A Phase 3, Open-label Study of Adjunctive Ganaxolone (GNX) Treatment in Children and Adults With Tuberous Sclerosis Complex (TSC)-Related Epilepsy (TrustTSC OLE)
Phase: PHASE3
Conditions: Tuberous Sclerosis Complex
Sponsor: Marinus Pharmaceuticals

Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3002 
Protocol Date and Version: 19 Apr 2023; v4.0 
 
CONFIDENTIAL 
Page 1 of 106 
 
TITLE PAGE 
Protocol Title: A Phase 3, Open-label Study of Adjunctive Ganaxolone (GNX) Treatment in 
Children and Adults with Tuberous Sclerosis Complex (TSC)-related Epilepsy 
(TrustTSC OLE) 
Protocol Number: 1042-TSC-3002 
Compound: Ganaxolone 
Brief Title: Open-label study of adjunctive GNX treatment in children and adults with 
TSC-related epilepsy 
Indication: TSC-related epilepsy 
Study Phase: Phase 3 
Sponsor Name: Marinus Pharmaceuticals Inc. 
Legal Registered Address: 5 Radnor Corporate Center 
100 Matsonford Rd, Suite 500 
Radnor, PA 19087 US 
Regulatory Agency Identifier Numbers: 
Registry 
ID 
IND 
155634 
EudraCT 
2021-003384-10 
EU CT 
2022-503067-15-00 
 
Protocol version/date 
Document Version 
Approval Date 
Protocol Amendment 3; v4.0 
19 Apr 2023 
Protocol Amendment 2; v3.0 
08 Dec 2022 
Protocol Amendment 1; v2.0 
01 Jun 2022 
Original (v1.0 [superseded]) 
14 Oct 2021 
CONFIDENTIALITY NOTICE 
The information contained in this protocol and all other information relevant to ganaxolone are 
the confidential and proprietary information of Marinus Pharmaceuticals Inc. and, except as may 
be required by federal, state, or local laws or regulation, may not be disclosed to others without 
the prior written permission of Marinus Pharmaceuticals Inc. 

Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3002 
Protocol Date and Version: 19 Apr 2023; v4.0 
 
CONFIDENTIAL 
Page 2 of 106 
Sponsor Signatory: 
Protocol Number: 1042-TSC-3002 
Protocol Title:  
A Phase 3, Open-label Study of Adjunctive Ganaxolone (GNX) Treatment in Children and 
Adults with Tuberous Sclerosis Complex (TSC)-related Epilepsy (TrustTSC OLE) 
 
I, the undersigned, have approved of the clinical trial protocol with the date of 19 Apr 2023 
 
 
Vice President, Clinical Development 
 
Date 
 
Medical Monitor Name and Contact Information is provided in Section 10.2. 
 
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Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3002 
Protocol Date and Version: 19 Apr 2023; v4.0 
 
CONFIDENTIAL 
Page 3 of 106 
INVESTIGATOR AGREEMENT 
Protocol Number: 1042-TSC-3002 
Protocol Title:  
A Phase 3, Open-label Study of Adjunctive Ganaxolone (GNX) Treatment in Children and 
Adults with Tuberous Sclerosis Complex (TSC)-related Epilepsy (TrustTSC OLE) 
 
I have read the protocol, including all appendices, and I agree that it contains all the necessary 
information for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein, in compliance with current Good Clinical Practice (GCP) standards as defined 
by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) Guideline for GCP, all applicable national, state, and local laws and 
regulations, and the applicable Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) and other institutional requirements.  
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Marinus Pharmaceuticals Inc. or 
specified designees. I will discuss the material with them to ensure that they are fully informed 
about ganaxolone (GNX), understand this study, and are able to comply. 
 
______________________________  
__________________________ 
Principal Investigator Name (printed)  
Signature 
______________________________ 
Date 
 

Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3002 
Protocol Date and Version: 19 Apr 2023; v4.0 
 
CONFIDENTIAL 
Page 4 of 106 
SUMMARY OF CHANGES FROM PREVIOUS VERSION 
Protocol Amendments 
Summary of Changes Since Last Version of Approved Protocol 
Amendment Number 
3 
Amendment Date 
19 Apr 2023 
Global/Country/ 
Site-Specific 
Global 
Rationale for the Amendment 
The following changes are made in this global protocol amendment from version 3.0 to version 4.0 to: 
• 
Reflect changes to the maximum overall study duration from 1 year to 3 years. 
• 
Include updated information regarding completed and ongoing clinical studies. 
• 
Add details on pregnancy testing. 
Description of Changes 
Section(s) Affected by 
Change 
Minor editorial updates throughout for administrative changes, grammar, 
consistency, and clarity. 
Throughout the document 
Updated Protocol amendment date and version. 
Protocol header, Title 
page, and Sponsor 
Signatory page 
Applied a correction to the Protocol Title on the signatory pages; “Trial” corrected to 
“Study” 
Sponsor Signatory page 
and Investigator 
Agreement page 
The estimated duration of the study was updated from 1 year to 3 years. 
Section 1.1, Section 1.3, 
Section 4.1.1, and 
Section 6.2. 
Updated rationale text to clarify the completion of Study 1042-TSC-2001 and added 
summary text for the ongoing Study 1042-TSC-3001. 
Section 1.1 and 
Section 2.2.2.1.1 
Updated secondary objectives and endpoints to specify objectives and endpoints 
which are only to be assessed in Year 1. 
Section 1.1, Section 3, 
and Section 9.2.3 
Added text to clarify that seizure eDiaries will be completed in Year 1 of the study 
only. 
Section 1.1, Section 4.1, 
Section 6.5, and 
Section 6.6.1 
Added text to clarify that after Year 1, study assessments will focus on safety 
evaluation and that caregiver and clinician impressions of improvement will continue 
to ensure continued treatment benefit. 
Section 1.1, and 
Section 4.1 
Updated text to align with the Visit numbers and dates in the revised Schedule of 
Activities (SoA) for inclusion of Years 2 and 3, including references to the Early 
Termination Visit and End of Study definition. 
Section 1.1, Section 4.1, 
Section 4.4, Section 7.1, 
Section 7.2, Section 8.1.2, 
Section 8.1.3, 
Section 8.2.2, 
Section 8.2.3, 
Section 8.3.1, 
Section 8.3.2, 
Section 8.3.3, 
Section 8.3.4, and 
Section 8.3.5 

Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3002 
Protocol Date and Version: 19 Apr 2023; v4.0 
 
CONFIDENTIAL 
Page 5 of 106 
New exclusion criterion 8. 
Added: 
• 
Exposed to any other investigational drug (except for GNX in Study 
1042-TSC-2001 or Study 1042-TSC-3001) or investigational device within 
30 days or fewer than 5 half-lives prior to Visit 1 (first visit of the OLE). For 
therapies in which half-life cannot be readily established, the Sponsor’s 
medical monitor should be consulted. 
Section 1.1, and 
Section 5.2 
Updated Study schematic diagram to reflect change to study duration. 
Section 1.2 
Updated SoA table to include assessments for Year 2 and Year 3. 
Section 1.3, Table 1 
Updated pregnancy testing information to clarify that urine pregnancy tests will be 
dispensed at Visit 1 for take-home pregnancy testing to occur every 4 weeks 
thereafter. 
Section 1.3, Table 1, and 
Table 1 (footnotes) 
Updated pregnancy assessment to include clarification for the reporting procedure in 
the case of a positive take home pregnancy test. 
Section 1.3, Table 1 
(footnotes), and 
Section 10.3, Table 3 
(footnotes) 
Deleted text describing a washout period which is not relevant to the present study.  
Section 6.6 
Added text to clarify that assessments conducted by travelling nurses only applies to 
sites located outsite of the European Union (EU). 
Section 8 
Updated text to clarify that an enrollment log will be maintained by the investigator 
for all participants from 1042-TSC-3001 and 1042-TSC-2001. 
Section 8 
Added a new section to describe pregnancy testing assessments. 
Section 8.3.8 
Deleted text describing site termination criteria which were not applicable for this 
study 
Section 10.1.9.2 
Updated sample retention requirements from 1 year to 6 months to comply with EU 
requirements. 
Section 10.1.11 
Updated plasma drug screen procedure to clarify that this will occur during the first 
visit of the open-label extension. 
Section 10.3, Table 3 
(footnotes) 

Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3002 
Protocol Date and Version: 19 Apr 2023; v4.0 
 
CONFIDENTIAL 
Page 6 of 106 
SUMMARY OF CHANGES FROM PREVIOUS VERSION 
Protocol Amendments 
Summary of Changes Since Last Version of Approved Protocol 
Amendment Number 
2 
Amendment Date 
08 Dec 2022 
Global/Country/ 
Site-Specific 
Global 
Rationale for the Amendment 
The following changes are made in this global protocol amendment from version 2.0 to version 3.0 to: 
• 
Add a section on contraception use, including acceptable barrier methods. 
• 
Elaborate on dose adjustments and rescue medications. 
• 
Updated information of the Investigational Product (IP) background and the ganaxolone (GNX) Clinical 
Development Program with the most current information and to align with the current version of the 
Investigator’s Brochure (IB). 
• 
Add a new section to include Suspected Unexpected Serious Adverse Reaction (SUSAR) language. 
• 
Update Informed consent form (ICF) processes to include that minor participants must be re-consented if 
they reach the age of majority during the course of the study and to delete any reference of separate 
section in the ICF for optional exploratory research. 
Description of Changes 
Section(s) Affected by 
Change 
Minor editorial updates throughout for grammar, consistency, and clarity. 
Removed “sexually active girls” when referring to women of childbearing potential 
(WOCBP).  
Replaced “subjects” with “participants”. 
Throughout the document 
Updated Protocol amendment date and version in the header. 
Protocol header 
Updated the list of abbreviations. 
List of Abbreviations 
Exploratory objective removed from Synopsis. 
Section 1.1 
Updated information of the IP background and the GNX Clinical Development 
Program with the most current information and to align with the current version of 
the IB. 
Section 1.1, Section 2.2.2, 
and Section 2.2.2.1 
Updated endpoints subheaders in “objectives and endpoints” 
Section 1.1 and Section 3 
Specified that version 2 of the Short Form 36 (SF-36) will be used during the study. 
Section 1.1 (footnote), 
Section 1.3 (footnote), 
Section 3 (footnote), 
Section 8.2.4, and 
Section 10.10 
Updates to inclusion criterion 2. 
Added:  
• 
If the participant is not qualified or able to provide written informed consent 
based on age, developmental stage, intellectual capacity, or other factors, 
parent(s)/LAR(s) must provide assent for study participation, if appropriate.  
Section 1.1 and 
Section 5.1 

Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3002 
Protocol Date and Version: 19 Apr 2023; v4.0 
 
CONFIDENTIAL 
Page 7 of 106 
Updated the first definition of seizure types that do not count towards the primary 
endpoint: 
Replaced: 
• 
Focal aware seizures without motor features (eg, absence or focal nonmotor 
seizures with or without impairment of awareness). 
With   
• 
Focal or generalized nonmotor seizures (eg, absence seizures or focal 
nonmotor seizures with or without impairment of awareness). 
Section 1.1, Section 3, 
Section 5.1, 
Section 8.1.1.2, and 
Section 8.2.1 
Revised contraception information throughout the protocol (inclusion criteria 5 and 
6). 
Removed abstinence as an acceptable form of birth control. 
Deleted: 
• 
Participants who are not sexually active, abstinence is an acceptable form. 
Section 1.1, Section 5.1, 
Section 10.5.1, 
Section 10.5.2, and 
Section 10.5.3 
Specified in Table 3 (Laboratory tests) that a urine drug screen could be performed if 
a plasma sample is difficult or impossible to obtain. 
Section 10.3  
Storage conditions updated to include a new window of temperature to store the IP in 
°F and °C. 
Section 6.1 and 
Section 6.3.1 
Dosing modifications language updated to indicate the approaches to GNX dosing to 
manage tolerability. 
Section 6.2 
Updated text for rescue medication to include additional information on seizure 
clusters and to include rescue medications permitted for the study. 
Section 6.6.1 
Revised text to include laboratory parameters for discontinuation. 
Section 7.2 
Removed 12-lead electrocardiograms (ECG) assessment to be completed by a mobile 
vendor. 
Section 8 
Added a note for Investigational Sites in the United Kingdom (UK) related to the 
study procedures. 
Added: 
Note for Investigational Sites in the UK: National Health Service (NHS) 
sites in the UK will be aware of the study by virtue of the investigators 
participating in the site initiation visit, and being trained on the study design, 
conduct, and participant protection policies. 
Section 8.1.1 
Text revised to change CKD-EPI formula to calculate estimated glomerular filtration 
rate (eGFR) with Cockcroft-Gault formula or pediatric GFR calculator or Bedside 
Schwartz. 
Added text related to maximum amount of blood that will be collected from 
participants (previously in Section 8). 
Section 8.3.4 
Added a new section to include Suspected Unexpected Serious Adverse Reaction 
(SUSAR) language.  
Section 8.4.4.1 

Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3002 
Protocol Date and Version: 19 Apr 2023; v4.0 
 
CONFIDENTIAL 
Page 8 of 106 
Updated ICF processes to include that minor participants must be re-consented if 
they reach the age of majority during the course of study and to delete any reference 
of separate section in the ICF for optional exploratory research. 
Added:   
• 
Minor participants must be re-consented if they reach the age of majority 
during the course of the study, in order to continue participating.  
Deleted:  
• 
The ICF will contain a separate section that addresses the use of remaining 
mandatory samples for optional exploratory research. The investigator or 
authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to 
participate and may withdraw their consent at any time and for any reason 
during the storage period. A separate signature will be required to document 
a participant’s agreement to allow any remaining specimens to be used for 
exploratory research. Participants who decline to participate in this optional 
research will not provide this separate signature. 
Section 10.1.3 
Updated sample storage period to 1 year instead of 2 years. 
Section 10.1.11 
Contact details for Marinus Project Managers updated. 
Section 10.2.2.2 
Minor pictures updates in Dosing Instructions. 
Section 10.7 

Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3002 
Protocol Date and Version: 19 Apr 2023; v4.0 
 
CONFIDENTIAL 
Page 9 of 106 
SUMMARY OF CHANGES FROM PREVIOUS VERSION 
Protocol Amendments 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 
1 
Amendment Date 
01 June 2022 
Global/Country/ 
Site-Specific 
Global 
Rationale for the Amendment 
The rationale for the major changes in this protocol amendment are as follows: 
• 
The maximum study duration was changed from 2 years to 1 year and study visits updated according to 
1-year duration. 
• 
12-lead electrocardiogram (ECG) and clinical safety laboratory tests (hematology, clinical chemistry, and 
urinalysis) were added as they will be evaluated as part of the safety assessment in the open-label 
extension (OLE) study. 
• 
The ganaxolone (GNX) suspension stability was updated from 2 years to 18 months. 
• 
The dosing instructions for the oral suspension were updated to match the package insert. 
• 
The Short Form 36 (SF-36) was updated for better clarity. 
Description of Changes 
Section(s) Affected by 
Change 
Minor editorial updates made throughout for grammar, consistency, and clarity. 
Throughout the document 
Updated cross references. 
Throughout the document 
Replaced the term anti-epileptic drugs (AEDs) with the preferred term anti-seizure 
medication (ASM) per TSC Alliance. 
Throughout the document 
Updated definition of mTOR from “mammalian target of rapamycin” to the preferred 
definition “mechanistic target of rapamycin” per TSC Alliance. 
Throughout the document 
Protocol date and version added to the header. 
Protocol header, Title 
Page 
The Investigational New Drug (IND) number was corrected, and the EudraCT 
number was added. 
Title Page 
Protocol short name “TrustTSC OLE” added to the protocol title. 
Title Page, Sponsor 
Signatory, Investigator 
Agreement, Section 1.1 
Updated the List of Abbreviations. 
List of Abbreviations 
The Data Monitoring Committee (DMC) was eliminated. 
List of Abbreviations, 
Section 2.3.1, Section 
8.4.7, Section 10.1.6 
Clarified the term children used along the document refers to the full range of 
pediatric participants to cover the full span of age per the International Council for 
Harmonisation (ICH) definition. 
Section 1.1, Section 4.1 
Updated the Synopsis to include the eligibility criteria from the main body of the 
protocol. 
Section 1.1 
The estimated duration of the study was updated from 2 years to 1 year.  
Section 1.1, Section 1.3, 
Section 4.1.1, Section 6.2 
Removed Study Visits at Weeks 65, 78, 91, and 104, and Safety Follow-up visit 
changed from Visit 10 (Week 108) to Visit 6 (Week 56). 
Section 1.1, Section 1.3, 
Section 4.1, Section 4.4, 

Ganaxolone 
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Protocol 1042-TSC-3002 
Protocol Date and Version: 19 Apr 2023; v4.0 
 
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Section 7.1, Section 7.2, 
Section 8.1.2, 
Section 8.1.3, 
Section 8.2.2, 
Section 8.2.3, 
Section 8.2.4, 
Section 8.3.1, 
Section 8.3.2, 
Section 8.3.5 
Added and described 12-lead ECG evaluation. 
Section 1.1, Section 2.3.1, 
Section 3, Section 8, 
Section 8.3.3, Section 
8.4.5, Section 9.2.2, 
Section 9.2.5, Section 10.3 
(Table 3) 
Added and described clinical safety laboratory testing (hematology, clinical, 
chemistry, and urinalysis). 
Section 1.1, Section 2.3.1, 
Section 3, Section 8.3.4, 
Section 8.4.5, 
Section 9.2.2, 
Section 9.2.5, 
Section 10.3 (Table 3) 
Revised male contraception requirements to state these should be continued for 
30 days after the last dose of investigational product (IP). 
Section 1.1, Section 5.1, 
Section 10.5.2 
Updated text to align with the most recent version of the Investigator’s Brochure 
(December 2021). 
Section 1.1, Section 2.2.2, 
Section 2.2.2.1, 
Section 2.2.2.1.1, 
Section 2.2.2.2, 
Section 2.3.1 
Indicated the duration of OLE long-term GNX treatment and maintenance period (52 
weeks) for better clarity. 
Section 1.2 
Central ASM level collection was eliminated. 
Section 1.3, Section 8.3.6, 
Section 10.3 (Table 3) 
The schedule of activities (SOA) was amended to: 
• 
Specify type of study visits (in person or phone visits). 
• 
Indicate visits for 12-lead ECG. 
• 
Indicate visits for clinical laboratory test (hematology, clinical chemistry, 
and urinalysis). 
• 
Add concomitant medication review visits. 
• 
Update and reorganize table footnotes. 
• 
Update table abbreviations. 
Section 1.3 
Number of study sites participating in the OLE study was updated from 60 to 75. 
Section 4.1.3 
Updated in scientific rationale for study design from “patient populations being 
pursued for development” to “patient populations that may benefit from GNX 
treatment”. 
Section 4.2 
Updated GNX suspension stability from “at least 2 years” to “at least 18 months”. 
Included the recommendation of using the suspension within 30 days after opening. 
Section 6.1 (Table 2) 
Indicated pediatric blood volumes collection should be minimized as much as 
possible. 
Section 8 

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Protocol 1042-TSC-3002 
Protocol Date and Version: 19 Apr 2023; v4.0 
 
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Eliminated statement related to GNX concentration that may unblind the study since 
it is not applicable to the OLE study. 
Section 8.6.1 
Updated criteria of study termination to describe reasons for study termination.  
Section 10.1.9.2 
Updated back-up Sponsor Project Managers. 
Section 10.2.2.2 
Included vital signs (blood pressure [BP], heart rate [HR], respiratory rate [RR], and 
body temperature) in Table 3. 
Section 10.3 (Table 3) 
Eliminated the statement “Data collection laws in France prohibit the collection of 
data on race and ethnicity” as the laws of this country allows these data collection. 
Section 10.6 
Updated dosing instructions for the oral suspension to match the package insert. 
Section 10.7 
Updated SF-36 to a more comprehensible format for participants. 
Section 10.10 
 
 

Ganaxolone 
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Protocol 1042-TSC-3002 
Protocol Date and Version: 19 Apr 2023; v4.0 
 
CONFIDENTIAL 
Page 12 of 106 
TABLE OF CONTENTS 
1 
PROTOCOL SUMMARY ................................................................................................. 19 
1.1 
Synopsis ........................................................................................................................ 19 
1.2 
Schema .......................................................................................................................... 26 
1.3 
Schedule of Activities .................................................................................................... 27 
2 
INTRODUCTION ............................................................................................................. 29 
2.1 
Study Rationale ............................................................................................................. 29 
2.2 
Background ................................................................................................................... 29 
2.2.1 
Disease Background ................................................................................................ 29 
2.2.2 
Investigational Product Background: Ganaxolone .................................................... 30 
2.3 
Benefit/Risk Assessment ............................................................................................... 33 
2.3.1 
Risk Assessment ...................................................................................................... 33 
2.3.2 
Benefit Assessment .................................................................................................. 33 
2.3.3 
Overall Benefit: Risk Conclusion ............................................................................. 33 
3 
OBJECTIVES AND ENDPOINTS .................................................................................... 34 
4 
STUDY DESIGN ............................................................................................................... 35 
4.1 
Overall Design............................................................................................................... 35 
4.1.1 
Study Duration for Participation .............................................................................. 36 
4.1.2 
Number of Participants ............................................................................................ 36 
4.1.3 
Number of Sites ....................................................................................................... 36 
4.2 
Scientific Rationale for Study Design ............................................................................ 36 
4.3 
Justification for Dose ..................................................................................................... 37 
4.4 
End of Study Definition ................................................................................................. 37 
5 
STUDY POPULATION ..................................................................................................... 37 
5.1 
Inclusion Criteria ........................................................................................................... 37 
5.2 
Exclusion Criteria .......................................................................................................... 38 
5.3 
Lifestyle Considerations ................................................................................................ 39 
5.3.1 
Meals and Dietary Restrictions ................................................................................ 39 
5.4 
Screen Failures .............................................................................................................. 39 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .................................. 39 
6.1 
Study Intervention(s) Administered ............................................................................... 39 
6.2 
Dose Modification ......................................................................................................... 41 
6.3 
Preparation, Handling, Storage, and Accountability ....................................................... 41 
6.3.1 
Storage .................................................................................................................... 41 
6.3.2 
Investigational Product Accountability..................................................................... 42 
6.4 
Measures to Minimize Bias............................................................................................ 44 
6.5 
Study Intervention Compliance ...................................................................................... 44 
6.6 
Concomitant Therapy .................................................................................................... 44 

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Protocol 1042-TSC-3002 
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6.6.1 
Rescue Medicine...................................................................................................... 45 
6.6.2 
Excluded Medications .............................................................................................. 45 
6.7 
Intervention After the End of the Study ......................................................................... 46 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................... 46 
7.1 
Discontinuation of Study Intervention ........................................................................... 46 
7.2 
Discontinuation/Withdrawal from the Study .................................................................. 47 
7.3 
Lost to Follow-up .......................................................................................................... 48 
8 
STUDY ASSESSMENTS AND PROCEDURES ............................................................... 48 
8.1 
General Study Periods ................................................................................................... 49 
8.1.1 
Screening, Enrollment, Randomization, and Baseline .............................................. 49 
8.1.2 
Open-label Treatment Phase .................................................................................... 50 
8.1.3 
Safety Follow-up ..................................................................................................... 50 
8.2 
Efficacy Assessments .................................................................................................... 51 
8.2.1 
Seizure Type and Frequency .................................................................................... 51 
8.2.2 
Clinical Global Impression – Improvement .............................................................. 52 
8.2.3 
Caregiver Global Impression of Change in Seizure Intensity/Duration ..................... 52 
8.2.4 
Short Form 36 .......................................................................................................... 52 
8.3 
Safety Assessments ....................................................................................................... 52 
8.3.1 
Physical/Neurological/Developmental Examinations ............................................... 53 
8.3.2 
Vital Signs ............................................................................................................... 54 
8.3.3 
Electrocardiograms .................................................................................................. 54 
8.3.4 
Clinical Safety Laboratory Tests .............................................................................. 55 
8.3.5 
Suicidal Ideation and Behavior Risk Monitoring (Columbia-Suicide Severity 
Rating Scale) .......................................................................................................... 56 
8.3.6 
Concomitant Anti-seizure Medicine Levels .............................................................. 56 
8.3.7 
Investigational Product Pharmacokinetics ................................................................ 56 
8.3.8 
Pregnancy Testing ................................................................................................... 57 
8.4 
Adverse Events and Serious Adverse Events ................................................................. 57 
8.4.1 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information ..................................................................................... 57 
8.4.2 
Method of Detecting Adverse Events and Serious Adverse Events ........................... 58 
8.4.3 
Follow-up of Adverse Events and Serious Adverse Events....................................... 58 
8.4.4 
Regulatory Reporting Requirements for Serious Adverse Events ............................. 59 
8.4.5 
Clinical Laboratory and Other Safety Evaluations .................................................... 60 
8.4.6 
Death Events............................................................................................................ 60 
8.4.7 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events ............................................................. 60 
8.4.8 
Adverse Events of Special Interest ........................................................................... 61 
8.4.9 
Pregnancy ................................................................................................................ 61 

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8.4.10 
Abuse, Misuse, Overdose, and Medication Error ...................................................... 62 
8.5 
Treatment of Overdose .................................................................................................. 62 
8.6 
Pharmacokinetics and Pharmacodynamics ..................................................................... 63 
8.6.1 
Pharmacokinetics ..................................................................................................... 63 
8.6.2 
Pharmacodynamics .................................................................................................. 63 
8.7 
Genetics ........................................................................................................................ 63 
8.8 
Biomarkers .................................................................................................................... 64 
8.9 
Immunogenicity Assessments ........................................................................................ 64 
8.10 
Health Economics .......................................................................................................... 64 
9 
STATISTICAL CONSIDERATIONS ................................................................................ 64 
9.1 
Analysis Sets ................................................................................................................. 64 
9.2 
Statistical Analyses ........................................................................................................ 64 
9.2.1 
General Considerations ............................................................................................ 64 
9.2.2 
Primary Endpoints ................................................................................................... 65 
9.2.3 
Secondary Endpoints Analysis ................................................................................. 65 
9.2.4 
Pharmacokinetic Analysis ........................................................................................ 65 
9.2.5 
Safety Analyses ....................................................................................................... 66 
9.2.6 
Subgroup Analysis ................................................................................................... 66 
9.3 
Interim Analysis ............................................................................................................ 66 
9.4 
Sample Size Determination ............................................................................................ 67 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ......... 68 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .......................... 68 
10.1.1 
Regulatory and Ethical Considerations ..................................................................... 68 
10.1.2 
Financial Disclosure ................................................................................................ 68 
10.1.3 
Informed Consent Process........................................................................................ 69 
10.1.4 
Data Collection ........................................................................................................ 69 
10.1.5 
Data Protection ........................................................................................................ 70 
10.1.6 
Dissemination of Clinical Study Data ...................................................................... 70 
10.1.7 
Data Quality Assurance ........................................................................................... 70 
10.1.8 
Source Documents ................................................................................................... 72 
10.1.9 
Study and Site Start and Closure .............................................................................. 72 
10.1.10 
Publication Policy .................................................................................................... 73 
10.1.11 
Sample Storage and Destruction .............................................................................. 73 
10.2 
Appendix 2: Emergency Contact Information ................................................................ 75 
10.2.1 
Serious Adverse Event Reporting............................................................................. 75 
10.2.2 
Sponsor Contacts ..................................................................................................... 75 
10.3 
Appendix 3: Clinical Laboratory Safety Tests ................................................................ 76 
10.4 
Appendix 4: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................... 78 
10.4.1 
Definition of AE ...................................................................................................... 78 

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10.4.2 
Definition of SAE .................................................................................................... 80 
10.4.3 
Recording and Follow-up of AE and/or SAE ........................................................... 81 
10.4.4 
Reporting of SAEs ................................................................................................... 83 
10.5 
Appendix 5: Contraceptive and Barrier Guidance .......................................................... 84 
10.5.1 
Female Contraception .............................................................................................. 84 
10.5.2 
Male Contraception.................................................................................................. 84 
10.5.3 
Acceptable Barrier Methods of Contraception .......................................................... 84 
10.6 
Appendix 6: Country-specific Requirements .................................................................. 85 
10.7 
Appendix 7: Dosing Instructions for Oral Suspension .................................................... 86 
11 REFERENCES ................................................................................................................ 105 
 
LIST OF TABLES 
Table 1. 
Schedule of Activities for Open-Label Phase...................................................... 27 
Table 2. 
Study Intervention(s) Administered .................................................................... 40 
Table 3. 
Protocol-required Safety Laboratory Tests ......................................................... 77 
 
LIST OF FIGURES 
Figure 1. 
Study Schematic Diagram .................................................................................. 26 
 

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LIST OF ABBREVIATIONS 
ACTH 
adrenocorticotropic hormone 
ADL 
activities of daily living  
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ASM 
anti-seizure medication 
AST 
aspartate aminotransferase 
ȕ-HCG 
ȕ-human chorionic growth hormone  
BP 
blood pressure 
CBD 
cannabidiol  
CDD 
cyclin-dependent kinase-like 5 deficiency disorder 
CGI-CSID 
Caregiver Global Impression of Change in Seizure Intensity/Duration  
CGI-I 
Clinical Global Impression of Improvement  
CIOMS 
Council for International Organizations of Medical Sciences 
CNS 
central nervous system  
CRF 
case report form 
CRO 
contract research organization  
CSA 
Controlled Substances Act 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DEA 
Drug Enforcement Agency 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eDiary 
electronic seizure diary  
eGFR 
estimated glomerular filtration rate 
FXS 
Fragile X syndrome  
GABA 
Ȗ-aminobutyric acid  
GCP 
Good Clinical Practice  
GFR 
glomerular filtration rate 
GNX 
ganaxolone 
GTP 
guanosine triphosphate 
HR 
heart rate 
IB 
Investigator´s Brochure 
ICF 
informed consent form 

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ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP/IP 
Investigational (Medicinal) Product 
IRB 
Institutional Review Board 
IS 
infantile spasms  
ITT 
intent-to-treat  
LAR 
legally authorized representative  
mTOR 
mechanistic target of rapamycin 
mTORC1 
mechanistic target of rapamycin complex 1  
NHS 
National Health Service 
OL 
open-label  
OLE 
open-label extension 
PCDH 
protocadherin 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PPD 
postpartum depression 
PRN 
pro re nata (as needed) 
PTSD 
posttraumatic stress disorder 
QTL 
quality tolerance limit 
Rheb 
Ras homolog enriched in brain  
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan  
SE 
status epilepticus  
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SF-36 
Short Form 36 
SIB 
suicidal ideation and behavior 
SIF/DRF 
Seizure Identification Form/Diagnostic Review Form  
SOA 
schedule of activities 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event  
THC 
tetrahydrocannabinol 
THP 
tetrahydroprogesterone  
tid 
3 times a day 
TQT 
thorough QT  

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TSC 
Tuberous Sclerosis Complex  
TSC1 
hamartin  
TSC2 
tuberin  
UK 
United Kingdom 
ULN 
upper limit of normal 
US 
United States 
VNS 
vagal nerve stimulator 
WOCBP 
women of childbearing potential  
 
 
 

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1 PROTOCOL SUMMARY 
1.1 Synopsis 
Protocol Title: 
A Phase 3, Open-label Study of Adjunctive Ganaxolone (GNX) Treatment in Children and 
Adults with Tuberous Sclerosis Complex (TSC)-related Epilepsy (TrustTSC OLE). 
Brief Title: 
Open-label study of adjunctive GNX treatment in children and adults with TSC-related epilepsy. 
Indication: TSC-related epilepsy. 
Rationale: 
TSC is a multi-system disorder of embryonal cortical development that can affect many organs 
through the overgrowth of benign tumors known as hamartomas. While the disease phenotype 
can be extremely variable, neurologic manifestations such as epilepsy can be seen in up to 90% 
of patients with TSC (Krueger and Northrup, 2013). The condition is caused by inherited 
mutations in either the TSC1 (hamartin) gene, located on chromosome 9q34, or the TSC2 
(tuberin) gene located on chromosome 16p13.3. TSC occurs with a frequency of 1:6,000 and a 
mutation is found in 85% of patients (Jülich and Sahin, 2014). The gene products hamartin 
(TSC1) and tuberin (TSC2) form a regulatory complex responsible for limiting the activity of 
mechanistic target of rapamycin complex 1 (mTORC1), an important intracellular regulator of 
growth and metabolism via its inhibition of the small GTPase Ras homolog enriched in brain 
(Rheb) (Krueger and Northrup, 2013). Everolimus (Afinitor®), a mechanistic target of rapamycin 
(mTORC1) inhibitor, has been shown to decrease seizures (Mizuguchi et al, 2019; 
French et al, 2016). More recently, cannabidiol (CBD; Epidiolex®) demonstrated seizure 
reduction efficacy in a randomized controlled trial (Thiele et al, 2021). 
TSC is one of the most common genetic causes of epilepsy, with seizure type and characteristics 
that vary by age (Jülich and Sahin, 2014). Infantile spasm (IS) is the most common seizure type 
presenting in infancy and represents the first manifestation of epilepsy in 50% of patients. In 
older children and adults, focal impaired awareness seizures (previously classified as complex 
partial seizures) are the most common (Chu-Shore et al, 2010); other focal and generalized 
seizures may also occur. Over 30% of patients develop treatment-refractory epilepsy 
(Jülich and Sahin, 2014). While seizures have typically been ascribed to cortical or subcortical 
tubers and subependymal nodules, epilepsy in TSC can be considered multifactorial in origin as 
seizures can originate in other brain areas or can occur in TSC patients without tubers 
(Jülich and Sahin, 2014). 
Gamma-aminobutyric acid (GABA) appears to play a central role in the development of 
TSC-related epilepsy, possibly due to altered expression of endogenous GABAA receptor 
modulators (Di Michele et al, 2003). The 3Į5-reduced-tetrahydroprogesterone (THP) metabolites 
of progesterone, including 3Į-, 5Į-THP (allopregnanolone), are positive allosteric modulators of 
the GABAA receptor. In contrast, 3ȕ5-THP acts as functional antagonists of the GABAA receptor 
by reducing the ability of 3Į5-THP to exert a potentiating effect on the GABAA receptor. Di 

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Michele et al, 2003 have demonstrated decreases in allopregnanolone and 3Į, 5ȕ-THP relative to 
3ȕ5-THP enantiomers in patients with TSC-related epilepsy but not in patients with TSC without 
epilepsy or in controls. This change in the ratio of 3Į5- and 3ȕ5-THP enantiomers could alter 
neuronal excitability mediated by GABAA receptors and predispose to the development of 
epilepsy in TSC. The role of GABAA receptor mediation is also supported by the greater efficacy 
of vigabatrin, a specific and irreversible inhibitor of GABA-aminotransferase leading to 
increased synaptic GABA levels, in seizures due to TSC relative to other epilepsies 
(Curatolo et al, 2001). These findings provide compelling evidence for the potential role of 
neuroactive steroids in the treatment of TSC-related epilepsy. 
GNX is the 3ȕ-methylated synthetic analog of allopregnanolone, an endogenous allosteric 
modulator of central nervous system (CNS) GABAA receptors. GNX has potency and efficacy 
comparable to allopregnanolone in activating synaptic and extrasynaptic GABAA receptors at a 
site distinct from benzodiazepines and barbiturates (Carter et al, 1997). GNX has protective 
activity in diverse rodent seizure models (Reddy and Rogwski, 2012; Bialer et al, 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 et al, 2017; Laxer et al, 2000; Kerrigan et al, 2000; Pieribone et al, 2007). Further, 
GNX reduces seizures in children with IS and refractory pediatric epilepsy. In an open-label 
(OL) study, pediatric participants 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 et al, 2000). There 
were 15 participants with a history of IS who completed treatment; 5 of the 15 participants 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%. There was 1 participant who became spasm-free and 1 non responder 
(with a decrease of < 25%) was spasm-free from Weeks 2 to 7.  
In addition to its anticonvulsant activity, GNX has been shown to reduce anxiety, hyperactivity, 
and attention in children with fragile X syndrome (Ligsay et al, 2016). Similar behavior 
problems occur in individuals with TSC, with rates of approximately 50% for attention 
deficit/hyperactivity disorder and autistic spectrum disorder  (Jülich and Sahin, 2014).  
In TSC-related epilepsy, Study 1042-TSC-2001 was a Phase 2, single-arm study with GNX. The 
primary objective was to assess the preliminary safety and efficacy of GNX as adjunctive 
therapy for the treatment of seizures in participants aged 2 to 65 years with genetically or 
clinically confirmed TSC-related epilepsy. The core phase of the study (Part A) consisted of a 
4-week baseline followed by a treatment phase, consisting of a 4-week titration and 8-week 
maintenance period. The primary efficacy endpoint was the percent reduction in countable, 
TSC-associated seizures from the baseline through the end of the Period A treatment phase. 
Review of data for the primary endpoint showed a median 16.6% reduction in 28-day primary 
endpoint seizure frequency relative to the 4-week baseline period, with 30.4% of patients 
achieving a 50% or more seizure reduction. The clinical study report for this study was 
completed on 08 Mar 2023. 
In the double-blind Phase 3 Study 1042-TSC-3001, the primary objective is to assess the safety 
and efficacy of GNX compared to placebo as adjunctive therapy for seizures associated with 
TSC-related epilepsy in participants aged 1 through 65 years. The study consists of a 4-week 

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baseline followed by a 16-week treatment phase, consisting of a 4-week titration and 12-week 
maintenance period. Study 1042-TSC-3001 began enrolling in 2022 and is ongoing. 
Study 1042-TSC-2001 and Study 1042-TSC-3001 are parent studies for this open-label 
extension (OLE). 
It is hypothesized that the augmentation of GABAA-receptor mediated signaling with GNX 
treatment will reduce seizures in patients with TSC. Changes in neurobehavioral symptoms, 
mood, sleep, and quality of life will also be assessed. 
Objectives and Endpoints: 
 
Objectives 
Primary Objective 
• To assess the long-term safety and tolerability of GNX as adjunctive therapy for seizures 
associated with TSC in children and adults. 
Secondary Objectives 
• For the first year, to determine the percentage of change from baselinea in 28-day seizureb 
frequency during open-label treatment.  
• For the first year, to assess the change in frequency of countable focal seizures frequency 
from baselinea during open-label treatment.  
• For the first year, to assess changes in mood, behavior, and quality of life using SF-36. 
• To assess overall clinical outcome using CGI-I scores by the clinician and the 
parent(s)/caregiver(s)/LAR(s). 
• To evaluate the changes in seizure intensity and duration using the CGI-CSID. 
Endpoints 
Primary Endpoints 
The primary endpoints are the following safety endpoints:  
• Incidence and severity of AEs, SAEs and withdrawals and dose-reductions due to AEs. 
• Vital sign measurements including blood pressure, heart rate, respiratory rate, body 
temperature, height, and body weight. 
• Physical, neurological, and developmental examination. 
• 12-lead ECG. 
• Clinical laboratory tests. 
• C-SSRS.  
Secondary Endpoints 
• Percentage change from baselinea in 28-day seizureb frequency during open-label treatment 
(first year only). 
• Percentage change from baselinea in 28-day seizureb frequency during the long-term 
treatment (first year only). 
• Number (%) of participants considered treatment respondersc (first year only). 
• CGI-I at the last scheduled study visit. 
• Change from baseline in the quality-of-life scale SF-36 (first year only). 

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• Change from baselinea in the percentage of seizure-free days during treatment, based on 
seizure typeb (first year only). 
• Change from baseline of CGI-CSID. 
AE = adverse event; CGI-CSID = Clinical Global Impression of Change in Seizure Intensity/Duration; 
CGI-I = Clinical Global Impression of Improvement; C-SSRS = Columbia Suicide Severity Rating Scale; 
ECG = electrocardiogram; GNX = ganaxolone; PK = pharmacokinetic(s); SAE = serious adverse events; 
SF-36 = Short Form 36 (version 2); SQS = Sleep Quality Scale; TSC = Tuberous Sclerosis Complex 
a 
Baseline for efficacy assessments is defined as based on the participant’s prior study as follows: 
• 
Study 1042-TSC-2001 – the original baseline is considered to be Visit 2 for participants continuing in 
Study 1042-TSC-3002. 
• 
Study 1042-TSC-3001 – the original baseline is considered to be Visit 2 for participants previously 
randomized to GNX. 
Note: For other assessments, the baseline is considered to be Visit 1, the first visit of the open-label 
extension (OLE).  
b 
Seizure types are defined as the following: focal motor seizures without impairment of consciousness or 
awareness, focal seizures with impairment of consciousness or awareness with motor features, focal seizures 
evolving to bilateral, tonic-clonic convulsive seizures, and generalized motor seizures including tonic-clonic, 
bilateral tonic, bilateral clonic, or atonic/drop seizures. Seizures must have a motor component sufficiently 
prominent and distinct to clearly establish the observed symptoms as epileptic in origin.  
 
Seizures that do not count towards the efficacy endpoints include focal or generalized nonmotor  seizures 
(eg, absence seizures or focal nonmotor seizures with or without impairment of awareness), infantile or 
epileptic spasms, and myoclonic seizures. 
c 
Treatment responders are defined as those participants with a  50% reduction from baseline in seizure 
frequency during open-label treatment. 
 
Overall Design: 
This is a Phase 3, global, OLE study of adjunctive GNX treatment in children and adults with 
TSC who previously participated in either Study 1042-TSC-3001 or Study 1042-TSC-2001. For 
this protocol, the term children will refer to the full range of pediatric participants. 
For all participants who enter the OLE, the last visit in the parent Study 1042-TSC-3001 or 
Study 1042-TSC-2001 will be the same as the First Visit in this OLE study and visit activities 
will not be duplicated.  
Procedures specific to this protocol and not otherwise considered standard of care, will not be 
performed until written informed consent/assent from the participant or their parent(s)/legally 
authorized representative(s) (LAR[s]), as appropriate, has been appropriately obtained.  
Participants or their parent(s)/caregiver(s) or LAR(s) are expected to complete electronic seizure 
diary (eDiary) entries to document the number and type(s) of seizures daily throughout the first 
year of the study. After the first year, study assessments will focus on safety evaluation. 
Caregiver and clinician global impressions of improvement will continue to be assessed to 
ensure that participants are continuing to receive benefit from treatment. A variety of clinician 
and caregiver administered instruments will be used to assess efficacy at the study visits 
including:  
• Clinical Global Impression of Improvement (CGI-I) by parent(s)/caregiver(s) and clinician. 
• Caregiver Global Impression of Change in Seizure Intensity/Duration (CGI-CSID). 

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• Short Form 36 (SF-36) (first year of the study only).   
Safety monitoring and assessments will be conducted throughout the study. 
The maximum dose for all participants is 1800 mg/day.  
Participants who discontinue the investigational product (IP) should undergo a 2-week taper 
period. The taper period may be shortened, if necessary, for participant safety. Participants who 
discontinue the IP before the scheduled completion of the study will have an Early Termination 
Visit, as per Visit 13 (Week 156), and return to the site 2 weeks after the end of the taper period 
to complete the safety follow-up assessments. 
The study design is presented in Figure 1.  
Disclosure Statement: 
This is an open-label, single arm study with no blinding as all participants will receive adjunctive 
GNX. 
Number of Participants: 
It is planned that approximately 169 participants from Study 1042-TSC-3001 and Study 
1042-TSC-2001 will be enrolled in this OLE study and continue treatment with GNX. 
Note: Enrolled means the participant, or their LAR(s), has agreed to participate in the study 
following completion of the informed consent process and screening. Potential participants who 
are screened for the purpose of determining eligibility for the study, but do not participate in the 
study, are not considered enrolled, unless otherwise specified by the protocol.  
Eligibility Criteria: 
Participants are eligible to be included in the study only if all the following inclusion criteria are 
met: 
1. Completion of Study 1042-TSC-3001 or participants who continue to meet study 
requirements in Study 1042-TSC-2001. 
2. Participant/parent(s)/LAR(s) willing and able 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. If the participant is not qualified or able to provide written 
informed consent based on age, developmental stage, intellectual capacity, or other factors, 
parent(s)/LAR(s) must provide assent for study participation, if appropriate. 
3. Parents/caregivers is (are) willing and able to maintain an accurate and complete daily 
seizure diary for the duration of the study. 
4. Willling and able to take IP (suspension) as directed with food 3 times a day (tid).  
5. WOCBP must be using a medically acceptable method of birth control and have a negative 
quantitative serum ȕ-human chorionic growth hormone (ȕ-HCG) test collected at the initial 
visit. Childbearing potential is defined as a female who is biologically capable of becoming 
pregnant. Medically acceptable methods of birth control include intrauterine devices (that 

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have been in place for at least 1 month prior to Visit 1 [first visit of the OLE]), hormonal 
contraceptives (eg, combined oral contraceptives, patch, vaginal ring, injectables, and 
implants), and surgical sterilization (such as oophorectomy or tubal ligation). When used 
consistently and correctly, “double-barrier” methods of contraception can be used as an 
effective alternative to highly effective contraception methods. Contraceptive measures such 
as Plan BTM, sold for emergency use after unprotected sex, are not acceptable methods for 
routine use.  
6. Male participants must agree to use highly effective contraceptive methods during the study 
and for 30 days after the last dose of IP. Highly effective methods of contraception include 
surgical sterilization (such as a vasectomy) and adequate “double-barrier” methods.  
Participants are excluded from the study if any of the following exclusion criteria apply: 
1. Pregnant or breastfeeding. 
2. An active central nervous system (CNS) infection, demyelinating disease, or degenerative 
neurological disease.  
3. History of psychogenic nonepileptic seizures.  
4. Any disease or condition (other than TSC) at the initial visit that could compromise the 
hematologic, cardiovascular (including any cardiac conduction defect), 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 participant at 
increased risk or interfere with the assessment of safety/efficacy. This may include any 
illness in the past 4 weeks which in the opinion of the investigator may affect seizure 
frequency. 
5. Unwillingness to avoid excessive alcohol use or cannabis use throughout the study.  
6. Have active suicidal plan/intent or have had active suicidal thoughts in the past 6 months or a 
suicide attempt in the past 6 months.  
7. Known sensitivity or allergy to any component in the IP(s), progesterone, or other related 
steroid compounds. 
8. Exposed to any other investigational drug (except for GNX in Study 1042-TSC-2001 or 
Study 1042-TSC-3001) or investigational device within 30 days or fewer than 5 half-lives 
prior to Visit 1 (first visit of the OLE). For therapies in which half-life cannot be readily 
established, the Sponsor’s medical monitor should be consulted. 
Intervention Groups and Duration: 
This is an OLE study and all participants will receive treatment with GNX after completing 
Study 1042-TSC-3001 (in this study participants previously randomized to placebo will be 
titrated to GNX under double-blind conditions prior to study completion) or 
Study 1042-TSC-2001.  
In both parent studies, GNX is to be titrated to a maximum dose of 1800 mg/day and given as an 
oral suspension (50 mg/mL) with food. Participants will continue the GNX dose determined in 
Study 1042-TSC-3001 or Study 1042-TSC-2001 in this OLE unless a dose change is clinically 
indicated.  

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Participants who discontinue the IP should undergo a 2-week taper period, which may be 
shortened, if necessary, for patient safety. Participants who discontinue the IP before the 
scheduled completion of the study will have an Early Termination Visit, as per 
Visit 13 (Week 156), and return to the site 2 weeks after the end of the taper period to complete 
the safety follow-up assessments. 
It is estimated that the maximum duration of participation in this study will be approximately 
3 years. 
Interim Analysis: 
No formal interim analysis is planned.

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1.2 
Schema 
Figure 1. Study Schematic Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
GNX = ganaxolone; TSC = Tuberous Sclerosis Complex. 
 
Open-label Extension - Long-term 
GNX treatment and maintenance 
period 
(156 weeks) 
GNX 
Taper/ 
down 
titration  
(2 weeks) 
Safety 
Follow-up 
Visit  
(2 weeks) 
Study 1042-TSC-3001: 
Participants on determined 
maintenance dose of GNX 
(including double-blind cross 
titration from placebo to 
GNX) transferred to this study 
N = 162 
Study 1042-TSC-2001: 
Participants on determined 
maintenance dose of GNX 
transferred to this study 
N = 7 

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1.3 
Schedule of Activities 
Table 1. 
Schedule of Activities for Open-Label Phase 
Week  
(All dates are relative to the first OLE 
dose on Day 1) 
0 
Open-Label Maintenance 
Safety  
Follow-up 
Year 1 
Year 2 
Year 3b 
 
13 
26 
39 
52 
65 
78 
91 
104 
117 
130 
143 
156 
160 
Visit and Visit Windows 
(Telehealth permitted where it is 
accepted as the standard of care) 
First Visit 
of the 
OLEa 
V1 
All windows for these visits are ± 14 days 
± 3 days 
V2 
Phone 
V3 
V4 
Phone 
V5 
V6 
Phone 
V7 
V8 
Phone 
V9 
V10 
Phone V11 
V12 
Phone 
V13 or 
ETc  
V14 
Screening and Diagnosis 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History Reviewd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
Vital signs (BP, HR, RR, body 
temperature, height, weight) 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Physical/Neurological/Developmental 
Examination 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
12-lead ECG 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Laboratory Testse 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Pregnancy Test (and dispense pregnancy 
test for monthly home testing; WOCBP)f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational Product PKg 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Concomitant ASM Level Review (if 
collected per standard of care)h 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS (since previous visit)i 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 

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Week  
(All dates are relative to the first OLE 
dose on Day 1) 
0 
Open-Label Maintenance 
Safety  
Follow-up 
Year 1 
Year 2 
Year 3b 
 
13 
26 
39 
52 
65 
78 
91 
104 
117 
130 
143 
156 
160 
Visit and Visit Windows 
(Telehealth permitted where it is 
accepted as the standard of care) 
First Visit 
of the 
OLEa 
V1 
All windows for these visits are ± 14 days 
± 3 days 
V2 
Phone 
V3 
V4 
Phone 
V5 
V6 
Phone 
V7 
V8 
Phone 
V9 
V10 
Phone V11 
V12 
Phone 
V13 or 
ETc  
V14 
Efficacy Assessments 
Seizure eDiary review 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
CGI-CSID 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
CGI-I by parents/ caregiver(s)/LAR(s) and 
clinician 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
SF-36 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Investigational Product 
Dispense IP 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
ASM = anti-seizure medication; BP = blood pressure; CGI-CSID = Caregiver Global Impression of Change in Seizure Intensity/Duration; CGI-I = Clinical 
Global Impression of Improvement; C-SSRS = Columbia-Suicide Severity Rating Scale; eCRF = electronic case report form; ECG = electrocardiogram; 
ET = early termination; HR = heart rate; IP = investigational product; LAR = legally authorized representative; OLE = open-label extension; 
PK = pharmacokinetic; QOL = quality of life; RR = respiratory rate; SF-36 = Short Form 36 (version 2); WOCBP = women of childbearing potential. 
a 
Any data collected at the final visit of the parent study will be carried over to Study 1042-TSC-3002. Any procedures not performed at the final visit of the 
parent study will be conducted at Visit 1 on Day 1 of this study. 
b 
It is estimated that the maximum duration of participation in this OLE study will be approximately 3 years.  
c 
For participants who discontinue treatment, either early, or at Visit 13 (Week 156) and prior to down-titration unless medically indicated. 
d 
Demographics and medical history will be reviewed to confirm there are no changes from the parent study. 
e 
Hematology, clinical chemistry, and urinalysis (see Section 8.3.4). 
f 
A serum pregnancy test is required for all WOCBP at Visit 1 on Day 1 of this OLE study. Urine pregnancy testing will then be performed every 4 weeks 
throughout the OLE using take-home pregnancy tests. Any positive home pregnany test will be followed up with a confirmatory serum pregnancy test. 
g 
Population PK will be conducted at Visit 3 and Visit 5 and the PK sample can be drawn when convenient during the specified study visit. 
h If the levels of ASM co-administered with the IP are measured routinely, this information will be recorded in the eCRF. 
i 
Only for participants  11 years of age, if appropriate, otherwise, clinical judgment will be used. 
 

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2 INTRODUCTION 
Ganaxolone (GNX) is a small molecule being developed for use as an anti-seizure medication 
(ASM) in rare pediatric seizure disorders including cyclin-dependent kinase-like 5 deficiency 
disorder (CDD),TSC-related epilepsy, and status epilepticus (SE).  
GNX has also been investigated in adults with post-traumatic stress disorder (PTSD), migraine, 
postpartum depression (PPD), and children with protocadherin (PCDH)-related epilepsy, and 
fragile X syndrome (FXS). 
2.1 
Study Rationale 
Gamma-aminobutyric acid (GABA) appears to play a central role in the development of 
TSC-related epilepsy, possibly due to altered expression of endogenous GABAA-receptor 
modulators (Di Michele et al, 2003). The 3Į5-reduced-tetrahydroprogesterone (THP) metabolites 
of progesterone, including 3Į, 5Į-THP (allopregnanolone), are positive allosteric modulators of 
the GABAA receptor. In contrast, 3ȕ5-THP acts as functional antagonists of the GABAA receptor 
by reducing the ability of 3Į5-THP to exert a potentiating effect on the GABAA receptor. 
Di Michele et al, 2003 have demonstrated decreases in allopregnanolone and 3Į, 5ȕ-THP relative 
to 3ȕ5-THP enantiomers in patients with TSC-related epilepsy but not in patients with TSC 
without epilepsy, or in controls. This change in the ratio of 3Į5- and 3ȕ5-THP enantiomers could 
alter neuronal excitability mediated by GABAA receptors and predispose to the development of 
epilepsy in TSC. The role of GABAA-receptor mediation is also supported by the greater efficacy 
of vigabatrin, a specific and irreversible inhibitor of GABA-aminotransferase leading to 
increased synaptic GABA levels, in seizures due to TSC relative to other epilepsies 
(Curatolo et al, 2001). These findings provide compelling evidence for the potential role of 
neuroactive steroids in the treatment of TSC-related epilepsy. 
It is hypothesized that the augmentation of GABAA-receptor mediated signaling with GNX 
treatment will reduce seizures in patients with TSC. Changes in neurobehavioral symptoms, 
mood, sleep, and quality of life will also be assessed. 
2.2 
Background 
2.2.1 
Disease Background  
TSC is a multi-system disorder of embryonal cortical development which can affect many organs 
through the overgrowth of benign tumors known as hamartomas. While the disease phenotype 
can be extremely variable, neurologic manifestations such as epilepsy can be seen in up to 
90% of TSC patients (Krueger and Northrup, 2013). The condition is caused by inherited 
mutations in either the TSC1 (hamartin) gene, located on chromosome 9q34, or the 
TSC2 (tuberin) gene located on chromosome 16p13.3. TSC occurs with a frequency of 
1:6,000 and a mutation is found in 85% of patients (Jülich and Sahin, 2014). The gene products 
TSC1 and TSC2 form a regulatory complex responsible for limiting the activity of mechanistic 
target of rapamycin complex 1 (mTORC1), an important intracellular regulator of growth and 

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metabolism via its inhibition of the small GTPase Ras homolog enriched in brain (Rheb) 
(Krueger and Northrup, 2013). Everolimus (Afinitor®), a mechanistic target of rapamycin  
(mTORC1) inhibitor, has been shown to decrease seizures (Mizuguchi et al, 2019; 
French et al, 2016). More recently, CBD (Epidiolex®) demonstrated seizure reduction efficacy in 
a randomized controlled trial (Thiele et al, 2021). 
TSC is one of the most common genetic causes of epilepsy, with seizure type and characteristics 
that vary by age (Jülich and Sahin, 2014). Infantile spasms (IS) are the most common seizure 
type presenting in infancy and represents the first manifestation of epilepsy in 50% of patients. In 
older children and adults, focal impaired awareness seizures (previously classified as complex 
partial seizures) are the most common (Chu-Shore et al, 2010); other focal and generalized 
seizures may also occur. Over 30% of patients develop treatment-refractory epilepsy 
(Jülich and Sahin, 2014). While seizures have typically been ascribed to cortical or subcortical 
tubers and subependymal nodules, epilepsy in TSC can be considered multifactorial in origin as 
seizures can originate in other brain areas or can occur in TSC participants without tubers 
(Jülich and Sahin, 2014). 
2.2.2 
Investigational Product Background: Ganaxolone 
GNX (3Į-hydroxy-3ȕ-methyl-5Į-pregnan-20-one) is a small molecule under investigation for 
use as an ASM in rare pediatric seizure disorders and SE. GNX is a Schedule V Controlled 
Substance in the United States (US). The 50 mg/mL GNX oral suspension is approved in the US 
for the treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency 
disorder (CDD) in patients 2 years of age and older. GNX is the 3ȕ-methylated synthetic analog 
of allopregnanolone, an endogenous allosteric modulator of central nervous system (CNS) 
GABAA receptors. GNX has potency and efficacy comparable to allopregnanolone in activating 
synaptic and extra-synaptic GABAA receptors at a site distinct from benzodiazepines and 
barbiturates (Carter et al, 1997). GNX has protective activity in diverse rodent seizure models 
(Reddy and Rogwski, 2012; Bialer et al., 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 et al, 2017; Pieribone et al, 2007; 
Kerrigan et al, 2000; Laxer et al, 2000). Further, GNX reduces seizures in children with IS and 
refractory pediatric epilepsy. In an open-label (OL) study, pediatric participants 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 et al, 2000). A total of 15 participants with a history of IS 
completed treatment; 5 of the 15 participants 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%. There was 
1 participant who became spasm-free and 1 non responder (with a decrease of < 25%) was 
spasm-free from Weeks 2 to 7.  
In addition to its anticonvulsant activity, GNX has been shown to reduce anxiety, hyperactivity, 
and attention in children with FXS (Ligsay et al., 2016). Similar behavior problems occur in 
individuals with TSC, with rates of approximately 50% for attention deficit/hyperactivity 
disorder and autistic spectrum disorder (Jülich and Sahin, 2014). 

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2.2.2.1 
Ganaxolone Clinical Development Program 
In the US, GNX, under the brand name ZTALMY®, is indicated for the treatment of seizures 
associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients 
2 years of age and older. GNX is a Schedule V controlled substance. 
Ganaxolone is being further evaluated for use as an ASM in adolescents and adults with status 
epilepticus (SE) and paediatric and adult patients with seizures associated with tuberous sclerosis 
complex (TSC). 
The completed GNX clinical program comprises Phase 1 studies conducted in healthy 
participants, adults with migraine, and adults with renal impairment and Phase 2/3 studies were 
conducted in adults with epilepsy, infants and children with seizure disorders, children with 
fragile X syndrome (FXS), adults with posttraumatic stress disorder (PTSD), women with 
postpartum depression (PPD), adults with migraine, adolescents, and adults with SE, and 
pediatric and adult participants with seizures associated with TSC. In these studies, the efficacy, 
safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GNX were evaluated 
with an oral dosing duration ranging from 1 day up to more than 5 years, using doses from 
50 to 3200 mg/day. Additionally, intravenous (IV) bolus doses ranging from 10 to 30 mg over 
durations of 2 to 5 minutes, continuous infusion of 10 to 30 mg/hour for 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 were 
evaluated in healthy participants. In participants with SE, IV infusions of up to 713 mg/day have 
been evaluated. 
As of 10 Oct 2022, an estimated 2172 participants have received at least 1 dose of GNX across 
the completed studies. This includes 511 participants in Phase 1 and 1661 participants in 
Phase 2/3 studies. Participants who received GNX ranged in age from 4 months to 88 years.  
Formulations used to date in the clinical development program are summarized and listed by 
study in the Investigator´s Brochure (IB).  
2.2.2.1.1 
TSC-related Epilepsy 
Study 1042-TSC-2001 and Study 1042-TSC-3001 are parent studies for this OLE. 
• In the single arm Phase 2 Study 1042-TSC-2001, the primary objective was to assess the 
preliminary safety and efficacy of GNX as adjunctive therapy for the treatment of seizures in 
participants aged 2 to 65 years with genetically or clinically confirmed TSC-related epilepsy. 
The core phase of the study (Part A) consisted of a 4-week baseline followed by a treatment 
phase, consisting of a 4-week titration and 8-week maintenance period. The primary efficacy 
endpoint was the percent reduction in countable TSC-associated seizures from the baseline 
through the end of the Period A treatment phase.  
o Review of data for the primary endpoint showed a median 16.6% reduction in 28-day 
primary endpoint seizure frequency relative to the 4-week baseline period, with 30.4% of 
patients achieving a 50% or more seizure reduction. The clinical study report (CSR) for 
the study was completed on 08 Mar 2023. 

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• In the double-blind Phase 3 Study 1042-TSC-3001, the primary objective is to assess the 
safety and efficacy of GNX compared to placebo as adjunctive therapy for seizures 
associated with TSC-related epilepsy in participants aged 1 through 65 years. The study 
consists of a 4-week baseline followed by a 16-week treatment phase, consisting of a 4-week 
titration and 12-week maintenance period.  
o Study 1042-TSC-3001 began enrolling in 2022 and is ongoing.  
Additional information detailing ongoing and completed clinical GNX studies may be found in 
the current IB. 
2.2.2.2 
Clinical Safety Overview 
In all completed placebo-controlled studies, 63.5% (742/1168) of participants who received 
GNX and 51.9% (443/853) of participants who received placebo experienced at least 1 
treatment-emergent adverse event (TEAE). In these studies, the most frequently reported (ie, 
in > 5% of participants) TEAEs in GNX-treated participants were: somnolence (23.84% GNX, 
7.7% placebo), dizziness (12.2% GNX, 3.5% placebo), fatigue (11.2% GNX, 4.8% placebo), and 
headache (6.3% GNX, 6.9% placebo). All these events, except headache, occurred more 
frequently in GNX treated participants than placebo participants. CNS-related events appeared to 
be dose related, with the majority of these events occurring at doses  500 mg and were non-
serious, mild to moderate in severity, and did not lead to discontinuation of treatment. These 
TEAEs were also anticipated based on the mechanism of action of GNX. 
In all completed placebo-controlled studies, the incidence of serious adverse events (SAEs) was 
balanced between the GNX-treated participants (33/1168 participants, 2.8%) and placebo 
participants (26/853 participants, 3.0%), respectively. In these studies, the only SAEs reported in 
more than 1 participant in the GNX treatment group were seizure and sedation. 
In all completed studies, including OL, long-term follow-up studies, 5.4% 
(118/2172 participants) of participants who received GNX experienced at least 1 SAE. With 
long-term exposure, no new safety findings were identified through the review of SAEs in these 
studies. The most frequently reported SAEs (ie, in > 2 participants) were seizure, SE, infantile 
spasms, epilepsy, pneumonia, pneumonia aspiration, pyrexia,  , seizure cluster, dehydration, 
gastro-esophageal reflux disease, rash, somnolence, and upper respiratory tract infection. In all 
studies, most of the SAEs were considered unrelated to treatment according to the investigator, 
and most resolved. 
The Phase 2 study (protocol 1042-TSC-2001) showed a consistent safety profile in a 
TSC population. Of the 24 participants screened, 4 discontinued the study due to adverse events 
(AEs), with somnolence, sedation, and fatigue being the most common treatment-emergent AEs. 
Additionally, 1 treatment-related SAE of seizure was reported. 
Additional information describing the safety of GNX may be found in the current IB. 

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2.3 
Benefit/Risk Assessment 
Based on clinical and non-clinical data from studies with GNX, the overall benefit/risk profile 
favors clinical development of GNX for the treatment of TSC-related epilepsy. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of GNX may be found in the IB. 
2.3.1 
Risk Assessment 
CNS-related effects (such as somnolence, sedation, and gait disturbance) have been identified as 
an important risk related to the mechanism of action of GNX. In placebo-controlled studies, the 
most common CNS effects were somnolence, dizziness, fatigue, sedation, and gait disturbance. 
Of the AEs present at frequency > 1% and 2 times the frequency of placebo in the aggregate AE 
data, all 12 AEs are related to CNS function. The most common CNS-related AEs that led to 
discontinuation reported in placebo-controlled studies were dizziness (GNX 1.1%; placebo 
0.4%); somnolence (GNX 0.9%; placebo 0.4%); and fatigue (GNX 0.8%; placebo 0.1%). These 
CNS effects were typically non-serious, mild to moderate in severity, and did not lead to 
discontinuation of treatment. However, in Study 1042-SE-2001, 2 SAEs of sedation were 
reported and led to early discontinuation and revision of the reference safety information. 
The safety assessments to be performed in this study include vital signs, physical, neurological, 
and developmental examinations, 12-lead electrocardiogram (ECG), clinical laboratory tests, AE 
assessments, and Columbia Suicide Severity Rating Scale (C-SSRS). These are standard 
evaluations to ensure participant safety in this clinical study.  
2.3.2 
Benefit Assessment 
This is an OLE study to evaluate long-term safety and efficacy of adjunctive GNX therapy for 
seizures associated with TSC in children and adults. This patient population may benefit from 
the development of GNX as participants will receive GNX treatment that may help control their 
epilepsy.  
2.3.3 
Overall Benefit: Risk Conclusion 
Taking into account the measures to minimize risk to participants participating in this study, the 
potential risks identified in association with GNX are justified by the anticipated benefits to 
participants with TSC-related epilepsy. 

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3 OBJECTIVES AND ENDPOINTS 
 
 
Objectives 
Primary Objective 
• To assess the long-term safety and tolerability of GNX as adjunctive therapy for seizures 
associated with TSC in children and adults. 
Secondary Objectives 
• For the first year, to determine the percentage of change from baselinea in 28-day seizureb 
frequency during open-label treatment.  
• For the first year, to assess the change in frequency of countable focal seizures frequency 
from baselinea during open-label treatment.  
• For the first year, to assess changes in mood, behavior, and quality of life using SF-36.  
• To assess overall clinical outcome using CGI-I scores by the clinician and the 
parent(s)/caregiver(s)/LAR(s). 
• To evaluate the changes in seizure intensity and duration using the CGI-CSID. 
Exploratory Objectives 
• To evaluate the long-term effects of GNX as add-on therapy to antiepileptic medications. 
Endpoints 
Primary Endpoints 
The primary endpoints are the following safety endpoints:  
• Incidence and severity of AEs, SAEs and withdrawals and dose-reductions due to AEs. 
• Vital sign measurements including blood pressure, heart rate, respiratory rate, body 
temperature, height, and body weight. 
• Physical, neurological, and developmental examination. 
• 12-lead ECG. 
• Clinical laboratory tests. 
• C-SSRS.  
Secondary Endpoints  
• Percentage change from baselinea in 28-day seizureb frequency during open-label treatment 
(first year only). 
• Percentage change from baselinea in 28-day seizureb frequency during the long-term 
treatment (first year only). 
• Number (%) of participants considered treatment respondersc (first year only). 
• CGI-I at the last scheduled study visit. 
• Change from baseline in the quality-of-life scale SF-36 (first year only).  
• Change from baselinea in the percentage of seizure-free days during treatment, based on 
seizure typeb (first year only). 
• Change from baseline of CGI-CSID. 

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AE = adverse event; CGI-CSID = Clinical Global Impression of Change in Seizure Intensity/Duration; 
CGI-I = Clinical Global Impression of Improvement; C-SSRS = Columbia Suicide Severity Rating Scale; 
ECG = electrocardiogram; GNX = ganaxolone; PK = pharmacokinetic(s); SAE = serious adverse events; 
SF-36 = Short Form 36 (version 2); SQS = Sleep Quality Scale; TSC = Tuberous Sclerosis Complex. 
a 
Baseline for efficacy assessments is defined as based on the participant’s prior study as follows: 
• 
Study 1042-TSC-2001 – the original baseline is considered to be Visit 2 for participants continuing in 
Study 1042-TSC-3002. 
• 
Study 1042-TSC-3001 – the original baseline is considered to be Visit 2 for participants previously 
randomized to GNX. 
Note: For other assessments, the baseline is considered to be Visit 1, the first visit of the OLE.  
b 
Seizure types are defined as the following: focal motor seizures without impairment of consciousness or 
awareness, focal seizures with impairment of consciousness or awareness with motor features, focal seizures 
evolving to bilateral, tonic-clonic convulsive seizures, and generalized motor seizures including tonic-clonic, 
bilateral tonic, bilateral clonic, or atonic/drop seizures. Seizures must have a motor component sufficiently 
prominent and distinct to clearly establish the observed symptoms as epileptic in origin.  
 
Seizures that do not count towards the efficacy endpoints include focal or generalized nonmotor  seizures 
(eg, absence seizures or focal nonmotor seizures with or without impairment of awareness), infantile or 
epileptic spasms, and myoclonic seizures. 
c 
Treatment responders are defined as those participants with a  50% reduction from baseline in seizure 
frequency during open-label treatment. 
4 STUDY DESIGN 
4.1 
Overall Design 
This is a Phase 3, global, OLE study of adjunctive GNX treatment in children and adults with 
TSC-related epilepsy who previously participated in either Study 1042-TSC-3001 or 
Study 1042-TSC-2001. For this protocol, the term children will refer to the full range of pediatric 
participants. 
For all participants who enter the OLE, the last visit in the parent Study 1042-TSC-3001 or 
Study 1042-TSC-2001 will be the same as the First Visit in this OLE study and visit activities 
will not be duplicated.  
Procedures specific to this protocol and not otherwise considered standard of care, will not be 
performed until written informed consent/assent from the participant or their parent(s)/LAR(s), 
as appropriate, has been appropriately obtained.  
Participants or their parent(s)/caregiver(s)/LAR(s) are expected to complete electronic seizure 
diary (eDiary) entries to document the number and type(s) of seizures daily throughout the first 
year of the study. After the first year, study assessments will focus on safety evaluation. 
Caregiver and clinician global impressions of improvement will continue to be assessed to 
ensure that participants are continuing to receive benefit from treatment. A variety of clinician 
and caregiver administered outcome measures will be used at the study visits to assess efficacy. 
These include:  
• Clinical Global Impression of Improvement (CGI-I) by parent(s)/caregiver(s) and clinician. 
• Caregiver Global Impression of Change in Seizure Intensity/Duration (CGI-CSID). 

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• Short Form 36 (SF-36) (first year of the study only).   
Safety monitoring assessments will be conducted throughout the study. 
The maximum dose for all participants is 1800 mg/day.  
Participants who discontinue the investigational product (IP) should undergo a 2-week taper 
period. The taper period may be shortened, if necessary, for participant safety. Participants who 
discontinue the IP before the scheduled completion of the study will have an Early Termination 
Visit, as per Visit 13 (Week 156), and return to the site 2 weeks after the end of the taper period 
to complete the safety follow-up assessments. 
The study design is presented in Figure 1.  
4.1.1 
Study Duration for Participation 
It is estimated that the maximum duration of participation in this study will be approximately 
3 years. 
4.1.2 
Number of Participants 
It is planned that approximately 169 participants from Study 1042-TSC-3001 and 
Study 1042-TSC-2001 will be enrolled in this OLE and continue treatment with GNX. 
Note: Enrolled means the participant, or their LAR(s), has agreed to participate in the study 
following completion of the informed consent process and screening. Potential participants who 
are screened for the purpose of determining eligibility for the study, but do not participate in the 
study, are not considered enrolled, unless otherwise specified by the protocol.  
4.1.3 
Number of Sites 
This global, multicenter study will be conducted at approximately 75 sites (US and ex-US). 
4.2 
Scientific Rationale for Study Design 
This is a Phase 3, OLE study of adjunctive GNX treatment in children and adults with 
TSC-related epilepsy. Children and adults with TSC-related epilepsy are included in the study as 
this is one of the patient populations that may benefit from GNX treatment. The eligibility 
criteria allow for the selection of participants comparable to the expected type of patient seen in 
clinical practice. 
All eligible participants will have the option to receive treatment with GNX in this study after 
participating in Study 1042-TSC-3001 or Study 1042-TSC-2001.  
All the efficacy and safety assessments included in this study are standard measures used in 
clinical studies in general and epilepsy trials in particular. 

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4.3 
Justification for Dose 
A minimum GNX dose of 33 mg/kg/day or 900 mg/day is generally required for assessment of 
efficacy during the study. 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 et al, 2017; Laxer et al, 2000; Kerrigan et al, 2000; 
Pieribone et al, 2007).  
Dosing will be based on doses that have been shown to be safe in children and adults in multiple 
studies with healthy volunteers and individuals with epilepsy.  
In both parent studies (Study 1042-TSC-3001 and Study 1042-TSC-2001), GNX is to be titrated 
to a maximum target dose of 1800 mg/day and given as an oral suspension (50 mg/mL) with 
food, eg, shortly after a meal or snack.  
Participants will continue the GNX dose determined in Study 1042-TSC-3001 or 
Study 1042-TSC-2001 in this OLE unless a dose change is clinically indicated.  
Additional dosing information can be found in Section 6.2. 
4.4 
End of Study Definition 
End of Study (Individual Patient): A participant is considered to have completed the study if 
they have completed all study visits up to and including Visit 14 (Week 160) (Table 1). 
A participant is considered to have ended their participation when they either complete the study, 
or when they withdraw and complete the Early Termination visit. 
End of Study (End of Trial): The end of the study is defined as the date of the last visit of the 
last participant in the study or last scheduled procedure shown in the Schedule of Activities 
(SOA; Table 1) for the last participant in the study globally. 
5 STUDY POPULATION 
Each participant and/or their parent(s)/LAR(s), as appropriate, must participate in the informed 
consent process and provide written informed consent or assent (Section 10.1.3) before any 
procedures specified in the protocol are performed.  
5.1 
Inclusion Criteria  
1. Completion of Study 1042-TSC-3001 or participants who continue to meet study 
requirements in Study 1042-TSC-2001. 
2. Participant/parent(s)/LAR(s) willing and able 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. If the participant is not qualified or able to provide written 
informed consent based on age, developmental stage, intellectual capacity, or other factors, 
parent(s)/LAR(s) must provide assent for study participation, if appropriate. 

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3. Parent(s)/caregiver(s) is(are) willing and able to maintain an accurate and complete daily 
seizure diary for the duration of the study. 
4. Willing and able to take IP (suspension) as directed with food 3 times a day (tid).  
5. WOCBP must be using a medically acceptable method of birth control and have a negative 
quantitative serum ȕ-human chorionic growth hormone (ȕ-HCG) test collected at the initial 
visit. Childbearing potential is defined as a female who is biologically capable of becoming 
pregnant. Medically acceptable methods of birth control include intrauterine devices (that 
have been in place for at least 1 month prior to Visit 1 [first visit of the OLE]), hormonal 
contraceptives (eg, combined oral contraceptives, patch, vaginal ring, injectables, and 
implants), and surgical sterilization (such as oophorectomy or tubal ligation). When used 
consistently and correctly, “double-barrier” methods of contraception can be used as an 
effective alternative to highly effective contraception methods (see Section 10.5.3 for 
“double-barrier” methods). Contraceptive measures such as Plan BTM, sold for emergency 
use after unprotected sex, are not acceptable methods for routine use. 
6. Male participants must agree to use highly effective contraceptive methods during the study 
and for 30 days after the last dose of IP. Highly effective methods of contraception include 
surgical sterilization (such as a vasectomy) and adequate “double-barrier” methods (see 
Section 10.5.3 for “double-barrier” methods). 
5.2 
Exclusion Criteria  
1. Pregnant or breastfeeding. 
2. An active CNS infection, demyelinating disease, or degenerative neurological disease.  
3. History of psychogenic nonepileptic seizures.  
4. Any disease or condition (other than TSC) at the initial visit that could compromise the 
hematologic, cardiovascular (including any cardiac conduction defect), 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 participant at 
increased risk or interfere with the assessment of safety/efficacy. This may include any 
illness in the past 4 weeks which in the opinion of the investigator may affect seizure 
frequency. 
5. Unwillingness to avoid excessive alcohol use or cannabis use throughout the study.  
6. Have active suicidal plan/intent or have had active suicidal thoughts in the past 6 months or a 
suicide attempt in the past 6 months.  
7. Known sensitivity or allergy to any component in the IP(s), progesterone, or other related 
steroid compounds. 
8. Exposed to any other investigational drug (except for GNX in Study 1042-TSC-2001 or 
Study 1042-TSC-3001) or investigational device within 30 days or fewer than 5 half-lives 
prior to Visit 1 (first visit of the OLE). For therapies in which half-life cannot be readily 
established, the Sponsor’s medical monitor should be consulted. 

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5.3 
Lifestyle Considerations 
5.3.1 
Meals and Dietary Restrictions 
Participants are requested to take the IP tid with food , eg, shortly after a meal or snack. 
In addition, participants should refrain from consumption grapefruit or grapefruit juice, Seville 
oranges, or starfruits during the study, or excessive consumption of alcohol during the study. 
During each visit when PK samples are collected, participants should abstain from ingesting 
caffeine- or xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 
approximately 24 hours before dosing until after collection of the PK sample such that these 
items are ingested the morning before the study visit and not consumed again until after the PK 
samples are collected. 
5.4 
Screen Failures 
There is no screening period in this OLE study and hence no screen failures. Participants 
enrolled into this study will continue to take the dose of GNX assigned to them in the parent 
Study 1042-TSC-3001 or Study 1042-TSC-2001.  
6 STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
Refer to the Pharmacy Manual for more detailed information regarding the storage, preparation, 
destruction, and administration of each treatment. 
6.1 
Study Intervention(s) Administered 
The IP for this study is GNX (Table 2). 

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Table 2. 
Study Intervention(s) Administered 
Intervention Label 
 
Intervention Name 
GNX. 
Intervention Description 
GNX oral suspension, tid. 
Dose Formulation 
Suspension in 4 fl oz bottles. 
Unit Dose Strength(s) 
50 mg/mL suspension containing 110 mL GNX. 
Dosage Level(s) 
Participants in the OLE will take the starting dose as determined in 
Study 1042-TSC-3001 or Study 1042-TSC-2001. The IP, GNX, is to be 
administered tid with food, eg, after a meal or snack. 
See Section 6.2 for details of permitted dose modifications. 
Route of Administration 
Oral. 
Use 
ASM in TSC-related epilepsy. 
IMP and NIMP/AxMP 
GNX. 
Sourcing 
Provided centrally by the sponsor. 
Packaging and Labeling 
Ganaxolone is a Schedule V Controlled Substance in the US. The GNX 
(50 mg/mL) oral suspensions will be provided in HDPE bottles with a 
child-resistant closure.  
For GNX, each bottle contains 110 mL of GNX suspension, and these bottles 
should be stored at room temperature (20°C to 25°C [68°F to 77°F]; excursions 
permitted from 15°C to 30°C [59°F to 86°F]. This suspension is stable for at least 
18 months at room temperature (20°C to 25°C [68°F to 77°F]; excursions permitted 
from 15°C to 30°C [59°F to 86°F]). After opening, suspension should be used 
within 30 days. 
Changes to sponsor-supplied packaging prior to dosing may not occur without full 
agreement in advance by the sponsor. 
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 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 to satisfy local 
or hospital requirements, but must not:  
• 
Contradict the clinical study label. 
• 
Obscure the clinical study label. 
• 
Identify the study participant by name, without consultation with the sponsor. 
Additional labels may not be added without the sponsor’s prior full agreement. 
ASM = anti-seizure medication; GNX = ganaxolone; HDPE = high density polyethylene; IP = investigational product; 
OLE = open label extension; tid = 3 times a day; TSC = tuberous sclerosis complex; US = United States. 

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6.2 
Dose Modification 
The protocol allows some alterations from the currently outlined dosing schedule. 
Adjustments to GNX titration or dose may be used to manage tolerability. The most common, 
dose-related AEs in clinical experience to date, are somnolence, sedation, and lethargy. If a 
participant experiences one of these AEs during titration (or any other event which is, in the 
investigator’s opinion, dose-related), there are several potential approaches to GNX dosing to 
manage tolerability:  
1. Maintain the dose of GNX to determine whether tolerability improves with additional time at 
the achieved dose. 
2. Reduce the dose of GNX: 
• Reduce the amount of GNX to the midpoint between the last well-tolerated dose and dose 
producing the adverse effect(s). 
• If the intermediate dose is tolerated after several days, the participant may escalate to the 
dose that previously produced the adverse effect(s). If tolerability is acceptable, they may 
maintain at that dose or continue the titration as scheduled if not at the maximal daily dose 
(63 mg/kg/day or 1800 mg/day). 
• If the participant does not tolerate the rechallenge with re-escalation of the dose, they may 
return to the highest dose that was previously well-tolerated. The investigator may maintain 
that dose or may attempt re-titration, based on their clinical judgment. 
Any adjustment in dose should be discussed with the medical monitor in advance, if possible. 
Other modifications in dose or titration may be warranted based on the participant’s clinical 
situation. Such adjustments may be instituted in consultation with the medical monitor. 
If the dose is interrupted for more than 48 hours, then the investigator should speak with the 
medical monitor regarding whether and how to re-initiate the medication.  
The maximum dose for all participants is up to 1800 mg/day. It is estimated that the maximum 
duration of participation in this OLE study will be approximately 3 years. 
Participants who discontinue the IP should undergo a 2-week taper period. The taper period may 
be shortened at the discretion of the investigator as clinically indicated. 
6.3 
Preparation, Handling, Storage, and Accountability 
6.3.1 
Storage 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit and storage for all IP received and any discrepancies are reported and 
resolved before use of the IP. 

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The investigator has overall responsibility for ensuring that IP is stored in a secure, 
limited-access location in accordance with applicable requirements under the Controlled 
Substance Act (CSA) and Drug Enforcement Administration (DEA) regulations. Limited 
responsibility may be delegated to the pharmacy or member of the study team, but this 
delegation must be documented. Investigational products are distributed by the pharmacy or by a 
nominated member of the study team. Details on how to store the IP can be found in the 
Pharmacy Manual. 
All study drugs will be transported, received, stored, and handled strictly in accordance with the 
container, study drug label, instructions provided to the pharmacy and applicable regulations. 
The IP must be stored in accordance with labeled storage conditions; the GNX oral suspension 
(50 mg/mL) should be stored at room temperature (20°C to 25°C [68°F to 77°F]; excursions 
permitted from 15°C to 30°C [59°F to 86°F]. Temperature monitoring of the IP is required at the 
storage location to ensure that the IP is maintained within an established temperature range. The 
investigator is responsible for ensuring that the temperature is monitored throughout the duration 
of the study and that records are maintained; the temperature should be monitored continuously 
by an in-house system, by a mechanical recording device such as a calibrated chart recorder, or 
by manual means, such that both minimum and maximum thermometric values over a specific 
time period can be recorded and retrieved as required. Such a device (ie, certified 
minimum/maximum thermometer) would require manual resetting upon each recording.  
The sponsor must be notified immediately upon discovery of any excursion from the established 
range. Temperature excursions will require site investigation as to cause and remediation. The 
sponsor will determine the ultimate impact of excursions on the IP and will provide supportive 
documentation as necessary. Under no circumstances should the product be dispensed to 
participants until the impact has been determined and the product is deemed appropriate for use 
by the sponsor. 
The sponsor should be notified immediately if there are any changes to the IP storage area, such 
as fumigation of a storage room, that could affect the integrity of the product(s). 
6.3.2 
Investigational Product Accountability 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study IP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
Investigators will be provided with sufficient amounts of the IP to carry out this protocol for the 
agreed number of participants. The investigator or designee will acknowledge receipt of the IP, 
documenting shipment content and condition. Accurate records of all IP dispensed, used, 
returned, and/or destroyed must be maintained as detailed further in this section. 
The investigator has 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 

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protocol and who works under the direct supervision of the investigator. This delegation must be 
documented in the applicable study delegation of authority form. 
The investigator or their designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer and/or dispense the IP only to participants included 
in this study following the procedures set out in the study protocol. Each participant will be 
given only the IP carrying his or her treatment assignment. All administered and/or dispensed IP 
will be documented on the electronic case report form (eCRFs) and/or other IP record. The 
investigator is responsible for ensuring the retrieval of all IP and study supplies from the 
participant.  
The participant’s parent(s)/caregiver(s)/LAR(s) 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, participant-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. IP 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 contract research organization [CRO]). Shipment 
return forms, when used, will be signed prior to shipment from the site. Returned IP 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, participant-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 IP must be in accordance with local, state, and national laws. 
Based on entries in the site’s drug accountability forms, it must be possible to reconcile IP 
delivered with those used and returned. All IP must be accounted for, and all discrepancies 
investigated and documented to the sponsor’s satisfaction. 
Further guidance and information for the final disposition of unused study IP are provided in the 
Pharmacy Manual. 

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6.4 
Measures to Minimize Bias 
This is an open-label study; all participants will be treated with GNX and there is no 
randomization or blinding of the IP. 
6.5 
Study Intervention Compliance 
When participants are dosed at the site, they will receive the IP directly from the investigator or 
designee, under medical supervision. The dose of the IP and study participant identification at 
this time will be confirmed at the time of dosing by a member of the study site staff other than 
the person administering the study intervention. 
When participants administer the IP at home, compliance with the IP will be assessed at each 
visit. Compliance will be assessed by inspecting the eDiary entries and returned supplies, with 
queries as necessary, during the site visits. Parent(s)/caregiver(s)/LAR(s) are to record daily 
seizure events in addition to study medication and non-study ASM administration in the eDiary 
device daily during the first year. Parent(s)/caregiver(s)/LAR(s) will be re-educated on the 
importance of adhering to daily seizure, IP and non-study ASM recording as needed. 
Deviation(s) from the prescribed dosage regimen should be recorded in the eCRF. 
A record of the number of bottles of the IP dispensed to and taken by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start and 
stop dates, including dates for intervention delays and/or dose reductions will also be recorded in 
the eCRF. 
6.6 
Concomitant Therapy 
Concomitant medications refer to all treatment taken between the date of informed 
consent/assent for the OLE and the date of the last dose of the IP. 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.  
Paracetamol/acetaminophen, at doses of £ 2 g/day, is permitted for use any time during the study. 
Other concomitant medication may be considered case-by-case by the investigator in 
consultation with the medical monitor.  

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Concomitant topical and intranasal steroids for dermatologic reactions and allergic rhinitis are 
allowed as needed and do not warrant exclusion from study.  
Use of dietary supplements or herbal preparations are permitted if the participant has been using 
them consistently for more than 6 months prior to entry into the OLE and does not plan on 
changing the dose for the duration of the maintenance period. Use of St. John’s Wort and 
Chinese medicine therapies is not permitted (Section 6.6.2). 
Concomitant treatment information must be recorded on the appropriate eCRF page. If the 
participant starts a new medication during the study, details of that medication including the dose 
and date and time of first administration, should be added to the participant’s list of concomitant 
medications, and recorded in the eCRF as appropriate. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.  
6.6.1 
Rescue Medicine  
The use of rescue medication is allowed at any time during the study for prolonged, severe, or 
repetitive seizures (seizure clusters). Rescue medication should be delayed for 1 hour following 
administration of IP unless it unsafe to wait due to the severity of the seizure(s). 
Permitted rescue medications include:  
• Alprazolam.  
• Clobazam. 
• Clonazepam.  
• Diazepam.  
• Lorazepam.  
• Levetiracetam. 
• Phenobarbital.  
Other rescue medications may be used if approved by the medical monitor. 
Participants are expected to record rescue medications, dose levels, date, and time of 
administration on the eDiary during the first year. The medication name, dose, start and stop 
dates, and frequency of dosing will also be recorded in the clinical database during the second 
and third year.  
The study site will not supply rescue medication that can be obtained locally.  
6.6.2 
Excluded Medications 
Excluded medications include all steroid medications, other Ips, as well as ketoconazole, 
St. John’s wort, and Chinese medicine therapies.  

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Concurrent use of adrenocorticotropic hormone (ACTH), prednisone or other glucocorticoid is 
not permitted, nor use of the strong inducers of cytochrome P450 3A4 (CYP3A4) (except 
approved ASMs: carbamazepine, phenytoin derivatives, phenobarbital, or primidone), rifampin, 
St. John’s Wort, and Chinese medicine therapies.  
Note: Concomitant intranasal or pro re nata (PRN) topical steroids for dermatologic reactions 
and allergic rhinitis are allowed. 
Products containing tetrahydrocannabinol (THC) or non-approved CBD are excluded during 
treatment. THC or non-approved CBD should be washed out for at least 4 weeks prior to the 
initial visit. Participants with a positive result on THC or CBD laboratory tests during the parent 
study, and who do not have an explanatory Epidiolex®/Epidyolex® prescription, will not be 
eligible to participate in this OLE. 
6.7 
Intervention After the End of the Study 
Treatment can continue until the sponsor terminates this study. 
7 DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If the IP is discontinued at any time, participants should follow the 2-week taper 
schedule unless otherwise medically indicated such, as drug-induced rash. If the participant 
discontinues the IP, evaluations listed for the Early Termination Visit (Visit 13 [Week 156]; as 
shown in the SOA [Table 1]) are to be performed as completely as possible along with the end of 
study and safety follow-up assessment, as appropriate. Comments (spontaneous or elicited) or 
complaints made by the participant 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 eCRF and 
source documents. Discontinuation of IP due to AEs must also be reflected on the AE eCRF 
page. Participants who discontinue IP should undergo a 2-week or shorter taper period, as 
clinically indicated. These participants will have a visit 2 weeks after the end of taper to 
complete the safety follow-up assessments. 
The reason for early discontinuation of the IP must be determined by the investigator and 
recorded in the participant’s source documents and on the eCRF. If a participant 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.  

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Reasons for early termination include but are not limited to the following: 
• AE (including pregnancy). 
• Protocol violation/protocol deviation. 
• Withdrawal by participant or parent(s)/LAR(s). 
• Lost to follow-up. 
• Lack of efficacy. 
• Death. 
• Investigator decision. 
7.2 
Discontinuation/Withdrawal from the Study 
All participants or his/her parent(s)/LAR(s) reserve the right to withdraw from the study at any 
time, as stated in the informed consent/assent form. The investigator may discontinue 
participants from the clinical study for any of the following reasons: 
• Participant is found to have entered the study in violation of the protocol. 
• Participant requires the use of a disallowed concomitant medication. 
• Participant’s condition changes after entering the clinical investigation so that the participant 
no longer meets the inclusion criteria or develops any of the exclusion criteria. 
• Participant or parent(s)/LAR(s) withdraws consent or assent to participate in the study. 
• Participant is noncompliant with the procedures set forth in the protocol. 
• Participant experiences an AE/SAE that warrants withdrawal from the study. 
• Any laboratory, medical, or clinical finding for which clinical intervention should take 
precedence over study participation. This includes: 
o Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) or 
alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase 
(SGPT) > 3 × upper limit of normal (ULN). 
o Total bilirubin levels > 1.5 × ULN. 
o Estimated glomerular filtration rate (eGFR) < 30 mL/min. 
• It is the investigator’s opinion that it is not in the participant’s best interest to continue in the 
study. 
Decisions to discontinue the study will be made at each participating site by the investigator. If 
feasible, the reason for discontinuation should be discussed with the sponsor’s medical monitor 
prior to participant’s discontinuation.  
At the time of discontinuing from the study, if possible, an Early Termination Visit (Visit 13 
[Week 156]) should be conducted as shown in the SOA (Table 1). At this visit, participants will 
start a 2-week taper and then return to the site 2 weeks later for safety follow-up assessments.  

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If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.  
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records.  
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits without stating an intention to withdraw consent and is unable to be contacted 
by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain whether the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant. A minimum of 3 documented attempts 
must be made to contact any participant 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 participant’s last known address via courier 
or mail (with an acknowledgment of receipt request) asking that they return to the site for 
final safety evaluations and return any unused IP. If contact is made but the participant 
refuses or is unable to return to the site for the early termination and final safety follow-up 
visit, it should be documented in the eCRF. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled in Section 10.1.9. 
8 STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SOA (Section 1.3). Study dates will be 
based on the date of the first dose of IP in this OLE and not the date of baseline visits. 
Study assessments can be conducted at the institution of the site investigator or remotely at the 
participant’s home. All assessments can be conducted remotely by the site staff using 
telemedicine video tools; and for sites located outside of the European Union only, by providing 
traveling nurses to take vital signs, draw blood samples, and collect specimens.  
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention.  

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Adherence to the study design requirements, including those specified in the SOA, is essential 
and required for study conduct.  
All evaluations must be completed and reviewed to confirm that potential participants meet all 
eligibility criteria. The investigator will maintain an enrollment log to record details of all 
participants from 1042-TSC-3001 and 1042-TSC-2001 studies who enter this OLE and to 
confirm eligibility or record reasons for participant exclusion, as applicable.  
Procedures conducted in the parent study or as part of the participant’s routine clinical 
management (eg, blood count) and obtained before signing of the ICF for the parent study may 
be utilized for baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the timeframe defined in the SOA.  
8.1 
General Study Periods 
8.1.1 
Screening, Enrollment, Randomization, and Baseline 
There is no screening period in this OLE study. Participants from Study 1042-TSC-3001 and 
Study 1042-TSC-2001 will be enrolled in this OLE if eligible and continue maintenance 
treatment with GNX. 
Note for Investigational Sites in the United Kingdom (UK): NHS sites in the UK will be aware 
of the study by virtue of the investigators participating in the site initiation visit, and being 
trained on the study design, conduct, and participant protection policies. 
Informed consent/assent will be obtained after the study has been fully explained to the 
participant/parent(s)/LAR(s) and before the conduct of any assessments (Section 10.1.3 for the 
informed consent procedure). This will occur at the end of the double-blind treatment period in 
Study 1042-TSC-3001 and before any dose adjustments are made or prior to entry into the OLE 
for participants in Study 1042-TSC-2001.  
8.1.1.1 
Demographics and Medical History 
Demographics including age, gender, ethnicity, and race, as allowed according to local 
regulations, will be collected in the parent study. In addition to the genetic evaluation of 
pathogenic or likely pathogenic TSC1/TSC2 variant, relevant medical history including but 
limited to the age of seizure onset, other physical disabilities such as scoliosis, visual 
impairment, sensory problems, and gastrointestinal difficulties will also be assessed in the parent 
study as will the participant’s developmental history. This will include the grade level of 
schoolwork that the participant has completed (for individuals who are chronologically school 
age), as well as the investigator’s estimate of the participant’s developmental age.  
Details of prior medications include all treatment, including but not limited to herbal treatments, 
vitamins, surgical implants (such as vagal nerve stimulator [VNS]), and prescribed medications, 
will be collected.  

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Demographics and Medical History will be reviewed at the end of the parent(s)/LAR(s) 
study/Visit 1 (First Visit of the OLE).  
8.1.1.2 
Seizure Identification and Diagnostic Review 
Per the inclusion criteria of the parent study, enrollment will be based on the presence and 
frequency of the seizure types defined as follows:  
• Focal motor seizures without impairment of consciousness or awareness. 
• Focal seizures with impairment of consciousness or awareness with motor features. 
• Focal seizures evolving to bilateral, tonic-clonic convulsive seizures. 
• Generalized motor seizures including tonic-clonic, bilateral tonic, bilateral clonic, or 
atonic/drop seizures.  
Seizures must have a motor component sufficiently prominent and distinct to clearly establish 
the observed symptoms as epileptic in origin. Seizures that do not count towards efficacy 
endpoints include:  
• Focal or generalized nonmotor seizures (eg, absence seizures or focal nonmotor seizures with 
or without impairment of awareness). 
• Infantile or epileptic spasms. 
• Myoclonic seizures.  
To standardize seizure identification and classification in the study, a Seizure Identification 
Form/Diagnostic Review Form (SIF/DRF) will be submitted and reviewed by the Epilepsy Study 
Consortium prior to the participant’s entry into the parent study and this information will be used 
in this OLE.  
8.1.2 
Open-label Treatment Phase 
Open-label treatment with the IP, at the dose determined in the parent study, will continue in this 
OLE. All dates during the open-label phase will be based off the date of the first dose of IP in the 
OLE.  
Participants who discontinue the study prematurely before Visit 13 (Week 156) are required to 
taper their IP for 2 weeks or shorter, unless otherwise medically indicated. Participants should 
also complete the eDiary during this time. The end of study assessments, as detailed in the SOA 
for Visit 13 should then be performed (Table 1). 
8.1.3 
Safety Follow-up 
A safety follow-up visit will be conducted at Visit 14 (Week 160), which will be 2 weeks after 
the end of the 2-week taper for participants who are not continuing commercially available GNX 
(Table 1). This will be the end of study visit for these participants. 

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8.2 
Efficacy Assessments 
Efficacy as determined by a reduction in seizures will be evaluated by collecting daily seizure 
type, duration, and frequency in a seizure diary. Days in which no seizures occur will also be 
noted. Changes in seizure intensity/duration, CGI-I, as well as changes in behavior and 
neuropsychiatric symptoms will be assessed by a variety of clinician and caregiver administered 
instruments.  
Planned timepoints for all efficacy assessments are provided in the SOA (Table 1). 
8.2.1 
Seizure Type and Frequency 
The Epilepsy Study Consortium will review participant seizure data and assign the seizure type 
for each participant in the parent study.  
Parent(s)/caregiver(s)/LAR(s) will record daily seizures denoting vernacular name for the seizure 
type, duration, and frequency in an eDiary.  
Seizure types that count towards the efficacy endpoints are defined as the following:  
• Focal motor seizures without impairment of consciousness or awareness. 
• Focal seizures with impairment of consciousness or awareness with motor features. 
• Focal seizures evolving to bilateral, tonic-clonic convulsive seizures. 
• Generalized motor seizures including tonic-clonic, bilateral tonic, bilateral clonic, or 
atonic/drop seizures. 
Seizures must have a motor component sufficiently prominent and distinct to clearly establish 
the observed symptoms as epileptic in origin.  
Seizures that do not count towards the efficacy endpoints include:  
• Focal or generalized nonmotor seizures (eg, absence seizures or focal nonmotor seizures with 
or without impairment of awareness). 
• Infantile or epileptic spasms. 
• Myoclonic seizures. 
Note: Every seizure reported by the family will be fully described in the study outputs, and each 
description will include the vernacular name used by the participant or 
parent(s)/caregiver(s)/LAR(s), as appropriate, to refer to that seizure event as well as the medical 
seizure type as adjudicated by the Epilepsy Study Consortium. If the parent uses a medically 
incorrect term to refer to a specific seizure (such as calling a focal seizure with impaired 
awareness “absence”) it will be permitted as long as they use the term consistently for a single 
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Participants or parent(s)/caregiver(s)/LAR(s) are to record administration of the IP and 
background ASMs in the eDiary during the first year. Compliance with the IP treatment will be 
assessed by inspecting the participants’ eDiary and returned supplies with queries, as necessary. 
8.2.2 
Clinical Global Impression – Improvement  
The CGI-I is a 7-point Likert scale that the parent(s)/caregiver(s)/LAR(s) and clinician uses to 
rate the change in overall seizure control, behavior, safety, and tolerability after initiation of IP 
relative to baseline (prior to treatment with IP). The participant will be rated as follows: 1- very 
much improved, 2- much improved, 3- minimally improved, 4- no change, 5- minimally worse, 
6- much worse, and 7- very much worse (Section 10.8). 
Clinical Global Impression – Improvement (parent/caregiver/LAR and clinician) will be assessed 
at Visit 1 (First Visit of the OLE), Visit 3 (Week 26), Visit 5 (Week 52), Visit 7 (Week 78), 
Visit 9 (Week 104), Visit 11 (Week 130), and Visit 13 (Week 156). 
8.2.3 
Caregiver Global Impression of Change in Seizure Intensity/Duration  
The CGI-CSID is a 7-point Likert scale in which the parent(s)/caregiver(s)/LAR(s) assesses 
change in seizure intensity and/or duration after initiation of investigational product relative to 
baseline (prior to treatment with investigational product). The scale ranges from 1- very much 
improved, 2- much improved, 3- minimally improved, 4- no change, 5- minimally worse, 6- 
much worse, and 7- very much worse (Section 10.9). 
CGI-CSID will be assessed at Visit 1 (First Visit of the OLE), Visit 3 (Week 26), Visit 5 
(Week 52), Visit 7 (Week 78), Visit 9 (Week 104), Visit 11 (Week 130), and Visit 13 
(Week 156). 
8.2.4 
Short Form 36 
The SF-36 is a multi-purpose survey designed to capture participant or 
parent(s)/caregiver(s)/LAR(s) perceptions of own health and well-being. The SF-36 has 36 items 
grouped in 8 dimensions: physical functioning, physical and emotional limitations, social 
functioning, bodily pain, general, and mental health. Version 2 of SF-36 will be used for this 
study (Section 10.10). 
The SF-36 will be conducted at Visit 1 (First Visit of the OLE), Visit 3 (Week 26), and 
Visit 5 (Week 52). 
8.3 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SOA (Section 1.3). 

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8.3.1 
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. 
• Reflexes. 
• Coordination/Cerebellar. 
The full developmental examination (applicable only to pediatric participants 1 to 17 years of 
age, inclusive) will include: 
• Speech/language 
o Makes identifiable sounds for specific objects/people. 
o Repeats sounds. 
o Single words. 
o Multiple words. 
o Makes a sentence. 
o Replies to questions using an identifiable sound, single word, multiple word, or sentence. 
o Other abilities. 
• Motor 
o Sits with support. 
o Sits independently. 
o Crawls. 
o Stands with support. 

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o Stands independently.  
o Takes steps with assistance. 
o Walks independently. 
o Other abilities. 
• Social 
o Smiles appropriately to situation. 
o Makes eye contact. 
The physical/neurological/developmental examinations will be conducted at Visit 1 (First Visit 
of the OLE), Visit 3 (Week 26), Visit 5 (Week 52), Visit 7 (Week 78), Visit 9 (Week 104), 
Visit 11 (Week 130), Visit 13 (Week 156), and Visit 14 (Week 160). 
8.3.2 
Vital Signs 
Vital signs including heart rate (HR [bpm]), respiratory rate (RR [breaths/minute]), body 
temperature measured orally or on the skin, and blood pressure (BP [mmHg]) will be collected at 
every in-clinic visit. 
BP and pulse measurements will be assessed in a sitting position with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
BP and pulse measurements should be preceded by at least 5 minutes of rest for the participant in 
a quiet setting without distractions (eg, television, cell phones). 
Vital signs will be measured in a sitting position after 5 minutes rest and will include 
temperature, systolic and diastolic BP, pulse, and RR. Three readings of BP and pulse will be 
taken. The first reading should be rejected. The second and third readings should be averaged to 
give the measurement to be recorded. 
Vital signs, body temperature, height, and weight will be collected at Visit 1 (First Visit of the 
OLE), Visit 3 (Week 26), Visit 5 (Week 52), Visit 7 (Week 78), Visit 9 (Week 104), Visit 11 
(Week 130), Visit 13 (Week 156), and Visit 14 (Week 160). 
8.3.3 
Electrocardiograms 
12-lead ECGs 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 
participant is enrolled in the study.  
12-lead ECGs will be obtained as outlined in the SOA (see Section 1.3) using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. 
12-lead ECGs will be performed at Visit 1 (First Visit of the OLE), Visit 3 (Week 26), and 
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8.3.4 
Clinical Safety Laboratory Tests 
Laboratory safety assessments will be collected to monitor participant safety. Clinical laboratory 
tests are listed in Section 10.3 and will be collected per the schedule listed in SOA 
(see Section 1.3). The laboratory reports must be filed with the source documents.  
These clinical laboratory assessments will include complete blood count with automated 
differential, creatinine, blood urea nitrogen, and eGFR calculation (mL/min), comprehensive 
metabolic panel, as well as serum pregnancy test for all WOCBP. A central laboratory will be 
utilized by the sites. 
The following liver function and eGFR tests will be monitored throughout the study as follows:  
• If AST (SGOT) or ALT (SGPT) increases > 3 times ULN during the study, participant 
should be followed with weekly laboratory repeat testing and continue in study if levels 
trending down. Participant will be discontinued if levels do not decline to under 3 × ULN.  
• If total bilirubin increases to 1.5 × ULN or more during study, the participant will be 
discontinued.  
• Participants with significant renal insufficiency, eGFR < 30 mL/min (calculated using the 
Cockcroft-Gault formula or pediatric glomerular filtration rate [GFR] calculator or Bedside 
Schwartz), will be discontinued if the criterion is met post baseline. 
• If any of the criteria above are deemed clinically significant by the investigator, then the 
sponsor’s medical monitor should be contacted. 
• If clinically significant values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the sponsor notified. 
• If laboratory values from non-protocol-specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or Common Terminology Criteria for 
Adverse Events [CTCAE] Grade 3 laboratory test), then the results must be recorded and 
discussed with the medical monitor. 
Blood samples will be collected for clinical laboratory tests at Visit 1 (First Visit for the OLE), 
Visit 3 (Week 26), Visit 5 (Week 52), Visit 7 (Week 78), Visit 9 (Week 104), Visit 11 
(Week 130), and Visit 13 (Week 156). 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 25 mL. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples, 
which may increase the total volume drawn. In the pediatric population, the blood volumes 
collected should be minimized as much as possible. 
In addition, urinalysis will be conducted at Visit 1 (First Visit for the OLE), Visit 3 (Week 26), 
Visit 5 (Week 52), Visit 7 (Week 78), Visit 9 (Week 104), Visit 11 (Week 130), and Visit 13 
(Week 156) for all participants. 

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8.3.5 
Suicidal Ideation and Behavior Risk Monitoring (Columbia-Suicide Severity 
Rating Scale) 
GNX is considered to be a CNS-active intervention. GNX is related to products with an 
increased risk of suicidal ideation or behavior. Participants with TSC may occasionally develop 
suicidal ideation or behavior. 
Participants being treated with GNX should be monitored appropriately and observed closely for 
suicidal ideation and behavior (SIB) or any other unusual changes in behavior, especially at the 
beginning and end of the course of intervention, or at the time of dose changes, either increases 
or decreases. Participants who experience signs of SIB should undergo a risk assessment. All 
factors contributing to SIB should be evaluated and consideration should be given to 
discontinuation of the study intervention.  
When informed consent or assent has been given, participants or parents/caregivers of 
participants being treated with GNX should be alerted about the need to monitor participants for 
the emergence of unusual changes in behavior, as well as the emergence of suicidal ideation and 
behavior and to report such symptoms immediately to the study investigator. 
The C-SSRS will be used to rate the participant’s degree of suicidal ideation on a scale ranging 
from “no suicidal ideation” to “active suicidal ideation with specific plan and intent” 
(Posner et al, 2011) (Section 10.11). The C-SSRS will be assessed in all participants  11 years 
of age, if appropriate, otherwise, clinical judgment will be used.  
If the participant has a positive result for C-SSRS, the medical monitor should be contacted 
within 24 hours and the medical monitor will determine if the individual should discontinue the 
trial. 
The C-SSRS will be completed at Visit 1 (First Visit of the OLE) (and compared with data 
collected in the parent study), and then 6-monthly at Visit 3 (Week 26), Visit 5 (Week 52), 
Visit 7 (Week 78), Visit 9 (Week 104), Visit 11 (Week 130), Visit 13 (Week 156), and Visit 14 
(Week 160) (and compared with data collected in the previous visit). 
8.3.6 
Concomitant Anti-seizure Medicine Levels 
If the levels of ASM co-administered with the IP are measured routinely, this information will be 
recorded in the eCRF during the study.  
Further details are provided in the SOA (Table 1).  
8.3.7 
Investigational Product Pharmacokinetics 
Please refer to Section 8.6 for additional details regarding PK assessments. 
The results, date, and time of last ASM dose will be recorded in the eCRF.  

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8.3.8 
Pregnancy Testing 
A serum pregnancy test is required for all WOCBP at Visit 1 on Day 1 of this OLE study. Urine 
pregnancy testing will then be performed every 4 weeks throughout the OLE using take-home 
pregnancy tests. Any positive home pregnany test will be followed up with a confirmatory serum 
pregnancy test. 
8.4 
Adverse Events and Serious Adverse Events 
The definitions of unsolicited and solicited AEs and SAEs can be found in Section 10.4. 
AEs will be reported by the participant (or, when appropriate, by parent/caregiver/LAR) 
throughout the study (Table 1).  
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs OR AEs that are serious, considered related to the study, or that caused the participant 
to discontinue the IP and the study (Section 7). 
The reference for safety information for this study is the GNX IB, which the sponsor has 
provided under separate cover to all investigators. For additional details, please consult the most 
current IB. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.4.  
All initial and follow-up SAE reports must be reported by the investigator to Marinus’ drug 
safety vendor within 24 hours of the first awareness of the event. Note: The 24-hour reporting 
requirement for SAEs does not apply to reports of abuse, misuse, overdose, or medication errors 
unless they result in an SAE.  
The investigator 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 Marinus’ drug safety vendor or its delegate.  
8.4.1 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
All AEs are collected from the time of the first dose of the IP in the OLE until the defined 
follow-up period at the timepoints specified in the SOA (Section 1.3). Any AE that begins in a 
parent study and is ongoing at the time of the first dose of IP in the OLE will be included as an 
AE in the OLE. This includes events occurring during the initial visit in 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 

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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. 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded as medical history/current medical conditions, not as AEs. 
All AEs must be followed to closure (the participant’s health has returned to baseline status or all 
variables have returned to normal), regardless of whether the participant is still participating in 
the study. Closure indicates that an outcome is reached, stabilization is achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented. 
All SAEs (regardless of relationship to study) are collected from the time the 
participant/parent(s)/LAR(s) signs the informed consent/assent until the defined follow-up period 
stated and must be reported to Marinus’ drug safety vendor within 24 hours of the first awareness 
of the event.  
In addition, any SAE considered “related” to the IP and discovered by the investigator at any 
interval after the study has completed must be reported to Marinus’ drug safety vendor within 24 
hours of the first awareness of the event. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must promptly 
notify the sponsor. 
8.4.2 
Method of Detecting Adverse Events and Serious Adverse Events 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.4. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.4.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs (and non-serious AEs of special interest (as defined in 
Section 8.4.8) will be followed until resolution, stabilization, the event is otherwise explained, or 
the participant is lost to follow-up (as defined in Section 7.3). Further information on follow-up 
procedures is provided in Section 10.4. 

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8.4.4 
Regulatory Reporting Requirements for Serious Adverse Events 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Board/Independent Ethics Committee (IRB/IEC), 
and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSARs) according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
8.4.4.1 
Suspected Unexpected Serious Adverse Reaction 
A SUSAR is defined as an SAE that meets both the following criteria with respect to IP: 
Suspected — is assessed as related to IP 
Unexpected — compared to the IP-related AEs described in the IB, Reference Safety 
Information, the event meets any of the following criteria: 
• The event has not been previously described. 
• The event is now characterized as more severe. 
• The event is now characterized more specifically (eg, an event of “interstitial nephritis” in a 
participant receiving an agent previously described as associated with “acute renal failure”). 
In clinical trials involving ill participants, events considered related to the natural history of the 
disease under study or to lack of efficacy (that is, the event is considered more likely related to 
those factors than to other factors, including study drug) are not considered “unexpected”. 
Requirements for Expedited and Periodic Reporting of Adverse Events: 
SUSARs are required to be reported rapidly to regulatory authorities and to IRBs/IECs (within 
7 days of initial notification for fatal or life-threatening SUSARs, within 15 days for all other 
SUSARs). Therefore, as with all SAEs, the site must report the event to Marinus’ drug safety 
vendor within 24 hours of being made aware of the event. The Sponsor and the Investigator will 
work together to meet these reporting requirements. 

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8.4.5 
Clinical Laboratory and Other Safety Evaluations 
A change in vital signs, physical, neurological, and developmental examinations, 12-lead ECG 
parameters, or clinical laboratory values 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. 
If, at the treatment period, there are abnormal vital signs, physical, neurological, and 
developmental, 12-lead ECG, or clinical laboratory 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 investigator should decide, based on the above criteria and the clinical condition of a 
participant, whether the change is clinically significant and therefore, represents an AE. 
8.4.6 
Death Events 
Any SAE that results in the participant’s death (ie, the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome, with the date of death recorded as the resolution 
date. For all other events ongoing at the time of death that did not contribute to the participant’s 
death, the outcome should be considered not resolved, without a resolution date recorded. 
For any SAE that results in the participant’s death or any ongoing events at the time of death, 
unless another IP action was previously taken (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 participant never received the IP). The IP action of “withdrawn” should not be 
selected solely as a result of the participant’s death. 
8.4.7 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events 
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. This includes seizures 
typical for that participant unless the seizures are changed in character, frequency, or duration. 
Significant worsening of the symptoms should be recorded as an AE. 
The following disease-related events are common in participants with epilepsy and can be 
serious/life-threatening:  
• Seizures. 
• SE. 

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• Falls/trauma/accidents. 
As these events are typically associated with the disease under study, they will not be reported 
according to the standard process for expedited reporting of SAEs even though the event may 
meet the definition of an SAE. These events will be recorded within 5 business days of when 
they are reported to the site. These disease-related events will be monitored on a routine basis.  
Note: However, if either of the following applies, then the event must be recorded and reported 
as an AE/SAE (instead of a disease-related event):  
• The event is, in the investigator’s opinion, of greater intensity, frequency, or duration than 
expected for the individual participant, or 
• The investigator considers that there is a reasonable possibility that the event was related to 
study intervention. 
8.4.8 
Adverse Events of Special Interest 
An adverse event of special interest (AESI) includes any non-serious conduction that falls under 
the system organ class (SOC) of ‘Breast and Reproductive disorders’. These AESIs will be 
submitted to Marinus’ drug safety vendor using the study specific AESI reporting form.  
8.4.9 
Pregnancy 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants are to be reported from the time informed consent is signed until the defined 
follow-up period. 
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Marinus’ drug safety vendor 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 female study participant 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 investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days after delivery.  
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported as outlined in Section 10.4 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. 
Any poststudy pregnancy-related SAE considered reasonably related to the study intervention by 
the investigator will be reported to the sponsor as described in Section 8.4.4. While the 
investigator is not obligated to actively seek this information in former study 

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participants/pregnant female partner, he or she may learn of an SAE through spontaneous 
reporting. 
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE to Marinus’ drug safety vendor as outlined in Section 10.4 of the 
protocol using the Marinus Clinical Study Serious Adverse Event Form. The test date of the first 
positive serum ȕ-human chorionic gonadotropin test or ultrasound result will determine the 
pregnancy onset date.  
Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention and be withdrawn from the study.  
8.4.10 
Abuse, Misuse, Overdose, and Medication Error 
Abuse, misuse, overdose, or medication error should not be reported per the SAE reporting 
procedure. Only a resulting AE, if it occurs, should be reported according to the procedures as 
described in Section 10.4. All IP provided to pediatric participants should be supervised by the 
parent(s)/caregiver(s)/LAR(s). 
The definitions below are not mutually exclusive; an 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. For studies, medication errors are reportable to the sponsor only as defined below. 
o Cases of participant’s missing doses of the IP are not considered reportable as 
medication errors. 
o Medication errors should be collected and reported for the IP under investigation. 
o The administration and/or use of an expired IP should be considered as a reportable 
medication error. 
8.5 
Treatment of Overdose 
For this study, any dose of GNX greater than up to 63 mg/kg/day or over the maximum of 
1800 mg/day (900 mg/day) within a 24-hour time period will be considered an overdose. 
Sponsor does not recommend specific treatment for an overdose, but participants should be 
closely monitored and receive supportive care.  

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In the event of an overdose, the investigator should: 
• Contact the medical monitor immediately. 
• Evaluate the participant to determine, in consultation with the medical monitor, whether 
study intervention should be interrupted or whether the dose should be reduced. 
• Closely monitor the participant for any AE/SAE and provide any appropriate supportive 
medical management. 
• Obtain a plasma sample for PK analysis within 1 day from the date of the last dose of study 
intervention if requested by the medical monitor (determined on a case-by-case basis). 
• Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
8.6 
Pharmacokinetics and Pharmacodynamics 
8.6.1 
Pharmacokinetics 
Whole blood samples of approximately 2 mL will be collected for measurement of the plasma 
concentrations of GNX as specified in the SOA (Section 1.3).  
There is no specified time window for collection of the blood sample for PK analyses.  
The time of the participants’ last dose of the IP and the time of their next dose of the IP should 
be specified in relation to the time of the PK draw. 
The actual date and time (24-hour clock time) each sample is collected must be accurately 
recorded in the source document and appropriate eCRF. 
Instructions for the collection and handling of biological samples will be provided by the 
sponsor. Please refer to the laboratory manual for processing instructions. 
Samples will be used to evaluate the PK of GNX. Each sample will be divided into 2 aliquots 
(1 for PK, 1 as a backup). Samples collected for analyses of GNX concentration may also be 
used to evaluate safety or efficacy aspects related to concerns arising during or after the study.  
Additional samples may be collected at additional timepoints during the study if warranted and 
agreed upon between the investigator and the sponsor. The timing of sampling may be altered 
during the course of the study based on newly available data (eg, to obtain data closer to the time 
of peak plasma concentrations) to ensure appropriate monitoring. 
8.6.2 
Pharmacodynamics 
PD parameters are not evaluated in this study. 
8.7 
Genetics 
Genetic parameters are not evaluated in this study. 

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8.8 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9 
Immunogenicity Assessments 
Immunogenicity is not evaluated in this study. 
8.10 Health Economics  
Health economics are not evaluated in this study. 
9 STATISTICAL CONSIDERATIONS 
The statistical analysis plan (SAP) will be finalized prior to database lock and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
All statistical analyses will be performed using SAS® (SAS Institute, Cary, NC 27513) software. 
9.1 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined: 
Participant Analysis Set 
Description 
Intent-to-treat (ITT) set 
All participants who receive at least 1 dose of the IP. Participants will 
be summarized overall and by the treatment group to which they were 
randomized in the parent study (placebo or GNX). This population will 
be used for efficacy analyses. 
Safety analysis set 
All participants who receive at least 1 dose of the IP. This population 
will be used for the safety analyses. 
GNX = ganaxolone; IP = investigational product/GNX. 
The intent-to-treat (ITT) analysis set is used to analyze endpoints related to the efficacy 
objectives and the safety analysis set is used to analyze the endpoints and assessments related to 
safety. The efficacy analyses will be performed within the ITT population. 
9.2 
Statistical Analyses 
9.2.1 
General Considerations 
The results of the primary, secondary, and exploratory endpoints will be summarized separately. 
The results will be summarized by the treatment received by participants in the parent study. 
Participant demographics, characteristics, and medical history at randomization or the start of the 
parent study will be summarized using descriptive statistics. 

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9.2.2 
Primary Endpoints 
The primary endpoints are the following safety endpoints:  
• Incidence and severity of AEs, SAEs and withdrawals and dose-reductions due to AEs. 
• Vital sign measurements including BP, HR, RR, body temperature, height, and body weight. 
• Physical, neurological, and developmental examination. 
• 12-lead ECG. 
• Clinical laboratory tests. 
• C-SSRS. 
Further details are provided in Section 9.2.5. 
9.2.3 
Secondary Endpoints Analysis 
The secondary endpoints are:  
• Percentage change from baseline in 28-day seizure frequency during open-label treatment 
(first year only). 
• Percentage change from baseline in 28-day seizure frequency during the long-term treatment  
(first year only). 
• Number (%) of participants considered treatment responders (first year only). 
• CGI-I at the last scheduled study visit. 
• Change from baseline in the quality-of-life scale SF-36 (first year only). 
• Change from baseline in the percentage of seizure-free days during treatment, based on 
seizure type (first year only). 
• Change from baseline of CGI-CSID. 
All the endpoints will be included in data listings. 
9.2.4 
Pharmacokinetic Analysis 
A population PK approach addressing the relationship between GNX PK parameters and 
individual characteristics will be implemented as follows:  
• Visit 3 (Week 26).  
• Visit 5 (Week 52). 
For PK assays there is no specified time to draw the PK sample and these can be drawn 
whenever convenient during the specified study visits.  
Exact time of sample withdrawal and drug intake will be recorded in the eCRF. 

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9.2.5 
Safety Analyses 
All safety analyses will be performed in the Safety Population. The results will be summarized 
overall and by the treatment received in the parent study (placebo or GNX). 
The number and percentage of days participants received IP, the highest percentage of the 
maximum allowable daily dose (1800 mg or 63 mg/kg) participants received, and the total 
amount of IP received will be summarized.  
A participant data listing will be provided with full details of the study drug dispensation. 
Safety assessments include: 
• AEs.  
• Vital signs including BP, HR, RR, body temperature, height, and body weight. 
• Physical, neurological, and developmental examinations. 
• 12-lead ECG. 
• Clinical laboratory tests. 
• Concomitant ASM levels (as detailed in Section 8.3.6).  
• C-SSRS. 
Detailed analysis and complete listings will be outlined in the SAP. 
9.2.6 
Subgroup Analysis 
The following subgroup summarizations of the efficacy parameter are planned as outlined in the 
SAP: 
• Gender (Female vs Male). 
• Age groups (1 to 6 years; 7 to 12 years; 13 to 17 years; and 18 years and above). 
All the analyses will follow the rules: 
• The results will be presented overall, for participants previously enrolled in 
Study 1042-TSC-2001, and for participants previously enrolled in Study 1042-TSC-3001 
results will also be classified according to the double-blind treatment received by participants 
in Study 1042-TSC-3001. 
• The seizure endpoints will be derived starting from the first dosing day of OLE treatment. 
• No per protocol analyses will be performed 
9.3 
Interim Analysis 
No formal interim analysis is planned. 

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9.4 
Sample Size Determination 
Approximately 169 participants will be enrolled, which is a combination of participants who 
completed Study 1042-TSC-3001 or Study 1042-TSC-2001. The total sample size is not 
powered for the primary and secondary endpoints. 
 

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
international ethical guidelines 
• Applicable ICH GCP guidelines 
• Applicable laws and regulations. 
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, advertisements) 
must be submitted to an IRB/IEC by the investigator and reviewed and approved by the IRB/IEC 
before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to study 
participants. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC. 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures. 
• Providing oversight of the conduct of the study at the site and adherence to requirements of 
21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies 
(if applicable), European Medical Device Regulation 2017/745 for clinical device research 
(if applicable), and all other applicable local regulations. 
10.1.2 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.  

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10.1.3 
Informed Consent Process 
The investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant/parent(s)/LAR(s) and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants/parents(s)/LAR(s) 
will be required to sign a statement of informed consent/assent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, privacy, and data protection requirements, where 
applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Participant/parent(s)/LAR(s) must be reconsented to the most current version of the ICF(s) 
during their participation in the study. 
Minor participants must be re-consented if they reach the age of majority during the course of the 
study, in order to continue participating.  
A copy of the ICF(s) must be provided to the participant/caregiver(s) or LAR(s). 
10.1.4 
Data Collection 
During each participant’s visit to the clinic, a clinician participating in the trial will record 
progress notes to document all significant observations. At a minimum, these notes will contain: 
• Documentation of the informed consent process, including any revisions. 
• The date of the visit and the corresponding visit or day in the trial schedule. 
• General participant status remarks, including any significant medical findings. The severity, 
frequency, duration, action taken, and outcome of any AEs and the investigator’s assessment 
of relationship to the IP must also be recorded. 
• Any changes in concomitant mediations and dosages. 
• A general reference to the procedures completed. 
• The signature (or initials or other unique identifier) and date of each clinician (or designee) 
who made an entry in the progress notes. 
In addition, any contact with the participant/parent(s)/caregiver(s)/LAR(s) via telephone or other 
means that provides significant clinical information will also be documented in the progress 
notes as described above. Any changes to information in the trial progress notes and other source 
documents will be initialed and dated on the day the change is made by a site staff member 
authorized to make the change. Changes will be made by striking a single line through erroneous 
data (so as not to obliterate the original data), and clearly entering the correct data (eg, wrong 
data right data). If the reason for the change is not apparent, a brief explanation for the change 
will be written in the source documentation by the clinician. 

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Information from the trial progress notes and other source documents will be data entered by 
investigative site personnel directly onto eCRFs in the sponsors electronic data capture system. 
10.1.5 
Data Protection 
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred. 
The participant/parent(s)/LAR(s) must be informed that the participant’s personal study-related 
data will be used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give consent for their 
data to be used as described in the informed consent. 
The participant/parent(s)/LAR(s) must be informed that the participant’s medical records may be 
examined by Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.6 
Dissemination of Clinical Study Data 
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by local laws and regulations. 
10.1.7 
Data Quality Assurance 
All participant data relating to the study will be recorded on printed or eCRFs unless transmitted 
to the sponsor or designee electronically (eg, laboratory data). The investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
case report form (CRF). 
Guidance on completion of CRFs will be provided in eCRF Completion Guidelines.  
The investigator’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 investigator’s meeting. Once a participant is screened, it is expected that site 
personnel will complete the eCRF entry within approximately 7 business days of the 
participant’s visit. 
The participant’s parent(s)/caregiver(s)/LAR(s) must enter the information required by the 
protocol in the diary. A study monitor will review all seizure eDiary entries in accordance with 
the monitoring plan for completeness and accuracy. Discrepancies will be addressed by the 
participants’ parent(s)/caregiver(s)/LAR(s) and qualified site personnel. When a data discrepancy 
warrants correction, the correction will be made by the participant’s 

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parent(s)/caregiver(s)/LAR(s) 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 
participant’s parent(s)/caregiver(s)/LAR(s) signs informed consent/assent, it is expected that all 
diary entries will be made daily and no longer than 48 hours after each day. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Quality tolerance limit(s) (QTL[s]) will be predefined in the IB to identify systematic issues that 
can impact participant safety and/or reliability of study results. These predefined parameters will 
be monitored during the study, and important deviations from the QTLs and remedial actions 
taken will be summarized in the CSR. 
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan. 
The sponsor or designee is responsible for the data management of this study, including quality 
checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organizations). 
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. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for a minimum of 2 years after the Sponsor’s receipt of final 
approval of a marketing application for the drug; or, if an application is not approved for the 
drug, until 2 years after the shipment and delivery of the drug for investigational use is 
discontinued and the FDA has been notified. No records may be destroyed during the retention 
period without the written approval of the sponsor. No records may be transferred to another 
location or party without written notification to the sponsor. 
Telephone follow-up visits are allowed to be conducted via secure email per institutional policy 
if granted by individual sites IRB/IEC. 

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10.1.8 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9 
Study and Site Start and Closure 
10.1.9.1 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants.  
The first act of recruitment is the first site open (activated for enrollment) and will be the study 
start date.  
10.1.9.2 
Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. The decision to terminate a study may 
be for administrative or safety reasons. A decision to terminate for safety reasons may be driven 
by any data collected on the investigational product which negatively influences the risk/benefit 
assessment. Study sites will be closed upon study completion. A study site is considered closed 
when all required documents and study supplies have been collected and a study-site closure visit 
has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further study intervention development. 

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For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor’s procedures, or GCP guidelines 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IRBs/IECs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
10.1.11 
Sample Storage and Destruction 
Any blood including PK samples collected according to the SOA (Section 1.3) can be analyzed 
for any of the tests outlined in the protocol and for any tests necessary to minimize risks to study 
participants. This includes testing to ensure analytical methods produce reliable and valid data 
throughout the course of the study. This can also include, but is not limited to, investigation of 
unexpected results, incurred sample reanalysis, and analyses for method transfer and 
comparability. 
All samples and associated results will be coded prior to being shipped from the site for analysis 
or storage. Samples will be tracked using a unique identifier that is assigned to the samples for 
the study. Results are stored in a secure database to ensure confidentiality.  
Samples can be retained for up to 6 months after the final study closure (defined as final CSR). 
Since the evaluations are not expected to benefit the participant directly or to alter the treatment 
course, the results of pharmacogenetic, or other exploratory studies are not placed in the 
participant’s medical record and are not to be made available to the participant, members of the 
family, the personal physician, or other third parties, except as specified in the informed consent. 
The participant retains the right to request that the sample material be destroyed by contacting 
the investigator. Following the request from the participant, the investigator is to provide the 
sponsor with the required study and participant number so that any remaining [sample types 

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(eg, blood, tumor)] samples and any other components from the cells can be located and 
destroyed. Samples will be destroyed once all protocol-defined procedures are completed. 
However, information collected from samples prior to the request for destruction, will be 
retained by the sponsor. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from the 
sample materials and is responsible for the destruction of the sample(s) at the request of the 
participant through the investigator, at the end of the storage period, or as appropriate (eg, the 
scientific rationale for experimentation with a certain sample type no longer justifies keeping the 
sample). If a commercial product is developed from this research project, the sponsor owns the 
commercial product. The participant has no commercial rights to such product and has no 
commercial rights to the data, information, discoveries, or derivative materials gained or 
produced from the sample. (See Section 10.1.4 for participant confidentiality). 
 

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10.2 Appendix 2: Emergency Contact Information 
10.2.1 
Serious Adverse Event Reporting  
In the event of an SAE, the investigator must notify the sponsor by email or fax the Marinus 
Clinical Study Serious Adverse Event Form within 24 hours to Marinus’ drug safety vendor at:  
• Email: safetyTSC3001@marinuspharma.com  
• Fax: +1 484-679-2138  
10.2.2 
Sponsor Contacts 
10.2.2.1 
Sponsor Medical Monitor 
 
Consultant Medical Monitor 
Mobile Telephone: 
 
Email:
If sponsor’s medical monitor cannot be reached in an emergency, the site should contact the 
Back-up Medical Monitor: 
 
VP, Clinical Development 
Mobile Telephone: 
 
Email:
(primary contact method) 
10.2.2.2 
Sponsor Project Managers  
 
Sr. Clinical Trial Manager, Clinical Development Operations 
Mobile Telephone: 
 (primary contact method) 
Email:
 
Back-up: 
 
Director, Clinical Development Operations 
Mobile Telephone: 
 (primary contact method) 
Email:
 

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10.3 Appendix 3: Clinical Laboratory Safety Tests 
The tests detailed in Table 3 will be performed by the central laboratory. 
• Local laboratory results are only required in the event that the central laboratory results are 
not available in time for either study intervention administration and/or response evaluation. 
If a local sample is required, it is important that the sample for central analysis is obtained at 
the same time. Additionally, if the local laboratory results are used to make either a study 
intervention decision or response evaluation, the results must be recorded. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5. 
• Additional tests such as hematology, clinical chemistry, or urinalysis may be performed at 
any time during the study as determined necessary by the investigator or required by local 
regulations.

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Table 3. 
Protocol-required Safety Laboratory Tests 
Laboratory Tests 
Parameters 
Hematology 
• 
Hemoglobin 
• 
Hematocrit 
• 
Erythrocytes 
• 
Leukocytes + differential 
• 
Thrombocytes (platelet count) 
Clinical Chemistry 
• 
BUN 
• 
Potassium 
• 
AST/SGOT 
• 
Total bilirubin 
• 
Creatinine 
• 
Sodium 
• 
ALT/SGPT 
• 
Total protein 
• 
Fasting blood glucose 
• 
Calcium 
• 
Alkaline phosphatase 
• 
CO2 
• 
eGFR 
• 
Chloride 
Routine Urinalysis 
• 
Specific gravity, color, clarity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
Pregnancy testinga 
• 
Quantitative serum ȕ-HCG serum pregnancy 
Other tests 
• 
Drug screenb 
• 
Follicle-stimulating hormone and estradiol (as needed in women of 
nonchildbearing potential only) 
• 
Vital signs (BP, HR, RR, and body temperature) 
• 
12-lead ECG 
AST = aspartate aminotransferase; ȕ-HCG = ȕ-human chorionic growth hormone; BP = blood pressure; 
BUN = blood urea nitrogen; CBD = cannabidiol; eGFR = estimated glomerular filtration rate; 
ECG = electrocardiogram; HR = heart rate; RR = respiratory rate; SGOT = serum glutamic oxaloacetic 
transaminase; THC = tetrahydrocannabinol. 
a Any positive home pregnany test will be followed up with a confirmatory serum pregnancy test. 
b A plasma (or urine, if plasma is difficult or impossible to obtain) drug screen will be performed to test for THC 
and non-approved CBD during the first visit of the OLE. 
 
 

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10.4 Appendix 4: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.4.1 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a clinical investigation participant who has 
been administered a pharmaceutical product; it does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product (International Council for Harmonisation [ICH] 
Guidance E2A, March 1995). 
Definition of Unsolicited and Solicited AE 
• An unsolicited AE is an AE that was not solicited using a participant diary and that is 
communicated by a participant/participant’s parent(s)/caregiver(s)/LAR(s) who has signed 
the informed consent. Unsolicited AEs include serious and nonserious AEs. 
• Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring a 
hospitalization, emergency room visit, or visit to/by a healthcare provider). The 
participants/participant’s parent(s)/caregiver(s)/LAR(s) will be instructed to contact the 
site as soon as possible to report medically attended event(s), as well as any events that, 
though not medically attended, are of participant/participant’s parent(s)/caregiver/LAR(s) 
concern. Detailed information about reported unsolicited AEs will be collected by 
qualified site personnel and documented in the participant’s records. 
• Unsolicited AEs that are not medically attended nor perceived as a concern by the 
participant/participant’s parent(s)/caregiver(s)/LAR(s) will be collected during an 
interview with the participant/participant’s parent(s)/caregiver(s)/LAR(s) and by review of 
available medical records at the next visit. 
• Solicited AEs are predefined local and systemic events for which the participant is 
specifically questioned, and which are noted by the participant in their diary. 
 

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Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, 12-lead ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator (ie, not related to progression of underlying 
disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New condition detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
• Lack of efficacy or failure of expected pharmacological action per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, 
the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE.  
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as an AE or SAE if they fulfill the definition of an AE or SAE. Lack of efficacy 
or failure of expected pharmacological action also constitutes an AE or SAE. 
 
Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 

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10.4.2 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
Results in death 
Is life threatening 
The term life threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether hospitalization occurred or was necessary, the AE 
should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent everyday 
life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Is a suspected transmission of any infectious agent via an authorized medicinal product 
Other situations: 
• Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These 
events should usually be considered serious. 
o Examples of such events include invasive or malignant cancers, intensive treatment 
for allergic bronchospasm, blood dyscrasias, convulsions or development of 
intervention dependency or intervention abuse. 
 

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10.4.3 
Recording and Follow-up of AE and/or SAE 
AE and SAE Recording 
• The monitoring period for AEs begins at the time of the first dose of IP in the OLE. 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to IRB/IEC in lieu of completion of the required reporting forms. 
• There may be instances when copies of medical records for certain cases are requested by 
IRB/IEC. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to 
IRB/IEC. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
• Every reasonable effect will be made to follow up with participants who have AEs. Any 
participant who has an ongoing AE at the last study visit will be followed up, where 
possible, until resolution, or until the unresolved AE is judged by the investigator (or 
designee) to have stabilized. This will be completed at the investigator’s discretion. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories:  
• Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Moderate: Minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL). Instrumental ADL refers to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc. 
• Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting self-care 
ADL. Self-care ADL refers to bathing, dressing, and undressing, feeding self, using the 
toilet, taking medications, and not bedridden. 
 

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Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. The investigator will use clinical judgment to determine the 
relationship. 
• The investigator will make a determination of the relationship of the AE to the study 
intervention using a 2-category system according to the following guidelines:  
o Not Related: The AE is definitely or most likely caused by the participant’s clinical 
state or the study procedure/conditions.  
o Related: The AE follows a reasonable temporal sequence from administration of the 
drug, abates upon discontinuation of the drug, follows a known or hypothesized cause-
effect relationship, and (if appropriate) reappears when the drug is reintroduced. 
• A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 
• The investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment. 
• For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to IRB/IEC. However, it is very important that 
the investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to IRB/IEC. 
• The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
 

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Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by IRB/IEC to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide IRB/IEC with a copy of any postmortem findings 
including histopathology.  
• New or updated information will be recorded in the originally submitted documents. 
• The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information.
 
10.4.4 
Reporting of SAEs 
SAE Reporting to IRB/IEC via Paper Data Collection Tool 
• Facsimile or email transmission of the SAE paper data collection tool are the preferred 
methods to transmit this information to the Pharmacovigilance team/vendor. 
• In rare circumstances and in the absence of available equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE data collection tool within the designated reporting timeframes. 
• Contacts for SAE reporting can be found in Section 10.2 and Study Operations Binder. 

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10.5 Appendix 5: Contraceptive and Barrier Guidance 
10.5.1 
Female Contraception 
WOCBP must be using a medically acceptable form of birth control and have a negative 
quantitative serum ȕ-HCG test collected at the initial visit. WOCBP must be advised to use 
medically acceptable birth control throughout the study period and for 30 days after the last dose 
of IP. These include intrauterine devices, hormonal contraceptives (eg, combined oral 
contraceptives, patch, vaginal ring, injectables, and implants), and surgical sterilization (such as 
oophorectomy or tubal ligation). When used consistently and correctly, “double-barrier" methods 
of contraception can be used as an effective alternative to highly effective contraception methods 
(see Section 10.5.3 for “double-barrier methods) . Contraceptive measures such as Plan BTM, 
sold for emergency use after unprotected sex, are not acceptable methods for routine use.  
10.5.2 
Male Contraception 
Male participants must agree to use highly effective contraceptive methods during the study and 
for 30 days after the last dose of IP. Highly effective methods of contraception include surgical 
sterilization (such as a vasectomy) and adequate “double-barrier” methods as described in 
Section 10.5.3.  
Male participants should not donate sperm during the study and for 30 days after the last dose of 
IP.  
10.5.3 
Acceptable Barrier Methods of Contraception 
“Double-barrier” methods of contraception include male condom with diaphragm, or male 
condom with cervical cap. 
 
 

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10.6 Appendix 6: Country-specific Requirements  
All local laws and regulatory requirements will be complied with during this study. 
 
 

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10.7 Appendix 7: Dosing Instructions for Oral Suspension 
GANAXOLONE 1042-TSC-3002 STUDY 
DOSING INSTRUCTIONS FOR ORAL SUSPENSION 
Dose Maintenance / Dose Taper           (Please circle phase) 
Participant ID and Initials: _________________________________________________ 
Next Appointment:  
__________________________________________________________ 
Study Doctor (PI):  
__________________________________________________________ 
PI Telephone Number: __________________________________________________________ 
 
These are your study drug dosing instructions from now until your next visit. 
Take the study drug three times each day with a meal or snack, plus approximately 4-8 oz of 
water. 
Weight:  _____________ (in kg).   
 
Start Date 
DOSE (mL) 
3 times/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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GANAXOLONE 1042-TSC-3002 STUDY 
DOSING INSTRUCTIONS FOR ORAL SUSPENSION 
Be sure that you read, understand, and follow these instructions carefully to ensure proper dosing 
of the oral suspension.  
Important:  
• Follow your study doctor’s instructions for the dose of study drug to take or give. Study drug 
must be taken or given with food and used within 30 days of opening. 
• Ask your study doctor if you are not sure how to prepare, take, or give the prescribed dose of 
study drug. 
• Always use the oral syringe provided by your study doctor with study drug to make sure you 
measure the right amount of study drug. 
• Do not consume grapefruit or grapefruit juice, Seville oranges, starfruits¸ or excessive 
quantities of alcohol during the study because it could interact with the study drug. 
• Each dose should be separated by at least 4 hours and not more than 12 hours. An example 
schedule would be 1 dose at 8 am after breakfast, the next dose at 3 pm with a snack, and the 
third dose at 9 pm with a snack before bed. 
• If you forget 1 dose and there is less than 4 hours before the next dose, skip that dose. 
• If you miss 2 days of dosing or more, call the study doctor for instructions how to restart 
• Save all empty, partially used, and unused bottles of the study drug and return the bottles at 
your next visit. 
• Some people may report feeling dizzy or tired, or experiencing other problems after taking 
the study drug. These side effects usually go away after 2 or 3 days. If you experience any 
side effects from the study drug that interfere with your daily activities or if you have any 
questions, please contact your study doctor to see if a dose adjustment is necessary. 

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Materials provided by your study doctor: 
Child-resistant cap: 
 
Press-in bottle adapter: 
 
Bottle of study drug:  
 
Reusable oral syringe to take or give the dose of study 
drug: 
Note: If you lose or damage an oral syringe, or cannot 
read the markings, use a new syringe. Contact your study 
doctor for extra syringes if you run out. 

 
 

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Prepare the bottle – to use study drug for the first time. 
1. Hold the bottle in your hand and shake it up and 
down well for 1 minute. 
Always shake the bottle well for 1 minute and then let 
the bottle stand for 1 minute so that any foam built up 
during shaking can settle before measuring and 
giving each dose of study medication. This helps you 
measure the correct amount of medicine. 
Note: This step is for each dose of the study drug. 
 
2. Remove the child-resistant cap by pushing 
down while turning the cap to the left 
(counter-clockwise). 
 
3. Puncture and peel off the induction seal from 
the bottle. 
 
Note: This step is only for the first use of the 
bottle. 
 
4. Push the press-in-bottle adapter firmly into 
the bottle. Firmly grasp the bottle in one hand 
and insert the press-in bottle adapter all the 
way in the bottle with other hand using 
constant pressure. Make sure the press-in 
bottle adaptor is fully inserted. If not fully 
inserted, small parts such as the bottle adaptor 
may become a choking hazard for children 
and pets. 
Note: Do not remove the press-in bottle 
adapter from the bottle after it is inserted. 
 
 

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Prepare the dose 
Your study doctor will tell you how much study drug to take or give. 
5. Gather the oral syringe, push the plunger all 
the way down and insert the tip of the oral 
syringe fully into the press-in bottle adapter. 
With the syringe in place, turn the bottle 
upside down. 
 
6. Slowly pull the plunger of the oral syringe to 
withdraw the dose of study drug needed. Line 
up the end of the plunger with the marking for 
your dose of study drug. 
What to do if you see air bubbles: If there 
are air bubbles in the oral syringe, keep the 
bottle upside down and slowly push the 
plunger so that all of the liquid flows back 
into the bottle. Repeat step 6 until air bubbles 
are gone. 
 

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7. When you have measured the correct amount 
of study drug, leave the oral syringe in the 
press-in bottle adapter and turn the bottle right 
side up. 
 
8. Carefully remove the oral syringe from the 
press-in bottle adapter. 
 

Take or give study drug 
9. Place the tip of the oral syringe against the 
inside of the cheek and gently push the 
plunger until all of the study drug in the 
syringe is taken or given. 
Do not forcefully push the plunger. 
Do not direct the medicine to the back of the 
mouth or throat. This may cause choking.



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Clean Up 
10. Screw the child-resistant cap back on the 
press-in bottle tightly by turning the cap to the 
right (clockwise). Do not remove the press-in 
bottle adapter. The child-resistant cap will fit 
over it. 
 
11. Fill a cup with warm soapy water and clean the 
oral syringe by drawing water in and out of the 
syringe using the plunger. 
 
12. Remove the plunger from the barrel of the oral 
syringe and rinse both parts under tap water. 
Do not wash the oral syringe in the dishwasher. 
 
13. Shake off any extra water from the plunger and 
oral syringe barrel and allow them to air dry 
until next use. Make sure the oral syringe is 
completely dry before the next use. A new 
dosing syringe should be used every day.  
 

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How do I store study drug? 
Store study drug in its original bottle in an upright position, at room temperature (20°C to 25°C 
[68°F to 77°F]) . Keep the child-resistant cap tightly closed. Save all empty, partially used, and 
unused bottles of the study drug and return the bottles at your next visit.  
Keep study drug out of the reach of children. 
Frequently asked Questions: 
Q:  What if there are air bubbles in the oral syringe? 
A:  
Slowly push the liquid back into the bottle and repeat step 6 until the air bubbles are gone. 
Q:  What should I do if the oral syringe is not completely dry before use? 
A:  
If the oral syringe is not completely dry, use a spare syringe provided by your study doctor. 
 
 

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