Conditions: PCDH19-Related Epilepsy
Keywords: refractory seizures epilepsy in children seizure disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 29
Healthy volunteers: no

Brief summary:
A clinical study to evaluate the efficacy, safety, and tolerability of adjunctive ganaxolone therapy compared to placebo for the treatment of seizures in female children and young adults with genetically confirmed PCDH19 gene mutation.

Detailed description:
The Violet Study is a global, double-blind, placebo-controlled, Phase 2 clinical trial that plans to enroll approximately 25 female patients between the ages of 1 and 17 with a confirmed disease-related PCDH19 gene variant. Patients will undergo a baseline period before being randomized to receive, in addition to their existing anti-seizure treatment, either ganaxolone or placebo for 17 weeks. Following the treatment period, all patients that meet certain eligibility requirements will have the opportunity to receive ganaxolone in the open label phase of the study. The study's primary efficacy endpoint is percent reduction in seizures. Secondary outcome measures will include non-seizure-related endpoints to capture certain behavioral and sleep disturbances that have been seen in previous clinical studies with ganaxolone.

Arms:
arm 1: placebo suspension 3x's /day for 17 weeks arm 2: ganaxolone suspension (50 mg/ml) 3x's /day for 17 weeks

Interventions: intervention 1: Ganaxolone intervention 2: Placebo
Intervention descriptions: intervention 1: active drug intervention 2: inactive

Protocol document:
Prot_002.pdf: 
 
 
 
Confidential 
 
Page 1 of 136 
 
PROTOCOL:   1042-PCDH19-3002 
TITLE: 
A double-blind, randomized, placebo-controlled trial of adjunctive 
ganaxolone treatment in female children with protocadherin 19 
(PCDH19)-related epilepsy followed by long-term open-label treatment 
DRUG: 
Ganaxolone 
IND: 
044020 
EUDRACT NO.: 
2018-004496-12 
SPONSOR: 
Marinus Pharmaceuticals, Inc. 
5 Radnor Corporate Center, 100 Matsonford Road, Suite 500 
Radnor, PA 19087 USA 
PRINCIPAL/ 
COORDINATING 
INVESTIGATOR: 
PROTOCOL 
HISTORY: 
Protocol Amendment 5: 20 January 2021: Version 6.0 
Protocol Amendment 4: 30 June 2020: Version 5.0 
Protocol Amendment 3: 16 August 2019: Version 4.0 
Protocol Amendment 2: 01 July 2019: Version 3.0 
Protocol Amendment 1:  05 March 2019:  Version 2.0 
Original Protocol:  06 February 2019:  Version 1.0 
 
 
This document contains confidential and proprietary information of Marinus and is disclosed pursuant to 
confidentiality and non-disclosure obligations.  This information should be used solely for the purposes for which it 
was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Marinus. 
M~RINl..JS 
PHARMACEUTICALS 


DocuSign Envelope ID: 849DFA2D-A974-4430-95E6-4F81AEA0A7F3 
IND 044020 
Protocol 1042-PCDH19-3002 
PROTOCOL SIGNATURE PAGE 
Sponsor's Approval 
Date: 
Marinus Pharmaceuticals Inc. 
20 January 2021 
Signature: 
anuary 25, 2021 I 9:07 AM PS 
Marinus Pharmaceuticals 
Clinical Develo ment 
Investigator's Acknowledgement 
I have read this protocol for Marinus Sn1dy 1042-PCDH19-3002. 
Title: 
A double-blind, randomized, placebo-controlled trial of adjunctive ganaxolone 
treatment in female children with protocadherin 19 (PCDH19)-related epilepsy followed by 
long-term open-label treatment 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the infonnation in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the sn1dy, 
without written authorization from the sponsor. It is, however, pem1issible to provide the 
infonnation contained herein to the parent/caregiver/legally authorized guardian (LAR) in order 
to obtain consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Hannonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
tennination of my paiticipation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely te1minate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the sn1dy I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and 
Instin1tion Name and Address: 
(please hand print or type) 
Signature: -----------------
Confidential 
Date: 
Page 2 of 136 


IND 044020 
Protocol 1042-PCDH19-3002 
Marinus Pha1maceuticals Inc. 
20 January 2021 
SUMMARY OF CHANGES FROM PREVIOUS VERSION 
Protocol Amendments 
Summary of Change(s) Since Last Version of Apprnved Protocol 
Amendment Number 
Amendment Date 
Global/Country/Site 
1 
05 March 2019 
Specific 
Global 
Section(s) Affected by 
Description of Change 
Change 
Updated to redefine the primary seizw-e types used to dete1mine patient eligibility 
Synopsis, Sections 4.1, 
and conduct the prima1y/secondary endpoint analyses 
7.3.6, 7.4.1, 9.13.1.2, and 
9.13.1.4 
Added watermark to BRIEF scale 
Section 12.5 (Appendix 5) 
Amendment Number 
Amendment Date 
Global/Country/Site 
2 
01 July 2019 
Specific 
Global 
Section(s) Affected by 
Description of Change 
Change 
Removed CRO Contacts section. 
CRO Contacts and Section 
6.3 
Added Table 5 and Table 6 to the List of Tables. 
List of Tables 
Revised: Updated from 30 to 50 total biomarker-positive subjects 
Synopsis (Number of 
subjects, Methodology), 
Section 3.1 
Revised: Updated total enrollment from 50-70 to approximately 70 subjects 
Synopsis (Number of 
subjects, Methodology), 
Section 3.1 
Updated total number of sites up to 45 sites 
Study Synopsis (Sites and 
Regions) 
Section 3.3 
Revised: 12-week historical 
Synopsis (Methodology), 
Section 3.1, 3.2, 4.1, 
7.2.1.1, 7.3, 7.3.4, 9.7, 
Table 1 Footnote c 
Revised: 
Synopsis (Methodology) 
Acceptable historical seizure data must include at least 12 consecutive weeks 
and Section 3 .1 
prior to the Screening visit of documenting seizure type and frequency (also 
noting seizure-free days). 
Removed: Acceptable historical seizure data must include seizure type, frequency, 
and denote seizure free days, with the historical seizure calendar starting at 
Week-16 (8-week histo,,ical [pre-baseline screen] + 8-week prospective [baseline} 
= 16,veeks). 
Added: treatment of primary seizw-e types 
Study Synopsis 
(Objectives) 
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Marinus Pharmaceuticals Inc.
Protocol 1042-PCDH19-3002 
20 January 2021
Added: treatment of primary seizure 
Study Synopsis 
(Objectives) & Section 
2.2.1 
 
Revised: To assess changes in other types of seizures (non-primary) in PCDH19 
Synopsis (Objectives), 
Section 2.2.3 
Revised: 
 
was a decrease of 25% (n = 11).   
 
had a 50% reduction in seizure 
 
had a 84% increase 
 
there were 4 SAEs (3 related to seizures and 1 related to rash) 
Synopsis (Rationale), 
Section 2.1 
Replaced “patient(s)” with “subject(s)” for consistency 
Throughout entire 
document 
Revised: Based on the completed 11-subject (Removed: OL study) 1042-0900 
Phase 2a study, it is estimated that approximately 65% of all subjects will be 
biomarker-positive. 
Synopsis (Methodology), 
Section 3.1 
Revised: (Removed “If available”), A 12-week daily historical 
Synopsis (Methodology, 
Rationale), Section 3.1,  
Revised: seizure calendar or genetic testing has not been performed 
Revised: historical seizure calendar and/or genetic testing has been completed 
Synopsis (Methodology) 
Revised:  To assess the long-term efficacy (Removed: safety, and tolerability) of 
GNX when administered as adjunctive therapy throughout the open-label phases. 
Added: To assess the long-term safety and tolerability of GNX when 
administered as adjunctive therapy throughout the open-label phases. 
Synopsis (Objectives) and 
Section 2.2.2 
Revised: To assess behavioral/neuropsychiatric changes in subjects receiving GNX 
compared with subjects receiving PBO as adjunctive therapy at the end of the 17-
week DB phase (Removed: using objective scales such as Behavior Rating Inventory 
of Executive Function (BRIEF), Aberrant Behavior Checklist–Community (ABC-C), 
and Children’s Sleep Habit Questionnaire (CSHQ)). 
 
Synopsis (Objectives) and 
Section 2.2.2 
Revised:  A minimum dose of 33 mg/kg/day or 900 mg/day is generally required 
following the escalation period during the double-blind phase unless a lower 
dose is agreed to with the sponsor due to tolerability issues such as 
somnolence.   
Dose changes including alternative dosing paradigm (e.g., lower dose during 
the daytime and higher dose in the evening) should be discussed with the 
sponsor medical monitor prior to making the change or within 48 hours of making 
the change. However, the final decision to adjust drug dosages lies with the PI.  
Synopsis (Methodology 
and Investigational 
product, dose, and mode of 
administration), Section 
3.1, 3.4 and 6.2.3 
Revised: For any subject who is unable to be maintained at the minimum dose, 
the investigator should contact the sponsor to discuss continued investigational 
product dosing. (Remove: Any subject who is unable to be maintained at the 
minimum dose should contact the sponsor to discuss continued IP dosing.)     
Synopsis (Investigational 
product, dose, and mode of 
administration) and 
Section 3.4 
Revised: Subjects who discontinue investigational product should undergo a 2-
week taper period, unless otherwise medically indicated 
Synopsis (Methodology, 
Duration of Treatment) 
Section 3.1, 3.2, 3.4, and 
4.5 


 
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Protocol 1042-PCDH19-3002 
20 January 2021
Revised: Subjects who discontinue investigational product treatment before the 
completion of the DB phase will continue to be followed per protocol and, at a 
minimum, subjects will be encouraged to maintain daily seizure eDiary entries 
until the DB phase is completed. 
Synopsis (Methodology, 
Investigational product, 
dose, and mode of 
administration, and 
Duration of Treatment) 
Section 3.1, 3.2, 3.4, 4.5, 
and 4.5.1  
 
Figure was revised to remove enrollment numbers.  
Synopsis (Methodology) 
and Section 3.1 
Revised:  Participants will be required to complete an eDiary to determine GNX’s 
effect on (removed “drug resistant”) seizures. 
Synopsis (Methodology) 
Revised Inclusion Criteria # 5 – Have at least 12 (Removed: 4) 
countable/witnessed primary seizures over an 84 day (12 week) (Removed: per 28 
days (average) over an 8 week) period prior to the screening visit (pre-baseline 
screening). 
Synopsis (Inclusion 
Criteria), Section 4.1 
Revised Inclusion Criteria # 10 – Parent/caregiver is able and willing to maintain 
an accurate and complete daily (remove “electronic”) seizure diary 
Synopsis (Inclusion 
Criteria), Section 3.1, 4.1, 
10.2.3.2,  
Revised Inclusion Criteria # 11 - or adequate barrier methods (eg, diaphragm or 
condom and foam) 
Synopsis (Inclusion 
Criteria), Section 4.1 
Removed Exclusion Criteria #3 - Known historical seizure frequency pattern that is 
highly variable with long remission periods per PI’s medical judgment. 
 
Synopsis (Exclusion 
Criteria), Section 4.2 
Revised: Exclusion Criteria #4 (now #3) - Subjects with >6 consecutive weeks (42 
consecutive days) of primary seizure freedom during the 12-week pre-baseline 
screening period 
Synopsis (Exclusion 
Criteria), Section 4.2, 5.4 
Revised Exclusion Criteria #5 - Subjects with a positive result on 
tetrahydrocannabinol (THC) or non-approved cannabidiol (CBD) test ((Removed: 
urine or) via plasma drug screen) (Removed: at the screening visit). (Removed: or a 
positive result on THC or non-regulated CBD test (via urine or plasma) at the 
baseline visit will be excluded from the study)  
Synopsis (Exclusion 
Criteria), Section 4.2 
There will be no urine drug screens, all drug tests will be plasma. 
 
Revised: ((Removed: via urine or) plasma drug screen) 
Synopsis (Exclusion 
Criteria), Section 4.2, 
Table 1 footnote,  
Updated non-regulated to non-approved 
Synopsis (Exclusion 
Criteria), Section 4.2, 5.4  
Revised Exclusion Criteria #14- Unwillingness to withhold grapefruit, Seville 
oranges, star fruit, or grapefruit containing products from diet at least 14 days 
prior to 1st dose and for the duration of the study.   
 
Synopsis (Exclusion 
Criteria), Section 4.2, 4.3, 
6.4 
Pl'll'IIN)'ffflc«VMWWNt .al0tOM111Clld11SW19fWOMOtf 
PCOH19 
(all-subjects) 
~70 
p= E ...... , 
.. WHO) 
screening 
Visit 
Placebo 
Ma11Unan0t(UWNU) 


 
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Protocol 1042-PCDH19-3002 
20 January 2021
Added table for Oral Suspension (50 mg/ml) Dosing for Subjects Weighing ≤ 28 
kg and Oral Suspension (50 mg/ml) Dosing for Subjects Weighing > 28 kg 
Synopsis (Investigational 
product, dose, and mode of 
administration) 
Revised table title:  Oral Suspension Dosinga for Subjects Weighing ≤ 28 kg (62 
pounds) b and  
Oral Suspension Dosinga for Subjects Weighing > 28 kg (62 pounds)c 
Synopsis (Investigational 
product, dose, and mode of 
administration) 
Revised: while subjects randomized to GNX will stay on 63 mg/kg/day suspension 
(1800 mg/day maximum), 
Synopsis (Duration of 
treatment), 6.2.3.1  
Revised: Placebo is to be administered as an oral suspension TID with food during 
the 4-week, titration period of the DB phase of the study. Removed:  as follows: 
PBO TID suspension Days 1-7/ PBO TID suspension Days 8-14/ PBO TID 
suspension Days 15-21/ PBO TID suspension Days 22-28. 
Synopsis (Reference 
Therapy, Dose, and Mode 
of Administration) 
Removed: Post-baseline 28-day seizure frequency will be calculated as the total 
number of seizures in the 17-week DB treatment phase divided by the number of 
days with seizure data, observed or imputed, in the phase, multiplied by 28.  
Baseline 28-day seizure frequency will be calculated as the total number of 
seizures in the baseline phase divided by the number of days with seizure data in 
the phase, multiplied by 28. 
 
Replaced with: Post-baseline 28-day seizure frequency will be calculated as 
the total number of seizures in the 17-week DB treatment phase divided by the 
number of days with seizure data in the phase, multiplied by 28. Baseline 28-
day seizure frequency will be calculated as the total number of seizures in the 
baseline phase divided by the number of days with seizure data in the phase, 
multiplied by 28. If a subject experiences no primary seizures during the 
baseline phase then the 28-day seizure frequency in the baseline phase will be 
set to 0.5, equivalent to having 1 seizure during the phase, and 0.5 will be 
added to the 28-day seizure frequency in the post-baseline phase. 
Synopsis (Primary 
Endpoint, Statistical 
Methods), Section 9.13.1.2 
Revised: The difference between the (removed “ganaxolone”) GNX and placebo 
groups in the percent changes within each stratum will be tested using the 
Wilcoxon Rank-Sum statistic.   
Synopsis (Primary 
Endpoint), Section 
9.13.1.2,  
Revised Secondary endpoints:  
 
Moved: “Arithmetic change in percentage of seizure-free days, based on 
all countable focal seizures that include progressive hypotonia and 
impaired awareness, or any countable focal or generalized seizure with a 
clear motor component.” from a secondary endpoint to an exploratory 
endpoint 
 
Added: Percentage of subjects experiencing a ≥ 50% reduction 
in 28-day primary seizure frequency compared to the 8-week 
baseline  
 
Synopsis (Secondary 
endpoints), Section 
9.13.1.3.1.1 
Removed: Additional time points will be analyzed including but not limited to Week 
34 and the end of the OL phase.   
Synopsis (Exploratory 
Endpoints, Statistical 
Methods), Section 9.13.1.4 


IND 044020 
Protocol 1042-PCDH19-3002 
Revised Explorato1y Endpoints: 
I 
I 
I 
I 
I 
I 
Revised: With few exceptions, all of the analyses for the DB phase (Removed: 
except for seizure frequencies during the titration and maintenance phases) will be 
repeated for the OL phase with the following differences. 
Revised: For all other PK draws, there is no specified time to draw the PK sample 
and can be dravm when convenient during the study visits for Visit 5 (Week 17), 
Visit 7 (Week 36), Visit 9 (Week 68), and eve1·y 16 weeks for the duration of the 
open-label phase. 
Added to 7. 7.: Exact time of sample withdrawal and drug intake will be 
recorded in the electronic case re ort form eC 
Removed: sufficiently complete concentration-time data. The following GNX 
plasma PK parameters will be calculated as data allows and as appropriate using 
noncompartmental approaches. 
• 
Maximum plasma concentration (Cmax) 
• 
Time of maximum concentration (tmax) 
• 
Area under the concentration versus time cUl'vefrom time Oto t hours (AUCt) 
• 
Area under the concentration versus time CUl'vefrom time Oto infinity (AUC,,,) 
• 
Clearance (CL}. Calculated as dose/A UC,,, 
• 
Additional parameters may be calculated at the discretion of the 
pharmacokineticist, pending review of the data. 
Added: The PK population will include all subjects who have received at least 1 
dose of IP and who have had at least 1 sample collected and a valid 
bioanalytical result obtained. The samples will be drawn between 1 and 5 
hours or between 4 and 8 hours after the last dose during the double-blind and 
open label periods. Pharmacokinetic analyses will be lilnited to listing of 
concentrations because sufficient concentration-time data will not be available 
Confidential 
Marinus Pha1maceuticals Inc. 
20 January 2021 
Synopsis (Exploratory 
Endpoints, Statistical 
Methods), Section 9.13.1.4 
Synopsis (Statistical 
Methods) and Section 
9.13.1.4 
Synopsis (Phannacokinetic 
Assessments), Section 7.7 
Synopsis (Phannacokinetic 
Assessments), Section 9.15 
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Protocol 1042-PCDH19-3002 
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for noncompartmental analyses such as Cmax, AUC or tmax. Pharmacokinetic 
data from this study may be used for a Population PK analyses to be 
conducted separately from this study and reported separately. 
Removed: Except for the exploratory endpoints of seizure frequency within the 
titration and maintenance phases of the DB phase, derived seizure exploratory 
endpoints will be based on data through the end of the 17-week DB phase relative 
to the 8-week prospective baseline period.   
Synopsis (Statistical 
Methods) 
Revised: Visit 3 (Week 5):  between 1 and 5 hours since the last investigational 
product dosing  
Added: Visit 6 (Week 21): between 1 and 5 hours since the last investigational 
product dosing 
Visit 8 (Week 52): between 1 and 5 hours since the last investigational product 
dosing 
For all other PK draws, there is no specified time to draw the PK sample and 
can be drawn when convenient during the study visits. 
 
Synopsis (Pharmacokinetic 
Analysis), Section 7.7 
Added: Interim Analysis: 
Formal interim analyses are planned, in addition to the final analysis, of 
treatment effect on the primary endpoint, in accordance with the SAP. 
Synopsis (Interim 
Analysis) 
Table 1, Schedule of Assessments for the 17-Week, Double Blind has been 
updated: 
 
Changed the Table header to state Double-blind Treatment Phase of the study  
 
Removed (Pre-baseline Screening Visit) week range to -20 to -9 
 
Added the visit window of + 6 days for Day 0 (Baseline -Randomization) 
  
Added an additional Phone Follow – up Visit on Day 3 with visit window of +/- 1 
days. The assessments include Adverse Event and Seizure and Medication eDiary 
Review,  
 
Added additional Phone Follow – up Visits on Week 11 with visit window of +/- 3 
days. The assessments include Adverse Event, Seizure and Medication eDiary 
Review. 
 
Revised per content in protocol to add X for Physical/Neurological/Developmental 
Exam for Visit 4 (Week 9) 
 
Added X to Genetic testing for Pre-Screening Visit.  
 
Added footnote g for Vital Signs to Visit 2, Visit 3, and Visit 4 
 
Added footnote r to Visit 2 
 
Table 1, Section 3.1, 
7.2.1.1, 7.2.1.3, Section 
7.2.2. Section 7.2.2.1, 
Section 7.2.2.4  


 
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Protocol 1042-PCDH19-3002 
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Updated the footnotes as follows:  
e. Added: Genetic testing to be performed to confirm pathogenic or likely 
pathogenic PCDH19 variant only.  If genetic testing is not performed as 
Standard of Care, a pre-baseline screening visit will be scheduled to obtain 
informed consent/assent and complete the genetic testing. If genetic testing 
results are available per SOC, the genetic testing will be done at screening to 
confirm the results by the Sponsors designated lab. Genetic testing is to be 
performed to confirm pathogenic or likely pathogenic PCDH19 variant only.   
g. Added: At each visit, dosing will be reviewed and adjusted as needed based 
on a subject’s current weight. 
j. A drug screen ((Removed: urine or) plasma) will be performed to test for THC 
and CBD at screening. (Removed: A negative drug test at screening meets the 
protocol eligibility criteria.) If the screening drug test is positive, (Removed: a 
plasma drug screen will be performed to test for THC and CBD at baseline.) the 
subject can be rescreened after 2 weeks.  
l. Revised: Visit 3:  between 1-5 hours since last IP dosing, 
r. The 8 weeks between Screening and Randomization can be no less than 56 
days and no more than 62 days. 
 
Table 2, Schedule of Assessments for the Open-Label has been updated: 
 
Added additional Phone Follow – up Visits on Day 3 after Visit 5 (+/- 1 day). The 
assessments include Adverse Event and Seizure and Medication eDiary Review. 
 
Updated the footnotes as follows:  
c. Revised: In addition, height will be measured annually after Visit 8 (Week 52), 
except the safety follow-up visit. 
i. Added: Population PK will be conducted at these visits (Visit 6: between 1-5 
hours since the last IP dosing and Visit 8: between 1-5 hours since last IP 
dosing) 
Table 2, Section 7.2.4.1 
Revised: however, the seizure frequency decreases, 
Section 1.1 and 2.1 
Removed: As of 10 October 2017, approximately 1,587 unique subjects have 
received treatment with GNX in ongoing and completed company-sponsored 
clinical trials ranging in duration from 1 day to more than 2 years, using doses 
from 50 to 2,000 mg/day.  In addition, 9 subjects are enrolled in the ongoing post-
partum depression study, which remains blinded (GNX Investigator Brochure [IB] 
version 08 Feb 2018). 
In 20 completed Phase 1 studies, 319 healthy subjects received GNX oral doses of 
50 to 2,000 mg/day for periods of up to 2 weeks or IV bolus doses ranging from 10 
to 30 mg over durations of 2 minutes to 1 hour or a bolus dose of 6 mg over 5 
minutes followed with a continuous infusion of 20 mg per hour for 4 hours. 
In the 20 completed Phase 2/3 clinical studies, 1238 unique subjects have received 
GNX in studies of adult subjects with epilepsy, pediatric subjects with seizure 
disorders, pediatric subjects with Fragile X Syndrome (FXS), adult subjects with 
post-traumatic stress disorder (PTSD), and adult subjects with migraine. 
Two company-sponsored clinical studies of GNX are ongoing and have 
enrolled approximately 39 unique subjects: one study in subjects with rare 
Section 1.2 


 
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genetic epilepsies including female pediatric subjects with protocadherin 19 
(PCDH19) and other genetic epilepsies (Study 1042-0900), including CDD, 
continuous spikes and waves during sleep (CSWS), and LGS, and one in 
females with post-partum depression (Study 1042-PPD-2002).  Enrollment is 
complete for Study 1042-0900; however, the study is still ongoing.  Enrollment 
is ongoing for Study 1042-PPD-2002 and results remain blinded. 
In addition to the company-sponsored studies, 18 subjects were treated with GNX 
in completed studies not sponsored by Marinus.  These included 16 subjects who 
received oral GNX doses from 400 mg/day to 1200 mg/day in a smoking cessation 
study.  In addition, one pediatric subject received oral GNX up to 63 mg/kg/day 
under a special access scheme in Australia for treatment of refractory seizures 
associated with PCDH19 genetic epilepsy and one pediatric subject received 
intravenous GNX up to a dose of 2880 mg/day in an emergency Investigational 
New Drug (IND) Application to treat super refractory status epilepticus.  
  
Added:  As of 10 Oct 2018, 1557 unique subjects have received treatment with 
GNX in completed company-sponsored clinical trials ranging in duration from 
1 day to more than 2 years, using doses from 50 to 2,000 mg/day. In addition, 
30 subjects received GNX in an ongoing open-label Phase 2 study, and an 
estimated 65 subjects received GNX in ongoing Phase 2/3 double-blind studies.  
Of these 1557 unique subjects, 319 healthy subjects have received GNX 
treatment in Phase 1 studies and 1238 subjects have received GNX treatment 
in Phase 2/3 studies. The completed trials include 20 Phase 1 studies in healthy 
subjects and 20 Phase 2/3 studies in adults with epilepsy, children with seizure 
disorders, children with FXS, adults with PTSD and adults with migraine. 
Four company-sponsored clinical studies of GNX are ongoing and have 
enrolled over 200 unique subjects:  
 
Study 1042-0900 in pediatric epilepsies including female pediatric 
subjects with PCDH19 epilepsy and other rare genetic epilepsies 
including CDKL5 deficiency disorder, LGS and continuous spikes 
and waves during sleep (CSWS)  
 
Study 1042-SE-2001 in adolescents and adults with SE  
 
Study 1042-PPD-2002 in women with PPD (GNX IV and oral capsule 
multiple-dose escalation double-blind study)  
 
Study 1042-PPD-2003 in women with PPD (GNX oral capsule multi-
dose escalation open label study) 
For these 4 ongoing clinical studies, enrollment is complete for Study 1042-
0900, 1042-PPD-2002 and 1042-PPD-2003 and is ongoing for Study 1042-
SE-2001. 
In addition to the company-sponsored studies, 29 subjects were treated with 
GNX in completed studies not sponsored by Marinus.  These included 16 
subjects who received oral GNX doses from 400 mg/day to 1200 mg/day in a 


 
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smoking cessation study and 10 subjects who received oral GNX in a 
postmenopausal depression study.  One pediatric subject received oral GNX 
up to 63 mg/kg/day under a special access scheme in Australia for treatment of 
refractory seizures associated with PCDH19 genetic epilepsy.  In addition, two 
pediatric subjects received GNX in separate emergency INDs to treat super-
refractory status epilepticus: 1 subject received IV GNX up to a dose of 2880 
mg/day and 1 subject received IV GNX infusion up to a dose of 192 mg/day 
and transitioned to a GNX oral suspension dose of 1260 mg/day that was 
tapered over 6 weeks.[SAE Section 5.6 IB] 
Furthermore, 3 non-company-sponsored clinical studies are ongoing. In these 
studies, a total of 7 subjects continue to receive treatment with GNX through 
investigator-initiated INDs following participation in Marinus-sponsored 
studies as follows:  
 
In one study, 3 subjects received GNX following participation in 
Study 1042-0603 of adult subjects with drug-resistant partial-onset 
seizures. 
 
In one study, 3 subjects (2 subjects with PCDH19 epilepsy and 1 
subject with LGS) received GNX following participation in 
Study 1042-0900.  
In another study, 1 subject with CDD received GNX following participation in 
Study 1042-0900 
Removed: Most rashes improved either while the drug was continued or following 
discontinuation.  Two subjects participating in the Phase 2 study investigating 
GNX in treatment of epilepsy developed a serious adverse event (SAE) of rash.  
Both events resolved after discontinuation of the investigational product. 
Added:  One of the events was also reported as an SAE and the event resolved 
after discontinuation of the study drug. In addition, in the ongoing study 1042-
0900, an additional event of rash was reported as an SAE. There have been no 
cases of Stevens-Johnson syndrome, toxic epidermal necrolysis or any other 
clinically important rashes reported in the clinical development program. 
Marinus considers rash as a potential risk associated with GNX and continues 
to monitor the occurrence of this AE in the clinical development program. 
Section 1.2 
Added: condition aggravated (10/59 subjects; 16.9%), and upper respiratory 
tract infection (9/59 subjects; 15.3%) 
Removed: vomiting (8/59 subjects; 13.6%), decreased appetite (8/59 subjects; 
13.6%), aggression (6/59 subjects; 10.2%) and rash (5/59 subjects; 8.5%).   
Section 1.2 
Revised: assess the effect of GNX on primary seizure rate 
Synopsis (Objectives) and 
Section 2.2.2 
Added: At each visit, dosing will be reviewed and adjusted as needed based on 
subject’s current weight. 
Section 3.1 and Section 
6.2.3.1 
Added: An electronic eDiary is the standard, in rare cases when an eDiary 
completion is not feasible, a paper seizure calendar will be used to log daily 
seizure type and frequency. These cases will need approval by the sponsor. 
Section 3.1 
Added: Additionally, if genetic testing is not completed as standard of care, a 
pre-baseline screening visit can be conducted to do so. 
Section 3.2 


 
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Added:  Abstinence is an acceptable method of birth control only if this is in 
line with the preferred and usual lifestyle of the subject.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
Section 4.4.1 
Revised: in the informed consent/ (and/or subject assent) form 
Revised: informed consent/assent form 
Section 4.5.1, 7.2.1.1, 
7.2.1.2, 7.3.1, 7.3.4, 8.1, 
8.1.6, 8.2.4, 8.2.5, 9.1, 9.7, 
10.3.1 
Added:  If a subject must be abruptly discontinued from investigational 
product, (e.g., severe rash), careful attention should be paid for possibility of 
withdrawal symptoms such as increase in seizure number or severity.   
Consideration should be made by the investigator for providing another 
GABA-A medication for 1-2 weeks such as clobazam to mitigate the potential 
risk of withdrawal from a positive modulator of GABA-A.   
Section 4.5.1 
Revised reasons for early termination: 
Added:  Adverse event in which the character, severity or frequency is new in 
comparison to the subject’s existing risk profile with the exception of 
somnolence and seizures.   
Added:  An Adverse Event that is associated with non-reversible target organ 
dysfunction, with the associated laboratory abnormalities as defined in 
exclusion criteria 11, 12 or 13.  An allowance may be made for continued 
treatment if the abnormality is not medically significant (non-life-threatening 
or does not require ongoing treatment that could be life-threatening)   
Added:  A laboratory abnormality or vital sign change that is irreversible and 
considered medically significant, associated with use of the investigational 
product 
Added:  Pregnancy 
Section 4.5.2 
Added: During the screening visit and after consent is obtained, 
Section 4.6 
Revised: assigned by the IWRS (removed “study staff”).   
Section 4.6 
Added:  Concomitant medications may be reduced or discontinued at the 
discretion of the investigator if medically warranted. 
Section 5.2, 5.2.1 
 


 
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Excluded medications include oral (removed: “all”) steroid medications, other IPs, 
and ketoconazole.  Use of St.  John’s Wort and concurrent use of strong inducers or 
inhibitors of CYP3A4/5/7 is not permitted.  A list of CYP3A4/5/7 inhibitors and 
inducers is included in Section 12.1.  Any strong inhibitor or inducer of 
CYP3A4/5/7 must be discontinued at least 28 days before Randomization Visit; 
note that this does not apply to (removed: “included”) approved AED 
medications. 
Products containing tetrahydrocannabinol (THC) or non-approved CBD are 
excluded in the DB phase of the study but allowed in the OL phase.  THC or non-
approved CBD should be washed out for at least 2 weeks before screening.  
Subjects with a positive result on THC or non-approved cannabidiol CBD test 
(plasma drug screen) (Removed: at the screening) visit can be re-screened after 2 
weeks. (Removed: or a positive result on THC or non-regulated CBD test (via 
urine or plasma at the baseline will be excluded from the study.) 
Added: Use of any herbal product or nutritional supplement must be reviewed 
and approved by Marinus Medical Monitor.  
 
Section 5.4 
Revised: Interactive Web Response System for Investigational 
Section 6.2.1 
Revised: Dose de-escalation (taper) will occur in decreasing increments of 
15 mg/kg/day or 450 mg every 3 days over 2 weeks whenever feasible 
Section 6.2.3.1 
Removed: Dosing Instructions in Sections 12.3.2 and 12.3.3.  
Revised: Examples of dosing for subjects of different weights are provided in 
Section 12.3. Dosing instructions for the DB dose titration, DB and OL 
maintenance and taper are provided in the Pharmacy Manual.  Dosing 
instructions for DB to OL transition are provided in the Pharmacy Manual. 
Section 6.2.3.2, 12.3.2, and 
12.3.3 
Revised: Typically, doses will be reduced by 15 mg/kg/day or 450 mg/day every 
(removed “at least”) 3 days until the subject is completely off IP.  Subjects should 
then return for a Safety Follow-up Post-Taper visit. 
Section 6.2.3.3 
Added Table 5  
Table 5: 
De-Escalation of Investigational Product 
Formulation 
Dose 
Frequency 
Suspension (weighing ≤ 28 
kg) 
Reduce 15mg/kg/day 
Every 3 days 
Suspension (weighing > 28 
kg) 
Reduce 450 mg/day 
Every 3 days 
Section 6.2.3.3 
Revised: Investigational product will be provided as an oral suspension.  
Ganaxolone must be taken with a meal or snack.  Note:  Grapefruit and grapefruit 
juice, Seville oranges, star fruit, and grapefruit containing products are prohibited 
14 days prior to 1st dose and for the duration of the study. 
Ganaxolone oral suspension will be administered through an oral dosing syringe 
administered by parents/caregivers 3 times daily (TID), following the morning, 
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noon, and evening meal or snack.  Each dose should be separated by a minimum of 
4 hours and a maximum of 12 hours.   
Added: Ganaxolone oral suspension: A missed dose of IP may be taken up to 
4 hours before the next scheduled dose; otherwise, the missed dose should not be 
given. 
Added:  The site will confer with the medical monitor to devise a dosing plan. 
Section 6.2.5 
Added Table 6 
Table 6: 
Missed Dose of Investigational Product 
Formulation 
Proceed to Dose 
DO NOT DOSE 
Suspension 
≥ 4 hours before next 
scheduled dose 
< 4 hours before 
next scheduled dose 
 
Section 6.2.5 
Added: Prior to unblinding or immediately following, the sponsor’s Medical 
Monitor must be contacted.  Removed: The sponsor’s Medical Monitor must be 
contacted to initiate unblinding in the IWRS system. If unavailable, the Sponsor’s 
Back-up Medical Monitor or Sponsor Project Managers should be contacted. 
Added: The Sponsor’s Medical Monitor does not have to be contacted to 
initiate unblinding in the IWRS system.    
Section 6.3 
Revised: Compliance with IP treatment will be monitored by inspecting the 
electronic diary (Removed: seizure and medication) entries and returned supplies 
with queries as necessary.   
Section 6.6 
Revised: Historical Seizure Type and Frequency and/or Genetic Testing   
Section 7.2.1.1 
Revised: maintain a daily seizure calendar or have genetic testing results with a 
confirmed PCDH19 diagnosis per standard of care, written informed 
consent/assent will be obtained. and the subject will be asked to return to the clinic 
for the Screening (Visit 1) after she has maintained a 3-month (12-week) daily 
historical seizure calendar and/or complete genetic testing.   
Section 3.1 and 7.2.1.1 
Revised: 3-month (12-week) daily 
Section 7.2.1.1 
Added: Genetic testing to confirm pathogenic or likely pathogenic PCDH19 
variant by Sponsor identified lab, if not done at prescreening.  
Section 7.2.1.2 
 
Added: Baseline Visit – Randomization (Visit 2, Week 0 + 6 days) 
The following study procedures/assessments to be completed, the results received, 
and the investigator must ensure the subject meets all inclusion and exclusion 
criteria prior to IP administration. The 8 weeks between Screening and 
Randomization can be no less than 56 days and no more than 62 days. 
 
Section 7.2.1.3 
Added weight to every visit with the exception of the safety follow-up.  
Revised: Vital signs (to include BP, HR, RR, body temperature, and weight) 
Section 7.2.1.3, 7.2.2.2, 
7.2.2.3, 7.2.4.2 


 
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Corrected error by adding CGI-C and CGI-I to assessments under Baseline Visit.  
Section 7.2.1.3 
Added: population PK 1-5 hours post dose or population PK 4-8 hours post dose 
Section 7.2.2.2, 7.2.2.3, 
7.2.4.2, 7.2.5.2, 7.7 
Revised: Telephone Follow-Up (3 days after Visit 5 ± 1 day, Weeks 18, 19 and 
20 ± 3 Days) 
A telephone follow-up visit will be conducted 3 days after Visit 5 and at Weeks, 
18, 19, and 20 of the OL phase to assess the following: 
 
Section 7.2.4.1 
Revised to correspond with Table 2. Follow-Up (Weeks 28, 44, and 60 ± 7 Days) 
 
Section 7.2.5.1 
Revised: Vital Signs (All Visits:  to include BP, HR, RR, body temperature, and 
weight; Visit 7 and 8:  to include height) 
Section 7.2.5.2 
Added: ECG (annually after Visit 8, Week 52) and Neurosteroid level sample 
draw (annually) 
 
 
Section 7.2.5.3 
Revised: Procedures specific to this protocol and not otherwise considered 
standard of care, will not be performed until written informed consent /Assent from 
the subject/parent/caregiver/LAR has been appropriately obtained.   
Section 7.3.1 
Revised: A drug screen ((Removed: urine or) plasma) will be performed to test for 
THC and non-approved (removed non-regulated) CBD at Visit 1 (screening). If 
the screening drug test is positive, a confirmatory plasma drug screen will be 
performed after 2 weeks. A positive drug test at Visit 2 will exclude the subject 
from the study. (Removed: to test for THC and CBD at Visit 2 (baseline).) 
Section 7.3.2 
Revised: The 33-question test is filled out by the parent/caregiver/LAR.   
Section 7.4.3 
Added: The EEGs will be compared for changes in overall background 
features of paired sets of EEGs from each subject (in blinded order) and 
determined which EEG has the better overall organization and complexity of 
background or identify them as equivalent overall. Quantitative EEG 
parameters will also be conducted and will include: total power, relative 
alpha, beta, theta, and delta, theta/delta ratio, and alpha/delta ratio. 
 
Section 7.5.1 
Revised: Blood samples will be drawn (removed at) during the DB phase at Visit 1 
(screening) and Visit 5 (Week 17; 
Section 7.5.2 
Revised text to correspond with Table 1. The CGI-C – target behavior will be 
assessed as follows:  in the DB phase at Visit 2 (baseline), Visit 3, Visit 4, and 
Visit 5 
Section 7.5.5 and 7.5.6 


 
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Added: If any of the baseline safety assessments are outside of normal limits, 
and the investigator feels is medically significant, the subject may not be 
randomized.  
Section 7.6 
, and weight will be collected at every clinic visit starting with Visit 1 other than 
the Safety Follow-Up Visit.  Height will be collected at Visit 1 (screening) (during 
DB phase) and during the OL phase at Visit 7 (Week 36), at Visit 8 (Week 52), 
annually thereafter (except for the Safety Follow-up Visit), and at the Final OL 
Visit.  Removed: Weight will be collected as follows:  during the DB phase at Visit 
1 (screening) and Visit 5 (Week 17; also Final DB Visit/First OL Visit in OL 
phase); during the OL phase at Visit 7 (Week 36) and every clinic visit thereafter; 
and at the Final OL Visit. 
Section 7.6.2 
Replaced OLE with OL  
Synopsis (Safety Analysis) 
Section 9.7, 9.8, 9.14 
Removed: A third party will provide central ECG services for this study including 
provision of equipment to clinical sites, project management, site training and 
education, and data analysis as well as delivery of clean quality data.  Complete 
details regarding the third party’s ECG services will be provided in the PI Site 
File. 
Section 7.6.4 
Revised language to correspond with Table 1 visits. Due to the difficulty in 
obtaining urine samples, urinalysis will be conducted as follows:  during the DB 
phase at Visit 1 (screening) or baseline (Visit 2), Visit 3, and at Week 17 (Visit 5; 
Section 7.6.5 
Removed Clinical Pharmacokinetic Blood Sample Collection and Handling 
Procedures 
Pharmacokinetic blood collection must not deviate from the nominal collection 
time set forth in the protocol by more than  30 minutes from samples drawn within 
4 hours post-dose or by more than  60 minutes for samples drawn beyond 4 hours 
post-dose.  Samples drawn outside these parameters will be considered a protocol 
deviation.  
Please refer to the central laboratory manual for processing instructions. 
Section 7.7.1 
Added:  If a relationship between the AE and the investigational product is at 
least reasonably possible (i.e. the relationship cannot be ruled out) the AE 
should be considered "related.”   
Removed: Otherwise, if there is any valid reason, even if undetermined or untested, 
for suspecting a possible cause-and-effect relationship between the investigational 
product and the occurrence of the AE, the AE should be considered “related.”   
Section 8.1.2 
8.3 Adverse Events of Special Interest 
8.3.1 Reference Safety Information 
The following represent the Adverse Events of Special Interest: 
 
Rash 
 
Adverse Events that would be classified under reproductive 
system and breast disorders system organ class 
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Removed: the standard deviation for the percent change in 28-day seizure 
frequency for all seizures is estimated to be 28.4, although other relevant data 
suggest the actual standard deviation could be meaningfully higher.  If we assume 
the percent change in 28-day seizure frequency on GNX minus that on PBO truly to 
be approximately 40%, then a trial with 30 (respectively, 50) biomarker-positive 
PCDH19-related epilepsy patients randomized in a 1:1 manner will have about 
96% (respectively, 99%) power to detect this effect when using a test statistic that 
preserves a (1-sided) 2.5% blinded positive error rate.  But if we assume the 
standard deviation to be 40, then a trial with 30 (respectively, 50) biomarker-
positive PCDH19 patients randomized in a 1:1 manner will have about 77% 
(respectively, 94%) power to detect this effect.   
 
The threshold for achieving statistical significance in the biomarker-positive cohort 
at the final analysis when 30 (respectively, 50) subjects have completed their 17-
week DB phase would be an estimate of the difference that is 72% (respectively, 
55.5%) of the standard deviation.  (If the standard deviation is 28.4, then the 
threshold for statistical significance is approximately 20.5%, (respectively, 
approximately 16%).  If the standard deviation is 40, then the threshold for 
statistical significance is approximately 29%, (respectively, approximately 23%). 
Added: the standard deviation for the percent change in 28-day seizure 
frequency is estimated to be 28.4, although other relevant data suggest the 
actual standard deviation could be meaningfully higher. If we assume the 
standard deviation to be 40 and the percent change in 28-day seizure 
frequency on GNX minus that on placebo truly to be ꟷ40%, then a trial with 
50 biomarker positive PCDH19 patients randomized in a 1:1 manner will have 
about 94% power to detect this effect when using a test statistic that preserves 
a (one-sided) 2.5% false positive error rate. The threshold for achieving 
statistical significance in the biomarker positive cohort at the final analysis 
when 50 subjects have completed their 17-week double-blind phase would be 
an estimate of the difference that is 55.5% of the standard deviation.  (If the 
standard deviation is 40, then the threshold for statistical significance is 
approximately ꟷ23%).   
Section 9.5 
Revised: The Safety and ITT populations comprise all randomized subjects who 
received at least one dose of study drug. In addition to being the population for the 
safety analyses, the biomarker-positive subjects in it is the primary population for 
the efficacy analyses. 
Removed: The Per-Protocol (PP) population consists of subjects who receive IP 
for at least 6 weeks, who provided at least 5 weeks of post-baseline seizure data, 
and who have no major protocol violations.    
Added: The Per-Protocol (PP) population includes all ITT subjects without 
major protocol violations (defined prior to database lock).   
Section 9.6 
Revised: in subjects daily seizure (Removed: “calendars”) eDiary, 
Section 9.7 


 
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Removed: For the primary outcome measure, if a subject stops recording 
measurements permanently (anticipated to be zero or minimal in occurrence) prior 
to the end of the 17-week DB phase, the corresponding median PBO data for the 
missing days will be imputed (irrespective of treatment arm) within each stratum, 
as follows: 
 
Compute the median 28-day seizure frequency in the PBO arm based on all 
available PBO measurements during the 17-week DB treatment phase.  Label 
that ‘X’ and define ‘A’ to be ‘X’/28, (ie, the daily average on PBO during the 
17-week during the DB phase). 
 
For any days (whether they be on the PBO or GNX arm) that occur AFTER a 
subject has become lost to follow up, impute ‘A’ on that day. 
A conceptually similar imputation approach will be used will be used for the 
secondary outcome measures when a subject stops recording measurements 
permanently prior to the end of the 17-week DB phase. 
Added: The primary analysis will use all available data. Careful educating 
and monitoring of the study sites will attempt to limit the amount of missing 
data to nearly zero, but despite these efforts, some missing data may still arise. 
Thus, a sensitivity analysis, in which the missing data will be 
replaced/imputed, will be performed on the primary efficacy endpoint. 
Section 9.13.1.1 
Removed: In order to explore the possibility that subjects who stop recording their 
seizure counts tend to have higher seizure counts than the other subjects, the 
imputation method described in the SAP will be modified to use the median of the 5 
highest counts, rather than the median count, among the PBO subjects with data. 
Added: Two sensitivity analyses of the primary efficacy endpoint of change in 
28-day frequency of the primary seizure types will be performed:  
 
Intermittent (random/sporadic) missing data during the 17-week DB phase 
and any missing data during the baseline phase will be assumed missing 
completely at random and the collected data will be used to calculate the 28-
day seizure frequencies. For early drug termination prior to the end of the 17-
week DB phase, caregivers will be instructed to continue to provide daily 
seizure records until the end of the 17-week DB phase (hence further 
preventing missingness). 
 
In the first sensitivity analysis, the following imputation approach will be used 
for the primary outcome measure when a subject stops recording 
measurements permanently (anticipated to be zero or minimal in occurrence) 
prior to the end of the 17-week DB phase: for the missing days, the 
corresponding median PBO data will be imputed (irrespective of treatment 
arm), within each stratum, as follows: 
 
Compute the median 28-day seizure frequency in the PBO arm based on all 
available PBO measurements during the 17-week DB treatment 
phase.  Label that ‘X’, and define ‘A’ to be ‘X’/28, (i.e., the daily average 
on placebo during the 17-week during the DB phase). 
 
For any days (whether they be on the PBO or GNX arm) that occur 
AFTER a subject has become lost to follow up, impute ‘A’ on that day. 
 
The second sensitivity analysis will explore the possibility that subjects 
who stop recording their seizure counts tend to have higher seizure counts 
than the other subjects. The imputation method described above will be 
modified to use the median of the 5 highest counts, rather than the median 
count, among the PBO subjects with data. 
Section 9.13.3 


 
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Revised: All of the analyses for the DB phase, (removed: except for seizure 
frequencies during the titration and maintenance phases,) will be repeated for the 
OL phase with the following differences: 
 
The results will be presented overall and also classified according to the 
DB (removed phase) treatment received by subjects. 
 
Post-baseline seizure endpoints will be derived based on the first day 
(Removed “following the start”) of OL treatment.  
 
(Removed: “No data will be imputed, and thus”) No sensitivity analyses 
will be performed.  
Added: The complete list of differences will be outlined in the SAP. 
Section 9.13.5 
Removed: The number of days that subjects received study drug, the total amount 
of study drug received, and the number and percent of subjects for whom dose 
reduction was required will be summarized, and a subject data listing will be 
provided with full details of the study drug dispensation. 
Added: The number and percentage of days that subjects received 
investigational product, the highest percentage of the maximum allowable 
daily dose (1800 mg or 63 mg/kg) that subjects received, and the total amount 
of investigational product received will be summarized. For the open-label 
phase, they will be summarized over just the open-label phase as well as over 
the entire study (combined DB and OL phases) but the classification by the 
double-blind treatment applies only for the open-label phase summary. The 
summarization over the entire study will include the double-blind data only 
from subjects who were in the GNX group during the double-blind phase, 
regardless of whether they entered the open-label phase, and all the subjects 
from the open-label phase. 
Added: Detailed analysis and complete listings will be outlined in the SAP. 
Section 9.14 
Revised: It will be conducted when 33 subjects in the biomarker-positive stratum 
Section 9.16 
Added: In rare cases when an eDiary completion is not feasible, a paper diary 
will be used to log daily seizure type and frequency.  The Sponsor will provide 
the paper diary template which should not be modified. 
Section 10.2.3.2 
Removed:  As the disease under consideration is a condition for which the subjects 
will not be capable of signing consent/assent for themselves, a 
parent/caregiver/LAR will be required to sign upon identification of the subject for 
participation.   
Section 10.3.1 
Revised: Appendix 3:   Examples of Dosing Titration for Oral Suspension 
Removed: 12.3.1 Examples of Dosing Transition  
 
 
Section 12.3 


 
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Removed: Appendices for Dosing Instructions and Scales.  
Section 12.3.2, 12.3.3, 
12.4, 12.5, 12.6, 12.7, 12.8, 
12.9, 12.10, 12.11, 12.12 
Administrative changes: Minor changes involving grammar, rephrasing for clarity, 
punctuation, and other editorial changes have been made throughout the document.  
 
Entire document 
Amendment Number 
3 
Amendment Date 
16 August 2019 
Global/Country/Site 
Specific 
Global 
Description of Change 
Section(s) Affected by 
Change 
Added: Exclusion Criteria - Subjects with ≤ 3 primary seizures during the 12-
week baseline period.    
 
Synopsis (Exclusion 
Criteria) and Section 4.2 
Revised: Subjects with >8 (Removed: 6) consecutive weeks (56 (Removed: 42) 
consecutive days) of primary seizure freedom during the 12-week pre-baseline 
screening period. 
 
Synopsis (Exclusion 
Criteria) and Section 4.2 
Updated: 8-week baseline period to 12-week baseline period 
Synopsis (Methodology, 
Duration of Treatment, 
Secondary Endpoint, 
Exploratory Endpoint, and 
Statistical Methods), Table 
1, Sections 3.1, 3.2, 5.2, 
7.2.1.2, 7.2.1.3, 9.7, 9.13.1, 
9.13.1.3, 9.13.1.3.1.1 
, 9.13.1.4, and 9.13.5 
 
Figure was revised to update Baseline.  
Synopsis (Methodology) 
and Section 3.1 
Removed: If a subject experiences no primary seizures during the baseline phase 
then the 28-day seizure frequency in the baseline phase will be set to 0.5, 
equivalent to having 1 seizure during the phase, and 0.5 will be added to the 28-
day seizure frequency in the post-baseline phase. 
Synopsis (Primary 
Endpoint and Statistical 
Methods) and Section 
9.13.1.2 
Added: N/A to Visit Windows in Table 1 for Pre-baseline Screening Visit and 
Screening Visit.  
Table 1 
PCDH19 
(all•subjects) 
__ ,, 
PrlmM)' e~~M411t»~~-t:dto/t 
Low !Jk>-S 
BiomaJ'ker+ 
R 
n: 50 
l : 
1~--------~ 
SCl'eening 
Visit 
Biomarker• 
n- 20 
' 
1:1 
Placebo 
Placebo 


 
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Revised: The 12 (removed: 8) weeks between Screening and Randomization can be no less 
than 84 (removed: 56) days and no more than 90 (removed: 62) days. 
Table 1, footnote r and 
Section 7.2.1.3 
Updated: Serum pregnancy tests were added to Visit 3, Visit 4, Visit 6, Visit 7, 
Visit 8, Visit 9, Visit X (every 16 weeks in OL), Final OL, and Safety Follow-Up 
Visit. 
Table 1 and Table 2, 
Sections 7.2.2.2, 7.2.2.3, 
7.2.3, 7.2.4.2, 7.2.5.2, 
7.2.5.3, 7.2.7 
Revised: Week 17 +3 Days (Removed Post Visit 5) 
Table 2 and Section 7.2.4.1 
Added: Line for Drug Screen in Table 2 to be consistent with Table 1 for Week 17 
Final DB Visit/First OL Visit 
Table 2 
Added: However, the final decision to adjust drug dosages lies with the PI. 
Section 3.1 
Added: If a subject fails to qualify because of Exclusion Criteria #4 (≤ 3 
primary seizures during the 12-week baseline period), she will not be 
randomized. However, she can be rescreened after collecting another 12 or 
more weeks of seizure history that satisfies all eligibility criteria including 
Inclusion Criteria #5 and Exclusion Criteria #3. Each subject is allowed a 
maximum of 1 rescreening visit. 
Section 3.1 and 7.2.1.2 
Updated: A minimum oral suspension dose of 33 mg/kg/day or 900 mg/day is 
generally required following the escalation period, during the DB phase unless 
a lower dose is agreed to with the sponsor due to tolerability issues such as 
somnolence (Removed: must be maintained).   
Section 3.4 
Updated: Subjects with a positive result on THC or non-approved cannabidiol 
CBD test (via plasma drug screen) can be retested, (Removed: re-screened) via 
plasma, after 2 weeks. 
Section 5.4, 7.3.2, and 
Table 1, footnote J 
Revised: A positive drug test during the DB phase will result in early 
termination. (Removed: at Visit 2 will exclude the subject from the study) 
Table 1 Footnote j 
j. Revised: A positive drug test during the DB phase will result in early 
termination. (Removed: at Visit 2 will exclude the subject from the study) 
Section 7.3.2 and Table 1, 
footnote J 
Revised: Note that if a subject is taking marketed Epidiolex (may go by another 
name in countries outside the United States) then the parent/caregiver will have 
to provide evidence of an active prescription or confirmation from prescriber. 
Section 5.4 
Revised: 450 mg/day 
Section 6.2.3.1 
Revised: Instructions for genetic testing sample collection and processing can be 
found in the central (Removed: genetic testing) laboratory manual 
Section 7.3.5 
Updated: The preschool version (BRIEF-P) is a 63-item modified form and is 
typically utilized in individuals 2-5 years of age.  For this study, the BRIEF-P 
will be used for any subject less than 5 years of age. 
Section 7.4.4 
Updated: Quantitative EEG parameters will also be conducted and will include the 
following 
Section 7.5.1 
Updated: (Removed: Laboratory safety assessments will be collected at every 
clinic visit throughout the study to monitor subject safety.) Clinical laboratory tests 
are listed in Section 12.12 and will be collected per the schedules listed in Table 1 
and Table 2.  (Removed: These clinical laboratory assessments will include CBC 
with automated differential, creatinine, blood urea nitrogen, and eGFR 
calculation, comprehensive metabolic panel, and serum pregnancy test for all 
females of childbearing potential.) 
Section 7.6.5 and 
Appendix 2 
Updated: Appendix 2. Drug Screen removed from urinalysis column. All drug 
tests are serum. 
Appendix 2 


 
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punctuation, and other editorial changes have been made throughout the document.  
 
Entire document 
Amendment Number 
4 
Amendment Date 
30 June 2020 
Global/Country/Site 
Specific 
Global 
Description of Change 
Section(s) Affected by 
Change 
Violet Study changed from a Phase 3 to a Phase 2 Study.  
Synopsis 
Protocol Signature Page 
Updated primary and back-up Medical Monitor contacts.  
Added: 
added as the 
 
Revised:
 moved from 
 
Revised:
 from 
 
Added:
Removed:
 
Removed: 
Emergency Contact 
Information and Section 
6.3 
Updated CHSQ to CSHQ  
Abbreviations, Synopsis 
(Methodology and 
Secondary Endpoints), 
Sections 3.1 and 
9.13.1.3.2.3 
Updated:  
A sufficient number of eligible PCDH19 subjects will be screened and enrolled, 
with a 1:1 randomization to either ganaxolone (GNX) or placebo (PBO).   As study 
enrollment was discontinued early (as of 01July2020) due to administrative 
reasons, the total number of the randomized patients is expected to be 
approximately 25 subjects resulting in approximately 15 randomized biomarker-
positive subjects.  
Previously: 
A sufficient number of eligible PCDH19 subjects will be screened and enrolled to 
include at least 50 total biomarker-positive subjects, with a 1:1 randomization to 
either ganaxolone (GNX) or placebo (PBO).  The number of biomarker-negative 
subjects will be based on the distribution of biomarker status in the enrolled 
population with a minimum of 10 biomarker-negative subjects required.  Total 
enrollment is planned to be approximately 70 subjects.  
Synopsis (Number of 
Subjects and 
Methodology), and Section 
3.1 
Updated:  
Global, multicenter study to be conducted at approximately 11 sites 
Previously: 45 sites 
Synopsis (Sites and 
Regions), Section 3.3 
Removed: from the subject’s parent or legally authorized representative (LAR) and 
(Removed: /or) subject assent has been appropriately obtained.   
Synopsis (Methodology 
and Inclusion), Table 1 – 
footnote c, Sections 3.1, 
3.2, 4, 7.2.1.1, 8.1, 8.1.6, 
8.2.5 and 9.1 
Updated figure.  
 
Synopsis (Methodology) 
and Section 3.1 


 
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Revised: during the DB phase unless a lower dose is agreed to with the sponsor 
due to tolerability issues (removed: such as somnolence).   
Synopsis (Methodology 
and Investigational 
product, dose, and mode of 
administration), Sections 
3.4, and 6.2.3.1 
Revised Inclusion #1: Molecular confirmation of a pathogenic or likely 
pathogenic PCDH19 variant. Genetic mutations will be confirmed by the sponsor’s 
chosen central laboratory.   
Removed: The principal investigator (PI) must review the results of the genetic 
analysis and confirm that the causal relationship to the epilepsy syndrome is likely.  
If the subject has a de novo variant of unknown significance (VUS) then the central 
assessor, PI, and Sponsor will review study inclusion.   
Synopsis (Inclusion 
Criteria) and Section 4.1 
Revised Inclusion #7: (removed: Subjects should be on a stable regimen of anti-
seizure medications, if any, for ≥ 1 month prior to the screening visit, without a 
foreseeable change in dosing for the duration of baseline and the DB phase.) 
Concomitant AED regimens must have been stable for at least 1 month prior 
to the screening visit and must remain stable from screening to the end of the 
DB phase. (removed: Vagus nerve stimulator (VNS)) Ketogenic diets and modified 
Atkins diets should be unchanged for 3 months prior to screening and must 
remain stable throughout baseline and the DB phase. 
 
Synopsis (Inclusion), 
Sections 4.1 and 5.2.1 
Update: All references to baseline visit or randomization visit updated to 
baseline/randomization visit 
Throughout Protocol 
Revised Exclusion #7:  
Chronic use of oral steroid medications, ketoconazole (except for topical 
formulations), St.  John’s Wort, or other investigational products is not permitted. 
Intermittent (<5 consecutive days/month or 10 cumulative days per month) 
use of corticosteroids as a rescue medication for breakthrough seizures may be 
allowed after sponsor approval. 
 
Synopsis (Exclusion) and 
Section 4.2 
Revised Exclusion #8: Changes in any chronic AED medication (i.e., changes in 
dose or starting a new chronic AED) within the last month prior to the screening 
visit (Visit 1) and during the 12 week baseline period (i.e., between Visit 1 and 
Visit 2).  Changes in rescue AED medications to treat acute breakthrough 
seizures may be permitted with Sponsor’s approval. Changes in other (i.e., 
non-AED) chronic medications may be permitted with Sponsor’s approval.  
Synopsis (Exclusion) and 
Section 4.2 
Revised Exclusion #11: An aspartate aminotransferase (AST/serum glutamic 
oxaloacetic transaminase [SGOT]) or alanine aminotransferase (ALT/serum 
glutamic pyruvic transaminase [SGPT]) > 3 × the upper limit of normal (ULN) at 
screening (removed: or baseline visit) and if applicable,  confirmed by a repeat 
test.  If the subject has another reason to be excluded, repeated liver enzymes 
are not required. 
Synopsis (Exclusion) and 
Section 4.2 
Revised Exclusion #12: Total bilirubin levels > 1.5 × ULN at screening (removed: 
or baseline visit) and if applicable, confirmed by a repeat test.  In cases of 
Synopsis (Exclusion) and 
Section 4.2 
screening .. 
Biomarker• 
..,.,,.,,.,._ 


 
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documented, stable medical condition (i.e., Gilbert’s Syndrome) resulting in levels 
of total bilirubin > ULN, the medical monitor can determine if a protocol exception 
can be made. 
Revised: The analyses of the primary endpoint will be performed on the sum of the 
individual countable seizures and each series of continuous uncountable 
(removed: series of) seizures (each contributes 1 to the sum).   
Synopsis (Primary 
Endpoint and Statistical 
Method), Sections 7.4.1 
and 9.13.1.2 
Added: As enrollment in the study was discontinued early due to 
administrative reasons, and only 15 biomarker-positive subjects are expected 
to be randomized, the study is not considered to have adequate power for 
formal testing of the statistical hypotheses. Since the reason for stopping 
enrollment is external to the study, the statistical analysis will be performed as 
planned. All p-values produced as part of the pre-specified analysis would 
therefore be considered as nominal.  
 
Previously: Formal interim analyses are planned, in addition to the final analysis, 
of treatment effect on the primary endpoint, in accordance with the SAP. 
Synopsis (Interim 
Analysis) and Section 9.16 
Added: A drug screen (plasma) will be performed to test for THC and CBD at 
screening. If the screening drug test is positive, the subject can be retested, via 
plasma, after two weeks. A drug screen may be performed at any time at 
Investigator’s discretion. A positive drug test during the DB phase will result in 
early termination.  
 
Table 1 – footnote j and 
Section 7.3.2 
Revised: Concomitant AEDs (removed: or their dose) must be stable for 1 month prior 
Table 1 – footnote m 
Revised: Changed windows for open label visits from ± 7 to ± 14 days 
Table 2, Table 2 (footnote 
a), Sections 7.2.5, 7.2.5.1, 
7.2.5.2, 7.5.2.3, and 7.2.6 
Added:  Urinalysis to Visit 7 
Table 2, Sections 7.2.5.2, 
and 7.6.5 
Added footnote j to Table 2: Subjects who discontinue IP treatment before the 
completion of the DB phase will continue to be followed per protocol and, at a 
minimum, subjects will be encouraged to maintain daily seizure eDiary entries 
until the DB phase is completed.  These subjects will also return to the site 2 to 
4 weeks after the taper for safety follow-up post-taper assessments. 
Table 2 – footnote j 
 
 
Revised: Any subject who completes the study or discontinues IP treatment at any 
time during the study should undergo a 2-week drug de-escalation (taper) period.   
Sections 3.1 and 6.2.3.3 
Revised: Concomitant medications, other than AEDs, may be reduced or 
discontinued at the discretion of the investigator if medically warranted. 
 
Section 5.2 
Revised: The use of rescue medication is allowed on an occasional basis and as 
medically needed.   
Section 5.3 
Revised: Excluded medications include oral steroid medications, (removed: other 
IPs) ketoconazole and other investigational drugs or devices (removed: 
investigational treatments). 
Section 5.4 
Revised: Investigational product may be stopped immediately and without down-
titration in the case of an emergency, although a down titration in the event of an 
early termination is recommended (removed for safety reasons).  Dose 
de-escalation (taper) will occur in decreasing increments of 15 mg/kg/day or 450 
mg/day approximately every 3 days over 2 weeks whenever feasible (See 
Sections 6.2.3.1 and 
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Section 6.2.3.3 for more details). Taper is not required if the subject is receiving 
the dose of 18 mg/kg/day or 450 mg/day (or lower). 
Revised: Any subject who completes the study or discontinues IP treatment at any 
time during the study should undergo a 2-week drug de-escalation (taper) period.   
Section 6.2.3.3 
Revised: As a generally accepted guideline, subjects should remain 80% 
compliant with diary entries. Parents/caregivers who fall short of this standard 
will be re-educated on the importance of adhering to daily seizure, IP and non-
study AED recording and a deviation recorded. 
Section 6.6 and 7.4.1 
Added: In the event of unforeseen circumstances, in-person study visit 
assessments may not be able to be performed. To conduct the study according 
to protocol while preserving patient safety, operational alternatives such as 
those listed below can be employed as long as the site’s actions are in 
compliance with the institution’s IRB/EC policies and regulations.  
 
Telemedicine visits (video and/or audio communication methods) 
 
In-home visits 
 
Local physician visits 
 
Use of local and/or off-site laboratories 
 
Site-to-patient IP distribution 
Section 7.1 
Revised: A drug screen (plasma) will be performed to test for THC and non-
approved CBD during the DB phase at Visit 1 (screening), Visit 2 
(baseline/randomization), and Visit 5 (final DB/first OL visit).  If the screening 
drug test is positive at Visit 1 (screening), a confirmatory retest, via plasma, will 
be performed after 2 weeks. A drug screen may be performed at any time at 
Investigator’s discretion.   
Sections 7.3.2 
Revised: If the subject has a de novo PCDH19 VUS then the central assessor, PI, 
and Sponsor will review study inclusion.  Some subjects may have multiple 
PCDH19 mutations that include both VUS and pathogenic variants.  In these 
cases, the subject is known to have a pathogenic variant and is eligible (does 
not require discussion with expert). 
Section 7.3.5 
Added: If any test result is unexpectedly out of range, a repeat test can be 
performed at any time as decided by the PI to confirm the initial result. 
Section 7.6.5 
Revised: Medication errors are reportable to the sponsor only as defined below. 
 
Cases of subjects missing doses of the IP are not considered reportable 
(removed: as medication errors). 
 
(Removed: Medication errors should be collected and reported)Applicable 
only for the IP under investigation. 
 
All IP provided to pediatric subjects should be supervised by the 
parent/caregiver/LAR. Lapses in supervision should be reported. 
 
Section 8.1.7 
Revised: Once the subject’s parent/caregiver/LAR signs informed consent (and 
subject assent), it is expected that all eDiary entries will be made daily (removed: 
and no longer than 72 hours after each day). 
Added: Retrospective entry of diary events (seizure and medication) can be 
completed by the caregiver up to 5 days later and proxy entry by the site is 
also available to the site staff (greater than 5 days), but neither method is 
encouraged. 
Section 9.1 
Revised: If nominal statistical significance is achieved in the biomarker-positive 
stratum, then efficacy will be assessed in the biomarker-negative stratum. 
 
GNX efficacy in the biomarker-positive stratum will be established if that stratum’s 
ITT analysis results are nominally statistically significant. 
Section 9.13.1.2 




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Revised wording for cla1·ification. No change to the content. 
Revised: Subjects who are not able to tolerate 63 mg/kg/day (or 1800 mg/day 
maximum) may be maintained on a lower dose. (Removed: after discussion with 
the sponsOI'). A minimum dose of33 mg/kg/day or 900 mg/day is generally 
required following the DB escalation period, (Removed: during the DB phase) 
unless a lower dose is agreed to with the sponsor due to tolerability issues such as 
somnolence. 
Revised: Of note (Removed: However, the final decision to adjust dn1g), the 
sponsor defers the final decision to adjust IP to the treating study clinician 
(Removed: dosage lies with the Pl}; dose changes may not exceed the maximum 
total daily dose defined by the protocol. 
Added throughout to be consistent with other sections of the protocol. No 
change to content. 
Added: Taper is not required if the subject is receiving the dose of 18 mg/kg/day 
or 450 mg/day (or lower). 
Revised : Focal and generalized nonmotor seizures and myoclonic seizures do not 
count as the primary seizure types for the prima1-y efficacy endpoint. 
Revised: The difference betv.•een the GNX and placebo groups in the percent 
changes (Removed: within each stratum) will be tested using the Wilcoxon Rank-
Sum statistic. 
Revised: 
• 
The primaiy analysis will be conducted in the ITT population (Removed: 
biomarker-positive stratum). 
• 
If notninal statistical significance is achieved in the ITT population 
(Removed: biomarker-positive stratum), the prima1-y analysis will be 
conducted in the biomai·ker-positive stratum of the ITT population as a 
seconda1-y endpoint (Removed: then efficacy ,vii/ be assessed in the 
biomarker-negative stratum). 
Added Seconda1-y Endpoint: The percent change in 28-day p1·ima1-y 
seizure frequency during the 17-week DB Phase relative to baseline in 
biomarker-positive subjects. 
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Synopsis 
(Methodology and 
Investigational product, 
dose, and mode of 
administration), Sections 
3.1, 3.4, and 6.2.3.1 
Synopsis 
(Methodology), Table 2, 
and Section 3.1 
Synopsis (Plima1-y 
Endpoint) and Section 
9.13.1.2 
Synopsis (Plima1-y 
Endpoint and Statistical 
Methods) and Section 
9.13.1.2 
Synopsis (Seconda1-y 
endpoints (seizure 
control)), Section 
9.13.1.3.1.1 
Synopsis (Explorato1-y 
Endpoints and Statistical 
Methods) and Section 
9.13.1.4 
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Added: No formal interim analysis is planned for this study. After all active 
subjects complete the17-week double-blind phase, the double-blind data in 
the database will be locked and used to perform endpoint analysis. Data 
collected during the open label phase will be analyzed separately.  
Removed: As enrollment in the study was discontinued early due to 
administrative reasons, and only 15 biomarker-positive subjects are 
expected to be randomized, the study is not considered to have adequate 
power for formal testing of the statistical hypotheses. Since the reason for 
stopping enrollment is external to the study, the statistical analysis will be 
performed as planned. All p-values produced as part of the pre-specified 
analysis would therefore be considered as nominal. 
Synopsis (Interim 
Analysis) and Section 
9.16 
Added: A total of 50 subjects (25 in each treatment group) was planned to be 
enrolled in the study.  
 
Note: Protocol versions 5 and 6 were implemented after enrollment was stopped 
early due to administrative reasons. The final sample size is not based on 
statistical considerations. Formal hypothesis testing will be performed based on 
all available sample size at the time of the study discontinuation. 
 
Removed: Based on data from the 7 biomarker-positive PCDH19-related epilepsy 
in Study 1042-0900 evaluating GNX, the standard deviation for the percent change 
in 28-day seizure frequency is estimated to be 28.4, although other relevant data 
suggest the actual standard deviation could be meaningfully higher. If we assume 
the standard deviation to be 40 and the percent change in 28-day seizure frequency 
on GNX minus that on placebo truly to be ꟷ40%, then a trial with 50 biomarker- 
positive PCDH19 patients randomized in a 1:1 manner will have about 94% power 
to detect this effect when using a test statistic that preserves a (one-sided) 2.5% 
false positive error rate. The threshold for achieving statistical significance in the 
biomarker positive cohort at the final analysis when 50 subjects have completed 
their 17-week double-blind phase would be an estimate of the difference that is 
55.5% of the standard deviation.  (If the standard deviation is 40, then the 
threshold for statistical significance is approximately ꟷ23%). The actual analysis 
will use a Wilcoxon rank-sum test, which has approximately the same power as the 
analysis of variance (ANOVA). 
 
As enrollment in the study was discontinued early due to administrative reasons 
and only 15 biomarker-positive subjects are expected to be randomized, the study 
is not considered to have adequate power for formal testing of the statistical 
hypotheses. Since the reason for stopping enrollment is external to the study and a 
purely administrative decision, the statistical analysis of this study will be 
performed as planned. All p-values produced as part of the planned pre-specified 
analysis would be considered as nominal. 
Section 9.5 
Added: The Randomized population comprises all subjects who are 
randomized to one of GNX or PBO treatment group. 
Revised: The Safety (Removed: and ITT) population comprises all randomized 
subjects who received at least one dose of study drug. (Removed: In addition to 
being the population for the safety analyses, the biomarker-positive subjects in it is 
the primary population for the efficacy analyses.) 
Section 9.6 


 
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Added: The ITT population comprises all randomized subjects who received 
at least one dose of study drug and have at least one post-baseline efficacy 
assessment. 
Revised wording for clarification. No change to the content.  
Baseline seizure activity will be determined by prospective recording in subject’s 
daily seizure eDiaries, which are provided after signing informed consent/assent.  
Within the DB phase of the study, determination of post-baseline seizure activity 
will begin on the day following the first day of DB treatment.  Determination of 
post-baseline seizure activity assigned to the OL phase will begin on the day 
following the first OL treatment. 
Section 9.7 
Revised: Tables will be provided using the ITT subject population as well as 
within each of the biomarker-positive and biomarker-negative strata (Removed: 
and the primary endpoint table as well as the subject background and safety tables 
will also be provided as pooling over the strata.) 
Section 9.7 
Revised: Medical history will be coded with the Medical Dictionary for Regulatory 
Activities (MedDRA) Terminology version 22.0 (Removed: version 16.0).   
Section 9.11 
Revised: For the analyses of seizures, the baseline phase consists of the 8- or -12 
week period before the first day of treatment, and the DB phase starts the day 
following the first day of DB treatment and continues until the final visit for 
subjects who do not enter the OL, and up to the day before the first dose of 
OL treatment for those who do. (Removed: The first day of treatment is not in 
either phase since the times of seizures are not collected.) 
Removed: The estimand that is most clinically relevant as well as estimable in a 
manner that protects the integrity of randomization is the outcome measure (eg, the 
percent change in 28-day seizure frequency), where ALL randomized subjects 
would be included in this analysis throughout the study period.  Hence, all 
available data will be used, even if they were collected after the subject stopped 
taking study medication, regardless of whether the subject took rescue medication.   
Section 9.13.1 
Revised: Careful educating and monitoring of the study sites will attempt to limit 
the amount of missing data. (Removed: to nearly zero, but despite these efforts, 
some missing data may still arise) Sensitivity analyses is, with replacement of 
missing data (Removed: will be replaced/imputed), will be performed for the 
primary efficacy endpoint. 
Section 9.13.1.1 
Added: Testing will be conducted in the following order: 
Added: In addition, as an exploratory analysis, 
 
 
 
Removed: The primary analysis will be conducted in the biomarker-positive 
stratum (defined as a baseline Allo-S level of less than or equal to 2500 pg/mL).  
Section 9.13.1.2 


 
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GNX efficacy in the biomarker-positive stratum will be established if that stratum’s 
ITT analysis results are nominally statistically significant.  Hierarchically, if GNX 
efficacy is established in the biomarker-positive stratum, its efficacy will then be 
assessed in the biomarker-negative stratum.  To be positive, the difference between 
the GNX and PBO groups in that stratum must be both clinically relevant and at 
least as large as would be required for statistical significance in an analysis of the 
pooled strata ITT population (Rothmann 2012).   
Added:  
9.13.1.3.1.1. Percent Change in Primary Seizure Frequency 
The percent change in 28-day primary seizure frequency during the 17-week 
DB Phase relative to baseline in biomarker-positive subjects.  
The same analysis methods for the primary endpoint will also be applied to 
this secondary endpoint. Please also refer to Section 9.13.1.2 for the hypothesis 
testing order. 
Section 9.13.1.3.1.1 
Revised: Except where indicated otherwise, all the seizure exploratory endpoints 
will be based on the primary seizure types defined for inclusion in the primary 
efficacy endpoint. 
Synopsis (Statistical 
Methods) and Section 
9.13.1.4. 
Added: To control the family-wise Type I error rate, hypothesis testing of the 
primary efficacy endpoint will be conducted sequentially in the order specified 
in Section 9.13.1.2.   
Removed: No formal hypothesis testing is planned in this study due to enrollment 
discontinuation for administrative reasons.  
Section 9.13.4 
Revised throughout the protocol for clarification. No change to the content. 
Revised: (removed: at the end of the 17-week DB phase) and replaced with: 
during the 17-week DB phase 
Revised: (Removed: 12-week) when referencing statistical language to read as 
just baseline or prospective baseline 
Revised: PCDH19-related epilepsy 
Entire document 
Administrative changes: Minor changes involving grammar, rephrasing for clarity, 
punctuation, and other editorial changes have been made throughout the document.  
Entire document 
 
 


 
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EMERGENCY CONTACT INFORMATION 
SERIOUS ADVERSE EVENT REPORTING:    
In the event of a serious adverse event (SAE), the investigator must notify the Sponsor Medical 
Monitor and the Sponsor Project Manager by e-mail or fax the Marinus Clinical Study Serious 
Adverse Event Form within 24 hours to Marinus Safety Department at:    
Email:   safetyPCDH3002@marinuspharma.com  
Fax:   +1 484-679-2138  
SPONSOR CONTACTS:    
Sponsor Medical Monitor:    
 MD, FAAP 
Mobile Telephone:  
(primary contact method/send text message if no 
immediate response) 
Email:  
If sponsor’s Medical Monitor cannot be reached in an emergency, the site should contact: 
 
mailto
, MD, PhD 
 Clinical Development 
Mobile Telephone:  
(primary contact method/send text message if no 
immediate response) 
Email:  
 
Sponsor Project Managers:    
 
Office Telephone:   
 
Mobile Telephone:  
Email:  
(primary contact method) 
 
Office Telephone:   
 
Mobile Telephone:  
Email:  
(primary contact method) 
 


 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................................2 
SUMMARY OF CHANGES FROM PREVIOUS VERSION ........................................................3 
EMERGENCY CONTACT INFORMATION ..............................................................................31 
TABLE OF CONTENTS ...............................................................................................................32 
LIST OF TABLES .........................................................................................................................38 
LIST OF FIGURES .......................................................................................................................38 
ABBREVIATIONS .......................................................................................................................39 
STUDY SYNOPSIS ......................................................................................................................41 
1. 
BACKGROUND INFORMATION ...........................................................................59 
1.1. 
Indication and Current Treatment Options .................................................................59 
1.2. 
Product Background and Clinical Information ...........................................................60 
2. 
STUDY OBJECTIVES AND PURPOSE ..................................................................64 
2.1. 
Rationale for the Study ...............................................................................................64 
2.2. 
Study Objectives .........................................................................................................65 
2.2.1. 
Primary Objective .......................................................................................................65 
2.2.2. 
Secondary Objectives .................................................................................................66 
 
 
3. 
STUDY DESIGN .......................................................................................................67 
3.1. 
Study Design and Flow Chart .....................................................................................67 
3.2. 
Duration and Study Completion Definition ................................................................70 
3.3. 
Sites and Regions ........................................................................................................71 
3.4. 
Discussion of Study Design, Including the Choice of Control Group ........................71 
4. 
STUDY POPULATION .............................................................................................72 
4.1. 
Inclusion Criteria ........................................................................................................72 
4.2. 
Exclusion Criteria .......................................................................................................73 
4.3. 
Restrictions .................................................................................................................74 
4.4. 
Reproductive Potential ................................................................................................74 
4.4.1. 
Contraception ..............................................................................................................74 
4.5. 
Discontinuation of Subjects ........................................................................................75 
4.5.1. 
Subject Withdrawal Criteria .......................................................................................75 
4.5.2. 
Reasons for Early Discontinuation .............................................................................76 


 
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4.5.3. 
Subjects Lost to Follow-up Prior to Last Scheduled Visit .........................................77 
4.6. 
Subject Numbering .....................................................................................................77 
5. 
EXCLUDED, PRIOR, AND CONCOMITANT MEDICATIONS ...........................78 
5.1. 
Prior Medications ........................................................................................................78 
5.2. 
Concomitant Medications ...........................................................................................78 
5.2.1. 
Concomitant Antiepileptic (AED) Medications .........................................................78 
5.3. 
Rescue Medications ....................................................................................................78 
5.4. 
Excluded Medications ................................................................................................79 
6. 
INVESTIGATIONAL PRODUCT ............................................................................80 
6.1. 
Identity of Investigational Product .............................................................................80 
6.1.1. 
Ganaxolone .................................................................................................................80 
6.1.2. 
Placebo ........................................................................................................................80 
6.1.3. 
Blinding the Treatment Assignment ...........................................................................80 
6.2. 
Administration of Investigational Products ................................................................81 
6.2.1. 
Interactive Web Response System for Investigational Product Management ............81 
6.2.2. 
Allocation of Subjects to Treatment ...........................................................................81 
6.2.3. 
Dosing .........................................................................................................................81 
6.2.3.1. 
Double-Blind Period ...................................................................................................81 
6.2.3.2. 
Open-Label Period ......................................................................................................82 
6.2.3.3. 
De-escalation (Taper) Period ......................................................................................84 
6.2.4. 
Dose Administration ...................................................................................................84 
6.2.5. 
Missing a Dose ...........................................................................................................84 
6.3. 
Unblinding the Treatment Assignment .......................................................................85 
6.4. 
Labeling, Packaging, Storage, and Handling ..............................................................85 
6.4.1. 
Labeling ......................................................................................................................85 
6.4.2. 
Packaging ....................................................................................................................86 
6.4.3. 
Storage ........................................................................................................................86 
6.5. 
Investigational Product Accountability ......................................................................87 
6.6. 
Subject Compliance ....................................................................................................88 
7. 
STUDY PROCEDURES ............................................................................................89 
7.1. 
Study Assessments......................................................................................................89 
7.2. 
Study Procedures (Double-Blind Phase) ....................................................................89 
7.2.1. 
Pre-Screen/Screen/Baseline ........................................................................................89 


 
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7.2.1.1. 
Historical Seizure Type and Frequency and/or Genetic Testing (Pre-Baseline 
Screening Visit (Visit 0)) ............................................................................................89 
7.2.1.2. 
Screening Visit – Start to Baseline (Visit 1, Week –12) ............................................90 
7.2.1.3. 
Baseline Visit – Randomization (Visit 2, Week 0 + 6 days) ......................................90 
7.2.2. 
Double-Blind Titration + Maintenance (3 Days, Weeks 1 to 4, 5, 9, 11, and 
13) ...............................................................................................................................91 
7.2.2.1. 
Telephone Follow-up (Day 3 ± 1 Day and Weeks 1, 2, 3, and 4 ± 3 days) ................91 
7.2.2.2. 
Visit 3 (Week 5 ± 3 days) ...........................................................................................91 
7.2.2.3. 
Visit 4 (Week 9 ± 3 days) ...........................................................................................92 
7.2.2.4. 
Telephone Follow-up Visit (Weeks 11, 13 ± 3 days) .................................................92 
7.2.3. 
Final Double-Blind Visit/First Open-Label Visit, Visit 5 ± 3 days (Week 17 
± 3 days) .....................................................................................................................92 
7.2.4. 
Open-Label Period Blinded Titration .........................................................................93 
7.2.4.1. 
Telephone Follow-Up (Week 17 + 3 days ± 1 day, Weeks 18, 19 and 20 ± 3 
Days) ...........................................................................................................................93 
7.2.4.2. 
Open-Label Period Blinded Titration, Visit 6 (Week 21 ± 3 days) ............................93 
7.2.5. 
Open-Label Period Maintenance (Weeks 28-68; ± 14 days window for each 
visit) ............................................................................................................................94 
7.2.5.1. 
Telephone Follow-Up (Weeks 28, 44, and 60 ± 14 Days) .........................................94 
7.2.5.2. 
Open-Label Period Maintenance, Visits 7, 8, and 9 (Weeks 36, 52 and 68 ± 
14 days) .......................................................................................................................94 
7.2.5.3. 
Visit X - Additional Maintenance Visits in the Open-Label Period Phase ................95 
7.2.6. 
Final Open-Label Period Visit or Taper Visit (or at time of Early 
Termination ±14 days) ................................................................................................95 
7.2.7. 
Safety Follow-up Post Taper (2 Weeks Post Last Dose/Investigational 
Product Taper ± 3 days) ..............................................................................................96 
7.3. 
Screening and Diagnosis .............................................................................................96 
7.3.1. 
Informed Consent / Assent .........................................................................................97 
7.3.2. 
Drug Screen ................................................................................................................97 
7.3.3. 
Demographics and Medical History ...........................................................................97 
7.3.4. 
Historical Seizure Calendar Review ...........................................................................97 
7.3.5. 
Genetic Testing ...........................................................................................................97 
7.3.6. 
Seizure Identification and Diagnostic Review ...........................................................98 
7.4. 
Efficacy Assessments .................................................................................................98 
7.4.1. 
Seizure Type and Frequency ......................................................................................98 


 
C o nfi de ntial 
P a ge 3 5  of 1 3 6 
I N D 0 4 4 0 2 0  
 
Mari n us P har mace uticals I nc.  
Pr ot oc ol 1 0 4 2 -P C D H 1 9 -3 0 0 2  
 
2 0 J a n uar y 2 0 2 1  
7. 4. 2.  
Resc ue Me dic ati o n  ......................................................................................................9 9  
7. 4. 3.  
C hil dre n’s Slee p Ha bits Q uesti o n naire ( C S H Q)  ........................................................9 9  
7. 4. 4.  
Be ha vi or Rati n g I n ve nt or y of E x ec uti ve F u ncti o n ( B RI E F, Presc h o ol 
Versi o n B RI E F -P)  ....................................................................................................1 0 0  
7. 4. 5.  
A berra nt Be h a vi or C hec klist –  C o m m u nit y ( A B C -C)  .............................................1 0 0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7. 6.  
Safet y Assess me nts  ...................................................................................................1 0 2  
7. 6. 1.  
A d verse E v e nts  .........................................................................................................1 0 2  
7. 6. 2.  
Vital Si g ns  ................................................................................................................1 0 2  
7. 6. 3.  
P h ysical/ Ne ur ol o gi cal/ D e vel o p me ntal E x a mi nati o ns  ..............................................1 0 2  
7. 6. 4.  
E C G  ..........................................................................................................................1 0 3  
7. 6. 5.  
Cli nical La b orat or y  Tests .........................................................................................1 0 4  
7. 6. 6.  
Ta n ner Sta gi n g  ..........................................................................................................1 0 4  
7. 6. 7.  
I n v esti gati o nal Pr o d uct P K .......................................................................................1 0 4  
7. 6. 8.  
C o nc o mita nt A E D l e vels  ..........................................................................................1 0 5  
7. 6. 9.  
A d verse E v e nts  .........................................................................................................1 0 5  
7. 7.  
P har mac o ki netic Assess me nts  ..................................................................................1 0 5  
8.  
A D V E R S E A N D S E RI O U S A D V E R S E E V E N T A S S E S S M E N T S  ......................1 0 6  
8. 1.  
Def i niti o n of A d vers e E ve nts, Peri o d of O bser vati o n, Re c or di n g of Ad v erse 
E ve nts  .......................................................................................................................1 0 6  
8. 1. 1.  
Se verit y Cat e g orizati o n  ............................................................................................1 0 6  
8. 1. 2.  
Relati o ns hi p Cate g orizati o n  ......................................................................................1 0 7  
8. 1. 3.  
O utc o me Cate g orizati o n  ...........................................................................................1 0 7  
8. 1. 4.  
S y m pt o ms of t he Disea se U n der St u d y ....................................................................1 0 7  
8. 1. 5.  
Cli nical La b orat or y a n d Ot her Safet y E v al uati o ns  ...................................................1 0 7  
8. 1. 6.  
Pre g n a nc y  .................................................................................................................1 0 8  
8. 1. 7.  
A b use, Mis use, O ver d os e, a n d Me dica ti o n Err or .....................................................1 0 8  
D


 
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8.2. 
Serious Adverse Event Procedures ...........................................................................109 
8.2.1. 
Reference Safety Information ...................................................................................109 
8.2.2. 
Reporting Procedures ................................................................................................109 
8.2.3. 
Serious Adverse Event Definition ............................................................................110 
8.2.4. 
Serious Adverse Event Collection Time Frame .......................................................110 
8.2.5. 
Serious Adverse Event Onset and Resolution Dates ................................................110 
8.2.6. 
Fatal Outcome ...........................................................................................................111 
8.2.7. 
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting ..................................................................................................................111 
8.3. 
Adverse Events of Special Interest ...........................................................................111 
8.3.1. 
Reference Safety Information ...................................................................................111 
9. 
DATA MANAGEMENT AND STATISTICAL METHODS .................................112 
9.1. 
Data Collection .........................................................................................................112 
9.2. 
Clinical Data Management .......................................................................................112 
9.3. 
Statistical Analysis Process ......................................................................................112 
9.4. 
Data Monitoring Committee .....................................................................................113 
9.5. 
Sample Size Calculation and Power Considerations ................................................113 
9.6. 
Study Populations .....................................................................................................113 
9.7. 
General Statistical Considerations ............................................................................113 
9.8. 
Subject Disposition ...................................................................................................114 
9.9. 
Eligibility Criteria and Protocol Deviations .............................................................114 
9.10. 
Demographics and Baseline Characteristics .............................................................114 
9.11. 
Medical History and Genetic Testing .......................................................................114 
9.12. 
Prior and Concomitant Therapies .............................................................................115 
9.13. 
Efficacy Analyses .....................................................................................................115 
9.13.1. 
Double-Blind Phase ..................................................................................................115 
9.13.1.1. 
Handling of Missing Data .........................................................................................115 
9.13.1.2. 
Primary Endpoint (Seizure Control) .........................................................................115 
9.13.1.3. 
Secondary Efficacy Endpoints ..................................................................................116 
 
 
9.13.2. 
Subgroup Analyses ...................................................................................................118 
9.13.3. 
Sensitivity Analyses ..................................................................................................118 
9.13.4. 
Protections for Multiplicity.......................................................................................119 


 
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9.13.5. 
Open-Label Period Analyses ....................................................................................119 
9.14. 
Safety Analyses ........................................................................................................120 
9.15. 
Pharmacokinetic Analyses ........................................................................................120 
9.16. 
Interim Analysis ........................................................................................................121 
10. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES .............................122 
10.1. 
Sponsor’s Responsibilities ........................................................................................122 
10.1.1. 
Good Clinical Practice (GCP) Compliance ..............................................................122 
10.1.2. 
Public Posting of Study Information ........................................................................122 
10.1.3. 
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees .............................................122 
10.1.4. 
Study Suspension, Termination, and Completion ....................................................122 
10.2. 
Investigator’s Responsibilities ..................................................................................123 
10.2.1. 
Good Clinical Practice Compliance..........................................................................123 
10.2.2. 
Protocol Adherence and Investigator Agreement .....................................................123 
10.2.3. 
Documentation and Retention of Records ................................................................124 
10.2.3.1. 
Electronic Case Report Forms (eCRF) .....................................................................124 
10.2.3.2. 
Electronic Diaries (eDiary) .......................................................................................124 
10.2.3.3. 
Recording, Access, and Retention of Source Data and Study Documents ...............124 
10.2.3.4. 
Audit/Inspection .......................................................................................................125 
10.2.3.5. 
Financial Disclosure .................................................................................................125 
10.3. 
Ethical Considerations ..............................................................................................125 
10.3.1. 
Informed Consent/Assent .........................................................................................125 
10.3.2. 
Institutional Review Board or Ethics Committee .....................................................126 
10.4. 
Privacy and Confidentiality ......................................................................................126 
10.5. 
Study Results/Publication Policy ..............................................................................127 
11. 
REFERENCES .........................................................................................................129 
12. 
APPENDICES ..........................................................................................................131 
12.1. 
Appendix 1:   CYP3A4/5/7 Inhibitors and Inducers ................................................131 
12.2. 
Appendix 2:   Clinical Laboratory Tests ...................................................................132 
12.3. 
Appendix 3:   Examples of Dosing Titration for Oral Suspension ...........................133 
 
 


 
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LIST OF TABLES 
Table 1: 
Schedule of Assessments for the 17-Week, Double-Blind Treatment Phase 
of the Study .................................................................................................................51 
Table 2: 
Schedule of Assessments for Open-Label Phase ........................................................55 
Table 3: 
Oral Suspension (50 mg/ml) Dosing for Subjects Weighing ≤ 28 kg and > 28 
kg ................................................................................................................................82 
Table 4: 
Transition from Double-Blind to Open-Label:  Dosing for Subjects ≤ 28 kg 
and Subjects > 28 kg ...................................................................................................83 
Table 5: 
De-Escalation of Investigational Product ...................................................................84 
Table 6: 
Missed Dose of Investigational Product .....................................................................84 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................69 
Figure 2: 
Seizure Cluster Designation Examples .......................................................................99 
 


 
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ABBREVIATIONS 
Term 
Definition 
AE 
adverse event 
ABC-C 
Aberrant Behavior Checklist-Community 
AED 
antiepileptic drug 
Allo-S 
allopregnanolone sulfate 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
β-HCG 
β-human chorionic growth hormone 
BP 
blood pressure 
BRIEF 
Behavior Rating Inventory of Executive Function 
CBC 
complete blood count 
CBD 
cannabidiol 
CDD 
cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder 
CDKL5 
cyclin-dependent kinase-like 5 
CGI-I 
Clinical Global Impression Improvement 
CGI-C 
Caregiver Global Impression of Change  
CGICA 
Caregiver Global Impression of Change in Attention 
CNS 
central nervous system 
CRA 
clinical research associate 
CRO 
clinical research organization 
CSHQ 
Children’s Sleep Habit Questionnaire 
CSWS 
continuous spike and wave during slow wave sleep 
CYP3A4 
cytochrome P450 3A4 
DB 
double-blind 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eDiary 
electronic seizure diary 
EEG 
electroencephalogram 
eGFR 
estimated glomerular filtration rate 
FDA 
Food and Drug Administration 
FXS 
Fragile X Syndrome 
GABA 
γ-Aminobutyric acid 
GABAA 
γ-Aminobutyric acid type A 
GCP 
Good Clinical Practice 
GNX 
ganaxolone 
HR 
heart rate 
IB 
Investigator Brochure 
IND 
Investigational New Drug 
IRB 
institutional review board 
ITT 
Intent-to-Treat Population 
IWRS 
interactive web response system 
LAR 
legally authorized representative 
LGS 
Lennox Gastaut syndrome 


 
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Term 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
Maximum Tolerated Dose 
OL 
open-label 
PBO 
Placebo 
PCDH19 
protocadherin 19 
PedsQL-FIM 
Pediatric Quality of Life Inventory – Family Impact Module 
PI 
principal investigator 
PK 
Pharmacokinetic 
QI-Disability 
Quality of Life Inventory-Disability 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SIF/DRF 
Seizure Identification and Diagnostic Review Form  
SOC 
standard of care 
TEAE 
Treatment-emergent adverse event 
THC 
tetrahydrocannabinol 
TID 
3 times daily 
ULN 
upper limit of normal 
UK 
United Kingdom 
US 
United States 
VNS 
Vagus nerve stimulator 
VUS 
variant of unknown significance 
 


IND 044020 
Protocol 1042-PCDH19-3002 
STUDY SYNOPSIS 
Protocol number: 
1042-PCDH19-3002 
Drug: 
ganaxolone 
Marinus Pha1maceuticals Inc. 
20 January 2021 
Title of the study: 
A double-blind, randomized, placebo-controlled trial of adjunctive ganaxolone treatment in 
female children with protocadherin 19 (PCDH19)-related epilepsy followed by long-te1m open-label treatment 
Number of subjects (total and fo1· each treatment arm): A sufficient number of eligible PCDH19 subjects will 
be screened and enrolled, with a 1: 1 randomization to either ganaxolone (GNX) or placebo (PBO). As study 
enrollment was discontinued early (as of01July2020) due to administrative reasons, the total number of the 
randomized patients is expected to be approxiniately 25 subjects resulting in approximately 15 randomized 
biomarker-positive subjects. 
Investigators: 
Multicenter study 
Sites and Regions: 
Global, multicenter study to be conducted at approximately 11 sites 
Study period (planned): 
Clinical phase: 
2 
March 2019 to June 2022 
Objectives: 
Prima1-y: 
To assess the efficacy of GNX compared with PBO as adjunctive therapy for the treatment of primary 
seizure types in children with genetically confomed PCDH19-related epilepsy dw-ing thel 7-week double-blind 
(DB) phase. 
Seconda1·y: 
• 
To assess the effect of GNX on prima1y seizw·e rate in biomarker-positive subjects 
• 
To assess behavioral/new·opsychiatric changes in subjects receiving GNX compared with subjects receiving 
PBO as adjunctive therapy dw-ing thel 7-week DB phase 
• 
To assess the safety and tolerability of GNX compared with PBO as adjunctive therapy dw-ing the 17-week 
DB phase 
• 
To assess pha1macokinetic (PK) parameters in subjects receiving GNX doses up to 63 mg/kg/day (or 
1800 mg/day maximum) throughout the study 
• 
To assess the long-term efficacy of GNX when administered as adjunctive therapy throughout the open-
label (OL) phase 
• 
To assess the long-te1m safety and tolerability of GNX when administered as adjunctive therapy 
throughout the open-label phase 
Explorato1-y Efficacy: 
• 
I 
I 
I 
Rationale: 
Protocadherinl9 (PCDH19)-related epilepsy is a serious epileptic condition characterized by early-onset cluster 
seizures, cognitive and senso1y impairment of varying degrees, and psychiatric and behavioral distw-bances 
affecting primarily females (Camacho 2012). The condition is caused by an inherited mutation of the PCDH19 
gene located on the X chromosome. This gene encodes for a calcium-dependent cell-cell adhesion molecule that 
is expressed in the central nervous system (CNS; eg, hippocampus, cerebral cortex, thalamus, amygdala) and 
which appears to be related to synaptic transmission and fo1mation of synaptic connections dw-ing brain 
development (Depienne 2009). 
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The mean age of seizure onset in this condition is approximately 10 months (range of 3-38 months) 
(Scheffer 2008, Specchio 2011, Dipienne 2011, Cappelletti 2015, van Harssel 2013).  The mean age of offset of 
epileptic seizures is approximately 12.5 years (1-35 years).  PCDH19-related epilepsy has been described as a 
“semiprogressive” condition, meaning that seizure frequency increases during the first few years of life 
(Specchio 2011).  However, over time the seizure frequency lessens, and seizures become less frequent with 
increased age.   
There is also evidence supporting an allopregnanolone deficiency as a proposed contributor to the onset of 
seizures in individuals with PCDH19-related epilepsy (Tan 2015).  It was found that individuals with this genetic 
mutation demonstrated a downregulation of steroid hormone-metabolizing enzymes resulting in reduced 
allopregnanolone levels compared to non-affected, age-matched controls.  Since this neurosteroid is known to 
have strong anti-convulsant properties, it is hypothesized that treatment with neurosteroids with similar action, or 
analogs such as GNX, may have therapeutic benefit to seizure control. 
Ganaxolone is the 3β-methylated synthetic analog of allopregnanolone, an endogenous allosteric modulator of 
CNS γ-Aminobutyric acid type A (GABAA) receptors.  Ganaxolone has potency and efficacy comparable to 
allopregnanolone (Carter 1997) in activating synaptic and extrasynaptic GABAA receptors at a site distinct from 
benzodiazepines and barbiturates.  Ganaxolone has protective activity in diverse rodent seizure models 
(Reddy 2012, Bialer 2010).  Clinical studies have demonstrated that GNX has anticonvulsant activity with an 
acceptable safety and tolerability profile in the dose range of 900 to 1800 mg in adults and children 
(Sperling 2017, Laxer 2000, Kerrigan 2000, Pieribone 2007).  Further, GNX reduces seizures in children with IS 
and refractory pediatric epilepsy.  In an OL study, pediatric subjects aged 2 to 60 months with refractory seizures 
and a history of IS were treated with GNX doses up to 36 mg/kg for up to 3 months (Kerrigan 2000).  Sixteen of 
the 20 subjects completed treatment, 15 of whom had a history of IS.  Five of the 15 subjects had a decrease from 
baseline in the number of spasms of ≥ 50%, 5 had a decrease of 25 to 50%, and 5 had a decrease of < 25%.  One 
subject became spasm-free and 1 non-responder (with a decrease of < 25%) was spasm-free from weeks 2 to 7.   
An anticonvulsant treatment effect signal of GNX in PCDH19-related epilepsy has emerged from an ongoing OL 
flexible-dose exploratory study (Study 1042-0900) of GNX in children (age range 2-15 years) with rare genetic 
epilepsies (including PCDH19) with uncontrolled seizures despite multiple antiepileptic drug (AED) regimens 
(ClinicalTrials.gov Identifier:   NCT02358538).  Following the screening and baseline evaluations, consenting 
subjects enrolled into a 26-week study during which investigators could dose GNX starting with a titration up to 
1,800 mg/day for subjects whose body weight was > 30 kg or up to 63 mg/kg /day for subjects whose body-
weight was < 30 kg.  The dose could also be reduced for tolerability reasons.  The primary efficacy measure was 
the percent change from baseline in the 28-day seizure frequency count.  Safety and tolerability assessments were 
among the secondary objectives.  The median change in 28-day seizure frequency from baseline in the intent-to-
treat (ITT) population (primary endpoint) was a decrease of 25% (n = 11).   
The median change from baseline in seizure-free days in the ITT population (key secondary endpoint) was an 
increase of 14% (n = 11).  Baseline levels of allopregnanolone sulfate (Allo-S, an endogenous neurosteroid) and 
28-day seizure rates were also assessed.  A ganaxolone-responder was specified by post-hoc definition, as having 
at least a 25% reduction in 28-day seizure rate.  In the PCDH19 cohort, responders (n = 6) and non-responders (n 
= 5) had plasma Allo-S concentrations (mean ± SD) of 501 ± 430 pg mL-1 and 9,829 ± 6,638 pg mL-1, 
respectively.  When performing a retrospective separation of the PCDH19 cohort according to their Allo-S level, 
the 7 subjects with Allo-S levels below 2,500 pg mL-1 (biomarker-positive) had a 50% reduction in seizure rates 
while the 4 subjects with Allo-S levels above 2,500 pg mL-1 (biomarker-negative) had a 84% increase (performed 
in the research lab of Dr.  Graziano Pinna at the University of Illinois, Chicago, the only laboratory during the 
conduct of the study that could reliably produce results for sulphated neurosteroids).  The Clinical Global 
Impression Scale rated by Investigators (CGI-I) and Caregivers (CGI-P) has been consistent with seizure control.  
In the OL study (1042-0900), there were 4 SAEs (3 related to seizures and 1 related to rash) possibly related to 
the study drug in the PCDH19 subjects.   
In addition to anticonvulsant activity, GNX has shown positive effects on anxiety, hyperactivity, and attention in 
children with fragile X syndrome (Ligsay 2016).  Similar behavior problems occur in individuals with PCDH19 
mutations (Smith 2018).  It is hypothesized that GNX treatment will increase and improve GABAA-mediated 
signaling by boosting the signaling capacity of existing receptors and improve not only seizure control, but also 
other behavioral abnormalities in individuals with the PCDH19 mutation.   


 
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Methodology:    This is a global, biomarker-stratified, DB, randomized, PBO-controlled trial of adjunctive GNX 
treatment in children with a confirmed pathogenic or likely pathogenic PCDH19 mutation.  The trial consists of a 
12-week prospective baseline period to collect seizure data, followed by a 17-week DB phase, which is then 
followed by a long-term OL phase.  An interactive web response system (IWRS) will be used to randomize 
subjects, dispense drug, track treatment, and maintain the blind throughout the duration of the study. 
A 12-week daily historical seizure calendar will be reviewed at the screening visit to determine eligibility per 
inclusion/exclusion criteria.  Acceptable historical seizure data must include at least 12 consecutive weeks prior 
to the Screening visit of documenting seizure type and frequency (also noting seizure-free days). Procedures 
specific to this protocol and not otherwise considered standard of care, will not be performed until written 
informed consent from the subject’s parent or legally authorized representative (LAR) and subject assent has 
been appropriately obtained.  In the event that parent/caregiver/LAR do not routinely maintain a daily seizure 
calendar or genetic testing has not been performed per standard of care, written informed consent will be obtained 
from the parent/LAR and subject assent, and the subject will be asked to return to the clinic for the screening visit 
after they have maintained a 12 week daily historical seizure calendar and/or genetic testing has been completed.   
During the screening visit, each subject’s biomarker level will be assessed via a blood draw and subsequent 
analytical quantification.  Each subject will then be assigned to 1 of 2 groups: biomarker-positive or biomarker-
negative.  A subject will be considered biomarker-positive if her baseline Allo-S level is less than or equal to 
2500 pg/mL (Pinna Lab method or similar).  The biomarker group assignment will remain blinded until database 
unblinding after the study has completed. Based on the completed 11-subject 1042-0900 Phase 2a study, it is 
estimated that approximately 65% of all subjects will be biomarker-positive. 
Subject rescreening is allowed as agreed by Sponsor and Investigator unless there is a general concern for subject 
safety or an inability for the subject to become eligible (eg, GNX allergy, sensitivity or exposure, non-PCDH19 
and/or other ineligible epilepsy, chronic prohibited medical condition or treatment).  Subsequent screening should 
take place at least 30 days from the subject’s last visit. 
The DB phase includes 4 weeks of investigational product titration followed by 13 weeks of dose maintenance.  
After meeting the eligibility criteria, approximately 25 children aged 1-17 years (inclusive) with PCDH19-related 
epilepsy will be randomly assigned to receive GNX or PBO (1:1 ratio within each biomarker stratum) for 17 
weeks in addition to their standard anti-seizure treatment.  Participants will be titrated to 63 mg/kg/day (max 1800 
mg/day) over 4 weeks, and then maintained at that dose for another 13 weeks.  Subjects who are not able to 
tolerate 63 mg/kg/day (or 1800 mg/day maximum) may be maintained on a lower dose.  A minimum dose of 
33 mg/kg/day or 900 mg/day is generally required following the DB escalation period, unless a lower dose is 
agreed to with the sponsor due to tolerability issues such as somnolence.   
Dose changes including alternative dosing paradigms (e.g., lower dose during the daytime and higher dose in the 
evening) should be discussed with the clinical research organization (CRO)/sponsor medical monitor prior to 
making the change or within 48 hours of making the change. Of note, the sponsor defers the final decision to 
adjust IP to the treating study clinician; dose changes may not exceed the maximum total daily dose defined by 
the protocol. For any subject who is unable to be maintained at the minimum dose, the investigator should contact 
the sponsor to discuss continued investigational product dosing.  Subjects who discontinue investigational 
product should undergo a 2-week taper period, unless otherwise medically indicated such as drug-induced rash.  
Subjects who discontinue investigational product treatment before the completion of the DB phase will continue 
to be followed per protocol and, at a minimum, subjects will be encouraged to maintain daily seizure eDiary 
entries until the DB phase is completed.  These subjects will also return to the site 2 to 4 weeks after the taper for 
safety follow-up assessments. 
After completing the initial 17-week, DB, PBO-controlled treatment phase, all subjects will be treated with GNX 
in the OL phase of the study.  Ganaxolone subjects will continue GNX treatment and PBO subjects will titrate 
onto GNX.  To maintain the blind, subjects initially randomized to GNX will undergo a blinded titration 
(increasing PBO doses) for 4 weeks, while PBO subjects will titrate up to 63 mg/kg/day GNX (1800 mg/day 
maximum) during the same time period.  Any subject who completes the study or discontinues investigational 
product treatment should undergo a 2-week drug de-escalation (taper) period and return to the site 2 weeks later 
for safety follow-up assessments.  Taper is not required if the subject is receiving the dose of 18 mg/kg/day or 
450 mg/day (or lower). 


 
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Participants will be required to complete an eDiary to determine GNX’s effect on seizures.  A variety of clinician 
and caregiver administered instruments will be used to assess the efficacy of GNX in PCDH19-related epilepsy, 
and include:   
 
Behavior Rating Inventory of Executive Function (BRIEF) 
 
Aberrant Behavior Checklist – Community (ABC-C) 
 
Children’s Sleep Habit Questionnaire (CSHQ) 
 
Pediatric Quality of Life Inventory – Family Impact Module (PedsQL-FIM) 
 
Quality of Life Inventory – Disability (QI-Disability) 
 
Caregiver Global Impression of Change (CGI-C) – Target Behavior, Clinical Global 
Impression-Improvement (caregiver), and Clinical Global Impression-Improvement (clinician) 
Inclusion and Exclusion criteria:   
Inclusion Criteria:   
1. Molecular confirmation of a pathogenic or likely pathogenic PCDH19 variant.  Genetic mutations will 
be confirmed by the sponsor’s chosen central laboratory.   
2. Female subjects aged 1 through 17 years, inclusive. 
3. Subject/parent or LAR willing to give written informed consent and subject assent, after being properly 
informed of the nature and risks of the study and prior to engaging in any study-related procedures. 
4. Failure to control seizures despite appropriate trial of 2 or more anti-seizure mediations at therapeutic 
doses. 
5. Have at least 12 countable/witnessed primary seizures over an 84-day (12 week) period prior to the 
screening visit (pre-baseline screening). The primary seizure types are defined as countable focal 
seizures that include progressive hypotonia and impaired awareness, or any countable focal or 
generalized seizure with a clear motor component. Focal and generalized nonmotor seizures and 
myoclonic seizures do not count as the primary seizure types. 
6. Subject must be approved to participate by sponsor or its designee (eg, Epilepsy Consortium) after 
review of medical history, genetic testing, seizure classification video (if available), and historical 
seizure calendars. 
7. Concomitant AED regimens must have been stable for at least 1 month prior to the screening visit and 
must remain stable from screening to the end of the DB phase. Ketogenic diets and modified Atkins diet 
should be unchanged for 3 months prior to screening and must remain stable throughout the baseline and 
the DB phase. 
8. Subjects with surgically implanted VNS will be allowed to enter the study provided that all of the 
following conditions are met: 
 
The VNS has been in place for ≥ 1 year prior to the screening visit. 
PCDH19 
(all-subjects) 
Screening 
Visit 
Baseline (12 weeks) 
Primary efficacy analyses will be conducted using this cohort 
Maimenance (13 weeks) 
Double-Blind Phase 
Open-Label Phase (52 weeks) 
"TlOCdrlWn lO ICllle" 


 
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Protocol 1042-PCDH19-3002 
20 January 2021
 
The settings must have remained constant for 3 months prior to the screening visit and remain 
constant throughout baseline and the DB phase. 
 
The battery is expected to last for the duration of baseline and the DB phase. 
9. Parent/caregiver is able and willing to maintain an accurate and complete daily seizure diary for the 
duration of the study. 
10. Able and willing to take investigational product (suspension) with food 3 times daily.  Ganaxolone must 
be administered with food. 
11. Sexually active female of childbearing potential must be using a medically acceptable method of birth 
control and have a negative quantitative serum β-human chorionic growth hormone (β-HCG) test 
collected at the initial screening visit.  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 prior to the screening visit, surgical sterilization, or adequate 
barrier methods (eg, diaphragm or condom 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 
(eg, a spermicidal cream) is acceptable.  In subjects who are not sexually active, abstinence is an 
acceptable form.   
Exclusion Criteria:   
1. Previous exposure to GNX. 
2. Pregnant or breastfeeding. 
3. Subjects with >8 consecutive weeks (56 consecutive days) of primary seizure freedom during the 12-
week pre-baseline screening period. 
4. Subjects with ≤ 3 primary seizures during the 12-week baseline period.    
5. Concurrent use of strong inducers or inhibitors of CYP3A4/5/7 is not permitted.  Any strong inhibitor or 
inducer of CYP3A4/5/7 must be discontinued at least 28 days before Baseline/Randomization Visit.  
This does not include approved AEDs. 
6. Subjects with a positive result on tetrahydrocannabinol (THC) or non-approved cannabidiol (CBD) test 
(via plasma drug screen). Tetrahydrocannabinol and/or non-approved CBD will be allowed in the OL 
phase.  
7. Chronic use of oral steroid medications, ketoconazole (except for topical formulations), St.  John’s Wort, 
or other investigational products is not permitted. Intermittent (<5 consecutive days/month or 10 
cumulative days per month) use of corticosteroids as a rescue medication for breakthrough seizures may 
be allowed after sponsor approval. 
8. Changes in any chronic AED medication (i.e., changes in dose or starting a new chronic AED) within 
the last month prior to the screening visit (Visit 1) and during the 12 week baseline period (i.e., between 
Visit 1 and Visit 2).    Changes in rescue AED medications to treat acute breakthrough seizures may be 
permitted with Sponsor’s approval. Changes in other (i.e., non-AED) chronic medications may be 
permitted with Sponsor’s approval. 
9. Have an active CNS infection, demyelinating disease, degenerative neurological disease, or CNS disease 
deemed progressive as evaluated by brain imaging (magnetic resonance imaging [MRI]).   
10. Have any disease or condition (medical or surgical; other than PCDH19-related epilepsy) at the 
screening visit that might compromise the hematologic, cardiovascular, pulmonary, renal, 
gastrointestinal, or hepatic systems; or other conditions that might interfere with the absorption, 
distribution, metabolism, or excretion of the investigational product, or would place the subject at 
increased risk.   
11. An aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase [SGOT]) or alanine 
aminotransferase (ALT/serum glutamic pyruvic transaminase [SGPT]) > 3 × the upper limit of normal 
(ULN) at screening and if applicable confirmed by a repeat test.  If the subject has another reason to be 
excluded, repeated liver enzymes are not required. 
12. Total bilirubin levels > 1.5 × ULN at screening and if applicable confirmed by a repeat test.  In cases of 
documented, stable medical condition (i.e., Gilbert’s Syndrome) resulting in levels of total bilirubin > 
ULN, the medical monitor can determine if a protocol exception can be made. 
13. Subjects with significant renal insufficiency, estimated glomerular filtration rate (eGFR) < 30 mL/min 
(calculated using the Cockcroft-Gault formula or Pediatric GFR calculator or Bedside Schwartz), will be 
excluded from study entry or will be discontinued if the criterion is met post baseline. 


 
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Marinus Pharmaceuticals Inc.
Protocol 1042-PCDH19-3002 
20 January 2021
14. Have been exposed to any other investigational drug within 30 days or fewer than 5 half-lives prior to 
the screening visit.   
15. Unwillingness to withhold grapefruit, Seville oranges, star fruit, or grapefruit-containing products from 
diet 14 days prior to 1st dose and for the duration of the study 
16. Unwillingness to withhold alcohol throughout the entire clinical trial. 
17. 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.   
18. Known sensitivity or allergy to any component in the investigational product(s), progesterone or other 
related steroid compounds. 
 
Investigational product, dose, and mode of administration:   Ganaxolone is to be administered in increments 
of 15 mg/kg/day up to 63 mg/kg/day given as an oral suspension with food. Subjects ≤ 28 kg will be dosed on an 
mg/kg basis.  Subjects > 28 kg will be dosed on a fixed regimen in increments of 450 mg/day up to 1800 mg/day.  
Ganaxolone is to be administered during the 4-week titration period of the DB phase of the study as follows: 
Oral Suspension Dosinga for Subjects Weighing ≤ 28 kg (62 pounds)b 
Dose 
Total mg/kg/day 
Days 
6 mg/kg TID 
18 
1-7 
11 mg/kg TID 
33 
8-14 
16 mg/kg TID 
48 
15-21 
21 mg/kg TID 
63 
22-28 
Oral Suspension Dosinga for Subjects Weighing > 28 kg (62 pounds)c 
Dose 
mL per Dose 
Total mg/day 
Days 
150 mg TID 
3 
450 
1-7 
300 mg TID 
6 
900 
8-14 
450 mg TID 
9 
1350 
15-21 
600 mg TID 
12 
1800 
22-28 
TID = 3 times daily. 
a  
To be administered in 3 divided doses following a meal or snack. 
b  
Subjects weighing ≤ 28 kg will be dosed according to the subject’s weight in kilograms. 
c  
Subjects > 28 kg will be dosed on a fixed regimen in increments of 450 mg/day up to 1800 mg/day. 
Any subject not tolerating the next dose level can be maintained at the lower dose for additional days before 
advancing to the next dose.  If the next dose level is still not tolerated, the subject can drop back to the last 
tolerated dose .  A minimum dose of 33 mg/kg/day or 900 mg/day is generally required following the DB 
escalation period, unless a lower dose is agreed to with the sponsor due to tolerability issues such as somnolence.   
Dose changes including alternative dosing paradigm (e.g., lower dose during the daytime and higher dose in the 
evening) should be discussed with the sponsor /CRO medical monitor prior to making the change or within 48 
hours of making the change. Of note, the sponsor defers the final decision to adjust IP  to the treating study 
clinician; dose changes may not exceed the maximum total daily dose defined by the protocol. For any subject 
who is unable to be maintained at the minimum dose, the investigator should contact the sponsor to discuss 
continued investigational product dosing. Subjects who discontinue investigational product treatment before the 
completion of the DB phase will continue to be followed per protocol and, at a minimum, subjects will be 
encouraged to maintain daily seizure eDiary entries until the DB phase is completed.  These subjects will also 
return to the site 2 to 4 weeks after the taper for safety follow-up assessments. 
During the OL phase, all subjects will be treated with GNX.  Those subjects who received GNX oral suspension 
in the 17-week DB phase will receive the same GNX dose in the OL phase of the study.  However, to maintain 
the study blind, GNX subjects will enter into a 4-week blinded titration phase by increasing PBO doses in 
addition to maintaining GNX.  Subjects who received PBO oral suspension in the 17-week DB phase will enter a 
4-week, GNX titration period in the OL phase of the study.   


IND 044020 
Protocol 1042-PCDH19-3002 
Marinus Pha1maceuticals Inc. 
20 January 2021 
Reference Therapy, Dose and Mode of Administration: Placebo is to be administered as an oral suspension 
TID with food during the 4-week, titration period of the DB phase of the study. 
Placebo will only be used in the OL phase of the study during the 4-week blinded titration phase for those subjects 
who were originally randomized to GNX in the 17-week DB phase. 
Duration of treatment: 
Eligible subjects will collect 12 weeks of prospective baseline seizure data. Subjects 
will be randomized (1: 1 within each biomarker stratum) to a 17-week DB phase with GNX or PBO ( 4 weeks 
titration and 13 weeks dose maintenance), followed by a long-tenn OL treatment phase with GNX. Following 
the completion of the 17-week DB phase, subjects randomized to PBO will transition to GNX (using blinded 
titration), while subjects randomized to GNX will stay on 63 mg/kg/day suspension (1800 mg/day maximum), or 
their maximum tolerated dose (MTD) and also receive a blinded titration of PBO. Subjects will begin the 4-week 
blinded dose titration to 63 mg/kg/day (1800 mg/day or MTD) after completing the final DB visit. The OL phase 
will continue until the sponsor tenninates the development of the investigational product in PCDH19-related 
epilepsy or GNX has been approved and marketed in the subjects' respective country. 
Participants who complete the study or discontinue investigational product treatment before the end of the study 
will undergo a 2-week taper period, unless otherwise medically indicated, after which she will return to the study 
site for a safety follow up visit. Subjects who discontinue investigational product treatment before the 
completion of the DB phase will continue to be followed per protocol and, at a minimum, subjects will be 
encouraged to maintain daily seizure eDiary entries until the DB phase is completed. 
Criteria for Evaluation: 
Seizw·es: All seizure types and frequency will be recorded daily in an eDiaiy. Days in which no seizures occur 
will also be noted. Subsets of seizw·e types will be defined below. 
Prima1-y Endpoint (seizure control) 
The prima1y efficacy endpoint is the percent change in 28-day primary seizw·e frequency during the 17-week DB 
phase relative to the baseline. The primaiy seizure types are defined as countable focal seizures that include 
progressive hypotonia and impaired awareness, or any countable focal or generalized seizure with a clear motor 
component. Focal and generalized nonmotor seizures and myoclonic seizw·es do not count as the prima1y seizure 
types for the prima1y efficacy endpoint. The analyses of the primary endpoint will be performed on the sum of the 
individual countable seizures and each series of continuous uncountable seizw·es (each contributes 1 to the sum). 
Post-baseline 28-day seizure frequency will be calculated as the total number of seizures in the 17-week DB 
treatment phase divided by the number of days with seizure data in the phase, multiplied by 28. Baseline 28-day 
seizure frequency will be calculated as the total number of seizw·es in the baseline phase divided by the number 
of days with seizure data in the phase, multiplied by 28. The difference bet\¥een the GNX and placebo groups in 
the percent changes will be tested using the Wilcoxon Rank-Sum statistic. The prima1y analysis will be 
conducted in the ITT population. If nominal statistical significance is achieved in the ITT population, the 
prima1y analysis will be conducted in the biomarker-positive stratum of the ITT population as a secondary 
endpoint. 
Seconda1·y endpoints (seizure control): 
• 
The percent change in 28-day prima1y seizure frequency dw·ing the 17-week DB Phase relative to 
baseline in biomarker-positive subjects. 
• 
Percentage of subjects experiencing a c::: 50% reduction in 28-day primary seizw·e frequency 
compared to the baseline 
Seconda1·y endpoints (behavioral/neuropsychiatlic): 
• 
Behavior Rating Invento1y of Executive Function (BRIEF, preschool version BRIEF-P) 
• 
Abe1rnnt Behavior Check - Community (ABC-C) 
• 
Children's Sleep Habit Questionnaire (CSHQ) 
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Protocol 1042-PCDH19-3002 
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Pharmacokinetic Assessments: 
Marinus Pha1maceuticals Inc. 
20 January 2021 
The PK population will include all subjects who have received at least 1 dose ofIP and who have had at least 1 
sample collected and a valid bioanalytical result obtained. The samples will be drawn between 1 and 5 hours or 
between 4 and 8 hours after the last dose during the double-blind and open label periods. Phaimacokinetic 
analyses will be limited to listing of concentrations because sufficient concentration-time data will not be 
available for noncompartmental analyses such as Cmax, AUC or fmax. Phanna.cokinetic data from this study may be 
used for a Population PK analyses to be conducted separately from this study and reported separately. Further 
details will be provided in the SAP. 
Safety and Tolerability Assessments: 
Safety and tolerability will be assessed by monitoring vital signs (blood pressure [BP], hea1t rate [HR], 
respirato1y rate [RR], body temperature, electrocardiograms (ECGs), clinical laborato1y tests (hematology, 
chemistty and urinalysis), physical, neurological, and developmental examinations, and frequency, type, and 
severity of AEs during the 17-week, DB phase and the OL phase. Height and weight will also be measured. 
Confidential 
Page 48 of 136 


IND 044020 
Protocol 1042-PCDH19-3002 
Statistical Methods: 
Marinus Pha1maceuticals Inc. 
20 January 2021 
The primaiy efficacy endpoint (seizure control) is the percent change in 28-day primaiy seizure frequency dw-ing 
the 17-week DB phase relative to the baseline, based on all countable focal seizures that include progressive 
hypotonia and impaired awareness, or any countable focal or generalized seizw-e with a clear motor component. 
The analyses of the primaty endpoint will be performed on the sum of the individual countable seizures and each 
series of continuous uncountable seizw-es (each contributes 1 to the sum). Post-baseline 28-day seizure frequency 
will be calculated as the total number of seizures in the 17-week DB treatment phase divided by the number of 
days with seizw·e data in the phase, multiplied by 28. Baseline 28-day seizure frequency will be calculated as the 
total number of seizures in the baseline phase divided by the number of days with seizure data in the phase, 
multiplied by 28. 
The prima1y analysis will be conducted in the ITT Population. 
All secondary efficacy endpoints will compare GNX and PBO during the 17-week DB treatment phase relative to 
the prospective baseline phase. 
The percentages of seizure-free days will be based on the primaiy seizure types. 
BRIEF (BRIEF-P where appropriate) will be assessed as follows: in the DB phase at Visit 2 
(baseline/randotnization) and Visit 5 (Week 17; also Final DB Visit/First OL Visit in open label phase); in the OL 
phase at Visit 7 (Week 36) and Visit 9 (Week 68) and thereafter eve1y 16 weeks for the duration of this phase; 
and at the Final OL Visit. 
The ABC-C will be assessed as follows: in the DB phase at Visit 2 (baseline/randotnization) and Visit 5 (Week 
17; also Final DB Visit/First OL Visit in open label phase); in the OL phase at Visit 7 (Week 36) and Visit 9 
(Week 68) and thereafter eve1y 16 weeks for the duration of this phase; and at the Final OL Visit. 
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IND 044020 
 
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Protocol 1042-PCDH19-3002 
20 January 2021
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With few exceptions, all of the analyses for the DB phase will be repeated for the OL phase with the following 
differences. 
Safety Analysis:    
All safety analyses will be performed in the Safety Population.  The results in the DB and OL phases will be 
summarized separately.  Adverse events will be tabulated by overall, system organ class, and Preferred Term 
using the Medical Dictionary for Regulatory Activities (MedDRA) coding system.  Incidence and percentage of 
AEs will be presented.  Additional tables, with AEs classified by severity and by only those related to drug as 
assessed by the PI will be presented.  Subset listings will be produced for AEs that cause withdrawal and for 
SAEs.  Clinical laboratory tests (hematology, chemistry and urinalysis), vital signs and ECGs will be summarized 
using descriptive statistics including changes from baseline.  Physical, neurological and developmental 
examinations will be summarized using number and percentage of subjects with abnormalities. 
Pharmacokinetic Analysis:   A population PK approach addressing the relationship between GNX PK 
parameters and individual characteristics will be implemented during the study.  One blood sample will be 
obtained at the following visits for PK analyses: 
 
During the DB Phase: 
- 
Visit 3 (Week 5):  between 1 and 5 hours since the last investigational product dosing  
- 
Visit 4 (Week 9):  between 4 and 8 hours since the last investigational product dosing 
 
During the OL Phase: 
- 
Visit 6 (Week 21): between 1 and 5 hours since the last investigational product dosing 
- 
Visit 8 (Week 52): between 1 and 5 hours since the last investigational product dosing 
For all other PK draws, there is no specified time to draw the PK sample and can be drawn when convenient during 
the study visits for Visit 5 (Week 17), Visit 7 (Week 36), Visit 9 (Week 68), and every 16 weeks for the duration 
of the open-label phase. 
Exact time of sample withdrawal and drug intake will be recorded in the electronic case report form (eCRF).   
Neurosteroid serum and Concomitant AED levels:   Blood samples will be drawn at screening visit, Week 17, 
and the final OL visit to measure neurosteroid levels allopregnanolone and related endogenous CNS-active 
steroids and sulfate metabolites.  Concomitant AED levels will not be mandatory but will be conducted per sites’ 
standard of care.  If AED levels are available, the results, date and time of last AED dose and date and time of 
AED PK sample will be recorded in the eCRF. 
Interim Analysis: No formal interim analysis is planned for this study. After all active subjects complete the17-
week double-blind phase, the double-blind data in the database will be locked and used to perform endpoint 
analysis. Data collected during the open label phase will be analyzed separately.  
Data Monitoring Committee:   The emerging study data will be reviewed on a regular basis by an independent 
Data Monitoring Committee (DMC).  The mission of the DMC will be to safeguard the interests of study 
participants and to enhance the integrity and credibility of the trial.  To enable the DMC to achieve their mission, 
the DMC will have ongoing access to efficacy and safety data and data regarding quality of trial conduct and will 
ensure the confidentiality of these data will be preserved.  A DMC Charter will provide the principles and 
guidelines for the DMC process.   


IND 044020 
Protocol 1042-PCDH19-3002 
Marinus Phannaceuticals Inc. 
20 January 2021 
Table 1: 
Schedule of Assessments for the 17-Week, Double-Blind Treatment Phase of the Study 
DB Titration + Maintenance 
Final DB 
Pre-screen/Screen/Baseline 
Visit 
- (Pre-
-12 
baseline 
(Screening 
0 
3 
WEEK 
Screening 
Visit-
(Baseline Visit -
days 
1, 2, 3, 4 
5 
9 
11, 13 
17 
Visit) 
Start of 
Randomization) 
Baseline) 
Visit Windows 
N/A 
NIA 
+ 6 days 
±1 day 
± 3 days 
± 3 days 
± 3 day 
± 3 days 
± 3 days 
VISIT 
Visit 0 
Visit 1• 
Visit 2' 
Phone 
Phone 
Visit 3 
Visit 4 
Phone 
Visit 5 
Follow-up 
Follow-up 
Follow-up 
Screening and Diagnosis 
Informed Consent" 
xc 
X 
Demographics & Medical 
X 
Xd 
Histo1y 
Historical Seizure Calendar 
X 
X 
Review 
Inclusion/Exclusion Criteria 
X 
X 
X 
Genetic testinge 
X 
X 
Seizure Identification and 
Diagnostic Review Form 
X 
X 
(Epilepsy Study Consortium) 
Safety Assessments 
Vital signs (BP, HR, RR, and 
:xr 
xg 
xg 
xg 
xg 
body temperature) 
Physical/Neurological/ 
X 
X 
X 
X 
X 
Developmental Exam 
ECG 
X 
X 
X 
Clinical Laboratory Testsh 
X 
X 
X 
X 
X 
Urinalysis 
)Ci 
)Ci 
X 
X 
Dmg screeni 
X 
X 
X 
Pregnancy Test (WCBP)k 
X 
X 
X 
X 
X 
Tanner Staging 
X 
Investigational Product PK 
X' 
X' 
X 
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IND 044020 
Protocol 1042-PCDH19-3002 
Marinus Phannaceuticals Inc. 
20 January 2021 
Table 1: 
Schedule of Assessments for the 17-Week, Double-Blind Treatment Phase of the Study 
Concomitant AED Review 
and levels if per standard of 
care"' 
Neurosteroid levels 
dverse Event 
fficacy Assessments 
Seizure and Medication 
eDiary review" 
Children's Sleep Habit 
Questionnaire (CSHQ) 
Behavior Rating Inventory of 
Executive Function (BRIEF) 
Aben-ant Behavior Checklist 
- Community (ABC-C) 
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Pre-screen/Screen/Baseline 
- (Pre-
-12 
baseline 
(Screening 
0 
Screening 
Visit-
(Baseline Visit -
Visit) 
Start of 
Randomization) 
Baseline) 
N/A 
NIA 
+ 6 days 
Visit 0 
Visit 1• 
Visit 2' 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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DB Titration + Maintenance 
3 
days 
1, 2, 3, 4 
5 
9 
±1 day 
±3 days 
±3 days 
± 3 day 
Phone 
Phone 
Visit 3 
Follow-up 
Follow-up 
Visit 4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
I 
I 
11, 13 
±3 days 
Phone 
Follow-up 
X 
X 
Final DB 
Visit 
17 
± 3 days 
Visit 5 
X 
X 
X 
X 
X 
X 
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IND 044020 
Protocol 1042-PCDH19-3002 
Marinus Phan naceuticals Inc. 
20 January 2021 
Table 1: 
Schedule of Assessments for the 17-Week, Double-Blind Treatment Phase of the Study 
Pre-screen/Screen/Baseline 
- (Pre-
-12 
baseline 
(Screening 
0 
Screening 
Visit-
(Baseline Visit -
Visit) 
Start of 
Randomization) 
Baseline) 
I 
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+ 
Visit 0 
Visit 1• 
Visit 2' 
I 
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X 
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DB Titration + Maintenance 
3 
days 
±1 
1, 2, 3, 4 
Phone 
Phone 
Follow-up 
Follow-up 
5 
± 
Visit 3 
I 
I 
X 
9 
± 
Visit 4 
I 
I 
X 
11, 13 
± 
Phone 
Follow-up 
Final DB 
Visit 
17 
s 
Visit 5 
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Page 54 of 136 
IND 044020 
 
Marinus Pharmaceuticals Inc.
Protocol 1042-PCDH19-3002 
 
20 January 2021
Table 1. 
Schedule of Assessments for the 17-Week, Double-Blind Phase of the Study:  Footnotes 
AED = antiepileptic drug, BP = blood pressure, CBD = cannabidiol, D/C = discontinuation, DB = double-blind, ECG = electrocardiogram, EEG = electroencephalogram, HR = 
heart rate, LAR = legally authorized representative, PK = pharmacokinetic, RR = respiratory rate, THC = tetrahydrocannabinol, WCBP = women of childbearing potential. 
a. 
Subject rescreening is allowed as agreed by Sponsor and Investigator unless there is a general concern for subject safety or an inability for the subject to become eligible (eg, 
GNX allergy, sensitivity or exposure, non-PCDH19 and/or other ineligible epilepsy, chronic prohibited medical condition or treatment).  Subsequent screening should take 
place at least 30 days from the subject’s last visit. 
b. 
Written informed consent/assent must be obtained from subject, parent or LAR before any study assessments are performed. 
c. 
In the event that the parent/caregiver/LAR does not routinely maintain a daily seizure calendar per standard of care, written informed consent will be obtained from the 
parent/LAR and subject assent, and the subject will be asked to return to the clinic for the screening visit after she has maintained a 12-week daily historical seizure calendar. 
d. 
Review of medical history only.   
e. 
Genetic testing to be performed to confirm pathogenic or likely pathogenic PCDH19 variant. If genetic testing is not performed as Standard of Care, a pre-baseline screening 
visit will be scheduled to obtain informed consent/assent and complete the genetic testing. If genetic testing results are available per SOC, the genetic testing will be done at 
screening to confirm the results by the Sponsors designated lab. 
f. 
In addition, height and weight will be measured. 
g. 
In addition, weight will be measured. At each visit, dosing will be reviewed and adjusted as needed based on a subject’s current weight.  
h. 
Chemistry & Hematology.   
i. 
An attempt should be made to collect a urine sample for a urinalysis at screening; otherwise, the urine sample can be collected at baseline for the urinalysis. 
j. 
A drug screen (plasma) will be performed to test for THC and CBD at screening. If the screening drug test is positive, the subject can be retested, via plasma, after two weeks. 
A drug screen may be performed at any time at Investigator’s discretion.  A positive drug test during the DB phase will result in early termination.  
k. 
Serum pregnancy test is required for all girls/women of childbearing potential.   
l. 
Population PK will be conducted at these visits (Visit 3:  between 1-5 hours since last IP dosing, Visit 4:  between 4-8 hours since the last investigational product dosing).   
m. Concomitant AEDs must be stable for 1 month prior to screening and cannot be changed at any time prior to Visit 5, but may be adjusted during the open-label phase of the 
study. 
n. 
For recording of seizures in the eDiary, seizure events will be recorded either as a countable seizure or a series of continuous uncountable seizures.  Both of these events will 
be counted as 1 seizure (equally weighted) in the efficacy analysis.  A seizure cluster will be defined as 3 or more seizure events (either a countable or a series of continuous 
uncountable seizures), occurring within a period of time, followed by a period of at least 24 hours of seizure-freedom. 
Examples: (Figure 2): 
 
If a child experiences 3 seizure events at 5:00, 5:30, and 6:00 PM on Monday, and the next seizure event occurs before 6:00 PM on Tuesday, the Monday and Tuesday 
seizure events are considered part of the same seizure cluster (Figure 2, Scenario 1).   
 
If a child experiences 3 seizure events at 5:00, 5:30, and 6:00 PM on Monday, and the next seizure event occurs at 6:00 PM or later on Tuesday, the Tuesday seizure 
event is not considered part of the same cluster (Figure 2, Scenario 2). 
o. 
Caregiver given eDiary and instructions for use. 
p. 
During the screening visit, the principal investigator and parent/caregiver/LAR will decide on a domain and identify the specific behavior that the subject exhibits that denotes 
the domain.  This behavior will be used at subsequent visits to assess change after the initiation of investigational product. 
q. 
Subjects who discontinue investigational product early will be encouraged to continue with all procedures and scheduled visits. 
r. 
The 12 weeks between Screening and Randomization can be no less than 84 days and no more than 90 days. 
 
 
 


IND 044020 
Protocol 1042-PCDH19-3002 
Marinus Phannaceuticals Inc. 
20 January 2021 
Table 2: 
Schedule of Assessments for Open-Label Phase 
Final 
DB 
Titration 
Open-Label Maintenance 
Final OL 
Safety 
Visit/ 
(4 weeks blinded) 
(Visits will be every 16 weeks with a telephone follow up in-
Visit 0 1· 
Follow-up 
First 
between, this schedule continues after 68 weeks) 
Taper 
post taperJ 
OL 
Visit' 
Visit 
Week 
18, 19, 
68" and 
X/or 
2weeks 
WEEK 
17 
17 +3 
21 
28 
36 
44 
52 
60 
early 
post last 
Days 
20 
X visit 
D/CJ 
dose 
Visit Windows 
±1 
± 3 
±3 
± 14 
± 14 
± 14 
±14 
± 14 
± 14 
±14 
±3 
day(s) 
days 
days 
days 
days 
days 
days 
days 
days 
days 
days 
Phone 
Phone 
Phone 
Phone 
Phone 
Visit 9 and 
VISIT 
Visit 5 Follow-
Follow-
Visit 6 
follow-up Visit 7 follow-up Visit 8 follow-up 
Visit X 
Visit X 
Visit X 
up 
up 
Safety Assessments 
Vital signs (BP, HR, 
RR, and body 
Xb 
Xb,c 
Xb,c 
Xb,c 
Xb,c 
X 
temperature )b 
Physical/Neurological/ 
X 
X 
X 
X 
X 
X 
X 
Developmental Exam 
ECG 
X 
X 
Xd 
X 
Clinical Laboratory 
X 
X 
X 
X 
X 
X 
X 
Tests• 
Urinalysis 
X 
X 
X 
xg 
X 
X 
DmgScre.en 
X 
Pregnancy Test 
X 
X 
X 
X 
X 
X 
X 
(WCBP)r 
Tanner Staging 
X 
xg 
X 
Investigational Product 
X 
)Ci 
X 
)Ci 
X 
X 
X 
PK 
Concomitant AED 
Review and levels if per 
X 
X 
X 
X 
X 
X 
X 
standard of care 
Neurosteroid Levels 
X 
X 
xg 
X 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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20 January 2021 
Table 2: 
Schedule of Assessments for Open-Label Phase 
Final 
DB 
Titration 
Open-Label Maintenance 
Final OL 
Safety 
Visit/ 
(4 weeks blinded) 
(Visits will be every 16 weeks with a telephone follow up in-
Visit 0 1· 
Follow-up 
First 
between, this schedule continues after 68 weeks) 
Taper 
post taperJ 
OL 
Visit' 
Visit 
Week 
18, 19, 
68" and 
X/or 
2weeks 
WEEK 
17 
17 +3 
21 
28 
36 
44 
52 
60 
early 
post last 
Days 
20 
X visit 
D/CJ 
dose 
Visit Windows 
±1 
± 3 
±3 
± 14 
± 14 
± 14 
±14 
± 14 
± 14 
±14 
±3 
day(s) 
days 
days 
days 
days 
days 
days 
days 
days 
days 
days 
Phone 
Phone 
Phone 
Phone 
Phone 
Visit 9 and 
VISIT 
Visit 5 Follow-
Follow-
Visit 6 
follow-up Visit 7 follow-up Visit 8 follow-up 
Visit X 
Visit X 
Visit X 
up 
up 
Efficacy Assessments 
Seizure eDiary reviev.,h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Children's Sleep Habit 
X 
X 
X 
X 
Questionnaire (CSHQ) 
Behavior Rating 
Inventory of Executive 
X 
X 
X 
X 
Function (BRIEF) 
Aben-ant Behavior 
Checklist - Community 
X 
X 
X 
X 
(ABC-C) 
Exploratory Assessments 
I 
I 
I 
I 
I 
I 
I 
I 
I 
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20 January 2021 
Table 2: 
Schedule of Assessments for Open-Label Phase 
Dispense 
Investigational 
Product 
Confidential 
Final 
DB 
Visit/ 
First 
OL 
Visit 
17 
Visit 5 
I 
I 
I 
X 
Titr ation 
(4 weeks blinded) 
Week 
18, 19, 
17 +3 
21 
Days 
20 
±1 
± 3 
± 3 
day(s) 
days 
days 
Phone 
Phone 
Follow-
Follow-
Visit 6 
up 
up 
X 
Open-Label Maintenance 
Final OL 
Safety 
(Visits will be every 16 weeks with a telephone follow up in-
Visit 0 1· 
Follow-up 
between, this schedule continues after 68 weeks) 
Taper 
post taperJ 
Visit' 
68" and 
X/or 
2weeks 
28 
36 
44 
52 
60 
early 
post last 
X visit 
D/CJ 
dose 
± 14 
± 14 
± 14 
±14 
± 14 
± 14 
±14 
± 3 
days 
days 
days 
days 
days 
days 
days 
days 
Phone 
Phone 
Phone 
Visit 9 and 
follow-up Visit 7 follow-up Visit 8 follow-up 
Visit X 
Visit X 
Visit X 
I 
I 
I 
I 
I 
I 
I 
I 
I 
X 
X 
X 
X 
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Protocol 1042-PCDH19-3002 
 
20 January 2021
Table 2. 
Schedule of Assessments for Open-Label Phase:  Footnotes 
AED = antiepileptic drug, BP = blood pressure, DB = double-blind, D/C = discontinuation, ECG = electrocardiogram, EEG = electroencephalogram, HR = heart 
rate, PK = pharmacokinetic, OL = open-label, RR = respiratory rate, WCBP = women of childbearing potential. 
Note: The timing of the final OL visit is not defined at this time, as the study is anticipated to continue until either the investigational product is approved and 
marketed, or the Sponsor discontinues development of investigational product in PCDH19-related epilepsy (approximately an additional 3 years).   
a. 
If the subject continues in the OL phase beyond Week 68, a telephone follow-up visit will occur in between clinic visits (8 weeks ± 14 days after each clinic 
visit) to assess the following adverse events and seizure and medication diary review. 
b. In addition, weight will be measured at every visit, except the safety follow-up visit. 
c. 
In addition, height will be measured annually after Visit 8 (Week 52), except the safety follow-up visit. 
d. After Visit 8 (Week 52), ECGs to be performed annually (and at last OL visit). 
e. 
Chemistry & Hematology. 
f. 
Serum pregnancy test is required for all girls/women of childbearing potential. 
g. Conduct annually and at the final OL visit. 
h. For recording of seizures in the eDiary, seizure events will be recorded either as a countable seizure or a series of continuous uncountable seizures.  Both of 
these events will be counted as 1 seizure (equally weighted) in the efficacy analysis.  For recording of seizures in the eDiary, seizure events will be recorded 
either as a countable seizure or a series of continuous uncountable seizures.  Both of these events will be counted as 1 seizure (equally weighted) in the 
efficacy analysis.  A seizure cluster will be defined as 3 or more seizure events (either a countable or a series of continuous uncountable seizures), occurring 
within a period of time, followed by a period of at least 24 hours of seizure-freedom. 
Examples: (Figure 2): 
 
If a child experiences 3 seizure events at 5:00, 5:30, and 6:00 PM on Monday, and the next seizure event occurs before 6:00 PM on Tuesday, the 
Monday and Tuesday seizure events are considered part of the same seizure cluster (Figure 2, Scenario 1).   
 
If a child experiences 3 seizure events at 5:00, 5:30, and 6:00 PM on Monday, and the next seizure event occurs at 6:00 PM or later on Tuesday, the 
Tuesday seizure event is not considered part of the same cluster (Figure 2, Scenario 2). 
i. 
Population PK will be conducted at these visits (Visit 6: between 1-5 hours since the last IP dosing and Visit 8: between 1-5 hours since last IP dosing) 
j. 
Subjects who discontinue IP treatment before the completion of the DB phase will continue to be followed per protocol and, at a minimum, subjects will be 
encouraged to maintain daily seizure eDiary entries until the DB phase is completed.  These subjects will also return to the site 2 to 4 weeks after the taper 
for safety follow-up post-taper assessments. Taper is not required if the subject is receiving the dose of 18 mg/kg/day or 450 mg/day (or lower). 
 
 
 
 


 
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Protocol 1042-PCDH19-3002 
 
20 January 2021
1. 
BACKGROUND INFORMATION 
1.1. 
Indication and Current Treatment Options 
Pediatric patients with rare epilepsy conditions, such as protocadherin 19 (PCDH19)-related 
epilepsy, cyclin-dependent kinase-like 5 (CDKL5) Disorder (CDD), 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 seizure disorders may overlap idiopathic 
Lennox-Gastaut syndrome (LGS) 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.  Other epileptic 
diagnostic conditions, such as continuous spike and wave during slow wave sleep (CSWS) or 
electrical status epilepticus in sleep, may also respond to corticosteroid 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 single anticonvulsant has 
been found to be uniformly effective, and often multiple anticonvulsants are needed; even then, 
patients still become treatment-resistant. 
The need for novel treatments to address seizure control is critical for pediatric patients living 
with these conditions.  This study will assess the efficacy and safety of ganaxolone as an 
experimental drug with a new and distinct mechanism of action. 
Ganaxolone (GNX) is the 3β -methylated synthetic analog of allopregnanolone, an endogenous 
allosteric modulator of γ-aminobutyric acid type A (GABAA) receptors in the central nervous 
system (CNS).  Ganaxolone has potency and efficacy comparable to allopregnanolone in 
activating synaptic and extrasynaptic GABAA receptors at a site distinct from the benzodiazepine 
site.  Ganaxolone has protective activity in diverse rodent seizure models (Bialer 2010, 
Reddy 2012). 
Clinical studies have demonstrated that GNX has anticonvulsant efficacy with an acceptable 
safety and tolerability profile in the dose range of 900 to 1800 mg in adults and children 
(Sperling 2017, Laxer 2000, Kerrigan 2000, Pieribone 2007).  The present study will investigate 
whether GNX provides efficacy for children with uncontrolled seizures and PCDH19-related 
epilepsy and other genetic epilepsies. 
Protocadherin 19- female-pediatric epilepsy, also known as PCDH19 female-limited epilepsy, or 
epilepsy in females with mental retardation (hereon referred to as PCDH19-related epilepsy), is a 
serious epileptic syndrome characterized by early-onset cluster seizures, cognitive and sensory 
impairment of varying degrees, and psychiatric and behavioral disturbances in some individuals 
(Camacho 2012, Depienne 2014).   
PCDH19-related epilepsy is associated with a mutation of the PCDH19 gene, the gene that 
encodes for protocadherin19 on the X chromosome (Depienne 2014a, Dibbens 2008).  The 
mechanism by which this mutation contributes to the development of epilepsy and intellectual 
impairment is not fully understood.  Protocadherin is, however, a transmembrane protein of 
calcium-dependent cell-cell adhesion molecules that is strongly expressed in neural tissue (eg, 
hippocampus, cerebral cortex, thalamus, and amygdale) and which appears to be related to 
synaptic transmission and formation of synaptic connections during brain development 


 
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(Depienne 2009).  Research suggests that impairment of γ-Aminobutyric acid (GABA)-ergic 
signaling both at the agonist and receptor levels is present in girls with PCDH19 mutations and 
pediatric-onset epilepsy (Tan 2015). 
The hallmark characteristics of PCDH19-related epilepsy are clusters of seizures which start in 
infancy or early childhood that are often associated with fever or immunization (Depienne 2012, 
Higurashi 2013, Marini 2010).  Patients with PCDH19-related epilepsy 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 (Camacho 2012, Specchio 2011, Scheffer 2008). 
The mean age of onset of PCDH19-related epilepsy is approximately 10 months (range of 3-38 
months) (Scheffer 2008, Specchio 2011, Dipienne 2011, Cappelletti 2015, van Harssel 2013).  
The mean age of offset of epileptic seizures is approximately 12.5 years (1-35 years).  PCDH19-
related epilepsy has been described as a “semiprogressive” condition, meaning that seizure 
frequency increases during the first few years of life (Specchio 2011); however, the seizure 
frequency decreases, and seizures become less frequent with increased age.   
There is also evidence supporting an allopregnanolone deficiency as a proposed contributor to 
the onset of seizures in individuals with PCDH19-related epilepsy (Tan 2015).  It was found that 
individuals with this genetic mutation demonstrated a downregulation of steroid hormone-
metabolizing enzymes, resulting in reduced allopregnanolone levels compared to non-affected, 
age-matched controls.  Since this neurosteroid is known to have strong anti-convulsant 
properties, it is hypothesized that treatment with neurosteroids with similar action, or analogs 
such as GNX, may have therapeutic benefit to seizure control. 
1.2. 
Product Background and Clinical Information 
Ganaxolone is the 3β-methylated synthetic analogue of the neuroactive steroid allopregnanolone, 
but it is designed to not activate nuclear (classical) progesterone receptors.  Ganaxolone differs 
from other GABA agents by interacting with both synaptic and extra-synaptic GABAA receptors 
and at binding sites distinct from benzodiazepines.  Whereas benzodiazepines might lose their 
inhibitory action, GNX does not because it selectively binds to GABAA receptors containing the 
α and δ subunits.  By enhancing GABAA receptor function, GNX provides an alternative 
mechanism in the treatment of seizures, and could serve as effective therapy in the management 
of benzodiazepine-resistant seizure conditions, such as CDD.   
The anticonvulsant activity of GNX was established in several in vivo models of seizure activity.  
Ganaxolone was effective at behaviorally non-toxic doses in rodent models of seizures induced 
by pentylenetetrazol, bicucilline, aminophylline, strychnine, and 
t-butylbicyclophosphorothionate and antagonized 4-AP lethality in mice.  Ganaxolone blocked 
tonic seizures induced by maximal electroshock in mice and rats, but only at doses that produced 
ataxia on the rotarod test.  Ganaxolone was a potent anticonvulsant against fully-kindled Stage-5 
seizures induced by corneal kindling in the rat at doses well below those that resulted in ataxia.  
Seizure threshold, as determined by the dose of intravenously-infused pentylenetetrazol required 
to induce clonus, was significantly elevated by non-toxic doses of GNX in the mouse.  These 
results indicate that GNX blocks seizure propagation and elevates seizure threshold (Carter 1997, 
Kaminski 2004, Reddy 2004). 


 
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Protocol 1042-PCDH19-3002 
 
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As of 10 Oct 2018, 1557 unique subjects have received treatment with GNX in completed 
company-sponsored clinical trials ranging in duration from 1 day to more than 2 years, using 
doses from 50 to 2,000 mg/day. In addition, 30 subjects received GNX in an ongoing open-label 
Phase 2 study, and an estimated 65 subjects received GNX in ongoing Phase 2/3 double-blind 
studies.  
Of these 1557 unique subjects, 319 healthy subjects have received GNX treatment in Phase 1 
studies and 1238 subjects have received GNX treatment in Phase 2/3 studies. The completed 
trials include 20 Phase 1 studies in healthy subjects and 20 Phase 2/3 studies in adults with 
epilepsy, children with seizure disorders, children with FXS, adults with PTSD and adults with 
migraine. 
Four company-sponsored clinical studies of GNX are ongoing and have enrolled over 200 
unique subjects:  
 Study 1042-0900 in pediatric epilepsies including female pediatric subjects with 
PCDH19 epilepsy and other rare genetic epilepsies including CDKL5 deficiency 
disorder, LGS and continuous spikes and waves during sleep (CSWS)  
 Study 1042-SE-2001 in adolescents and adults with SE  
 Study 1042-PPD-2002 in women with PPD (GNX IV and oral capsule multiple-dose 
escalation double-blind study)  
 Study 1042-PPD-2003 in women with PPD (GNX oral capsule multi-dose escalation 
open label study) 
For these 4 ongoing clinical studies, enrollment is complete for Study 1042-0900, 1042-PPD-
2002 and 1042-PPD-2003 and is ongoing for Study 1042-SE-2001. 
In addition to the company-sponsored studies, 29 subjects were treated with GNX in completed 
studies not sponsored by Marinus.  These included 16 subjects who received oral GNX doses 
from 400 mg/day to 1200 mg/day in a smoking cessation study and 10 subjects who received 
oral GNX in a postmenopausal depression study.  One pediatric subject received oral GNX up to 
63 mg/kg/day under a special access scheme in Australia for treatment of refractory seizures 
associated with PCDH19 genetic epilepsy.  In addition, two pediatric subjects received GNX in 
separate emergency INDs to treat super-refractory status epilepticus: 1 subject received IV GNX 
up to a dose of 2880 mg/day and 1 subject received IV GNX infusion up to a dose of 192 mg/day 
and transitioned to a GNX oral suspension dose of 1260 mg/day that was tapered over 6 weeks. 
[SAE Section 5.6 IB] 
Furthermore, 3 non-company-sponsored clinical studies are ongoing. In these studies, a total of 
7 subjects continue to receive treatment with GNX through investigator-initiated INDs following 
participation in Marinus-sponsored studies as follows:  
 In one study, 3 subjects received GNX following participation in Study 1042-0603 of 
adult subjects with drug-resistant partial-onset seizures. 
 In one study, 3 subjects (2 subjects with PCDH19 epilepsy and 1 subject with LGS) 
received GNX following participation in Study 1042-0900.  


 
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 In another study, 1 subject with CDD received GNX following participation in 
Study 1042-0900 
The overall frequency of treatment-emergent adverse events (TEAE) in company-sponsored 
placebo (PBO)-controlled studies was 61.7% (613/993 subjects) in subjects who received GNX 
and 51.8% (330/637 subjects) in subjects who received PBO.  The most frequently reported 
TEAEs in GNX-treated subjects were somnolence, dizziness, fatigue, and headache.  All of these 
events, except for headache, occurred more frequently in GNX-treated subjects than PBO-treated 
subjects.  Central nervous system-related events appeared to be dose-related, with the majority of 
these events occurring at doses ≥ 500 mg, and were anticipated based on the mechanism of 
action of GNX.  These events were non-serious, mild to moderate in severity, and did not lead to 
discontinuation of treatment.   
In the GNX development program overall, no clinically significant trends have been noted for 
electrocardiogram (ECG) intervals, vital signs, physical or neurologic examinations, or mean 
changes from baseline in clinical laboratory results.  Overall, there have been a few clinically 
significant individual changes from baseline in clinical laboratory measurements in clinical trials 
of GNX.  In the completed PBO-controlled Phase 1, 2, and 3 studies, 0.3% of subjects treated 
with GNX and 0.5% of subjects treated with PBO exhibited elevated liver function tests during 
the study (aspartate aminotransferase or alanine aminotransferase > 3 × the upper limit of normal 
[ULN]).  There have been no cases of Hy’s law considered to be related to GNX in the GNX 
development program. 
In controlled clinical trials of GNX, 1.1% of subjects receiving PBO and 1.7% of subjects 
receiving GNX reported an adverse event (AE) of rash suggesting there is no obvious imbalance 
between drug and PBO in terms of frequency of this AE.  However, in PBO-controlled studies, 
rash led to discontinuation in GNX-treated subjects in 6 cases (0.6%) compared to no cases (0%) 
in PBO-treated subjects.   One of the events was also reported as an SAE and the event resolved 
after discontinuation of the study drug. In addition, in the ongoing study 1042-0900, an 
additional event of rash was reported as an SAE. There have been no cases of Stevens-Johnson 
syndrome, toxic epidermal necrolysis or any other clinically important rashes reported in the 
clinical development program. Marinus considers rash as a potential risk associated with GNX 
and continues to monitor the occurrence of this AE in the clinical development program. 
Pediatric Safety 
Marinus has completed 2 double-blind (DB), randomized trials and 5 open-label (OL), 
uncontrolled clinical trials of GNX in the pediatric population.  One additional pediatric trial, OL 
Study 1042-0900 in children with various genetic epilepsies and LGS, is ongoing.  This study 
has enrolled 30 subjects of which 7 are subjects with the CDKL5 mutation.   
Approximately 224 pediatric subjects aged 4 months to 17 years (data cutoff October 10, 2017) 
have received at least 1 dose of GNX.  The largest cohorts received 12 to 54 mg/kg/day, 
although some subjects received doses as high as 63 mg/kg/day or 1800 mg/day for adolescents.  
As of October 10, 2017, 4 subjects were treated ≥ 4 years, 9 subjects were treated ≥ 2 years, 
39 subjects were treated ≥ 1 year, and 66 subjects were treated ≥ 6 months. 
The majority of the pediatric subjects were refractory epilepsy patients who had uncontrolled 
seizures despite trying other antiepileptic drugs (AEDs) (range 1-8).  Overall, GNX was 


 
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Protocol 1042-PCDH19-3002 
 
20 January 2021
generally safe and well tolerated.  In the incomplete crossover Study 1042-0500 (N = 56; all 
subjects received GNX during the trial), 39 subjects with infantile spasms (IS) treated with GNX 
doses up to 54 mg/kg/day for up to 20 days reported at least 1 TEAE.  The most frequently 
reported AEs (≥ 8% of subjects) were vomiting (7 subjects), somnolence (5 subjects), and cough 
(5 subjects).  Most AEs were mild or moderate; 1 severe AE of lethargy occurred in 1 GNX 
subject.  During the 8-day PBO-controlled treatment period, the most frequent AEs noted were 
vomiting (11% in both GNX and PBO groups) and cough (8% GNX, 5% PBO).  Other AEs 
attributed to GNX included flatulence, insomnia, irritability, lethargy, and somnolence.  Adverse 
events reported in the other uncontrolled refractory pediatric epilepsy studies were consistent 
with the GABAergic mechanism of action or disease under study.   
In another randomized, DB, PBO-controlled study of 59 subjects (aged 5-17 years) with fragile 
X syndrome who were treated with GNX up to 36 mg/kg/day (maximum 1800 mg/day) or PBO, 
the percentage of subjects who reported at least 1 TEAE was comparable between the treatment 
groups (85.2% versus 83.1% in the PBO and GNX treatment groups, respectively).  The most 
frequently reported TEAEs among subjects who received GNX included fatigue (29/59 subjects; 
49.2%), somnolence (20/59 subjects; 33.9%), condition aggravated (10/59 subjects; 16.9%), and 
upper respiratory tract infection (9/59 patients; 15.3%).  Both fatigue (49.2% vs 20.4%) and 
somnolence (33.9% vs 5.6%) occurred more frequently in GNX-treated subjects compared with 
PBO-treated subjects, respectively.  
Among subjects who received PBO, headache (6 subjects; 11.1%) and agitation (8 subjects; 
14.8%) were reported more frequently compared with GNX-treated subjects.  Severe TEAEs 
were reported for 3/59 (5.1%) GNX subjects and 1/54 (1.9%) PBO subjects.  Severe events in 
the GNX group were somnolence and fatigue in 1 subject each and agitation and aggression in 1 
subject. 
To date, AEs have been consistent with the GABAergic mechanism of GNX, disease understudy, 
or pediatric studies.  There have not been any emerging safety concerns with respect to vital 
signs, ECG, physical/neurological examinations, or clinical laboratory measures. 
 
 


 
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2. 
STUDY OBJECTIVES AND PURPOSE 
2.1. 
Rationale for the Study 
Protocadherin19 (PCDH19)-related epilepsy is a serious epileptic condition characterized by 
early-onset cluster seizures, cognitive and sensory impairment of varying degrees, and 
psychiatric and behavioral disturbances affecting primarily females (Camacho 2012).  The 
condition is caused by an inherited mutation of the PCDH19 gene located on the X chromosome.  
This gene encodes for a calcium-dependent cell-cell adhesion molecule that is expressed in the 
CNS (hippocampus, cerebral cortex, thalamus, amygdala) and which appears to be related to 
synaptic transmission and formation of synaptic connections during brain development 
(Depienne 2009). 
The mean age of seizure onset in this condition is approximately 10 months (range of 
3-38 months) (Scheffer IE 2008, Specchio N 2011, Dipienne 2011, Cappelletti 2015, 
van Harssel 2013).  The mean age of offset of epileptic seizures is approximately 12.5 years 
(1-35 years).  PCDH19-related epilepsy has been described as a “semiprogressive” condition, 
meaning that seizure frequency increases during the first few years of life (Specchio 2011).  
However, over time the seizure frequency decreases, and seizures become less frequent with 
increased age.   
There is also evidence supporting an allopregnanolone deficiency as a proposed contributor to 
the onset of seizures in individuals with PCDH19-related epilepsy (Tan 2015).  It was found that 
individuals with this genetic mutation demonstrated a downregulation of steroid hormone-
metabolizing enzymes resulting in reduced allopregnanolone levels compared to non-affected, 
age-matched controls.  Since this neurosteroid is known to have strong anti-convulsant 
properties, it is hypothesized that treatment with neurosteroids with similar action, or analogs 
such as GNX, may have therapeutic benefit to seizure control. 
Ganaxolone is the 3β-methylated synthetic analog of allopregnanolone, an endogenous allosteric 
modulator of CNS GABAA receptors.  Ganaxolone has potency and efficacy comparable to 
allopregnanolone (Carter 1997) in activating synaptic and extrasynaptic GABAA receptors at a 
site distinct from benzodiazepines and barbiturates.  Ganaxolone has protective activity in 
diverse rodent seizure models (Reddy 2012, Bialer 2010).  Clinical studies have demonstrated 
that GNX has anticonvulsant activity with an acceptable safety and tolerability profile in the dose 
range of 900 to 1800 mg in adults and children (Sperling 2017, Laxer 2000, Kerrigan 2000, 
Pieribone 2007).  Further, GNX reduces seizures in children with IS and refractory pediatric 
epilepsy.  In an OL study, pediatric subjects aged 2 to 60 months with refractory seizures and a 
history of IS were treated with GNX doses up to 36 mg/kg for up to 3 months (Kerrigan 2000).  
Sixteen of the 20 subjects completed treatment, 15 of whom had a history of IS.  Five of the 15 
subjects had a decrease from baseline in the number of spasms of ≥ 50%, 5 had a decrease of 25 
to 50%, and 5 had a decrease of < 25%.  One subject became spasm-free and 1 non-responder 
(with a decrease of < 25%) was spasm-free from weeks 2 to 7.   
An anticonvulsant treatment effect signal of GNX in PCDH19-related epilepsy has emerged 
from an ongoing OL flexible-dose exploratory study (Study 1042-0900) of GNX in children (age 
range 2-15 years) with rare genetic epilepsies (including PCDH19) with uncontrolled seizures 
despite multiple AED regimens (ClinicalTrials.gov Identifier:  NCT02358538).  Following the 


 
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screening and baseline evaluations, consenting subjects enrolled into a 26-week study during 
which investigators could dose GNX starting with a titration up to 1,800 mg/day for subjects 
whose body weight was > 30 kg or up to 63 mg/kg /day for subjects whose body-weight was 
< 30 kg.  The dose could also be reduced for tolerability reasons.  The primary efficacy measure 
was the percent change from baseline in the 28-day seizure frequency count.  Safety and 
tolerability assessments were among the secondary objectives.  The median change in 28-day 
seizure frequency from baseline in the intent-to-treat (ITT) population (primary endpoint) was a 
decrease of 25% (n = 11).   
The median change from baseline in seizure-free days in the ITT population (key secondary 
endpoint) was an increase of 14% (n = 11).  Baseline levels of allopregnanolone sulfate (Allo-S, 
an endogenous neurosteroid) and 28-day seizure rates were also assessed.  A ganaxolone-
responder was specified by post-hoc definition, as having at least a 25% reduction in 28-day 
seizure rate.  In the PCDH19 cohort, responders (n = 6) and non-responders (n = 5) had plasma 
Allo-S concentrations (mean ± SD) of 501 ± 430 pg mL-1 and 9,829 ± 6,638 pg mL-1, 
respectively.  When performing a retrospective separation of the PCDH19 cohort according to 
their Allo-S level, the 7 subjects with Allo-S levels below 2,500 pg mL-1 (biomarker-positive) 
had a 50% reduction in seizure rates while the 4 subjects with Allo-S levels above 2,500 pg mL-1 
(biomarker-negative) had a 84% increase (performed in the research lab of Dr.  Graziano Pinna 
at the University of Illinois, Chicago, the only laboratory during the conduct of the study that 
could reliably produce results for sulphated neurosteroids).  The Clinical Global Impression 
Scale rated by Investigators (CGI-I) and Caregivers (CGI-P) has been consistent with seizure 
control.  In the OL study (1042-0900), there were 4 SAEs (3 related to seizures and 1 related to 
rash) possibly related to the study drug in the PCDH19 subjects.   
In addition to anticonvulsant activity, GNX has shown positive effects on anxiety, hyperactivity, 
and attention in children with fragile X syndrome (Ligsay 2016).  Similar behavior problems 
occur in individuals with PCDH19 mutations (Smith 2018). 
It is hypothesized that GNX treatment will increase and improve GABAA-mediated signaling by 
boosting the signaling capacity of existing receptors and improve not only seizure control, but 
also other behavioral abnormalities in individuals with the PCDH19 mutation. 
2.2. 
Study Objectives 
2.2.1. 
Primary Objective 
The primary objective of this study is to assess the efficacy of GNX compared with PBO  as 
adjunctive therapy for the treatment of primary  seizures in children with genetically-confirmed 
PCDH19-related epilepsy during the17-week DB phase. 


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2.2.2. 
Secondary Objectives 
The secondaiy objectives of this study are the following: 
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• 
To assess the effect of GNX on primai·y seizure rate in biomai·ker-positive subjects. 
• 
To assess behavioraVneuropsychiatric changes in subjects receiving GNX compai·ed with 
subjects receiving PBO as adjunctive therapy during thel 7-week DB phase. 
• 
To assess the safety and tolerability of GNX compai·ed with PBO as adjunctive therapy 
during thel 7-week DB phase. 
• 
To assess phaimacokinetic (PK) parameters in subjects receiving GNX doses up to 63 
mg/kg/day (1800 mg/day maximum) throughout the study. 
• 
To assess the long-tenn efficacy of GNX when administered as adjunctive therapy 
throughout the OL phase. 
• 
To assess the long-tenn safety and tolerability of GNX when administered as adjunctive 
therapy throughout the OL phase. 
2.2.3. 
Exploratory Objectives 
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3. 
STUDY DESIGN 
3.1. 
Study Design and Flow Chart 
This is a global, biomarker-stratified, DB, randomized, PBO-controlled trial of adjunctive GNX 
treatment in female children with a confirmed pathogenic or likely pathogenic PCDH19 
mutation.  The trial consists of a 12-week prospective baseline period to collect seizure data, 
followed by a 17-week DB treatment phase, which is then followed by a long-term OL phase 
(Figure 1).  An interactive web response system (IWRS) will be used to randomize subjects, 
dispense drug, track treatment, and maintain the blind throughout the duration of the study 
(Section 6.2.1). 
A 12-week daily historical seizure calendar will be reviewed at the screening visit to determine 
eligibility per inclusion/exclusion criteria (Section 4). Acceptable historical seizure data must 
include at least 12 consecutive weeks prior to the Screening visit of documenting seizure type 
and frequency (also noting seizure-free days). If genetic testing is not performed as Standard of 
Care, a pre-baseline screening visit will be scheduled to obtain informed consent/assent and 
complete the genetic testing. If genetic testing results are available from SOC, the genetic testing 
will be done at screening to confirm the results by the Sponsors designated lab. Genetic testing is 
to be performed to confirm pathogenic or likely pathogenic PCDH19 variant.  Procedures 
specific to this protocol and not otherwise considered standard of care will not be performed 
until written informed consent from the subject’s parent or legally authorized representative 
(LAR) and subject assent has been appropriately obtained.  In the event that 
parent/caregiver/LAR does not routinely maintain a daily seizure calendar or have genetic testing 
results per standard of care, written informed consent will be obtained from the parent/LAR and 
subject assent. The subject will be asked to return to the clinic for the screening visit after she 
has maintained a 12-week daily historical seizure calendar.   
During the screening visit, each subject’s biomarker level will be assessed via a blood draw and 
subsequent analytical quantification.  Each subject will then be assigned to 1 of 2 groups: 
biomarker-positive or biomarker-negative.  A subject will be considered biomarker-positive if 
her baseline Allo-S level is less than or equal to 2500 pg/mL (Pinna Lab method or similar). The 
biomarker group assignment will remain blinded until database unblinding after the study has 
completed.  Based on the 11-subject OL study, it is estimated that approximately 65% of 
all-comers will be biomarker-positive. 
Subject rescreening is allowed as agreed by Sponsor and Investigator unless there is a general 
concern for subject safety or an inability for the subject to become eligible (eg, GNX allergy, 
sensitivity or exposure, non-PCDH19 and/or other ineligible epilepsy, or chronic prohibited 
medical condition or treatment).  Subsequent screening should take place at least 30 days from 
the subject’s last visit. If a subject fails to qualify because of Exclusion Criteria #4 (≤ 3 primary 
seizures during the 12-week baseline period), she will not be randomized. However, she can be 
rescreened after collecting another 12 or more weeks of seizure history that satisfies all eligibility 
criteria including Inclusion Criteria #5 and Exclusion Criteria #3. Each subject is allowed a 
maximum of 1 rescreening visit.  
The DB phase includes 4 weeks of IP titration (Section 6.2.3.1) followed by 13 weeks of dose 
maintenance.  After meeting the eligibility criteria, approximately 25 children aged 1 to 17 years 


 
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(inclusive) with PCDH19-related epilepsy will be randomly assigned to receive GNX or PBO 
(1:1 ratio within each biomarker stratum) for 17 weeks in addition to their standard anti-seizure 
treatment.  Subjects will be titrated to 63 mg/kg/day (max 1800 mg/day) over 4 weeks and then 
maintained at that dose for another 13 weeks.  Subjects who are not able to tolerate 63 mg/kg/day 
(or 1800 mg/day maximum) may be maintained on a lower dose.  A minimum dose of 
33 mg/kg/day or 900 mg/day is generally required following the DB escalation period, unless a 
lower dose is agreed to with the sponsor due to the tolerability such as somnolence. At each visit, 
dosing will be reviewed and adjusted as needed based on subject’s current weight. 
Dose changes, including alternative dosing paradigm (e.g. lower dose during the daytime and 
higher dose in the evening), should be discussed with the clinical research organization 
(CRO)/sponsor medical monitor prior to making the change or within 48 hours of making the 
change.  Of note, the sponsor defers the final decision to adjust IP to the treating study clinician; 
dose changes may not exceed the maximum total daily do defined by the protocol. For any 
subject who is unable to be maintained at the minimum dose, the investigator should contact the 
sponsor to discuss continued IP dosing.  Subjects who discontinue IP should undergo a 2-week 
taper period, unless otherwise medically indicated (Section 6.2.3.3).  Subjects who discontinue 
IP treatment before the completion of the DB phase will continue to be followed per protocol 
and, at a minimum, subjects will be encouraged to maintain daily seizure eDiary entries until the 
DB phase is completed.  These subjects will also return to the site 2 to 4 weeks after the taper for 
safety follow-up post-taper assessments. 
After completing the initial 17-week, DB, PBO-controlled phase, all subjects will be treated with 
GNX in the OL phase of the study.  Ganaxolone subjects will continue GNX treatment and PBO 
subjects will titrate onto GNX.  To maintain the blind, subjects initially randomized to GNX will 
undergo a blinded titration (increasing PBO doses) for 4 weeks, whereas PBO subjects will 
titrate up to 63 mg/kg/day GNX (1800 mg/day maximum) during the same time period 
(Section 6.2.3.2).  Any subject who completes the study or discontinues IP treatment should 
undergo a 2-week drug de-escalation (taper) period (Section 6.2.3.3) and return to the site 2 
weeks later for safety follow-up post-taper assessments.   Taper is not required if the subject is 
receiving the dose of 18 mg/kg/day or 450 mg/day (or lower).  


 
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Figure 1: 
Study Design 
 
 
PCDH19 
(all-subjects) 
re- ase ,ne 
Screenin 
Screening 
Visit 
LowAllo-S 
Biomarker+ 
High Allo-S 
Biomarker-
Baseline (12 weeks) 
Primary efficacy analyses will be conducred using rhis cohort 
Titrauon (4 
weeks) 
Maintenance (13 weeks) 
Double-Blind Phase 
Titration (4 
weeks) 
Open-Label Phase (52 weeks) 
•not drawn 10 scale• 


 
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Subjects will be required to complete an eDiary to determine the effect of GNX on drug-resistant 
seizures.  An electronic eDiary is the standard, in rare cases when an eDiary completion is not 
feasible, a paper diary will be used. These cases will need approval by the sponsor. A variety of 
clinician- and caregiver- administered instruments will be used to assess the efficacy of 
adjunctive GNX in PCDH19, and will include the following: 
 Behavior Rating Inventory of Executive Function (BRIEF) 
 Aberrant Behavior Checklist – Community (ABC-C) 
 Children’s Sleep Habit Questionnaire (CSHQ) 
 Pediatric Quality of Life Inventory – Family Impact Module (PedsQL-FIM) 
 Quality of Life Inventory – Disability (QI-Disability) 
 Caregiver Global Impression of Change (CGI-C) – Target Behavior, Clinical Global 
Impression – Improvement [caregiver], and Clinical Global Impression – Improvement 
[clinician].   
Safety and tolerability will be assessed by monitoring vital signs (blood pressure [BP], heart rate 
[HR], respiratory rate [RR], body temperature, weight, and height); 12-lead ECGs, clinical 
laboratory tests (hematology, chemistry, and urinalysis); physical, neurological, and 
developmental examinations; and frequency, type, and severity of AEs during the 17-week, DB 
phase and the OL phase. 
3.2. 
Duration and Study Completion Definition 
In the event that the parent/caregiver/LAR does not routinely maintain a daily seizure calendar 
per standard of care, written informed consent will be obtained from the parent/LAR and subject 
assent, and the subject will be asked to return to the clinic for the screening visit after she has 
maintained a 12-week daily historical seizure calendar. Additionally, if genetic testing is not 
completed as standard of care, a pre-baseline screening visit can be conducted to do so. 
Eligible subjects will collect 12 weeks of prospective baseline seizure data.  During the screening 
visit, each subject’s biomarker level will be assessed via a blood draw and subsequent analytical 
quantification.  Each subject will then be assigned to 1 of 2 groups: biomarker-positive or 
biomarker-negative.  A subject will be considered biomarker-positive if her baseline Allo-S level 
is less than or equal to 2500 pg/mL (Pinna Lab method or similar). Subjects will then be 
randomized (1:1 GNX:  PBO within each biomarker stratum) to a 17-week DB treatment phase 
(4 weeks titration and 13 weeks dose maintenance), followed by a long-term OL treatment phase 
with GNX. The biomarker group assignment will remain blinded until database unblinding after 
the study has completed. 
Following completion of the 17-week DB phase, subjects randomized to PBO will transition to 
GNX (using blinded titration, Section 6.2.3.2), while subjects randomized to GNX will stay on 
63 mg/kg/day (1800 mg/day or MTD) suspension or their maximum tolerated dose (MTD) and 
also receive a blinded titration of PBO.  Subjects will begin the 4-week blinded dose titration to 
63 mg/kg/day (1800 mg/day or MTD) after completing the final DB visit.  The OL phase will 
continue until the sponsor terminates the development of the IP in PCDH19-related epilepsy or 
GNX has been approved and marketed in the subjects’ respective country. 


 
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Subjects who complete the study or discontinue IP treatment before the end of the study will 
undergo a 2-week taper period (Section 6.2.3.3), unless otherwise medically indicated, after 
which they will return to the study site for a safety follow up visit.  Subjects who discontinue IP 
treatment before completion of the DB phase will continue to be followed per protocol and, at a 
minimum, subjects will be encouraged to maintain daily seizure eDiary entries until the DB 
phase is completed.   
3.3. 
Sites and Regions 
This multicenter study is to be conducted globally, with approximately 11 sites planned to 
participate.   
3.4. 
Discussion of Study Design, Including the Choice of Control Group 
Treatment will be based on doses that have been shown to be safe in multiple studies with 
normal volunteers and children with epilepsy.  In this study, subjects will be randomized to 
receive either oral suspension GNX or PBO (1:1 ratio within each biomarker stratum), prescribed 
in increments of 15 mg/kg/day up to 63 mg/kg/day (maximum 1800 mg/day).  Full details of 
GNX dosing is provided in Section 6.2.3. 
The DB phase will be followed by an OL phase in which all subjects will receive GNX up to an 
additional 3 years or more, providing long-term safety and tolerability data on GNX.  
Ganaxolone subjects will continue GNX treatment and PBO subjects will titrate onto GNX.  To 
maintain the study blind, GNX subjects will enter into a 4-week blinded titration phase by 
increasing PBO doses in addition to maintaining GNX.  Subjects who received PBO oral 
suspension in the 17-week DB phase will enter a 4-week, GNX titration period in the OL phase 
of the study.  Administration of GNX adjunctive therapy to background AEDs provides 
standard-of-care therapy in addition to any benefit that IP might provide. 
Any subject not tolerating the next dose level can be maintained at the lower dose for additional 
days before advancing to next dose.  If the next dose level is still not tolerated, the subject can 
drop back to the last tolerated dose.  A minimum oral suspension dose of 33 mg/kg/day or 900 
mg/day is generally required following the DB escalation period, unless a lower dose is agreed to 
with the sponsor due to tolerability issues such as somnolence. 
Dose changes including alternative dosing paradigm (e.g., lower dose during the daytime and 
higher dose in the evening) should be discussed with the sponsor/CRO medical monitor prior to 
making the change or within 48 hours of making the change. Of note, the sponsor defers the final 
decision to adjust IP to the treating clinician; dose changes may not exceed the maximum daily 
dose defined by the protocol. For any subject who is unable to be maintained at the minimum 
dose, the investigator should contact the sponsor to discuss continued investigational product 
dosing. Subjects who discontinue IP should undergo a 2-week taper period, unless otherwise 
medically indicated.  Subjects who discontinue IP treatment before the completion of the DB 
phase will continue to be followed per protocol and, at a minimum, subjects will be encouraged 
to maintain daily seizure eDiary entries until the DB phase is completed.  These subjects should 
also return to the site after the taper for safety follow-up post-taper assessments.   


 
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4. 
STUDY POPULATION 
Each subject’s parent/LAR must participate in the informed consent process and provide written 
informed consent (and subject assent) before any procedures specified in the protocol are 
performed.   
4.1. 
Inclusion Criteria 
The subject will not be considered eligible for the study without meeting all the criteria below. 
1. Molecular confirmation of a pathogenic or likely pathogenic PCDH19 variant.  Genetic 
mutations will be confirmed by the sponsor’s chosen central laboratory.   
2. Female subjects aged 1 through 17 years, inclusive. 
3. Subject/parent or LAR willing to give written informed consent/assent, after being 
properly informed of the nature and risks of the study and prior to engaging in any 
study-related procedures. 
4. Failure to control seizures despite appropriate trial of 2 or more anti-seizure mediations at 
therapeutic doses. 
5. Have at least 12 countable/witnessed primary seizures over an 84-day (12 week) period 
prior to the screening visit (pre-baseline screening). The primary seizure types are 
defined as countable focal seizures that include progressive hypotonia and impaired 
awareness or any countable focal or generalized seizure with a clear motor component. 
Focal and generalized nonmotor seizures and myoclonic seizures do not count as the 
primary seizure types. 
6. Subject must be approved to participate by sponsor or its designee (eg, Epilepsy 
Consortium) after review of medical history, genetic testing, seizure classification video 
(if available), and historical seizure calendars. 
7. Ketogenic diets and modified Atkins diets should be unchanged for 3 months prior to 
screening and must remain stable throughout baseline and the DB phase. 
8. Subjects with surgically implanted VNS will be allowed to enter the study provided that 
all of the following conditions are met: 
 The VNS has been in place for ≥ 1 year prior to the screening visit. 
 The settings must have remained constant for 3 months prior to the screening visit 
and remain constant throughout baseline and the DB phase. 
 The battery is expected to last for the duration of baseline and the DB phase. 
9. Parent/caregiver is able and willing to maintain an accurate and complete daily electronic 
seizure diary for the duration of the study. 
10. Able and willing to take IP (suspension) with food 3 × daily.  Ganaxolone must be 
administered with food. 
11. Sexually active female of childbearing potential must be using a medically acceptable 
method of birth control and have a negative quantitative serum β-human chorionic 
growth hormone (β-HCG) test collected at the initial screening visit.  Childbearing 


 
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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 prior to the screening visit, surgical sterilization, or adequate barrier 
methods (eg, diaphragm or condom 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 (eg, a spermicidal cream) is acceptable.  In subjects 
who are not sexually active, abstinence is an acceptable form. 
4.2. 
Exclusion Criteria 
1. Previous exposure to GNX. 
2. Pregnant or breastfeeding. 
3. Subjects with >8 consecutive weeks (56 consecutive days) of primary seizure freedom 
during the 12-week pre-baseline screening period. 
4. Subjects with Subjects with ≤ 3 primary seizures during the 12-week baseline period.    
5. Concurrent use of strong inducers or inhibitors of CYP3A4/5/7 is not permitted.  A list of 
CYP3A4/5/7 inhibitors and inducers is included in Section 12.1.  Any strong inhibitor or 
inducer of CYP3A4/5/7 must be discontinued at least 28 days before 
Baseline/Randomization Visit.  This does not include approved AEDs. 
6. Subjects with a positive result on tetrahydrocannabinol (THC) or non-approved 
cannabidiol (CBD) test (via plasma drug screen). Tetrahydrocannabinol and/or non-
approved CBD will be allowed in the OL phase.    
7. Chronic use of oral steroid medications, ketoconazole (except for topical formulations), 
St.  John’s Wort, or other IPs is not permitted (Section 12.1). Intermittent (<5 consecutive 
days/month or 10 cumulative days per month) use of corticosteroids as a rescue 
medication for breakthrough seizures may be allowed after sponsor approval. 
8. Changes in any chronic AED medications (i.e., changes in dose or starting a new chronic 
AED) within the last month prior to the screening visit (Visit 1) and during the 12 week 
baseline period (i.e., between Visit 1 and Visit 2).  Changes in rescue AED medications 
to treat acute breakthrough seizures may be permitted with Sponsor’s approval. Changes 
in other (i.e., non-AED) chronic medications may be permitted with Sponsor’s approval. 
9. Have an active CNS infection, demyelinating disease, degenerative neurological disease, 
or CNS disease deemed progressive as evaluated by brain imaging (magnetic resonance 
imaging [MRI]).   
10. Have any disease or condition (medical or surgical; other than PCDH19-related epilepsy) 
at the screening visit that might compromise the hematologic, cardiovascular, pulmonary, 
renal, gastrointestinal, or hepatic systems; or other conditions that might interfere with 
the absorption, distribution, metabolism, or excretion of the IP, or would place the subject 
at increased risk.  
11. An aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase [SGOT]) 
or alanine aminotransferase (ALT/serum glutamic pyruvic transaminase [SGPT]) > 3 × 
the upper limit of normal (ULN) at screening and if applicable, confirmed by a repeat 
test. If the subject has another reason to be excluded, repeated liver enzymes are not 
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12. Total bilirubin levels > 1.5 × ULN at screening and if applicable, confirmed by a repeat 
test.  In cases of documented, stable medical condition (i.e., Gilbert’s Syndrome) 
resulting in levels of total bilirubin > ULN, the medical monitor can determine if a 
protocol exception can be made. 
13.  Subjects with significant renal insufficiency, estimated glomerular filtration rate 
(eGFR) < 30 mL/min (calculated using the Cockcroft-Gault formula or Pediatric GFR 
calculator or Bedside Schwartz), will be excluded from study entry or will be 
discontinued if the criterion is met post baseline. 
14. Have been exposed to any other investigational drug within 30 days or fewer than 5 
half-lives prior to the screening visit. 
15. Unwillingness to withhold grapefruit, Seville oranges, star fruit, or grapefruit containing 
products from diet 14 days prior to 1st dose and for the duration of the study 
16. Unwillingness to withhold alcohol throughout the entire clinical trial. 
17. 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. 
18. Known sensitivity or allergy to any component in the IP(s), progesterone or other related 
steroid compounds. 
4.3. 
Restrictions  
Subjects must abstain from the use of alcohol and from consuming grapefruit, Seville oranges, 
star fruit, or grapefruit containing products from diet at least 14 days prior to the 1st dose and for 
the duration of the study.  Excluded medications are described in Section 5.4. 
4.4. 
Reproductive Potential 
4.4.1. 
Contraception 
Sexually active females of childbearing potential should be using a medically acceptable form of 
birth control.  Females of childbearing potential must be advised to use medically acceptable 
birth control throughout the study period and for 30 days after the last dose of IP.  If hormonal 
contraceptives are used, they should be administered per the package insert.   
Females of childbearing potential who are not currently sexually active, but who become 
sexually active during the period of the study and 30 days after the last dose of IP must agree to 
use acceptable contraception, as defined below: 
 Premenarchal and either Tanner stage 1 or < 9 years or age, or 
 Surgically sterile (having undergone 1 of the following surgical acts:  hysterectomy, bilateral 
tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) and at least 8 weeks’ post-
sterilization, or 
 Females of childbearing potential must have a negative serum pregnancy test prior to taking 
the first dose of IP and must agree to abstain from sexual activity that could result in 
pregnancy or agree to use a medically acceptable method of birth control. 


 
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 Abstinence is an acceptable method of birth control only if this is in line with the preferred 
and usual lifestyle of the subject.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception.  
 Medically acceptable methods of birth control include: 
a. Intrauterine device plus condoms 
b. Double-barrier methods (eg, condoms and diaphragm with spermicidal gel or 
foam) 
c. Hormonal contraceptives (oral, patch, injectable, or vaginal ring), stabilized for at 
least 1 month prior to screening visit, plus condoms.  Note:  If a subject becomes 
sexually active during the study, she should use 1 of the other acceptable methods 
noted above in addition to the hormonal contraceptive until it has been stabilized 
for 30 days prior to screening visit.   
4.5. 
Discontinuation of Subjects 
A subject may withdraw — or their parent/LAR may withdraw the subject — from the study at 
any time for any reason without prejudice to their future medical care by the physician or at the 
hospital.  The PI or sponsor may withdraw the subject at any time (eg, in the interest of subject 
safety).  The PI is encouraged to discuss withdrawal of a subject from IP with the medical 
monitor when possible. 
Subjects who discontinue IP treatment before the completion of the DB phase will continue to be 
followed per protocol and, at a minimum, subjects will be encouraged to maintain daily seizure 
eDiary entries until the DB phase is completed.  These subjects should also return to the site after 
the taper for safety follow-up post taper assessments (Section 7.2.7).   
If the IP is discontinued at any time, subjects should follow the 2-week taper schedule, unless 
otherwise medically indicated (Section 7.2.6).  If the subject discontinues during the OL phase, 
evaluations listed for the Taper Visit are to be performed as completely as possible.  Whenever 
possible, all subjects who discontinue should also undergo the protocol-specified Safety Follow-
up Post-Taper visit (Section 7.2.7).  Comments (spontaneous or elicited) or complaints made by 
the subject must be recorded in the source documents.  The reason for termination, date of 
stopping IP, and total amount of IP taken must be recorded in the electronic case report form 
(eCRF) and source documents.  Discontinuation of IP due to AEs must also be reflected on the 
AE eCRF page. 
4.5.1. 
Subject Withdrawal Criteria 
All subjects or her parent/LAR reserve the right to withdraw from the clinical study at any time, 
as stated in the informed consent/assent form.  The PI may discontinue subjects from the clinical 
study for any of the following reasons: 
 Subject is found to have entered the study in violation of the protocol; 
 Subject requires the use of a disallowed concomitant medication; 
 Subject’s condition changes after entering the clinical investigation so that the subject no 
longer meets the inclusion criteria or develops any of the exclusion criteria; 


 
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 Subject or parent/LAR withdraws consent or assent to participate in the study; 
 Subject is noncompliant with the procedures set forth in the protocol; 
 Subject experiences an AE/SAE that warrants withdrawal from the study; 
 It is the PI’s opinion that it is not in the subject’s best interest to continue in the study; 
 Subject has an AST or ALT increase > 3 × upper limit of normal (ULN) during the study.  
NOTE:  If this occurs, the subject should be followed with weekly laboratory repeat testing 
and continue in the study if levels are trending down.  Discontinuation of treatment should be 
considered if levels do not decline to under 3 x ULN and if presented with the appearance of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%) and if there are no initial findings of cholestasis (elevated serum ALP) or 
other reason can be found to explain the combination of increased ALT or AST and total 
bilirubin, such as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug 
capable of causing the observed injury; or 
 Subject has a total bilirubin increase to 1.5 x ULN or more during study.  NOTE:  if this 
occurs, the subject should be followed with weekly laboratory repeat testing and continue in 
the study if levels are trending down.  Discontinuation of treatment should be considered if 
levels do not decline to under 1.5 x ULN within the time period that is considered reasonably 
safe per PIs’ judgment.  Laboratory, medical, or clinical finding for which clinical 
intervention should take precedence over study participation. 
Decisions to discontinue the study will be made at each participating site by the PI.  If feasible, 
the reason for discontinuation should be discussed with the sponsor’s medical monitor prior to 
subject discontinuation.  Subjects who discontinue IP during the DB phase will continue to 
record daily seizure frequency at minimum until the completion of the DB phase. 
If a subject must be abruptly discontinued from the investigational product (e.g., severe rash), 
careful attention should be paid for the possibility of withdrawal symptoms such as increase in 
seizure number or severity.   Consideration should be made by the investigator for providing 
another GABAA receptor modulator medication for 1-2 weeks such as clobazam to mitigate the 
potential risk of withdrawal from a positive modulator of GABAA receptors.   
4.5.2. 
Reasons for Early Discontinuation 
The reason for early discontinuation must be determined by the PI and recorded in the subject’s 
source documents and on the eCRF.  If a subject is withdrawn for more than 1 reason, each 
reason should be documented in the source document and the most clinically relevant reason 
should be entered on the eCRF.   
Reasons for early termination include but are not limited to the following: 
 Adverse event in which the character, severity or frequency is new in comparison to the 
subject’s existing risk profile with the exception of somnolence and seizures.   
 An Adverse Event that is associated with non-reversible target organ dysfunction, with the 
associated laboratory abnormalities as defined in exclusion criteria 11, 12 or 13.  An 
allowance may be made for continued treatment if the abnormality is not medically 


 
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significant (non-life-threatening or does not require ongoing treatment that could be life-
threatening)   
 A laboratory abnormality or vital sign change that is irreversible and considered medically 
significant, associated with use of the investigational product 
 Protocol violation/protocol deviation 
 Withdrawal by subject or parent/LAR 
 Lost to follow-up 
 Lack of efficacy 
 Death 
 Physician decision 
 Other (must be specified in the subject source document and eCRF) 
 Pregnancy 
4.5.3. 
Subjects Lost to Follow-up Prior to Last Scheduled Visit 
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact).  At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgment of receipt request) asking that she 
return to the site for final safety evaluations and return any unused IP.  If contact is made but the 
subject refuses or is unable to return to the site for the final Safety Follow-up Post-Taper visit 
(Section 7.2.7), it should be documented in the eCRF. 
4.6. 
Subject Numbering 
During the screening visit and after consent is obtained, each subject will be assigned a unique 
6-digit subject number by the IWRS.  The subject number will consist of a 3-digit clinical 
investigational site number assigned by the sponsor, followed by a 3-digit subject number 
(eg, 001) assigned by the IWRS.  This subject number will also serve as the screening number.  
A separate randomization number will be assigned once the subject is randomized, but the 
randomization number will not be used to track the subject.  The unique 6-digit subject number 
will serve as the subject number and be used to track the subject throughout the study.  Each 
randomized subject’s number will correspond with a treatment (active or PBO) as determined by 
the randomization schedule.   
The clinical site is responsible for maintaining a current log of subject number assignments and 
bottle numbers of the IP administered to each subject.  The unique subject number is required to 
be entered on all clinical investigation documentation (eCRFs, labeling of clinical materials and 
samples containers, drug accountability logs, etc.).   
 
 


 
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5. 
EXCLUDED, PRIOR, AND CONCOMITANT MEDICATIONS 
The study physician should assess all concomitant medications at every visit, and at the 
screening visit in particular to ensure that the subject is not taking excluded medications.   
5.1. 
Prior Medications 
Prior medications include all treatment, including but not limited to herbal treatments, vitamins, 
surgical implants (such as VNS), and prescribed medications received within 30 days (or PK 
equivalent of 5 half-lives, whichever is longer) of the date prior to screening.  Prior treatment 
information, if available, must be recorded on the appropriate eCRF page. 
5.2. 
Concomitant Medications 
Concomitant medications refer to all treatment taken between the date of the first dose of IP and 
the date of the last dose of IP.  Concomitant treatment information must be recorded on the 
appropriate eCRF page.  Concomitant as needed (PRN) topical and intranasal steroids for 
dermatologic reactions and allergic rhinitis are allowed and do not warrant exclusion from study.  
If the subject is currently taking an excluded medication at the time of the screening visit, then 
the subject must undergo a washout period equivalent to 5 half-lives of the drug before they may 
enter the prospective 12-week baseline period. 
Concomitant medications, other than AEDs, may be reduced or discontinued at the discretion of 
the investigator if medically warranted. 
5.2.1. 
Concomitant Antiepileptic (AED) Medications 
Concomitant AED regimens must have been stable for at least 1 month prior to the screening 
visit and must remain stable from screening to the end of the DB phase. Ketogenic diets and 
modified Atkins diets should be unchanged for 3 months prior to the screening visit and must 
remain stable throughout baseline and the DB phase. 
Subjects with surgically implanted VNS will be allowed to enter the study provided that all of 
the following conditions are met: 
 The VNS has been in place for ≥ 1 year prior to the screening visit. 
 The settings must have remained constant for 3 months prior to the screening visit and 
remain constant throughout baseline and the DB phase. 
 The battery is expected to last for the duration of baseline and the DB phase. 
Concomitant AEDs may be reduced or discontinued at the discretion of the investigator if 
medically warranted. 
5.3. 
Rescue Medications 
The use of rescue medication is allowed on an occasional basis and as medically needed.  The 
type, dose, date, and frequency will be recorded. 


 
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5.4. 
Excluded Medications 
Excluded medications include oral steroid medications, other IPs, ketoconazole and other 
investigational drugs or devices.  Use of St.  John’s Wort and concurrent use of strong inducers 
or inhibitors of CYP3A4/5/7 is not permitted.  A list of CYP3A4/5/7 inhibitors and inducers is 
included in Section 12.1.  Any strong inhibitor or inducer of CYP3A4/5/7 must be discontinued 
at least 28 days before Baseline/Randomization Visit; note that this does not apply to approved 
AED medications. 
Products containing tetrahydrocannabinol (THC) or non-approved CBD are excluded in the DB 
phase of the study but allowed in the OL phase.  THC or non-approved CBD should be washed 
out for at least 2 weeks before screening.  Subjects with a positive result on THC or non-
approved cannabidiol CBD test (via plasma drug screen) can be retested, via plasma, after 2 
weeks.  
Note that if a subject is taking marketed Epidiolex (may go by another name in countries outside 
the United States) then the parent/caregiver will have to provide evidence of an active 
prescription or confirmation from prescriber. 
Use of any herbal product or nutritional supplement must be reviewed and approved by Marinus 
Medical Monitor.  
 


 
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6. 
INVESTIGATIONAL PRODUCT 
Both GNX and PBO will be packaged in high-density polyethylene (HDPE) bottles with a child 
resistant closure. 
GNX will be supplied at a concentration of 50 mg/mL (GNX equivalent) in 120 mL bottles, 
containing 110 mL GNX.  A PBO suspension, which is identical in taste and appearance, will be 
supplied at an equal volume. 
All IP will be labeled according to regional regulatory requirements.  At minimum, labels will 
contain the study number; a blinded bottle number; contents including quantity; dose and form; 
route of administration; storage conditions; instructions for IP administration; caution that this 
compound is an investigative drug intended for clinical trial use only; warning to keep out of 
reach of children; and the identity of manufacturer and sponsor.  For those regions that require it, 
a blinded lot number and an expiry date will also be listed. 
All IP will be stored at the research pharmacy prior to dispensing, or in a locked cabinet 
accessible only to members of the investigative research team after the completion of each study 
visit.  Study medication should be stored at room temperature 15°C to 25°C (59°F to 77°F). 
6.1. 
Identity of Investigational Product 
6.1.1. 
Ganaxolone 
Manufacturer:   Catalent Pharma Solutions, Somerset, NJ 08873 USA 
Vehicle:   The suspension contains GNX (50 mg/mL), hydroxypropyl methylcellulose, polyvinyl 
alcohol, sodium lauryl sulfate, simethicone, methylparaben, propylparaben, sodium benzoate, 
citric acid, and sodium citrate at pH 3.8 to 4.2, and is sweetened with sucralose and flavored with 
artificial cherry.   
Strength:   50 mg/mL suspension; 110 mL in 120 mL high-density polyethylene bottles 
6.1.2. 
Placebo 
Manufacturer:   Catalent Pharma Solutions, Somerset, NJ 08873 USA 
Vehicle:  The PBO suspension consists of titanium dioxide, microcrystalline cellulose, sodium 
lauryl sulfate, simethicone, methylparaben, propylparaben, sodium benzoate, citric acid, sodium 
citrate and is sweetened with sucralose and flavored with artificial cherry. 
6.1.3. 
Blinding the Treatment Assignment 
The contents of each bottle will be blinded using labels with unique bottle numbers.  Only the IP 
supplier and the sponsor’s IP manager will be unblinded as to the bottle number and the contents 
of each bottle of IP. 


 
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6.2. 
Administration of Investigational Products 
6.2.1. 
Interactive Web Response System for Investigational Product Management 
For the DB phase and the titration period of the OL phase and thereafter an IWRS will be 
utilized for the following IP tasks: 
 Randomization 
 Supply management 
 Inventory management and supply ordering 
 Expiration date tracking 
 Emergency unblinding 
6.2.2. 
Allocation of Subjects to Treatment  
Subjects will be stratified into 2 groups during the Screening period as either Allo-S biomarker-
positive or Allo-S biomarker-negative. A subject will be considered biomarker-positive if her 
baseline Allo-S level is less than or equal to 2500 pg/mL.  Eligible subjects will then be 
randomly assigned at a 1:1 ratio (GNX:PBO) based on a randomization schedule at Visit 2 
(Week 0).  Only the IP supplier and the sponsor’s IP manager will be unblinded as to the 
contents of each bottle of IP.  Study staff as well as subject and caregiver will be blinded to 
treatment assignments. In addition, the biomarker group assignment will remain blinded until 
database unblinding after the study has completed. 
An IWRS will centrally randomize subjects.  The randomization schedule will be generated 
using a standard, validated method and maintained by the IWRS vendor and an unblinded 
statistician.  The PI will be instructed by the IWRS, which numbered bottle to use to dose a 
subject.  The PI and research staff will be aware of the ascending dose design of the clinical 
investigation; however, the PI, the research staff, and the subjects will be blinded with respect to 
who is receiving active drug versus PBO.   
The contents of each bottle will be blinded using labels.  The IWRS will use the randomization 
schedule to match a subject number to a bottle number.  Upon completion of baseline evaluations 
for each subject, the PI or appropriate designee will log into the IWRS to receive assigned 
bottle(s).  Complete instructions for obtaining a bottle number will be provided to the clinical 
sites prior to initiating the study.  The designated personnel at the clinical site will match the 
assigned bottle number with the correct bottle of IP and distribute the bottle to the PI or designee.   
6.2.3. 
Dosing 
6.2.3.1. 
Double-Blind Period 
Ganaxolone is to be administered in increments of 15 mg/kg/day up to 63 mg/kg/day (maximum 
1800 mg/day) given as an oral suspension with food.  Any subject not tolerating the next dose 
level can be maintained at the lower dose for additional days before advancing to next dose.  If 
the next dose level is still not tolerated, the subject can drop back to the last tolerated dose.  A 
minimum dose of 33 mg/kg/day or 900 mg/day is generally required following the DB escalation 


 
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period, unless a lower dose is agreed to with the Sponsor due to tolerability issues such as 
somnolence.  Dose changes, including alternative dosing paradigm (e.g., lower dose during the 
daytime and higher dose in the evening) should be discussed with the CRO/sponsor medical 
monitor prior to making the change or within 48 hours of making the change. Of note,  the 
sponsor defers the final decision to adjust IP to the treating study clinician; dose changes may not 
excess the maximum total daily dose defined by the protocol.  At each visit, dosing will be 
reviewed and adjusted as needed based on subject’s current weight. Dosing for subjects weighing 
≤ 28 kg and > 28 kg is described in Table 3. 
Table 3: 
Oral Suspension (50 mg/ml) Dosing for Subjects Weighing ≤ 28 kg 
and > 28 kg 
Dosinga for Subjects Weighing ≤ 28 kg (62 pounds)b 
Dose 
Total mg/kg/day 
Days 
6 mg/kg TID 
18 
1-7 
11 mg/kg TID 
33 
8-14 
16 mg/kg TID 
48 
15-21 
21 mg/kg TID 
63 
22-28 
Dosinga for Subjects Weighing > 28 kg (62 pounds)c 
Dose 
mL per Dose 
Total mg/day 
Days 
150 mg TID 
3 
450 
1-7 
300 mg TID 
6 
900 
8-14 
450 mg TID 
9 
1350 
15-21 
600 mg TID 
12 
1800 
22-28 
TID = 3 times daily. 
a  
To be administered in 3 divided doses following a meal or snack. 
b  
Subjects weighing ≤ 28 kg (62 pounds) will be dosed according to the subject’s weight in 
kilograms. 
c  
Subjects > 28 kg will be dosed on a fixed regimen in increments of 150 mg/day up to 1800 mg/day. 
 
Investigational product may be stopped immediately and without down-titration in the case of an 
emergency, although a down titration in the event of an early termination is recommended.  Dose 
de-escalation (taper) will occur in decreasing increments of 15 mg/kg/day or 450 mg/day 
approximately every 3 days over 2 weeks whenever feasible (See Section 6.2.3.3 for more 
details). Taper is not required if the subject is receiving the dose of 18 mg/kg/day or 450 mg/day 
(or lower). 
6.2.3.2. 
Open-Label Period 
Following the completion of the 17-week, DB phase, subjects randomized to PBO will transition 
to GNX, whereas subjects randomized to GNX will stay on their MTD (minimum of 33 
mg/kg/day [900 mg/day]; maximum of 63 mg/kg/day [1800 mg/day]) in a blinded fashion.   
Subjects will begin the 4-week blinded dose titration up to 63 mg/kg/day or 1800 mg/day (or 
MTD) after completing Visit 5.  To maintain the blind of the DB phase, subjects initially 
randomized to GNX will undergo a blinded titration (increasing PBO doses) for 4 weeks, while 


 
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PBO subjects will titrate up to 63 mg/kg/day GNX (1800 mg/day maximum or MTD) during the 
same time period.   
Dosing transition from DB to OL for subjects weighing ≤ 28 kg and > 28 kg is described in 
Table 4. All subjects will be dispensed 2 groups of bottles:   Bottle Group A (Maintenance) and 
Bottle Group B (Titration).  In addition to the maintenance dose from Bottle Group A, subjects 
will be instructed to take a second dose from Bottle Group B: 
 Subjects initially randomized to GNX:  Bottle Group A will contain GNX; Bottle Group 
B will contain PBO. 
 Subjects initially randomized to PBO:  Bottle Group A will contain PBO; Bottle Group B 
will contain GNX.   
Dosing from both Bottle Group A and Bottle Group B will begin at the end of Visit 5 (Week 17), 
the last visit in the DB phase, and continue until the end of the OL 4-week titration period, when 
subjects return to the site for evaluation (Visit 7, Week 21).  Subjects will have an interim safety 
visit at Visit 6 (Week 19), 2 weeks after starting the OL phase, in which they will receive a new 
set of medication bottles.   
Table 4: 
Transition from Double-Blind to Open-Label:  Dosing for Subjects ≤ 28 kg 
and Subjects > 28 kg 
Dosing for Subjects ≤ 28 kg (62 pounds) 
Titration Day 
Bottle Group A Dosea 
Bottle Group B Doseb 
1-7 
63 mg/kg/day (21 mg/kg TID) 
18 mg/kg/day (6 mg/kg TID) 
8-14 
63 mg/kg/day (21 mg/kg TID) 
33 mg/kg/day (11 mg/kg TID) 
15-21 
63 mg/kg/day (21 mg/kg TID) 
48 mg/kg/day (16 mg/kg TID) 
22-28 
63 mg/kg/day (21 mg/kg TID) 
63 mg/kg/day (21 mg/kg TID) 
Visit 6, Week 21 
One set of GNX bottles dispensed, return to dosing from a single bottle (not 2 different 
ones):  63 mg/kg/day (21 mg/kg TID) 
Dosing for Subjects > 28 kg (62 pounds) 
Titration Day 
Bottle Group A Dosea 
Bottle Group B Doseb 
1-7 
1800 mg/day; 12 mL per dose TID 
450 mg/day; 3 mL per dose TID 
8-14 
1800 mg/day; 12 mL per dose TID 
900 mg/day; 6 mL per dose TID 
15-21 
1800 mg/day; 12 mL per dose TID 
1350 mg/day; 9 mL per dose TID 
22-28 
1800 mg/day; 12 mL per dose TID 
1800 mg/day; 12 mL per dose TID 
Visit 6, Week 21 
One set of GNX bottles dispensed, return to dosing from a single bottle at a time (not 2 
different ones):  1800 mg/day; 12 mL per dose TID 
DB = double-blind, GNX = ganaxolone, TID = 3 times daily. 
a  For subjects initially randomized to GNX, Bottle Group A will contain GNX; for subjects initially 
randomized to placebo, Bottle Group A will contain placebo. 
b  For subjects initially randomized to GNX, Bottle Group B will contain placebo; for subjects initially 
randomized to placebo, Bottle Group B will contain GNX. 
Examples of dosing for subjects of different weights are provided in Section 12.3.  Dosing 
instructions for the DB dose titration, DB and OL maintenance and taper are provided in the 
Pharmacy Manual.  Dosing instructions for DB to OL transition are provided in the Pharmacy 
Manual. 


 
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6.2.3.3. 
De-escalation (Taper) Period  
Any subject who completes the study or discontinues IP treatment at any time during the study 
should undergo a 2-week drug de-escalation (taper) period.  The schedule will be dependent on 
the maintenance dose.  Typically, doses will be reduced by 15 mg/kg/day or 450 mg/day 
approximately every 3 days until the subject is completely off IP.  Subjects should then return for 
a Safety Follow-up Post-Taper visit. Taper is not required if the subject is receiving the dose of 
18 mg/kg/day or 450 mg/day (or lower).   
Table 5: 
De-Escalation of Investigational Product 
Formulation 
Dose 
Frequency 
Suspension (weighing ≤ 28 kg) 
Reduce 15mg/kg/day 
Every 3 days 
Suspension (weighing > 28 kg) 
Reduce 450 mg/day 
Every 3 days 
6.2.4. 
Dose Administration 
Investigational product will be provided as an oral suspension.  Ganaxolone must be taken 
with a meal or snack.  Note:  Grapefruit and grapefruit juice, Seville oranges, star fruit, and 
grapefruit containing products are prohibited 14 days prior to 1st dose and for the duration of the 
study 
Ganaxolone oral suspension will be administered through an oral dosing syringe administered 
by parents/caregivers 3 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 12 hours.  A 
missed dose of IP may be taken up to 4 hours before the next scheduled dose; otherwise, the 
missed dose should not be given.  Subjects and their parent or legal guardian will be informed 
about possible side effects from the IP and cautioned to avoid quick postural changes, at least 
until they know how the IP affects them.  Subjects will be advised that the IP might affect mental 
alertness.  They will also be cautioned that non-adherence to the dosing instructions (eg, 
increasing the dose or taking the IP doses too close together) could produce side effects.   
6.2.5. 
Missing a Dose 
Ganaxolone oral suspension: A missed dose of IP may be taken up to 4 hours before the next 
scheduled dose; otherwise, the missed dose should not be given. 
Parents/caregivers should be instructed that if the subject misses IP 2 days in a row or more, the 
site should be contacted to determine whether any adjustment in IP is needed. The site will 
confer with the medical monitor to devise a dosing plan.   
Parents/caregivers should be instructed to minimize the number of missed doses the subject 
experiences and be re-educated on proper dosing procedures at each visit to ensure that missed 
doses are avoided.   
Table 6: 
Missed Dose of Investigational Product 
Formulation 
Proceed to Dose 
DO NOT DOSE 
Suspension 
≥ 4 hours before next 
scheduled dose 
< 4 hours before next 
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6.3. 
Unblinding the Treatment Assignment 
If it is deemed necessary to unblind a subject’s treatment in order to provide medical 
management of an AE or to provide emergency treatment, unblinding will be conducted through 
the IWRS.  Unblinding should only occur if necessary, for the medical management of the 
subject.  The sponsor’s Medical Monitor does not have to be contacted to initiate unblinding in 
the IWRS system. Prior to unblinding or immediately following, the sponsor’s Medical Monitor 
must be contacted.  Subjects who are unblinded during the DB phase will be discontinued from 
investigational drug treatment but asked to continue seizure charting until the completion of the 
DB phase.  To initiate unblinding procedures anytime, please contact: 
SPONSOR CONTACTS:   
   
 MD, FAAP 
 
Mobile Telephone: 
(primary contact method/send text message if no 
immediate response) 
Email: 
If sponsor’s Medical Monitor cannot be reached in an emergency, the site should contact: 
 
, MD, PhD 
 Clinical Development 
Mobile Telephone:  
(primary contact method/send text message if no 
immediate response) 
Email:  
:   
 
Office Telephone:  
 
Mobile Telephone: 
Email: 
(primary contact method) 
 
Office Telephone:   
 
Mobile Telephone:  
Email:  
(primary contact method) 
6.4. 
Labeling, Packaging, Storage, and Handling 
6.4.1. 
Labeling 
Labels containing study information and bottle identification are applied to the IP container.   
All IP is labeled with a minimum of the following:  protocol number, medication identification 
number (if applicable), dosage form (including product name and quantity in pack), directions 


 
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for use, storage conditions, batch number and/or packaging reference, the statements “For 
investigational use only” and/or “Caution:  New Drug—Limited by Federal (or US) Law to 
Investigational Use” and “Keep out of reach of children,” and the sponsor’s name and address. 
Additional labels may, on a case-by-case basis, be applied to the IP in order to satisfy local or 
hospital requirements, but must not: 
 Contradict the clinical study label 
 Obscure the clinical study label 
 Identify the study subject by name, without consultation with the sponsor 
Additional labels may not be added without the sponsor’s prior full agreement. 
6.4.2. 
Packaging 
Investigational product will be supplied as an oral suspension.  The suspension formulation can 
be used for subjects regardless of weight.   
IP will be provided to the site as individual bottles containing 110 mL in 120-mL HDPE bottles 
at a concentration of 50 mg/mL.   
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor. 
6.4.3. 
Storage 
The PI has overall responsibility for ensuring that IP is stored in a secure, limited-access 
location.  Limited responsibility may be delegated to the pharmacy or member of the study team, 
but this delegation must be documented.  Investigational products are distributed by the 
pharmacy or by a nominated member of the study team.   
Investigational product should be stored at room temperature 15°C to 25°C (59°F to 77°F). 
Investigational product must be stored in accordance with labeled storage conditions.  
Temperature monitoring of the IP is required at the storage location to ensure that the IP is 
maintained within an established temperature range.  The PI is responsible for ensuring that the 
temperature is monitored throughout the duration of the study and that records are maintained; 
the temperature should be monitored continuously by an in-house system, by a mechanical 
recording device such as a calibrated chart recorder, or by manual means, such that both 
minimum and maximum thermometric values over a specific time period can be recorded and 
retrieved as required.  Such a device (i.e., certified min/max thermometer) would require manual 
resetting upon each recording.  The sponsor must be notified immediately upon discovery of any 
excursion from the established range.  Temperature excursions will require site investigation as 
to cause and remediation.  The sponsor will determine the ultimate impact of excursions on the 
IP and will provide supportive documentation as necessary.  Under no circumstances should the 
product be dispensed to subjects until the impact has been determined and the product is deemed 
appropriate for use by the sponsor. 
The sponsor should be notified immediately if there are any changes to the storage area of the IP 
that could affect the integrity of the product(s), such as fumigation of a storage room. 


 
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6.5. 
Investigational Product Accountability 
Investigators will be provided with sufficient amounts of the IP to carry out this protocol for the 
agreed number of subjects.  The PI or designee will acknowledge receipt of the IP, documenting 
shipment content and condition.  Accurate records of all IP dispensed, used, returned, and/or 
destroyed must be maintained as detailed further in this section. 
The PI has overall responsibility for administering/dispensing IP.  Where permissible, tasks may 
be delegated to a qualified designee (eg, a pharmacist) who is adequately trained in the protocol 
and who works under the direct supervision of the PI.  This delegation must be documented in 
the applicable study delegation of authority form. 
The PI or their designee (as documented by the PI in the applicable study delegation of authority 
form) will administer and/or dispense the IP only to subjects included in this study following the 
procedures set out in the study protocol.  Each subject will be given only the IP carrying her 
treatment assignment.  All administered and/or dispensed IP will be documented on the eCRFs 
and/or other IP record.  The PI is responsible for ensuring the retrieval of all IP and study 
supplies from subjects.   
The subject’s parent/caregiver must be instructed to save and bring their unused IP and 
empty/used IP packaging to the clinic and final follow-up visit or to ship it back to the site via 
secure courier.  Investigational product accountability must be assessed at the 
container/packaging level for unused IP that is contained within the original tamper-evident 
sealed container (eg, bottles) or at the individual count level for opened containers/packaging.  
The pharmacist/nominated person will record details on the IP accountability form. 
No IP stock or returned inventory from a Marinus-sponsored study may be removed from the site 
where originally shipped without prior knowledge and consent by the sponsor.  If such transfer is 
authorized by the sponsor, all applicable local, state, and national laws must be adhered to for the 
transfer. 
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records. 
At the end of the study, or as instructed by the sponsor, all unused stock, subject-returned, or 
expired IP are either to be sent to a nominated contractor on behalf of the sponsor for destruction 
or are to be destroyed by the site.  Investigational products being returned to the sponsor’s 
designated contractors or approved to be destroyed by the site counted/measured and verified 
will be reconciled by clinical site personnel and the sponsor (or designated CRO).  Shipment 
return forms, when used, will be signed prior to shipment from the site.  Returned IPs will be 
packed in a tamper-evident manner to ensure product integrity.  Shipment of all returned IP must 
comply with local, state, and national laws. 
With the written agreement of the sponsor, unused stock, subject-returned, and expired IP may 
be destroyed at the site or a local facility.  In this case, destruction records identifying what was 
destroyed, when, and how must be obtained with copies provided to the sponsor.  Destruction of 
IPs must be in accordance with local, state, and national laws. 


 
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Based on entries in the site’s drug accountability forms, it must be possible to reconcile IPs 
delivered with those used and returned.  All IPs must be accounted for and all discrepancies 
investigated and documented to the sponsor’s satisfaction. 
6.6. 
Subject Compliance 
Subject compliance will be tracked through the electronic seizure and medication diary.  
Parent/caregiver are to record daily seizure frequency and type in addition to study medication 
and non-study AED administration.  Compliance with IP treatment will be monitored by 
inspecting the electronic diary entries and returned supplies with queries as necessary.  As a 
generally accepted guideline, subjects should remain 80% compliant with diary entries. 
Parents/caregivers who fall short of this standard will be re-educated on the importance of 
adhering to daily seizure, IP and non-study AED recording and a deviation recorded.  


 
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7. 
STUDY PROCEDURES 
7.1. 
Study Assessments 
See Schedule of Assessments (Table 1 and Table 2) for details regarding scheduled assessments 
and procedures in this study.   
In the event of unforeseen circumstances, in-person study visit assessments may not be able to be 
performed. To conduct the study according to protocol while preserving patient safety, 
operational alternatives such as those listed below can be employed as long as the site’s actions 
are in compliance with the institution’s IRB/EC policies and regulations.  
 Telemedicine visits (video and/or audio communication methods) 
 In-home visits 
 Local physician visits 
 Use of local and/or off-site laboratories 
 Site-to-patient IP distribution 
7.2. 
Study Procedures (Double-Blind Phase) 
7.2.1. 
Pre-Screen/Screen/Baseline 
7.2.1.1. 
Historical Seizure Type and Frequency and/or Genetic Testing (Pre-Baseline 
Screening Visit (Visit 0)) 
Potential subjects will have already been pre-identified by the site because of confirmed or 
suspected PCDH19 genetic mutation testing as part of their standard of care epilepsy work-up.   
It is also very common that parents/caregivers/LARs of PCDH19-related epilepsy subjects 
maintain daily seizure calendars, which capture both seizure type and frequency and days when 
no seizures occur as part of their standard of care treatment regimen.  A 12-week daily historical 
seizure calendar will be reviewed at the screening visit to determine eligibility per 
inclusion/exclusion criteria.  Acceptable daily historical seizure calendars will need to denote 
seizure types, frequency, and days that no seizures occurred. 
If genetic testing is not done as Standard of Care, a pre-screen visit will be scheduled where 
informed consent/assent is obtained to complete the genetic testing. If genetic testing results are 
available per SOC, the genetic testing will be done at screening to confirm the results by the 
Sponsors designated lab.  
Procedures specific to this protocol and not otherwise considered standard of care, will not be 
performed until written informed consent (and subject assent) from the subject’s parent or legal 
guardian has been appropriately obtained.  In the event that parents/caregivers/LAR do not 
routinely maintain a daily seizure calendar or in a situation where the child’s PCDH19-related 
epilepsy diagnosis has not been confirmed with genetic testing per standard of care, written 
informed consent/assent will be obtained and the subject will be asked to return to the clinic for 
the Screening (Visit 1) after she has maintained a 12-week daily historical seizure calendar 
and/or completed genetic testing.   


 
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7.2.1.2. 
Screening Visit – Start to Baseline (Visit 1, Week –12) 
Additional procedures/assessments to be completed during the screening period may include the 
following: 
 Informed consent from parent/LAR (or subject assent) 
 Demographics and medical history 
 Historical seizure calendar review 
 Review of inclusion/exclusion criteria 
 Genetic testing to confirm pathogenic or likely pathogenic PCDH19 variant by Sponsor 
identified lab, if not done at prescreening.  
 Seizure Identification and Diagnostic Review Form (SIF/DRF) (Epilepsy Study Consortium) 
 Vital signs (to include BP, HR, RR, body temperature, weight, and height) 
 Physical, neurological, and developmental examination 
 Clinical laboratory tests (to include complete blood count [CBC] with automated differential, 
creatinine, blood urea nitrogen, and comprehensive metabolic panel) 
 Urinalysis (An attempt should be made to collect a urine sample at this screening visit.  
Otherwise, the urine sample can be collected at baseline) 
 Drug screen (plasma) 
 Serum pregnancy test for females of childbearing potential  
 Tanner staging 
 Concomitant AED review and levels if per standard of care (SOC) 
 Neurosteroid level sample draw 
 Adverse events 
 Electronic seizure and medication diary set up and review 
A screen failure is a subject for whom full informed consent/assent has been obtained and has 
failed to meet the inclusion criteria and/or met at least 1 of the exclusion criteria and has not been 
administered the IP. 
Subject rescreening is allowed as agreed by Sponsor and PI unless there is a general concern for 
subject safety or an inability for the subject to become eligible (eg, GNX allergy, sensitivity or 
exposure, non-PCDH19 and/or other ineligible epilepsy, chronic prohibited medical condition or 
treatment).  Subsequent screening should take place at least 30 days from the subject’s last visit. 
If a subject fails to qualify because of Exclusion Criteria #4 (≤ 3 primary seizures during the 
12-week baseline period), she will not be randomized. However, she can be rescreened after 
collecting another 12 or more weeks of seizure history that satisfies all eligibility criteria 
including Inclusion Criteria #5 and Exclusion Criteria #3. Each subject is allowed a maximum of 
1 rescreening visit. 
7.2.1.3. 
Baseline Visit – Randomization (Visit 2, Week 0 + 6 days) 
The following study procedures/assessments to be completed, the results received, and the 
investigator must ensure the subject meets all inclusion and exclusion criteria prior to IP 
administration. The 12 weeks between Screening and Randomization can be no less than 84 days 
and no more than 90 days. 


 
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 Review of inclusion/exclusion criteria 
 Demographics and medical history review 
 SIF/DRF (Epilepsy Study Consortium) approval 
 Vital signs (to include BP, HR, RR, body temperature, and weight) 
 Physical, neurological, and developmental follow-up examination 
 ECG 
 Clinical laboratory tests (to include CBC with automated differential, creatinine, blood urea 
nitrogen, and comprehensive metabolic panel) 
 Urinalysis (If the urine sample was not collected at screening, it must be collected at baseline 
in order to complete the study-related procedures per protocol) 
 Drug screen (plasma) 
 Serum pregnancy test for females of childbearing potential 
 Concomitant AED review and levels if per SOC 
 Adverse events 
 Seizure and medication diary review 
 CSHQ 
 BRIEF 
 ABC-C 
 EEG 
 PedsQL-FIM 
 QI-Disability 
 CGI-C (parent/caregiver/LAR identified behavioral target) 
 CGI-I (parent/caregiver/LAR and clinician) 
 Dispense IP 
7.2.2. 
Double-Blind Titration + Maintenance (3 Days, Weeks 1 to 4, 5, 9, 11, and 13) 
7.2.2.1. 
Telephone Follow-up (Day 3 ± 1 Day and Weeks 1, 2, 3, and 4 ± 3 days) 
A telephone follow-up visit will be conducted at Day 3 and Weeks 1, 2, 3, and 4 to assess the 
following: 
 Adverse events 
 Seizure and medication diary review 
7.2.2.2. 
Visit 3 (Week 5 ± 3 days) 
The following study procedures/assessments will be completed at Week 5 DB phase: 
 Vital signs (to include BP, HR, RR, body temperature, and weight) 
 Physical, neurological, and developmental examination (Visit 3, Week 5 only) 
 ECG (Visit 3, Week 5 only) 


 
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 Clinical laboratory tests (to include CBC with automated differential, creatinine, blood urea 
nitrogen, and comprehensive metabolic panel) 
 Urinalysis (Visit 3, Week 5 only) 
 Serum pregnancy test for females of childbearing potential  
 Investigational Product PK (population PK 1-5 hours post dose) 
 Concomitant AED review and levels if per SOC 
 Adverse events 
 Seizure and medication diary review 
 CGI-C (parent/caregiver/LAR identified behavioral target) 
 CGI-I (parent/caregiver/LAR and clinician) 
 Dispense IP 
7.2.2.3. 
Visit 4 (Week 9 ± 3 days) 
The following study procedures/assessments will be completed at Week 9 of the DB phase: 
 Vital signs (to include BP, HR, RR, body temperature, and weight) 
 Physical, neurological, and developmental follow-up examination (Visit 4, Week 9 only) 
 Clinical laboratory tests (to include CBC with automated differential, creatinine, blood urea 
nitrogen, and comprehensive metabolic panel) 
 Serum pregnancy test for females of childbearing potential  
 Investigational Product PK (population PK 4-8 hours post dose) 
 Concomitant AED review and levels if per SOC 
 Adverse events 
 Seizure and medication diary review 
 CGI-C (parent/caregiver/LAR identified behavioral target) 
 CGI-I (parent/caregiver/LAR and clinician) 
 Dispense IP 
7.2.2.4. 
Telephone Follow-up Visit (Weeks 11, 13 ± 3 days) 
A telephone follow-up visit will be conducted at Weeks 11 and 13 to assess the following: 
 Adverse events 
 Seizure and medication diary review 
7.2.3. 
Final Double-Blind Visit/First Open-Label Visit, Visit 5 ± 3 days (Week 17 ± 
3 days) 
The following study procedures/assessments will be completed during the final DB visit or taper 
visit or at the time of early termination: 
 Vital signs (to include BP, HR, RR, body temperature, and weight) 
 Physical, neurological, and developmental examination 
 ECG 


 
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 Clinical laboratory tests (to include CBC with automated differential, creatinine, blood urea 
nitrogen, and comprehensive metabolic panel) 
 Urinalysis 
 Serum pregnancy test for females of childbearing potential  
 Drug screen (plasma) 
 Investigational Product PK 
 Concomitant AED review and levels if per SOC 
 Neurosteroid level sample draw 
 Adverse events 
 Seizure and medication diary review 
 CSHQ 
 BRIEF 
 ABC-C 
 EEG 
 PedsQL-FIM 
 QI-Disability 
 CGI-C (parent/caregiver/LAR identified behavioral target) 
 CGI-I (parent/caregiver/LAR and clinician) 
 Dispense IP (note that this will be the last dose of study medication for the DB phase and the 
first dose of study medication for the OL phase) 
7.2.4. 
Open-Label Period Blinded Titration 
7.2.4.1. 
Telephone Follow-Up (Week 17 + 3 days ± 1 day, Weeks 18, 19 and 20 ± 3 Days) 
A telephone follow-up visit will be conducted 3 days after Visit 5 and at Weeks, 18, 19, and 20 
of the OL phase to assess the following: 
 Adverse events 
 Seizure and medication diary review 
7.2.4.2. 
Open-Label Period Blinded Titration, Visit 6 (Week 21 ± 3 days) 
The following study procedures/assessments will be completed at the OL Blinded Titration (Visit 
6) in the OL phase of the study: 
 Vital signs (to include BP, HR, RR, body temperature, and weight) 
 Physical, neurological, and developmental follow-up examination 
 ECG 
 Clinical laboratory tests (to include CBC with automated differential, creatinine, blood urea 
nitrogen, and comprehensive metabolic panel) 
 Serum pregnancy test for females of childbearing potential  
 Investigational Product PK (population PK between 1-5 hours post dose) 
 Concomitant AED review and levels if per SOC  


 
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 Adverse events 
 Seizure and medication diary review 
 Dispense IP  
7.2.5. 
Open-Label Period Maintenance (Weeks 28-68; ± 14 days window for each visit) 
7.2.5.1. 
Telephone Follow-Up (Weeks 28, 44, and 60 ± 14 Days) 
A telephone follow-up visit will be conducted between Visit 6 and Visit 7, Visit 7 and Visit 8, 
and Visit 8 and Visit 9 of the OL phase to assess the following: 
 Adverse events 
 Seizure and medication diary review 
7.2.5.2. 
Open-Label Period Maintenance, Visits 7, 8, and 9 (Weeks 36, 52 and 68 ± 14 
days) 
The following study procedures/assessments will be completed at Weeks 36, 52 and 68 and 
every 16 weeks thereafter for the duration of the OL phase: 
 Vital signs (All Visits:  to include BP, HR, RR, body temperature, and weight; Visit 7 and 8:  
to include height) 
 Physical, neurological, and developmental examination  
 ECG (Visit 8, Week 52 only) 
 Clinical laboratory tests (to include CBC with automated differential, creatinine, blood urea 
nitrogen and comprehensive metabolic panel) 
 Urinalysis (Visit 7 and Visit 8) 
 Serum pregnancy test for females of childbearing potential  
 Tanner staging (Visit 8, Week 52 only) 
 Investigational Product PK (Visit 8 only: population PK draw between 1-5 hours post dose) 
 Concomitant AED review and levels if per SOC 
 Neurosteroid level sample draw (Visit 8, Week 52 only) 
 Adverse events 
 Seizure and medication diary review 
 CSHQ (Visits 7 and 9; Weeks 36 and 68) 
 BRIEF (Visits 7 and 9; Weeks 36 and 68) 
 ABC-C (Visits 7 and 9; Weeks 36 and 68) 
 PedsQL-FIM (Visits 7 and 9; Weeks 36 and 68) 
 QI-Disability (Visits 7 and 9; Weeks 36 and 68) 
 CGI-C (parent/caregiver/LAR identified behavioral target) (Visits 7 and 9; Weeks 36 and 68) 
 CGI-I (parent/caregiver/LAR and clinician) (Visits 7 and 9; Weeks 36 and 68) 
 Dispense IP (Visits 7, 8, and 9; Weeks 36, 52, and 68) 


 
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7.2.5.3. 
Visit X - Additional Maintenance Visits in the Open-Label Period Phase  
If the subject continues in the OL phase beyond Week 68, the subject must return for a clinic 
visit every 16 weeks (± 14 days) to complete the following study procedures/assessments: 
 Vital signs (All Visits:  to include BP, HR, RR, body temperature, and weight; only height 
will be measured annually) 
 Physical, neurological, and developmental examination  
 Clinical laboratory tests (to include CBC with automated differential, creatinine, blood urea 
nitrogen, and comprehensive metabolic panel) 
 Urinalysis (annually) 
 Serum pregnancy test for females of childbearing potential  
 Tanner staging (annually) 
 ECG (annually) 
 Investigational Product PK 
 Concomitant AED review and levels if per SOC 
 Neurosteroid level sample draw (annually) 
 Adverse events 
 Seizure and medication diary review 
 CSHQ 
 BRIEF  
 ABC-C  
 PedsQL-FIM  
 QI-Disability  
 CGI-C (parent/caregiver/LAR identified behavioral target) 
 CGI-I (parent/caregiver/LAR and clinician) 
 Dispense IP 
If the subject continues in the OL phase beyond Week 68, a telephone follow-up visit will occur 
in between clinic visits (8 weeks ± 7 days after each clinic visit) to assess the following: 
 Adverse events 
 Seizure and medication diary review 
7.2.6. 
Final Open-Label Period Visit or Taper Visit (or at time of Early Termination 
±14 days) 
The following study procedures/assessments to be completed during the final OL visit or taper 
visit at the time of early termination: 
 Vital signs (to include BP, HR, RR, body temperature, weight, and height) 
 Physical, neurological, and developmental examination 
 ECG 
 Clinical laboratory tests (to include CBC with automated differential, creatinine, blood urea 
nitrogen, and comprehensive metabolic panel) 


 
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 Urinalysis 
 Serum pregnancy test for females of childbearing potential  
 Tanner staging 
 Investigational Product PK 
 Concomitant AED review and levels if SOC 
 Neurosteroid level sample draw 
 Adverse events 
 Seizure and medication diary review 
 CSHQ 
 BRIEF 
 ABC-C 
 EEG 
 PedsQL-FIM 
 QI-Disability 
 CGI-C (parent/caregiver/LAR identified behavioral target) 
 CGI-I (parent/caregiver/LAR and clinician) 
 Dispense IP 
7.2.7. 
Safety Follow-up Post Taper (2 Weeks Post Last Dose/Investigational Product 
Taper ± 3 days) 
The following study procedures/assessments to be completed during the safety follow-up 
post-taper visit: 
 Vital signs (to include BP, HR, RR, and body temperature) 
 Physical, neurological, and developmental examination 
 Clinical laboratory tests (to include CBC with automated differential, creatinine, blood urea 
nitrogen and comprehensive metabolic panel) 
 Urinalysis 
 Serum pregnancy test for females of childbearing potential  
 Investigational Product PK 
 Concomitant AED review and levels if SOC 
 Adverse events 
 Seizure and medication diary review 
7.3. 
Screening and Diagnosis 
Potential subjects will be pre-identified by the site because of confirmed or suspected PCDH19 
genetic mutation testing as part of their standard of care epilepsy work-up.  Potential subjects 
will have historical seizure diary charting 12 weeks prior to screening.  Eligible historical seizure 
diaries will need to include daily logs of seizure types and frequency and denote the absence of 
seizures on those days where no seizures occurred.   


 
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7.3.1. 
Informed Consent / Assent 
Procedures specific to this protocol and not otherwise considered standard of care, will not be 
performed until written informed consent/Assent from the subject/parent/caregiver/LAR has 
been appropriately obtained.   
7.3.2. 
Drug Screen 
A drug screen (plasma) will be performed to test for THC and non-approved CBD during the DB 
phase at Visit 1 (screening), Visit 2 (baseline/randomization), and Visit 5 (final DB/first OL 
visit).  If the screening drug test is positive at Visit 1 (screening), a confirmatory retest, via 
plasma, will be performed after 2 weeks. A drug screen may be performed at any time at 
Investigator’s discretion.  A positive drug test during the DB phase will result in early 
termination. 
7.3.3. 
Demographics and Medical History 
Demographics including age, gender, ethnicity and race will be collected. In addition to the 
genetic confirmation of pathogenic or likely pathogenic PCDH19 variant, relevant medical 
history, including but not limited to the age of seizure onset, other physical disabilities such as 
scoliosis, visual impairment, sensory problems and gastrointestinal difficulties will also be 
assessed; the subject’s developmental history will also be assessed.  Demographics and Medical 
History will be reviewed and collected at the Visit 1 (screening).  A review of the subject’s 
Medical History will be performed again at Visit 2 (baseline/randomization). 
7.3.4. 
Historical Seizure Calendar Review 
It is very common for parent/caregivers/LARs to maintain daily seizure calendars for this subject 
population, which capture both seizure type and frequency.  A 12-week historical seizure 
calendar will be reviewed at the screening visit to determine eligibility per inclusion/exclusion 
criteria.  Acceptable historical seizure calendars will need to denote both seizure type and 
frequency and days that no seizures occur. 
In the event the subject is not able to provide eligible historical seizure diary (at least 12 weeks 
prior to screening), the informed consent/assent will need to be obtained and the parent/caregiver 
will need to chart prospectively.   
7.3.5. 
Genetic Testing 
Molecular confirmation of a pathogenic or likely pathogenic PCDH19 mutation is required.  
Genetic mutations will be confirmed by the sponsor’s chosen central laboratory.  The PI must 
review the results of the genetic analysis and confirm that the causal relationship to the epilepsy 
syndrome is likely.  If the subject has a de novo PCDH19 VUS then the central assessor, PI, and 
Sponsor will review study inclusion. Some subjects may have multiple PCDH19 mutations that 
include both VUS and pathogenic variants.  In these cases, the subject is known to have a 
pathogenic variant and is eligible (does not require discussion with expert). 


 
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In the event that parents/caregivers/LAR do not have genetic testing results with a confirmed 
PCDH19-related epilepsy diagnosis per standard of care, written informed consent/assent will be 
obtained.  
Instructions for genetic testing sample collection and processing can be found in the central 
laboratory manual. 
7.3.6. 
Seizure Identification and Diagnostic Review 
Per the inclusion criteria, enrollment into the study will be based on the presence and frequency 
of all countable focal seizures that include progressive hypotonia and impaired awareness, or any 
countable focal or generalized seizure with a clear motor component.   
To standardize seizure identification and classification in the study, a SIF/DRF will be submitted 
and reviewed by the Epilepsy Study Consortium.  Approval of the SIF/DRF will be required 
prior to randomization.  In addition to this form, videos of the subject’s seizure types will also be 
reviewed to confirm proper classification provided that the parent/caregiver is able to capture 
video of these seizure types, parents/caregivers are able to provide videos to the site for upload 
onto a secure encrypted server in a manner consistent with ICH/GCP and if local IRB/EC 
regulations grants approval for collection of such videos.  Parents/caregivers must make every 
effort to capture 1 example of each of the primary seizure types that their child experiences.  
Although it is acknowledged that some seizure types (e.g., atonic/drop seizures) may be more 
difficult to capture on video, this information will provide valuable verification of this seizure 
type and the attempt should be made. 
Instructions for completion of the SIF/DRF and submission of videos can be found in the 
Investigator Site File. 
7.4. 
Efficacy Assessments 
Efficacy as determined by a reduction in seizures will be evaluated by collecting daily seizure 
type and frequency in an electronic seizure diary.   
7.4.1. 
Seizure Type and Frequency 
Parent/caregiver/LAR will record daily seizure frequency denoting seizure type and frequency in 
an electronic seizure diary (eDiary).  In rare cases when an eDiary completion is not feasible, a 
paper diary will be used to log daily seizure type and frequency.  These cases will need approval 
by the sponsor.  Primary seizure types of countable focal seizures that include progressive 
hypotonia and impaired awareness, or any countable focal or generalized seizure with a clear 
motor component, will be counted towards the primary endpoint.   
Subjects or parent/caregiver/LAR are to record administration of IP and background AEDs in the 
eDiary/seizure calendar.  Compliance with IP treatment will be assessed by inspecting the 
subjects’ eDiary/seizure calendar and returned supplies with queries as necessary. As a generally 
accepted guideline, subjects should remain 80% compliant with diary entries. Parents/caregivers 
who fall short of this standard will be re-educated on the importance of adhering to daily seizure, 
IP and non-study AED recording and a deviation recorded. 


 
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For recording of seizures in the eDiary, seizure events will be recorded either as a countable 
seizure or a series of continuous uncountable seizures.  Both of these events will be counted as 1 
seizure (equally weighted) in the efficacy analysis. 
A seizure cluster will be defined as 3 or more seizure events (either a countable or a series of 
continuous uncountable seizures), occurring within a period of time, followed by a period of at 
least 24 hours of seizure-freedom.  For example (Figure 2): 
1. If a child experiences 3 seizure events at 5:00, 5:30, and 6:00 PM on Monday, and the 
next seizure event occurs before 6:00 PM on Tuesday, the Monday and Tuesday seizure 
events are considered part of the same seizure cluster (Figure 2, Scenario 1).   
2. If a child experiences 3 seizure events at 5:00, 5:30, and 6:00 PM on Monday, and the 
next seizure event occurs at 6:00 PM or later on Tuesday, the Tuesday seizure event is 
not considered part of the same cluster (Figure 2, Scenario 2). 
Figure 2: 
Seizure Cluster Designation Examples 
 
7.4.2. 
Rescue Medication 
The type, dose, date, and frequency of rescue medication will be recorded in the eDiary and 
reviewed every visit. 
7.4.3. 
Children’s Sleep Habits Questionnaire (CSHQ) 
The Children’s Sleep Habits Questionnaire (CSHQ) is a psychological questionnaire designed to 
measure sleep behaviors in children and adolescents.  The 33-question test is filled out by the 
parent/caregiver/LAR.   
CSHQ will be assessed as follows:  in the DB phase at Visit 2 (baseline/randomization) and Visit 
5 (Week 17; also Final DB Visit/First OL Visit in OL phase); in the OL phase at Visit 7 (Week 
36) and Visit 9 (Week 68) and thereafter every 16 weeks for the duration of this phase; and at the 
Final OL Visit. 
SC:E1 ARIO 1 
Seizure Event 
Monday: S:00 PM 
Seizure Event 
Monday: S:30 PM 
Seizure Event 
Monday: 6 :00 PM 
Seizure Event 
Tuesday: < 6,:00PM 
Seizur,e Cluster -
-
--
SCENARIO 2 
Seizure Event 
Monday: S: o,o, PM 
Seizure Event 
Monday: S: 3 O PM 
Seizure Event 
Monday: 6,: 00 PM 
Seizure Event 
Tuesday: 
6,: 00 PM 


 
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7.4.4. 
Behavior Rating Inventory of Executive Function (BRIEF, Preschool Version 
BRIEF-P)  
The Behavior Rating Inventory of Executive Function (BRIEF) is an 86-item questionnaire 
designed to assess executive function behaviors in the school and home environments in 
individuals 5-18 years of age.  The preschool version (BRIEF-P) is a 63-item modified form and 
is typically utilized in individuals 2-5 years of age.  For this study, the BRIEF-P will be used for 
any subject less than 5 years of age. The questionnaire is completed by the 
parents/caregiver/LAR.   
BRIEF (BRIEF-P where appropriate) will be assessed as follows:  in the DB phase at Visit 2 
(baseline/randomization) and Visit 5 (Week 17; also Final DB Visit/First OL Visit in OL phase); 
in the OL phase at Visit 7 (Week 36) and Visit 9 (Week 68) and thereafter every 16 weeks for 
the duration of this phase; and at the Final OL Visit. 
7.4.5. 
Aberrant Behavior Checklist – Community (ABC-C) 
The ABC-C is a questionnaire designed to assess problematic behavior at home, in educational 
and work setting, and in residential and community-based facilities. 
The ABC-C will be assessed as follows:  in the DB phase at Visit 2 (baseline/randomization) and 
Visit 5 (Week 17; also Final DB Visit/First OL Visit in OL phase); in the OL phase at Visit 7 
(Week 36) and Visit 9 (Week 68) and thereafter every 16 weeks for the duration of this phase; 
and at the Final OL Visit. 


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7.6. 
Safety Assessments 
Safety will be evaluated by collecting the assessments detailed in the sections below.   
Baseline is defined as the last non-missing value obtained before the first DB treatment.  If any 
of the baseline safety assessments are outside of normal limits, and the investigator feels is 
medically significant, the subject may not be randomized. Assessments performed at multiple 
post-baseline time points will be summarized at each time point for which they are scheduled, 
but the listings will also include any assessments performed at unscheduled time points. 
7.6.1. 
Adverse Events 
Details regarding AEs and SAEs are provided in Section 8.   
7.6.2. 
Vital Signs 
Vital signs including HR (bpm), RR (breaths/minute), body temperature (C/F), BP (mmHg), and 
weight will be collected at every clinic visit starting with Visit 1 other than the Safety Follow-Up 
Visit.  Height will be collected at Visit 1 (screening) (during DB phase) and during the OL phase 
at Visit 7 (Week 36), at Visit 8 (Week 52), annually thereafter (except for the Safety Follow-up 
Visit), and at the Final OL Visit.   
7.6.3. 
Physical/Neurological/Developmental Examinations 
The full physical examination will include the following systems: 
 General appearance 
 Head (eyes, ears, nose and throat) 
 Cardiovascular 
 Respiratory 
 Gastrointestinal 
 Genitourinary 
 Musculoskeletal 
 Endocrine/Metabolic 
 Hematologic/lymphatic 
 Skin 
 Other systems as appropriate 
The full neurological examination will include: 
 Cranial nerves 
 Motor exam 
 Sensory exam 


 
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 Reflexes 
 Coordination/Cerebellar 
The full developmental examination will include: 
 Speech/language 
 Makes identifiable sounds for specific objects/people 
 Repeats sounds 
 Single words 
 Multiple words 
 Makes a sentence 
 Replies to question in an identifiable sound, single word, multiple word, sentence 
 Other abilities 
 Motor 
 Sits with support 
 Sits independently 
 Crawls 
 Stands with support 
 Stands independently  
 Takes steps with assistance 
 Walks independently 
 Other abilities 
 Social 
 Smiles appropriately to situation 
 Makes eye contact 
Follow up physical, neurological, and developmental examinations are abbreviated examinations 
that ask whether there have been clinically significant changes or new abnormalities in the 
subject’s physical, neurological, and developmental examinations since the last full examination.   
7.6.4. 
ECG 
Electrocardiograms will be performed to collect the electrical activity of the heart throughout the 
study to monitor safety.  An evaluation of normal by a physician must be obtained before the 
subject is randomized to the DB phase.   
ECGs will be performed as follows: 
 DB phase: 
- 
Visit 2 (baseline/randomization) 
- 
Visit 3 (Week 5) 
- 
Visit 5 (Week 17 = Final DB Visit/First OL phase visit) 


 
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 OL phase: 
- 
Visit 6 (Week 21) 
- 
Visit 8 (Week 52 and then yearly) 
- 
Final OL Visit 
7.6.5. 
Clinical Laboratory Tests 
Clinical laboratory tests are listed in Section 12.2 and will be collected per the schedules listed in 
Table 1 and Table 2.  If any test result is unexpectedly out of range, a repeat test can be 
performed at any time as decided by the PI to confirm the initial result. 
The following liver function and eGFR tests will be monitored throughout the study as follows.   
 If AST or ALT increases > 3 times ULN during the study, subject should be followed with 
weekly laboratory repeat testing and continue in study if levels trending down.  Subject will 
be discontinued if levels do not decline to under 3 x ULN.   
 If total bilirubin increases to 1.5 x ULN or more during study, the subject will be 
discontinued.   
 Subjects with significant renal insufficiency, eGFR < 30 mL/min (calculated using the 
Cockcroft-Gault formula), will be discontinued if the criterion is met post baseline. 
If any of the criteria above are deemed clinically significant by the PI, then the sponsor’s medical 
monitor should be contacted. 
Due to the difficulty in obtaining urine samples, urinalysis will be conducted as follows:  during 
the DB phase at Visit 1 (screening) or baseline/randomization (Visit 2), Visit 3, and at Week 17 
(Visit 5; also Final DB Visit/First OL Visit in OL phase); in the OL phase at Visit 7 (Week 36), 
Visit 8 (Week 52) and annually thereafter, or at the Safety Follow-up Post-Taper visit if IP is 
discontinued; and at the Final OL Visit.  An attempt will be made to collect a urine sample at 
screening to perform the study-related urinalysis.  Otherwise, the urine sample for the urinalysis 
can be collected at baseline. 
7.6.6. 
Tanner Staging 
The Tanner scale (also known as the Tanner stages) is a scale of physical development in 
children, adolescents, and adults.  The scale defines physical measurements of development 
based on external primary and secondary sex characteristics.  Subjects will be evaluated and 
rated as Tanner I, Tanner II, Tanner III, Tanner IV, and Tanner V.  Tanner staging will occur 
during the DB phase at Visit 1 (screening); during the OL phase at Visit 8 (Week 52) and 
thereafter assessed annually for the duration of the subject’s participation in this phase; and at the 
Final OL Visit.   
7.6.7. 
Investigational Product PK 
Please refer to Section 7.7 for additional details regarding Pharmacokinetic Assessments.   


 
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7.6.8. 
Concomitant AED levels 
Concomitant AED levels are not mandatory but will be collected per sites’ standard of care.  If 
AED levels are considered SOC, they will be assessed as follows:  during the DB phase at Visit 
1 (screening), Visit 2 (baseline/randomization), Visit 3 (Week 5), Visit 4 (Week 9), and Visit 5 
(Week 17; also Final DB Visit/First OL Visit in OL phase); in the OL phase of the study at the 
timepoints noted in Table 1 and Table 2; at the Final OL Visit; and at the Safety Follow-Up Post-
Taper Visit.  The results, date, and time of last AED dose and date and time of AED PK sample 
will be recorded in the eCRF. 
7.6.9. 
Adverse Events 
Details regarding AEs and SAEs are provided in Section 8.   
7.7. 
Pharmacokinetic Assessments 
A population PK approach addressing the relationship between GNX PK parameters and 
individual characteristics will be implemented during the study.   
Blood sampling for PK evaluation must be performed at the protocol-scheduled times within the 
windows specified in Table 1 and Table 2.  Exact time of sample withdrawal and drug intake will 
be recorded in the electronic case report form (eCRF).  One blood sample will be obtained at the 
following visits for PK analyses: 
During the DB Phase: 
 Visit 3 (Week 5):  between 1 and 5 hours since the last investigational product dosing  
 Visit 4 (Week 9):  between 4 and 8 hours since the last investigational product dosing 
During the OL Phase: 
 Visit 6 (Week 21): between 1 and 5 hours since the last investigational product dosing 
 Visit 8 (Week 52): between 1 and 5 hours since the last investigational product dosing 
For all other PK draws, there is no specified time to draw the PK sample and can be drawn when 
convenient during the study visit for Visit 5 (Week 17), Visit 7 (Week 36), Visit 9 (Week 68), 
and every 16 weeks for the duration of the open-label phase.  
Exact time of sample withdrawal and drug intake will be recorded in the electronic case report 
form (eCRF).   


 
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8. 
ADVERSE AND SERIOUS ADVERSE EVENT ASSESSMENTS  
8.1. 
Definition of Adverse Events, Period of Observation, Recording of 
Adverse Events 
An AE is any untoward medical occurrence in a clinical investigation subject who has been 
administered a pharmaceutical product; it does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (International Conference on Harmonisation [ICH] Guidance E2A March 1995).   
All AEs are collected from the time the informed consent (and subject assent) is signed until the 
defined follow-up period.  This includes events occurring during the screening phase of the 
study, regardless of whether or not the IP has been administered.  All AEs reported after the 
initiation of IP will be considered treatment-emergent AEs.  Where possible, a diagnosis rather 
than a list of symptoms should be recorded.  If a diagnosis has not been made, then each 
symptom should be listed individually.  All AEs should be captured on the appropriate AE pages 
in the eCRF and in source documents.  In addition to untoward AEs, unexpected benefits outside 
the IP indication should also be captured on the AE eCRF page.   
All AEs must be followed to closure (the subject’s health has returned to baseline status or all 
variables have returned to normal), regardless of whether the subject is still participating in the 
study.  Closure indicates that an outcome is reached, stabilization is achieved (the PI does not 
expect any further improvement or worsening of the event), or the event is otherwise explained.  
When appropriate, medical tests and examinations are performed so that resolution of event(s) 
can be documented. 
8.1.1. 
Severity Categorization 
The severity of AEs must be recorded during the course of the event, including the start and stop 
dates for each change in severity.  An event that changes in severity should be captured as a new 
event.  Worsening of pretreatment events, after initiation of the IP, must be recorded as new AEs 
(eg, if a subject experiences mild intermittent dyspepsia prior to dosing of the IP, but the 
dyspepsia becomes severe and more frequent after the first dose of the IP has been administered, 
a new AE of severe dyspepsia [with the appropriate date of onset] is recorded on the appropriate 
eCRF page). 
The medical assessment of severity is determined by using the following definitions: 
Mild: 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual 
activities of daily living. 
Moderate: 
A type of AE that is usually alleviated with specific therapeutic intervention.  The 
event interferes with usual activities of daily living, causing discomfort, but poses 
no significant or permanent risk of harm to the research subject. 
Severe: 
A type of AE that interrupts usual activities of daily living, that significantly 
affects clinical status, or that may require intensive therapeutic intervention. 


 
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8.1.2. 
Relationship Categorization 
A physician/investigator must make the assessment of relationship between the IP and each AE.  
The PI should decide whether, in their medical judgment, there is a reasonable possibility that 
the event may have been caused by the IP.  If there is no valid reason for suggesting a 
relationship, the AE should be classified as “not related.”    If a relationship between the AE and 
the investigational product is at least reasonably possible (i.e. the relationship cannot be ruled 
out) the AE should be considered "related.” The causality assessment must be documented in the 
source document. 
The following additional guidance may be helpful: 
Term 
Relationship definition 
Related 
The temporal relationship between the event and the administration of the IP is compelling and/or 
follows a known or suspected response pattern to that product, and the event cannot be explained 
by the subject’s medical condition, other therapies, or accident. 
Not related 
The event can be readily explained by other factors, such as the subject’s underlying medical 
condition, concomitant therapy, or accident, and no plausible temporal or biologic relationship 
exists between the IP and the event. 
8.1.3. 
Outcome Categorization 
The outcome of AEs must be recorded during the course of the study on the eCRF.  Outcomes 
are as follows: 
 Fatal 
 Not recovered/not resolved 
 Recovered/resolved 
 Recovered/resolved with sequelae  
 Recovering/resolving 
 Unknown 
8.1.4. 
Symptoms of the Disease Under Study 
Symptoms of the disease under study should not be classified as AEs as long as they are within 
the normal day-to-day fluctuation or expected progression of the disease and are part of the 
efficacy data to be collected in the study; however, significant worsening of the symptoms 
should be recorded as an AE.   
8.1.5. 
Clinical Laboratory and Other Safety Evaluations 
A change in the value of a clinical laboratory, vital sign, ECG assessment can represent an AE if 
the change is clinically significant or if, during treatment with the IP, a shift of a parameter is 
observed from a normal value to an abnormal value, or there is a further worsening of an already 
abnormal value.  When evaluating such changes, the extent of deviation from the reference 
range, the duration until return to the reference range (either while continuing treatment or after 
the end of treatment with the IP), and the range of variation of the respective parameter within its 
reference range must be taken into consideration. 


 
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If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values that were not present in the pretreatment findings observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values. 
The PI should decide, based on the above criteria and the clinical condition of a subject, whether 
a change in a clinical laboratory, vital sign, or ECG parameter is clinically significant and 
therefore represents an AE. 
8.1.6. 
Pregnancy 
All pregnancies are to be reported from the time informed consent (and subject assent) is signed 
until the defined follow-up period. 
Any report of pregnancy for any study subject must be reported within 24 hours to the Marinus 
Safety Department or its delegate using the Pregnancy Report Form.  A copy of the Pregnancy 
Report Form (and any applicable follow-up reports) must also be sent to the CRO/Marinus 
medical monitor using the details specified in the emergency contact information section at the 
beginning of the protocol.  The pregnant study subject must be withdrawn from the study. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant.  It is the responsibility of the PI to obtain this information within 30 
calendar days after the initial notification and approximately 30 calendar days after delivery.   
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported as outlined in Section 8.2.2 of the protocol using the 
Marinus Clinical Study Serious Adverse Event Form.  Non-serious AEs are to be reported as per 
clinical eCRF guidelines.  Note:  An elective abortion is not considered an SAE. 
In addition to the above, if the PI determines that the pregnancy meets serious criteria, it must be 
reported as an SAE to the Marinus Safety Department or delegate as outlined in Section 8.2.2 of 
the protocol using the Marinus Clinical Study Serious Adverse Event Form.  The test date of the 
first positive serum/urine -human chorionic gonadotropin test or ultrasound result will 
determine the pregnancy onset date. 
8.1.7. 
Abuse, Misuse, Overdose, and Medication Error 
Abuse, misuse, overdose, or medication error must be reported to the sponsor per the SAE 
reporting procedure whether or not it results in an AE/SAE as described in Section 8.2.2.  Note:  
The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication errors unless these result in an SAE.   


 
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The categories below are not mutually exclusive; the event can meet more than 1 category. 
 Abuse:  Persistent or sporadic intentional intake of an IP for a nonmedical purpose (eg, to 
alter one’s state of consciousness or get high) in a manner that may be detrimental to the 
individual and/or society. 
 Misuse:  Intentional use of an IP other than as directed or indicated at any dose.  (Note:  This 
includes a situation in which the IP is not used as directed at the dose prescribed by the 
protocol.) 
 Overdose:  Intentional or unintentional intake of a dose of an IP exceeding a prespecified 
total daily dose of the product.   
 Medication error:  An error made in prescribing, dispensing, administering, and/or use of an 
IP.  Medication errors are reportable to the sponsor only as defined below. 
 Cases of subjects missing doses of the IP are not considered reportable. 
 Applicable only for the IP under investigation. 
 The administration and/or use of an expired IP should be considered as a reportable 
medication error. 
 All IP provided to pediatric subjects should be supervised by the parent/caregiver/LAR. 
Lapses in supervision should be reported. 
8.2. 
Serious Adverse Event Procedures 
8.2.1. 
Reference Safety Information 
The reference for safety information for this study is the GNX Investigator’s Brochure, which 
the sponsor has provided under separate cover to all PIs. 
8.2.2. 
Reporting Procedures 
All initial and follow-up SAE reports must be reported by the PI to the Marinus Safety 
Department or its delegate and the CRO/Marinus medical monitor within 24 hours of the first 
awareness of the event.  Note:  The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors unless they result in an SAE.   
The PI must complete, sign, and date the Marinus Clinical Study Serious Adverse Event Form 
and verify the accuracy of the information recorded on the form with the corresponding source 
documents (Note:  Source documents are not to be sent unless requested) and fax or e-mail the 
form to the Marinus Safety Department or its delegate.  A copy of the Marinus Clinical Study 
Serious Adverse Event Form (and any applicable follow-up reports) must also be sent to the 
CRO/Marinus medical monitor using the details specified in the emergency contact information 
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8.2.3. 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence (whether considered to be related to IP or not) that 
at any dose: 
 Results in death 
 Is life-threatening.  Note:  The term “life-threatening” in the definition of “serious” refers to 
an event in which the subject was at risk of death at the time of the event; it does not refer to 
an event that hypothetically might have caused death if it were more severe. 
 Requires inpatient hospitalization or prolongation of existing hospitalization.  Note:  
Hospitalizations, which are the result of elective or previously scheduled surgery for 
preexisting conditions that have not worsened after initiation of treatment, should not be 
classified as SAEs.  For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, a complication resulting from a 
hospitalization for an elective or previously scheduled surgery that meets serious criteria 
must be reported as an SAE. 
 Results in persistent or significant disability or incapacity 
 Is a congenital abnormality or birth defect 
 Is an important medical event.  Note:  Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAEs when, based on 
appropriate medical judgment, they jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse.   
8.2.4. 
Serious Adverse Event Collection Time Frame 
All SAEs (regardless of relationship to study) are collected from the time the 
parent/caregiver/LAR/subject signs the informed consent/assent until the defined follow-up 
period stated and must be reported to the Marinus Safety Department and the CRO/Marinus 
medical monitor within 24 hours of the first awareness of the event.   
In addition, any SAE considered “related” to the IP and discovered by the PI at any interval after 
the study has completed must be reported to the Marinus Safety Department within 24 hours of 
the first awareness of the event. 
8.2.5. 
Serious Adverse Event Onset and Resolution Dates 
The onset date of the SAE is defined as the date the event meets serious criteria.  The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic.  In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively. 
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form (and subject assent) or leading up to the onset date of the SAE, or following the resolution 
date of the SAE, must be recorded as an AE, if appropriate. 


 
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8.2.6. 
Fatal Outcome 
Any SAE that results in the subject’s death (i.e., the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome, with the date of death recorded as the resolution 
date.  For all other events ongoing at the time of death that did not contribute to the subject’s 
death, the outcome should be considered not resolved, without a resolution date recorded. 
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another IP action was previously taken (eg, the drug was interrupted, reduced, or withdrawn), the 
action taken with the IP should be recorded as “dose not changed” or “not applicable” (if the 
subject never received the IP).  The IP action of “withdrawn” should not be selected solely as a 
result of the subject’s death.   
8.2.7. 
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The sponsor is responsible for notifying the relevant regulatory authorities in the United States 
(US) and the CRO is responsible for notifying the relevant regulatory authorities in rest of world 
of related, unexpected SAEs. 
In addition, the sponsor or the CRO is responsible for notifying active sites and central 
institutional review boards (IRBs) of all related, unexpected SAEs occurring during all 
interventional studies across the GNX program.   
The PI is responsible for notifying the local IRBs, local ethics committee, or the relevant local 
regulatory authority of all SAEs that occur at their site as required. 
8.3. 
Adverse Events of Special Interest 
8.3.1. 
Reference Safety Information 
The following represent the Adverse Events of Special Interest: 
 Rash 
 Adverse Events that would be classified under reproductive system and breast disorders 
system organ class 
 
 
 


 
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9. 
DATA MANAGEMENT AND STATISTICAL METHODS 
9.1. 
Data Collection 
The PI’s authorized site personnel must enter the information required by the protocol on the 
eCRF.  A study monitor will visit each site in accordance with the monitoring plan and review 
the eCRF data against the source data for completeness and accuracy.  Discrepancies between 
source data and data entered on the eCRF will be addressed by qualified site personnel.  When a 
data discrepancy warrants correction, the correction will be made by authorized site personnel.  
Data collection procedures will be discussed with the site at the site initiation visit and/or at the 
PI’s meeting.  Once a subject is screened, it is expected that site personnel will complete the 
eCRF entry within approximately 7 business days of the subject’s visit. 
The subject’s parent/caregiver/LAR must enter the information required by the protocol in the 
eDiary.  A study monitor will review all seizure diary entries in accordance with the monitoring 
plan for completeness and accuracy.  Discrepancies will be addressed by the subjects’ 
parent/caregiver/LAR and qualified site personnel.  When a data discrepancy warrants 
correction, the correction will be made by the subjects’ parent/caregiver/LAR and authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  Once the subject’s parent/caregiver/LAR signs informed 
consent (and subject assent), it is expected that all eDiary entries will be made daily. 
Retrospective entry of diary events (seizure and medication) can be completed by the caregiver 
up to 5 days later and proxy entry by the site is also available to the site staff (greater than 5 
days), but neither method is encouraged. 
Telephone Follow-up visits are allowed to be conducted via secure email per institutional policy 
if granted by individual sites IRB/EC. 
9.2. 
Clinical Data Management 
Data will be entered into a clinical database as specified in the CRO data management plan.  
Quality control and data validation procedures will be applied to ensure the validity and accuracy 
of the clinical database. 
Data will be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures.  Data queries requiring clarification 
will be communicated to the site for resolution.  Only authorized personnel will make corrections 
to the clinical database, and all corrections will be documented in an auditable manner. 
9.3. 
Statistical Analysis Process 
The study will be analyzed by the sponsor or its agent.  The statistical analysis plan (SAP) will 
provide the statistical methods and definitions for the analysis of the efficacy and safety data, as 
well as describe the approaches to be taken for summarizing other study information, such as 
subject disposition, demographics, and baseline characteristics; IP exposure; and prior and 
concomitant medications.  The SAP will also include a description of how missing data will be 
addressed.  To preserve the integrity of the statistical analysis and study conclusions, the SAP 
will be finalized prior to database lock. 


 
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All statistical analyses will be performed using SAS® (SAS Institute, Cary, NC 27513).  A 
summary of the statistical analyses is provided below; full, updated details are provided in a 
SAP. 
9.4. 
Data Monitoring Committee 
The emerging study data will be reviewed on a regular basis by an independent Data Monitoring 
Committee (DMC).  The mission of the DMC will be to safeguard the interests of study subjects 
and to enhance the integrity and credibility of the trial.  To enable the DMC to achieve its 
mission, the DMC will have ongoing access to efficacy and safety data and data regarding 
quality of trial conduct and will ensure the confidentiality of these data will be protected.  A 
DMC charter will provide the principles and guidelines for the DMC process. 
9.5. 
Sample Size Calculation and Power Considerations 
A total of 50 subjects (25 in each treatment group) was planned to be enrolled in the study.  
 
Note: Protocol versions 5 and 6 were implemented after enrollment was stopped early due to 
administrative reasons. The final sample size is not based on statistical considerations. Formal 
hypothesis testing will be performed based on all available sample size at the time of the study 
discontinuation. 
 
9.6. 
Study Populations 
The Randomized population comprises all subjects who are randomized to one of GNX or PBO 
treatment group. 
The Safety population comprises all randomized subjects who received at least one dose of study 
drug. 
The ITT population comprises all randomized subjects who received at least one dose of study 
drug and have at least one post-baseline efficacy assessment. 
The Per-Protocol (PP) population includes all ITT subjects without major protocol violations 
(defined prior to database lock).  There will be no PP population for the OL period of the study. 
9.7. 
General Statistical Considerations 
Source data for the summary tables and statistical analyses will be presented as subject data 
listings, which include data collected on the electronic case report forms (eCRFs) as well as any 
derived efficacy variables for all enrolled subjects. 
Except where noted, separate tables and data listings will be prepared for the DB and OL phases 
of the study.  Only events occurring before entry into the OL phase will be included in the DB 
phase outputs, and except where indicated, only baseline events and events occurring after entry 
into the OL phase will included in the OL phase outputs. 
Baseline seizure activity will be determined by prospective recording in subject’s daily seizure 
eDiaries, which are provided after signing informed consent/assent.  Within the DB phase of the 
study, determination of post-baseline seizure activity will begin on the day following the first day 


 
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of DB treatment.  Determination of post-baseline seizure activity assigned to the OL phase will 
begin on the day following the first OL treatment. 
Tables will be provided using the ITT subject population as well as within each of the biomarker-
positive and biomarker-negative strata. The within-stratum PBO group will consist of only the 
subjects within the corresponding stratum.  The tables for the DB phase will show the results for 
each DB treatment group and, where noted, combined over the groups as well.  The tables for the 
OL phase will show the results for each DB treatment group (all subjects will be receiving GNX 
in the OL phase) and combined over them.  For the efficacy endpoints, the results will be derived 
according to the randomized treatment group; for the other endpoints, they will be derived 
according to the treatment actually received. 
Baselines for non-seizure efficacy and safety assessments are defined as the last non-missing 
value of the assessment before the first dose of treatment.   
The OL phase will use the same baseline as the DB phase. 
9.8. 
Subject Disposition 
Disposition will be summarized within the DB treatment groups and overall among all subjects 
within both the DB and extension phases of the study. 
Subjects completing the DB phase of the study are those who completed the 17-week DB 
treatment phase, regardless of whether they entered the OL.  A listing of dispositions will be 
provided for all randomized subjects. 
9.9. 
Eligibility Criteria and Protocol Deviations 
The clinical team will identify deviations; these will be provided in a data listing.  A data listing 
of subjects who violate any of the inclusion/exclusion characteristics will also be provided, as 
well as a data listing of subjects with other protocol violations. 
9.10. 
Demographics and Baseline Characteristics 
Demographic data (age, gender, race, height, weight and body mass index (BMI), and ethnicity) 
and baseline characteristics (Tanner staging) collected prior to the first dose will be summarized 
using descriptive statistics. 
9.11. 
Medical History and Genetic Testing 
Medical history will be coded with the Medical Dictionary for Regulatory Activities (MedDRA) 
Terminology version 22.0.  The number and percent of subjects with clinically significant 
medical history at screening will be summarized by system organ class and preferred term (PT) 
by treatment and overall in the safety population. 
The results of the genetic testing, historical seizure information, and seizure identification and 
diagnostic review will be summarized and listed. 


 
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9.12. 
Prior and Concomitant Therapies 
Prior medications are defined as medications that started and stopped prior to the first dose of 
DB study drug.  Concomitant medications are defined as medications (other than the study drug) 
taken on or after the first dose of the DB study drug, regardless of when the medications started.   
9.13. 
Efficacy Analyses 
9.13.1. 
Double-Blind Phase 
For the analyses of seizures, the baseline phase consists of the 8- or -12 week period before the 
first day of treatment, and the DB phase starts the day following the first day of DB treatment 
and continues until the final visit for subjects who do not enter the OL, and up to the day before 
the first dose of OL treatment for those who do.    
Tests of significance between the 2 treatment groups will be performed for the primary endpoint 
with a 2-sided significance level of 0.05. 
9.13.1.1. Handling of Missing Data 
Careful educating and monitoring of the study sites will attempt to limit the amount of missing 
data to nearly zero, but despite these efforts, some missing data may still arise.   
Intermittent (random/sporadic) missing data during the 17-week double blind phase and any 
missing data during the baseline phase will be assumed missing at random and the collected data 
will be used to calculate the 28-day seizure frequencies. 
For early drug termination prior to the end of the 17-week DB phase, caregivers will be 
instructed to continue to provide daily seizure records until the end of the 17-week DB phase 
(hence further preventing missingness). 
The primary analysis will use all available data. Careful educating and monitoring of the study 
sites will attempt to limit the amount of missing data. Sensitivity analyses, with replacement of 
missing data, will be performed for the primary efficacy endpoint. 
9.13.1.2. Primary Endpoint (Seizure Control) 
The primary efficacy endpoint is the percent change in 28-day primary seizure frequency during 
the 17-week DB phase relative to the baseline. The primary seizure types are defined as 
countable focal seizures that include progressive hypotonia and impaired awareness, or any 
countable focal or generalized seizure with a clear motor component. Focal and generalized 
nonmotor seizures and myoclonic seizures do not count as the primary seizure types. 
The analyses of the primary endpoint will be performed on the sum of the individual countable 
seizures and each series of continuous uncountable seizures (each contributes 1 to the sum).   
Post-baseline 28-day seizure frequency will be calculated as the total number of seizures in the 
17-week DB treatment phase divided by the number of days with seizure data in the phase, 
multiplied by 28. Baseline 28-day seizure frequency will be calculated as the total number of 
seizures in the baseline phase divided by the number of days with seizure data in the phase, 
multiplied by 28. The difference between the GNX and placebo groups in the percent changes 
will be tested using the Wilcoxon Rank-Sum statistic.  Testing will be conducted in the following 


 
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order: 
 
The primary analysis will be conducted in the ITT Population. 
 
If nominal statistical significance is achieved in the ITT Population, the primary analysis will be 
conducted in the biomarker-positive stratum of the ITT population as a secondary endpoint. 
In addition, as an exploratory analysis, efficacy will be assessed in the biomarker-negative 
stratum and compared with the biomarker-positive result. 
 
9.13.1.3. Secondary Efficacy Endpoints 
All secondary efficacy endpoints will compare GNX and PBO during the 17-week DB treatment 
phase relative to the prospective baseline phase, unless specifically indicated otherwise.   
9.13.1.3.1. Seizure Control Endpoints 
9.13.1.3.1.1. Percent Change in Primary Seizure Frequency 
The percent change in 28-day primary seizure frequency during the 17-week DB Phase relative 
to baseline in biomarker-positive subjects.  
The same analysis methods for the primary endpoint will also be applied to this secondary 
endpoint. Please also refer to Section 9.13.1.2 for the hypothesis testing order. 
 
9.13.1.3.1.2. Percentage of Subjects Experiencing Primary Seizure Reduction  
Percentage of subjects experiencing a ≥ 50% reduction in 28-day primary seizure frequency 
compared to baseline. 
9.13.1.3.2. Behavioral/Neuropsychiatric Endpoints 
9.13.1.3.2.1. Behavior Rating Inventory of Executive Function (BRIEF, preschool version 
BRIEF-P) 
The Behavior Rating Inventory of Executive Function (BRIEF) is an 86-item questionnaire 
designed to assess executive function behaviors in the school and home environments in 
individuals 5-18 years of age.  The preschool version (BRIEF-P) is a 63-item modified form and 
is utilized in individuals 2-5 years of age.  The questionnaire is completed by the 
parents/caregiver/LAR.   
BRIEF (BRIEF-P where appropriate) will be assessed as follows:  in the DB phase at Visit 2 
(baseline/randomization) and Visit 5 (Week 17; also Final DB Visit/First OL Visit in open label 
phase); in the OL phase at Visit 7 (Week 36) and Visit 9 (Week 68) and thereafter every 16 
weeks for the duration of this phase; and at the Final OL Visit. 
9.13.1.3.2.2. Aberrant Behavior Checklist - Community (ABC-C) 
The ABC-C is a questionnaire designed to assess problematic behavior at home, in educational 
and work setting, and in residential and community-based facilities. 


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The ABC-C will be assessed as follows: in the DB phase at Visit 2 (baseline/randomization) and 
Visit 5 (Week 17; also Final DB Visit/First OL Visit in open label phase); in the OL phase at 
Visit 7 (Week 36) and Visit 9 (Week 68) and thereafter eve1y 16 weeks for the duration of this 
phase; and at the Final OL Visit. 
9.13.1.3.2.3. Children's Sleep Habit Questionnaire (CSHQ) 
The CSHQ is a psychological questionnaire designed to measure sleep behaviors in children and 
adolescents and is filled out by the parent/caregiver/LAR. An abbreviated version contains 33 
items. The first 31 items are scored as 1 = Rarely (0-1 times per week), 2 = Sometimes (2-4 
times per week), or 3 = Usually (5 - 7 times per week). Item 32 (Watching TV) and 33 (Riding 
in car) ask how sleepy the child has appeared during those activities (1 = Not sleepy, 2 = Ve1y 
sleepy, or 3 = Falls asleep). The questionnaire includes 2 other quantitative questions: 
• 
Child's usual amount of sleep each day 
• 
Number of minutes a night waking usually lasts 
The 33 items are pa1iitioned into 8 domains: 
1. Bedtime resistance (items 1, 3, 4, 5, 6, 8) 
2. Sleep onset delay (item 2) 
3. Sleep duration (items 9, 10, 11) 
4. Sleep anxiety (items 5, 7, 8, 21) 
5. Night wakings (items 16, 24, 25) 
6. Parasomnias (items 12-15, 17, 22, 23) 
7. Sleep disordered breathing (items 18, 19, 20) 
8. Daytime sleepiness (items 26-33) 
For scoring, first items 1, 2, 3, 10, 11, and 26 are reversed (4-score). The item scores are then 
summed within each domain. The domain subtotals, the total of the 33 items, and the 2 other 
quantitative questions will be summarized with descriptive statistics of the baseline and 
post-baseline values and the arithmetic changes from baseline. The usual amount of sleep each 
day will be sUllllllarized in hours. 
9.13.1.4. Exploratory Efficacy Endpoints 
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Other than the within-stratum analyses, no subgroup analyses are planned at this time. 
9.13.3. 
Sensitivity Analyses 
Two sensitivity analyses of the primaiy efficacy endpoint of change in 28-day frequency of the 
primaiy seizure types will be perfo1med: 
futennittent (random/sporadic) missing data during the 17-week DB phase and any missing data 
during the baseline phase will be assumed missing completely at random and the collected data 
will be used to calculate the 28-day seizure frequencies. For eai·ly diug te1mination prior to the 
end of the 17-week DB phase, cai·egivers will be instructed to continue to provide daily seizure 
records until the end of the 17-week DB phase (hence further preventing missingness). 
fu the first sensitivity analysis, the following imputation approach will be used for the primaiy 
outcome measure when a subject stops recording measurements pennanently (anticipated to be 
zero or minimal in occmTence) prior to the end of the 17-week DB phase: for the missing days, 
the con esponding median PBO data will be imputed (nTespective of treatinent aim ), within each 
sti·atum, as follows: 
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 Compute the median 28-day seizure frequency in the PBO arm based on all available PBO 
measurements during the 17-week DB treatment phase.  Label that ‘X’ and define ‘A’ to be 
‘X’/28, (i.e., the daily average on placebo during the 17-week during the DB phase). 
 For any days (whether they be on the PBO or GNX arm) that occur AFTER a subject has 
become lost to follow up, impute ‘A’ on that day. 
 
The second sensitivity analysis will explore the possibility that subjects who stop recording their 
seizure counts tend to have higher seizure counts than the other subjects. The imputation method 
described above will be modified to use the median of the 5 highest counts, rather than the 
median count, among the PBO subjects with data. 
9.13.4. 
Protections for Multiplicity 
To control the family-wise Type I error rate, hypothesis testing of the primary efficacy endpoint 
will be conducted sequentially in the order specified in Section 9.13.1.2.   
9.13.5. 
Open-Label Period Analyses 
All of the analyses for the DB phase, will be repeated for the OL phase with the following 
differences: 
 The results will be presented overall and also classified according to the DB treatment 
received by subjects. 
 Post-baseline seizure endpoints will be derived based on the first day of OL treatment. 
 No sensitivity analyses will be performed 
 The seizure frequencies during the titration and maintenance phases will not be analyzed. 
 The time points for the efficacy, exploratory, and quality of life endpoints will be after 19 
weeks, 51 weeks, and every 16 weeks thereafter of OL treatment relative to the prospective 
baseline phase. 
 The differences between the DB treatment groups in the percent changes from baseline of the 
28-day seizure frequencies will not be tested for statistical significance. 
 No PP analyses will be performed. 


 
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The complete list of differences will be outlined in the SAP. 
9.14. 
Safety Analyses 
All safety analyses will be performed in the Safety Population.  The results in the DB and OL 
phases will be summarized separately.  In both phases, the results will be summarized by the DB 
treatment actually received and, for the OL phase of the study, combined over the treatment 
groups.  The number and percentage of days that subjects received investigational product, the 
highest percentage of the maximum allowable daily dose (1800 mg or 63 mg/kg) that subjects 
received, and the total amount of investigational product received will be summarized. For the 
open-label phase, they will be summarized over just the open-label phase as well as over the 
entire study (combined DB and OL phases) but the classification by the double-blind treatment 
applies only for the open-label phase summary.  The summarization over the entire study will 
include the double-blind data only from subjects who were in the GNX group during the double-
blind phase, regardless of whether they entered the open-label phase, and all the subjects from 
the open-label phase. 
Adverse events will be tabulated by overall, system organ class, and Preferred Term using the 
Medical Dictionary for Regulatory Activities (MedDRA) coding system.  Incidence and 
percentage of AEs will be presented.  Additional tables, with AEs classified by severity and by 
only those related to drug as assessed by the PI will be presented.  Subset listings will be 
produced for AEs that cause withdrawal and for SAEs.  Clinical laboratory tests (hematology, 
chemistry and urinalysis), vital signs and ECGs will be summarized using descriptive statistics 
including changes from baseline.  In addition, shift tables cross-tabulating the baseline and post-
baseline low/normal/high classifications by visit will be provided for the laboratory tests.  
Physical, neurological and developmental examinations will be summarized using number and 
percentage of subjects with abnormalities. 
The Tanner scale (also known as the Tanner stages) is a scale of physical development in 
children, adolescents and adults.  The scale defines physical measurements of development based 
on external primary and secondary sex characteristics.  Subjects will be evaluated and rated as 
Tanner I, Tanner II, Tanner III, Tanner IV and Tanner V.  The Tanner scale is administered 
following the first dose, only during the OL phase of the study. 
The baseline and post-baseline values and the arithmetic changes from baseline of the 
neurosteroid levels will be summarized using descriptive statistics.   
Concomitant AED levels are not mandatory but will be collected per sites’ standard of care.  A 
subject listing, including date and time of last AED dose and date and time of AED PK sample, 
will be provided. 
Detailed analysis and complete listings will be outlined in the SAP. 
9.15. 
Pharmacokinetic Analyses 
A listing of the PK collection times will be provided, but the analyses will be described in a 
separate report (analyses details will be provided in the SAP).   
The PK population will include all subjects who have received at least 1 dose and who have had 
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between 1 and 5 hours or between 4 and 8 after the last dose during the double-blind and open 
label periods. Pharmacokinetic analyses will be limited to listing of concentrations because 
sufficient concentration-time data will not be available for noncompartmental analyses such as 
Cmax, AUC or tmax. Pharmacokinetic data from this study may be used for a Population PK 
analyses to be conducted separately from this study and reported separately. 
9.16. 
Interim Analysis 
No formal interim analysis is planned for this study. After all active subjects complete the17-
week double-blind phase, the double-blind data in the database will be locked and used to 
perform endpoint analysis. Data collected during the open label phase will be analyzed 
separately.  
The emerging study data will be reviewed on a regular basis by an independent DMC.  The 
mission of the DMC will be to safeguard the interests of study participants and to enhance the 
integrity and credibility of the trial.  To enable the DMC to achieve their mission, the DMC will 
have ongoing access to efficacy and safety data and data regarding quality of trial conduct and 
will ensure the confidentiality of these data will be preserved.  A DMC Charter will provide the 
principles and guidelines for the DMC process.  Specific details of the monitoring boundaries are 
provided in the SAP and the DMC Charter. 


 
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10. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This study is conducted in accordance with current applicable regulations, ICH, European Union 
(EU) Directive 2001/20/EC and its updates, and local ethical and legal requirements.   
The name and address of each third-party vendor (e.g., CRO) used in this study will be 
maintained in the investigators’ and sponsor’s files, as appropriate. 
10.1. 
Sponsor’s Responsibilities 
10.1.1. 
Good Clinical Practice (GCP) Compliance 
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), and EU Directive 2001/20/EC, 
as well as all applicable national and local laws and regulations. 
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, eDiaries/seizure calendars and eCRFs in accordance with current GCP and the 
respective local and (inter)national government regulations and guidelines.  Records and data 
may additionally be reviewed by auditors or by regulatory authorities.  
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study.  The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of IP for 
shipment to the site. 
10.1.2. 
Public Posting of Study Information 
The sponsor, or their designee, is responsible for posting appropriate study information on 
applicable websites such as ClinicalTrials.gov.  Information included in clinical study registries 
may include participating investigators’ names and contact information. 
10.1.3. 
Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees 
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP.  This requirement will be fulfilled within 6 months of the study 
completion date for pediatric studies and within 1 year for non-pediatric studies as per guidance.   
10.1.4. 
Study Suspension, Termination, and Completion 
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason.  
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies, and IRBs/ECs are notified as appropriate.  Additionally, the discontinuation of a 
registered clinical study that has been posted to a designated public website will be updated 
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10.2. 
Investigator’s Responsibilities 
10.2.1. 
Good Clinical Practice Compliance 
The PI must undertake to perform the study in accordance with ICH GCP Guideline E6 (1996), 
EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines. 
It is the PI’s responsibility to ensure that adequate time and appropriately trained personnel are 
available at the site prior to commitment to participate in this study.  The PI should also be able 
to estimate or demonstrate a potential for recruiting the required number of suitable subjects 
within the agreed recruitment period. 
The PI will maintain a list of appropriately qualified persons to whom the PI has delegated 
significant study-related tasks, and shall, upon request of the sponsor, provide documented 
evidence of any licenses and certifications necessary to demonstrate such qualification.  
Curriculum vitae for PIs and sub-investigators are provided to the study sponsor (or designee) 
before starting the study. 
If a potential research subject has a primary care physician, the PI should, with the subject’s 
consent, inform them of the subject’s participation in the study. 
A coordinating PI is appointed to review the final clinical study report for multicenter studies.  
Agreement with the final clinical study report is documented by the signed and dated signature 
of the PI (single-site study) or coordinating PI (multicenter study), in compliance with Directive 
2001/83/EC as amended by Directive 2003/63/EC and ICH Guidance E3 (1995).   
10.2.2. 
Protocol Adherence and Investigator Agreement 
The PI and any sub-investigators must adhere to the protocol as detailed in this document.  The 
PI is responsible for enrolling only those subjects who have met protocol eligibility criteria.  
Investigators are required to sign an investigator agreement to confirm acceptance and 
willingness to comply with the study protocol. 
If the PI suspends or terminates the study at their site, the PI will promptly inform the sponsor 
and the IRB/EC and provide them with a detailed written explanation.  The PI will also return all 
IP, containers, and other study materials to the sponsor.  Upon study completion, the PI will 
provide the sponsor, IRB/EC, and regulatory agency with final reports and summaries as 
required by international regulations. 
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, PI, or, for multicenter 
studies, the coordinating PI according to national provisions and will be documented in the 
investigator agreement. 


 
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10.2.3. 
Documentation and Retention of Records 
10.2.3.1. Electronic Case Report Forms (eCRF) 
The eCRFs are supplied by the study team and should be handled in accordance with instructions 
from the Sponsor. 
The PI is responsible for maintaining adequate and accurate medical records from which 
accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation.  eCRFs must be completed by 
the PI or designee as stated in the site delegation log. 
All data will have separate source documentation; no data will be recorded directly onto the 
eCRF. 
All data sent to the sponsor must be endorsed by the PI. 
The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan.  If the data are unclear or contradictory, queries are sent for 
corrections or verification of data. 
Incorrect entries must be crossed with a single line as to not obscure the original entry.  
Corrections must be made adjacent to the item to be altered, initialed, and dated by an authorized 
PI or designee as stated in the site delegation log.  Overwriting of this information or use of 
liquid correction fluid is not allowed. 
10.2.3.2. Electronic Diaries (eDiary) 
The eDiaries are supplied by the Sponsor designee and should be handled in accordance with 
instructions from the sponsor. In rare cases when an eDiary completion is not feasible, a paper 
diary will be used to log daily seizure type and frequency.  The Sponsor will provide the paper 
diary template which should not be modified.  
All data collected and sent to the sponsor must be endorsed by the PI. 
The CRA/study monitor will verify the contents of the eDiary data per the monitoring plan.  If 
the data are unclear or contradictory, queries are sent for corrections or verification of data. 
10.2.3.3. Recording, Access, and Retention of Source Data and Study Documents 
Original source data to be reviewed during this study will include, but are not limited to, the 
subject’s medical file, the subject’s electronic or paper seizure diaries, and original clinical 
laboratory reports.   
All key data must be recorded in the subject’s medical records. 
The PI must permit authorized representatives of the sponsor; the respective national, local, or 
foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have direct 
access to original source records relevant to this study, regardless of media. 
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) may check the eCRF 
entries against the source documents.  The consent form includes a statement by which the 
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local regulatory authorities, or the IRB/EC to have access to source data (eg, subject’s medical 
file, appointment books, original laboratory reports, EEGs, ECGs, etc.).   
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US Food and 
Drug Administration [FDA], European Medicines Agency [EMA], United Kingdom [UK] 
Medicines and Healthcare Products Regulatory Agency) or an auditor. 
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor. 
10.2.3.4. Audit/Inspection 
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the UK Medicines and Healthcare Products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site. 
10.2.3.5. Financial Disclosure 
The PI is required to disclose any financial arrangement during the study and for 1 year after, 
whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the PI received from the sponsor.  The following 
information is collected:  any significant payments from the sponsor or subsidiaries, such as a 
grant to fund ongoing research, compensation in the form of equipment, or retainer for ongoing 
consultation or honoraria; any proprietary interest in IP; and any significant equity interest in the 
sponsor or subsidiaries as defined in 21 Code of Federal Regulations 54 2(b) (1998). 
10.3. 
Ethical Considerations 
10.3.1. 
Informed Consent/Assent 
It is the responsibility of the PI to obtain written informed consent/assent from the 
subject/parent/caregiver/LAR for all study subjects prior to any study-related procedures, 
including screening assessments.   
All consent documentation must be in accordance with applicable regulations and GCP.  Each 
subject’s parent/caregiver/LAR/subject, as applicable, is requested to sign and date the subject’s 
informed consent/assent form or a certified translation, if applicable, after they have received and 
read (or been read) the written subject information and received an explanation of what the study 
involves, including but not limited to the objectives, potential benefits and risk, inconveniences, 
and the subject’s rights and responsibilities.  A copy of the informed consent documentation 
(i.e., a complete set of subject information sheets and fully executed signature pages) must be 
given to the subject’s parent/caregiver/LAR, as applicable.  This document may require 
translation into the local language.  Signed consent forms must remain in each subject’s study 
file and must be available for verification at any time. 
Site personnel should document providing instruction for and understanding by the 
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The PI provides the sponsor with a copy of the consent form that was reviewed by the IRB/EC 
and received their favorable opinion/approval.  A copy of the IRB/EC’s written favorable 
opinion/approval of these documents must be provided to the sponsor prior to the start of the 
study unless it is agreed to and documented (abiding by regulatory guidelines and national 
provisions) prior to study start that another party (ie, sponsor or coordinating PI) is responsible 
for this action.  Additionally, if the IRB/EC requires modification of the sample subject 
information and consent document provided by the sponsor, the documentation supporting this 
requirement must be provided to the sponsor. 
10.3.2. 
Institutional Review Board or Ethics Committee 
For sites outside the EU, it is the responsibility of the PI to submit this protocol, the informed 
consent document (approved by the sponsor or their designee), relevant supporting information, 
and all types of subject recruitment information to the IRB/EC for review, and all must be 
approved prior to site initiation. 
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement. 
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue. 
Investigational product supplies will not be released until the CRO has received written IRB/EC 
approval of and copies of revised documents. 
For sites outside the EU, the PI is responsible for keeping the IRB/EC informed of the progress 
of the study and of any changes made to the protocol, but in any case, at least once a year.  This 
can be done by the sponsor or PI for sites within the EU, or for multicenter studies, it can be 
done by the coordinating PI, according to national provisions.  The PI must also keep the local 
IRB/EC informed of any SAEs and significant AEs. 
10.4. 
Privacy and Confidentiality 
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with Health Insurance Portability and Accountability Act (HIPAA) of 1996.  
A site that is not a covered entity as defined by HIPAA must provide documentation of this fact 
to the CRO. 
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After the subject’s parent/caregiver/LAR have consented to take part in the study, the sponsor 
and/or its representatives review the medical records and data collected during the study.  These 
records and data may, in addition, be reviewed by others, including the following:  independent 
auditors who validate the data on behalf of the sponsor; third parties with whom the sponsor may 
develop, register, or market GNX; national or local regulatory authorities; and the IRB/EC that 
gave approval for the study to proceed.  The sponsor and/or its representatives accessing the 
records and data will take all reasonable precautions in accordance with applicable laws, 
regulations, and guidelines to maintain the confidentiality of subjects’ identities.  
 


 
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Subjects are each assigned a unique identifying number; however, their initials and date of birth 
may also be collected and used to assist the sponsor in verifying the accuracy of the data (eg, to 
confirm that laboratory results have been assigned to the correct subject).   
The results of studies—containing subjects’ unique identifying numbers, relevant medical 
records, and possibly initials and dates of birth—will be recorded.  They may be transferred to, 
and used in, other countries that may not afford the same level of protection that applies within 
the countries where this study is conducted.  The purposes of any such transfer would include to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, and to answer questions asked by regulatory or health authorities. 
10.5. 
Study Results/Publication Policy 
Marinus will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative.  Additionally, Marinus adheres to external guidelines 
(eg, Good Publication Practices 2) when forming a publication steering committee, which may 
be done for large, multicenter Phase 2 to 4 and certain other studies as determined by Marinus.  
The purpose of the publication steering committee is to act as a noncommercial body that advises 
or decides on dissemination of scientific study data in accordance with the scope of this policy. 
All publications relating to Marinus products or projects must undergo appropriate technical and 
intellectual property review, with Marinus agreement to publish prior to release of information.  
The review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study.  To the extent permitted by the 
publisher and copyright law, the PI will own (or share with other authors) the copyright on 
his/her publications.  To the extent that the PI has such sole, joint, or shared rights, the PI grants 
the sponsor a perpetual, irrevocable, royalty-free license to make and distribute copies of such 
publications. 
The term “publication” refers to any public disclosure, including original research articles, 
review articles, oral presentations, abstracts and posters at medical congresses, journal 
supplements, letters to the editor, invited lectures, opinion pieces, book chapters, electronic 
postings on medical/scientific websites, or other disclosure of the study results, in printed, 
electronic, oral, or other form. 
Subject to the terms of the paragraph below, the PI shall have the right to publish the study 
results, and any background information provided by the sponsor that is necessary to include in 
any publication of study results or necessary for other scholars to verify such study results.  
Notwithstanding the foregoing, no publication that incorporates the sponsor’s confidential 
information shall be submitted for publication without the sponsor’s prior written agreement to 
publish and shall be given to the sponsor for review at least 60 days prior to submission for 
publication.  If requested in writing by Marinus, the hospital and PI shall withhold submission of 
such publication for up to an additional 60 days to allow for filing of a patent application. 
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results.  If such a multicenter publication is not submitted to 
a journal for publication by the sponsor within an 18-month period after conclusion, 


 
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abandonment, or termination of the study at all sites, or after the sponsor confirms there shall be 
no multicenter study publication of the study results, an PI may individually publish the study 
results from the specific site in accordance with this section.  The PI must, however, 
acknowledge in the publication the limitations of the single-site data being presented. 
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards.  Participation as an investigator does not confer any rights to authorship of 
publications. 


 
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11. 
REFERENCES 
Bialer M., Johannessen SI, Levy RH, Perucca E, Tomson T, White HS.  Progress report on new 
antiepileptic drugs:  A summary of the Tenth Eilat Conference (EILAT X).  Epilepsy Res. 
2010;92(2-3):89-124. 
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; 24:134–7. 
Carter RB, Wood PL, Wieland S, Hawkinson JE, Belelli D, Lambert JJ, et al.  Characterization 
of the anticonvulsant properties of ganaxolone (CCD 1042; 3alpha-hydroxy- 3beta-methyl-
5alpha-pregnan-20-one), a selective, high-affinity, steroid modulator of the gamma-aminobutyric 
acid(A) receptor.  J Pharmacol Exp Ther.  1997;280(3):1284-95. 
Cappelletti S, Specchio N, Romina Moavero R, et al.  Cognitive development in females with 
PCDH19 gene-related epilepsy.  Epilepsy Behav.  2015;(42):36-40.  doi:  
https://doi.org/10.1016/j.yebeh.2014.10.019.  Accessed November 14, 2018. 
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 November 8, 2018. 
Depienne C., LeGuern E.  PCDH19-related infantile epileptic encephalopathy:  an unusual X-
linked inheritance disorder.  Hum Mutat.  2012; 33:627-34. 
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. 
Depienne C, Trouillard O, Bouteiller D, et al.  Mutations and deletions in PCDH19 account for 
various Familial or isolated epilepsies in females.  Hum Mutat.  2011; 32(1):  E1959–E1975. 
doi:  10.1002/humu.21373.  Accessed November 14, 2018. 
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):776–81. 
Ganaxolone Investigator’s Brochure.  Marinus Pharmaceuticals, Inc., Dated 08-Feb-2018. 
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. 
International Conference on Harmonisation (ICH) Guideline for Industry. Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting. ICH E2A: March 1995 
Kaminski RM, Livingood MR, Rogawski MA.  Allopregnanolone analogs that positively 
modulate GABA receptors protect against partial seizures induced by 6-Hz electrical stimulation 
in mice.  Epilepsia.  2004;45(7):864-67. 


 
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Kerrigan JF, Shields WD, Nelson TY, Bluestone DL, Dodson WE, Bourgeois BF, et al.  
Ganaxolone for treating intractable infantile spasms:  a multicenter, OL, add-on trial.  Epilepsy 
Res.  2000;42(2-3):133-39. 
Laxer K, Blum D, Abou-Khalil BW, Morrell MJ, Lee DA, Data JL, et al.  Assessment of 
ganaxolone's anticonvulsant activity using a randomized, DB, presurgical trial design. 
Ganaxolone Presurgical Study Group.  Epilepsia.  2000;41(19):1187-94. 
Ligsay A, Van Dijck A, Kooy RF, and Hagerman R.  Ganaxolone in Children with FXS. 
International FXS Conference San Antonio, TX 2016. 
Marini C, Mei D, Parmeggiani L, et al.  Protocadherin 19 mutations in girls with infantile-onset 
epilepsy.  Neurology.  2010; 75:646–53. 
Pieribone VA, Tsai J, Soufflet C, Rey E, Shaw K, Giller E, Dulac O.  Clinical evaluation of 
ganaxolone in pediatric and adolescent patients with refractory epilepsy.  Epilepsia. 
2007;48(10):1870-74. 
Reddy DS, Castaneda DC, O'Malley BW, Rogawski MA, Anticonvulsant activity of 
progesterone and neurosteroids in progesterone receptor knockout mice.  J Pharmacol Exp Ther. 
2004;310(1):230-39. 
Reddy DS, Rogwski MA.  Neurosteroids — Endogenous regulators of seizure susceptibility and 
role in the treatment of epilepsy (Chapter 77).  In, 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.  2012; pp. 984–1002. 
Rothmann MD, Zhang JJ, Lu L, Fleming TR (2012).  Testing in a prespecified subgroup and the 
intent-to-treat population.  Drug Info Journ 46:175-179. 
Scheffer IE, Turner SJ, Dibbens LM, et al.  Epilepsy and mental retardation limited to females:  
an under-recognized disorder.  Brain.  2008;131:918–27. 
Smith L, Singhal N, El Achkar CM, et al.  PCDH19‐related epilepsy is associated with a broad 
neurodevelopmental spectrum.  Epilepsia.  2018;(59):679-89. 
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):1251–7. 
Sperling MR, Klein P, Tsai J.  Randomized, DB, placebo-controlled phase 2 study of ganaxolone 
as add-on therapy in adults with uncontrolled partial-onset seizures.  Epilepsia.  
2017;58(4):558-64. 
Tan C, Shard C, Ranieri E, et al.  Mutations of protocadherin 19 in female epilepsy 
(PCDH19-FE) lead to allopregnanolone deficiency.  Hum Mol Genet.  2015;24(18):5250-59. 
van Harssel JJT, Weckhuysen S, van Kempen MJA, et al.  Clinical and genetic aspects of 
PCDH19-related epilepsy syndromes and the possible role of PCDH19 mutations in males with 
autism spectrum disorders.  Neurogenetics.  2013;(14):23-34. 
 


 
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12. 
APPENDICES 
12.1. 
Appendix 1:   CYP3A4/5/7 Inhibitors and Inducers 
Strong Inhibitors of CYP3Aa 
Strong Inducers of CYP3Ae 
boceprevir 
rifampinf  
clarithromycinb 
St John's wortf  
conivaptinb 
 
grapefruit juicec 
 
indinavir 
 
itraconazoleb 
 
ketoconazoleb 
 
lopinavir/ritonavirb (combination drug) 
 
mibefradild 
 
nefazodone 
 
nelfinavir 
 
posaconazole 
 
ritonavirb 
 
saquinavir 
 
telaprevir 
 
telithromycin 
 
voriconazole 
 
Note:  The list of drugs in these tables is not exhaustive.  Any questions about drugs not on this list should be 
addressed to the medical monitor of the protocol. 
a 
A strong inhibitor for CYP3A is defined as an inhibitor that increases the AUC of a substrate for CYP3A by 
≥ 5-fold. 
b 
In vivo inhibitor of P-glycoprotein. 
c 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent.  Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (eg, high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (eg, low dose, single strength). 
d 
Withdrawn from the United States market because of safety reasons. 
e 
A strong inducer for CYP3A is defined as an inducer that results in ≥ 80% decrease in the AUC of a substrate 
for CYP3A. 
f 
In vivo inducer of P-glycoprotein. 
Source:  FDA Drug Development and Drug Interactions:  Table of Substrates, Inhibitors and Inducers.  Web 
link Accessed 08 November 2018:  
http://www fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/uc
m093664.htm#inVivo 


 
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12.2. 
Appendix 2:   Clinical Laboratory Tests 
Clinical Chemistry 
Hematology 
Urinalysis 
Other 
Total Bilirubina 
Hemoglobin 
pH 
Drug Screend 
AST (SGOT)b 
Hematocrit 
Color 
ALT (SGPT)b 
Erythrocytes 
Clarity 
BUN 
Leukocytes + differential 
Specific Gravity 
Glucose 
Thrombocytes (platelet count) 
Urobilinogen 
Potassium 
Ketones 
Sodium 
Protein 
Calcium 
Glucose 
Alkaline Phosphatase 
Bilirubin 
Chloride 
Blood 
Creatinine 
Leukocyte esterase 
CO2 
Nitrite 
eGFRc 
Quantitative serum -human 
chorionic growth hormone 
(-HCG) serum pregnancy 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, BUN = blood urea nitrogen, eGFR = estimated 
glomerular filtration rate. 
a 
If total bilirubin increases to 1.5 x ULN or more during study, the subject will be discontinued. 
b 
If AST or ALT increases > 3 × ULN during the study, subject should be followed with weekly laboratory repeat 
testing and continue in study if levels trending down.  Subject will be discontinued if levels do not decline to 
under 3 x ULN. 
c 
Subjects with significant renal insufficiency, eGFR < 30 mL/min (calculated using the Cockcroft-Gault 
formula), will be discontinued if the criterion is met post baseline. 
d 
Plasma drug screen for tetrahydrocannabinol (THC) and unapproved cannabidiol (CBD). 
 
 
 
 
 


 
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12.3. 
Appendix 3:   Examples of Dosing Titration for Oral Suspension 
An example of the transition from DB to OL dosing is shown below for a 20-kg subject who was 
initially randomized to GNX during the DB phase: 
Titration Day 
Bottle Group A- Maintenance 
Treatment:  GNX 
Bottle Group B- Titration 
Treatment:  Placebo 
Days 1-7 
63 mg/kg/day (21 mg/kg TID) 
18 mg/kg/day (6 mg/kg TID) 
Morning dose 
21 mg/kg; 8.4 mL 
6 mg/kg; 2.4 mL 
Afternoon dose 
21 mg/kg; 8.4 mL 
6 mg/kg; 2.4 mL 
Evening dose 
21 mg/kg; 8.4 mL 
6 mg/kg; 2.4 mL 
Continue dosing from Group A and B as above until the end of Day 7 
Days 8-14 
63 mg/kg/day (21 mg/kg TID) 
33 mg/kg/day (13 mg/kg TID) 
Morning dose 
21 mg/kg; 8.4 mL 
11 mg//kg; 4.4 mL 
Afternoon dose 
21 mg/kg; 8.4 mL 
11 mg/kg; 4.4 mL 
Evening dose 
21 mg/kg; 8.4 mL 
11 mg/kg; 4.4 mL 
Continue dosing from Group A and B as above until end of Day 14 
Days 15-21 
63 mg/kg/day (21 mg/kg TID) 
48 mg/kg/day (16 mg/kg TID) 
Morning dose 
21 mg/kg; 8.4 mL 
16 mg/kg; 6.4 mL 
Afternoon dose 
21 mg/kg; 8.4 mL 
16 mg/kg; 6.4 mL 
Evening dose 
21 mg/kg; 8.4 mL 
16 mg/kg; 6.4 mL 
Continue dosing from Group A and B as above until the end of Day 21 
Days 22-28 
63 mg/kg/day (21 mg/kg TID) 
63 mg/kg/day (21 mg/kg TID) 
Morning dose 
21 mg/kg; 8.4 mL 
21 mg/kg; 8.4 mL 
Afternoon dose 
21 mg/kg; 8.4 mL 
21 mg/kg; 8.4 mL 
Evening dose 
21 mg/kg; 8.4 mL 
21 mg/kg; 8.4 mL 
Continue dosing from Group A and B as above until Visit 6, Week 21 
Visit 6, Week 21 
One set of GNX bottles dispensed, return to dosing from 1 bottle at a time 
Day 29 
63 mg/kg/day (21 mg/kg TID) 
Morning dose 
21 mg/kg; 8.4 mL 
Afternoon dose 
21 mg/kg; 8.4 mL 
Evening dose 
21 mg/kg; 8.4 mL 
GNX = ganaxolone, TID = 3 times daily. 
 
 
 


 
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An example of the transition from DB to OL dosing is shown below for a 20-kg subject who was 
initially randomized to PBO during the DB phase:   
Titration Day 
Bottle Group A- Maintenance 
Treatment:  Placebo 
Bottle Group B- Titration Treatment:  
GNX 
Days 1-7 
63 mg/kg/day (21 mg/kg TID) 
18 mg/kg/day (6 mg/kg TID) 
Day 1 morning dose 
21 mg/kg; 8.4 mL 
6 mg/kg; 2.4 mL 
Day 1 afternoon dose 
21 mg/kg; 8.4 mL 
6 mg/kg; 2.4 mL 
Day 1 evening dose 
21 mg/kg; 8.4 mL 
6 mg/kg; 2.4 mL 
Continue dosing from Group A and B as above until the end of Day 7 
Days 8-14 
63 mg/kg/day (21 mg/kg TID) 
33 mg/kg/day (11 mg/kg TID) 
Day 8 morning dose 
21 mg/kg; 8.4 mL 
11 mg/kg; 4.4 mL 
Day 8 afternoon dose 
21 mg/kg; 8.4 mL 
11 mg/kg; 4.4 mL 
Day 8 evening dose 
21 mg/kg; 8.4 mL 
11 mg/kg; 4.4 mL 
Continue dosing from Group A and B as above until end of Day 14 
Days 15-21 
63 mg/kg/day (21 mg/kg TID) 
48 mg/kg/day (16 mg/kg TID) 
Day 15 morning dose 
21 mg/kg; 8.4 mL 
16 mg/kg; 6.4 mL 
Day 15 afternoon dose 
21 mg/kg; 8.4 mL 
16 mg/kg; 6.4 mL 
Day 15 evening dose 
21 mg/kg; 8.4 mL 
16 mg/kg; 6.4 mL 
Continue dosing from Group A and B as above until the end of Day 21 
Days 22-28 
63 mg/kg/day (21 mg/kg TID) 
63 mg/kg/day (21 mg/kg TID) 
Day 15 morning dose 
21 mg/kg; 8.4 mL 
21 mg/kg; 8.4 mL 
Day 15 afternoon dose 
21 mg/kg; 8.4 mL 
21 mg/kg; 8.4 mL 
Day 15 evening dose 
21 mg/kg; 8.4 mL 
21 mg/kg; 8.4 mL 
Continue dosing from Group A and B as above until Visit 6, Week 21 
Visit 6, Week 21 
One set of GNX bottles dispensed, return to dosing from 1 bottle at a time 
Day 29 
63 mg/kg/day (21 mg/kg TID) 
Day 29 morning dose 
21 mg/kg; 8.4 mL 
Day 29 afternoon dose 
21 mg/kg; 8.4 mL 
Day 29 evening dose 
21 mg/kg; 8.4 mL 
GNX = ganaxolone, TID = 3 times daily. 
 
 
 


 
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An example of the transition from DB to OL dosing is shown below for a > 28-kg subject who 
was initially randomized to GNX during the DB phase:   
Titration Day 
Bottle Group A- Maintenance 
Treatment:  GNX 
Bottle Group B- Titration Treatment:  
Placebo 
Days 1-7 
1800 mg/day (600 mg TID) 
450 mg/day (150 mg TID) 
Day 1 morning dose 
600 mg; 12 mL 
150 mg; 3 mL 
Day 1 afternoon dose 
600 mg; 12 mL 
150 mg; 3 mL 
Day 1 evening dose 
600 mg; 12 mL 
150 mg; 3 mL 
Continue dosing from Group A and B as above until the end of Day 7 
Days 8-14 
1800 mg/day (600 mg TID) 
900 mg/day (300 mg TID) 
Day 8 morning dose 
600 mg; 12 mL 
300 mg; 6 mL 
Day 8 afternoon dose 
600 mg; 12 mL 
300 mg; 6 mL 
Day 8 evening dose 
600 mg; 12 mL 
300 mg; 6 mL 
Continue dosing from Group A and B as above until end of Day 14  
Days 15-21 
1800 mg/day (600 mg TID) 
1350 mg/day (450 mg TID) 
Day 15 morning dose 
600 mg; 12 mL 
450 mg; 9 mL 
Day 15 afternoon dose 
600 mg; 12 mL 
450 mg; 9 mL 
Day 15 evening dose 
600 mg; 12 mL 
450 mg; 9 mL 
Continue dosing from Group A and B as above until the end of Day 21 
Days 22-28 
1800 mg/day (600 mg TID) 
1800 mg/day (600 mg TID) 
Day 15 morning dose 
600 mg; 12 mL 
600 mg; 12 mL 
Day 15 afternoon dose 
600 mg; 12 mL 
600 mg; 12 mL 
Day 15 evening dose 
600 mg; 12 mL 
600 mg; 12 mL 
Continue dosing from Group A and B as above until Visit 6, Week 21 
Visit 6, Week 21 
One set of GNX bottles dispensed, return to dosing from 1 bottle at a time 
Day 29 
1800 mg/day (600 mg TID) 
Day 29 morning dose 
600 mg; 12 mL 
Day 29 afternoon dose 
600 mg; 12 mL 
Day 29 evening dose 
600 mg; 12 mL 
GNX = ganaxolone, TID = 3 times daily. 
 
 
 


 
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An example of the transition from DB to OL dosing is shown below for a > 28-kg subject who 
was initially randomized to PBO during the DB phase.   
Titration Day 
Bottle Group A- Maintenance 
Treatment:  Placebo 
Bottle Group B- Titration Treatment:  
GNX 
Days 1-7 
1800 mg/day (600 mg TID) 
450 mg/day (150 mg TID) 
Day 1 morning dose 
600 mg; 12 mL 
150 mg; 3 mL 
Day 1 afternoon dose 
600 mg; 12 mL 
150 mg; 3 mL 
Day 1 evening dose 
600 mg; 12 mL 
150 mg; 3 mL 
Continue dosing from Group A and B as above until the end of Day 7 
Days 8-14 
1800 mg/day (600 mg TID) 
900 mg/day (300 mg TID) 
Day 8 morning dose 
600 mg; 12 mL 
300 mg; 6 mL 
Day 8 afternoon dose 
600 mg; 12 mL 
300 mg; 6 mL 
Day 8 evening dose 
600 mg; 12 mL 
300 mg; 6 mL 
Continue dosing from Group A and B as above until end of Day 14  
Days 15-21 
1800 mg/day (600 mg TID) 
1350 mg/day (450 mg TID) 
Day 15 morning dose 
600 mg; 12 mL 
450 mg; 9 mL 
Day 15 afternoon dose 
600 mg; 12 mL 
450 mg; 9 mL 
Day 15 evening dose 
600 mg; 12 mL 
450 mg; 9 mL 
Continue dosing from Group A and B as above until the end of Day 21 
Days 22-28 
1800 mg/day (600 mg TID) 
1800 mg/day (600 mg TID) 
Day 15 morning dose 
600 mg; 12 mL 
600 mg; 12 mL 
Day 15 afternoon dose 
600 mg; 12 mL 
600 mg; 12 mL 
Day 15 evening dose 
600 mg; 12 mL 
600 mg; 12 mL 
Continue dosing from Group A and B as above until Visit 7, Week 21 
Visit 6, Week 21 
One set of GNX bottles dispensed, return to dosing from 1 bottle at a time 
Day 29 
1800 mg/day (600 mg TID) 
Day 29 morning dose 
600 mg; 12 mL 
Day 29 afternoon dose 
600 mg; 12 mL 
Day 29 evening dose 
600 mg; 12 mL 
GNX = ganaxolone, TID = 3 times daily. 
 
  

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Statistical Analysis Plan, 
Amendment 1 
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Final, Amendment 1 
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Statistical Analysis Plan 
 
 
 
 
 
Protocol No.: 1042-PCDH19-3002 
 
A double-blind, randomized, placebo-controlled trial of 
adjunctive ganaxolone treatment in female children with 
protocadherin 19 (PCDH19)-related epilepsy followed by long- 
term open-label treatment 
 
 
 
 
 
 
 
 
 
 
 
Investigational Product: 
Ganaxolone (GNX) 
Reference Product： 
Placebo 
Indication: 
PCDH19 (Protocadherin 19-related 
epilepsy) 
Phase： 
2 
Document Type： 
Statistical Analysis Plan 
Version： 
Final 
Date of Issue： 
25 January 2021 


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Statistical Analysis Plan Approval Form 
Author: 
Review: 
Approval: 
[jiiiillllll ________ _ 
-
2PhD 
Statistics 
CR Medicon Research, fuc. 
[iiil ~---------
PhD 
(dd/mm/yyyy) 
-
CR Medicon Research, fuc. 
of Biostatistics 
Marinus Phannaceuticals, fuc. 
11
oocuSigned by: 
~
10BA7D3D5C61 4FD ... 
MD, PhD 
Clinical Development 
Marinus Phannaceuticals, fuc. 
Biometi·ics 
Marinus Phannaceuticals, fuc. 
Final, Amendment 1 
Confidential 
3/ 1/ 2021 
Date (dd/mm/yyyy) 
3/ 1/ 2021 
Date 
3/ 1/ 2021 
Date (dd/mm/yyyy) 
3/ 1/ 2021 
Date (dd/mm/yyyy) 
3/ 1/ 2021 
Date (dd/mm/yyyy) 
Page 2 of54 


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Change Log 
Version No. 
Effective Date 
Reason for 
Change/Revision 
Supersedes 
Amendment 
1 
01 March 2021 
1) Revised definition of 
baseline primary seizure 
count for subjects with 28- 
day seizure count from 
prospective baseline period 
< 4 
2) Corrected hyperlinks in 
Section 7.1.7. 
Final, 25 January 
2021 


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TABLE OF CONTENTS 
ABBREVIATIONS .................................................................................................................7 
INTRODUCTION..................................................................................................... 9 
1.1 
STUDY OBJECTIVES ..................................................................................................................... 9 
1.1.1 
Primary Objective ....................................................................................... 9 
1.1.2 
Secondary Objectives .................................................................................. 9 
 
 
1.2 
STUDY ENDPOINTS ..................................................................................................................... 10 
1.2.1 
Primary Efficacy Endpoint ....................................................................... 10 
1.2.2 
Secondary Efficacy Endpoints .................................................................. 10 
1.2.2.1 
Seizure Control Endpoints: ................................................................... 10 
1.2.2.2 
Behavioral/Neuropsychiatric Endpoints ............................................... 10 
 
 
1.2.4 
Pharmacokinetic Assessments ................................................................... 12 
1.2.5 
Safety and Tolerability Endpoints ............................................................. 12 
1.2.6 
Open-Label Extension Phase Endpoints ................................................... 12 
1.3 
STUDY DESIGN ............................................................................................................................ 12 
1.3.1 
General Study Design and Plan ................................................................ 12 
1.3.2 
Sample Size and Power Considerations ................................................... 14 
STATISTICAL METHODS ................................................................................... 15 
2.1 
GENERAL CONSIDERATIONS ................................................................................................... 15 
2.1.1 
Reporting Precision .................................................................................. 16 
2.2 
DEFINITIONS OF ANALYSIS POPULATIONS (ANALYSIS SETS) .............................. 16 
2.2.1 
Randomized Population ............................................................................ 16 
2.2.2 
Intention-to-Treat Population (ITT) ......................................................... 17 
2.2.3 
Safety Population ...................................................................................... 17 
2.2.4 
Per-Protocol Population (PP) .................................................................. 17 
2.3 
TIME WINDOWS FOR ANALYSIS ................................................................................................. 17 
2.4 
POOLING OF CENTERS ............................................................................................................... 17 
2.5 
HANDLING OF MISSING DATA ........................................................................................................................... 17 
2.6 
ANALYSIS SOFTWARE............................................................................................................................. 17 
STUDY SUBJECTS ................................................................................................ 17 
3.1 
DISPOSITION OF SUBJECTS ...................................................................................................... 17 
3.2 
ELIGIBILITY CRITERIA AND PROTOCOL DEVIATIONS ........................................................ 18 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .......................... 18 
MEDICAL HISTORY AND GENETIC TESTING............................................. 18 
PRIOR AND CONCOMITANT MEDICATIONS AND THERAPIES ............. 19 
EFFICACY ANALYSES ................................................................................................ 20 


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7.1 
DOUBLE-BLIND PHASE ............................................................................................................. 20 
7.1.1 
Handling of Missing Data ......................................................................... 21 
7.1.2 
Primary Efficacy Endpoint ....................................................................... 21 
7.1.3 
Secondary Efficacy Endpoints .................................................................. 22 
7.1.3.1 
Percent Change in Primary Seizure Frequency in Biomarker Positive 
Stratum 23 
7.1.3.2 
Percentage of Subjects Experiencing Primary Seizure Reduction ........ 23 
7.1.3.3 
Behavior Rating Inventory of Executive Function (BRIEF, preschool 
version BRIEF-P) .................................................................................................. 23 
7.1.3.4 
Aberrant Behavior Checklist – Community (ABC-C) .......................... 24 
7.1.3.5 
Children’s Sleep Habit Questionnaire (CSHQ) .................................... 24 
7.1.4 
Exploratory Endpoints .............................................................................. 25 
7.1.5 
Subgroup Analyses .................................................................................... 28 
7.1.6 
Sensitivity Analyses ................................................................................... 28 
7.1.7 
Protections for Multiplicity ....................................................................... 29 
7.2 
OPEN LABEL EXTENSION ......................................................................................................... 29 
PHARMACOKINETICS ....................................................................................... 30 
SAFETY ANALYSIS ....................................................................................................... 30 
9.1 
ADVERSE EVENTS ...................................................................................................................... 30 
9.2 
CLINICAL LABORATORY PARAMETERS ................................................................................ 33 
9.3 
OTHER SAFETY ENDPOINTS .................................................................................................... 34 
9.3.1 
Vital Signs ................................................................................................. 34 
9.3.2 
Electrocardiogram (ECG) ........................................................................ 34 
9.3.3 
Physical, Neurological, and Developmental Examinations ...................... 34 
9.3.4 
Neurosteroid Levels .................................................................................. 34 
9.3.5 
Tanner Staging .......................................................................................... 34 
INTERIM ANALYSES AND DATA MONITORING COMMITTEE (DMC) . 35 
SUMMARY OF MAJOR CHANGES IN THE PLANNED ANALYSES ........... 35 
PROGRAMMING SPECIFICATIONS ............................................................... 35 


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12.1 
FORMAT OF APPENDIX TABLES/FIGURES/LISTINGS ........................................................ 35 
12.2 
SAS PROCEDURES FOR SEIZURE ANALYSES ......................................................................... 37 
REFERENCES ........................................................................................................ 38 
APPENDICES ......................................................................................................... 39 
14.1 
SCHEDULE OF ASSESSMENTS .................................................................................................. 40 
14.1.1 
Schedule of Assessments for the 17-Week, Double-Blind Phase of the 
Study: 
40 
14.1.2 
Schedule of Assessments for Open-Label Phase ....................................... 45 
14.2 
CLINICAL LABORATORY TESTS AND NORMAL RANGES ................................................. 50 
14.2.1 
Clinical Laboratory Tests ................................................................................ 50 
14.2.2 
Normal Ranges.......................................................................................... 50 
14.3 
CRITERIA FOR POTENTIALLY CLINICALLY SIGNIFICANT ABNORMAL VALUES ...... 51 
14.3.1 
Potentially Clinically Significant Abnormal Laboratory Values ................ 51 
14.3.2 
Potentially Clinically Significant ECG Criteria ....................................... 52 
14.3.3 
Potentially Clinically Significant Vital Signs Values.................................... 53 


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ABBREVIATIONS 
 
Abbreviation 
Term 
ABC-C 
Aberrant Behavior Checklist – Community 
AE 
adverse event 
AED 
anti-epilepsy drug 
Allo-S 
Allopregnanolone Sulfate 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
bpm 
beats per minute 
BMI 
body mass index 
BRIEF 
Behavior Rating Inventory of Executive Function 
BUN 
blood urea nitrogen 
CGI-C 
Clinical Global Impression of Change 
CGI-I 
Clinical Global Impression of Improvement 
cm 
centimeter 
CO2 
carbon dioxide 
CRF 
case report form 
CSHQ 
Children’s Sleep Habit Questionnaire 
D/C 
discontinuation 
DB 
double-blind 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
EEG 
electroencephalogram 
eCRF 
electronic case report form 
°C 
degrees Celsius 
FDA 
Food and Drug Administration 
GNX 
ganaxolone 
ICH 
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use 
IP 
investigational product 
ITT 
intent-to-treat 
IWRS 
Interactive Web Response System 
kg 
kilogram 
kg/m2 
kilogram per square meter 
LAR 
legally authorized representative 


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Abbreviation 
Term 
lb 
pound 
LLN 
lower limit of normal 
m 
meter 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mmHg 
millimeters mercury 
OL 
open-label 
OLE 
open-label extension 
PBO 
placebo 
PCDH19 
protocadherin 19 
PedsQL-FIM 
Pediatric Quality of Life Inventory – Family Impact 
Module 
PK 
pharmacokinetics 
PP 
per protocol 
PT 
preferred perm 
QI 
Quality of Life Inventory 
SAEs 
serious adverse events 
SAP 
statistical analysis plan 
SD 
standard deviation 
SI 
Système International 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
WHO 
World Health Organization 
wks 
weeks 


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INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze and report results for Protocol 1042- 
PCDH19-3002 (Version 6.0, Protocol Amendment 5, 20 January 2021). This statistical 
plan does not include the analyses of the pharmacokinetic and pharmacodynamic 
(exposure response analysis) data. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA) and International Conference on 
Harmonization of Technical Requirements for Registration of Pharmaceuticals for 
Human Use (ICH): Guidance on Statistical Principles in Clinical Trials.1 All work 
planned and reported for this SAP will follow international accepted guidelines published 
by the American Statistical Association2 for statistical practice. 
The following documents were also considered in preparation for writing this SAP: 
• International Conference on Harmonization (ICH) E3 Guideline: Structure and 
Content of Clinical Study Reports3 
• ICH E6 Guideline on Good Clinical Practice4 
• ICH E8 General Considerations for Clinical Trials5 
• ICH E9 Statistical Principles for Clinical Trials6 
The SAP is a supplement to the study protocol, which should be referred to for additional 
details on study design, study conduct, and other operational aspects of the study. 
1.1 STUDY OBJECTIVES 
1.1.1 Primary Objective 
• To assess the efficacy of ganaxolone (GNX) compared with placebo (PBO) as 
adjunctive therapy for the treatment of primary seizures in children with 
genetically confirmed PCDH19-related epilepsy during the 17-week double-blind 
(DB) phase. 
1.1.2 Secondary Objectives 
• To assess the effect of GNX on primary seizure rate in biomarker-positive 
subjects. 
• To assess behavioral/neuropsychiatric changes in subjects receiving GNX 
compared with subjects receiving PBO as adjunctive during the 17-week double- 
blind (DB) phase. 
• To assess the safety and tolerability of GNX compared with PBO as adjunctive 
therapy during the 17-week DB phase. 
• To assess pharmacokinetic (PK) parameters in subjects receiving GNX doses up 


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to 63 mg/kg/day (1800 mg/day maximum) throughout the study. 
• To assess the long-term efficacy of GNX when administered as adjunctive therapy 
throughout the open-label (OL) phase. 
• To assess the long-term safety and tolerability of GNX when administered as 
adjunctive therapy throughout the OL phase. 
1.1.3 Exploratory Objectives 
1.2 STUDY ENDPOINTS 
1.2.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the percent change in 28-day primary seizure frequency 
during the 17-week DB phase relative to the baseline in all subjects. The primary seizure 
types are defined as countable focal seizures that include progressive hypotonia and 
impaired awareness, or any countable focal or generalized seizure with a clear motor 
component. Focal and generalized nonmotor seizures and myoclonic seizures do not 
count as the primary seizure types. 
1.2.2 Secondary Efficacy Endpoints 
1.2.2.1 Seizure Control Endpoints: 
• The percent change in 28-day primary seizure frequency during the 17-week DB 
phase relative to baseline in biomarker positive subjects. 
• Percentage of subjects experiencing a ≥ 50% reduction in 28-day primary seizure 
frequency compared to baseline. 
1.2.2.2 Behavioral/Neuropsychiatric Endpoints 
• Behavior Rating Inventory of Executive Function (BRIEF, preschool version 
BRIEF-P) 
• Aberrant Behavior Checklist – Community (ABC-C) 


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• 
Children's Sleep Habit Questionnaire (CSHQ) 
1.2.3 
Exploratory Efficacy Endpoints 
I 
I 
I 
I 
I 
I 
I 
I 
I 
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I 
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1.2.4 Pharmacokinetic Assessments 
• Pharmacokinetic concentrations 
The samples will be drawn between 1 and 5 hours or between 4 and 8 hours after the 
last dose during the double-blind and open-label periods. 
 
1.2.5 Safety and Tolerability Endpoints 
• Vital signs: blood pressure [BP], heart rate [HR], respiratory rate [RR], body 
temperature, weight, and height. 
• Electrocardiograms (ECGs). 
• Clinical laboratory tests - hematology, chemistry, and urinalysis. 
• Physical, neurological, and developmental examinations. 
• Concomitant Anti-Epilepsy Drug (AED) levels. 
• Concomitant medications and therapies. 
• Frequency, type and severity of adverse events (AEs) 
1.2.6 Open-Label Extension Phase Endpoints 
Except for the changes in seizure frequency during the titration portion and during the 
maintenance portion, the same efficacy, exploratory, quality of life, and safety endpoints 
for the DB phase will also be used for the OL phase. Analyses of OL phase data will be 
summarized separately. 
 
1.3 STUDY DESIGN 
1.3.1 General Study Design and Plan 
This is a global, biomarker-stratified, DB, randomized, PBO-controlled trial of adjunctive 
GNX treatment of primary seizures in female children with a confirmed pathogenic or 
likely pathogenic PCDH19 mutation. The trial consists of a prospective baseline period 
of 8 to 12 weeks in duration to collect seizure data, followed by a 17-week DB treatment 
phase, which is then followed by a long-term OL phase (Figure 1). An interactive web 
response system (IWRS) will be used to randomize subjects, dispense drug, track 
treatment, and maintain the blind throughout the duration of the study. 
During the screening visit, each subject’s allopregnanolone sulfate (Allo-S) biomarker 
level will be assessed via a blood draw and subsequent analytical quantification. Each 
subject will then be assigned to 1 of 2 groups: biomarker-positive or biomarker-negative. 
A subject will be considered biomarker-positive if the baseline Allo-S level is less than or 
equal to 2500 pg/mL (Pinna Lab method or similar). A subject with a baseline Allo-S 
level greater than 2500 pg/mL will be classified as biomarker-negative. The biomarker 
group assignment will remain blinded until database unblinding. Based on the 11-subject 


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OL study, it is estimated that approximately 65% of subjects will be biomarker-positive. 
The DB phase includes 4 weeks of investigational product (IP) titration followed by 13 
weeks of dose maintenance. After meeting the eligibility criteria, approximately 25 
children aged 1 to 17 years (inclusive) with PCDH19-related epilepsy will be randomly 
assigned to receive GNX or PBO (1:1 ratio within each biomarker stratum) for 17 weeks 
in addition to their standard anti-seizure treatment. Subjects will be titrated to 63 
mg/kg/day (max 1800 mg/day) over 4 weeks and then maintained at that dose for another 
13 weeks. Subjects who are not able to tolerate 63 mg/kg/day (or 1800 mg/day 
maximum) may be maintained on a lower dose. A minimum dose of 33 mg/kg/day or 900 
mg/day is generally required following the DB escalation period, unless a lower dose is 
agreed to with the sponsor due to the tolerability such as somnolence. At each visit, 
dosing will be reviewed and adjusted as needed based on subject’s current weight. 
Subjects who discontinue IP treatment before the completion of the DB phase will 
continue to be followed per protocol and, at a minimum, subjects will be encouraged to 
maintain daily seizure eDiary entries until the DB phase is completed. These subjects will 
also return to the site 2 to 4 weeks after the taper for safety follow-up post-taper 
assessments. 
After completing the initial 17-week, DB, PBO-controlled phase, all subjects will be 
treated with GNX in the OL phase of the study. Ganaxolone subjects will continue GNX 
treatment and PBO subjects will titrate onto GNX. To maintain the blind, subjects 
initially randomized to GNX will undergo a blinded titration (increasing PBO doses) for 
4 weeks, whereas PBO subjects will titrate up to 63 mg/kg/day GNX (1800 mg/day 
maximum) during the same time period. Any subject who completes the study or 
discontinues IP treatment at any time during the study should undergo a 2-week drug de- 
escalation (taper) period and return to the site 2 weeks later for safety follow-up post- 
taper assessments. Taper is not required if the subject is receiving the dose of 18 
mg/kg/day or 450 mg/day (or lower). 


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Figure 1. Study Design 
 
 
 
Subjects will be required to complete an eDiary to determine the effect of GNX on drug- 
resistant seizures. An electronic eDiary is the standard. In rare cases when an eDiary 
completion is not feasible, a paper diary will be used. These cases will need approval by 
the sponsor. A variety of clinician- and caregiver- administered instruments will be used 
to assess the efficacy of adjunctive GNX in PCDH19, and will include the following: 
• Behavior Rating Inventory of Executive Function (BRIEF) 
• Aberrant Behavior Checklist – Community (ABC-C) 
• Children’s Sleep Habit Questionnaire (CSHQ) 
• Pediatric Quality of Life Inventory – Family Impact Module (PedsQL-FIM) 
• Quality of Life Inventory – Disability (QI-Disability) 
• Caregiver Global Impression of Change (CGI-C) – Target Behavior, Clinical 
Global Impression – Improvement [caregiver], and Clinical Global Impression – 
Improvement [clinician]. 
Safety and tolerability will be assessed by monitoring vital signs (blood pressure [BP], 
heart rate [HR], respiratory rate [RR], body temperature, weight, and height); 12-lead 
ECGs, clinical laboratory tests (hematology, chemistry, and urinalysis); physical, 
neurological, and developmental examinations; and frequency, type, and severity of AEs 
during the 17-week, DB phase and the OL phase. 
The Schedule of Assessments for the 17-week pre-randomization and DB phase and for 
the OL is presented in the Appendix 14.1. 
1.3.2 Sample Size and Power Considerations 
A total of 50 subjects (25 in each treatment group) was planned to be enrolled in the 
PCDH19 
(all-subjects) 
Screening 
Visit 
LowAJlo•S 
Basehne (12 weeks) 
Primary efficacy analyses will be conducted using rhis cohorr 
Placebo 
Placebo 
Mamtenance (13 weeks) 
Oouble-BUnd Phase 
Tlcrallon(4 
_,, 
Open-Labe Phase (S weeks 
"noldr-lOICN" 


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study. 
As indicated in Protocol Amendment 4, Version 5 (dated 30 June 2020), enrollment in the 
study was discontinued early due to administrative reasons. As a result, the final sample 
size is not based on statistical considerations. Formal hypothesis testing will be 
performed based on all available sample size at the time of the study discontinuation. 
STATISTICAL METHODS 
2.1 GENERAL CONSIDERATIONS 
In general, non-categorical variables will be summarized by number of subjects, mean, 
standard deviation (SD), median, 25th and 75th percentiles, minimum, and maximum 
values. Categorical variables will be summarized by counts and percentage of subjects in 
each category. 
Except where noted, separate tables and data listings will be prepared for the DB and OL 
phases of the study. Only events occurring before entry into the OL phase will be 
included in the DB phase outputs, and except where indicated, only baseline events and 
events occurring after entry into the OL phase will be included in the OL phase outputs. 
Tables will be provided using the intent-to-treat (ITT) subject population as well as 
within each of the biomarker positive and biomarker negative strata. The within-stratum 
placebo group will consist of only the subjects within the corresponding stratum. The 
tables for the DB phase will show the results for each DB treatment group, and, where 
noted, combined over the groups as well. The tables for the OL phase, during which all 
subjects will be receiving GNX, will show the results by assigned DB treatment group 
and for all OL subjects combined. For the efficacy endpoints, the results will be derived 
according to the randomized treatment group; for the other endpoints, data will be 
analyzed according to the treatment actually received. As such, any subject randomized to 
receive PBO but taking at least one dose of GNX will be reported in GNX group. 
Source data for the summary tables and statistical analyses will be presented as subject 
data listings, which include data collected on the electronic case report forms (eCRFs) as 
well as any derived efficacy variables for all randomized subjects. 
Baseline seizure activity will be determined by the subject’s daily seizure eDiary entries 
for the 8 or 12 week period immediately prior to Visit 2 (Day 0), depending on eligibility 
criteria in the applicable protocol version. For primary seizures only, if a subject’s 
baseline seizure count from this prospective baseline period is less than 4, the primary 
seizure count from the Historical Seizure Calendar Review CRF will be used to calculate 
a baseline 28-day seizure count. Within the DB phase of the study, determination of post- 
baseline seizure activity will begin on the day following the first day of DB treatment. 
The first day of DB treatment (Day 0) is included in neither the baseline nor DB phase 
since seizures could occur both before and after the initiation of treatment. Determination 
of post-baseline seizure activity assigned to the OL phase will begin on the day following 
the first OL treatment. 


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Baseline values for non-seizure efficacy and safety assessments are defined as the last 
non-missing value of the assessment before the first dose of treatment. 
The OL phase will use the same baseline as the DB phase. 
The study day for all assessments that are performed on or after the first day of treatment 
will be calculated as: 
Study Day = date of the assessment − date of first treatment + 1. 
For assessments performed before the first day of treatment, the study day calculation is: 
Study day = date of the assessment – date of first treatment. 
2.1.1 Reporting Precision 
Summary statistics will be presented to the degree of precision specified in Table 1, 
unless otherwise specified: 
Table 1: Reporting Precision 
 
Statistics 
Degree of Precision 
Mean, Median, Quartiles, 
Confidence limit boundaries 
One decimal place more than the raw data. 
Standard deviation 
Two decimal places more than the raw data. 
Minimum, Maximum 
The same as the raw data. 
p-value 
Rounded to 4 decimal places and therefore 
presented as 0.xxxx; p-values smaller than 
0.0001 as ‘<0.0001’; p-values greater than 
0.9999 as ‘>0.9999’. 
Percentage 
One decimal place. A percentage of 100% 
will be reported as 100%. Percentages of zero 
will be reported as 0. 
For weight and height, one decimal place will be used for summary statistics. Fractional 
numeric values will be presented with a zero to the left of the decimal point (for example, 
0.12 – 0.30). 
2.2 DEFINITIONS OF ANALYSIS POPULATIONS (ANALYSIS SETS) 
2.2.1 Randomized Population 
The randomized population comprises all subjects who are randomized to one of GNX or 
PBO treatment group. 


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2.2.2 Intention-to-Treat Population (ITT) 
The ITT population comprises all randomized subjects who received at least one dose of 
study drug and have at least one post-baseline efficacy assessment. 
 
2.2.3 Safety Population 
The Safety population comprises all randomized subjects who received at least one dose 
of study drug. 
2.2.4 Per-Protocol Population (PP) 
The PP population includes all ITT subjects without major protocol violations (defined 
prior to database lock). There will be no PP population for the OL phase of the study. 
2.3 TIME WINDOWS FOR ANALYSIS 
For by-visit safety or efficacy summaries, only scheduled visits will be analyzed. 
In the analysis of seizure diary data, entries after the date of the first dose of study drug in 
the DB phase of the study but prior to the date of the first dose of study drug in the OL 
phase will be considered DB data. For subjects participating in the OL phase, entries 
dated after the date of first dose of study drug in the OL phase, including during the OL 
titration period, will be considered OL data. 
2.4 POOLING OF CENTERS 
Data from all sites will be pooled for analysis. 
2.5 HANDLING OF MISSING DATA 
Missing data will not be replaced except as noted. Missing efficacy data will be imputed 
in a sensitivity analysis as described in Section 7.1.6. 
2.6 ANALYSIS SOFTWARE 
All summaries and statistical analyses will be generated using SAS® version 9.4 or later. 
STUDY SUBJECTS 
3.1 DISPOSITION OF SUBJECTS 
A data listing of Screening failures for the DB phase of the study will be provided. 
Disposition will be summarized within the DB treatment groups and overall among all 
subjects within both the DB and OL phases of the study. 
The summary of disposition will include the following: 
• Subjects screened (DB phase only) 
• Screen failures (DB phase only) 
• Subjects in the Safety Population 


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• Subjects in the ITT Population 
• Subjects in the PP Population 
• Subjects who entered OL phase 
• Subjects who completed the DB phase 
• Subjects who discontinued from the study before the end of the DB phase 
• Reasons for study discontinuation before the end of the DB phase 
• Subjects who discontinued study drug before the end of the DB phase 
• Reasons for study drug discontinuation before the end of the DB phase 
Subjects completing the DB phase of the study are those who completed the 17-week DB 
treatment phase, regardless of whether they entered the OL. A listing of dispositions will 
be provided for all randomized subjects. 
3.2 ELIGIBILITY CRITERIA AND PROTOCOL DEVIATIONS 
The clinical team will identify protocol deviations before database lock. 
A data listing of subjects who violate any of the inclusion/exclusion characteristics will 
be provided as well as a data listing of subjects with other protocol violations. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographic data (age, sex race, height, weight and body mass index (BMI), and 
ethnicity) and baseline characteristics (Tanner staging and number of AED medications 
taken and stopped) collected prior to the first dose of IP will be summarized using 
descriptive statistics in the ITT population, the Safety population and the PP population. 
The statistics will be shown by DB treatment group and for all subjects combined. Tables 
will be provided for the ITT population overall and by biomarker stratum. Subject data 
listings will also be provided. 
 
Where units differ across data points, the following conversions will be applied: 
 
• Height (cm) = Height (inches) * 2.54 
• Weight (kg) = Weight (lbs) * 0.4536 
• BMI (kg/m2) = Weight (kg)/[Height(m)2] 
MEDICAL HISTORY AND GENETIC TESTING 
Medical history will be coded with the Medical Dictionary for Regulatory Activities 
(MedDRA) Terminology version 22.0 or higher. The number and percent of subjects 
reporting each diagnosis will be summarized by system organ class (SOC) and preferred 


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term (PT) by treatment and overall in the Safety population. 
The results of the genetic testing and historical seizure information will be summarized 
and listed as available. 
PRIOR AND CONCOMITANT MEDICATIONS AND THERAPIES 
Prior medications/therapies are defined as medications/therapies that started and stopped 
prior to the first dose of DB study drug. Concomitant medications/therapies are defined 
as medications/therapies (other than the study drug) administered on or after the first dose 
of the DB study drug, regardless of when the medications/therapies started. The summary 
of concomitant medications/therapies for the main 17-week DB treatment phase of the 
study will not include concomitant medications/therapies that start after that phase; i.e., 
they will not include any starting on or after the first dosing day of the OL phase. 
The summary of concomitant medications/therapies for the OL phase will include all 
medications/therapies, other than study drug, administered on or after the first dosing day 
of the OL phase. There will be no summary of prior medications/therapies for the OL 
phase. 
All investigator terms for medications recorded on the CRF will be coded using the 
World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) drug 
dictionary (Version WHO Drug Dictionary, March 2014 or later). The number and 
percentage of subjects who took prior and concomitant medications will be summarized 
by treatment and overall in the Safety population and, if it differs substantially from the 
Safety population, the PP population as well, by ATC Classification and WHO Drug PT. 
Prior and Concomitant AEDs will be summarized and listed separately. 
Rescue medications and associated prescribed doses reported as concomitant medications 
will be summarized and listed as described above. In addition, rescue medication usage 
data, including date and time of dosing and administered dose, which are obtained from 
eDiary entries, will be analyzed as exploratory endpoints as described in Section 7.1.4.6. 
Dose levels reported in these two sources of rescue medication data may differ. 
The number (percentage) of subjects who received prior and concomitant therapies will 
be summarized by treatment and overall in the Safety population and, if it differs 
substantially from the Safety population, the PP population as well. The therapies will 
also be presented in a subject data listing. 
To define prior or concomitant medications/therapies, Table 2 describes how missing date 
information will be handled; however, the actual dates, not the imputed ones, will be 
displayed in the listing. 


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Table 2: Handling of Partial or Missing Medication Dates 
 
Partial Missing Start or 
Stop Date 
Imputed Start Date 
Imputed Stop Date 
Missing year, month, and 
day 
First dose date 
Missing month and day, 
and the year is present 
First dose date if the year is the 
same as the year of first dose 
date, else first dose date of the 
OL if the year is the same as the 
year of the first OL dose date, 
else January 1 of the start year. 
December 31 of that 
year 
Missing day, but year and 
month are present 
First dose date if the year and 
month are the same as the year 
and month of first dose date, else 
first dose date of the OL if the 
year and month are the same as 
the year and month of the first OL 
dose date, else the 1st of the start 
month. 
Last day of that month 
Missing month, but year 
and day are present 
Assume day is also missing and 
impute as above 
Missing month imputed 
as December 
If an imputed start date is later than the stop date, then the stop date (after any needed 
imputations) will be used instead for the imputed start date. 
 
EFFICACY ANALYSES 
In addition to the descriptive statistics mentioned in Section 2.1, the baseline, post- 
baseline, and relevant changes from baseline for the seizure endpoints will also be 
summarized. Wilcoxon rank-sum tests will be used to compare differences in percent 
change from baseline between the two treatment groups. 
Fisher’s exact test will be used to compare the percentage of subjects achieving notable 
reductions, e.g. ≥ 25% reduction, ≥ 50% reduction, etc., in seizure rates between the two 
treatment groups. 
The baseline, post-baseline, and changes from baseline for the other non-categorical 
endpoints will be summarized descriptively with 95% confidence intervals for the means 
and differences in means between the treatment groups. 
7.1 DOUBLE-BLIND PHASE 
All efficacy analyses will be conducted in the ITT population as well as by biomarker 
stratum. A supportive analysis of the primary efficacy endpoint also will be conducted in 


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the PP population. 
All analyses in the ITT population will include all available data, even if they were 
collected after the subject stopped taking study medication, regardless of whether the 
subject took rescue medication. Section 7.1.1 details the handling of missing data. 
For the analyses of seizures, the baseline phase consists of the 8- to 12-week period 
before the first day of treatment, and the DB phase starts the day following the first day 
of DB treatment until the final visit for subjects who do not enter the OL and up to the 
day before the first dose of OL treatment for those who do. Also, if a subject’s baseline 
primary seizure count based on the prospective baseline period is less than 4, the primary 
seizure count from the Historical Seizure Calendar Review CRF will be used to calculate 
a baseline 28-day seizure count. 
Tests of significance between the two treatment groups will be performed for the primary 
endpoint with a 2-sided significance level of 0.05. 
Seizure diary compliance for the baseline and post-baseline DB phase intervals will be 
calculated as: 
100 x (Number of Days with Available Seizure Diary) / (Last Available Seizure Diary 
Date – First Available Seizure Diary Date + 1). 
Seizure diary compliance between visits will be calculated as: 
100 x (Number of days with available seizure data between visits) / Number of days 
between visits), with the days between visits defined as the day of the prior visit up to the 
day before the current visit. 
Diary compliance values will be summarized with descriptive statistics and the 
percentage of subjects at least 80% compliant. 
7.1.1 Handling of Missing Data 
The primary analysis will use all available data. Careful educating and monitoring of the 
study sites will attempt to limit the amount of missing data. Sensitivity analyses, with 
replacement of missing data, will be performed for the primary efficacy endpoint; see 
Section 7.1.6. 
For non-seizure variables, data for subjects prematurely discontinuing from the study will 
be assigned to the first visit subsequent to the discontinuation at which the assessment 
was scheduled, as long as the discontinuation visit is within 32 days of the next scheduled 
performance of that assessment. 
7.1.2 Primary Efficacy Endpoint 
The primary efficacy endpoint is the percent change in 28-day primary seizure frequency 
during the 17-week DB phase relative to the baseline. The primary seizure types are 
defined as countable focal seizures that include progressive hypotonia and impaired 
awareness, or any countable focal or generalized seizure with a clear motor component. 
Focal and generalized nonmotor seizures and myoclonic seizures do not count as the 


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primary seizure types. 
The analyses of the primary endpoint will be performed on the sum of the individual 
countable seizures and each series of continuous uncountable seizures (each contributes 1 
to the sum). 
Post-baseline 28-day seizure frequency will be calculated as the total number of seizures 
in the 17-week DB treatment phase divided by the number of days with seizure data in 
the phase, multiplied by 28. Baseline 28-day seizure frequency will be calculated as the 
total number of seizures in the baseline phase divided by the number of days with seizure 
data in the phase, multiplied by 28. For primary seizures only, if a subject’s baseline 
seizure count from this prospective baseline period is less than 4, the primary seizure 
count from the Historical Seizure Calendar Review CRF will be used to calculate a 
baseline 28-day seizure count. 
The calculation for percent change from baseline in 28-day seizure frequency will be 
done as follows for each subject: 
 
 
The baseline, post-baseline, and arithmetic and percent changes from baseline in 28-day 
seizure frequency will be summarized using descriptive statistics. A subject data listing 
will be provided. 
The difference between the GNX and placebo groups in the percent changes will be 
tested using the Wilcoxon Rank-Sum statistic. Testing will be conducted in the following 
order: 
• The primary analysis will be conducted in the ITT population. 
• If nominal statistical significance is achieved in the ITT population, the primary 
analysis will be similarly conducted in the biomarker-positive stratum of the ITT 
population as a secondary endpoint (Section 7.1.3). 
• In addition, as an exploratory analysis, efficacy will be assessed in the biomarker- 
negative stratum. (Section 7.1.4.1) and compared with the biomarker positive 
result. 
The analysis of the primary efficacy endpoint will be conducted in the ITT population 
and within the biomarker strata of the ITT population; a supportive analysis in the PP 
population will also be done. 
7.1.3 Secondary Efficacy Endpoints 
All secondary efficacy endpoints will compare GNX and PBO during the 17-week DB 
treatment phase relative to the prospective baseline phase, unless specifically indicated 
otherwise. 
( [(Post-lbaseli11e 28-d!ay.seiizl!.lr.e frequency) - (Baseline 28~day seiizure freq1U:ency)]) x1 00% 
(Basehne 2-8-day seiizure frequency) 


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All secondary analyses will be done in the ITT population for all subjects and by 
biomarker stratum, and if the ITT and PP analyses notably differ for the primary 
endpoint, they will also be done in the PP population. All seizure control endpoints will 
be included in data listings. 
7.1.3.1 Percent Change in Primary Seizure Frequency in Biomarker Positive Stratum 
If the results of the primary endpoint analysis in the full ITT population indicate efficacy 
in the GNX treatment arm, the primary efficacy analysis described in Section 7.1.2 will 
be repeated for subjects in the biomarker-positive stratum. 
7.1.3.2 Percentage of Subjects Experiencing Primary Seizure Reduction 
Percentages of subjects experiencing a ≥ 50% reduction in 28-day primary seizure 
frequency relative to baseline will be compared between GNX and PBO for both 
biomarker-positive and negative strata, separately, and for the combined strata. A Fisher’s 
Exact test will be used to compare rates between treatment groups. 
7.1.3.3 Behavior Rating Inventory of Executive Function (BRIEF, preschool version 
BRIEF-P) 
The BRIEF is an 86-item questionnaire designed to assess executive function behaviors 
in the school and home environments in individuals 5-18 years of age. The preschool 
version (BRIEF-P) is a 63-item modified form and will be administered to individuals 2- 
5 years of age. The BRIEF version to be administered will be based on the subject’s age 
at Screening. The same version of the BRIEF will be administered during the entire study 
regardless of the subject’s age at the time of post-screening assessment. The 
questionnaire is completed by the parents/caregiver/ legally authorized representative 
(LAR). 
The BRIEF items are partitioned to create 8 component scores: 
• Inhibit 
• Shift 
• Emotional Control 
• Initiate 
• Working Memory 
• Plan/Organize 
• Organization of Materials 
• Monitor 
The first three components are summed to create a Behavioral Regulation Index (BRI), 
and the remaining five components are summed to create a Metacognition Index (MI). 
The BRI and MI are then summed to create a Global Executive Composite (GEC). 


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The BRIEF-P items are partitioned to create 5 component scores: 
• Inhibit 
• Shift 
• Emotional Control 
• Working Memory 
• Plan/Organize Scales 
The Inhibit and Emotional Control components are summed to create an Inhibitory Self- 
Control Index (ISCI), the Shift and Emotional Control components are summed to create 
a Flexibility Index (FI), the Working Memory and Plan/Organize components are 
summed to create an Emergent Metacognition Index (EMI), and all five components are 
summed to create a Global Executive Composite (GEC). 
All component scores, index scores, and composite scores will be descriptively 
summarized. Both baseline, post-baseline, and change from baseline will be summarized. 
These scores will also be listed. Statistical comparison between treatment groups will not 
be performed. 
7.1.3.4 Aberrant Behavior Checklist – Community (ABC-C) 
The ABC-C is a 58-item questionnaire designed to assess problematic behavior at home, 
in educational and work setting, and in residential and community-based facilities. The 
item scores range from 0=”not at all a problem” to 3=”the problem is severe in degree”. 
The items are partitioned into 5 domains: 
1. Irritability (items 2, 4, 8, 10, 14, 19, 25, 29, 34, 36, 41, 47, 50, 52, 57) 
2. Social withdrawal (items 3, 5, 12, 16, 20, 23, 26, 30, 32, 37, 40, 42, 43, 53, 55, 
58) 
3. Stereotypy behavior (items 6, 11, 17, 27, 35, 45, 49) 
4. Hyperactivity (items 1, 7, 13, 15, 18, 21, 24, 28, 31, 38, 39, 44, 48, 51, 54, 56) 
5. Inappropriate speech (items 9, 22, 33, 46) 
The domain subtotals and the total of all the items will be summarized with descriptive 
statistics of the baseline and post-baseline values and the arithmetic changes from 
baseline. Difference in mean scores between two treatment groups will be provided along 
with 95% confidence intervals. 
7.1.3.5 Children’s Sleep Habit Questionnaire (CSHQ) 
The CSHQ is a psychological questionnaire designed to measure sleep behaviors in 
children and adolescents and is filled out by the parent/caregiver/LAR. An abbreviated 
version contains 33 items. 


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The first 31 items are scored as 1 = Rarely (0-1 times per week), 2 = Sometimes (2-4 
times per week), or 3 = Usually (5 - 7 times per week). Item 32 (Watching TV) and 33 
(Riding in car) ask how sleepy the child has appeared dming those activities (1 = Not 
sleepy, 2 = Ve1y sleepy, or 3 = Falls asleep). The questionnaire includes 2 other 
quantitative questions: 
• 
Child's usual amount of sleep each day 
• 
Number of minutes a night waking usually lasts 
The 33 items are pa1iitioned into 8 domains: 
1. Bedtime resistance (items 1, 3, 4, 5, 6, 8) 
2. Sleep onset delay (item 2) 
3. Sleep duration (items 9, 10, 11) 
4. Sleep anxiety (items 5, 7, 8, 21) 
5. Night wakings (items 16, 24, 25) 
6. Parasomnias (items 12-15, 17, 22, 23) 
7. Sleep disordered breathing (items 18, 19, 20) 
8. Daytime sleepiness (items 26-33) 
For scoring, first, items 1, 2, 3, 10, 11, and 26 are reversed (4-score). The item scores are 
then summed within each domain. The domain subtotals, the total of the 33 items, and the 
2 other quantitative questions will be summarized with descriptive statistics of the 
baseline and post-baseline values and the arithmetic changes from baseline. Differences 
in mean scores between two treatment groups will be provided along with 95% 
confidence intervals. 
The usual amount of sleep each day will be summarized in hours. 
7.1.4 Exploratory Endpoints 
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7.1.5 Subgroup Analyses 
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Other than the within-stratum analyses, no subgroup analyses are planned at this time. 
7.1.6 Sensitivity Analyses 
Two sensitivity analyses of the primaiy efficacy endpoint of change in 28-day frequency 
of the primaiy (i.e., all countable motor) seizure types will be perfonned: 
futennittent (random/sporadic) missing data during the 17-week DB phase and any 
missing data during the baseline phase will be assumed missing completely at random 
and the collected data will be used to calculate the 28-day seizure frequencies. For early 
drng tennination prior to the end of the 17-week DB phase, caregivers will be instrncted 
to continue to provide daily seizure records until the end of the 17-week DB phase (hence 
further preventing missingness). 
fu the first sensitivity analysis, the following imputation approach will be used for the 
primaiy outcome measure when a subject stops recording measurements pennanently 
( anticipated to be zero or minimal in occunence) prior to the end of the 17-week DB 
phase. For days with missing seizure count data, the con esponding median PBO data will 
be imputed (in espective ofti·eatment ann), within each sti·atum, as follows: 
• 
Compute the median 28-day seizure frequency in the PBO aim based on all 
available PBO measurements during the 17-week DB treatment phase. Label that 
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‘X’ and define ‘A’ to be ‘X’/28, (i.e., the daily average on placebo during the 17- 
week during the DB phase). 
• For any days (whether they be in the PBO or GNX arm) that occur AFTER a 
subject has become lost to follow up, impute ‘A’ on that day. 
The second sensitivity analysis will explore the possibility that subjects who stop 
recording their seizure counts tend to have higher seizure counts than the other subjects. 
The imputation method described above will be modified to use the median of the 5 
highest counts, rather than the median count, among the PBO subjects with data. 
7.1.7 Protections for Multiplicity 
As explained in Section 7.1.2, analyses of the 28-day seizure frequency will be conducted 
in the following sequence: 
• The primary analysis will be conducted using all subjects in the ITT population. 
• If nominal statistical significance is achieved in the ITT population, the primary 
analysis will be similarly conducted in the biomarker-positive stratum of the ITT 
population as a secondary endpoint (Section 7.1.3). 
• In addition, as an exploratory analysis, efficacy will be assessed in the biomarker- 
negative stratum. (Section 7.1.4.1) 
7.2 
OPEN LABEL EXTENSION 
All of the analyses for the DB phase will be repeated for the OL phase, with the following 
differences: 
• All results will only be summarized descriptively. 
• The results will be presented overall and classified according to the DB treatment 
received by the subjects 
• The post-baseline seizure endpoints will be derived based on the first full day of 
OL treatment (one day after OL start). 
• No sensitivity analyses will be performed. 
• Analyses of seizure frequencies during titration and maintenance phases are only 
applicable to the DB phase and will not be included in the OL phase analyses. 
• The time points for the efficacy, exploratory, and quality of life endpoints will be 
after 19 weeks, 51 weeks, and every 16 weeks thereafter of open-label treatment 
relative to the prospective baseline phase. 
• The differences between the DB treatment groups in the percent changes from 
baseline of the 28-day seizure frequencies will not be tested for statistical 
significance. 


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• No PP analyses will be performed. 
PHARMACOKINETICS 
A listing of the pharmacokinetic collection times will be provided, but the analyses will 
be described in a separate report. 
SAFETY ANALYSIS 
All safety analyses will be performed in the Safety Population. The results in the DB and 
OL phases will be summarized separately. In both phases, the results will be summarized 
by the DB treatment actually received and, for the OL phase of the study, combined over 
the treatment groups. Baseline for safety endpoints is defined as the last non-missing 
value obtained before the first day of DB treatment. Assessments performed at multiple 
post-baseline time points will be summarized at each time point for which they are 
scheduled, but the listings will also include any assessments performed at unscheduled 
time points. 
The number and percentage of days that subjects received investigational product, the 
highest percentage of the maximum allowable daily dose (1800 mg or 63 mg/kg) that 
subjects received, and the total amount of investigational product received will be 
summarized. For the OL phase, they will be summarized over just the OL phase as well 
as over the entire study (combined DB and OL phases) but the classification by the DB 
treatment applies only for the OL phase summary. The summarization over the entire 
study will include only subjects who were in the GNX group during the DB phase, 
regardless of whether they entered the OL, and all the subjects from the OL phase. A 
subject data listing will be provided with full details of the study drug dispensation. 
Safety assessments include: 
• AEs 
• Clinical laboratory tests 
• Vital signs including BP, HR, RR, body temperature, weight, and height 
• 12-lead Electrocardiogram (ECG) 
• Physical, neurological and developmental examinations 
• Neurosteroid levels 
• Tanner staging (OL phase only) 
9.1 ADVERSE EVENTS 
AEs will be coded by System Organ Class (SOC) and Preferred Term (PT) using 
MedDRA®, version 22.0 or higher. The verbatim term will be included in the AE 
listings. Except where indicated, the summary tables will include only treatment- 
emergent adverse events (TEAEs). All AEs, treatment-emergent or otherwise, will be 


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presented in subject data listings. 
A TEAE is defined as an AE that starts or worsens on or after the first dosing day of 
study drug. The AE analyses for the DB treatment phase of the study will include AEs 
that start or worsen during that phase and will not include AEs that start or worsen during 
the OL phase; i.e., they will not include any AEs starting or worsening on or after the first 
dosing day of the OL phase. 
For the OL phase of the study, the adverse event results will be summarized over just the 
OL phase as well as over the entire study (DB and OL phases) but the classification by 
the DB treatment applies only for the OL phase summary. The summarization over the 
entire study will include only subjects who were in the GNX group during the DB phase, 
regardless of whether they entered the OL, and all the subjects from the OL phase; i.e., it 
will include only the TEAEs following GNX exposure. The summarizations over just the 
OL phase will include TEAEs that occur or worsen on or after the first day of the OL 
phase; the summarizations over the entire study will include TEAEs that start or worsen 
on or after the first dosing day of GNX. 
The TEAEs will be summarized as the number of events and the number and percentage 
of subjects with TEAEs. Subjects who report the same PT on multiple occasions will be 
counted once for the PT: under the highest severity (severe > moderate > mild) when 
summarized by severity and under the closest relationship (related > not related) to study 
drug when summarized by relationship. 
If a subject reports multiple PTs for a SOC, the subject will be counted only once for that 
SOC. For the counting of events, all the PTs will be included in the counts, even when 
subjects have multiple PTs. 
Non-treatment emergent AEs will only be listed. 
TEAEs will be summarized as follows: 
• An overview table of TEAEs, including number of events and number (%) of 
subjects with: 
o TEAEs 
o Serious AEs (SAEs) 
o Study drug related TEAEs 
o TEAEs by severity 
o TEAEs leading to study discontinuation 
o TEAEs leading to death 
o Adverse events of special interest (AESI) 
• TEAEs by SOC and PT 


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• TEAE by SOC, PT, and Severity 
• Study drug related TEAEs by SOC, PT 
• SAEs by SOC and PT 
• TEAEs leading to study drug discontinuation by SOC and PT 
• TEAEs leading to dose reduction by SOC and PT 
• Adverse events of special interest (AESI) 
All AE tables will be sorted by SOC and PT in decreasing frequency of the number of 
subjects in the GNX group, in the DB summaries and the combined groups in the OL 
summaries; in case of tied frequencies, the sorting will be alphabetical. 
Adverse event listing will identify serious AEs, AE leading to study drug discontinuation, 
AEs leading to dose reduction, AEs of special interest, and subjects who died during the 
study. 
For purposes of determining treatment emergence, missing start dates will be imputed as 
shown in Table 3; however, the actual dates, not the imputed ones, will be displayed in 
the data listing. 


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Table 3: Handling of Partial or Missing Adverse Event Dates 
 
Partial Missing Start or 
Stop Date 
Imputed Start Date 
Imputed Stop Date 
Missing month, day, and 
First dose date 
year 
Missing month and day, 
First dose date if the year is the 
December 31 of that 
and the year is present 
same as the year of first dose 
year 
date, else first dose date of the 
OL if the year is the same as the 
year of the first OL dose date, 
else January 1 of the AE start 
year. 
Missing day, but year and 
First dose date if the year and 
Last day of that month 
month are present 
month are the same as the year 
and month of first dose date, else 
first dose date of the OL if the 
year and month are the same as 
the year and month of the first 
OL dose date, else the 1st of the 
AE start month. 
Missing month, but year 
Assume day is also missing and 
Missing month imputed 
and day are present 
impute as above 
as December 
9.2 CLINICAL LABORATORY PARAMETERS 
Laboratory assessments include hematology, clinical chemistry, and urinalysis: 
• Clinical Chemistry: Total Bilirubin, Aspartate Aminotransferase (AST), Alanine 
Aminotransferase (ALT), Blood Urea Nitrogen (BUN), Glucose, Potassium, 
Sodium, Calcium, Alkaline Phosphatase, Chloride, Creatinine, Carbon Dioxide 
(CO2). 
• Hematology: Hemoglobin, Hematocrit, Erythrocytes, Leukocytes + differential, 
Thrombocytes (platelet count). 
• Urinalysis: pH, Color, Transparency, Specific Gravity, Urobilinogen, Ketones, 
Protein, Glucose 
All laboratory parameters will be presented in Système International (SI) units. 
Quantitative results (including actual values and change from baseline) will be 
summarized using descriptive statistics by baseline and post-baseline visit for each 
laboratory test group above. Laboratory test results will be assigned an LH classification 
according to whether the value was below (L) or above (H) the normal reference range 
(some urinalysis labs are assigned only normal and abnormal classifications) (See also 
Appendix 14.2). Values outside the normal range will also be classified as to whether 


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they were potentially clinically significant (Appendix 14.3). Shift tables cross-tabulating 
the baseline and post-baseline classifications (below (L), Normal (N), or above (H) the 
reference range), by visit, will be provided. 
All laboratory data will be included in the listings. A pregnancy listing will be provided 
separately. 
9.3 OTHER SAFETY ENDPOINTS 
9.3.1 Vital Signs 
Vital signs include weight (kg), height (cm), temperature (°C), systolic and diastolic 
blood pressure (mmHg), respiration rate (breaths per minute), and pulse rate (bpm). 
Quantitative results (including actual value and change from baseline to each post- 
baseline visit) will be summarized using descriptive statistics by baseline and post- 
baseline visit for each parameter. 
Listings of vital signs will be provided. 
9.3.2 Electrocardiogram (ECG) 
The 12-lead ECG parameters including value and change from baseline will be 
summarized using descriptive statistics by baseline and post-baseline visit. Overall ECG 
results are interpreted as normal, abnormal (not clinically significant) or abnormal 
(clinically significant). The number and percentage of subjects in each category will be 
summarized by baseline and post-baseline visit. 
A subject listing will be provided. 
9.3.3 Physical, Neurological, and Developmental Examinations 
Physical examination results were interpreted as normal, abnormal (not clinically 
significant) or abnormal (clinically significant). Neurological examination results were 
interpreted as normal or abnormal. Physical, neurological, and developmental 
examination findings will be summarized and listed. 
9.3.4 Neurosteroid Levels 
The baseline and post-baseline values and the arithmetic changes from baseline of the 
neurosteroid levels will be summarized using descriptive statistics and listed. 
To examine response by neurosteroid levels, change from baseline in 28-day seizure 
frequency will be summarized in the subsets of the ITT subject population with low 
allopregnanolone-sulfate (Allo-S) levels, defined as baseline Allo-S ≤ 2,500 pg/mL, mid 
Allo-S levels, defined as baseline Allo-S > 2,500 pg/mL and <6,000 pg/mL, and high All- 
S levels, defined as Allo-S ≥ 6,000 pg/mL. 
9.3.5 Tanner Staging 
The Tanner scale (also known as the Tanner stages) is a scale of physical development in 
children, adolescents, and adults. The scale defines physical measurements of 


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development based on external primary and secondary sex characteristics. Subjects will 
be evaluated and rated as Tanner I, Tanner II, Tanner III, Tanner IV and Tanner V. Tanner 
staging will occur at Screening (Visit 1), Visit 8 (Week 52) and will continue to be 
assessed annually for the duration of the subject’s participation in the open-label phase 
and at the final OL visit. 
The number and percentage of subjects of each category will be summarized by 
Screening and OL visit, and a listing will be provided. 
INTERIM ANALYSES AND DATA MONITORING COMMITTEE 
(DMC) 
No formal interim analysis is planned for this study. After all active subjects complete the 
17-week DB phase, the DB data in the database will be locked and used to perform 
endpoint analysis. Data collected during the open label phase will be analyzed separately. 
The emerging study data will be reviewed on a regular basis by an independent DMC. 
The mission of the DMC will be to safeguard the interests of study participants and to 
enhance the integrity and credibility of the trial. To enable the DMC to achieve their 
mission, the DMC will have ongoing access to efficacy and safety data and data 
regarding quality of trial conduct and will ensure the confidentiality of these data will be 
preserved. A DMC Charter will provide the principles and guidelines for the DMC 
process. Specific details of the monitoring guidelines are provided in the DMC Charter. 
SUMMARY OF MAJOR CHANGES IN THE PLANNED ANALYSES 
There are no major changes in the planned analyses. The contents of this SAP are 
consistent with the most current version of the protocol. 
Any future changes to these analyses will be documented in an SAP amendment or 
described in the clinical study report (CSR). 
PROGRAMMING SPECIFICATIONS 
12.1 FORMAT OF APPENDIX TABLES/FIGURES/LISTINGS 
1. Unless otherwise specified, all computer-generated tables, figures and listings 
(TFL) will be produced (via SAS ODS) into RTF output, which can be imported 
in table format via Microsoft Word. The TFLs should be in landscape mode with 
required margins: at least 1.5 inches on top (the binding margin or left for portrait 
output) and 1 inch on left, right, and bottom. All output should have the following 
headers on each page: 
• Two-line header at the upper left margin: 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-PCDH19-3002 
• Header with page number and date/time at the upper right margin: 
Page X of N 
ddMMMyyyy: hh:mm 


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TFLs should be internally paginated in relation to total length (i.e., page number 
should appear sequentially as page X of N, where N is the total number of pages 
within a table or listing). 
2. Each TFL should be identified by in a sequential numeric order, and the TFL 
number should be centered above the title. The title is centered in initial capital 
characters and should include the population type analyzed (e.g. Safety 
Population). The title and designation are single-spaced, but are separated from 
the TFL by at least a double space. 
 
Table xx.x.x.x 
First Line of Title 
Second Line of Title (if needed) 
Population Type Analyzed 
 
3. Column headings for tables and listings should be in initial upper-case characters. 
4. Footnotes should be single spaced but separated by at least a double space from 
the bottom line of the TFL. The notes are left justified, with each note starting on 
a new line. Following the last footnote insert a single space. Tables and listings 
should then display the source listing number and all outputs should display the 
source SAS program name. For example, the set of footnotes for a table: 
 
 
Note: [1] Footnote 1 
[2]Footnote 2 
 
Data Sets: xxxx, xxxx 
Program Name: xxxx.sas 
5. All data listings should be sorted by, treatment group and biomarker stratum with 
a page break between them, subject number, parameter (where appropriate), and 
study visit date/time where appropriate. If data for a subject and/or parameter is 
displayed on multiple lines, then display the subject number and/or parameter on 
only the first line. However, if the data for a subject or parameter is split between 
pages, then the subject number and parameter should be displayed on the page 
following the split. 
6. For tables that summarize categorical (discrete) data, all categories between the 
maximum and minimum category should be presented in the table, even if there is 
a zero count for a particular category. A Missing category should be added to any 
variables to indicate missing information, if appropriate, but the percentages 
should be based on the number of subjects with non-missing categories. 
7. If the categories are not ordered (e.g., Medical History, Reasons for 
Discontinuation from the Study, etc.), then only those categories for which there 
is at least 1 patient represented in 1 or more groups should be included. 
8. All fractional numeric values should be printed with a zero to the left of the 
decimal point (e.g., 0.12, 0.3). 


DocuSign Envelope ID: 90C2F347-C987-46E5-9577-D4E0A508C0AD 
Marinus Pharmaceuticals, Inc. 
Statistical Analysis Plan, 
Amendment 1 
01 March 2021 
Study 1042-PCDH19-3002 
Final, Amendment 1 
Confidential 
Page 37 of 54 
 
 
 
9. Missing descriptive statistics or p-values due to non-estimability in tables, as well 
as missing data in patient listings should be represented as either a hyphen (“-“) 
with a corresponding footnote (“ - = unknown or not evaluated”), or as “N/A” 
with the footnote “N/A = not applicable” whichever is appropriate. 
10. Date values in the listings should be in the format ddMMMyyyy. If part of the 
date is unknown then leave it out; e.g., APR2019. (In the unlikely event that the 
date and year are available but the month is not, insert a hyphen between the date 
and year.) 
11. Any data listing for which there were no events should be produced, stating, 
“There were no events.” 
In addition, Section 2.1.1 contains information on reporting precision. 
12.2 SAS PROCEDURES FOR SEIZURE ANALYSES 
The following code will provide the Wilcoxon rank-sum test: 
 
proc npar1way data=dataset (where=(specify analysis 
population, endpoint, study phase, and time point) 
wilcoxon 
HL(refclass=’formatted value of Placebo group’); 
by stratum; *stratum is the name of the stratum variable 
class trtp; *trtp is the name of the randomized 
treatment variable; 
var pchg; *pchg is the name of the percent change 
variable; 
run; 


DocuSign Envelope ID: 90C2F347-C987-46E5-9577-D4E0A508C0AD 
Marinus Pharmaceuticals, Inc. 
Statistical Analysis Plan, 
Amendment 1 
01 March 2021 
Study 1042-PCDH19-3002 
Final, Amendment 1 
Confidential 
Page 38 of 54 
 
 
 
REFERENCES 
1. International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite 
Guideline, Statistical Principles for Clinical Trials (E9), September 1998. 
2. ASA. (2018) Ethical Guidelines for Statistical Practice. Prepared by the Committee 
on 
Professional 
Ethics, 
April, 
2018. 
http://www.amstat.org/ASA/Your- 
Career/EthicalGuidelines-for-Statistical-Practice.aspx. 
3. International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite 
Guideline, Structure and Content of Clinical Study Reports (E3), November 1995. 
4. International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite 
Guideline, Good Clinical Practice (E6), April 1996. 
5. International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite 
Guideline, General Considerations for Clinical Trials (E8), July 1997. 
6. International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite 
Guideline, Statistical Principles for Clinical Trials (E9), September 1998. 


DocuSign Envelope ID: 90C2F347-C987-46E5-9577-D4E0A508C0AD 
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Statistical Analysis Plan, 
Amendment 1 
01 March 2021 
Study 1042-PCDH19-3002 
Final, Amendment 1 
Confidential 
Page 39 of 54 
 
 
 
APPENDICES 


DocuSign Envelope ID: 90C2F347-C987-46E5-9577-D4E0A508C0AD 
Marinus Phannaceuticals, fuc. 
Study 1042-PCDH19-3002 
14.1 SCHEDULE OF A SSESSMENTS 
Statistical Analysis Plan, Amendment 1 
01 March 2021 
14.1.1 Schedule of Assessments for the 17-Week, Double-Blind Phase of the Study: 
DB Titration + Maintenance 
Final DB 
Pre-screen/Screen/Baseline 
Visit 
- (Pre-
-12 
0 
baseline 
(Screening 
(Baseline 
3 
WEEK 
Screening 
Visit -
Visit-
days 
1, 2, 3, 4 
5 
9 
11, 13 
17 
Visit) 
Sta11 of 
Randomizatio 
Baseline) 
n) 
Visit Windows 
NIA 
NIA 
+ 6 days 
± 1 day 
±3 days 
± 3 days 
± 3 day 
± 3 days 
±3 days 
VISIT 
Visit 0 
Visit l3 
Visit 2' 
Phone 
Follow-up 
Phone 
Follow-up 
Visit 3 
Visit 4 
Phone 
Follow-up 
Visit 5 
Sc1·eening and Diagnosis 
Info1med Consentb 
xc 
X 
Demographics & Medical 
X 
Xd 
History 
Historical Seizure Calendar 
X 
X 
Review" 
Inclusion/Exclusion Criteria 
X 
X 
X 
Genetic testing• 
X 
X 
Seizure Identification and 
Diagnostic Review Fo1m 
X 
X 
(Epilepsy Study Consortium) 
Safety Assessments 
Vital signs (BP, HR, RR, and 
xr 
xg 
xg 
xg 
xg 
body temperature) 
Physical/Neurological/ 
X 
X 
X 
X 
X 
Developmental Exam 
Final, Amendment 1 
Confidential 
Page 40 of54 


DocuSign Envelope ID: 90C2F347-C987-46E5-9577-D4E0A508C0AD 
Marinus Phannaceuticals, fuc. 
Study 1042-PCDH19-3002 
Pre-screen/Screen/Baseline 
- (Pre-
-12 
0 
baseline 
(Screening 
(Baseline 
3 
WEEK 
Screening 
Visit -
Visit -
days 
Visit) 
Sta11 of 
Randomizatio 
Baseline) 
n) 
Visit Windows 
NIA 
NIA 
+ 6 days 
±1 day 
VISIT 
Visit 0 
Visit l3 
Visit 2' 
Phone 
Follow-up 
ECG 
X 
Clinical Laborato1y Testsh 
X 
X 
Urinalysis 
Xi 
Xi 
Drug scre.eni 
X 
X 
Pregnancy Test (WCBP)k 
X 
X 
Tanner Staging 
X 
Investigational Product PK 
Concomitant AED Review 
and levels if per standard of 
X 
X 
care"' 
Neurosteroid levels 
X 
Adverse Event 
X 
X 
X 
Efficacy Assessments 
Seizure and Medication 
xo 
X 
X 
eDiaiy reviewn 
Children's Sleep Habit 
X 
Questionnaire (CSHQ) 
Behavior Rating Invento1y of 
X 
Final, Amendment 1 
Confidential 
Statistical Analysis Plan, Amendment 1 
01 March 2021 
DB Titration + Maintenance 
Final DB 
Visit 
1, 2, 3, 4 
5 
9 
11, 13 
17 
±3 days 
± 3 days 
± 3 day 
±3 days 
±3 days 
Phone 
Visit 3 
Visit 4 
Phone 
Visit 5 
Follow-up 
Follow-up 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xi 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 41 of 54 


DocuSign Envelope ID: 90C2F347-C987-46E5-9577-D4E0A508C0AD 
Marinus Phannaceuticals, fuc. 
Study 1042-PCDH19-3002 
Pre-screen/Screen/Baseline 
EK 
c tive Fune · o ( 
EF) 
Aben-ant Behavior Checklist 
- Community (ABC-C) 
Explo1·atory Assessments 
Final, Amendment 1 
- (Pre-
baseline 
Screening 
Visit) 
NIA 
Visit 0 
-12 
(Screening 
Visit -
Sta11 of 
Baseline) 
NIA 
Visit l3 
0 
(Baseline 
3 
Visit -
days 
Randomizati 
n) 
+ 6 days 
±1 day 
Visit 2' 
Phone 
Follow-up 
X 
I 
I 
I 
I 
Confidential 
Statistical Analysis Plan, Amendment 1 
01 March 2021 
DB Titration + Maintenance 
Final DB 
Visit 
1, 2, 3, 4 
5 
9 
11, 13 
17 
±3 days 
± 3 days 
± 3 day 
±3 days 
±3 days 
Phone 
Visit 3 
Visit 4 
Phone 
Visit 5 
Follow-up 
Follow-up 
X 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
Page 42 of54 


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Marinus Pharmaceuticals, Inc. 
Study 1042-PCDH19-3002 
Statistical Analysis Plan, Amendment 1 
01 March 2021 
Final, Amendment 1 
Confidential 
Page 43 of 54 
 
 
 
 
Pre-screen/Screen/Baseline 
DB Titration + Maintenance 
Final DB 
Visit 
WEEK 
- (Pre- 
baseline 
Screening 
Visit) 
-12 
(Screening 
Visit – 
Start of 
Baseline) 
0 
(Baseline 
Visit – 
Randomizatio
n) 
3 
days 
1, 2, 3, 4 
5 
9 
11, 13 
17 
Visit Windows 
N/A 
N/A 
+ 6 days 
± 1 day 
± 3 days 
± 3 days 
± 3 day 
± 3 days 
± 3 days 
VISIT 
Visit 0 
Visit 1a 
Visit 2r 
Phone 
Follow-up 
Phone 
Follow-up 
Visit 3 
Visit 4 
Phone 
Follow-up 
Visit 5 
Dispense Investigational 
Productq 
X 
X 
X 
X 
AED = antiepileptic drug, BP = blood pressure, CBD = cannabidiol, D/C = discontinuation, DB = double-blind, ECG = electrocardiogram, EEG = electroencephalogram, HR = 
heart rate, LAR = legally authorized representative, PK = pharmacokinetic, RR = respiratory rate, THC = tetrahydrocannabinol, WCBP = women of childbearing potential. 
a. 
Subject rescreening is allowed as agreed by Sponsor and Investigator unless there is a general concern for subject safety or an inability for the subject to become eligible (eg, 
GNX allergy, sensitivity or exposure, non-PCDH19 and/or other ineligible epilepsy, chronic prohibited medical condition or treatment). Subsequent screening should take 
place at least 30 days from the subject’s last visit. 
b. 
Written informed consent/assent must be obtained from subject, parent or LAR before any study assessments are performed. 
c. 
In the event that the parent/caregiver/LAR does not routinely maintain a daily seizure calendar per standard of care, written informed consent will be obtained from the 
parent/LAR and subject assent, and the subject will be asked to return to the clinic for the screening visit after she has maintained a 12-week daily historical seizure calendar. 
d. 
Review of medical history only. 
e. 
Genetic testing to be performed to confirm pathogenic or likely pathogenic PCDH19 variant. If genetic testing is not performed as Standard of Care, a pre-baseline screening 
visit will be scheduled to obtain informed consent/assent and complete the genetic testing. If genetic testing results are available per SOC, the genetic testing will be done at 
screening to confirm the results by the Sponsors designated lab. 
f. 
In addition, height and weight will be measured. 
g. 
In addition, weight will be measured. At each visit, dosing will be reviewed and adjusted as needed based on a subject’s current weight. 
h. 
Chemistry & Hematology. 
i. 
An attempt should be made to collect a urine sample for a urinalysis at screening; otherwise, the urine sample can be collected at baseline for the urinalysis. 
j. 
A drug screen (plasma) will be performed to test for THC and CBD at screening. If the screening drug test is positive, the subject can be retested, via plasma, after two weeks. 
A drug screen may be performed at any time at Investigator’s discretion. A positive drug test during the DB phase will result in early termination. 
k. 
Serum pregnancy test is required for all girls/women of childbearing potential. 
l. 
Population PK will be conducted at these visits (Visit 3: between 1-5 hours since last IP dosing, Visit 4: between 4-8 hours since the last investigational product dosing). 
m. Concomitant AEDs must be stable for 1 month prior to screening and cannot be changed at any time prior to Visit 5, but may be adjusted during the open-label phase of the 
study. 


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Study 1042-PCDH19-3002 
Statistical Analysis Plan, Amendment 1 
01 March 2021 
Final, Amendment 1 
Confidential 
Page 44 of 54 
 
 
 
 
n. 
For recording of seizures in the eDiary, seizure events will be recorded either as a countable seizure or a series of continuous uncountable seizures. Both of these events will 
be counted as 1 seizure (equally weighted) in the efficacy analysis. A seizure cluster will be defined as 3 or more seizure events (either a countable or a series of continuous 
uncountable seizures), occurring within a period of time, followed by a period of at least 24 hours of seizure-freedom. 
Examples: (Protocol Figure 2): 
• 
If a child experiences 3 seizure events at 5:00, 5:30, and 6:00 PM on Monday, and the next seizure event occurs before 6:00 PM on Tuesday, the Monday and Tuesday 
seizure events are considered part of the same seizure cluster (Protocol Error! Reference source not found., Scenario 1). 
• 
If a child experiences 3 seizure events at 5:00, 5:30, and 6:00 PM on Monday, and the next seizure event occurs at 6:00 PM or later on Tuesday, the Tuesday seizure 
event is not considered part of the same cluster (Protocol Error! Reference source not found., Scenario 2). 
o. 
Caregiver given eDiary and instructions for use. 
p. 
During the screening visit, the principal investigator and parent/caregiver/LAR will decide on a domain and identify the specific behavior that the subject exhibits that denotes 
the domain. This behavior will be used at subsequent visits to assess change after the initiation of investigational product. 
q. 
Subjects who discontinue investigational product early will be encouraged to continue with all procedures and scheduled visits. 
r. 
The 12 weeks between Screening and Randomization can be no less than 84 days and no more than 90 days. 


DocuSign Envelope ID: 90C2F347-C987-46E5-9577-D4E0A508C0AD 
Marinus Phannaceuticals, fuc. 
Study 1042-PCDH19-3002 
14.1.2 Schedule of Assessments for Open-Label Phase 
Final 
DB 
Titration 
Visit/ 
(4 weeks blinded) 
First 
OL 
Visit 
Week 
18, 19, 
!WEEK 
17 
17+3 
21 
Days 
20 
!Visit Windows 
±1 
±3 
±3 
day(s) 
days 
days 
Phone 
Phone 
IVISIT 
Visit 5 Follow-
Follow-
Visit 6 
up 
up 
Safety Assessments 
Vital signs (BP, HR, 
RR, and body 
X1> 
X1> 
temperature? 
Physical/Neurological/ 
X 
X 
Developmental Exam 
ECG 
X 
X 
Clinical Laboratory 
X 
X 
Tests• 
Urinalysis 
X 
Drng Sere.en 
X 
Pregnancy Test 
X 
X 
(WCBP)f 
Tanner Staging 
Investigational Product 
X 
Xi 
PK 
Final, Amendment 1 
Statistical Analysis Plan, Amendment 1 
01 March 2021 
Open-Label Maintenance 
FinalOL 
Safety 
(Visits will be eve1·y 16 weeks with a telephone follow up in-
Visit or 
Follow-up 
between, this schedule continues after 68 weeks) 
Taper 
post taperJ 
Visif 
68" and 
X/ or 
2 weeks 
28 
36 
44 
52 
60 
early 
post last 
X visit 
DIC1 
dose 
± 14 
± 14 
± 14 
± 14 
± 14 
± 14 
± 14 
± 3 
days 
days 
days 
days 
days 
days 
days 
days 
Phone 
Phone 
Phone 
Visit 9 and 
follow-up Visit 7 follow-up Visit 8 follow-up 
Visit X 
Visit X 
VisitX 
)(1>,c 
)(1>,c 
)(1>,c 
)(1>,c 
X 
X 
X 
X 
X 
X 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
xg 
X 
X 
X 
X 
X 
X 
X 
X 
xg 
X 
X 
Xi 
X 
X 
X 
Confidential 
Page 45 of 54 


DocuSign Envelope ID: 90C2F347-C987-46E5-9577-D4E0A508C0AD 
Marinus Phannaceuticals, fuc. 
Study 1042-PCDH19-3002 
Final 
DB 
Titration 
Visit/ 
(4 weeks blinded) 
First 
OL 
Visit 
Week 
18, 19, 
!WEEK 
17 
17+3 
21 
Days 
20 
!Visit Windows 
±1 
±3 
±3 
day(s) 
days 
days 
Phone 
Phone 
IVISIT 
Visit 5 Follow-
Follow-
Visit 6 
up 
up 
Concomitant AED 
Review and levels if per 
X 
X 
standard of care 
Neurosteroid Levels 
X 
Adverse Event 
X 
X 
X 
X 
00:fficacy Assessments 
Seizure eDia1y reviewh 
X 
X 
X 
X 
Children's Sleep Habit 
X 
Questionnaire (CSHQ) 
Behavior Rating 
Invento1y of Executive 
X 
Function (BRIEF) 
Aben-ant Behavior 
Checklist - Community 
X 
(ABC-C) 
Final, Amendment 1 
Statistical Analysis Plan, Amendment 1 
01 March 2021 
Open-Label Maintenance 
FinalOL 
Safety 
Visit or 
(Visits will be eve1·y 16 weeks with a telephone follow up in-
Taper 
Follow-up 
between, this schedule continues after 68 weeks) 
Visif 
post taperJ 
68" and 
X/ or 
2 weeks 
28 
36 
44 
52 
60 
early 
post last 
X visit 
D/CJ 
dose 
± 14 
± 14 
± 14 
± 14 
± 14 
± 14 
± 14 
± 3 
days 
days 
days 
days 
days 
days 
days 
days 
Phone 
Visit 7 
Phone 
Visit 8 
Phone 
Visit 9 and 
Visit X 
VisitX 
follow-up 
follow-up 
follow-up 
VisitX 
X 
X 
X 
X 
X 
X 
xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Confidential 
Page 46 of54 


DocuSign Envelope ID: 90C2F347-C987-46E5-9577-D4E0A508C0AD 
Marinus Phannaceuticals, fuc. 
Study 1042-PCDH19-3002 
Final 
DB 
Titration 
Visit/ 
(4 weeks blinded) 
First 
OL 
Visit 
Week 
18, 19, 
17 
17+3 
21 
Days 
20 
±1 
±3 
±3 
isit Windows 
day(s) 
days 
days 
Phone 
Phone 
Visit 5 Follow-
Follow-
Visit 6 
up 
up 
Final, Amendment 1 
Statistical Analysis Plan, Amendment 1 
01 March 2021 
Open-Label Maintenance 
FinalOL 
Safety 
Visit or 
(Visits will be every 16 weeks with a telephone follow up in-
Taper 
Follow-up 
between, this schedule continues after 68 weeks) 
Visif 
post taper1 
68" and 
X/ 0 1· 
2 weeks 
28 
36 
44 
52 
60 
early 
post last 
X visit 
DIC1 
dose 
±14 
± 14 
± 14 
± 14 
±14 
± 14 
±14 
±3 
days 
days 
days 
days 
days 
days 
days 
days 
Phone 
Visit 7 
Phone 
Visit 8 
Phone 
Visit 9 and 
Visit X 
Visit X 
follow-up 
follow-up 
follow-up 
Visit X 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
Confidential 
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DocuSign Envelope ID: 90C2F347-C987-46E5-9577-D4E0A508C0AD 
Marinus Phannaceuticals, fuc. 
Study 1042-PCDH19-3002 
Statistical Analysis Plan, Amendment 1 
01 March 2021 
isit Windows 
Dispense 
Investigational 
Product 
Final 
DB 
Visit/ 
First 
OL 
Visit 
17 
Visit 5 
I 
X 
Titration 
(4 weeks blinded) 
Week 
18, 19, 
17+3 
21 
Days 
20 
±1 
±3 
±3 
day(s) 
days 
days 
Phone 
Phone 
Follow-
Follow-
Visit 6 
up 
up 
X 
Open-Label Maintenance 
FinalOL 
Safety 
Visit or 
(Visits will be eve1·y 16 weeks with a telephone follow up in-
Taper 
Follow-up 
between, this schedule continues after 68 weeks) 
Visif 
post taper1 
68" and 
X/ or 
2 weeks 
28 
36 
44 
52 
60 
early 
post last 
X visit 
D!C1 
dose 
± 14 
± 14 
± 14 
± 14 
± 14 
± 14 
± 14 
± 3 
days 
days 
days 
days 
days 
days 
days 
days 
Phone 
Visit 7 
Phone 
Visit 8 
Phone 
Visit 9 and 
Visit X 
Visit X 
follow-up 
follow-up 
follow-up 
Visit X 
I 
I 
I 
X 
X 
X 
X 
AED = antiepileptic <hug, BP = blood pressure, DB = double-blind, DIC = discontinuation, ECG = electrocardiogram, EEG = electroencephalogram, HR = heart rate, PK = 
phaimacokinetic, OL = open-label, RR = respirato1y rate, WCBP = women of childbearing potential. 
Note: The timing of the final OL visit is not defined at this time, as the study is anticipated to continue until either the investigational product is approved and marketed, or the 
Sponsor discontinues development of investigational product in PCDH19 (approximately an additional 3 years). 
a. 
If the subject continues in the OL phase beyond Week 68, a telephone follow-up visit will occur in between clinic visits (8 weeks ± 14 days after each clinic visit) to assess 
the following adverse events and seizure and medication dia1y review. 
b. 
In addition, weight will be measured at eve1y visit, except the safety follow-up visit. 
c. 
In addition, height will be measm·ed annually after Visit 8 (Week 52), except the safety follow-up visit. 
d. 
After Visit 8 (Week 52), ECGs to be performed annually (and at last OL visit). 
e. 
Chemistry & Hematology. 
f. 
Serum pregnancy test is required for all girls/women of childbearing potential. 
g. 
Conduct annually and at the final OL visit. 
Final, Amendment 1 
Confidential 
Page 48 of54 


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Marinus Pharmaceuticals, Inc. 
Study 1042-PCDH19-3002 
Statistical Analysis Plan, Amendment 1 
01 March 2021 
Final, Amendment 1 
Confidential 
Page 49 of 54 
 
 
 
 
h. 
For recording of seizures in the eDiary, seizure events will be recorded either as a countable seizure or a series of continuous uncountable seizures. Both of these events will 
be counted as 1 seizure (equally weighted) in the efficacy analysis. For recording of seizures in the eDiary, seizure events will be recorded either as a countable seizure or a 
series of continuous uncountable seizures. Both of these events will be counted as 1 seizure (equally weighted) in the efficacy analysis. A seizure cluster will be defined as 3 
or more seizure events (either a countable or a series of continuous uncountable seizures), occurring within a period of time, followed by a period of at least 24 hours of 
seizure-freedom. 
Examples: (Protocol Error! Reference source not found.): 
• 
If a child experiences 3 seizure events at 5:00, 5:30, and 6:00 PM on Monday, and the next seizure event occurs before 6:00 PM on Tuesday, the Monday and Tuesday 
seizure events are considered part of the same seizure cluster (Protocol Error! Reference source not found., Scenario 1). 
• 
If a child experiences 3 seizure events at 5:00, 5:30, and 6:00 PM on Monday, and the next seizure event occurs at 6:00 PM or later on Tuesday, the Tuesday seizure 
event is not considered part of the same cluster (Protocol Error! Reference source not found., Scenario 2). 
i. 
Population PK will be conducted at these visits (Visit 6: between 1-5 hours since the last IP dosing and Visit 8: between 1-5 hours since last IP dosing) 
j. 
Subjects who discontinue IP treatment before the completion of the DB phase will continue to be followed per protocol and, at a minimum, subjects will be encouraged to 
maintain daily seizure eDiary entries until the DB phase is completed. These subjects will also return to the site 2 to 4 weeks after the taper for safety follow-up post-taper 
assessments. 


DocuSign Envelope ID: 90C2F347-C987-46E5-9577-D4E0A508C0AD 
Marinus Pharmaceuticals, Inc. 
Statistical Analysis Plan, 
Amendment 1 
01 March 2021 
Study 1042-PCDH19-3002 
Final, Amendment 1 
Confidential 
Page 50 of 54 
 
 
 
14.2 CLINICAL LABORATORY TESTS AND NORMAL RANGES 
14.2.1 Clinical Laboratory Tests 
Clinical Chemistry 
Hematology 
Urinalysis 
Other 
 
Total Bilirubina 
Hemoglobin 
pH 
Drug Screend 
AST 
(SGOT)b 
Hematocrit 
Color 
 
 
ALT (SGPT)b 
Erythrocytes 
Clarity 
BUN 
Leukocytes + differential 
Specific Gravity 
 
Glucose 
Thrombocytes (platelet count)Urobilinogen 
Potassium 
 
Ketones 
Sodium 
Protein 
Calcium 
Glucose 
 
Alkaline Phosphatase 
Bilirubin 
Chloride 
Blood 
 
Creatinine 
Leukocyte esterase 
CO2 
Nitrite 
 
eGFRc 
Quantitative serum -human 
chorionic growth hormone 
( -HCG) serum pregnancy 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, BUN = blood urea nitrogen, eGFR = estimated 
glomerular filtration rate. 
a 
If total bilirubin increases to 1.5 x ULN or more during study, the subject will be discontinued. 
b 
If AST or ALT increases > 3 × ULN during the study, subject should be followed with weekly laboratory repeat 
testing and continue in study if levels trending down. Subject will be discontinued if levels do not decline to 
under 3 x ULN. 
c 
Subjects with significant renal insufficiency, eGFR < 30 mL/min (calculated using the Cockcroft-Gault formula), 
will be discontinued if the criterion is met post baseline. 
d 
Plasma drug screen for tetrahydrocannabinol (THC) and unapproved cannabidiol (CBD). 
 
 
14.2.2 Normal Ranges 
Age-adjusted normal ranges for laboratory tests assessed by the central lab are defined in 
the laboratory manual for the study and are imported with laboratory data. Normal ranges 
for local laboratories are captured directly in the clinical database with results. 


DocuSign Envelope ID: 90C2F347-C987-46E5-9577-D4E0A508C0AD 
Marinus Pharmaceuticals, Inc. 
Statistical Analysis Plan, 
Amendment 1 
01 March 2021 
Study 1042-PCDH19-3002 
Final, Amendment 1 
Confidential 
Page 51 of 54 
 
 
 
14.3 CRITERIA FOR POTENTIALLY CLINICALLY SIGNIFICANT ABNORMAL VALUES 
14.3.1 Potentially Clinically Significant Abnormal Laboratory Values 
 
 
 
Clinical Chemistry 
Hematology 
Urinalysis 
Total Bilirubin ≥ 1.5x 
ULN 
Hemoglobin < 0.85x LLN or >1.25x 
ULN 
pH ≤ 4 or >9 
AST (SGOT) ≥ 3x ULN 
Hematocrit < 0.85x LLN or >1.25x 
ULN 
Color N/A 
ALT (SGPT) ≥ 3x ULN 
Erythrocytes < 0.85x LLN or >1.25x 
ULN 
Clarity N/A 
BUN ≥ 1.5x ULN 
Leukocytes + differential (total) < 
0.50x LLN or >1.50x ULN 
Specific Gravity < 1.001 or > 
1.035 
Glucose < 0.8x LLN or 
>1.5x ULN 
Thrombocytes (platelet count) < 0.50x 
LLN or >1.50x ULN 
Urobilinogen > 4.0 mg/dL 
Potassium < 0.9x LLN 
or >1.1x ULN 
Ketones positive value if negative 
pre-Rx or ≥2 unit increase from 
pre-Rx 
Sodium < 0.95x LLN or 
>1.05x ULN 
Protein positive value if negative 
pre-Rx or ≥2 unit increase from 
pre-Rx 
Calcium < 0.9x LLN or 
>1.1x ULN 
Glucose positive value if negative 
pre-Rx or ≥2 unit increase from 
pre-Rx 
Alkaline Phosphatase ≥ 
1.5x ULN 
Bilirubin positive value if negative 
pre-Rx or ≥2 unit increase from 
pre-Rx 
Chloride < 0.9x LLN or 
>1.1x ULN 
Blood positive value if negative 
pre-Rx or ≥2 unit increase from 
pre-Rx 
Creatinine ≥ 1.5x ULN 
Leukocyte esterase positive value 
if negative pre-Rx or ≥2 unit 
increase from pre-Rx 
CO2 < 0.8x LLN or 
>1.2x ULN 
Nitrite positive value if negative 
pre-Rx or ≥2 unit increase from 
pre-Rx 


DocuSign Envelope ID: 90C2F347-C987-46E5-9577-D4E0A508C0AD 
Marinus Pharmaceuticals, Inc. 
Statistical Analysis Plan, 
Amendment 1 
01 March 2021 
Study 1042-PCDH19-3002 
Final, Amendment 1 
Confidential 
Page 52 of 54 
 
 
 
 
eGFRc < 0.8 x LLN 
(LLN=90, regardless of 
calculation method) 
 
 
14.3.2 Potentially Clinically Significant ECG Criteria 
HR: 
See criteria in Vital Signs 
PR interval: 
< 0.9 x LLN or >1.1 x ULN 
QRS: 
>1.1 x ULN 
QTc B/FN interval: 
 
≥ 470 msec (females) 
or increase ≥ 60 msec from baseline (note. QTc is not changing with age) 
QT Prolongation analysis uses the reported, corrected QT interval from the study data, 
and it also computes corrected QTc intervals using the following three industry-standard 
formulas, which are the same except for the correction factor applied to the RR interval: 
• 
QTcB is the length of the QT interval corrected for the RR interval by Bazett’s 
formula: QTcB = QTmsec / (RR sec)0.5 
• 
QTcN is the length of the QT interval corrected for the RR interval by FDA 
Neuropharmacological Division’s formula: QTcN = QTmsec / (RR sec)0.37 
• 
QTcF is the length of the QT interval corrected for the RR interval by Fridericia’s 
formula: QTcF = QTmsec / (RR sec)0.33 


DocuSign Envelope ID: 90C2F347-C987-46E5-9577-D4E0A508C0AD 
Marinus Pharmaceuticals, Inc. 
Statistical Analysis Plan, 
Amendment 1 
01 March 2021 
Study 1042-PCDH19-3002 
Final, Amendment 1 
Confidential 
Page 53 of 54 
 
 
 
PR, QRS Normal Ranges: 
 
Age 
PR Interval 
(sec)* 
QRS Duration 
(sec)† 
1–3 yr 
0.10–0.14 
<= 0.07 
4–5 yr 
0.11–0.15 
<= 0.08 
6–8 yr 
0.12–0.16 
<= 0.08 
9–11 yr 
0.12–0.17 
<= 0.09 
12–16 yr 
0.12–0.17 
<= 0.10 
>16 yr 
0.12–0.20 
<= 0.10 
 
14.3.3 Potentially Clinically Significant Vital Signs Values 
HR: 
High: 1.20 x ULN; or an ≥ 15 bpm increase from baseline if clinically significant 
at baseline 
Low: 0.80 x LLN; or an ≥ 15 bpm decrease from baseline if clinically significant 
at baseline 
Systolic BP: 
High: 1.5 x ULN; or an ≥ 20 increase from baseline if clinically significant at 
baseline 
Low: 0.75 x LLN; or an ≥ 20 decrease from baseline if clinically significant at 
baseline 
Diastolic BP: 
High: 1.3 x ULN; or an ≥ 15 increase from baseline if clinically significant at 
baseline 
Low: 0.70 x LLN; or an ≥ 15 decrease from baseline if clinically significant at 
baseline 
Respiratory Rate 


DocuSign Envelope ID: 90C2F347-C987-46E5-9577-D4E0A508C0AD 
Marinus Pharmaceuticals, Inc. 
Statistical Analysis Plan, 
Amendment 1 
01 March 2021 
Study 1042-PCDH19-3002 
Final, Amendment 1 
Confidential 
Page 54 of 54 
 
 
 
Low: 0.80 x LLN 
High 1.25 x ULN 
Vital Signs Normal Ranges by Age 
 
Age 
HR (beats/min) 
BP (mm Hg) 
RR (breaths /min) 
1 – 3 yrs 
80 - 125 
90 – 105 / 55 - 70 
20 - 30 
3 – 6 yrs 
70 - 115 
95 – 110 / 60 - 75 
20 - 25 
6 – 12 yrs 
60 – 100 
100 – 120 / 60 – 75 
14 - 22 
>12 yrs 
60 – 100 
100 – 120 / 70 – 80 
12 - 18