Impression of Change – Improvement (CGI-I; 
Investigator) and  Patient Global Impression of Change – Improvement (PGI-I; Patient or 
Caregiver) will be assessed at Weeks 5 and 9 for Cohort 1 during the double-blind phase 
and at Weeks 22, 42 and 61 during the open-label phase. PGI-I and CGI-I will be 
assessed at Weeks 8 and 14 during the double-blind phase and Weeks 28, 44 and 66 
during the open-label phase for Cohort 2. Additional analyses may be considered as 
appropriate.   
 
Additional assessments may be conducted as considered appropriate. 
 
9.5.3 
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 
Columbia Suicide Severity Rating Scale (C-SSRS) 
AE monitoring:  frequency, severity, duration, causality, outcome 
 
Clinical labs, 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 eCRF. 
 
See Appendix 1 Schedule of Events for timing of Safety Assessments. 
Adverse events will be presented for these time periods for Cohorts 1 & 2: ganaxolone vs 
placebo Titration + Maintenance (Cohort 1: Weeks 1-9, Cohort 2: Weeks 1-14), 1200 


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mg/d vs placebo (Cohort 1: Weeks 2-5), and 1800 mg/d vs placebo (Cohort 2: Weeks 6-9) 
for the safety population; open-label (Cohort 1: Weeks 10-61, Cohort 2: 15-66).  In 
addition, tolerability of ganaxolone during the up-titration phases of the study will be 
compared between the two cohorts. AEs with onset during the titration phase in Cohort 2 
will be compared to AEs with onset during the weeks 1-5 in Cohort 1 (1 week titration + 
4 week treatment with 1200 mg/day). In addition, in Cohort 2, AEs with onset during the 
titration phase will be compared to AEs with onset during the maintenance phase. AEs 
that emerge during the de-escalation period will be tabulated to investigate whether 
discontinuation of ganaxolone is associated with withdrawal symptoms. Secondary safety 
outcome measures include those listed below. 
Secondary Safety 
Parameters for 
Cohorts 1 & 2 
Cohort 1 
 
Cohort 2 
Combine 
Cohorts 1 & 2  
DB 
Phase 
OL 
Phase 
DB 
Phase 
OL 
Phase 
DB 
Phase 
OL 
Phase 
Number of subjects at 
each dose 
X 
X 
X 
X 
 
X 
The frequency and 
proportion of subjects 
with AEs 
X 
X 
X 
X 
 
X 
Severity of AEs 
X 
X 
X 
X 
 
X 
AEs leading to DC 
X 
X 
X 
X 
 
X 
Incidence of subjects 
with early DC 
X 
X 
X 
X 
 
X 
Change from baseline 
in vital signs (blood 
pressure, respiration 
rate and heart rate), 
body weight and ECG 
X 
X 
X 
X 
 
X 
Change in clinical 
hematology and 
chemistry parameters 
X 
X 
X 
X 
 
X 
Assessment of 
suicidality via the 
Columbia Suicide 
Severity Rating Scale 
(C-SSRS) 
X 
X 
X 
X 
 
X 
 


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Additional assessments may be conducted as considered appropriate. 
 
9.5.4 
Other Assessments 
Blood samples will be obtained from subjects in both cohorts for pharmacokinetic 
assessment of concomitant anti-epilepsy drugs. Blood samples will be drawn at Visits 1, 
2, 3, 4, 5, 7, 8, 9 and 10. 
Blood samples for pharmacokinetic assessment of ganaxolone from both cohorts will be 
drawn at Visits 4, 5, 7, 8, 9 and 10. 
The time of the blood sample collection, and the time of the most recent dose prior to the 
blood sample collection will be recorded.  Samples of blood will be centrifuged to 
obtained plasma, which will be stored frozen (-20°C) until analysis. 
Both sets of pharmacokinetic samples will be drawn and retained for assessment on an 
as-needed basis, for example, to evaluate compliance or drug-drug interactions. 
Procedures will be put in place to ensure maintenance of the blind should analysis occur 
during double-blind treatment. For the purposes of this protocol, ganaxolone and 
concomitant AED PK assessments will not be considered as safety assessments. 
9.5.5 
Schedule of Study Procedures 
Refer to Appendix I. for tabular Schedule of Study Procedures. 
The visit window for Phase 1 Double-blind Randomization Visit 2 is +3 days, however, 
subjects must have a minimum of 28 days of prospective baseline seizure charting. Visit 
windows are ± 3 days for Phase 1 Double-blind (Visits 3-5) and Visit 6 of Phase 2 Open-
label and ± 7 days Phase 2 Open-label (Visits 7- Post taper Safety Follow up), 
respectively. 
9.5.5.1 
Visit 1 (Screening Visit) 
Written informed consent (signed informed consent form) obtained; demographics and 
medical history obtained; inclusion/exclusion criteria reviewed; seizure identification 
review and diagnostic review form submission; concomitant AEDs reviewed; physical 
and neurological examinations performed; vital signs taken; ECG performed; blood 
samples drawn for hematology, chemistry, and concomitant AED levels; urine sample 


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obtained for urinalysis and drug screen; qualitative serum pregnancy test for WCBP; 
Columbia Suicide Scale assessed; retrospective seizure diary collected and reviewed; 
subject calendar reviewed. 
9.5.5.2 
Visit 2 (Randomization; Week 0) 
Approval of seizure identification and diagnostic review form required.  
Inclusion/exclusion criteria reviewed; concomitant AEDs reviewed; physical and 
neurological follow-up examinations performed; vital signs taken; blood samples drawn 
for hematology, chemistry, and concomitant AED levels; urine sample obtained for 
urinalysis and pregnancy test for WCBP; Columbia Suicide Scale assessed; AEs 
assessed; subject calendar reviewed; randomization; study medication dispensed. 
9.5.5.3 
Visit 3 (Up-Titration; Cohort 1: Week 1; Cohort 2: Week 2) 
Concomitant AEDs reviewed; physical and neurological examinations performed; vital 
signs taken; ECG performed 2-3 hours after dosing; blood samples drawn for 
hematology, chemistry, and concomitant AED levels; urine sample obtained for urinalysis 
and pregnancy test for WCBP; Columbia Suicide Scale assessed; AEs assessed; subject 
calendar reviewed; study medication compliance assessed; study medication dispensed. 
9.5.5.4 
Telephone Follow Up (Cohort 2: Week 5) 
AEs assessed; concomitant AEDs and medications reviewed. Subject queried regarding 
any planned or unplanned changes in dose regimen. 
9.5.5.5 
Visit 4 (Evaluation; Cohort 1: Week 5; Cohort 2: Week 8) 
Concomitant AEDs reviewed; physical and neurological follow-up examinations 
performed; vital signs taken; blood samples drawn for hematology, chemistry, and study 
medication and concomitant AED levels; urine sample obtained for urinalysis and 
pregnancy test for WCBP; Columbia Suicide Scale assessed; AEs assessed; subject 
calendar reviewed; Clinician Global Impression of Improvement and Patient Global 
Impression of Improvement assessed; study medication compliance assessed; study 
medication dispensed. 


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9.5.5.6 
Telephone Follow Up (Cohort 2: Week 11) 
AEs assessed; concomitant AEDs and medications reviewed. Subject queried regarding 
any planned or unplanned changes in dose regimen. 
9.5.5.7 
Visit 5 (Final DB Evaluation; Cohort 1: Week 9; Cohort 2: Week 14) 
Concomitant AEDs reviewed; physical and neurological examinations performed; vital 
signs taken; ECG performed 2-3 hours after dosing; blood samples drawn for 
hematology, chemistry, and study medication and concomitant AED levels; urine sample 
obtained for urinalysis and pregnancy test for WCBP; Columbia Suicide Scale assessed; 
AEs assessed; subject calendar reviewed; Clinician Global Impression of Improvement 
and Patient Global Impression of Improvement assessed; study medication compliance 
assessed; study medication dispensed. 
9.5.5.8 
Visit 6 (DB Conversion; Cohort 1: Week 10; Cohort 2: Week 16) 
Concomitant AEDs reviewed; physical and neurological follow-up examinations 
performed; vital signs taken; blood samples drawn for hematology, chemistry; urine 
sample obtained for urinalysis and pregnancy test for WCBP; Columbia Suicide Scale 
assessed; AEs assessed; subject calendar reviewed; study medication compliance 
assessed; study medication dispensed. 
9.5.5.9 
Visit 7 (Cohort 1: Week 14; Cohort 2: Week 20) 
Concomitant AEDs reviewed; physical and neurological examinations performed; vital 
signs taken; ECG performed; blood samples drawn for hematology, chemistry, and study 
medication and concomitant AED levels; urine sample obtained for urinalysis and 
pregnancy test for WCBP; Columbia Suicide Scale assessed; AEs assessed; subject 
calendar reviewed; study medication compliance assessed; study medication dispensed. 
9.5.5.10 
Visit 8 (Cohort 1: Week 22; Cohort 2: Week 28) 
Concomitant AEDs reviewed; physical and neurological follow-up examinations 
performed; vital signs taken; blood samples drawn for hematology, chemistry, and study 
medication and concomitant AED levels; urine sample obtained for urinalysis and 
pregnancy test for WCBP; Columbia Suicide Scale assessed; AEs assessed; subject 
calendar reviewed; Clinician Global Impression of Improvement and Patient Global 


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Impression of Improvement assessed; study medication compliance assessed; study 
medication dispensed. 
9.5.5.11 
Telephone Follow Up (Cohort 1: Week 32; Cohort 2: Week 36) 
AEs assessed; concomitant AEDs and medications reviewed. Subject queried regarding 
any planned or unplanned changes in dose regimen. 
9.5.5.12 
Visit 9 (Cohort 1:  Week 42; Cohort 2:  Week 44) 
Concomitant AEDs reviewed; physical and neurological follow-up examinations 
performed; vital signs taken; blood samples drawn for hematology, chemistry, and study 
medication and concomitant AED levels; urine sample obtained for urinalysis and 
pregnancy test for WCBP; Columbia Suicide Scale assessed; AEs assessed; subject 
calendar reviewed; Clinician Global Impression of Improvement and Patient Global 
Impression of Improvement assessed; study medication compliance assessed; study 
medication dispensed. 
9.5.5.13 
Telephone Follow Up (Cohort 1: Week 52; Cohort 2:  Week 52) 
AEs assessed; concomitant AEDs and medications reviewed. Subject queried regarding 
any planned or unplanned changes in dose regimen. 
 
9.5.5.14 
Visit 10 Pre-Taper/ET Visit (Cohort 1: Week 61; Cohort 2: Week 66)  
Concomitant AEDs reviewed; physical and neurological examinations performed; vital 
signs taken; ECG performed; blood samples drawn for hematology, chemistry, and study 
medication and concomitant AED levels; urine sample obtained for urinalysis and 
pregnancy test for WCBP; Columbia Suicide Scale assessed; AEs assessed; subject 
calendar reviewed; Clinician Global Impression of Improvement and Patient Global 
Impression of Improvement assessed; study medication compliance assessed; study 
medication dispensed. 
9.5.5.15 
Visit 11 Post-Taper Safety Follow-up Visit (Cohort 1: Week 63; Cohort 2: 
Week 68) 
Concomitant AEDs reviewed; physical and neurological follow-up examinations 
performed; vital signs taken; urine sample obtained for pregnancy test for WCBP; 


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Columbia Suicide Scale assessed; AEs assessed; subject calendar reviewed; study 
medication compliance assessed. 
9.5.6 
Appropriateness of Measurements 
Reduction in seizure frequency is the standard measure of antiepileptic drug efficacy. 
 
9.6 
Data Quality Assurance 
Steps to be taken to assure the accuracy and reliability of 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 and 
site audits by the Sponsor or their designee.  Electronic case report forms will be 
reviewed for accuracy and completeness by the Sponsor or their designee during on-site 
monitoring visits and after their return to the Sponsor, and any discrepancies will be 
resolved with the Investigator or a designee, as appropriate.  The data will be entered into 
the clinical trial database and verified for accuracy.   
9.7 
Statistical Methods Planned and Determination of Sample Size 
 
9.7.1 
Randomization 
Subjects will be randomized to receive ganaxolone or placebo during Phase 1 in a 1:1 
ratio by the interactive web response system (IWRS) system.  Randomization for Cohort 
2 will be stratified by country. 
9.7.2 
Analysis Populations 
Three populations will be evaluated in this study.   
Modified Intent to Treat Population (mITT) 
The modified intent to treat (mITT) population (Full Analysis Population in the earlier 
version of the protocol) includes all randomized subjects who received at least 1 dose of 
study medication and provided any post baseline seizure outcome data.  The mITT 
population is the primary population for efficacy analysis.  Subjects will be analyzed 
based on their randomized treatment assignment.  
 
 


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Per Protocol Population (PP) 
The per protocol (PP) population includes all mITT subjects without major protocol 
violations during the double-blind phase. The PP population is for supportive efficacy 
analysis. Major protocol violations will be defined prior to database lock. 
Safety Population (SP) 
The safety population (SP) includes all patients who received at least one dose of study 
medication. This population is defined for safety analysis. Subjects will be analyzed 
based on the actual treatment received.  
9.7.3 
Missing Data 
Unless otherwise specified, missing data will not be imputed. All analyses will be based 
on available data. 
9.7.4 
Baseline and Demographic Characteristics 
Subject demographic data and baseline characteristics will be summarized by cohort and 
overall for the mITT population. Categorical variables will be summarized by counts and 
percentages and continuous variables by number of subjects, mean, standard deviation, 
median, minimum, and maximum. 
9.7.5 
Analysis of the Primary Efficacy Variable 
The primary efficacy measure is the percentage change in seizure (POS with or without 
secondary generalization) frequency per 28 days in the Cohort 2 double-blind period 14-
week titration + maintenance period relative to baseline in the mITT analysis. Seizure 
frequency will be based on the number of seizures per 28 days, calculated as (the number 
of seizures over the time interval multiplied by 28) and divided by the number of days in 
the interval. 
The hypothesis for percent change in seizure frequency per 28 days is: 
H0: µ1- µ2 = 0                             Ha: µ1- µ2 ≠ 0          
where µ1 and µ2 are the median percent change in seizure frequency. 
A rank analysis of covariance (ANCOVA) will be conducted on ranked percent change 
data, with treatment and country as factors and the ranked baseline seizure frequency per 


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28 days as a covariate.  The p-value based on the rank ANCOVA will be presented.  
Hodges-Lehmann estimator and its 95% confidence interval (CI) will also be calculated. 
An analysis of covariance (ANCOVA) as a sensitivity analysis will be conducted on the 
rank of percent change data from baseline, with treatment and pooled center (either US or 
ROW) as factors and the rank of baseline seizure frequency as a covariate. P-value to test 
treatment effect will be determined by permutation test with seed=123456, and 2000 
iterations. This analysis provides a robustness assessment of the results. 
The primary efficacy endpoint for European Medicines Agency registration is 50% 
responder rate during the maintenance treatment period of the DB phase for Cohort 2. A 
50% responder is an individual who experiences at least a 50% decrease in seizure 
frequency compared to baseline. This end-point is analyzed independently of the US 
registration end-point. The key-secondary end-point analysis (below) is not predicated on 
the results of this end-point.  
 
9.7.6 
Analysis of Secondary Efficacy Variables 
 
Key Secondary Endpoints: 
 
The three key secondary endpoints (below) will be tested using a fixed sequence procedure 
to protect the familywise error rate at 0.05. If the primary outcome measure is statistically 
significant, the p-values of the secondary measures will be examined in the order listed 
below. The process stops at the first p-value above 0.05.  
 Responder rate (experiencing a ≥ 50% reduction) during the titration + maintenance 
treatment periods of the DB phase for Cohort 2 
 Change in the number of seizure free days per 28-day period from baseline during 
the titration + maintenance treatment periods of the DB phase for Cohort 2  
 Clinical Global Impression of Change – Improvement (CGI-I; Investigator) at 
Week 14 of the double  blind treatment phase relative to the baseline for Cohort 2 
 


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All remaining secondary efficacy endpoints listed in the protocol will be tested at alpha 
=.05 so all p-values are nominal.    
Secondary efficacy outcome measures are listed below. 
a) Percent change in the 28-day seizure frequency from baseline to the DB phase 
during the maintenance treatment period for Cohort 2 
b) Change from baseline in 28-day seizure frequency during the DB phase for Cohort 
2 (titration + maintenance and maintenance only) 
c) Change in the number of seizure free days per 28-day period from baseline during 
the maintenance treatment period of the DB phase for Cohort 2 
d) Proportion of responders experiencing a ≥R% reduction from baseline to the end of 
treatment period in 28-day seizure frequency (titration + maintenance and 
maintenance only) for Cohort 2. R% will be 20%, 40%, 60%, and 80% 
e) Proportion of subjects who completed the DB portion of the study (Cohort 2) and 
did not experience any seizures during the maintenance phase of the study 
f) Proportion of subjects who experienced at least one 28-day seizure free period 
during the DB phase of the study (titration + maintenance) for Cohort 2  
g) Longest period of time seizure free (%) (longest period of seizure free days divided 
by number of days with available seizure data) during the double blind phase 
(titration + maintenance) for Cohort 2  
h) Change from baseline in 28-day seizure frequency for different subtypes of seizures 
during the DB portion of the study (titration + maintenance) for Cohort 2 (SPS, 
SPS-motor, CPS, SGTC)  
i) Patient Global Impression of Change – Improvement (PGI-I; Patient/Caregiver) at 
each assessment visit 
j) Clinical Global Impression of Change – Improvement (CGI-I; Investigator) at each 
assessment visit 
 
 


 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
   
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   


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9.7.7 
Analysis of Safety Variables 
Adverse events (AEs) will be tabulated by Overall, system organ class (SOC), and 
Preferred Term using the MedDRA v.16.1 coding system.  Frequency and percentage of 
subjects with adverse events will be calculated for each cohort in each phase of the study, 
by treatment and overall, and in Cohort 1 double-blind phase, by dose level 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. 
Actual values and changes from baseline for laboratory data, vital signs and ECGs will be 
summarized using descriptive statistics by visit, by treatment and overall for each cohort 
and phase separately in safety population. Shifts from baseline in low/normal/high 
classification will be summarized for each laboratory and vital sign parameter. Critically 
significant changes in laboratory and ECG values and vital signs will be flagged in data 
listings. Columbia-Suicide Severity Rating Scale data will be summarized and listed for 
each question each visit by treatment and overall, cohort and study phase for safety 
population. Pregnancy test and urine drug screen test results will be listed. 
9.7.8 
PK Analysis 
Plasma samples will be collected (Cohort 1: Weeks -4, 0, 1, 5, 9, 14, 22, 42 and 61; 
Cohort 2: Weeks -8*, 0, 2, 8, 14, 20, 28, 44 and 66) for analysis of levels of concomitant 
AEDs and if analyzed will be tabulated and reported in a separate report.  Plasma samples 
for ganaxolone levels will be collected at Weeks 5, 9, 14, 22, 42, and 61 for Cohort 1 and 
Weeks 8, 14, 20, 28, 44, and 66 for Cohort 2.  Data from these samples may be used for 
evaluation of compliance or drug-drug interactions, or a population PK analysis to be 
conducted. Results may be issued under separate analysis plans and separate reports.   
* Subjects entered in Protocol Amendment 2 or before will have the first sample collected 
at Week -4. 
9.7.9 
Determination of Sample Size 
Marinus 1042-0600 study results using a medium dose (1500mg/day oral suspension) 
showed that mean difference of percentage change in seizure frequency was -19.58%, 
with standard deviation of 54.019% and thus giving an effect size of 0.3625. Assuming 


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an effect size of 0.30 could be achieved in Cohort 2 comparing placebo to high dose 
ganaxolone (1800 mg/day capsule) in a 1:1 ratio, a sample size of 178 in each group 
provides approximately 80% power when the estimated difference is -15% and standard 
deviations are approximately 50% in each group when Wilcoxon rank sum test is used 
with the two-sided α of 0.05. 


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10. 
INVESTIGATOR REQUIREMENTS 
10.1 
Prior to Study Initiation 
The following documentation must be received by the Sponsor or their designee prior to 
initiation of the trial: 
1. Completed original Form FDA 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 and any advertising materials 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. Written documentation of IRB/EC approval of any advertising materials to be 
used for study recruitment and a copy of approved advertising materials. 
7. 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. 
8. A signed Clinical Research (Protocol) Agreement. 
9. Certified translations of IRB/EC approval letters, pertinent correspondence, and 
approved ICF (when applicable). 
10. Financial disclosure form for Principal Investigator and all sub-investigators. 
10.2 
Prior to 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 screening through the end of the study (e.g., clinical data, all 
special test results). 


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2. Information properly recorded in the eCRFs by appropriate study personnel and 
electronically 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). 
10.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating the 
study may include but are not limited to the following: 
1. 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. 
2. Subject enrollment is unsatisfactory. 
3. Data recording is inaccurate or incomplete, adversely affecting the ability to 
interpret results from the study. 
10.4 
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 (if permitted in your 
country/region) 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. 


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Signed consent forms must remain in each subject’s study file and must be available for 
verification by study monitors at any time. 
10.5 
Adverse Events 
The AE definitions and reporting procedures provided in this protocol comply with 
current CFR 21 Part 312. The Investigator will carefully monitor each subject throughout 
the study for possible adverse events.  All necessary information about an AE (onset, 
duration, severity, seriousness, causality to study drug, action taken, and outcome) should 
be documented on adverse event eCRFs (AE eCRFs) and the AEs should be followed 
until either completely resolved or until a stable chronic outcome is determined by the 
Investigator 
10.5.1 
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 


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(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 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse.  
10.5.2 
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 eCRF 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. 


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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, 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 
should be observed if the study drug is withdrawn or dose 
reduced. 
 
If discernible at the time of completing an AE eCRF, a specific disease or syndrome 
rather than individual associated signs and symptoms should be recorded on the 
AE eCRF.  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 eCRF 
(clinically significant laboratory abnormalities are those that are identified as such by the 
Investigator and/or those that require intervention). 


 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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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-study603-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-study603-Bulgaria@gctrials.com 
 
SAE reporting for Australian Sites: 
Fax SAE reports to INC Global Fax Number (24 hours; 7 days/week; 365 days; can be 
used during holiday period): 8-10-8002-8631012 
 
 


 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
  
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
  
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
  
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
  
 
  
 
 


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10.6 
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, 
eCRFs, 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.). 
10.7 
Electronic Case Report Forms 
An eCRF will be used to store and transmit subject information.  The file structure and 
format for the eCRF will be provided by the Sponsor or their representative and should 
be handled in accordance with the instructions provided.  The eCRF must be reviewed 
and electronically signed, and dated by the Investigator.   
Access to the eCRF will be strictly password protected and limited to personnel directly 
participating in the study.  Data should be entered into the eCRF completely by 
examining personnel or the study coordinator.  The eCRF must be completed as soon as 
possible after any subject evaluation or communication.  If data is to be changed due to 
erroneous input or other reason, an electronic audit trail will track these changes.  The 
eCRFs and computers that store them must be accessible to study monitors and other 
regulatory auditors. 
10.8 
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.  


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10.9 
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. 
10.10 
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 eCRFs, 
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 
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. 
10.11 
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.  Each Investigator will be responsible for enrolling only 
those subjects who have met protocol eligibility criteria. 


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11. 
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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12. 
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. 
Jacqueline AF, et al.  (2012) Adjunctive perampanel for refractory partial-onset seizures: 
Randomized phase III study 304. Neurology 79 August 7, 2012. 
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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APPENDICES 
 
12.1 
Appendix 1: Schedule of Events 
 
Cohort 1 Period 1: Double-blind Phase (Weeks -8 thru 9) 
Period/Phase 
 
Determination of Baseline and 
Eligibility 
Titration+ Maintenance 
WEEK
-8 
-4 
0 
1 
5 
9 
VISIT 
Historical 
baseline 
Screening 
visit 
V1 
Randomizat
ion  
visit 
V2 
 
Up-
titration  
V3 
 
Evaluation 
visit 
V4 
Final DB 
Evaluation 
visit 
V5 
Screening and Diagnosis 
Informed consent 
 
X 
 
 
 
 
Demographics & Medical 
 
X 
 
 
 
 
Seizure Identification & 
Diagnostic Review Form 
Approval 
 
X 
 
 
 
 
Inclusion/Exclusion criteria 
 
X 
X 
 
 
 
Concomitant AEDs1 Review 
 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
Safety Assessments 
Physical examination 
 
X 
 
X 
 
X 
Physical follow-up exam 
 
 
X 
 
X 
Vital signs 
 
X 
X 
X 
X 
X 
Neurological examination 
 
X 
 
X 
 
X 
Neurological follow-
up exam 
 
 
X 
 
X 
 
ECG 
 
X4 
 
X2 
 
X2 
Safety Labs 
 
X8 
X 
X 
X 
X8 
Urine Drug Screen 
 
X3 
 
 
 
 
Pregnancy test (WCBP) 
 
X6 
X7 
X7 
X7 
X7 
Columbia Suicide Scale 
 
X 
X 
X 
X 
X 
Review safety and record 
AEs 
 
 
X 
X 
X 
X 
Efficacy Assessments 
Retrospective Seizure Diary5 
(weeks -8 to -4) 
X 
 
 
 
 
 
Retrospective Seizure Diary  
Collection and Review 
 
X 
 
 
 
 
Subject Calendar Review 
(prospective) 
 
X 
X 
X 
X 
X 
Clinician’s Global 
Impression of Improvement 
 
 
 
 
X 
X 
Patient/Caregiver Global 
Impression of Improvement 
 
 
 
 
X 
X 
Continued on next page 
 


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Cohort 1 Period 1: Double-blind Phase (Weeks -8 thru 9) 
Period/Phase 
 
Determination of Baseline and 
Eligibility 
Titration+ Maintenance 
WEEK 
-8 
-4 
0 
1 
5 
9 
VISIT 
Historical 
baseline 
Screening 
visit 
V1 
Randomizat
ion  
visit 
V2 
 
Up-
titration  
V3 
 
Evaluation 
visit 
V4 
Final DB 
Evaluation 
visit 
V5 
PK Assessments 
Concomitant AED 
blood sample  
 
X 
X 
X 
X 
X 
Study drug blood samples 
 
 
 
 
 
X 
X 
Study Medication 
Dispense study medication 
 
 
X 
X 
X 
X 
Study medication 
compliance check 
 
 
 
X 
X 
X 
1 Concomitant AEDs or their dose must be stable for 1 month prior to historical baseline and cannot be changed at any time prior to Visit 
5, but may be adjusted during the Open-Label Phase of the study; if the subject is using VNS, the settings cannot be changed during the 
course of the study 
2 12-lead ECG at study drug Tmax, which is 2 to 3 hours after dosing. 
3 Drug Screen mandatory at Screening Visit and at Investigator’s discretion at subsequent visits 
4  ECG can be repeated at baseline, if medically necessary 
5  Retrospective Seizure Diary contains seizure information provided by the patient for Week -8 through Week-4 at time of screening, and 
reviewed following ICF. Combinations of 4-week retrospective seizure diary contiguous with 4-week prospective seizure calendar (week 
-4 through week 0) will be used to determine qualifications for study entry. 
6 Qualitative serum pregnancy test 
7 Urine pregnancy test 
8 Thyroxine and TSH will only be conducted at Screening Visit and Visit 5 
AEs = adverse events; AED = antiepileptic drug; ECG = electrocardiogram; Tmax = time to maximum concentration; WCBP = women 
 
Continued on next page 
 
 


Marinus Pharmaceuticals, Inc. 
 
 
 
 
 
Page 74 of 132 
Protocol 1042-0603 Amendment 4, V 1.0 
 
 
 
 
 
  08 April 2016 
 
CONFIDENTIAL INFORMATION 
Cohort 1 Period 2: Open-label Phase (Weeks 10-63) 
 
Period/Phase 
 
Open-label Phase 
 
De-escalation 
period 
WEEK 
10 
14 
22 
32 
42 
52 
61 
63 
VISIT 
Visit 6  
(DB  
conversion,  
Wk 1) 
Visit 7 
 
Visit 8 
 
Telephone 
Follow-up 
 
Visit 9 
 
Telephone 
Follow-up 
 
Visit 10 
(Pre-
taper/ ET) 
Post-Taper 
Safety Follow 
up 
 
Screening and Diagnosis 
Informed consent 
 
 
 
 
 
 
 
 
Demographics & Medical HX 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
 
 
 
 
 
 
 
 
Concomitant AEDs1 
X 
X 
X 
 
X 
 
X 
X 
Randomization 
 
 
 
 
 
 
 
 
Safety Assessments 
Physical examination 
 
X 
 
 
 
 
X 
 
Physical follow-up exam 
X 
 
X 
 
X 
 
 
X 
Vital signs 
X 
X 
X 
 
X 
 
X 
X 
Neurological examination 
 
X 
 
 
 
 
X 
 
    Neurological brief exam 
X 
 
X 
 
X 
 
 
X 
ECG 
 
X 
 
 
 
 
X 
 
Safety Labs 
X 
X 
X 
 
X 
 
X 
 
Urine pregnancy test (WCBP) 
X 
X 
X 
 
X 
 
X 
X 
Columbia Suicide Scale 
X 
X 
X 
 
X 
 
X 
X 
Review safety and record AEs 
X 
X 
X 
 
X 
 
X 
X 
Telephone Follow Up 
 
 
 
X2 
 
X2 
 
 
Efficacy Assessments 
Subject Calendar Review (prospective) 
X 
X 
X 
 
X 
 
X 
X 
Clinician’s Global Impression of 
Improvement 
 
 
X 
 
X 
 
X 
 
Patient/Caregiver Global Impression of 
Improvement 
 
 
X 
 
X 
 
X 
 


Marinus Pharmaceuticals, Inc. 
 
 
 
 
 
Page 75 of 132 
Protocol 1042-0603 Amendment 4, V 1.0 
 
 
 
 
 
  08 April 2016 
 
CONFIDENTIAL INFORMATION 
Cohort 1 Period 2: Open-label Phase (Weeks 10-63) 
 
Period/Phase 
 
Open-label Phase 
 
De-escalation 
period 
WEEK 
10 
14 
22 
32 
42 
52 
61 
63 
VISIT 
Visit 6  
(DB  
conversion,  
Wk 1) 
Visit 7 
 
Visit 8 
 
Telephone 
Follow-up 
 
Visit 9 
 
Telephone 
Follow-up 
 
Visit 10 
(Pre-
taper/ ET) 
Post-Taper 
Safety Follow 
up 
 
PK Assessments 
Concomitant AED blood sample1  
 
X 
X 
 
X 
 
X 
 
Study drug blood samples 
 
 
X 
X 
 
X 
 
X 
 
Study Medication 
Dispense study medication 
X 
X 
X 
 
X 
 
X 
 
Study med compliance check 
X 
X 
X 
 
X 
 
X 
X 
1 Concomitant AEDs or their dose must be stable for 1 month prior to screening and cannot be changed at any time prior to Visit 5, but may be adjusted during the Open-Label Phase of the study; if 
the subject is using VNS, the settings cannot be changed during the course of the study. 
2 Review safety and record AEs. Review and record changes to concomitant AEDs & medications  
 


Marinus Pharmaceuticals, Inc. 
 
 
 
 
 
Page 76 of 132 
Protocol 1042-0603 Amendment 4, V 1.0 
 
 
 
 
                08 April 2016 
 
CONFIDENTIAL INFORMATION 
Cohort 2 Period 1: Double-blind Phase (Weeks -8 thru 14) 
Period/Phase 
 
Determination of Baseline* and 
Eligibility 
Titration+ Maintenance 
WEEK 
-8 
0 
2 
5 
8 
11 
14 
VISIT 
 
Screening 
 
 
V1 
 
Randomiza-
tion 
 
V2 
 
Up-titration 
 
 
V3 
Telephone 
Follow up 
 
Evaluation  
 
V4 
Telephone 
Follow up 
 
Final DB 
Evaluation  
 
V5 
Screening and Diagnosis  
Informed consent 
X 
 
 
 
 
 
 
Demographics & Medical HX 
X 
 
 
 
 
 
 
Seizure Identification & Diagnostic 
Review Form Approval 
X 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
Concomitant AEDs1 Review 
X 
X 
X 
 
X 
 
X 
Randomization 
 
X 
 
 
 
 
 
Safety Assessments 
Physical examination 
X 
 
X 
 
 
 
X 
Physical follow-up exam 
 
X 
 
X 
Vital signs 
X 
X 
X 
X 
X 
Neurological examination 
X 
 
X 
 
X 
Neurological follow-up exam 
 
X 
 
X 
 
ECG 
X4 
 
X2 
 
X2 
Safety Labs 
X8 
X 
X 
X 
X8 
Urine Drug Screen 
X3 
 
 
 
 
Pregnancy test (WCBP) 
X6 
X7 
X7 
X7 
X7 
Columbia Suicide Scale 
X 
X 
X 
X 
X 
Review safety and record AEs 
 
X 
X 
X 
X 
Telephone Follow Up 
 
 
 
X9 
 
X9 
 
* Subjects who entered into Cohort 2 under Protocol Amendment 2 and prior attended the Screening Visit at Week -4. 


Marinus Pharmaceuticals, Inc. 
 
 
 
 
 
Page 77 of 132 
Protocol 1042-0603 Amendment 4, V 1.0 
 
 
 
 
                08 April 2016 
 
CONFIDENTIAL INFORMATION 
Cohort 2 Period 1: Double-blind Phase (Weeks -8 thru 14) 
Period/Phase 
Determination of Baseline and 
Eligibility 
Titration+ Maintenance 
WEEK 
-8 
0 
2 
5 
8 
11 
14 
 
 
 
 
VISIT 
 
 
 
Screening 
V1 
 
Randomiza-
tion 
 
V2 
 
Up-titration 
V3 
 
 
Telephone 
Follow up 
 
Evaluation 
V4 
 
Telephone 
Follow up 
 
Final DB 
Evaluation  
V5 
 
Efficacy Assessments 
Subject Calendar Review (prospective)5 
X 
X 
X 
 
X 
 
X 
Clinician’s Global Impression of 
Improvement 
 
 
 
 
X 
 
X 
Patient/Caregiver Global 
Impression of Improvement 
 
 
 
 
X 
 
X 
PK Assessments 
Concomitant AED blood sample 
X 
X 
X 
 
X 
 
X 
Study drug blood samples 
 
 
 
 
X 
 
X 
Study Medication 
Dispense study medication 
 
X 
X 
 
X 
 
X 
Study medication compliance check 
 
 
X 
 
X 
 
X 
1 Concomitant AEDs or their dose must be stable for 1 month prior to Screening and cannot be changed at any time prior to Visit 5, but may be adjusted during the Open-Label Phase of the study; 
if the subject is using VNS, the settings cannot be changed during the course of the study 
2 12-lead ECG at study drug Tmax, which is 2 to 3 hours after dosing. 
3 Drug Screen mandatory at Screening Visit and at Investigator’s discretion at subsequent visits 
4  ECG can be repeated at baseline, if medically necessary 
5  Prospective 8 week seizure calendar will be used to determine qualifications for study entry. 
6 Qualitative serum pregnancy test 
7 Urine pregnancy test 
8 Thyroxine and TSH will only be conducted at Screening Visit and Visit 5 
9Review safety and record AEs. Review and record changes to concomitant AEDs & medications 
AEs = adverse events; AED = antiepileptic drug; ECG = electrocardiogram; Tmax = time to maximum concentration; WCBP = women 


Marinus Pharmaceuticals, Inc. 
 
 
 
 
 
Page 78 of 132 
Protocol 1042-0603 Amendment 4, V 1.0 
 
 
 
                              08 April 2016 
 
 
 
CONFIDENTIAL INFORMATION 
Cohort 2 Period 2: Open-label Phase (Weeks 16-68) 
 
Period/Phase 
 
Open-label Phase 
 
De-escalation 
period 
WEEK 
16 
20 
28 
36 
44 
56 
66 
68 
VISIT 
Visit 6  
(DB  
conversion,  
Wk 2) 
Visit 7 
 
Visit 8 
 
Telephon
e 
Follow-up 
 
Visit 9 
 
Telephone 
Follow-up 
 
Visit 10  
(Pre-
Taper/ 
ET) 
Post-Taper 
Safety Follow 
up 
 
Screening and Diagnosis 
Informed consent 
 
 
 
 
 
 
 
 
Demographics & Medical HX 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
 
 
 
 
 
 
 
 
Concomitant AEDs1 
X 
X 
X 
 
X 
 
X 
X 
Randomization 
 
 
 
 
 
 
 
 
Safety Assessments 
Physical examination 
 
X 
 
 
 
 
X 
 
Physical follow-up exam 
X 
 
X 
 
X 
 
 
X 
Vital signs 
X 
X 
X 
 
X 
 
X 
X 
Neurological examination 
 
X 
 
 
 
 
X 
 
    Neurological brief exam 
X 
 
X 
 
X 
 
 
X 
ECG 
 
X 
 
 
 
 
X 
 
Safety Labs 
X 
X 
X 
 
X 
 
X 
 
Urine pregnancy test (WCBP) 
X 
X 
X 
 
X 
 
X 
X 
Columbia Suicide Scale 
X 
X 
X 
 
X 
 
X 
X 
Review safety and record AEs 
X 
X 
X 
 
X 
 
X 
X 
Telephone Follow Up 
 
 
 
X2 
 
X2 
 
 
Efficacy Assessments 
Subject Calendar Review (prospective) 
X 
X 
X 
 
X 
 
X 
X 
Clinician’s Global Impression of 
Improvement 
 
 
X 
 
X 
 
X 
 
Patient/Caregiver Global Impression of 
Improvement 
 
 
X 
 
X 
 
X 
 


Marinus Pharmaceuticals, Inc. 
 
 
 
 
 
Page 79 of 132 
Protocol 1042-0603 Amendment 4, V 1.0 
 
 
 
                              08 April 2016 
 
 
 
CONFIDENTIAL INFORMATION 
Cohort 2 Period 2: Open-label Phase (Weeks 16-68) 
 
Period/Phase 
 
Open-label Phase 
 
De-escalation 
period 
WEEK 
16 
20 
28 
36 
44 
56 
66 
68 
VISIT 
Visit 6  
(DB  
conversion,  
Wk 2) 
Visit 7 
 
Visit 8 
 
Telephon
e 
Follow-up 
 
Visit 9 
 
Telephone 
Follow-up 
 
Visit 10  
(Pre-
Taper/ 
ET) 
Post-Taper 
Safety Follow 
up 
 
PK Assessments 
Concomitant AED blood sample1  
 
X 
X 
 
X 
 
X 
 
Study drug blood samples 
 
 
X 
X 
 
X 
 
X 
 
Study Medication 
Dispense study medication 
X 
X 
X 
 
X 
 
X 
 
Study med compliance check 
X 
X 
X 
 
X 
 
X 
X 
1 Concomitant AEDs or their dose must be stable for 1 month prior to screening and cannot be changed at any time prior to Visit 5, but may be adjusted during the Open-Label Phase of the study; 
if the subject is using VNS, the settings cannot be changed during the course of the study. 
2 Review safety and record AEs. Review and record changes to concomitant AEDs & medications  
 


Marinus Pharmaceuticals, Inc. 
 
Page 80 of 132 
Protocol 1042-0603 Amendment 4, V 1.0 
 
08 April 2016  
 
CONFIDENTIAL INFORMATION 
12.2 
Appendix 2: 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 
 
Drug screen* 
CO2 
 
 
Total Protein 
 
 
Serum Albumin 
 
 
Thyroxine 
 
 
Thyroid Stimulating 
Hormone 
 
 
 
 
 
Qualitative serum -human 
chorionic growth hormone 
(-HCG) pregnancy 
 
 
 
ALT = alanine transferase; AST = aspartate transferase; BUN = blood urea nitrogen 
* At Screening and as needed at the Investigator’s discretion; includes phencyclidine, 
opiates, THC, methamphetamines/amphetamine, cocaine and oxycodone. 
 


Marinus Pharmaceuticals, Inc. 
 
Page 81 of 132 
Protocol 1042-0603 Amendment 4, V 1.0 
 
08 April 2016  
 
CONFIDENTIAL INFORMATION 
12.3 
Appendix 3: 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  
diltiazem 
erythromycin 
fluconazole  
fluvoxamine 
fosamprenavir 
grapefruit juice 
imatinib 
indinavir 
itraconazole 
ketoconazole 
mibefradil (not sold in US, 
Russia) 
nefazodone (not sold in US, 
Russia) 
nelfinavir 
posaconazole  
ritonavir 
saquinavir 
telaprevir  
telithromycin 
troleandomycin (not sold in US, 
Russia) 
verapamil 
voriconazole 
avasimibe  
bosentan 
efavirenz 
etravirine 
modafinil 
nafcillin 
rifabutin 
rifampin 
St. John's wort 
troglitazone (not sold in US, Russia) 
 
*Carbamazepine and phenytoin are both 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/DrugInteractio
nsLabeling/ucm080499.htm and http://medicine.iupui.edu/clinpharm/ddis/ClinicalTable.aspx; 
accessed 12June13 
 


Marinus Pharmaceuticals, Inc. 
 
Page 82 of 132 
Protocol 1042-0603 Amendment 4, V 1.0                                                                                 08 April 2016        
 
 
 
CONFIDENTIAL INFORMATION 
12.4 
Appendix 4: Titration Dosing Instructions for Subjects 
Translations in Bulgarian, German and Polish are available upon request. 
 
 


Marinus Pharmaceuticals, Inc. 
 
Page 83 of 132 
Protocol 1042-0603 Amendment 4, V 1.0                                                                                 08 April 2016        
 
 
 
CONFIDENTIAL INFORMATION 
 
M arinu sPharm aceu ticals,Inc

Dosing Instru ctionsv1.0 
Protocol10 42-0 60 3

18Ju ly13


P age1of2

GAN AXO L O N EIN ADU L TPARTIAL O N SETSEIZU RESTU DY
SU BJECTDO SIN GIN STRU CTIO N S


N am e:________________________________________________________

N extA ppoin tm en t:_______________________________________________

Th eseareyourdosin gin struction sforth en ext________w eek s/m on th spleasecircleon e)from 
____/_____/_____startdate)to____/_____/_____en ddate).D epen din gon w h ich ph aseyou
arein th estudy,youm aybegraduallyin creasin gtitration ),m ain tain in gth esam eam oun t
m ain ten an ce)orgraduallydecreasin gth eam oun tofstudydrugde-escalation )durin gth istim e.Th e
ch artbelow liststh edayorw eek ,dose,an dh ow m an ycapsulesyoush ouldtak eforeach dose.Please
tak eeach doseju stbeforeorupto2h ou rsafteram ealorsn ack w ith 8oun ces240m l)ofw ater.
Grapefru itan dgrapefru itju icearen otallow edatan ytim edu rin gyourparticipation in th isclin ical
trial.Each dosesh ouldbeseparatedbyam in im um of8h oursan dam axim um of12h ours.A m issed
doseofstudym edication m aybetak en upto8h oursbeforeth en extsch eduleddose;oth erw ise,th e
dosesh ouldn otbetak en .P leasek eeptrack ofth edaysyoum issedadosean dcon tactth estudy
coordin atorifyoum iss4dosesin arow orm ore.P leasesaveallem pty,partiallyusedan dun used
bottlesofth estudydrugan dreturn th ebottlesatyourn extvisit.
Example 1: 
 
Dose Titration / Dose Maintenance / Dose De-Escalation (Please circle phase) 

Day/ W eek _________       Date___/ ___/ ___
Dosem g)
N u m berofcapsu lestotak e
atEACH DO SExTW ICE/ DAY
D ay1;9/23/13
400
1
D ay2;9/24/13
400
1
D ay3;9/25/13
800
2
D ay4;9/30/13
800m g
2

Example 2: 
 
Dose Titration / Dose Maintenance / Dose De-Escalation (Please circle phase) 

Day/ W eek _________       Date___/ ___/ ___
Dosem g)
N u m berofcapsu lestotak e
atEACH DO SExTW ICE/ DAY
W eek 2-5;9/30/13to10/28/13
1200m g
3
 


Marinus Pharmaceuticals, Inc. 
 
Page 84 of 132 
Protocol 1042-0603 Amendment 4, V 1.0                                                                                 08 April 2016        
 
 
 
CONFIDENTIAL INFORMATION 
M arinu sPharm aceu ticals,Inc

Dosing Instru ctionsv1.0 
Protocol10 42-0 60 3

18Ju ly13


P age2of2

 

Dose Titration / Dose Maintenance / Dose De-Escalation (Please circle phase) 

Day/ W eek _________       Date___/ ___/ ___
Dosem g)
N u m berofcapsu lestotak e
atEACH DO SExTW ICE/ DAY

















































D urin gth efirst9w eek softh estudy,youw illn otk n ow ifyouaretak in gstu dydrugw ith th eactive
in gredien t-gan axolon eorth estudydrugw ith outth ein gredien t-placebo.Som epeoplem ayreport
feelin gdizzy,tired,orsleepyaftertak in ggan axolon e.Th esesideeffectsusuallygoaw ayafter2-3days.
Ifyouexperien cean ysideeffectsfrom th estudym edication th atin terferew ith yourdailyactivitiesor
h avean yquestion s,pleasecon tactyourstudydoctoratth eteleph on en um berbelow toseeifadose
adjustm en tisn ecessary.

StudyD octor:________________________________________________________

Teleph on eN um ber:__________________________________________________


Marinus Pharmaceuticals, Inc. 
 
 
 
 
 
Page 87 of 132 
Protocol 1042-0603 Amendment 4, V 1.0 
                                            
 
 
 
                08 April 2016  
 
CONFIDENTIAL INFORMATION 
12.5 
Appendix 5:  Subject Seizure Calendar 
Translations in Bulgarian, German and Polish are available upon request. 
 




Marinus Pharmaceuticals, Inc. 
 
 
 
 
 
Page 89 of 132 
Protocol 1042-0603 Amendment 4, V 1.0 
                                            
 
 
 
                08 April 2016  
 
CONFIDENTIAL INFORMATION 
 


Marinus Pharmaceuticals, Inc. 
 
 
 
 
 
Page 90 of 132 
Protocol 1042-0603 Amendment 4, V 1.0 
                                            
 
 
 
                08 April 2016  
 
CONFIDENTIAL INFORMATION 
 


Marinus Pharmaceuticals, Inc. 
 
 
 
 
 
Page 91 of 132 
Protocol 1042-0603 Amendment 4, V 1.0 
                                            
 
 
 
                08 April 2016  
 
CONFIDENTIAL INFORMATION 
 
Sunday
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
__ __ / __ __ __
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
¨  No Seizures
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Study Drug Taken? ¨Y ¨N 
Non-Study AEDs Taken? ¨Y ¨N
Date: 
 
 
Description of illness, injury, side effect, or missed doses 
 
 
 
 
 
 
Any action taken including medication
Subject ID: __ __ __ __ __ __  Subject Initials: __ __ __ 
 
 
Month: __ __ __  
Year: __ __ __ __
Marinus Pharmaceuticals, Inc 
 
 
 
Protocol 1042-0603 Seizure Calendar v24Jul2013 USA  
 
 
 
 
Page 4


Marinus Pharmaceuticals, Inc. 
 
Page 96 of 132 
Protocol 1042-0603 Amendment 4, V 1.0 
                                            
08 April 2016 
 
CONFIDENTIAL INFORMATION 
12.6 
Appendix 6: Clinical Global Impression- Improvement (Patient/Caregiver) 
Translations in Bulgarian, German, and Polish are available upon request. 


Marinus Pharmaceuticals, Inc. 
 
Page 97 of 132 
Protocol 1042-0603 Amendment 4, V 1.0 
                                            
08 April 2016 
 
CONFIDENTIAL INFORMATION 
 
 
 

ParticipantID:
Visit :
VisitDate:
Check iftheassessm entw asnotcom pleted:

Protocol10 42-0 60 3v.26Ju l13
C linicalGlobalIm pression–Im provem entC GI-I)S u bject

Circletheappropriateresponsethatadequ atelydescribeshow you rsym ptom shave
im provedorw orsenedrelativetobaselinebeforethebeg inning ofthestu dy(before
thedou ble-blindportionofthestu dy).

1= verym u chim proved 
2= m u chim proved
3= m inim allyim proved
4= nochang e
5= m inim allyw orse
6= m u chw orse
7= verym u chw orse




Marinus Pharmaceuticals, Inc. 
 
Page 99 of 132 
Protocol 1042-0603 Amendment 4, V 1.0 
 
08 April 2016 
 
CONFIDENTIAL INFORMATION 
12.7 
Appendix 7: Columbia Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screen 
Baseline version (1/14/09) 
To be used at Screen and Baseline Visits 
 
Translations in Bulgarian, German and Polish are available upon request. 
 
 
 
 


Marinus Pharmaceuticals, Inc. 
 
Page 100 of 132 
Protocol 1042-0603 Amendment 4, V 1.0 
 
08 April 2016 
 
CONFIDENTIAL INFORMATION 
 
 
 
 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Baseline 
Version 1/14/09 
 
 Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@childpsych.columbia.edu  
© 2008 The Research Foundation for Mental Hygiene, Inc.  


 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
    
 
 
 
 
 
 
 
  
 
  
   
 
 
 
  
    
 
  
  
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
  
 
 
 
  
  
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
       
 
      
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
      
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
      
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
       
 
      
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
      
 
      
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
                                             
 
 
         
                                                   
                      
 
                                                                                                           
  
                                         
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
    
 
  
   
  
 
  
    
 
  
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
                                                 
 
 
  
 
 
 
  
  
 
                                                 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
                                                      
 
 
 
 
  
 
 
 
 
 
 
 
 
 
                                     
 
  
 
 
 
 
 
 
 
 
                                    
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
            
 
 
 
 
 
 
 
  
 
 
 
 
                                                    
 
 
 
 
 
 
  
 
 
 
 
 
                                             
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
  
 
 
   
 
 
       
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
                     
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
               
 
  
 
 
 
 
 
 
 
 
  
       
  
 
 
                                                                        
 
 
 
   
 
 
 
 
                                                                                                                 
  
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
  
 
  
  
 
 
  
 
 
  
  
 
 
 
 
 
  
 
   
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
   
 
 
  
 
 
 
 
 
  
 
 
   
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
  
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
       
    
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
    
 
    
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
  
   
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       
    
 
 
   
 
 
 
 
 
   
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       
    
 
   
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
       
    
 
 
 
 
 
 
 
 
 
 
       
    
 
 
 
 
 
 
  
 
 
 
         
 
 
  
 
 
 
 
   
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
  
  
 
 
 
  
 
 
  
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Marinus Pharmaceuticals, Inc. 
 
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08 April 2016 
 
CONFIDENTIAL INFORMATION 
Appendix 7 Continued: Columbia Suicide Severity Rating Scale (C-SSRS)-Since 
Last Visit 
Since Last Visit version (1/14/09) 
To be used at visits post Baseline/Randomization 
Translations in Bulgarian, German and Polish are available upon request. 
 
 


Marinus Pharmaceuticals, Inc. 
 
Page 107 of 132 
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08 April 2016 
 
CONFIDENTIAL INFORMATION 
 
 
 
 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
© 2008 The Research Foundation for Mental Hygiene, Inc. 


Marinus Pharmaceuticals, Inc. 
 
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08 April 2016 
 
CONFIDENTIAL INFORMATION 
 
SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”, 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
 
Since Last 
Visit 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up   
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e g , “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan during the assessment period   
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period  This is different than a specific plan with time, 
place or method details worked out (e g , thought of method to kill self but not a specific plan)   Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 
 Yes      No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out  
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
If yes, describe: 
 
 
 Yes      No 
 □    □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe 
and 5 being the most severe).  
                                             
Most Severe Ideation:             _____                      _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time                                                                    
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention, 
revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain                                                                         living with the pain or  how you were feeling) 
                                                                                                                 (0)  Does not apply 
 
 
 
 
____ 
Version 1/14/09 


Marinus Pharmaceuticals, Inc. 
 
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08 April 2016 
 
CONFIDENTIAL INFORMATION 
 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
Visit 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself  Intent 
does not have to be 100%   If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt  There does not 
have to be any injury or harm, just the potential for injury or harm  If person pulls trigger while gun is in mouth but gun is broken so no injury results, 
this is considered an attempt    
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances  For example, a highly 
lethal act that is clearly not an accident so no other intent but suicide can be inferred (e g , gunshot to head, jumping from window of a high floor/story)  
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred   
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get 
sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred). 
Overdose: Person has pills in hand but is stopped from ingesting   Once they ingest any pills, this becomes an attempt rather than an interrupted attempt  
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger  Once they pull the trigger, 
even if the gun fails to fire, it is an attempt  Jumping: Person is poised to jump, is grabbed and taken down from ledge  Hanging: Person has noose around 
neck but has not yet started to hang - is stopped from doing so  
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
interrupted 
 
 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior  
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else  
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
 
 
Yes      No 
□   □ 
 
Total # of 
aborted 
 
 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt  This can include anything beyond a verbalization or thought, such as assembling a 
specific method (e g , buying pills, purchasing a gun) or preparing for one’s death by suicide (e g , giving things away, writing a suicide note)   
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes      No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Suicide: 
   Yes    No 
□   □ 
Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0   No physical damage or very minor physical damage (e g , surface scratches)  
1   Minor physical damage (e g , lethargic speech; first-degree burns; mild bleeding; sprains)  
2   Moderate physical damage; medical attention needed (e g , conscious but sleepy, somewhat responsive; second-degree burns; bleeding of major vessel)  
3   Moderately severe physical damage; medical hospitalization and likely intensive care required (e g , comatose with reflexes intact; third-degree burns 
less than 20% of body; extensive blood loss but can recover; major fractures)  
4   Severe physical damage; medical hospitalization with intensive care required (e g , comatose without reflexes; third-degree burns over 20% of body; 
extensive blood loss with unstable vital signs; major damage to a vital area)  
5   Death 
 
Enter Code 
 
 
 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious 
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away 
before run over)  
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter Code 
 
 
 
______ 
 




Marinus Pharmaceuticals, Inc. 
 
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CONFIDENTIAL INFORMATION 
evaluation of seizure frequency, 
response rate and seizure-free 
rate by dose in double-blind 
phase, and in open-label phase.  
See Section 9.5.2. 
factors and the rank baseline seizure 
frequency per 28 days as a covariate. 
The primary efficacy endpoint for 
European registration is 50% responder 
rate during the maintenance treatment 
phase of the double-blind phase for 
Cohort 2. A 50% responder is an 
individual who experiences at least a 50% 
decrease in seizure frequency compared to 
baseline. 
Key secondary end-points: 
The three key secondary endpoints will be 
tested using a fixed sequence procedure to 
protect the familywise error rate at 0.05. If 
the primary outcome measure is 
statistically significant, the p-values of the 
secondary measures will be examined in 
the order listed below. The process stops 
at the first p-value above 0.05.  
 Responder rate (experiencing a ≥ 50% 
reduction) during the titration + 
maintenance treatment periods of the 
DB phase for Cohort 2 
 
Change in the number of seizure free days 
per 28-day period from baseline during the 
titration + maintenance treatment periods 
of the DB phase for Cohort 2  
 
Clinical Global Impression of Change – 
Improvement (CGI-I; Investigator) at 
Week 14 of the double  blind treatment 
phase relative to the baseline for Cohort 2 
All 
remaining 
secondary 
efficacy 
endpoints listed in the protocol will be 
tested at alpha =.05 so all p-values are 
nominal.    
Secondary efficacy outcome measures are 
listed below. 
k) Percent change in the 28-day seizure 
frequency from baseline to the DB phase 
during the maintenance treatment period 
for Cohort 2 
l) Change from baseline in 28-day 
seizure frequency during the DB phase 
for Cohort 2 (titration + maintenance 
and maintenance only). 
m) Change in the number of seizure free days 
per 28-day period from baseline during the 


 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
  
 
 
  
 
 
 
 
 
  
 
 


Marinus Pharmaceuticals, Inc. 
 
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CONFIDENTIAL INFORMATION 
h) Ganaxolone Maintenance 1200 mg/day + 
Maintenance 1800 mg/day vs Placebo 
(Cohort 1: Weeks 2-9). 
i) Ganaxolone Titration + Maintenance 
1200 mg/d vs placebo (Cohort 1: Weeks 
1-5). 
j) Ganaxolone Maintenance 1800 mg/d 
vs placebo (Cohort 1: Weeks 6-9). 
k)  Ganaxolone Maintenance 1200 mg/d 
vs placebo (Cohort 1: Weeks 2-5) 
l) OL (Cohort 1: Weeks 10-61; Cohort 2: 
Weeks 16-66) 
6 
Synopsis – 
Safety 
 
Added:  Columbia Suicide Severity Scale 
(C-SSRS) 
6 
Synopsis-
Statistical 
Methods 
The primary endpoint analysis 
will consist of analysis of 
covariance (ANCOVA) 
conducted on the log-transformed 
percent change data, with 
treatment and pooled countries as 
factors and the logged baseline 
seizure frequency per 28 days as 
a covariate.  
All secondary efficacy variables 
will be summarized using 
descriptive statistics. The 
responder rates and seizure-free 
rates between ganaxolone and 
placebo will be compared using a 
Cochran-Mantel-Haenszel 
analysis.  Mean monthly seizure 
frequency for each week after 
dosing will be analyzed in a 
manner similar to the primary 
endpoint analysis. Change and 
percent change of mean monthly 
seizure frequencies will be 
analyzed by Kruskal-Wallis test. 
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 will be for each 
phase of the study, and in Phase 1, 
by dose level and overall.  
The primary endpoint analysis will consist 
of rank analysis of covariance 
(ANCOVA) conducted on the percent 
change data, with treatment and pooled 
countries as factors and the rank baseline 
seizure frequency per 28 days as a 
covariate.  
Added: The responder rates and seizure-
free rates between ganaxolone and 
placebo will be compared using a logistic 
regression analysis.  To take into account 
the ordinal nature of the response to 
Clinical Global Impression of Change and 
Patient Global Impression of Change 
scales (CGI-I, PGI-I), the Row Mean 
Score Difference, and the p-value based 
on Cochran-Mantel-Haenszel test 
adjusting for pooled center (either US or 
ROW), will be used to test if there is a 
treatment effect.  
Adverse events (AEs) will be tabulated by 
Overall, system organ class (SOC), and 
Preferred Term using the MedDRA v.16.1 
coding system.  Frequency and percentage 
of subjects with adverse events will be 
calculated for each cohort in each phase 
of the study, by treatment and overall, and 
in Cohort 1 double-blind phase, by dose 
level and overall.  


Marinus Pharmaceuticals, Inc. 
 
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CONFIDENTIAL INFORMATION 
Reason for Change: The sample size calculations for this study were based on results from one previous study. 
After analysis of blinded data, including the rate of discontinuations from this study, it was determined that 
additional patients may be needed to ensure an appropriate sample size. 
19 
9.1 Overall 
Study Design 
and Plan, 
Paragraph 1, 
Line 1, 5 & 8 
This is a 2-cohort study with each 
cohort comprised of 2 treatment 
phases in each cohort. 
 
Cohort 1 (N=approximately 50)… 
 
Cohort 2 (N=292) will enroll into a 
76-week study comprising an 8-
week baseline phase and two 
treatment phases: a 14-week double-
blind treatment phase followed by a 
52-week open label treatment phase.   
This is a 2-cohort study with each cohort 
comprised of 2 treatment phases. 
 
 
Cohort 1 (N=approximately 46)… 
 
Cohort 2 (N=359) will enroll into a 76-week 
study comprising an 8-week baseline phase 
and two treatment phases: a 14-week double-
blind treatment phase followed by a 52-week 
open label treatment phase.   
19 
9.1 Overall 
Study Design 
and Plan, 
Paragraph 8, 
Line 2 
The complete list of tasks per 
visit is described in Section 
9.5.1.5…  
The complete list of tasks per visit is 
described in Section 9.5.5… 
Reason for Change: Clarification of the CSP section location for Schedule of Study Procedures 
21 
Figure 1. Cohort 
1 Trial Design 
WK 46 – Visit 9 
WK 42 – Visit 9 
22 
9.3.1 Number of 
Subjects 
Approximately 400 subjects will 
be screened to randomize 
approximately 50 subjects into 
Cohort 1 and approximately 292 
subjects into Cohort 2 at a 1:1 
ratio of ganaxolone to placebo, 
assuming a screen-failure rate of 
15%.  It is estimated that 
approximately 263 subjects will 
complete the 14-week Double-
Blind Phase of Cohort 2, which 
assumes approximately 10% 
discontinuation rate. 
Approximately 525 subjects will be 
screened to randomize approximately 46 
subjects into Cohort 1 and approximately 
356 subjects into Cohort 2 at a 1:1 ratio of 
ganaxolone to placebo, assuming a 
screen-failure rate of 15%.  It is estimated 
that approximately 320 subjects will 
complete the 14-week Double-Blind 
Phase of Cohort 2, which assumes 
approximately 10% discontinuation rate. 
Reason for Change: Clarification of the revised visit week and number of subjects to be screened and 
randomized in each Cohort 
22 
9.3.2 Inclusion 
Criteria #1, Line 
2 
 
Added: …, if permitted in your 
country/region,  
22 
9.3.2 Inclusion 
Criteria #4 
 
Added:  For Poland, a CT or MRI of the 
brain to rule out progressive structural 
lesions should be performed within 2 
years prior to screening visit. 
22 
9.3.2 Inclusion 
Criteria #6 
 
Added:  (AEDs may be adjusted during the 
open-label phase of the study). 


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CONFIDENTIAL INFORMATION 
25 
9.3.3 Exclusion 
Criteria #11  
11. Current use of vigabatrin is 
not permitted, as well as prior use 
of vigabatrin without stable 
visual fields tested twice over the 
12 months after the last dose of 
vigabatrin. 
11. Current use of vigabatrin is not 
permitted, as well as prior use of 
vigabatrin without stable visual fields 
tested prior to screening.  If used during 
the last 12 months two visual fields tests 
are required. 
25 
9.3.3 Exclusion 
Criteria #25 
 
… (See Section 9.4.1: Excluded, Prior, 
and Concomitant Medications). 
Reason for Change:  Clarification that local regulations may apply; addition of country-specific criteria and 
clarification of AED dosing adjustments 
28 
9.3.4.1 
Investigator-
initiated 
Withdrawal of 
Subject 
Investigator-initiated Withdrawal of 
Subject 
Criteria for Withdrawal 
28 
9.3.4.1 
Investigator-
initiated 
Withdrawal of 
Subject, #10 
d. An “actual suicide attempt” as 
classified by the Columbia-Suicide 
Severity Rating Scale (C-SSRS). 
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. 
28 
9.3.4.1 
Investigator-
initiated 
Withdrawal of 
Subject 
 
Added: 11. Any subject who has the 
following liver enzyme findings should be 
immediately contacted and instructed to stop 
the study drug or start 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 x 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.  


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CONFIDENTIAL INFORMATION 
More frequent monitoring of the liver tests 
should be initiated. 
Reason for Change:  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) 
31 
9.4.2 Identity of 
Investigational 
Products 
 
Added:  All study medication will be labeled 
according to regional regulatory requirements.  
At minimum labels will contain the study 
number; a blinded bottle number; contents 
including quantity; dose and form; route of 
administration; storage conditions, 
instructions for study drug administration; 
caution that this compound is an investigative 
drug intended for clinical trial use only; 
warning to keep out of reach of children; and 
the identity of manufacturer and Sponsor.  For 
those regions that require it, a blinded lot 
number and an expiry date will also be listed. 
Reason for Change: Provided Investigational Product labeling content 
33 
9.4.5 Study 
Dosing and 
Dosage 
Adjustments, 
Open-Label 
Phase 
 
Subjects will start with 450 mg/d in 
divided doses BID for 3 days, 900 mg/d in 
divided doses BID for 3 days, 1350 mg/d 
in divided doses BID for 4 days, and 1800 
mg/d in divided doses BID for 4 days 
until their Visit 6 (Table 2). At Visit 6, all 
subjects in both cohorts will be evaluated 
for tolerability and the investigator will 
make the determination to maintain the 
subject on 1800 mg/d or adjust their dose.  
Added: If the patient experiences any 
tolerability issues during the transition to 
OL, such as sedation or dizziness, 
changes to the titration schedule (e.g., 
conducting the titration over 3 weeks vs. 2 
weeks) may be approved after discussion 
with the medical monitor.  
33 
9.4.5 Study 
Dosing and 
Dosage 
Adjustments, 
De-Escalation 
Period 
De-escalation Period: The study 
drug will be decreased in 
increments of 450mg/d in 3-day 
intervals over 12 days for 1800 
mg.   
De-escalation Period: The study drug will 
be decreased in increments of 450mg/d in 
4-day intervals over 12 days for 1800 mg.   


 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
   
 
 
 
   
 
 
 
 
   
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
  
 
  
 
 
 
 
 
  
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
  
 
 
 
 
 
  
 
 
  
  
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
  
   
 
  
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
  
 
 
 
  
 
 
 
  
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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08 April 2016 
 
CONFIDENTIAL INFORMATION 
Paragraph 2, 
Line 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
Results will be expressed and mean 
and median. 
end-points. Clinical Global Impression of 
Change – Improvement (CGI-I; Investigator) 
and  Patient Global Impression of Change – 
Improvement (PGI-I; Patient or Caregiver) 
will be assessed at Weeks 5 and 9 for Cohort 
1 during the double-blind phase and at Weeks 
22, 42 and 61 during the open-label phase. 
PGI-I and CGI-I will be assessed at Weeks 8 
and 14 during the double-blind phase and 
Weeks 28, 44 and 66 during the open-label 
phase for Cohort 2. Additional analyses may 
be considered as appropriate.   
 
Deleted 
45 
9.5.2 Efficacy 
Assessments, 
Paragraph 3 
Secondary efficacy outcome 
measures include those listed below. 
All outcome variables will be 
assessed for these time periods for 
Cohort 1 & 2: ganaxolone vs 
placebo Titration + Maintenance 
(Cohort 1:Weeks 1-9, Cohort 2: 
Weeks 1-14), ganaxolone vs placebo 
Maintenance only (Cohort 1: Weeks 
2-9, Cohort 2: Weeks 3-14), 1200 
mg/d vs placebo (Cohort 1: Weeks 
2-5), and 1800 mg/d vs placebo 
(Cohort 1: Weeks 6-9) for the ITT 
and Completer populations; open-
label (Cohort 1: Weeks 10-61, 
Cohort 2: 16-66), double-blind plus 
open-label (Cohort 1: Weeks 1-61, 
Cohort 2: Weeks 1-66).  
Deleted 
45 
Table - 
Secondary 
Efficacy 
Parameters  
 
Deleted   
Reason for Change: These changes are intended to simplify this section be removing duplication of text 
elsewhere in the protocol and in the Statistical Analysis Plan.  
46 
9.5.3 Safety 
Assessments 
 
Added:  Columbia Suicide Severity Scale 
(C-SSRS) 
46 
9.5.3 Safety 
Assessments 
Secondary safety outcome 
measures include those listed 
below. All outcome variables will 
be presented for these time 
periods for Cohorts 1 & 2: 
ganaxolone vs placebo Titration 
+ Maintenance (Cohort 1: Weeks 
1-9, Cohort 2: Weeks 1-14), 1200 
Adverse events will be presented for these 
time periods for Cohorts 1 & 2: 
ganaxolone vs placebo Titration + 
Maintenance (Cohort 1: Weeks 1-9, 
Cohort 2: Weeks 1-14), 1200 mg/d vs 
placebo (Cohort 1: Weeks 2-5), and 1800 
mg/d vs placebo (Cohort 2: Weeks 6-9) 
for the safety population; open-label 


Marinus Pharmaceuticals, Inc. 
 
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Protocol 1042-0603 Amendment 4, V 1.0 
 
08 April 2016 
 
CONFIDENTIAL INFORMATION 
mg/d vs placebo (Cohort 1: 
Weeks 2-5), and 1800 mg/d vs 
placebo (Cohort 2: Weeks 6-9) 
for the ITT population; open-
label (Cohort 1: Weeks 10-61, 
Cohort 2: 15-66, and total open-
label), double-blind plus open-
label (Cohort 1: Weeks 1-61, 
Cohort 2: 1-66). 
 
(Cohort 1: Weeks 10-61, Cohort 2: 15-
66,).   
Added: In addition, tolerability of 
ganaxolone during the up-titration phases 
of the study will be compared between the 
two cohorts. AEs with onset during the 
titration phase in Cohort 2 will be 
compared to AEs with onset during the 
weeks 1-5 in Cohort 1 (1 week titration + 
4 week treatment with 1200 mg/day). In 
addition, in Cohort 2, AEs with onset 
during the titration phase will be 
compared to AEs with onset during the 
maintenance phase. AEs that emerge 
during the de-escalation period will be 
tabulated to investigate whether 
discontinuation of ganaxolone is 
associated with withdrawal symptoms. 
Secondary safety outcome measures 
include those listed below. 
 
46 
9.5.3 Secondary 
Safety 
Parameters for 
Cohorts 1 & 2 - 
Table 
Secondary Safety Parameters 
for Cohorts 1 & 2 
Type and incidence of AES 
 
Combine Cohorts 1 & 2 
DB Phase 
“X” populated for 7 parameters 
listed in table 
 
 
The frequency and proportion of subjects 
with AEs 
Combine Cohorts 1 & 2 
DB Phase 
“X” deleted  
50 
9.5.5.9 Visit 7 
Visit 7 (Open-Label Month 1; 
Cohort 1: Week 14; Cohort 2: 
Week 20) 
Visit 7 (Cohort 1: Week 14; Cohort 2: 
Week 20) 
50 
9.5.5.10 Visit 8 
Visit 8 (Open-Label Month 3; 
Cohort 1: Week 22; Cohort 2: 
Week 28) 
Visit 8 (Cohort 1: Week 22; Cohort 2: 
Week 28) 
51 
9.5.5.11 
Telephone 
Follow Up 
Telephone Follow Up (Month 5; 
Cohort 1: Week 32; Cohort 2: 
Week 36) 
Telephone Follow Up (Cohort 1: Week 
32; Cohort 2: Week 36) 
51 
9.5.5.12 Visit 9 
Visit 9 (Cohort 1: Open Label 
Month 8, Week 42; Cohort 2: 
Open Label Month 7, Week 44) 
Visit 9 (Cohort 1: Week 42; Cohort 2: 
Week 44) 
 


Marinus Pharmaceuticals, Inc. 
 
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Protocol 1042-0603 Amendment 4, V 1.0 
 
08 April 2016 
 
CONFIDENTIAL INFORMATION 
51 
9.5.5.13 
Telephone 
Follow Up 
Telephone Follow Up (Cohort 1: 
Month 10, Week 52; Cohort 2: 
Month 10, Week 56) 
 
Telephone Follow Up (Cohort 1: Week 
52; Cohort 2: Week 56) 
 
51 
9.5.5.14 Visit 10 Visit 10 (Open Label Month 12; 
Cohort 1: Week 61; Cohort 2: 
Week 66)/ Pre-Taper/ET Visit 
 
Visit 10 Pre-Taper/ET Visit (Cohort 1: 
Week 61; Cohort 2: Week 66) 
 
Reason for Change: Clarification of the revised Visit labels/schedule 
52 
9.7.2 Analysis 
Population – 
Modified Intent 
to Treat 
Population 
(mITT) 
 
Added: The modified intent to treat 
(mITT) population (Full Anaysis 
Population in the earlier version of the 
protocol) includes all randomized subjects 
who received at least 1 dose of study 
medication and provided any post 
baseline seizure outcome data.  The mITT 
population is the primary population for 
efficacy analysis.  Subjects will be 
analyzed based on their randomized 
treatment assignment. 
52 
9.7.2 Analysis 
Population – Per 
Protocol 
Population (PP) 
The per protocol (PP) population 
includes all FAP subjects who 
received at least 12 weeks of 
treatment without major protocol 
violations. The PP population is 
for supportive efficacy analysis. 
Major protocol violations will be 
defined prior to database lock. 
The per protocol (PP) population includes 
all FAP subjects without major protocol 
violations during the double-blind phase. 
The PP population is for supportive 
efficacy analysis. Major protocol 
violations will be defined prior to 
database lock. 
 
53 
9.7.3 Missing 
Data 
Before performing any statistical 
analyses, a complete review of all 
data, both quantitative and 
qualitative, will be conducted in 
order to account for all missing 
values. A missing value code(s) 
will be documented and 
incorporated into the database. 
Similarly, when data are recorded 
on official eCRFs and not 
subsequently used in any formal 
statistical analysis the reasons for 
such actions will be documented. 
Deleted 


Marinus Pharmaceuticals, Inc. 
 
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08 April 2016 
 
CONFIDENTIAL INFORMATION 
All quantitative data will be 
assessed for the presence of 
spurious or outlying results, both 
from a descriptive examination of 
the frequency distribution for 
each variable, as well as, 
examination of logical 
multivariate distributions and, if 
necessary, the use of appropriate 
univariate and multivariate 
outlier screening tests.  The 
removal or correction of any data 
value will be documented. 
53 
9.7.4 Baseline 
and 
Demographic 
Characteristics, 
Line 2 
…overall for the FAP population. 
…overall for the mITT population. 
53 
9.7.5 Analysis 
of Primary 
Efficacy 
Variable, 
Paragraphs 1 
(Line 3), 2 & 3  
…period relative to baseline in the 
FAP analysis. 
 
The hypothesis for percent change 
in seizure frequency per 28 days is: 
H0: µ1- µ2 = 0      Ha: µ1- µ2 ≠ 0       
where µ1 and µ2 are the mean 
percent change in seizure frequency. 
 
An analysis of covariance 
(ANCOVA) will be conducted on 
the log-transformed percent change 
data, with treatment and country as 
factors and the logged baseline 
seizure frequency per 28 days as a 
covariate. Rank-transformation 
based ANCOVA to explore the 
median difference of percentage 
change is also conducted to assess 
the robustness of the analysis 
method. Both the baseline seizure 
frequencies per 28 days and the 
percentage change per 28 days will 
be rank-transformed before applying 
the ANCOVA model. Point 
estimates and associated 95% 
confidence interval and p-values 
will be reported.  
…period relative to baseline in the mITT 
population. 
 
The hypothesis for percent change in seizure 
frequency per 28 days is: 
H0: µ1- µ2 = 0      Ha: µ1- µ2 ≠ 0          
where µ1 and µ2 are the median percent 
change in seizure frequency. 
 
A rank analysis of covariance (ANCOVA) 
will be conducted on ranked percent change 
data, with treatment and country as factors 
and the ranked baseline seizure frequency per 
28 days as a covariate. The p-value based on 
the rank ANCOVA will be presented.  
Hodges-Lehmann estimator and its 95% 
confidence interval (CI) will also be 
calculated.  
Added: 
An 
analysis 
of 
covariance 
(ANCOVA) as a sensitivity analysis will 
be conducted on the rank of percent change 
data from baseline, with treatment and 
pooled center (either US or ROW) as 
factors and the rank of baseline seizure 
frequency as a covariate. P-value to test 
treatment effect will be determined by 
permutation test with seed=123456, and 


Marinus Pharmaceuticals, Inc. 
 
Page 126 of 132 
Protocol 1042-0603 Amendment 4, V 1.0 
 
08 April 2016 
 
CONFIDENTIAL INFORMATION 
2000 iterations. This analysis provides a 
robustness assessment of the results. 
Added: The primary efficacy endpoint for 
European Medicines Agency registration 
is 
50% responder rate during the 
maintenance treatment period of the DB 
phase for Cohort 2. A 50% responder is an 
individual who experiences at least a 50% 
decrease in seizure frequency compared to 
baseline. This end-point is analyzed 
independently of the US registration end-
point. 
The 
key-secondary 
end-point 
analysis (below) is not predicated on the 
results of this end-point.  
54 
9.7.6 Analysis 
of Secondary 
Endpoints 
Secondary efficacy outcome 
measures include those listed below. 
All outcome variables will be 
assessed for these time periods in 
both Cohort 1 and 2: ganaxolone vs 
placebo Titration + Maintenance 
(Cohort 1: Weeks 1-9, Cohort 2: 
Weeks 1-14), ganaxolone vs placebo 
Maintenance only (Cohort 1: Weeks 
2-9, Cohort 2: Weeks 3-14), 1200 
mg/d vs placebo (Cohort 1: Weeks 
2-5), and 1800 mg/d vs placebo 
(Cohort 1: Weeks 6-9) for the FAP 
and Completer populations; open-
label (Cohort 1: Weeks 10-61; 
Cohort 2: Weeks 15-66), double-
blind plus open-label (Cohort 1: 
Weeks 1-61; Cohort 2: Weeks 1-66). 
 
The three key secondary endpoints (below) 
will be tested using a fixed sequence 
procedure to protect the familywise error rate 
at 0.05. If the primary outcome measure is 
statistically significant, the p-values of the 
secondary measures will be examined in the 
order listed below. The process stops at the 
first p-value above 0.05.  
 
Responder rate (experiencing a ≥ 50% 
reduction) during the titration + 
maintenance treatment periods of the DB 
phase for Cohort 2 
 
Change in the number of seizure free days 
per 28-day period from baseline during 
the titration + maintenance treatment 
periods of the DB phase for Cohort 2  
 
Clinical Global Impression of Change – 
Improvement (CGI-I; Investigator) at 
Week 14 of the double  blind treatment 
phase relative to the baseline for Cohort 2 
 
All remaining secondary efficacy endpoints 
listed in the protocol will be tested at alpha 
=.05 so all p-values are nominal.    
Secondary efficacy outcome measures are 
listed below. 
a) Percent change in the 28-day seizure 
frequency from baseline to the DB phase 
during the maintenance treatment period 
for Cohort 2 
b) Change from baseline in 28-day seizure 
frequency during the DB phase for Cohort 
2 (titration + maintenance and 
maintenance only) 


 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
  
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
   
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
  
  
  
 
 
  
 
 
  
 
 
 
 
 
  
 
 


 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
   
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


Marinus Pharmaceuticals, Inc. 
 
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Protocol 1042-0603 Amendment 4, V 1.0 
 
08 April 2016 
 
CONFIDENTIAL INFORMATION 
percent change of mean monthly 
seizure frequencies will be analyzed 
by Kruskal-Wallis test.  
57 
9.7.7 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 will be for each 
phase of the study, and in Phase 1, 
by dose level 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 by treatment 
including changes from baseline.  
Critically significant changes in 
laboratory and ECG values and vital 
signs will be flagged in data listings. 
Listings of most abnormal changes 
will be provided. 
 
Adverse events (AEs) will be tabulated by 
Overall, system organ class (SOC), and 
Preferred Term using the MedDRA v.16.1 
coding system.  Frequency and percentage of 
subjects with adverse events will be 
calculated for each cohort in each phase of the 
study, by treatment and overall, and in Cohort 
1 double-blind phase, by dose level 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. 
Actual values and changes from baseline 
for laboratory data, vital signs and ECGs 
will be summarized using descriptive 
statistics by visit, by treatment and overall 
for each cohort and phase separately in 
safety population. Shifts from baseline in 
low/normal/high classification will be 
summarized for each laboratory and vital 
sign parameter. Critically significant 
changes in laboratory and ECG values 
and vital signs will be flagged in data 
listings. Columbia-Suicide Severity 
Rating Scale data will be summarized and 
listed for each question each visit by 
treatment and overall, cohort and study 
phase for safety population. Pregnancy 
test and urine drug screen test results will 
be listed. 
 
57 
9.7.9 
Determination 
of Sample Size 
Marinus 1042-0600 study results 
using a medium dose (1500mg/day 
oral suspension) showed that mean 
difference of percentage change in 
seizure frequency was -19.58%, 
with standard deviation of 54.019% 
and thus giving an effect size of 
0.3625. Assuming an effect size of 
0.38 could be achieved in Cohort 
2 comparing placebo to high dose 
ganaxolone (1800 mg/day capsule), 
a sample size of 146 in each group 
produces a two-sided 95% 
confidence interval around 
Marinus 1042-0600 study results using a 
medium dose (1500mg/day oral suspension) 
showed that mean difference of percentage 
change in seizure frequency was -19.58%, 
with standard deviation of 54.019% and thus 
giving an effect size of 0.3625. Assuming 
an effect size of 0.30 could be achieved in 
Cohort 2 comparing placebo to high dose 
ganaxolone (1800 mg/day capsule) in a 1:1 
ratio, a sample size of 178 in each group 
provides approximately 80% power when the 
estimated difference is -15% and standard 
deviations are approximately 50% in each 


 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
  
  
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
   
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
   
 
 
   
 
   
 
 
  
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 


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CONFIDENTIAL INFORMATION 
Double-blind 
Phase (Weeks -
8-14) – 
footnote 
course of the study; if the subject is 
using VNS, the settings cannot be 
changed during the course of the 
study 
Label Phase of the study; if the subject is 
using VNS, the settings cannot be changed 
during the course of the study 
 
78 
12.1 Appendix 
1: Schedule of 
Events – Cohort 
2 Period 2: 
Open-label 
Phase (Weeks 
16-68) –  
VISIT labels 
Visit 7 (1 month) 
Visit 8 (3 month) 
Telephone Follow-up (5 month) 
Visit 9 (8 month) 
Telephone Follow-up (10 month) 
Visit 10 (12 month Pre-taper/ET)  
 
Visit 7 
Visit 8 
Telephone Follow-up 
Visit 9 
Telephone Follow-up 
Visit 10 (Pre-taper/ET) 
79 
12.1 Appendix 
1: Schedule of 
Events – Cohort 
2 Period 2: 
Open-label 
Phase (Weeks 
16-68) – 
footnote 
 
1 Concomitant AEDs or their dose 
must be stable for 1 month prior to 
historical baseline and cannot be 
changed at any time during the 
course of the study; if the subject is 
using VNS, the settings cannot be 
changed during the course of the 
study 
1Concomitant AEDs or their dose must be 
stable for 1 month prior to historical baseline 
and cannot be changed at any time prior to 
Visit 5, but may be adjusted during the Open-
Label Phase of the study; if the subject is 
using VNS, the settings cannot be changed 
during the course of the study 
Reason for Change: Clarification  when AED dosing can and cannot be adjusted; clarification of Visit 
numbers/labels 
113 
12.8 Appendix 8 
Protocol History 
Amendment 3 Summary of Changes 
from version March 10, 2014 to 
September 23, 2014 
Amendment 4 Summary of Changes from 
version September 23, 2014 to April 08, 2016 
 

SAP_001.pdf: 
Clinical Study Report 
 
Study 1042-0603 
Marinus Pharmaceuticals, Inc. 
 
 
 
16.1.9 
Documentation of Statistical Methods 
 






IND 044020 
 
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Statistical Analysis Plan 
 
 
 
Confidential 
Page 3 of 48 
SAP Version 3.0, 24 May 2016 
TABLE OF CONTENTS 
 
GLOSSARY OF ABBREVIATIONS ...............................................................................6 
1
 
PURPOSE ..........................................................................................................................8 
2
2.1 
Responsibilities ........................................................................................................8 
2.2 
Timings of Analyses ................................................................................................8 
 
STUDY OBJECTIVES ......................................................................................................8 
3
3.1 
Primary Objective ....................................................................................................8 
3.2 
Secondary Objectives...............................................................................................8 
3.3 
Brief Description ......................................................................................................8 
3.4 
Subject Selection ....................................................................................................10 
 
Inclusion Criteria .........................................................................................10 
3.4.1
 
Exclusion Criteria ........................................................................................12 
3.4.2
3.5 
Determination of Sample Size ...............................................................................13 
3.6 
Treatment Assignment & Blinding ........................................................................13 
3.7 
Administration of Study Medication .....................................................................14 
3.8 
Study Procedures and Flowchart ...........................................................................14 
 
ENDPOINTS ...................................................................................................................15 
4
4.1 
Primary Efficacy Endpoint ....................................................................................15 
4.2 
Secondary Efficacy Endpoints ...............................................................................16 
4.3 
Safety Endpoints ....................................................................................................17 
 
ANALYSIS POPULATIONS .........................................................................................18 
5
5.1 
Randomized Population .........................................................................................18 
5.2 
Safety Population ...................................................................................................18 
5.3 
Modified Intent To Treat Population .....................................................................18 
5.4 
Per Protocol Population .........................................................................................18 
5.5 
Protocol Deviations ................................................................................................18 
 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS .............................................19 
6
6.1 
General Methods ....................................................................................................19 
6.2 
Key Definitions ......................................................................................................19 
6.3 
Missing Data ..........................................................................................................19 
6.4 
Visit Windows .......................................................................................................21 
6.5 
Pooling of Centers..................................................................................................21 
 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND MEDICATION21 
7
7.1 
Subject Disposition and Withdrawals ....................................................................21 
7.2 
Demographic and Other Baseline Characteristics .................................................22 
7.3 
Medical History .....................................................................................................22 
7.4 
Epilepsy History.....................................................................................................22 
7.5 
Medication .............................................................................................................22 


 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IND 044020 
 
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Statistical Analysis Plan 
 
 
 
Confidential 
Page 5 of 48 
SAP Version 3.0, 24 May 2016 
 MOCK-UPS .....................................................................................................................40 
14
 APPENDICIES ................................................................................................................41 
15
 
LIST OF FIGURES 
Figure 1. Cohort 1 Trial Design ...............................................................................................14 
Figure 2. Cohort 2 Trial Design ...............................................................................................15 
 
 
 


IND 044020 
 
Marinus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
 
 
 
Confidential 
Page 6 of 48 
SAP Version 3.0, 24 May 2016 
 
GLOSSARY OF ABBREVIATIONS 
1
Abbreviation 
Description 
AE 
adverse event 
AEDs 
anti-epilepsy drugs 
ALT 
alanine transferase (SGPT) 
ANCOVA 
analysis of covariance 
AST 
aspartate transferase (SGOT) 
BID 
bis in die; two times per day 
BMI 
body mass index 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CPS 
complex partial seizures 
CRF 
case report form 
DB 
double-blind 
DC 
discontinuation 
DSM-V 
Diagnostic and Statistical Manual of mental disorders, 5th edition 
EEG 
electroencephalogram 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
HCG 
human chorionic growth hormone 
IWRS 
interactive web randomization system 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
modified intent to treat 
MRI 
magnetic resonance imaging 
OL 
open label 
POS 
partial-onset seizure 
PP 
per protocol 
PT 
preferred term 
QC 
quality control 
ROW 
Rest of World 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SPS 
simple partial seizure 
SPS-motor 
simple partial seizure with motor/observable component 
SGTC 
secondarily generalized tonic-clonic (seizures) 
SI 
standard international system of units 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment emergent adverse event 
TLF 
Table, Listing and Figure 


IND 044020 
 
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Statistical Analysis Plan 
 
 
 
Confidential 
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SAP Version 3.0, 24 May 2016 
Abbreviation 
Description 
ULN 
upper limits of normal 
VAS 
visual analogue scale 
VNS 
vagal nerve stimulator 
WHO 
World Health Organization 
 


IND 044020 
 
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Statistical Analysis Plan 
 
 
 
Confidential 
Page 8 of 48 
SAP Version 3.0, 24 May 2016 
 
PURPOSE 
2
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary 
tables and figures which will be produced, and the statistical methodologies that will be used, are 
completely specified and appropriate to allow valid conclusions regarding the study objectives.   
2.1 
Responsibilities 
FMD K&L Inc. will perform the statistical analyses and is responsible for the production and 
quality control of all tables, figures and listings as specified in the SAP.  Data Management will 
be conducted by Numoda, based in Philadelphia, PA.  Pharmacokinetic analysis of the study 
drug will be performed by QPS LLC and NMS, a sub-contractor for ACM will conduct the 
ConAED PK analysis.  The results of ConAED and study drug PK levels will be included in the 
listing. 
2.2 
Timings of Analyses 
The primary analysis of efficacy, safety, and tolerability is planned after all subjects in Cohort 2 
complete the 14-week double-blind (DB) phase of the study.  Unless otherwise specified, the 
analysis includes all DB phase of Cohort 2 data collected in the database through database lock 
for the DB phase of the study for all subjects randomized.   
A follow-up analysis will be conducted when all subjects complete the final visit of the study, 
which includes a 1-year open-label (OL) phase that follows the 14-week DB phase of the study.  
Analyses that include data collected after the DB phase database lock from the primary analysis 
of the study will be issued as an addendum to the study report.  
 
STUDY OBJECTIVES 
3
3.1 
Primary Objective 
To evaluate efficacy of ganaxolone compared to placebo as adjunctive therapy in adults with 
partial-onset seizures (POS), with or without secondary generalization. 
3.2 
Secondary Objectives 
To evaluate the safety and tolerability of ganaxolone compared to placebo as adjunctive therapy 
in adults with POS, with or without secondary generalization. 
To evaluate pharmacokinetics of ganaxolone at 1200 mg/d and 1800 mg/d after chronic dosing. 
To evaluate the safety and tolerability of ganaxolone when administered as adjunctive therapy in 
adults with POS, with or without secondary generalization, over a 12-month period. 
3.3 
Brief Description 
This is a 2-cohort study with each cohort comprised of 2 phases, a DB phase (Phase 1) followed 
by an OL phase (Phase 2).  Cohort 1 will provide efficacy, tolerability, safety, and PK 


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information for ganaxolone 1200 mg/d, 1800 mg/d compared to placebo.  Cohort 2 will 
investigate the efficacy, tolerability and safety of ganaxolone 1800 mg/d compared to placebo.  
Cohort 1 (N = approximately 50) will enroll into a 67-week protocol comprising a 4-week 
retrospective and 4-week prospective baseline period and 2 treatment phases:  a 9-week DB 
phase followed by a 52-week OL phase.  Cohort 2 (N = 292) will enroll into a 76-week study 
comprising an 8-week prospective baseline period and 2 phases:  a 14-week DB phase followed 
by a 52-week OL phase.  In each cohort, the final safety assessment will be conducted 2 weeks 
following the end of the OL phase. 
Baseline seizure activity will be determined by 8 weeks of recording in subject daily seizure 
calendars.  In Cohort 1, the 8 weeks are obtained from a 4-week retrospective baseline period 
and a 4-week prospective baseline.  The baseline for Cohort 2 is an 8-week prospective baseline, 
though some subjects randomized into Cohort 2, under Protocol version Amendment 2, will have 
baseline comprised of 4 weeks retrospective and 4 weeks prospective data.  After completing the 
8-week baseline period, eligible subjects will be randomized to receive either ganaxolone or 
placebo. 
Cohort 1, Phase 1 of treatment includes a 9-week DB placebo-controlled phase to evaluate oral 
study medication as add-on therapy in adults with epilepsy consisting of POS, with or without 
secondary generalization.  Study subjects will be randomized to one of the 2 study treatment 
arms:  ganaxolone (1200 mg/day (mg/d) followed by 1800 mg/d), or placebo.  Phase 1 
(DB phase) is comprised of a Baseline period (8 weeks; 4 weeks retrospective and 4 weeks 
prospective seizure calendar data to be used for baseline assessment), followed by 2 treatment 
periods:  Titration (1 week; step titration up to 1200 mg/d) and Maintenance (8 weeks; 4 weeks 
on 1200 mg/d followed by 4 weeks on 1800 mg/d). 
Between DB (Phase 1) and OL (Phase 2) study phases, Cohort 1 has a 1-week, double-blinded, 
step transition for placebo subjects to 900 mg/d followed by 1800 mg/d while ganaxolone 
subjects are maintained on their current dose.  For the purpose of entering dosing information on 
the eCRFs, the sites are instructed to assume that all patients transitioning to the OL phase are on 
placebo and will enter dose-escalation information accordingly.  After unblinding K&L will 
correct the actual dosing, and the patients who were on ganaxolone during the DB phase will be 
changed to have received 1800 mg/day during the transition period. 
Cohort 1, Phase 2 is the OL phase, consisting of 2 treatment phases:  Flexible Dosing (51-week 
flexible dosing during which time the dose may be adjusted based on efficacy and tolerability 
guidelines), and De-escalation (2 weeks, at study termination).  Subjects discontinued during the 
study will be de-escalated over 2 weeks based on dose, duration, and tolerability in the opinion 
of the investigator. 
Cohort 2, Phase 1 of treatment includes a 14-week DB phase placebo-controlled treatment period 
to evaluate oral study medication as add-on therapy in adults with epilepsy consisting of POS, 
with or without secondary generalization.  Study subjects will be randomized to one of the 
2 study treatment arms:  ganaxolone at 1800 mg/d or placebo.  Phase 1 (DB phase) is comprised 
of a Baseline period (8 weeks), followed by 2 treatment periods:  Titration (2 weeks up to 
1800 mg/d) and Maintenance (12 weeks on 1800 mg/d).  Subjects entered into Cohort 2, under 


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Protocol Amendment 2, will have a baseline assessment based on 4 weeks retrospective and 
4 weeks prospective seizure data. 
Between the study phases, Cohort 2 has a 2-week, blinded, step transition for placebo subjects to 
ganaxolone, starting at 900 mg/d to 1800 mg/d, while ganaxolone subjects are maintained on 
their current dose.  For the purpose of entering dosing information on the eCRFs, the sites are 
instructed to assume that all patients transitioning to the OL phase are on placebo and will enter 
dose-escalation information accordingly.  After unblinding K&L will correct the actual dosing, 
and the patients who were on ganaxolone during the DB phase will be changed to have received 
1800 mg/day during the transition period. 
Cohort 2, Phase 2 is the OL Phase consisting of 2 treatment periods:  Flexible Dosing (50-week 
flexible dosing during which time the dose may be adjusted between 900 – 1800 mg/day based 
on efficacy and tolerability), and De-escalation (2 weeks, at study termination).  Subjects 
discontinued during study will be de-escalated over 2 weeks based on dose, duration, and 
tolerability in the opinion of the investigator.   
At all dose levels, ganaxolone capsules or matching placebo will be administered BID in divided 
doses.  Subjects will maintain seizure calendars to record the number and type of seizures 
throughout the entire study.  Subjects will also record concomitant medications and any errors in 
study medication dosing in their seizure calendars. 
A graphic representation of the design of this study is provided in SAP Section 3.8, Figure 1 and 
Figure 2.   
3.4 
Subject Selection 
The study will randomize approximately 50 subjects into Cohort 1 and approximately 356 
subjects into Cohort 2 at a 1:1 ratio of ganaxolone to placebo.  It is estimated that approximately 
320 subjects will complete the 14-week DB Phase of Cohort 2, which assumes approximately 
10% discontinuation rate.  
 
Inclusion Criteria 
3.4.1
Subjects must meet all inclusion criteria to be eligible for entry in the study.  The option for re-
screening of subjects who do not meet all criteria must be discussed with the medical monitor. 
1. 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. 
2. Willing to enter and participate for the full term of either the 9 or 14-week DB phase and 
willing to enter into the 52-week OL phase.  
3. Male or female outpatients ≥18 years of age at time of consent. 
4. Have a confident diagnosis of drug-resistant epilepsy with POS with or without secondary 
generalization (classified according to International League Against Epilepsy Guidelines 
[Guy, 1981] and as determined by secondary review by the Epilepsy Consortium) for 
≥2 years and is having POS, with or without secondary generalization despite having been 
treated in the past with ≥2 approved anti-epilepsy drugs (AEDs) either alone or in 


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combination at adequate doses for a sufficient length of time in the opinion of the 
investigator.  Diagnosis should have been established by clinical history, 
electroencephalogram (EEG) or video EEG with results consistent with partial-onset 
epilepsy, and computerized tomography (CT) or magnetic resonance imaging (MRI) of the 
brain to rule out progressive structural lesions within the last 10 years. 
5. Based on documented history of POS, the investigator judges that the subject is likely to have 
3 or more POS*, with or without secondary generalization, during any 4-week period prior to 
study treatment, i.e, rarely falls below that threshold with usual fluctuations.  Further, the 
pattern of seizures makes it unlikely the subject will have 21 seizure-free days in any 4-week 
period prior to study treatment. 
* POS includes complex partial seizures [CPS], and simple partial seizures [SPS] with motor 
expression.  Partial seizures may be seizures secondarily generalized [SGTC].  Subjects who 
only have simple partial seizures without any observable motor component will NOT be 
eligible to participate in this study. 
6. Currently being treated and maintained with a stable regimen of 1, 2, or 3 AEDs for 
≥1 month prior to the screening visit, without a foreseeable change in dosing for the duration 
of the DB phase of the study. 
Barbituates:  If the subject is taking barbiturates (e.g, phenobarbital), the dose of the barbiturate 
must have been stable for ≥3 months prior to the screening visit. 
Vagus Nerve Stimulator (VNS):  VNS will not be counted towards the number of concomitant 
AEDs.  Subjects with surgically implanted VNS will be allowed to enter the study provided that 
all of the following conditions are met: 
◦ 
The VNS has been in place for ≥1 year prior to the screening visit 
◦ 
The settings must have remained constant for ≥3 months prior to the screening visit 
and remain constant throughout the study 
◦ 
The battery is expected to last for the duration of DB Phase 1 (9 or 14 weeks) of the 
study 
Benzodiazepines:  The chronic use of a benzodiazepine as a concurrent AED is permitted as long 
as the dose has been stable for ≥1 month prior to the screening visit and remains constant 
throughout the study.  See Protocol Section 9.4.10 for use of benzodiazepines for seizure rescue 
or for other indications. 
Felbamate:  The use of felbamate is allowed provided that the subject has been maintained on a 
stable dose of felbamate for greater than 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. 
Perampanel:  The use of perampanel is allowed provided that the subject has been maintained on 
a stable dose of perampanel for greater than 3 months and has not experienced any serious 
psychiatric and behavioral reactions such as hostility- and aggression- related adverse reactions. 
7. 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. 
8. Able and willing to take drug with food twice daily.  Ganaxolone must be administered with 
food. 
9. Sexually active women of childbearing potential must be using a medically acceptable 
method of birth control and have a negative qualitative serum β- human chorionic growth 


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hormone (HCG) pregnancy test from a blood sample collected at the screening visit and 
negative urine pregnancy tests at baseline line and 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 and β-HCG will be tested per protocol.  Birth control should be 
continued for a minimum of 3 days after the last dose of study drug. 
 
 
Exclusion Criteria 
3.4.2
1. Have had previous exposure to ganaxolone. 
2. Known sensitivity or allergy to any component in the study drug, progesterone, or other 
related steroid compounds. 
3. Exposure to any investigational drug or device less than 30 days prior to screening, or plans 
to take another investigational drug at any time during the study. 
4. Time of onset of epilepsy treatment less than 2 years prior to enrollment. 
5. Have generalized epilepsy, such as Lennox-Gastaut syndrome, juvenile myoclonic epilepsy, 
absence epilepsy, or non-epileptic seizures within the last 12-month period prior to study 
entry. 
6. Have less than 3 POS seizures, with or without secondary generalization, in a 28-day period 
or more than 21 consecutive seizure-free days during the 8-week baseline period.  
7. Have only simple partial seizures without any observable motor component. 
8. Have innumerable seizures or status epilepticus within the last 12-months prior to screening.  
9. Have more than 100 POS total (complex partial seizures [CPS] only + simple partial seizures 
[SPS] with motor (both types with or without secondary generalized tonic-clonic seizures 
[SGTC]) per each 4-week baseline period. 
10. 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. 
11. Current use of vigabatrin is not permitted, as well as prior use of vigabatrin without stable 
visual fields tested twice over the 12 months after the last dose of vigabatrin. 
12. Current use of ezogabine (retigabine; Potiga; Trobalt) is not permitted.  Subjects who may 
have used this agent in the past should have been off this medication for at least 3 months 
prior to screening and should have had a documented normal fundoscopic exam by an 
ophthalmologist.  
13. Are planning surgery, or to be evaluated for surgery, during the 9 or 14-week DB phase to 
control seizures including those subjects who are considering implantation of a VNS device.  
14. Are suffering from acute or progressive neurological disease, moderate or severe psychiatric 
disease, or severe mental abnormalities that are likely to require changes in pharmacotherapy 
during the 9 or 14-week DB portion of the study or interfere with the objectives of the study 
or the ability to adhere to the protocol requirements. 
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16. 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). 
17. Have a positive urine drug screen at Screening or meet criteria for current or historical 
Substance Use Disorder (DSM-V criteria) within the past 5 years.  As with other AEDs, the 
use of alcohol is not advised. 
18. 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. 
19. Have Alanine transferase (ALT; SGPT) or Aspartate transferase (AST; SGOT) levels greater 
than 3 times upper limits of normal (ULN), or total bilirubin greater than 1.5 time ULN at the 
screening and baseline visits. 
20. Have a history of malignancy within the past 2 years, with the exception of basal cell 
carcinoma. 
21. Are currently following or planning to follow a ketogenic diet. 
22. Use of dietary supplements or herbal preparations are not permitted if subject has been using 
them consistently for less than 6 months prior to screening, or does not plan on remaining on 
stable doses for the duration of the DB phase.  Use of St. John’s Wort is not permitted (See 
Protocol Section 9.4.10:  Excluded, Prior, and Concomitant Medications). 
23. Females who are pregnant, currently breastfeeding or planning to become pregnant during 
the duration of the study. 
24. A history of chronic noncompliance with drug regimens. 
25. Inability to withhold grapefruit and grapefruit juice from diet during the entire clinical trial 
(See Protocol Section 9.4.10:  Excluded, Prior, and Concomitant Medications).  
 
3.5 
Determination of Sample Size 
Using a medium dose (1500 mg/day oral suspension,) the Marinus study 1042-0600 found a 
mean difference in percentage change in seizure frequency from BL of -19.58%, with a standard 
deviation of 54.019%.  This is equivalent to an effect size of 0.3625.  Because a higher dose of 
ganaxolone (1800 mg/day oral capsule) is used in study 1042-0603, we have assumed an effect 
size of at least 0.30 can be achieved in Cohort 2.  A sample size of 178 in each group has 
approximately 0.8 power to detect a treatment difference, where the effect size is 0.30, based on 
Wilcoxon rank sum test with two-sided alpha = 0.05 by using PASS 11 software.  Assuming a 
dropout of 10%, the sample size (160 in each group) will still have a power of approximately 
85% to detect an effect size of 0.35.  The sample size (178 per group) also provides 
approximately 88% power when the 50% responder rates are assumed to be 26% for ganaxolone 
and 13% for placebo, and a large 2 sample Z test is used with the two-sided alpha of 0.05. 
3.6 
Treatment Assignment & Blinding 
Subjects will be randomized to receive ganaxolone or placebo during Phase 1 in a 1:1 ratio by 
the interactive web response system (IWRS) system. Randomization for Cohort 2 will be 
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All study medication will be provided as identically appearing gelatin capsules.  The contents of 
each bottle will be blinded using labels that contain a unique bottle number and a manuracturing 
lot code.  The randomization schedule will match a subject number to a bottle number.  Upon 
completion of the 8 week baseline evaluations for each subject, the Investigator, or appropriate 
designee, will log into the IWRS to randomize the subject to the study drug assignment and 
receive bottle numbers.  The designated personnel at the clinical site will match the assigned 
bottle numbers with the correct bottles of investigational product and distribute the bottle to the 
Investigator or designee.  Only the investigational product supplier will be unblinded to the 
bottle number and the contents of each bottle of investigational product.  An unblinded 
representative of the manufacturer will have access to the manufacturing lot codes for active and 
placebo.  
3.7 
Administration of Study Medication 
All study medication will be provided as identically appearing white/opaque gelatin capsules.  
Study drug will be packaged in bottles.  Ganaxolone or placebo capsules will be administered 
2 times daily (BID), following the morning and evening meals.  No study-related tests or 
treatments, including screening, will be conducted before the subject has signed the Informed 
Consent Form. 
3.8 
Study Procedures and Flowchart 
Figure 1. Cohort 1 Trial Design 
 
 


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Figure 2. Cohort 2 Trial Design 
 
See Appendix 1:  Schedule of Events in the protocol for detailed information regarding the 
timing of all assessments. 
 
ENDPOINTS  
4
4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint for US Food and Drug Administration registration is the percent 
change in the 28-day seizure frequency (POS with or without secondary generalization) from 
baseline to the DB phase for Cohort 2.  Frequency of POS, with or without secondary 
generalization, for primary and secondary efficacy endpoints only includes 3 seizure subtypes 
that are SPS-motor, CPS and SGTC.  Per patient 28-day seizure frequency will be based on the 
number of seizures in the Cohort 2 14-week titration + maintenance period of the DB Phase, 
relative to the 8- week prospective baseline period of the Cohort 2 DB Phase, per 28 days.  It will 
be calculated as the number of seizures over the time interval divided by the number of days with 
available seizure data in the interval and multiplied by 28 to obtain both the baseline 28-day 
seizure frequency and the post-baseline 28-day seizure frequency. 
The primary efficacy endpoint for European Medicines Agency registration is 50% responder 
rate during the maintenance treatment period of the DB phase for Cohort 2.  A 50% responder is 
an individual who experiences at least a 50% decrease in seizure frequency compared to 
baseline.  This end-point is analysed independently of the US registration end-point.  The 
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4.2 
Secondary Efficacy Endpoints 
Key Secondary Endpoints: 
The 3 key secondary endpoints will be tested using a fixed sequence procedure to protect the 
familywise error rate at 0.05.  If the primary outcome measure is statistically significant, the 
p-values of the secondary measures will be examined in the order listed below.  The process 
stops at the first p-value above 0.05.  
• Responder rate (experiencing a ≥50% reduction) during the titration + maintenance treatment 
periods of the DB phase for Cohort 2 
• Change in the number of seizure free days per 28-day period from baseline during the 
titration + maintenance treatment periods of the DB phase for Cohort 2  
• Clinical Global Impression of Change – Improvement (CGI-I; Investigator) at Week 14 of 
the double blind treatment phase relative to the baseline for Cohort 2 
All remaining secondary efficacy endpoints listed in the protocol will be tested at alpha =.05 so 
all p-values are nominal.   
Secondary efficacy outcome measures are listed below. 
a) Percent change in the 28-day seizure frequency from baseline to the DB phase during the 
maintenance treatment period for Cohort 2 
b) Change from baseline in 28-day seizure frequency during the DB phase for Cohort 2 
(titration + maintenance and maintenance only). 
c) Change in the number of seizure free days per 28-day period from baseline during the 
maintenance treatment period of the DB phase for Cohort 2 
d) Proportion of responders experiencing a ≥R% reduction from baseline to the end of 
treatment period in 28-day seizure frequency (titration + maintenance and maintenance 
only) for Cohort 2.  R% will be 20%, 40%, 60%, and 80% 
e) Proportion of subjects who completed the DB portion of the study (Cohort 2) and did not 
experience any seizures during the maintenance phase of the study 
f) Proportion of subjects who experienced at least one 28-day seizure free period during the 
DB phase of the study (titration + maintenance) for Cohort 2  
g) Longest period of time seizure free (%) (longest period of seizure free days divided by 
number of days with available seizure data) during the double blind phase (titration + 
maintenance) for Cohort 2  
h) Change from baseline in 28-day seizure frequency for different subtypes of seizures 
during the DB portion of the study (titration + maintenance) for Cohort 2 (SPS, 
SPS-motor, CPS, SGTC)  
i) Patient Global Impression of Change – Improvement (PGI-I; Patient/Caregiver) at each 
assessment visit 
j) Clinical Global Impression of Change – Improvement (CGI-I; Investigator) at each 
assessment visit 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
   
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
   
   
 
 
 
  
 
 
 
  
 
 
 
 
   
   
 
 
 
 
 
 
 
  
 
 
 
   
   
 
 
 
 
 
 
 
 
   
 
  
 
 
 
   
 
  
 
   
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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In addition, tolerability of ganaxolone during the up-titration periods of the study will be 
compared between the 2 cohorts.  Cohort 1 went through a 1-week titration period, followed by a 
4-week period at 1200 mg/day, before the start of a 4-week treatment with 1800 mg/day.  In 
comparison, Cohort 2 was treated with a 2-week titration period followed by maintenance 
treatment with 1800 mg/day.  AEs with onset during the titration period in Cohort 2 will be 
compared to AEs with onset during the weeks 1-5 in Cohort 1 (1 week titration + 4 week 
treatment with 1200 mg/day).  In addition, in Cohort 2, AEs with onset during the titration period 
will be compared to AEs with onset during the maintenance period.  AEs that emerge during the 
de-escalation period will also be tabulated to investigate whether discontinuation of ganaxolone 
is associated with withdrawal symptoms.  
 
ANALYSIS POPULATIONS 
5
5.1 
Randomized Population 
All subjects randomized will be used for summaries of subject disposition. 
5.2 
Safety Population  
The safety population includes all randomized subjects who received at least 1 dose of study 
medication.  This population is defined for safety analysis.  Subjects will be analyzed based on 
the actual treatment received.  The safety population will be used for all analyses of safety 
endpoints. 
5.3 
Modified Intent To Treat Population  
The modified intent to treat (MITT) population (full analysis population in protocol) includes all 
randomized subjects who received at least 1 dose of study medication and provided any post 
baseline seizure outcome data.  The MITT population is the primary population for efficacy 
analysis.  Subjects will be analyzed based on their randomized treatment assignment. 
5.4 
Per Protocol Population  
The per protocol (PP) population includes all MITT subjects who received at least 1 dose of 
treatment without major protocol violations that would potentially impact efficacy.  The PP 
population is used for supportive efficacy analyses.  PP population will be finalized by the study 
team prior to database lock.  Per protocol analysis will be conducted on the primary and 
key-secondary end-points only.  
5.5 
Protocol Deviations 
Major protocol violations leading to exclusion from the per protocol population will be 
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GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6
6.1 
General Methods 
• All analyses and summaries will be produced using SAS version 9.2 or above. 
• Unless otherwise specified, summaries will be presented by cohort, treatment and overall. 
• Continuous variables will be summarized by number of subjects, mean, standard deviation, 
median, minimum, and maximum.  
• Categorical variables will be summarized by counts and percentages. 
 
6.2 
Key Definitions 
Calculation of Baseline: 
For the primary efficacy endpoint(s): 
For subjects enrolled under and prior to Amendment 2, baseline will be calculated based upon a 
combination of 4 weeks of prospective recording in a daily seizure calendar contiguous with 
4 weeks of retrospective seizure history (seizure diary) which will be collected after obtaining 
informed consent.  Acceptable retrospective daily seizure data include a diary record of the 
frequency and type of seizures by day, subjects without acceptable retrospective daily seizure 
data will not be randomized.  After completing the 4-week prospective baseline period, eligible 
subjects are to be randomized to receive either ganaxolone or placebo. 
For subjects enrolled under Amendment 3, baseline will be calculated based upon the 8 weeks 
prospective recording in a daily seizure calendar, which will be collected after obtaining 
informed consent. 
For subjects still in the study at time of the primary analysis, last dose date will be considered the 
date of the most recent DB study visit in the database for that subject.  
For safety endpoints, non-missing value of last assessment before first dose will be set as 
baseline value for both Cohort 1 and Cohort 2. 
See Tables 1 and 2 in the protocol for details of the dosing regimen for each cohort/phase.  
6.3 
Missing Data 
If a subject has missing seizure count information during the baseline or treatment periods, these 
days will be not be imputed or considered in the calculation of the seizure frequency (i.e., the 
seizure frequency will be computed only over the non-missing days of the period).  
If a subject withdraws from the study before the end of the treatment period, the seizure 
information collected up until the time of withdrawal will be used to calculate the seizure 
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However, a set of sensitivity analyses will conducted as outlined below to understand the impact 
of missing data due to subject withdrawal from the study. 
Imputation of Missing Diary Seizure Frequency Data 
 The imputation process consists of a sequence of multiple imputation (MI) steps, with each step 
imputing missing values at one time-point only. The approach differentiates those who withdrew 
for treatment-related reasons (lack of efficacy or adverse events) and those who withdrew for 
other reasons (e.g. withdrawal of consent due to a move).   
A. Dropout Reason-based Multiple Imputation (DRMI) 
The not missing at random (NMAR) model assumes that observed data obtained from the pre-
specified subset of withdrawn GNX subjects who dropped out for treatment-related reasons are 
correlated with unobserved future visits similar to subjects in the placebo arm. This is equivalent 
to assuming that the unobserved trajectory of patients in the GNX arm is similar to that of the 
placebo subjects. Treatment related reasons include AEs, death and insufficient clinical response. 
B. Dropout Missing at Random Imputation (MAR) 
The missing data of the remaining GNX patients who have dropped out (due to non-treatment-
related reasons) are imputed assuming MAR. Missing data for placebo patients who withdrew 
for any reason will always be imputed based on placebo diary seizure frequency data. 
A summary of reasons for patients withdrawing from the GNX treatment arm and the 
corresponding treatment arm used to calculate the imputation of diary seizure frequency data 
under DRMI will be populated after the blind is broken as shown in the Table below.   
The MNAR imputation is achieved by using prior data and previously imputed values at each 
stage of the imputation. Imputation will be carried out in two steps; first, the non-monotone 
(intermediate—having a previous and subsequent observation) missing seizure frequencies will 
be imputed based on a Markov chain Monte Carlo (MCMC) method using SAS PROC MI. Next, 
missing values in each period will be imputed using a sequential regression method using 
MONOTONE REG option of SAS PROC MI. The lengths of the period will be two weeks. 
For example, to impute missing values in a two week period ending at time t for subjects in the 
GNX arms who dropped out due to one of treatment related reasons, placebo observations up to 
and including time t and observations from subjects in the GNX arms who dropped out due to 
one of the treatment related reasons, up to and including time t-1 will be used to develop the 
model. This is repeated sequentially for each bi-weekly time period using observed data and 
previously imputed values in the new model.  
Ten replicate study imputations will be carried out using a seed of 123456.  The analysis of each 
of the imputed dataset will be based on rank ANCOVA, the analytical method described in the 
Section 8.1 of the primary analysis; these imputations will be combined using Rubin’s formula 
implemented in the SAS procedure PROC MIANALYZE. 


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Statistical Analysis Plan 
 
 
 
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Reason for withdrawal 
DRMI 
Adverse Event 
Placebo 
Insuff. clinical response 
Placebo 
Death 
Placebo 
Non-compliance or Protocol Violation 
GNX 
Ineligible Per Inclusion/Exclusion Criteria 
GNX 
Lost to follow up 
GNX 
Withdrawal of Consent By Subject 
GNX 
Other  
GNX 
 
6.4 
Visit Windows 
Subjects must have a minimum of 28 days of prospective baseline seizure charting.  Visit 
windows are time intervals between the mid-points of 2 consecutive scheduled visits for Phase 1 
DB and Phase 2 OL (Visits 2- Post taper Safety Follow up) . 
6.5 
Pooling of Centers 
Sites will be pooled as follows: US sites and Rest of the World sites, for the analysis of the 
primary and secondary efficacy endpoints. 
 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
7
MEDICATION 
7.1 
Subject Disposition and Withdrawals 
The disposition table will include the number of subjects present at each phase, and discontinued 
along with the reason for discontinuation.  Data will be summarized by cohort, treatment, phase, 
and period, as appropriate.  
Additionally, duration in study will be summarized.   


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Statistical Analysis Plan 
 
 
 
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7.2 
Demographic and Other Baseline Characteristics 
Subject demographic data (age, gender, race, and ethnicity), height, weight and body mass index 
(BMI) will be collected at study screening and will be summarized by using descriptive statistics 
by cohort and overall.  
Height (in cm) = height (in inches) * 2.54 
Weight (in kg) = weight (in lbs) * 0.4536 
BMI (kg/m2) = Weight(kg)/(Height[m]2) 
7.3 
Medical History  
Medical history will be listed.  The medical history conditions will be summarized for each of 
the 4 periods within the 2 phases and cohorts combinations by treatment group and overall using 
frequencies and percentages on the body system levels and preferred term.  Medical history will 
be sorted alphabetically by body system and preferred term.  Medical history terms were coded 
using MedDRA version 16.0. 
7.4 
Epilepsy History 
Epilepsy history will be documented via eCRF at screening and includes the following 
information:  age in years and in months at first seizure, followed by the family history(Y/N) in 
first degree relatives (parent, sibling, and child).  For each ‘Y’, the following are collected:  
seizure type (if applicable and known), IQ (with date), Neurological Dysfunction.  Additionally, 
seizure calendars will be collected at the each visit and includes the following: date and type for 
each seizure.  These data will be summarized via appropriate summary statistics (see 
Section 6.1), and will be listed.  Percentage of patients with VNS will be summarized.  
7.5 
Medication 
Subjects participating in the study must 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: 
Vigabatrin:  Current use of vigabatrin (Sabril) is not permitted for the duration of the study due 
to its ophthalmologic toxicity, as well as prior use of vigabatrin without stable visual fields tested 
twice over the 12 months after the last dose of vigabatrin. 
Ezogabine (retigabine; Potiga; Trobalt):  Current use of ezogabine (retigabine) is not permitted. 
Subjects who may have used this agent in the past should have been off this medication for at 
least 3 months prior to screening and should have had a documented normal fundoscopic exam 
by an ophthalmologist. 
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 screening and has not experienced any 
serious psychiatric and behavioral reactions and is expected to remain on a constant dose 
throughout the study. 


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Statistical Analysis Plan 
 
 
 
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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 and the dose cannot be changed 
during the study. 
Vagal Nerve Stimulator:  Subjects receiving treatment with a VNS may be included as long as 
the VNS has been in place for at least 1 year prior to entry into the study, the VNS battery is not 
due for replacement during the DB phase (Cohort 1 weeks 1 to 9 and Cohort 2 weeks 1 to 14), 
and stimulation parameters have been kept constant for 3 months prior to screening.  VNS will 
not be counted as one of the 3 concomitant AEDs. 
AED medications will be coded using WHODrug Dictionary (December 2013), and will be 
summarized by standard medication name and medication class and sorted by descending 
incidence of standard medication name then alphabetical within medication class.  Data listings 
will be sorted in the same manner. 
The following table describes how missing date information regarding AED medications 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 
 
 
Prior Medication 
7.5.1
Prior medications will be summarized by WHO Drug Dictionary (December 2013) standard 
medication name, cohort, and treatment group.  Prior medication will be listed.  Prior AED 
medications will be summarized separately.  
A prior medication will be defined as any drug that has a start date before the first dose date of 
study drug.  Any medication that starts on the first dose date of study drug will not be considered 
prior.  Medications with a completely missing start date will be considered prior. 
Partial start dates will be used to determine if a medication is prior.  Medications with a 
completely missing start date will be considered prior.  If only a start month and year are present, 
then medications for which the month is before or the same as the first dose month will be 


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Statistical Analysis Plan 
 
 
 
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considered prior.  If only the start year is present, then medications for which the start year is 
before or the same as the first dose year will be considered prior. 
 
Concomitant Medication 
7.5.2
Concomitant medications will be summarized by WHO Drug Dictionary (December 2013) 
standard medication name, cohort, treatment phase and treatment group.  Concomitant AED 
medications will be summarized separately.  Concomitant medication will be listed. 
Concomitant medications will be defined as any drug that has a start date on or after the first 
dose date of study drug.  A medication that starts prior to first dose and stops after first dose will 
be considered as both Prior and Concomitant medications.  Medications with a completely 
missing end date will be considered concomitant.   
 
EFFICACY  
8
8.1 
Primary Efficacy Endpoint and Analysis 
The primary efficacy endpoint for US FDA registration is the percent change in 28-day seizure 
frequency (POS with or without secondary generalization) in Cohort 2 DB phase (14-week 
titration + maintenance treatment periods) relative to the baseline in the MITTP, frequency of 
POS seizures only includes 3 seizure subtypes which are SPS-motor, CPS and SGTC. 
Post-baseline 28-day seizure frequency will be calculated as the number of seizures in the entire 
treatment phase divided by the number of days with available seizure data in the treatment phase, 
multiplied by 28.  Baseline 28-day seizure frequency will be calculated as the number of seizures 
in the baseline period 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 group using descriptive statistics. 
The null hypothesis is that there is no difference in the medians between the 2 treatment groups 
with respect to percent change in seizure frequency. 
A rank analysis of covariance (ranked ANCOVA) will be used as primary analysis.  A 
nonparametric rank analysis of covariance will be used to analyze rank of percent change data 
from baseline, with treatment and pooled center (either US or ROW) as factors and the rank of 
baseline 28-day seizure frequency as a covariate in the model.  The baseline, post-baseline, and 
percent change from baseline in 28-day seizure frequency will be summarized by treatment 
group by using descriptive statistics.  The 2-sided significance level of 0.05 will be used for 
comparison.  Hodges−Lehmann estimator and 95% confidence interval (CI) for the estimator 
will be calculated. 


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Statistical Analysis Plan 
 
 
 
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An analysis of covariance (ANCOVA) as a sensitivity analysis will be conducted on the rank of 
percent change data from baseline, with treatment and pooled center (either US or ROW) as 
factors and the rank of baseline seizure frequency as a covariate.  P-value to test treatment effect 
will be determined by permutation test with seed = 123456 and 2000 iterations.  To deal with the 
missing data after subjects dropout, the multiple imputation method describled in Section 6.3 
will be utilized to perform additional sensitivity analyses.  These analyses provide a robustness 
assessment of the results. 
The MITT population of Cohort 2 is the primary population for efficacy analysis.  The PP 
population of Cohort 2 will be considered as supportive.  
There are 2 different types of baselines in the study; Cohort 1 has a baseline composed of 
4 weeks retrospective + 4 weeks prospective data collection, while subjects in Cohort 2, 
randomized under protocol amendment 3, has a baseline composed of 8 weeks of prospective 
data collection; however subjects randomized under protocol amendment 2 will have baseline 
data that is collected in the same fashion as Cohort 1 subjects.  Summary statistics will be 
generated by type of baseline to provide information regarding the robustness of the endpoint 
with respect to the choice of baseline.  Wilcoxon rank sum test will be used to test if there is 
difference between these 2 types of baseline.  Hodges−Lehmann estimator and 95% confidence 
interval (CI) for the estimator will be calculated. 
For European (EMA) Registration 
The primary efficacy endpoint for EMA registration is 50% responder rate during the 
maintenance treatment phase of DB phase for Cohort 2.  A 50% responder is an individual who 
experiences at least a 50% decrease in seizure frequency compared to baseline.  This end-point is 
analysed independently of the FDA registration end-point, and analysis of the key secondary 
end-points (below) is not predicated on the results of this end-point.  
The responder rates between ganaxolone and placebo will be compared using a logistic 
regression model, with terms for treatment, pooled center (either US or ROW), and baseline 
28-day seizure frequency in the model.  The number and percentage of responders will be 
summarized by treatment, odds ratio and associated 95% confidence interval and p-values will 
be reported. 
8.2 
Secondary, Exploratory Efficacy Endpoints and Analyses 
Key Secondary Endpoints: 
The 3 endpoints immediately following this paragraph will be tested by using a fixed sequence 
procedure to protect the familywise error rate at 0.05.  If the primary outcome measure is 
statistically significant, the p-values of the secondary measures will be examined in the order 
listed below.  The process stops at the first p-value above 0.05.  
• Responder rate (experiencing a ≥ 50% reduction) during the titration + maintenance 
treatment periods of the DB phase for Cohort 2  
• Change in the number of seizure free days per 28-day period from baseline during the 
titration + maintenance treatment phases of the DB phase for Cohort 2  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
  
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
  
 
  
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
   
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
  
 
 
 
  
 
 
 
  
  
 
 
  
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
   
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
   
 
  
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
   
   
 
 
 
  
 
 
 
  
 
 
 
 
   
   
 
 
 
 
 
 
  
 
 
 
 
   
   
 
 
 
 
 
 
 
 
   
 
  
 
 
 
   
 
  
 
   
 
  
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
  
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
   
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
  
 
  
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
   
  
 
 


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Statistical Analysis Plan 
 
 
 
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coefficient of the treatment term is equal to zero.  The number and percentage of responders will 
be summarized, odds ratio and associated 95% confidence interval and p-values will be reported. 
Summary table with descriptive statistics also will be provided in OL phase for both Cohort 1 
and Cohort 2, the baseline is the same as for the DB phase. 
Summary table of subjects by treatment in each following category for each phase and each 
cohort will be provided, the cut off of reduction of percent change from baseline will be 
classified in the following categories: ≤0%, ≤20%, ≤40%, ≤60%, ≤80%, and ≤100% in the 
summary table, and the corresponding graph will be displayed also.  
 
Change in the Number of Seizure Free Days per 28-day Period from Baseline 
8.2.4
Post-baseline number of seizure free days per 28-day period will be calculated as:  (the number 
of seizure free days in the maintenance treatment period during the double blind phase) divided 
by the number of days with available seizure data in the treatment phase and multiplied by 28. 
Baseline number of seizure free days per 28-day period will be calculated as:  the number of 
seizure free days in the entire baseline phase divided by the number of days with available 
seizure data in the baseline phase, multiplied by 28. 
The calculation of change in number of seizure free days per 28-day period from baseline will be 
done as follows for each subject: 
Post-baseline number of seizure free days per 28-day period – Baseline number of seizure free 
days per 28-day period. 
Change in number of seizure free days between ganaxolone and placebo will be analyzed using a 
rank ANCOVA, with treatment and pooled center (either US or ROW) as factors and the rank of 
baseline number of seizure free days per 28-day period as a covariate in the model.  The 
baseline, post-baseline, and change in number of seizure free days per 28-day period from 
baseline will be summarized by using descriptive statistics.  The 95% confidence interval of the 
median by treatment group will be presented also.  The 2-sided significance level of 0.05 will be 
used for comparison.  Hodges−Lehmann estimator of the difference in medians together with 
95% confidence interval (CI) will be calculated. 
Summary table with descriptive statistics also will be provided in OL phase for both Cohort 1 
and Cohort 2, the baseline is same as DB phase. 
 
Proportion of Seizure Free Subjects 
8.2.5
Proportion of subjects who completed the DB portion of the study and did not experience any 
seizures during the maintenance period of the study, and proportion of subjects who experienced 
at least one 28-day seizure free period anytime during the DB phase of the study (titration + 
maintenance) will be calculated.  
A frequency table will summarize the responses for each treatment in DB phase for Cohort 1 and 
Cohort 2.  The proportions of seizure free subjects between treatment groups will be compared 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
   
  
 
 
  
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
 
  
 
 
 
  
 
  
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
  
 
  
 
 
 
 
 
   
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
   
 
 
 
   
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
   
 
 
  
 
   
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
   
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 


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• Percent change in 28-day seizure frequency from baseline. 
• Change in 28-day seizure frequency. 
Descriptive statistics for the efficacy endpoints listed above will be produced for the titration+ 
maintenance period in the DB phase and the OL phase for both Cohort 1 and Cohort 2 by seizure 
subtype:  CPS, SGTC, SPS-motor and SPS (without motor).  
 
Other Subgroup Analyses 
8.3.3
Subgroup analyses on age group (<65, >65), gender, ethnicity and geographical region will be 
conducted also. For each of the subgroups, a separate rank ANCOVA model will be fitted using 
the same model terms as used for the primary analysis, with additional terms for the subgroup 
main effect and the treatment by subgroup interaction. The p value to test if the treatment by 
subgroup interaction is 0 will be presented. Similar output will be displayed for each subgroup as 
for the primary analysis in Cohort 2.  Descriptive summaries only will be displayed for all 
subgroup analyses in Cohort 1. 
Results (Hodge-Lehman estimator and its 95% CI) for all subgroups will be presented in tabular 
form and forest plots. 
 
SAFETY 
9
The population used for safety analyses will be the Safety Population (SP). 
9.1 
Extent of Exposure 
Exposure information will be calculated from the study drug log.  Capsule level accountability is 
not being collected, so 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.  Doses should be taken just before or up to 2 hours after a meal 
or snack, with 240 mL (8 oz.) of water.  Each dose should be separated by a minimum of 8 hours 
and a maximum of 12 hours.  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.  
Exposure data will be summarized using the Safety population for both cohorts.  


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See tables below for the titration schedules for the transition from DB to OL for both cohorts: 
Cohort 1, Phase 2 - Open-Label 
DB Transition to OL 
Visit 
Study Day 
Dose (mg)/day 
Bottle A 225 mg or PBO 
cap/day 
Bottle B 225 mg or 
PBO cap/day 
GNX:  225mg 
GNX:  225mg 
GNX/GNX 
PBO/PBO 
PBO:  225mg 
PBO:  PBO 
Visit 5 
64 
1800 
900 
4 
4 
 
65 
1800 
900 
4 
4 
 
66 
1800 
1350 
6 
2 
 
67 
1800 
1350 
6 
2 
 
68 
1800 
1350 
6 
2 
 
69 
1800 
1800 
8 
0 
 
70 
1800 
1800 
8 
0 
 
Cohort 2, Phase 2 - Open-Label 
DB Transition to OL 
Visit 
Study Day 
Dose (mg)/day 
Bottle A 225 mg or 
PBO cap/day 
Bottle B 225 mg or 
PBO cap/day 
GNX:  225mg 
GNX:  225mg 
GNX/GNX 
PBO/PBO 
PBO:  225mg 
PBO:  PBO 
Visit 5 
99 
1800 
450 
2 
6 
 
100 
1800 
450 
2 
6 
 
101 
1800 
450 
2 
6 
 
102 
1800 
900 
4 
4 
 
103 
1800 
900 
4 
4 
 
104 
1800 
900 
4 
4 
 
105 
1800 
1350 
6 
2 
 
106 
1800 
1350 
6 
2 
 
107 
1800 
1350 
6 
2 
 
108 
1800 
1350 
6 
2 
 
109 
1800 
1800 
8 
0 
 
110 
1800 
1800 
8 
0 
 
111 
1800 
1800 
8 
0 
 
112 
1800 
1800 
8 
0 
 
These schedules will be used to calculate the exposure for placebo subjects. 
Exposure to study medication and cumulative number of days on study medication will be 
summarized in the DB phase and OL phase for both Cohort 1 and Cohort 2.  A summary table of 
overall exposure to study medication combining the DB phase with OL phase in both Cohort 1 


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and Cohort 2 will be provided.  Ganaxolone group in Cohort 1 will be separated into 2 groups by 
dose level which are Ganaxolone 1200 mg and Ganaxolone 1800 mg. 
A summary table of subjects who reached and maintained maintenance dose of 1800 mg will be 
provided in each treatment phase for both cohorts.  Study drug dosing will be listed.  
9.2 
Treatment Compliance  
A record of all investigational products used 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 and strength), the date 
unused investigational product and empty investigational product containers are returned from 
the subject, and the quantity returned during Visits 3 through 10 and final post-taper safety 
assessment.  Investigational product and associated accountability forms that are maintained at 
the clinical site will be present for review by Clinical Research Monitors at each monitoring 
visit.  
At each visit all subjects will receive monthly Subject Seizure Calendars.  Each day 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.  The Study Drug compliance 
is a variable in the database calculated using the following formula:  (Stop date-Start date) + 1-
number of day’s drug not taken divided by (Stop date-Start Date) + 1 multiplied 100.  This value 
is calculated for visits 3, 5, 7, 9, 10, 12, 15, and 16.  If value is not calculated, a reason should be 
provided.  Per protocol, compliance with background AED medication will be accessed using 
data from the PK analysis of the AED medication, per SAP Section 2.1 this should be described 
and issued under a separate analysis plan. 
Study treatment compliance will be summarized in DB phase and OL phase for both Cohort 1 
and Cohort 2.  The ganaxolone group in Cohort 1 will be separated into 2 groups by dose level 
which are Ganaxolone 1200 mg and Ganaxolone 1800 mg.  Study treatment compliance will be 
listed. 
9.3 
Adverse Events 
The summary of AEs (or SAEs) will be limited to treatment emergent adverse events (TEAEs).  
A TEAE is any AE (or SAE) occurring on or after administration of the first dose of study 
medication and before the end of study.  An existing AE which worsens on or after 
administration of the first dose of study medication is also considered a TEAE.  AEs will be 
tabulated by treatment and Overall, system organ class (SOC), and Preferred Term using the 
MedDRA v.16.0 coding system.  The number and percentage of subjects with adverse events 
will be calculated for each cohort in each phase of the study, by treatment and overall, and in 
Cohort 1 DB phase, by dose and overall.  Additional tables with AEs subset by severity and by 
relationship to drug as assessed by the investigator will also be presented.  Subset listings will be 


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produced for adverse events that cause withdrawal and for SAEs.  Any AE with completely 
missing start and end dates will be considered a TEAE. 
All necessary information about an AE (onset, duration, severity, seriousness, causality to study 
drug, action taken, and outcome) should be documented by the investigator on the adverse event 
eCRFs (AE eCRFs).  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, 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 should be observed 
if the study drug is withdrawn or dose reduced. 
If discernible at the time of completing an AE eCRF, a specific disease or syndrome rather than 
individual associated signs and symptoms should be recorded.  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 eCRF (clinically significant laboratory abnormalities are those that are 
identified as such by the Investigator and/or those that require intervention). 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose (including 
overdose) that meets 1 or more of the following criteria: 
• Is fatal, as a direct outcome of the AE 
• Is life threatening  


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• Requires or prolongs inpatient hospitalization 
• Results in permanent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
 
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. 
Adverse events will be summarized by treatment group and overall for each cohort and phase 
separately for subjects in the Safety Population.  In Cohort 1 tables, AE’s will be summarized by 
treatment, dose level, and overall for subjects in the Safety Population, adverse events of subjects 
pooled in Cohort 1 and Cohort 2 for each treatment phase will be summarized.  The following 
AE tables will be generated:  
• An overall summary of the number and percentage of subjects reporting AEs, serious SAEs, 
treatment-related AEs, AEs leading to treatment discontinuation and AEs leading to death   
• AEs overall and by system organ class and preferred term 
• AEs by maximum severity, overall and by system organ class and preferred term 
• AEs by relationship to study treatment, overall and by system organ class and preferred term 
• AEs with onset (or worsening) during titration + 1200 mg/day dose (weeks 1 to 5) and 
1800 mg/d (weeks 6 to 9) by preferred term in Cohort 1 DB phase  
• AEs with onset (or worsening) during titration phase and maintenance phase by preferred 
term in Cohort 2 DB phase  
• AEs with onset (or worsening) during the de-escalation phase (time interval between 
Pre-Taper/Early Termination visit and Post-Taper Safety Follow Up visit) by preferred term 
in Cohort 1 and 2 OL phase 
 
All AEs, SAEs, AEs leading to drug discontinuation and AEs leading to death will be listed. 
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 


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9.4 
Laboratory Evaluations 
Laboratory data (including change from baseline) will be summarized using descriptive statistics 
by treatment and overall for each cohort and phase separately for subjects in the Safety 
Population.  Laboratory data of subjects pooled in Cohort 1 and Cohort 2 for each treatment 
phase will be summarized.  SI units will be used for both summarization and data listings. 
Separate summary tables and listings will be produced for each laboratory test group 
(Hematology, Serum Chemistry, Urinalysis, and other tests: See Protocol Appendix 2: Clinical 
Laboratory Tests).   
Hematology, Serum Chemistry, Urinalysis, and other tests will be summarized for baseline, each 
visit assessed, and for change from baseline by treatment group using descriptive statistics. 
Low, normal, and high classifications will be applied according to the central lab’s definitions to 
determine whether the worst laboratory test value within the visit window was below (low), 
within (normal), or above (high) its reference range.  Shifts from baseline in low/normal/high 
classification for each parameter will be summarized by treatment group. 
If there are multiple records within a visit window the last record will be used for summary 
tables, all results will be used for tables that assess maximum grade or toxicity, and included in 
data listings.  
9.5 
Vital Signs  
The actual values of each vital sign and change from baseline will be summarized descriptively 
at each visit by treatment group and overall for each cohort and phase separately for subjects in 
the Safety Population.  Shifts from baseline in low/normal/high classification for each parameter 
will be summarized by treatment group.  Vital sign of subjects pooled in Cohort 1 and Cohort 2 
for each treatment phase will be summarized. 
Listings of vital signs with abnormal flags will be provided. 
9.6 
ECG  
The 12-lead ECG parameters including changes from baseline will be summarized using 
descriptive statistics by treatment and overall for each cohort and phase separately for subjects in 
the Safety Population.  ECG data of subjects pooled in Cohort 1 and Cohort 2 for each treatment 
phase will be summarized.  SI units will be used for both summarization and data listings.  The 
QTc interval will be calculated using Fridericia’s formula. 
ECG result with Investigator comments will be listed for safety population. 
The Investigator may discontinue subjects from the clinical study for any of the following 
reasons:  Post-treatment QTc interval greater than 500 msec or uncorrected QT interval greater 
than 600 msec; for subjects with bundle branch block, post-treatment QTc greater than 530 msec 


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based on average QTc value of triplicate ECGs.  A subject with a post-treatment increase in QTc 
of greater than 60 msec from Baseline must also be withdrawn. 
If the initial electrocardiogram (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. 
9.7 
Physical and Neurological Examinations 
Physical and Neurological examination data will be summarized using descriptive statistics by 
treatment and overall for each cohort and phase separately, and data of subjects pooled in Cohort 
1 and Cohort 2 for each treatment phase will be summarized.  Listings for both physical and 
neurological examinations will be provided.  
9.8 
Other Safety 
Columbia-Suicide Severity Rating Scale data will be summarized and listed for each question 
each visit by treatment and overall, cohort and study phase for safety population. 
Pregnancy test result will be listed. 
Urine drug screen test result will be listed. 
 CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
10
10.1 Primary efficacy analysis will use only Cohort 2 data  
Primary efficacy analysis will be done when last subject in Cohort 2 completes the DB Phase of 
the study.  Analyses performed after last subject has completed the entire study, will be 
considered follow-up analyses. 
Rationale: 
Amendments to the original protocol changed the baseline seizure frequency from a combination 
of 4-week retrospective + 4-week prospective to 8-weeks prospective baseline period, which is 
more consistent with regulatory standards for registration studies, thus the desire to focus on 
Cohort 2 for the primary efficacy analysis.  The OL phase focuses on acquiring more safety data, 
specifically those that may appear with long term use.   


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 REFERENCE LIST 
11
1. Jacqueline AF, et al. (2012) Adjunctive perampanel for refractory partial-onset seizures: 
Randomized phase III study 304. Neurology 79 August 7, 2012. 
2. Hodges J. L., Jr. and Lehmann E. L. (1983). "Hodges-Lehmann Estimators," in Encyclopedia 
of Statistical Sciences, vol. 3, ed. S. Kotz, N. L. Johnson, and C. B. Read, New York: John 
Wiley & Sons, 463–465.  
 
 
 


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 PROGRAMMING CONSIDERATIONS 
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All tables, data listings, figures (TLFs), and statistical analyses will be generated using SAS® for 
Windows, Release 9.2 or above (SAS® Institute Inc., Cary, NC, USA).  Computer-generated 
table, listing and figure output will adhere to the following specifications.   
12.1 General Considerations 
• A separate SAS program will be created for each output. 
• Each output will be stored in a separate file. 
• Output files will be delivered in Word (RTF) format/pdf format. 
• Numbering of TLFs will follow ICH E3 guidance. 
 
12.2 Table, Listing, and Figure Format 
Unless otherwise specified, the estimated mean and median for a set of values should be printed 
out to 1 more significant digit than the original values, and standard deviations should be printed 
out to 2 more significant digits than the original values.  The minimum and maximum should 
report the same significant digits as the original values. 
Mock-up’s can be found in a separate document. 
12.3 Special Consideration Regarding Site 463 
Eight subjects participating in the 1042-0603 study in Bulgaria at site 463 ran out of drug 
supplies during the double-blind phase of the study due insufficient drug supplies available at the 
European drug depot.  Seven of the 8 patients had a break-in dosing up to 21 days and 1 patient 
lowered her study drug dose in order to sustain the drug supplies until the new supplies arrived.  
After the supplies arrived at the site the subjects were allowed to re-start or re-titrate the study 
drug under the same patient identification number and treatment assignment.  All 8 patients were 
re-titrated to 1800-mg/day dose and allowed to complete another 12 weeks of the study.  Seven 
patients have a gap period when they were not receiving the double-blind treatment.  The 
patients continued to record seizures in their diaries during the gap period.  
For the statistical analysis these subject’s titration periods and maintenance periods will be 
combined.  For example, a subject who had two 2-week titration period, a 4-week maintenance 
period, a 10-day gap, a 2-week re-titration period, and another 12-week maintenance phase 
would have a 4-week titration period and a 16-week maintenance period.  The 10 day gap 
without dosing would be counted towards the maintenance phase in keeping with the principles 
of mITT. All diary data will be included in the mITT analysis irrespective of whether the patient 
was receiving treatment or whether the patient’s treatment was on hold due to lack of drug 
supplies. All 8 patients will be excluded from the per protocol analysis population.  A table 
explaining the handling of each subject’s titration and maintenance phases and the gap is 
included in the appendix of this document. 


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 QUALITY CONTROL 
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SAS programs are developed to produce clinical trial output such as analysis data sets, summary 
tables, data listings, figures or statistical analyses.  
 MOCK-UPS 
14
All Mock-ups will be provided in a separate file.