Clinical trial NCT05323734
Conditions: Tuberous Sclerosis Complex
Keywords: Tuberous Sclerosis Complex-Related Epilepsy Ganaxolone Adjunctive
Sponsor: Marinus Pharmaceuticals
Start date: 2022-04-01; Completion date: 2024-10-14
Enrollment: 129 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3, global, double-blind, randomized, placebo-controlled study of adjunctive GNX treatment in children and adults with TSC-related epilepsy. The study consists of a 4-week prospective Baseline phase, defined as the first 28 days following screening, followed by a double-blind phase consisting of a 4-week titration period (Day 1 to Day 28) and a 12-week maintenance period (Day 29 to Week 16).

Detailed description:

Arms: arm 1: oral suspension, 3 times a day (TID) arm 2: oral suspension, TID
Interventions: intervention 1: Ganaxolone intervention 2: Placebo
Intervention descriptions: intervention 1: GNX will be administered intervention 2: Placebo will be administered

Protocol documents:
Prot_000.pdf: 
Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 1 of 175 
 
 
 
TITLE PAGE 
Protocol Title: A Phase 3, Double-blind, Randomized, Placebo-controlled Trial of Adjunctive 
Ganaxolone (GNX) Treatment in Children and Adults with Tuberous Sclerosis 
Complex (TSC)-related Epilepsy (TrustTSC) 
Protocol Number: 1042-TSC-3001 
Compound: Ganaxolone 
Brief Title: Adjunctive GNX treatment compared with placebo 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 
2021-003441-38 
 
Protocol version/date 
Document Version 
Approval Date 
Protocol Amendment 3; v4.0 
12 Sep 2023 
Protocol Amendment 2; v3.1 
08 Dec 2022 
Protocol Amendment 2; v3.0 
07 Dec 2022 
Protocol Amendment 1; v2.0 
01 Feb 2022 
Original (v1.0 [superseded]) 
16 Sep 2021 


Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 2 of 175 
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-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 3 of 175 
Sponsor Signatory:  
Protocol Number: 1042-TSC-3001 
Protocol Title: A Phase 3, Double-blind, Randomized, Placebo-controlled Trial of Adjunctive 
Ganaxolone (GNX) Treatment in Children and Adults with Tuberous Sclerosis Complex 
(TSC)-related Epilepsy (TrustTSC)  
 
I, the undersigned, have approved of the clinical trial protocol with the date of 12 Sep 2023. 
 
 
, MD 
, Clinical Development 
 
Date 
 
Medical Monitor Name and Contact Information is provided Section 10.2. 
 
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	


Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 4 of 175 
INVESTIGATOR AGREEMENT 
Protocol Number: 1042-TSC-3001 
Protocol Title: A Phase 3, Double-blind, Randomized, Placebo-controlled Trial of Adjunctive 
Ganaxolone (GNX) Treatment in Children and Adults with Tuberous Sclerosis Complex 
(TSC)-related Epilepsy (TrustTSC)  
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.  
______________________________  
__________________________ 
 Investigator Name (printed)  
 
 
 
Signature 
_____________________________ 
Date 
 
 
 
 
 
 
 
 


Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 5 of 175 
SUMMARY OF CHANGES FROM PREVIOUS VERSION 
 
Protocol Amendments 
Summary of Changes Since Last Version of Approved Protocol 
Amendment Number 
3 
Amendment Date 
12 Sep 2023 
Applicable To 
Global 
Rationale for the Amendment 
The following changes are made in this global protocol amendment from version 3.0 to version 4.0 to: 
• 
Include updated information regarding completed and ongoing clinical studies. 
• 
Editorial updates throughout. 
• 
Sample size, subject age, and inclusion criteria were updated. 
• 
References to interim analysis were removed as no interim analysis was performed. 
• 
SAE contact details were updated. 
• 
Country-specific amendment for China/North America has been combined with the global protocol. 
• 
 
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 
Updated rationale text to clarify the completion of Study 1042-TSC-2001. 
Section 1.1, 
Section 2.2.2.1.1. 
Participant number was updated. 
Section 1.1, Section 4.1.2 
Inclusion criteria number 3 was updated. 
Section 1.1, Section 5.1 
Inclusion criteria number 6 was made clearer. 
Section 1.1, Section 5.1 
Midazolam added to approved rescue medications. 
Section 6.6.1 
Added text to clarify that assessments conducted by travelling nurses only applies to 
sites located within the United States. 
Section 8 
Clarification regarding laboratory testing added. 
Section 8.3.6 
Deleted:  
‘A copy of the Marinus Clinical Study Serious Adverse Event Form (and any 
applicable follow-up reports) must also be sent to the CRO/Marinus medical monitor 
using the details specified in the emergency contact information section of the 
protocol.’ 
 
Section 8.4 
Deleted “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.” 
Section 8.4.1 
Added text that 
 will not be performed in China. 
Section 1.3, Section 8.7, 
Section 10.6, Section 10.7 
Updated language for safety monitoring contact. 
Section 8.4, Section 8.4.1, 
Section 8.4.4.1, 


Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 6 of 175 
Section 8.4.8, Section 
8.4.9, Section 10.2.1. 
Interim analysis removed. 
With the smaller sample size, the interim analysis will not read out before the entire 
cohort is expected to be enrolled. As a result, there is no benefit of the interim 
analysis. 
Section 1.1, Section 9.4 
Sample size determination updated. 
The original efficacy assumption (22%) for the power analysis were unnecessarily 
conservative. The current sample size of 128 retains a 90% power if a treatment effect 
of 25% is assumed. 
Section 9.4 
Sponsor project managers updated 
Section 10.2.2.2 
 
SUMMARY OF CHANGES FROM PREVIOUS VERSION 
 
Protocol Amendments 
Summary of Changes Since Last Version of Approved Protocol 
Amendment Number 
2.1 
Amendment Date 
08 Dec 2022 
Applicable To 
North America 
(United States and Canada) 
and China 
Rationale for the Amendment 
The following changes are made in this protocol amendment from version 3.0 (applicable to Europe [EU], Middle 
East and North Africa [MENA] and Oceania [OC]) to version 3.1 (applicable to North America [United States and 
Canada] and China) to: 
• 
Revise inclusion criteria to include participants aged 1 to 65 years of age. 
• 
Specify that 
 will not be permitted under this protocol in China. 
• 
Specified that investigational product will be stored in accordance with applicable requirements under the 
Controlled Substance Act and Drug Enforcement Administration regulations. 
Description of Changes 
Section(s) Affected by 
Change 
Revised inclusion criterion 2 to include participants aged 1 to 65 years of age. 
Deleted:  
• 
Male or female participants aged 2 through 65 years, inclusive. 
Added:  
• 
Male or female participants aged 1 through 65 years, inclusive. 
Section 1.1 and Section 5.1 
Specified that 
 will not be permitted under this protocol in China. 
Section 1.3 (footnote), 
Section 8.7, Section 10.6, 
and Section 10.7 
Addition of the rationale for selecting participants aged 1 through 65 years, 
inclusive. 
Added:  
• 
This study plans to enroll participants as young as 1 year of age. Based on 
the known clearance pathway of GNX (which is primarily CYP3A4/5) 
and CYP3A4 maturation by the age of 1 month, the dosing strategy for 
pediatric participants 1 to 2 years was guided by a recently completed 
Section 4.3 


Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 7 of 175 
population PK analysis which incorporated allometric principles. The 
similarity of model maximum plasma concentration (Cmax) and the area 
under the plasma concentration-time curve (AUC) with the proposed 
dosing regimen across a range of doses administered in previous clinical 
trials in participants 2 years of age and older coupled with the known 
maturation of CYP3A4 indicates that a similar exposure will be achieved 
in participants 1 to 2 years of age with the proposed dosing regimen. 
Specified that investigational product will be stored in accordance with applicable 
requirements under the Controlled Substance Act and Drug Enforcement 
Administration regulations. 
Section 6.3.1 
 
 
 


Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 8 of 175 
 
SUMMARY OF CHANGES FROM PREVIOUS VERSION 
 
Protocol Amendments 
Summary of Changes Since Last Version of Approved Protocol 
Amendment Number 
2 
Amendment Date 
07 Dec 2022 
Applicable To 
Europe (EU), Middle East 
and North Africa 
(MENA), and Oceania 
(OC) 
Rationale for the Amendment 
The following changes are made in this global protocol amendment from version 2.0 to version 3.0 to: 
• 
Revise inclusion criteria to include participants aged 2 to 65 years of age. 
• 
Add a section on contraception use to include acceptable barrier methods and donation of sperm and ova. 
• 
Add details on pregnancy testing. 
• 
Elaborate on dose adjustments and rescue medications. 
• 
Update endpoint analyses to incorporate analyses related to European Medicines Agency (EMA). 
• 
Add details on blood volumes approval by investigator for participants < 15 kg weight. 
• 
The dosing instructions for the oral suspension were updated to match the package insert. 
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 the term anti-epileptic drugs (AEDs) with the preferred term anti-seizure 
medication (ASM) per Tuberous Sclerosis Complex (TSC) Alliance. 
Replaced “subjects” with “participants”. 
Updated definition of the abbreviation mTOR from “mammalian target of rapamycin” 
to the preferred definition “mechanistic target of rapamycin” per TSC Alliance. 
Throughout the document 
Updated Protocol amendment date and version in the header 
Protocol header 
Added updates to the list of abbreviations 
List of Abbreviations 
Updated information of the Investigational Product (IP) background and Clinical 
Development Program updated with current available information to align with the 
current updated version of the Investigator’s Brochure (IB). 
Section 1.1, Section 2.2.2, 
and Section 2.2.2.1 
Specified that version 2 of the Short Form 36 (SF-36) will be used. 
Section 1.1 (footnote), 
Section 1.3 (footnote), 
Section 3 (footnote), 
Section 8.2.8, and 
Section 10.15 
Updates to inclusion criterion 1: 
• 
Criteria for clinical or mutational diagnosis of TSC updated from Northrup 
and Krueger, 2013 to Northrup et al. 2021: updates in major and minor 
features for clinical diagnosis of definite TSC. 
Section 1.1 and 
Section 5.1 


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Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
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Updates to inclusion criterion 2: 
• 
Male or female participants aged 2 through 65 years, inclusive. 
Updates to inclusion criterion 3. 
Removal of inclusion criterion 4. 
Updates to inclusion criterion 7:  
• 
Requirements amended to state the requirement that at least 8 primary 
endpoint seizures are required in the first 28 days following the screening 
visit. 
Updates to inclusion criterion 9:  
• 
Vagal nerve stimulator (VNS) requirement changed from 1 year to 6 months. 
Minor clarification in exclusion criterion 5. 
Addition of 2 new exclusion criterions (18 and 19):  
18. Participants deprived of their liberty by a judicial or administrative decision, 
or for psychiatric treatment, or participants admitted to a health or social 
services facility for purposes other than research. 
19. Participants receiving traditional Chinese medicine therapies within the prior 
28 days of the screening. 
Section 1.1 and 
Section 5.2 
Combined definitions of seizure types that do not count towards the primary endpoint: 
Replaced: 
a. 
Focal aware seizures without motor features. 
b. Focal and generalized nonmotor seizures (eg, absence or focal nonmotor 
seizures with or without impairment of awareness). 
With   
a. 
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 8.1.1.3, 
Section 8.2.1, and 
Section 9.3.2 
Updated general considerations to differentiate primary and secondary endpoint 
analyses for the Food and Drug Administration (FDA) and EMA. 
Section 1.1, Section 3, 
Section 9.3.1, 
Section 9.3.2, 
Section 9.3.3, 
Section 9.3.3.2 
Revised contraception information throughout the protocol. 
Removal of 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 5.3.2, 
Section 10.5.1, 
Section 10.5.2, and 
Section 10.5.3 
Minor update to schema: 
• 
“Enter Open-label extension (OLE)”changed to “Crossover to OLE”. 
Section 1.2 
Schedule of Activities (SOA) updated to remove Seizure Identification and 
Diagnostic Review Form (SIF/DRF) from baseline visit. 
Visit header for Part B of SOA updated to specify which visits are phone visits. 
Section 1.3 
Specified that a urine drug screen could be performed if a plasma sample is difficult 
or impossible to obtain. 
Section 1.3 (footnote)  
Specified that a urine drug screen could be performed if a plasma sample is difficult 
or impossible to obtain. 
Section 1.3 (footnote)  
Specified that the Pediatric Quality of Life – Family Impact Module (Peds-QL-FIM) 
for past 1 month is for baseline visit, and past 7 days is for on-study visits. 
Sections 1.3 and 
Section 8.2.7 


Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 10 of 175 
Included pregnancy testing at in person visits, Revised text for pregnancy testing, 
including pregnancy testing at in person visits and indicating what type of pregnancy 
test (serum or urine) will occur during the study visits.  
Section 1.3, Section 8.3.4, 
Section 8.3.8, and 
Section 10.3 
Clarified that 
 is not required but may be conducted. 
Section 1.3 (footnote) and  
Section 8.7 
Specified that 
 will not be permitted under this protocol in Israel. 
Section 1.3 (footnote), 
Section 8.7, Section 10.6, 
and Section 10.7 
Number of study sites updated to 80-85. 
Section 4.1.3 
Removed information related to justification of enrolling participants as young as 
1 year of age. 
Section 4.3 
Rescreening criteria updated to state that the medical monitor should be contacted for 
subsequent screening. 
Section 5.4 
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 ganaxolone 
(GNX) dosing to manage tolerability. 
Section 6.2 
Text “stratified for concomitant cannabidiol (CBD) use” replaced with “stratified for 
current CBD use”. 
Section 6.4.1.1 and 
Section 8.1.1 
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 electrocardiogram (ECG) assessment to be completed by a mobile 
vendor. 
Section 8 
Section revised to include information on the process of identification for participants. 
Added: 
• 
The process of identification of participants is performed by the investigator. 
If an investigator is seeing a patient with TSC in their clinic who is having 8 
or more seizures per month, they will make a judgment regarding whether 
the benefits of clinical trial participation may outweigh the risks of clinical 
trial participation (with any alternative treatments taken into account). If the 
clinician feels that they do, then they will explain the study to the participant 
(or legally authorized representative [LAR]). If the participant/LAR is fully 
informed and provides consent, then this will be documented, and the 
screening activities can begin. 
Note for Investigational Sites in the United Kingdom (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 
Specified that only the numbered items in the Sleep Habit Questionnaire (ie, the items 
that are scored) will be asked to the participant´s parent/caregiver/LAR. 
Section 8.2.5 and 
Section 10.12.1 


Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 11 of 175 
Text revised to change CKD-EPI formula to calculate estimated glomerular filtration 
rate (eGFR) with Cockcroft-Gault formula or pediatric glomerular filtration rate 
(GFR) calculator or Bedside Schwartz. 
Total blood volume collected from participants corrected from 45 mL to 60 mL. 
Added details on blood volumes approval by investigator for participants < 15 kg 
weight. 
Added: 
• 
Note: For participants < 15 kg the maximum blood volume taken during a 
single day or during a 4-week period may exceed recommendations; 
therefore, for all participants < 15 kg, the medical monitor should be 
consulted regarding which labs can be omitted. For all participants, 
regardless of weight, if additional labs are required, the medical monitor 
should be consulted to ensure that recommended blood volume limits are not 
unnecessarily exceeded. 
Section 8.3.4 
Addition of a new section to include Suspected Unexpected Serious Adverse Reaction 
(SUSAR) language. 
Section 8.4.4.1 
Clarification made for the multiplicity adjustment. 
Added:  
• 
The testing will stop if the result is non-statistically significant. All other 
non-key secondary and
Section 9.1.1 
Added the evaluation of the primary endpoint for the EMA. 
Section 9.3.2 
Amended the definition of primary seizure type. 
Section 9.3.2 
Updated the sensitivity analyses to be different for EMA and FDA. 
Deleted: 
• 
To examine the primary outcome measure when a participant stops recording 
measurements permanently prior to the end of the double-blind phase using 
the imputation approach outlined in the Statistical Analysis Plan (SAP). 
• 
To explore the possibility that participants who stop recording their seizure 
counts tend to have higher counts than the other participants. 
• 
To examine the primary outcome measure by using modified intent-to-treat 
(mITT) population. 
Added:   
• 
For the first sensitivity analysis, intermittent (random/sporadic) missing data 
during the double-blind phase and any missing data during the baseline phase 
will be assumed missing completely at random and the collected data will be 
used to calculate the 28-day seizure frequencies. 
• 
The second sensitivity analysis is to explore the possibility that participants 
who stop recording their seizure counts tend to have higher counts than the 
other participants. 
• 
The third sensitivity analysis will be performed on participants who achieved 
their maintenance dose at the start of the maintenance period. This analysis 
will exclude those participants who are still titrated continuously during 
maintenance period. 
• 
The fourth sensitivity analysis will be performed for the primary outcome 
measure by using the mITT population. 
• 
The fifth sensitivity analysis will be performed for the primary outcome 
measure by excluding all intercurrent events. 
Section 9.3.2.1 


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Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 12 of 175 
Updated subgroup analyses. 
Deleted:  
• 
Age groups (1 to 6 years; 7 to 12 years; […]). 
Added:  
• 
Age groups (2 to 6 years; 7 to 12 years; […]). 
Section 9.3.7 
Updated 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
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 
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 10.1.12 
Updated Study/Site Termination. 
Added: 
• 
The decision to terminate a study may be for business reasons or for safety 
reasons. A decision to terminate for safety reasons may be driven by any data 
collected on the IP which negatively influences the risk/benefit assessment. 
Section 10.1.10.2 
Contact details for Marinus Project Managers updated. 
Section 10.2.2.2 
Added an alternative pregnancy testing in Table 3. 
Section 10.3 
Excluded references to future use of 
 samples and clarify that not 
 
will be performed in Israel. 
Deleted: 
• 
DNA samples will be used for research related to TSC and related diseases. 
They may also be used to develop tests/assays, including diagnostic tests 
related to GNX and TSC.
may consist of the analysis of one 
or more candidate genes or the analysis of
throughout the 
genome or analysis of the entire genome (as appropriate). 
• 
The samples may be analyzed as part of a multistudy assessment of
involved in the response to study intervention of this class to 
understand the study disease or related conditions. 
Added:   
• 
No 
 will be performed in Israel. 
Section 10.6 
Reference for not collecting race ethnicity in France removed. 
Section 10.7 
Updated dosing instructions for the oral suspension to match the package insert. 
Section 10.8 
Updated SF-36 questionnaire to a more comprehensible format for participants.  
Section 10.15 


Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
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SUMMARY OF CHANGES FROM PREVIOUS VERSION 
 
Protocol Amendments 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 
1 
Amendment Date 
01 Feb 2022 
Global/Country/ 
Site-Specific 
Global 
Rationale for the Amendment 
The rationale for the major changes in this protocol amendment are as follows: 
• 
The availability of new Phase 2 data raised the question of a cannabidiol (CBD) interaction. As a result, 
patients taking CBD will be monitored closely for adverse events (AEs), and specifically sedation-related 
AEs throughout the study. Patients were also stratified according to concomitant CBD use. 
• 
The allowance of an additional 2 weeks of titration after the 4 weeks titration period at the start of the 
maintenance period was removed as were specific dosing paradigms for participants taking Epidiolex 
> 10 mg/kg/day. This change will ensure that all patients will have the same target dose regardless of their 
background CBD therapy. 
Description of Changes 
Section(s) Affected by 
Change 
Minor editorial updates throughout for grammar, consistency, and clarity. 
Throughout the document 
Protocol date and version added to the header. 
Protocol header 
Protocol short name ‘TrustTSC’ added to the protocol title.  
Title page, sponsor 
signatory, Investigator 
agreement and Section 1.1 
The Investigational New Drug (IND) number was updated and the EudraCT 
number was added.   
Title page 
Updated the key secondary efficacy endpoint. 
Added: 
• 
Number (%) of participants considered treatment responders during the 
maintenance phase.  
Section 1.1, Section 3, 
Section 9.3.3  
Updated the overall study design so that there was no longer an additional 
allowance for titration during the maintenance period and to remove specific 
dosing paradigms for patients taking Epidiolex > 10 mg/kg/day as this will ensure 
all patients have the same target dose regardless of background therapy.  
Removed: 
• 
With 2 additional weeks allowed, if necessary, for tolerance and use of 
concomitant cannabidiols (Epidiolex/Epidyolex) as follows.  
• 
For participants not taking concomitant Epidiolex or taking Epidiolex at a 
dose of 10 mg/kg/day or less, the target dose is:   
• 
63 mg/kg/day for those weighing 28 kg or less, or  
• 
1800 mg/day for those weighing more than 28 kg. 
• 
For participants taking concomitant Epidiolex at a dose greater than 
10 mg/kg/day, the target dose is:  
• 
42 mg/kg/day for those weighing 28 kg or less, or  
• 
1200 mg/day for those weighing more than 28 kg.  
• 
The reduction of the GNX target dose for patients on cannabidiol 
> 10 mg/kg/day is based on 
Section 1.1, Section 1.2, 
Section 4.1, Section 4.3, 
Section 6.2, Section 8.1.2 


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Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
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Page 14 of 175 
• 
Incorporates a lower target dose for participants receiving concomitant 
Epidiolex, and a titration schedule with smaller increments in initial 
dosing for all participants 
• 
Any participant may extend upward titration of IP into the first 2 weeks of 
the maintenance period based on tolerability and the desire to attempt 
additional seizure control, following which they must maintain the 
attained dose for the duration of the double-blind phase 
• 
Dose adjustments to manage AEs, including alternative dosing paradigms 
Added: 
• 
63 mg/kg/day with a maximum daily dose of 1800 mg (for patients 
> 28 kg) 
• 
The phase 2 data for GNX in TSC raised the question of a CBD 
interaction 
• 
Patients taking CBD should be monitored closely for any sedation-related 
AEs throughout 
• 
Any dose adjustments that are not part of the prespecified titration 
schedule  
Revised the text on study duration for participants to remove the extension of the 
4 weeks titration period into the maintenance period.  
Removed: 
Any participant may extend upward titration of IP into the first 2 weeks of the 
maintenance period based on tolerability and the desire to attempt additional 
seizure control, following which they must maintain the dose for the duration of the 
double-blind phase. 
Section 1.1, Section 4.1.1 
Updated the synopsis to include the eligibility criteria from the main body of the 
protocol. 
Section 1.1 
Revised the text throughout the protocol to specify that subjects will be stratified 
based on whether the patient is taking concomitant CBD or not. 
Section 1.1, Section 4.2, 
Section 6.4.1, Section 8.1.1 
The schedule of activities was amended as follows: 
• 
A concomitant medication review was added in Part A.  
• 
Footnote k and l were updated for clarity.  
• 
Informed consent for open label extension (OLE) entry was updated, and a 
corresponding footnote was added.  
• 
Concomitant AED levels were added to Part B and a corresponding 
footnote was added.  
• 
A concomitant medication review was added in Part B.  
• 
The dispensing of investigational product was updated and corresponding 
footnote added.   
Section 1.3 
Updated the scientific rationale for study design to include stratification according 
to concomitant CBD use. 
Added: 
• 
In order to facilitate subgroup analysis, randomization will be stratified 
with respect to whether the participant is taking concomitant CBD or not. 
Section 4.2 
Revised the exclusion criteria to specify exclusion of patients with hepatic, biliary, 
and renal impairment if this was sufficient to affect patient safety.  
Section 5.2 
Deleted the dose titration table for patients receiving concomitant Epidiolex as all 
patients will be titrated to 63 mg/kg/day up to a maximum daily dose of 1800 mg.  
Section 6.1 


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Updated the dose modification section to specify that all patients were dosed at 
63 mg/kg/day up to a maximum daily dose of 1800 mg for participants > 28 kg 
regardless of concomitant Epidiolex use. Also added dosing requirements for 
patients who continue in the OLE.  
Added: 
In Part B, for participants who continue to the OLE, the total daily dose that the 
participant was taking at the completion of Part A will be maintained. The titration 
schedule in Table 2 will be followed until the target total daily dose for the 
participant is reached. 
Section 6.2 
Updated the requirements for discontinuation of study intervention to remove 
mention of drug-induced rash. 
Section 7.1 
Removed the additional 2 weeks of dose titration, for tolerance, that was specified 
and in additional to the standard 4 weeks dose titration period.  
Section 8.1.2 
Updated details for the physical/neurological/developmental examinations to 
specify this was applicable from ages 1 to 17 years instead of 2 to 17 years.  
Section 8.3.1 
Updated to specify concomitant anti-epileptic drug (AED) levels will be obtained 
centrally and collected at Visit 17 for patients who continue in the OLE. 
Added:  
• 
Participants who continue in the OLE will also have the above 
concomitant AED levels collected at Visit 17 (Week 20) 
Section 8.3.6 
Updated the drug screen section to state that this could be performed at any time 
during the study at the investigator’s discretion and that concomitant use of THC 
and non-approved CBD was not permitted. 
Added:  
The plasma drug screen can be performed at any time during the study per the 
investigator’s discretion. Concomitant use of THC and non-approved CBD is not 
permitted on study and will result in participant withdrawal from the study. 
Section 8.3.7 
Updated the multiplicity adjustment to specify that statistical hypothesis testing 
will be performed on 4 rather than the previously stated 3 key secondary endpoints 
as an additional endpoint has been added as part of this amendment.  
Section 9.1.1 
Updated the specified analysis sets to include the modified intent-to-treat (ITT) and 
amended the ITT set so that it no longer required patients to have received at least 
1 dose of the IP. The exclusion of subjects from the efficacy analyses who failed to 
reach at least 50% of their respective target dose was also removed. 
Added:  
Modified Intent-to-treat (mITT) set - All randomized participants who receive at 
least 1 dose of the IP. Participants will be summarized within the treatment group 
to which they were randomized. This population will be used for sensitivity 
analysis for efficacy. 
Section 9.2 
Updated the sensitivity analyses planned for the primary efficacy endpoint to 
include 3 rather than 2 analyses. 
Added: 
• 
To examine the primary outcome measure by using mITT population. 
Section 9.3.2.1 


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Updated secondary endpoint analysis to add an additional analysis for treatment 
responders during the maintenance period. 
Added: 
• 
Treatment responders are defined as those participants with ≥ 50% 
reduction from baseline in primary endpoint seizure frequency during given 
period. 
Section 9.3.3 
Revised male contraception requirements to state these should be continued for 
30 days after the last dose of IP. 
Section 10.5.2 
Updated the dosing instruction for oral suspension in Appendix 8 to remove the 
example dose titration and maintenance tables and to add instructions for Part A 
(double-bind dose titrate, maintenance and taper) and Part B (double-blind 
crossover to open-label extension period). The patient instructions were also 
updated to match the package insert. 
Section 10.8 
Revised the title for Clinical Global Impression – Improvement (CGI-I) in 
Appendix 10 to specify that this was to be used for Clinicians as well as for 
Caregivers. 
Section 10.10 
 


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TABLE OF CONTENTS 
1 
PROTOCOL SUMMARY ................................................................................................. 25 
1.1 
Synopsis ........................................................................................................................ 25 
1.2 
Schema .......................................................................................................................... 36 
1.3 
Schedule of Activities .................................................................................................... 37 
2 
INTRODUCTION ............................................................................................................. 45 
2.1 
Study Rationale ............................................................................................................. 45 
2.2 
Background ................................................................................................................... 45 
2.2.1 
Disease Background ................................................................................................ 45 
2.2.2 
Investigational Product Background: Ganaxolone .................................................... 46 
2.3 
Benefit/Risk Assessment ............................................................................................... 48 
2.3.1 
Risk Assessment ...................................................................................................... 49 
2.3.2 
Benefit Assessment .................................................................................................. 49 
2.3.3 
Overall Benefit: Risk Conclusion ............................................................................. 49 
3 
OBJECTIVES AND ENDPOINTS .................................................................................... 50 
4 
STUDY DESIGN ............................................................................................................... 53 
4.1 
Overall Design............................................................................................................... 53 
4.1.1 
Study Duration for Participation .............................................................................. 54 
4.1.2 
Number of Participants ............................................................................................ 55 
4.1.3 
Number of Sites ....................................................................................................... 55 
4.2 
Scientific Rationale for Study Design ............................................................................ 55 
4.3 
Justification for Dose ..................................................................................................... 55 
4.4 
End of Study Definition ................................................................................................. 56 
5 
STUDY POPULATION ..................................................................................................... 56 
5.1 
Inclusion Criteria ........................................................................................................... 57 
5.2 
Exclusion Criteria .......................................................................................................... 59 
5.3 
Lifestyle Considerations ................................................................................................ 60 
5.3.1 
Meals and Dietary Restrictions ................................................................................ 60 
5.3.2 
Contraception Use and Donation of Sperm and Ova ................................................. 61 
5.4 
Screen Failures .............................................................................................................. 61 
6 
STUDY INTERVENTION AND CONCOMITANT THERAPY ....................................... 62 
6.1 
Study Intervention(s) Administered ............................................................................... 62 
6.2 
Dose Modification ......................................................................................................... 63 
6.3 
Preparation, Handling, Storage, and Accountability ....................................................... 64 
6.3.1 
Storage .................................................................................................................... 64 
6.3.2 
Investigational Product Accountability..................................................................... 65 
6.4 
Measures to Minimize Bias............................................................................................ 67 
6.4.1 
Randomization ......................................................................................................... 67 


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6.4.2 
Blinding ................................................................................................................... 68 
6.5 
Study Intervention Compliance ...................................................................................... 68 
6.6 
Concomitant Therapy .................................................................................................... 69 
6.6.1 
Rescue Medicine...................................................................................................... 70 
6.6.2 
Excluded Medications .............................................................................................. 70 
6.7 
Intervention After the End of the Study ......................................................................... 71 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................... 71 
7.1 
Discontinuation of Study Intervention ........................................................................... 71 
7.2 
Discontinuation/Withdrawal From the Study ................................................................. 72 
7.3 
Lost to Follow-up .......................................................................................................... 72 
8 
STUDY ASSESSMENTS AND PROCEDURES ............................................................... 73 
8.1 
General Study Periods ................................................................................................... 74 
8.1.1 
Screening, Enrollment, Randomization, and Baseline .............................................. 74 
8.1.2 
Double-blind Phase .................................................................................................. 76 
8.1.3 
Safety Follow-up ..................................................................................................... 76 
8.2 
Efficacy Assessments .................................................................................................... 77 
8.2.1 
Seizure Type and Frequency .................................................................................... 77 
8.2.2 
Clinical Global Impression – Severity ...................................................................... 78 
8.2.3 
Clinical Global Impression – Improvement .............................................................. 78 
8.2.4 
Caregiver Global Impression of Change in Seizure Intensity/Duration ..................... 78 
8.2.5 
Sleep Habit Questionnaire........................................................................................ 79 
8.2.6 
Anxiety, Depression, and Mood Scale ...................................................................... 79 
8.2.7 
Pediatric Quality of Life Inventory - Family Impact Module .................................... 79 
8.2.8 
Short Form 36 .......................................................................................................... 80 
8.2.9 
Epilepsy and Learning Disabilities Quality of Life Scale.......................................... 80 
8.3 
Safety Assessments ....................................................................................................... 80 
8.3.1 
Physical/Neurological/Developmental Examinations ............................................... 80 
8.3.2 
Vital Signs ............................................................................................................... 82 
8.3.3 
Electrocardiograms .................................................................................................. 82 
8.3.4 
Clinical Safety Laboratory Tests .............................................................................. 83 
8.3.5 
Suicidal Ideation and Behavior Risk Monitoring (Columbia-Suicide Severity 
Rating Scale) .......................................................................................................... 84 
8.3.6 
Concomitant Anti-epileptic Drug Levels .................................................................. 85 
8.3.7 
Drug Screen ............................................................................................................. 85 
8.3.8 
Pregnancy Testing ................................................................................................... 85 
8.3.9 
Tanner Staging......................................................................................................... 86 
8.3.10 
Investigational Product Pharmacokinetics ................................................................ 86 
8.4 
Adverse Events and Serious Adverse Events ................................................................. 86 


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8.4.1 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information ..................................................................................... 87 
8.4.2 
Method of Detecting Adverse Events and Serious Adverse Events ........................... 87 
8.4.3 
Follow-up of Adverse Events and Serious Adverse Events....................................... 88 
8.4.4 
Regulatory Reporting Requirements for Serious Adverse Events ............................. 88 
8.4.5 
Clinical Laboratory and Other Safety Evaluations .................................................... 89 
8.4.6 
Death Events............................................................................................................ 89 
8.4.7 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events ............................................................. 89 
8.4.8 
Adverse Events of Special Interest ........................................................................... 90 
8.4.9 
Pregnancy ................................................................................................................ 90 
8.4.10 
Abuse, Misuse, Overdose, and Medication Error ...................................................... 91 
8.5 
Treatment of Overdose .................................................................................................. 92 
8.6 
Pharmacokinetics and Pharmacodynamics ..................................................................... 92 
8.6.1 
Pharmacokinetics ..................................................................................................... 92 
8.6.2 
Pharmacodynamics .................................................................................................. 93 
8.8 
Biomarkers .................................................................................................................... 93 
8.9 
Immunogenicity Assessments ........................................................................................ 93 
8.10 
Health Economics .......................................................................................................... 93 
9 
STATISTICAL CONSIDERATIONS ................................................................................ 94 
9.1 
Statistical Hypotheses .................................................................................................... 94 
9.1.1 
Multiplicity Adjustment ........................................................................................... 94 
9.2 
Analysis Sets ................................................................................................................. 95 
9.3 
Statistical Analyses ........................................................................................................ 95 
9.3.1 
General Considerations ............................................................................................ 95 
9.3.2 
Primary Endpoint(s) ................................................................................................. 96 
9.3.3 
Secondary Endpoint(s) Analysis .............................................................................. 97 
9.3.6 
Safety Analyses ....................................................................................................... 99 
9.3.7 
Subgroup Analyses ................................................................................................ 100 
9.4 
Sample Size Determination .......................................................................................... 100 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....... 101 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........................ 101 
10.1.1 
Regulatory and Ethical Considerations ................................................................... 101 
10.1.2 
Financial Disclosure .............................................................................................. 101 
10.1.3 
Informed Consent Process...................................................................................... 102 
10.1.4 
Data Collection ...................................................................................................... 102 
10.1.5 
Data Protection ...................................................................................................... 103 


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10.1.6 
Data Monitoring Committee Structure and Function .............................................. 103 
10.1.7 
Dissemination of Clinical Study Data .................................................................... 103 
10.1.8 
Data Quality Assurance ......................................................................................... 103 
10.1.9 
Source Documents ................................................................................................. 105 
10.1.10 
Study and Site Start and Closure ............................................................................ 105 
10.1.11 
Publication Policy .................................................................................................. 106 
10.1.12 
Sample Storage and Destruction ............................................................................ 107 
10.2 
Appendix 2: Emergency Contact Information .............................................................. 108 
10.2.1 
Serious Adverse Event Reporting........................................................................... 108 
10.2.2 
Sponsor Contacts ................................................................................................... 108 
10.3 
Appendix 3: Safety Laboratory Tests ........................................................................... 109 
10.4 
Appendix 4: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ....................................................................... 111 
10.4.1 
Definition of AE .................................................................................................... 111 
10.4.2 
Definition of SAE .................................................................................................. 113 
10.4.3 
Recording and Follow-up of AE and/or SAE ......................................................... 113 
10.4.4 
Reporting of SAEs ................................................................................................. 116 
10.5 
Appendix 5: Contraceptive and Barrier Guidance ........................................................ 117 
10.5.1 
Female Contraception ............................................................................................ 117 
10.5.2 
Male Contraception................................................................................................ 117 
10.5.3 
Acceptable Barrier Methods of Contraception ........................................................ 117 
10.6 
Appendix 6: Genetics .................................................................................................. 118 
10.7 
Appendix 7: Country-specific Requirements ................................................................ 119 
10.8 
Appendix 8: Dosing Instructions for Oral Suspension .................................................. 120 
10.9 
Appendix 9: Clinical Global Impression – Severity (CGI-S) ........................................ 129 
10.10 Appendix 10: Clinical Global Impression – Improvement (CGI-I) ............................... 132 
10.11 Appendix 11: Caregiver Global Impression of Change in Seizure 
Intensity/Duration (CGI-CSID) ................................................................................. 133 
10.12 Appendix 12: Sleep Questionnaires ............................................................................. 134 
10.12.2 
Sleep Quality Scale ................................................................................................ 137 
10.13 Appendix 13: Anxiety, Depression, and Mood Scale (ADAMS) .................................. 139 
10.14 Appendix 14: Pediatric Quality of Life Inventory – Family Impact Module 
(Peds-QL-FIM) ......................................................................................................... 141 
10.15 Appendix 15: Short Form 36 (version 2) ...................................................................... 147 
10.16 Appendix 16: Epilepsy and Learning Disabilities Quality of Life Scale ....................... 153 
10.17 Appendix 17: Columbia-Suicide Severity Rating Scale (C-SSRS) ............................... 168 
11 REFERENCES ................................................................................................................ 174 
 
 


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LIST OF TABLES 
Table 1. 
Schedule of Activities – Screening/Baseline and Double-blind Phase (Titration 
and Maintenance Periods) Plus Part A for Participants who Do Not Continue in 
the OLE or Part B for Participants who Continue in the OLE ............................. 37 
Table 2. 
Study Intervention(s) Administered .................................................................... 62 
Table 3. 
Protocol-required Safety Laboratory Tests ....................................................... 110 
 
LIST OF FIGURES 
Figure 1. 
 Study Schematic Diagram ................................................................................. 36 
 


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LIST OF ABBREVIATIONS 
ACTH 
adrenocorticotropic hormone 
ADAMS 
Anxiety, Depression, and Mood Scale 
ADL 
activities of daily living  
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase  
ANOVA 
Analysis of Variance 
ASM 
anti-seizure medication 
AST 
aspartate aminotransferase  
β-HCG 
β-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 
CGI-S 
Clinical Global Impression - Severity 
CIOMS 
Council for International Organizations of Medical Sciences 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
EEG 
electroencephalogram 
eCRF 
electronic case report form 
eDiary 
electronic seizure diary 
eGFR 
estimated glomerular filtration rate 
ELDQOL 
Epilepsy and Learning Disabilities Quality of Life 
EMA 
European Medicines Agency 
EU 
Europe 
FDA 
Food and Drug Administration 


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FXS 
fragile X syndrome  
GABA 
γ-aminobutyric acid 
GFR 
glomerular filtration rate 
GCP 
Good Clinical Practice 
GNX 
ganaxolone 
HR 
heart rate 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP/IP 
Investigational (Medicinal) Product 
IRB 
Institutional Review Board 
IS 
infantile spasm 
ITT 
intent-to-treat 
IV 
intravenous(ly) 
IWRS 
Interactive Web Response System 
LAM 
Lymphangioleiomyomatosis 
LAR 
legally authorized representative 
MENA 
Middle East and North Africa 
MRI 
magnetic resonance imaging 
mITT 
modified intent-to-treat 
mTOR 
mechanistic target of rapamycin 
mTORC1 
mechanistic target of rapamycin complex 1 
NHS 
National Health Service 
OC  
Oceania 
OL 
open-label 
OLE 
open-label extension 
PCDH 
protocadherin 
PD 
Pharmacodynamic(s) 
Peds-QL-FIM 
Pediatric Quality of Life – Family Impact Module 
PI 
principal investigator  
PK 
pharmacokinetic(s)  
PP 
Per-Protocol 
PPD 
postpartum depression 
PRN 
pro re nata (as needed) 
PTSD 
post-traumatic stress disorder 
QTL 
quality tolerance limit 


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RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SE 
status epilepticus 
SF-36 
Short Form 36 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SIB 
suicidal ideation and behavior 
SIF/DRF 
Seizure Identification and Diagnostic Review Form 
SOA 
schedule of activities 
SOC 
system organ class 
SQS 
Sleep Quality Scale 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
THC 
tetrahydrocannabinol 
THP 
tetrahydroprogesterone 
tid 
3 times a day 
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, Double-blind, Randomized, Placebo-controlled Trial of Adjunctive Ganaxolone 
(GNX) Treatment in Children and Adults with Tuberous Sclerosis Complex (TSC)-related 
Epilepsy (TrustTSC).  
Brief Title:  
Adjunctive GNX Treatment Compared with Placebo 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 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 metabolism 
via its inhibition of the small GTPase Rheb (Krueger and Northrup, 2013). Everolimus 
(Afinitor®), amTORC1 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 3α5-reduced-tetrahydroprogesterone (THP) metabolites 
of progesterone, including 3α, 5α-THP (allopregnanolone), are positive allosteric modulators of 
the GABAA receptor. In contrast, 3β5-THP acts as functional antagonists of the GABAA receptor 


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by reducing the ability of 3α5-THP to exert a potentiating effect on the GABAA receptor. 
Di Michele et al, 2003 have demonstrated decreases in allopregnanolone and 3α, 5β-THP relative 
to 3β5-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 3α5- and 3β5-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 3β-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 
study (OL), 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 study 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 (CSR) for this study was completed on 08 Mar 2023. 
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.  


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Objectives and Endpoints:  
 
Objectives 
Primary Objective 
• To assess the safety and efficacy of GNX compared to placebo as adjunctive therapy for 
seizures associated with TSC in children and adults as assessed by the change from 
baselinea in the frequency of countable major motor and focal seizures (primary endpoint 
seizuresb) during the double-blind phase.  
Secondary Objectives 
• To determine the percentage of change from baselinea in 28-day primary endpoint 
seizureb frequency during the maintenance period.  
• To assess the change in focal seizure frequency from baselinea during the double-blind 
phase.  
• To assess changes in mood, behavior, and quality of life using the following:  
o ADAMS. 
o Peds-QL-FIM. 
o SF-36. 
o ELDQOL . 
• To assess overall clinical outcome using the 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.  
Safety Objectives 
• To assess the safety and tolerability of GNX compared with placebo as adjunctive 
therapy.  
Endpoints 
Primary Endpoint 
• The primary efficacy endpoint is the percentage change from baselinea in 28-day primary 
endpoint seizureb frequency during the double-blind phase.  
Secondary Endpoints 
Key Secondary Efficacy Endpoints:  
• Percentage change from baselinea in 28-day primary endpoint seizureb frequency during 
the maintenance period (FDA). For EMA this is the primary endpoint.  
• Number (%) of participants considered treatment respondersc during the double-blind 
phase (FDA). For the EMA, this endpoint will be evaluated over the maintenance period 
only. 
• Number (%) of participants considered treatment respondersc during the maintenance 
period.  
• CGI-I at the last scheduled visit in the double-blind phase.  
Secondary Efficacy Endpoints (Behavior/Neuropsychiatric/Quality of life):  
• Change from baseline in ADAMS total score and sub-score.  
• Change from baseline in quality-of-life scales: Peds-QL-FIM, SF-36, and ELDQOL.  
Secondary Efficacy Endpoints (Seizure Control):  


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• Change from baselinea in the percentage of seizure-free days during the double-blind 
phase, based on primary endpoint seizureb type (FDA). For the EMA, this endpoint will 
be evaluated over the maintenance period only.  
• Change from baselinea in the CGI-CSID at the end of the double-blind phase (FDA). For 
the EMA, this endpoint will be evaluated over the maintenance period only.  
• Participants with a ≥ 25% and ≥ 75% reduction from baseline in primary endpoint 
seizureb frequency during the double-blind phase (FDA). For the EMA, this endpoint will 
be evaluated over the maintenance period only.  
• Participants with a ≥ 25%, ≥ 50%, and ≥ 75% reduction from baselinea in primary 
endpoint seizureb frequency during the maintenance period.  
• Responder analysis for primary endpoint seizuresb and all seizures during the 
double-blind phase using the following response categories: ≤ 0%, > 0% to < 25%, 
≥ 25% to < 50%, ≥ 50% to < 75%, and ≥ 75% to 100% (FDA). For the EMA, this 
endpoint will be evaluated over the maintenance period only.   
• Percent change in 28-day frequency of all seizures.  
• Change from baselinea in the percentage of seizure-free days, based on all seizure types.  
• Change from baselinea in the longest seizure-free interval, based on primary endpoint 
seizure typeb and all seizure types.  
Safety Endpoints 
• Incidence and severity of AEs, SAEs, and withdrawals and dose-reductions due to AEs 
• Other measures of safety including physical/neurological/developmental examinations, 
vital sign measurements (eg, blood pressure, heart rate, respiratory rate, and body 
temperature), 12-lead ECGs, clinical laboratory tests, and suicidal ideation and behavior 
risk monitoring.  
The primary and secondary endpoints (unless otherwise defined) for the United States FDA will be based on the 
double-blind phase (titration and maintenance period). The primary and secondary endpoints (unless otherwise 
defined) for the EMA will be based on the maintenance period only. 
ADAMS = Anxiety, Depression, and Mood Scale; AE = adverse event; CGI-CSID = Clinical Global Impression 
of Change in Seizure Intensity/Duration; CGI-I = Clinical Global Impression of Improvement; 
ECG = electrocardiogram; ELDQOL = Epilepsy and Learning Disabilities Quality of Life; EMA = European 
Medicines Agency; FDA = Food and Drug Administration; GNX = ganaxolone; LAR = legally authorized 
representative; Peds-QL-FIM = Pediatric Quality of Life - Family Impact Module;; SAE = serious adverse 
events; SF-36 = Short Form 36 (version 2); TSC = Tuberous Sclerosis Complex. 
a 
Baseline is defined as the first 28 days following screening. 
b 
Primary endpoint 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 primary endpoint 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 primary 
endpoint seizure frequency during the double-blind or maintenance phase. 
 


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Overall Design:  
This is a Phase 3, global, double-blind, randomized, placebo-controlled study of adjunctive GNX 
treatment in children and adults with TSC-related epilepsy. The study consists of a 4-week 
prospective baseline phase, defined as the first 28 days following screening, followed by a 
double-blind phase consisting of a 4-week titration period and a 12-week maintenance period.  
Participants eligible for inclusion in this double-blind study must have inadequately controlled 
seizures after exposure to at least 2 anti-seizure medication (ASMs) administered at adequate 
doses and for adequate durations, with approximately 8 seizures per month in the 2 months prior 
to screening and seizure-free periods of not more than 1 week.  
Procedures specific to this protocol and not otherwise considered standard of care, will not be 
performed until written informed consent from the participant or their parent(s)/legally 
authorized representative (s) (LARs), as appropriate, has been appropriately obtained.  
An interactive response technology system will be used to randomize participants, dispense drug, 
track treatment, and maintain the blind throughout the duration of the study.  
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 study. 
A variety of clinician and caregiver administered instruments will be used to assess efficacy, and 
will include:  
• 
Clinical Global Impression - Severity (CGI-S). 
• 
Clinical Global Impression of Improvement (CGI-I) by parent(s)/caregiver(s)/LAR(s) and 
clinician. 
• 
Caregiver Global Impression of Change in Seizure Intensity/Duration (CGI-CSID). 
• 
Anxiety, Depression, and Mood Scale (ADAMS). 
• 
Pediatric Quality of Life – Family Impact Module (Peds-QL-FIM). 
• 
Short Form 36 (SF-36). 
• 
Epilepsy and Learning Disabilities Quality of Life (ELDQOL). 
The titration schedule is as follows: 
• 
Start – Day 1. 
• 
Titration 1 – Day 7. 
• 
Titration 2 – Day 14. 
• 
Titration 3 – Day 21. 
• 
Final titration – Day 28. 
• 
Maintenance begins on Day 29 (Start of Week 5). 
GNX (or matching volumes of placebo suspension) will be titrated at approximately weekly 
intervals over 4 weeks to a maximum dose based on the participant’s starting weight 63 mg/kg/day 
with a maximum daily dose of 1800 mg (for patients more than 28 kg).  


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The Phase 2 data for GNX in TSC raised the question of a CBD interaction. In the trial of 
23 treated patients, approximately half were on cannabidiol, and there was an association 
between higher CBD doses and increased somnolence. Given the small sample size, more 
definitive conclusions were not possible. As a result, patients taking CBD should be monitored 
closely for any sedation-related adverse events (AEs) throughout this Phase 3 protocol. 
Participants may have the dose of investigational product (IP) temporarily or permanently 
decreased at any point in the maintenance period to manage tolerability.  
Any dose adjustments that are not part of the prespecified titration schedule should be discussed 
with the sponsor medical monitor prior to making the change. If it is not possible to contact the 
medical monitor prior to the dose adjustment, the medical monitor should be notified as soon as 
possible after making the change.  
The maximum dose for all participants is 1800 mg/day. The total double-blind phase (titration 
and maintenance periods) should not exceed 16 weeks.  
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. Participants who 
discontinue the IP before the scheduled completion of the study will return to the site 2 weeks 
after the end of taper to complete the safety follow-up assessments.  
Following completion of the double-blind phase, participants who are compliant with study 
conduct will have the option to enroll and be treated with GNX in a separate open-label 
extension study (OLE), 1042-TSC-3002. All participants entering the OLE will have their dose 
of study medication adjusted in a double-blind cross-titration over 4 weeks such that all are 
receiving GNX at study completion. Participants who do not continue in the OLE will undergo a 
2- to 4-weeks double-blind down-titration and taper if discontinuing IP (See Figure 1). 
Disclosure Statement:  
This is a randomized, double-blind, placebo-controlled, 2-arm treatment study that is participant, 
caregiver, and investigator blinded.  
Number of Participants:  
Approximately 200 participants with TSC will be screened with the aim of randomizing 
approximately 128 participants (64 per arm), aged 1 to 65 years (inclusive). For Europe (EU), 
Middle East and North Africa (MENA), and Oceania (OC) Male or Female participants aged 
2 through 65 years, inclusive. Participants will be randomized (1:1) to either GNX or placebo as 
adjunctive therapy with their standard ASMs.  
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 who subsequently are 
not eligible for study entry, are not considered enrolled, unless otherwise specified by the 
protocol.  


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Protocol 1042-TSC-3001 
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Eligibility Criteria: 
Participants are eligible to be included in the study only if all the following inclusion criteria are 
met:  
1. Clinical or mutational diagnosis of TSC consistent with (Northrup et al, 2021):  
a. Molecular confirmation of a pathogenic mutation in TSC1 or TSC2. A pathogenic 
mutation is defined as a mutation that clearly prevents protein synthesis and/or inactivates 
the function of the TSC1 or TSC2 proteins (eg, nonsense mutation or frameshift 
mutations, large genomic deletions) or is a missense mutation whose effect on protein 
function has been established by functional assessment. The principal investigator (PI) or 
designee must review the results of the genetic analysis and confirm that the causal 
relationship to the epilepsy syndrome is likely.  
OR 
b. Clinical diagnosis of definite TSC which includes 2 major features or 1 major feature 
with ≥ 2 minor features. 
Major features 
Minor features 
Hypomelanotic macules (≥ 3, at least 5-mm diameter) 
Angiofibroma (≥ 3) or fibrous cephalic plaque 
Ungual fibromas (≥ 2) 
Shagreen patch 
Multiple retinal hamartomas 
Multiple cortical tubers and/or radial migration lines 
Subependymal nodules (≥ 2) 
Subependymal giant cell astrocytoma 
Cardiac rhabdomyoma 
Lymphangioleiomyomatosis (LAM)* 
Angiomyolipomas (≥ 2)* 
“Confetti” skin lesions 
Dental enamel pits (≥ 3) 
Intraoral fibromas (≥ 2) 
Retinal achromic patch 
Multiple renal cysts 
Nonrenal hamartomas 
Sclerotic bone lesions 
 
* 
A combination of the 2 major clinical features (LAM and angiomyolipomas) without other features does not 
meet criteria for a definite diagnosis. 
The investigator must document which of the features (major or minor) fulfill the clinical 
diagnostic criteria. 
2. Male or female participants aged 1 through 65 years, inclusive. For Europe (EU), Middle 
East and North Africa (MENA), and Oceania (OC) Male or Female participants aged 
2 through 65 years, inclusive. 
3. Participant/parent(s) or 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 nor able to provide written 
informed consent based on age, developmental stage, intellectual capacity, or other factors, 
parent(s)/LAR(s) must provide consent for study participation, if appropriate. 


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4. Failure to control seizures despite appropriate trial of 2 or more ASMs at therapeutic doses 
and for adequate duration of treatment per PI judgment. 
5. Participants should be on a stable regimen of ASMs (including moderate or strong inducer or 
inhibitor ASM eg, carbamazepine, phenytoin, etc.) at therapeutic doses for ≥ 28 days prior to 
the screening visit, and without a foreseeable change in dosing for the duration of the study. 
(Note: Minor dose adjustment to address tolerability and safety events may be allowed on 
case-by-case basis and it should be discussed with the study medical monitor.) 
6. A history of at least 8 countable seizures per month in the 2 months prior to screening with 
no more than 1 seizure free week in each month. This includes seizures of any kind. 
7. Have at least 8 primary endpoint seizures in the first 28 days following the screening visit.  
The primary endpoint seizure types are defined as the following:  
a. Focal motor seizures without impairment of consciousness or awareness 
b. Focal seizures with impairment of consciousness or awareness with motor features 
c. Focal seizures evolving to bilateral, tonic-clonic seizures 
d. Generalized motor seizures including tonic-clonic, bilateral tonic, bilateral clonic, or 
atonic/drop seizures.  
Seizures that do not count towards the primary endpoint include: 
a. Focal or generalized nonmotor seizures (eg, absence seizures or focal nonmotor seizures 
with or without impairment of awareness) 
b. Infantile or epileptic spasms  
c. Myoclonic seizures  
8. Participants with surgically implanted vagal nerve stimulator (VNS) will be allowed to enter 
the study provided that all of the following conditions are met:  
a. The VNS has been in place for ≥ 6 months prior to the screening visit 
b. The settings must have remained constant for 3 months prior to the screening visit and 
are expected to remain constant throughout the study 
c. The battery is expected to last for the duration of the study. 
9. Parent(s)/caregiver(s)/LAR(s) or the participant, as appropriate, is (are) willing and able to 
maintain an accurate and complete daily seizure eDiary for the duration of the study.  
10. Willing and able to take IP (suspension) as directed with food 3 times a day (tid).  
11. WOCBP must be using a medically acceptable method of birth control and have a negative 
quantitative serum β-human chorionic growth hormone (β-HCG) test collected at the initial 
screening and baseline visits. 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 the 
screening visit), 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.  


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Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
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12 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. 
Note: The Epilepsy Study Consortium will review and classify all seizure types reported by the 
investigator, incorporating the medical history,
seizure description, and historical 
records (including electroencephalogram [EEG], when available). This review and classification 
does not need to be completed prior to study entry but should be completed in parallel, and may 
complete after the participant has been enrolled in the study. 
Participants are excluded from the study if any of the following exclusion criteria apply:  
1. Previous exposure to GNX. 
2. Pregnant or breastfeeding. 
3. Participants who have been taking felbamate for less than 1 year prior to screening. 
4. Participants taking CBD preparations other than Epidiolex®. 
5. A positive result on drug screen for CBD or tetrahydrocannabinol (THC) at Visit 1 
(screening), with the exception of results that are fully explained by prescribed Epidiolex®, 
which can be adjusted by the investigator in the event of any AEs.  
6. Concurrent use of adrenocorticotropic hormone (ACTH), prednisone or other glucocorticoid 
is not permitted, nor use of the strong inducers of cytochrome P450 3A4 (CYP3A4), rifampin 
and St. John’s Wort.  
Participants on ACTH, prednisone, or other systemically (non-inhaled or topical) 
administered steroids should be off the product > 28 days prior to screening.  
Rifampin and St. John’s Wort must be discontinued at least 28 days before Visit 2, study 
drug initiation.  
Note:  
a. Use of concomitant intranasal or pro re nata (PRN) topical steroids for dermatologic 
reactions and allergic rhinitis are allowed during the study.  
b. This exclusion criterion does not prohibit the use of approved ASMs. 
7. Changes in any chronic medications within the 4 weeks prior to the screening visit. All 
chronic concomitant medications must be relatively stable in dose for at least 4 weeks prior 
to the screening visit unless otherwise noted. Small dose adjustment to manage tolerability 
and safety events is permitted and should be discussed with the study medical monitor. 
8. Participants who have epilepsy surgery planned during the study or who have undergone 
surgery for epilepsy within the 6 months prior to screening. 
9. An active CNS infection, demyelinating disease, degenerative neurological disease, or CNS 
disease deemed progressive as evaluated by brain magnetic resonance imaging (MRI). This 
includes tumor growth which in the opinion of the investigator could affect primary endpoint 
seizure control.  
10. Any disease or condition (medical or surgical; other than TSC) at the screening visit that 
might compromise the hematologic, cardiovascular (including any cardiac conduction 


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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. 
11. Hepatic impairment sufficient to affect patient safety, or an aspartate aminotransferase 
(AST)/serum glutamic oxaloacetic transaminase (SGOT) or alanine aminotransferase 
(ALT)/serum glutamic pyruvic transaminase (SGPT) > 3 × the upper limit of normal (ULN) 
at screening or baseline visits and confirmed by a repeat test.  
12. Biliary impairment sufficient to affect patient safety, or total bilirubin levels > 1.5 × ULN at 
screening or baseline visit and confirmed by a repeat test. In cases of Gilbert’s Syndrome, 
resulting in stable levels of total bilirubin greater than ULN, the medical monitor can 
determine if a protocol exception can be made.  
13. Renal impairment sufficient to affect patient safety, or estimated glomerular filtration rate 
(eGFR) < 30 mL/min (calculated using the Cockcroft-Gault formula or pediatric glomerular 
filtration rate [GFR] calculator or Bedside Schwartz), will be excluded from study entry or 
will be discontinued if the criterion is met post baseline (Levey et al, 2006). Cases of 
temporary renal insufficiency should be discussed with the medical monitor to determine the 
participant’s study continuation. 
14. Exposed to any other investigational drug or investigational device within 30 days or fewer 
than 5 half-lives prior to the screening visit. For therapies in which half-life cannot be readily 
established, the Sponsor’s medical monitor should be consulted. 
15. Unwillingness to avoid excessive alcohol use throughout the study.  
16. Have active suicidal plan/intent, active suicidal thoughts or a suicide attempt in the past 
6 months. 
17. Known sensitivity or allergy to any component in the IP(s), progesterone, or other related 
steroid compounds. 
18. Participants deprived of their liberty by a judicial or administrative decision, or for 
psychiatric treatment, or participants admitted to a health or social services facility for 
purposes other than research. 
19. Participants receiving traditional Chinese medicine therapies within the prior 28 days of the 
screening. 
Intervention Groups and Duration:  
Eligible participants will collect 4 weeks of prospective baseline seizure data prior to starting 
treatment. Participants will be randomized (1:1) to double-blind treatment with GNX or placebo. 
Stratification of randomization will be performed based on whether the patient is taking 
concomitant CBD or not. GNX is to be titrated to the target dose over 4 weeks. The total double-
blind phase (titration and maintenance periods) should not exceed 16 weeks.  
Participants who complete the study may be eligible to participate in the OLE. However, 
participants who discontinue IP should undergo a 2-week or shorter taper period, as clinically 
indicated, and complete the safety follow-up assessments 2 weeks after the final dose. 


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Protocol 1042-TSC-3001 
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Data Monitoring/Other Committee:  
The Data Monitoring Committee (DMC) will review emerging study data on a periodic basis.  
The DMC is a group of independent scientists who are appointed to monitor the safety and 
scientific integrity of a human research intervention, and to make recommendations to the 
sponsor regarding the stopping of a study for safety concerns. The composition of the committee 
is dependent upon the scientific skills and knowledge required for monitoring the particular 
study.  
The mission of the DMC will be to safeguard the interests of study participants and to enhance 
the integrity and credibility of the trial. To enable the DMC to achieve their mission, the DMC 
will have periodic access to unblinded safety data and data regarding quality of trial conduct and 
will ensure the confidentiality of these data is preserved. A DMC Charter will provide the 
principles and guidelines for the DMC process.  


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1.2 
Schema 
Figure 1.  Study Schematic Diagram 
Baseline 
period
TSC
n≈200 screened
Screening and 
enrollment
Titration 
period
Titration 
period
Maintenance period
Maintenance period
Crossover 
to OLEc
(1042-TSC-3002)
4 weeks
4 weeksb
12 weeks
Double-bind Treatment Period
4 weeks
D/C 
studyd
Safety 
follow-up
GANAXOLONEa
PLACEBO
Randomize
1:1
 
DC = double-blind down cross-titration; GNX = ganaxolone; IP = investigational product; OLE = open-label extension; TSC = Tuberous Sclerosis Complex. 
a GNX or matching volumes of placebo suspension will be titrated at approximately weekly intervals over 4 weeks: The target dose is: 63 mg/kg/day for those 
weighing 28 kg or less, or 1800 mg/day for those weighing more than 28 kg.  
b The participant may have the dose of IP temporarily or permanently decreased at any point in the maintenance period to manage tolerability.  
c All participants entering the OLE will have their dose of study medication adjusted in a double-blind cross-titration over 4 weeks such that all are receiving 
GNX at study completion.  
d Participants who do not continue in the OLE will undergo a 2- to 4-weeks double-blind down titration and taper if discontinuing IP and safety follow-up visit 
at the end of 4 weeks 
 


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1.3 
Schedule of Activities 
Table 1. 
Schedule of Activities – Screening/Baseline and Double-blind Phase (Titration and Maintenance Periods) Plus Part 
A for Participants who Do Not Continue in the OLE or Part B for Participants who Continue in the OLE 
Screening/Baseline and Double-blind Phase (Titration and Maintenance Periods) 
Part A: 
Participants 
who Do Not 
Continue in the 
OLE 
 
Screening/Baseline 
Double-blind Phase (Titration + Maintenance Periods) 
End of 
Study/Safety 
Follow-up 
Visit/a 
Discontinuation 
WEEK 
(All dates are relative to the 
first dose) 
-4 
(Screening) 
Baseline and 
First Dose on 
Day 1 
(Randomization) Day 4 Wk 1 
Wk 2 Wk 3 Wk 4 Wk 5 Wk 9 Wk 11 Wk 13 Wk 16 
Wk  
20 
Visit and Visit Window 
(visits are either in person or 
telehealth) 
 
+ 6 days 
± 1 day ± 1 day 
All windows for these visits are ± 3 days 
± 7 days 
V1 
V2 
V3 
Phone  
V4 
V5 
Phone 
V6 
Phone 
V7 
Phone 
V8 
V9 
V10 
Phone  
V11 
Phone 
V12 or 
ET 
V13A 
Screening and Diagnosis 
 
Informed Consentb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical 
History 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
Historical Seizure Calendar 
Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Seizure Identification and 
Diagnostic Review Form 
(Epilepsy Study Consortium) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Screening/Baseline and Double-blind Phase (Titration and Maintenance Periods) 
Part A: 
Participants 
who Do Not 
Continue in the 
OLE 
 
Screening/Baseline 
Double-blind Phase (Titration + Maintenance Periods) 
End of 
Study/Safety 
Follow-up 
Visit/a 
Discontinuation 
WEEK 
(All dates are relative to the 
first dose) 
-4 
(Screening) 
Baseline and 
First Dose on 
Day 1 
(Randomization) Day 4 Wk 1 
Wk 2 Wk 3 Wk 4 Wk 5 Wk9 Wk 11 Wk 13 Wk 16 
Wk  
20 
Visit and Visit Window 
(visits are either in person or 
telehealth) 
 
+ 6 days 
± 1 day ± 1 day 
All windows for these visits are ± 3 days 
± 7 days 
V1 
V2 
V3 
Phone  
V4 
V5 
Phone 
V6 
Phone 
V7 
Phone 
V8 
V9 
V10 
Phone  
V11 
Phone 
V12 or 
ET 
V13A 
Safety Assessments 
 
Vital Signs (BP, HR, and RR), 
Body temperature, Height, and 
Weight 
X 
X 
 
X 
 
 
 
X 
X 
 
 
X 
X 
Physical/Neurological/ 
Developmental Exame 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical/Neurological/ 
Developmental Exam 
Follow-up 
 
X 
 
X 
 
 
 
X 
X 
 
 
X 
 
12-lead ECG 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
Clinical Laboratory Testsf 
X 
X 
 
X 
 
 
 
X 
X 
 
 
X 
 
Urinalysis 
Xg 
Xg 
 
X 
 
 
 
 
 
 
 
X 
 
Drug screenh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (WOCBP)i 
X 
X 
 
X 
 
 
 
X 
X 
 
 
X 
X 
Tanner Staging 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Investigational Product PKj 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
Concomitant ASM Levelsk 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 


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Protocol 1042-TSC-3001 
Protocol Date and Version: 06 Sep 2023; v 4.0 
 
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Screening/Baseline and Double-blind Phase (Titration and Maintenance Periods) 
Part A: 
Participants 
who Do Not 
Continue in the 
OLE 
 
Screening/Baseline 
Double-blind Phase (Titration + Maintenance Periods) 
End of 
Study/Safety 
Follow-up 
Visit/a 
Discontinuation 
WEEK 
(All dates are relative to the 
first dose) 
-4 
(Screening) 
Baseline and 
First Dose on 
Day 1 
(Randomization) Day 4 Wk 1 
Wk 2 Wk 3 Wk 4 Wk 5 Wk9 Wk 11 Wk 13 Wk 16 
Wk  
20 
Visit and Visit Window 
(visits are either in person or 
telehealth) 
 
+ 6 days 
± 1 day ± 1 day 
All windows for these visits are ± 3 days 
± 7 days 
V1 
V2 
V3 
Phone  
V4 
V5 
Phone 
V6 
Phone 
V7 
Phone 
V8 
V9 
V10 
Phone  
V11 
Phone 
V12 or 
ET 
V13A 
Concomitant ASM Level 
Review (if collected per 
standard of care)l 
X 
X 
 
X 
 
 
 
X 
X 
 
 
X 
 
Adverse Events 
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 
C-SSRS (baseline form)m 
 
X 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS (since previous visit)l 
 
 
 
X 
 
 
 
X 
X 
 
 
X 
X 
Efficacy Assessments 
Seizure eDiary review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-S 
 
X 
 
 
 
 
 
 
 
 
 
 
 
CGI-CSID 
 
 
 
X 
 
 
 
X 
X 
 
 
X 
 
CGI-I by 
Parent(s)/Caregiver(s)/LAR(s) 
and Clinician 
 
 
 
X 
 
 
 
X 
X 
 
 
X 
 
Exploratory Assessments 


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Screening/Baseline and Double-blind Phase (Titration and Maintenance Periods) 
Part A: 
Participants 
who Do Not 
Continue in the 
OLE 
 
Screening/Baseline 
Double-blind Phase (Titration + Maintenance Periods) 
End of 
Study/Safety 
Follow-up 
Visit/a 
Discontinuation 
WEEK 
(All dates are relative to the 
first dose) 
-4 
(Screening) 
Baseline and 
First Dose on 
Day 1 
(Randomization) Day 4 Wk 1 
Wk 2 Wk 3 Wk 4 Wk 5 Wk9 Wk 11 Wk 13 Wk 16 
Wk  
20 
Visit and Visit Window 
(visits are either in person or 
telehealth) 
 
+ 6 days 
± 1 day ± 1 day 
All windows for these visits are ± 3 days 
± 7 days 
V1 
V2 
V3 
Phone  
V4 
V5 
Phone 
V6 
Phone 
V7 
Phone 
V8 
V9 
V10 
Phone  
V11 
Phone 
V12 or 
ET 
V13A 
ADAMS 
 
X 
 
X 
 
 
 
X 
X 
 
 
X 
 
Peds-QL–FIMp 
 
X 
 
 
 
 
 
X 
X 
 
 
X 
 
ELDQOL 
 
X 
 
X 
 
 
 
X 
X 
 
 
X 
 
SF-36 
 
X 
 
X 
 
 
 
X 
X 
 
 
X 
 
Investigational Product 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense IP 
 
X 
 
 
 
 
 
X 
X 
 
 
X 
 
ADAMS = Anxiety, Depression, and Mood Scale; ASM = anti-seizure medication; BP = blood pressure; CBD = cannabidiol; CGI-CSID = Caregiver Global Impression of Change 
in Seizure Intensity/Duration; CGI-I = Clinical Global Impression of Improvement; CGI-S = Clinical Global Impression of Improvement; eCRF = Electronic case report form; 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; eDiary = electronic seizure diary; 
ELDQOL = Epilepsy and Learning Disabilities Quality of Life; ET = early termination; HR = heart rate; IP = investigational product; LAR = legally authorized representative; 
OLE = open-label extension; Peds-QL–FIM = Pediatric Quality of Life - Family Impact Module; PI = principal investigator; PK = pharmacokinetic; QOL = quality of life; 
RR = respiratory rate; SF-36 = Short Form 36 (version 2); SQS = Sleep Quality Scale; THC = tetrahydrocannabinol; WOCBP = women of childbearing potential. 
a. Only for participants who discontinue treatment, either early or at Visit 12 prior to down-titration as they are not continuing in the OLE study. This visit will occur 2 weeks 
after the last dose of IP.  
b. Written informed consent/assent must be obtained from participant/parent(s)/caregiver(s)/LAR(s) before any study assessments are performed. 
c. Review of medical history only.  
e. Developmental examination is limited to pediatric participants 1 to 17 years of age, inclusive. 


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f. Chemistry and Hematology (See Section 8.3.4)  
g. An attempt should be made to collect a urine sample for a urinalysis at screening. Otherwise, the urine sample can be collected at baseline for the urinalysis. 
h. 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 at Visit 1 (screening). A positive test 
for CBD or THC will exclude the participants from the study, unless the participant is taking prescribed Epidiolex®. 
i. Serum pregnancy test is required for all WOCBP at Visits 1 and 2. At Visits 4, 8, 9, 12, and 13A, the investigator may choose to do either a serum or urine pregnancy test. 
j. PK samples will be collected at these visits; Visit 8 (Week 5): between 1 to 5 hours since last IP dosing, Visit 9 (Week 9): between 4 to 8 hours since the last IP dosing, and 
Visit 12 (Week 16) where there is no specified time window relative to dosing).  
k. Concomitant ASMs or their dose must be stable for 4 weeks prior to screening and should not be changed at any time prior to Visit 12. Concomitant ASM levels at Visit 1 
(Screening), Visit 8, and on study completion will be obtained centrally for the following if the participant is prescribed these medications: cannabidiol, clobazam (which 
requires clobazam and desmethylclobazam levels), any mTOR inhibitor (including everolimus, sirolimus, etc.), and/or valproate.  
l. If the levels of any ASM co-administered with the IP are measured routinely per standard of care, this information will be recorded in the eCRF.  
m. Only for participants ≥ 11 years of age, if appropriate, otherwise, clinical judgment will be used. 
n. For participants aged 4 to 12 years of age, if appropriate (Section 8.2.5). 
o. For participants ≥ 13 years of age, if appropriate. 
p. For parent(s)/caregiver(s)/LAR(s) of the participant to complete, if appropriate. Peds-QL-FIM for past 1 month at baseline visit and Peds-QL-FIM for past 7 days at on-study 
visits (see Section 8.2.7). 


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Table 1 
Schedule of Assessments Continued - Part B for Participants who Continue in the OLEa 
Part B (For Participants who Continue in the OLE) 
 
 
Last Visit in 
Period 
Double-blind Phase (Titration) 
(4 Weeks) 
End of Study Visit/ET 
/First Visit of the OLE 
WEEK 
(All dates are relative to the first dose) 
Wk 16 
Wk 16(3 Days 
Post-V12) 
Wk 17 
Wk 18 
Wk 19 
Wk 20 
Visit and Visit Window 
(visits are either in person or 
telehealth) 
± 3 days 
± 1 day 
All windows for these visits are ± 3 days 
± 3 days 
VISIT 
V12 
V13B 
Phone 
V14 
Phone 
V15 
V16 
Phone 
V17 
Screening and Diagnosis 
Informed Consent for OLE entryb  
 
 
 
 
 
X 
Inclusion/Exclusion Criteria for OLE 
X 
 
 
 
 
X 
Safety Assessments 
Vital signs (BP, HR, and RR), Body 
temperature, Height, and Weight 
X 
 
 
X 
 
X 
Physical/Neurological/ 
Developmental Exam Follow-up 
X 
 
 
 
 
X 
12-Lead ECG 
X 
 
 
X 
 
X 
Clinical Laboratory Testsc 
X 
 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
X 
Drug Screen 
 
 
 
 
 
X 
Pregnancy Test (WOCBP)d 
X 
 
 
 
 
X 
Tanner Staging 
 
 
 
 
 
X 
Investigational Product PKe 
X 
 
 
X 
 
X 


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Part B (For Participants who Continue in the OLE) 
 
 
Last Visit in 
Period 
Double-blind Phase (Titration) 
(4 Weeks) 
End of Study Visit/ET 
/First Visit of the OLE 
WEEK 
(All dates are relative to the first dose) 
Wk 16 
Wk 16(3 Days 
Post-V12) 
Wk 17 
Wk 18 
Wk 19 
Wk 20 
Visit and Visit Window 
(visits are either in person or 
telehealth) 
± 3 days 
± 1 day 
All windows for these visits are ± 3 days 
± 3 days 
VISIT 
V12 
V13B 
Phone 
V14 
Phone 
V15 
V16 
Phone 
V17 
Concomitant ASM Levelsf 
X 
 
 
 
 
X 
Concomitant ASM Level Review (if 
collected per standard of care) 
X 
 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
C-SSRS (since previous visit)g 
X 
 
 
X 
 
X 
Efficacy Assessments 
Seizure eDiary Review 
X 
X 
X 
X 
X 
X 
CGI-I by Parent(s)/Caregiver(s)/LAR(s) 
and Clinician 
X 
 
 
X 
 
X 
CGI-CSID 
X 
 
 
X 
 
X 
Exploratory Assessments 
ADAMS 
X 
 
 
X 
 
X 
Peds-QL-FIMj 
X 
 
 
X 
 
X 
ELDQOL 
X 
 
 
X 
 
X 


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Part B (For Participants who Continue in the OLE) 
 
 
Last Visit in 
Period 
Double-blind Phase (Titration) 
(4 Weeks) 
End of Study Visit/ET 
/First Visit of the OLE 
WEEK 
(All dates are relative to the first dose) 
Wk 16 
Wk 16(3 Days 
Post-V12) 
Wk 17 
Wk 18 
Wk 19 
Wk 20 
Visit and Visit Window 
(visits are either in person or 
telehealth) 
± 3 days 
± 1 day 
All windows for these visits are ± 3 days 
± 3 days 
VISIT 
V12 
V13B 
Phone 
V14 
Phone 
V15 
V16 
Phone 
V17 
SF-36 
X 
 
 
X 
 
X 
Investigational Product 
Dispense Investigational Productk 
X 
 
 
 
 
X 
ADAMS = Anxiety, Depression, and Mood Scale; 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; 
D/C = discontinuation; ECG = electrocardiogram; eDiary = electronic seizure diary; ELDQOL = Epilepsy and Learning Disabilities Quality of Life; ET = early termination; 
HR = heart rate; IWRS = interactive web-based response system; OLE = open-label extension; LAR = legally authorized representative; Peds-QL-FIM = Pediatric Quality of Life 
– Family Impact Module; PK = pharmacokinetic; QOL = quality of life; SF-36 = Short Form 36 (version 2); SQS = Sleep Quality Scale; RR = respiratory rate; WOCBP = women 
of childbearing potential. 
a. For participants continuing into the OLE, relevant data from the 1042-TSC-3001 study database will be shared with the 1042-TSC-3002 study database. 
b. The timing of consent for the 1042-TSC-3002 OLE study should occur at or before Visit 17.  
c. Chemistry and Hematology (Section 8.4.5). 
d. The investigator may choose to do either a serum or urine pregnancy test for all WOCP at Visit 12. At Visit 17, serum pregnancy test is required for all WOCBP.  
e. Population PK will be conducted at these visits: Visit 12 (Week 16), Visit 15 (Week 18), and Visit 17 (Week 20) where there are no specified time windows relative to dosing. 
f. Concomitant ASMs or their dose must be stable for 4 weeks prior to this visit. Concomitant ASM levels will be obtained centrally for the following if the participant is 
prescribed these medications: cannabidiol, clobazam (which requires clobazam and desmethylclobazam levels), any mTOR inhibitor (including everolimus, sirolimus, etc.), 
and/or valproate.  
g. Only for participants ≥ 11 years of age, if appropriate, otherwise, clinical judgment will be used. 
h. For participants aged 4 to 12 years of age, if appropriate (Section 8.2.5). 
i. For participants ≥ 13 years of age, if appropriate (Section 8.2.5).  
j. For the parent(s)/caregiver(s)/LAR(s) of the participant to complete, if appropriate. Peds-QL-FIM for past 7 days at on-study visits (see Section 8.2.7). 
k. The IP dispensation at Visit 17 is the first visit of the OLE and will occur using the 1042-TSC-3002 IWRS.


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2 INTRODUCTION 
Ganaxolone (GNX) is a small molecule being developed for use as an ASM in rare pediatric 
seizure disorders including cyclin-dependent kinase-like 5 deficiency disorder (CDD), tuberous 
sclerosis complex (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 3α5-reduced-tetrahydroprogesterone (THP) metabolites 
of progesterone, including 3α, 5α-THP (allopregnanolone), are positive allosteric modulators of 
the GABAA receptor. In contrast, 3β5-THP acts as functional antagonists of the GABAA receptor 
by reducing the ability of 3α5-THP to exert a potentiating effect on the GABAA receptor. 
Di Michele et al (2003) have demonstrated decreases in allopregnanolone and 3α, 5β-THP 
relative to 3β5-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 3α5- and 3β5-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 mTORC1, an important intracellular 
regulator of growth and metabolism via its inhibition of the small GTPase Ras homolog enriched 


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in brain (Krueger and Northrup, 2013). Everolimus (Afinitor®), a mechanistic target of 
rapamycin complex 1 (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 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, 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 
Ganaxolone (GNX) (3α-hydroxy-3β-methyl-5α-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 
3β-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 CDKL5 deficiency disorder (CDD) in patients 2 years of age and older. GNX is 
a Schedule V controlled substance. 
GNX is being further evaluated for use as an ASM in adolescents and adults with SE and 
pediatric and adult patients with seizures associated with TSC. 
The completed GNX clinical program comprises Phase 1 studies conducted in healthy 
participants, adults with migraine, and adults with renal impairment. Phase 2/3 studies were 
conducted in adults with epilepsy, infants and children with seizure disorders, children with FXS, 
adults with PTSD, women with 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 
In TSC-related epilepsy, Study 1042-TSC-2001  is 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 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 CSR for the study was completed on 08 Mar 2023. 
Additional information detailing ongoing and completed clinical GNX studies may be found in 
the current IB.  


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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 (23.8% 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, IS, 
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 pure TSC 
population. Of the 24 patients screened, 4 discontinued the study due to adverse events (AEs). 
Somnolence, sedation, and fatigue were the most common treatment emergent AEs.  
Additional information describing the safety of GNX may be found in the current IB.  
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.  


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2.3.1 
Risk Assessment 
CNS-related effects (such as somnolence and sedation) 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, sedation, and gait disturbance. Of the AEs present at 
frequency > 1% and 2 times the frequency of placebo in the aggregate AE data, 12/13 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.  
Unblinded safety data will be reviewed on an ongoing basis by an independent Data Monitoring 
Committee (DMC) who will monitor safety and safeguard the interests of study participants.  
The dose titration phase included in this study will minimize risk to participants from 
CNS-related effects as well as other treatment-related AEs.  
The safety assessments to be performed in this study including clinical laboratory tests, vital 
signs, 12-lead electrocardiogram (ECG), physical and neurological examinations, AE 
assessments, Columbia-Suicide Severity Rating Scale (C-SSRS), and Tanner staging. These are 
all standard evaluations to ensure participant safety in this clinical study.  
2.3.2 
Benefit Assessment 
This study will evaluate the efficacy of GNX compared to placebo as adjunctive therapy for 
seizures associated with TSC in children and adults. This population may benefit from the 
development of GNX as participants randomized to GNX will receive treatment that may help 
with control of their epilepsy. These participants as well as participants randomized to placebo 
have the option to continue GNX treatment in the Open-label extension (OLE) study for up to an 
additional 3 years.  
2.3.3 
Overall Benefit: Risk Conclusion 
Taking into account the measures to minimize risk to study participants, the potential risks 
associated with GNX are justified by the anticipated benefits that may be afforded to participants 
with TSC-related epilepsy.  


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3 OBJECTIVES AND ENDPOINTS 
Objectives 
Primary Objective 
• To assess the safety and efficacy of GNX compared to placebo as adjunctive therapy for 
seizures associated with TSC in children and adults as assessed by the change from 
baselinea in the frequency of countable major motor and focal seizures (primary endpoint 
seizuresb) during the double-blind phase. 
Secondary Objectives 
• To determine the percentage of change from baselinea in 28-day primary endpoint 
seizureb frequency during the maintenance period.  
• To assess the change in focal seizure frequency from baselinea during the double-blind 
phase.  
• To assess changes in mood, behavior, and quality of life using the following:  
o ADAMS. 
o Peds-QL-FIM. 
o SF-36. 
o ELDQOL. 
• To assess overall clinical outcome using the 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 
Safety Objectives 
• To assess the safety and tolerability of GNX compared with placebo as adjunctive 
therapy. 
Endpoints 
Primary Endpoint 
• The primary efficacy endpoint is the percentage change from baselinea in 28-day primary 
endpoint seizureb frequency during the double-blind phase.   
Secondary Endpoints 
Key Secondary Efficacy Endpoints:  
• Percentage change from baselinea in 28-day primary endpoint seizureb frequency during 
the maintenance period (FDA). For EMA this is the primary endpoint. 
• Number (%) of participants considered treatment respondersc during the double-blind 
phase (FDA). For the EMA, this endpoint will be evaluated over the maintenance period 
only.  


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• Number (%) of participants considered treatment respondersc during the maintenance 
period. 
• CGI-I at the last scheduled visit in the double-blind phase. 
Secondary Efficacy Endpoints (Behavior/Neuropsychiatric/Quality of life):  
• Change from baseline in ADAMS total score and sub-score. 
• Change from baseline in quality-of-life scales: Peds-QL-FIM, SF-36, and ELDQOL. 
Secondary Efficacy Endpoints (Seizure Control):  
• Change from baselinea in the percentage of seizure-free days during the double-blind 
phase, based on primary endpoint seizureb type (FDA). For the EMA, this endpoint will 
be evaluated over the maintenance period only. 
• Change from baselinea in the CGI-CSID at the end of the double-blind phase (FDA). For 
the EMA, this endpoint will be evaluated over the maintenance period only. 
• Participants with a ≥ 25% and ≥ 75% reduction from baseline in primary endpoint 
seizureb frequency during the double-blind phase (FDA). For the EMA, this endpoint will 
be evaluated over the maintenance period only.  
• Participants with a ≥ 25%, ≥ 50%, and ≥ 75% reduction from baselinea in primary 
endpoint seizureb frequency during the maintenance period.  
• Responder analysis for primary endpoint seizuresb and all seizures during the 
double-blind phase using the following response categories: ≤ 0%, > 0% to < 25%, 
≥ 25% to < 50%, ≥ 50% to < 75%, and ≥ 75% to 100% (FDA). For the EMA, this 
endpoint will be evaluated over the maintenance period only. 
• Percent change in 28-day frequency of all seizures.  
• Change from baselinea in the percentage of seizure-free days, based on all seizure types.  
• Change from baselinea in the longest seizure-free interval, based on primary endpoint 
seizure typeb and all seizure types. 
Exploratory Endpoints 


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Safety Endpoints 
• Incidence and severity of AEs, SAEs, and withdrawals and dose-reductions due to AEs. 
• Other measures of safety including physical/neurological/developmental examinations, 
vital sign measurements (eg, blood pressure, heart rate, respiratory rate, and body 
temperature), 12-lead ECGs, clinical laboratory tests, and suicidal ideation and behavior 
risk monitoring. 
The primary and secondary endpoints (unless otherwise defined) for the United States FDA will be based on the 
double-blind phase (titration and maintenance period). The primary and secondary endpoints (unless otherwise 
defined) for the EMA will be based on the maintenance period only. 
ADAMS = Anxiety, Depression, and Mood Scale; AE = adverse event; CGI-CSID = Clinical Global Impression 
of Change in Seizure Intensity/Duration; CGI-I = Clinical Global Impression of Improvement; 
ELDQOL = Epilepsy and Learning Disabilities Quality of Life; 
EMA = European Medicines Agency; FDA =  Food and Drug Administration; GNX = ganaxolone; 
LAR = legally authorized representative; Peds-QL-FIM = Pediatric Quality of Life - Family Impact Module; 
PK = pharmacokinetic(s); SAE = serious adverse events; SF-36 = Short Form 36 (version 2); SQS = Sleep 
Quality Scale; TSC = Tuberous Sclerosis Complex. 
a 
Baseline is defined as the first 28 days following screening. 
b 
Primary endpoint 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 primary endpoint 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 primary 
endpoint seizure frequency during the double-blind or maintenance phase. 
 
 


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4 STUDY DESIGN 
4.1 
Overall Design 
This is a Phase 3, global, double-blind, randomized, placebo-controlled study of adjunctive GNX 
treatment in children and adults with TSC-related epilepsy. The study consists of a 4-week 
prospective baseline phase, defined as the first 28 days following screening, followed by a 
double-blind phase consisting of a 4-week titration period and a 12-week maintenance period.  
Participants eligible for inclusion in this double-blind study must have inadequately controlled 
seizures after exposure to at least 2 ASMs administered at adequate doses and for adequate 
durations, with approximately 8 seizures per month in the 2 months prior to screening and 
seizure-free periods of not more than 1 week.  
Procedures specific to this protocol and not otherwise considered standard of care, will not be 
performed until written informed consent from the participant or their parent(s)/LAR(s), as 
appropriate, has been appropriately obtained.  
An interactive response technology system will be used to randomize participants, dispense drug, 
track treatment, and maintain the blind throughout the duration of the study.  
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 study. 
A variety of clinician and caregiver administered instruments will be used to assess efficacy, and 
will include:  
• 
Clinical Global Impression — Severity (CGI-S). 
• 
Clinical Global Impression of Improvement (CGI-I) by parent(s)/caregiver(s)/LAR(s) and 
clinician. 
• 
Caregiver Global Impression of Change in Seizure Intensity/Duration (CGI-CSID). 
• 
Anxiety, Depression, and Mood Scale (ADAMS). 
• 
Pediatric Quality of Life – Family Impact Module (Peds-QL-FIM). 
• 
Short Form 36 (SF-36). 
• 
Epilepsy and Learning Disabilities Quality of Life (ELDQOL). 
The titration schedule is as follows: 
• 
Start – Day 1. 
• 
Titration 1 – Day 7. 
• 
Titration 2 – Day 14. 
• 
Titration 3 – Day 21. 
• 
Final titration – Day 28. 
• 
Maintenance begins on Day 29 (Start of Week 5). 


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GNX (or matching volumes of placebo suspension) will be titrated at approximately weekly 
intervals over 4 weeks to a maximum dose based on the participant’s starting weight 
63 mg/kg/day with a maximum daily dose of 1800 mg (for patients > 28 kg). 
The participant may have the dose of Investigational Product (IP) temporarily or permanently 
decreased at any point in the maintenance period to manage tolerability. Additional dosing 
information can be found in Section 6.2.  
Any dose adjustments that are not part of the prespecified titration schedule, including alternative 
dosing paradigms, should be discussed with the sponsor medical monitor prior to making the 
change. If it is not possible to contact the medical monitor prior to the dose adjustment, the 
medical monitor should be notified as soon as possible after making the change.  
The maximum dose for all participants is 1800 mg/day. The total double-blind phase (titration 
and maintenance periods) should not exceed 16 weeks.  
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. Participants who 
discontinue the IP before the scheduled completion of the study will return to the site 2 weeks 
after the end of taper to complete the safety follow-up assessments.  
Following completion of the double-blind phase, participants who are compliant with study 
conduct will have the option to enroll and be treated with GNX in a separate open-label 
extension study (OLE), 1042-TSC-3002. All participants entering the OLE will have their dose 
of study medication adjusted in a double-blind cross-titration over 4 weeks such that all are 
receiving GNX at study completion. Participants who do not continue in the OLE will undergo a 
2- to 4-weeks double-blind down-titration and taper if discontinuing IP (See Figure 1).  
4.1.1 
Study Duration for Participation  
Eligible participants will collect 4 weeks of prospective baseline seizure data prior to starting 
treatment. Participants will be randomized (1:1) to double-blind treatment with GNX or placebo. 
GNX is to be titrated to target dose over 4 weeks. The total double-blind phase (titration and 
maintenance period) should not exceed 16 weeks.  
Following completion of the treatment period, participants who are compliant with study conduct 
will have the option to enroll and be treated with GNX in a separate OLE study, 1042-TSC-3002. 
All participants entering the OLE will have their dose of study medication adjusted in a 
double-blind cross-titration over 4 weeks such that all are receiving GNX at study completion. 
Participants who do not continue in the OLE will undergo a 2- to 4-week double-blind 
down-titration and taper if discontinuing IP. 


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4.1.2 
Number of Participants  
Approximately 200 participants with TSC will be screened with the aim of randomizing 
approximately 128 participants (64 per arm), aged 1 to 65 years (2 – 65 for EU, MENA, and OC) 
(inclusive). Participants will be randomized (1:1) to either GNX or placebo as adjunctive therapy 
with their standard anti-seizure medication (ASMs).  
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 who subsequently are 
not eligible for study entry, 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 80-85 sites (US and ex-US).  
4.2 
Scientific Rationale for Study Design 
This is a Phase 3, double-blind, randomized, placebo-controlled 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 populations being pursued for 
development. The eligibility criteria allow for the selection of participants comparable to the 
patients seen in clinical practice.  
Randomization will be used in this study to avoid bias in the assignment of participants to 
treatment, to prevent introducing bias into the study evaluations and statistical analyses, and to 
ensure participant characteristics are balanced between the GNX and placebo arms. In order to 
facilitate subgroup analysis, randomization will be stratified with respect to whether the 
participant is taking concomitant CBD or not.  
All the efficacy and safety assessments included in this study are standard measures used in 
clinical studies in general and epilepsy trials in particular.  
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; Pieribone et al, 2007; Kerrigan et al, 2000; 
Laxer et al, 2000).  
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.  


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GNX is to be given as an oral suspension (50 mg/mL) with food, eg, shortly after a meal or 
snack.  
This study plans to enroll participants as young as 1 year of age. Based on the known clearance 
pathway of GNX (which is primarily CYP3A4/5) and CYP3A4 maturation by the age of 
1 month, the dosing strategy for pediatric participants 1 to 2 years was guided by a recently 
completed population PK analysis which incorporated allometric principles. The similarity of 
model maximum plasma concentration (Cmax) and the area under the plasma concentration-time 
curve (AUC) with the proposed dosing regimen across a range of doses administered in previous 
clinical trials in participants 2 years of age and older coupled with the known maturation of 
CYP3A4 indicates that a similar exposure will be achieved in participants 1 to 2 years of age 
with the proposed dosing regimen. 
GNX (or matching volumes of placebo suspension) will be titrated at approximately weekly 
intervals over 4 weeks to a maximum dose based on the participant’s starting weight 
63 mg/kg/day with a maximum daily dose of 1800 mg (for patients > 28 kg). 
In the Phase 2 data for GNX in TSC there was the suggestion of a possible interaction with CBD. 
In the trial of 23 treated patients, approximately half were on cannabidiol, and there was an 
association between higher CBD doses and increased somnolence. Given the small sample size, 
more definitive conclusions were not possible. As a result, patients taking concomitant CBD 
(Epidiolex®) must be monitored closely throughout this Phase 3 protocol and discussed with the 
medical monitor if AEs are seen (particularly those that are somnolence-related).  
The maximum dose for all participants is 1800 mg/day. The total double-blind phase (titration 
and maintenance periods) should not exceed 16 weeks.  
Additional dosing information can be found in Section 6.2. 
4.4 
End of Study Definition 
End of Study (Individual Participant): A participant is considered to have completed the study 
if they have completed all study visits up to and including Week 20 (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 (see Section 10.1.3) before any 
procedures specified in the protocol are performed.  


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5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria are met:  
1. Clinical or mutational diagnosis of TSC consistent with (Northrup et al, 2021):  
a. Molecular confirmation of a pathogenic mutation in TSC1 or TSC2. A pathogenic 
mutation is defined as a mutation that clearly prevents protein synthesis and/or inactivates 
the function of the TSC1 or TSC2 proteins (eg, nonsense mutation or frameshift 
mutations, large genomic deletions) or is a missense mutation whose effect on protein 
function has been established by functional assessment. The principal investigator (PI) or 
designee must review the results of the
and confirm that the causal 
relationship to the epilepsy syndrome is likely.  
OR 
b. Clinical diagnosis of definite TSC which includes 2 major features or 1 major feature 
with ≥ 2 minor features. 
Major features 
Minor features 
Hypomelanotic macules (≥ 3, at least 5-mm diameter) 
Angiofibroma (≥ 3) or fibrous cephalic plaque 
Ungual fibromas (≥ 2) 
Shagreen patch 
Multiple retinal hamartomas 
Multiple cortical tubers and/or radial migration lines 
Subependymal nodules (≥ 2) 
Subependymal giant cell astrocytoma 
Cardiac rhabdomyoma 
Lymphangioleiomyomatosis (LAM)* 
Angiomyolipomas (≥ 2)* 
“Confetti” skin lesions 
Dental enamel pits (≥ 3) 
Intraoral fibromas (≥ 2) 
Retinal achromic patch 
Multiple renal cysts 
Nonrenal hamartomas 
Sclerotic bone lesions 
 
* 
A combination of the 2 major clinical features (LAM and angiomyolipomas) without other features does not 
meet criteria for a definite diagnosis. 
The investigator must document which of the features (major or minor) fulfill the clinical 
diagnostic criteria. 
2. Male or female participants aged 1 through 65 years, inclusive. For Europe (EU), Middle 
East and North Africa (MENA), and Oceania (OC) Male or Female participants aged 
2 through 65 years, inclusive. 
3. Participant/parent(s) or 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 nor able to provide written 
informed consent based on age, developmental stage, intellectual capacity, or other factors, 
parent(s)/LAR(s) must provide consent for study participation, if appropriate. 


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4. Failure to control seizures despite appropriate trial of 2 or more ASMs at therapeutic doses 
and for adequate duration of treatment per PI judgment. 
5. Participants should be on a stable regimen of ASMs (including moderate or strong inducer or 
inhibitor anti-seizure medications eg, carbamazepine, phenytoin, etc.) at therapeutic doses for 
≥ 28 days prior to the screening visit, and without a foreseeable change in dosing for the 
duration of the study. (Note: Minor dose adjustment to address tolerability and safety events 
may be allowed on case-by-case basis and it should be discussed with the study medical 
monitor.) 
6. A history of at least 8 countable seizures per month in the 2 months prior to screening with 
no more than 1 seizure free week in each month. This includes seizures of any kind. 
7. Have at least 8 primary endpoint seizures in the first 28 days following the screening visit.  
The primary endpoint seizure types are defined as the following:  
a. Focal motor seizures without impairment of consciousness or awareness. 
b. Focal seizures with impairment of consciousness or awareness with motor features. 
c. Focal seizures evolving to bilateral, tonic-clonic seizures. 
d. Generalized motor seizures including tonic-clonic, bilateral tonic, bilateral clonic, or 
atonic/drop seizures.  
Seizures that do not count towards the primary endpoint include: 
a. Focal or generalized nonmotor seizures (eg, absence seizures or focal nonmotor seizures 
with or without impairment of awareness). 
b. Infantile or epileptic spasms.  
c. Myoclonic seizures.  
8. Participants with surgically implanted vagal nerve stimulator (VNS) will be allowed to enter 
the study provided that all of the following conditions are met:  
a. The VNS has been in place for ≥ 6 months prior to the screening visit. 
b. The settings must have remained constant for 3 months prior to the screening visit and 
are expected to remain constant throughout the study. 
c. The battery is expected to last for the duration of the study. 
9. Parent(s)/caregiver(s)/LAR(s) or the participant, as appropriate, is (are) willing and able to 
maintain an accurate and complete daily seizure eDiary for the duration of the study.  
10. Willing and able to take IP (suspension) as directed with food (tid).  
11. Women of childbearing potential (WOCBP) must be using a medically acceptable method of 
birth control and have a negative quantitative serum β-human chorionic growth hormone 
(β-HCG) test collected at the initial screening and baseline visits. 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 the screening visit), 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 


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measures such as Plan BTM, sold for emergency use after unprotected sex, are not acceptable 
methods for routine use 
12. 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). 
Note: The Epilepsy Study Consortium will review and classify all seizure types reported by the 
investigator, incorporating the medical history,
seizure description, and historical 
records (including electroencephalogram [EEG], when available). This review and classification 
does not need to be completed prior to study entry but should be completed in parallel, and may 
complete after the participant has been enrolled in the study. 
5.2 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:  
1. Previous exposure to GNX. 
2. Pregnant or breastfeeding. 
3. Participants who have been taking felbamate for less than 1 year prior to screening. 
4. Participants taking CBD preparations other than Epidiolex®. 
5. A positive result on drug screen for CBD or THC at Visit 1 (screening), with the exception of 
results that are fully explained by prescribed Epidiolex®, which can be adjusted by the 
investigator in the event of any AEs.  
6. Concurrent use of adrenocorticotropic hormone (ACTH), prednisone or other glucocorticoid 
is not permitted, nor use of the strong inducers of cytochrome P450 3A4 (CYP3A4), rifampin 
and St. John’s Wort.  
Participants on ACTH, prednisone, or other systemically (non-inhaled or topical) 
administered steroids should be off the product > 28 days prior to screening.  
Rifampin and St. John’s Wort must be discontinued at least 28 days before Visit 2, study 
drug initiation.  
Note:  
a. Use of concomitant intranasal or pro re nata (PRN) topical steroids for dermatologic 
reactions and allergic rhinitis are allowed during the study.  
b. This exclusion criterion does not prohibit the use of approved ASMs. 
7. Changes in any chronic medications within the 4 weeks prior to the screening visit. All 
chronic concomitant medications must be relatively stable in dose for at least 4 weeks prior 
to the screening visit unless otherwise noted. Small dose adjustment to manage tolerability 
and safety events is permitted and should be discussed with the study medical monitor. 
8. Participants who have epilepsy surgery planned during the study or who have undergone 
surgery for epilepsy within the 6 months prior to screening. 
9. An active CNS infection, demyelinating disease, degenerative neurological disease, or CNS 
disease deemed progressive as evaluated by brain magnetic resonance imaging (MRI). This 


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includes tumor growth which in the opinion of the investigator could affect primary endpoint 
seizure control.  
10. Any disease or condition (medical or surgical; other than TSC) at the screening visit that 
might 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. 
11. Hepatic impairment sufficient to affect patient safety, or an aspartate aminotransferase 
(AST)/ serum glutamic oxaloacetic transaminase (SGOT) or alanine aminotransferase 
(ALT)/ serum glutamic pyruvic transaminase (SGPT) > 3 × the upper limit of normal (ULN) 
at screening or baseline visits and confirmed by a repeat test.  
12. Biliary impairment sufficient to affect patient safety, or total bilirubin levels > 1.5 × ULN at 
screening or baseline visit and confirmed by a repeat test. In cases of Gilbert’s Syndrome, 
resulting in stable levels of total bilirubin greater than ULN, the medical monitor can 
determine if a protocol exception can be made.  
13. Renal impairment sufficient to affect patient safety, or estimated glomerular filtration rate 
(eGFR) < 30 mL/min (calculated using the Cockcroft-Gault formula or Pediatric glomerular 
filtration rate [GFR] calculator or Bedside Schwartz), will be excluded from study entry or 
will be discontinued if the criterion is met post baseline (Levey et al, 2006). Cases of 
temporary renal insufficiency should be discussed with the medical monitor to determine the 
participant’s study continuation. 
14. Exposed to any other investigational drug or investigational device within 30 days or fewer 
than 5 half-lives prior to the screening visit. For therapies in which half-life cannot be readily 
established, the Sponsor’s medical monitor should be consulted. 
15. Unwillingness to avoid excessive alcohol use throughout the study.  
16. Have active suicidal plan/intent, active suicidal thoughts or a suicide attempt in the past 
6 months. 
17. Known sensitivity or allergy to any component in the IP(s), progesterone, or other related 
steroid compounds. 
18. Participants deprived of their liberty by a judicial or administrative decision, or for 
psychiatric treatment, or participants admitted to a health or social services facility for 
purposes other than research. 
19. Participants receiving traditional Chinese medicine therapies within the prior 28 days of the 
screening. 
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. 


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In addition, participants should refrain from grapefruit or grapefruit juice, Seville oranges, 
starfruits¸ or excessive consumption of alcohol during the study. 
During each visit when PK samples are collected, participants will 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. 
5.3.2 
Contraception Use and Donation of Sperm and Ova  
WOCBP must be using a medically acceptable form of birth control and have a negative 
quantitative serum β-HCG test collected at the initial screening and baseline visits.  
Pregnancy testing will be performed at all in-person visits for all WOCBP to monitor participant 
safety throughout the duration of participation in the trial.  
WOCBP and male participants must be advised to use a medically acceptable, highly effective 
method of birth control throughout the study period and for 30 days after the last dose of IP.  
Participants should not donate sperm or ova during the study and for 30 days after the last dose.  
See Appendix 10.5 for further details on what constitutes a medically acceptable, highly 
effective method of birth control. 
5.4 
Screen Failures 
A screen failure occurs when a participant for whom informed consent/assent has been obtained 
is not randomized into the study and does not receive IP, regardless of reason. 
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the Consolidated Standards of Reporting Trials publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes date of informed consent/assent, screen failure date and details, demography, eligibility 
criteria, and any SAE. 
Participant rescreening is allowed as agreed by the sponsor and the investigator unless there is a 
general concern for participant safety or an inability for the participant to become eligible (eg, 
GNX allergy, sensitivity, or exposure, non-TSC and/or other ineligible epilepsy, chronic 
prohibited medical condition, or treatment). Rescreened participants should be assigned a new 
participant number for every screening/rescreening event. The medical monitor should be 
contacted for subsequent rescreening.  


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6 STUDY INTERVENTION 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 and the control drug is placebo (see Table 2).  
Table 2. 
Study Intervention(s) Administered 
Intervention Label 
 
 
Intervention Name 
GNX 
Placebo 
Intervention 
Description 
GNX oral suspension, tid 
Identical to GNX suspension, tid 
Dose Formulation 
Suspension in 4 fl oz bottles 
Matched suspension in 4 fl oz bottles 
Unit Dose Strength(s) 
50 mg/mL suspension containing 
110 mL GNX 
Not applicable 
Dosage Level(s) 
GNX (or matching volumes of placebo suspension) will be administered tid 
with food, eg, shortly after a meal or snack, and titrated at approximately 
weekly intervals over 4 weeks based on the participant’s starting weight. The 
titration will start on Day 1 and end on Day 28 (see table below), with 
maintenance beginning on Day 29 at the start of Week 5. 
28 kg (62 pounds) or less 
Day 
Per dose 
(mg/kg) 
Per day 
(mg/kg) 
% target 
(63 mg/kg/day) 
1 
2 
6 
10 
7 
4 
12 
19 
14 
8 
24 
38 
21 
14 
42 
67 
28 
21 
63 
100 
Greater than 28 kg (62 pounds) 
Day 
Per dose (mg) 
Per day (mg) 
% target (1800 mg/day) 
1 
50 
150 
8 
7 
100 
300 
17 
14 
200 
600 
33 
21 
400 
1200 
67 
28 
600 
1800 
100 
See Section 6.2 for details of permitted dose modifications. 
Route of 
Administration 
Oral 
 


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Use 
ASM in TSC-related epilepsy 
 
IMP and 
NIMP/AxMP 
GNX 
Matched placebo 
Sourcing 
Provided centrally by the sponsor 
Packaging and 
Labeling 
GNX is a Schedule V Controlled Substance in the US. The GNX 
(50 mg/mL) and placebo 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. A placebo suspension, 
identical in taste and appearance with GNX suspension, will be supplied at 
an equal volume. 
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; HPDE = high density polyethylene; IP = investigational 
product; tid = 3 times a day; US = United States. 
6.2 
Dose Modification 
The protocol allows some alterations from the currently outlined dosing schedule. 
GNX (or matching volumes of placebo suspension) will be titrated at approximately weekly 
intervals over 4 weeks to a maximum dose based on the participant’s starting weight 
63 mg/kg/day up to a maximum daily dose of 1800 mg (for participants > 28 kg). Any 
participant may have the dose of IP temporarily or permanently decreased at any point in the 
maintenance period to manage tolerability.  


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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 re-challenge 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 1800 mg/day. The total double-blind phase (titration 
and maintenance periods) should not exceed 16 weeks. In Part B, for participants who continue 
to the OLE, the total daily dose that the participant was taking at the completion of Part A will be 
maintained. The titration schedule in Table 2 will be followed until the target total daily dose for 
the participant is reached. 
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 and Drug Enforcement Administration 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 storage area of the IP 
that could affect the integrity of the product(s), such as fumigation of a storage room. 
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 
protocol and who works under the direct supervision of the investigator. This delegation must be 
documented in the applicable study delegation of authority form. 


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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. Investigational product 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 IPs 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 
6.4.1 
Randomization  
Randomization procedures to minimize bias in this randomized, double-blind study are shown 
below. 
6.4.1.1 
Study using IWRS  
All participants will be centrally assigned to randomized study intervention using an Interactive 
Web Response System (IWRS). Before the study is initiated, the log-in information and 
directions for the IWRS will be provided to each site. An IWRS will be utilized for the following 
IP tasks:  
• Randomization, stratified for current CBD use. 
• Supply management. 
• Inventory management and supply ordering. 
• Expiration date tracking. 
• Emergency unblinding. 
An IWRS will centrally randomize participants. The randomization schedule (comprised of a kit 
list and randomization list) will be generated using standard, validated methods, and maintained 
by the respective supplier and IWRS vendor. The investigator will be instructed by the IWRS, 
which numbered bottle to use to dose a participant. The investigator and research staff will be 
aware of the ascending dose design of the clinical investigation; however, the investigator, the 
research staff, and the participants will be blinded with respect to who is receiving active drug 
versus placebo. The maximum placebo period is 18 weeks.  
The contents of each bottle will be blinded using labels. The randomization schedule will match 
a participant number to a bottle number. Upon completion of baseline evaluations for each 
participant, the investigator or appropriate designee will log into the IWRS to receive a bottle 
number allocated according to the randomization schedule. Complete instructions for obtaining a 
bottle number will be provided to the clinical sites prior to initiating the study. The designated 
personnel at the clinical site will match the assigned bottle number with the correct bottle of IP 
and distribute the bottle to the investigator or designee. 
Study medication will be dispensed at the study visits as summarized in the SOA (Section 1.3).  
Returned study medication should not be redispensed to the participants. 
6.4.1.2 
Participant Numbering 
During the screening visit, each participant will be assigned a unique 6-digit participant number. 
The participant number will consist of a 3-digit clinical investigational site number assigned by 
the sponsor, followed by a 3-digit participant number (eg, 001) assigned by the electronic data 


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capture system. This participant number will also serve as the screening number. The unique 
6-digit participant number will serve as the participant ID and be used to track the participant 
throughout the study. 
The clinical site is responsible for maintaining a current log of participant number assignments 
and bottle numbers of the IP administered to each participant. The unique participant number is 
required to be entered on all clinical investigation documentation (eCRFs, labeling of clinical 
materials and samples containers, drug accountability logs, etc.). 
6.4.2 
Blinding 
6.4.2.1 
Blinded Investigational Product 
This is a double-blind study in which study staff as well as study participant and caregiver(s) are 
blinded to study intervention. The contents of each bottle will be blinded using labels with 
unique bottle numbers. 
Only the IP supplier and the sponsor’s IP manager will be unblinded as to the contents of each 
bottle of IP. 
6.4.2.2 
Blind Break (IWRS) 
The IWRS will be programmed with blind-breaking functionality. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participants’ 
intervention assignment is warranted. Participant safety must always be the first consideration in 
making such a determination. 
If a participant’s intervention assignment is unblinded, the sponsor must be notified 
within 24 hours of this occurrence. The date and reason for the unblinding must be recorded. 
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. 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 


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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 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. 
Participants must abstain from taking prescription or nonprescription drugs (including vitamins 
and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 half-lives of the respective drug, if known (whichever is longer), before the start of 
study intervention until completion of the follow-up visit, unless, in the opinion of the 
investigator and sponsor, the medication will not interfere with the study.  
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. 
Concomitant topical and intranasal steroids for dermatologic reactions and allergic rhinitis are 
allowed as needed and do not warrant exclusion from study. If the participant is currently taking 
an excluded medication at the time of the screening visit, then the participant must undergo a 
washout period equivalent to 5 half-lives of the drug before they may enter the prospective 
4-week baseline phase. 
Use of dietary supplements or herbal preparations are permitted if participant has been using 
them consistently for more than 6 months prior to screening and does not plan on changing the 
dose for the duration of the maintenance period. Use of St. John’s Wort is not permitted (see 
Section 5.2). 
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 that 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.  


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6.6.1 
Rescue Medicine 
The use of rescue medication is allowable 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 
• Midazolam. 
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. The medication name, dose, start and stop dates, and frequency of 
dosing will also be recorded in the clinical database.  
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.  
Concurrent use of ACTH, prednisone or other glucocorticoid is not permitted, nor use of the 
strong inducers of CYP3A4 (except approved ASMs: carbamazepine, phenytoin derivatives, 
phenobarbital, or primidone), rifampin and St. John’s Wort. Participants on ACTH, prednisone, 
or other systemically (non-inhaled or topical) administered steroids should be off the 
product > 28 days prior to screening. Rifampin and St John’s Wort must be discontinued at 
least 28 days before Visit 2, study drug initiation. Chinese medicine therapies must be 
discontinued at least > 28 days prior to screening. 
Note: Concomitant intranasal or PRN topical steroids for dermatologic reactions and allergic 
rhinitis are allowed. 
Products containing THC or non-approved CBD are excluded during treatment. 
Tetrahydrocannabinol or non-approved CBD should be washed out for at least 4 weeks prior to 
screening. Participants with a positive result on THC or CBD laboratory tests, and who do not 


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have an explanatory Epidiolex®/Epidyolex® prescription, will be excluded or withdrawn from 
the study. 
6.7 
Intervention After the End of the Study 
Participants may be eligible for continued treatment with GNX in an OLE. In the OLE, treatment 
can continue until the sponsor terminates the development of the IP in TSC or GNX has been 
approved and marketed in the participants’ respective country. 
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. If the participant discontinues during the 
maintenance period, evaluations listed for the Early Termination Visit (Visit 12; 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 the IP, and total amount of the IP taken must be recorded in the eCRF and source 
documents. Discontinuation of the 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.  
See the SOA (Section 1.3) for data to be collected at the time of discontinuation of study 
intervention and follow-up and for any further evaluations that need to be completed. 
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.  
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. 


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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 AST/SGOT or ALT/SGPT > 3 × ULN. 
o Total bilirubin levels > 1.5 × ULN. 
o 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. Participants who discontinue the IP during the maintenance 
period will continue to record daily seizure frequency at minimum until the completion of the 
maintenance period.  
At the time of discontinuing from the study, if possible, an Early Termination Visit (Visit 12) 
should be conducted as shown in the SOA (Section 1.3). At this visit, participants will start a 
2-week taper and then return to the site 2 weeks later for safety follow-up assessments.  
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. 


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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 10.1.10. 
8 STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SOA (see Section 1.3). Study dates will 
be based on the date of the first dose of IP and not the date of screening or 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 with the use of 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.  
Adherence to the study design requirements, including those specified in the SOA, is essential 
and required for study conduct.  
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable.  
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of the informed consent form (ICF) may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the timeframe defined in the SOA. 


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Safety, laboratory, and analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded. Exceptions to 
this are if there is an urgent medical need (Section 6.4.2).  
8.1 
General Study Periods 
8.1.1 
Screening, Enrollment, Randomization, and Baseline 
Potential participants will be pre-identified by the site because of a previous TSC diagnosis 
based on clinical features and/or
results and those still experience refractory 
seizures. 
The process of identification of participants is performed by the investigator. If an investigator is 
seeing a patient with TSC in their clinic who is having 8 or more seizures per month, they will 
make a judgment regarding whether the benefits of clinical trial participation may outweigh the 
risks of clinical trial participation (with any alternative treatments taken into consideration). If 
the clinician feels that they do, then they will explain the study to the participant (or LAR). If the 
participant/LAR is fully informed and provides consent, then this will be documented, and the 
screening activities can begin. 
Note for Investigational Sites in the United Kingdom (UK): National Health Services (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 screening procedures or assessments 
(see Section 10.1.3 for the informed consent procedure). This includes the collection of historical 
seizure frequency data, or if this information is not available from medical records, the 
participants will be asked to provide this information for the 8 weeks prior to the Screening Visit 
based on their own recall/records. This Screening Visit will occur 4 weeks before baseline 
(Week 0).  
At screening, informed consent will be confirmed and the participants eligibility checked. 
Demographics and Medical history including prior treatment information (Section 8.1.1.1), 
historical seizure calendar review (Section 8.1.1.2), and a seizure identification and diagnostic 
review (Section 8.1.1.3) will be performed as well as other study specific procedures as outlined 
in the SOA (Table 1). 
Randomization will occur approximately 4 weeks after screening at baseline and all participants 
will be centrally assigned to randomized study intervention (stratified for current CBD use) using 
an IWRS. Details are provided in Section 6.4.1.  


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8.1.1.1 
Demographics and Medical History 
Demographics including age, gender, ethnicity, and race will be collected, as allowed according 
to local regulations. 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. The participant’s developmental history will 
also be assessed. This will include the grade level of school work 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. Prior medications include all treatment, 
including but not limited to herbal treatments, vitamins, surgical implants (such as VNS), and 
prescribed medications received within 30 days (or PK equivalent of 5 half-lives, whichever is 
longer) of the date prior to screening.  
Demographics and Medical History will be reviewed and collected at the Visit 1 (screening). A 
review of the participant’s Medical History will be performed again at Visit 2 (baseline). All 
findings on the medical history will be recorded on the eCRF. Prior treatment information 
(therapy name, start and stop date), if available, must be recorded on the appropriate eCRF page. 
8.1.1.2 
Historical Seizure Calendar Review 
A 2-month (8-week) daily historical seizure calendar will be reviewed at the screening visit to 
determine eligibility per inclusion/exclusion criteria. Acceptable daily historical seizure 
calendars will need to denote seizure types (or sufficient description), frequency, and days that 
no seizures occurred.  
Procedures specific to this protocol and not otherwise considered standard of care, will not be 
performed until written informed consent/assent from the 
participant/parent(s)/caregiver(s)/LAR(s) has been appropriately obtained. 
8.1.1.3 
Seizure Identification and Diagnostic Review 
Per the inclusion criteria, enrollment into the study will be based on the presence and frequency 
of the primary endpoint seizure types.  
Primary endpoint 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 primary endpoint 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.  


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To standardize seizure identification and classification in the study, a SIF/DRF will be submitted 
and reviewed by the Epilepsy Study Consortium. The Epilepsy Study Consortium will review 
participant seizure data and assign the seizure type for each participant. This categorization of 
seizure type by the Epilepsy Study Consortium should not delay the participant’s entry into the 
study as this will be determined by the investigator’s assessment of eligibility.  
Final confirmation and approval of a participant’s seizure type is required prior to dispensing the 
IP.  
Instructions for completion of the Seizure Identification and Diagnostic Review Form (SIF/DRF) 
can be found in the Investigator Site File. 
8.1.2 
Double-blind Phase 
Double-blind treatment with the IP will begin after baseline assessment at Visit 2. All dates 
during the double-blind phase will be based off the date of randomization and the first dose of 
the IP. The double-blind phase will include a 4-week titration period (Day 1 to Day 28 
inclusive), and a 12-week maintenance period starting on Day 29 to Visit 12 (Week 16).   
Participants who discontinue the study prematurely before Visit 12 (Week 16) 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 
Part A for Visit 13A (Table 1), should then be performed. 
Participants who are not continuing in the OLE will then begin a double-blind taper period where 
the IP will be withdrawn from Visit 12 (Week 16) as shown in the SOA for Part A as shown in 
Table 1. This taper period will last for 2 weeks but may be shortened at the discretion of the 
investigator. 
All participants entering the OLE will have their dose of study medication adjusted in a double-
blind cross-titration over 4 weeks after Visit 12 (Week 16) as shown in Table 2. This will be 
performed under blinded conditions and participants previously treated with GNX will complete 
a dummy titration period. 
8.1.3 
Safety Follow-up 
A safety follow-up visit will be conducted at Visit 13A (Week 20) after a 2- to 4-week down 
titration for participants who are not continuing in the OLE as shown in the SOA for Part A 
(Table 1). This will be the end of study visit for these participants. 
For participants who plan to continue in the OLE, additional visits will be conducted as shown in 
in the SOA for Part B (Table 1).  


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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 eDiary. Days in which no seizures occur will also be 
noted. CGI-CSID and 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 (see Section 1.3). 
8.2.1 
Seizure Type and Frequency 
The Epilepsy Study Consortium will review participant seizure data and assign the seizure type 
for each participant. This categorization of seizure type by the Epilepsy Study Consortium 
should not delay the participant’s entry into the study as this will be determined by the 
investigator’s assessment of eligibility.  
Parent(s)/caregiver(s)/LAR(s) will record daily seizures denoting vernacular name for the seizure 
type, duration, and frequency in an eDiary.  
Primary endpoint seizure types will be counted towards the primary endpoint. These 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 primary endpoint 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 


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awareness “absence”) it will be permitted as long as they use the term consistently for a single 
seizure type. 
Participants or parent(s)/caregiver(s)/LAR(s) are to record administration of the IP and 
background ASMs in the eDiary. 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 – Severity 
The CGI-S is a 7-point Likert scale that will be completed by the clinician to rate the severity of 
illness in the participant at baseline, relative to other individuals with TSC. This should take into 
account overall seizure control, behavior, safety, tolerability of medications, and any 
involvement of non-neurological organ systems. The participant will be rated as follows: 
1 – Normal, not at all a problem, 2 – Borderline problem, 3 – Mild problem, 4 – Moderate 
problem, 5 – Marked problem, 6 – Severe problem, 7 – Very severe problem (see Section 10.9).  
CGI-S will be assessed at the baseline (Visit 2). 
8.2.3 
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 the 
IP relative to baseline (prior to treatment with the 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 (See Section 10.10). 
CGI-I (parent[s]/caregiver[s]/LAR[s] and clinician) will be assessed at Visit 4 (Week 1), 
Visit 8 (Week 5), Visit 9 (Week 9), and Visit 12 (Week 16). 
Participants who continue in the OLE will also have the CGI-I conducted at Visit 15 (Week 18) 
and Visit 17 (Week 20). 
8.2.4 
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 IP relative to baseline (prior to 
treatment with IP). 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 (See Section 10.11). 
CGI-CSID will be assessed at Visit 4 (Week 1), Visit 8 (Week 5), Visit 9 (Week 9), and 
Visit 12 (Week 16). 
Participants who continue in the OLE will also have the CGI-CSID conducted at 
Visit 15 (Week 18) and Visit 17 (Week 20). 


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8.2.6 
Anxiety, Depression, and Mood Scale 
The ADAMS is a rating scale designed to screen for anxiety and depression in individuals with 
intellectual disability (Esbensen et al, 2003). The 28-question scale is filled out by the 
parent(s)/caregiver(s)/LAR(s) and is based on the participant’s behavior. Each question will be 
rated on 4-point Likert scale as follows: 0- behavior has not occurred or is not a problem; 
1- behavior occurs occasionally or is a mild problem; 2- behavior occurs quite often or is a 
moderate problem; and 3- behavior occurs a lot or is a severe problem (see Section 10.13). 
The ADAMS will be conducted at Visit 2 (baseline), Visit 4 (Week 1), Visit 8 (Week 5), 
Visit 9 (Week 9), and Visit 12 (Week 16).  
Participants who continue in the OLE will also have the ADAMS conducted at 
Visit 15 (Week 18) and Visit 17 (Week 20). 
8.2.7 
Pediatric Quality of Life Inventory - Family Impact Module 
Peds-QL-FIM is designed to measure the impact of pediatric chronic health conditions on 
parents and the family. The Peds-QL-FIM measures parent self-reported physical, emotional, 
social, and cognitive functioning, communication, and worry. The module also measures 
parent-reported family daily activities and family relationships (see Section 10.14). 
The Peds-QL-FIM will be conducted at Visit 2 (baseline), Visit 8 (Week 5), Visit 9 (Week 9), 
and Visit 12 (Week 16). Peds-QL-FIM for past 1 month will be conducted at baseline visit and 
Peds-QL-FIM for past 7 days will be conducted at on-study visits (see Section 10.14). 
Participants who continue in the OLE will also have the Peds-QL-FIM conducted at 
Visit 15 (Week 18) and Visit 17 (Week 20). 


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8.2.8 
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 (see Section 10.15).  
The SF-36 will be conducted at Visit 2 (baseline), Visit 4 (Week 1), Visit 8 (Week 5), 
Visit 9 (Week 9), and Visit 12 (Week 16).  
Participants who continue in the OLE will also have the SF-36 conducted at Visit 15 (Week 18) 
and Visit 17 (Week 20). 
8.2.9 
Epilepsy and Learning Disabilities Quality of Life Scale 
The ELDQOL is a 70-item parent/caregiver/LAR-reported measure that examines seizure 
severity, seizure related injury, ASM side effects, behavior, mood, physical status, cognitive and 
social functioning, communication, overall health and quality of life, and family concerns. The 
higher the score, the poorer the participant’s quality of life, see Section 10.16. 
The ELDQOL will be conducted at Visit 2 (baseline), Visit 4 (Week 1), Visit 8 (Week 5), 
Visit 9 (Week 9), and Visit 12 (Week 16).  
Participants who continue in the OLE will also have the ELDQOL conducted at 
Visit 15 (Week 18) and Visit 17 (Week 20). 
8.3 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SOA (Table 1). 
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. 


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• 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 question in an identifiable sound, single word, multiple word, sentence. 
o Other abilities. 
• Motor 
o Sits with support. 
o Sits independently. 
o Crawls. 
o Stands with support. 
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 during 
Visit 1 (screening).  
The physical/neurological/developmental follow-up examinations will be conducted during 
Visit 2 (baseline), Visit 4 (Week 1), Visit 8 (Week 5), Visit 9 (Week 9), and Visit 12 (Week 16).  


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Participants who continue in the OLE will also have the physical/neurological/developmental 
follow-up examinations conducted at Visit 17 (Week 20). 
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 blood pressure, pulse, and RR. Three readings of blood 
pressure 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 assessed during Visit 1 (screening), 
Visit 2 (baseline), Visit 4 (Week 1), Visit 8 (Week 5), Visit 9 (Week 9), and Visit 12 (Week 16).  
Participants who do not continue in the OLE will have vital signs, body temperature, height and 
weight assessed at their end of study visit, Visit 13A, on Week 20. 
Participants who continue in the OLE will also have vital signs, body temperature, height and 
weight assessed at Visit 15 (Week 18) and Visit 17 (Week 20). 
Note: Length will be measured if height cannot be obtained. 
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 HR and measures PR, QRS, QT, and QTc intervals.  
12-lead ECGs will be performed at Visit 1 (screening), Visit 2 (baseline), Visit 4 (Week 1), and 
Visit 8 (Week 5), and Visit 12 (Week 16). 
Participants who continue in the OLE will also have 12-lead ECGs conducted at Visit 15 
(Week 18) and Visit 17 (Week 20). 


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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 10.2 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 serum pregnancy test for all WOCBP (at Visits 1 and 2 in the 
double-blind phase and Visit 17 for participants continuing in OLE). 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 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. 
Samples will be collected for clinical laboratory tests at Visit 1 (screening), Visit 2 (baseline), 
Visit 4 (Week 1), Visit 8 (Week 5), Visit 9 (Week 9), and Visit 12 (Week 16).  
In addition, urinalysis will be conducted at Visit 1 (screening) or Visit 2 (baseline), Visit 
4 (Week 1), and Visit 12 (Week 16) for all participants.  
Participants who continue in the OLE will also have clinical laboratory tests and urinalysis 
conducted at Visit 17 (Week 20). 
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 60 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. 


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Note: For participants < 15 kg, the maximum blood volume taken during a single day or during a 
4-week period may exceed recommendations; therefore, for all participants < 15 kg, the medical 
monitor should be consulted regarding which labs can be omitted. For all participants, regardless 
of weight, if additional labs are required, the medical monitor should be consulted to ensure that 
recommended blood volume limits are not unnecessarily exceeded. 
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/LARs 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 SIB and to report 
such symptoms immediately to the study investigator. 
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) (See Section 10.17). 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 (baseline form) will be completed at Visit 2 (baseline), while the C-SSRS (since 
previous visit) will be completed at Visit 4 (Week 1), Visit 8 (Week 5), Visit 9 (Week 9), and 
Visit 12 (Week 16). Participants who do not continue in the OLE will have their final C-SSRS 
assessment at their end of study visit, Visit 13A, on Week 20.  
Participants who continue in the OLE will also have the C-SSRS conducted at 
Visit 15 (Week 18) and Visit 17 (Week 20). 


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8.3.6 
Concomitant Anti-epileptic Drug Levels 
Concomitant ASM levels at Visit 1 (Screening), Visit 8 (end of titration), and Visit 12 (study 
completion) will be obtained centrally for the following if the participant is prescribed these 
medications: 
• CBD. 
• Clobazam (in which case clobazam and desmethylclobazam levels should be obtained). 
• mTOR inhibitors (including everolimus, sirolimus, etc.). 
• Valproate. 
Participants who continue in the OLE will also have the above concomitant ASM levels 
collected at Visit 17 (Week 20). 
If the ASM levels cannot be performed centrally local testing is permitted. 
If the levels of any ASM co-administered with the IP are measured routinely per standard of 
care, this information will be recorded in the eCRF during the study.  
Further details are provided in the SOA (Section 1.3). 
8.3.7 
Drug Screen 
A plasma drug screen will be performed to test for THC and non-approved CBD at 
Visit 1 (screening). If the screening drug test is positive, a confirmatory retest, via plasma, will 
be performed after 2 weeks. A positive test for CBD or THC will exclude the participant from 
the study, unless the result is fully explained by an Epidiolex® prescription, which is provided 
and managed by the investigator. 
The plasma drug screen can be performed at any time during the study per the investigator’s 
discretion. Concomitant use of THC and non-approved CBD is not permitted on study and will 
result in participant withdrawal from the study. 
8.3.8 
Pregnancy Testing 
Pregnancy testing will be performed at all in-person visits for all WOCBP to monitor participant 
safety throughout the duration of participation in the trial.  
Pregnancy tests are listed in Section 10.3 and will be collected per the schedule listed in SOA 
(see Section 10.3). Test results must be filed with the source documents.  
A serum pregnancy test will occur at Visits 1 and 2. Participants who continue in the OLE will 
also have a serum pregnancy test at Visit 17. At Visits 4, 8, 9, 12, and 13A, the investigator may 
choose to do either a serum or urine pregnancy test.  


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8.3.9 
Tanner Staging 
The Tanner Staging (also known as the Tanner Scales) is a scale of physical development in 
children, adolescents, and adults. The scale defines physical measurements of development based 
on external primary and secondary sex characteristics. Participants will be evaluated and rated as 
Tanner I, Tanner II, Tanner III, Tanner IV, and Tanner V.  
Tanner staging will occur at Visit 1 (screening) for all participants. Participants who do not 
continue in the OLE will have Tanner staging at their end of study visit, Visit 13A, on Week 20.   
Participants who continue in the OLE will also have Tanner staging conducted at 
Visit 17 (Week 20).  
8.3.10 
Investigational Product Pharmacokinetics 
Please refer to Section 8.5 for additional details regarding PK assessments. 
The results, date, and time of last ASM dose will be recorded in the eCRF. 
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[s]/caregiver[s]/LAR[s]).  
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 (see 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.  


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8.4.1 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
All AEs are collected from the time the informed consent/assent is signed until the defined 
follow-up period at the timepoints specified in the SOA (Section 10.3). This includes events 
occurring during the screening period of the study, regardless of whether or not the IP has been 
administered. All AEs reported after the initiation of the IP will be considered TEAEs. Where 
possible, a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not 
been made, then each symptom should be listed individually. All AEs should be captured on the 
appropriate AE pages in the eCRF and in source documents. In addition to untoward AEs, 
unexpected benefits outside the IP indication should also be captured on the AE eCRF page. 
All AEs must be followed to closure (the 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)/caregiver(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 the 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. 


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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. 
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 
(SUSAR) 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”. 


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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 the 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. 
8.4.5 
Clinical Laboratory and Other Safety Evaluations 
A change in the value of a clinical laboratory, vital sign, 12-lead ECG assessment can represent 
an AE if the change is clinically significant or if, during treatment with the IP, a shift of a 
parameter is observed from a normal value to an abnormal value, or there is a further worsening 
of an already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range (either while continuing 
treatment or after the end of treatment with the IP), and the range of variation of the respective 
parameter within its reference range must be taken into consideration. 
If, at the end of the double-blind treatment phase, there are abnormal clinical laboratory, vital 
sign, or 12-lead ECG values that were not present in the pretreatment findings observed closest 
to the start of study treatment, further investigations should be performed until the values return 
to within the reference range or until a plausible explanation (eg, concomitant disease) is found 
for the abnormal values. 
The investigator should decide, based on the above criteria and the clinical condition of a 
participant, whether a change in a clinical laboratory, vital sign, or the 12-lead ECG parameter 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 


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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. 
• 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 by the DMC on a 
routine basis. See Section 10.1.6. 
Note: However, if either of the following conditions 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 events of special interest (AESI) includes any non-serious condition 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 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.  


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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 
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 or delegate 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 β-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. 


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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 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.  
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 


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8.6.2 
Pharmacodynamics 
PD parameters are not evaluated in this study. 
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. 


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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 
Statistical Hypotheses 
Hypothesis testing will be performed for the primary endpoint: the percentage change in 28-day 
primary endpoint seizure frequency during the double-blind phase relative to the baseline, based 
on the primary endpoint seizure types. Summary statistics including confidence intervals for the 
treatment differences will be used to summarize the results. The hypothesis testing is: 
Ho: θ PBO = θ GNX 
 
Ha: θ PBO ≠ θ GNX 
where θGNX is the percentage change of seizure frequency relative to the baseline for participants 
who treated with GNX and θPBO is similarly defined for participants receiving placebo.  
9.1.1 
Multiplicity Adjustment 
All endpoints will be assessed descriptively, by the treatment to which the participants are 
randomized, with point estimates and 95% confidence intervals. The primary and secondary 
endpoints will be assessed in an inferential manner. Multiplicity control will be used for the 
primary and secondary endpoints. A gate keeping approach will be used to control the study 
wide Type-I error rate. There is a single primary efficacy endpoint, and formal hypothesis testing 
will be performed for this endpoint first. If the null hypothesis is rejected for the primary efficacy 
endpoint at the 2-sided α-level allocated to the final analysis of the primary endpoint, then 
statistical hypothesis testing will be performed on the 4 key secondary endpoints. The testing 
will stop if the result is non-statistically significant. All other non-key secondary and 


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9.2 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined:  
Participant Analysis Set 
Description 
Intent-to-treat (ITT) set 
All randomized participants. Participants will be summarized 
within the treatment group to which they were randomized. This 
population will be used for efficacy analyses. 
Modified Intent-to-treat (mITT) set 
All randomized participants who receive at least 1 dose of the 
IP. Participants will be summarized within the treatment group 
to which they were randomized. This population will be used 
for sensitivity analysis for efficacy. 
Per-protocol (PP) set 
All participants in the ITT analysis set participants who received 
IP for at least 6 weeks, provided at least 5 weeks of post-
baseline seizure data, and without major protocol deviations that 
affect the efficacy endpoints (defined prior to database lock). 
Safety analysis set 
All randomized participants who receive at least 1 dose of the 
IP. Participants will be summarized within the treatment group 
for which they actually received treatment. This population will 
be used for the safety analyses. 
IP = investigational product. 
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 primary analysis will be performed within the ITT population; a supportive analysis 
in the per-protocol (PP) and modified intent-to-treat (mITT) population will also be conducted. 
9.3 
Statistical Analyses 
9.3.1 
General Considerations 
The results of the primary, secondary, and exploratory endpoints will be summarized separately. 
The results will be summarized by the treatment to which the participants were randomized. 
Participant demographics, characteristics, and medical history at randomization will be 
summarized using descriptive statistics. 
The primary and secondary endpoints (unless otherwise defined) for the Food and Drug 
Administration (FDA) will be based on the double-blind phase (titration and maintenance 
period).  
The primary and secondary endpoints (unless otherwise defined) for the European Medicines 
Agency (EMA) will be based on the maintenance period only. 


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9.3.2 
Primary Endpoint(s) 
The primary efficacy endpoint is the percentage change from baseline in 28-day primary 
endpoint seizure frequency during the double-blind phase (FDA). For the EMA, this endpoint 
will be evaluated over the maintenance period only. 
Primary endpoint 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 
• Generalized motor seizures including tonic-clonic, bilateral tonic, bilateral clonic, or 
atonic/drop seizures.   
Seizures that do not count towards the primary endpoint 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. 
Post-baseline 28-day seizure frequency will be calculated as the total number of seizures in the 
double-blind phase divided by the number of days with seizure data in the period, multiplied by 
28. Baseline 28-day seizure frequency will be calculated as the total number of seizures in the 
baseline phase divided by the number of days with seizure data in the period, multiplied by 28. 
The calculation for percent change from baseline in 28-day seizure frequency will be done as 
follows for each participant:  
 
The baseline, post-baseline, and arithmetic and percent changes from baseline in 28-day seizure 
frequency will be summarized using descriptive statistics.  
The difference between the treatment groups in the percent changes will be tested for statistical 
significance. Since the percent differences are anticipated to display skewness and/or outliers, the 
test will be performed using the Wilcoxon Rank-Sum statistic using a 2-sided significance level 
of 0.05.  


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9.3.2.1 
Sensitivity Analysis 
There are 5 sensitivity analyses of the primary efficacy endpoint planned and these will be 
performed as outlined in the SAP:  
• For the first sensitivity analysis, intermittent (random/sporadic) missing data during the 
double-blind phase and any missing data during the baseline phase will be assumed missing 
completely at random and the collected data will be used to calculate the 28-day seizure 
frequencies. 
• The second sensitivity analysis is to explore the possibility that participants who stop 
recording their seizure counts tend to have higher counts than the other participants. 
• The third sensitivity analysis will be performed on participants who achieved their 
maintenance dose at the start of the maintenance period. This analysis will exclude those 
participants who are still titrated continuously during maintenance period. 
• The fourth sensitivity analysis will be performed for the primary outcome measure by using 
the mITT population. 
• The fifth sensitivity analysis will be performed for the primary outcome measure by 
excluding all intercurrent events. 
9.3.3 
Secondary Endpoint(s) Analysis 
All secondary and
will compare GNX and placebo at the end of the 
double-blind phase and maintenance period relative to the 4-week prospective baseline phase. 
The primary analyses of all secondary and
will be performed on the ITT 
population. All the endpoints will be included in data listings. 
The key secondary endpoints are:  
• Percentage change from baseline in 28-day primary endpoint seizure frequency during the 
maintenance period (FDA). For the EMA this is the primary endpoint. 
• Number (%) of participants considered treatment responders during the double-blind phase 
(FDA). For the EMA, this endpoint will be evaluated over the maintenance period only. 
Treatment responders are defined as those participants with ≥ 50% reduction from baseline in 
primary endpoint seizure frequency during given period. 
• Number (%) of participants considered treatment responders during the maintenance period. 
Treatment responders are defined as those participants with ≥ 50% reduction from baseline in 
primary endpoint seizure frequency during a given period. 
• CGI-I at the last scheduled visit in the double-blind phase. 
9.3.3.1 
Secondary Efficacy: Behavioral/Neuropsychiatric/Quality of Life 
Secondary efficacy endpoints in behavior, neuropsychiatric, and quality of life domains are:  
• Change from baseline in ADAMS total score and sub-score. 
• Change from baseline in quality-of-life scales: SF-36, Peds-QL-FIM, and ELDQOL. 


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9.3.3.2 
Secondary Efficacy: Seizure Control  
Secondary efficacy endpoints in seizure control are:  
• Change from baseline in the percentage of seizure-free days during the double-blind phase, 
based on primary endpoint seizure types (FDA). For the EMA, this endpoint will be 
evaluated over the maintenance period only. 
• Change from baseline in the CGI-CSID at the end of the double-blind phase (FDA). For the 
EMA, this endpoint will be evaluated over the maintenance period only.  
• Participants with a ≥ 25% and ≥ 75% reduction from baseline in primary endpoint seizure 
frequency during the double-blind phase (FDA). For the EMA, this endpoint will be 
evaluated over the maintenance period only. 
• Participants with a ≥ 25%, ≥ 50%, and ≥ 75% reduction from baseline in primary endpoint 
seizure frequency during the maintenance period. 
• Responder analysis for primary endpoint seizures and all seizures during the double-blind 
phase using the following response categories: ≤ 0%, > 0% to < 25%, ≥ 25% to < 50%, 
≥ 50% to < 75%, and ≥ 75% to 100% (FDA). For the EMA, this endpoint will be evaluated 
over the maintenance period only. 
• Percent change in 28-day frequency of all seizures.  
• Change from baseline in the percentage of seizure-free days, based on all seizure types. 
• Change from baseline in the longest seizure-free interval, based on primary endpoint seizure 
types and all seizure types. 
9.3.4 
Exploratory Endpoint(s) Analysis 


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9.3.6 
Safety Analyses 
All safety analyses will be performed in the Safety Population. The results will be summarized 
by the treatment received.  
The number and percentage of days that participants received IP, the highest percentage of the 
maximum allowable daily dose (63 mg/kg or 1800 mg) that participants received, and the total 
amount of IP received will be summarized.  
A participant data listing will be provided with full details of the IP dispensation. 
Safety assessments include:  
• AEs.  
• Clinical laboratory tests.  
• Vital signs including BP, HR, RR, body temperature, height, and weight. 
• 12-lead ECG. 
• Physical, neurological, and developmental examinations. 
• Concomitant ASM levels (if collected as part of standard of care by the study site).  
• C-SSRS. 
Detailed analysis and complete listings will be outlined in the SAP. 


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9.3.7 
Subgroup Analyses 
The following subgroup summarizations of the primary efficacy parameter are planned as 
outlined in the SAP:  
• Gender (Female vs Male). 
• Age groups (12 months to 23 months; 2 to 11 years; 12 to 17 years; 18 to 64 years; and 
65 years). 
9.4 
Sample Size Determination 
Approximately 200 participants with TSC will be screened with the aim of randomizing 
approximately 128 participants into 2 treatment groups in a 1:1 ratio.  
Testing of treatment effect (the actual analysis will use a Wilcoxon rank-sum test, which has 
approximately the same power as the Analysis of Variance [ANOVA]) for GNX vs placebo will 
be performed using a 5% 2-sided alpha level. A total of 64 participants per group provides at 
least 90% power for the primary endpoint assuming an estimate of the treatment effect difference 
that is at least 25% and a common standard deviation of 43% or less. 
 
 


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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 subinvestigators 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)/caregiver(s)/LAR(s) and answer all questions regarding 
the study. 
Participants must be informed that their participation is voluntary. Participants/parent(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. 
Participants/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/parent(s) or LAR(s). 
If a participant is rescreened, that participant/parent(s)/LAR(s) is required to sign a new ICF. 
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 investigators 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 also will 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 


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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. 
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 
Data Monitoring Committee Structure and Function 
The DMC will review emerging study data on a periodic basis. The DMC is a group of 
independent scientists who are appointed to monitor the safety and scientific integrity of a human 
research intervention, and to make recommendations to the sponsor regarding the stopping of a 
study for safety concerns. The composition of the committee is dependent upon the scientific 
skills and knowledge required for monitoring the particular study.  
The mission of the DMC will be to safeguard the interests of study participants and to enhance 
the integrity and credibility of the trial. To enable the DMC to achieve their mission, the DMC 
will have periodic access to unblinded safety data and data regarding quality of trial conduct and 
will ensure the confidentiality of these data will be preserved. A DMC Charter will provide the 
principles and guidelines for the DMC process. 
10.1.7 
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. 
10.1.8 
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). 


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Guidance on completion of CRFs will be provided in the 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 
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)/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. 


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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. 
10.1.9 
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. 
10.1.10 
Study and Site Start and Closure 
10.1.10.1 
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. 


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10.1.10.2 
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 IP 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. 
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. 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants by 
the investigator. Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, 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. 
10.1.11 
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. 


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10.1.12 
Sample Storage and Destruction 
Any blood including PK samples collected according to the SOA (Section 10.3) 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 1 year 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 [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 SAE, the investigator must notify the sponsor by email or fax the Marinus 
Clinical Study Serious Adverse Event Form within 24 hours to Marinus’ 
 at:  
• Email: 
  
• Fax: 
  
10.2.2 
Sponsor Contacts 
10.2.2.1 
Sponsor Medical Monitor 
, MBChB 
 
Mobile Telephone: 
 
Email: 
 
If sponsor’s medical monitor cannot be reached in an emergency, the site should contact the 
back-up medical monitor:  
, MD 
, Clinical Development 
Mobile Telephone: 
  
Email: 
 (primary contact method) 
10.2.2.2 
Sponsor Project Managers  
 
, Clinical Development Operations 
Mobile Telephone: 
 (primary contact method) 
Email:


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10.3 Appendix 3: Safety Laboratory 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 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 testing 
•
Quantitative serum β-HCG serum or urine pregnancy test
ASM drug levels 
•
CBD, clobazam (including clobazam and desmethylclobazam),
mTOR inhibitors (eg, everolimus, sirolimus, etc.), valproate
Other tests 
•
Drug screena
•
Follicle-stimulating hormone and estradiol (as needed in women of
nonchildbearing potential only)
•
Vital signs (BP, HR, RR, and body temperature)
•
12-lead ECG
ALT = alanine aminotransferase; ASM =  anti-seizure medication; AST = aspartate aminotransferase; β-HCG = β-
human chorionic growth hormone; BP = blood pressure; BUN = blood urea nitrogen; CBD = cannabinol; 
ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; HR = heart rate; mTOR = mechanistic 
mammalian target of rapamycin; RR = respiratory rate; SGPT = serum glutamic pyruvic transaminase; 
SGOT = serum glutamic oxaloacetic transaminase; THC = tetrahydrocannabinol. 
a 
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. 


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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 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) after signing 
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/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 ECGs, 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: 
a. Results in death 
b. 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. 
c. 
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. 
d. 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. 
e. 
Is a congenital anomaly/birth defect 
f. 
Is a suspected transmission of any infectious agent via an authorized medicinal 
product 
g. 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. 
10.4.3 
Recording and Follow-up of AE and/or SAE 


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AE and SAE Recording 
• The monitoring period for AEs begins at the time that informed consent is obtained. 
• 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 form. 
• 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 the 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 β-HCG test collected at the initial screening visit and baseline visits. 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 (that have been in place for at 
least 1 month prior to the screening visit), 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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10.7 Appendix 7: Country-specific Requirements  
All local laws and regulatory requirements will be complied with during this study.  
 
 


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10.8 Appendix 8: Dosing Instructions for Oral Suspension 
GANAXOLONE 1042-TSC-3001 STUDY  
DOSING INSTRUCTIONSFOR ORAL SUSPENSION 
 
PART A DOSING INSTRUCTIONS FOR ORAL SUSPENSION 
(DOUBLE-BLIND DOSE TITRATION, MAINTENANCE, AND TAPER) 
 
Dose Titration / 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 kgs). 
 
Start Date    
DOSE (mL) 
3 times/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PART B DOSING INSTRUCTIONS FOR ORAL SUSPENSION 
(DOUBLE-BLIND CROSSOVER TO OPEN-LABEL EXTENSION) 


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Crossover to Open-Label Extension 
 
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 kgs). 
 
Type A Bottle Number(s)_________________________________________________________ 
 
Type B Bottle Number(s)_________________________________________________________ 
 
Start Date    
Type A Dose (mL) 
3 times/day 
Type B Dose (mL) 
3 times/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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GANAXOLONE 1042-TSC-3001 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 always 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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Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 123 of 175 
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. 
 
 
 
The picture can't be displayed.
el 
~ 
Tip 
....--
Barre I 
.._ Plunger 


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Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 124 of 175 
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 manually 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 drug. This helps you 
measure the correct amount of study drug. 
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 adapter is fully inserted. If not fully 
inserted, small parts such as the press-in 
bottle adapter 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. 
 
 
SHAKE WELL 
I 


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Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 125 of 175 
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. 
 
= 
Desired dose 
== I 
"" 
==--j_ 


Ganaxolone 
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Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 126 of 175 
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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Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 127 of 175 
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 
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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Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 3.0 
 
CONFIDENTIAL 
Page 128 of 175 
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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Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 129 of 175 
10.9 Appendix 9: Clinical Global Impression – Severity (CGI-S) 
 
Clinician Completed Clinical Global Impression - Severity (CGI-S): 
Baseline Interview Guide 
Instructions 
Clinicians should interview caregivers about the participant's current overall functioning. 
Specifically, consider seizure control and behavioral presentation, as listed below. Enough 
detail should be captured in clinical notes to enable the CGI rater to reconstruct the 
participant's functioning in order to rate changes at subsequent visits. 
Specific example behaviors for consideration are listed here to help guide your overall 
description of the participant. Please also include any additional relevant information 
about the participant's functioning. 
1. Seizures 
Specific seizure considerations: 
• Seizure type 
• Seizure frequency 
• Seizure intensity 
• Seizure duration 
• Postictal severity and duration 
2. Sleep 
Specific behavioral considerations: 
• Difficulty falling asleep 
• Nighttime wakening 
• Difficulty waking in the morning 
3. Communication 
Specific behavioral considerations: 
Receptive communication 
• Responds to sound in the environment 
• Responds to person's voice 
• Responds to "no" or other inhibitory words 
• Responds to simple instructions 
• Responds to multi-step instructions 
• Understands informational presentations 
Expressive communication 
• Produces sounds 
• Social vocalizing/laughing (vocalizes or laughs in response to caregiver) 
• Uses gestures 
• Babbles 
• Uses words 
1042-TSC-3001_Baseline Clinician CGI-S_US-English 
© 2020 Cogslale Lid. All rights reserved 
Page 1 of 3 


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Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 130 of 175 
 
• Uses sentences 
• Gives instructions with multiple steps 
• Relays experiences 
4. Socialization 
Specific behavioral considerations: 
• Responds to name/social bids 
• Shows affection 
• Seeks to share interests/enjoyment with others 
• Enjoys talking and/or playing with peers 
• Goes out with friends 
• Engages in age-appropriate leisure time activities 
5. Hyperactivity 
Specific behavioral considerations: 
• Easily distracted 
• Difficulty sustaining attention 
• Hypermotoric (restless, constantly moving, fidgety) 
• Impulsive (acts without thinking) 
6. Irritability 
Specific behavioral considerations: 
• Tantrums 
• Outbursts 
• Aggression 
• Agitation 
• Self-injury 
Notes: ___________________________ _ 
1042-TSC-3001_Baseline Clinician CGI-S_US-English 
© 2020 Cogslale Lid. All rights reserved 
Page 2of3 


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Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 131 of 175 
 
Please indicate the severity of the participant's presentation, overall, relative to the range 
of symptoms seen in Tuberous Sclerosis Complex, using the rating scale below. 
CGI Severity (CGI-S) 
1. Normal, not at all a problem 
2. Borderline problem 
3. Mild problem 
4. Moderate problem 
5. Marked problem 
6. Severe problem 
7. Very severe problem 
Severity Rating: ___ _ 
1042-TSC-3001_Baseline Clinician CGI-S_US-English 
© 2020 Cogslale Lid. All rights reserved 
Page 3of3 


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Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 132 of 175 
10.10 Appendix 10: Clinical Global Impression – Improvement (CGI-I) 
Clinical Global Impression - Improvement (CGI-I) for the 
Clinician/Parent/Caregiver/LAR 
 
 
Date:   
 
 
 
 
 
Participant No:   
 
 
 
 
 
 
Rater Initials:  
 
 
 
Participant Initials:  
 
 
 
 
 
 
 
  Rate the overall global impression of change after the start of 
investigational product relative to baseline (prior to investigational 
product). Please circle the appropriate number. 
 
 
 
1. Very much improved 
2. Much improved 
3. Minimally improved 
4. No change 
5. Minimally worse 
6. Much worse 
7. Very much worse 
 
 
 
 
 


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Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 133 of 175 
10.11 Appendix 11: Caregiver Global Impression of Change in Seizure 
Intensity/Duration (CGI-CSID) 
Caregiver Global Impression of Change in Seizure Intensity/Duration  
(CGI-CSID) 
 
Date:   
 
 
 
 
 
Participant No:   
 
 
 
 
 
 
Rater Initials:  
 
 
 
Participant Initials:  
 
 
 
 
 
 
 
   
Rate the change in seizure intensity and/or duration after the start of 
investigational product. Please circle the appropriate number. 
 
 
 
1. Very much improved 
2. Much improved 
3. Minimally improved 
4. No change 
5. Minimally worse 
6. Much worse 
7. Very much worse 
 
 
 
 
 
 


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Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 134 of 175 
10.12 Appendix 12: Sleep Questionnaires 


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Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 135 of 175 


Ganaxolone 
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Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 136 of 175 
 


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CONFIDENTIAL 
Page 137 of 175 
10.12.2 
Sleep Quality Scale 
 
Sleep Quality Scale (SQS) 
85 
Purpose Consisting of 28 items, the SQS evalu-
ates six domains of sleep quality: daytime symp-
toms, restoration after sleep, problems initiating 
and maintaining sleep, difficulty waking, and 
sleep satisfaction. Developers hoped to create a 
scale that could be used as an all-inclusive assess-
ment tool - a general, efficient measure suitable 
for evaluating sleep quality in a variety of patient 
and research populations. 
Population for Testing The scale has been vali-
dated in individuals aged 18-59 years. 
Administration Requiring between 5 and 10 min 
for administration, the scale is a simple self-report, 
pencil-and-paper measure. 
Reliability and Validity An initial psychometric 
evaluation conducted by Yi and colleagues [l] 
found an internal consistency of .92, a test-retest 
reliability of .81. The SQS is strongly correlated 
with results obtained on the Pittsburgh Sleep Quality 
Index (Chap. 67). Scores achieved by the insomnia 
sample were significantly higher than those of con-
trols, indicating good construct validity. 
Obtaining a Copy A list of the scale's 28 items 
can be found in the original article published by 
developers [1]. 
Direct correspondence to: 
Chol Shin 
Division of Pulmonary and Critical Care 
Medicine 
Department of Internal Medicine 
Korea University Ansan Hospital 
516, Gojan 1-dong, Danwon-gu, Ansan-si, 
Gyeonggi-do 4 25- 707 
Republic of Korea 
Email: shinchol@pol.net 
Scoring Using a four-point, Likert-type scale, 
respondents indicate how frequently they exhibit 
certain sleep behaviors (0 = "few," 1 ="some-
times," 2 = "often," and 3 = "almost always"). 
Scores on items belong to factors 2 and 5 (resto-
ration after sleep and satisfaction with sleep) and 
are reversed before being tallied. Total scores can 
range from 0 to 84, with higher scores demoting 
more acute sleep problems. 
A. Shahid et al. (eds.), STOP, THAT and One Hundred Other Sleep Scales, 
345 
DOI 10.1007/978-1-4419-9893-4_85, © Springer Science+Business Media, LLC 2012 


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Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 138 of 175 
The following survey is to know the quality of sleep you had for the last one month. Read the 
questions and check the closest answer. 
Examples 
Rarely: None or 1-3 times a month 
Sometimes: 1-2 times a week 
Often: 3-5 times a week 
Almost always: 6-7 times a week 
 
 
 
Rarely 
Sometimes 
Often 
Almost 
always 
1 
I have difficulty falling asleep 
 
 
 
 
2 
I fall into a deep sleep 
 
 
 
 
3 
I wake up while sleeping 
 
 
 
 
4 
I have difficulty getting back to sleep once I wake 
up in the middle of the night 
 
 
 
 
5 
I wake up easily because of noise 
 
 
 
 
6 
I toss and turn 
 
 
 
 
7 
I never go back to sleep after awaking during sleep 
 
 
 
 
8 
I feel refreshed after sleep 
 
 
 
 
9 
I feel unlikely to sleep after sleep 
 
 
 
 
10 
Poor sleep gives me headaches 
 
 
 
 
11 
Poor sleep makes me irritated 
 
 
 
 
12 
I would like to sleep more after waking up 
 
 
 
 
13 
My sleep hours are enough 
 
 
 
 
14 
Poor sleep makes me lose my appetite 
 
 
 
 
15 
Poor sleep makes it hard for me to think 
 
 
 
 
16 
I feel vigorous after sleep 
 
 
 
 
17 
Poor sleep makes me lose interest in work or others 
 
 
 
 
18 
My fatigue is relieved after sleep 
 
 
 
 
19 
Poor sleep causes me to make mistakes at work 
 
 
 
 
20 
I am satisfied with my sleep 
 
 
 
 
21 
Poor sleep makes me forget things more easily 
 
 
 
 
22 
Poor sleep makes it hard to concentrate at work 
 
 
 
 
23 
Sleepiness interferes with my daily life 
 
 
 
 
24 
Poor sleep makes me lose desire in all things 
 
 
 
 
25 
I have difficulty getting out of bed 
 
 
 
 
26 
Poor sleep makes me easily tired at work 
 
 
 
 
27 
I have a clear head after sleep 
 
 
 
 
28 
Poor sleep makes my life painful 
 
 
 
 


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Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 139 of 175 
10.13 Appendix 13: Anxiety, Depression, and Mood Scale (ADAMS) 
 
Anxiety, Depression, and Mood Scale (ADAMS) - Baseline 
Instructions 
The Anxiety, Depression and Mood Scale (ADAMS) contains a list of behaviors that can be 
found among individuals with intellectual disability. Please describe the individual’s 
behavior over the last 6 months  
 
0 
behavior has not occurred, or is not a problem. 
1 
behavior occurs occasionally, or is a mild problem. 
2 
Behavior occurs quite often, or is a moderate problem. 
3 
behavior occurs a lot, or is a severe problem. 
 
 
not a 
problem 
mild 
problem moderate 
problem 
severe 
problem 
1. 
Nervous  
0 
1 
2 
3 
2. 
Problems initiating communication  
0 
1 
2 
3 
3. 
Does not relax or settle down  
0 
1 
2 
3 
4. 
Has periods of over-activity  
0 
1 
2 
3 
5. 
Sleeps more than normal  
0 
1 
2 
3 
6. 
Withdraws from other people  
0 
1 
2 
3 
7. 
Tense  
0 
1 
2 
3 
8. 
Engages in ritualistic behaviors  
0 
1 
2 
3 
9. 
Depressed mood 
0 
1 
2 
3 
10. 
Sad  
0 
1 
2 
3 
11. 
Worried  
0 
1 
2 
3 
12. 
Has developed difficulty staying on task or completing work 
0 
1 
2 
3 
13. 
Shy  
0 
1 
2 
3 
14. 
Easily fatigued (not due to being overweight) 
0 
1 
2 
3 
15. 
Anxious  
0 
1 
2 
3 
16. 
Repeatedly checks items  
0 
1 
2 
3 
17. 
Easily distracted  
0 
1 
2 
3 
18. 
Lacks energy  
0 
1 
2 
3 
19. 
Avoids others, spends much of time alone 
0 
1 
2 
3 
20. 
Easily upset if ritualistic behaviors are interrupted  
0 
1 
2 
3 
21. 
Lacks emotional facial expressions 
0 
1 
2 
3 
22. 
Has shown difficulty in starting routine tasks 
0 
1 
2 
3 
23. 
Listless 
0 
1 
2 
3 
24. 
Experiences panic attacks 
0 
1 
2 
3 
25. 
Avoids eye contact 
0 
1 
2 
3 
26. 
Trembles when frightening situations are not present 
0 
1 
2 
3 
27. 
Avoids peers 
0 
1 
2 
3 
28. 
Tearful 
0 
1 
2 
3 
 


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Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 140 of 175 
 
Anxiety, Depression, and Mood Scale (ADAMS) – Post-baseline Visits 
Instructions 
The Anxiety, Depression and Mood Scale (ADAMS) contains a list of behaviors that can be 
found among individuals with intellectual disability. Please describe the individual’s 
behavior since the last visit (post-baseline visits). 
 
0 behavior has not occurred, or is not a problem. 
1 behavior occurs occasionally, or is a mild problem. 
2 behavior occurs quite often, or is a moderate problem. 
3 behavior occurs a lot, or is a severe problem. 
 
 
not a 
problem 
mild 
problem 
moderate 
problem 
severe 
problem 
1. 
Nervous  
0 
1 
2 
3 
2. 
Problems initiating communication  
0 
1 
2 
3 
3. 
Does not relax or settle down  
0 
1 
2 
3 
4. 
Has periods of over-activity  
0 
1 
2 
3 
5. 
Sleeps more than normal  
0 
1 
2 
3 
6. 
Withdraws from other people  
0 
1 
2 
3 
7. 
Tense  
0 
1 
2 
3 
8. 
Engages in ritualistic behaviors  
0 
1 
2 
3 
9. 
Depressed mood 
0 
1 
2 
3 
10. 
Sad  
0 
1 
2 
3 
11. 
Worried  
0 
1 
2 
3 
12. 
Has developed difficulty staying on task or completing work 
0 
1 
2 
3 
13. 
Shy  
0 
1 
2 
3 
14. 
Easily fatigued (not due to being overweight) 
0 
1 
2 
3 
15. 
Anxious  
0 
1 
2 
3 
16. 
Repeatedly checks items  
0 
1 
2 
3 
17. 
Easily distracted  
0 
1 
2 
3 
18. 
Lacks energy  
0 
1 
2 
3 
19. 
Avoids others, spends much of time alone 
0 
1 
2 
3 
20. 
Easily upset if ritualistic behaviors are interrupted  
0 
1 
2 
3 
21. 
Lacks emotional facial expressions 
0 
1 
2 
3 
22. 
Has shown difficulty in starting routine tasks 
0 
1 
2 
3 
23. 
Listless 
0 
1 
2 
3 
24. 
Experiences panic attacks 
0 
1 
2 
3 
25. 
Avoids eye contact 
0 
1 
2 
3 
26. 
Trembles when frightening situations are not present 
0 
1 
2 
3 
27. 
Avoids peers 
0 
1 
2 
3 
28. 
Tearful 
0 
1 
2 
3 
 
 


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Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 141 of 175 
10.14 Appendix 14: Pediatric Quality of Life Inventory – Family Impact Module 
(Peds-QL-FIM)  
PedsQL 
I ID# 
Date: 
TM 
Family Impact Module 
Version 2.0 
PARENT REPORT 
DIRECTIONS 
Families of children sometimes have special concerns or difficulties because of the 
child's health. On the following page is a list of things that might be a problem for 
you. Please tell us how much of a problem each one has been for you during the 
past ONE month by circling: 
0 if it is never a problem 
1 if it is almost never a problem 
2 if it is sometimes a problem 
3 if it is often a problem 
4 if it is almost always a problem 
There are no right or wrong answers. 
If you do not understand a question, please ask for help. 
PedsQL 3.0 - Parent Family Impact 
06/04 
Not to be reproduced without permission 
Copyright© 1998 JW Varni, PhD. 
All rights reserved 


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PedsQL 2 
In the past ONE month, as a result of your child's health, how much of a problem have you had with .. . 
PHYSICAL FUNCTIONING (problems with ... ) 
Never 
Almost 
Some-
Never 
times 
1 . I feel tired during the day 
0 
1 
2 
2. I feel tired when I wake up in the morning 
0 
1 
2 
3. I feel too tired to do the things I like to do 
0 
1 
2 
4. I get headaches 
0 
1 
2 
5. I feel physically weak 
0 
1 
2 
6. I feel sick to my stomach 
0 
1 
2 
EMOTIONAL FUNCTIONING (problems with ... ) 
Never 
Almost 
Some-
Never 
times 
1 . I feel anxious 
0 
1 
2 
2. I feel sad 
0 
1 
2 
3. I feel angry 
0 
1 
2 
4. I feel frustrated 
0 
1 
2 
5. I feel helpless or hopeless 
0 
1 
2 
SOCIAL FUNCTIONING (problems with ... ) 
Never 
Almost 
Some-
Never 
times 
1 . I feel isolated from others 
0 
1 
2 
2. I have trouble getting support from others 
0 
1 
2 
3. It is hard to find time for social activities 
0 
1 
2 
4. I do not have enough energy for social activities 
0 
1 
2 
COGNITIVE FUNCTIONING (problems with ... ) 
Never 
Almost 
Some-
Never 
times 
1 . II is hard for me to keep my attention on things 
0 
1 
2 
2. II is hard for me to remember what people tell me 
0 
1 
2 
3. II is hard for me to remember what I just heard 
0 
1 
2 
4. II is hard for me to think quickly 
0 
1 
2 
5. I have trouble remembering what I was just thinking 
0 
1 
2 
COMMUNICATION (problems with ... ) 
Never 
Almost 
Some-
Never 
times 
1 . I feel that others do not understand my family's 
0 
1 
2 
situation 
2. II is hard for me to talk about my child's health with 
0 
1 
2 
others 
3. II is hard for me to tell doctors and nurses how I feel 
0 
1 
2 
PedsQL 3.0 - Parent Family Impact 
All rights reserved 
Copyright © 1998 JW Varni, PhD. 6/04 
Often 
Almost 
Alwavs 
3 
4 
3 
4 
3 
4 
3 
4 
3 
4 
3 
4 
Often 
Almost 
Alwavs 
3 
4 
3 
4 
3 
4 
3 
4 
3 
4 
Often 
Almost 
Alwavs 
3 
4 
3 
4 
3 
4 
3 
4 
Often 
Almost 
Alwavs 
3 
4 
3 
4 
3 
4 
3 
4 
3 
4 
Often 
Almost 
Alwavs 
3 
4 
3 
4 
3 
4 


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CONFIDENTIAL 
Page 143 of 175 
PedsQL 3 
In the past ONE month, as a result of your child's health, how much of a problem have you had with .. . 
WORRY (problems with ... ) 
Never 
Almost 
Some-
Often 
Never 
times 
1 . 
2. 
3. 
4. 
5. 
I worry about whether or not my child's medical 
0 
1 
2 
3 
treatments are working 
I worry about the side effects of my child's 
0 
1 
2 
3 
medications/medical treatments 
I worry about how others will react to my child's 
0 
1 
2 
3 
condition 
I worry about how my child's illness is affecting 
0 
1 
2 
3 
other family members 
I worry about my child's future 
0 
1 
2 
3 
DIRECTIONS 
Below is a list of things that might be a problem for your family. Please tell us how 
much of a problem each one has been for your family during the past ONE month. 
Almost 
Alwavs 
4 
4 
4 
4 
4 
In the past ONE month, as a result of your child's health, how much of a problem has your family 
had with ... 
DAILY ACTIVITIES (problems with ... ) 
Never 
Almost 
Some-
Never 
times 
1 . Family activities taking more time and effort 
0 
1 
2 
2. Difficulty finding time to finish household tasks 
0 
1 
2 
3. Feeling too tired to finish household tasks 
0 
1 
2 
Never 
Almost 
Some-
FAMILY RELATIONSHIPS (problems with ... ) 
Never 
times 
1 . Lack of communication between family members 
0 
1 
2 
2. Conflicts between family members 
0 
1 
2 
3. Difficulty making decisions together as a family 
0 
1 
2 
4. Difficulty solving family problems together 
0 
1 
2 
5. Stress or tension between family members 
0 
1 
2 
PedsQL 3.0 - Parent Family Impact 
All rights reserved 
Copyright © 1998 JW Varni, PhD. 6/04 
Often 
Almost 
Always 
3 
4 
3 
4 
3 
4 
Often 
Almost 
Always 
3 
4 
3 
4 
3 
4 
3 
4 
3 
4 


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Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 144 of 175 
PedsQL 
I ID# 
Date: 
TM 
Family Impact Module 
Version 2.0 
PARENT REPORT 
DIRECTIONS 
Families of children sometimes have special concerns or difficulties because of the 
child's health. On the following page is a list of things that might be a problem for 
you. Please tell us how much of a problem each one has been for you during the 
past 7 days by circling: 
0 if it is never a problem 
1 if it is almost never a problem 
2 if it is sometimes a problem 
3 if it is often a problem 
4 if it is almost always a problem 
There are no right or wrong answers. 
If you do not understand a question, please ask for help. 
PedsQL 2.0 - Parent Family Impact Acute 
12/09 
Not to be reproduced without permission 
Copyright© 1998 JW Varni, PhD. 
All rights reserved 


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CONFIDENTIAL 
Page 145 of 175 
PedsQL 2 
In the past 7 days, as a result of your child's health, how much of a problem have you had with ... 
PHYSICAL FUNCTIONING (problems with ... ) 
Never 
1 . I feel tired during the day 
0 
2. I feel tired when I wake up in the morning 
0 
3. I feel too tired to do the things I like to do 
0 
4. I get headaches 
0 
5. I feel physically weak 
0 
6. I feel sick to my stomach 
0 
EMOTIONAL FUNCTIONING (problems with ... ) 
Never 
1 . I feel anxious 
0 
2. I feel sad 
0 
3. I feel angry 
0 
4. I feel frustrated 
0 
5. I feel helpless or hopeless 
0 
SOCIAL FUNCTIONING (problems with ... ) 
Never 
1 . I feel isolated from others 
0 
2. I have trouble getting support from others 
0 
3. It is hard to find time for social activities 
0 
4. I do not have enough energy for social activities 
0 
COGNITIVE FUNCTIONING (problems with ... ) 
Never 
1 . II is hard for me to keep my attention on things 
0 
2. II is hard for me to remember what people tell me 
0 
3. II is hard for me to remember what I just heard 
0 
4. II is hard for me to think quickly 
0 
5. I have trouble remembering what I was just thinking 
0 
COMMUNICATION (problems with ... ) 
Never 
1 . I feel that others do not understand my family's 
0 
situation 
2. II is hard for me to talk about my child's health with 
0 
others 
3. II is hard for me to tell doctors and nurses how I feel 
0 
PedsQL 2.0 - Parent Family Impact Acute 
12/09 
Not to be reproduced without permission 
Almost 
Some-
Often 
Almost 
Never 
times 
Alwavs 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
Almost 
Some-
Often 
Almost 
Never 
times 
Alwavs 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
Almost 
Some-
Often 
Almost 
Never 
times 
Alwavs 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
Almost 
Some-
Often 
Almost 
Never 
times 
Alwavs 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
Almost 
Some-
Often 
Almost 
Never 
times 
Alwavs 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
Copyright © 1998 JW Varni, PhD. 
All rights reserved 


Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 146 of 175 
 
PedsQL 3 
In the past 7 days, as a result of your child's health, how much of a problem have you had with ... 
WORRY (problems with ... ) 
Never 
Almost 
Some-
Often 
Almost 
Never 
times 
Alwavs 
1 . I worry about whether or not my child's medical 
0 
1 
2 
3 
4 
treatments are working 
2. I worry about the side effects of my child's 
0 
1 
2 
3 
4 
medications/medical treatments 
3. I worry about how others will react to my child's 
0 
1 
2 
3 
4 
condition 
4. 
I worry about how my child's illness is affecting 
0 
1 
2 
3 
4 
other family members 
5. I worry about my child's future 
0 
1 
2 
3 
4 
DIRECTIONS 
Below is a list of things that might be a problem for your family. Please tell us how 
much of a problem each one has been for your family during the past 7 days. 
In the past 7 days, as a result of your child's health, how much of a problem has your family had 
with ... 
DAILY ACTIVITIES (problems with ... ) 
Never 
1 . Family activities taking more time and effort 
0 
2. Difficulty finding time to finish household tasks 
0 
3. Feeling too tired to finish household tasks 
0 
Never 
FAMILY RELATIONSHIPS (problems with ... ) 
1 . Lack of communication between family members 
0 
2. Conflicts between family members 
0 
3. Difficulty making decisions together as a family 
0 
4. Difficulty solving family problems together 
0 
5. Stress or tension between family members 
0 
PedsQL 2.0 - Parent Family Impact Acute 
12/09 
Not to be reproduced without permission 
Almost 
Some-
Often 
Almost 
Never 
times 
Always 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
Almost 
Some-
Often 
Almost 
Never 
times 
Always 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
Copyright© 1998 JW Varni, PhD. 
All rights reserved 


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Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 147 of 175 
10.15 Appendix 15: Short Form 36 (version 2) 
Your Health and Well-Being 
This survey asks for your views about your health. This information will 
help keep track of how you feel and how well you are able to do your usual 
activities. Thank you for completing this survey! 
For each of the following questions, please mark an C8:J in the one box that best 
describes your answer. 
1. In general, would yon say your health is: 
Excellent 
Ve1y good 
Good 
Fair 
Poor 
T 
T 
T 
T 
T 
□· 
02 
03 
0 4 
D, 
2. Compared to one year ago, how would you rate your health in general 
now? 
Much better 
Somewhat 
About the 
Somewhat 
Much worse 
now than one 
better 
same as 
worse 
now than one 
year ago 
now than one 
one year ago 
now than one 
year ago 
year ago 
year ago 
T 
T 
T 
T 
T 
□· 
02 
03 
04 
Os 
SF-36v2 Health Survey© 1992, 1996, 2000 Medical Outcomes Trost and Quality 1etric Inco,porated. All rights reserved. 
SF-36' is a registered trademark of Medical Outcomes Trust 
(SF-36,·2 Health Sun·ey Standard, United States (English)) 


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3. The following questions are about activities you might do during a typical 
day. Does your health now limit you in these activities? If so, how much? 
Yes, 
Yes, 
No not 
limited 
limited 
limited 
a lot 
a little 
at all 
T 
T 
T 
• Vigorous activities such as tunning lifting 
heavy objects participating in strenuous sports ...................... D 1 ••.••• . •• . ••• D 2 ••• . ••. ••• . •• D i 
b 
Moderate activities, such as moving a table pushing 
a vacuum cleaner, bowling, or playing golf ............................ D 1 •••••••••• •• • 0 2 ••••••••••••• D i 
c 
Lifting or canying groceries .................................................... D 1 ••• ••• •••••• • D 2 •• •• •• ••••••• D i 
d 
Climbing several flights of stairs ............................................. 0 1 .. ........... 0 2 ............. 0 i 
• Climbing one flight of stairs .................................................... D 1 ...... .... ... D 2 ...... .. ..... D i 
r Bending, kneeling or stooping ................................................ D 1 .. .......... . D 2 ............. Di 
g 
Walking more than a mile ....................................................... 0 1 .. ........ ... 0 2 .. .. .. .. .. .. . 0 i 
h 
Walking several hundred yards ............................................... 0 1 ••.••• .•• .• .• 0 2 •••.•..•••. •• 0 i 
; Walking one hundred yards ..................................................... 0 1. •.• ••. ••.••• 0 2. ...... . ... . . 0 i 
Bathing or dressing yourself.. .................................................. D 1 ••• ••••••• ••• D 2 •••••• ••• ••• • D i 
SF-36v2 Health Survey© 1992, 1996, 2000 Medical Outcomes Trust and Quality 1etric Incorporated. All rights reserved. 
SF-36 is a registered trademark of Medical Outcomes Trust 
(SF-36v2' Health Survey Standard, United States (English)) 


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Protocol Date and Version: 12 Sep 2023; v 3.0 
 
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4. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of your physical health? 
• Cut down on the amount of 
time you spent on work or 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
None of 
the time 
the time 
other activities ......................... ........ 0 1. . •. •. •• . •. •. • 0 2 •••. ••• .. •... • 0 3 •. ••• . .• ... ••• 0 4 •• . •••. . •••• • □ 
s 
b 
Accomplished less than you 
,vould like ........................................ □ 
1. .•.•.• •.•. •.• 0 2 •• •.•• •..•... • 0 3 •.•••.• •...••• 0 4 ••. •••..•••• • □ 
s 
c Were limited in the kind of 
work or other activities .................... □ 
1. . ... .. . . . . . .. 0 2 . .. .... . .. . . . . 0 3 .. . . . .. . ... .. . 0 4 .. .... .. ..... □ 
s 
d 
Had difficulty performing the 
work or other activities (for 
example, it took extra effo1t) ........... □ 
1. .•.•.• •.•. •.• 0 2 •••.•• •.. •... • 0 3 •.•• •.• •...••• 0 4 ••. ••• .. •••. • □ 
s 
5. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of anv emotional problems (such as feeling depressed or anxious)? 
• Cut down on the amount of 
time you spent on work or 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
None of 
the time 
the time 
other activities ................ ................. 0 1. . ... .. . . . . . .. 0 2 .. . .... .. . ... . 0 3 .. ... .. . ... .. . 0 4 .. . . .. .. .... . □ 
s 
b 
Accomplished less than you 
would like ........................................ □ 
1. . ... . .. . ... .. 0 2 . .. .... . .. . . . . 0 3 . .... . .. .. ... . 0 4 .. .... . .. ... . □ 
s 
c Did work or other activities 
less carefully than usual .................. □ 
1. . •. •.••. •. •.• 0 2 •• •.•• •.. •... • 0 3 •. •• •.. •... ••• 0 4 ••. ••• .. ••• .• □ 
s 
SF-36v2 Health Survey© 1992, 1996, 2000 Medical Outcomes Trust and Quality 1etric Incorporated. All rights reserved. 
SF-36 is a registered trademark of Medical Outcomes Trust 
(SF-36v2' Health Survey Standard, United States (English)) 


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Protocol Date and Version: 12 Sep 2023; v 3.0 
 
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6. During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered with your normal social activities with 
family, friends, neighbors, or groups? 
Not at all 
Slightly 
Moderately 
T 
T 
02 
03 
Quite a bit 
T 
04 
Extremely 
T 
Os 
7. How much bodily pain have you had during the past 4 weeks? 
None 
Ve1y mild 
Mild 
Moderate 
Severe 
Ve1y severe 
T 
T 
T 
T 
T 
T 
0 1 
02 
03 
04 
Os 
□6 
8. During the past 4 weeks, how much did pain interfere with your normal 
work (including both work outside the home and housework)? 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
T 
T 
T 
T 
T 
0 1 
02 
03 
04 
Os 
SF-36v2 Health Swvey © 1992, 1996, 2000 Medical Outcomes Trust and Quality ietric Incorporated. All rights reserlied. 
SF-36 is a registered trademark of Medical Outcomes Trust 
(SF-36v2 Heahh Survey Standard, Ututed States (English)) 


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9. These questions are about how you feel and how things have been with 
you during the past 4 weeks. For each question, please 2ive the one answer 
that comes closest to the way you have been feeling. How much of the time 
durin2 the past 4 weeks. 
All of 
the time 
Most of 
the time 
Some of A little of the None of 
the time 
time 
the time 
• Did you feel full of life? .................. □ 
1 .............. 0 2 .. .... ........ 0 3 .. .. .... .. .... 0 4 .............. 0 s 
b Have you been ve1y nervous? .......... □
! .............. □ 
2 .............. 0 3 .. .. .... .. .... o 4 .............. o 5 
c Have you felt so down in the 
dumps that nothing could 
cheer you up? ................................... □ 
1 .............. 0 2 ............. . 0 3 .. .. .... .. .... 0 4 .............. 0 s 
d Have you felt calm and 
peaceful? .......................................... □ 
1 .. .... ........ 0 2 ........ .... .. 0 3 .... .. .... .... 0 4 .. ...... .... .. 0 s 
• Did you have a lot of energy? .......... □ 
1 .............. 0 2 .............. 0 3 .............. 0 4 .. ...... ...... 0 s 
r Have you felt downhearted 
and depressed? ................................. □ 
1 .......... .... 0 2 .... .. ...... .. 0 3 .............. 0 4 ...... .. .. .... 0 s 
g Did you feel worn out? .................... □ 
1 .............. 0 2 .. .... .... .... 0 3 .............. 0 4 .............. 0 s 
h Have you been happy? ..................... □
! .............. □ 
2 .............. 0 ) .............. □ 
4 .......... .... o 5 
; Did you feel tired? ........................... □ 
1 .............. 0 2 .... .. .... .... 0 3 .............. 0 4 ...... .. .. .... 0 s 
10. 
During the past 4 weeks, how much of the time has your physical health or 
emotional prnblems interfered with your social activities (like visiting with 
friends, relatives, etc.)? 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
one of 
the time 
SF-36v2 Health Sur,;ey © 1992, 1996, 2000 Medical Outcomes Trust and Quality Metric Incorporated. All rights resen:ed. 
SF-36 is a registered trademark of Medical Outcomes Trust 
(SF-36v2 Health Survey Standard, United States (English)) 


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11. 
How TRUE or FALSE is each of the following statements for you? 
• I seem to get sick a little 
Definitely 
true 
Mostly 
true 
Don t 
know 
Mostly 
false 
Definitely 
false 
easier than other people ................... □ 
1. .. . .. .. .. . .. . 0 2 •• •••• • •• • •• • 0 3 •••• ••• •• ••• •• □ 
4 •• •••• ••••••• • 0 s 
b 
I am as healthy as 
anybody I know ............................... □ 
1. .. . .. .. .. . .. . 0 2 •• •••• •• •••• • 0 3 •••• •• ••• •• ••• □ 
4 •• •••• ••••••• • 0 s 
, I expect my health to 
get worse .......................................... □!. .. . .. .. .. .. . . □ 
2 ••• ••• •• •• •• • 0 3 ••• • •• ••• •• ••• □ 
4 •• •••• •••••• •• o s 
d 
My health is excellent ...................... □ 
1. .. . .. .. .. . .. . 0 2 •• •••• ••••••• 0 J ••• ••• ••••• ••• □ 
4 •••••• ••••• • •• 0 s 
Thank you for completing these questions! 
SF-36v2 Health Survey© 1992. 1996. 2000 Medical Outcomes Trust and Quality 1etric Incorporated. All ngbts reserved. 
SF-36' is a registered trademark: of Medical Outcomes Trust. 
(SF-36v2 Health Survey Standard, United States (Engli.sh)) 


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Protocol 1042-TSC-3001 
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10.16 Appendix 16: Epilepsy and Learning Disabilities Quality of Life Scale  
Departments of Primary Care 
and Neurosciences, 
University of Liverpool, 
Whelan Building (2nd Floor), 
Brownlow Hill, 
Liverpool, 
L69 3GB 
EPILEPSY AND LEARNING DISABILITIES 
QUALITY OF LIFE QUESTIONNAIRE 
ABOUT THESE QUESTIONS 
1. 
These questions ask about how your child has been in the last four 
weeks. We are interested in how much your child's daily life and 
activities have been affected by his/her epilepsy and its treatment. 
Serial No. 1-3 
2. 
We are interested in your views about how things have been for your 
child. Your opinions are very important to us, and we hope you will take 
time to complete the questionnaire. We do not think it will take more 
than 15-20 minutes for you to do so. 
3. 
Some people with epilepsy have more than one type of seizure. If your 
child experiences different types of seizures, please answer the 
questions as they apply to the most severe seizures, in your opinion, 
that he/she has. 
4. 
Most of the questions can be answered simply by ringing a number next 
to the answer that applies to your child. Sometimes you are asked to 
write in a number. 
5. 
We want to know how things have been in the lastfour weeks. If you 
cannot remember, do not know, or are unable to answer a particular 
question, please write that in. 
6. 
Your name and address do not appear anywhere in this booklet. The 
information you give us will be treated as strictly confidential. 


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Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
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First some questions about the seizures your child has. Please answer about seizures in 
the last four weeks. If your child has more than one type of seizure, please think about 
the most severe seizures he/she has, when answering the questions. Please be sure to 
answer every question. 
1. 
How severe have your child's seizures been in the last four weeks? 
Very severe ............... 1 
Somewhat severe ............... 2 
Moderate ............... 3 
Mild .............. 4 
Can't say ............... 5 
2. 
In the last four weeks, do you think your child was aware of his/her surroundings 
during seizures? 
Yes, during all seizures ............... 1 
Yes, during most seizures ............... 2 
Yes, during some seizures .............. 3 
No, not during any seizures .............. 4 
Can't say ............... 5 
3. 
In the last four weeks, did your child blank out/lose consciousness during any of 
his/her seizures? If yes, generally for how long? 
Yes, for less than 1 minute ............... 1 
Yes, for between 1-2 minutes .............. 2 
Yes, for between 2-5 minutes ............... 3 
Yes, for more than 5 minutes ............... 4 
No, did not blank out or lose consciousness in any seizures .............. 5 
Can't say......... 
.. 6 
4. 
In the last four weeks, when your child had seizures, how often did he/she fall to 
the ground? 
Always ............... 1 
Usually ............... 2 
Sometimes/rarely .............. 3 
Never ............... 4 
Does not apply- child does not stand 
independently/child wheelchair bound ............... 5 
Can't say ............... 6 
4 
5 
6 
7 


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5. 
In the last four weeks, was your child ever confused, disorientated or non-
responsive after seizures? 
Yes, always .............. 1 
Yes, often 
..... 2 
Yes, sometimes/rarely 
.. 3 
No, never 
..... 4 
Can't say 
..... 5 
6. 
In the last four weeks, if your child was confused, disorientated or non-
responsive after seizures, how long did this usually last? 
Usually lasted less than 1 minute 
........... 1 
Usually lasted for between 1-5 minutes .............. 2 
Usually lasted for between 6 minutes - 1 hour .............. 3 
Usually lasted for more than 1 hour ............... 4 
Child never seemed confused/disorientated/non-responsive ............... 5 
Can't say ............... 6 
7. 
How often was your child distressed after seizures in the last four weeks? 
Always 
..... 1 
Usually ............... 2 
Sometimes/rarely 
........... 3 
Never .............. 4 
Can't say .............. 5 
8. 
In the last four weeks, how often did your child wet him/herself during seizures? 
Always ............... 1 
Usually ............... 2 
Sometimes/rarely ............... 3 
Never 
.. 4 
Can't say - child has no control of bladder 
.... 5 
9. 
In the last four weeks, how often did your child soil him/herself during seizures? 
Always .............. 1 
Usually 
.. 2 
Sometimes/rarely 
.. 3 
Never 
..... 4 
Can't say - child has no control of bowels 
..... 5 
2 
8 
9 
10 
11 
12 


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10. 
In the last four weeks, did your child suffer any injury to the mouth, cheek or 
tongue during a seizure? 
Always ............... 1 
Usually ............... 2 
Sometimes/rarely ............... 3 
Never ............... 4 
Can't say ............... 5 
11. 
In the last four weeks, did your child suffer any injury other than to the mouth, 
cheek or tongue during a seizure? 
Always .............. 1 
Usually ............... 2 
Sometimes/rarely ............... 3 
Never ............... 4 
Can't say ............... 5 
12. 
How upset was your child by the injury/injuries he/she suffered during seizures 
in the last four weeks? 
Very upset ............... 1 
Somewhat upset ............... 2 
Not very upset ............... 3 
Not at all upset ............... 4 
Does not apply - no injuries ............... 5 
Can't say 
..... 6 
13. 
In the last four weeks, when your child recovered from his/her seizures, how 
often did he/she appear sleepy or subdued? 
Always ............... 1 
Usually ............... 2 
Sometimes/rarely ............... 3 
Never........ 
.4 
Can't say ... 
.5 
14. 
In the last four weeks, when your child had seizures, how quickly could he/she 
usually return to what he/she was doing? 
In less than 1 minute 
..... 1 
In between 1-5 minutes 
.... 2 
In between 6 minutes - 1 hour ............... 3 
In over 1 hour ............... 4 
Can't say ............... 5 
3 
13 
14 
15 
16 
17 


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Now some more detailed questions about any injuries your child experienced in 
the last four weeks, as a result of his/her seizures. 
15. 
In the past four weeks, how many times did your child injure him/herself during a 
seizure? 
Not at all ............... O 
Number of times (please write in) 
l111111111•1■B!llillli1111111I 
l1111111W111111il111111111I 
16. 
Did he/she suffer any of the following injuries as a result of having a seizure in 
the last four weeks? 
a) 
An injury to his/her head which required assessment and/or 
treatment at hospital? 
Yes ............... 1 
No ............... 2 
b) 
An injury to his/her teeth or mouth which required dental or 
medical treatment? 
Yes .............. 1 
No .............. 2 
c) 
A fracture/broken bone? 
Yes ............... 1 
No ............... 2 
d) 
Bruising or friction burns to any part of the body? 
Yes .............. 1 
No .............. 2 
e) 
Cuts or grazes to any part of the body? 
Yes .............. 1 
No .............. 2 
f) 
Any other injury? (please tell us wha~: 
Yes ............... 1 
No ............... 2 
4 
18 
19 
20 
21 
22 
23 
24 


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Now a few questions about the drugs your child takes for epilepsy 
17. 
In the last four weeks, how well do you think your child's seizures have been 
controlled by the drugs he/she is taking? 
Very well controlled 
....... 1 
Fairly well controlled ............... 2 
Not very well controlled ............. .. 3 
Not controlled at all . 
. ... 4 
Can't say ........ .. .. ... 5 
25 
18. 
Below is a list of problems people sometimes have with the drugs they take for their 
epilepsy. During the last four weeks, has your child had any of the problems listed which 
you think may have been caused by the drugs he/she takes for epilepsy? 
For each of the things listed, if it has always or often been a problem in the last four weeks, 
ring 4; if it has sometimes been a problem, ring 3, and so on. Please answer every item. 
Unsteadiness/dizziness 
Tiredness. 
Restlessness 
Hyperactivity .. 
Nervousness 
Headache 
Problems with skin, e.g. rash 
Disturbed vision 
Always 
a problem 
Often a 
problem 
........ 1 ............... 2 
....... 1 ............... 2 
........ 1 ............... 2 
. 1 .. 
........ 1 ............... 2 
....... 1 ............... 2 
Upset stomach/nausea .... .... ... . ....... 1 
...... 2 
Difficulty paying attention 
....... 1 
....... 2 
....... 2 
Trouble with mouth or gums 
....... 1 
Shaky hands/tremor 
Weight gain 
....... 1 
....... 2 
........ 1 ............... 2 
Weight loss 
Sleepiness/drowsiness 
Memory problems. 
Disturbed sleep 
.................. 1 ............... 2 
........ 1 ............... 2 
.... 1 ............ 2 .. 
........ 1 ............... 2 
Loss of appetite ................................... 1 ............... 2 
Behaviour problems (e.g. temper 
tantrums, irritability or agitation) ... 
. 1 
Any other problems (please list in the spaces below): 
......................................................................... 1 
2 ......................... ...... ......... .. ........... ........... ....... 1 
5 
Sometimes/rarely 
a problem 
Never a 
problem 
Can't 
say 
....... 3 
. .. .. .. 3 
........ 3 
. . 3. 
. 3 
....... 3 
....... 3 
........ 3 
....... 3 
....... 3 
....... 3 
....... 3 
....... 3 
....... 4 
...... 4 
....... 4 
.. 4 
....... 4 
....... 4 
.. .. ... 4 
....... 4 
... ... 4 
....... 4 
....... 4 
....... 4 
....... 4 
....... 3 ................... 4 
... .... 3 
....... 4 
. ...... 3 ....... ········4 
.. .... 4 
.. 5 
.. 5 
.. 5 
.. 5 
..5 
.. 5 
.. 5 
.5 
.5 
.5 
.5 
.5 
.5 
.5 
.5 
.5 
.5 
.. 5 
........ 4 
........ 4 
26 
44 
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Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 159 of 175 
Now some questions about how your child has been generally. Please think about how 
your child has been over the last four weeks, compared to how he/she is normally. 
19. 
How aware has your child been of his/her surroundings/things going on around 
him/her, in the last four weeks? 
Very aware ............... 1 
Fairly aware 
.... .. 2 
Not very aware .. 
. .... 3 
Not at all aware 
.... .. 4 
Can't say ............... 5 
20. 
How often, in the last four weeks, did your child have problems sleeping (either 
difficulty falling asleep, waking during the night, or waking early)? 
Always a problem ............... 1 
Often a problem ............... 2 
Sometimes/rarely a problem ............... 3 
Never a problem ............... 4 
Can't say ....... .. .... .. 5 
21. 
How often was your child's appetite a problem - either eating too much or too 
little? 
Always a problem ............. .. 1 
Often a problem 
Sometimes/rarely a problem ............... 3 
Never a problem ............... 4 
Can't say ............... 5 
22. 
In the last four weeks, how good overall has your child's bladder control been? 
Very good .............. 1 
Good ............. 2 
Poor .............. 3 
Very poor ............... 4 
Does not apply - does not have control of his/her bladder ............... 5 
Can't say ............... 6 
6 
47 
48 
49 
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Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 160 of 175 
23. 
In the last four weeks, how good overall has your child's bowel control been? 
24. 
25. 
26. 
27. 
Very good 
..... 1 
Good. 
.. ... 2 
Poor 
..... 3 
Very poor 
..... 4 
Does not apply - does not have control of his/her bowels. 
... 5 
Can't say 
In the last four weeks, how well has your child been able to let you know what 
he/she w ants? 
Very well 
..... 1 
Fairly well 
..... 2 
Not very well 
..... 3 
Not at all well 
..... 4 
Can't say 
..... 5 
In the last four weeks, how well has he/she been able to understand what you 
tell him/her? 
Very well .. .... ....... 1 
Fairly well 
..... 2 
Not very well 
..... 3 
Not at all well 
..... 4 
Can't say 
..... 5 
In the last four weeks, how well has your child been able to pay attention to 
his/her favourite activities? 
Very well 
..... 1 
Fairly well 
..... 2 
Not very well 
..... 3 
Not at all well 
..... 4 
Can't say 
..... 5 
How often in the last four weeks has your child been prevented from taking part 
in his/her normal activities (e.g. going to school, playing, seeing friends and 
relatives) by his/her seizures/epilepsy? 
Always 
..... 1 
Often 
... 2 
Sometimes/rarely 
..... 3 
Never 
.... .4 
Can't say 
..... 5 
7 
51 
52 
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Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 161 of 175 
Now some questions about your child's mood in the last four weeks 
28. 
Here is a list of words that parents have used to describe their child's moods. In 
the last four weeks, has your child appeared:-
Happy 
Aggressive 
Calm 
Irritable 
Tearful . . 
Always 
Often 
........... 1 ... .............. 2 
..... .... 1 ................. 2 
..... 1 ... .............. 2 
........... 1 ................. 2 
. ....... 1.. 
·········2 
Friendly ........................ 1 ................. 2 
Hyperactive ............ ...... 1 ... .............. 2 
Relaxed 
Sad 
Agitated 
Cheerful 
Restless .. 
........... 1 ................. 2 
...... ..... 1 ........ ......... 2 
Tantrum-prone ............. 1 
......... 2 
Frustrated 
........... 1 ... .............. 2 
Withdrawn .................... 1 ................. 2 
Cooperative/helpful ...... 1 
Sometimes/ 
rarely 
........... 3 
..... 3 
........... 3 
........... 3 
........... 3 
........... 3 
........... 3 
......... 3 
8 
Never 
........... 4 
.4 
........... 4 
. . 4 
......... 4 
........... 4 
......... 4 
Can't say 
.. 5 
.. 5 
.. 5 
.. 5 
.. 5 
.. 5 
.. 5 
.. 5 
.. 5 
.. 5 
.. 5 
..5 
.. 5 
.. 5 
.. 5 
.. 5 
56 
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Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 162 of 175 
29. 
30. 
31. 
In the last four weeks, how would you say your child's general health has been 
overall? 
Very good 
..... 1 
Good 
..... 2 
Fair 
..... 3 
Poor ...... ........ 4 
Very poor 
..... 5 
How would you describe the quality of your child's life overall in the last four 
weeks? 
Very good 
..... 1 
Good 
..... 2 
Fair 
..... 3 
Poor 
..... 4 
Very poor 
.. .. 5 
In the last four weeks, how concerned have you been about your child because 
of his/her epilepsy? 
Very concerned 
..... 1 
Fairly concerned 
..... 2 
Not very concerned 
..... 3 
Not concerned ....... ........ 4 
32. 
How severe a condition do you think his/her epilepsy is? 
Very severe 
..... 1 
Somewhat severe 
... 2 
Moderate 
..... 3 
Mild 
..... 4 
Can't say ....... ........ 5 
9 
72 
73 
74 
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Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 163 of 175 
The following questions are about yourself and your family. 
33. 
During the past 4 weeks, how much emotional worry or concern did each of the 
following cause you? 
None at all 
A little bit 
Some Quite a bit A lot 
Your child's physical health 
Your child's emotional well-
being or behaviour ... .. ... ... ... .. ... .. ... ... . 0 
Your child's attention or 
learning difficulties 
........ O 
34. 
During the past 4 weeks, were you limited in the amount of time you had for 
your own needs because of: 
Your child's physical health 
Your child's emotional well-
Yes, limited 
a lot 
being or behaviour ... .. ... ... ... .. ... .. ... ... . O 
Your child's attention or 
learning difficulties 
Yes,limited 
Yes, limited 
No, 
some 
a little 
not limited 
.. ... . 2 ... ... .. .. ... .. ... 3 
.. .... . 1 ... .. ... ... ... .. ... . 2 ... ... .. ... .. ... ... 3 
35. 
During the past 4 weeks, how often has your child's health or behaviour: 
Very 
Fairly 
Sometimes 
Almost 
Never 
often 
often 
never 
limited the types of activities 
you could do as a family? ... .. ... .. ... ... ... ... 0 
interrupted various everyday family 
activities (eating meals, watching Iv)? ... 0 
limited your ability as a family to "pick 
up and go" on a moment's notice? ...... .. 0 
caused tension or conflict 
in your home? ........................................ O 
been a source of disagreements 
or arguments in your family? ... .. ... .. ... ... . 0 
caused you to cancel or change 
plans (personal or work) at 
the last minute? ..................................... O 
...... 4 
...... 4 
10 
36. 
Sometimes families may have difficulty getting along with one another. They do not always 
agree and they may get angry. In general, how would you rate your family's ability to get along 
with one another? 
Excellent .... ... ... .. ... 1 
Very good .. .. ... ... .. ... 2 
Good ... 
. .. 3 
Fair ............... 4 
Poor ............... 5 
17 
10 
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Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 164 of 175 
The next section is about your child's behaviour in the last four weeks. 
37. 
Please read each statement and rate your child's behaviour in the last four 
weeks. For each item, decide whether the behaviour is a problem and circle the 
appropriate number. 
Injures self on purpose 
Aggressive to other children 
Not at all 
a problem 
A slight 
problem 
or adults (verbally or physically) ............ 0 .................. 1 
Screams inappropriately 
Temper tantrums/outbursts ................... 0 ................... 1 
Irritable and whiny 
....... 0 ................... 1 
Yells at inappropriate times 
........ 0 ................... 1 
Depressed mood ........ ........................... 0 ................... 1 
Demands must be met immediately ...... 0 
Cries over minor annoyances and 
hurts.. 
. .................... 0 
........ 1 
Mood changes quickly ................ ..... ... . 0 
.. . .. . 1 
Cries and screams inappropriately ........ 0 ................... 1 
Stamps feet or bangs objects 
or slams doors ....................................... 0 ................... 1 
Deliberately hurts himself/herself .......... 0 
Does physical violence to self ............... 0 
Has temper outbursts or tantrums 
when he/she does not get own way ... .. . 0 
Excessively active at home, school, 
work, or elsewhere .............................. 0 
Boisterous (inappropriately 
....... 1 
....... 1 
noisy and rough) .................................... 0 ................... 1 
Does not stay in seat (e.g. during 
lesson or training periods, meals etc) .... 0 
11 
A moderately 
serious 
problem 
A severe 
problem 
...... 2 
..... 2 
...... 2 
...... 2 
...... 2 
.... 2 .. 
.... 2 
..... 2 . 
..... 2 
....... 3 
...... 3 
...... 3 
.. ..... 3 
... ... 3 
. 3 
.. ... 3 
.. .... 3 
...... 3 
......... 2 ................. 3 
...... 2 
.. ..... 3 
18 
35 


Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 165 of 175 
The following statements are also about your child's behaviour in the last four weeks. Please circle the 
appropriate number. 
Not at all 
A slight 
A moderately A severe 
a problem 
problem 
serious 
problem 
problem 
Impulsive (acts without thinking) . ... . ... 0 .. 
....... L
. 
.. ... 2 
.3 
36 
Restless, unable to sit still ........ ............. 0 
....... 1 
...... 2 
...... 3 
Disobedient; difficult to control ............... 0 
........ 1 
........ 2 
...... 3 
Disturbs others 
.. ..... 0 
........ 1 
........ 2 . ..... .......... 3 
Uncooperative 
........ 0 
........ 1 
........ 2 
...... 3 
Does not pay attention to 
instructions 
......... 0 
........ 1 
....... 2 
....... 3 
Disrupts group activities 
..... 0 
.... ... 1 
....... 2 
...... 3 
Will not sit still for any 
length of time 
......... 0 
..... ... 1 
....... 2 
....... 3 
Easily distractible 
......... 0 
... ..... 1 
....... 2 
...... 3 
Constantly runs or jumps 
around the room 
........ 0 
........ 1 
....... 2 
.. ..... 3 
Pays no attention 
when spoken to .. 
0. 
.. .. . .. 1 
. ..... 2 
..... 3 
Tends to be excessively active 
.0 
........ 1 
........ 2 
...... 3 
Deliberately ignores directions .............. 0 
........ 1 
........ 2 
........ 3 
48 
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Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 166 of 175 
The next few items are about your child's general ability to function with daily activities. 
For each item, please decide which statement best describes your child's situation and 
circle the appropriate number. 
38. My child can walk independently for at least 100 metres ....................... . 
My child can walk independently, but for less than 100 metres 
My child can walk only with support or aids 
My child cannot walk at all but can stand 
My child's mobility is limited to wheelchair use only 
39. My child is able to move and use his/her arms and hands normally 
My child is unable to use a pencil or a knife and fork, but can use a spoon 
My child is unable to use a spoon to feed, but can feed him/herself with 
his/her fingers 
My child is unable to feed him/herself with his/her fingers, and is fed 
orally by another person ... 
My child is fed exclusively or almost exclusively by a tube 
. .......... .. 1 
... ... . 4 
. ... 4 
............. 5 
40. My child can dress and undress him/herself, including laces and/or buttons ........ ..... .... ... 1 
My child can dress and undress him/herself, excluding laces and/or buttons ................... 2 
My child can only undress him/herself, alone or with assistance 
My child can only dress him/herself, alone or with assistance 
My child is unable to undress or dress at all ............. .. ............ . 
41 . My child has normal speech ........................................................................... .. 
My child has some understandable speech, but it is not normal .. 
My child uses only a few 2-word or 3-word phrases . . ............ . 
My child uses only single words and no phrases 
My child uses no recognisable words, but may make some sounds 
13 
. ............ 1 
. .. 2 
. .. 3 
49 
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Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 167 of 175 
 
42. Finally, please tell us your relationship to your child. Are you: 
His/her mother 
. 1 
His/her father 
..... 2 
Another relative 
..... 3 
A formal carer ...... ........ 4 
43. Did you find any of these questions difficult to answer? If so, please tell us which 
ones and why. 
44. Are there any other comments you would like to make, either about your child and 
his/her epilepsy, or about this questionnaire? If so, please write in the space below. 
Please check that you have answered all the questions. 
Thank you for taking the time to complete this questionnaire. We are very grateful for 
your help. 
14 
53 
55 


Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 168 of 175 
10.17 Appendix 17: Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Baseline 
VeISionl/141W 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanliy, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, !,I.; i\,/ann, J. 
Oisdaimer: 
T1Hs scde is intended to be used by mdividuals who have rea1ved troiniQg in its administration. The questions oontained 
;, the C..lumbi<>Su;<ide Severity Raunc Scale a,e suggested probes. Ulr.imatdy, the decerm;naoon of the presence of 
su;<idal N/eoiion o, beh<wior depend. on the judgment of the ;,><fi,;dual administering the scale. 
O.~nicrMS of ~IMO,of sulddd ~wnm in mi.s scote ore bose<I on thou used in lbs Columbia Sufdsk Hist9Q( 
bl.cm. de~d by Jolin Monn, MD ond Mono Oquendo, MO, Coor, C.nter for the Neuro.sden<e of Mental Dlsordot> 
(CCNMD), New Yen Stote PsydNatric lll$li<ute. 1051 l!M1side Drioe, New Yorlt. NY. 10032. (Oq.,endo M. A, 
Halberstam 8. & Monn}. }. Plsk focttXS for w;<ido/ behO>rior: utility ond limitations of research insrrumell!S. In M.8. First 
(Ed,] St>.odardized Evaluation in Clinical Practice, pp. 103 • I 30, 2003.) 
~ 
reprin<> of the C.SSRS contoa Kelly Posner, Ph.D., N ew York Stote P,ydNotric Ins,nme, 105 I R;ven,de Drive, New 
Yorlt, New Y orlc. I 0032; inquiries ond troining requiremeni, concoa posnerk@nyspi.co1umbio.~ 
C 2008 The Research Foundation for Mental Hygiene, Inc. 


Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 169 of 175 
 
 
 
 
 
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, 


Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 170 of 175 
 
 
 
SVJCJDA.L BEHA.l'JOR 
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Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 171 of 175 
 
 
Visit 
Day 0: Admission 
Patfeot No. _____ _ 
Patient Initials ____ _ 
Date _______ _ 
lime _______ _ 
Rater 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
Vernon 1/14/09 
Posner, K.; Brent, D.; Lucas, C; GouM, 111.; S tanuy, B.; Brown, G.; Fisher, P.; Zela;,ny, J.; 
Burke, A.; Oquendo, Jlf.; Jlfann, J. 
DlsdoJrner. 
This-S(a/~ k Intend~ to ~ uwd by indMduo& who bav~ tt(.~~ ua'ining in Its administration. Th~ qu~stions c-on.cained 
in Ibo Columblo-Suiddo s .... ,uy Ro~ng Scar. oro sugg..,«1 p,obos. Ultlmot•o/, Ibo ooonninaclon of,~ preson<o of 
,widdo/ idootlon or bMOvior doponds on tho judgment of Ibo ln&.ld<Jd odministo,ing ,~ u ole. 
Oe~nitions of behcv;orof sl.Hcidaf events in tms scale are based on those used in Th« Columbia Suicide HitWQ'. 
f= do~d by John Monn, MD ond Mono Oqu-,ndo, MD, Conte Cooter for tbo Nourowonco of MMtof Oiso,don 
(CCNMD), Now Yo.-k Stcu P:syd!lottl< lmtit<Jt-. 105 / Rivots/do Drlvo, Now Yorl<, NY, 10032. (Oquondo M. A, 
Ho/bor.stom & & MoM ). }, F/i.sk foao,s for S<ttddo/ b,t,,,vfor. utility and flmlrctlons of rosoor<h insuumonts. In M.& Flm 
[E.d.J Standardized Evaluation in Oinlcal Practice, pp. 103 -130, 2003.) 
For roprina of tho C.SSRS <ontoct k lfy Posnor, Ph.D, Now York Stoto Psy<hlouk 14Stiwr-. 1051 RIV'fflldo 0,/w, N<w 
York, Now Yorl:, I 0032; inquiries and troinir>f requirement, contoa posnerk@ny,pi.cofumbio.edu 
@ 2006 The Re>earch Foundation for Mental Hygiene. Inc. 


Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 172 of 175 
 
 
SUICIDAL IDEA1 JON 
Ask quer,ir;n.s I pfl(! 1.. ,fbt;t.11 Prt 11teg,uf",;lE'. prt;JCJ1Xd tr; "-SuicidtJI fkJuni,ur"' stth/),11, J/ rite tJfl$lrlVF tr; qwstit,,1 2 is )'-es .. , 
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O:,c1,eo111""'.:.:. - . 


Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 173 of 175 
 
 
 
 
S()/CJDA.L BEHA J-IOR 
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Ganaxolone 
Marinus Pharmaceuticals Inc. 
Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 174 of 175 
11 REFERENCES 
AFINITOR (everolimus) tablets [Prescribing Information]. East Hanover, New Jersey, USA: 
Novartis Pharmaceuticals Corporation; Updated Feb 2020. 
Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress report on new 
antiepileptic drugs: A summary of the Tenth Eilat Conference (EILAT X). Epilepsy Res. 
2010;92(2-3):89–124. 
Carter RB, Wood PL, Wieland S, et al. Characterization of the anticonvulsant properties of 
ganaxolone (CCD 1042; 3alpha-hydroxy- 3beta-methyl-5alpha-pregnan-20-one), a selective, 
high-affinity, steroid modulator of the gamma-aminobutyric acid(A) receptor. J Pharmacol Exp 
Ther. 1997;280(3):1284–1295. 
Chu-Shore CJ, Major P, Camposano S, Muzykewicz D, Thiele EA. The natural history of 
epilepsy in tuberous sclerosis complex. Epilepsia. 2010:51:1236–1241. 
Curatolo P, Verdecchia M, Bombardieri R. Vigabatrin for tuberous sclerosis complex. Brain 
Dev. 2001;23:649–653. 
Di Michele F, Verdecchia M, Dorofeeva M, Costamagna L, Bernardi G, Curatolo P, Romeo E. 
GABAA receptor active steroids are altered in epilepsy patients with tuberous sclerosis. J Neurol 
Neurosurg Psychiatry. 2003:74:667–670. 
Esbensen AJ, Rojahn J, Aman MG, Ruedrich S. Reliability and validity of an assessment 
instrument for anxiety, depression, and mood among individuals with mental retardation. 
J Autism Dev Disord. 2003;33(6):617–629. 
French JA, Lawson JA, Yapici Z et al. Adjunctive everolimus therapy for treatment-resistant 
focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomized, 
double-blind placebo-controlled study. Lancet. 2016;388:2153–2163. 
International Council for Harmonisation Guidance E2A March 1995. Accessed 20-Feb-2018. 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/Step4/
E2A_Guideline.pdf. 
Jülich K, Sahin M. Mechanism-based treatment in tuberous sclerosis complex. Pediatric Neurol. 
2014;50:290–296. 
Kerrigan JF, Shields WD, Nelson TY, et al. Ganaxolone for treating intractable infantile spasms: 
a multicenter, open-label, add-on trial. Epilepsy Res. 2000;42(2-3):133–139. 
Krueger DA, Northrup H, International Tuberous Sclerosis Complex Consensus Group. 
Tuberous sclerosis complex surveillance and management: Recommendations of the 
2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatric Neurol. 
2013;49:255–265. 


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Protocol 1042-TSC-3001 
Protocol Date and Version: 12 Sep 2023; v 4.0 
 
CONFIDENTIAL 
Page 175 of 175 
Laxer K, Blum D, Abou-Khalil BW, Morrell MJ, Lee DA, Data JL, Monaghan EP. Assessment 
of ganaxolone's anticonvulsant activity using a randomized, double-blind, presurgical trial 
design. Ganaxolone Presurgical Study Group. Epilepsia. 2000;41(19):1187–1194. 
Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the 
modification of diet in renal disease study equation for estimating glomerular filtration rate 
[published correction appears in Ann Intern Med. 2008 Oct 7;149(7):519]. Ann Intern Med. 
2006;145(4):247–254. 
Ligsay A, Van Dijck A, Kooy RF, Hagerman R. Ganaxolone in Children with FXS. International 
FXS Conference San Antonio, TX 2016. 
Mizuguchi M, Ikeda H, Kagitani-Shimono K et al. Everolimus for epilepsy and autism spectrum 
disorder in tuberous sclerosis complex: EXIST-3 substudy in Japan. Brain Dev. 2019;41:1–10. 
Northrup H, Aronow ME, Bebin EM, Bissler J, Darling TN, de Vries PJ, Frost MD, Fuchs Z, 
Gosnell ES, Gupta N, Jansen AC, Jóźwiak S, Kingswood JC, Knilans TK, McCormack FX, 
Pounders A, Roberds SL, Rodriguez-Buritica DF, Roth J, Sampson JR, Sparagana S, Thiele EA, 
Weiner HL, Wheless JW, Towbin AJ, Krueger DA; International Tuberous Sclerosis Complex 
Consensus Group. Updated International Tuberous Sclerosis Complex Diagnostic Criteria and 
Surveillance and Management Recommendations. Pediatr Neurol. 2021; Oct;123:50-66.  
Pieribone VA, Tsai J, Soufflet C, Rey E, Shaw K, Giller E, Dulac O. Clinical evaluation of 
ganaxolone in pediatric and adolescent patients with refractory epilepsy. Epilepsia. 
2007;48(10):1870–1874. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266–1277. 
Reddy DS, Rogwski MA. Neurosteroids — Endogenous regulators of seizure susceptibility and 
role in the treatment of epilepsy (Chapter 77). In, Jasper’s Basic Mechanisms of the Epilepsies, 
Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds.), 
Contemporary Neurology Series 80, Oxford University Press. 2012;984–1002. 
Sperling MR, Klein P, Tsai J. Randomized, double-blind, placebo-controlled phase 2 study of 
ganaxolone as add-on therapy in adults with uncontrolled partial-onset seizures. Epilepsia. 
2017;58(4):558–564. 
Thiele EA, Bebin EM, Bhathal H, et al. Add-on Cannabidiol Treatment for Drug-Resistant 
Seizures in Tuberous Sclerosis Complex: A Placebo-Controlled Randomized Clinical Trial. 
JAMA Neurol. 2021;78(3):285–292. 
 

SAP_001.pdf: 
Statistical Analysis Plan 
 
 
 
1042-TSC-3001 
 
A Phase 3, Double-blind, Randomized, Placebo-controlled Trial of Adjunctive 
Ganaxolone (GNX) Treatment in Children and Adults with Tuberous Sclerosis 
Complex (TSC)-related Epilepsy (TrustTSC) 
 
 
 
Protocol Numbers 
1042-TSC-3001 
 
Investigational Product 
Ganaxolone (GNX) 
 
Indication 
Tuberous Sclerosis Complex (TSC) 
 
Reference Product 
Placebo 
Phase  
3 
Final 
25 March 2022, Version 1.0 
Amendment 1 
14 September 2023, Version 2.0 
Amendment 2 
02 August 2024, Version 3.0 
 
 
 
 
Confidentiality Statement 
 
 
The information contained in this document is privileged and confidential. Do not copy, 
circulate, or otherwise distribute without written authorization from 
Marinus Pharmaceuticals, Inc. 
 
 
 


Marinus Pharmaceuticals, Inc. 
 
1042-TSC-3001 Statistical Analysis Plan 
02 August 2024, Version 3.0 
 
Confidential 
Page 2 of 41 
Statistical Analysis Plan Approval  
 
Author:   
  
_______________________________ 
 
________________ 
, Ph.D. 
 
 
 
 
Date (mm/dd/yyyy) 
 Biostatistics 
Marinus Pharmaceuticals, Inc. 
Review:         
_______________________________ 
 
________________ 
, M.D.  
 
 
            Date (mm/dd/yyyy) 
Marinus Pharmaceuticals, Inc. 
Approval: 
 ________________________________ 
 
________________ 
 
 
 
                                    Date (mm/dd/yyyy) 
 Biostatistics 
Marinus Pharmaceuticals, Inc. 
 


Marinus Pharmaceuticals, Inc. 
 
1042-TSC-3001 Statistical Analysis Plan 
02 August 2024, Version 3.0 
 
Confidential 
Page 3 of 41 
Table of Contents 
LIST OF ABBREVIATIONS ............................................................................................. 5 
1. 
INTRODUCTION ...................................................................................................... 7 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS .................................... 8 
2.1. 
Protocol and Case Report Form Version ........................................................... 8 
2.2. 
Study Objectives ............................................................................................... 8 
2.2.1. 
Primary Objective ....................................................................................... 8 
2.2.2. 
Secondary Objectives ................................................................................ 8 
2.2.4 
Safety Objectives ....................................................................................... 9 
2.3. 
Study Endpoints ................................................................................................ 9 
2.3.1. 
Primary Endpoint ....................................................................................... 9 
2.3.2. 
Key Secondary Efficacy Endpoints ............................................................. 9 
2.3.3. 
Secondary Efficacy Endpoints (Behavior/Neuropsychiatric/Quality of life): . 9 
2.3.4. 
Secondary Efficacy Endpoints (Seizure Control): ....................................... 9 
2.3.5. 
Exploratory Endpoints .............................................................................. 10 
2.3.6. 
Safety Endpoints ...................................................................................... 10 
3. 
STUDY DESIGN .................................................................................................... 11 
3.1. 
Randomization ................................................................................................ 11 
3.2. 
Sample Size Considerations ........................................................................... 11 
3.3. 
Multiplicity ....................................................................................................... 11 
4. 
STATISTICAL METHODOLOGY............................................................................ 12 
4.1. 
General Methodology ...................................................................................... 12 
4.2. 
Analysis Sets .................................................................................................. 12 
4.3. 
Statistical Methods for Efficacy Analyses ........................................................ 13 
4.3.1. 
Estimand Framework for the Primary Endpoint ........................................ 13 
4.3.2. 
Primary Efficacy Endpoint ........................................................................ 13 
4.3.3. 
Sensitivity Analysis ................................................................................... 14 
4.3.4. 
Key Secondary Efficacy Endpoints ........................................................... 15 
4.3.5. 
Secondary Efficacy Endpoints .................................................................. 17 
4.3.7. 
Subgroup Analyses for Primary Endpoint ................................................. 27 
4.3.8. 
Handling of Missing Data ......................................................................... 28 
5. 
BASELINE, DISPOSITION, AND EXPOSURE ....................................................... 31 


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5.1. 
Study Day and Analysis Window ..................................................................... 31 
5.2. 
Definition of Baseline ...................................................................................... 31 
5.3. 
Analysis Visit Windows.................................................................................... 31 
5.4. 
Demographics and Baseline Characteristics ................................................... 32 
5.5. 
Subject Disposition .......................................................................................... 32 
5.6. 
Eligibility Criteria and Protocol Deviations ....................................................... 32 
5.7. 
Prior and Concomitant Medications ................................................................. 33 
5.8. 
Medical History ............................................................................................... 33 
5.9. 
Study Drug Exposure ...................................................................................... 33 
5.10. Study Drug Compliance .................................................................................. 34 
5.11. Cross-Over Titration Summary ........................................................................ 34 
6. 
ANALYSIS OF SAFETY ENDPOINTS ................................................................... 35 
6.1. 
Adverse Events ............................................................................................... 35 
6.2. 
Clinical Laboratory Evaluations ....................................................................... 36 
6.3. 
Vital Signs, Physical, Neurological and Developmental Examination Findings 37 
6.4. 
Electrocardiogram (ECG) ................................................................................ 38 
6.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ......................................... 38 
6.6. 
Pregnancies .................................................................................................... 39 
6.7. 
Tanner Staging ............................................................................................... 39 
7. 
Appendix ................................................................................................................ 40 
8. 
SUMMARY OF MAJOR CHANGES IN THE PLANNED ANALYSES ..................... 41 
 
List of Tables 
Table 1: 
Recoding Items for SF-36 .............................................................................. 19 
Table 2: 
Averaging Items to Form Scales for SF-36 ...................................................... 20 
Table 3: 
Adverse Event Start/Stop Date Imputation ....................................................... 29 
Table 4: 
Imputation for Prior/Concomitant Medication Missing and Partial Dates ............. 30 
Table 5: 
C-SSRS Categories for Analysis..................................................................... 39 
 


Marinus Pharmaceuticals, Inc. 
 
1042-TSC-3001 Statistical Analysis Plan 
02 August 2024, Version 3.0 
 
 
 
 
 
Confidential 
Page 5 of 41 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase   
ADAMS 
 
Anxiety, Depression, and Mood Scale 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate aminotransferase 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel  
CRF 
Case Report Form 
CGI-CSID 
Caregiver Global Impression of Change in Seizure Intensity/Duration 
CGI-S 
Clinical Global Impression - Severity 
CGI-I 
Clinical Global Impression of Improvement 
DB 
Double-blind 
ECG 
Electrocardiogram 
eDiary 
Electronic Diary 
ELDQOL 
Epilepsy and Learning Disabilities Quality of Life 
EMA 
European Medicines Agency 
GNX 
Ganaxolone 
kg 
Kilogram 
kg/m2 
Kilogram per Meter Squared 
MedDRA 
Medical Dictionary for Regulatory Activities 


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1042-TSC-3001 Statistical Analysis Plan 
02 August 2024, Version 3.0 
 
 
 
 
 
Confidential 
Page 6 of 41 
mg 
Milligram 
Peds-QL-FIM 
Pediatric Quality of Life – Family Impact Module 
ROW 
Rest of World 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SF-36 
Short Form 36 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event 
TLF 
Table, Listing and Figure 
ULN 
Upper Limit of Normal 
 


Marinus Pharmaceuticals, Inc. 
 
1042-TSC-3001 Statistical Analysis Plan 
02 August 2024, Version 3.0 
 
 
 
 
 
Confidential 
Page 7 of 41 
1. 
INTRODUCTION 
This is a Phase 3, global, double-blind, randomized, placebo-controlled study of 
adjunctive Ganaxolone (GNX) treatment in children and adults with TSC-related 
epilepsy. The study consists of a 4-week prospective baseline phase, defined as the first 
28 days following screening, followed by a double-blind phase consisting of a 4-week 
titration period and a 12-week maintenance period.  
Following completion of the treatment period, participants who are compliant with study 
conduct will have the option to enroll and be treated with GNX in a separate OLE study, 
1042-TSC-3002. All participants entering the OLE will have their dose of study 
medication adjusted in a double-blind cross-titration over 4 weeks such that all are 
receiving GNX at study completion. Participants who do not continue in the OLE will 
undergo a 2- to 4-week double-blind down-titration and taper if discontinuing IP. 
Sections 2 and 5 of the Protocol provides a detailed description of the investigational 
product, target patient population, and potential risks and benefits of treatment with 
GNX.  The purpose of this Statistical Analysis Plan (SAP) is to define the methodology 
for analyzing and summarizing the data collected during the conduct of 
Study 1042-TSC-3001.  
 
 


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1042-TSC-3001 Statistical Analysis Plan 
02 August 2024, Version 3.0 
 
Confidential 
Page 8 of 41 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS 
2.1. 
Protocol and Case Report Form Version 
This SAP is based on 1042-TSC-3001 Protocol Amendment 3 v4.0 dated 12SEP2023, 
Protocol Addendum (Amd 2) dated 18AUG2023, and case report forms (CRFs) approved 
20APR2023.  Unless superseded by an amendment, this SAP will be effective for all 
subsequent Protocol amendments and CRF versions. 
2.2. 
Study Objectives 
2.2.1. 
Primary Objective 
The primary objective of the study is: to assess the safety and efficacy of GNX compared 
to placebo (PBO) as adjunctive therapy for seizures associated with TSC in children and 
adults as assessed by the change from baseline in the frequency of countable major motor 
and focal seizures (primary endpoint seizures) during the double-blind phase. 
2.2.2. 
Secondary Objectives 
The secondary objectives of the study are to evaluate the efficacy of GNX vs. PBO: 
• To determine the percentage of change from baseline in 28-day primary 
endpoint seizure frequency during the maintenance period.  
• To assess the change in focal seizure frequency from baseline during the 
double-blind phase.  
• To assess changes in mood, behavior, and quality of life using the following:  
− ADAMS 
− Peds-QL-FIM 
− SF-36 
− ELDQOL  
• To assess overall clinical outcome using the CGI-I scores by the clinician and 
the parent/caregiver. 
• To evaluate the changes in seizure intensity and duration using the CGI CSID. 


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1042-TSC-3001 Statistical Analysis Plan 
02 August 2024, Version 3.0 
 
Confidential 
Page 9 of 41 
2.2.4 Safety Objectives 
To assess the safety and tolerability of GNX compared with placebo as adjunctive 
therapy for seizures associated with TSC. 
2.3. 
Study Endpoints 
2.3.1. 
Primary Endpoint 
The primary efficacy endpoint is the percentage change from baseline in 28-day primary 
endpoint seizure frequency during the double-blind phase.   
2.3.2. 
Key Secondary Efficacy Endpoints 
• Percentage change from baseline in 28-day primary endpoint seizure 
frequency during the maintenance period. 
• Number (%) of participants considered treatment responders during the 
double-blind phase.    
• Number (%) of participants considered treatment responders during the 
maintenance period. 
• CGI-I at the last scheduled visit in the double-blind phase. 
2.3.3. 
Secondary Efficacy Endpoints (Behavior/Neuropsychiatric/Quality of 
life): 
• Change from baseline in ADAMS total score and sub-score. 
• Change from baseline in quality-of-life scales: Peds-QL-FIM, SF-36, and 
ELDQOL. 
2.3.4. 
Secondary Efficacy Endpoints (Seizure Control): 
• Change from baseline in the percentage of seizure-free days during the 
double-blind phase, based on primary endpoint seizure type. 
• Change from baseline in the percentage of seizure-free days during the 
maintenance phase, based on primary endpoint seizure type. 
• CGI-CSID at the last scheduled visit in the double-blind phase. 
• Participants with a ≥ 25% and ≥ 75% reduction from baseline in primary 
endpoint seizure frequency during the double-blind phase.  


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• Participants with a ≥ 25%, ≥ 50%, and ≥ 75% reduction from baseline in 
primary endpoint seizure frequency during the maintenance period.  
• Responder analysis for primary endpoint seizures and all seizures during the 
double-blind phase using the following response categories: ≤ 0%, > 0% to 
< 25%, ≥ 25% to < 50%, ≥ 50% to < 75%, and ≥ 75% to 100%.   
• Percent change in 28-day frequency of all seizures.  
• Change from baseline in the percentage of seizure-free days, based on all 
seizure types.  
• Change from baseline in the longest seizure-free interval, based on primary 
endpoint seizure types and all seizure types. 
2.3.5. 
Exploratory Endpoints 
Except for the endpoints of seizure frequency during the titration and maintenance 
periods of the study,
 
2.3.6. 
Safety Endpoints 
• Incidence and severity of AEs, SAEs, and withdrawals and dose-reductions 
due to AEs 
• Other measures of safety including physical/neurological/developmental 
examinations, vital sign measurements (eg, blood pressure, heart rate, 
respiratory rate, and body temperature), 12-lead ECGs, clinical laboratory 
tests, and suicidal ideation and behavior risk monitoring. 


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3. 
STUDY DESIGN 
3.1. 
Randomization 
Subjects will be randomized to receive either GNX or PBO in a 1:1 ratio and 
randomization will be stratified based on current use of Epidiolex. Block randomization 
will be used with a block size specified in Rave RTSM (randomization and trial supply 
management) study randomization list settings document. 
3.2. 
Sample Size Considerations 
The planned sample size for this study is 128 randomized and dosed subjects. These 
subjects will be allocated into 2 treatment groups, GNX vs. PBO, in a 1:1 ratio. Sixty-
four subjects per group provides at least 90% power for the primary endpoint assuming 
an estimate of the treatment effect (the actual analysis will use a Wilcoxon rank-sum test, 
which has approximately the same power as the ANOVA) difference that is at least 25% 
and a common standard deviation of 43% or less. 
3.3. 
Multiplicity 
All endpoints will be assessed descriptively, by the treatment to which the participants 
are randomized, with point estimates and 95% confidence intervals. The primary and 
secondary endpoints will be assessed in an inferential manner. Multiplicity control will 
be used for the primary and key secondary endpoints. A gate keeping approach will be 
used to control the study-wide Type-I error rate. There is a single primary efficacy 
endpoint, and formal hypothesis testing will be performed for this endpoint first. If the 
null hypothesis is rejected for the primary efficacy endpoint at the 2-sided 5% alpha 
level, then statistical hypothesis testing will be performed sequentially on the 4 key 
secondary endpoints as the order listed in Section 2.3.2. The testing will stop if the testing 
result is non-statistically significant.  All other non-key secondary and exploratory 
endpoints will use a 2-sided 5% alpha with no adjustment for multiplicity. 
 
 
 
 


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4. 
STATISTICAL METHODOLOGY 
4.1. 
General Methodology 
Unless otherwise stated, SASsoftware (SAS Institute Inc, Cary, NC; SAS Enterprise 
Guide 8.3 Version or later) will be used for the generation of all tables, graphs, and 
statistical analyses.  Summary statistics including the number of subjects (n), mean, 
standard deviation, median, minimum and maximum will be presented for continuous 
variables. Generally, the minimum and maximum values will be presented to the same 
decimal precision as the raw values, the mean and median values to one more, and the 
standard deviation, to two more decimal places than the raw values. For categorical 
variables, per category, the absolute counts (n) and percentages (%) of subjects with data, 
and if appropriate, the number of subjects with missing data, will be presented. 
Percentages will be presented to one decimal place. 
For AEs, medical history and concomitant medications reported on a per-subject basis, 
the denominator for the percentage calculation will be the number of subjects in each 
treatment group. A subject will be considered at risk if the subject is in the analysis set 
and in the subgroup of interest. 
If a p-value is less than 0.0001 it will be displayed as “< 0.0001”. All p-values larger than 
0.0001 will be rounded to 4 decimal places. 
4.2. 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined: 
• Intent-to-treat (ITT) Set – Includes all randomized participants, who dosed 
and had at least one post-baseline efficacy assessment. Participants will be 
summarized within the treatment group to which they were randomized. This 
set will be used for efficacy analyses. 
• Per-protocol (PP) Set – Includes all participants in the ITT set who received 
IP for at least 6 weeks, provided at least 5 weeks of post-baseline seizure data, 
and without major protocol deviations that affect the efficacy endpoints 
(defined prior to database lock). 
• Safety Analysis Set – Includes all randomized participants who receive at 
least 1 dose of the IP. Participants will be summarized within the treatment 
group for which they received treatment. This set will be used for the safety 
analyses. 


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The 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 primary analysis will be performed within the ITT population; supportive analyses in 
the PP population will also be conducted. 
4.3. 
Statistical Methods for Efficacy Analyses 
4.3.1. 
Estimand Framework for the Primary Endpoint  
Population: The target study population comprises children and adults with TSC-related 
epilepsy who also meet the inclusion and exclusion criteria as specified in the study 
protocol. The analysis population is the Intent-to-Treat (ITT) Population defined as all 
randomized participants. 
Variable: The variable is the primary efficacy endpoint, the percentage change from 
baseline in 28-day primary endpoint seizure frequency during the double-blind phase.    
Population-Level Summary: The population-level summary will be the difference of the 
percentage change on primary efficacy endpoint between GNX and PBO groups and its 
2-sided 95% confidence interval.  
Accounting for Intercurrent Events (ICEs): Intercurrent events and their handling 
rules are as follows:  
• Discontinuations due to lack of efficacy; 
• Discontinuations due to expected (per IB) adverse events.  
Both ICEs will be addressed by the treatment policy strategy. The use of rescue 
medication is allowable at any time during the study. A patient may require rescue 
medication during the trial but continues with the trial post-rescue medication. The 
efficacy of the trial treatment will be assessed regardless of the need for rescue 
medication. Alternative approaches to handling ICEs will be addressed in sensitivity 
analyses, see Section 4.3.3. 
4.3.2. 
Primary Efficacy Endpoint 
Hypothesis testing will be performed for the primary endpoint: the percentage change in 
28-day primary endpoint seizure frequency during the DB phase relative to the baseline, 
based on the primary endpoint seizure types. The hypothesis testing is: 
Ho:  PBO =  GNX 
 
Ha:  PBO ≠  GNX 
where GNX is the percentage change of seizure frequency during the DB phase relative to 
the baseline for participants who treated with GNX and PBO is similarly defined for 
participants receiving placebo.  


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Primary endpoint 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 seizures, and generalized motor seizures including tonic-clonic, bilateral 
tonic, bilateral clonic, or atonic/drop seizures. Seizures that do not count toward the 
primary endpoint include: focal aware seizures without motor features (eg, focal 
nonmotor seizures with or without impaired awareness, absence or myoclonic seizures), 
infantile or epileptic spasms, and myoclonic seizures. 
Post-baseline 28-day seizure frequency will be calculated as the total number of seizures 
in the double-blind phase divided by the number of days with seizure data in the same 
period, multiplied by 28. Baseline 28-day seizure frequency will be calculated as the total 
number of seizures in the baseline phase divided by the number of days with seizure data 
in the same period, multiplied by 28. The calculation for percent change from baseline in 
28-day seizure frequency will be done as follows for each participant:  
 
The baseline, post-baseline, and arithmetic and percent changes from baseline in 28-day 
seizure frequency will be summarized using descriptive statistics.  
The difference between the treatment groups in the percent changes will be tested for 
statistical significance. The estimate of the median difference and corresponding 95% 
confidence interval based on the Hodges–Lehmann approach will be provided. Since the 
percent differences are anticipated to display skewness and/or outliers, the test will be 
performed using the Wilcoxon Rank-Sum statistic using a 2-sided significance level of 
0.05.  
4.3.3. 
Sensitivity Analysis 
Five sensitivity analyses of the primary efficacy endpoint of change in 28-day frequency 
of the primary seizure types will be performed: 
1. Intermittent (random/sporadic) missing data during the DB phase and any missing 
data during the baseline phase will be assumed missing completely at random and 
the collected data will be used to calculate the 28-day seizure frequencies. For 
early drug termination prior to the end of the DB phase, caregivers will be 
instructed to continue to provide daily seizure records until the end of the 
16-week DB phase (hence further preventing missingness). 
In the first sensitivity analysis, the following imputation approach will be used for 
the primary outcome measure when a subject stops recording measurements 
permanently prior to the end of the DB phase: for those missing days, the 
corresponding median PBO data will be imputed (irrespective of treatment arm) 
as follows: 


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• Partition the subjects in the PBO arm into quartiles, where the quartile equals 
Floor [Rank*4/(n+1)], where Floor [.] is the integer floor function, Rank is the 
rank of the 28- day seizure frequency in the PBO arm based on all available 
PBO measurements during the 4-week baseline phase (tied scores receive tied 
ranks), and n is the number of subjects in the PBO arm. 
• Assign each subject for whom imputation is needed into the quartile that 
covers the 28-day seizure frequency based on that subject’s available 
measurements during the 4-week baseline phase. If a frequency is lower than 
the lower bound of the lowest quartile (which could happen only in the GNX 
arm), then assign that subject to the lowest frequency quartile; likewise, if a 
frequency is higher than the upper bound of the highest quartile, then assign 
that subject to the highest frequency quartile. If a frequency falls between two 
quartiles (which, again, could happen only in the GNX arm), then based on 
the distances between the frequency and the upper and lower bounds of the 
lower and higher quartiles, respectively, assign the subject to the closer 
quartile (in case of a tie, assign to the lower quartile). 
• Within each quartile, compute the median 28-day seizure frequency in the 
PBO arm based on all available PBO measurements during the DB treatment 
phase. Label that ‘X’ and define ‘A’ to be ‘X’/28, (i.e., the daily average on 
placebo during the DB phase). 
• For any days (whether they be on the PBO or GNX arm) with missing counts 
due to a subject stopping recording measurements permanently, impute ‘A’ 
from the corresponding quartile on that day. 
2. The second sensitivity analysis will explore the possibility that subjects who stop 
recording their seizure counts tend to have higher seizure counts than the other 
subjects. The imputation method described in the 3rd and 4th bullets above, 
except that quartiles are not used, will be modified to use the median of the 5 
highest counts (equivalent to the 3rd highest count) among all the PBO subjects 
with data. 
3. The third sensitivity analysis will be performed on subjects who achieved their 
maintenance dose at the start of the maintenance period. This analysis will 
exclude those subjects who are still titrated continuously during maintenance 
period. 
4. The fourth sensitivity analysis will be performed for the primary outcome 
measure by excluding all intercurrent events. 
4.3.4. 
Key Secondary Efficacy Endpoints 
Hypothesis testing will be performed for the three key secondary endpoints:  


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1. Percentage change from baseline in 28-day primary endpoint seizure frequency 
during the maintenance period. 
The hypothesis testing is: 
Ho:  PBO =  GNX 
 
Ha:  PBO ≠  GNX 
where GNX is the percentage change of seizure frequency during the maintenance 
period relative to the baseline for participants who treated with GNX and PBO is 
similarly defined for participants receiving placebo. 
Similar to the primary efficacy endpoint, the test will be performed using the 
Wilcoxon Rank-Sum statistic using a 2-sided significance level of 0.05. 
 
2. Number (%) of participants considered treatment responders during the DB phase. 
   
The hypothesis testing is: 
       𝐻0: 𝛾PBO = 𝛾GNX      𝑣𝑠.       𝐻𝑎: 𝛾PBO ≠ 𝛾GNX 
where 𝛾GNX is the proportion of participants who treated with GNX experiencing 
≥ 50% reduction from baseline in 28-day seizure frequency based on the primary 
seizure types and 𝛾PBO is similarly defined for participants receiving placebo. 
The test comparison will be analyzed using Fisher’s Exact test and the 
corresponding p-value will be provided. The difference in proportions along with 
the 95% confidence interval for the difference also will be presented. The number 
and percentage of subjects experiencing a reduction (improvement) of at least 
50% from baseline in the 28-day seizure frequency of the primary seizure types 
will be summarized. In addition, a cumulative responder curve figure will be 
provided, in which the X-axis represents amount of improvement in increments of 
5%, and the Y-axis represents the percentage of subjects improving by at least the 
amount on the X-axis. The treatment groups will be presented separately within 
the figure. 
3. Number (%) of participants considered treatment responders during the 
maintenance phase.  
This is similar to #2 above. The only difference will be replacing the DB phase by 
the maintenance phase. 
 
4. CGI-I at the last scheduled visit in the DB phase. 
The hypothesis testing is: 
       𝐻0: 𝑂𝑅GNX/PBO = 1      𝑣𝑠.       𝐻𝑎: 𝑂𝑅GNX/PBO ≠1 
where 𝑂𝑅GNX/PBO is the odd ratio between GNX and PBO in regard to CGI-I. 


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The CGI-I is 7-point scale, and the number and percentage of subjects with each 
score will be summarized. The scores range from 1=very much improved and 
7=very much worse. The CGI-I is completed by both parent/caregiver/LAR and 
clinician. The score at the last visit in the DB treatment phase will be analyzed 
using ordinal logistic regression. Proportional odds modelling will be carried out 
by including treatment group as a factor. The estimated odds ratios (GNX vs. 
PBO), 95% CI for the odds ratios, and the p-value testing the null hypothesis that 
the odds ratio is equal to 1, will be presented. 
4.3.5. 
Secondary Efficacy Endpoints 
Summary statistics including confidence intervals for the treatment differences will be 
used to summarize the results for the secondary endpoints. Testing, as outlined below, 
will be used for the secondary endpoints. 
Change from baseline in ADAMS total score and sub-score. 
The ADAMS (Anxiety, Depression, and Mood Scale) is a rating scale designed to screen 
for anxiety and depression in individuals with intellectual disability. The 28-question 
scale is filled out by the parent/caregiver/LAR and is based on the subject’s behavior 
during the past 6 months at the Baseline visit and since the last visit at the subsequent 
visits. Each of the questions are scored as 0 = Not a problem, 1 = Mild problem, 
2 = Moderate problem, or 3 = Severe problem.  The questions are grouped into 
5 subscales: 
Manic/ 
Hyperactive 
Behavior 
Depressed Mood 
Social Avoidance 
General Anxiety 
Obsessive/ 
Compulsive 
Behavior 
3. 
5. 
2. 
1. 
8. 
4. 
9. 
6. 
3. 
16. 
12. 
10. 
13. 
7. 
20. 
17. 
14. 
19. 
11. 
 
22. 
18. 
21. 
15. 
 
 
23. 
25. 
24. 
 
 
28. 
27. 
26. 
 
 
The subscale totals will be summarized with descriptive statistics of the baseline and 
post-baseline values and the arithmetic changes from baseline. 
 


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Change from baseline in quality-of-life scales: Peds-QL-FIM, SF-36, and ELDQOL. 
• Peds-QL-FIM 
The Peds-QL-FIM is designed to measure the impact of pediatric chronic 
health conditions on parents and the family. The Peds-QL-FIM measures 
parent self-reported physical, emotional, social, and cognitive functioning, 
communication, and worry. The module also measures parent reported family 
daily activities and family relationships (see Protocol Section 10.14). 
Total Score is computed by averaging all 36 items. Parent HRQOL Summary 
Score is computed by averaging 20 items in Physical, Emotional, Social, and 
Cognitive Functioning. Family Summary Score is computed by averaging 
8 items in Daily Activities and Family Relationships. 
• SF-36 
The SF-36 is a multi-purpose survey designed to capture participant or 
parent/caregiver perceptions of own health and well-being. The SF-36 has 
36 items grouped in 8 dimensions: physical functioning, physical and 
emotional limitations, vitality, social functioning, bodily pain, general, and 
mental health (see Protocol Section 10.15). 
Scoring the 36-Item Health Survey is a two-step process. First, precoded 
numeric values are recoded per the scoring key given in Table 1. Note that all 
items are scored so that a high score defines a more favorable health state. In 
addition, each item is scored on a 0 to 100 range so that the lowest and highest 
possible scores are 0 and 100, respectively. Scores represent the percentage of 
total possible score achieved. In step 2, items in the same scale are averaged 
together to create the 8 scale scores. Table 2 lists the items averaged together 
to create each scale. Items that are left blank (missing data) are not taken into 
account when calculating the scale scores. Hence, scale scores represent the 
average for all items in the scale that the respondent answered. 
 


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Table 1: 
Recoding Items for SF-36 
Item numbers 
Change original 
response category 
To recoded 
value of: 
1, 2, 20, 22, 34, 36 
1 → 
100 
 
2 → 
75 
 
3 → 
50 
 
4 → 
25 
 
5 → 
0 
3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
1 → 
0 
 
2 → 
50 
 
3 → 
100 
13, 14, 15, 16, 17, 18, 19 
1 → 
0 
 
2 → 
100 
21, 23, 26, 27, 30 
1 → 
100 
 
2 → 
80 
 
3 → 
60 
 
4 → 
40 
 
5 → 
20 
 
6 → 
0 
24, 25, 28, 29, 31 
1 → 
0 
 
2 → 
20 
 
3 → 
40 
 
4 → 
60 
 
5 → 
80 
 
6 → 
100 


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Item numbers 
Change original 
response category 
To recoded 
value of: 
32, 33, 35 
1 → 
0 
 
2 → 
25 
 
3 → 
50 
 
4 → 
75 
 
5 → 
100 
 
Table 2: 
Averaging Items to Form Scales for SF-36 
Scale 
Number of 
items 
After recoding per Table 1, 
average the following items 
Physical functioning 
10 
3 4 5 6 7 8 9 10 11 12 
Role limitations due to physical health 
4 
13 14 15 16 
Role limitations due to emotional problems  
3 
17 18 19 
Energy/fatigue 
4 
23 27 29 31 
Emotional well-being 
5 
24 25 26 28 30 
Social functioning 
2 
20 32 
Pain 
2 
21 22 
General health 
5 
1 33 34 35 36 
 
• ELDQOL 
The ELDQOL is a 70-item parent/caregiver-reported measure that examines 
seizure severity, seizure related injury, AED side effects, behavior, mood, 
physical status, cognitive and social functioning, communication, overall 
health and quality of life, and family concerns. The higher the score, the 
poorer the participant’s quality of life (see Protocol Section 10.16). See the 
scoring instructions below: 


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Scoring instructions for 4 subscales of the re-validated version of ELDQOL 
 
Seizure Severity Scale (Qs. 1 – 14) 
 
 
Qs. 1, 5, 7, 8, 9, 10, 11, 13 
 
Reverse the individual item scoring so that  
 
1 = 4 
2 = 3 
3 = 2 
4 =1 
5 - define as a missing value so that it is not included in the calculation  
      of the scale score 
 
Qs. 4, 12    
 
Reverse the individual item scoring so that  
 
1 = 4 
2 = 3 
3 = 2 
4 =1 
5 = 0 
6 - define as a missing value 
 
Qs. 2, 14 
 
5 - Define 5 as a missing value. 
Other scores unchanged. 
 
 
Qs. 3, 6    
 
5 = 0 
Define 6 as a missing value. 
Other scores unchanged 
 
Total scale score range = 10-56  


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Side-effects Profile  (Qs. 17 & 18) (Only items in Q.18 used to compute sub-scale.) 
 
Score is the sum of the individual scores for each of the 19 items in Q.18 
 
For each item, score of 5 - define as a missing value. 
 
Any additional problems itemised by respondents should be recorded, but are not added 
to the total scale score. 
 
Total scale score range = 19-76, where high scores = high level of side effects reported. 
 
  
Behaviour (Qs. 19 – 27) 
 
Qs.19, 24, 25, 26 
 
 
Define 5 as a missing value 
 
Other scores unchanged 
 
Qs. 20, 21, 27  
 
Reverse scoring so that: 
 
1 = 4 
2 = 3 
3 = 2 
4 =1 
5 - define as a missing value 
 
Qs.22, 23  
 
Recode so that: 
 
 
5 = 4 
 
6 – define as a missing value 
 
Other scores unchanged 
 
Total scale score range = 9-36 
 
 


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Mood Scale (Q. 28) 
 
Reverse scoring of negative items (aggressive, irritable, tearful, hyperactive, sad, 
agitated, restless, tantrum-prone, frustrated, withdrawn), so that: 
 
1 = 4 
2 = 3 
3 = 2 
4 =1 
5 - define as a missing value 
 
Total Scale score range = 16-64 
 
 
General points 
 
For each subscale, higher score = poorer QOL / functioning. 
 
Give non-responses a missing value (suggest 9 or -9).  
 
The mean score for each subscale is computed as the sum of the items divided by the 
number of items answered. To take account of any missing data in a subscale, the mean 
of the completed items can be imputed, providing at least 50% of the items are 
completed. If more than 50% of the items in the subscale are missing, then the total 
subscale score should be classed as a missing value.  
All scales and subscales will be summarized separately with descriptive statistics of the 
baseline and post-baseline values and the arithmetic changes from baseline. 
 
Change from baseline in the percentage of seizure-free days during the DB phase, 
based on primary endpoint seizure type. 
The percentages of seizure-free days will be based on the primary seizure types. Post-
baseline percentage of seizure-free days will be calculated as the number of days in the 
DB treatment phase with zero seizures divided by the number of days with seizure data in 
the phase, multiplied by 100. The baseline percentage of seizure-free days will be 
calculated as the number of days in the 4-week baseline phase with zero seizures divided 
by the number of days with seizure data in the baseline phase, multiplied by 100. 
The baseline and post-baseline values and the arithmetic changes from baseline will be 
summarized using descriptive statistics. 
 


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CGI-CSID at the last scheduled visit in the DB phase. 
The CGI-CSID is from the 7-point Caregiver Global Impression of Change in Seizure 
Intensity/Duration instrument. The scores range from 1=very much improved and 7=very 
much worse.  The number and percentage of subjects with each score will be 
summarized.  
 
Participants with a ≥ 25% and ≥ 75% reduction from baseline in primary endpoint 
seizure frequency during the DB phase.  
Number (%) of subjects considered treatment responders, defined as those with a ≥25% 
and ≥75% reduction from baseline in primary seizure frequency during the DB phase will 
be summarized. 
 
Participants with a ≥ 25%, ≥ 50%, and ≥ 75% reduction from baseline in primary 
endpoint seizure frequency during the maintenance period.  
Number (%) of subjects considered treatment responders, defined as those with a ≥25%, 
≥ 50%, and ≥75% reduction from baseline in primary seizure frequency during the 
maintenance period will be summarized. 
 
Responder analysis for primary endpoint seizures and all seizures during the 
double-blind phase using the following response categories: ≤ 0%, > 0% to < 25%, 
≥ 25% to < 50%, ≥ 50% to < 75%, and ≥ 75% to 100%.  
Number (%) of subjects considered treatment responders categories, defined as those 
with a ≤ 0%, > 0% to < 25%, ≥ 25% to < 50%, ≥ 50% to < 75%, and ≥ 75% to 100% 
reduction from baseline in seizure frequency during the DB phase will be summarized 
using descriptive statistics (in both a table and a figure). The analysis will be conducted 
for primary endpoint seuzures and all seizures, respectively. 
 
Percent change in 28-day frequency of all seizures.  
This analysis is similar to primary efficacy endpoint during the DB phase, except all 
seizure types will be applied. 
 


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Change from baseline in the percentage of seizure-free days, based on all seizure 
types.  
The percentages of seizure-free days will be based on all seizure types. Post-baseline 
percentage of seizure-free days will be calculated as the number of days in the DB 
treatment phase with zero seizures divided by the number of days with seizure data in the 
phase, multiplied by 100. The baseline percentage of seizure-free days will be calculated 
as the number of days in the 4-week baseline phase with zero seizures divided by the 
number of days with seizure data in the baseline phase, multiplied by 100. 
The baseline and post-baseline values and the arithmetic changes from baseline will be 
summarized using descriptive statistics. 
Change from baseline in the longest seizure-free interval, based on primary 
endpoint seizure type and all seizure types.  
The longest seizure-free intervals (percentage of days) will be based on both the primary 
seizure types and all seizure types. The post-baseline longest period of time seizure-free 
is defined as the longest seizure-free period (days) in the DB treatment phase divided by 
the days with seizure data during the phase, and then multiplied by 100%. The baseline 
longest period of time seizure-free is defined as the longest individual seizure-free period 
(days) in the baseline phase divided by the days with seizure data during the baseline 
phase, and then multiplied by 100%. For both phases, the longest period is based on the 
number of days without an interruption of a day with a seizure. If there is an interruption 
of a day without any seizure data, then that day will not count. For example, if there are 
seizures on January 1st, no seizures on January 2nd through 4th, no seizure data on 
January 5th, no seizures on January 6th, and there are seizures on January 7th, then the 
longest period of time seizure free in this interval would be 4 days (January 2nd through 
4th and January 6th).  
The longest seizure-free interval will be summarized using descriptive statistics for the 
baseline and post-baseline values, as well as the arithmetic changes from baseline. 


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4.3.7. 
Subgroup Analyses for Primary Endpoint 
Summaries with descriptive statistics and frequency counts on the primary efficacy 
endpoint for both groups will be provided for the subgroups indicated below. Forest plots 
will also be created for subgroup analyses and will display treatment differences. The 
subgroups will be: 
• Gender (female vs. male) 
• Age Group (12 months to 23 months; 2 to 11 years; 12 to 17 years; 18 to 
64 years; and 65 years and above) 
• Country/Region (US, China, EU, ROW)  
•  
• Concomitantly taking everolimus (yes vs. no)  
• Concomitantly taking cannabidiol (yes vs. no) 
• mTOR medication (taking sirolimus, everolimus, tacrolimus vs. no) 


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4.3.8. 
Handling of Missing Data 
Available data from patients who withdraw from the study prematurely will be included 
in analyses, unless otherwise indicated. Summary statistics will be reported based upon 
observed data. No data will be imputed or carried forward for missing values or for 
patients who discontinue early. All missing data and missing or partial dates for AEs and 
medications will be queried for a value. In the unlikely event that no value can be 
obtained, substitutions will be made as described below. 
• Missing and Partial Start/Stop Dates - AEs and Concomitant Medications 
The handling of partial start and stop dates for AEs are described in Table 3 
below. Similar algorithms for handling missing and partial dates of 
concomitant medication usage are described in Table 4. In both cases, if a stop 
date is complete and an imputed start date is after the stop date, the start date 
will be set to the stop date. 
• Missing Seizure/Medication Diary Entries  
The calculation of seizure frequency endpoints will include only days for 
which diary entries are available. Missing seizure data will not be imputed. 
 


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Table 3: 
Adverse Event Start/Stop Date Imputation 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date for 
AEs 
 
D 
M and Y same as M and Y of first dose 
of IP 
Date of first dose of IP 
Y same but M prior to month of first 
dose of IP 
Last day of month 
Y same but M after month of first dose 
of IP  
First day of month 
Y is prior to year of first dose of IP 
Last day of month 
Y is after year of first dose of IP 
First day of month 
M 
Y is same as Y of first dose of IP 
Month of first dose of IP 
Y is prior to year of first dose of IP 
M = December 
Y is after Y of first dose of IP 
M = January 
D and M 
Y same as Y of first dose of IP 
Date of first dose of treatment 
Y prior to Y of first dose of IP 
M and D will be December 31 
Y after Y of first dose of IP 
M and D will be January 1 
Y, or M, D, Y 
Y and/or start date missing 
Date of first dose of treatment 
Stop date for 
AEs 
 
D 
M and Y not missing 
Use last day of month (i.e. D 
may take on values of 28, 29, 
30, or 31, depending on 
month) 
M 
Y not missing; if D also missing, 
impute D as described above 
M = December 
 
Y, or M, D, Y 
Y and/or stop date missing. 
No imputation. Date left 
missing. 
D=day, M=month, Y=year 
Note:  In all cases, if an estimated start date is after a complete stop date, the start date will be set to the 
AE stop date. Similarly, if the estimated stop date is before a complete or imputed start date, use the 
last day of the start day month. 
 


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Table 4: Imputation for Prior/Concomitant Medication Missing and Partial Dates 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date for 
con meds  
D only 
M and Y are not missing or imputed. 
Use 1st day of M. 
M only 
D and Y are not missing or imputed. 
M = January 
M and D 
Y is not missing or imputed. 
Use Jan 01 of Y 
M, D, and 
Y 
None - date completely missing 
No imputation but considered 
concomitant unless stop date is 
prior to first dose of IP. 
Stop date for 
con meds  
D only 
M and Y are not missing or imputed.  
Last day of month 
M only 
D and Y are not missing or imputed. 
M = December 
M and D 
Y is not missing or imputed 
Use Dec 31 of Y 
M, D, and 
Y 
None - date completely missing and 
NOT ongoing 
No imputation 
Note:  In all cases, if an estimated start date is after a complete stop date, the start date will be set to the 
end date of medication. 
 
 
 
 


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5. 
BASELINE, DISPOSITION, AND EXPOSURE 
5.1. 
Study Day and Analysis Window 
For reporting purposes, Study Day will be calculated from the date of the Baseline 
Treatment Visit (Visit 2, Day 1). Similarly, Study Week will be calculated from the date 
of the Baseline Treatment Visit. 
For all assessments performed on or after the first day of treatment, i.e. reference date 
≥ date of first dose of IP, Study Day is calculated as: 
• 
Study Day = (date of assessments/events - first day of treatment) + 1 
For assessments performed prior to the first day of treatment, i.e. reference date < date of 
first dose of IP, Study Day is calculated as: 
• 
Study Day = date of assessment/event – first day of treatment. 
5.2. 
Definition of Baseline 
The Baseline Visit is defined as Visit 2 (Day 1). Baseline values for non-seizure efficacy 
and safety assessments will be the last values collected prior to the first administration of 
IP (i.e., GNX), unless otherwise specified. 
Baseline seizure frequency data is collected during the four weeks between the Screening 
Visit (Visit 1, Week -4) and the Baseline Visit (Visit 2, Day 1). This interval may range 
from no less than 28 days to no more than 34 days. 
5.3. 
Analysis Visit Windows 
Efficacy Analyses 
Efficacy analyses will use data only from scheduled visits. Data will be reported by 
designated visit. Data collected at unscheduled visits will be provided in listings. For 
analysis of data collected across specific study periods, the following definitions will be 
applied: 
• Baseline period: Visit 1 to Visit 2; Study Week -4 (Day -28) through 
Study Day 1 (date of first dose of IP) 
• Titration period: Visit 2 + 1 day to Visit 7; Study Day 1 through Study 
Week 7 (Day 28 ± 3 days; date of Visit 7) 
• Maintenance period: Visits 7 + 1 day to Visit 12; Study Week 5 (± 3 days) 
through Study Week 16 (± 3 days) 
• 16-week treatment period: titration period + maintenance period (including 
taper and safety visits if not continuing in OLE) 


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Safety Analyses 
Safety data will be summarized by actual visit. No visit windowing will be applied. 
5.4. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized and listed for all patients 
in the Safety Population. Demographic characteristics, including age, height, weight, and 
BMI, will be summarized with descriptive statistics (n, mean, median, SD, minimum and 
maximum). Categorical characteristics such as age group (≤ 17 years, > 17 years), weight 
group (≤ 28 kg, > 28 kg), sex, race and ethnicity, will be summarized as counts and 
percentages. 
Additionally, baseline clinical characteristics including results of genetic testing for 
pathogenic or likely pathogenic TSC1 or TSC2 variant, Tanner Staging, number of AEDs 
taken and stopped prior to screening, neurological exam results, developmental 
examination results (pediatric patients aged 2 to 17, inclusive), and Seizure Identification 
and Diagnostic Review Form (SIF/DRF) responses including baseline seizure types 
reported as primary and non-primary, IQ, intellectual disabilities, and EEG findings will 
be summarized.  
Baseline values of efficacy and safety parameters will be summarized in the respective 
analysis tables.    
5.5. 
Subject Disposition 
The number of patients screened for this study, the number of screen failures and the 
number of patients who received at least one dose of IP will be summarized. Reasons for 
screen failure will be provided in the data listing. The final disposition of all patients who 
receive IP will be summarized. Reasons for discontinuation of study treatment and for 
discontinuation of study participation will be summarized. The total number and 
percentage of patients who complete the study will be summarized.  
A listing of patient disposition will be provided. In addition, a summary of the number of 
patients included in each analysis set will be presented. 
5.6. 
Eligibility Criteria and Protocol Deviations 
The clinical team will review and identify deviations and the deviations will be recorded 
into the database. A data listing of subjects who violate any of the inclusion/exclusion 
characteristics will be provided as well as a data listing of subjects with other protocol 
violations. 


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5.7. 
Prior and Concomitant Medications 
All investigator terms for medications recorded on the CRF will be coded using the 
World Health Organization Drug Dictionary Enhanced (WHODDE) Anatomical 
Therapeutic Chemical (ATC) drug dictionary. The number (percentage) of subjects who 
took prior and concomitant medications will be summarized in the Safety population by 
Anatomic Therapeutic Chemical (ATC) classification level 2 and Preferred Term (PT). 
Prior medications are defined as medications/therapies that started and stopped prior to 
the first dose of study drug. Concomitant medications are defined as medications (other 
than the study drug) administered on or after the first dose of the study, regardless of 
when the medications started. 
The number and percentage of patients in the Safety population reporting use of prior and 
concomitant treatments will be summarized and listed separately. In addition, 
antiepileptic prior and concomitant drugs (AEDs) and rescue medications will be 
presented separately.  
5.8. 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA), version 25.1. The number and percent of subjects with clinically significant 
medical history at screening will be summarized by system organ class (SOC) and 
preferred term (PT) in the Safety population. Medical history will also be listed. 
5.9. 
Study Drug Exposure 
Exposure to study medication (GNX) will be summarized as the number of days on 
treatment, percentage of days dosed, maximum daily dose received, and total dosage 
received. The denominator for the percentage of days of study drug is the number of days 
the patient is on treatment in the respective part of the study. If the patient stops taking IP 
during the study, the last day that drug was taken will be used as the last day of treatment. 
For patients who are ongoing at the end of a specific part of the study, the last known 
treatment date will be used for the last day on treatment. 
A listing of exposure data for each patient including total daily dose, start and end dates, 
and reason for any dose change will also be provided. 


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5.10. 
Study Drug Compliance 
The percent compliance with study drug will be estimated using dosing information as 
follows: 
[𝑡𝑜𝑡𝑎𝑙 𝑑𝑜𝑠𝑒𝑎𝑔𝑒 𝑑𝑢𝑟𝑖𝑛𝑔 𝑚𝑎𝑖𝑛𝑡𝑒𝑛𝑎𝑛𝑐𝑒 𝑝𝑒𝑟𝑖𝑜𝑑]
[(𝑙𝑎𝑠𝑡 𝑑𝑎𝑦 𝑜𝑓 𝑚𝑎𝑖𝑛𝑡𝑒𝑛𝑎𝑛𝑐𝑒 𝑝𝑒𝑟𝑖𝑜𝑑) −(𝑓𝑖𝑟𝑠𝑡 𝑑𝑎𝑦 𝑜𝑓 𝑚𝑎𝑖𝑛𝑡𝑒𝑛𝑎𝑛𝑐𝑒 𝑝𝑒𝑟𝑖𝑜𝑑) + 1] × (𝑡𝑎𝑟𝑔𝑒𝑡 𝑑𝑎𝑖𝑙𝑦 𝑑𝑜𝑠𝑒)  𝑥100 
Reported dosing by visit and calculated compliance values will be listed. 
 
5.11. 
Cross-Over Titration Summary 
The end date of Double-Blind Maintenance Period and the start date of Cross-over 
Titration period are supposed to be two different days. However, one overlapped day may 
exist in some rare scenarios. When this appears in the EDC data, the following rule will 
be implemented to handle the analysis and data summary:  
1. The last visit date in DB maintenance period will not be changed. This date will 
be set as the end date of the DB phase. 
2. All scheduled/unscheduled tests (Lab, Vital Sign, ECG etc.) have been done on 
the last visit date in DB maintenance period will be summarized in the DB phase. 
3. All the TEAEs, CMs and seizures occurred on the last visit date in DB 
maintenance period will also be summarized in the DB phase. 
The following safety endpoints will be summarized descriptively: 
• Incidence and severity of AEs, SAEs, and withdrawals and dose-reductions 
due to AEs 
• Physical/neurological/developmental examinations 
• Vital sign measurements  
• 12-lead ECGs 
• Clinical laboratory tests 
• Suicidal ideation and behavior risk monitoring 
 
 


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6. 
ANALYSIS OF SAFETY ENDPOINTS 
6.1. 
Adverse Events 
Adverse events (AEs) are collected from the time of informed consent/assent through the 
defined follow-up period. AEs are coded using MedDRA dictionary, version 25.1 and are 
categorized by system organ class (SOC) and preferred term (PT). A treatment-emergent 
AE (TEAE) is defined as an AE that starts or worsens on or after the first day of dosing 
with IP. Detailed by-patient listings of all AEs reported during the study will be provided 
and will include verbatim and coded terms for each AE. 
For the safety population, the following tabular summaries will be created: 
• An overall summary of TEAEs will present the number and percentage of 
subjects with at least 1 reported TEAE, study drug related TEAE, serious 
TEAE, TEAE of Grade 3 or higher, study drug infusion interruption, and 
death 
• TEAEs by system organ class and preferred term 
• TEAEs by system organ class, preferred term, and maximum severity 
• Study drug related TEAEs by system organ class and preferred term 
• TEAEs by decreasing frequency of preferred term 
• Grade 3 or higher TEAEs by system organ class and preferred term 
• Grade 3 or higher study drug related TEAEs by system organ class and 
preferred term 
• TEAEs that led to study drug infusion interruption by system organ class and 
preferred term 
• TEAEs that led to study discontinuation by system organ class and preferred 
term 
• Serious TEAEs by system organ class and preferred term 
• Serious study drug related TEAEs by system organ class and preferred term 
For incidence reporting, if a subject reported more than 1 AE that was coded to the same 
preferred term/system organ class, the subject will be counted only once for that specific 
preferred term/system organ class. For TEAEs presented by severity, the worst severity 
for each event during the clinical trial will be presented for each subject. If the severity is 
missing for a TEAE, then a “Serious” will be assigned. The imputed values for severity 
assessment will be used for incidence summaries, while the actual values will be used in 
data listings. 


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For TEAEs presented by relationship to study drug, the closest relationship to study drug 
for each event during the clinical trial will be presented for each subject. If the 
relationship to investigational product is missing for a TEAE, a causality of “Related” 
will be assigned. The imputed values for relationship assessment will be used for 
incidence summaries, while the actual values will be presented in data listings. 
All AEs, SAEs, TEAEs leading to study drug interruption, TEAE leading to study 
discontinuation, SAEs leading to death and Grade 4 or higher AEs will be displayed in 
separate listings. 
6.2. 
Clinical Laboratory Evaluations 
Laboratory data collected in this study include serum chemistry, hematology values and 
urinalysis results. The baseline laboratory value is defined as the last value observed prior 
to the first administration of study drug. Any values collected after the administration of 
study drug are regarded as post-baseline. Change from baseline will be calculated as the 
post-baseline value minus the baseline value. Only the numeric part in laboratory values 
that contain non-numeric qualifiers, such as less than (<) a certain value or greater than 
(>) a certain value, will be used in the summary statistics. 
Laboratory values and change from baseline in these values will be listed and 
summarized for patients in the Safety Population by group (chemistry, hematology or 
urinalysis) and by visit. Listings of patients with positive drug screen or pregnancy results 
will be provided. 
Descriptive summaries of continuous laboratory values and change from baseline in these 
values will include the number of observations, mean, SD, median, minimum and 
maximum values at each time point. Data will be summarized in SI units. Shift tables 
comparing baseline classification based on reference range (i.e., normal, low, or high) to 
the worst classification recorded post-baseline will be presented. In the case that a patient 
has both “low” and “high” post-baseline results for the same laboratory parameter, the 
patient will be counted under both “low” and “high”. A patient will be counted under the 
“normal” category post-baseline only if all post-baseline results are categorized as 
“normal”. 
For non-numeric urinalysis data, a shift table comparing baseline results (negative, trace 
or positive) to the maximum post-baseline result will be presented. 
Listings of laboratory results for each patient will be presented. Values outside of the 
laboratory’s reference range will be flagged in the listing. A by-patient listing of 
laboratory values outside the normal reference range for the parameter will be produced. 


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6.3. 
Vital Signs, Physical, Neurological and Developmental 
Examination Findings 
Vital Signs 
Vital signs measured in this study include systolic and diastolic blood pressure, heart rate, 
respiratory rate, and body temperature. Baseline for vital signs will be the values obtained 
at the last assessment prior to the first dose of IP, typically Visit 2, Day 1. Change from 
baseline is calculated as the post-baseline value minus the baseline value. Missing values 
will not be imputed. 
Absolute values and changes from baseline in vital signs at each visit will be summarized 
in the Safety Population using descriptive statistics (n, mean, SD, median, minimum, and 
maximum). A by-patient, by-visit listing of vital signs collected and height and weight 
recorded will be provided. 
All vital signs included the parameter values and overall interpretations will be listed. 
Changes from baseline physical examination findings will also be listed individually by 
patient. 
The observed data at baseline and change from baseline for each measurement day will 
be summarized for each parameter with descriptive statistics. Plots of mean vital signs 
values (and standard error bars) over week 4 will be produced. 
Physical Examination Findings 
Physical examinations will be conducted at all clinic visits and findings will be recorded 
as normal, abnormal but not clinically significant, and abnormal and clinically 
significant. Abnormal changes in baseline physical examinations findings will be 
summarized using counts and percentages of patients in the Safety Population. Abnormal 
findings noted at baseline will be listed for each patient. Any changes in physical 
examination findings at post-baseline visits relative to the previous visit will be listed.  
Neurological Examination Findings 
Neurological examinations will be conducted at all clinic visits and will include 
evaluation of cranial nerves, motor function, sensory function, reflexes and 
coordination/cerebellar function. Findings will be recorded as normal, abnormal but not 
clinically significant, and abnormal and clinically significant. The number and percentage 
of patients with abnormal neurological findings will be summarized by parameter. 
Abnormal neurological findings at baseline will be listed for each patient. Any changes in 
neurological findings at post-baseline visits relative to the previous visit will be listed. 


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Developmental Examination Findings 
Developmental examinations will be conducted on pediatric patients 2 to 17 years of age, 
inclusive. Developmental parameters assessed include speech and language skills, motor 
skills and social skills. The number and percentage of pediatric patients will be 
summarized by each parameter.  
6.4. 
Electrocardiogram (ECG) 
Safety ECG measurements will be collected throughout the study. Baseline ECG values 
are those collected at Visit 2 (Day 1) prior to the first dose of IP. 
ECG parameters include heart rate, PR interval, RR interval, QRS interval, QT 
(uncorrected) interval, QTcF interval, and QTcB interval. In addition, the overall 
interpretation of the investigator will be documented as normal, abnormal but not 
clinically significant (NCS), or abnormal and clinically significant (CS). All clinically 
significant abnormal findings will be reported as AEs also. Absolute values and change 
from baseline in post-baseline values will be summarized. By-patient listings of ECG 
data and overall interpretations will be provided. 
6.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a patient questionnaire that 
evaluates suicidal ideation and behaviors. The results (yes/no) from the 5 questions under 
suicidal ideation and the 5 questions under suicidal behavior will be summarized at 
baseline and post baseline using percentages and counts. The denominator for 
percentages will be the number of subjects with a C-SSRS assessment at baseline or at 
any time post baseline. The post-baseline by-question summary will list a subject as "yes" 
if they selected yes at any time after baseline. 
The C-SSRS suicidal behavior and suicidal ideation scores recorded at baseline and any 
changes in post-baseline scores from the previous visit will be summarized descriptively 
by visit, including the number and percentage of subjects reporting any suicidal behavior 
and any suicidal ideation as defined in Table 5. Adult and pediatric C-SSRS data will be 
summarized separately.  
C-SSRS data collected, including scores for suicidal ideation, intensity of ideation and 
actual suicide attempts, will be listed by patient and visit. 


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Table 5: 
C-SSRS Categories for Analysis 
Category 
C-SSRS Item response is “YES” 
Suicidal behavior 
Preparatory acts or behavior 
Aborted attempt 
Interrupted attempt 
Actual attempt 
Complete suicide 
Suicidal ideation 
Wish to be dead 
Non-specific active suicidal thoughts 
Active suicidal ideation with any methods (not plan) without intent to act 
Active suicidal ideation with some intent to act, without specific plan 
Active suicidal ideation with specific plan and intent 
Non-suicidal self-injurious 
behavior 
Non-suicidal self-injurious behavior 
 
6.6. 
Pregnancies 
Any reported positive pregnancy results or reported pregnancies will be listed. 
6.7. 
Tanner Staging 
The Tanner scale is a scale of physical development in children, adolescent and adults. 
Patients will be rated as Tanner I, Tanner II, Tanner III, Tanner IV or Tanner V at 
baseline and end of the study. The number and percentage of patients in each category 
will be summarized and listed by visit. 


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7. 
APPENDIX 
The following analysis will be included for the submission to EMA.  
• The primary endpoint analysis will be based on the maintenance period only. 
• All secondary endpoints analyses will be based on the maintenance period 
only. 


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8. 
SUMMARY OF MAJOR CHANGES IN THE PLANNED 
ANALYSES 
The ITT definition is updated in this SAP. 
• Intent-to-treat (ITT) Set – Includes all randomized participants, who dosed 
and had at least one post-baseline efficacy assessment. Participants will be 
summarized within the treatment group to which they were randomized. This 
set will be used for efficacy analyses. 
In protocol, it was: 
• All randomized participants. Participants will be summarized within the 
treatment group to which they were randomized. This population will be used 
for efficacy analyses. 


Signature Page for VV-CLIN-000496 v3.0
Signature Page for VV-CLIN-000496 v3.0
Approval Task Task
Verdict: Approved
Biometrics
20-Aug-2024 19:42:19 GMT+0000
Approval Task Task
Verdict: Approved
Clinical
21-Aug-2024 00:05:24 GMT+0000
Approval Task Task
Verdict: Approved
Biometrics
21-Aug-2024 05:15:00 GMT+0000