Conditions: Epilepsy
Keywords: PCDH19 ganaxolone neurosteroid CDKL5 LGS CSWS
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
To evaluate the efficacy of open-label ganaxolone as adjunctive therapy for uncontrolled seizures in female children with PCDH19 mutation and other rare genetic epilepsies in an open-label proof-of-concept study.

Detailed description:
The purpose of this proof-of-concept study is to evaluate ganaxolone as adjunctive therapy for uncontrolled seizures in female children with PCDH19 mutations and other rare genetic epilepsies. After establishing baseline seizure frequency, qualifying subjects will enter the study and be treated with open-label ganaxolone for up to six months.

Arms:
arm 1: Maximum of 1800 mg/day or 63 mg/kg/day

Interventions: intervention 1: Ganaxolone
Intervention descriptions: intervention 1: oral suspension or capsules

Protocol document:
Prot_002.pdf: 
CONFIDENTIAL INFORMATION 
 
   
CLINICAL STUDY PROTOCOL 
 
STUDY TITLE: A Multicenter, 26 week Open-Label Proof-of-Concept Trial of 
Ganaxolone in Children with PCDH19 Female Pediatric Epilepsy And Other Rare 
Genetic Epilepsies Followed by 52 Week Open Label Treatment  
 
PROTOCOL NUMBER: 1042-0900 
STUDY PHASE: 2a 
STUDY DRUG(S): Ganaxolone (CCD 1042:3-hydroxy-3-methyl-5-pregnan-20-one) 
IND NUMBER:  44,020 
INDICATION:  PCDH19 Female Pediatric Epilepsy 
 
 
SPONSOR: 
Marinus Pharmaceuticals, Inc. 
142 Temple St. Suite 205 
New Haven, CT 06510 
 
SPONSOR CONTACT:   
Clinical Study Manager 
Telephone:
 
 
SPONSOR’S MEDICAL 
REPRESENTATIVE:  
 
Chief Medical Officer 
Telephone:
 
 
VERSION/DATE:  
version 6.0: 08 April 2016 


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1. 
SIGNATURE PAGE 
 
Sponsor Approval 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
Name (print): 
 
 
MD 
 
 
 
Chief Medical Officer 
 
 
Investigator Agreement:  I have read the protocol and agree to conduct the study as 
outlined herein. 
 
 
 
Signature: 
 
 
 
Date: 
 
 
 
Name (print): 
 
 
 
 
 
 
Institution 
(Print) 
 
 
 
 
 
 


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2. 
SYNOPSIS 
 
Name of Sponsor/Company: Marinus Pharmaceuticals, Inc. 
Protocol Number: 1042-0900 
Phase of Development: 2a 
Title of Protocol: A 26 week Multicenter, Open-Label Proof-of-Concept Trial of 
Ganaxolone in Children with PCDH19 Female Pediatric Epilepsy And Other Rare 
Genetic Epilepsies Followed by a 52 Week Open Label Treatment 
Primary Objectives: To evaluate the efficacy of open-label ganaxolone as adjunctive 
therapy for uncontrolled seizures in children with genetic epilepsies. These include, but 
are not limited to children with protocadherin19 (PCDH19) mutation, cyclin-dependent 
kinase like 5 (CDKL5) Disorder, Dravet Syndrome and other epileptic syndromes such 
as idiopathic or genetic types of Lennox-Gastaut syndrome (LGS), Continuous Spike 
Wave in Sleep (CSWS) and other potential genetic or clinical conditions with or 
without corresponding genetic condition (referred to as genetic epilepsies) in an open-
label proof-of-concept study. 
Secondary Objectives: To evaluate the safety and tolerability of open-label 
ganaxolone as adjunctive therapy for uncontrolled seizures in children with genetic 
epilepsies. 
Study Design and Methodology: After establishing baseline seizure frequency, 
qualifying subjects will enter the study and be treated with ganaxolone oral suspension 
or ganaxolone capsules at doses up to 63 mg/kg but not more than 1800 mg/day for up 
to six months.  
Study Population and Main Criteria for Inclusion/Exclusion: Subjects between 2 
and 18 years of age with a confirmed PCDH19 mutation, or a confirmed CDKL5 
mutation or Dravet syndrome with a confirmed SCN1A mutation or LGS, or CSWS or 
potential other genetic or clinical conditions with or without corresponding genetic 
condition and consent of a parent or guardian may be eligible to enter the study.  
Seizure criteria as follows: 
a. Have uncontrolled cluster seizures (3 or more seizures over the course 
of 12 hours) every 6 weeks or less during baseline, or bouts of status 
epilepticus on intermittent basis, or 
 
b. Have uncontrolled non-clustered seizures (focal dyscognitive, focal 
convulsive, atypical absences, hemiclonic seizures, spasms, or tonic-
spasm seizures) with a frequency 4 seizures per 28-day period during 
baseline, or 
 
c. Have ≥4 generalized convulsive (tonic-clonic, tonic, clonic, atonic 
seizures) per 28-day baseline period during baseline, or 
 


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CONFIDENTIAL INFORMATION 
 
d. Have subclinical CSWS syndrome with or without clinical events on 
electroencephalogram (EEG). 
 
Subjects should be on a stable regimen of AED medication, and generally in good 
health without active central nervous system (CNS) infection or progressive disease or 
clinically unstable psychiatric disorder likely to require new treatment during the study 
Subjects who have completed all scheduled clinical study visits and have shown a 
minimum 35% improvement in mean seizure frequency per 28 days vs. baseline may 
be enrolled in the 52 week open label extension. 
Number of Subjects: Approximately ten (10) subjects with PCDH19, 10 subjects with 
CDKL5 Disorder, 10 subjects with Dravet Syndrome, and up to 10 subjects with LGS, 
CSWS, encephalopathic epilepsy or other genetic epilepsies will be enrolled. 
Test Product, Dose and Mode of Administration: Ganaxolone oral suspension 50 
mg/mL dosed TID, or ganaxolone 200 mg or 225 mg capsules administered in BID. 
Oral suspension or capsules to be administered up to a total of 63 mg/kg/day but not 
more than 1800 mg/day.  
Duration of Treatment: After establishing baseline seizure type and frequency for a 
minimum of 4 weeks and up to 12 weeks, subjects entering the study will be treated 
with ganaxolone for 26 weeks, in the main portion of the study, and up to an additional 
52 weeks if clinical response is established plus additional time to down-titrate (1 to 4 
weeks). 
Reference Therapy, Dose and Mode of Administration: Not applicable 
 
Criteria for Evaluation:  
Primary Efficacy: Primary efficacy will be percent change in seizure frequency (focal 
dyscognitive or focal convulsive) per 28 days relative to the baseline. 
 
Secondary Efficacy: Secondary efficacy assessments include evaluation of inter-
cluster interval, time to reach baseline number of seizures, seizure-free interval, 50% 
responder proportion, proportion with 50% increase in inter-cluster interval, CGI-I. 
Safety: Neurological and physical examinations, clinical laboratory tests, 
electrocardiogram (ECG), vital signs, EEG and spontaneously reported adverse events 
(AEs). 
Serum Levels: Blood samples will be drawn at baseline, 2 weeks, 8 weeks, 26 weeks 
and at each visit in the open labeled extension and at unscheduled visits as needed for 
evaluation of blood chemistry and hematology, and to measure levels of ganaxolone, 
concomitant AED medications, allopregnanolone, and related endogenous CNS-active 
steroids.   
Statistical Methods:  
The primary and secondary efficacy variables will be summarized and using 
descriptive statistics for the populations of all subjects and completers. Individual 
subject data will also be presented. 


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Adverse events (AEs) will be tabulated by Overall, system organ class (SOC), and 
Preferred Term using the MedDRA coding system.  Incidence and percentage of 
adverse events will be presented by dose and overall.  Additional tables, with AEs 
subset by severity and by relationship to drug as assessed by the investigator will be 
presented. Subset listings will be produced for adverse events that cause withdrawal 
and for SAEs. 
Laboratory data, vital signs and ECGs will be summarized using descriptive statistics 
including changes from baseline.   


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3. 
TABLE OF CONTENTS 
1. 
SIGNATURE PAGE .............................................................................................................. 2 
2. 
SYNOPSIS ............................................................................................................................. 3 
3. 
TABLE OF CONTENTS ...................................................................................................... 6 
4. 
LIST OF ACRONYMS, ABBREVIATIONS AND DEFINITIONS OF TERMS ............ 8 
5. 
ETHICS ............................................................................................................................... 10 
5.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) . 10 
5.2 
Ethical Conduct of Study ................................................................................................. 10 
5.3 
Subject Information and Consent ................................................................................ 10 
6. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ....................... 11 
7. 
INTRODUCTION ............................................................................................................. 12 
8. 
STUDY OBJECTIVES ....................................................................................................... 19 
8.1 
Primary Objective ............................................................................................................. 19 
8.2 
Secondary Objectives ....................................................................................................... 19 
9. 
INVESTIGATION PLAN .................................................................................................. 20 
9.1 
Overall Study Design and Plan ...................................................................................... 20 
9.2 
Discussion of Study Design ............................................................................................ 20 
9.3 
Selection of study population ....................................................................................... 20 
9.3.1 
Number of Subjects .................................................................................................................... 20 
9.3.2 
Inclusion Criteria ......................................................................................................................... 20 
9.3.3 
Exclusion Criteria ........................................................................................................................ 22 
9.3.4 
Removal of Subjects from the Study .................................................................................... 23 
9.4 
Treatments .......................................................................................................................... 24 
9.4.1 
Treatments administered ........................................................................................................ 24 
9.4.2 
Identity of Investigational Products .................................................................................... 24 
9.4.3 
Subject Numbering ..................................................................................................................... 25 
9.4.4 
Study Dosing and Dosage Adjustments .............................................................................. 25 
9.4.5 
Dose Administration .................................................................................................................. 26 
9.4.6 
Missing a Dose .............................................................................................................................. 27 
9.4.7 
Background AED medication: ................................................................................................ 27 
9.4.8 
Concomitant Medications ........................................................................................................ 28 
9.4.9 
Treatment Compliance .............................................................................................................. 28 
9.5 
Efficacy and Safety Variables......................................................................................... 28 
9.5.1 
Calculation of Baseline .............................................................................................................. 28 
9.5.2 
Efficacy Assessments ................................................................................................................. 29 
9.5.3 
Safety Assessments ..................................................................................................................... 29 
9.5.4 
Other Assessments ..................................................................................................................... 30 
9.5.5 
Schedule of Study Procedures ................................................................................................ 31 
9.5.6 
Appropriateness of Measurements ...................................................................................... 37 
9.6 
Data Quality Assurance ................................................................................................... 37 
9.7 
Statistical Methods ............................................................................................................ 37 
9.7.1 
Analysis Populations .................................................................................................................. 37 
9.7.2 
Missing Data .................................................................................................................................. 38 
9.7.3 
Baseline and Demographic Characteristics ...................................................................... 38 
9.7.4 
Analysis of Primary Efficacy Variable ................................................................................. 38 


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9.7.5 
Analysis of Secondary Efficacy Variables .......................................................................... 38 
9.7.6 
Analysis of Safety Variables .................................................................................................... 38 
9.7.7 
Serum levels of AEDs, Ganaxolone and neurosteroids ................................................ 39 
9.7.8 
Determination of Sample Size ................................................................................................ 39 
10. 
INVESTIGATOR REQUIREMENTS .......................................................................... 40 
10.1 
Prior to Study Initiation .................................................................................................. 40 
10.2 
Prior to Study Completion .............................................................................................. 40 
10.3 
Study Discontinuation ..................................................................................................... 41 
10.4 
Informed Consent .............................................................................................................. 41 
10.5 
Adverse Events ................................................................................................................... 41 
10.5.1 
Definitions ................................................................................................................................. 42 
10.5.2 
Evaluating and Recording of Adverse Events ............................................................ 43 
10.5.3 
Reporting of Adverse Events ............................................................................................. 44 
10.6 
Study Monitoring and Audit Requirements ............................................................. 44 
10.7 
Electronic Case Report Forms ....................................................................................... 45 
10.8 
Study Drug Accountability ............................................................................................. 45 
10.9 
Confidentiality of Data ..................................................................................................... 45 
10.10 
Retention of Records ................................................................................................... 46 
10.11 
Protocol Adherence ..................................................................................................... 46 
11. 
PUBLICATION PLAN ................................................................................................. 47 
12. 
REFERENCES ............................................................................................................... 48 
13. 
Appendices .................................................................................................................. 50 
13.1 
Appendix 1: Clinical Laboratory Tests ....................................................................... 50 
13.2 
Appendix 2: Schedule of Events – 26 Week Treatment Period ......................... 51 
Schedule of Events – 52 Week Open-Label Extension ....................................................... 54 
13.3 
Appendix 3: Strong and Moderate Cytochrome P450 CYP 3A4, 5, 7 Inducers 
and Inhibitors Prohibited During Study 1042-0900 .......................................................... 57 
13.4 
Appendix 4:  Dose Escalation Suggested Schedules .............................................. 58 
13.5 
Appendix 5: Protocol History ........................................................................................ 60 
13.6 
Appendix 6: Amendment #5.2 Summary of Changes ........................................... 63 
13.7 
Appendix 7:  Seizure Calendar & Ratings.................................................................. 65 
 
 


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4. 
LIST OF ACRONYMS, ABBREVIATIONS AND DEFINITIONS OF 
TERMS 
Term 
Definition 
3,5-P 
ACTH 
3-hydroxy-5-pregnan-20-one; allopregnanolone 
adrenocorticotropic hormone 
AE 
adverse event 
AE CRF 
adverse event case report form 
AED 
antiepileptic drug 
ALT 
alanine transferase (SGPT) 
ARS 
acute repetitive seizures 
AST 
aspartate transferase (SGOT) 
BID 
CBD 
bis in die; two times per day 
cannabadiol 
CDKL5 
cyclin-dependent kinase like 5 
CFR 
Code of Federal Regulations 
°C 
CGII-C 
CGII-P 
degrees centigrade 
Clinical Global Impression of Improvement -Clinician 
Clinical Global Impression of Improvement – 
Patient/Caregiver 
CNS 
central nervous system 
CRF 
case report form 
C-SSRS 
CSWS 
Columbia-Suicide Severity Rating Scale 
Continuous Spike Wave in Sleep 
DDI 
drug-drug interaction 
EC 
Ethics Committee 
EEG 
ESES 
electroencephalogram 
Epileptic Status Epilepticus in Sleep 
ET 
early termination 
°F 
degrees Fahrenheit 
FDA 
Food and Drug Administration 
FLE 
Female-limited epilepsy 
FPE 
Female pediatric epilepsy 
GABAA 
-aminobutyric acidA 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IND 
investigational new drug 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
Kg 
LGS 
kilogram 
Lennox-Gastaut Syndrome 
m 
meter 
MedDRA 
MEG 
Medical Dictionary for Regulatory Activities 
magnetoencephalography 
mg 
milligram 
mg/day 
milligram per day 
min 
minutes 
mL 
MRI 
millilitre 
magnetic resonance imaging 
MTD 
maximum tolerated dose 


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Term 
Definition 
n 
number of subjects 
oz 
ounces 
PCDH19 
protocadherin19 
PK 
pharmacokinetics 
SAE 
serious adverse event 
SAE CRF 
serious adverse event case report form 
SOC 
system organ class 
TID 
three times daily 
Tmax  
time to maximum concentration  
ULN 
upper limits of normal 
USA 
VAS 
United States of America 
Visual Analogue Scale 
 
 
 
 
 
 
 
 
 
 
 


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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, subject's legal guardian will give their written 
consent to the subject's participation 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 8 participating centers in the USA, 
and Italy with ~1-3 subjects per condition enrolled at each site.  
Study enrollment is planned for 6 months from the time of first subject visit.  After 
signing informed consent, subjects may be asked to chart seizures in order to establish 
baseline frequency for up to 12 weeks.  Eligible subjects will be treated with open-label 
ganaxolone for up to 26 weeks, 52 weeks of additional open-label treatment and at the 
end of the study or at discontinuation they will be down-titrated for up to 4 weeks.  
 


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7. 
INTRODUCTION 
Patients with rare epilepsy conditions such as PCDH19 Female Pediatric Epilepsy, CDKL5 
Disorder, and Dravet Syndrome as well as many other refractory genetic epilepsy 
conditions that may share common seizure types and often their seizures become treatment 
resistant.   These may overlap idiopathic Lennox-Gastaut syndrome (LGS) patients or other 
genetically based conditions with intractable epilepsy clinically resembling LGS.  This 
population has been, at times, treated with and responsive to classes of corticosteroids like 
prednisone or adrenocorticotropic hormone (ACTH).  Another epileptic diagnostic 
condition Continuous Sleep Wave in Sleep (CSWS) or Epileptic Status Epilepticus in Sleep 
(ESES) may also respond to steroid medications and be refractive to standard antiepileptic 
agents.  The mechanism by which any of these mutations contributes to the development 
of epilepsy is not well understood. No one anticonvulsant has been found to be uniformly 
effective, and often multiple anticonvulsants are needed.  Even then, patients still become 
treatment resistant. Therefore the need for novel treatments to address seizure control is 
critical for patients living with these conditions. 
This study will test ganaxolone as an experimental drug with a new and distinct mechanism 
of action.  Ganaxolone is the 3-methylated synthetic analog of allopregnenolone, an 
endogenous allosteric modulator of GABAA receptors in the CNS. Ganaxolone has potency 
and efficacy comparable to allopregnanolone11 in activating synaptic and extrasynaptic 
GABAA receptors at a site distinct from the benzodiazepine site.  Ganaxolone has 
protective activity in diverse rodent seizure models. 12, 13, 15 and has been shown in clinical 
trials to be effective as adjunctive treatment for partial-onset seizures.  
Clinical studies have demonstrated ganaxolone has anticonvulsant efficacy with an 
acceptable safety and tolerability profile in the dose range of 900-1800 mg in adults and 
children, the present study is planned to investigate whether ganaxolone provides efficacy 
for children with uncontrolled seizures and PCDH19 Female-Pediatric Epilepsy, and other 
genetic epilepsies.  
 
 
 
 


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BACKGROUND ON PCDH19 
Protocadherin (PCDH)19- female-pediatric epilepsy (FPE), also known as PCDH19 
female-limited epilepsy (FLE) or epilepsy in females with mental retardation (EFMR), is 
a serious epileptic syndrome characterized by early-onset cluster seizures, cognitive and 
sensory impairment of varying degrees, and behavioral disturbances in some individuals.1 
This disorder is associated with a mutation of the PCDH19 gene, the gene that encodes for 
protocadherin19 on the X chromosome.2,3  The mechanism by which this mutation 
contributes to the development of epilepsy and intellectual impairment is not fully 
understood, however protocadherin19 is a transmembrane protein of calcium-dependent 
cell-cell adhesion molecules that is strongly expressed in neural tissue (e.g., hippocampus, 
cerebral cortex, thalamus, amygdale), and which appears to be related to synaptic 
transmission and formation of synaptic connections during brain development.3   Research 
suggests impairment of GABAergic signaling both at the agonist and receptor levels is 
present in girls with PCDH19 mutations and pediatric-onset epilepsy.4 
The hallmark characteristics of PCDH19-FPE are clusters of seizures which start in infancy 
or early childhood often associated with fever or immunization.5-7 Patients with PCDH19-
FPE may experience individual seizures in addition to clusters and multiple seizure types. 
In some patients, seizures improve as patients reach puberty, possibly due to increased 
endogenous levels of progesterone and allopregnanolone.8-10  
Background on CDKL5 Disorder 
CDKL5 disorder or CDKL5 stands for cyclin dependent kinase like 5, and is located on 
the X chromosome.  The CDKL5 gene was previously called STK9. CDKL5 is a rare X 
linked genetic disorder that results in early onset, difficult to control seizures, and severe 
neuro-developmental impairment. 19    
Most of the children affected by CDKL5 present with irritability in the perinatal period, 
early epilepsy, hand stereotypies, severely impaired psychomotor development and severe 
hypotonia. In contrast to classical Rett syndrome they also may have absence of a classic 
regression period, poor eye contact, generally normal head circumference and other growth 
parameters and relative absence of autonomic dysfunction. 19 


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Other 
symptoms 
of 
a 
CDKL5 
disorder 
often 
include: 
Low muscle tone, hand wringing movements or mouthing of the hands, marked 
developmental delay, limited or absent speech, lack of eye contact or poor eye contact, 
gastroesophageal reflux, constipation, small, cold feet, breathing irregularities such as 
hyperventilation, grinding of the teeth, episodes of laughing or crying for no reason, 
low/Poor muscle tone, very limited hand skills, some autistic-like tendencies, scoliosis, 
Cortical Visual Impairment (CVI), aka “cortical blindness”, apraxia, eating/drinking 
challenges, sleep difficulties and  characteristics such as a sideways glance, and habit of 
crossing leg. 20 
BACKGROUND ON DRAVET SYNDROME 
Dravet syndrome is a rare genetic epileptic encephalopathy described in 1978. It begins in 
the first year of life in an otherwise healthy infant. Prior to 1989, this syndrome was known 
as epilepsy with polymorphic seizures, polymorphic epilepsy in infancy (PMEI) or severe 
myoclonic epilepsy in infancy (SMEI). The disease begins in infancy but is lifelong. 17,18 
 
About 80% of people with this syndrome have a gene mutation (SCN1A is the most 
frequent) that causes problems in the way that ion channels in the brain work. 
Approximately 95% of patients with Dravet syndrome have de novo heterozygous 
mutations, which explains the unaffected status of many siblings and parents. 17,18  
 
The first seizure is often associated with a fever and may be a tonic clonic seizure or a 
seizure involving clonic movements on one side of the body. The seizures are refractory in 
most cases. Most children develop some level of developmental disability and have other 
conditions that are associated with the syndrome. Infants have normal development at the 
time the seizures begin, magnetic resonance imaging (MRI) and electroencephalogram 
(EEG) tests are also normal in infancy. 17,18 
 
Myoclonic seizures appear between 1 and 5 years in 85% of children with Dravet 
syndrome. Seizures early in life are often prolonged (lasting more than 2 minutes) or 
repetitive and can result in status epilepticus. Children with Dravet syndrome can develop 


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many different seizure types: myoclonic seizures, tonic clonic seizures, absence or atypical 
absence seizures, atonic seizures, partial seizures, non-convulsive status epilepticus. 17,18 
 
Seizures occur without a fever. However, these children are very sensitive to infections and 
frequently have seizures when they are ill or have a fever. Seizures can also be triggered 
by slight changes in body temperature that are not caused by infection for example a warm 
or hot bath water or hot weather. Many children have photosensitive seizures. Emotional 
stress or excitement can also trigger seizures in some children. 17,18 
 
Children usually develop normally in the early years. After age 2, they may lose 
developmental milestones or do not progress as quickly as they get older and have more 
seizures. There seems to be a correlation between frequency of seizures, how often status 
epilepticus occurs, and the degree of developmental delay in children. Around 6 years of 
age, cognitive problems in some children may stabilize or may start improving. However, 
most children with Dravet syndrome have some degree of developmental disability that 
persists. 17,18 
 
Other problems that may be seen include: low motor tone – can lead to painful foot 
problems, unsteady walking, some may develop a crouched gait, chronic infections, low 
humoral immunity, growth and nutrition problems, problems with the autonomic nervous 
system and behavioral or developmental problems such as autism spectrum disorder. 17,18 
 
BACKGROUND ON LGS AND CSWS 
Lennox-Gastaut syndrome is a severe form of epilepsy. Seizures usually begin before 4 
years of age. Seizure types, which vary among patients, include tonic, atonic, atypical 
absence, and myoclonic. There may be periods of frequent seizures mixed with brief, 
relatively seizure-free periods. Most children with LGS experience some degree of 
impaired intellectual functioning or information processing, along with developmental 
delays, and behavioral disturbances. Lennox-Gastaut syndrome can be caused by brain 
malformations, perinatal asphyxia, severe head injury, central nervous system infection and 
inherited degenerative or metabolic conditions. In 30-35 percent of cases, no cause can be 


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found. Many cases of LGS have had genetic mutations associated with the diagnosis 
clinically. These can include known encephalopathic epilepsy genes in Rett Syndrome, 
CNTNAP1, XP22.33, SCN2A, GABR3, Shank2, Shank3, and other genetic conditions 
associated with LGS-type clinical epilepsy. Non –degenerative genetic types of LGS or 
idiopathic refractive cases may respond to the neurosteroid mechanism of ganaxolone. 
 
Continuous spike way in sleep starts with seizures between 2 to 12 years; peaks at 4 to 5 
years with EEG continuous spikes and waves during slow-wave sleep, usually 1 to 2 
years from seizure onset. Males (62%) show preponderance and up to 1/3 of the patients 
have abnormal mental state. The clinical manifestations include three stages of evolution: 
• 
First stage before CSWS: infrequent nocturnal motor focal seizures, often 
hemiclonic status epilepticus, absences, atonic, complex focal seizures, and 
generalized tonic-clonic seizures occur. 
• 
Second stage with CSWS: seizures more frequent and complicated with typical or 
more frequent atypical absences, myoclonic absences, absence status epilepticus, 
rarely atonic or clonic seizures, and focal simple or partial complex dyscognitive 
seizures, usually nocturnally during CSWS condition on EEG and some secondary 
or primary generalized tonic-clonic seizures. Tonic seizures do not occur.  Eminent 
psychomotor decline and behavioral abnormalities, and a Wernicke’s type or global 
language regression occurs with localization of perisylvian cortex on EEG and 
magnetoencephalography (MEG) studies. 
• 
Third stage (after months to usually 2 to 10 years) with remission of CSWS and 
seizures and general improvement, normalization of CSWS pattern, and residual 
language or other learning difficulties.  
• 
New genetic overlap to autism genetics and epilepsy genetics have been noted, 
mainly Grin2A or Grin2B among others. Many may be idiopathic to testing. 
 
BACKGROUND ON GANAXOLONE 
More than 1,000 adult and pediatric subjects have received treatment with ganaxolone in 
clinical trials, ranging in duration from one day to more than two years using doses from 
50 to 2000 mg/day. In the Phase 2 program, 697 adults received ganaxolone in 9 completed 


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trials, 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 tid) adjunctive therapy significantly reduced partial onset seizures, with or without 
secondary generalizations, compared to placebo (p= 0.014). Ganaxolone-treated subjects 
experienced a median decrease of 26% (17.6% mean) compared to a 10.2% median 
decrease in placebo (2.0% mean increase for the placebo arm). 
Ganaxolone has been studied in 5 studies of pediatric seizure disorders in children aged 4 
months through 15 years.  Genotyping was not performed in any of these trials. Four open-
label studies tested ganaxolone oral suspension at doses up to 36 mg/kg/day in subjects 
with history or current infantile spasms plus other seizure types including focal and 
generalized tonic-clonic, resistant to available medications. Across the four studies, 
approximately two thirds of subjects experienced some improvements in seizures and one 
third of subjects in these open-label investigations experienced improvements of 50% or 
greater from baseline seizure frequency. A double-blind, placebo controlled partial 
crossover trial of ganaxolone in infants (N=57) with infantile spasms did not show a 
statistically significant reduction in spasms between treatment groups over the 8-10 day 
treatment period, though only 18 subjects were exposed to placebo. Fifty-four subjects 
entered the long term open-label extension study, where 25% were recorded as seizure-free 
on the video EEG at study endpoint.   
Most of the adverse events reported in the clinical development program were mild or 
moderate in severity, dose-related, resolved upon treatment discontinuation, and expected 
based on ganaxolone pharmacology. The most common adverse events across clinical trials 
are dizziness, fatigue and somnolence.  The adverse event profile of ganaxolone in pediatric 
studies is similar to that seen in adults, without evidence of unique, clinically meaningful 
adverse events specific to the pediatric population. Adult and pediatric subjects in open 
label extension studies to the epilepsy trials have been dosed with ganaxolone for > 2 years 
(a few children as long as 4 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. 


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In Study 1042-0600 and in the ganaxolone development program overall, no clinically 
significant trends in changes from baseline electrocardiogram (ECG) recordings, vital 
signs, or physical or neurological examinations have been noted in the clinical studies, and 
no mean changes from baseline in clinical labs have been identified. Transient increases in 
LFTs (>3xULN) have been noted in less than 1% of subjects treated with ganaxolone. 
Serious adverse events (SAEs) reported in the ganaxolone epilepsy trials were considered 
by a Scientific Advisory Board to be usual for the population without any pattern 
attributable to ganaxolone (References 13-16 and Marinus, data on file).  
Preclinical safety pharmacology and toxicology testing with ganaxolone has not revealed 
any end organ toxicity nor potential for ganaxolone to cause cellular mutations or 
carcinogenicity in studies to date.  In reproductive toxicology testing, ganaxolone did not 
cause any malformations of the embryo or fetus in rats or mice and did not significantly 
affect the development of offspring. Ganaxolone is primarily metabolized by the CYP3A 
family of liver enzymes, but interactions based on hepatic metabolism are limited to those 
caused by induction or inhibition of CYP3A4/5 by other drugs such as ketoconazole.  
As studies have demonstrated ganaxolone has anticonvulsant efficacy with an acceptable 
safety and tolerability profile in the dose range of 900-1800 mg in adults and children, the 
present study is planned to investigate whether ganaxolone provides anticonvulsant 
efficacy for female children with uncontrolled seizures and PCDH19 mutation.  
 
 


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8. 
STUDY OBJECTIVES 
8.1 
Primary Objective 
To evaluate the efficacy of open-label ganaxolone as adjunctive therapy for uncontrolled 
seizures in children with PCDH19 Female Pediatric Epilepsy, CDKL5 Disorder, Dravet 
Syndrome, and other epileptic syndromes such as LGS, CSWS and other potential 
genetic or clinical conditions with or without corresponding genetic condition  (referred 
to as genetic epilepsies) in an open-label proof-of-concept study. 
8.2 
Secondary Objectives 
To evaluate the safety and tolerability of open-label ganaxolone as adjunctive therapy for 
uncontrolled seizures in children with genetic epilepsies. 


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9. 
INVESTIGATION PLAN 
9.1 
Overall Study Design and Plan 
The purpose of this proof-of-concept study is to evaluate ganaxolone as adjunctive 
therapy for uncontrolled seizures in female children with PCDH19 mutations, CDKL5 
mutation and SCN1A mutation (Dravet syndrome) and other epileptic syndromes such as 
LGS, CSWS and other potential genetic or clinical conditions with or without 
corresponding genetic condition (referred to as genetic epilepsies) in an open-label proof-
of-concept study.  After establishing baseline seizure frequency, qualifying subjects will 
enter the study and be treated with open-label ganaxolone oral suspension or ganaxolone 
capsules at doses up to a maximum of 1800 mg/day for up to six months. Maximum 
study participation will be 94 weeks:  a screening period to establish baseline seizure 
frequency, 26 weeks treatment, and a 52 week extension for patients who benefit from 
ganaxolone treatment and up to 4 weeks down-titration. 
9.2 
Discussion of Study Design 
This proof-of-concept study was designed to evaluate ganaxolone in a small number of 
pediatric subjects with open-label treatment.  The open-label design eliminates exposure 
to placebo, and the flexible dose selection allows optimization of the dose for these 
pediatric subjects. Administration of the test article as adjunctive therapy to background 
antiepileptic drugs (AEDs) provides standard-of-care therapy in addition to any benefit 
that study medication might provide. 
9.3 
Selection of study population 
9.3.1 
Number of Subjects 
Approximately 10 subjects with PCDH19, 10 subjects with CDKL5 Disorder, 10 subjects 
with Dravet Syndrome, and up to 10 subjects with LGS, CSWS, encephalopathic 
epilepsy or other genetic epilepsy cases will participate. 
9.3.2 
Inclusion Criteria 
1. Have parent or legal guardian available and willing to give written informed 
consent, after being properly informed of the nature and risks of the study and 
prior to engaging in any study-related procedures.  
2. Outpatients between 2 and 18 years of age at time of consent. 


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3. In the opinion of the investigator have confirmed PCDH19 genetic mutation, 
confirmed CDKL5 genetic mutation or Dravet Syndrome confirmed by a SCN1A 
mutation, or genetic epilepsy testing confirming a LGS or CSWS condition 
associated with this genetic phenotype. Refractive cases of LGS or CSWS that 
remain idiopathic or have prior history of steroid or ACTH response can also be 
entered if documentation confirms specific genetic defects are not found and prior 
steroid response clinically occurred. 
4. Seizure criteria: 
a. Have uncontrolled cluster seizures (3 or more seizures over the course of 12 
hours) every 6 weeks or less during baseline, or bouts of status epilepticus on 
intermittent basis, or 
 
b. Have uncontrolled non-clustered seizures (focal dyscognitive, focal 
convulsive, atypical absences, hemiclonic seizures, spasms, or tonic-spasm 
seizures) with a frequency 4 seizures per 28-day period during baseline, or 
 
c. Have ≥4 generalized convulsive (tonic-clonic, tonic, clonic, atonic seizures) 
per 28-day baseline period during baseline, or 
 
d. Have subclinical CSWS syndrome with or without clinical events on EEG 
 
5. Subjects should be on a stable regimen of AED medication, and generally in good 
health. 
6. Parent or guardian is able and willing to maintain an accurate and complete daily 
written seizure calendar for the duration of the study. 
7. Able and willing to take study medication with food, two or three times daily. 
Ganaxolone must be administered with food. 
8. Sexually active women of child bearing potential (WCBP) must be using a 
medically acceptable method of birth control and have a negative urine sample at 
the baseline visit. 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 urine will be tested per protocol. 
 
9. Subject must be approved to participate by Sponsor and Principal Investigator 


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after review of medical history and baseline seizure calendars.   
 
10. For entry into the 52 week open label extension, subjects must have completed all 
scheduled clinical study visits and have shown a minimum 35% improvement in 
mean seizure frequency per 28 days vs. baseline over the 28 day periods 
preceding study entry. 
 
 
 
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. For PCDH19 FPE subjects, have a combination of PCDH19 and SCN1A genetic 
mutation. 
4. Exposure to any investigational drug or device < 90 days prior to screening, or 
plans to participate in another drug or device trial at any time during the study. 
5. Seizures secondary to illicit drug or alcohol use, infection, neoplasm, 
demyelinating disease, degenerative neurological disease, or central nervous 
system (CNS) disease deemed progressive, metabolic illness, or progressive 
degenerative disease. 
6. Concurrent use of vigabatrin, tiagabine, ezogabine or finasteride is not permitted, 
nor use of moderate or severe inducers or inhibitors of CYP3A4/5/7. Individuals 
with prior use of vigabatrin must have had stable visual fields tested twice over 
the 12 months after the last dose of vigabatrin.  A list of CYP3A4/5/7 inhibitors 
and inducers is included in the Appendix. For Dravet Syndrome subjects the 
following are also excluded: phenytoin, fosphenytoin, carbamazepine, 
oxcarbazepine, lamotrigine, rufinamide and stiripentol (Italy specific).  
• Patients on cannabadiol (CBD) products that have shown < 75% improvement 
must be withdrawn from CBD and be off product >28 days prior to Visit 2. 
• Patients on CBD products that have shown > 75% improvement and have 
completed or discontinued from the blinded clinical study, are on maintenance 
CBD for > 6 months or taking epidolex with stable laboratory values and no 
SAEs will, on a case by case basis, be considered for enrollment.  The 
decision to taper or leave the patient on the drug before adding ganaxolone 
will be made, if it is believed to be unethical to take the patient off drug and 


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promote status epilepticus or loss of gained > 75% improvement of seizure 
control. The patient will need to meet criteria for current entry seizure 
frequency for ganaxolone study. 
7. 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. 
8. Have active suicidal plan/intent, or have had active suicidal thoughts in the past 
6 months or a suicide attempt in the past 3 years. 
9. 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 baseline visit. 
10. Are planning to follow a ketogenic diet. If on ketogenic diet for more than 6 
months with stable laboratory values and seizure control then enrollment will be 
made on a case by case basis. 
11. Is sexually active or pregnant. 
12. Unwilling to forgo grapefruit and grapefruit juice from diet during the entire 
clinical trial.  
 
9.3.4 
Removal of Subjects from the Study 
9.3.4.1 
Investigator-initiated withdrawal of a subject 
All subjects have 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 if the subject's condition changes such that the Investigator feels it is not in 
her best interest to continue, or if she develops a concomitant illness that necessitates 
treatment which might affect the outcome of the investigation, or if the subject is non-
compliant. 
Discontinuation decisions will be made at each participating site by the Investigator.  If 
feasible, the process of discontinuation should be discussed with the Study Principal 
Investigator and the Sponsor.  


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9.3.4.2 
Early Termination Procedures 
Subjects who are terminated from the study will be asked to return to the study center for 
a final safety assessment, initiate a down-titration, and to return unused study medication 
and to deliver remaining seizure calendars. 
9.3.4.3 
Consequences of Early Termination 
The protocol suggests dose de-escalation of study medication over one to four 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 down-titration.   
9.4 
Treatments  
9.4.1 
Treatments administered 
Study medication will be provided as either oral suspension or capsules.  Ganaxolone oral 
suspension should be administered through an oral dosing syringe three times daily (TID) 
by a parent or guardian, following the morning, midday, and evening meal or snack. Each 
dose should be separated by a minimum of 4 hours and a maximum of 8 hours. A missed 
dose of ganaxolone suspension may be taken up to 4 hours before the next scheduled 
dose, otherwise, the missed dose should not be given. 
Ganaxolone capsules will be administered two times daily (BID), following the morning 
and evening meal or snack. A missed dose of ganaxolone capsules may be taken up to 8 
hours before the next scheduled dose, otherwise, the missed dose should not be given. 
9.4.2 
Identity of Investigational Products 
Ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one) suspension contains ganaxolone 
(50 mg ganaxolone/mL), hydroxypropyl methylcellulose, polyvinyl alcohol, sodium 
lauryl sulfate, simethicone, methyl paraben, propyl paraben, sodium benzoate, citric acid, 
and sodium citrate at pH 3.8 – 4.2 and is sweetened with sucralose and flavored with 
artificial cherry. The suspension has a milky appearance and is packaged in HDPE bottles 
with a child resistant closure. Ganaxolone will be supplied at a concentration of 50 
mg/mL (ganaxolone equivalent) in 120 mL bottles, containing 110 mL ganaxolone.  


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Ganaxolone capsules will be provided in size 00 white/opaque gelatin capsules packaged 
in HDPE bottles with a foil induction seal and child resistant closure. Each capsule 
contains either 200 mg or 225mg 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. 
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 (oral suspension and capsules) should 
be stored at room temperature 15°C to 25°C (59°F to 86°F). 
9.4.3 
Subject Numbering 
Each subject will be assigned a unique 6-digit subject number by the study staff.  The 
subject number will consist of a 3-digit clinical investigational site number assigned by 
the Sponsor, followed by a three-digit subject number (e.g., 001) assigned by the study 
staff.  
The clinical site is responsible for maintaining a current log of subject number 
assignments and bottle numbers of the investigational product administered to each 
subject.  The subject’s initials (first/middle/last) and unique subject number are required 
to be entered on all clinical investigation documentation (i.e., CRFs, labeling of clinical 
materials and samples containers, drug accountability logs, etc.) 
9.4.4 
Study Dosing and Dosage Adjustments 
For subjects >30 kg 
 
After Sponsor and Principal Investigator have reviewed subject's history, baseline seizure 
data and inclusion/exclusion criteria and determined a subject to be eligible for the study, 
ganaxolone treatment will be initiated at a dose of 900 mg/day in divided doses. The dose 
will be increased by approximately 20 to 50% (e.g., an increase from 900 mg/day to 1200 
mg/day is a 33% increase) at intervals of not less than 3 days and not more than 2 weeks 
provided current dose is reasonably tolerated, until desired efficacy is achieved or a 
maximally tolerated dose (MTD) level is reached. Subsequent dose adjustments should 


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be made in increments of approximately 20 to 50% with a minimum of three days 
between dose changes, unless required for safety.  Any and each dose escalation above 
1500 mg/day requires a clinic visit scheduled 4-6 days after the dose increase to assess 
safety and tolerability.  The maximum allowable dose is 1800 mg/day.  
For subjects ≤30 kg 
 
For children weighing 30 kg (66 lbs) or less, dosing should start at 18 mg/kg/day and be 
increased in ~20-50% increments at intervals of not less than 3 days and not more than 2 
weeks provided current dose is reasonably tolerated, until desired efficacy is achieved or a 
maximally tolerated dose (MTD) level is reached. Subsequent dose adjustments should be 
made in increments of ~20-50% with a minimum of three days between dose changes, 
unless required for safety.  Any and each dose escalation above 54 mg/kg/day requires a 
clinic visit scheduled 4-6 days after the dose increase to assess safety and tolerability.  The 
maximum allowable dose is 63 mg/kg/day. (see Appendix 4 for suggested dose escalation 
schedule.) 
 
DOWN TITRATION 
 
At the conclusion of the study, or upon discontinuation if the subject is terminated from 
the study prior to Week 26, a period of down-titration from 1 to 4 weeks should be 
initiated. The down-titration duration will be determined by the site investigator with 
input from the Sponsor based on subject's age, weight, dose and duration on study 
medication.  
9.4.5 
Dose Administration 
Study medication will be provided as either oral suspension or capsules. Ganaxolone 
should be taken with a meal or snack, whether oral suspension or capsules. 
Ganaxolone capsules should be administered with a glass of water or other liquid. Note 
that grapefruit and grapefruit juice are prohibited during the study. 
 Ganaxolone oral suspension will be administered through an oral dosing syringe 
administered or supervised by parents/guardians three times daily (TID), following the 
morning, noon, and evening meal or snack. Each dose should be separated by a minimum 
of 4 hours and a maximum of 8 hours. A missed dose of study medication may be taken 


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up to 4 hours before the next scheduled dose, otherwise, the missed dose should not be 
given. 
Ganaxolone capsules will be administered two times daily (BID), following the morning 
and evening meal or snack. Each dose should be separated by a minimum of 8 hours and 
a maximum of 12 hours.  A missed dose of medication may be taken up to 8 hours before 
the next dose, otherwise it should not be given.  The capsules should be swallowed whole 
and not opened, crushed, or chewed.   
Subjects and their parent or legal guardian 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 that the medication 
might affect mental alertness. They will also be cautioned that non-adherence to the 
dosing instructions (e.g. increasing the dose, taking the study medication doses too close 
together) could produce side effects.   
9.4.6 
Missing a Dose 
Ganaxolone oral suspension: A missed dose of study medication may be taken up to 4 
hours before the next scheduled dose, otherwise, the missed dose should not be given. 
Ganaxolone capsules: A missed dose of medication may be taken up to 8 hours before 
the next dose, otherwise it should not be given. 
Subjects and their parent or legal guardian should be instructed that if s/he misses two 
days in a row or more, the site should be contacted to determine whether any adjustment 
in study medication is needed.  
9.4.7 
Background AED medication: 
Marketed medications indicated for the treatment of seizures are acceptable with the 
exception of vigabatrin, tiagabine, and ezogabine.  Felbamate has restricted use. 
Chronic and rescue benzodiazepine use should be discussed with the Principal 
Investigator and Sponsor.  Note: 
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. 


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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. 
9.4.8 
Concomitant Medications 
A list of medications that are inducers or inhibitors of CYP 3A4/5 and are not permitted 
during the study are included in the Appendix. Note that phenytoin and carbamazepine 
are permitted as background AEDs though they are moderate CYP 3A4 inducers. 
Finasteride is not permitted as it inhibits synthesis of endogenous allopregnanolone.  
Generally, concomitant medications including non-prescription medication can be used if 
medically necessary 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. Concomitant medications prescribed by a physician other than the 
Investigator should be communicated to the Investigator promptly. 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 Sponsor and the study Principal Investigator 
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 the case report 
form (CRF). 
9.4.9 
Treatment Compliance 
Subjects who are not compliant with study visits, study medications and seizure calendars 
may be removed from the study at the discretion of the Investigator or Sponsor. 
 
9.5 
Efficacy and Safety Variables 
 
9.5.1 
Calculation of Baseline 
Baseline will be calculated from a maximum of 12 weeks' of seizure calendar data with a 
minimum of 4 weeks of data required, which should include contiguous retrospective 
ratings provided after signing informed consent.  Acceptable retrospective daily seizure 


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data include a diary record of the frequency and type of seizures by day.  Source data may 
include a seizure diary or calendar, recorded data from smart phones or other devices. 
Seizure clusters are to be identified, and the number of seizures in the daily cluster should 
be counted or given as best estimate.   
9.5.2 
Efficacy Assessments 
Parent or legal guardian will record the type and number of seizures daily in the Subject 
Seizure Calendars that will be used for the primary analysis of efficacy.  
The primary outcome measure is the percentage change in seizure (focal dyscognitive or 
focal convulsive) frequency per 28 days relative to baseline.  
Secondary efficacy outcome measures include evaluation of inter-cluster interval; time to 
reach baseline number of seizures (per 28 days); seizure-free intervals; proportion of 
subjects with 50% improvement in number of seizures compared with baseline: and 
proportion of subjects whose inter-cluster interval increases by 50% or more. Additional 
measures may be added. Data will be analyzed for the ITT and Per Protocol populations 
if they differ. 
The Clinical Global Impression of Improvement: Clinician (CGII-C) and Clinical Global 
Impression of Improvement: Patient/Caregiver (CGII-P) are secondary efficacy 
assessments. 
 
9.5.3 
Safety Assessments 
Planned safety assessments include: 
 
Neurological and physical examinations 
Clinical laboratory tests 
12-lead ECG 
EEG 
Vital signs including temperature, blood pressure, pulse rate, and weight 
AE monitoring:  frequency, severity, duration, causality, outcome 
Columbia-Suicide Severity Rating Scale (CSSRS) 
 
Clinical labs, vitals, EEG and ECG measurements may be repeated if needed to 
corroborate or refute abnormal findings.  Both the original and replicate assessments 
should be recorded in the CRF. 
 


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See Appendix 1 Schedule of Study Events for timing of Safety Assessments. 
 
Additional assessments may be conducted as considered appropriate. 
 
 
9.5.4 
Other Assessments 
Blood samples will be drawn at baseline, 2 weeks, 8 weeks, 26 weeks, all visits in the 52 
week extension and at unscheduled visits as needed for evaluation of blood chemistry and 
hematology, and/or to measure levels of ganaxolone, concomitant AED medications, 
allopregnanolone, and related endogenous CNS-active steroids.  (See Appendix 2 
Schedule of Events).   
EEG will be collected at baseline and at visit 4, 5, 6 and 7 and at all visits in the 52 week 
extension. 
The Visual Analogue Scale (VAS-Targeted Behavior) will be collected at baseline and at 
Visits 5, 7, 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. 
 
 


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9.5.5 
Schedule of Study Procedures 
9.5.5.1 
Visit 1 (Screening) 
• Obtain written informed consent (signed informed consent form)  
• Collect demographics, medical history, background AEDs and other concomitant 
medications  
• Review inclusion/exclusion criteria  
• Collect and review retrospective seizure calendars if available 
• Instruct and provide study Subject Seizure Calendar 
• Perform physical and neurological examinations (Physical and neurological exam 
records performed at the same center within 60 days of screening visits may be 
used in place of screening exam) 
• 12-lead ECG 
• Measure vital signs 
 
9.5.5.2 
Visit 2 (Baseline; Week 0) 
• Review medical history, background AEDs and other concomitant medications  
• Review inclusion/exclusion criteria  
• Collect and review seizure calendars 
• VAS 
• Administer Columbia Suicide Scale assessed for children 7 years and older  
• Perform physical and neurological examinations 
• Measure vital signs 
• Draw blood sample for, hematology, chemistry, trough concomitant AED levels, 
and allopregnanolone, and related endogenous CNS-active steroids; obtain urine 
sample from subjects who are toilet trained for urinalysis and pregnancy test for 
WCBP. 
• Dispense study medication and dosing instructions 
• Instruct and provide study Subject Seizure Calendar 
• EEG 


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• Screening and Baseline visits may be one visit if the seizure calendar data are 
sufficient. 
9.5.5.3 
Visit 3 (end of Week 2 +/- 3 days) 
• Review background AEDs and other concomitant medications  
• Collect and review seizure calendars; provide new calendars 
• Administer Columbia Suicide Scale assessed for children 7 years and older  
• Perform follow-up physical and neurological examinations 
• Assess for adverse events 
• Measure vital signs  
• Collect bottles from prior visit study medication 
• Adjust dose if necessary 
• Dispense study medication  
 
9.5.5.4 
Visit 4 (end of Week 4 +/- 3 days) 
• Review background AEDs and other concomitant medications  
• Collect and review seizure calendars; provide new calendars 
• Complete CGII-Clinician Ratings 
• Instruct and collect CGII-Patient/Caregiver Ratings 
• Administer Columbia Suicide Scale assessed for children 7 years and older  
• Perform follow-up physical and neurological examinations 
• Assess for adverse events 
• Measure vital signs  
• 12-lead ECG 
• EEG 
• Collect bottles from prior visit study medication 
• Adjust dose if necessary 
• Dispense study medication  
• Urine Pregnancy Test for WCBP 
 


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9.5.5.5 
Visit 5 (end of Week 8 +/-3 days) 
• Review background AEDs and other concomitant medications  
• Collect and review seizure calendars; provide new calendars 
• Complete CGII-Clinician Ratings 
• Collect CGII-Patient/Caregiver Ratings 
• VAS 
• Administer Columbia Suicide Scale assessed for children 7 years and older  
• Perform follow-up physical and neurological examinations 
• Assess for adverse events 
• Measure vital signs 
• EEG 
• Draw blood sample for hematology, chemistry, trough study drug, concomitant 
AED levels, and allopregnanolone, related endogenous CNS-active steroids; 
obtain urine sample from subjects who are toilet trained for urinalysis and 
pregnancy test for WCBP. 
• Collect bottles from prior visit study medication 
• Adjust dose if necessary & Dispense study medication  
 
9.5.5.6 
Visit 6 (end of Week 17 +/-7 days) 
• Review background AEDs and other concomitant medications  
• Collect and review seizure calendars; provide new calendars 
• Complete CGII-Clinician rating 
• Collect CGII-Patient/Caregiver rating 
• Administer Columbia Suicide Scale assessed for children 7 years and older  
• Perform follow-up physical and neurological examinations 
• Assess for adverse events 
• Measure vital signs 


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• EEG 
• Collect bottles from prior visit study medication 
• Adjust dose if necessary 
• Dispense study medication  
• Urine Pregnancy Test for WCBP 
 
9.5.5.7 
Visit 7 (end of Week 26 +/-7 days; final investigative visit) 
• Review background AEDs and other concomitant medications  
• Collect and review seizure calendars; provide new calendars 
• Complete CGII-Clinician rating 
• Collect CGII-Patient/Caregiver rating 
• VAS 
• Perform physical and neurological examinations 
• Assess for adverse events 
• Measure vital signs 
• EEG 
• Draw blood sample for study drug, hematology, chemistry, and allopregnanolone, 
related endogenous CNS-active steroids; obtain urine sample from subjects who 
are toilet trained for urinalysis and pregnancy test for WCBP. 
• Administer Columbia Suicide Scale assessed for children 7 years and older 
• Collect bottles from prior visit study medication 
• Instruct on down-titration 
• Dispense study medication  
• Confirm eligibility for 52 week extension  
 
9.5.5.8 
Visit 8 (end of Week 44 +/-14 days) 
• Review background AEDs and other concomitant medications  
• Collect and review seizure calendars; provide new calendars 
• Complete CGII-Clinician rating 


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• Collect CGII-Patient/Caregiver rating 
• Perform physical and neurological examinations 
• Assess for adverse events 
• Measure vital signs 
• Draw blood sample for trough study drug, hematology, chemistry, and 
allopregnanolone, related endogenous CNS-active steroids; obtain urine sample 
from subjects who are toilet trained for urinalysis and pregnancy test for WCBP. 
• EEG 
• Administer Columbia Suicide Scale assessed for children 7 years and older 
• Collect bottles from prior visit study medication 
• Dispense study medication  
 
9.5.5.9 
Visit 9 (end of Week 62 +/-14 days) 
• Review background AEDs and other concomitant medications  
• Collect and review seizure calendars; provide new calendars 
• Complete CGII-Clinician rating 
• Collect CGII-Patient/Caregiver rating 
• VAS 
• Perform physical and neurological examinations 
• Assess for adverse events 
• Measure vital signs 
• Draw blood sample for trough study drug, hematology, chemistry, and 
allopregnanolone, related endogenous CNS-active steroids; obtain urine sample 
from subjects who are toilet trained for urinalysis and pregnancy test for WCBP. 
• EEG 
• Administer Columbia Suicide Scale assessed for children 7 years and older 
• Collect bottles from prior visit study medication 
• Dispense study medication  
 


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9.5.5.10 
Visit 10 (end of Week 78 +/- 14 days; final investigative visit) 
• Review background AEDs and other concomitant medications  
• Collect and review seizure calendars; provide new calendars 
• Complete CGII-Clinician rating 
• Collect CGII-Patient/Caregiver rating 
• VAS 
• Perform physical and neurological examinations 
• Assess for adverse events 
• Measure vital signs 
• Draw blood sample for trough study drug, hematology, chemistry, and 
allopregnanolone, related endogenous CNS-active steroids; obtain urine sample 
from subjects who are toilet trained for urinalysis and pregnancy test for WCBP. 
• EEG 
• Administer Columbia Suicide Scale assessed for children 7 years and older 
• Collect bottles from prior visit study medication 
• Instruct on down-titration 
• Dispense study medication  
 
9.5.5.11 
Visit 11 (end of Week 82 +/-7 days; Post-Drug Follow up visit) 
• Review background AEDs and other concomitant medications  
• Collect and review seizure calendars 
• Assess for adverse events 
• Measure vital signs 
• EEG 
• Administer Columbia Suicide Scale assessed for children 7 years and older  
• Collect bottles from prior visit study medication 
• Provide information on follow up care 
 


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9.5.5.12 
Dose Escalation Visit and Unscheduled Visits 
• Review background AEDs and other concomitant medications  
• Collect and review seizure calendars; provide new calendars 
• Administer Columbia Suicide Scale assessed for children 7 years and older  
• Perform follow-up physical and neurological examinations 
• Assess for adverse events 
• Measure vital signs  
• Draw blood sample for hematology, chemistry; obtain urine sample from subjects 
who are toilet trained for urinalysis and pregnancy test for WCBP. 
• Collect bottles from prior visit study medication 
• Adjust dose if necessary 
• Dispense study medication 
 
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. The data will be entered into the clinical trial 
database and verified for accuracy.   
9.7 
Statistical Methods  
 
9.7.1 
Analysis Populations 
All subjects entered into the study who are administered at least one dose of study drug 
will be included in the ITT population. 
Subjects who receive study drug for at least 6 weeks, at doses between 900 and 1800 
mg/day, and are without major protocol violations will be included in a Per Protocol 


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analysis if the population differs from the ITT population. Subjects in each cohort will be 
analyzed per cohort using the criteria described above. 
Overall efficacy for all subjects will be done as well. Safety will be reported per cohort 
and for all subjects. 
 
9.7.2 
Missing Data 
Unless otherwise specified, missing data will not be imputed. All analyses will be based 
on available data. 
9.7.3 
Baseline and Demographic Characteristics 
Subject demographic data and baseline characteristics will be listed individually and 
summarized overall for the ITT population per cohort and as a whole for the study. 
Categorical variables will be summarized by counts and percentages and continuous 
variables by number of subjects, mean, standard deviation, median, minimum, and 
maximum. 
9.7.4 
Analysis of Primary Efficacy Variable 
The primary efficacy measure is the percentage change in seizure (focal dyscognitive or 
focal convulsive) frequency per 28 days relative to baseline in the ITT population. 
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 percent change in seizure frequency will be reported with 
descriptive statistics.  Individual data will also be presented. 
9.7.5 
Analysis of Secondary Efficacy Variables 
All secondary efficacy variables will be summarized using descriptive statistics. 
Individual data will also be presented. 
9.7.6 
Analysis of Safety Variables 
Adverse events (AEs) will be tabulated by Overall, system organ class (SOC), and 
Preferred Term using the MedDRA coding system.  Incidence and percentage of adverse 
events will be presented for each cohort and for the study as a whole.   Additional tables, 
with AEs subset by severity and by relationship to drug as assessed by the investigator 


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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.  
9.7.7 
Serum levels of AEDs, Ganaxolone and neurosteroids 
Serum levels of concomitant AEDs will be presented in subject listings. Serum levels of 
ganaxolone will be presented by administered dose by scatterplot per cohort and for the 
study as a whole.  Levels of neurosteroids will be provided in a companion report, in 
tables and scatterplots as appropriate. 
Serum levels of concomitant AEDs will be analyzed at site laboratories.  Study drug 
samples will be analyzed at Quest Pharmaceutical Services (QPS).  The Neurosteroid 
samples will be analyzed at the University of Illinois at Chicago. The addresses are 
below. 
 
Study Drug PK Samples: 
Neurosteroid Levels Samples: 
Quest Pharmaceutical Services (QPS) 
Delaware Technology Park 
3 Innovation Way; Suite 240 
Newark, Delaware 19711 
 
The Psychiatric Institute 
University of Illinois at Chicago 
1601 W. Taylor Street, Office #409 
Chicago, IL 60612 
 
  
9.7.8 
Determination of Sample Size 
Approximately ten (10) subjects with PCDH19, 10 subjects with CDKL5 Disorder, 10 
subjects with Dravet Syndrome, and up to 10 subjects with LGS, CSWS, encephalopathic 
epilepsy or other genetic epilepsies will be enrolled in this open-label, uncontrolled, proof 
of concept study. 


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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. Complete original USA FDA Form 1572, signed by the 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). 
2. Information properly recorded in the CRFs by appropriate study personnel and 
signed and dated by the Investigator. 
3. Completed drug accountability records. 
4. Copies of protocol or ICF amendments and IRB/IEC approval/notification, if 
appropriate. 
5. Copies of IRB/EC notification of approval for safety updates. 


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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 
It is recommended that the Sponsor 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’s legal guardian 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 
legal guardian.  When applicable, it will be provided in a certified translation of the local 
language. 
Signed consent forms must remain in each subject’s study file and must be available for 
verification by study monitors at any time. 
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 in the case report form and the AEs should be followed until either 
completely resolved or until a stable chronic outcome is determined by the Investigator 


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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 
(in the US) or a minimum 24-hour inpatient hospitalization (outside US) or, if in the 
opinion of the Investigator, prolongs an existing hospitalization.  A hospitalization for 
an elective procedure, a routinely scheduled treatment or a social admission is not an 
SAE. 
• Results in permanent or significant disability/incapacity 
This serious criterion applies if the “disability” caused by the reported AE results in a 
substantial disruption of the subject’s ability to carry out normal life functions. 
• Results in a congenital anomaly/birth defect 
This serious criterion applies if a subject exposed to the investigational product gives 
birth to a child with congenital anomaly or birth defect. 
Important medical events that do not meet any of the criteria above may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 


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


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should be observed if the study drug is withdrawn or dose 
reduced. 
 
When applicable, a syndrome ("flu syndrome") that describes a constellation of AEs 
should be recorded in the CRF in place of the individual AE terms (fever, sore throat, 
rhinitis).  
10.5.3 
Reporting of Adverse Events 
10.5.3.1 
Serious Adverse Events 
Any SAEs, including death due to any cause, which occurs to any subject who has signed 
Informed Consent (personally or by legal guardian) in this study or within 30 days 
following cessation of the last dose of treatment with the study drug, whether or not 
considered related to the investigational product, must be reported within 24 hours to the 
Sponsor or their designee.  SAEs that occur more than 30 days after the last dose of study 
drug and are suspected to be related to study treatment should also be reported. All 
subjects with SAEs must be followed up for outcome. 
SAEs can entered into the database and submitted to the sponsor.  
SAE reporting numbers: 
Telephone number +1 (484-801-4677) (Medical)  
Fax Number (610)-640-4323  
 
10.5.3.2 
Pregnancy 
If a subject in the study becomes pregnant, the Sponsor should be notified immediately. 
 
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, CRFs, 
etc. 


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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 
Paper case report forms (CRFs) will be supplied by the Sponsor.  Forms are to be filled 
out in pen, and any changes or corrections are to be initialed and dated by the individual 
responsible for the change.   
An eCRF will 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. 
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.  
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. 


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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 CRFs, 
consent forms, laboratory test results, and medical inventory records, must be retained by 
the Principal Investigator for 2 years after marketing application approval.  If no 
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 
 
1. Depienne C, Gourfinkel-An I, Baulac S, et al. Genes in infantile epileptic 
encephalopathies. In: Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's 
Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): 
National Center for Biotechnology Information (US); 2012. Available from: 
http://www.ncbi.nlm.nih.gov/books/NBK98182/.  Accessed June 29, 2014. 
2. Dibbens LM, Tarpey PS, Hynes K, et al. X-linked protocadherin 19 mutations 
cause female-limited epilepsy and cognitive impairment. Nat Genet. 2008 
Jun;40(6):776–781. 
3. Depienne C, Bouteiller D, Keren B, et al. Sporadic infantile epileptic 
encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but 
mainly affects females.  PLoS Genet. Feb 2009; 5(2): e1000381. Published online 
Feb 13, 2009. doi:  10.1371/journal.pgen.1000381. Accessed June 29, 2014. 
4. Tan C, Shard C, Ranieri E, et al. Gecz J. Mutations of protocadherin 19 in female 
epilepsy (PCDH19-FE) lead to allopregnanolone deficiency. Hum Mol Genet. 2015 
Jun 29. 
5. Depienne C., LeGuern E.  PCDH19-related infantile epileptic encephalopathy: an 
unusual X-linked inheritance disorder. Hum. Mutat. 2012; 33:627-634.  
6. Higurashi N, Nakamura M, Sugai M, et al. PCDH19-related female-limited 
epilepsy: further details regarding early clinical features and therapeutic efficacy. 
Epilepsy Res. 2013 Sep;106(1-2):191-9. doi: 10.1016/j.eplepsyres.2013.04.005. 
Epub 2013 May 24.  
7. Marini C, Mei D, Parmeggiani L, et al. Protocadherin 19 mutations in girls with 
infantile-onset epilepsy. Neurology, 2010;75:646–653. 
8. Specchio N, Marini C, Terracciano A, et al. Spectrum of phenotypes in female 
patients with epilepsy due to protocadherin 19 mutations. Epilepsia. 
2011;52(7):1251–1257. 
9. Scheffer IE, Turner SJ, Dibbens LM, et al. Epilepsy and mental retardation 
limited to females: an under-recognized disorder. Brain. 2008;131:918–27. 
10. Camacho A, Simon R, Sanz R, et al. Cognitive and behavioral profile in females 
with epilepsy with PDCH19 mutation: two novel mutations and review of the 
literature. Epilepsy Behav. 2012;24:134–37. 
11. Carter, R.B., Wood, P.L., Wieland, S., Hawkinson, J.E., Belelli, D., Lambert, J.J., 
White, H.S., Wolf, H.H., Mirsadeghi, S., Tahir, S.H., Bolger, M.B., Lan, N.C., 
Gee, K.W., 1997. Characterization of the anticonvulsant properties of ganaxolone 
(CCD 1042; 3α-hydroxy-3β-methyl-5α-pregnan-20-one), a selective, high-
affinity, steroid modulator of the gamma-aminobutyric acidA receptor. J 
Pharmacol Exp Ther 280, 1284-1295. 
12. Reddy, D.S., Rogwski, M.A., 2012. Neurosteroids — Endogenous regulators of 
seizure susceptibility and role in the treatment of epilepsy (Chapter 77). In, 


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Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli 
M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds.), Contemporary 
Neurology Series 80, Oxford University Press, pp. 984–1002. 
13. Bialer, M., Johannessen, S.I., Levy, R.H., Perucca, E., Tomson, T., White, H.S., 
2010.  Progress report on new antiepileptic drugs: A summary of the Tenth Eilat 
Conference (EILAT X). Epilepsy Res 92, 89-124. 
14. Kerrigan, J. F., Shields, W. D., Nelson, T. Y., Bluestone, D. L., Dodson, W. E., 
Bourgeois, B. F., Pellock, J. M., Morton, L. D., Monaghan, E. P., 2000. 
Ganaxolone for treating intractable infantile spasms: a multicenter, open-label, 
add-on trial. Epilepsy Res 42, 133-139. 
15. Laxer, K., Blum, D., Abou-Khalil, B. W., Morrell, M. J., Lee, D. A., Data, J. L., 
Monaghan, E. P. and the Ganaxolone Presurgical Study Group, 2000. Assessment 
of ganaxolone's anticonvulsant activity using a randomized, double-blind, 
presurgical trial design. Epilepsia 41, 1187-1194. 
16. Pieribone, V.A., Tsai, J., Soufflet, C., Rey, E., Shaw, K., Giller, E., Dulac, O., 
2007. Clinical evaluation of ganaxolone in pediatric and adolescent patients with 
refractory epilepsy. Epilepsia 48, 1870-1874. 
17. Vadlamudi, L., Dibbens, L. M., Lawrence, K. M., Iona, X., McMahon, J. M., 
Murrell, W., Mackay-Sim, A., Scheffer, I. E., Berkovic, S. F. Timing of de novo 
mutagenesis--a twin study of sodium-channel mutations. New Eng. J. Med. 363: 
1335-1340, 2010 
18. Harkin, L. A., McMahon, J. M., Iona, X., Dibbens, L., Pelekanos, J. T., Zuberi, S. 
M., Sadleir, L. G., Andermann, E., Gill, D., Farrell, K., Connolly, M., Stanley, T., 
and 12 others. The spectrum of SCN1A-related infantile epileptic 
encephalopathies. Brain 130: 843-852, 2007 
19. Fehr S, Wilson M, Downs J, Williams S, Murgia A, Sartori S, Vecchi M, Ho G, 
Polli R, Psoni S, Bao X, de Klerk N, Leonard H, Christodoulou J. The CDKL5 
disorder is an independent clinical entity associated with early-onset 
encephalopathy. European Journal of Human Genetics. 2013;21(3):266-73. 
20. Artuso R, Mencarelli MA, Polli R, Sartori S, Ariani F, Pollazzon M, et al. 
Early-onset seizure variant of Rett syndrome: Definition of the clinical 
diagnostic criteria. Brain Dev. 2010 Apr 9;32(1):17-24. 
http://www.ncbi.nlm.nih.gov/pubmed/19362436 


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13. 
APPENDICES 
 
 
13.1 
Appendix 1: Clinical Laboratory Tests 
 
Clinical Chemistry 
 
Hematology 
Urinalysis 
Total Bilirubin 
Hemoglobin 
pH 
AST (SGOT) 
Hematocrit 
Color 
ALT (SGPT) 
Erythrocytes 
Transparency 
BUN 
Leukocytes + differential 
Specific Gravity 
Glucose 
Thrombocytes (platelet count) 
Urobilinogen 
Potassium 
 
Ketones 
Sodium 
 
Protein 
Calcium 
 
Glucose 
Alkaline Phosphatase 
 
Hemoglobin 
Chloride 
 
 
Creatinine 
 
 
CO2 
 
 
 
ALT = alanine transferase; AST = aspartate transferase; BUN = blood urea nitrogen






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1. Physical and neurological exam records performed at the same center within 60 days of screening visit may be used in 
place of screening exam.  Visits 3, 4, 5 and 6 may be follow-up exams. Tanner Scores will be collected. 
2. Obtain urine sample for those who are toilet trained. 
3. Adjust dose if necessary. 
4. This visit could also be an Early Termination visit. At this visit, investigator confirms if the subject qualifies for the 52 
week extension, subjects must have completed all scheduled clinical study visits and have shown a minimum 35% 
improvement in mean seizure frequency per 28 days vs. baseline.  
5. Vital signs including temperature, blood pressure, pulse, height and weight. 
6. A dose escalation visit is required 4-6 days after escalation to any dose level above 54 mg/kg/day or above 1500 
mg/day. A regularly scheduled visit may serve as a dose escalation visit. An unscheduled visit can occur at any time 
during the 26 week open-label treatment period or the 52 week extension.  Samples for concomitant AEDs and study 
drug levels may also be drawn if warranted in the opinion of the investigator. 
7. Safety labs can be collected at any visit if warranted in the opinion of the investigator. 
8. If this is the last study visit, the subject should be instructed on down-titration and scheduled for Visit 11 which is the 
follow-up visit. 
AEs = adverse events; AED = antiepileptic drug; ECG = electrocardiogram; C-SSR=Columbia Suicide Severity Rating; 
EEG= Electroencephalography; VAS=Visual Analogue Scale 
 
 
 




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Collect bottles from prior visit study 
medication 
X 
X 
X 
X 
Instruct on Down-titration 
 
 
X8 
 


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CONFIDENTIAL INFORMATION 
 
1. Physical and neurological exam records performed at the same center within 60 days of screening visit may be used in 
place of screening exam.  Visits 3, 4, 5 and 6 may be follow-up exams. Tanner Scores will be collected. 
2. Obtain urine sample for those who are toilet trained. 
3. Adjust dose if necessary. 
4. This visit could also be an Early Termination visit. At this visit, investigator confirms if the subject qualifies for the 52 
week extension, subjects must have completed all scheduled clinical study visits and have shown a minimum 35% 
improvement in mean seizure frequency per 28 days vs. baseline.  
5. Vital signs including temperature, blood pressure, pulse, height and weight. 
6. A dose escalation visit is required 4-6 days after escalation to any dose level above 54 mg/kg/day or above 1500 
mg/day. A regularly scheduled visit may serve as a dose escalation visit. An unscheduled visit can occur at any time 
during the 26 week open-label treatment period or the 52 week extension.  Samples for concomitant AEDs and study 
drug levels may also be drawn if warranted in the opinion of the investigator. 
7. Safety labs can be collected at any visit if warranted in the opinion of the investigator. 
8. If this is the last study visit, the subject should be instructed on down-titration and scheduled for Visit 11 which is the 
follow-up visit. 
AEs = adverse events; AED = antiepileptic drug; ECG = electrocardiogram; C-SSR=Columbia Suicide Severity Rating; 
EEG= Electroencephalography 
 
 


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CONFIDENTIAL INFORMATION 
 
 
13.3 
Appendix 3: Strong and Moderate Cytochrome P450 CYP 3A4, 5, 7 
Inducers and Inhibitors Prohibited During Study 1042-0900 
 
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) 
nefazodone (not sold in US) 
nelfinavir 
Group aconazole  
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. 
Data from 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm080499.htm and http://medicine.iupui.edu/clinpharm/ddis/ClinicalTable.aspx; 
access


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Protocol 1042-0900, Version 6.0 
 
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13.4 
Appendix 4:  Dose Escalation Suggested Schedules 
 




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13.5 
Appendix 5: Protocol History 
 
Revision 
# 
Date 
Revisions 
V0: 
 
November 
25, 2014 
 
V1: 
December 
10, 2014 
Minor edits and clarifications. 
V2: 
January 
12, 2015 
Minor edits and clarifications. 
pgs. 25, 26 and 42  
For consistency with Section 9.5.4 Other Assessment and the 
Synopsis, a statement was added regarding the blood collection to 
measure allopregnanolone, and related neurosteroids in the Visit 2 and 
Visit 4 Schedule of Study Procedures section and Schedule of Events.   
V3: 
January 
23, 2015 
Dosing regimen revised for subjects: p 3, 15, 19-20. 
A visit at Week 2 and procedures for unscheduled visits have been 
added: p. 4, 24, 26, 29, and Appendix 2. 
Collection of blood for Liver Function Test and other laboratory 
assessments have been added at the Week 26 visit: p. 4, 28, 31 and 
Appendix 2. 
Guidance on missed doses for the capsules and suspension has been 
clarified: p. 18. 
V4: 
June 8, 
2015 
Collection of EEG’s have been added on Visits 2, 5 and 7. See 
Synopsis, p.23, 25, 27, 28 and Appendix 2. 
V5: 
July 15, 
2015 
See Appendix 5.1 for complete summary of changes. 
Addition of CDKL5 and Dravet Syndrome Subjects: 
• Background has been updated. 
• Seizure criteria has been updated for the CDKL5 and Dravet 
Syndrome subjects. 
• Contraindicated medications for Dravet patients have been added. 
• Male children are also eligible for inclusion. 
• Age has been increased from 2-10 years to 2-18 years age.   
o Pregnancy Testing has been added for WCBP.  
o Tanner Scale score has been added under Physical Exam 


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Protocol 1042-0900, Version 6.0 
 
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52 week extension for subjects who respond to ganaxolone:  
• Criteria for inclusion has been added. 
• 3 additional visits have been added. 
Study Assessments Added:  
• Additional study drug PK samples and concomitant AED samples 
to be drawn at existing blood draw at Week 26. 
Administrative Changes:  
• Study Title has been updated. 
• Sponsor Contact information has been updated.   
• Clarifying statements that the screening and baseline visit can be 
combined. 
 
V5.1 
 
September 
30, 2015 
Local Amendment – (Site #006) 
• Stiripentol has been added as an Exclusion Criteria in section 9.3.3 
and to the list in Appendix 3 of “Prohibited Strong and 
Moderate CYP 3A4 Inhibitors” 


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V 6.0 
April 
2016 
Local Amendment (Site #001) 
See Appendix 6 for Summary of Changes 
• Inclusion of other genetic epilepsies. These include, but are not 
limited to children with PCDH19 mutation, CDKL5 Disorder, 
Dravet Syndrome and other epileptic syndromes such as LGS, 
CSWS, and other potential genetic or clinical conditions with or 
without corresponding genetic condition (referred as genetic 
epilepsies) in an open-label proof-of-concept study. 
• Inclusion of additional EEG assessments 
• Addition of the Visual Analogue Scale (VAS-Targeted Behavior) 
at baseline, Visits 5, Visit 7, Visit 9 and Visit 10. 
• Stiripentol (Italy specific) has been added as an Exclusion Criteria 
in section 9.3.3 
• Stiripentol (not sold in the US) has been added to the list in 
Appendix 3 of “Prohibited Strong and Moderate CYP 3A4 
Inhibitors” 
• Visual Analogue Scale (VAS-Target Behavior) has been added to 
Appendix 7 
 
 
 
 
 
 
 
 
 
 


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13.6 
 
Appendix 6: Amendment #5.2 Summary of Changes 
 
There is one major revision to this protocol.   
 
Addition of LGS, CSWS, encephalopathic epilepsy and other potential genetic epilepsies 
subjects.  Despite trying multiple AEDs, many of these patients still do not have adequate 
seizure control.  Since ganaxolone does have a unique mechanism of action and the safety 
and efficacy of ganaxolone has been well studied, it is reasonable to believe that 
ganaxolone could be beneficial to these subjects as well. 
 
A number of sections have been revised to accommodate the addition of these epilepsies.  
In addition, administrative information has been updated.  The revisions to the updated 
sections are described below:  
 
Section 9.3.2 Inclusion Criteria 
 
#3 Revised to include LGS, CSWS, or other genetic epilepsies and reads as follows: 
 
“In the opinion of the investigator have confirmed PCH19 genetic mutation, confirmed 
CDKL5 genetic mutation or Dravet Syndrome confirmed by a SCN1A mutation, or 
genetic epilepsy testing confirming a LSG or CSWS condition associated with this 
genetic phenotype.  Refractive cases of LGS or CSWS that remain idiopathic or 
have prior history of steroid or ACTH response can also be entered if 
documentation confirms specific genetic defects are not found and prior steroid 
response clinically occurred” 
 
#4 Revised to include seizure criteria relevant for LGS, CSW and other genetic epilepsies 
and reads as follows: 
 
a. “Have uncontrolled cluster seizures (3 or more seizures over the course of 
12 hours) every 6 weeks or less during baseline, or bouts of status 
epilepticus on intermittent basis, or” 
b. No revisions made 
c. No revisions made 
d. Have subclinical CSWS syndrome with or without clinical events on 
EEG 
 
Section 9.3.3 Exclusion Criteria 
 
#6 Revised to include stiripentol as an exclusionary medication for subjects with Dravet 
Syndrome enrolled in Italy and reads as follows: 
 
For Dravet Syndrome subjects the following are also excluded: phenytoin, fosphenytoin, 
carbamazepine, oxcarbazepine, lamotrigine, rufinamide and stiripentol (Italy specific). 


Marinus Pharmaceuticals, Inc. 
 
 
Protocol 1042-0900, Version 6.0 
 
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CONFIDENTIAL INFORMATION 
 
 
 
#6 Revised to include criteria for the use of cannabadiol and epidolex for LGS, CSWS or 
other genetic epilepsies per standard practice and reads as follows: 
 
“Patients on cannabadiol (CBD) products that have shown <75 improvement must 
be withdrawn from CBD and be off product >28 days before Visit 2” 
“Patients on CBD products that have shown >75% improvement and have 
completed or discontinued from the blinded clinical study, are on maintenance CBD 
for >6 months or taking epidolex with stable laboratory values and no SAEs will, on 
a case by case basis, be considered for enrollment. The decision to taper or leave the 
patient on the drug before adding ganaxolone will be made, if it  is believes to be 
unethical to take the patient off drug and promote status epilepticus or loss of 
gained >75% improvement of seizure control.  The patient will need to meet criteria 
for current entry seizure frequency for the ganaxolone study.” 
 
#10 Revised to include conditions for subjects who are on a ketogenic diet and reads as 
follows: 
“Are planning to follow a ketogenic diet.  If on ketogenic diet more than 6 months 
with stable laboratory values and seizure control then enrollment will be made on a 
case by case basis” 
Section 9.5.5 Schedule of Study Procedures and Appendix 2 Schedule of Events 
EEG added to Visit 4, Visit 6, Visit 8, Visit 9 and Visit 10 
Visual Analogue Scale (VAS-Target Behavior) added at baseline, Visit 5, Visit 7, Visit 9 
and Visit 10 
Section 13.7 Appendix 7 
Section 13.7.4 Visual Analogue Scale (VAS-Target Behavior) added 
Administrative Change 
• Sponsor Contact information has been updated 
 
 
 
 
 
 
 


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Protocol 1042-0900, Version 6.0 
 
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13.7 
Appendix 7:  Seizure Calendar & Ratings 
 
13.7.1: Clinical Global Impression of Improvement: Clinician &  
            Clinical Global Impression of Improvement: Patient/Caregiver 
13.7.2: Columbia-Suicide Severity Rating Scale Baseline & Visit 
13.7.3: Subject Seizure Calendar & Investigator Instructions 
13.7.4: Visual Analogue Scale (VAS-Targeted Behavior) 
 


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13.7.1  Clinical Global Impression of Improvement: Clinician &  
            Clinical Global Impression of Improvement: Patient/Caregiver 
 
 
Clinical Global Impression–Improvement (CGI-I) - Clinician 
 
Circle the appropriate response that adequately describes how the subject’s symptoms 
have improved or worsened relative to baseline before the beginning of the study (ie. 
before study drug was taken). 
 
1=very much improved 
2= much improved 
3= minimally improved 
4= no change  
5= minimally worse 
6= much worse  
7= very much worse 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Clinical Global Impression–Improvement (CGI-I) - Patient/Caregiver 
 
Circle the appropriate response that adequately describes how your (or your child’s) 
symptoms have improved or worsened relative to baseline before the beginning of the 
study (ie. before study drug was taken). 
 
1=very much improved 
2= much improved 
3= minimally improved 
4= no change  
5= minimally worse 
6= much worse  
7= very much worse 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol 1042-0900, Version 6.0 
 
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13.7.2  Columbia Suicide Severity Scale: Baseline/Screening (Version 6/23/10) 
            Columbia Suicide Severity Scale: Children’s Since Last Visit (Version 6/23/10) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol 1042-0900, Version 6.0 
 
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13.7.3 Seizure Calendar and Investigator Instructions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol 1042-0900, Version 6.0 
 
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13.7.4 Visual Analogue Scale (VAS-Target Behavior) 

SAP_003.pdf: 
Sponsor: Marinus Phannaceuticals, 
Inc. Study 1042-0900, Version 2.0 
Statistical Analysis Plan 
Protocol No.: 1042-0900 
Statistical Analysis Plan 
17 July 2018 
A Multicenter, 26 week Open-Label Proof-of-Concept Trial of 
Ganaxolone in Children with PCDH19 Female Pediatric Epilepsy 
and Other Rare Genetic Epilepsies Followed by 52 Week Open-
Label Treatment 
Sponsor: 
Marinus Phaimaceuticals, Inc. 
Version: 
2.0 
Issue Date: 
17 July 2018 
Version: 2.0 
Confidential 
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