Clinical trial NCT04285346
Conditions: Tuberous Sclerosis
Sponsor: Marinus Pharmaceuticals
Start date: 2020-04-08; Completion date: 2022-08-30
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To assess preliminary safety and efficacy of ganaxolone as adjunctive therapy for the treatment of primary seizure types in patients with genetically- or clinically-confirmed TSC-related epilepsy through the end of the 12 week treatment period.

Detailed description:
This is an OL proof of concept study of adjunctive GNX treatment in patients with a confirmed clinical diagnosis of TSC and/or a mutation in either the TSC1 or TSC2 gene. The trial consists of two parts: Part A consists of a 4-week baseline period followed by a 12-week treatment period (4-week titration and 8-week maintenance). For patients not continuing in the 24-week OLE period (Part B), a 2-week taper period followed by a 2-week safety period would follow. The main difference between Part A and Part B is the length of treatment, less frequent assessments, and the ability to alter drug doses (both GNX and other antiepileptic drug \[AED\] treatments which includes initiating and stopping other medications) based on investigator evaluation of the patient's clinical course during Part B. Patients with a seizure frequency reduction during the 12-week treatment period in Part A compared to baseline may continue into Part B ("OLE eligible"), to assess long-term safety, efficacy and tolerability in patients with TSC-related Epilepsy.

Arms: arm 1: ganaxolone suspension (50 mg/ml) TID for 12 weeks with 24 week extension
Interventions: intervention 1: Ganaxolone
Intervention descriptions: intervention 1: titration followed by maintenance and extension period

Protocol documents:
Prot_000.pdf: 
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Page 1 of 88
PROTOCOL:  1042-TSC-2001
TITLE:
A Phase 2 Open-label 12-Week Trial of Adjunctive Ganaxolone 
Treatment (Part A) in Tuberous Sclerosis Complex-related Epilepsy 
followed by Long-term Treatment (Part B)
DRUG:
Ganaxolone
IND:
044,020
SPONSOR:
Marinus Pharmaceuticals, Inc.
5 Radnor Corporate Center
100 Matsonford Rd, Suite 500
Radnor, PA 19087 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR:
PROTOCOL 
HISTORY:
Protocol Amendment 2: 11 Jun 2021, Version 3.0
Protocol Amendment 1: 12 May 2020, Version 2.0
Original Protocol: 07 Feb 2020
This document contains confidential and proprietary information of Marinus and is disclosed pursuant to 
confidentiality and non-disclosure obligations.  This information should be used solely for the purposes for which it 
was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Marinus.
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NCT Number: NCT04285346
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


 
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PROTOCOL SIGNATURE PAGE 
Sponsor’s (Marinus) Approval 
Signature: 
Date: 
 
{Note: Signature date must 
not precede the approval date} 
 
Investigator’s Acknowledgement 
I have read this protocol for Marinus Study 1042-TSC-2001. 
Title:  A Phase 2 Open-label 12-Week Trial of Adjunctive Ganaxolone Treatment (Part A) 
in Tuberous Sclerosis Complex-related Epilepsy followed by Long-term Treatment 
(Part B) 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor’s representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor.  It is, however, permissible to provide the 
information contained herein to the parent/caregiver/legally authorized guardian (LAR) in order 
to obtain consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation guidelines on Good Clinical Practice 
and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing.  Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and 
Institution Name and Address: 
(please hand print or type) 
 
 
 
Signature: 
 
Date: 
 
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PPD


 
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Protocol 1042-TSC-2001 
 
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SUMMARY OF CHANGES FROM PREVIOUS VERSION 
Protocol Amendments 
Summary of Change(s) Since Last Version of Approved Protocol 
 
 
Amendment Number 
2 
Amendment Date 
11 Jun 2021 
Description of Change 
Section(s) Affected by Change 
Protocol version and date updated 
Protocol History 
Sponsor contact information updated 
Emergency Contact Information 
Study period (planned) 
Study Synopsis 
OL extension 
Methodology Part B 
Formatting update 
4.1 Inclusion Criteria 
PK sample collection clarification 
7.8 Pharmacokinetic Assessments 
Unscheduled visits clarification 
7.3.5 Unscheduled visits 
Study design updated 
3.1 Study Design and Flow Chart 
Duration of study extended 
3.2 Duration and Study Completion 
Definition 
Amendment Number 
1 
Amendment Date 
12 May 2020 
Description of Change 
Section(s) Affected by Change 
Update protocol version and date 
Protocol History 
Add table for Summary of Changes 
Summary of Changes 
Add Day 1 and Day 2 Follow-up phone calls 
Schedule of Assessments -Part A 
Add CGI-I assessments to Baseline Visit 
Schedule of Assessments -Part A 
Change footnote “m” from screening to baseline 
Schedule of Assessments -Part A 
Add remote / home visits details 
7.1 Study Assessments 
Add CGI-I assessments (caregiver and clinician) 
7.2.2 Baseline 
Add Day 1 and Day 2 Follow-up phone calls 
7.2.3 Telephone Follow-up 
Change from screening to baseline visit 
7.5.2 CGI-C 
Add Baseline visit 
7.5.3 CGI-I 
Plasma drug screen moved to hematology from urinalysis 
12.2 Appendix 2 
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EMERGENCY CONTACT INFORMATION 
SERIOUS ADVERSE EVENT REPORTING:  
In the event of a serious adverse event (SAE), the investigator must notify the sponsor medical 
monitor and the sponsor project manager by e-mail or fax the Marinus Clinical Study Serious 
Adverse Event Form within 24 hours to Marinus Safety Department at:  
Email: safetyTSC2001@marinuspharma.com  
Fax: +1 484-679-2138  
SPONSOR CONTACTS:  
Sponsor Medical Monitor:  
, MBChB 
Mobile Telephone:  
 
Email:  
 
 
If sponsor’s Medical Monitor cannot be reached in an emergency, the site should contact: 
Back-up Medical Monitor: 
, MD  
 Clinical Development 
Mobile Telephone: 
 
Email: 
 (primary contact method) 
Sponsor Project Managers:  
 
 Clinical Operations 
Office Telephone:
Mobile Telephone: 
 
Email: 
 (primary contact method) 
 
 Clinical Development Operations 
Office Telephone:
Mobile Telephone: 
 (primary contact method) 
Email: 
 
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PPD
PPD
PPD
PPD
PPD
PPD


 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................................2 
SUMMARY OF CHANGES FROM PREVIOUS VERSION ........................................................3 
EMERGENCY CONTACT INFORMATION ................................................................................4 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES .........................................................................................................................10 
LIST OF FIGURES .......................................................................................................................10 
ABBREVIATIONS .......................................................................................................................11 
STUDY SYNOPSIS ......................................................................................................................14 
1. 
BACKGROUND INFORMATION ...........................................................................31 
1.1. 
Indication and Current Treatment Options .................................................................31 
1.2. 
Product Background and Clinical Information ...........................................................31 
2. 
STUDY OBJECTIVES AND PURPOSE ..................................................................34 
2.1. 
Rationale for the Study ...............................................................................................34 
2.2. 
Study Objectives .........................................................................................................35 
2.2.1. 
Primary Objective .......................................................................................................35 
2.2.2. 
Secondary Objectives .................................................................................................36 
2.2.3. 
Exploratory Objectives ...............................................................................................36 
3. 
STUDY DESIGN .......................................................................................................36 
3.1. 
Study Design and Flow Chart .....................................................................................36 
3.2. 
Duration and Study Completion Definition ................................................................38 
3.3. 
Sites and Regions ........................................................................................................38 
3.4. 
Discussion of Study Design ........................................................................................38 
4. 
STUDY POPULATION .............................................................................................39 
4.1. 
Inclusion Criteria (Part A) ..........................................................................................39 
4.1.1. 
Inclusion Criterion (Part B) ........................................................................................41 
4.2. 
Exclusion Criteria (Part A) .........................................................................................41 
4.2.1. 
Exclusion Criterion (Part B) .......................................................................................43 
4.3. 
Restrictions .................................................................................................................43 
4.4. 
Reproductive Potential................................................................................................43 
4.4.1. 
Female Contraception .................................................................................................43 
4.4.2. 
Male Contraception ....................................................................................................43 
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4.5. 
Discontinuation of Patients .........................................................................................43 
4.5.1. 
Patient Withdrawal Criteria ........................................................................................44 
4.5.2. 
Reasons for Early Discontinuation .............................................................................44 
4.5.3. 
Patients Lost to Follow-up Prior to Last Scheduled Visit ..........................................45 
4.6. 
Patient Numbering ......................................................................................................45 
5. 
EXCLUDED, PRIOR, AND CONCOMITANT MEDICATIONS ...........................45 
5.1. 
Prior Medications........................................................................................................45 
5.2. 
Concomitant Medications ...........................................................................................45 
5.2.1. 
Concomitant AED Medications ..................................................................................46 
5.3. 
Rescue Medications ....................................................................................................46 
5.4. 
Excluded Medications ................................................................................................46 
6. 
INVESTIGATIONAL PRODUCT ............................................................................47 
6.1. 
Identity of Investigational Product .............................................................................47 
6.1.1. 
Blinding the Treatment Assignment ...........................................................................47 
6.2. 
Administration of Investigational Products ................................................................47 
6.2.1. 
Allocation of Patients to Treatment ............................................................................47 
6.2.2. 
Dosing .........................................................................................................................47 
6.2.2.1. 
De-escalation Period ...................................................................................................48 
6.2.3. 
Dose Administration ...................................................................................................49 
6.2.4. 
Missing a Dose ...........................................................................................................49 
6.3. 
Labeling, Packaging, Storage, and Handling ..............................................................49 
6.3.1. 
Labeling ......................................................................................................................49 
6.3.2. 
Packaging ....................................................................................................................50 
6.3.3. 
Storage ........................................................................................................................50 
6.4. 
Investigational Product Accountability ......................................................................51 
6.5. 
Patient Compliance .....................................................................................................52 
7. 
STUDY PROCEDURES ............................................................................................52 
7.1. 
Study Assessments......................................................................................................52 
7.2. 
Study Procedures (Part A:  Treatment Period) ...........................................................52 
7.2.1. 
Screening Period .........................................................................................................52 
7.2.1.1. 
Screening (Visit 1, Week -4) ......................................................................................52 
7.2.2. 
Baseline (Visit 2, Week 0 + 4 days) ...........................................................................53 
7.2.3. 
Telephone Follow-up (Day 1, 2 and 3 + 1 days) ........................................................54 
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7.2.4. 
Titration Period (Visit 3, Week 1 ± 3 days) ................................................................54 
7.2.5. 
Titration Period (Phone Follow-ups, Weeks 2, 3, and 4 ± 3 days) .............................55 
7.2.6. 
Maintenance Period (Visits 4 and 5, Weeks 5 and 12 ± 3 days) ................................55 
7.2.7. 
Maintenance Period (Phone Follow-up, Week 9 ± 3 days) ........................................56 
7.2.8. 
Taper and Safety Visits (Visit 5a, Week 16 ± 3 days) ................................................56 
7.3. 
Study Procedures (Part B:  OLE Period) ....................................................................56 
7.3.1. 
First OLE Visit (Visit 5, Week 12) .............................................................................56 
7.3.2. 
OLE Period and Final OLE Visit or Taper Visit (Visits 6, 7, and 8 [or Early 
Discontinuation], Weeks 20, 28, and 36 [or Early Discontinuation] ± 7 days) ..........57 
7.3.3. 
Telephone Follow-up (Weeks 16, 24 and 32 ± 7 days) ..............................................58 
7.3.4. 
Safety Follow-up Post Taper (Visit X, 2 Weeks Post Last Dose ± 3 days) ...............58 
7.3.5. 
Unscheduled Visits .....................................................................................................58 
7.4. 
Screening and Diagnosis.............................................................................................58 
7.4.1. 
Informed Consent/Assent ...........................................................................................59 
7.4.2. 
Drug Screen ................................................................................................................59 
7.4.3. 
Demographics and Medical History ...........................................................................59 
7.4.4. 
Genetic Testing ...........................................................................................................59 
7.4.5. 
Seizure Identification and Diagnostic Review ...........................................................59 
7.5. 
Efficacy Assessments .................................................................................................59 
7.5.1. 
Seizure Type and Frequency ......................................................................................60 
7.5.2. 
Caregiver Global Impression of Change (CGI-C - Target Behavior) ........................60 
7.5.3. 
Clinical Global Impression – Improvement (CGI-I) ..................................................60 
7.6. 
Exploratory Efficacy Assessments .............................................................................60 
 
 
 
 
7.7. 
Safety Assessments .....................................................................................................61 
7.7.1. 
Adverse Events ...........................................................................................................61 
7.7.2. 
Vital Signs ..................................................................................................................61 
7.7.3. 
Height and Weight ......................................................................................................61 
7.7.4. 
Physical/Neurological/Developmental Examinations ................................................61 
7.7.5. 
ECG ............................................................................................................................63 
7.7.6. 
Clinical Laboratory Tests ...........................................................................................63 
7.7.7. 
Tanner Staging ............................................................................................................63 
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7.7.8. 
Investigational Product PK .........................................................................................64 
7.7.9. 
Concomitant AED Levels ...........................................................................................64 
7.8. 
Pharmacokinetic Assessments ....................................................................................64 
7.8.1. 
Clinical Pharmacokinetic Blood Sample Collection and Handling Procedures .........64 
8. 
ADVERSE AND SERIOUS ADVERSE EVENT ASSESSMENTS ........................65 
8.1. 
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events .........................................................................................................................65 
8.1.1. 
Severity Categorization ..............................................................................................65 
8.1.2. 
Relationship Categorization........................................................................................66 
8.1.3. 
Outcome Categorization .............................................................................................66 
8.1.4. 
Symptoms of the Disease Under Study ......................................................................66 
8.1.5. 
Clinical Laboratory and Other Safety Evaluations .....................................................66 
8.1.6. 
Pregnancy ...................................................................................................................67 
8.1.7. 
Abuse, Misuse, Overdose, and Medication Error .......................................................67 
8.2. 
Serious Adverse Event Procedures .............................................................................68 
8.2.1. 
Reference Safety Information .....................................................................................68 
8.2.2. 
Reporting Procedures..................................................................................................68 
8.2.3. 
Serious Adverse Event Definition ..............................................................................68 
8.2.4. 
Serious Adverse Event Collection Time Frame .........................................................69 
8.2.5. 
Serious Adverse Event Onset and Resolution Dates ..................................................69 
8.2.6. 
Fatal Outcome .............................................................................................................69 
8.2.7. 
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting ....................................................................................................................70 
9. 
DATA MANAGEMENT AND STATISTICAL METHODS ...................................71 
9.1. 
Data Collection ...........................................................................................................71 
9.2. 
Clinical Data Management .........................................................................................71 
9.3. 
Statistical Analysis Process ........................................................................................71 
9.4. 
Sample Size Calculation and Power Considerations ..................................................72 
9.5. 
Analysis Populations ..................................................................................................72 
9.6. 
Efficacy Analyses .......................................................................................................72 
9.6.1. 
Primary Efficacy Endpoint .........................................................................................72 
9.6.2. 
Secondary Efficacy Endpoints ....................................................................................72 
9.6.2.1. 
Secondary Efficacy:  Seizure control .........................................................................73 
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9.6.2.2. 
Secondary Efficacy:  Other .........................................................................................73 
9.6.3. 
Exploratory Efficacy Endpoints .................................................................................73 
9.6.4. 
Subgroup Analyses .....................................................................................................74 
9.7. 
Safety Analyses ..........................................................................................................74 
9.8. 
Other Analyses............................................................................................................74 
9.9. 
Pharmacokinetic Analyses ..........................................................................................74 
9.10. 
Interim Analysis..........................................................................................................74 
10. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ...............................75 
10.1. 
Sponsor’s Responsibilities ..........................................................................................75 
10.1.1. 
Good Clinical Practice (GCP) Compliance ................................................................75 
10.1.2. 
Public Posting of Study Information ..........................................................................75 
10.1.3. 
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees ...............................................75 
10.1.4. 
Study Suspension, Termination, and Completion ......................................................75 
10.2. 
Investigator’s Responsibilities ....................................................................................76 
10.2.1. 
Good Clinical Practice Compliance ............................................................................76 
10.2.2. 
Protocol Adherence and Investigator Agreement .......................................................76 
10.2.3. 
Documentation and Retention of Records ..................................................................76 
10.2.3.1. 
Electronic Case Report Forms (eCRF) .......................................................................76 
10.2.3.2. 
Seizure and Medication Diaries ..................................................................................77 
10.2.3.3. 
Recording, Access, and Retention of Source Data and Study Documents .................77 
10.2.3.4. 
Audit/Inspection .........................................................................................................78 
10.2.3.5. 
Financial Disclosure ...................................................................................................78 
10.3. 
Ethical Considerations ................................................................................................78 
10.3.1. 
Informed Consent/Assent ...........................................................................................78 
10.3.2. 
Institutional Review Board or Ethics Committee .......................................................79 
10.4. 
Privacy and Confidentiality ........................................................................................79 
10.5. 
Study Results/Publication Policy ................................................................................80 
11. 
REFERENCES ...........................................................................................................82 
12. 
APPENDICES ............................................................................................................84 
12.1. 
Appendix 1:  CYP3A4/5/7 Inhibitors and Inducers ...................................................84 
12.2. 
Appendix 2:  Clinical Laboratory Tests ......................................................................85 
12.3. 
Appendix 3:  Dosing Instructions for Oral Suspension ..............................................86 
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LIST OF TABLES 
Table 1: 
Schedule of Assessments - Part A ..............................................................................24 
Table 2: 
Schedule of Assessments - Part B ..............................................................................28 
Table 3: 
Oral Suspension Dosinga for Patients Weighing ≤ 28 kg (62 lbs)b ............................48 
Table 4: 
Oral Suspension Dosinga for Patients Weighing > 28 kg (62 lbs)b .............................48 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................37 
 
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ABBREVIATIONS 
Term 
Definition 
ACTH 
Adrenocorticotropic hormone 
AE 
adverse event 
AED 
antiepileptic drug 
ASM 
anti-seizure medication  
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration versus time curve 
β-HCG 
β-human chorionic growth hormone 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CBD 
cannabidiol 
CDKL5 
cyclin-dependent kinase-like 5 
CGI-C 
Caregiver Global Impression of Change  
CGI-I 
Clinical Global Impression – Improvement 
Cmax  
maximum plasma concentration 
CNS 
central nervous system 
CRA 
clinical research associate 
CRO 
clinical research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CYP 
cytochrome P450 
DB 
double-blind 
eCRF 
electronic case report form 
EC 
ethics committee 
ECG 
electrocardiogram 
 
 
eGFR 
estimated glomerular filtration rate 
FDA 
Food and Drug Administration 
FXS 
fragile X syndrome 
GABA 
γ-Aminobutyric acid 
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Term 
Definition 
GABAA 
γ-Aminobutyric acid type A 
GCP 
Good Clinical Practice 
GNX 
ganaxolone 
HDPE 
high-density polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
IP 
investigational product 
IRB 
institutional review board 
IS 
infantile spasms 
ITT 
intent-to-treat 
IV 
intravenous 
LAM 
lymphangioleiomyomatosis 
LAR 
legally authorized representative 
MedDRA 
Medical Dictionary for Regulatory Activities 
mTOR 
mammalian target of rapamycin 
OL 
open-label 
OLE 
open-label extension 
PBO 
placebo 
PCDH19 
protocadherin 19 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PP 
Per-Protocol 
Rheb 
Ras homolog enriched in brain 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
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Term 
Definition 
SIF/DRF 
Seizure Identification and Diagnostic Review Form  
TEAE 
Treatment-emergent adverse event 
THC 
tetrahydrocannabinol 
THP 
tetrahydroprogesterone  
TID 
three times daily 
tmax  
time of maximum concentration 
TSC 
Tuberous Sclerosis Complex 
ULN 
upper limit of normal 
US 
United States 
VNS 
Vagus nerve stimulator 
WCBP 
women of childbearing potential 
 
 
 
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STUDY SYNOPSIS 
Protocol number:  1042-TSC-2001 
Drug:  ganaxolone (GNX) 
Title of the study:  A Phase 2 open-label 12-week trial of adjunctive ganaxolone treatment (Part A) in tuberous 
sclerosis complex-related epilepsy followed by long-term treatment (Part B). 
Number of patients (total and for each treatment arm):  Approximately 36 tuberous sclerosis complex (TSC) 
patients will be screened to achieve 30 TSC patients enrolled in Part A. 
Investigators:  Multicenter study 
Sites and Regions:  Multicenter study to be conducted at approximately 6 sites in the United States 
Study period (planned): 
March 2020 – January 2022 
Clinical phase: 
2 
Objectives: 
Primary: 
x 
To assess preliminary safety and efficacy of GNX as adjunctive therapy for the treatment of primary 
seizure types in patients with genetically- or clinically-confirmed TSC-related epilepsy through the end of 
the 12-week treatment period.  The primary seizure types (defined later) are identified to be the most 
common, easily identifiable/countable by a parent/caregiver/legally authorized representative (LAR), and 
most consequential to the patient’s quality of life 
Secondary: 
x 
To assess the long-term efficacy of GNX when administered as adjunctive therapy throughout the 
open-label extension (OLE) period (Part B) 
x 
To assess the long-term safety and tolerability of GNX when administered as adjunctive therapy 
throughout the OLE period (Part B) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale:  
Tuberous sclerosis complex is a multi-system disorder of embryonal cortical development which can impact 
many organs through the overgrowth of hamartomas, benign, tumorous growths that can occur in the brain and 
other organs.  While the phenotype of TSC can be extremely variable, neurologic manifestations such as epilepsy 
are seen in up to 90% of TSC patients (Krueger and Northrup, 2013).  The condition is caused by inherited 
mutations in either the TSC1 gene, located on chromosome 9q34, or the TSC2 gene located on chromosome 
16p13.3.  TSC occurs with a frequency of 1:6,000 and a mutation is found in 85% of patients (Jülich and Sahin, 
2014).  The gene products hamartin (TSC1) and tuberin (TSC2) form a regulatory complex responsible for 
limiting the activity of mammalian target of rapamycin (mTOR) complex 1, an important intracellular regulator 
of growth and metabolism that acts via inhibition of the small GTPase Ras homolog enriched in brain (Rheb) 
(Krueger and Northrup, 2013).  Everolimus, an mTOR inhibitor, has been shown to decrease seizures 
(French et al., 2016; Mizuguchi et al., 2019). 
Tuberous sclerosis complex is one of the most common genetic causes of epilepsy, with seizure semiology that 
varies by age of onset (Jülich and Sahin, 2014).  Infantile spasms (IS) are the most common seizure type 
presenting in infancy and represent the first manifestation of epilepsy in 50% of patients.  In older children and 
adults, focal impaired awareness seizures (previously known as complex partial seizures) are the most common 
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(Chu-Shore et al., 2010).  Other focal and generalized seizures may also occur, with over 30% of patients 
developing treatment-refractory epilepsy (Jülich and Sahin, 2014).  While seizures have typically been ascribed to 
tubers and the surrounding cortex, 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; van der Poest 
Clement et al., 2020). 
γ-Aminobutyric acid (GABA)ergic signaling may play a meaningful role in the development and severity of 
TSC-related epilepsy, possibly due to altered expression of endogenous GABA type A (GABAA) receptor 
modulators (Di Michele et al., 2003).  There is evidence supporting a deficiency of the neuroactive steroid, 3α, 
5α-tetrahydroprogesterone (THP), or allopregnanolone, as a contributor to epileptogenesis in TSC.  
Allopregnanolone is a positive modulator of the GABAA receptor and has been shown to have antiepileptic 
effects in experimental animals and humans.  There is a decrease in allopregnanolone relative to its functional 
GABAA antagonist, 3β-THP, in patients with TSC-related epilepsy but not in TSC patients without epilepsy or in 
controls (Di Michele et al., 2003).  This reduced ratio could alter neuronal excitability mediated by GABAA 
receptors, leading to the development of epilepsy.  The role of GABAA receptor mediation is also supported by 
the efficacy of vigabatrin, a specific and irreversible inhibitor of GABA-aminotransferase, in seizures due to TSC 
relative to other epilepsies (Di Michele et al., 2003).  These findings provide compelling evidence for the 
potential role of neuroactive steroids with anticonvulsant properties, or analogues such as GNX, in the treatment 
of TSC-related epilepsy. 
Ganaxolone is the 3β-methylated synthetic analog of allopregnanolone, an endogenous positive allosteric 
modulator of central nervous system (CNS) GABAA receptors.  Ganaxolone has potency comparable to 
allopregnanolone in activating synaptic and extrasynaptic GABAA receptors at a site distinct from 
benzodiazepines and barbiturates (Carter et al., 1997).  Ganaxolone has protective activity in diverse rodent 
seizure models (Bialer et al., 2010; Reddy and Rogwski, 2012).  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 
given orally in adults and children (Kerrigan et al., 2000; Laxer et al., 2000; Pieribone et al., 2007; 
Sperling et al., 2017).  Further, GNX reduces seizures in children with IS and refractory pediatric epilepsy.  In an 
open-label (OL) study, pediatric patients 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).  Fifteen patients with a history 
of IS completed treatment.  Five of the 15 patients had a decrease from baseline in the number of spasms of ≥ 
50%, 5 had a decrease of 25% to 50%, and 5 had a decrease of < 25%.  One patient became spasm-free and 1 
non-responder (with a decrease of < 25%) was spasm-free from Weeks 2 to 7.   
A double-blind (DB) study (Study 1042-0500) of GNX in IS was also conducted.  In this study, patients aged 4 to 
24 months with IS received placebo or GNX doses of up to 54 mg/kg/day for up to 20 days in an incomplete 
crossover design.  A total of 55 of the 57 patients completed treatment, 54 of whom continued GNX treatment in 
Study 1042-0501, an OLE.  Although the GNX group had numerically higher reductions in frequency of spasm 
clusters, no statistically significant differences were observed in change from baseline between the treatment 
groups in the frequency of spasm clusters or in any of the secondary efficacy parameters at the end of the DB 
period (Day 9 ± 1 day). 
In addition to its anticonvulsant activity, GNX has been shown to reduce anxiety, hyperactivity, and attention in 
children with fragile X syndrome who had higher baseline levels of anxiety (Ligsay et al., 2016).  Similar 
behavioral problems occur in individuals with TSC, with rates of approximately 50% for attention deficit 
hyperactivity disorder and autism (Jülich and Sahin, 2014).  It is hypothesized that GNX treatment will increase 
GABAA-receptor signaling and improve not only seizure control but may also ameliorate the behavioral 
abnormalities in individuals with TSC.  
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Methodology:  This is an OL proof of concept study of adjunctive GNX treatment in patients with a confirmed 
clinical diagnosis of TSC and/or a mutation in either the TSC1 or TSC2 gene.  The trial consists of two parts:  
Part A consists of a 4-week baseline period followed by a 12-week treatment period (4-week titration and 8-week 
maintenance).  For patients not continuing in the OLE period (Part B), a 2-week taper period followed by a 2-
week safety period would follow.  The main difference between Part A and Part B is the length of treatment, less 
frequent assessments, and the ability to alter drug doses (both GNX and other antiepileptic drug [AED] 
treatments which includes initiating and stopping other medications) based on investigator evaluation of the 
patient’s clinical course during Part B.  Patients with a seizure frequency reduction rate of ≥ 35% during the 12-
week treatment period in Part A compared to baseline may continue into Part B (“OLE eligible”).  If the 
investigator believes there is a medical benefit for the patient who does not meet the seizure reduction criterion to 
enter the OLE, they must discuss the patient with the sponsor medical monitor and receive sponsor approval for 
that patient to continue into the OLE.  
Part A 
x 
4-week baseline period 
x 
4-week titration period 
x 
8-week maintenance period  
x 
2-week taper period (For patients who do not complete Part A or after completing Part A but do not 
continue into Part B) 
x 
2-week safety follow-up visit post taper (For patients who taper off GNX) 
Part B (Optional for OLE-eligible patients) 
x 
OLE period (until the Sponsor markets ganaxolone or terminates the study) 
x 
2-week taper period (For patients who discontinue GNX due to early termination or completion) 
x 
2-week safety follow-up visit post taper (For patients who taper off GNX) 
 
 
GNX = ganaxolone 
During the screening visit, each patient’s baseline 
 
, will be collected and analyzed for post-study evaluation. 
Patient rescreening is allowed as agreed by the sponsor and the investigator unless there is a general concern for 
patient safety or an inability for the patient to become eligible (e.g., GNX allergy, sensitivity or exposure, non-
TSC and/or other ineligible epilepsy, chronic prohibited medical condition or treatment).  Subsequent screening 
should take place at least 30 days from the patient’s last visit, unless otherwise noted. 
Part A includes a 4-week baseline and 4 weeks of investigational product (IP) titration followed by 8 weeks of 
dose maintenance followed by 2-week taper for those patients not continuing into the Part B OLE period.  After 
meeting all eligibility criteria, approximately 30 patients aged 2 to 65 years (inclusive) with TSC-related epilepsy 
will be enrolled to receive GNX for a total of 12 weeks (4-week titration, 8-week maintenance) in addition to 
their standard anti-seizure medication(s) (ASMs).  Patients will be titrated to 63 mg/kg/day (maximum 
1800 mg/day) over 4 weeks, and then maintained at that dose for another 8 weeks.  Patients who are not able to 
tolerate 63 mg/kg/day (or maximum 1800 mg/day) may be maintained on a lower dose after discussion with the 
sponsor medical monitor.  A minimum dose of 33 mg/kg/day or 900 mg/day is generally required during the 
maintenance period. 
For Part A, dose changes including alternative dosing paradigm (e.g., lower dose during the daytime and higher 
dose in the evening) should be discussed with the sponsor medical monitor prior to making the change or within 
48 hours of making the change.  Patients who discontinue GNX should undergo a 2-week taper period, unless 
otherwise medically indicated.  Patients who discontinue GNX before the completion of the maintenance period 
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will continue to be followed per protocol and, at a minimum, patients will be encouraged to maintain daily 
seizure diaries until the maintenance period in Part A is completed.  These patients will also return to the site 
2 weeks after the taper for safety follow-up assessments. 
After completing the initial 16-week period, Part A, patients with a seizure reduction of ≥ 35% compared to the 
4-week baseline period and who do not have any other contraindications for continued treatment can continue to 
be treated with GNX in the OLE period (Part B).  Patients will continue GNX treatment at the dose that they were 
taking at completion of Part A.  Doses of other ASMs may be adjusted (including tapering and initiating 
treatments) during Part B based on investigator discretion.  Any patient who completes Part A and does not 
continue in Part B, or discontinues GNX treatment should undergo a 2-week drug de-escalation (taper) period and 
return to the site 2 weeks later for safety follow-up assessments.   
Patients will be required to complete a daily diary to determine GNX’s effect on seizures.  Days without seizures 
should also be noted.  Additional clinician- and caregiver-administered instruments will be used to assess the 
efficacy of GNX in TSC, and will include:   
x 
Caregiver Global Impression of Change (CGI-C) - Target Behavior  
x 
Clinical Global Impression – Improvement (CGI-I) caregiver and CGI-I clinician. 
Inclusion and Exclusion criteria:  Inclusion Criteria (Part A):   
1. Clinical or mutational diagnosis of TSC consistent with Northrup and Krueger, 2013. 
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 (e.g., 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 investigator 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 two major features or one major feature with ≥ 2 
minor features. The investigator must document which of the features (Major or Minor) fulfill the 
clinical diagnostic criteria. 
 
 
Major features 
Minor features 
1. Hypomelanotic macules (≥ 3, at least 
5-mm diameter) 
2. Angiofibromas (≥ 3) or fibrous 
cephalic plaque 
3. Ungual fibromas (≥ 2) 
4. Shagreen patch 
5. Multiple retinal hamartomas 
6. Cortical dysplasiasa 
7. Subependymal nodules 
8. Subependymal giant cell 
astrocytomas 
9. Cardiac rhabodomyoma 
10. Lymphangioleiomyomatosis (LAM)b 
11. Angiomyolipomas (≥ 2)b 
1. “Confetti” skin lesions 
2. Dental enamel pits (≥ 3) 
3. Intraoral fibromas (≥ 2) 
4. Retinal achromic patch 
5. Multiple renal cysts 
6. Nonrenal hamartomas 
a. 
Includes tubers and cerebral white matter radial migration lines 
b. 
A combination of the two major clinical features (LAM and angiomyolipomas) without other features that does 
not meet criteria for a definite diagnosis. 
 
2. Male or female patients aged 2 through 65 years, inclusive. 
3. Patient/parent/caregiver or LAR willing to give written informed consent/assent, after being properly 
informed of the nature and risks of the study and prior to engaging in any study-related procedures.  
Assent for patients over 7 years of age should be obtained, if appropriate. 
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4. Failure to control seizures despite appropriate trial of 2 or more ASMs at therapeutic doses. 
5. Have at least 8 countable/witnessed primary seizures during the 4-week baseline period with at least 
1 primary seizure occurring in at least 3 of the 4 weeks of baseline.  The primary seizure types are 
defined as the following:  focal motor seizures without impairment of consciousness or awareness, focal 
seizures with impairment of consciousness or awareness, focal seizures evolving to bilateral, 
tonic-clonic convulsive seizures, and generalized motor seizures including tonic-clonic, bilateral tonic, 
bilateral clonic, or atonic/drop seizures.  Focal aware non-motor and generalized seizures without motor 
features, infantile or epileptic spasms, and myoclonic seizures do not count as the primary seizure types. 
6. Patient must be approved to participate by the sponsor or its designee (e.g., Epilepsy Consortium) after 
review of medical history, genetic testing, and patients’ seizure types. 
7. Patients should be on a stable regimen of ASMs at therapeutic doses for ≥ 1 month prior to the screening 
visit, without a foreseeable change in dosing for the duration of Part A.  Vagus nerve stimulator (VNS), 
ketogenic diet, and modified Atkins diet should be unchanged for 3 months prior to screening and will 
not count towards the number of ASMs. 
8. Patients with surgically implanted 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 ≥ 1 year prior to the screening visit. 
b. The settings must have remained constant for 3 months prior to the screening visit and remain 
constant throughout the baseline and Part A. 
c. 
The battery is expected to last for the duration of baseline and Part A. 
9. Parent/caregiver is able and willing to maintain an accurate and complete daily seizure diary for the 
duration of the study. 
10. Able and willing to take IP (suspension) with food 3 times daily.  (GNX must be administered with 
food.) 
11. Sexually active female of childbearing potential must be using a medically acceptable method of birth 
control and have a negative quantitative serum β-human chorionic growth hormone (β-HCG) test 
collected at the initial screening visit.  Childbearing potential is defined as a female who is biologically 
capable of becoming pregnant.  A medically acceptable method of birth control includes intrauterine 
devices in place for at least 3 months prior to the screening visit, surgical sterilization, or adequate 
barrier methods (e.g., diaphragm or condom and foam).  An oral contraceptive alone is not considered 
adequate for the purpose of this study.  Use of oral contraceptives in combination with another method 
(e.g., a spermicidal cream) is acceptable.  In patients who are not sexually active, abstinence is an 
acceptable form of birth control.   
Inclusion Criteria (Part B) 
1. Patients have experienced ≥ 35% reduction in primary seizure frequency during the Part A treatment 
period compared to the 4-week Baseline Period. 
Exclusion Criteria (Part A):   
1. Previous exposure to GNX. 
2. Pregnant or breastfeeding. 
3. Concurrent use of strong inducers or inhibitors of cytochrome P450 (CYP)3A4/5/7.  Any strong 
inhibitor or inducer of CYP3A4/5/7 must be discontinued at least 28 days before Visit 2, study drug 
initiation.  This does not include approved ASMs. 
4. Patients who have been taking felbamate for less than 1 year prior to screening. 
5. Patients who test positive for tetrahydrocannabinol (THC) or non-approved cannabidiol (CBD) via 
plasma drug screen.  
6. Chronic use of oral steroid medications, ketoconazole (except for topical formulations), St. John’s Wort, 
or other IPs is not permitted. 
7. Adrenocorticotropic hormone (ACTH), prednisone, or other systemically administered (non-inhaled) 
steroids must be discontinued > 28 days prior to screening.  Concomitant topical, inhaled or intranasal 
steroids are allowed and do not warrant exclusion from the study.  
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8. Changes in any chronic medications within the month (e.g., 30 days) prior to the screening visit.  All 
concomitant medications must have been at a stable in dose for at least 1-month prior to the screening 
visit unless otherwise noted.   
9. Patient is being considered for epilepsy surgery or has undergone surgery for epilepsy within the 
6 months prior to screening. 
10. Have an active CNS infection, demyelinating disease, degenerative neurological disease, or CNS disease 
deemed progressive.  This includes tumor growth which in the opinion of the investigator could affect 
primary seizure control. 
11. Have any disease or condition (medical or surgical; other than TSC) at the screening visit that might 
compromise the hematologic, cardiovascular, pulmonary, renal, gastrointestinal, or hepatic systems; or 
other conditions that might interfere with the absorption, distribution, metabolism, or excretion of the IP, 
or would place the patient at increased risk.  This may include any illness in the past 4 weeks which in 
the opinion of the investigator may affect seizure frequency.  
12. 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.   
13. Total bilirubin levels > 1.5 × ULN at screening or baseline visit and confirmed by a repeat test.  In cases 
of documented, stable medical condition (i.e., Gilbert’s Syndrome) resulting in levels of total bilirubin 
> ULN, the medical monitor can determine if a protocol exception can be made. 
14. Patients with significant renal insufficiency, estimated glomerular filtration rate (eGFR) < 30 mL/min 
(calculated using the Cockcroft-Gault formula or Pediatric GFR calculator or Bedside Schwartz), will be 
excluded from study entry or will be discontinued if the criterion is met post baseline. 
15. Have been exposed to any other investigational drug within 30 days or fewer than 5 half-lives 
(whichever is shorter) prior to the screening visit.   
16. Unwillingness to withhold grapefruit, Seville oranges, star fruit, or grapefruit containing products from 
diet 7 days prior to first dose and for the duration of the study. 
17. Have had an active suicidal plan/intent or active suicidal thoughts in the past 6 months or have made a 
suicide attempt in the past 3 years.   
18. Known sensitivity or allergy to any component in the IP(s), progesterone or other related steroid 
compounds. 
Exclusion Criteria (Part B): 
1. Patient developed a medical condition that would make it unsafe for patients to received GNX as 
determined by the investigator. 
Number of patients:  Approximately 36 TSC patients, aged 2 to 65 inclusive, will be screened to achieve 
30 TSC patients enrolled in Part A.  Since this is an OL proof of concept study, sample size was not determined 
by statistical methods. 
Investigational product, dose, and mode of administration:  Ganaxolone is to be administered in increments 
of 15 mg/kg/day up to 63 mg/kg/day (maximum 1800 mg/day) given as an oral suspension with food.  Patients 
weighing ≤ 28 kg will be dosed on an mg/kg basis.  Patients weighing > 28 kg will be dosed on a fixed regimen 
in increments of 450 mg/day up to 1800 mg/day.  Ganaxolone is to be administered during the 4-week titration 
period as follows: 
Oral Suspension Dosinga for Patients Weighing ≤ 28 kg (62 lbs)b 
Dose mg/kg 
Total mg/kg/day 
Days 
6 TID 
18 
1-7 
11 TID 
33 
8-14 
16 TID 
48 
15-21 
21 TID 
63 
22-28 
Oral Suspension Dosinga for Patients Weighing > 28 kg (62 lbs)c 
Dose mg 
mL per Dose 
Total mg/day 
Days 
150 TID 
3 
450 
1-7 
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300 TID 
6 
900 
8-14 
450 TID 
9 
1350 
15-21 
600 TID 
12 
1800 
22-28 
TID = 3 times daily. 
a. 
To be administered in 3 divided doses following a meal or snack. 
b. Patients weighing ≤ 28 kg will be dosed according to the patient’s weight in kilograms. 
c. 
Patients weighing > 28 kg will be dosed on a fixed regimen in increments of 450 mg/day up to 
1800 mg/day. 
Any patient not tolerating the next dose step can be maintained at the lower dose step for additional days before 
advancing to the next dose.  If the next dose is still not tolerated, the patient can drop back to the next lower dose 
step.  A minimum dose of 33 mg/kg/day or 900 mg/day is generally required following the escalation period, 
during the maintenance period.  
Dose changes including alternative dosing paradigms (e.g., lower dose during the daytime and higher dose in the 
evening) should be discussed with the sponsor medical monitor prior to making the change or within 48 hours of 
making the change.  However, the final decision to adjust drug dosages lies with the investigator.  For any patient 
who is unable to be maintained at the minimum dose, the investigator should contact the sponsor medical monitor 
to discuss continued IP dosing.  Patients who discontinue GNX treatment before the completion of the 
maintenance period in Part A will continue to be followed per protocol and, at a minimum, patients will be 
encouraged to maintain daily seizure diary entries until Part A is completed. 
During Part B, patients who meet all of the inclusion criteria and none of the exclusion criteria will initiate 
treatment in Part B with GNX at the same dose they were on at the completion of Part A.  During Part B, doses of 
GNX may be adjusted to a maximum of 600 mg three times daily (TID) for patients weighing > 28 kg and a 
maximum dose of 21/mg/kg TID for patients weighing ≤ 28 kg.  
Duration of treatment:  After 4 weeks of baseline seizure charting, patients will initiate a 4-week GNX titration 
period followed by an 8-week GNX maintenance period (Part A).  Patients completing Part A and deemed 
eligible for Part B will continue taking GNX. Patients will have the option to continue longer-term treatment on 
ganaxolone until commercially available or the study is terminated by the Sponsor. Anyone discontinuing GNX 
will undergo a 2-week taper and a 2-week follow-up safety visit.   
The planned study duration is approximately 64 weeks for patients who stay on the study through Part B. 
Criteria for Evaluation:   
Seizures:  All seizure types and number of seizures will be recorded daily in a diary.  Days in which no seizures 
occur will also be noted.  Subsets of seizure types will be defined below.  
Primary Efficacy Endpoint:  The primary efficacy endpoint is the percent change in 28-day primary seizure 
frequency through the end of the 12-week treatment period (4-week titration and 8-week maintenance) relative to 
the 4-week baseline.  The primary seizure types are defined as the following:  focal motor seizures without 
impairment of consciousness or awareness, focal seizures with impairment of consciousness or awareness, focal 
seizures evolving to bilateral, tonic-clonic seizures, and generalized motor seizures including tonic-clonic, 
bilateral tonic, bilateral clonic, and atonic/drop seizures.  Focal aware non-motor and generalized seizures without 
motor features, infantile or epileptic spasms, and myoclonic seizures are not considered primary seizure types.  
Post-baseline 28-day seizure frequency will be calculated as the total number of seizures in the 12-week treatment 
period (4-week titration and 8-week maintenance periods) divided by the number of days for which seizure data 
are reported in that period, multiplied by 28.  Baseline 28-day seizure frequency will be calculated as the total 
number of seizures in the baseline period divided by the number of days for which seizure data are reported in the 
baseline period multiplied by 28.  Descriptive statistics will be used to summarize changes in seizure frequency.  
No inferential statistical testing will be performed.  
Secondary Efficacy Endpoints (Seizure control):  Derived seizure secondary efficacy endpoints will be based 
on data through the end of the 12-week treatment period relative to the 4-week prospective baseline period.  
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x 
Percentage of patients experiencing a ≥ 50% reduction in 28-day primary seizure frequency 
through the end of the 12-week treatment period compared to the 4-week Baseline Period. 
Secondary Efficacy Endpoints (Other): 
x 
CGI-I, parent/caregiver and clinician 
x 
CGI-C - Target Behavior 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic Assessments: 
The pharmacokinetic (PK) population will include all patients who have received at least 1 dose of GNX and who 
have had at least 1 sample collected and a valid bioanalytical result obtained.  The samples will be drawn between 
1 and 5 hours or between 4 and 8 hours after the last dose during Part A and Part B.  Pharmacokinetic analyses 
will be limited to listing of concentrations because sufficient concentration-time data will not be available for 
noncompartmental analyses such as maximum plasma concentration (Cmax), area under the concentration versus 
time curve (AUC), or time of maximum concentration (tmax).  Pharmacokinetic data from this study may be used 
for a Population PK analyses to be conducted separately from this study and reported separately.  Further details 
will be provided in the Statistical Analysis Plan. 
Safety and Tolerability Assessments: 
Safety and tolerability will be assessed by monitoring vital signs (blood pressure [BP], heart rate [HR], 
respiratory rate [RR], body temperature, electrocardiograms (ECGs), clinical laboratory tests (hematology, 
chemistry and urinalysis), physical, neurological, and developmental examinations, Columbia-Suicide Severity 
Rating Scale (C-SSRS) if appropriate and frequency, type, and severity of adverse events (AEs) during Part A 
and Part B.  Height and weight will also be measured. 
Statistical Methods:  
The intent-to-treat (ITT) population comprises all patients who received at least one dose of IP.  The ITT 
population will be the primary population for efficacy analyses.  The Per-Protocol (PP) population includes all 
ITT patients without major protocol violations (defined prior to database lock).  Safety will be reported in all 
patients. 
Since this is an OL proof of concept study, no inferential statistical testing will be conducted, and all efficacy 
outcomes will be descriptive. 
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Primary Endpoint:  Definition and Analysis: 
The primary efficacy endpoint (change in seizure frequency) is the percent change in 28-day seizure frequency 
through the end of the 12-week treatment period (4-week titration and 8-week maintenance) relative to the 
baseline, based on the primary seizure types.  The primary seizure types are defined as the following:  focal motor 
seizures without impairment of consciousness or awareness, focal seizures with impairment of consciousness or 
awareness, focal seizures evolving to bilateral, tonic-clonic convulsive seizures, and generalized motor seizures 
including tonic-clonic, bilateral tonic, bilateral clonic, or atonic/drop seizures.  Focal aware non-motor and 
generalized seizures without motor features, infantile or epileptic spasms, and myoclonic seizures do not count as 
the primary seizure types.  
Post-baseline 28-day seizure frequency will be calculated as the total number of seizures in the 12-week treatment 
periods (4-week titration plus 8-week maintenance period) during Part A 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 primary seizures in the baseline period divided by the number of days with seizure data in the baseline 
period, multiplied by 28.   
 
 
 
The baseline, post-baseline, and arithmetic and percent changes from baseline in 28-day seizure frequency will be 
summarized using descriptive statistics.  
Since this is an OL proof of concept study, all efficacy analyses will be based on descriptive statistics. 
Sample Size: 
Since this is an OL proof of concept study, sample size was not determined by statistical methods. 
Secondary and Exploratory Endpoints - Descriptive Evaluation: 
Seizure control: 
x 
Percentage of patients experiencing a ≥ 50% reduction in 28-day primary seizure frequency 
through the end of the 12-week treatment period compared to the 4-week Baseline Period.  
Other: 
x 
CGI-I, parent/caregiver and clinician. 
x 
CGI-C - Target Behavior. 
Exploratory Endpoints - Descriptive Evaluation:  
All secondary and 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
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Page 23 of 88 
IND 044,020 
 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
 
11 Jun 2021 
 
 
 
 
 
Safety Analysis:  Safety will be reported for all patients.  The results in Part A and Part B will be summarized 
separately and then the combined results in Part A and Part B will be summarized together.  Adverse events will 
be tabulated by overall, system organ class, and Preferred Term using the Medical Dictionary for Regulatory 
Activities (MedDRA) coding system.  Incidence and percentage of AEs will be presented.  Additional tables, 
with AEs classified by severity and by only those related to drug as assessed by the investigator will be presented.  
Subset listings will be produced for AEs that cause withdrawal and for serious adverse events (SAEs).  Clinical 
laboratory tests (hematology, chemistry and urinalysis), vital signs (temperature, BP, pulse rate), weight, and 
ECGs will be summarized using descriptive statistics including changes from baseline.  Change in C-SSRS scores 
where applicable will be determined.  Physical, neurological and developmental examinations will be 
summarized using number and percentage of patients with abnormalities. 
Pharmacokinetic Analysis:  A population PK approach addressing the relationship between GNX PK 
parameters and individual characteristics will be implemented during the study.  One blood sample will be 
obtained at the following visits for PK analyses: 
x 
During Part A: 
- 
Visit 4 (Week 5):  between 1 and 5 hours since the last IP dosing  
- 
Visit 5 (Week 12):  between 4 and 8 hours since the last IP dosing 
x 
During Part B:  There is no specified time to draw the PK sample and can be drawn when convenient 
during the study visits. 
Exact time of sample withdrawal and drug intake will be recorded in the electronic case report form (eCRF).   
 and Concomitant AED levels:  Blood samples will be drawn at screening visit, 
  Concomitant AED levels will not be mandatory but 
will be conducted per sites’ standard of care.  If AED levels are available, the results, date and time of last AED 
dose and date and time of AED PK sample will be recorded in the eCRF.  
 and concomitant AED 
levels will be analyzed according to the SAP. 
Interim Analysis:  No formal interim analysis is planned.   
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IND 044,020 
 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
 
11 Jun 2021 
 
Confidential 
Page 24 of 88 
Table 1: 
Schedule of Assessments - Part A 
 
 
 
Part A 
 
Screen/Baseline 
 
 
 
Titration and Maintenance 
WEEK 
-4 
(Screening 
Visit –  
Start of 
Baseline) 
0 
(Baseline 
Treatment 
Visit) 
 
 
 
 
Day 
1 
 
 
 
 
Day 
2 
Day 
3 
1 
2, 3, 
4 
5 
9 
12 
16 
Taper/Safety Visitsp 
Visit Windows 
 
+ 4 days 
 
 
± 1 day 
± 3 
days 
± 3 
days 
± 3 
days 
± 3 days 
± 3 
days 
± 3 days 
VISIT 
Visit 1a 
Visit 2o 
Phone 
Follow-
up 
Phone 
Follow-
up 
Phone 
Follow-
up 
Visit 
3 
Phone 
Follow-
up 
Visit 
4 
Phone 
Follow-up 
Visit 
5 
Visit 5a 
Informed Consentb 
X 
 
 
 
 
 
 
 
 
 
 
Demographics & 
Medical History 
X 
Xs 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Genetic testing 
Xc 
Xr 
 
 
 
 
 
 
 
 
 
Seizure Identification 
and Diagnostic 
Review Form 
(Epilepsy Study 
Consortium) 
X 
X 
 
 
 
 
 
 
 
 
 
Vital Signs (BP, HR, 
RR, and body 
temperature) 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
Height / weight 
Xd 
Xe 
 
 
 
Xe 
 
Xe 
 
Xe 
 
Physical/Neurological/ 
Developmental Examt 
X 
X 
 
 
 
X 
 
X 
 
X 
 
ECG 
 
X 
 
 
 
X 
 
X 
 
X 
 
Clinical Laboratory 
Testsf 
X 
X 
 
 
 
X 
 
X 
 
X 
 
Urinalysis 
Xg 
Xg 
 
 
 
X 
 
X 
 
X 
 
Drug Screenh 
X 
X 
 
 
 
 
 
 
 
X 
 
Pregnancy Test 
(WCBP)i 
X 
X 
 
 
 
 
 
X 
 
X 
 
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IND 044,020 
 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
 
11 Jun 2021 
 
Confidential 
Page 25 of 88 
Table 1: 
Schedule of Assessments - Part A 
 
 
 
Part A 
 
Screen/Baseline 
 
 
 
Titration and Maintenance 
WEEK 
-4 
(Screening 
Visit –  
Start of 
Baseline) 
0 
(Baseline 
Treatment 
Visit) 
 
 
 
 
Day 
1 
 
 
 
 
Day 
2 
Day 
3 
1 
2, 3, 
4 
5 
9 
12 
16 
Taper/Safety Visitsp 
Visit Windows 
 
+ 4 days 
 
 
± 1 day 
± 3 
days 
± 3 
days 
± 3 
days 
± 3 days 
± 3 
days 
± 3 days 
VISIT 
Visit 1a 
Visit 2o 
Phone 
Follow-
up 
Phone 
Follow-
up 
Phone 
Follow-
up 
Visit 
3 
Phone 
Follow-
up 
Visit 
4 
Phone 
Follow-up 
Visit 
5 
Visit 5a 
Tanner Staging 
X 
 
 
 
 
 
 
 
 
 
X 
IP PK 
 
 
 
 
 
 
 
Xj 
 
Xj 
 
Concomitant AED 
Review and Levels if 
Per Standard of Carek 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Seizure and 
Medication Diary 
Reviewl 
Xl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CGI-C - Target 
Behavior 
 
Xm 
 
 
 
 
 
X 
 
X 
 
CGI-I (caregiver) 
 
X 
 
 
 
 
 
X 
 
X 
 
CGI-I (clinician) 
 
X 
 
 
 
 
 
X 
 
X 
 
C-SSRS (baseline 
form)q 
 
X 
 
 
 
 
 
 
 
 
 
C-SSRS (since previous 
visit)q 
 
 
 
 
 
 
 
X 
 
X 
X 
Dispense GNXn 
 
X 
 
 
 
 
 
X 
 
X 
 
AED = antiepileptic drug, BP = blood pressure, CBD = cannabidiol, CGI-C = Caregiver Global Impression of Change, CGI-I = Clinical Global Impression – Improvement, 
C-SSRS = Columbia-Suicide Severity Rating Scale, D/C = discontinuation, ECG = electrocardiogram, 
, GNX = ganaxolone, HR = heart rate, 
IP = investigational product, LAR = legally authorized representative, PK = pharmacokinetic, RR = respiratory rate, THC = tetrahydrocannabinol, WCBP = women of 
childbearing potential. 
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IND 044,020 
 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
 
11 Jun 2021 
 
Confidential 
Page 26 of 88 
Table 1: 
Schedule of Assessments - Part A 
 
 
 
Part A 
 
Screen/Baseline 
 
 
 
Titration and Maintenance 
WEEK 
-4 
(Screening 
Visit –  
Start of 
Baseline) 
0 
(Baseline 
Treatment 
Visit) 
 
 
 
 
Day 
1 
 
 
 
 
Day 
2 
Day 
3 
1 
2, 3, 
4 
5 
9 
12 
16 
Taper/Safety Visitsp 
Visit Windows 
 
+ 4 days 
 
 
± 1 day 
± 3 
days 
± 3 
days 
± 3 
days 
± 3 days 
± 3 
days 
± 3 days 
VISIT 
Visit 1a 
Visit 2o 
Phone 
Follow-
up 
Phone 
Follow-
up 
Phone 
Follow-
up 
Visit 
3 
Phone 
Follow-
up 
Visit 
4 
Phone 
Follow-up 
Visit 
5 
Visit 5a 
a. 
Patient rescreening is allowed as agreed by the sponsor and the investigator unless there is a general concern for patient safety or an inability for the patient to become 
eligible (e.g., GNX allergy, sensitivity or exposure, non-TSC and/or other ineligible epilepsy, chronic prohibited medical condition or treatment).  Subsequent screening 
should take place at least 30 days from the patient’s last visit. 
b. 
Written informed consent/assent must be obtained from patient, parent or LAR before any study assessments are performed.  Pediatric assent should be obtained, if 
appropriate. 
c. 
Previous genetic testing results will be accepted and reviewed to assess if a pathogenic TSC1 or TSC2 variant is present.  If genetic testing has not previously been 
performed, then a biological sample will be obtained to complete genetic testing at the sponsor’s designated lab.  Note:  TSC diagnosis does not require pathogenic TSC1 
or TSC2 mutations if the clinical criteria are met.   
d. 
Height and weight will be measured.  Length will be measured if height cannot be obtained. 
e. 
Only weight will be measured.  At each visit, dosing will be reviewed and adjusted as needed based on a patient’s current weight.  
f. 
Chemistry and Hematology.   
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 if possible. 
h. 
A drug screen (plasma) will be performed to test for THC and CBD at screening.  If the screening drug test is positive, the patient can be retested, via plasma, after two 
weeks.  A positive drug test during the treatment period will result in early termination.  
i. 
Serum pregnancy test is required for all girls/women of childbearing potential.   
j. 
Population PK will be conducted at these visits (Visit 4:  between 1-5 hours since last IP dosing, Visit 5:  between 4-8 hours since the last IP dosing).   
k. 
Concomitant AEDs or their dose must be stable for 1 month prior to screening and cannot be changed at any time prior to Visit 4, but may be adjusted during Part B. 
l. 
Caregiver given seizure and medication diary and instructions for use. 
m. During the baseline visit, the investigator and parent/caregiver/LAR will decide on a domain and identify the specific behavior that the patient exhibits that denotes the 
domain.  This behavior will be used at subsequent visits to assess change after the initiation of IP. 
n. 
Patients who discontinue IP early will be encouraged to continue with all procedures and scheduled visits. 
o. 
The 4 weeks between Screening Visit and Baseline Treatment Visit can be no less than 28 days and no more than 32 days. 
p. 
Only for patients who do not continue into Part B.  This will occur after 2 weeks of taper and 2 weeks after completion of treatment. 
q. 
Only for patients ≥ 7 years old if appropriate.  Otherwise clinical judgment will be used. 
r. 
Only for patients that were Screened without previous genetic testing results and had a genetic test performed at the sponsor’s designated lab. 
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IND 044,020 
 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
 
11 Jun 2021 
 
Confidential 
Page 27 of 88 
Table 1: 
Schedule of Assessments - Part A 
 
 
 
Part A 
 
Screen/Baseline 
 
 
 
Titration and Maintenance 
WEEK 
-4 
(Screening 
Visit –  
Start of 
Baseline) 
0 
(Baseline 
Treatment 
Visit) 
 
 
 
 
Day 
1 
 
 
 
 
Day 
2 
Day 
3 
1 
2, 3, 
4 
5 
9 
12 
16 
Taper/Safety Visitsp 
Visit Windows 
 
+ 4 days 
 
 
± 1 day 
± 3 
days 
± 3 
days 
± 3 
days 
± 3 days 
± 3 
days 
± 3 days 
VISIT 
Visit 1a 
Visit 2o 
Phone 
Follow-
up 
Phone 
Follow-
up 
Phone 
Follow-
up 
Visit 
3 
Phone 
Follow-
up 
Visit 
4 
Phone 
Follow-up 
Visit 
5 
Visit 5a 
s. 
Review of medical history only. 
t. 
Developmental examination is limited to pediatric patients 2 to 17 years of age, inclusive. 
 
 
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IND 044,020 
 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
 
11 Jun 2021 
 
Confidential 
Page 28 of 88 
Table 2: 
Schedule of Assessments - Part B 
Part B 
 
Final 
Part A 
Visit/ 
First 
Part B 
Visit 
Open-Label Extension 
(Visits will be every 8 weeks with a telephone follow-up in-between) 
Final OLE Visit or 
Taper Visit 
Safety 
Follow-up 
Post-taper 
WEEK 
12 
16 
20 
24 
28 
32 
36 or early D/C 
2 weeks 
post last 
dose 
Visit Windows 
 
± 7 days 
± 7 days 
± 7 days 
± 7 days 
± 7 days 
± 7 days 
± 3 days 
VISIT 
Visit 5 
Phone 
follow-up 
Visit 6 
Phone 
follow-up 
Visit 7 
Phone 
follow-up 
Visit 8 (Week 36)g 
or Visit X (early 
D/C) 
Visit X 
Confirm patient is “OLE 
eligible” (≥ 35% reduction in 
seizure frequency) 
X 
 
 
 
 
 
 
 
Vital signs (BP, HR, RR, 
and body temperature)  
X 
 
X 
 
X 
 
X 
X 
Weighta 
X 
 
X 
 
X 
 
X 
 
Physical/Neurological/ 
Developmental Exam 
X 
 
X 
 
X 
 
X 
X 
ECG 
X 
 
 
 
X 
 
Xd 
 
Clinical Laboratory Testsb 
X 
 
X 
 
X 
 
X 
X 
Urinalysis 
X 
 
 
 
X 
 
X 
X 
Drug Screen  
X 
 
 
 
X 
 
 
 
Pregnancy Test (WCBP)c 
X 
 
X 
 
X 
 
X 
X 
Tanner Staging 
 
 
 
 
 
 
Xd 
 
IP PKe 
X 
 
X 
 
X 
 
X 
X 
Concomitant AED Review 
and levels if per standard of 
care 
X 
 
X 
 
X 
 
X 
X 
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IND 044,020 
 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
 
11 Jun 2021 
 
Confidential 
Page 29 of 88 
Table 2: 
Schedule of Assessments - Part B 
Part B 
 
Final 
Part A 
Visit/ 
First 
Part B 
Visit 
Open-Label Extension 
(Visits will be every 8 weeks with a telephone follow-up in-between) 
Final OLE Visit or 
Taper Visit 
Safety 
Follow-up 
Post-taper 
WEEK 
12 
16 
20 
24 
28 
32 
36 or early D/C 
2 weeks 
post last 
dose 
Visit Windows 
 
± 7 days 
± 7 days 
± 7 days 
± 7 days 
± 7 days 
± 7 days 
± 3 days 
VISIT 
Visit 5 
Phone 
follow-up 
Visit 6 
Phone 
follow-up 
Visit 7 
Phone 
follow-up 
Visit 8 (Week 36)g 
or Visit X (early 
D/C) 
Visit X 
 
 
 
 
 
 
 
 
 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
Seizure and Medication 
Diary Review 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
CGI-C - Target Behavior 
X 
 
 
 
 
 
X 
 
CGI-I (caregiver) 
X 
 
 
 
 
 
X 
 
CGI-I (clinician) 
X 
 
 
 
 
 
X 
 
C-SSRS (since last visit 
form)f 
X 
 
X 
 
X 
 
X 
 
Dispense GNX 
X 
 
X 
 
X 
 
X 
 
AED = antiepileptic drug, BP = blood pressure, CGI-C = Caregiver Global Impression of Change, CGI-I = Clinical Global Impression – Improvement, 
C-SSRS = Columbia-Suicide Severity Rating Scale, D/C = discontinuation, ECG = electrocardiogram, 
, GNX = ganaxolone, 
HR = heart rate, IP = investigational product, OLE = open-label extension, PK = pharmacokinetic, RR = respiratory rate, WCBP = women of childbearing 
potential. 
a. 
Weight will be measured at every visit, except the safety follow-up visit. 
b. Chemistry and Hematology. 
c. 
Serum pregnancy test is required for all girls/women of childbearing potential. 
d. Conduct at Week 36/Visit 8 or the last open-label extension visit if prior to Week 36/Visit 8. 
e. 
PK samples can be drawn when convenient during the study visits. 
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IND 044,020 
 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
 
11 Jun 2021 
 
Confidential 
Page 30 of 88 
Table 2: 
Schedule of Assessments - Part B 
Part B 
 
Final 
Part A 
Visit/ 
First 
Part B 
Visit 
Open-Label Extension 
(Visits will be every 8 weeks with a telephone follow-up in-between) 
Final OLE Visit or 
Taper Visit 
Safety 
Follow-up 
Post-taper 
WEEK 
12 
16 
20 
24 
28 
32 
36 or early D/C 
2 weeks 
post last 
dose 
Visit Windows 
 
± 7 days 
± 7 days 
± 7 days 
± 7 days 
± 7 days 
± 7 days 
± 3 days 
VISIT 
Visit 5 
Phone 
follow-up 
Visit 6 
Phone 
follow-up 
Visit 7 
Phone 
follow-up 
Visit 8 (Week 36)g 
or Visit X (early 
D/C) 
Visit X 
f. 
Only for patients ≥ 7 years old if appropriate.  Otherwise clinical judgment will be used. 
g.    Consistent with V8 (Week 36) or Visit X, patients can be seen at Investigator’s discretion for unscheduled visits. 
 
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IND 044,020 
 
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Protocol 1042-TSC-2001 
 
11 Jun 2021 
1. 
BACKGROUND INFORMATION 
1.1. 
Indication and Current Treatment Options 
Tuberous Sclerosis Complex (TSC) is a multi-system disorder of embryonal cortical 
development which can impact many organs through the overgrowth of hamartomas, benign, 
tumorous growths that can occur in the brain and other organs.  While the phenotype of TSC can 
be extremely variable, neurologic manifestations such as epilepsy are seen in up to 90% of TSC 
patients. (Krueger and Northrup, 2013).  The condition is caused by inherited mutations in either 
the TSC1 gene, located on chromosome 9q34, or the TSC2 gene located on chromosome 
16p13.3.  Tuberous Sclerosis Complex occurs with a frequency of 1:6,000 and a mutation is 
found in 85% of patients (Jülich and Sahin, 2014).  The gene products hamartin (TSC1) and 
tuberin (TSC2) form a regulatory complex responsible for limiting the activity of mammalian 
target of rapamycin (mTOR) complex 1, an important intracellular regulator of growth and 
metabolism that acts via inhibition of the small GTPase Ras homolog enriched in brain (Rheb) 
(Krueger and Northrup, 2013).  Everolimus, an mTOR inhibitor, has been shown to decrease 
seizures (French et al., 2016; Mizuguchi et al., 2019). 
Tuberous Sclerosis Complex is one of the most common genetic causes of epilepsy, with seizure 
semiology that varies by age of onset (Jülich and Sahin, 2014).  Infantile spasms (IS) are the 
most common seizure type presenting in infancy and represent the first manifestation of epilepsy 
in 50% of patients.  In older children and adults, focal impaired awareness seizures (previously 
known as complex partial seizures) are the most common (Chu-Shore et al., 2010).  Other focal 
and generalized seizures may also occur, with over 30% of patients developing treatment-
refractory epilepsy (Jülich and Sahin, 2014).  While seizures have typically been ascribed to 
tubers and the surrounding cortex, 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; van der Poest Clement et al., 2020). 
Treatment options depend on the type and severity of seizures.  Vigabatrin is widely accepted as 
the first-line treatment for IS associated with TSC.  For other seizure types, conventional 
antiepileptic drugs (AEDs) such as valproic acid, topiramate, and oxcarbazepine are often used 
as first-line AEDs in TSC although there are no data supporting TSC-specific efficacy.  
Additionally, there are disease-modifying drugs that target inhibition of the mTOR pathway such 
as everolimus.  A randomized clinical trial demonstrated efficacy of everolimus on seizure 
frequency reduction and is Food and Drug Administration (FDA)-approved for treatment of 
focal-onset seizures associated with TSC.  More recently, cannabidiol (CBD) (EPIDIOLEX®) 
demonstrated seizure reduction efficacy in a randomized controlled trial. 
1.2. 
Product Background and Clinical Information 
Ganaxolone (GNX) is the 3β-methylated synthetic analogue of the neuroactive steroid 
allopregnanolone, but it is designed to not activate nuclear (classical) progesterone receptors.  
Ganaxolone differs from other γ-Aminobutyric acid (GABA) agents by interacting with both 
synaptic and extra-synaptic GABA type A (GABAA) receptors and at binding sites distinct from 
benzodiazepines.  Whereas benzodiazepines might lose their inhibitory action, GNX does not 
because it selectively binds to GABAA receptors containing the α and δ subunits.  By enhancing 
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Page 32 of 88 
IND 044,020 
 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
 
11 Jun 2021 
synaptic and extrasynaptic GABAA receptor function, GNX provides an alternative mechanism 
in the treatment of seizures.   
The anticonvulsant activity of GNX was established in several in vivo models of seizure activity.  
Ganaxolone was effective at behaviorally non-toxic doses in rodent models of seizures induced 
by pentylenetetrazol, bicucilline, aminophylline, strychnine, and 
t-butylbicyclophosphorothionate and antagonized 4-AP lethality in mice.  Ganaxolone blocked 
tonic seizures induced by maximal electroshock in mice and rats, but only at doses that produced 
ataxia on the rotarod test.  Ganaxolone was a potent anticonvulsant against fully-kindled Stage-5 
seizures induced by corneal kindling in the rat at doses well below those that resulted in ataxia.  
Seizure threshold, as determined by the dose of intravenously (IV)-infused pentylenetetrazol 
required to induce clonus, was significantly elevated by non-toxic doses of GNX in the mouse.  
These results indicate that GNX blocks seizure propagation and elevates seizure threshold 
(Carter et al., 1997; Kaminski et al., 2004; Reddy et al., 2004). 
The completed GNX clinical program comprises 20 Phase 1 studies in healthy subjects and 
20 Phase 2 studies in adults with epilepsy, children with seizure disorders, children with 
fragile X syndrome (FXS), adults with post-traumatic stress disorder and adults with migraine.  
In these studies, the efficacy, safety, tolerability, pharmacokinetics (PK), and PD of GNX were 
evaluated with an oral dosing duration ranging from 1 day up to more than 2 years, using doses 
from 50 to 2000 mg/day.  Additionally, IV bolus doses ranging from 10 to 30 mg over durations 
of 2 minutes to 1 hour or a bolus dose of 6 mg over 5 minutes followed with a continuous 
infusion of 20 mg per hour for 4 hours were evaluated in healthy subjects (Ganaxolone, 2019). 
As of 10 Oct 2019, 1557 patients and healthy volunteers have received at least 1 dose of GNX 
across the 40 completed studies.  This includes 319 patients in Phase 1 and 1238 patients in 
Phase 2/3 studies. 
In 20 completed Phase 1 studies, 319 healthy subjects received GNX oral doses of 50 to 
2000 mg/day for periods of up to 2 weeks, or IV bolus doses ranging from 10 to 30 mg over 
durations of 2 minutes to 1 hour or a bolus dose of 6 mg over 5 minutes followed with a 
continuous infusion of 20 mg per hour for 4 hours. 
In the 20 completed Phase 2/3 clinical studies, 1238 unique patients have received GNX 
in studies of adult patients with epilepsy, pediatric patients with seizure disorders, 
pediatric patients with FXS, adult patients with post-traumatic stress disorder, and adult 
patients with migraine. 
The ongoing GNX clinical program consists of 6 Phase 2/3 studies evaluating GNX in women 
with postpartum depresssion, children with refractory epilepsy including protocadherin 19 
(PCDH19) epilepsy, cyclin dependent kinase-like 5 (CDKL5) deficiency disorder and other rare 
genetic epilepsies, and in adolescents and adults with SE.  Additionally, two Phase 1 studies 
designed to evaluate metabolites of GNX in healthy lactating females and healthy males are 
ongoing. 
In addition to the company-sponsored studies, 18 patients were treated with GNX in completed 
studies not sponsored by Marinus.  These included 16 patients who received oral GNX doses 
from 400 to 1200 mg/day in a smoking cessation study.  In addition, 
 
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IND 044,020 
 
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Protocol 1042-TSC-2001 
 
11 Jun 2021 
 
 
   
The overall frequency of treatment-emergent adverse events (TEAE) in company-sponsored 
placebo (PBO)-controlled studies was 61.7% (613/993 patients) in patients who received GNX 
and 51.8% (330/637 patients) in patients who received PBO.  The most frequently reported 
TEAEs in GNX-treated patients were somnolence, dizziness, fatigue, and headache.  All of these 
events, except for headache, occurred more frequently in GNX-treated patients than PBO-treated 
patients.  Central nervous system (CNS)-related events appeared to be dose-related, with the 
majority of these events occurring at doses ≥ 500 mg and were anticipated based on the 
mechanism of action of GNX.  These events were non-serious, mild to moderate in severity, and 
did not lead to discontinuation of treatment.   
In the GNX development program overall, no clinically significant trends have been noted for 
electrocardiogram (ECG) intervals, vital signs, physical or neurologic examinations, or mean 
changes from baseline in clinical laboratory results.  Overall, there have been a few clinically 
significant individual changes from baseline in clinical laboratory measurements in clinical trials 
of GNX.  In the completed PBO-controlled Phase 1, 2, and 3 studies, 0.3% of patients treated 
with GNX and 0.5% of patients treated with PBO exhibited elevated liver function tests during 
the study (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] > 3 × the upper 
limit of normal [ULN]).  There have been no cases of Hy’s law considered to be related to GNX 
in the GNX development program. 
In controlled clinical trials of GNX, 1.1% of patients receiving PBO and 1.7% of patients 
receiving GNX reported an adverse event (AE) of rash suggesting there is no obvious imbalance 
between drug and PBO in terms of frequency of this AE.  However, in PBO-controlled studies, 
rash led to discontinuation in GNX-treated patients in 6 cases (0.6%) compared to no cases (0%) 
in PBO-treated patients.  Most rashes improved either while the drug was continued or following 
discontinuation.  Two patients participating in the Phase 2 study investigating GNX in treatment 
of epilepsy developed a serious adverse event (SAE) of rash.  Both events resolved after 
discontinuation of the investigational product (IP). 
Pediatric Safety 
Marinus has completed 2 double-blind (DB), randomized trials and 5 open-label (OL), 
uncontrolled clinical trials of GNX in the pediatric population.  One additional pediatric trial, OL 
Study 1042-0900 in children with various genetic epilepsies and Lennox Gastaut syndrome, is 
clinically complete and analysis is ongoing. 
Approximately 250 pediatric patients aged 4 months to 17 years (data cutoff 10 Oct 2019) have 
received at least 1 dose of GNX.  The largest cohorts received 12 to 54 mg/kg/day, although 
some patients received doses as high as 63 mg/kg/day or 1800 mg/day for adolescents.   
The majority of the pediatric patients were refractory epilepsy patients who had uncontrolled 
seizures despite trying other AEDs (range 1-8).  Overall, GNX was generally safe and well 
tolerated.  In the incomplete crossover Study 1042-0500 (N = 56; all patients received GNX 
during the trial), 39 patients with IS treated with GNX doses up to 54 mg/kg/day for up to 
20 days reported at least 1 TEAE.  The most frequently reported AEs (≥ 8% of patients) were 
vomiting (7 patients), somnolence (5 patients), and cough (5 patients).  Most AEs were mild or 
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moderate; 1 severe AE of lethargy occurred in 1 GNX patients.  During the 8-day 
PBO-controlled treatment period, the most frequent AEs noted were vomiting (11% in both 
GNX and PBO groups) and cough (8% GNX, 5% PBO).  Other AEs attributed to GNX included 
flatulence, insomnia, irritability, lethargy, and somnolence.  Adverse events reported in the other 
uncontrolled refractory pediatric epilepsy studies were consistent with the GABAergic 
mechanism of action or disease under study.   
In another randomized, DB, PBO-controlled study of 59 patients (aged 5-17 years) with FXS 
who were treated with GNX up to 36 mg/kg/day (maximum 1800 mg/day) or PBO, the 
percentage of patients who reported at least 1 TEAE was comparable between the treatment 
groups (85.2% versus 83.1% in the PBO and GNX treatment groups, respectively).  The most 
frequently reported TEAEs among patients who received GNX included fatigue 
(29/59 patients; 49.2%), somnolence (20/59 patients; 33.9%), vomiting (8/59 patients; 13.6%), 
decreased appetite (8/59 patients; 13.6%), aggression (6/59 patients; 10.2%) and rash 
(5/59 patients; 8.5%).  Both fatigue (49.2% vs 20.4%) and somnolence (33.9% vs 5.6%) 
occurred more frequently in GNX-treated patients compared with PBO-treated patients, 
respectively.  
Among patients who received PBO, headache (6 patients; 11.1%) and agitation 
(8 patients; 14.8%) were reported more frequently compared with GNX-treated patients.  Severe 
TEAEs were reported for 3/59 (5.1%) GNX patients and 1/54 (1.9%) PBO patients.  Severe 
events in the GNX group were somnolence and fatigue in 1 patient each and agitation and 
aggression in 1 patient. 
To date, AEs have been consistent with the GABAergic mechanism of GNX or the underlying 
condition.  There have not been any emerging safety concerns with respect to vital signs, ECG, 
physical/neurological examinations, or clinical laboratory measures. 
2. 
STUDY OBJECTIVES AND PURPOSE 
2.1. 
Rationale for the Study 
GABAergic signaling may play a meaningful role in the development and severity of 
TSC-related epilepsy, possibly due to altered expression of endogenous GABAA receptor 
modulators (Di Michele et al., 2003).  There is evidence supporting a deficiency of the 
neuroactive steroid, 3α, 5α-tetrahydroprogesterone (THP), or allopregnanolone, as a contributor 
to epileptogenesis in TSC.  Allopregnanolone is a positive modulator of the GABAA receptor 
and has been shown to have antiepileptic effects in experimental animals and humans.  There is a 
decrease in allopregnanolone relative to its functional GABAA antagonist, 3β-THP, in patients 
with TSC-related epilepsy but not in TSC patients without epilepsy or in controls 
(Di Michele et al., 2003).  This reduced ratio could alter neuronal excitability mediated by 
GABAA receptors, leading to the development of epilepsy.  The role of GABAA receptor 
mediation is also supported by the efficacy of vigabatrin, a specific and irreversible inhibitor of 
GABA-aminotransferase, in seizures due to TSC relative to other epilepsies 
(Di Michele et al., 2003).  These findings provide compelling evidence for the potential role of 
neuroactive steroids with anticonvulsant properties, or analogues such as GNX, in the treatment 
of TSC-related epilepsy. 
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Ganaxolone is the 3β-methylated synthetic analog of allopregnanolone, an endogenous positive 
allosteric modulator of CNS GABAA receptors.  Ganaxolone has potency comparable to 
allopregnanolone in activating synaptic and extrasynaptic GABAA receptors at a site distinct 
from benzodiazepines and barbiturates (Carter et al., 1997).  Ganaxolone has protective activity 
in diverse rodent seizure models (Bialer et al., 2010; Reddy and Rogwski, 2012).  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 given orally in adults and children 
(Kerrigan et al., 2000; Laxer et al., 2000; Pieribone et al., 2007; Sperling et al., 2017).  Further, 
GNX reduces seizures in children with IS and refractory pediatric epilepsy.  In an OL study, 
pediatric patients 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).  Fifteen patients with 
a history of IS completed treatment.  Five of the 15 patients had a decrease from baseline in the 
number of spasms of ≥ 50%, 5 had a decrease of 25% to 50%, and 5 had a decrease of < 25%.  
One patient became spasm-free and 1 non-responder (with a decrease of < 25%) was spasm-free 
from Weeks 2 to 7.   
A DB study (Study 1042-0500) of GNX in IS was also conducted.  In this study, patients aged 4 
to 24 months with IS received PBO or GNX doses of up to 54 mg/kg/day for up to 20 days in an 
incomplete crossover design.  A total of 55 of the 57 patients completed treatment, 54 of whom 
continued GNX treatment in Study 1042-0501, an open-label extension (OLE).  Although the 
GNX group had numerically higher reductions in frequency of spasm clusters, no statistically 
significant differences were observed in change from baseline between the treatment groups in 
the frequency of spasm clusters or in any of the secondary efficacy parameters at the end of the 
DB period (Day 9 ± 1 day). 
In addition to its anticonvulsant activity, GNX has been shown to reduce anxiety, hyperactivity, 
and attention in children with FXS who had higher baseline levels of anxiety (Ligsay et al., 
2016).  Similar behavioral problems occur in individuals with TSC, with rates of approximately 
50% for attention deficit hyperactivity disorder and autism (Jülich and Sahin, 2014). 
It is hypothesized that GNX treatment will increase and improve GABAA-receptor mediated 
signaling by boosting the signaling capacity of existing receptors and improve not only seizure 
control but may also ameliorate the behavioral abnormalities in individuals with TSC. 
This present study is planned to assess preliminary safety and efficacy of GNX as adjunctive 
therapy for the treatment of primary seizure types in patients with genetically- or 
clinically-confirmed TSC-related epilepsy through the end of the 12-week treatment period.  
Pharmacokinetic assessments and population PK analyses will also be performed during this 
time.  The 12-week treatment period (4-week titration and 8-week maintenance periods) will be 
followed by an optional long-term OLE period.  Efficacy, safety and tolerability, and PK 
assessments will continue to be performed.  
2.2. 
Study Objectives 
2.2.1. 
Primary Objective 
The primary objective of this study is to assess preliminary safety and efficacy of GNX as 
adjunctive therapy for the treatment of primary seizure types in patients with genetically- or 
clinically-confirmed TSC-related epilepsy through the end of the 12-week treatment period.  The 
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primary seizure types (defined later) are identified to be the most common, easily 
identifiable/countable by a parent/caregiver/legally authorized representative (LAR), and most 
consequential to the patient’s quality of life. 
2.2.2. 
Secondary Objectives 
The secondary objectives of this study are the following:  
x To assess the long-term efficacy of GNX when administered as adjunctive therapy 
throughout the OLE period (Part B). 
x To assess the long-term safety and tolerability of GNX when administered as adjunctive 
therapy throughout the OLE period (Part B).  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
3. 
STUDY DESIGN 
3.1. 
Study Design and Flow Chart 
This is an OL proof of concept study of adjunctive GNX treatment in patients with a confirmed 
clinical diagnosis of TSC and/or a mutation in either the TSC1 or TSC2 gene.  The trial consists 
of two parts:  Part A consists of a 4-week baseline period followed by a 12-week treatment 
period (4-week titration and 8-week maintenance).  For patients not continuing in the OLE 
period (Part B), a 2-week taper period followed by a 2-week safety period would follow.  The 
main difference between Part A and Part B is the length of treatment, less frequent assessments, 
and the ability to alter drug doses (both GNX and other AED treatments which includes initiating 
and stopping other medications) based on investigator evaluation of the patient’s clinical course 
during Part B.  Patients with a seizure frequency reduction rate of ≥ 35% during the 12-week 
treatment period in Part A compared to baseline may continue into Part B (“OLE eligible”).  If 
the investigator believes there is a medical benefit for the patient who does not meet the seizure 
reduction criterion to enter the OLE, they must discuss the patient with the sponsor medical 
monitor and receive sponsor approval for that patient to continue into the OLE.  
Part A 
x 4-week baseline period 
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x 4-week titration period 
x 8-week maintenance period  
x 2-week taper period (For patients who do not complete Part A or after completing Part A 
but do not continue into Part B) 
x 2-week safety follow-up visit post taper (For patients who taper off GNX) 
Part B (Optional for OLE-eligible patients) 
x OLE period (until the Sponsor markets ganaxolone or terminates the study  
x 2-week taper period (For patients who discontinue GNX due to early termination or 
completion) 
x 2-week safety follow-up visit post-taper (For patients who taper off GNX) 
Figure 1: 
Study Design 
 
 
GNX = ganaxolone 
During the screening visit, each patient’s baseline 
 
 will be collected and analyzed for post-study evaluation. 
Patient rescreening is allowed as agreed by the sponsor and the investigator unless there is a 
general concern for patient safety or an inability for the patient to become eligible (e.g., GNX 
allergy, sensitivity or exposure, non-TSC and/or other ineligible epilepsy, chronic prohibited 
medical condition or treatment).  Subsequent screening should take place at least 30 days from 
the patient’s last visit, unless otherwise noted. 
Part A includes a 4-week baseline and 4 weeks of IP titration followed by 8 weeks of dose 
maintenance followed by 2-week taper for those patients not continuing into the Part B OLE 
period.  After meeting all eligibility criteria, approximately 30 patients aged 2 to 65 years 
(inclusive) with TSC-related epilepsy will be enrolled to receive GNX for a total of 12 weeks 
(4-week titration, 8-week maintenance) in addition to their standard anti-seizure medication(s) 
(ASMs).  Patients will be titrated to 63 mg/kg/day (maximum 1800 mg/day) over 4 weeks, and 
then maintained at that dose for another 8 weeks.  Patients who are not able to tolerate 
63 mg/kg/day (or maximum 1800 mg/day) may be maintained on a lower dose after discussion 
with the sponsor medical monitor.  A minimum dose of 33 mg/kg/day or 900 mg/day is generally 
required during the maintenance period. 
For Part A, dose changes including alternative dosing paradigm (e.g., lower dose during the 
daytime and higher dose in the evening) should be discussed with the sponsor medical monitor 
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prior to making the change or within 48 hours of making the change.  Patients who discontinue 
GNX should undergo a 2-week taper period, unless otherwise medically indicated.  Patients who 
discontinue GNX before the completion of the maintenance period will continue to be followed 
per protocol and, at a minimum, patients will be encouraged to maintain daily seizure diaries 
until the maintenance period in Part A is completed.  These patients will also return to the site 
2 weeks after the taper for safety follow-up assessments. 
After completing the initial 16-week period, Part A, patients with a seizure reduction of ≥ 35% 
compared to the 4-week baseline period and who do not have any other contraindications for 
continued treatment can continue to be treated with GNX in the OLE period (Part B).  Patients 
will continue GNX treatment at the dose that they were taking at completion of Part A.  Doses of 
other ASMs may be adjusted (including tapering and initiating treatments) during Part B based 
on investigator discretion.  Any patient who discontinues GNX treatment should undergo a 2-
week drug de-escalation (taper) period and return to the site 2 weeks later for safety follow-up 
assessments.   
Patients will be required to complete a daily diary to determine GNX’s effect on seizures.  Days 
without seizures should also be noted.  Additional clinician- and caregiver-administered 
instruments will be used to assess the efficacy of GNX in TSC, and will include:   
x Caregiver Global Impression of Change (CGI-C) – Target Behavior 
x Clinical Global Impression – Improvement (CGI-I) caregiver and CGI-I clinician. 
3.2. 
Duration and Study Completion Definition 
After 4 weeks of baseline seizure charting, patients will initiate a 4-week GNX titration period 
followed by an 8-week GNX maintenance period (Part A).  Patients completing Part A and 
deemed eligible for Part B will continue taking GNX for an additional 24 weeks of treatment.  
Anyone discontinuing GNX will undergo a 2-week taper and a 2-week follow-up safety visit.  
Patients who discontinue IP treatment before the completion of the maintenance period in Part A 
will continue to be followed per protocol and at minimum maintain daily seizure diary entry until 
the maintenance period is completed.   
The planned study duration will be approximately 64 weeks for patients who stay on the study 
through Part B, or until ganaxolone is commercially available.   
3.3. 
Sites and Regions 
This multicenter study is to be conducted at approximately 6 sites in the United States (US).   
3.4. 
Discussion of Study Design 
Dosing will be based on doses that have been shown to be safe in children and adults in multiple 
studies with normal volunteers and individuals with epilepsy.  In this current study, patients will 
receive OL GNX, prescribed in increments of 15 mg/kg/day up to 63 mg/kg/day given as an oral 
suspension with food, during a 4-week titration period, 8-week maintenance period, and optional 
extension period.  Patients weighing ≤ 28 kg will be dosed on an mg/kg basis.  Patients weighing 
> 28 kg will be dosed on a fixed regimen in increments of 450 mg/day up to 1800 mg/day.   
Ganaxolone will be administered during the 4-week titration period as follows: 
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1. For patients weighing ≤ 28 kg (62 lbs): 
x 6 mg/kg three times daily (TID) (18 mg/kg/day) suspension - Days 1-7 
x 11 mg/kg TID (33 mg/kg/day) suspension - Days 8-14 
x 16 mg/kg TID (48 mg/kg/day) suspension - Days 15-21 
x 21 mg/kg TID (63 mg/kg/day) suspension - Days 22-28 
 
2. For patients weighing > 28 kg (62 lbs): 
x 150 mg TID (450 mg/day) suspension - Days 1-7 
x 300 mg TID (900 mg/day) suspension - Days 8-14 
x 450 mg TID (1350 mg/day) suspension - Days 15-21 
x 600 mg TID (1800 mg/day) suspension - Days 22-28 
Any patient not tolerating the next dose step can be maintained at the lower dose step for 
additional days before advancing to the next dose.  If the next dose is still not tolerated, the 
patient can drop back to the next lower dose step.  A minimum dose of 33 mg/kg/day or 
900 mg/day is generally required following the escalation period and during the maintenance 
period. 
Patients will initiate treatment in Part B with GNX at the same dose they were on at the 
completion of the maintenance period.  During the extension period, doses of GNX may be 
adjusted to a maximum of 600 mg TID for patients weighing > 28 kg and a maximum dose of 
21 mg/kg TID for patients ≤ 28 kg. 
4. 
STUDY POPULATION 
Each patient’s parent/LAR must participate in the informed consent process and provide written 
informed consent (and/or patient assent) before any procedures specified in the protocol are 
performed.  
4.1. 
Inclusion Criteria (Part A) 
The patient will not be considered eligible for the study without meeting all the criteria below.  
1. Clinical or mutational diagnosis of TSC consistent with Northrup and Krueger, 2013.  
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 (e.g., 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 investigator 
must review the results of the genetic analysis and confirm that the causal relationship 
to the epilepsy syndrome is likely.  OR 
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b. Clinical diagnosis of definite TSC which includes two major features or one major 
feature with ≥ 2 minor features. The investigator must document which of the features 
(Major or Minor) fulfill the clinical diagnostic criteria.   
 
 
Major features 
Minor features 
1. Hypomelanotic macules (≥ 3, 
at least 5-mm diameter) 
2. Angiofibromas (≥ 3) or fibrous 
cephalic plaque 
3. Ungual fibromas (≥ 2) 
4. Shagreen patch 
5. Multiple retinal hamartomas 
6. Cortical dysplasiasa 
7. Subependymal nodules 
8. Subependymal giant cell 
astrocytomas 
9. Cardiac rhabodomyoma 
10. Lymphangioleiomyomatosis 
(LAM)b 
11. Angiomyolipomas (≥ 2)b 
1. “Confetti” skin lesions 
2. Dental enamel pits (≥ 3) 
3. Intraoral fibromas (≥ 2) 
4. Retinal achromic patch 
5. Multiple renal cysts 
6. Nonrenal hamartomas 
a. 
Includes tubers and cerebral white matter radial migration lines 
b. 
A combination of the two major clinical features (LAM and angiomyolipomas) without other features that does not meet 
criteria for a definite diagnosis. 
 
2. Male or female patients aged 2 through 65 years, inclusive. 
3. Patient/parent/caregiver or LAR willing to give written informed consent/assent, after 
being properly informed of the nature and risks of the study and prior to engaging in any 
study-related procedures.  Assent for patients over 7 years of age should be obtained, if 
appropriate. 
4. Failure to control seizures despite appropriate trial of 2 or more ASMs at therapeutic 
doses. 
5. Have at least 8 countable/witnessed primary seizures during the 4-week baseline period 
with at least 1 primary seizure occurring in at least 3 of the 4 weeks of baseline.  The 
primary seizure types are defined as the following:  focal motor seizures without 
impairment of consciousness or awareness, focal seizures with impairment of 
consciousness or awareness, focal seizures evolving to bilateral, tonic-clonic convulsive 
seizures, and generalized motor seizures including tonic-clonic, bilateral tonic, bilateral 
clonic, or atonic/drop seizures.  Focal aware non-motor and generalized seizures without 
motor features, infantile or epileptic spasms, and myoclonic seizures do not count as the 
primary seizure types. 
6. Patient must be approved to participate by the sponsor or its designee (e.g., Epilepsy 
Consortium) after review of medical history, genetic testing, and patients’ seizure types. 
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7. Patients should be on a stable regimen of ASMs at therapeutic doses for ≥ 1 month prior 
to the screening visit, without a foreseeable change in dosing for the duration of Part A.  
Vagus nerve stimulator (VNS), ketogenic diet, and modified Atkins diet should be 
unchanged for 3 months prior to screening and will not count towards the number of 
ASMs. 
8. Patients with surgically implanted 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 ≥ 1 year prior to the screening visit. 
b. The settings must have remained constant for 3 months prior to the screening visit 
and remain constant throughout the baseline and Part A. 
c. The battery is expected to last for the duration of baseline and Part A. 
9. Parent/caregiver is able and willing to maintain an accurate and complete daily seizure 
diary for the duration of the study. 
10. Able and willing to take IP (suspension) with food 3 times daily.  (GNX must be 
administered with food).  
11. Sexually active female of childbearing potential must be using a medically acceptable 
method of birth control and have a negative quantitative serum β-human chorionic 
growth hormone (β-HCG) test collected at the initial screening visit.  Childbearing 
potential is defined as a female who is biologically capable of becoming pregnant.  A 
medically acceptable method of birth control includes intrauterine devices in place for at 
least 3 months prior to the screening visit, surgical sterilization, or adequate barrier 
methods (e.g., diaphragm or condom and foam).  An oral contraceptive alone is not 
considered adequate for the purpose of this study.  Use of oral contraceptives in 
combination with another method (e.g., a spermicidal cream) is acceptable.  In patients 
who are not sexually active, abstinence is an acceptable form of birth control. 
4.1.1. 
Inclusion Criterion (Part B) 
1. Patients have experienced ≥ 35% reduction in primary seizure frequency during the Part 
A treatment period compared to the 4-week Baseline Period. 
4.2. 
Exclusion Criteria (Part A) 
Patients are excluded from the study if any of the following criteria apply: 
1. Previous exposure to GNX. 
2. Pregnant or breastfeeding. 
3. Concurrent use of strong inducers or inhibitors of cytochrome P450 (CYP)3A4/5/7.  Any 
strong inhibitor or inducer of CYP3A4/5/7 must be discontinued at least 28 days before 
Visit 2, study drug initiation.  This does not include approved ASMs. 
4. Patients who have been taking felbamate for less than 1 year prior to screening. 
5. Patients who test positive for tetrahydrocannabinol (THC) or non-approved CBD via 
plasma drug screen.  
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6. Chronic use of oral steroid medications, ketoconazole (except for topical formulations), 
St. John’s Wort, or other IPs is not permitted. 
7. Adrenocorticotropic hormone (ACTH), prednisone, or other systemically administered 
(non-inhaled) steroids must be discontinued > 28 days prior to screening.  Concomitant 
topical, inhaled or intranasal steroids are allowed and do not warrant exclusion from the 
study.  
8. Changes in any chronic medications within the month (e.g., 30 days) prior to the 
screening visit.  All concomitant medications must have been at a stable in dose for at 
least 1-month prior to the screening visit unless otherwise noted. 
9. Patient is being considered for epilepsy surgery or has undergone surgery for epilepsy 
within the 6 months prior to screening. 
10. Have an active CNS infection, demyelinating disease, degenerative neurological disease, 
or CNS disease deemed progressive.  This includes tumor growth which in the opinion of 
the investigator could affect primary seizure control. 
11. Have any disease or condition (medical or surgical; other than TSC) at the screening visit 
that might compromise the hematologic, cardiovascular, pulmonary, renal, 
gastrointestinal, or hepatic systems; or other conditions that might interfere with the 
absorption, distribution, metabolism, or excretion of the IP, or would place the patient at 
increased risk.  This may include any illness in the past 4 weeks which in the opinion of 
the investigator may affect seizure frequency.  
12. An AST/serum glutamic oxaloacetic transaminase (SGOT) or ALT/serum glutamic 
pyruvic transaminase (SGPT) >3 × the ULN at screening or baseline visits and confirmed 
by a repeat test.   
13. Total bilirubin levels > 1.5 × ULN at screening or baseline visit and confirmed by a 
repeat test.  In cases of documented, stable medical condition (i.e., Gilbert’s Syndrome) 
resulting in levels of total bilirubin > ULN, the medical monitor can determine if a 
protocol exception can be made. 
14. Patients with significant renal insufficiency, estimated glomerular filtration rate (eGFR) 
< 30 mL/min (calculated using the Cockcroft-Gault formula or Pediatric GFR calculator 
or Bedside Schwartz), will be excluded from study entry or will be discontinued if the 
criterion is met post baseline. 
15. Have been exposed to any other investigational drug within 30 days or fewer than 
5 half-lives (whichever is shorter) prior to the screening visit.   
16. Unwillingness to withhold grapefruit, Seville oranges, star fruit, or grapefruit containing 
products from diet 7 days prior to the first dose and for the duration of the study. 
17. Have had an active suicidal plan/intent or active suicidal thoughts in the past 6 months or 
have made a suicide attempt in the past 3 years.   
18. Known sensitivity or allergy to any component in the IP(s), progesterone or other related 
steroid compounds. 
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4.2.1. 
Exclusion Criterion (Part B) 
1. Patient developed a medical condition that would make it unsafe for patients to received 
GNX as determined by the investigator. 
4.3. 
Restrictions  
Patients must abstain from the use of alcohol, and from consuming grapefruit, Seville oranges, 
starfruit, or grapefruit containing products from 7 days prior to the first dose and for the duration 
of the study. 
4.4. 
Reproductive Potential 
4.4.1. 
Female Contraception 
Sexually active girls/women of childbearing potential should be using a medically acceptable 
form of birth control and have a negative quantitative serum β-HCG test collected at the initial 
screening visit.  Girls/women of childbearing potential must be advised to use medically 
acceptable birth control throughout the study period and for 30 days after the last dose of IP.  A 
medically acceptable method of birth control includes intrauterine devices in place for at least 3 
months prior to the screening visit, surgical sterilization, or adequate barrier methods (e.g., 
diaphragm or condom and foam).  An oral contraceptive alone is not considered adequate for the 
purpose of this study.  Use of oral contraceptives in combination with another method (e.g., a 
spermicidal cream) is acceptable.  Contraceptive measures such as Plan BTM, sold for emergency 
use after unprotected sex, are not acceptable methods for routine use.  Patients who are not 
sexually active, abstinence is an acceptable form. 
4.4.2. 
Male Contraception 
Male patients must agree to take all necessary measures to avoid causing pregnancy in their 
sexual partners during the study and for 3 months after the last dose of IP.  Medically acceptable 
contraceptives include surgical sterilization (such as a vasectomy) and a condom used with a 
spermicidal gel or foam.   
Male patients should not donate sperm during the study and for 30 days after the last dose of IP.  
Patients who are not sexually active, abstinence is an acceptable form. 
4.5. 
Discontinuation of Patients 
A patient may withdraw - or their parent/LAR may withdraw the patient - from the study at any 
time for any reason without prejudice to their future medical care by the physician or at the 
hospital.  The investigator or sponsor may withdraw the patient at any time (e.g., in the interest 
of patient safety).  The investigator is encouraged to discuss withdrawal of a patient from IP with 
the medical monitor when possible. 
If the IP is discontinued at any time, patients should follow the 2-week taper schedule unless 
otherwise medically indicated such as drug-induced rash.  If the patient discontinues during the 
maintenance period of Part A, evaluations listed for Taper and Safety Visit (Section 7.2.8) are to 
be performed as completely as possible.  If the patient discontinues during the OLE period 
(Part B), evaluations listed for the Taper Visit (Section 7.3.2) and Safety Follow-up Post Taper 
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Visit (Section 7.3.4) are to be performed as completely as possible.  Comments (spontaneous or 
elicited) or complaints made by the patient must be recorded in the source documents.  The 
reason for termination, date of stopping IP, and total amount of IP taken must be recorded in the 
electronic case report form (eCRF) and source documents.  Discontinuation of IP due to AEs 
must also be reflected on the AE eCRF page. 
4.5.1. 
Patient Withdrawal Criteria 
All patients or his/her parent/LAR reserve the right to withdraw from the clinical study at any 
time, as stated in the informed consent/assent form.  The investigator may discontinue patients 
from the clinical study for any of the following reasons: 
x Patient is found to have entered the study in violation of the protocol; 
x Patient requires the use of a disallowed concomitant medication; 
x Patient’s condition changes after entering the clinical investigation so that the patient no 
longer meets the inclusion criteria or develops any of the exclusion criteria; 
x Patient or parent/LAR withdraws consent or assent to participate in the study; 
x Patient is noncompliant with the procedures set forth in the protocol; 
x Patient experiences an AE/SAE that warrants withdrawal from the study;  
x Laboratory, medical, or clinical finding for which clinical intervention should take 
precedence over study participation; or 
x It is the investigator’s opinion that it is not in the patient’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 patient’s discontinuation.  Patients who discontinue IP during the maintenance period of 
Part A will continue to record daily seizure frequency at minimum until the completion of the 
maintenance period. 
4.5.2. 
Reasons for Early Discontinuation 
The reason for early discontinuation must be determined by the investigator and recorded in the 
patient’s source documents and on the eCRF.  If a patient 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: 
x AE 
x Protocol violation/protocol deviation 
x Withdrawal by patient or parent/LAR 
x Lost to follow-up 
x Lack of efficacy 
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x Death 
x Physician decision 
x Other (must be specified in the patient source document and eCRF) 
4.5.3. 
Patients Lost to Follow-up Prior to Last Scheduled Visit 
A minimum of 3 documented attempts must be made to contact any patient 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 patient’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 
patient refuses or is unable to return to the site for the final safety follow-up visit, it should be 
documented in the eCRF. 
4.6. 
Patient Numbering 
During the screening visit, each patient will be assigned a unique 6-digit patient number by the 
site.  The patient number will consist of a 3-digit clinical investigational site number assigned by 
the sponsor, followed by a 3-digit patient number (e.g., 001) assigned by the study staff.  This 
patient number will also serve as the screening number.  The unique 6-digit patient number will 
serve as the patient ID and be used to track the patient throughout the study. 
The clinical site is responsible for maintaining a current log of patient number assignments and 
bottle numbers of the IP administered to each patient.  The unique patient number is required to 
be entered on all clinical investigation documentation (eCRFs, labeling of clinical materials and 
samples containers, drug accountability logs, etc.).   
5. 
EXCLUDED, PRIOR, AND CONCOMITANT MEDICATIONS 
The investigator should assess all concomitant medications at every visit, and at the screening 
visit in particular to ensure that the patient is not taking excluded medications.  
5.1. 
Prior Medications 
Prior medications include all treatment, including but not limited to herbal treatments, vitamins, 
surgical implants (such as VNS), and prescribed medications received within 30 days (or PK 
equivalent of five half-lives, whichever is longer) of the date prior to screening.  Prior treatment 
information, if available, must be recorded on the appropriate eCRF page. 
5.2. 
Concomitant Medications 
Concomitant medications refer to all treatment taken between the date of Informed 
Consent/Assent and the date of the last dose of IP.  Concomitant treatment information must be 
recorded on the appropriate eCRF page.  Concomitant topical and intranasal steroids for 
dermatologic reactions and allergic rhinitis are allowed as needed and do not warrant exclusion 
from study.  If the patient is currently taking an excluded medication at the time of the screening 
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visit, then the patient must undergo a washout period equivalent to 5 half-lives of the drug before 
they may enter the prospective 4-week baseline period. 
Use of dietary supplements or herbal preparations are permitted if patient 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 12.1). 
5.2.1. 
Concomitant AED Medications 
Patients in the study should be on a stable regimen of AED medications at therapeutic doses for 
≥ 1 month prior to the screening visit, and cannot be changed at any time prior to Visit 5 during 
Part A, but may be adjusted during Part B.   
Vagus nerve stimulator, ketogenic diet, and modified Atkins diet should be unchanged for 3 
months prior to screening and will not count towards the number of ASMs. 
Patient with surgically implanted VNS will be allowed to enter the study provided that all of the 
following conditions are met: 
x The VNS has been in place for ≥ 1 year prior to the screening visit. 
x The settings must have remained constant for 3 months prior to the screening visit and 
remain constant throughout the baseline and Part A. 
x The battery is expected to last for the duration of the baseline and Part A. 
The use of felbamate is allowed provided that the patient has been maintained on a stable dose of 
felbamate for at least 1 year, and has had stable liver function (AST/ALT) and hematology 
during the course of treatment, and is expected to remain constant throughout the 12-week 
treatment period. 
5.3. 
Rescue Medications 
The use of rescue medication is allowed.  The type, dose, date, and frequency will be recorded. 
5.4. 
Excluded Medications 
Excluded medications include all steroid medications, other IPs, as well as ketoconazole, and St. 
John’s wort.  Concurrent use of ACTH, prednisone or other glucocorticoid is not permitted, nor 
use of moderate or strong inducers or inhibitors of CYP3A4/5/7.  Patients on ACTH, prednisone, 
or other systemically (non-inhaled) administered steroids should be off the product greater than 
28 days prior to screening.  Any strong inhibitor or inducer of CYP3A4/5/7 must be discontinued 
at least 28 days before Visit 2, study drug initiation.  A list of CYP3A4/5/7 inhibitors and 
inducers is included in Section 12.1.  Concomitant topical and intranasal steroids for 
dermatologic reactions and allergic rhinitis are allowed as needed and do not warrant exclusion 
from the study.   
Products containing THC or non-approved CBD are excluded in the treatment period (Part A) of 
the study but allowed in the OLE period (Part B).  Tetrahydrocannabinol or non-approved CBD 
should be washed out for at least 6 weeks.  Patients with a positive result on THC at the 
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screening and baseline visit will be excluded.  Patients with a positive result on CBD without a 
prescription for an approved CBD would also be excluded. 
6.
INVESTIGATIONAL PRODUCT
6.1. 
Identity of Investigational Product 
Drug name:  GNX suspension 
Manufacturer:  Catalent Pharma Solutions, Somerset, NJ 08873 USA 
Vehicle:  The suspension contains GNX (50 mg/mL), hydroxypropyl methylcellulose, polyvinyl 
alcohol, sodium lauryl sulfate, simethicone, methylparaben, propylparaben, sodium benzoate, 
citric acid, and sodium citrate at pH 
 to 
, and is sweetened with sucralose and flavored with 
artificial cherry.   
Strength:  50 mg/mL suspension  
Ganaxolone will be supplied at a concentration of 50 mg/mL (GNX equivalent) in 120 mL 
bottles, containing 110 mL GNX.   
All IP will be stored at the research pharmacy prior to dispensing, or in a locked cabinet 
accessible only to members of the investigative research team after the completion of each study 
visit.  Study medication should be stored at room temperature 15°C to 25°C (59°F to 77°F). 
6.1.1. 
Blinding the Treatment Assignment 
This is an OL study. 
6.2. 
Administration of Investigational Products 
6.2.1. 
Allocation of Patients to Treatment 
All eligible patients will receive treatment with GNX in this OL study.  
6.2.2. 
Dosing 
Ganaxolone will be administered in increments of 15 mg/kg/day up to 63 mg/kg/day (maximum 
1800 mg/day) given as an oral suspension with food.  Patients weighing ≤ 28 kg will be dosed on 
an mg/kg basis.  Patients weighing > 28 kg will be dosed on a fixed regimen in increments of 
450 mg/day up to 1800 mg/day.  All IP prescribed per day will be administered in 3 divided 
doses following a meal or snack.  Ganaxolone is to be administered during the 4-week titration 
period as follows: 
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Table 3: 
Oral Suspension Dosinga for Patients Weighing ≤ 28 kg (62 lbs)b 
Dose mg/kg 
Total mg/kg/day 
Days 
6 TID 
18 
1-7 
11 TID 
33 
8-14 
16 TID 
48 
15-21 
21 TID 
63 
22-28 
TID = three times daily 
a. 
To be administered in 3 divided doses following a meal or snack. 
b. 
Patients weighing ≤ 28 kg will be dosed according to the patient’s weight in kilograms. 
 
Table 4: 
Oral Suspension Dosinga for Patients Weighing > 28 kg (62 lbs)b 
Dose mg 
ml per Dose 
Total mg/day 
Days 
150 TID 
3 
450 
1-7 
300 TID 
6 
900 
8-14 
450 TID 
9 
1350 
15-21 
600 TID 
12 
1800 
22-28 
TID = three times daily 
a. 
To be administered in 3 divided doses following a meal or snack. 
b. 
Patients weighing > 28 kg will be dosed on a fixed regimen in increments of 450 mg/day up to 1800 mg/day. 
 
Any patient not tolerating the next dose step can be maintained at the lower dose step for 
additional days before advancing to the next dose.  If the next dose is still not tolerated, the 
patient can drop back to the next lower dose step.  A minimum dose of 33 mg/kg/day or 
900 mg/day is generally required following the escalation period, during the maintenance period.   
Dose changes including alternative dosing paradigms (e.g., lower dose during the daytime and 
higher dose in the evening) should be discussed with the sponsor medical monitor prior to 
making the change or within 48 hours of making the change.  However, the final decision to 
adjust drug dosages lies with the investigator.  For any patient who is unable to be maintained at 
the minimum dose, the investigator should contact the sponsor medical monitor to discuss 
continued IP dosing.  Patients who discontinue GNX treatment before the completion of the 
maintenance period in Part A will continue to be followed per protocol and, at a minimum, 
patients will be encouraged to maintain daily seizure diary entries until Part A is completed. 
Patients who meet all of the inclusion criteria and none of the exclusion criteria will initiate 
treatment in Part B with GNX at the same dose they were on at the completion of Part A.  During 
Part B, doses of GNX may be adjusted to a maximum of 600 mg TID for patients weighing > 28 
kg and a maximum dose of 21 mg/kg TID for patients weighing ≤ 28 kg.  
6.2.2.1. 
De-escalation Period 
Any patient who discontinues IP treatment should undergo a 2-week drug de-escalation (taper) 
period, unless otherwise medically indicated such as drug-induced rash.  The schedule will be 
dependent on the maintenance dose.  Typically, doses will be reduced by 15 mg/kg/day or 450 
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mg/day every 3 days until the patient is completely off IP.  Patients should then return for a post-
taper safety follow-up visit. 
6.2.3. 
Dose Administration 
Investigational product will be provided as an oral suspension.  Ganaxolone must be taken 
with a meal or snack.  Note:  grapefruit and grapefruit juice, Seville oranges and star fruit are 
prohibited during the study.  
Ganaxolone oral suspension will be administered through an oral dosing syringe administered 
by parents/caregivers TID, following the morning, noon, and evening meal or snack.  Each dose 
should be separated by a minimum of 4 hours and a maximum of 12 hours.  A missed dose of IP 
may be taken up to 4 hours before the next scheduled dose; otherwise, the missed dose should 
not be given.  
Prior to each dose, the following instructions should be followed:  
1. Manually shake bottle end to end, 2-3 times per second, for 1 minute  
2. Allow the bottle to stand for 1 minute  
3. Attach the dosing apparatus (adaptor with syringe), invert the bottle and remove the 
indicated dose  
4. Administer dose as indicated  
Please use a new dosing syringe and adapter every day.  Dosing syringes should be cleaned with 
hot water rinse and air-drying between first, second, and third daily doses.  
Patients and their parent or legal guardian will be informed about possible side effects from the 
IP and cautioned to avoid quick postural changes, at least until they know how the IP affects 
them.  Patients will be advised that the IP might affect mental alertness.  They will also be 
cautioned that non-adherence to the dosing instructions (e.g., increasing the dose, taking the IP 
doses too close together) could produce side effects.  
6.2.4. 
Missing a Dose 
A missed dose of IP may be taken up to 4 hours before the next scheduled dose; otherwise, the 
missed dose should not be given. 
Parents/caregivers should be instructed that if the patient misses 2 days in a row or more, the site 
should be contacted to determine whether any adjustment in IP is needed.  
Parents/caregivers should be instructed to minimize the number of missed doses the patient 
experiences and be re-educated on proper dosing procedures at each visit to ensure that missed 
doses are avoided.   
6.3. 
Labeling, Packaging, Storage, and Handling 
6.3.1. 
Labeling 
Labels containing study information and bottle identification are applied to the IP container.  
All IP is labeled with a minimum of the following:  protocol number, medication identification 
number (if applicable), dosage form (including product name and quantity in pack), directions 
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for use, storage conditions, batch number and/or packaging reference, the statements “For 
investigational use only” and/or “Caution:  New Drug—Limited by Federal (or US) Law to 
Investigational Use” and “Keep out of reach of children,” and the sponsor’s name and address. 
Additional labels may, on a case-by-case basis, be applied to the IP in order to satisfy local or 
hospital requirements, but must not: 
x Contradict the clinical study label 
x Obscure the clinical study label 
x Identify the study patient by name, without consultation with the sponsor 
Additional labels may not be added without the sponsor’s prior full agreement. 
6.3.2. 
Packaging 
Ganaxolone will be supplied as an oral suspension formulation.    
Ganaxolone for oral suspension formulation will be provided to the site as individual suspension 
bottles containing 110 mL in 120-mL high-density polyethylene (HDPE) bottles.  Ganaxolone 
will be supplied at a concentration of 50 mg/mL.  
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor. 
6.3.3. 
Storage 
The investigator has overall responsibility for ensuring that IP is stored in a secure, limited-
access location.  Limited responsibility may be delegated to the pharmacy or member of the 
study team, but this delegation must be documented.  Investigational products are distributed by 
the pharmacy or by a nominated member of the study team.  
Investigational product should be stored at room temperature 15°C to 25°C (59°F to 77°F).  
Excursions between 5°C (for less than 24 hours) and 40°C are acceptable.  If a temperature 
excursion below 5°C or above 40°C (41°F to 104°F) occurs, Marinus must be notified. 
Investigational product must be stored in accordance with labeled storage conditions.  
Temperature monitoring of the IP is required at the storage location to ensure that the IP is 
maintained within an established temperature range.  The 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 (i.e., 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 patients until the impact has been determined 
and the product is deemed appropriate for use by the sponsor. 
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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. 
6.4. 
Investigational Product Accountability 
Investigators will be provided with sufficient amounts of the IP to carry out this protocol for the 
agreed number of patients.  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 (e.g., 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. 
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 patients included in 
this study following the procedures set out in the study protocol.  Each patient will be given only 
the IP carrying his or her treatment assignment.  All administered and/or dispensed IP will be 
documented on the eCRFs and/or other IP record.  The investigator is responsible for ensuring 
the retrieval of all IP and study supplies from patient.  
The patient’s parent/caregiver must be instructed to save and bring their unused IP and 
empty/used IP packaging to the clinic and final follow-up visit or to ship it back to the site via 
secure courier.  Investigational product accountability must be assessed at the 
container/packaging level for unused IP that is contained within the original tamper-evident 
sealed container (e.g., 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, patient-returned, or 
expired IP are either to be sent to a nominated contractor on behalf of the sponsor for destruction 
or are to be destroyed by the site.  Investigational products being returned to the sponsor’s 
designated contractors or approved to be destroyed by the site counted/measured and verified 
will be reconciled by clinical site personnel and the sponsor (or designated clinical research 
organization [CRO]).  Shipment return forms, when used, will be signed prior to shipment from 
the site.  Returned IPs will be packed in a tamper-evident manner to ensure product integrity.  
Shipment of all returned IP must comply with local, state, and national laws. 
With the written agreement of the sponsor, unused stock, patient-returned, and expired IP may be 
destroyed at the site or a local facility.  In this case, destruction records identifying what was 
destroyed, when, and how must be obtained with copies provided to the sponsor.  Destruction of 
IPs must be in accordance with local, state, and national laws. 
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Based on entries in the site’s drug accountability forms, it must be possible to reconcile IPs 
delivered with those used and returned.  All IPs must be accounted for and all discrepancies 
investigated and documented to the sponsor’s satisfaction. 
6.5. 
Patient Compliance 
Patient compliance will be tracked through the seizure and medication diary.  Parent/caregiver 
are to record daily seizure frequency and type in addition to study medication and non-study 
AED administration.  Compliance with IP treatment will be assessed by inspecting the seizure 
and medication diary entries and returned supplies with queries as necessary.  Parent/caregiver 
will be re-educated on the importance of adhering to daily seizure, IP and non-study AED 
recording as needed.  Patients that fall below 80% compliance at 2 consecutive visits during the 
maintenance period will not be in the Per-Protocol (PP) population. 
7. 
STUDY PROCEDURES 
7.1. 
Study Assessments 
See Schedule of Assessments (Table 1 and Table 2) for details regarding scheduled assessments 
and procedures in this study.  
Study Assessments can be conducted at the institution of the site Investigator or remotely at the 
patient’s home. All assessments can be conducted remotely with the use of telemedicine video 
tools used by the site staff; and providing traveling nurses to take vital signs, draw blood 
samples, and collect specimens. 
 and ECGs can be completed by a mobile vendor that is 
contracted to perform these tasks. 
7.2. 
Study Procedures (Part A:  Treatment Period) 
7.2.1. 
Screening Period 
7.2.1.1. 
Screening (Visit 1, Week -4) 
Additional procedures/assessments to be completed during the screening period may include the 
following: 
x Informed consent from parent/LAR (or patient assent) 
x Demographics and medical history 
x Review of inclusion/exclusion criteria 
x Review previous genetic testing results to evaluate pathogenic or likely pathogenic TSC1 
or TSC2 variant.  If genetic testing has not previously been performed, then a biological 
sample will be obtained to complete genetic testing at the sponsor’s designated lab.  
Note:  Tuberous Sclerosis Complex diagnosis does not require pathogenic TSC1 or TSC2 
mutations if the clinical criteria are met. 
x Seizure Identification and Diagnostic Review Form (SIF/DRF) (Epilepsy Study 
Consortium) 
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x Vital signs (to include blood pressure [BP], heart rate [HR], respiratory rate [RR], and 
body temperature). 
x Height and weight.  Length will be measured if height cannot be obtained. 
x Physical, neurological, and developmental examination (developmental examination is 
limited to pediatric patients 2 to 17 years of age, inclusive) 
x Clinical laboratory tests (chemistry and hematology) 
x Urinalysis (an attempt should be made to collect a urine sample at this screening visit.  
Otherwise, the urine sample can be collected at baseline.) 
x Drug screen (plasma) for THC and CBD.  If the screening drug test is positive, the patient 
can be retested after two weeks.   
x Serum pregnancy test for all girls/women of childbearing potential  
x Tanner staging 
x Concomitant AED review and levels if per standard of care 
x 
 
x AEs 
x Seizure and medication diary set up and review.  Caregiver given seizure diary and 
instructions for use. 
A screen failure is a patient for whom informed consent/assent has been obtained and has failed 
to meet the inclusion criteria and/or met at least one of the exclusion criteria and has not been 
administered the IP.  
Patient rescreening is allowed as agreed by the sponsor and the investigator unless there is a 
general concern for patient safety or an inability for the patient to become eligible (e.g., GNX 
allergy, sensitivity or exposure, non-TSC and/or other ineligible epilepsy, chronic prohibited 
medical condition or treatment).  Subsequent screening should take place at least 30 days from 
the patient’s last visit. 
7.2.2. 
Baseline (Visit 2, Week 0 + 4 days) 
The 4 weeks between the Screening Visit and the Baseline Visit can be no less than 28 days and 
no more than 32 days.  The following study procedures/assessments are to be completed prior to 
IP administration: 
x Review of inclusion/exclusion criteria 
x Medical history review 
x Review genetic testing results for patients that were screened without previous genetic 
testing results and had a genetic test performed at the sponsor’s designated lab 
x SIF/DRF (Epilepsy Study Consortium) approval 
x Vital signs (to include BP, HR, RR, and body temperature) 
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x Weight 
x Physical, neurological, and developmental examination (developmental examination is 
limited to pediatric patients 2 to 17 years of age, inclusive) 
x ECG 
x Clinical laboratory tests (chemistry and hematology) 
x Urinalysis (If the urine sample was not collected at screening, it must be collected at 
baseline) 
x Drug screen (plasma) for THC and CBD 
x Serum pregnancy test for all girls/women of childbearing potential 
x Concomitant AED review and levels if per standard of care 
x AEs 
x Seizure and medication diary review 
x 
 
x CGI-C (parent/caregiver/LAR identified behavioral target).  During the baseline visit, the 
investigator and parent/caregiver/LAR will decide on a domain and identify the specific 
behavior that the patient exhibits that denotes the domain.  This behavior will be used at 
subsequent visits to assess change after the initiation of IP. 
x CGI-I (parent/caregiver/LAR and clinician) 
x Columbia-Suicide Severity Rating Scale (C-SSRS) (baseline form) for patients ≥ 7 years 
old if appropriate.  Otherwise clinical judgment will be used. 
x Dispense IP 
7.2.3. 
Telephone Follow-up (Day 1, 2 and 3 + 1 days) 
A telephone follow-up visit will be conducted each of the 3 (± 1) days after the Week 0 Baseline 
Visit to assess the following: 
x AEs 
x Seizure and medication diary review 
7.2.4. 
Titration Period (Visit 3, Week 1 ± 3 days) 
The following study procedures/assessments will be completed at Week 1 (± 3 days): 
x Vital signs (to include BP, HR, RR, and body temperature) 
x Weight 
x Physical, neurological, and developmental examination (developmental examination is 
limited to pediatric patients 2 to 17 years of age, inclusive) 
x ECG  
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x Clinical laboratory tests (chemistry and hematology) 
x Urinalysis 
x Concomitant AED review and levels if per standard of care 
x AEs 
x Seizure and medication diary review 
7.2.5. 
Titration Period (Phone Follow-ups, Weeks 2, 3, and 4 ± 3 days) 
A telephone follow-up visit will be conducted at Weeks 2, 3, and 4 (± 3 days) to assess the 
following: 
x AEs 
x Seizure and medication diary review 
7.2.6. 
Maintenance Period (Visits 4 and 5, Weeks 5 and 12 ± 3 days) 
The following study procedures/assessments will be completed at Weeks 5 and 12 (± 3 days): 
x Vital signs (to include BP, HR, RR, and body temperature) 
x Weight 
x Physical, neurological, and developmental examination (developmental examination is 
limited to pediatric patients 2 to 17 years of age, inclusive) 
x ECG  
x Clinical laboratory tests (chemistry and hematology) 
x Urinalysis 
x Drug screen (plasma) for THC and CBD (Visit 5 [Week 12]) 
x Serum pregnancy test for all girls/women of childbearing potential 
x IP PK sample (Visit 4 [Week 5], between 1-5 hours after last IP dose and Visit 5 
[Week 12], between 4-8 hours after last IP dose) 
x Concomitant AED review and levels if per standard of care 
x 
 
x AEs 
x Seizure and medication diary review 
x 
 
x CGI-C (parent/caregiver/LAR identified behavioral target) 
x CGI-I (parent/caregiver/LAR and clinician) 
x C-SSRS (since previous visit).  Only for patients ≥ 7 years old if appropriate, otherwise 
clinical judgement will be used. 
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x Dispense IP 
7.2.7. 
Maintenance Period (Phone Follow-up, Week 9 ± 3 days) 
A telephone follow-up visit will be conducted at Week 9 (± 3 days) to assess the following: 
x AEs 
x Seizure and medication diary review 
7.2.8. 
Taper and Safety Visits (Visit 5a, Week 16 ± 3 days) 
For patients who do not continue into study Part B, the following assessments will be completed 
after 2 weeks of taper and 2 weeks after completion of treatment (± 3 days): 
x 
Vital signs (to include BP, HR, RR, and body temperature) 
x Tanner staging 
x 
AEs 
x 
Seizure and medication diary review 
x C-SSRS (since previous visit).  Only for patients ≥ 7 years old if appropriate, otherwise 
clinical judgement will be used. 
7.3. 
Study Procedures (Part B:  OLE Period) 
7.3.1. 
First OLE Visit (Visit 5, Week 12) 
Patients who complete Part A with a seizure reduction of ≥ 35% compared to the 4-week 
baseline period and who do not have any other contraindications for continued treatment will 
continue to be treated with GNX in the OLE period (Part B) of the study.  Ganaxolone patients 
will continue GNX treatment at the dose that they were on at the completion of Part A.  The 
following study procedures/assessments will be completed during the final maintenance period 
visit in Part A (Visit 5, Week 12): 
x Confirm patient OLE eligibility (≥ 35% reduction in seizure frequency) 
x Vital signs (to include BP, HR, RR, and body temperature). 
x Height and weight.  Length will be measured if height cannot be obtained. 
x Physical, neurological, and developmental examination (developmental examination is 
limited to pediatric patients 2 to 17 years of age, inclusive) 
x ECG 
x Clinical laboratory tests (chemistry and hematology) 
x Urinalysis 
x Drug screen (plasma) for THC and CBD 
x Serum pregnancy test for all girls/women of childbearing potential  
x IP Population PK sample (drawn when convenient during the visits) 
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x Concomitant AED review and levels if per standard of care 
x 
 
x AEs 
x Seizure and medication diary review 
x 
 
x CGI-C (parent/caregiver/LAR identified behavioral target) 
x CGI-I (parent/caregiver/LAR and clinician) 
x C-SSRS (since previous visit).  Only for patients ≥ 7 years old if appropriate, otherwise 
clinical judgement will be used. 
x Dispense IP 
7.3.2. 
OLE Period and Final OLE Visit or Taper Visit (Visits 6, 7, and 8 [or Early 
Discontinuation], Weeks 20, 28, and 36 [or Early Discontinuation] ± 7 days) 
The following study procedures/assessments will be completed during the OLE period of the 
study at Visits 6, 7, and 8 (± 7 days): 
x Vital signs (to include BP, HR, RR, and body temperature) 
x Weight 
x Physical, neurological, and developmental examination (developmental examination is 
limited to pediatric patients 2 to 17 years of age, inclusive) 
x ECG (Visit 7, Week 28 and Visit 8, Week 36) 
x Clinical laboratory tests (chemistry and hematology) 
x Urinalysis (Visit 7, Week 28 and Visit 8, Week 36) 
x Drug screen (plasma) for THC and CBD (Visit 7, Week 28) 
x Serum pregnancy test for all girls/women of childbearing potential 
x Tanner staging (Visit 8, Week 36) 
x IP PK sample (drawn when convenient during the visits) 
x Concomitant AED review and levels if per standard of care  
x 
 
x AEs 
x Seizure and medication diary review 
x 
 
x CGI-C (Visit 8, Week 36, parent/caregiver/LAR identified behavioral target) 
x CGI-I (Visit 8, Week 36, parent/caregiver/LAR and clinician) 
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x C-SSRS (since previous visit).  Only for patients ≥ 7 years old, otherwise clinical 
judgement will be used. 
x Dispense IP 
7.3.3. 
Telephone Follow-up (Weeks 16, 24 and 32 ± 7 days) 
A telephone follow-up visit will be conducted at Weeks 16, 24, and 32 (± 7 days) of the OLE 
period to assess the following: 
x AEs 
x Seizure and medication diary review 
7.3.4. 
Safety Follow-up Post Taper (Visit X, 2 Weeks Post Last Dose ± 3 days) 
The following study procedures/assessments to be completed during the Safety Follow-up Post 
Taper Visit (± 3 days): 
x Vital signs (to include BP, HR, RR, and body temperature) 
x Physical, neurological, and developmental examination (developmental examination is 
limited to pediatric patients 2 to 17 years of age, inclusive) 
x Clinical laboratory tests (chemistry and hematology) 
x Urinalysis 
x Serum pregnancy test for all girls/women of childbearing potential 
x IP PK sample (drawn when convenient during the visits) 
x Concomitant AED review and levels if standard of care 
x AEs 
x Seizure and medication diary review 
7.3.5. 
Unscheduled Visits 
Unscheduled visits can occur between regularly scheduled visits. For patients who are remaining 
in Part B (on the OLE)after Visit 8, unscheduled visits may take place as decided by Investigator, 
but no longer than six months after the prior visit, or prior to exiting the study.  Unscheduled 
Visits assessments will be conducted at the discretion of the PI. These assessments may include 
vital signs, laboratory testing, etc. 
 
7.4. 
Screening and Diagnosis 
Potential patients will be pre-identified by the site because of a previous TSC diagnosis based on 
clinical features and/or genetic testing results and those still experience refractory seizures.  
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7.4.1. 
Informed Consent/Assent 
Procedures specific to this protocol and not otherwise considered standard of care, will not be 
performed until written informed consent/assent from the parent/caregiver/LAR has been 
appropriately obtained.   
7.4.2. 
Drug Screen 
A drug screen (plasma) 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 drug test during the treatment phase will result in early 
termination. 
7.4.3. 
Demographics and Medical History 
Demographics including age, gender, ethnicity and race will be collected.  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 patient’s developmental history will also be assessed.  Demographics and Medical 
History will be reviewed and collected at the Visit 1 (screening).  A review of the patient’s 
Medical History will be performed again at Visit 2 (baseline). 
7.4.4. 
Genetic Testing 
Genetic testing to assess if the patient has a pathogenic or likely pathogenic TSC1/TSC2 variant 
will be conducted by the sponsor’s central genetic laboratory if the patient does not have 
previous genetic testing.  Previous genetic testing results are acceptable for review.  
Instructions for genetic testing sample collection and processing can be found in the genetic 
testing laboratory manual. 
7.4.5. 
Seizure Identification and Diagnostic Review 
Per the inclusion criteria, enrollment into the study will be based on the presence and frequency 
of the primary seizure types.  The primary seizure types are defined as the following:  focal 
motor seizures without impairment of consciousness or awareness, focal seizures with 
impairment of consciousness or awareness, focal seizures evolving to bilateral, tonic-clonic 
convulsive seizures, and generalized motor seizures including tonic-clonic, bilateral tonic, 
bilateral clonic, or atonic/drop seizures.  Focal and generalized nonmotor seizures, infantile or 
epileptic spasms, and myoclonic seizures do not count as the primary seizure types.  
To standardize seizure identification and classification in the study, a SIF/DRF will be submitted 
and reviewed by the Epilepsy Study Consortium.  Approval of the SIF/DRF will be required 
prior to IP dosing.   
Instructions for completion of the SIF/DRF can be found in the Investigator Site File. 
7.5. 
Efficacy Assessments 
Efficacy as determined by a reduction in seizures will be evaluated by collecting daily seizure 
type and frequency in a seizure diary.  Days in which no seizures occur will also be noted.  
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Changes in seizure intensity/duration, CGI-I, as well as changes in behavior and neuropsychiatric 
symptoms will be assessed by a variety of clinician and caregiver administered instruments.  
7.5.1. 
Seizure Type and Frequency 
Parent/caregiver/LAR will record daily seizure frequency denoting seizure type and frequency in 
a seizure diary.  Primary seizure types of focal motor seizures without impairment of 
consciousness or awareness, focal seizures with impairment of consciousness or awareness, focal 
seizures evolving to bilateral, tonic-clonic convulsive seizures, and generalized motor seizures 
including tonic-clonic, bilateral tonic, bilateral clonic, or atonic/drop seizures will be counted 
towards the primary endpoint. 
Patients or parent/caregiver/LAR are to record administration of IP and background AEDs in the 
daily seizure calendar.  Compliance with IP treatment will be assessed by inspecting the patients’ 
diary/seizure calendar and returned supplies with queries as necessary.  Patients that fall below 
80% compliance at 2 consecutive visits during the maintenance period will not be included in the 
PP population. 
7.5.2. 
Caregiver Global Impression of Change (CGI-C - Target Behavior) 
The CGI-C in Target Behavior is a 7-point Likert scale in which the caregiver chooses one 
domain from possible domains of sociability, communication, irritability, and hyperactivity to 
assess change in target behavior after the initiation of IP relative to baseline (prior to treatment 
with IP).  This domain should be chosen based on behavior the parent/caregiver/LAR identifies 
to be the most impactful.  During the baseline visit, the investigator and parent/caregiver/LAR 
will decide on a domain and identify the specific behavior that the patient exhibits that denotes 
the domain.  This behavior will be used at subsequent visits to assess change after the initiation 
of 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. 
Caregiver Global Impression of Change - Target Behavior will be assessed at Baseline (Visit 2, 
Week 0), Visit 4 (Week 5), and Visit 5 (Week 12) in the treatment period (Part A), and will be 
assessed at Visit 8 (Week 36) and the Final Visit or Taper Visit of the OLE period (Part B). 
7.5.3. 
Clinical Global Impression – Improvement (CGI-I) 
The CGI-I is a 7-point Likert scale that the parent/caregiver/LAR and clinician uses to rate the 
change in overall seizure control, behavior, safety and tolerability after initiation of IP relative to 
baseline (prior to treatment with IP).  The patient 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. 
Clinical Global Impression – Improvement (parent/caregiver/LAR and clinician) will be assessed 
at Baseline (Visit 2, Week 0), Visit 4 (Week 5), and Visit 5 (Week 12) in the treatment period 
(Part A), and will be assessed at Visit 8 (Week 36) and the Final Visit or Taper Visit of the OLE 
period (Part B). 
7.6. 
Exploratory Efficacy Assessments 
 
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7.7. 
Safety Assessments 
Safety will be evaluated by collecting the assessments detailed in the sections below.  
7.7.1. 
Adverse Events 
Details regarding AEs and SAEs are provided in Section 8. 
7.7.2. 
Vital Signs 
Vital signs including HR (bpm), RR (breaths/minute), body temperature (C/F), BP (mmHg) will 
be collected at every clinic visit. 
7.7.3. 
Height and Weight 
Height will be collected at Visit 1 (screening).  Length will be measured if height cannot be 
obtained.  Weight will be collected at Visit 1 (screening), Visit 2 (baseline), Visit 3 (Week 1), 
and every clinic visit thereafter, including the Final OLE Visit or Taper Visit and Safety 
Follow-up Post Taper Visit. 
7.7.4. 
Physical/Neurological/Developmental Examinations 
The full physical examination will include the following systems: 
x General appearance 
x Head (eyes, ears, nose and throat) 
x Cardiovascular 
x Respiratory 
x Gastrointestinal 
x Genitourinary 
x Musculoskeletal 
x Endocrine/Metabolic 
x Hematologic/lymphatic 
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x Skin 
x Other systems as appropriate 
The full neurological examination will include: 
x Cranial nerves 
x Motor exam 
x Sensory exam 
x Reflexes 
x Coordination/Cerebellar 
The full developmental examination (applicable only to pediatric patients 2 to 17 years of age, 
inclusive) will include: 
x Speech/language 
 Makes identifiable sounds for specific objects/people 
 Repeats sounds 
 Single words 
 Multiple words 
 Makes a sentence 
 Replies to question in an identifiable sound, single word, multiple word, sentence 
 Other abilities 
x Motor 
 Sits with support 
 Sits independently 
 Crawls 
 Stands with support 
 Stands independently  
 Takes steps with assistance 
 Walks independently 
 Other abilities 
x Social 
 Smiles appropriately to situation 
 Makes eye contact 
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7.7.5. 
ECG 
Electrocardiograms will be performed to collect the electrical activity of the heart throughout the 
study to monitor safety.  An evaluation of normal by a physician must be obtained before the 
patient is enrolled in the treatment period.   
Electrocardiograms will be performed at Visit 2 (baseline), Visit 3 (Week 1), Visit 4 (Week 5), 
and Visit 5 (Week 12) in the treatment period (Part A), and will be assessed at Visit 7 (Week 28) 
and the Final OLE Visit or Taper Visit in the OLE period (Part B). 
7.7.6. 
Clinical Laboratory Tests 
Laboratory safety assessments will be collected at every clinic visit throughout the study to 
monitor patient safety.  Clinical laboratory tests are listed in Section 12.2 will be collected per the 
schedule listed in Table 1 and Table 2.  These clinical laboratory assessments will include 
complete blood count with automated differential, creatinine, blood urea nitrogen, and eGFR 
calculation, comprehensive metabolic panel, as well serum pregnancy test for all girls/women of 
childbearing potential.  Local laboratories will be utilized by the sites. 
The following liver function and eGFR tests will be monitored throughout the study as follows.  
x If AST or ALT increases > 3 times ULN during the study, patient should be followed 
with weekly laboratory repeat testing and continue in study if levels trending down.  
Patient will be discontinued if levels do not decline to under 3 x ULN.  
x If total bilirubin increases to 1.5 x ULN or more during study, the patient will be 
discontinued.  
x Patients with significant renal insufficiency, eGFR < 30 mL/min (calculated using the 
Cockcroft-Gault formula), will be discontinued if the criterion is met post baseline. 
If any of the criteria above are deemed clinically significant by the investigator, then the 
sponsor’s medical monitor should be contacted. 
Urinalysis will be conducted at Visit 1 (screening) or Visit 2 (baseline), Visit 3 (Week 1), Visit 4 
(Week 5), and Visit 5 (Week 12) in the treatment period (Part A), and Visit 7 (Week 28), Visit 8 
(Week 36), the Final Visit or Taper Visit, and the Safety Follow-up or Post Taper Visit in the 
OLE period (Part B). 
An attempt will be made to collect a urine sample at screening in order to perform the 
study-related urinalysis.  Otherwise, the urine sample for the urinalysis can be collected at 
baseline. 
7.7.7. 
Tanner Staging 
The Tanner scale (also known as the Tanner stages) is a scale of physical development in 
children, adolescents and adults.  The scale defines physical measurements of development based 
on external primary and secondary sex characteristics.  Patients 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) and Visit 5a (only for patients who do not continue into Part B) of the treatment 
period (Part A), and at the Final OLE Visit or Taper Visit (Part B).  
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7.7.8. 
Investigational Product PK 
Please refer to Section 7.8 for additional details regarding PK assessments. 
7.7.9. 
Concomitant AED Levels 
Concomitant AED levels are not mandatory but will be collected per sites’ standard of care.  If 
AED levels are available for Visit 1 (screening), Visit 2 (baseline), Visit 3 (Week 1), Visit 4 
(Week 5) and Visit 5 (Week 12), and throughout the OLE period of the study at the time points 
noted in Table 1 and Table 2, the results, date and time of last AED dose and date and time of 
AED PK sample will be recorded in the eCRF. 
7.8. 
Pharmacokinetic Assessments 
Blood sampling for PK evaluation must be performed at the precise protocol scheduled time.  
Actual sampling time(s) must be accurately recorded in the source document and appropriate 
eCRF. 
One blood sample will be obtained at Visit 4 (Week 5), and Visit 5 (Week 12) in the treatment 
period (Part A), and at Visit 6 (Week 20), Visit 7 (Week 28), Visit 8 (Week 36), Final OLE Visit 
or Taper Visit, and Safety Follow-up Post Taper Visit of the OLE period (Part B).   
A population PK approach addressing the relationship between GNX PK parameters and 
individual characteristics will be implemented at Visit 4 (Week 5) and Visit 5 (Week 12) in the 
treatment period.  
During Part A: 
x Visit 4 (Week 5):  between 1 and 5 hours since the last IP dosing.  
x Visit 5 (Week 12):  between 4 and 8 hours since the last IP dosing.  
During Part B: 
There is no specified time to draw the PK sample and can be drawn when convenient during the 
study visit.  Exact time of sample withdrawal and IP intake will be recorded in the eCRF. 
7.8.1. 
Clinical Pharmacokinetic Blood Sample Collection and Handling Procedures 
Pharmacokinetic blood collection must not deviate from the nominal collection time set forth in 
the protocol by more than ± 30 minutes from samples drawn within 4 hours post-dose or by more 
than ± 60 minutes for samples drawn beyond 4 hours post-dose.  Samples drawn outside these 
parameters will be considered a protocol deviation.  
Please refer to the laboratory manual for processing instructions. 
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8. 
ADVERSE AND SERIOUS ADVERSE EVENT ASSESSMENTS  
8.1. 
Definition of Adverse Events, Period of Observation, Recording of 
Adverse Events 
An AE is any untoward medical occurrence in a clinical investigation patient who has been 
administered a pharmaceutical product; it does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (International Council for Harmonisation [ICH] Guidance E2A March 1995).   
All AEs are collected from the time the informed consent/assent is signed until the defined 
follow-up period.  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 IP will be considered treatment-emergent AEs.  Where possible, a diagnosis rather than a list 
of symptoms should be recorded.  If a diagnosis has not been made, then each symptom should 
be listed individually.  All AEs should be captured on the appropriate AE pages in the eCRF and 
in source documents.  In addition to untoward AEs, unexpected benefits outside the IP indication 
should also be captured on the AE eCRF page. 
All AEs must be followed to closure (the patient’s health has returned to baseline status or all 
variables have returned to normal), regardless of whether the patient 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. 
8.1.1. 
Severity Categorization 
The severity of AEs must be recorded during the course of the event, including the start and stop 
dates for each change in severity.  An event that changes in severity should be captured as a new 
event.  Worsening of pretreatment events, after initiation of the IP, must be recorded as new AEs 
(e.g., if a patient experiences mild intermittent dyspepsia prior to dosing of the IP, but the 
dyspepsia becomes severe and more frequent after the first dose of the IP has been administered, 
a new AE of severe dyspepsia [with the appropriate date of onset] is recorded on the appropriate 
eCRF page). 
The medical assessment of severity is determined by using the following definitions: 
Mild: 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual 
activities of daily living. 
Moderate: 
A type of AE that is usually alleviated with specific therapeutic intervention.  The 
event interferes with usual activities of daily living, causing discomfort, but poses 
no significant or permanent risk of harm to the research patient. 
Severe: 
A type of AE that interrupts usual activities of daily living, that significantly 
affects clinical status, or that may require intensive therapeutic intervention. 
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8.1.2. 
Relationship Categorization 
A physician/investigator must make the assessment of relationship between the IP and each AE.  
The investigator should decide whether, in their medical judgment, there is a reasonable 
possibility that the event may have been caused by the IP.  If there is no valid reason for 
suggesting a relationship, the AE should be classified as “not related.”  Otherwise, if there is any 
valid reason, even if undetermined or untested, for suspecting a possible cause-and-effect 
relationship between the IP and the occurrence of the AE, the AE should be considered “related.”  
The causality assessment must be documented in the source document. 
The following additional guidance may be helpful: 
Term 
Relationship definition 
Related 
The temporal relationship between the event and the administration of the IP is 
compelling and/or follows a known or suspected response pattern to that product, and 
the event cannot be explained by the patient’s medical condition, other therapies, or 
accident. 
Not related 
The event can be readily explained by other factors, such as the patient’s underlying 
medical condition, concomitant therapy, or accident, and no plausible temporal or 
biologic relationship exists between the IP and the event. 
8.1.3. 
Outcome Categorization 
The outcome of AEs must be recorded during the course of the study on the eCRF.  Outcomes 
are as follows: 
x Fatal 
x Not recovered/not resolved 
x Recovered/resolved 
x Recovered/resolved with sequelae  
x Recovering/resolving 
x Unknown 
8.1.4. 
Symptoms of the Disease Under Study 
Symptoms of the disease under study should not be classified as AEs as long as they are within 
the normal day-to-day fluctuation or expected progression of the disease and are part of the 
efficacy data to be collected in the study; however, significant worsening of the symptoms 
should be recorded as an AE.  
8.1.5. 
Clinical Laboratory and Other Safety Evaluations 
A change in the value of a clinical laboratory, vital sign, ECG assessment can represent an AE if 
the change is clinically significant or if, during treatment with the IP, a shift of a parameter is 
observed from a normal value to an abnormal value, or there is a further worsening of an already 
abnormal value.  When evaluating such changes, the extent of deviation from the reference 
range, the duration until return to the reference range (either while continuing treatment or after 
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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 treatment period, there are abnormal clinical laboratory, vital sign, or ECG 
values that were not present in the pretreatment findings observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (e.g., concomitant disease) is found for the 
abnormal values. 
The investigator should decide, based on the above criteria and the clinical condition of a patient, 
whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically significant 
and therefore represents an AE. 
8.1.6. 
Pregnancy 
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period. 
Any report of pregnancy for any female study patient or the partner of a male study patient must 
be reported within 24 hours to the Marinus Safety Department or its delegate using the 
Pregnancy Report Form.  A copy of the Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Marinus medical monitor using the details specified in the 
emergency contact information section at the beginning of the protocol.  The pregnant female 
study patient must be withdrawn from the study. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant.  It is the responsibility of the investigator to obtain this information 
within 30 calendar days after the initial notification and approximately 30 calendar days after 
delivery.  
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported as outlined in Section 8.2.2 of the protocol using the 
Marinus Clinical Study Serious Adverse Event Form.  Non-serious AEs are to be reported as per 
clinical eCRF guidelines.  Note:  An elective abortion is not considered an SAE. 
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE to the Marinus Safety Department or delegate as outlined in 
Section 8.2.2 of the protocol using the Marinus Clinical Study Serious Adverse Event Form.  The 
test date of the first positive serum E-human chorionic gonadotropin test or ultrasound result will 
determine the pregnancy onset date. 
8.1.7. 
Abuse, Misuse, Overdose, and Medication Error 
Abuse, misuse, overdose, or medication error must be reported to the sponsor per the SAE 
reporting procedure whether or not it results in an AE/SAE as described in Section 8.2.2.  Note:  
The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication errors unless these result in an SAE.  
The categories below are not mutually exclusive; the event can meet more than 1 category. 
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x Abuse:  Persistent or sporadic intentional intake of an IP for a nonmedical purpose (e.g., 
to alter one’s state of consciousness or get high) in a manner that may be detrimental to 
the individual and/or society. 
x 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.) 
x Overdose:  Intentional or unintentional intake of a dose of an IP exceeding a prespecified 
total daily dose of the product.  
x 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. 
Cases of patient’s missing doses of the IP are not considered reportable as medication errors. 
Medication errors should be collected and reported for the IP under investigation. 
The administration and/or use of an expired IP should be considered as a reportable medication 
error. 
All IP provided to pediatric patients should be supervised by the parent/caregiver/LAR. 
8.2. 
Serious Adverse Event Procedures 
8.2.1. 
Reference Safety Information 
The reference for safety information for this study is the GNX Investigator's Brochure, which the 
sponsor has provided under separate cover to all investigators. 
8.2.2. 
Reporting Procedures 
All initial and follow-up SAE reports must be reported by the investigator to the Marinus Safety 
Department or its delegate and the CRO/Marinus medical monitor within 24 hours of the first 
awareness of the event.  Note:  The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors unless they result in an SAE.  
The 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 the Marinus Safety Department or its delegate.  A copy of the 
Marinus Clinical Study Serious Adverse Event Form (and any applicable follow-up reports) must 
also be sent to the CRO/Marinus medical monitor using the details specified in the emergency 
contact information section of the protocol. 
8.2.3. 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence (whether considered to be related to IP or not) that 
at any dose: 
x Results in death 
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x Is life-threatening.  Note:  The term “life-threatening” in the definition of “serious” refers 
to an event in which the patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe. 
x Requires inpatient hospitalization or prolongation of existing hospitalization.  Note:  
Hospitalizations, which are the result of elective or previously scheduled surgery for 
preexisting conditions that have not worsened after initiation of treatment, should not be 
classified as SAEs.  For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, a complication resulting from a 
hospitalization for an elective or previously scheduled surgery that meets serious criteria 
must be reported as an SAE. 
x Results in persistent or significant disability or incapacity 
x Is a congenital abnormality or birth defect 
x Is an important medical event.  Note:  Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAEs when, 
based on appropriate medical judgment, they jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.  
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or convulsions that do not 
result in inpatient hospitalization; or the development of drug dependency or drug abuse.  
8.2.4. 
Serious Adverse Event Collection Time Frame 
All SAEs (regardless of relationship to study) are collected from the time the 
parent/caregiver/LAR signs the informed consent/assent until the defined follow-up period stated 
and must be reported to the Marinus Safety Department and the CRO/Marinus medical monitor 
within 24 hours of the first awareness of the event.  
In addition, any SAE considered “related” to the IP and discovered by the investigator at any 
interval after the study has completed must be reported to the Marinus Safety Department within 
24 hours of the first awareness of the event. 
8.2.5. 
Serious Adverse Event Onset and Resolution Dates 
The onset date of the SAE is defined as the date the event meets serious criteria.  The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic.  In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively. 
In addition, any signs or symptoms experienced by the patient after signing the informed 
consent/assent form or leading up to the onset date of the SAE, or following the resolution date 
of the SAE, must be recorded as an AE, if appropriate. 
8.2.6. 
Fatal Outcome 
Any SAE that results in the patient’s death (i.e., the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome, with the date of death recorded as the resolution 
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date.  For all other events ongoing at the time of death that did not contribute to the patient’s 
death, the outcome should be considered not resolved, without a resolution date recorded. 
For any SAE that results in the patient’s death or any ongoing events at the time of death, unless 
another IP action was previously taken (e.g., 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 
patient never received the IP).  The IP action of “withdrawn” should not be selected solely as a 
result of the patient’s death.  
8.2.7. 
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The sponsor is responsible for notifying the relevant regulatory authorities in the US and the 
CRO is responsible for notifying the relevant regulatory authorities in rest of world of related, 
unexpected SAEs. 
In addition, the sponsor or the CRO is responsible for notifying active sites and central 
institutional review boards (IRBs) of all related, unexpected SAEs occurring during all 
interventional studies across the GNX program.  
The investigator is responsible for notifying the local IRBs, local ethics committee (EC), or the 
relevant local regulatory authority of all SAEs that occur at their site as required. 
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9. 
DATA MANAGEMENT AND STATISTICAL METHODS 
9.1. 
Data Collection 
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 patient is screened, it is expected that site personnel 
will complete the eCRF entry within approximately 7 business days of the patient’s visit. 
The patient’s parent/caregiver/LAR must enter the information required by the protocol in the 
diary.  A study monitor will review all seizure diary entries in accordance with the monitoring 
plan for completeness and accuracy.  Discrepancies will be addressed by the patients’ 
parent/caregiver/LAR and qualified site personnel.  When a data discrepancy warrants 
correction, the correction will be made by the patients’ parent/caregiver/LAR and authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  Once the patient’s parent/caregiver/LAR signs informed 
consent/assent, it is expected that all diary entries will be made daily and no longer than 48 hours 
after each day. 
Telephone Follow-up visits are allowed to be conducted via secure email per institutional policy 
if granted by individual sites IRB/EC. 
9.2. 
Clinical Data Management 
Data will be entered into a clinical database as specified in the CRO data management plan.  
Quality control and data validation procedures will be applied to ensure the validity and accuracy 
of the clinical database. 
Data will be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures.  Data queries requiring clarification 
will be communicated to the site for resolution.  Only authorized personnel will make corrections 
to the clinical database, and all corrections will be documented in an auditable manner. 
9.3. 
Statistical Analysis Process 
The study will be analyzed by the sponsor or its agent.  The statistical analysis plan (SAP) will 
provide the statistical methods and definitions for the analysis of the efficacy and safety data, as 
well as describe the approaches to be taken for summarizing other study information, such as 
patient disposition, demographics, and baseline characteristics; IP exposure; and prior and 
concomitant medications.  The SAP will also include a description of how missing data will be 
addressed. 
All statistical analyses will be performed using SAS® (SAS Institute, Cary, NC 27513) software. 
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9.4. 
Sample Size Calculation and Power Considerations 
Approximately 36 TSC patients, aged 2 to 65 inclusive, will be screened to achieve 30 TSC 
patients enrolled in Part A.  Since this is an OL proof of concept study, sample size was not 
determined by statistical methods. 
9.5. 
Analysis Populations 
The intent-to-treat (ITT) population comprises all patients who receive at least one dose of IP.  
The ITT population will be the primary population for efficacy analyses.  The PP population 
includes all ITT patients without major protocol violations (defined prior to database lock).  
Safety will be reported for all patients. 
9.6. 
Efficacy Analyses 
Since this is an OL proof of concept study, no inferential statistical testing will be conducted.  
All efficacy outcomes will be assessed descriptively with point estimates and 95% confidence 
intervals. 
9.6.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint (change in seizure frequency) is the percent change in 28-day 
seizure frequency through the end of the 12-week treatment period (4-week titration and 8-week 
maintenance) relative to the baseline, based on the primary seizure types.  The primary seizure 
types are defined as the following:  focal motor seizures without impairment of consciousness or 
awareness, focal seizures with impairment of consciousness or awareness, focal seizures 
evolving to bilateral, tonic-clonic convulsive seizures, and generalized motor seizures including 
tonic-clonic, bilateral tonic, bilateral clonic, or atonic/drop seizures.  Focal aware non-motor and 
generalized seizures without motor features, infantile or epileptic spasms, and myoclonic 
seizures do not count as the primary seizure types.  
Post-baseline 28-day seizure frequency will be calculated as the total number of seizures in the 
12-week treatment periods (4-week titration plus 8-week maintenance period) during Part A 
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 primary seizures in the baseline 
period divided by the number of days with seizure data in the baseline period, multiplied by 28.   
 
The baseline, post-baseline, and arithmetic and percent changes from baseline in 28-day seizure 
frequency will be summarized using descriptive statistics.  
The percentages of seizure-free days will be based on the primary seizure types (primary 
seizure-free-days) and infantile/epileptic spasms (infantile/epileptic spasms free days). 
9.6.2. 
Secondary Efficacy Endpoints 
In addition to evidence about effects of GNX on 28-day seizure frequency, the clinical trial will 
assess GNX’s effects on several secondary endpoints that capture important symptoms and 
activities of daily living that are meaningfully compromised by TSC.  The 
behavioral/neuropsychiatric secondary endpoints will provide information about the overall 
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impact of GNX on the treatment of patients with TSC.  The CGI-C and the CGI-I are 7-point 
scales, and the number and percentage of patients with each score will be summarized.  The 
scores range from 1 = very much improved to 7 = very much worse.  
Derived seizure secondary efficacy endpoints will be based on data through the end of the 
12-week treatment period relative to the 4-week baseline period.  
9.6.2.1. 
Secondary Efficacy:  Seizure control 
x Percentage of patients experiencing a ≥ 50% reduction in 28-day primary seizure 
frequency through the end of the 12-week treatment period compared to the 4-week 
Baseline Period  
9.6.2.2. 
Secondary Efficacy:  Other 
x CGI-I, parent/caregiver and clinician 
x CGI-C – Target Behavior 
9.6.3. 
Exploratory Efficacy Endpoints 
All secondary and
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
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9.6.4. 
Subgroup Analyses 
A subgroup analysis of the primary endpoint is not planned at this time. 
9.7. 
Safety Analyses 
Safety will be reported for all patients.  The results in Part A and Part B will be summarized 
separately and then the combined results in Part A and Part B will be summarized together.  
Adverse events will be tabulated by overall, system organ class, and Preferred Term using the 
Medical Dictionary for Regulatory Activities (MedDRA) coding system.  Incidence and 
percentage of AEs will be presented.  Additional tables, with AEs classified by severity and by 
only those related to drug as assessed by the investigator will be presented.  Subset listings will 
be produced for AEs that cause withdrawal and for SAEs.  Clinical laboratory tests (hematology, 
chemistry and urinalysis), vital signs (temperature, BP, pulse rate), weight, and ECGs will be 
summarized using descriptive statistics including changes from baseline.  Change in C-SSRS 
scores where applicable will be determined.  Physical, neurological and developmental 
examinations will be summarized using number and percentage of patients with abnormalities. 
9.8. 
Other Analyses 
 and concomitant AED levels will be analyzed according to the SAP. 
9.9. 
Pharmacokinetic Analyses 
The PK population will include all patients who have received at least 1 dose of GNX and who 
have had at least 1 sample collected and a valid bioanalytical result obtained.   
Pharmacokinetic analyses will be limited to listing of concentrations because sufficient 
concentration-time data will not be available for noncompartmental analyses such as maximum 
plasma concentration (Cmax), area under the concentration versus time curve (AUC), or time of 
maximum concentration (tmax). 
Pharmacokinetic data from this study may be used for a Population PK analyses to be conducted 
separately from this study and reported separately.  Further details will be provided in the SAP. 
9.10. 
Interim Analysis 
No formal interim analysis is planned. 
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10. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This study is conducted in accordance with current applicable regulations, ICH, and local ethical 
and legal requirements. 
The name and address of each third-party vendor (e.g., CRO) used in this study will be 
maintained in the investigators’ and sponsor’s files, as appropriate. 
10.1. 
Sponsor’s Responsibilities 
10.1.1. 
Good Clinical Practice (GCP) Compliance 
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6(R2) (2016), as well as all applicable 
national and local laws and regulations. 
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data patients’ 
medical records, diaries/seizure calendars and eCRFs in accordance with current GCP and the 
respective local and (inter)national government regulations and guidelines.  Records and data 
may additionally be reviewed by auditors or by regulatory authorities. 
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study.  The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of IP for 
shipment to the site. 
10.1.2. 
Public Posting of Study Information 
The sponsor, or their designee, is responsible for posting appropriate study information on 
applicable websites such as ClinicalTrials.gov.  Information included in clinical study registries 
may include participating investigators’ names and contact information. 
10.1.3. 
Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees 
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP.  This requirement will be fulfilled within 6 months of the study 
completion date for pediatric studies and within 1 year for non-pediatric studies as per guidance.  
10.1.4. 
Study Suspension, Termination, and Completion 
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason.  
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies, and IRBs/ECs are notified as appropriate.  Additionally, the discontinuation of a 
registered clinical study that has been posted to a designated public website will be updated 
accordingly. 
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10.2. 
Investigator’s Responsibilities 
10.2.1. 
Good Clinical Practice Compliance 
The investigator must undertake to perform the study in accordance with ICH GCP 
Guideline E6(R2) (2016) and applicable regulatory requirements and guidelines. 
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
personnel are available at the site prior to commitment to participate in this study.  The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable patients within the agreed recruitment period. 
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification.  Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study. 
If a potential research patient has a primary care physician, the investigator should, with the 
patient’s consent, inform them of the patient’s participation in the study. 
A coordinating principal investigator (PI) is appointed to review the final clinical study report for 
multicenter studies.  Agreement with the final clinical study report is documented by the signed 
and dated signature of the PI (single-site study) or coordinating PI (multicenter study), in 
compliance with Directive 2001/83/EC as amended by Directive 2003/63/EC and 
ICH Guidance E3 (1995).  
10.2.2. 
Protocol Adherence and Investigator Agreement 
The investigator and any sub-investigators must adhere to the protocol as detailed in this 
document.  The investigator is responsible for enrolling only those patients who have met 
protocol eligibility criteria.  Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol. 
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation.  The 
investigator will also return all IP, containers, and other study materials to the sponsor.  Upon 
study completion, the investigator will provide the sponsor, IRB/EC, and regulatory agency with 
final reports and summaries as required by international regulations. 
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or, for 
multicenter studies, the coordinating PI according to national provisions and will be documented 
in the investigator agreement. 
10.2.3. 
Documentation and Retention of Records 
10.2.3.1. Electronic Case Report Forms (eCRF) 
The eCRFs are supplied by the CRO and should be handled in accordance with instructions from 
the sponsor. 
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The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation.  Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log. 
All data will have separate source documentation; no data will be recorded directly onto the 
eCRF. 
All data sent to the sponsor must be endorsed by the investigator. 
The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan.  If the data are unclear or contradictory, queries are sent for 
corrections or verification of data. 
Incorrect entries must be crossed with a single line as to not obscure the original entry.  
Corrections must be made adjacent to the item to be altered, initialed, and dated by an authorized 
investigator or designee as stated in the site delegation log.  Overwriting of this information or 
use of liquid correction fluid is not allowed. 
10.2.3.2. Seizure and Medication Diaries  
The seizure diaries are supplied by the sponsor designee and should be handled in accordance 
with instructions from the sponsor. 
All data collected and sent to the sponsor must be endorsed by the investigator. 
The CRA/study monitor will verify the contents of the diary data per the monitoring plan.  If the 
data are unclear or contradictory, queries are sent for corrections or verification of data. 
10.2.3.3. Recording, Access, and Retention of Source Data and Study Documents 
Original source data to be reviewed during this study will include, but are not limited to, the 
patient’s medical file, the patient’s electronic or paper seizure diaries, and original clinical 
laboratory reports.  
All key data must be recorded in the patient’s medical records. 
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media. 
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) may check the eCRF 
entries against the source documents.  The consent form includes a statement by which the 
patient agrees to allow the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC to have access to source data (e.g., patient’s medical 
file, appointment books, original laboratory reports, 
, ECGs, etc.).  
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (e.g., the US FDA, 
European Medicines Agency, United Kingdom Medicines and Healthcare Products Regulatory 
Agency) or an auditor. 
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Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor. 
10.2.3.4. Audit/Inspection 
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency, the United Kingdom 
Medicines and Healthcare Products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site. 
10.2.3.5. Financial Disclosure 
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor.  The 
following information is collected:  any significant payments from the sponsor or subsidiaries, 
such as a grant to fund ongoing research, compensation in the form of equipment, or retainer for 
ongoing consultation or honoraria; any proprietary interest in IP; and any significant equity 
interest in the sponsor or subsidiaries as defined in 21 Code of Federal Regulations 54 2(b) 
(1998). 
10.3. 
Ethical Considerations 
10.3.1. 
Informed Consent/Assent 
It is the responsibility of the investigator to obtain written informed consent/assent from the 
parent/caregiver/LAR for all study patients prior to any study-related procedures, including 
screening assessments.  As the disease under consideration is a condition for which the patients 
will not be capable of signing consent/assent for themselves, a parent/caregiver/LAR will be 
required to sign upon identification of the patient for participation.  
All consent documentation must be in accordance with applicable regulations and GCP.  Each 
patient’s parent/caregiver/LAR, as applicable, is requested to sign and date the patient’s 
informed consent/assent form or a certified translation, if applicable, after they have received and 
read (or been read) the written patient information and received an explanation of what the study 
involves, including but not limited to the objectives, potential benefits and risk, inconveniences, 
and the patient’s rights and responsibilities.  A copy of the informed consent/assent 
documentation (i.e., a complete set of patient information sheets and fully executed signature 
pages) must be given to the patient’s parent/guardian/LAR, as applicable.  This document may 
require translation into the local language.  Signed consent forms must remain in each patient’s 
study file and must be available for verification at any time. 
Site personnel should document providing instruction for and understanding by the 
parent/caregiver/LAR of the safe, responsible storage and administration of the oral IP. 
The investigator provides the sponsor with a copy of the consent form that was reviewed by the 
IRB/EC and received their favorable opinion/approval.  A copy of the IRB/EC’s written 
favorable opinion/approval of these documents must be provided to the sponsor prior to the start 
of the study unless it is agreed to and documented (abiding by regulatory guidelines and national 
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provisions) prior to study start that another party (i.e., sponsor or coordinating PI) is responsible 
for this action.  Additionally, if the IRB/EC requires modification of the sample patient 
information and consent document provided by the sponsor, the documentation supporting this 
requirement must be provided to the sponsor. 
10.3.2. 
Institutional Review Board or Ethics Committee 
It is the responsibility of the investigator to submit this protocol, the informed consent/assent 
document (approved by the sponsor or their designee), relevant supporting information, and all 
types of patient recruitment information to the IRB/EC for review, and all must be approved 
prior to site initiation. 
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement. 
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent/assent documents and amendments to the protocol unless there 
is a patient safety issue. 
Investigational product supplies will not be released until the CRO has received written IRB/EC 
approval of and copies of revised documents. 
The investigator is responsible for keeping the IRB/EC informed of the progress of the study and 
of any changes made to the protocol at least once a year.  The investigator must also keep the 
local IRB/EC informed of any SAEs and significant AEs. 
10.4. 
Privacy and Confidentiality 
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with Health Insurance Portability and Accountability Act (HIPAA) of 1996.  
A site that is not a covered entity as defined by HIPAA must provide documentation of this fact 
to the CRO. 
The confidentiality of records that may be able to identify patients will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After the patient’s parent/caregiver/LAR have consented to take part in the study, the sponsor 
and/or its representatives review the medical records and data collected during the study.  These 
records and data may, in addition, be reviewed by others, including the following:  independent 
auditors who validate the data on behalf of the sponsor; third parties with whom the sponsor may 
develop, register, or market GNX; national or local regulatory authorities; and the IRB/EC that 
gave approval for the study to proceed.  The sponsor and/or its representatives accessing the 
records and data will take all reasonable precautions in accordance with applicable laws, 
regulations, and guidelines to maintain the confidentiality of patients’ identities. 
Patients are each assigned a unique identifying number; however, their initials and date of birth 
may also be collected and used to assist the sponsor in verifying the accuracy of the data (e.g., to 
confirm that laboratory results have been assigned to the correct patient).  
The results of studies—containing patient unique identifying numbers, relevant medical records, 
and possibly initials and dates of birth—will be recorded.  They may be transferred to, and used 
in, other countries that may not afford the same level of protection that applies within the 
countries where this study is conducted.  The purposes of any such transfer would include to 
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support regulatory submissions, to conduct new data analyses to publish or present the study 
results, and to answer questions asked by regulatory or health authorities. 
10.5. 
Study Results/Publication Policy 
Marinus will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative.  Additionally, Marinus adheres to external guidelines 
(e.g., Good Publication Practices 2) when forming a publication steering committee, which may 
be done for large, multicenter Phase 2 to 4 and certain other studies as determined by Marinus.  
The purpose of the publication steering committee is to act as a noncommercial body that advises 
or decides on dissemination of scientific study data in accordance with the scope of this policy. 
All publications relating to Marinus products or projects must undergo appropriate technical and 
intellectual property review, with Marinus agreement to publish prior to release of information.  
The review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study.  To the extent permitted by the 
publisher and copyright law, the PI will own (or share with other authors) the copyright on 
his/her publications.  To the extent that the PI has such sole, joint, or shared rights, the PI grants 
the sponsor a perpetual, irrevocable, royalty-free license to make and distribute copies of such 
publications. 
The term “publication” refers to any public disclosure, including original research articles, 
review articles, oral presentations, abstracts and posters at medical congresses, journal 
supplements, letters to the editor, invited lectures, opinion pieces, book chapters, electronic 
postings on medical/scientific websites, or other disclosure of the study results, in printed, 
electronic, oral, or other form. 
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results or necessary for other scholars to verify such study 
results.  Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication.  If requested in writing by Marinus, the hospital and PI shall 
withhold submission of such publication for up to an additional 60 days to allow for filing of a 
patent application. 
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results.  If such a multicenter publication is not submitted to 
a journal for publication by the sponsor within an 18-month period after conclusion, 
abandonment, or termination of the study at all sites, or after the sponsor confirms there shall be 
no multicenter study publication of the study results, an investigator may individually publish the 
study results from the specific site in accordance with this section.  The investigator must, 
however, acknowledge in the publication the limitations of the single-site data being presented. 
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
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current standards.  Participation as an investigator does not confer any rights to authorship of 
publications. 
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Protocol 1042-TSC-2001 
 
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11. 
REFERENCES 
Bialer M., Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress report on new 
antiepileptic drugs: A summary of the Tenth Eilat Conference (EILAT X). Epilepsy Res. 
2010;92(2-3):89-124. 
Carter RB, Wood PL, Wieland S, Hawkinson JE, Belelli D, Lambert JJ, White HS, Wolf HH, 
Mirsadeghi S, Tahir SH, Bolger MB, Lan NC, Gee KW. Characterization of the anticonvulsant 
properties of ganaxolone (CCD 1042; 3alpha-hydroxy- 3beta-methyl-5alpha-pregnan-20-one), a 
selective, high-affinity, steroid modulator of the gamma-aminobutyric acid(A) receptor. J 
Pharmacol Exp Ther. 1997;280(3):1284-95. 
Chu-Shore J, Major P, Camposano S, et al. The natural history of epilepsy in tuberous sclerosis 
complex. Epilepsia 2010;51:1236-41. 
Di Michele F, Verdecchia M, Dorofeeva M, et al. GABAA receptor active steroids are altered in 
epilepsy patients with tuberous sclerosis. J Neurol Neurosurg Psychiatry. 2003;74:667-70. 
French JA, Lawson JA, Yapici 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;388:2153-63. 
Ganaxolone Investigator’s Brochure. Marinus Pharmaceuticals, Inc., Dated 03 Dec 2019. 
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;50:290-6. 
Kaminski RM, Livingood MR, Rogawski MA. Allopregnanolone analogs that positively 
modulate GABA receptors protect against partial seizures induced by 6-Hz electrical stimulation 
in mice. Epilepsia. 2004;45(7):864-7. 
Kerrigan JF, Shields WD, Nelson TY, Bluestone DL, Dodson WE, Bourgeois BF, Pellock JM, 
Morton LD, Monaghan EP. Ganaxolone for treating intractable infantile spasms: a multicenter, 
open-label, add-on trial. Epilepsy Res. 2000;42(2-3):133-9. 
Krueger DA, Northrup H. Tuberous sclerosis complex surveillance and management: 
Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus 
Conference. Pediatric Neurol. 2013;49:255-65. 
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):1187-94. 
Ligsay A, Van Dijck A, Kooy RF, and Hagerman R. Ganaxolone in Children with FXS. 
International FXS Conference San Antonio, TX 2016. 
Mizuguchi M, Ikeda H, Kagitani-Shimono et al. Everolimus for epilepsy and autism spectrum 
disorder in tuberous sclerosis complex: EXIST-3 substudy in Japan. Brain & Development. 
2019;41:1-10.  
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Protocol 1042-TSC-2001 
 
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Northrup H, Krueger DA. Tuberous sclerosis complex diagnostic criteria update: 
Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus 
Conference. Pediatric Neurol. 2013;49:243-54. 
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):1870-4. 
Reddy DS, Castaneda DC, O'Malley BW, Rogawski MA. Anticonvulsant activity of 
progesterone and neurosteroids in progesterone receptor knockout mice. J Pharmacol Exp Ther. 
2004;310(1):230-9. 
Reddy DS, Rogwski MA. Neurosteroids — Endogenous regulators of seizure susceptibility and 
role in the treatment of epilepsy (Chapter 77). In, Jasper’s Basic Mechanisms of the Epilepsies, 
Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds.), 
Contemporary Neurology Series 80, Oxford University Press. 2012; pp. 984–1002. 
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):558-64. 
van der Poest Clement E, Jansen, F.E., Braun, K.P.J. et al. Update on Drug Management of 
Refractory Epilepsy in Tuberous Sclerosis Complex. Pediatric Drugs (2020). 
https://doi.org/10.1007/s40272-019-00376-0 
 
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12. 
APPENDICES 
12.1. 
Appendix 1:  CYP3A4/5/7 Inhibitors and Inducers 
Strong Inhibitors of CYP3Aa 
Strong Inducers of CYP3Ae 
boceprevir 
rifampinf  
clarithromycinb 
St John's wortf  
conivaptinb 
 
grapefruit juicec 
 
indinavir 
 
itraconazoleb 
 
ketoconazoleb 
 
lopinavir/ritonavirb (combination drug) 
 
mibefradild 
 
nefazodone 
 
nelfinavir 
 
posaconazole 
 
ritonavirb 
 
saquinavir 
 
telaprevir 
 
telithromycin 
 
voriconazole 
 
AUC = area under the concentration versus time curve, CYP = cytochrome P450 
a. 
A strong inhibitor for CYP3A is defined as an inhibitor that increases the AUC of a substrate for CYP3A by ≥ 5-fold. 
b. 
In vivo inhibitor of P-glycoprotein. 
c. 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent.  Studies 
have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (e.g., high dose, 
double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, single strength). 
d. 
Withdrawn from the United States market because of safety reasons. 
e. 
A strong inducer for CYP3A is defined as an inducer that results in ≥ 80% decrease in the AUC of a substrate for CYP3A. 
f. 
In vivo inducer of P-glycoprotein.   
 
Note:  The list of drugs in these tables is not exhaustive.  Any questions about drugs not on this list should be addressed to 
the medical monitor of the protocol. 
 
Source:  FDA Drug Development and Drug Interactions:  Table of Substrates, Inhibitors and Inducers.  Web link Accessed 
21 Jan 2015:  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.ht
m#inVivo 
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12.2. 
Appendix 2:  Clinical Laboratory Tests 
Clinical Chemistry 
Hematology 
Urinalysis 
Total Bilirubin 
Hemoglobin 
pH 
AST (SGOT)1 
Hematocrit 
Color 
ALT (SGPT)2 
Erythrocytes 
Clarity 
BUN3 
Leukocytes + differential 
Specific Gravity 
Glucose 
Thrombocytes (platelet count) 
Urobilinogen 
Potassium 
Drug screen5 
Ketones 
Sodium 
Protein 
Calcium 
Glucose 
Alkaline Phosphatase 
Bilirubin 
Chloride 
Blood 
Creatinine 
Leukocyte esterase 
CO2 
Nitrite 
eGFR4 
 
Quantitative serum E-human 
chorionic growth hormone 
(E-HCG) serum pregnancy 
1AST = aspartate aminotransferase, SGOT = serum glutamic oxaloacetic transaminase 
2ALT = alanine aminotransferase, SGPT = serum glutamic pyruvic transaminase 
3BUN = blood urea nitrogen 
4eGFR = estimated glomerular filtration rate 
5Plasma drug screen for THC, CBD 
 
 
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Protocol 1042-TSC-2001
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12.3.
Appendix 3:  Dosing Instructions for Oral Suspension
GANAXOLONE 1042-TSC-2001 STUDY
DOSING INSTRUCTIONS FOR ORAL SUSPENSION 
(OPEN-LABEL DOSE TITRATION, OPEN-LABEL MAINTENANCE, OPEN-LABEL 
EXTENSION, AND TAPER)
Name: ________________________________________________________ 
Next Appointment:  _______________________________________________ 
These are your dosing instructions for Ganaxolone Oral Suspension from ____ / _____ / _____ 
(start date) to ____ / _____ / _____ (end date), until your next visit.  
Take the study medication three times each day with a meal or snack, plus an 8 oz glass of water.
Example 1:
For a 15 kg child, please dose the following:
Dose Titration / Dose Maintenance / Dose Extension/Dose Taper (Please circle study period)
Date___/___/___ to Date ___/___/___
Dose 
(mg/kg)
Number of mls to take at 
EACH DOSE x 3 
TIMES/DAY
9/23/18-9/29/18; Days 1-7
6
1.8
9/30/18-10/6/18; Days 8-14
11
3.3
10/7/18-10/13/18; Days 15-21
16
4.8
10/14/18-10/20/18; Days 22-28
21
6.3
Example 2:
For a 15 kg child, please dose the following:
Dose Titration / Dose Maintenance / Dose Extension/ Dose Taper (Please circle period)
Date___/___/___ to Date___/___/___ 
Dose 
(mg/kg)
Number of mls to take at 
EACH DOSE x 3 
TIMES/DAY
10/21/18 to 1/20/19
21
6.3
Dose Titration /
Dose Titration
/ Dose Maintenance / 
Dose Maintenance /
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Please take the study medication as outlined below: 
 
Dose Titration / Dose Maintenance / Dose Extension / Dose Taper (Please circle study period) 
 
Date___/___/___ to Date___/___/___ 
Dose 
(mg/kg) 
Number of mls to take at 
EACH DOSE x 3 
TIMES/DAY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SHAKE THE BOTTLE WELL BEFORE DISPENSING 
 
Prior to each dose, the following instructions should be followed: 
1. Manually shake bottle end to end, 2 to 3 times per second, for 1 minute 
2. Allow the bottle to stand for 1 minute 
3. Attach the dosing apparatus (adaptor with syringe), invert the bottle and remove the indicated 
dose 
4. Administer dose as indicated 
Use the dosing syringe provided.  Do not use a household spoon.  A new dosing syringe and adapter 
should be used every day.  Dosing syringes should be cleaned with hot water rinse and air-drying between 
first, second, and third daily doses.  
 
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Each dose should be separated by at least 4 hours and not more than 12 hours.  An example schedule 
would be one 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 one dose and there is less than 4 hours before the next dose, skip that dose. 
 
If you miss two days of dosing or more, call the study doctor for instructions how to restart. 
 
Do not consume alcohol, grapefruit or grapefruit juice, Seville oranges, or starfruits during the study 
because it could interact with the study medication. 
 
Study medication should be stored at room temperature (59°F-77°F/15°C-25°C) in a safe place.  
 
Save all empty, partially used and unused bottles of the investigational product and return the bottles at 
your next visit.  
 
Some people may report feeling dizzy or tired, or experiencing other problems after taking the study 
medication, ganaxolone.  These side effects usually go away after 2 or 3 days.  If you experience any side 
effects from the study medication that interfere with your daily activities or if you have any questions, 
please contact your study doctor at the telephone number below to see if a dose adjustment is necessary. 
 
Study Doctor: ________________________________________________________  
 
Telephone Number:  ___________________________________________________  
 
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SAP_001.pdf: 
Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
Statistical Analysis Plan 
22MAR2021, Final 1.0 
Confidential 
Statistical Analysis Plan 
Protocol No.: 1042-TSC-2001 
 A Phase 2 Open-label 12-Week Trial of Adjunctive 
Ganaxolone Treatment (Part A) in Tuberous Sclerosis 
Complex-related Epilepsy followed by Long-term Treatment 
(Part B) 
Investigational Product: 
Ganaxolone 
Reference Product： 
NA 
Indication: 
Tuberous Sclerosis Complex-related 
Epilepsy (TSC) 
Phase： 
2 
Document Type： 
Statistical Analysis Plan 
Version： 
1.0 
Date of Issue： 
22MAR2021 
NCT Number: NCT04285346
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
Statistical Analysis Plan 
22MAR2021, Final 1.0 
Confidential 
Statistical Analysis Plan Approval Form 
 
 
 
 
Author:   
 
_______________________  
 
________________ 
               
 
, Ph.D. 
 
 
 
            Date (mm/dd/yyyy) 
              
 Statistics 
              
 CR Medicon Research, Inc. 
 
 
 
Review:          
_______________________ 
            ________________ 
, Ph.D. 
             
 
 
Date (mm/dd/yyyy) 
  
  
CR Medicon Research, Inc. 
 
______________________ 
 
________________ 
, Ph.D. 
 
 
 
 
Date (mm/dd/yyyy) 
 Biostatistics 
Marinus Pharmaceuticals, Inc. 
 
_____________________ 
 
________________ 
, M.D., Ph.D. 
 
 
 
Date (mm/dd/yyyy) 
 Clinical Development 
Marinus Pharmaceuticals, Inc. 
 
 
Approval: 
 
________________________ 
 
________________ 
, PhD 
 
 
                        Date (mm/dd/yyyy) 
Biometrics 
Marinus Pharmaceuticals, Inc. 
 
 


Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
Statistical Analysis Plan 
22MAR2021, Final 1.0 
Confidential 
 
Change Log 
Version No. 
Effective Date 
Reason for Change/Revision 
Supersedes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
Statistical Analysis Plan 
22MAR2021, Final 1.0 
Confidential 
TABLE OF CONTENTS 
ABBREVIATIONS ........................................................................................................... 6 
1 
INTRODUCTION..................................................................................................... 8 
1.1 
STUDY OBJECTIVES .............................................................................................. 8 
1.1.1 Primary Objective ........................................................................................... 8 
1.1.2 Secondary Objectives ...................................................................................... 8 
1.1.3 Exploratory Objectives ................................................................................... 9 
1.2 
STUDY ENDPOINTS ............................................................................................... 9 
1.2.1 Primary Efficacy Endpoint ............................................................................. 9 
1.2.2 Secondary Efficacy Endpoints ........................................................................ 9 
1.2.3 Exploratory Efficacy Endpoints .................................................................... 10 
1.2.4 Safety Endpoints............................................................................................. 11 
1.2.5 Open-Label Extension Endpoints .................................................................. 11 
1.3 
STUDY DESIGN ................................................................................................... 12 
1.3.1 General Study Design and Plan .................................................................... 12 
1.3.2 Sample Size Estimation ................................................................................. 13 
1.3.3 Randomization and Blinding......................................................................... 13 
2 
STATISTICAL CONSIDERATIONS ................................................................... 13 
2.1 
GENERAL CONSIDERATIONS ............................................................................... 13 
2.2 
ANALYSIS SETS .................................................................................................. 14 
2.3 
POOLING OF CENTERS ........................................................................................ 14 
2.4 
MULTIPLE COMPARISONS/MULTIPLICITY ........................................................... 14 
2.5 
EXAMINATION OF SUBGROUPS ........................................................................... 14 
3 
DATA HANDLING CONVENTIONS .................................................................. 15 
3.1 
DERIVED AND TRANSFORMED DATA ................................................................... 15 
3.1.1 Baseline Definition........................................................................................ 15 
3.1.2 Study Day ...................................................................................................... 15 
3.1.3 Derivations .................................................................................................... 15 
3.2 
ANALYSIS VISIT WINDOWS ................................................................................ 17 
3.3 
PREMATURE WITHDRAWAL AND MISSING DATA ................................................. 17 
3.3.1 Missing and Partial Start/Stop Dates - AEs and Concomitant Medications 18 
3.3.2 Missing Seizure/Medication Diary Entries ................................................... 20 
4 
STATISTICAL ANALYSES ................................................................................... 20 
4.1 
SUBJECT INFORMATION ...................................................................................... 20 
4.1.1 Disposition of Subjects .................................................................................. 20 
4.1.2 Protocol Violations........................................................................................ 21 
4.1.3 Demographics and Baseline Characteristics................................................ 21 
4.1.4 Medical History ............................................................................................ 21 
4.1.5 Prior and Concomitant Medications ............................................................ 21 
4.1.6 Treatment Compliance .................................................................................. 22 
4.2 
EFFICACY ANALYSES ......................................................................................... 22 
4.2.1 Primary Efficacy Analysis ............................................................................. 22 


Mruinus Phrumaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 1042-TSC-2001 
22MAR2021, Final 1.0 
4.2.2 Seconda,y Efficacy Ana~ysis ......................................................................... 22 
4.3 
SAFETY ANALYSIS ............................................................................................. 23 
4. 3.1 
Extent of Exposure ........................................................................................ 23 
4.3.2 Adverse Events .............................................................................................. 24 
4.3.3 Clinical Laboratory Tests .............................................................................. 25 
4.3.4 Vital Signs and Physical, Neurological and Developmental Examination 
Findings .................................................................................................................... 26 
4.3.5 Electrocardiogram (ECG) ............................................................................ 27 
4.3.6 Other Sae Anal sis .................................................................................... 27 
5 
PLANNED ANALYSES ......................................................................................... 30 
5.1 
INTERIM ANALYSIS ............................................................................................ 30 
5.2 
F INAL ANALYSIS ................................................................................................ 30 
6 
SUMMARY OF MAJOR CHANGES IN THE PLANNED ANALYSES .......... 31 
7 
PROGRAMMING SPECIFICATIONS ............................................................... 31 
8 
TABLES/LISTINGS/FIGURES TEMPLATES ................................................... 31 
9 
REFERENCES ........................................................................................................ 32 
10 
APPENDICES ......................................................................................................... 33 
10 .1 
A PPENDIX A: SCHEDULE OF A SSESSMENTS PART A ........................................... 3 3 
10.2 
A PPENDIX B: SCHEDULE OF A SSESSMENTS PART B ........................................... 36 
Confidential 


Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
Statistical Analysis Plan 
22MAR2021, Final 1.0 
Confidential 
ABBREVIATIONS 
Abbreviation Term 
AE 
Adverse Event 
AED 
Anti-Epileptic Drug 
Allo-S 
Allopregnanolone Sulfate 
ATC 
Anatomical Therapeutic Class 
BMI 
Body Mass Index 
bpm 
Beats per minute 
CGI-C 
Caregiver Global Impression of Change  
CGI-I 
Clinical Global Impression of Improvement 
CI 
Confidence Interval 
cm 
centimeters 
CRF 
Case Report Form 
CS 
Clinically Significant 
ECG 
Electrocardiogram 
 
 
FDA 
US Food and Drug Administration 
GNX 
Ganaxolone 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IP 
Investigational Product 
IQ 
Intelligence Quotient 
ITT 
Intent-to-Treat 
kg 
kilograms 
LAR 
Legally Authorized Representative 
LLN 
Lower limit of normal 
m 
meters 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
Not Clinically Significant 
OL 
Open label 
OLE 
Open-label extension 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
PT 
Preferred Term 
Q1 
1st quartile; 25th percentile 
Q3 
3rd quartile; 75th percentile 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SI 
Systeme International 
SIF/DIF 
Seizure Identification and Diagnostic Form 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event 
TSC 
Tuberous Sclerosis Complex 


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ULN 
Upper limit of normal 
US 
United States 
WHODDE 
World Health Organization Drug Dictionary Enhanced 


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1 
INTRODUCTION 
This statistical analysis plan (SAP) provides details and specifications for the statistical 
analyses of data collected under Marinus Pharmaceuticals, Inc. Protocol 1042-SC-2001, 
“A Phase 2 Open-label 12-Week Trial of Adjunctive Ganaxolone Treatment (Part A) in 
Tuberous Sclerosis Complex-related Epilepsy followed by Long-term Treatment (Part 
B)” (Version 2, Protocol Amendment 1, 12 May 2020). 
The structure and content of this SAP provide sufficient detail to meet the requirements 
identified by the US Food and Drug Administration (FDA) and International Conference 
on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals 
for Human Use: Guidance on Statistical Principles in Clinical Trials.1 All work planned 
and reported for this SAP will follow internationally accepted guidelines for statistical 
practice published by the American Statistical Association2.  
The following documents were also considered in preparation in writing this SAP: 
• ICH E3 Guideline: Structure and Content of Clinical Study Reports3 
• ICH E6 Guideline: Good Clinical Practice4 
• ICH E8: General Considerations for Clinical Trial5 
• ICH E9: Statistical Principles for Clinical Trials6 
 
The SAP is a supplement to the study protocol which should be references for additional 
details on study design, study conduct, and other operational aspects of the study. 
1.1 STUDY OBJECTIVES 
1.1.1 Primary Objective 
The primary objective of this study is to assess preliminary safety and efficacy of 
Ganaxolone (GNX) adjunctive therapy for the treatment of primary seizure types in 
patients with genetically- or clinically-confirmed Tuberous Sclerosis Complex (TSC) -
related epilepsy through the end of the 12-week treatment period. The primary seizure 
types (focal motor seizures without impairment of consciousness or awareness, focal 
seizures with impairment of consciousness or awareness, focal seizures evolving to 
bilateral, tonic-clonic convulsive seizures, and generalized motor seizures including 
tonic-clonic, bilateral tonic, bilateral clonic, or atonic/drop seizures) are identified to be 
the most common, easily identifiable/countable by a parent/caregiver/legally authorized 
representative (LAR), and are most consequential to the patient’s quality of life. 
1.1.2 Secondary Objectives 
The secondary objectives of this study are the following: 
• To assess the long-term efficacy of GNX when administered as adjunctive therapy 
throughout the open-label extension (OLE) period (Part B). 
• To assess the long-term safety and tolerability of GNX when administered as 
adjunctive therapy throughout the OLE period (Part B). 


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1.2 
STUDY ENDPOINTS 
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Prima1y, secondaiy and explorato1y efficacy endpoints described below suppo1t the 
primaiy study objective of assessing the efficacy of investigational product (IP), GNX, as 
adjunctive therapy for the treatment of primaiy seizure types in patients with TSC-related 
epilepsy through the end of the 12-week treatment period (Pait A) and explorato1y 
objectives related to Pait A of the study. 
Endpoints suppo1ting the secondaiy study objective of assessing long-te1m efficacy of 
GNX with administered as adjunctive therapy throughout the OLE period (Part B) ai·e 
described in Section 1.2.5 (Open-Label Extension Endpoints). 
1.2.1 
Primary Efficacy Endpoint 
The prima1y efficacy endpoint (change in seizure frequency) is the percent change in 28-
day seizure frequency through the end of the 12-week treatment period (4-week titration 
and 8-week maintenance) relative to the baseline, based on the primaiy seizure types. The 
primaiy seizure types ai·e defined as the following: focal motor seizures without 
impai1ment of consciousness or awai·eness, focal seizures (motor or non-motor) with 
impai1ment of consciousness or awareness, focal seizures evolving to bilateral, tonic-
clonic convulsive seizures, and generalized motor seizures including tonic-clonic, 
bilateral tonic, bilateral clonic, or atonic/drop seizures. Focal aware non-motor and 
generalized seizures without motor features, infantile or epileptic spasms, and myoclonic 
seizures do not count as the primaiy seizure types. 
The calculation of post-baseline 28-day seizure frequency and percent change in 28-day 
seizure frequency are explained in Section 3 .1. 3. 
1.2.2 Secondary Efficacy Endpoints 
In addition to evidence about effects of GNX on 28-day seizure frequency, the clinical 
trial will assess GNX's effects on several secondai·y endpoints that capture impo1tant 
symptoms and activities of daily living that are meaningfully compromised by TSC. 
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1.2.2.1 Secondaiy Efficacy Endpoint - Seizure Control 
Protocol 1042-TSC-2001 
22MAR2021, Final 1.0 
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Percentage of patients experiencing a 
50% reduction in 28-day primaiy seizure 
frequency through the end of the 12-week treatment period compared to the 4-
week baseline period. 
Derived seizure secondaiy efficacy endpoints will be based on data through the end of the 
12-week treatment period relative to the 4-week baseline period as defined in Section 
3.1.3. 
1.2.2.2 Secondaiy Efficacy Endpoint - Other 
• 
CGI-I- pai·ent/caregiver and clinician 
• 
CGI-C - tai·get behavior 
These behavioral/neuropsychiatric secondary endpoints will provide info1mation about 
the overall impact of GNX on the treatment of patients with TSC. The CGI-C and the 
CGI-I ai·e 7-point scales used to assess change after initiation of GNX. The scores range 
from 1 = ve1y much improved to 7 = ve1y much worse. Separate CGI-I responses will be 
collected the patient's pai·ent/cai·egiver and the clinician at baseline, Week 5 and Week 12 
of Pait A of the study and at the final visit in Pait B, if applicable. The CGI-C will be 
completed by the patient's parent/caregiver at the same study visits. 
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1.2.4 Safety Endpoints 
Safety and tolerability endpoints for Paii A and Paii B include: 
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Vital signs (height, weight, blood pressure [BP], heaii rate [HR], respirat01y rate 
[RR], body temperature) 
• 
Electrocai·diograms (ECGs) 
• 
Clinical laborato1y tests (hematology, chemistiy and urinalysis) 
• 
Physical exam findings 
• 
Neurological exam findings 
• 
Developmental exam findings 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS), if appropriate 
• 
Adverse events (frequency, type and severity) 
1.2.5 
Open-Label Extension Endpoints 
To evaluate the secondaiy study objectives of assessing the long-te1m efficacy and safety 
of GNX, the following endpoints defined above for Paii A of the study will be examined 
in patients paiiicipating in Pa1i B of the study: 
• 
Primaiy seizure frequency during OLE: change in 28-day primaiy seizure 
frequency from baseline (Visit 1 to Visit 2) to the OLE period (Visit 5 through 
Visit 8) 
• 
Percent change in primaiy seizure frequency dming OLE relative to the baseline 
period. 
• 
Prima1y seizure frequency across 12-week treatment period and OLE: change in 
28-day primaiy seizure frequency from baseline (Visit 1 to Visit 2) to the 
cumulative treatment periods A and B (Visit 2 through 8) 
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• Percent change in primary seizure frequency baseline versus cumulative treatment 
periods (12-week treatment period + OLE) 
• Seizure frequency for all types of seizures in OLE versus baseline and cumulative 
treatment Parts A and B versus baseline 
• Percent change in all-types seizure frequency in OLE versus baseline and 
cumulative treatment Parts A and B versus baseline 
• CGI-C for target behaviour: Week 36 and final visit of the OLE 
• CGI-I, parent/caregiver and clinician: Week 36 and final visit of the OLE. 
• 
 at the final OLE visit. 
• Safety endpoints listed in Section 1.2.4.  
1.3 STUDY DESIGN 
1.3.1 General Study Design and Plan 
This is an open-label (OL) proof of concept study of adjunctive GNX treatment in 
patients with a confirmed clinical diagnosis of TSC and/or a mutation in either the TSC1 
or TSC2 gene. The trial consists of two parts (Figure 1): Part A consists of a 4-week 
baseline period followed by a 12-week treatment period (4-week titration and 8-week 
maintenance). For patients not continuing in the 24-week OLE period (Part B), a 2-week 
taper period followed by a 2-week safety period would follow. The main difference 
between Part A and Part B is the length of treatment, less frequent assessments, and the 
ability to alter drug doses (both GNX and other antiepileptic drug [AED] treatments 
which includes initiating and stopping other medications) based on investigator 
evaluation of the patient’s clinical course during Part B. Patients with a seizure frequency 
reduction rate of ≥ 35% during the 12-week treatment period in Part A compared to 
baseline may continue into Part B (“OLE eligible”). If the investigator believes there is a 
medical benefit for the patient who does not meet the seizure reduction criterion to enter 
the OLE, they must discuss the patient with the sponsor medical monitor and receive 
sponsor approval for that patient to continue into the OLE. 
The Schedule of Assessments from the protocol for both Part A and Part B are included in 
Appendix A and Appendix B, respectively, of this document. 
Part A 
• 4-week baseline period  
• 4-week titration period  
• 8-week maintenance period   
• 2-week taper period (For patients who do not complete Part A or after completing 


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Part A but do not continue into Part B)  
• 2-week safety follow-up visit post taper (For patients who taper off GNX)  
Part B (Optional for OLE-eligible patients)  
• 24-week OLE period   
• 2-week taper period (For patients who discontinue GNX due to early termination 
or completion)  
• 2-week safety follow-up visit post-taper (For patients who taper off GNX) 
Figure 1: 
Study Design 
 
1.3.2 Sample Size Estimation 
Approximately 36 TSC patients, aged 2 to 65 inclusive, will be screened to achieve 30 
TSC patients given IP in Part A. Since this is an OL proof of concept study, sample size 
was not determined by statistical methods. 
1.3.3 Randomization and Blinding 
This is an open-label study. Randomization and blinding are not applicable for this study. 
2 
STATISTICAL CONSIDERATIONS 
2.1 GENERAL CONSIDERATIONS 
Statistical analyses will be performed using SAS System, Version 9.4 or higher (SAS 
Institute, Inc., Cary, NC).  
No formal hypothesis testing will be performed for this study. Data will be summarized 
descriptively. Separate summaries will be presented for data collected in Part A and data 
collected in Part B of the study. Unless otherwise specified, descriptive statistics for 
continuous variables will include number of non-missing observations (n), arithmetic 
mean, standard deviation (SD), 25th and 75th percentiles, minimum, median and 
maximum. For categorical variables, descriptive statistics including counts and 
percentages will be used. Only observed data will be summarized. Missing data will not 
Part A 
Part B 
Baseline 
GNX Titration 
GNX Maintenance 
Open-Label Extension (OLE) 
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be imputed. Scheduled assessments will be included in summaries with the exception of 
reports of abnormal laboratory, vital sign, or ECG values. 
Study data from all assessments (scheduled and unscheduled) will be displayed in 
individual data listings by study part (Part A or Part B), patient and visit, if applicable. 
2.2 ANALYSIS SETS 
Analysis sets for this study are defined as: 
• Screened population: all patients who have signed informed consent for the study. 
• Safety population: all patients who have received at least one dose of GNX 
• Intent-to-treat (ITT) population: all patients who receive at least one dose of GNX 
and have at least one post-baseline efficacy assessment. 
• Per-protocol (PP) population: includes all ITT patients without major protocol 
violations, as will be defined prior to database lock. Patients that fall below 80% 
compliance at two consecutive visits during the maintenance period (i.e. Visits 4 
and 5, Weeks 5 and 12) will not be included in the PP population. 
• Open-label extension (OLE) population: includes all ITT patients who participate 
in the OLE (Part B) of the study and receive at least one dose of GNX in the Part 
B. 
• Pharmacokinetic (PK) population: all ITT patients who have had at least one PK 
sample collected and a valid bioanalytical result obtained. Pharmacokinetic data 
collected from this population may be reported separately. 
2.3 POOLING OF CENTERS 
This multicenter study is to be conducted at approximately 6 sites in the United States. 
No significant differences between centers are anticipated. Data from all centers will be 
pooled for analysis. 
2.4 MULTIPLE COMPARISONS/MULTIPLICITY 
All analyses of study data will be descriptive. No adjustments for multiple comparisons 
will be made.  
2.5 EXAMINATION OF SUBGROUPS 
No subgroup analyses are planned for this study. 


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3 
DATA HANDLING CONVENTIONS 
3.1 DERIVED AND TRANSFORMED DATA 
3.1.1 Baseline Definition 
The Baseline Visit is defined as Visit 2 (Week/Day 0). 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 0). This interval may range 
from no less than 28 days to no more than 32 days.  
3.1.2 Study Day 
For reporting purposes, Study Day will be calculated from the date of the Baseline 
Treatment Visit (Visit 2, Week/Day 0). 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. 
3.1.3 Derivations 
3.1.3.1 Baseline seizure frequency 
Baseline 28-day seizure frequency will be calculated as the total number of primary 
seizures in the baseline period, i.e. between screening (Visit 1, Week -4) and baseline 
treatment (Visit 2, Week/Day 0), divided by the number of days with non-missing seizure 
data in the baseline period, multiplied by 28. 
𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 = 
# 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠, 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝  
# 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑥𝑥 28 
3.1.3.2 Post-baseline seizure frequency – Maintenance Period, Part A, Part B and Overall 
Post-baseline 28-day seizure frequency will be calculated as the total number of seizures 
in the specified post-baseline period divided by the number of days with non-missing 
seizure data in the same post-baseline period, multiplied by 28. Within Part A of the 
study, post-baseline seizure activity will be determined based on the days following the 
first day after the date of the first dose of IP. The first day of treatment is included in 
neither the baseline nor the post-baseline period since seizures reported on that date could 
have occurred either before or after the initiation of treatment. Within Part B (OLE 


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period), post-baseline seizure activity will be determined by the first day of OLE 
treatment. 
Separate frequencies will be calculated for the 8-week maintenance period of Part A 
(Maintenance), Parts A (12-week treatment period consisting of a 4-week titration period 
and an 8-week maintenance period) and B of the study (OLE period of up to 24 weeks) 
and across both study parts.  
𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃-𝑏𝑏𝑏𝑏𝑏𝑏𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 28-𝑑𝑑𝑑𝑑𝑑𝑑 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 =  
# 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠, 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
# 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑥𝑥 28 
3.1.3.3 Percent change in 28-day seizure frequency – Maintenance Period, Part A, Part B 
and Overall 
% 𝑐𝑐ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏= 
[(𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝-𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 28-𝑑𝑑𝑑𝑑𝑑𝑑 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓) −(𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 28-𝑑𝑑𝑑𝑑𝑑𝑑 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓)]
(𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 28-𝑑𝑑𝑑𝑑𝑑𝑑 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓)
 𝑥𝑥 100 
3.1.3.4 Frequency of seizure-free days per 28 days – Baseline 
The frequency of seizure-free days per 28 days total for all seizure types during the 
baseline period will be calculated as the total number of days reported as seizure-free, 
i.e., with seizure diary response to “Did you have seizures on this date?” equal to “no” or 
with no approved seizures for a date, multiplied by 28, and divided by the number of days 
with non-missing seizure data in the baseline period. 
𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠-𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑝𝑝𝑝𝑝𝑝𝑝 28-𝑑𝑑𝑑𝑑𝑑𝑑 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝  
= # 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠-𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑, 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑥𝑥 28  
# 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑤𝑤𝑖𝑖𝑖𝑖ℎ 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑  
The frequency of seizure-free days per 28 days total for the primary seizure types only 
will be calculated in the same manner except defining seizure-free as days with seizure 
diary response to “Did you have seizures on this date?” equal to “no” or with a response 
to this question equal to “yes” but no primary seizure types reported and approved for 
that day. 
3.1.3.5 Frequency of seizure-free days per 28 days – Part A, Part B and Overall 
The percentage of post-baseline seizure-free days per 28 days total within a specified 
post-baseline study period will be calculated as the  
𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃-𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠-𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑝𝑝𝑝𝑝𝑝𝑝 28-𝑑𝑑𝑑𝑑𝑑𝑑 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝  
= # 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠-𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑, 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑥𝑥 28  
# 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑝𝑝𝑒𝑒𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 


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3.1.3.6 Percent change from baseline in seizure-free days per 28 days 
The percent change from baseline in seizure-free days will be  
% 𝑐𝑐ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑖𝑖𝑖𝑖 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠-𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑝𝑝𝑒𝑒𝑒𝑒 28 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑= 
[(𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝-𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠-𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑/28 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) −(𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠-𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑/28 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑)]
(𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠-𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑝𝑝𝑝𝑝𝑝𝑝 28 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑)
 𝑥𝑥100 
 
3.1.3.7 Percent compliance with IP 
The percent compliance with study drug will be estimated using dosing information 
reported in the eDiary as follows: 
[𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡= 𝑌𝑌𝑌𝑌𝑌𝑌]
(𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑐𝑐𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟)  𝑥𝑥100 
3.2 
 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 -32 ± 4) through Study 
Day 0 (date of first dose of IP) 
• Titration period: Visit 2 + 1 day to Visit 4; Study Day 1 through Study Week 4 
(Day 28 ± 3 days; date of Visit 4) 
• Maintenance period: Visits 4 + 1 day and 5; Study Week 5 (± 3 days) through 
Study Week 12 (± 3 days) 
• 12-week treatment period: titration period + maintenance period (including taper 
and safety visits if not continuing in OLE) 
• OLE period if continuing in OLE: Visit 5 + 1 day through final visit 
 
Safety Analyses 
Safety data will be summarized by actual visit. No visit windowing will be applied. 
3.3 PREMATURE WITHDRAWAL AND MISSING DATA 
Available data from patients who withdraw from the study prematurely will be included 
in analyses, unless otherwise indicated. Only observed data will be summarized. No data 


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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.  
3.3.1 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. 


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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. 
 
 
3.3.2 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. 
4 
STATISTICAL ANALYSES 
4.1 SUBJECT INFORMATION 
4.1.1 Disposition of Subjects 
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 in each part of the study (Part A 
and Part B) 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 by study part (Part 
A and Part B). Reasons for discontinuation of study treatment and for discontinuation of 
study participation will be summarized. The total number and percentage of patients who 
complete Part A of the study will be summarized as will the number and percentage of 
these patients who continue participation in Part B of the study. In addition, the number 
and percentage of patients who complete Part B of the study will be summarized 


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separately. 
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.  
4.1.2 Protocol Violations 
Protocol violations will be identified prior to database lock. Protocol violations will be 
listed for patients in the Safety Population.   
4.1.3 Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized and listed for all patients 
in the Safety Population participating in Part A of the study and OLE patients 
participating in Part B of the study. 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 
.  
Baseline values of efficacy and safety parameters will be summarized in the respective 
analysis tables.    
4.1.4 Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA), version 22.0. 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. 
4.1.5 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 (Version WHODDE, September 2019). 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). September 2019. 
Prior medications are defined as medications that started prior to the first dose of study 
drug. Concomitant medications are defined as medications (other than the study drug) 


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taken on or after the first dose of the study drug. Medications started before the first dose 
of study drug and continuing at the time of the first dose of study drug are considered 
both prior medication and concomitant medication. The summary of concomitant 
medications for Part A of the study will not include concomitant medications that start 
after Part A; i.e., they will not include any concomitant medications starting on or after 
the first dosing day of the OLE phase. 
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. Prior medications will be summarized for Part A only. All other 
summaries and listings will be presented separately for Parts A and B of the study. 
4.1.6 Treatment Compliance 
Compliance with GNX treatment will be assessed by inspecting the seizure and 
medication diary entries and returned drug supply with queries as necessary. Treatment 
compliance will be calculated as explained in Section 3.1.3.7. Percent compliance for 
Parts A and B of the study will be summarized for the Safety Population and OLE 
Population, respectively. Reported dosing by visit and calculated compliance values will 
be listed.  
4.2 EFFICACY ANALYSES  
4.2.1 Primary Efficacy Analysis 
4.2.1.1 Primary Analysis 
The primary efficacy endpoints, the percent change in 28-day primary seizure type 
frequency through the end of the 12-week treatment period (Part A; 4-week titration and 
8-week maintenance) relative to the baseline, is defined in Section 1.2.1. The calculation 
of the primary endpoint is described in Section 3.1.3. 
Descriptive summaries including the number of patients with non-missing primary 
seizure data, mean arithmetic change and percent change in 28-day primary seizure type 
frequency from baseline and associated 95% confidence intervals, SD, minimum, median 
and maximum values will be presented for the baseline period, 4-week titration period, 8-
week maintenance period and 12-week treatment period. All patients in the ITT 
population and all available seizure data within Part A of the study will be included in 
these analyses regardless of whether the patient stopped taking IP or took rescue 
medication. 
Additionally, a by-patient listing of seizure data collected during Part A will be provided.    
4.2.1.2 Sensitivity Analysis 
The primary analysis will be repeated in the PP population. 
4.2.2 Secondary Efficacy Analysis 
Secondary efficacy endpoints are defined in Section 1.2.2. Analyses of secondary 


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efficacy endpoints will be based on the ITT population. 
4.2.2.1 Seizure Control 
To assess seizure control during the 12-week treatment period, the subset of ITT patients 
who achieve ≥ 50% reduction in 28-day primary type seizure frequency during the 12-
week treatment period compared to baseline will be summarized as was described for the 
primary efficacy analysis. The calculation of percent reduction from baseline in seizure 
frequency is described in Section 3.1.3.6. 
Percent change values meeting criteria of interest, i.e. ≥ 25% reduction, ≥ 50% reduction 
and ≥ 75% reduction from baseline will be flagged in the by-patient listing of seizure 
data. 
4.2.2.2 CGI-I and CGI-C 
The CGI-C in target behavior includes two 7-point Likert items which the parent or 
caregiver uses to rate the severity of the target behavior at baseline and to assess change 
in the target behavior after initiation of IP relative to baseline. The severity scale ranges 
from 1 = normal to 7 = very severe problem, and the change scale ranges from 1 = very 
much improved to 7 = very much worse.  
The target behavior chosen and the baseline severity of this behavior will be summarized. 
For post-baseline visits, change in this severity since the start of the study will be 
summarized. The number and percentage of ITT patients receiving each CGI-C change  
rating will be summarized by visit. 
The CGI-I contains two 7-point Likert scales for baseline overall severity of the patient’s 
presentation (ranging from 1 = normal to 7 = very severe problem) and overall global 
impression of change relative to baseline (ranging from 1 = very much improved to 7 = 
very much worse). The number and percentage of patients receiving each CGI-C rating 
will be summarized. The CGI-I responses from the clinician and from the 
parent/caregiver will be presented separately by visit. 
A listing of CGI-C and CGI-I data collected by visit for each patient will be provided. 
4.3 SAFETY ANALYSIS 
Safety analyses will be based on all patients in the Safety population, unless otherwise 
indicated. Data will be summarized for Part A, Part B and across the entire study for 
those patients participating in both parts. 
4.3.1 Extent of 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 


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treatment date will be used for the last day on treatment. Exposure data will be 
summarized for Parts A and B of the study separately as well as overall exposure for all 
patients. 
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. 
4.3.2 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 22.0 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. Analyses of TEAEs for Part A of the study will include AEs that start or worsen 
during Part A and will not include any AE that starts or worsens during Part B. For Part B 
of the study, TEAEs will be include events that start or worsen after the first day of Part B 
relative to the first day of Part B. TEAEs over the entire study will be summarized for 
patients who participate in both Parts A and B of the study. 
Tabulations of AEs will be by patient such that an individual is only counted once per 
summary category. Detailed by-patient listings of all AEs reported during the study will 
be provided and will include verbatim and coded terms for each AE. 
4.3.2.1 Overview of Adverse Events 
A summary of AEs reported during the study will be presented. The number and 
percentage of patients in the Safety Population who reported at least one occurrence of an 
event in one of the following categories will be summarized: 
• Any TEAE 
• TEAE with causality related to study drug 
• Any SAE 
• TEAE leading to discontinuation of study drug  
• TEAEs by worst severity 
• TEAEs with an outcome of death 
4.3.2.2 Incidence of TEAEs 
The number and percentage of patients reporting at least one TEAE during Part A, Part B 
and overall will be summarized by MedDRA System Organ Class (SOC) and preferred 
term (PT). The summary will be sorted by descending frequency within SOC and PT 
within SOC. 
A detailed listing of AEs for each patient will be provided. The listing will include the 


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Protocol 1042-TSC-2001 
Statistical Analysis Plan 
22MAR2021, Final 1.0 
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verbatim term reported by the Investigator, MedDRA SOC and PT, onset date/time, end 
date/time, severity, seriousness (yes/no), seriousness reason, relationship to study drug, 
action taken, withdrawal from study, treatment required, and outcome.  
4.3.2.3 Incidence of TEAEs by Severity 
The number and percentage of patients reporting a TEAE will be tabulated by 
investigator-specified severity, i.e. intensity of mild, moderate or severe. A patient 
experiencing AEs of the same SOC and PT multiple times during the study will be 
counted once for the PT based on the worst severity reported. Similarly, if a patient 
experiences multiple AEs within the same SOC, the patient will be counted once for that 
SOC at the worst severity reported. 
Missing severity for an event will be assigned to severe.   
4.3.2.4 Incidence of TEAEs by Relationship to Study Drug 
The number and percentage of patients reporting a TEAE will be summarized by SOC, 
PT, and relationship to study drug (related or not related). A patient experiencing AEs of 
the same SOC and PT multiple times during the study will be counted once for the PT 
based on the highest level of relatedness reported (related > not related). Similarly, if a 
patient experiences multiple AEs within the same SOC, the patient will be counted once 
for that SOC at the highest level of relatedness reported. 
Events missing relationship will be summarized as related to study drug if the AE occurs 
on or after the administration of study drug. 
4.3.2.5 Serious Adverse Events (SAEs) 
The number and percentage of patients reporting at least one AE that meets with criteria 
for an SAE will be summarized by MedDRA SOC and PT. A similar summary of SAEs 
reported as related to study drug will be presented. The seriousness reason will be 
provided in the by-patient SAE listing. 
4.3.2.6 AEs Leading to Study Discontinuation 
A listing of any AEs reported as leading to study discontinuation will be presented as 
described in Section 4.3.2.2 above. 
4.3.2.7 AEs Leading to Death 
All deaths occurring during the study, including AEs leading to death and deaths during 
the post-treatment follow-up period, will be listed.  
4.3.3 Clinical Laboratory Tests 
Laboratory data collected in this study include serum chemistry and hematology values, 
urinalysis results and 
 levels. 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 


Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
Statistical Analysis Plan 
22MAR2021, Final 1.0 
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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. 
will be 
presented separately 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.  
4.3.4 Vital Signs and Physical, Neurological and Developmental Examination 
Findings 
4.3.4.1 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 0. 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 
for Parts A and B and overall 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.  


Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
Statistical Analysis Plan 
22MAR2021, Final 1.0 
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4.3.4.2 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.  
4.3.4.3 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. 
4.3.4.4 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 with findings recorded as normal, abnormal but not clinically 
significant, and abnormal and clinically significant. The number and percentage of 
pediatric patients with abnormal developmental findings will be summarized by 
parameter. Abnormal developmental findings at baseline and any changes in neurological 
findings at post-baseline visits relative to the previous visit will be listed for each patient.  
4.3.5 Electrocardiogram (ECG) 
Safety ECG measurements will be collected throughout the study. Baseline ECG values 
are those collected at Visit 2 (Day 0) 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 study part (Part A and Part 
B). By-patient listings of ECG data and overall interpretations collected during Part A and 
Part B will be provided. 
4.3.6 Other Safety Analysis 
4.3.6.1 Columbia-Suicide Severity Rating Scale (C-SSRS) 
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 


Mruinus Phrumaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 1042-TSC-2001 
22MAR2021, Final 1.0 
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. 
Table 5: C-SSRS Categories for Analysis 
Category 
C-SSRS Item response is "YES" 
Suicidal behavior 
Preparatory acts or behavior 
Abo1ted attempt 
Intenupted 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 
Non-suicidal self-injurious behavior 
behavior 
4.3.6.2 Tanner Scale 
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 Vat baseline 
and end of Paits A and B of the study. The number and percentage of patients in each 
catego1y will be sUilllllai·ized and listed by visit. 
I 
I 
Confidential 




Mruinus Phrumaceuticals, Inc. 
Statistical Analysis Plan 
4.5 
PHARMACOKINETIC (PK) ANALYSES 
A listing of phannacokinetic collection times will be provided. 
Protocol 1042-TSC-2001 
22MAR2021, Final 1.0 
Phaimacokinetic analyses will be conducted using data from patients in the PK Population. 
Analyses will be limited to listings of concentrations because sufficient concentration-time 
data will not be available for noncompartmental analyses. 
Phaimacokinetic data from this study may be used for Population PK analyses to be 
conducted and reported sepai·ately from this study. 
5 
PLANNED ANALYSES 
5.1 
INTERIM ANALYSIS 
No fonnal interim analysis is planned. 
5.2 
FINAL.ANALYSIS 
Data collected during this study will be SllIIllnai·ized descriptively. 
Confidential 


Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
Statistical Analysis Plan 
22MAR2021, Final 1.0 
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6 
SUMMARY OF MAJOR CHANGES IN THE PLANNED ANALYSES 
No changes to planned analyses are anticipated. Any further analysis changes made after 
this SAP is finalized will be documented with an SAP amendment or described in the 
clinical study report (CSR). 
7 
PROGRAMMING SPECIFICATIONS  
Detailed programming specifications will be provided in a separate document.  
8 
TABLES/LISTINGS/FIGURES TEMPLATES  
Templates for planned tables, listings and figures will be provided in a separate document.  
 
 


Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
Statistical Analysis Plan 
22MAR2021, Final 1.0 
Confidential 
 
9 
REFERENCES 
1. International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite 
Guideline, Statistical Principles for Clinical Trials (E9), September 1998.  
2. ASA. (2018) Ethical Guidelines for Statistical Practice. Prepared by the Committee 
on Professional Ethics, April, 2018. http://www.amstat.org/ASA/Your-
Career/EthicalGuidelines-for-Statistical-Practice.aspx.  
3. International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite 
Guideline, Structure and Content of Clinical Study Reports (E3), November 1995.  
4. International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite 
Guideline, Good Clinical Practice (E6), April 1996.  
5. International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite 
Guideline, General Considerations for Clinical Trials (E8), July 1997.  
6. International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, 
Statistical Principles for Clinical Trials (E9), September 1998.  


Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
Statistical Analysis Plan 
22MAR2021, Final 1.0 
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10 APPENDICES 
10.1 APPENDIX A: SCHEDULE OF ASSESSMENTS PART A 
 
T able 1 : 
S c h edu le o f A sse ssm ent s - P art A 
I 
P an.-\. 
Screen/Bas eline 
T inkation and l\.la.intenance 
-.t 
(Screening 
0 
, -isir -
(Baseline 
S tart of 
T reatment 
D ay 
Day 
Day 
2. 3. 
16 
\VLE K 
B aseline) 
Yisir) 
l 
2 
3 
l 
-t 
5 
9 
12 
T aper/S afet)- YisitsP 
±3 
±3 
± 3 
±3 
Yisir \Yin dows 
+ 4 days 
± 1 day 
d ays 
days 
clays 
± 3 days 
days 
± 3 days 
Phone 
P h one 
P hon e 
P h one 
F ollow-
F ollow-
F ollow-
Yisir 
F ollow-
,-isir 
P hone 
,-isir 
Y-I SIT 
Yisi r l" 
,~isit 2° 
u p 
u p 
u p 
3 
up 
-' 
F ollow -up 
5 
,~isit Sa 
Informed Consent" 
X 
Demographics & 
X 
x• 
Medical History 
Inclusion/E.-s:d usion 
X 
X 
Criteria 
Genetic testing 
XC 
)CT 
Seizure Identification 
X 
X 
and D iagnostic 
Review Form 
(Epilepsy Smdy 
Consortium) 
V ital Signs (BP, HR, 
X 
X 
X 
X 
X 
X 
RR, and body 
temperature) 
Height / weight 
Xd 
x• 
x• 
x• 
x• 
Physical/Neurological/ 
X 
X 
X 
X 
X 
D evelopmental Exam' 
ECG 
X 
X 
X 
X 
Clinical Laboratory 
Tests£ 
X 
X 
X 
X 
X 
Urinalysis 
X" 
xg 
X 
X 
X 
Drug Screenh 
X 
X 
X 
Pregnancy Test 
X 
X 
X 
X 
(WCBP)' 


Mruinus Phrumaceuticals, Inc. 
Statistical Analysis Plan 
Table 1 : 
S chedule of A ssessments - Part A 
\YEEK 
VISIT 
Tanner Staging 
IPPK 
Concomitant AE D 
Review and Levels if 
Per Standard of Carel' 
CGI-C - Target 
Behavior 
CGI-I (caregiver) 
CGI-I (clinician) 
C -SSRS (baseline 
form)q 
C -SSRS (since previous 
visit)q 
Dispense GNX0 
Screen/Baseline 
--' 
(Scre ening 
Visit -
Starr ol 
Baseline) 
X 
X 
0 
(Baseline 
Treacmen, 
Yisit) 
+ 4 claYs 
X 
xm 
X 
X 
X 
X 
Day 
I 
P hone 
F ollow-
up 
Day 
Day 
2 
3 
I 
± 3 
± I daY 
da,s 
P hone 
P hone 
F ollow-
F ollow-
'\.-i-tit 
u p 
up 
3 
X 
PartA 
.?, 3:, 
-' 
5 
± 3 
± 3 
daYs 
daT's 
P hone 
F ollon--
'\,-idt 
up 
4 
Xi 
X 
X 
X 
X 
X 
X 
Protocol 1042-TSC-2001 
22MAR2021, Final 1.0 
Tin-arion and l\f ainrenance 
16 
9 
12 
Taper/Safery ,-isitsP 
±3 
± 3 daYs 
d a,s 
± 3 daYs 
Phone 
, -isit 
F ollow-up 
5 
, -isir Sa 
X 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AED = antiepileptic drug, BP= blood pressure, CBD = cannabidiol, CGI-C = Caregiver Global Impression of Change, CGI-I = Clinical G lobal Impression - hnprovement, 
C -SSRS = Columbia-Suicide Severity Rating Scale, DIC = discontinuation, ECG = electrocardiogram, EEG = electroencephalogram, G~X = gana.xolone, HR = heart rate, 
IP - inYcs tigational product, LAR - legally authorized representative, PK - pharmacolcinetic, RR - respiratory rate, THC - tetrahydrocannabinol, 'I.VCBP - w omc,n of 
childbearing potential_ 
Confidential 


Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
Statistical Analysis Plan 
22MAR2021, Final 1.0 
Confidential 
 
 
 
 
T able 1 : 
Sch e clule o f A ssess1nents - P a r t A 
I 
Part A 
Sere-en/Baseline 
Titration and l\I aintenance 
--4 
(Screening 
0 
,-isit -
(Baseline 
Start of 
T reatment 
D ay 
D a y 
D ay 
2,3. 
16 
W EEK 
B aseline) 
Yisit) 
l 
2 
3 
l 
.. 
5 
9 
12 
T aper /Safety YisitsP 
±3 
±3 
± 3 
±3 
Yisit Windows 
+ 4 da~·s 
± I day 
days 
d a ys 
days 
±3 days 
days 
± 3 days 
P h one 
Phone 
Phone 
P hone 
F ollow -
F ollow-
F ollow-
Yisit 
F ollow-
,Tsit 
Phone 
, -isir 
YISIT 
\ ·isitl3 
, ..-i.sic 2° 
up 
u p 
up 
3 
up 
4 
F o llow-up 
5 
,-isif Sa 
a_ 
Patient rescreerung 1s allowed as agreed by the sponsor and the mvest1gator unle ss there is a general concern for patient safety or an inab1hty for the pallent to become 
eligible (e_g_, GNX allergy_ sensitivity or exposure . non-TSC and/or other ineligible epilepsy, c hronic prohibited medical condition or treatment)_ Subsequent screening 
should take place at least 30 days from the patient's last visit_ 
b_ 
\Vritten informed consent/assent must be obtained from patient, parent or LAR before any study assessments are performed_ Pediatric assent should be obtained , if 
appropriate_ 
c_ 
Previous genetic testing re sults will be accepted and reviewed to assess if a pathogenic TSCJ or TSC2 variant is present_ If genetic testing has not previously been 
performed, then a biological sample will be obtained to complete genetic testing at the spo11Sor' s designated lab_ Note : TSC diagnosis does not require pathogenic TSCJ 
or TSC2 n1utations if the clinical criteria are met. 
d_ 
Height and w eight will be measured_ Length will be measured if height cannot be obtained_ 
e _ 
Only w eight will b e measured_ At each visit, dos ing will be reviewed and adjusted as needed based on a patient"s current weight_ 
f_ 
Chemistry and Hematology_ 
g_ 
An attempt s hould be made to collect a urine sample for a urinalysis at sc reening; otherwise,. the urine sample can be collected at baseline for the urinalysis if possible_ 
h _ 
A drug s creen (plasma) will be perfom1ed to test for THC and C B D at screening_ If the screening drug test is positive, the patient can be retested, via plasma, after two 
w eeks_ A positive drug test during the treatment period will result in early termination_ 
i_ 
Serum pregnancy test is required for all girls/women of childbearing potential. 
j_ 
Population PK will be conducted at these visits (Visit 4 : between 1- 5 hours since last IP dosing, Visit S: between 4-8 hours since the last IP dos ing)_ 
k _ 
Concomitant _-1\..EDs oc their dose must~ stable for 1 month prior to screening and cannot be changed at any ti.m..c prior to Visit 4 " but n'l.ay be adjusted during Pa.rt D . 
L 
Caregiver given seizure and medication diary and instructions for use. 
m_ 
During the baseline visit, the investigator and parent/caregiver/LAR will decide on a domain and identify the specific behavior that the patient exhibits that denotes the 
domain_ This behavior will be used at subsequent visits to assess change after the initiation of IP. 
n_ 
Patients w ho discontinue IP early will be encouraged to continue with all procedures and scheduled visits_ 
o_ 
The 4 weeks between Screening Visit and Baseline Treatment Visit c an be no less than 2 8 days and no more than 32 days_ 
P-
Only for patients who do not continue into Part 8- This will occur after 2 weeks of taper and 2 w eeks after comp letion of treatment_ 
q_ 
Only for patients :c". 7 years old if appropriate_ Otherwise clinical judgment will be used_ 
r_ 
Only for patients that w ere Screened without previous genetic testing results and had a genetic test performed at the sponsor' s designated lab_ 
s. 
Review of medical history only_ 
L 
Developmental examination is limited to pediatric patients 2 to 1 7 years of age. inclusive. 


Marinus Pharmaceuticals, Inc. 
Protocol 1042-TSC-2001 
Statistical Analysis Plan 
22MAR2021, Final 1.0 
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10.2 APPENDIX B: SCHEDULE OF ASSESSMENTS PART B 
 
 
 
Tab le 2 : 
S chedule of A ss essm ents - P art B 
Part B 
Final 
Part A 
Yi.sit/ 
Fir s t 
Safe ty 
P a rtB 
O p en-L a b el E xten sio n 
Final OLE Yi.sit or 
Follow-up 
Visit 
(' ·isits ,viii b e ever·y 8 weeks Tii th a teleph o n e follow-up in-between ) 
T ape r V isit 
P os t-ta per 
2 weeks 
pos t last 
·w EEK 
12 
16 
20 
24 
28 
32 
36 or early D /C 
d os e 
V isit "\-Yindows 
± 7 days 
± 7 days 
± 7 day s 
± 7 days 
± 7 days 
± 7 days 
± 3 days 
Yisit 8 ('\leek 3 6) 
Pho n e 
Pho ne 
P hone 
or Y isit X ( ead y 
\'"IS IT 
Y i sit 5 
follow-up 
Y isit 6 
follow-up 
V isit 7 
fo llow-up 
D IC) 
Y is it X 
Confirm patient is «OLE 
X 
eligible" (~ 35% reduction in 
seizure frequency) 
Vital signs (BP. HR, RR. 
X 
X 
X 
X 
X 
and body temperature) 
Weighta 
X 
X 
X 
X 
Physical/Neurological/ 
X 
X 
X 
X 
X 
Developmental Exam 
ECG 
X 
X 
:xd 
Clinical L ab oratory Testsb 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
Drug Screen 
X 
X 
Pregnancy T est ('WCBP)c 
X 
X 
X 
X 
X 
T anner Staging 
:xd 
IPPKe 
X 
X 
X 
X 
X 
Concomitant AED Review 
X 
X 
X 
X 
X 
and lev els if per standard of 
care 


Mruinus Phrumaceuticals, Inc. 
Statistical Analysis Plan 
Table 2: 
S che dule o f A ssessments - Part B 
Final 
P art A 
Visit/ 
First 
P artB 
Open-Lab el Exten sio n 
Part B 
Yisit 
(Visits 1'ill b e eYery 8 weeks 1'ith a teleph o n e follow-up in-betw een) 
'WEEK 
12 
16 
20 
24 
28 
32 
, ·isit Windows 
± 7 d ays 
± 7 d ays 
± 7 d ays 
± 7 days 
± 7 d ays 
CGI-C - Target Beha·vior 
X 
CGI-1 (caregiver) 
X 
CGI-1 (clinician) 
X 
C -SSRS (since last visit 
X 
X 
X 
fonn)f 
D ispense GNX 
X 
X 
X 
Protocol 1042-TSC-2001 
22MAR2021, Final 1.0 
Final OLE Visit 0 1· 
Tape r \'isit 
36 or early D /C 
± 7 days 
Visit 8 (',Ye .. k 36) 
X 
X 
X 
X 
X 
Safe ty 
F ollow-up 
P ost-taper 
2 -wee ks 
post last 
dose 
± 3 d ays 
Y isit X 
X 
X 
AED = antiepileptic drug, BP = blood pressure, CGI- C = Caregiver Global L:npres~-ion of Change, CGI-1 = Clinical Global Lnpression - Improvement, 
C -SSRS = Columbia-Suicide Severity Rating Scal e , D IC = discontinuation, E CG= electrocardiograni, E EG= e lectroencephalogra,:n,. GNX = gana..--..olone, 
HR = hcan rate, IP = invcstigational product. OLE = opcn-labcl extension, PK = phannacokinctic, RR = respiratory rate, WCBP = womcn of childbearing 
potential. 
a. 
Weight will be measured at every visit, except the safety follow-up visit. 
b . 
Chemistry and Hematology. 
c. 
Serum pregnancy test is required for all girls/women of childbearing potential . 
d . 
Conduct at Week 36/Visit 8 or the last open-label extension v--i_sit if prior to Week 36/Visit 8. 
c. 
PK saniplcs can be dra\.vu "vhc:n convcn.ie:nt du.ring tbc study visi ts. 
f. 
Only for patients ~ 7 years· old if appr~priate. Othen~ise clinical jud~ent will be used. 
Confidential