Clinical trial NCT03572933
Conditions: CDKL5 Deficiency Disorder
Keywords: refractory seizures genetic pediatric encephalopathies epilepsy in children seizure disorder
Sponsor: Marinus Pharmaceuticals
Start date: 2018-06-30; Completion date: 2021-05-28
Enrollment: 101 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A clinical study to evaluate the efficacy, safety, and tolerability of adjunctive ganaxolone therapy compared to placebo for the treatment of seizures in children and young adults with genetically confirmed CDKL5 gene mutation.

Detailed description:
The Marigold Study is a global, double-blind, placebo-controlled, Phase 3 clinical trial that will enroll approximately 70 patients between the ages of 2 and 21 with a confirmed disease-related CDKL5 gene variant. Patients will undergo a baseline period before being randomized to receive, in addition to their existing anti-seizure treatment, either ganaxolone or placebo for 17 weeks. Following the treatment period, all patients that meet certain eligibility requirements will have the opportunity to receive ganaxolone in the open label phase of the study. The study's primary efficacy endpoint is percent reduction in seizures. Secondary outcome measures will include non-seizure-related endpoints to capture certain behavioral and sleep disturbances that have been seen in previous clinical studies with ganaxolone.

Arms: arm 1: ganaxolone suspension (50 mg/ml) 3x's /day for 17 weeks arm 2: placebo suspension 3x's /day for 17 weeks
Interventions: intervention 1: ganaxolone intervention 2: Placebo
Intervention descriptions: intervention 1: active drug intervention 2: inactive

Protocol documents:
Prot_002.pdf: 
 
 
 
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PROTOCOL: 1042-CDD-3001 
TITLE: 
A Double-blind, Randomized, Placebo-controlled Trial of Adjunctive 
Ganaxolone Treatment in Children and Young Adults with Cyclin-
dependent Kinase-like 5 (CDKL5) Deficiency Disorder (CDD) Followed by 
Long-term Open-label Treatment 
DRUG: 
Ganaxolone  
IND: 
44,020 
EUDRACT NO.: 
2018-001180-23 
SPONSOR: 
Marinus Pharmaceuticals, Inc. 
5 Radnor Corporate Center 
100 Matsonford Road, Suite 500 
Radnor, PA 19087 USA 
PRINCIPAL/ 
COORDINATING 
INVESTIGATOR: 
PROTOCOL 
HISTORY: 
Original Protocol: 08 Jun 2018, version 1.0 
Global Protocol Amendment 1.0: 05 May 2019 
Global Protocol Amendment 2.0: 26 May 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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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 Safety Reporting Form 
within 24 hours to Marinus Safety Department at:  
Email: safetyCDD3001@marinuspharma.com  
Fax: +1 484-679-2138  
SPONSOR CONTACTS:  
Sponsor Medical Monitor:  
 MD, FAAP 
Mobile Telephone: 
(primary contact method/send text message if no immediate 
response)Email:
 
If sponsor’s Medical Monitor cannot be reached in an emergency, the site should contact: 
 MD 
Office Telephone: +1  484 801 4677  
 
Mobile Telephone:
 
Email:
 
Sponsor Project Managers:  
BS 
Office Telephone: +1 484-801-4686 
Mobile Telephone:
(primary contact method) 
Email:
 
 
 BS 
 
Office Telephone: + 1 484 801 4565 
Mobile Telephone: 
(primary contact method) 
Email:
 
 


 
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CRO CONTACTS:  
 
 
 PhD 
 
Office Telephone: +1 914 223 9460 
Email: 
  
Office Telephone: +1  267 645 3791 
Mobile Telephone:
Email: 
 
Mobile Telephone :
Email: 
 
 
 


 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................................2 
SUMMARY OF CHANGES FROM PREVIOUS VERSION ........................................................3 
EMERGENCY CONTACT INFORMATION ..............................................................................16 
TABLE OF CONTENTS ...............................................................................................................18 
LIST OF TABLES .........................................................................................................................24 
LIST OF FIGURES .......................................................................................................................24 
ABBREVIATIONS .......................................................................................................................25 
STUDY SYNOPSIS ......................................................................................................................29 
1. 
BACKGROUND INFORMATION ...........................................................................49 
1.1. 
Indication and Current Treatment Options .................................................................49 
1.2. 
Product Background and Clinical Information ...........................................................51 
2. 
STUDY OBJECTIVES AND PURPOSE ..................................................................55 
2.1. 
Rationale for the Study ...............................................................................................55 
2.2. 
Study Objectives .........................................................................................................56 
2.2.1. 
Primary Objective .......................................................................................................56 
2.2.2. 
Secondary Objectives .................................................................................................56 
 
 
3. 
STUDY DESIGN .......................................................................................................58 
3.1. 
Study Design and Flow Chart .....................................................................................58 
3.2. 
Duration and Study Completion Definition ................................................................59 
3.3. 
Sites and Regions ........................................................................................................60 
3.4. 
Discussion of Study Design, Including the Choice of Control Group ........................60 
4. 
STUDY POPULATION .............................................................................................62 
4.1. 
Inclusion Criteria ........................................................................................................62 
4.2. 
Exclusion Criteria .......................................................................................................63 
4.3. 
Restrictions .................................................................................................................65 
4.4. 
Reproductive Potential ................................................................................................65 
4.4.1. 
Female Contraception .................................................................................................65 
4.4.2. 
Male Contraception ....................................................................................................66 
4.5. 
Discontinuation of Subjects ........................................................................................66 
4.5.1. 
Subject Withdrawal Criteria .......................................................................................66 


 
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4.5.2. 
Reasons for Early Discontinuation .............................................................................67 
4.5.3. 
Subjects Lost to Follow-up Prior to Last Scheduled Visit .........................................68 
4.6. 
Subject Numbering .....................................................................................................68 
5. 
EXCLUDED, PRIOR, AND CONCOMITANT MEDICATIONS ...........................69 
5.1. 
Prior Medications ........................................................................................................69 
5.2. 
Concomitant Medications ...........................................................................................69 
5.2.1. 
Concomitant AED Medications ..................................................................................69 
5.3. 
Rescue Medications ....................................................................................................70 
5.4. 
Excluded Medications ................................................................................................70 
6. 
INVESTIGATIONAL PRODUCT ............................................................................71 
6.1. 
Identity of Investigational Product .............................................................................71 
6.1.1. 
Blinding the Treatment Assignment ...........................................................................71 
6.2. 
Administration of Investigational Products ................................................................71 
6.2.1. 
Interactive Response Technology for Investigational Product Management .............71 
6.2.2. 
Allocation of Subjects to Treatment ...........................................................................72 
6.2.3. 
Dosing .........................................................................................................................72 
6.2.4. 
Dose Administration ...................................................................................................80 
6.2.5. 
Missing a Dose ...........................................................................................................81 
6.3. 
Unblinding the Treatment Assignment .......................................................................81 
6.4. 
Labeling, Packaging, Storage, and Handling ..............................................................83 
6.4.1. 
Labeling ......................................................................................................................83 
6.4.2. 
Packaging ....................................................................................................................83 
6.4.3. 
Storage ........................................................................................................................83 
6.5. 
Investigational Product Accountability ......................................................................84 
6.6. 
Subject Compliance ....................................................................................................85 
7. 
STUDY PROCEDURES ............................................................................................86 
7.1. 
Study Assessments......................................................................................................86 
7.2. 
Study Procedures (Double-blind Phase) .....................................................................86 
7.2.1. 
Screening Period .........................................................................................................86 
7.2.1.1. 
Historical Seizure Type and Frequency (Week -14) ..................................................86 
7.2.1.2. 
Screening (Visit 1, Week -6) ......................................................................................86 
7.2.1.3. 
Baseline (Visit 2, Week 0 + 6 days, Randomization) .................................................87 


 
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7.2.2. 
Titration + Maintenance (3 Days, Weeks 1, 2, 3, 4, 5, 9, and 13) ..............................88 
7.2.2.1. 
Telephone Follow-up (Day 3 ± 2 days and Weeks 1, 2, 3, and 4 ± 3 days) ...............88 
7.2.2.2. 
Titration + Maintenance (Visits 3 and 4, Weeks 5 ± 3 days and 9± 3 days) ..............88 
7.2.2.3. 
Telephone Follow-up Visit (Weeks 11, 13 ± 3 days) .................................................89 
7.2.3. 
Final Double-blind Visit /First Open-label Visit (Visit 5, Week 17 ± 3 days) ...........89 
7.2.4. 
Telephone Follow-up (3 days after Visit 5 ± 1 day, Weeks 18 and 20 ± 3 
days) ............................................................................................................................90 
7.2.5. 
Open-Label Blinded Titration (Visit 6, Week 19 ± 3 days) .......................................90 
7.2.5.1. 
Open-Label Blinded Titration (Visit 7, Week 21 ± 3 days) .......................................90 
7.2.6. 
Open-Label Maintenance (Weeks 28-68; ± 7 days window for each visit) ...............91 
7.2.6.1. 
Telephone Follow-up (Weeks 28, 43 and 60; ± 7 days window for each visit) .........91 
7.2.6.2. 
Open-Label Maintenance (Visits 8, 9, and 10, Weeks 34, 52 and 68; ± 7 days 
window for each visit) ................................................................................................91 
7.2.6.3. 
Visit X - Additional Maintenance Visits in the Open-Label Phase (every 
16 weeks with a telephone follow-up in between ± 7 days window for each 
visit) ............................................................................................................................92 
7.2.7. 
Final Open-Label Visit or Taper Visit; ± 7 days (or at time of Early 
Termination) ...............................................................................................................93 
7.2.8. 
Safety Follow-up Post-taper (2 Weeks; ± 3 days Post Investigational Product 
Taper) ..........................................................................................................................94 
7.3. 
Screening and Diagnosis .............................................................................................94 
7.3.1. 
Informed Consent .......................................................................................................94 
7.3.2. 
Drug Screen ................................................................................................................94 
7.3.3. 
Demographics and Medical History ...........................................................................95 
7.3.4. 
Historical Seizure Calendar Review ...........................................................................95 
7.3.5. 
Genetic Testing ...........................................................................................................95 
7.3.6. 
Seizure Identification and Diagnostic Review ...........................................................96 
7.4. 
Efficacy Assessments .................................................................................................96 
7.4.1. 
Seizure Type and Frequency ......................................................................................96 
7.4.2. 
Caregiver Global Impression of Change in Seizure Intensity/ Duration (CGI-
CSID) ..........................................................................................................................97 
7.4.3. 
Caregiver Global Impression of Change in Attention (CGICA) ................................97 
7.4.4. 
Caregiver Global Impression of Change (CGI-C– target behavior) ...........................97 
7.4.5. 
Clinical Global Impression of Improvement (CGI-I) .................................................98 


 
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7.6. 
Safety Assessments .....................................................................................................99 
7.6.1. 
Adverse Events ...........................................................................................................99 
7.6.2. 
Vital Signs ..................................................................................................................99 
7.6.3. 
Physical/Neurological/Developmental Examinations ..............................................100 
7.6.4. 
ECG ..........................................................................................................................101 
7.6.5. 
Clinical Laboratory Tests .........................................................................................101 
7.6.6. 
Tanner Staging ..........................................................................................................102 
7.6.7. 
Investigational Product PK .......................................................................................102 
7.6.8. 
Concomitant AED levels ..........................................................................................102 
7.6.9. 
Neurosteroid levels ...................................................................................................102 
7.6.10. 
Adverse Events .........................................................................................................102 
7.7. 
Pharmacokinetic Assessments ..................................................................................103 
8. 
ADVERSE AND SERIOUS ADVERSE EVENT ASSESSMENTS ......................104 
8.1. 
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events .......................................................................................................................104 
8.1.1. 
Severity Categorization ............................................................................................104 
8.1.2. 
Relationship Categorization ......................................................................................105 
8.1.3. 
Outcome Categorization ...........................................................................................105 
8.1.4. 
Symptoms of the Disease Under Study ....................................................................105 
8.1.5. 
Clinical Laboratory and Other Safety Evaluations ...................................................106 
8.1.6. 
Pregnancy .................................................................................................................106 
8.1.7. 
Abuse, Misuse, Overdose, and Medication Error .....................................................107 
8.2. 
Serious Adverse Event Procedures ...........................................................................107 
8.2.1. 
Reference Safety Information ...................................................................................107 
8.2.2. 
Reporting Procedures ................................................................................................107 
8.2.3. 
Serious Adverse Event Definition ............................................................................108 


 
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8.2.4. 
Serious Adverse Event Collection Time Frame .......................................................108 
8.2.5. 
Serious Adverse Event Onset and Resolution Dates ................................................109 
8.2.6. 
Fatal Outcome ...........................................................................................................109 
8.2.7. 
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting ..................................................................................................................109 
8.3. 
Adverse Events of Special Interest ...........................................................................109 
8.3.1. 
Reference Safety Information ...................................................................................109 
9. 
DATA MANAGEMENT AND STATISTICAL METHODS .................................110 
9.1. 
Data Collection .........................................................................................................110 
9.2. 
Clinical Data Management .......................................................................................110 
9.3. 
Statistical Analysis Process ......................................................................................110 
9.4. 
Data Monitoring Committee .....................................................................................111 
9.5. 
Sample Size Calculation and Power Considerations ................................................111 
9.6. 
Study Population .......................................................................................................111 
9.7. 
Efficacy Analyses .....................................................................................................112 
9.7.1. 
Primary Efficacy Endpoint .......................................................................................112 
9.7.2. 
Key Secondary Efficacy Endpoints ..........................................................................112 
9.7.3. 
Secondary Efficacy Endpoints ..................................................................................112 
9.7.3.1. 
Secondary Efficacy: Seizure control ........................................................................113 
9.7.3.2. 
Secondary Efficacy: Behavioral/Neuropsychiatric ...................................................113 
 
 
9.7.5. 
Subgroup Analyses ...................................................................................................114 
9.7.6. 
Analysis of Weeks 5 and 9 .......................................................................................114 
9.7.7. 
Sensitivity Analyses ..................................................................................................115 
9.7.8. 
Open-Label Analyses ................................................................................................115 
9.8. 
Safety Analyses ........................................................................................................115 
9.9. 
Other Analyses ..........................................................................................................116 
9.10. 
Pharmacokinetic Analyses ........................................................................................116 
9.11. 
Interim Analysis ........................................................................................................117 
10. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES .............................118 
10.1. 
Sponsor’s Responsibilities ........................................................................................118 
10.1.1. 
Good Clinical Practice (GCP) Compliance ..............................................................118 


 
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10.1.2. 
Public Posting of Study Information ........................................................................118 
10.1.3. 
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees .............................................118 
10.1.4. 
Study Suspension, Termination, and Completion ....................................................118 
10.2. 
Investigator’s Responsibilities ..................................................................................119 
10.2.1. 
Good Clinical Practice Compliance..........................................................................119 
10.2.2. 
Protocol Adherence and Investigator Agreement .....................................................119 
10.2.3. 
Documentation and Retention of Records ................................................................119 
10.2.3.1. 
Electronic Case Report Forms (eCRF) .....................................................................119 
10.2.3.2. 
Electronic Seizure Diaries (eDiary) ..........................................................................120 
10.2.3.3. 
Recording, Access, and Retention of Source Data and Study Documents ...............120 
10.2.3.4. 
Audit/Inspection .......................................................................................................121 
10.2.3.5. 
Financial Disclosure .................................................................................................121 
10.3. 
Ethical Considerations ..............................................................................................121 
10.3.1. 
Informed Consent .....................................................................................................121 
10.3.2. 
Institutional Review Board or Ethics Committee .....................................................122 
10.4. 
Privacy and Confidentiality ......................................................................................122 
10.5. 
Study Results/Publication Policy ..............................................................................123 
11. 
REFERENCES .........................................................................................................125 
12. 
APPENDICES ..........................................................................................................127 
12.1. 
Appendix 1:  CYP3A4/5/7 Inhibitors and Inducers .................................................127 
12.2. 
Appendix 2:  Clinical Laboratory Tests ....................................................................128 
12.3. 
Appendix 3:  Dosing Instructions for Oral Suspension ............................................129 
12.4. 
Appendix 4:  Caregiver Global Impression of Change in Attention (CGICA) ........135 
12.5. 
Appendix 5:  Caregiver Global Impression of Change (CGI-C) – Target 
Behavior ....................................................................................................................136 
12.6. 
Appendix 6:  Caregiver Global Impression of Change in Seizure 
Intensity/Duration (CGI-CSID) ................................................................................137 
12.7. 
Appendix 7:  Clinical Global Impression - Improvement (CGI-I) ...........................138 
12.8. 
Appendix 8:  Children’s Sleep Habit Questionnaire (CSHQ) ..................................140 
12.9. 
Appendix 9:  Anxiety, Depression, and Mood Scale (ADAMS) - Baseline ............142 
12.10. 
Appendix 10:  Anxiety, Depression, and Mood Scale (ADAMS) – Post 
Baseline Visits ..........................................................................................................143 


 
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12.11. 
Appendix 11:  Quality of Life Inventory – Disability (QI-Disability) .....................144 
12.12. 
Appendix 12:  Parenting Stress Index (PSI) .............................................................149 
LIST OF TABLES 
Table 1: 
Schedule of Assessment for the 17-week, Double-blind Treatment Phase of 
the Study .....................................................................................................................41 
Table 2: 
Schedule of Assessments for Open-Label Phase ........................................................45 
Table 3: 
Certain Pediatric Epilepsies with Encephalopathy .....................................................50 
Table 4: 
Oral Suspension (50 mg/ml) Dosing for Subjects Weighing ≤ 28 kg ........................72 
Table 5: 
Oral Suspension (50 mg/ml) Dosing for Subjects Weighing > 28 kg ........................73 
Table 6: 
Transition from Double-blind to Open-label: Oral Suspension (50 mg/ml) 
Dosing for Subjects ≤ 28 kg .......................................................................................74 
Table 7: 
Example of Double-blind to Open-label: DB GNX Subject Weighing 20 kg- 
Suspension Dosing (50 mg/ml) ..................................................................................75 
Table 8: 
Example of Double-blind to Open-label: Placebo Subject Weighing 20 kg- 
Suspension Dosing (50 mg/ml) ..................................................................................76 
Table 9: 
Transition from Double-blind to Open-label: Suspension (50 mg/ml) Dosing 
for Subjects > 28 kg ....................................................................................................77 
Table 10: Example of Double-blind to Open-label: DB GNX Subject Weighing > 28 - 
Suspension Dosing (50 mg/ml) ..................................................................................78 
Table 11: Example of Double-blind to Open-label: Placebo Subject Weighing > 28 kg- 
Suspension Dosing (50 mg/ml) ..................................................................................79 
Table 12: De-Escalation of Investigational Product ...................................................................80 
Table 13: Missed Dose of Investigational Product .....................................................................81 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................59 
 


 
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ABBREVIATIONS 
Term 
Definition 
ACTH 
Adrenocorticotropic hormone 
ADAMS 
Anxiety, Depression, and Mood Scale 
AE 
adverse event 
AED 
antiepileptic drug 
ANOVA 
analysis of variance 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUCt 
area under the concentration versus time curve from 
time 0 to t hours  
AUC∞  
area under the concentration versus time curve from 
time 0 to infinity  
β-HCG 
β-human chorionic growth hormone 
BID 
twice daily 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CBD 
cannabidiol 
CDD 
cyclin-dependent kinase-like 5 (CDKL5) deficiency 
disorder 
CDKL5 
cyclin-dependent kinase-like 5 
CGI-I 
Clinical Global Impression Improvement 
CGI-C 
Caregiver Global Impression of Change  
CGICA 
Caregiver Global Impression of Change in Attention 
CGI-CSID 
Caregiver Global Impression of Change in Seizure 
Intensity/Duration 
CL 
clearance 
Cmax  
maximum plasma concentration 
CNS 
central nervous system 
CRA 
clinical research associate 
CRO 
clinical research organization 


 
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Term 
Definition 
CSHQ 
Children’s Sleep Habit Questionnaire 
CSWS 
continuous spikes and waves during sleep 
CYP 3A4 
cytochrome P450 3A4 
DB 
double-blind 
DMC 
Data Monitoring Committee 
eCRF 
electronic case report form 
EC 
ethics committee 
ECG 
electrocardiogram 
eDiary 
electronic seizure diary 
EEG 
electroencephalogram 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
Food and Drug Administration 
FXS 
Fragile X Syndrome 
GABA 
γ-Aminobutyric acid 
GABAA 
γ-Aminobutyric acid type A 
GCP 
Good Clinical Practice 
GGT 
Gamma-gamma transferase 
GNX 
ganaxolone 
HDPE 
high-density polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
IRB 
institutional review board 
IS 
infantile spasms 
ITT 
Intent-to-Treat Population 
IWRS 
interactive web response system 


 
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Term 
Definition 
LAR 
legally authorized representative 
LGS 
Lennox Gastaut syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
Maximum Tolerated Dose 
OL 
open-label 
PBO 
placebo 
PCDH19 
protocadherin 19 
PI 
principal investigator 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
PRN 
as needed 
PSI 
Parenting Stress Index 
PTSD 
post-traumatic stress disorder 
PTZ 
pentylenetetrazol 
QI-Disability 
Quality of Life Inventory-Disability 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SIF/DRF 
Seizure Identification and Diagnostic Review Form  
SOC 
standard of care 
TEAE 
Treatment-emergent adverse event 
THC 
tetrahydrocannabinol 
TID 
three times daily 
tmax  
time of maximum concentration 
ULN 
upper limit of normal 
UK 
United Kingdom 
US 
United States 


 
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Term 
Definition 
VAS 
Visual Analog Scale 
VNS 
Vagus nerve stimulator 
VUS 
variant of unknown significance 
WCBP 
women of childbearing potential 




 
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development, (Fuchs et al., 2014) and helps regulate expression of genes involved in synaptic function, structure, 
and plasticity (Carouge et al., 2010; Kameshita et al., 2008).  
Cyclin-dependent kinase-like 5 deficiency disorder is characterized by early onset intractable seizures, severe 
developmental delay, disturbed sleep and severe intellectual/gross motor impairment (Bahi-Buisson et al., 2008).  
Typically, the seizures are resistant to conventional antiepileptic medication.  Treatment-resistant epilepsy can be 
fatal and patients are often treated with high doses of multiple antiepileptic drugs (AEDs) that worsen the 
cognitive, behavioral and physical consequences of the underlying disorder.  Together, these children and young 
adults experience major impairments to quality-of life.  Any therapy that can reduce the frequency, duration or 
severity of seizures can positively impact quality of life for the child and family (Müller et al., 2016).  
Ganaxolone is the 3β-methylated synthetic analog of allopregnanolone, an endogenous allosteric modulator of 
CNS γ-Aminobutyric acid type A (GABAA) receptors. Ganaxolone has potency and efficacy comparable to 
allopregnanolone (Carter et al., 1997) in activating synaptic and extrasynaptic GABAA receptors at a site distinct 
from benzodiazepines.  GNX has protective activity in diverse rodent seizure models (Reddy and Rogwski, 2012; 
Bialer et al., 2010).  Clinical studies have demonstrated GNX has anticonvulsant activity with an acceptable 
safety and tolerability profile in the dose range of 900 to 1800 mg per day in adults and children (Sperling et al., 
2017; Laxer et al., 2000; Kerrigan et al., 2000; Pieribone et al., 2007).  Further, GNX reduces seizures in children 
with infantile spasms (IS) and refractory pediatric epilepsy.  In an open-label study, pediatric subjects aged 2 to 
60 months with refractory seizures and a history of IS were treated with GNX doses up to 36 mg/kg for up to 3 
months (Kerrigan et al., 2000).  Sixteen of the 20 subjects completed treatment, 15 of whom had a history of IS.  
Five of the 15 subjects had a decrease from baseline in the number of spasms of ≥ 50%, 5 had a decrease of 25 to 
50%, and 5 had a decrease of < 25%.  One subject became spasm free and 1 non-responder (with a decrease of 
<25%) was spasm-free from weeks 2 to 7.  
An anticonvulsant treatment effect signal of GNX in CDD has emerged from an ongoing open-label flexible-dose 
exploratory study (1042-0900) of GNX in children (age range 2-15 years) with rare genetic epilepsies (including 
CDKL5) with uncontrolled seizures despite multiple AED regimens (ClinicalTrials.gov Identifier: 
NCT02358538).  Following the screening and baseline evaluations, consenting subjects enrolled into a 26-week 
study during which investigators were allowed to dose GNX flexibly up to 1,800 mg/day for subjects whose body 
weight was > 30 kg or up to 63 mg/kg /day for subjects whose body-weight was < 30 kg.  The primary efficacy 
measure was the percent change from baseline in the 28-day seizure frequency count.  Safety and tolerability 
assessments were among the secondary objectives.  The median change in 28-day seizure frequency from 
baseline in the intent-to-treat (ITT) population (primary endpoint) was a decrease of 48% (n=7).  The median 
change from baseline in seizure-free days in the ITT population (key secondary endpoint) was an increase of 78% 
(n=5; 2 subjects could not be calculated due to 0 baseline seizure-free days).  The Clinical Global Impression- 
Improvement Scale scores rated by investigators and caregivers were consistent with seizure control for all the 
children.  Children with a 43% or higher seizure reduction were rated as “much improved” or “very much 
improved” by the investigators and caregivers.  Investigators and caregivers reported improvements in attention, 
mood, behavior and sleep via investigator narratives.  Ganaxolone was generally safe and well tolerated with no 
serious adverse events (SAEs).  To date, there have been no adverse event (AE) reports of somnolence or 
dizziness in the CDKL5 population. The safety and tolerability profile in these subjects was similar to earlier 
studies. 
In addition to anticonvulsant activity, GNX has shown positive effects on anxiety, hyperactivity, and attention in 
children with fragile X syndrome (Ligsay et al., 2016).  Similar behavior problems occur in children with CDKL5 
mutations.  
It is hypothesized that GNX treatment will increase and improve GABAA mediated signaling by boosting the 
signaling capacity of existing receptors and improve not only seizure control, but also other behavioral 
abnormalities in children with the CDKL5 mutation.  
Methodology:  This is a global, double-blind, randomized, PBO-controlled trial of adjunctive GNX treatment in 
children and young adults with CDD.  The trial consists of a 6-week prospective baseline period to collect seizure 
data, followed by a 17-week double-blind treatment phase, which is then followed by a long-term open-label 
phase.  


 
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If available, a 2-month (8-week) daily historical seizure calendar will be reviewed at the screening visit to 
determine eligibility per inclusion/exclusion criteria.  Acceptable historical seizure data must include seizure 
type, frequency, and denote seizure free days, with the historical seizure calendar starting at Week -14 (8-week 
historical + 6-week prospective = 14 weeks).  Procedures specific to this protocol and not otherwise considered 
standard of care, will not be performed until written informed consent from the subject’s parent or legally 
authorized representative (LAR) and/or subject assent has been appropriately obtained.  In the event that 
parent/caregiver/LAR do not routinely maintain a daily seizure calendar per standard of care, written informed 
consent will be obtained from the parent/LAR and/or subject assent, and the subject will be asked to return to the 
clinic for the screening visit after they have maintained a 2-month (8 week) daily historical seizure calendar.   
The double-blind phase includes 6 weeks prospective baseline, 4 weeks of titration followed by 13 weeks of dose 
maintenance.  After meeting the eligibility criteria, approximately 100 children and young adults aged 2-21 years 
(inclusive) with CDD will be randomly assigned to receive GNX or PBO (1:1 ratio) for 17 weeks in addition to 
their standard anti-seizure treatment.  Participants will be titrated to 63 mg/kg/day (max 1800 mg/day) over 4 
weeks, and then maintained at that dose for another 13 weeks.  Subjects who are not able to tolerate 63 mg/kg/day 
(or 1800 mg/day maximum) may be maintained on a lower dose after discussion with the sponsor.  A minimum 
dose of 33 mg/kg/day or 900 mg/day is generally required during the double-blind phase unless a lower dose is 
agreed to with the sponsor.   
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.  The higher dose in the evening is expected to be better tolerated due to proximity to bedtime. 
However, tolerability management and the final decision to adjust drug dosages lies with the principal 
investigator. For any subject who is unable to be maintained at the minimum dose, the investigator should contact 
the sponsor to discuss continued investigational product dosing.  Subjects who discontinue investigational 
product should undergo a 2-week taper period, unless otherwise medically indicated.  Subjects who discontinue 
investigational product treatment before the completion of the double-blind phase will continue to be followed 
per protocol and at minimum maintain daily seizure electronic seizure diary (eDiary) entry until the double-blind 
phase is completed.  These subjects will also return to the site 2 weeks after the taper for safety follow-up 
assessments. 
After completing the initial 17-week, double-blind, PBO-controlled phase, all subjects will be treated with GNX 
in the open-label phase of the study.  Ganaxolone subjects will continue GNX treatment and PBO subjects will 
titrate onto GNX.  To maintain the blind, subjects initially randomized to GNX will undergo a false titration 
(increasing PBO doses) for 4 weeks, while PBO subjects will titrate up to 63 mg/kg/day GNX (1800 mg/day 
maximum) during the same time period.  An interactive web response system (IWRS) will be used to randomize 
subjects, dispense drug, track treatment, and maintain the blind throughout the duration of the study.  Any 
participant who discontinues from the open-label portion of the study will undergo a 2-week taper and return to 
the site 2 weeks later for safety follow-up assessments.  
 
Participants will be required to complete an eDiary to determine GNX’s effect on seizures.  A variety of clinician 


 
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and caregiver administered instruments will be used to assess the efficacy of GNX in CDKL5, and include:  
Caregiver Global Impression of Change in Attention (CGICA), Caregiver Global Impression of Change (CGI-C) 
in parent/caregiver identified behavioral target- potential domains of sociability, communication, irritability, and 
hyperactivity, Clinical Global Impression of Improvement (CGI-I) by parent/caregiver and clinician, Caregiver 
Global Impression of Change in Seizure Intensity/Duration (CGI-CSID), Children’s Sleep Habit Questionnaire 
(CSHQ), ADAMS, QI-Disability and PSI.  
Inclusion and Exclusion criteria:  
 
Inclusion Criteria:  
1. (a) Molecular confirmation of a pathogenic or likely pathogenic CDKL5 variant, early onset, difficult to 
control seizures, and neurodevelopmental impairment are required.  The principal investigator (PI) must 
review the results of the genetic analysis and confirm that gene mutation is likely to be the cause of the 
epilepsy syndrome.  If the subject has a de novo variant of unknown significance (VUS) in the kinase 
domain of the CDKL5, parental testing is negative and meets all other inclusion criteria, then the subject 
can be included.    Genetic mutations will be confirmed by the sponsor’s chosen central laboratory.  In 
France, genetic mutations may be confirmed by an approved French organization, in compliance with 
French legislation prior to Screening Visit 1. Subjects must have (b) seizure onset by 1 year of age and 
(c) lack of independent ambulation by 2 years of age. 
2. Male or female subjects aged 2 through 21 years, inclusive. 
3. Subject/parent or LAR willing to give written informed consent/assent, after being properly informed of 
the nature and risks of the study and prior to engaging in any study-related procedures. 
4. Failure to control seizures despite appropriate trial of 2 or more anti-seizure mediations at therapeutic 
doses. 
5. Have at least 16 seizures of primary seizure types: bilateral tonic (sustained motor activity ≥ 3 seconds), 
generalized tonic-clonic, atonic/drop, bilateral clonic or focal to bilateral tonic-clonic per 28 days in each 
1-month period in the 2-month period prior to screening.   
6. Subject must be approved to participate by sponsor and/or designee (i.e., Epilepsy Consortium) after 
review of medical history, genetic testing, seizure classification, and historical seizure calendars. 
7. Participants should be on a stable regimen of 0-4 anti-seizure medications (including moderate or strong 
inducer or inhibitor anti-seizure medications e.g. carbamazepine, phenytoin, etc.) for ≥ 1 month prior to 
the screening visit, without a foreseeable change in dosing for the duration of the double-blind phase.  
Vagus nerve stimulator (VNS), ketogenic diet, and modified Atkins diet do not count towards this limit 
but must be unchanged for 3 months prior to screening. 
8. Subjects 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 double-blind phase. 
c. 
The battery is expected to last for the duration of the double-blind phase. 
9. Felbamate: The use of felbamate is allowed provided that the subject has been maintained on a stable 
dose of felbamate for > 6 months and has had stable liver function (aspartate aminotransferase [AST] 
and alanine aminotransferase [ALT]) and hematology during the course of treatment and is expected to 
remain constant throughout the double-blind phase. 
10. Parent/caregiver is able and willing to maintain an accurate and complete daily electronic seizure 
calendar for the duration of the study. 
11. Able and willing to take investigational product with food 3 times daily.  Ganaxolone must be 
administered with food. 
12. 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 screening, surgical sterilization, or adequate barrier 
methods (e.g., diaphragm and foam).  An oral contraceptive alone is not considered adequate for the 


 
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purpose of this study. Hormonal oral contraceptives must also be used when a condom is used.  In 
subjects who are not sexually active, abstinence is an acceptable form.  
Exclusion Criteria:  
1. Previous exposure to GNX. 
2. Pregnant or breastfeeding. 
3. West Syndrome with hypsarrhythmia pattern on EEG or seizures predominantly of Infantile Spasms (IS) 
type; if EEG pattern/seizure type is uncertain, study inclusion should be reviewed and determined by the 
sponsor/sponsor delegate. 
4. Concurrent use of adrenocorticotropic hormone (ACTH), prednisone or other glucocorticoid is not 
permitted, nor use of moderate or strong inducers or inhibitors of CYP3A4/5/7. A list of CYP3A4/5/7 
inhibitors and inducers is included in Section 12.1.  Moderate or strong inducer or inhibitor anti-epileptic 
drugs will be allowed (e.g., carbamazepine, phenytoin, etc.) 
5. Subjects on ACTH, prednisone or other systemically (non-inhaled) administered steroids should be off 
the product greater than 28 days prior to screening.  Concomitant PRN topical or intranasal steroids for 
dermatologic reactions and allergic rhinitis are allowed and do not warrant exclusion from the study. 
6. Subjects with a positive result on tetrahydrocannabinol (THC) or cannabidiol (CBD) test (via urine or 
plasma drug screen) at the screening visit, and a positive result on THC or CBD test (via plasma) at the 
baseline visit without prescription for Epidiolex (may go by another name in countries outside the 
United States) in epilepsy will be excluded from the study.  Concomitant Epidiolex (CBD) use will be 
allowed in the double-blind phase provided the subject has been on a stable dose for at least 1 month 
prior to screening and is expected to remain on a stable dose without a foreseeable change for the 
duration of the double-blind phase.  THC and/or CBD will be allowed in the open-label phase.   
7. Use of dietary supplements or herbal preparations are not permitted if subject has been using them 
consistently for less than 3 months prior to screening or does not plan on remaining on stable doses for 
the duration of the double-blind phase. Use of St. John’s Wort is not permitted (See Section 12.1). 
8. Changes in anti-epileptic drugs (AEDs) within the last month prior to screening. All AEDs must be 
stable in dose for at least 1-month prior to screening unless otherwise noted.  
9. Have an active CNS infection, demyelinating disease, degenerative neurological disease, or CNS disease 
deemed progressive as evaluated by brain imaging (magnetic resonance imaging [MRI]).  
10. Have any disease or condition (medical or surgical; other than CDKL5) at screening that might 
compromise the hematologic, cardiovascular, pulmonary, renal, gastrointestinal, or hepatic systems; or 
other conditions that might interfere with the absorption, distribution, metabolism, or excretion of the 
investigational product, or would place the subject at increased risk.  
11. An AST (serum glutamic oxaloacetic transaminase [SGOT]) or ALT (serum glutamic pyruvic 
transaminase [SGPT]) greater than 3 times the upper limit of normal (ULN) at study entry.  If AST or 
ALT increases > 3 times ULN during the study, subject should be followed with weekly laboratory 
repeat testing and continue in study if levels trending down.  Subject will be discontinued if levels do not 
decline to under 3 x ULN.  
12. Total bilirubin levels greater than ULN at study entry. In cases of documented, stable medical condition 
(i.e., Gilbert’s Syndrome) resulting in levels of total bilirubin greater than ULN, the medical monitor can 
determine if a protocol exception can be made.  If total bilirubin increases to 1.5 x ULN or more during 
study, the subject will be discontinued.  
13. Subjects with significant renal insufficiency, estimated glomerular filtration rate (eGFR) < 30 mL/min 
(calculated using the Cockcroft-Gault formula or Pediatric GFR calculator or Bedside Schwartz), will be 
excluded from study entry or will be discontinued if the criterion is met post baseline. 
14. Have been exposed to any other investigational drug within 30 days or less than 5 half-lives prior to 
screening.  
15. Unwillingness to withhold grapefruit, Seville oranges or star fruit from diet during the entire clinical 
trial.  
16. Unwillingness to withhold alcohol throughout the entire clinical trial. 
17. Have active suicidal plan/intent or have had active suicidal thoughts in the past 6 months or a suicide 
attempt in the past 3 years.  
18. Known sensitivity or allergy to any component in the investigational product(s), progesterone or other 
related steroid compounds. 


 
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19. Plasma allopregnanolone – sulfate (Allo-S) levels ≥ 6.0 ng/ml at the screening visit. 
Number of subjects:  A sufficient number of subjects will be screened to enroll 100 children and young adults 
aged 2-21 years (inclusive) with CDD 
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 (1800 mg/day maximum) given as an oral suspension (50 mg/mL) with food.  
Subjects ≤ 28 kg will be dosed on an mg/kg basis.  Ganaxolone is to be administered with food during the 4-week 
titration period of the double-blind phase of the study as follows: 
Oral Suspension (50 mg/ml) Dosing for Subjects Weighing ≤ 28 kg 
Dose 
Total mg/kg/day 
Days 
6 mg/kg TID 
18 
1-7 
11 mg/kg TID 
33 
8-14 
16 mg/kg TID 
48 
15-21 
21 mg/kg TID 
63 
22-28 
TID = three times daily 
 
Oral Suspension (50 mg/ml) Dosing for Subjects Weighing > 28 kg 
Dose 
ml per Dose 
Total mg/day 
Days 
150 mg TID 
3 
450 
1-7 
300 mg TID 
6 
900 
8-14 
450 mg TID 
9 
1350 
15-21 
600 mg TID 
12 
1800 
22-28 
TID = three times daily 
Any subject 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 subject can drop back to the next lower dose 
step.  A minimum dose of 33 mg/kg/day and 900 mg/day is generally required during the double-blind phase 
unless a lower dose is agreed to with the Sponsor.  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. The higher dose in the evening is 
expected to be better tolerated due to proximity to bedtime. However, tolerability management and the final 
decision to adjust drug dosages lies with the principal investigator. Any subject who is unable to be maintained at 
the minimum dose should contact the sponsor to discuss continued investigational product dosing.  Subjects who 
discontinue investigational product treatment before the completion of the double-blind phase will continue to be 
followed per protocol and at minimum maintain daily seizure eDiary entry until the double-blind phase is 
completed.  These subjects will also return to the site 2 weeks after the taper for safety follow-up assessments. 
During the open-label phase, all subjects will be treated with GNX.  Subjects will receive the same GNX dose 
given in the 17-week double-blind phase in the open-label phase of the study.  However, to maintain the study 
blind, GNX subjects will enter into a 4-week false titration phase by increasing PBO doses in addition to 
maintaining GNX.  Subjects who received PBO in the 17-week double-blind phase will enter a 4-week, GNX 
titration period in the open-label phase of the study.  
Reference Therapy, Dose and Mode of Administration:  PBO is to be administered as an oral suspension with 
food during the 4-week, titration period of the double-blind phase of the study as follows: 






 
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(hematology, chemistry and urinalysis), physical, neurological, and developmental examinations, and frequency, 
type, and severity of AEs during the 17-week, double-blind phase and the open-label phase. 
Statistical Methods:  
The safety and ITT populations comprise all randomized subjects who received at least one dose of 
investigational product. In addition to being the population for safety and ITT analyses, it is the primary 
population for the efficacy analyses and for the neurosteroid level analyses. The Per-Protocol (PP) population 
includes all ITT subjects who received study drug for at least 6 weeks, provided 
at least 5 weeks of post-baseline seizure data, and without major protocol violations (defined prior to database 
lock). There will be no PP population for the open-label phase of the study. The primary analysis is in the ITT 
population; a supportive analysis in the PP population will also be conducted. 
All endpoints will be assessed descriptively, by the double-blind treatment to which the subjects are randomized, 
with point estimates and 95% confidence intervals. Only the primary endpoint will be assessed in an inferential 
manner since it is unlikely the trial will be powered to achieve statistical significance regarding effects on these 
measures 
The results of the primary, secondary and exploratory endpoints in the double-blind and open-label phases will be 
summarized separately. In both phases, the results will be summarized by the double-blind treatment to which the 
subjects were randomized and, for the open-label phase of the study, combined over the treatment groups.  Subject 
demographics, characteristics, and medical history at randomization will be summarized using descriptive statistics. 
Primary Endpoint: Definition and Analysis: 
The primary efficacy endpoint is the percent change in 28-day primary seizure frequency at the end of the 17-
week double-blind treatment phase relative to the baseline, based on the primary seizure types including bilateral 
tonic (sustained motor activity ≥ 3 seconds), generalized tonic-clonic, bilateral clonic, atonic/drop seizures and 
focal to bilateral tonic-clonic).  
 
Post-baseline 28-day seizure frequency will be calculated as the total number of seizures in the 17-week double-
blind treatment phase divided by the number of days with seizure data in the period, multiplied by 28. Baseline 
28-day seizure frequency will be calculated as the total number of seizures in the baseline period divided by the 
number of days with seizure data in the period, multiplied by 28. The calculation for percent change from 
baseline in 28-day seizure frequency will be done as follows for each subject: 
 
 
The baseline, post-baseline, and arithmetic and percent changes from baseline in 28-day seizure frequency will be 
summarized using descriptive statistics.  
The difference between the treatment groups in the percent changes will be tested for statistical significance.  Since 
the percent differences are anticipated to display skewness and/or outliers, the test will be performed using the 
Wilcoxon Rank-Sum statistic using a 2-sided significance level of 0.05.  
Three sensitivity analyses of the primary efficacy endpoint will be performed for subjects who stop recording 
their seizure counts (1) To examine the primary outcome measure when a subject stops recording measurements 
permanently prior to the end of the 17-week DB phase using the imputation approach outlined in the Statistical 
Analysis Plan (SAP), (2) to explore the possibility that subjects who stop recording seizure counts tend to have 
higher seizure counts than other subjects, and  (3) To examine  the effect of GNX compared to PBO among 
subjects with low Allo-S levels. 
 
Sample Size: 
Based on data from the 7 subjects in Study 1042-0900 evaluating GNX in CDKL5 patients, the standard 
deviation for the percent change in 28-day seizure frequency for seizure types tonic (sustained motor activity ≥ 3 
seconds), tonic-clonic, atonic/drop, epileptic spasms, or clonic (generalized or unilateral) is estimated to be 44.5.  




 
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 
The only sensitivity analysis to be performed is the analysis of the primary endpoint among subjects 
with low plasma allopregnanolone sulfate (Allo-S) levels. 
 
The seizure frequencies during the titration and maintenance phases will not be Analyzed separately 
 
The time points for the efficacy, exploratory, and quality of life endpoints will be at Weeks 21, 34, 52, 
and every 16 weeks thereafter of open-label treatment relative to the 6-week prospective baseline phase. 
For the seizure endpoints, this corresponds to the first 4, 17, 35, 51, etc. weeks from the start of the 
open-label phase 
 
The differences between the double-blind treatment groups in the percent changes from baseline of the 
28-day seizure frequencies will not be tested for statistical significance. 
 
No PP analyses will be performed 
If a subject prematurely discontinues from the OLE phase , the EEG comparison to baseline at the Final 
OL/Taper Visit cannot be reassigned for analysis purposes since the EEG is performed only at that visit 
in the OLE phase; hence the tabulation at that visit will include all the subjects, regardless of whether 
they discontinued. (Taper Visit assessments among the subjects who prematurely discontinue from the 
DB phase are reassigned if possible; if they cannot be reassigned then they are not tabulated.) 
 
Safety Analysis:  All safety analyses will be performed in the Safety Population. The results in the double-blind 
and open-label phases will be summarized separately. In both phases, the results will be summarized by the 
double-blind treatment received and, for the open-label phase of the study, combined over the treatment groups.   
The number and percentage of days that subjects received investigational product, the highest percentage of the 
maximum allowable daily dose (1800 mg or 63 mg/kg) that subjects received, and the total amount of 
investigational product received will be summarized. For the open-label phase, they will be summarized over just 
the open-label phase as well as over the entire study (combined DB and OL phases) but the classification by the 
double-blind treatment applies only for the open-label phase summary. The summarization over the entire study 
will include the double-blind data only from subjects who were in the GNX group during the double-blind phase, 
regardless of whether they entered the open-label phase, and all the subjects from the open-label phase. 
A subject data listing will be provided with full details of the study drug dispensation. 
Safety assessments include: 
 
AEs  
 
Clinical laboratory tests  
 
Vital signs including temperature, blood pressure, pulse rate, and weight 
 
12-lead ECG 
 
Physical, neurological and developmental examinations 
 
Tanner staging (OL phase only) 
 
Concomitant AED levels (If available) 
Detailed analysis and complete listings will be outlined in the SAP. 
Pharmacokinetic Analysis:  A population PK approach addressing the relationship between GNX PK 
parameters and individual characteristics will be implemented in the double-blind and open-label phase as 
follows:  


 
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 
Visit 3 (Week 5): between 1 and 5 hours since the last investigational product dosing.  
 
Visit 4 (Week 9): between 4 and 8 hours since the last investigational product dosing. 
 
Visit 7 (Week 21): between 1 and 5 hours since the last investigational product dosing.  
 
Visit 9 (Week 52): between 1 and 5 hours since the last investigational product dosing.  
 
For all other PK draws, there is no specified time to draw the PK sample and can be drawn when convenient during 
the study visit for Visit 5 (Week 17), Visit 6 (Week 19), Visit 8 (Week 34), Visit 10 (Week 68), and every 16 weeks 
for the duration of the open-label phase.   
Exact time of sample withdrawal and drug intake will be recorded in the electronic case report form (eCRF).   
Neurosteroid serum and Concomitant AED levels:   
A blood sample will be drawn at the screening visit to confirm the subject meets eligibility criteria and does not 
have plasma allopregnanolone – sulfate (Allo-S) levels ≥ 6.0 ng/ml. 
Blood samples will also be drawn at Week 17 and the final open-label visit to measure neurosteroid levels 
allopregnanolone and related endogenous CNS-active steroids and sulfate metabolites.  Concomitant AED levels 
will not be mandatory but will be conducted per sites’ standard of care.  If AED levels are available, the results, 
date and time of last AED dose and date and time of AED PK sample will be recorded in the eCRF. 
Interim Analysis: 
Formal interim analyses are planned, in addition to the final analysis, of treatment effect on the primary endpoint, 
in accordance with the SAP. 
Data Monitoring Committee:  Emerging study data will be reviewed on a regular basis by an independent Data 
Monitoring Committee (DMC).  The mission of the DMC will be to safeguard the interests of study participants 
and to enhance the integrity and credibility of the trial.  To enable the DMC to achieve their mission, the DMC 
will have ongoing access to unblinded efficacy and safety data and data regarding quality of trial conduct and will 
ensure the confidentiality of these data will be preserved.  A DMC Charter will provide the principles and 
guidelines for the DMC process. 








 
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Table 1: 
Schedule of Assessment for the 17-week, Double-blind Treatment Phase of the Study 
Screen/Baseline 
DB Titration + Maintenance 
Final DB Visit  
WEEK 
-14 
-6 
(Screening) 
0 
Baseline 
(Randomization) 
3  
days 
1, 2, 3, 4 
5 
9 
11, 13 
17 
Visit Windows 
 
 
+6 daysn 
± 1 day 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
Historical 
Seizure 
frequency 
Visit 1 
Visit 2 
Phone 
Follow-up 
Phone  
Follow-up 
Visit 3 
Visit 4 
Phone  
Follow-up 
Visit 5 
AED = antiepileptic drug; BP = blood pressure; CBD = cannabidiol; D/C = discontinuation; DB = double-blind; ECG = electrocardiogram; EEG = electroencephalogram; HR = 
heart rate; LAR = legally authorized representative; PK = pharmacokinetic; RR = respiratory rate; THC = tetrahydrocannabinol; WCBP = women of childbearing potential. 
a. 
Written informed consent/assent must be obtained from subject, parent or LAR before any study assessments are performed. 
b. 
Written informed consent/assent from subject, parent or LAR needed if 8-week historical control is not available and need to chart prospectively. 
c. 
Review of medical history only.  
d. 
Genetic testing to be performed to confirm pathogenic or likely pathogenic CDKL5 variant. 
e. 
In addition, height and weight will be measured.  If weight unable to be collected at Visit 1, may be collected at Visit 2. 
f. 
In addition, weight will be measured. 
g. 
Chemistry & Hematology (Section 12.2).  
h. 
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. 
i. 
A drug screen (urine or plasma) will be performed to test for THC and CBD at screening. A negative drug test at screening meets the protocol eligibility criteria. If the screening drug test is 
positive, a plasma drug screen will be performed to test for THC and CBD at baseline. A positive drug test at baseline will exclude the subject from the study. 
j. 
Serum pregnancy test is required for all girls/women of childbearing potential.  
k. 
Population PK will be conducted at these visits (Visit 3: between 1-5 hours since last IP dosing, Visit 4: between 4-8 hours since the last IP dosing).  
l. 
Concomitant AEDs or their dose must be stable for 1 month prior to screening and cannot be changed at any time prior to Visit 5 but may be adjusted during the open-label phase of the study. 
m. During the Screening visit, the investigator and parent/caregiver/LAR will decide on a specific behavior that the patient exhibits that denotes assessment measured.  This behavior will be used at 
subsequent visits to assess change after the initiation of investigational product. 
n. 
Visit 2 to occur minimum of 6 weeks (42 days) after Visit 1 and maximum of 6 weeks + 6 days (48 days) 
 
 
 
 








 
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Table 2: 
Schedule of Assessments for Open-Label Phase 
Final DB 
Visit/ First 
OL Visit 
Titration 
(4 weeks blinded) 
Open-Label Maintenance 
(Visits will be every 16 weeks with a telephone 
follow up in-between after 52 weeks) 
Final 
OL 
Visit or 
Taper 
Safety  
Follow-
up 
post 
WEEK 
17 
3 Days 
Post 
Visit 5 
18 
19 
20 
21 
28 
34 
43 
52 
60 
68 
and 
X 
visit 
X/ 
or 
early 
D/C 
2 
weeks 
post 
last 
d
Visit Windows 
 
± 1 
± 3 days 
± 3 
days 
± 3 
days 
± 3 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7  
days 
± 3 
days 
Visit 5 
Phone 
follow-up 
Phone 
follow-up 
Visit 6 Phone 
follow-
up 
Visit 7 Phone 
follow-
up 
Visit 8 Phone 
follow-
up 
Visit 9 Phone 
follow-
up 
Visit 10 
and 
Visit X 
Visit X Visit X 
Dispense 
Investigational 
Product 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
AED = antiepileptic drug; BP = blood pressure; DB = double-blind; D/C = discontinuation; ECG = electrocardiogram; EEG = electroencephalogram; HR = heart rate; PK = 
pharmacokinetic; OL = open-label; RR = respiratory rate; WCBP = women of childbearing potential.  
a. 
In addition, weight will be measured at every visit, except the safety follow-up visit. 
b. 
In addition, height will be measured.  Height will be measured annually after Visit 9 (Week 52), except the safety follow-up visit. 
c. 
Chemistry & Hematology (Section 12.2). 
d. 
Serum pregnancy test is required for all girls/women of childbearing potential. 
e. 
Conduct annually and at the final open-label visit. 
f. 
Population PK will be conducted at these visits: Visit 7: between 1-5 hours since last IP dosing and Visit 9: between 1-5 hours since last IP dosing 
 


 
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1. 
BACKGROUND INFORMATION 
1.1. 
Indication and Current Treatment Options 
The cyclin-dependent kinase-like 5 (CDKL5) gene is located on the X chromosome and was 
previously called STK9.  Mutations in certain regions of the CDKL5 gene results in a rare 
X-linked disorder that manifests as early onset, difficult to control seizures, severe 
neuro-developmental impairment and behavioral abnormalities.  
Most children affected by CDKL5 are already symptomatic in the perinatal period, presenting 
with irritability, early epilepsy including infantile spasms (IS), hand stereotypies, severely 
impaired psychomotor development and severe hypotonia.  They may have a temporary 
regression in seizures in the first 1-2 years of life.  They generally have poor eye contact, often 
due to cortical blindness, but have normal head circumference and generally normal autonomic 
function. 
Other symptoms of a CDKL5 disorder often include limited or absent speech, gastroesophageal 
reflux, constipation, small, cold feet, breathing irregularities such as hyperventilation, grinding of 
the teeth, episodes of laughing or crying for no reason, low/poor muscle tone, very limited hand 
skills, some autistic tendencies, apraxia, eating/drinking challenges, sleep difficulties and 
stereotypic movements and posturing such as sideways glances, and sitting with one leg crossed 
over the other. 
Although previously called “atypical Rett Syndrome” or the “Hanefeld variant of Rett 
Syndrome,” since the discovery of the pathogenic gene mutations of CDKL5 by John 
Christodoulou and others, the ultra-rare pediatric epilepsy with encephalopathy now known as 
CDKL5 deficiency disorder (CDD) is considered an independent clinical entity associated with 
early-onset encephalopathy (Fehr et al., 2013).  The median age of epilepsy onset is much earlier 
in females with the CDD (median 6.0 weeks) than Rett syndrome (median 4.9 years) and the risk 
of developing seizures is much greater in CDKL5 affected females.  
CDKL5 deficiency disorder has also been mistaken for other epileptic encephalopathies grouped 
purely by seizure semiology and not via a common etiology, such as Lennox Gastaut Syndrome 
(LGS) and West syndrome.  Table 3 summarizes the key differences between these other 
epilepsies associated with encephalopathy and the distinct entity CDD. 


 
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Table 3: 
Certain Pediatric Epilepsies with Encephalopathy 
 
CDD 
Rett Syndrome 
Lennox Gastaut 
West Syndrome 
Etiology 
CDKL5 gene 
mutation X 
chromosome 
(catalytic domain) 
MECP2 mutation of 
X chromosome 
Multitude of 
etiologies including 
Perinatal birth 
injury, infection 
Multitude but 
commonly hypoxia 
and tuberous 
sclerosis (overlaps 
with LGS) 
Gender 
Very predominantly 
female; males more 
severely impacted 
Virtually 
exclusively female 
Either 
Either, but x-linked 
form more common 
in males than 
females (x-linked 
infantile spasms) 
Seizure Types 
Focal seizures first 
weeks to months, 
infantile spasms 
first months to 1-2 
years. Brief 
“honeymoon” can 
occur followed by 
tonic and myoclonic 
seizures. 
No specific pattern 
of development with 
mixed types 
including atonic, 
tonic, focal, 
absence, generalized 
tonic clonic 
Many types 
including infantile 
spasms, atonic 
(drop), tonic, 
absence 
Infantile spasms 
associated with 
hypsarrhythmia on 
EEG 
Non-CNS Features 
Scoliosis, severe GI 
issues 
scoliosis 
Uncommon 
Uncommon 
CDD = CDKL5 deficiency disorder; CDKL5 = cyclin-dependent kinase-like 5; CNS = central nervous system; EEG = 
electroencephalogram; GI = gastrointestinal; LGS = Lennox Gastaut Syndrome. 
Source:  Mangatt et al., 2016; Markand, 2003; NIH, 2017  
In a subsequent 2016 review of 167 children with confirmed pathogenic mutation of the CDKL5 
gene with CDD (median age 5.9 years), Mangatt et al, concluded, “This study captured a much 
clearer picture of the CDKL5 disorder than previously possible using the largest sample 
available to date. There were differences in the presentation of clinical features occurring in the 
CDKL5 disorder and in Rett syndrome, reinforcing the concept that CDKL5 is an independent 
disorder with its own distinctive characteristics” (Mangatt et al., 2016). 
CDKL5 deficiency disorder is a genetically defined neonatal onset pediatric epilepsy with early 
encephalopathy that responds poorly to all available therapies including ketogenic diet.  There is 
currently no standard of care for treating this epilepsy or the associated behavioral aberrations 
associated with the encephalopathy.  In a 2016 review of the efficacy of 22 anti-epileptic drugs, 
ketogenic diet and steroids, the major finding was that seizure reduction was minor and short-
lived. This led the authors to conclude that for now, even short-lived slight reductions in seizure 
frequency might improve both the patient’s and parent’s quality of life (Müller, 2016). 
Preliminary clinical evidence has suggested that patients that are deficient in endogenous 
neurosteroids exhibit an improved efficacy response to ganaxolone when compared to patients 
that have normal/elevated levels.  In specific, a Phase 2 study of ganaxolone in a genetic 
pediatric epilepsy similar to CDD, called PCDH19-related epilepsy, showed that patients with a 
baseline allopregnanolone-sulfate (Allo-S) level below 6.0 ng mL-1 had a greater antiseizure 
response when compared to those with baseline values greater than 6.0 ng mL-1.  An 
allopregnanolone deficiency in the PCDH19 population had previously been implicated as a 
potential cause of the epilepsy phenotype in PCDH19 patients.  To date, no studies have 


 
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explored neurosteroid up/down-regulation in patients with CDD as a potential result of the gene 
mutation.  Based on these preliminary data, the hypothesis that patients with a neurosteroid (e.g., 
Allo-S) deficiency experience an enhanced treatment effect is planned to be further studied. 
1.2. 
Product Background and Clinical Information 
Ganaxolone is the 3β-methylated synthetic analogue of the neuroactive steroid allopregnanolone, 
but it is designed not to activate nuclear (classical) progesterone receptors.  Ganaxolone differs 
from other γ-Aminobutyric acid (GABA) agents by interacting with both synaptic and 
extra-synaptic γ-Aminobutyric acid 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 
GABAA receptor function, GNX provides an alternative mechanism in the treatment of seizures 
and could serve as effective therapy in the management of benzodiazepine-resistant seizure 
conditions, such as CDD.  
The anticonvulsant activity of GNX was established in several in vivo models of seizure activity.  
Ganaxolone was effective at behaviorally non-toxic doses in rodent models of seizures induced 
by pentylenetetrazol (PTZ), bicucilline, aminophylline, strychnine, and 
t-butylbicyclophosphorothionate and antagonized 4-AP lethality in mice.  Ganaxolone blocked 
tonic seizures induced by maximal electroshock in mice and rats but only at doses that produced 
ataxia on the rotarod test.  Ganaxolone was a potent anticonvulsant against fully-kindled Stage-5 
seizures induced by corneal kindling in the rat at doses well below those that resulted in ataxia.  
Seizure threshold, as determined by the dose of intravenously infused PTZ 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). 
As of 
 1557 unique subjects have received treatment with GNX in completed 
company-sponsored clinical trials ranging in duration from 1 day to more than 2 years, using 
doses from 50 to 2,000 mg/day. In addition, 30 subjects received GNX in an ongoing open-label 
Phase 2 study, and an estimated 65 subjects received GNX in ongoing Phase 2/3 double-blind 
studies.  
Of these 1557 unique subjects, 319 healthy subjects have received GNX treatment in Phase 1 
studies and 1238 subjects have received GNX treatment in Phase 2/3 studies. The completed 
trials include 20 Phase 1 studies in healthy subjects and 20 Phase 2/3 studies in adults with 
epilepsy, children with seizure disorders, children with FXS, adults with PTSD and adults with 
migraine. 
Four company-sponsored clinical studies of GNX are ongoing and have enrolled over 200 
unique subjects:  
 Study 1042-0900 in pediatric epilepsies including female pediatric subjects with 
PCDH19 epilepsy and other rare genetic epilepsies including CDKL5 deficiency 
disorder, LGS and continuous spikes and waves during sleep (CSWS)  
 Study 1042-SE-2001 in adolescents and adults with SE  


 
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 Study 1042-PPD-2002 in women with PPD (GNX IV and oral capsule multiple-dose 
escalation study)  
 Study 1042-PPD-2003 in women with PPD 
For these 4 ongoing clinical studies, enrollment is complete for Study 1042-0900, 1042-PPD-
2002 and 1042-PPD-2003 and is ongoing for Study 1042-SE-2001. 
In addition to the company-sponsored studies, 29 subjects were treated with GNX in completed 
studies not sponsored by Marinus.  These included 16 subjects who received oral GNX doses 
from 400 mg/day to 1200 mg/day in a smoking cessation study and 10 subjects who received 
oral GNX in a postmenopausal depression study.  One pediatric subject received oral GNX up to 
63 mg/kg/day under a special access scheme in Australia for treatment of refractory seizures 
associated with PCDH19 genetic epilepsy.  In addition, two pediatric subjects received GNX in 
separate emergency INDs to treat super-refractory status epilepticus: 1 subject received IV GNX 
up to a dose of 2880 mg/day and 1 subject received IV GNX infusion up to a dose of 192 mg/day 
and transitioned to a GNX oral suspension dose of 1260 mg/day that was tapered over 
6 weeks.[SAE Section 5.6 IB] 
Furthermore, 3 non-company-sponsored clinical studies are ongoing. In these studies, a total of 
7 subjects continue to receive treatment with GNX through investigator-initiated INDs following 
participation in Marinus-sponsored studies as follows:  
 In one study, 3 subjects received GNX following participation in Study 1042-0603 of 
adult subjects with drug-resistant partial-onset seizures. 
 In one study, 3 subjects (2 subjects with PCDH19 epilepsy and 1 subject with LGS) 
received GNX following participation in Study 1042-0900.  
 In another study, 1 subject with CDD received GNX following participation in 
Study 1042-0900 
The overall frequency of treatment-emergent adverse events (TEAE) in company-sponsored 
PBO-controlled studies was 61.7% (613/993 subjects) in subjects who received GNX and 51.8% 
(330/637 subjects) in subjects who received PBO.  The most frequently reported TEAEs in 
GNX-treated subjects were somnolence, dizziness, fatigue, and headache.  All of these events, 
except for headache, occurred more frequently in GNX-treated subjects than PBO-treated 
subjects.  Central nervous system (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.  
The majority of TEAEs were anticipated based on the mechanism of action of GNX and 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 in electrocardiogram 
(ECG) intervals, vital signs, or physical or neurologic examinations have been noted, and no 
mean changes from baseline in clinical laboratory results have been identified.  Overall, there 
have been only a few clinically significant individual changes from baseline in clinical 
laboratory measurements in clinical trials of GNX.  In the completed PBO-controlled Phase 1, 2, 
and 3 studies, 0.3% of subjects treated with GNX and 0.5% of subjects treated with PBO 
exhibited elevated liver function tests during the study (aspartate aminotransferase or alanine 


 
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aminotransferase > 3 times the upper limit of normal [ULN]).  There have been no cases of Hy’s 
law considered to be related to GNX in the GNX development program.  In controlled clinical 
trials of GNX, 1.1% of subjects receiving PBO and 1.7% of subjects receiving GNX reported an 
adverse event (AE) of rash suggesting there is no obvious imbalance between drug and PBO in 
terms of frequency of this AE.  However, in PBO-controlled studies rash led to discontinuation 
in GNX-treated subjects in 6 cases (0.6%) compared to no cases (0%) in PBO-treated subjects.  
One of the events was also reported as an SAE and the event resolved after discontinuation of the 
study drug. In addition, in the ongoing study 1042-0900, an additional event of rash was reported 
as an SAE. There have been no cases of Stevens-Johnson syndrome, toxic epidermal necrolysis 
or any other clinically important rashes reported in the clinical development program. Marinus 
considers rash as a potential risk associated with GNX and continues to monitor the occurrence 
of this AE in the clinical development program. 
 
Pediatric Safety 
Marinus has completed 2 double blind, randomized trials and 5 open-label, uncontrolled clinical 
trials of GNX in the pediatric population.  One additional pediatric trial, open-label Study 
1042-0900 in children with various genetic epilepsies and LGS is ongoing.  This study has 
enrolled 30 subjects of which 7 are subjects with the CDKL5 mutation.  
Approximately 224 pediatric subjects aged 4 months to 17 years (data cutoff
) 
have received at least 1 dose of GNX.  The largest cohorts received 12-54 mg/kg/day, although 
some subjects received doses as high as 63 mg/kg/day or 1800 mg/day for adolescents.  As of 
 4 subjects were treated ≥ 4 years, 9 subjects were treated ≥ 2 years, 
39 subjects were treated ≥ 1 year and 66 subjects were treated ≥ 6 months. 
The majority of the pediatric subjects were refractory epilepsy patients who had uncontrolled 
seizures despite trying other antiepileptic drugs (AEDs) (range 1-8).  Overall, GNX was 
generally safe and well tolerated.   
In the incomplete crossover Study 1042-0500 (N=56; all received GNX during the trial), 39 
subjects 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 subjects) were vomiting (7 subjects), 
somnolence (5 subjects), and cough (5 subjects).  Most AEs were mild or moderate; 1 severe AE 
of lethargy occurred in 1 GNX subject.  During the 8-day PBO-controlled treatment period, the 
most frequent AEs noted were vomiting (11% in both GNX and PBO groups) and cough (8% 
GNX, 5% PBO).  Other AEs attributed to GNX included flatulence, insomnia, irritability, 
lethargy, and somnolence.   
Adverse events reported in the other uncontrolled refractory pediatric epilepsy studies were 
consistent with the GABAergic mechanism of action or disease under study.  
In another randomized, double-blind, PBO-controlled study of 59 subjects (aged 5-17 years) with 
fragile X syndrome who were treated with GNX up to 36 mg/kg/day (maximum 1800 mg/day) or 
PBO, the percentage of subjects who reported at least 1 TEAE was comparable between the 
treatment groups (85.2% versus 83.1% in the PBO and GNX treatment groups, respectively).  
The most frequently reported TEAEs among subjects who received GNX included fatigue 
(29/59 subjects; 49.2%), somnolence (20/59 subjects; 33.9%),condition aggravated (10/59 


 
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subjects; 16.9%), and upper respiratory tract infection (9/59 patients; 15.3%)Both fatigue (49.2% 
vs 20.4%) and somnolence (33.9% vs 5.6%) occurred more frequently in GNX-treated subjects 
compared with PBO.  Among subjects who received PBO, headache (6 subjects; 11.1%) and 
agitation (8 subjects; 14.8%) were reported more frequently compared with GNX-treated 
subjects.  Severe TEAEs were reported for 3/59 (5.1%) GNX subjects and 1/54 (1.9%) PBO 
subjects.  Severe events in the GNX group were somnolence and fatigue in 1 subject each and 
agitation and aggression in 1 subject. 
To date, AEs have been consistent with the GABAergic mechanism of GNX, disease understudy, 
or pediatric studies.  There have not been any emerging safety concerns with respect to vital 
signs, ECG, physical/neurological examinations, or clinical laboratory measures.   


 
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2. 
STUDY OBJECTIVES AND PURPOSE 
2.1. 
Rationale for the Study 
Cyclin-dependent kinase-like 5 (CDKL5) deficiency- mediated early-onset infantile epileptic 
encephalopathy is a rare genetic disorder with approximately 1,600 documented cases world-
wide (Loulou Foundation).  The CDKL5 gene is on the X chromosome; consequently, the 
condition affects mainly girls, although boys can also be affected.  The CDKL5 gene produces a 
protein that is important for neuronal morphogenesis and brain development, (Fuchs et al., 2014) 
and helps regulate expression of genes involved in synaptic function, structure, and plasticity 
(Carouge et al., 2010; Kameshita et al., 2008).  
Cyclin-dependent kinase-like 5 deficiency disorder is characterized by early-onset intractable 
seizures, severe developmental delay, disturbed sleep and severe intellectual/gross motor 
impairment (Bahi-Buisson et al., 2008).  Typically, the seizures are resistant to conventional 
antiepileptic medication.  Treatment-resistant epilepsy can be fatal and patients are often treated 
with high doses of multiple AEDs that worsen the cognitive, behavioral and physical 
consequences of the underlying disorder.  Together, these children and young adults experience 
major impairments to quality-of life.  Any therapy that can reduce the frequency, duration or 
severity of seizures can positively impact quality of life for the child and family (Müller et al., 
2016).  
Ganaxolone is the 3β -methylated synthetic analog of allopregnanolone, an endogenous allosteric 
modulator of CNS GABAA receptors. GNX has potency and efficacy comparable to 
allopregnanolone (Carter et al., 1997) in activating synaptic and extrasynaptic GABAA receptors 
at a site distinct from benzodiazepines. GNX has protective activity in diverse rodent seizure 
models (Reddy and Rogwski, 2012; Bialer et al., 2010).  Clinical studies have demonstrated 
GNX has anticonvulsant activity with an acceptable safety and tolerability profile in the dose 
range of 900 to 1800 mg in adults and children (Sperling et al., 2017; Laxer et al., 2000; 
Kerrigan et al., 2000; Pieribone et al., 2007).  Further, GNX reduces seizures in children with IS 
and refractory pediatric epilepsy. In an open-label study, pediatric subjects aged 2 to 60 months 
with refractory seizures and a history of IS were treated with GNX doses up to 36 mg/kg for up 
to 3 months (Kerrigan et al., 2000).  Sixteen of the 20 subjects completed treatment, 15 of whom 
had a history of IS.  Five of the 15 subjects had a decrease from baseline in the number of 
spasms of ≥ 50%, 5 had a decrease of 25 to 50%, and 5 had a decrease of <25%. One subject 
became spasm free and 1 non-responder (with a decrease of <25%) was spasm-free from weeks 
2 to 7. 
An anticonvulsant treatment effect signal of GNX in CDD has emerged from an ongoing open-
label flexible-dose exploratory study of GNX in children with rare genetic epilepsies (including 
CDKL5) with uncontrolled seizures despite multiple AED regimens (ClinicalTrials.gov 
Identifier: NCT02358538).  Following screening and baseline evaluations, consenting patients 
enrolled into a 26-week study during which investigators were allowed to dose GNX flexibly up 
to 1,800 mg/day for patients whose body weight was > 30 kg, or up to 63 mg/kg/day for patients 
whose body-weight was < 30 kg.  The primary efficacy measure was percent change from 
baseline in the 28-day seizure frequency count.  Safety and tolerability were among secondary 
objectives.  The median change in 28-day seizure frequency from baseline in the intent-to-treat 
(ITT) population (primary endpoint) was a decrease of 48% (n=7).  The median change from 


 
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baseline in seizure-free days in the ITT population (key secondary endpoint) was an increase of 
78% (n=5; two subjects cannot be calculated due to 0 baseline seizure-free days).  The Clinical 
Global Impression Improvement Scale scores rated by investigators and caregivers were 
consistent with seizure control for all the children.  Children with a 43% or higher seizure 
reduction were rated as “much improved” or “very much improved” by the investigators and 
caregivers.  Investigators and caregivers reported improvements in attention, mood, behavior and 
sleep via investigator narratives.  Ganaxolone was generally safe and well tolerated with no 
serious adverse events.  To date, there have been no adverse event reports of somnolence or 
dizziness.  The safety and tolerability profile in these patients was similar to earlier studies. 
In addition to anticonvulsant activity, GNX has shown positive effects on anxiety, hyperactivity 
and attention in children with fragile X syndrome (Ligsay et al., 2016).  Similar behavior 
problems occur in children with CDKL5 mutations.  
It is hypothesized that GNX treatment will increase and improve GABAA-mediated signaling by 
boosting the signaling capacity of existing receptors and improve not only seizure control, but 
also other behavioral abnormalities in children with the CDKL5 mutation. 
This present study is planned to assess the efficacy, safety, and tolerability of GNX compared 
with PBO as adjunctive therapy to the subject’s standard anti-seizure medication for the 
treatment of seizures in children and young adults with genetically confirmed CDD during the 
17-week, double-blind phase. Pharmacokinetic (PK) assessments and population PK analyses 
will also be performed during this time. The 17-week, double-blind phase will be followed by an 
optional long-term open-label phase at which time all subjects will receive GNX as an adjunct to 
their standard anti-seizure medication.  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 the efficacy of GNX compared with PBO as 
adjunctive therapy for treatment of primary seizures in children and young adults with 
genetically confirmed CDD at the end of the 17-week double-blind phase. 
2.2.2. 
Secondary Objectives 
The secondary objectives of this study are the following:  
 To assess behavioral/neuropsychiatric changes correlated with domains of attention, 
sleep, and a target behavior chosen by the parent/caregiver, using objective tests of CNS 
function for GNX compared with PBO as adjunctive therapy at the end of the 
17-week double-blind phase. 
 To assess the safety and tolerability of GNX compared with PBO as adjunctive 
therapy at the end of the 17-week double-blind phase.  
 To assess PK parameters in subjects receiving GNX doses up to 63 mg/kg/day 
(1800 mg/day maximum) throughout the study. 




 
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3. 
STUDY DESIGN 
3.1. 
Study Design and Flow Chart 
This is a global, double-blind, randomized, PBO-controlled trial of adjunctive GNX treatment in 
children and young adults with CDD.  The trial consists of a 6-week prospective baseline period 
to collect seizure data, followed by a 17-week double-blind treatment phase, which is then 
followed by a long-term open-label phase. 
If available, a 2-month (8-week) daily historical seizure calendar will be reviewed at the 
screening visit to determine eligibility per inclusion/exclusion criteria.  Acceptable historical 
seizure data must include seizure type, frequency, and denote seizure free days, with the 
historical seizure calendar starting at Week -14 (8-week historical + 6-week prospective = 14 
weeks).  Procedures specific to this protocol and not otherwise considered standard of care, will 
not be performed until written informed consent from the subject’s parent or legally authorized 
representative (LAR) and/or subject assent has been appropriately obtained.  In the event that 
parent/caregiver/LAR do not routinely maintain a daily seizure calendar per standard of care, 
written informed consent will be obtained from the parent/LAR and/or subject assent, and the 
subject will be asked to return to the clinic for the screening visit after they have maintained a 
2-month (8-week) daily historical seizure calendar.   
The double-blind phase includes 6 weeks prospective baseline, 4 weeks of titration followed by 
13 weeks of dose maintenance.  After meeting the eligibility criteria, approximately 100 children 
and young adults aged 2-21 years (inclusive) with CDD will be randomly assigned to receive 
GNX or PBO (1:1 ratio) for 17 weeks in addition to their standard anti-seizure treatment.  
Participants will be titrated to 63 mg/kg/day (max 1800 mg/day) over 4 weeks, and then 
maintained at that dose for another 13 weeks.  Subjects who are not able to tolerate 63 mg/kg/day 
(or 1800 mg/day maximum) may be maintained on a lower dose after discussion with the 
sponsor.  A minimum dose of 33 mg/kg/day or 900 mg/day is generally required during the 
double-blind phase unless a lower dose is agreed to with the Sponsor.   
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.  The higher dose in the evening is 
expected to be better tolerated due to the proximity to bedtime. However, tolerability 
management and the final decision to adjust drug dosages lies with the Principal Investigator.  
For any subject who is unable to be maintained at the minimum dose, the investigator should 
contact the sponsor to discuss continued investigational product dosing.  Subjects who 
discontinue investigational product should undergo a 2-week taper period unless otherwise 
medically indicated.  Subjects who discontinue investigational product treatment before the 
completion of the double-blind phase will continue to be followed per protocol and at minimum 
maintain daily seizure electronic diary (eDiary) entry until the double-blind phase is completed.  
These subjects will also return to the site 2 weeks after the taper for safety follow-up 
assessments. 
After completing the initial 17-week, double-blind, PBO-controlled phase, all subjects will be 
treated with GNX in the open-label phase of the study.  Ganaxolone subjects will continue GNX 


 
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treatment and PBO subjects will titrate onto GNX.  To maintain the blind, subjects initially 
randomized to GNX will undergo a false titration (increasing PBO doses) for 4 weeks, while 
PBO subjects will titrate up to 63 mg/kg/day GNX (1800 mg/day maximum) during the same 
time period (Figure 1).  An interactive web response system (IWRS) will be used to randomize 
subjects, dispense drug, track treatment, and maintain the blind throughout the duration of the 
study.  Any participant who discontinues early from the study at any time will undergo a 2-week 
taper, unless otherwise medically indicated, and return to the site 2 weeks later for safety follow-
up assessments. 
 
Figure 1: 
Study Design 
 
Participants will be required to complete a daily seizure calendar noting seizure type and 
frequency in an eDiary calendar to determine GNX’s effect on seizures. In rare cases when an 
eDiary completion is not feasible, a paper seizure calendar will be used to log in daily seizure 
type and frequency. These cases will need approval by the sponsor. A variety of clinician and 
caregiver administered instruments will be used to assess the efficacy of GNX in CDKL5, and 
included:  Caregiver Global Impression of Change in Attention (CGICA), Caregiver Global 
Impression of Change (CGI-C) in parent/caregiver identified behavioral target- potential 
domains of sociability, communication, irritability, and hyperactivity, Clinical Global Impression 
of Improvement (CGI-I) by parent/caregiver and clinician, Caregiver Global Impression of 
Change in Seizure Intensity/Duration (CGI-CSID), Children’s Sleep Habit Questionnaire 
(CSHQ), ADAMS, QI-Disability, and PSI.  
Safety and tolerability will be assessed by monitoring vital signs (blood pressure [BP], heart rate 
[HR], respiratory rate [RR], body temperature, weight, and height), ECGs, clinical laboratory 
tests (hematology, chemistry, and urinalysis), physical, neurological, and developmental 
examinations, and frequency, type, and severity of AEs during the 17-week, double-blind phase 
and the open-label phase. 
3.2. 
Duration and Study Completion Definition 
Eligible subjects after screening will collect 6 weeks of prospective baseline seizure data. 
Subjects will then be randomized into a 17-week, double-blind treatment phase.  Participants 


 
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who complete the study or discontinue investigational product treatment before the end of the 
study will undergo a 2-week taper period, unless otherwise medically indicated, after which 
he/she will return to the site 2 weeks post last dose for a safety follow up visit.  Subjects who 
discontinue investigational product treatment before the completion of the double-blind phase 
will continue to be followed per protocol and at minimum maintain daily seizure eDiary entry 
until the double-blind phase is completed.  These subjects will also return to the site 2 weeks 
after the taper for safety follow-up assessments. 
It is estimated that the maximum duration of subject participation in the double-blind phase will 
be 23 weeks, including the 17-week double-blind treatment phase and 6-week prospective 
baseline period, and approximately an additional 3 years for the long-term open label phase. The 
open-label phase will continue until the sponsor terminates the program or GNX has been 
approved and marketed the investigational product in the subjects’ respective country. 
3.3. 
Sites and Regions 
This multicenter study is to be conducted globally, with up to 50 sites planned to participate.   
3.4. 
Discussion of Study Design, Including the Choice of Control Group 
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, subjects will 
be randomized (1:1 ratio) to receive either GNX or PBO, prescribed in increments of 
15 mg/kg/day up to 63 mg/kg/day (maximum 1800 mg/day), as an oral suspension for up to 
17-weeks.  The double-blind phase will be followed by an open-label phase in which all subjects 
will receive GNX up to an additional 3 years or more, providing long-term safety and tolerability 
data on GNX.  Administration of GNX adjunctive therapy to background AEDs provides 
standard-of-care therapy in addition to any benefit that investigational product might provide. 
Subjects will be randomized to receive either GNX or PBO, prescribed in increments of 
15 mg/kg/day up to 63 mg/kg/day (maximum 1800 mg/day) as an oral suspension. 
 6 mg/kg three times daily (TID) (18 mg/kg/day) suspension -Days 1-7 
 11 mg/kg TID (33 mg/kg/day) suspension -Days 8-14 
 16 mg/kg TID (48 mg/kg/day) suspension - Days 15-21 
 21 mg/kg TID (63 mg/kg/day) suspension - Days 22-28 
Any subject not tolerating the next dose step can be maintained at the lower dose step for 
additional days before advancing to next dose.  If the next dose is still not tolerated, they can 
drop back to the next lower dose step.  A minimum dose of 33 mg/kg/day and 900 mg/day must 
be maintained. 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.  The higher dose in the 
evening is expected to be better tolerated due to the proximity to bedtime. However, tolerability 
management and the final decision to adjust drug dosages lies with the Principal Investigator. 
Any subject who is unable to be maintained at the minimum dose should contact the sponsor to 
discuss continued investigational product dosing.  Subjects who discontinue investigational 


 
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product should undergo a 2-week taper period unless otherwise medically indicated. Subjects 
who discontinue investigational product treatment before the completion of the double-blind 
phase will continue to be followed per protocol and at minimum maintain daily seizure diary 
entry until the double-blind phase is completed.  These subjects should also return to the site 
after the taper for safety follow-up assessments. 


 
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4. 
STUDY POPULATION 
Each subject’s parent/LAR must participate in the informed consent process and provide written 
informed consent (and/or subject assent) before any procedures specified in the protocol are 
performed.  
4.1. 
Inclusion Criteria 
The subject will not be considered eligible for the study without meeting all the criteria below. 
1. (a) Molecular confirmation of a pathogenic or likely pathogenic CDKL5 variant, early 
onset, difficult to control seizures, and neurodevelopmental impairment are required.  The 
principal investigator (PI) must review the results of the genetic analysis and confirm that 
gene mutation is likely to be the cause of the epilepsy syndrome.  If the patient has a de 
novo variant of unknown significance (VUS) in the kinase domain of the CDKL5, 
parental testing is negative and meets all other inclusion criteria, then the subject can be 
included.  Genetic mutations will be confirmed by the sponsor’s chosen central 
laboratory.  In France, genetic mutations may be confirmed by an approved French 
organization, in compliance with French legislation prior to Screening Visit 1.  Patients 
must have (b) seizure onset by 1 year of age and (c) lack of independent ambulation by 2 
years of age.   
2. Male or female patients aged 2 through 21 years, inclusive. 
3. Subject/parent or LAR willing to give written informed consent/assent, after being 
properly informed of the nature and risks of the study and prior to engaging in any 
study-related procedures. 
4. Failure to control seizures despite appropriate trial of 2 or more anti-seizure mediations at 
therapeutic doses 
5. Have at least 16 seizures of primary seizure types: bilateral tonic (sustained motor 
activity ≥ 3 seconds), generalized tonic-clonic, bilateral clonic, atonic/drop or focal to 
bilateral tonic-clonic per 28 days in each 1-month period in the 2-month period prior to 
screening. 
6. Subject must be approved to participate by sponsor and/or designee (i.e., Epilepsy 
Consortium) after review of medical history, genetic testing, seizure classification, and 
historical seizure calendars. 
7. Participants should be on a stable regimen of 0-4 anti-seizure medications (including 
moderate or strong inducer or inhibitor anti-seizure medications e.g. carbamazepine, 
phenytoin, etc.) for ≥ 1 month prior to the screening visit, without a foreseeable change in 
dosing for the duration of the double-blind phase. Vagus nerve stimulator (VNS), 
ketogenic diet, and modified Atkins diet do not count towards this limit but must be 
unchanged for 3 months prior to screening. 
8. Subjects 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. 


 
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b. The settings must have remained constant for 3 months prior to the screening visit 
and remain constant throughout the double-blind phase. 
c. The battery is expected to last for the duration of the double-blind phase. 
9. Felbamate: The use of felbamate is allowed provided that the subject has been maintained 
on a stable dose of felbamate for > 6 months and has had stable liver function (aspartate 
aminotransferase [AST] and alanine aminotransferase [ALT]) and hematology during the 
course of treatment, and is expected to remain constant throughout the double-blind 
phase. 
10. Parent/caregiver is able and willing to maintain an accurate and complete daily electronic 
seizure calendar for the duration of the study.  
11. Able and willing to take investigational product with food 3 times daily.  Ganaxolone 
must be administered with food. 
12. 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 screening, surgical sterilization, or adequate barrier methods (e.g., 
diaphragm and foam).  An oral contraceptive alone is not considered adequate for the 
purpose of this study. Hormonal oral contraceptives must also be used when a condom is 
used.  In subjects who are not sexually active, abstinence is an acceptable form.  
4.2. 
Exclusion Criteria 
1. Previous exposure to GNX. 
2. Pregnant or breastfeeding. 
3. West Syndrome with hypsarrhythmia pattern on EEG or seizures predominantly of 
Infantile Spasm (IS) type; if EEG pattern/seizure type is uncertain, study inclusion should 
be reviewed and determined by the sponsor/sponsor delegate. 
4. Concurrent use of adrenocorticotropic hormone (ACTH), prednisone or other 
glucocorticoid is not permitted, nor use of moderate or strong inducers or inhibitors of 
CYP3A4/5/7. A list of CYP3A4/5/7 inhibitors and inducers is included in Section 12.1.    
Moderate or strong inducer or inhibitor anti-epileptic drugs will be allowed (e.g., 
carbamazepine, phenytoin, etc.)  
5. Patients on ACTH, prednisone or other systemically (non-inhaled) administered steroids 
should be off the product greater than 28 days prior to screening.  Concomitant PRN 
topical or intranasal steroids for dermatologic reactions and allergic rhinitis are allowed 
and do not warrant exclusion from the study. 
6. Subjects with a positive result on tetrahydrocannabinol (THC) or cannabidiol (CBD) test 
(via urine or plasma drug screen) at the screening visit, and a positive result on THC or 
CBD test (via plasma) at the baseline visit without prescription for Epidiolex (may go by 
another name in countries outside the United States) in epilepsy will be excluded from 
the study.  Concomitant Epidiolex (CBD) use will be allowed in the double-blind phase 


 
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provided the subject has been on a stable dose for at least 1 month prior to screening and 
is expected to remain on a stable dose without a foreseeable change for the duration of 
the double-blind phase.  THC and/or CBD will be allowed in the open-label phase.  
7. Use of dietary supplements or herbal preparations are not permitted if subject has been 
using them consistently for less than 3 months prior to screening or does not plan on 
remaining on stable doses for the duration of the double-blind phase. Use of St. John’s 
Wort is not permitted (See Section 12.1). 
8. Changes in Anti-Epileptic Drugs (AEDs) within the last month prior to screening.  All 
AEDs must be stable in dose for at least 1-month prior to screening unless otherwise 
noted.  
9. Have an active CNS infection, demyelinating disease, degenerative neurological disease, 
or CNS disease deemed progressive as evaluated by brain imaging (magnetic resonance 
imaging [MRI]).  
10. Have any disease or condition (medical or surgical; other than CDKL5) at screening that 
might compromise the hematologic, cardiovascular, pulmonary, renal, gastrointestinal, or 
hepatic systems; or other conditions that might interfere with the absorption, distribution, 
metabolism, or excretion of the investigational product, or would place the subject at 
increased risk.  
11. An AST (serum glutamic oxaloacetic transaminase [SGOT]) or ALT (serum glutamic 
pyruvic transaminase [SGPT]) greater than 3 times the upper limit of normal (ULN) at 
study entry.  If AST or ALT increases > 3 times ULN during the study, subject should be 
followed with weekly laboratory repeat testing and continue in study if levels trending 
down.  Subject will be discontinued if levels do not decline to under 3 x ULN. 
12. Total bilirubin levels greater than ULN at study entry.  In cases of documented, stable 
medical condition (i.e., Gilbert’s Syndrome) resulting in levels of total bilirubin greater 
than ULN, the medical monitor can determine if a protocol exception can be made. If 
total bilirubin increases to 1.5 x ULN or more during study, the subject will be 
discontinued.  
13. Subjects with significant renal insufficiency, estimated glomerular filtration rate (eGFR) 
< 30 mL/min (calculated using the Cockcroft-Gault formula, Pediatric GFR calculator or 
Bedside Schwartz), will be excluded from study entry or will be discontinued if the 
criteria is met post baseline. 
14. Have been exposed to any other investigational drug within 30 days or less than 
5 half-lives prior to screening.  
15. Unwillingness to withhold grapefruit, Seville oranges or star fruit from diet during the 
entire clinical trial. 
16. Unwillingness to withhold alcohol throughout the entire clinical trial. 
17. Have active suicidal plan/intent or have had active suicidal thoughts in the past 6 months 
or a suicide attempt in the past 3 years.  
18. Known sensitivity or allergy to any component in the investigational product(s), 
progesterone or other related steroid compounds. 


 
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19. Plasma allopregnanolone – sulfate (Allo-S) levels ≥ 6.0 ng/ml at the screening visit. 
4.3. 
Restrictions  
Subjects must abstain from the use of alcohol and from consuming grapefruit, Seville oranges 
and starfruit until completion of the study. 
4.4. 
Reproductive Potential 
4.4.1. 
Female Contraception 
Sexually active women of childbearing potential should be using a medically acceptable form of 
birth control.  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 investigational 
product.  If hormonal contraceptives are used, they should be administered per the package 
insert.  
Women of childbearing potential who are not currently sexually active must agree to use 
acceptable contraception, as defined below, if they become sexually active during the period of 
the study and 30 days after the last dose of investigational product.  
Female subjects should be: 
 Premenarchal and either Tanner stage 1 or less than 9 years or age, or 
 Surgically sterile (having undergone one of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) and at 
least 6 weeks’ post-sterilization, or 
 Women of childbearing potential must have a negative serum pregnancy test prior to 
taking the first dose of investigational product and must agree to abstain from sexual 
activity that could result in pregnancy or agree to use a medically acceptable method 
of birth control. 
 Abstinence is an acceptable method of birth control only if this is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.  
 Medically acceptable methods of birth control include: 
a. Intrauterine device plus condoms 
b. Double-barrier methods (e.g., condoms and diaphragm with spermicidal gel or 
foam) 
c. Hormonal contraceptives (oral, patch, injectable, or vaginal ring), stabilized for at 
least 1 month prior to screening visit, plus condoms.  Note: If a woman becomes 
sexually active during the study, she should use one of the other acceptable 
methods noted above in addition to the hormonal contraceptive until it has been 
stabilized for 30 days prior to screening visit.  Hormonal oral contraceptives must 
also be used when a condom is used.   


 
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4.4.2. 
Male Contraception 
Male participants 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 investigational product.  
Medically acceptable contraceptives include surgical sterilization (such as a vasectomy) and a 
condom used with a spermicidal gel or foam.  The female partner of a male subject must use 
hormonal oral contraceptives when the male subject uses a condom.  Contraceptive measures 
such as Plan BTM, sold for emergency use after unprotected sex, are not acceptable methods for 
routine use. 
Male subjects should not donate sperm during the study and for 30 days after the last dose of 
investigational product. 
4.5. 
Discontinuation of Subjects 
A subject may withdraw — or their parent/LAR may withdraw the subject — from the study at 
any time for any reason without prejudice to their future medical care by the physician or at the 
hospital.  The investigator or sponsor may withdraw the subject at any time (e.g., in the interest 
of subject safety).  The investigator is encouraged to discuss withdrawal of a subject from 
investigational product with the medical monitor when possible. 
Subjects who discontinue investigational product treatment before the completion of the double-
blind phase will continue to be followed per protocol and at minimum maintain daily seizure 
eDiary entry until the double-blind phase is completed.  These subjects should also return to the 
site after the taper for safety follow-up assessments.   
If the investigational product is discontinued at any time, subjects should follow the 2-week taper 
schedule.  If the subject discontinues during the open-label phase, evaluations listed for Taper 
Visit are to be performed as completely as possible.  Whenever possible, all subjects who 
discontinue should also undergo the protocol-specified Safety Follow-up Post Taper visit.  
Comments (spontaneous or elicited) or complaints made by the subject must be recorded in the 
source documents.  The reason for termination, date of stopping investigational product, and total 
amount of investigational product taken must be recorded in the electronic case report form 
(eCRF) and source documents.  Discontinuation of investigational product due to AEs must also 
be reflected on the AE eCRF page. 
4.5.1. 
Subject Withdrawal Criteria 
All subjects or his/her parent/LAR reserve the right to withdraw from the clinical study at any 
time, as stated in the informed consent form.  The investigator may discontinue subjects from the 
clinical study for any of the following reasons: 
 Subject is found to have entered the study in violation of the protocol; 
 Subject requires the use of a disallowed concomitant medication; 
 Subject’s condition changes after entering the clinical investigation so that the subject 
no longer meets the inclusion criteria or develops any of the exclusion criteria; 
 Subject or parent/LAR withdraws consent or assent to participate in the study; 
 Subject is noncompliant with the procedures set forth in the protocol; 


 
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 Subject experiences an AE/SAE that warrants withdrawal from the study;  
 Laboratory, medical, or clinical finding for which clinical intervention should take 
precedence over study participation; or 
 It is the investigator’s opinion that it is not in the subject’s best interest to continue in 
the study. 
Decisions to discontinue the study will be made at each participating site by the PI.  If feasible, 
the reason for discontinuation should be discussed with the sponsor’s medical monitor prior to 
subject discontinuation.  Subjects who discontinue investigational product during the 
double-blind phase will continue to record daily seizure frequency at minimum until the 
completion of the double-blind phase. 
If a subject must be abruptly discontinued from the investigational product (e.g., severe rash), 
careful attention should be paid for the possibility of withdrawal symptoms such as increase in 
seizure number or severity.   Consideration should be made by the investigator for providing 
another GABA-A medication for 1-2 weeks such as clobazam to mitigate the potential risk of 
withdrawal from a positive modulator of GABA-A.   
4.5.2. 
Reasons for Early Discontinuation 
The reason for early discontinuation must be determined by the investigator and recorded in the 
subject’s source documents and on the eCRF.  If a subject is withdrawn for more than 1 reason, 
each reason should be documented in the source document and the most clinically relevant 
reason should be entered on the eCRF.  
Reasons for early termination include but are not limited to the following: 
 Adverse event in which the character, severity or frequency is new in comparison to 
the patient’s existing risk profile with the exception of seizures.   
 An Adverse Event that is associated with non-reversible target organ dysfunction, 
with the associated laboratory abnormalities as defined in exclusion criteria 11, 12 or 
13.  An allowance may be made for continued treatment if the abnormality is not 
medically significant (non-life-threatening or does not require ongoing treatment that 
could be life-threatening)   
 A laboratory abnormality or vital sign change that is irreversible and considered 
medically significant, associated with use of the investigational product 
 Protocol violation/protocol deviation 
 Withdrawal by subject or parent/LAR 
 Lost to follow-up 
 Lack of efficacy 
 Death 
 Physician decision 
 Pregnancy 


 
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 Other (must be specified in the subject source document and eCRF) 
4.5.3. 
Subjects Lost to Follow-up Prior to Last Scheduled Visit 
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact).  At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgment of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.  If 
contact is made but the subject 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. 
Subject Numbering 
During the screening visit, each subject will be assigned a unique 6-digit subject number by the 
Interactive Web Response System (IWRS).  The subject number will consist of a 3-digit clinical 
investigational site number assigned by the sponsor, followed by a 3-digit subject number (e.g., 
001) assigned by the study staff.  This subject number will also serve as the screening number.  
A separate randomization number will be assigned once the subject is randomized, but the 
randomization number will not be used to track the subject.  The unique 6-digit subject number 
will serve as the subject ID and be used to track the subject throughout the study.  Each subject 
number will correspond with a treatment (active or PBO) as determined by the randomization 
schedule.  
The clinical site is responsible for maintaining a current log of subject number assignments and 
bottle numbers of the investigational product administered to each subject.  The unique subject 
number is required to be entered on all clinical investigation documentation (eCRFs, labeling of 
clinical materials and samples containers, drug accountability logs, etc.).  


 
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5. 
EXCLUDED, PRIOR, AND CONCOMITANT MEDICATIONS 
The study physician should assess all concomitant medications at every visit, and at the 
screening visit in particular to ensure that the subject is not taking excluded medications.  
5.1. 
Prior Medications 
5.2. 
Concomitant Medications 
Concomitant medications refer to all treatment taken between the date of the first dose of 
investigational product and the date of the last dose of investigational product.  Concomitant 
treatment information must be recorded on the appropriate eCRF page.  Concomitant as needed 
(PRN) topical and intranasal steroids for dermatologic reactions and allergic rhinitis are allowed 
and do not warrant exclusion from study.  If the subject is currently taking an excluded 
medication at the time of the screening visit, then the subject must undergo a washout period 
equivalent to 5 half-lives of the drug before they may enter the prospective 6-week baseline 
period. 
Use of dietary supplements or herbal preparations are permitted if subject 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 double-blind phase. Use of St. John’s Wort is not permitted (See 
Section 12.1). 
Concomitant medications may be reduced or discontinued at the discretion of the investigator if 
medically warranted. 
5.2.1. 
Concomitant AED Medications 
Subjects participating in the study can take between 0-4 AEDs in addition to the investigational 
medication. Vagus nerve stimulator, ketogenic diet, and modified Atkins diet do not count 
towards this limit but must be unchanged for 3 months prior to the screening visit. 
Subjects with surgically implanted VNS will be allowed to enter the study provided that all of 
the following conditions are met: 
 The VNS has been in place for ≥ 1 year prior to the screening visit. 
 The settings must have remained constant for 3 months prior to the screening visit 
and remain constant throughout the double-blind phase. 
 The battery is expected to last for the duration of the double-blind phase. 
Concomitant AEDs or their dose must be stable for 1 month prior to the screening visit and 
should not be changed at any time prior to Visit 5 in the double-blind phase but may be adjusted 


 
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during the open-label phase of the study.  Concomitant AEDs may be reduced or discontinued at 
the discretion of the investigator if medically warranted. 
Felbamate: The use of felbamate is allowed provided that the subject has been maintained on a 
stable dose of felbamate for > 6 months, and has had stable liver function (AST/ALT) and 
hematology during the course of treatment, and is expected to remain constant throughout the 
double-blind phase. 
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 investigational products, as well as 
ketoconazole.  Concurrent use of ACTH, prednisone or other glucocorticoid is not permitted, nor 
use of moderate or strong inducers or inhibitors of CYP3A4/5/7.  A list of CYP3A4/5/7 
inhibitors and inducers is included in Section 12.1.  Moderate or strong inducer or inhibitor anti-
epileptic drugs will be allowed (e.g., carbamazepine, phenytoin, etc.) Concomitant PRN topical 
and intranasal steroids for dermatologic reactions and allergic rhinitis are allowed and do not 
warrant exclusion from the study.   
Only Epidiolex (cannabidiol; GW Pharmaceuticals, may go by another name in countries outside 
the US) is allowed during the double-blind phase provided the subject has been on a stable dose 
for at least 1 month prior to screening and is expected to remain on a stable dose without a 
foreseeable change for the duration of the double-blind phase. Other products containing THC or 
CBD are excluded in the double-blind phase of the study but allowed in the open-label phase. 
Tetrahydrocannabinol or CBD should be washed out for at least 6 weeks.  Subjects with a 
positive result on THC or CBD test (via urine or plasma drug screen) at the screening visit, and a 
positive result on THC or CBD test (via plasma) at the baseline visit will be excluded from the 
study.   


 
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6. 
INVESTIGATIONAL PRODUCT 
6.1. 
Identity of Investigational Product 
Drug name:  GNX suspension 
 
Vehicle:  The suspension contains GNX (50 mg/mL), hydroxypropyl methylcellulose, polyvinyl 
alcohol, sodium lauryl sulfate, simethicone, methylparaben, propylparaben, sodium benzoate, 
citric acid, and sodium citrate at pH 3.8 to 4.2, and is sweetened with sucralose and flavored with 
artificial cherry.   
Strength:  50 mg/mL suspension; 110 mL in 125 mL high-density polyethylene bottles 
PBO suspension 
 
Vehicle: The PBO suspension consists of titanium dioxide, microcrystalline cellulose, sodium 
lauryl sulfate, simethicone, methylparaben, propylparaben, sodium benzoate, citric acid, sodium 
citrate and is sweetened with sucralose and flavored with artificial cherry. 
Both GNX and PBO will be packaged in high-density polyethylene (HDPE) bottles with a child 
resistant closure. 
GNX will be supplied at a concentration of 50 mg/mL (GNX equivalent) in 125 mL bottles, 
containing 110 mL GNX.  A PBO suspension, which is identical in taste and appearance, will be 
supplied at an equal volume. 
6.1.1. 
Blinding the Treatment Assignment 
The contents of each bottle will be blinded using labels with unique bottle numbers.  Only the 
investigational product supplier and the sponsor’s investigational product manager will be 
unblinded as to the bottle number and the contents of each bottle of investigational product. 
6.2. 
Administration of Investigational Products 
6.2.1. 
Interactive Response Technology for Investigational Product Management 
For the double-blind phase and the titration period of the open-label phase and thereafter an 
IWRS will be utilized for the following investigational product tasks: 
 Randomization 
 Supply management 
 Inventory management and supply ordering 
 Expiration date tracking 
 Emergency unblinding 


 
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6.2.2. 
Allocation of Subjects to Treatment  
Subjects will be randomly assigned at a 1:1 ratio (GNX: PBO) based on a randomization 
schedule at Visit 2 (Week 0).  Subjects will be stratified into 2 groups based on baseline seizure 
frequency.  Only the investigational product supplier and the sponsor’s investigational product 
manager will be unblinded as to the contents of each bottle of investigational product.  Study 
staff as well as subject and caregiver will be blinded to treatment assignments. 
An IWRS will centrally randomize subjects.  The randomization schedule will be generated 
using a standard, validated method and maintained by the investigational product supplier and 
IWRS vendor.  The investigator will be instructed by the IWRS, which numbered bottle to use to 
dose a subject.  The investigator and research staff will be aware of the ascending dose design of 
the clinical investigation; however, the investigator, the research staff, and the subjects will be 
blinded with respect to who is receiving active drug versus PBO.  The maximum PBO period is 
17 weeks. 
The contents of each bottle will be blinded using labels.  The randomization schedule will match 
a subject number to a bottle number.  Upon completion of baseline evaluations for each subject, 
the investigator or appropriate designee will log into the IWRS to receive a bottle number.  
Complete instructions for obtaining a bottle number will be provided to the clinical sites prior to 
initiating the study.  The designated personnel at the clinical site will match the assigned bottle 
number with the correct bottle of investigational product and distribute the bottle to the 
investigator or designee.   
6.2.3. 
Dosing 
Ganaxolone will be prescribed in increments of 15 mg/kg/day up to 63 mg/kg/day (maximum 
1800 mg/day) as an oral suspension.  Subjects ≤ 28 kg will be dosed on an mg/kg basis. 
For subjects weighing ≤ 28 kg 
Subjects weighing 28 kg (61.6 lbs.) or less will be dosed according to the subject’s weight in 
kilograms and use oral suspension (Table 4).  All investigational product prescribed per day will 
be administered in 3 divided doses following a meal or snack. 
Table 4: 
Oral Suspension (50 mg/ml) Dosing for Subjects Weighing ≤ 28 kg 
Dose 
Total mg/kg/day 
Days 
6 mg/kg TID 
18 
1-7 
11 mg/kg TID 
33 
8-14 
16 mg/kg TID 
48 
15-21 
21 mg/kg TID 
63 
22-28 
TID = three times daily 


 
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For subjects weighing > 28 kg 
Subjects weighing greater than 28 kg (61.6 lbs.) will be dosed by mg/day using oral suspension 
(Table 5).  Suspension dosing will be administered in 3 divided doses following a meal or snack.   
Table 5: 
Oral Suspension (50 mg/ml) Dosing for Subjects Weighing > 28 kg 
Dose 
ml per Dose 
Total mg/day 
Days 
150 mg TID 
3 
450 
1-7 
300 mg TID 
6 
900 
8-14 
450 mg TID 
9 
1350 
15-21 
600 mg TID 
12 
1800 
22-28 
TID = three times daily 
 
The maximum allowable dose is 63 mg/kg/day or a maximum of 1800 mg a day.  Any subject 
not tolerating the next dose step can be maintained at the lower dose step for additional days 
before advancing to next dose.  If the next dose is still not tolerated, they can drop back to the 
next lower dose step.  A minimum dose of 33 mg/kg/day and 900 mg/day is generally required 
during the double-blind phase unless a lower dose is agreed to with the Sponsor. 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.  The higher dose in the evening is expected to be better 
tolerated due to the proximity to bedtime. However, tolerability management and the final 
decision to adjust drug dosages lies with Principal Investigator.  
Investigational product may be stopped immediately and without down titration in the case of an 
emergency, although a down titration in the event of an early termination is recommended.  Dose 
de-escalation will occur in decreasing increments of 15 mg/kg/day or 450 mg every 4 days over 
2 weeks whenever feasible. 
Open-Label  
Following the completion of the 17-week, double-blind phase, subjects randomized to PBO will 
transition to GNX while subjects randomized to GNX will stay on 63 mg/kg/day suspension 
(maximum 1800 mg/day or Maximum Tolerated Dose [MTD]).  Subjects will begin the 4-week 
blinded dose titration to 63 mg/kg/day or 1800 mg/day (or MTD) after completing Visit 5.  
In order to maintain the blind of the double-blind phase, all subjects will be required to dose 
from 2 groups of bottles:  Bottle Group A- maintenance and Bottle Group B- titration.  In 
addition to the maintenance dose from Bottle Group A, subjects will be instructed to take a 
second dose from Bottle Group B.  For subjects initially randomized to GNX, Bottle Group A 
will contain GNX while Bottle Group B will contain PBO.  For subjects initially randomized to 
PBO, Bottle Group A will contain PBO while Bottle Group B will contain GNX.  
Dosing from both Bottle Group A and Bottle Group B will begin at the end of Visit 5 (Week 17), 
the last visit in the double-blind phase, and continue until the end of the open-label 4-week 
titration period when subjects return to the site for evaluation (Visit 7, Week 21).  Subjects will 
have an interim safety visit at Visit 6 (Week 19) 2 weeks after starting the open-label phase in 
which they will receive a new set of medication bottles (Table 6).  


 
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Table 6: 
Transition from Double-blind to Open-label: Oral Suspension (50 mg/ml) 
Dosing for Subjects ≤ 28 kg 
Titration Day 
Bottle Group A- Maintenance 
Bottle Group B- Titration 
 
DB GNX: GNX bottle 
DB GNX: Placebo bottle 
 
DB Placebo: Placebo bottle 
DB Placebo: GNX bottle 
 
Bottle Group A Dose 
Bottle Group B Dose 
1-7 
63 mg/kg/day (21 mg/kg TID) 
18 mg/kg/day (6 mg/kg TID) 
8-14 
63 mg/kg/day (21 mg/kg TID) 
33 mg/kg/day (11 mg/kg TID) 
Visit 6, Week 19 
Safety visit and new set of Group A and Group B bottles issued 
15-21 
63 mg/kg/day (21 mg/kg TID) 
48 mg/kg/day (16 mg/kg TID) 
22-28 
63 mg/kg/day (21 mg/kg TID) 
63 mg/kg/day (21 mg/kg TID) 
Visit 7, Week 21 
One set of GNX bottles dispensed, return to dosing from 1 bottle at a time 
63 mg/kg/day (21 mg/kg TID) 
DB = double-blind; GNX = ganaxolone; TID = three times daily. 
 


 
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An example of the transition from double-blind to open-label dosing is shown in Table 7 for a 
20 kg subject who was initially randomized to GNX during the double-blind phase.  
Table 7: 
Example of Double-blind to Open-label: DB GNX Subject Weighing 20 kg- 
Suspension Dosing (50 mg/ml) 
Titration Day 
Bottle Group A- Maintenance 
Treatment: GNX 
Bottle Group B- Titration 
Treatment: Placebo 
Days 1-7 
63 mg/kg/day (21 mg/kg TID) 
18 mg/kg/day (6 mg/kg TID) 
Day 1 morning dose 
21 mg/kg; 8.4ml 
6 mg/kg; 2.4ml 
Day 1 afternoon dose 
21 mg/kg; 8.4ml 
6 mg/kg; 2.4ml 
Day 1 evening dose 
21 mg/kg; 8.4ml 
6 mg/kg; 2.4ml 
Continue dosing from Group A and B as above until the end of Day 7 
Days 8-14 
63 mg/kg/day (21 mg/kg TID) 
33 mg/kg/day (11 mg/kg TID) 
Day 8 morning dose 
21 mg/kg; 8.4ml 
11 mg//kg; 4.4ml 
Day 8 afternoon dose 
21 mg/kg; 8.4ml 
11 mg//kg; 4.4ml 
Day 8 evening dose 
21 mg/kg; 8.4ml 
11 mg//kg; 4.4ml 
Continue dosing from Group A and B as above until Visit 6, Week 19  
Visit 6, Week 19 
Safety visit and receive new bottles 
Days 15-21 
63 mg/kg/day (21 mg/kg TID) 
48 mg/kg/day (16 mg/kg TID) 
Day 15 morning dose 
21 mg/kg; 8.4ml 
16 mg//kg; 6.4ml 
Day 15 afternoon dose 
21 mg/kg; 8.4ml 
16 mg//kg; 6.4ml 
Day 15 evening dose 
21 mg/kg; 8.4ml 
16 mg//kg; 6.4ml 
Continue dosing from Group A and B as above until the end of Day 21 
Days 22-28 
63 mg/kg/day (21 mg/kg TID) 
63 mg/kg/day (21 mg/kg TID) 
Day 15 morning dose 
21 mg/kg; 8.4ml 
21 mg/kg; 8.4ml 
Day 15 afternoon dose 
21 mg/kg; 8.4ml 
21 mg/kg; 8.4ml 
Day 15 evening dose 
21 mg/kg; 8.4ml 
21 mg/kg; 8.4ml 
Continue dosing from Group A and B as above until Visit 7, Week 21 
Visit 7, Week 21 
One set of GNX bottles dispensed, return to dosing from 1 bottle at a 
time 
Day 29 
63 mg/kg/day (21 mg/kg TID) 
Day 29 morning dose 
21 mg/kg; 8.4ml 
Day 29 afternoon dose 
21 mg/kg; 8.4ml 
Day 29 evening dose 
21 mg/kg; 8.4ml 
DB = double-blind; GNX = ganaxolone; TID = three times daily. 
 


 
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An example of the transition from double-blind to open-label dosing is shown in Table 8 for a 
20 kg subject who was initially randomized to PBO during the double-blind phase.  
Table 8: 
Example of Double-blind to Open-label: Placebo Subject Weighing 20 kg- 
Suspension Dosing (50 mg/ml) 
Titration Day 
Bottle Group A- Maintenance 
Treatment: Placebo 
Bottle Group B- Titration 
Treatment: GNX 
Days 1-7 
63 mg/kg/day (21 mg/kg TID) 
18 mg/kg/day (6 mg/kg TID) 
Day 1 morning dose 
21 mg/kg; 8.4ml 
6 mg/kg; 2.4ml 
Day 1 afternoon dose 
21 mg/kg; 8.4ml 
6 mg/kg; 2.4ml 
Day 1 evening dose 
21 mg/kg; 8.4ml 
6 mg/kg; 2.4ml 
Continue dosing from Group A and B as above until the end of Day 7 
Days 8-14 
63 mg/kg/day (21 mg/kg TID) 
33 mg/kg/day (11 mg/kg TID) 
Day 8 morning dose 
21 mg/kg; 8.4ml 
11 mg/kg; 4.4ml 
Day 8 afternoon dose 
21 mg/kg; 8.4ml 
11 mg/kg; 4.4ml 
Day 8 evening dose 
21 mg/kg; 8.4ml 
11 mg/kg; 4.4ml 
Continue dosing from Group A and B as above until Visit 6, Week 19  
Visit 6, Week 19 
Safety visit and receive new bottles 
Days 15-21 
63 mg/kg/day (21 mg/kg TID) 
48 mg/kg/day (16 mg/kg TID) 
Day 15 morning dose 
21 mg/kg; 8.4ml 
16 mg/kg; 6.4ml 
Day 15 afternoon dose 
21 mg/kg; 8.4ml 
16 mg/kg; 6.4ml 
Day 15 evening dose 
21 mg/kg; 8.4ml 
16 mg/kg; 6.4ml 
Continue dosing from Group A and B as above until the end of Day 21 
Days 22-28 
63 mg/kg/day (21 mg/kg TID) 
63 mg/kg/day (21 mg/kg TID) 
Day 15 morning dose 
21 mg/kg; 8.4ml 
21 mg/kg; 8.4ml 
Day 15 afternoon dose 
21 mg/kg; 8.4ml 
21 mg/kg; 8.4ml 
Day 15 evening dose 
21 mg/kg; 8.4ml 
21 mg/kg; 8.4ml 
Continue dosing from Group A and B as above until Visit 7, Week 21 
Visit 7, Week 21 
One set of GNX bottles dispensed, return to dosing from 1 bottle at a 
time 
Day 29 
63 mg/kg/day (21 mg/kg TID) 
Day 29 morning dose 
21 mg/kg; 8.4ml 
Day 29 afternoon dose 
21 mg/kg; 8.4ml 
Day 29 evening dose 
21 mg/kg; 8.4ml 
GNX = ganaxolone; TID = three times daily. 


 
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Subjects weighing > 28 kg and dosed using suspension will follow the dosing schedule in 
Table 9.  
 
Table 9: 
Transition from Double-blind to Open-label: Suspension (50 mg/ml) 
Dosing for Subjects > 28 kg 
Titration Day 
Bottle Group A- Maintenance 
Bottle Group B- Titration 
 
DB GNX: GNX bottle 
DB GNX: Placebo bottle 
 
DB Placebo: Placebo bottle 
DB Placebo: GNX bottle 
 
Bottle Group A Dose 
Bottle Group B Dose 
1-7 
1800 mg/day; 12 ml per dose TID 
450 mg/day; 3 ml per dose TID 
8-14 
1800 mg/day; 12 ml per dose TID 
900 mg/day; 6 ml per dose TID 
Visit 6, Week 19 
Safety visit and new set of Group A and Group B bottles issued 
15-21 
1800 mg/day; 12 ml per dose TID 
1350 mg/day; 9 ml per dose TID 
22-28 
1800 mg/day; 12 ml per dose TID 
1800 mg/day; 12 ml per dose TID 
Visit 7, Week 21 
One set of GNX bottles dispensed, return to dosing from 1 bottle at a time 
1800 mg/day; 12 ml per dose TID 
DB = double-blind; GNX = ganaxolone; TID = three times daily. 
 
 


 
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An example of the transition from double-blind to open-label dosing is shown in Table 10 for a > 
28 kg subject who was initially randomized to GNX during the double-blind phase using 
suspension. 
 
Table 10: 
Example of Double-blind to Open-label: DB GNX Subject Weighing > 28 - 
Suspension Dosing (50 mg/ml) 
Titration Day 
Bottle Group A- Maintenance 
Treatment: GNX 
Bottle Group B- Titration 
Treatment: Placebo 
Days 1-7 
1800 mg/day (600 mg TID) 
450 mg/day (150 mg TID) 
Day 1 morning dose 
600 mg; 12ml 
150 mg; 3ml 
Day 1 afternoon dose 
600 mg; 12ml 
150 mg; 3ml 
Day 1 evening dose 
600 mg; 12ml 
150 mg; 3ml 
Continue dosing from Group A and B as above until the end of Day 7 
Days 8-14 
1800 mg/day (600 mg TID) 
900 mg/day (300 mg TID) 
Day 8 morning dose 
600 mg; 12ml 
300 mg; 6ml 
Day 8 afternoon dose 
600 mg; 12ml 
300 mg; 6ml 
Day 8 evening dose 
600 mg; 12ml 
300 mg; 6ml 
Continue dosing from Group A and B as above until Visit 6, Week 19  
Visit 6, Week 19 
Safety visit and receive new bottles 
Days 15-21 
1800 mg/day (600 mg TID) 
1350 mg/day (450 mg TID) 
Day 15 morning dose 
600 mg; 12ml 
450mg; 9ml 
Day 15 afternoon dose 
600 mg; 12ml 
450mg; 9ml 
Day 15 evening dose 
600 mg; 12ml 
450mg; 9ml 
Continue dosing from Group A and B as above until the end of Day 21 
Days 22-28 
1800 mg/day (600 mg TID) 
1800 mg/day (600 mg TID) 
Day 15 morning dose 
600 mg; 12ml 
600 mg; 12ml 
Day 15 afternoon dose 
600 mg; 12ml 
600 mg; 12ml 
Day 15 evening dose 
600 mg; 12ml 
600 mg; 12ml 
Continue dosing from Group A and B as above until Visit 7, Week 21 
Visit 7, Week 21 
One set of GNX bottles dispensed, return to dosing from 1 bottle at a time 
Day 29 
1800 mg/day (600 mg TID) 
Day 29 morning dose 
600 mg; 12ml 
Day 29 afternoon dose 
600 mg; 12ml 
Day 29 evening dose 
600 mg; 12ml 
DB = double-blind; GNX = ganaxolone; TID = three times daily. 
 
 


 
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An example of the transition from double-blind to open-label dosing is shown in Table 11 for a > 
28 kg subject who was initially randomized to PBO during the double-blind phase using 
suspension. 
 
Table 11: 
Example of Double-blind to Open-label: Placebo Subject Weighing > 
28 kg- Suspension Dosing (50 mg/ml) 
Titration Day 
Bottle Group A- Maintenance 
Treatment: Placebo 
Bottle Group B- Titration 
Treatment: GNX 
Days 1-7 
1800 mg/day (600 mg TID) 
450 mg/day (150 mg TID) 
Day 1 morning dose 
600 mg; 12ml 
150 mg; 3ml 
Day 1 afternoon dose 
600 mg; 12ml 
150 mg; 3ml 
Day 1 evening dose 
600 mg; 12ml 
150 mg; 3ml 
Continue dosing from Group A and B as above until the end of Day 7 
Days 8-14 
1800 mg/day (600 mg TID) 
900 mg/day (300 mg TID) 
Day 8 morning dose 
600 mg; 12ml 
300 mg; 6ml 
Day 8 afternoon dose 
600 mg; 12ml 
300 mg; 6ml 
Day 8 evening dose 
600 mg; 12ml 
300 mg; 6ml 
Continue dosing from Group A and B as above until Visit 6, Week 19  
Visit 6, Week 19 
Safety visit and receive new bottles 
Days 15-21 
1800 mg/day (600 mg TID) 
1350 mg/day (450 mg TID) 
Day 15 morning dose 
600 mg; 12ml 
450mg; 9ml 
Day 15 afternoon dose 
600 mg; 12ml 
450mg; 9ml 
Day 15 evening dose 
600 mg; 12ml 
450mg; 9ml 
Continue dosing from Group A and B as above until the end of Day 21 
Days 22-28 
1800 mg/day (600 mg TID) 
1800 mg/day (600 mg TID) 
Day 15 morning dose 
600 mg; 12ml 
600 mg; 12ml 
Day 15 afternoon dose 
600 mg; 12ml 
600 mg; 12ml 
Day 15 evening dose 
600 mg; 12ml 
600 mg; 12ml 
Continue dosing from Group A and B as above until Visit 7, Week 21 
Visit 7, Week 21 
One set of GNX bottles dispensed, return to dosing from 1 bottle at a time 
Day 29 
1800 mg/day (600 mg TID) 
Day 29 morning dose 
600 mg; 12ml 
Day 29 afternoon dose 
600 mg; 12ml 
Day 29 evening dose 
600 mg; 12ml 
GNX = ganaxolone; TID = three times daily. 
 
 


 
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De-escalation Period 
Any subject who completes the study or discontinues investigational product treatment should 
undergo a 2-week drug de-escalation (taper) period.  The schedule will be dependent on the 
maintenance dose.  Typically, doses will be reduced by 15 mg/kg/day or 450 mg/day every 3 
days until the subject is completely off investigational product. Subjects should then return for a 
post-taper safety follow up visit. 
Table 12: 
De-Escalation of Investigational Product 
Formulation 
Dose 
Frequency 
Suspension (weighing ≤ 28 kg) 
Reduce 15mg/kg/day 
Every 3 days 
Suspension (weighing > 28 kg) 
Reduce 450 mg/day 
Every 3 days 
 
6.2.4. 
Dose Administration 
Investigational product will be provided as an oral suspension.  Ganaxolone must be taken 
with a meal or snack.  Note: grapefruit and grapefruit juice, Seville oranges 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 
investigational product 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 
 
Use the bottle adapter and dosing syringes provided. Do not use a household spoon. The syringe 
should be replaced daily and cleaned between each dose that day by rinsing for 30 seconds using 
hot water and allowing it to air dry. The bottle adapter should stay in the bottle once it’s inserted.  
It should not be removed. 
 
Subjects and their parent or legal guardian will be informed about possible side effects from the 
investigational product and cautioned to avoid quick postural changes, at least until they know 
how the investigational product affects them.  Subjects will be advised that the investigational 
product might affect mental alertness.  They will also be cautioned that non-adherence to the 
dosing instructions (e.g., increasing the dose, taking the investigational product doses too close 
together) could produce side effects. 


 
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6.2.5. 
Missing a Dose 
Ganaxolone oral suspension:  A missed dose of investigational product may be taken up to 
4 hours before the next scheduled dose; otherwise, the missed dose should not be given. 
Parents/caregivers should be instructed that if the subject misses 2 days in a row or more, the site 
should be contacted to determine whether any adjustment in investigational product is needed.  
The site will confer with the medical monitor to devise a dosing plan.   
Parents/caregivers should be instructed to minimize the number of missed doses the subject 
experiences and be re-educated on proper dosing procedures at each visit to ensure that missed 
doses are avoided. 
Table 13: 
Missed Dose of Investigational Product 
Formulation 
Proceed to Dose 
DO NOT DOSE 
Suspension 
≥ 4 hours before next 
scheduled dose 
< 4 hours before next 
scheduled dose 
 
6.3. 
Unblinding the Treatment Assignment 
If it is deemed necessary to unblind a subject’s treatment in order to provide medical 
management of an AE or to provide emergency treatment, unblinding will be conducted through 
the IWRS.  Unblinding should only occur if necessary, for the medical management of the 
subject.  Prior to unblinding or immediately following, the sponsor’s Medical Monitor must be 
contacted.  The sponsor’s Medical Monitor does not have to be contacted to initiate unblinding in 
the IWRS system. Subjects who are unblinded during the double-blind phase will be 
discontinued from investigational drug treatment but asked to continue seizure charting until the 
completion of the double-blind phase.  If unblinding occurs, please contact: 
SPONSOR CONTACTS:  
Sponsor Medical Monitor 
MD, FAAP 
Mobile Telephone:
(primary contact method/send text message if no immediate 
response) Email: 
 
If sponsor’s Medical Monitor cannot be reached in an emergency, the site should contact: 
 
Back-up Medical Monitor: 
mailto:
MD 
 
Office Telephone:
 
Mobile Telephone:
 
Email:


 
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Sponsor Project Managers:  
 
Office Telephone: 
Mobile Telephone:
primary contact method) 
Email:
 
 
 BS 
 
Office Telephone: 
Mobile Telephone: 
(primary contact method) 
Email:
 
 
CRO CONTACTS:  
mailto: 
 PhD 
 
Office Telephone: 
Email: 
 
Office Telephone: 
Mobile Telephone:
Email: 
Global Clinical Trials (GCT): Russia 
 
 
Mobile Telephone :
Email: 
 
 
 
 


 
 
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6.4. 
Labeling, Packaging, Storage, and Handling 
6.4.1. 
Labeling 
Labels containing study information and bottle identification are applied to the investigational 
product container.  
All investigational product is labeled with a minimum of the following: protocol number, 
medication identification number (if applicable), dosage form (including product name and 
quantity in pack), directions for use, storage conditions, batch number and/or packaging 
reference, the statements “For investigational use only” and/or “Caution: New Drug—Limited by 
Federal (or US) Law to Investigational Use” and “Keep out of reach of children,” and the 
sponsor’s name and address. 
Additional labels may, on a case-by-case basis, be applied to the investigational product in order 
to satisfy local or hospital requirements, but must not: 
 Contradict the clinical study label 
 Obscure the clinical study label 
 Identify the study subject by name, without consultation with the sponsor 
Additional labels may not be added without the sponsor’s prior full agreement. 
6.4.2. 
Packaging 
Ganaxolone and PBO oral suspension formulation will be provided to the site as individual 
suspension bottles containing 110 mL in 125-mL 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. 
6.4.3. 
Storage 
The investigator has overall responsibility for ensuring that investigational product 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.  
Ganaxolone and PBO suspension should be stored at room temperature 15°C to 25°C (59°F to 
77°F). 
Investigational product must be stored in accordance with labeled storage conditions.  
Temperature monitoring of the investigational product is required at the storage location to 
ensure that the investigational product 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 


 
 
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a specific time period can be recorded and retrieved as required.  Such a device (i.e., certified 
min/max thermometer) would require manual resetting upon each recording.  The sponsor must 
be notified immediately upon discovery of any excursion from the established range.  
Temperature excursions will require site investigation as to cause and remediation.  The sponsor 
will determine the ultimate impact of excursions on the investigational product and will provide 
supportive documentation as necessary.  Under no circumstances should the product be 
dispensed to subjects until the impact has been determined and the product is deemed appropriate 
for use by the sponsor. 
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), such as fumigation of a 
storage room. 
6.5. 
Investigational Product Accountability 
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects.  The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition.  Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section. 
The investigator has overall responsibility for administering/dispensing investigational product.  
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 investigational product only to 
subjects included in this study following the procedures set out in the study protocol.  Each 
subject will be given only the investigational product carrying his or her treatment assignment.  
All administered and/or dispensed investigational product will be documented on the eCRFs 
and/or other investigational product record.  The investigator is responsible for ensuring the 
retrieval of all investigational product and study supplies from subjects.  
The subject’s parent/caregiver must be instructed to save and bring their unused investigational 
product and empty/used investigational product 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 investigational product 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 
investigational product accountability form. 
No investigational product 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. 


 
 
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At the end of the study, or as instructed by the sponsor, all unused stock, subject-returned, or 
expired investigational product are either to be sent to a nominated contractor on behalf of the 
sponsor for destruction or are to be destroyed by the site.  Investigational products being returned 
to the sponsor’s designated contractors or approved to be destroyed by the site counted/measured 
and verified will be reconciled by clinical site personnel and the sponsor (or designated CRO).  
Shipment return forms, when used, will be signed prior to shipment from the site.  Returned 
investigational products will be packed in a tamper-evident manner to ensure product integrity.  
Shipment of all returned investigational product must comply with local, state, and national laws. 
With the written agreement of the sponsor, unused stock, subject-returned, and expired 
investigational product 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 investigational products must be in accordance with local, state, 
and national laws. 
Based on entries in the site’s drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned.  All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction. 
6.6. 
Subject Compliance 
Subject compliance will be tracked through the electronic seizure and medication diary.  
Parent/caregiver are to record daily seizure frequency and type in addition to study medication 
and non-study AED administration throughout the study including the prospective 6-wk baseline 
seizure-charting period.  Compliance with investigational product treatment will be assessed by 
inspecting the electronic 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, investigational product and non-study AED recording as needed.  Subjects that fall 
below 80% compliance at 2 consecutive visits during the double-blind phase will not be included 
in the per-protocol population.  
 


 
 
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7. 
STUDY PROCEDURES 
7.1. 
Study Assessments 
See Schedule of Assessments (Table 1 and Table 2) for details regarding scheduled assessments 
and procedures in this study.  
7.2. 
Study Procedures (Double-blind Phase) 
7.2.1. 
Screening Period 
7.2.1.1. 
Historical Seizure Type and Frequency (Week -14) 
Potential subjects will have already been pre-identified by the site because of confirmed or 
suspected CDKL5 genetic mutation testing as part of their standard of care epilepsy work-up.  
It is also very common that parents/caregivers/LARs of CDKL5 patients maintain daily seizure 
calendars, which capture both seizure type and frequency and days when no seizures occur as 
part of their standard of care treatment regimen.  A 2-month (8-week) daily historical seizure 
calendar will be reviewed at the screening visit to determine eligibility per inclusion/exclusion 
criteria.  Acceptable daily historical seizure calendars will need to denote seizure types, 
frequency, and days that no seizures occurred.  Procedures specific to this protocol and not 
otherwise considered standard of care, will not be performed until written informed 
consent/assent from the subject’s parent or legal guardian has been appropriately obtained.  In 
the event that parents/caregivers/LAR do not routinely maintain a daily seizure calendar per 
standard of care, written informed consent will be obtained, and the subject will be asked to 
return to the clinic for the Screening (Visit 1) after they have maintained a 2-month (8-week) 
daily historical seizure calendar. 
7.2.1.2. 
Screening (Visit 1, Week -6) 
Additional procedures/assessments to be completed during the screening period may include the 
following: 
 Informed consent from parent/LAR (or subject assent) 
 Demographics and medical history 
 Historical seizure calendar review 
 Review of inclusion/exclusion criteria 
 Genetic testing to confirm pathogenic or likely pathogenic CDKL5 variant 
 Seizure Identification and Diagnostic Review Form (SIF/DRF) (Epilepsy Study 
Consortium) 
 Vital signs (to include BP, HR, RR, body temperature, weight, and height) 
 Physical, neurological, and developmental examination 
 ECG 


 
 
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 Clinical laboratory tests (to include complete blood count [CBC] with automated 
differential, creatinine, blood urea nitrogen, and comprehensive metabolic panel) 
 Urinalysis (An attempt should be made to collect a urine sample at this screening 
visit. Otherwise, the urine sample can be collected at baseline.) 
 Drug screen (urine or plasma) 
 Investigator and parent/caregiver/LAR establish baseline patient behavior for 
CGICA, CGI-C and CGI-I  
 Serum pregnancy test for girls/women of childbearing potential  
 Tanner staging 
 Concomitant AED review and levels if per standard of care (SOC) 
 Neurosteroid level sample draw 
 Adverse events 
 Electronic seizure and medication diary set up and review 
A screen failure is a subject for whom informed consent has been obtained and has failed to meet 
the inclusion criteria and/or met at least 1 of the exclusion criteria and has not been administered 
the investigational product.  
7.2.1.3. 
Baseline (Visit 2, Week 0 + 6 days, Randomization) 
The following study procedures/assessments must be completed, the results must be received, 
and the investigator must ensure the subject meets all inclusion and exclusion criteria prior to 
investigational product administration.  Visit 2 must occur a minimum of 6 weeks (42 days) after 
Visit 1 and no later than 6 weeks + 6 days (48 days) after Visit 1: 
 Review of inclusion/exclusion criteria 
 Medical history review 
 SIF/DRF (Epilepsy Study Consortium) approval 
 Vital signs (to include BP, HR, RR, and body temperature. Weight will only be 
collected if unable to collect at Visit 1) 
 Physical, neurological, and developmental follow-up examination 
 ECG 
 Clinical laboratory tests (to include CBC with automated differential, creatinine, 
blood urea nitrogen, and comprehensive metabolic panel) 
 Urinalysis (If the urine sample was not collected at screening, it must be collected at 
baseline in order to complete the study-related procedures per protocol.) 
 Serum pregnancy test for girls/women of childbearing potential 
 Concomitant AED review and levels if per SOC 


 
 
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 Adverse events 
 Seizure and medication diary review 
 EEG 
 CSHQ 
 ADAMS 
 QI-Disability 
 PSI 
 Dispense investigational product 
7.2.2. 
Titration + Maintenance (3 Days, Weeks 1, 2, 3, 4, 5, 9, and 13) 
7.2.2.1. 
Telephone Follow-up (Day 3 ± 2 days and Weeks 1, 2, 3, and 4 ± 3 days) 
A telephone follow-up visit will be conducted at Day 3 ± 2 days and Weeks 1, 2, 3, and 4 to 
assess the following: 
 Adverse events 
 Seizure and medication diary review 
7.2.2.2. 
Titration + Maintenance (Visits 3 and 4, Weeks 5 ± 3 days and 9± 3 days) 
The following study procedures/assessments will be completed at Weeks 5 and 9 of the 
double-blind phase: 
 Vital signs (to include BP, HR, RR, and body temperature) 
 Physical, neurological, and developmental examination (Visit 3, Week 5 only) 
 Physical, neurological, and developmental follow-up examination (Visit 4, Week 9 
only) 
 ECG (Visit 3, Week 5 only) 
 Clinical laboratory tests (to include CBC with automated differential, creatinine, 
blood urea nitrogen, and comprehensive metabolic panel) 
 Investigational Product PK (population PK at Visit 3:1-5 hours post dose and Visit 4: 
4-8 hours post dose) 
 Concomitant AED review and levels if per SOC 
 Adverse events 
 Seizure and medication diary review 
 CGICA 
 CGI-C (parent/caregiver/LAR identified behavioral target) 


 
 
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 CGI-I (parent/caregiver/LAR and clinician) 
 CGI-CSID 
 CSHQ 
 ADAMS 
 QI-Disability 
 PSI 
 Dispense investigational product 
7.2.2.3. 
Telephone Follow-up Visit (Weeks 11, 13 ± 3 days) 
A telephone follow-up visit will be conducted at Weeks 11 and 13 to assess the following: 
 Adverse events 
 Seizure and medication diary review 
7.2.3. 
Final Double-blind Visit /First Open-label Visit (Visit 5, Week 17 ± 3 days) 
The following study procedures/assessments will be completed during the final double-blind 
visit or taper visit or at the time of early termination: 
 Vital signs (to include BP, HR, RR, body temperature, and weight) 
 Physical, neurological, and developmental examination 
 ECG 
 Clinical laboratory tests (to include CBC with automated differential, creatinine, 
blood urea nitrogen, and comprehensive metabolic panel) 
 Urinalysis 
 Investigational Product PK  
 Concomitant AED review and levels if per SOC 
 Neurosteroid level sample draw 
 Adverse events 
 Seizure and medication diary review 
 CGICA 
 CGI-C (parent/caregiver/LAR identified behavioral target) 
 CGI-I (parent/caregiver/LAR and clinician) 
 CGI-CSID 
 EEG 
 CSHQ 


 
 
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 ADAMS 
 QI-Disability 
 PSI 
 Dispense investigational product  
 
7.2.4. 
Telephone Follow-up (3 days after Visit 5 ± 1 day, Weeks 18 and 20 ± 3 days)  
A telephone follow-up visit will be conducted 3 days after Visit 5 and at Weeks 18 and 20 to 
assess the following: 
 Adverse events 
 Seizure and medication diary review 
 
7.2.5. 
Open-Label Blinded Titration (Visit 6, Week 19 ± 3 days) 
The following study procedures/assessments will be completed at the Open-label Blinded 
Titration (Visit 6) in the open-label phase of the study: 
 Vital signs (to include BP, HR, RR, and body temperature) 
 Physical, neurological, and developmental follow-up examination  
 Clinical laboratory tests (to include CBC with automated differential, creatinine, 
blood urea nitrogen, and comprehensive metabolic panel) 
 Investigational Product PK 
 Concomitant AED review and levels if per SOC  
 Adverse events 
 Seizure and medication diary review 
 CGI-I (clinician and parent/caregiver/LAR)  
 Dispense Investigational Product  
7.2.5.1. 
Open-Label Blinded Titration (Visit 7, Week 21 ± 3 days) 
 Vital signs (to include BP, HR, RR, and body temperature) 
 Physical, neurological, and developmental examination 
 ECG 
 Clinical laboratory tests (to include CBC with automated differential, creatinine, 
blood urea nitrogen, and comprehensive metabolic panel) 
 Investigational Product PK (population PK between 1-5 hours post dose) 


 
 
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 Concomitant AED review and levels if per SOC 
 Adverse events 
 Seizure and medication diary review 
 CGICA 
 CGI-C (parent/caregiver/LAR identified behavioral target) 
 CGI-I (parent/caregiver/LAR and clinician) 
 CGI-CSID 
 CSHQ 
 ADAMS 
 QI-Disability 
 PSI 
 Dispense Investigational Product 
7.2.6. 
Open-Label Maintenance (Weeks 28-68; ± 7 days window for each visit) 
7.2.6.1. 
Telephone Follow-up (Weeks 28, 43 and 60; ± 7 days window for each visit) 
A telephone follow-up visit will be conducted at Weeks 28, 43, and 60 of the open-label phase to 
assess the following: 
 Adverse events 
 Review and medication seizure diary 
7.2.6.2. 
Open-Label Maintenance (Visits 8, 9, and 10, Weeks 34, 52 and 68; ± 7 days 
window for each visit) 
The following study procedures/assessments will be completed at Weeks 34, 52 and 68 and 
every 16 weeks thereafter for the duration of the open-label phase: 
 Vital signs (All Visits: to include BP, HR, RR, and body temperature; Visits 8, 9, and 
10: to include weight; Visits 8 and 9: to include height) 
 Physical, neurological, and developmental examination  
 ECG  
 Clinical laboratory tests (to include CBC with automated differential, creatinine, 
blood urea nitrogen and comprehensive metabolic panel) 
 Urinalysis (Visit 9, Week 52 only) 
 Tanner staging (Visit 9, Week 52 only) 
 Investigational Product PK (Visit 9 only: population PK draw between 1-5 hours post 
dose) 


 
 
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 Concomitant AED review and levels if per SOC 
 Adverse events 
 Seizure and medication diary review 
 CGICA 
 CGI-C (parent/caregiver/LAR identified behavioral target) 
 CGI-I (parent/caregiver/LAR and clinician) 
 CGI-CSID 
 CSHQ 
 ADAMS 
 QI-Disability 
 PSI 
 Dispense investigational product 
7.2.6.3. 
Visit X - Additional Maintenance Visits in the Open-Label Phase (every 
16 weeks with a telephone follow-up in between ± 7 days window for each visit) 
If the subject continues in the open-label phase beyond Week 68, the subject must return for a 
clinic visit every 16 weeks to complete the following study procedures/assessments: 
 Vital signs (All Visits: to include BP, HR, RR, body temperature, and weight; only 
height will be measured annually) 
 Physical, neurological, and developmental examination  
 ECG  
 Clinical laboratory tests (to include CBC with automated differential, creatinine, 
blood urea nitrogen, and comprehensive metabolic panel) 
 Urinalysis (annually) 
 Tanner staging (annually) 
 Investigational Product PK 
 Concomitant AED review and levels if per SOC 
 Adverse events 
 Seizure and medication diary review 
 CGICA 
 CGI-C (parent/caregiver/LAR identified behavioral target) 
 CGI-I (Parent/caregiver/LAR and clinician) 
 CGI-CSID 


 
 
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 CSHQ 
 ADAMS 
 QI-Disability 
 PSI 
 Dispense investigational product 
If the subject continues in the open-label phase beyond Week 68, a telephone follow-up visit will 
occur in between every clinic visit (8 weeks after each clinic visit) to assess the following: 
 Adverse events 
 Review and medication seizure diary 
7.2.7. 
Final Open-Label Visit or Taper Visit; ± 7 days (or at time of Early 
Termination) 
The timing of the final open-label visit is not defined at this time, as the study is anticipated to 
continue until either the investigational product is approved and marketed or the sponsor 
discontinues development of investigational product in CDD (approximately an additional 3 
years).  The following study procedures/assessments to be completed during the final open-label 
visit or taper visit at the time of early termination: 
 Vital signs (to include BP, HR, RR, body temperature, weight, and height) 
 Physical, neurological, and developmental examination 
 ECG 
 Clinical laboratory tests (to include CBC with automated differential, creatinine, 
blood urea nitrogen, and comprehensive metabolic panel) 
 Urinalysis 
 Serum pregnancy test for girls/women of childbearing potential  
 Tanner staging 
 Investigational Product PK 
 Concomitant AED review and levels if SOC 
 Neurosteroid level sample draw 
 Adverse events 
 Seizure and medication diary review 
 CGICA 
 CGI-C (parent/caregiver/LAR identified behavioral target) 
 CGI-I (parent/caregiver/LAR and clinician) 
 CGI-CSID 


 
 
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 EEG 
 CSHQ 
 ADAMS 
 QI-Disability 
 PSI 
 Dispense investigational product 
7.2.8. 
Safety Follow-up Post-taper (2 Weeks; ± 3 days Post Investigational Product 
Taper) 
The following study procedures/assessments to be completed during the safety follow-up 
post-taper visit: 
 Vital signs (to include BP, HR, RR, and body temperature) 
 Physical, neurological, and developmental follow-up examination 
 Clinical laboratory tests (to include CBC with automated differential, creatinine, 
blood urea nitrogen and comprehensive metabolic panel) 
 Urinalysis 
 Serum pregnancy test for women of childbearing potential 
 Investigational Product PK 
 Concomitant AED review and levels if SOC 
 Adverse events 
 Seizure and medication diary review 
7.3. 
Screening and Diagnosis 
Potential subjects will be pre-identified by the site because of confirmed or suspected CDKL5 
genetic mutation testing as part of their standard of care epilepsy work-up.  Potential subjects 
will have historical seizure diary charting 2 months prior to screening.  Eligible historical seizure 
diary will need to include daily logs of seizure types and frequency and denote the absence of 
seizures on those days where no seizures occurred.  
7.3.1. 
Informed Consent 
Procedures specific to this protocol and not otherwise considered standard of care, will not be 
performed until written informed consent from the parent/caregiver/LAR has been appropriately 
obtained.   
7.3.2. 
Drug Screen 
A drug screen (urine or plasma) will be performed to test for THC and CBD at Visits 1 
(screening) and Visit 2 (baseline).  Concomitant use of Epidioloex (may go by another name in 


 
 
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countries outside the US) will be allowed in the double-blind phase provided the subject has 
been on a stable dose for at least 1 month prior to screening and is expected to remain on a stable 
dose without a foreseeable change for the duration of the double-blind phase.  THC and/or CBD 
will be allowed in the open-label phase.  All other THC and CBD products will not be allowed in 
the double-blind phase.  Therefore, a negative drug test at Visit 1 meets the protocol eligibility 
criteria.  If the screening drug test is positive, a plasma drug screen will be performed to test for 
THC and CBD at Visit 2 (baseline) if a prescription for Epidiolex (CBD) in epilepsy is not 
available. A positive drug test at Visit 2 will exclude the subject from the study.   Dosing should 
not commence until confirmation of a negative drug screen from Visit 2.  
7.3.3. 
Demographics and Medical History 
Demographics including age, gender, ethnicity and race will be collected. 
In addition to the genetic confirmation of pathogenic or likely pathogenic CDKL5 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 subject’s developmental history will also be assessed, as 
the subject will have to lack independent ambulation by 2 years of age.  Demographics and 
Medical History will be reviewed and collected at the Visit 1 (screening).  A review of the 
subject’s Medical History will be performed again at Visit 2 (baseline). 
7.3.4. 
Historical Seizure Calendar Review 
It is very common for parent/caregivers/LARs to maintain daily seizure calendars for this patient 
population, which capture both seizure type and frequency.  A 2-month historical seizure 
calendar will be reviewed at the screening visit to determine eligibility per inclusion/exclusion 
criteria.  Acceptable historical seizure calendars will need to denote both seizure type and 
frequency and days that no seizures occur. 
In the event the participant is not able to provide eligible historical seizure diary (2-months prior 
to screening), the informed consent will need to be obtained and the parent/caregiver will need to 
chart prospectively.   
7.3.5. 
Genetic Testing 
Genetic testing to confirm pathogenic or likely pathogenic CDKL5 variant will be confirmed by 
the sponsor’s central genetic laboratory. In France, genetic mutations may be confirmed by an 
approved French organization, in compliance with French legislation prior to Screening Visit 1.  
If the subject has a de novo VUS in the kinase domain of the CDKL5 gene, parental testing is 
negative and meets all other inclusion criteria, then the subject is eligible for enrollment.  If 
subject already has confirmation of pathogenic or likely pathogenic CDKL5 variant that has been 
confirmed by the sponsor’s selected central genetic laboratory and can provide documentation 
that the same panel was used, this genetic testing will be waived. 
Instructions for genetic testing sample collection and processing can be found in the laboratory 
manual. 


 
 
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7.3.6. 
Seizure Identification and Diagnostic Review 
Per the inclusion criteria, enrollment into the study will be based on the presence and frequency 
of the primary seizure types which includes bilateral tonic (sustained motor activity ≥ 3 seconds), 
generalized tonic-clonic, bilateral clonic, atonic/drop or seizures or focal to bilateral tonic-clonic 
seizures.  
To standardize seizure identification and classification in the study, a SIF/DRF will be submitted 
and reviewed by the Epilepsy Study Consortium.  Approval of the SIF/DRF will be required 
prior to randomization.  In addition to this form, videos of the subject’s seizure types will also be 
reviewed to confirm proper classification provided that the parent/caregiver is able to capture 
video of these seizure types, parents/caregivers are able to provide videos to the site for upload 
onto a secure encrypted server in a manner consistent with ICH/GCP and if local IRB/EC 
regulations grants approval for collection of such videos.  Parents/caregivers must make every 
effort to capture one example of each of the primary seizure types that their child experiences.  
Although it is acknowledged that drop seizures may be more difficult to capture on video, this 
information will provide valuable verification of this seizure type and the attempt should be 
made. 
Instructions for completion of the SIF/DRF and submission of videos can be found in the 
Investigator Site File. 
7.4. 
Efficacy Assessments 
Efficacy as determined by a reduction in seizures will be evaluated by collecting daily seizure 
type and frequency in an electronic seizure diary.  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.  
7.4.1. 
Seizure Type and Frequency 
Parent/caregiver/LAR will record daily seizure frequency denoting seizure type and frequency in 
an electronic seizure diary (eDiary).  Seizures will be noted as occurring as individual seizures, 
seizures occurring in a cluster with countable seizures or seizures occurring in a cluster with 
uncountable seizures. In rare cases when an eDiary completion is not feasible, a paper seizure 
calendar will be used to log in daily seizure type and frequency.  These cases will need approval 
by the sponsor.  Primary seizure types of bilateral tonic (sustained motor activity ≥ 3 seconds), 
generalized tonic-clonic, bilateral clonic, atonic/drop or focal to bilateral tonic-clonic seizures 
will be counted towards the primary endpoint.   
Subjects or parent/caregiver/LAR are to record administration of investigational product and 
background AEDs in the eDiary/seizure calendar.  Compliance with investigational product 
treatment will be assessed by inspecting the subjects’ eDiary/seizure calendar and returned 
supplies with queries as necessary.  Subjects that fall below 80% compliance at 2 consecutive 
visits during the double-blind phase will not be included in the per-protocol population.  


 
 
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7.4.2. 
Caregiver Global Impression of Change in Seizure Intensity/ Duration (CGI-
CSID) 
The CGI-CSID is a 7-point Likert scale in which the parent/caregiver/LAR assesses change in 
seizure intensity and/or duration after initiation of investigational product relative to baseline 
(prior to treatment with investigational product).  The scale ranges from 1- very much improved, 
2- much improved, 3-minimally improved, 4- no change, 5- minimally worse, 6- much worse, 
and 7- very much worse (Section 12.6).  CGI-CSID will be assessed at Visit 3 (Week 5), Visit 4 
(Week 9), Visit 5 (Week 17) in the double-blind phase, and will be assessed at Visit 7 (Week 
21), Visit 8 (Week 34), Visit 9 (Week 52), Visit 10 (Week 68) and will continue to be assessed 
every 16 weeks for the duration of the open-label phase and at the Final open-label (OL) Visit.  
7.4.3. 
Caregiver Global Impression of Change in Attention (CGICA) 
The CGICA is a 7-point Likert scale in which the parent/caregiver/LAR assesses change in 
attention after the initiation of investigational product relative to baseline (prior to treatment with 
investigational product).  During the screening visit, the investigator and parent/caregiver/LAR 
will decide on a specific behavior that the patient exhibits that denotes attention.  This behavior 
will be used at subsequent visits to assess change after the initiation of investigational product.  
The scale ranges from 1- very much improved, 2- much improved, 3-minimally improved, 4- no 
change, 5- minimally worse, 6- much worse, and 7- very much worse (Section 12.4). 
CGICA will be assessed at Visit 3 (Week 5), Visit 4 (Week 9), Visit 5 (Week 17) in the double-
blind phase, and will be assessed at Visit 7 (Week 21), Visit 8 (Week 34), Visit 9 (Week 52), 
Visit 10 (Week 68) and will continue to be assessed every 16 weeks for the duration of the open-
label phase and at the Final OL Visit. 
7.4.4. 
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 investigational product relative to baseline 
(prior to treatment with investigational product).  This domain should be chosen based on 
behavior the parent/caregiver/LAR identifies to be the most impactful.  During the screening 
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 investigational product.  The scale ranges 
from 1- very much improved, 2- much improved, 3-minimally improved, 4- no change, 
5 - minimally worse, 6- much worse, and 7- very much worse (Section 12.5). 
CGI-C – target behavior will be assessed at Visit 3 (Week 5), Visit 4 (Week 9), Visit 5 (Week 
17) in the double-blind phase, and will be assessed at Visit 7 (Week 21), Visit 8 (Week 34), 
Visit 9 (Week 52), Visit 10 (Week 68) and will continue to be assessed every 16 weeks for the 
duration of the open-label phase and at the Final OL Visit. 
 






 
 
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7.6.3. 
Physical/Neurological/Developmental Examinations 
The full physical examination will include the following systems: 
 General appearance 
 Head (eyes, ears, nose and throat) 
 Cardiovascular 
 Respiratory 
 Gastrointestinal 
 Genitourinary 
 Musculoskeletal 
 Endocrine/Metabolic 
 Hematologic/lymphatic 
 Skin 
 Other systems as appropriate 
The full neurological examination will include: 
 Cranial nerves 
 Motor exam 
 Sensory exam 
 Reflexes 
 Coordination/Cerebellar 
The full developmental examination will include: 
 Speech/language 
 Makes identifiable sounds for specific objects/people 
 Repeats sounds 
 Single words 
 Multiple words 
 Makes a sentence 
 Replies to question in an identifiable sound, single word, multiple word, sentence 
 Other abilities 
 Motor 
 Sits with support 
 Sits independently 


 
 
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 Crawls 
 Stands with support 
 Stands independently  
 Takes steps with assistance 
 Walks independently 
 Other abilities 
 Social 
 Smiles appropriately to situation 
 Makes eye contact 
Follow up physical, neurological, and developmental examinations are abbreviated examinations 
that ask whether there have been clinically significant changes or new abnormalities in the 
subject’s physical, neurological, and developmental examinations since the last full examination.  
7.6.4. 
ECG 
Electrocardiograms will be performed to collect the electrical activity of the heart throughout the 
study to monitor safety.  An evaluation of normal by a physician must be obtained before the 
subject is randomized to the double-blind phase.  A third party will provide central ECG services 
for this study including provision of equipment to clinical sites, project management, site 
training and education, data analysis as well as delivery of clean quality data.  Complete details 
regarding the third party’s ECG services will be provided in the Investigator Site File. 
ECGs will be performed at Visit 1 (screening), Visit 2 (baseline), Visit 3 (Week 5), Visit 5 
(Week 17) in the double-blind phase, and will be assessed at Visit 7 (Week 21), Visit 8 (Week 
34), Visit 9 (week 52), Visit 10 (Week 68) and will continue to be assessed every 16 weeks for 
the duration of the open-label phase and at the Final OL Visit. 
7.6.5. 
Clinical Laboratory Tests 
Laboratory safety assessments will be collected at every clinic visit throughout the study to 
monitor subject safety.  Clinical laboratory tests are listed in Section 12.2 will be collected per the 
schedule listed in Table 1 and Table 2.  These clinical laboratory assessments will include CBC 
with automated differential, creatinine, blood urea nitrogen, and eGFR calculation, 
comprehensive metabolic panel, as well serum pregnancy test for all women of childbearing 
potential. 
The following liver function and eGFR tests will be monitored throughout the study as follows.  
 If AST or ALT increases > 3 times ULN during the study, subject should be followed 
with weekly laboratory repeat testing and continue in study if levels trending down.  
Subject will be discontinued if levels do not decline to under 3 x ULN.  
 If total bilirubin increases to 1.5 x ULN or more during study, the subject will be 
discontinued.  


 
 
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 Subjects with significant renal insufficiency, eGFR < 30 mL/min (calculated using 
the Cockcroft-Gault formula or Pediatric GFR calculator or Bedside Schwartz) will 
be discontinued if the criterion is met post baseline. 
If any of the criteria above are deemed clinically significant by the investigator, then the 
sponsor’s medical monitor should be contacted. 
Due to the difficulty in obtaining urine samples, urinalysis will be conducted at Visit 1 
(screening) or baseline (Visit 2), Week 17 (Visit 5), Week 52 (Visit 9), and annually thereafter or 
at the safety follow up visit if investigational product is discontinued.  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. 
7.6.6. 
Tanner Staging 
The Tanner scale (also known as the Tanner stages) is a scale of physical development in 
children, adolescents and adults.  The scale defines physical measurements of development based 
on external primary and secondary sex characteristics.  Subjects will be evaluated and rated as 
Tanner I, Tanner II, Tanner III, Tanner IV, and Tanner V.  Tanner staging will occur at Visit 1 
(screening), Visit 9 (Week 52) and will continue to be assessed annually for the duration of the 
subject’s participation in the open-label phase and at the Final OL Visit.  
7.6.7. 
Investigational Product PK 
Please refer to Section 7.7 for additional details regarding Pharmacokinetic Assessments.  
7.6.8. 
Concomitant AED levels 
Concomitant AED levels are not mandatory but will be collected per sites’ standard of care.  If 
AED levels are available for Visit 1 (screening), Visit 2 (baseline), Visit 3 (Week 5), Visit 4 
(Week 9) and Visit 5 (Week 17), and throughout the open-label phase of the study at the 
timepoints 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. 
7.6.9. 
Neurosteroid levels 
A blood sample will be drawn at the screening visit to confirm the subject meets eligibility 
criteria and does not have plasma allopregnanolone – sulfate (Allo-S) levels ≥ 6.0 ng/ml. 
Additional blood samples will be drawn at Visit 5 (Week 17) and at the Final OL Visit.  The goal 
of this assessment is to measure levels of various neurosteroids. 
Instructions for neurosteroid sample collection and processing can be found in the laboratory 
manual. 
 
7.6.10. 
Adverse Events 
Details regarding AEs and SAEs are provided in Section 8.  




 
 
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8. 
ADVERSE AND SERIOUS ADVERSE EVENT ASSESSMENTS  
8.1. 
Definition of Adverse Events, Period of Observation, Recording of 
Adverse Events 
An AE is any untoward medical occurrence in a clinical investigation subject who has been 
administered a pharmaceutical product; it does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (International Conference on Harmonisation [ICH] Guidance E2A March 1995).   
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period.  This includes events occurring during the screening phase of the study, regardless of 
whether or not the investigational product has been administered.  All AEs reported after the 
initiation of investigational product 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 investigational product indication should also be captured on the AE eCRF 
page.   
All AEs must be followed to closure (the subject’s health has returned to baseline status or all 
variables have returned to normal), regardless of whether the subject is still participating in the 
study.  Closure indicates that an outcome is reached, stabilization is achieved (the 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 investigational product, must be 
recorded as new AEs (e.g., if a subject experiences mild intermittent dyspepsia prior to dosing of 
the investigational product, but the dyspepsia becomes severe and more frequent after the first 
dose of the investigational product has been administered, a new AE of severe dyspepsia [with 
the appropriate date of onset] is recorded on the appropriate eCRF page). 
The medical assessment of severity is determined by using the following definitions: 
Mild: 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual 
activities of daily living. 
Moderate: 
A type of AE that is usually alleviated with specific therapeutic intervention.  The 
event interferes with usual activities of daily living, causing discomfort, but poses 
no significant or permanent risk of harm to the research subject. 


 
 
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Severe: 
A type of AE that interrupts usual activities of daily living, that significantly 
affects clinical status, or that may require intensive therapeutic intervention. 
8.1.2. 
Relationship Categorization 
A physician/investigator must make the assessment of relationship between the investigational 
product 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 investigational product.  If 
there is no valid reason for suggesting a relationship, the AE should be classified as “not 
related.”  If a relationship between the AE and the investigational product is at least reasonably 
possible (i.e. the relationship cannot be ruled out) the AE should be considered "related.”  The 
causality assessment must be documented in the source document. 
The following additional guidance may be helpful: 
Term 
Relationship definition 
Related 
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident. 
Not related 
The event can be readily explained by other factors, such as the subject’s underlying 
medical condition, concomitant therapy, or accident, and no plausible temporal or 
biologic relationship exists between the investigational product and the event. 
8.1.3. 
Outcome Categorization 
The outcome of AEs must be recorded during the course of the study on the eCRF.  Outcomes 
are as follows: 
 Fatal 
 Not recovered/not resolved 
 Recovered/resolved 
 Recovered/resolved with sequelae  
 Recovering/resolving 
 Unknown 
8.1.4. 
Symptoms of the Disease Under Study 
Symptoms of the disease under study should not be classified as AEs as long as they are within 
the normal day-to-day fluctuation or expected progression of the disease and are part of the 
efficacy data to be collected in the study; however, significant worsening of the symptoms 
should be recorded as an AE.  
 
 


 
 
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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 investigational product, a shift 
of a parameter is observed from a normal value to an abnormal value, or there is a further 
worsening of an already abnormal value.  When evaluating such changes, the extent of deviation 
from the reference range, the duration until return to the reference range (either while continuing 
treatment or after the end of treatment with the investigational product), 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 phase, there are abnormal clinical laboratory, vital sign, or ECG 
values that were not present in the pretreatment findings observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (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 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE. 
8.1.6. 
Pregnancy 
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period. 
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Marinus 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 participant must be withdrawn from the study. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant.  It is the responsibility of the investigator to obtain this information 
within 30 calendar days after the initial notification and approximately 30 calendar days after 
delivery.  
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported as outlined in Section 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/urine -human chorionic gonadotropin test or ultrasound 
result will determine the pregnancy onset date. 


 
 
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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. 
 Abuse: Persistent or sporadic intentional intake of an investigational product 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. 
 Misuse: Intentional use of an investigational product other than as directed or 
indicated at any dose.  (Note: This includes a situation in which the investigational 
product is not used as directed at the dose prescribed by the protocol.) 
 Overdose: Intentional or unintentional intake of a dose of an investigational product 
exceeding a prespecified total daily dose of the product.  
 Medication error: An error made in prescribing, dispensing, administering, and/or 
use of an investigational product.  For studies, medication errors are reportable to the 
sponsor only as defined below. 
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors. 
Medication errors should be collected and reported for the investigational product under 
investigation. 
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects 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 


 
 
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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 investigational 
product or not) that at any dose: 
 Results in death 
 Is life-threatening. Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the subject was at risk of death at the time of the event; it 
does not refer to an event that hypothetically might have caused death if it were more 
severe. 
 Requires inpatient hospitalization or prolongation of existing hospitalization.  Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
preexisting conditions that have not worsened after initiation of treatment, should not 
be classified as SAEs.  For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, a complication resulting 
from a hospitalization for an elective or previously scheduled surgery that meets 
serious criteria must be reported as an SAE. 
 Results in persistent or significant disability or incapacity 
 Is a congenital abnormality or birth defect 
 Is an important medical event.  Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAEs 
when, based on appropriate medical judgment, they jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization; or the development of drug 
dependency or drug abuse.  
8.2.4. 
Serious Adverse Event Collection Time Frame 
All SAEs (regardless of relationship to study) are collected from the time the 
parent/caregiver/LAR signs the informed consent 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 investigational product 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. 


 
 
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8.2.5. 
Serious Adverse Event Onset and Resolution Dates 
The onset date of the SAE is defined as the date the event meets serious criteria.  The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic.  In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively. 
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form 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 subject’s death (i.e., the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome, with the date of death recorded as the resolution 
date.  For all other events ongoing at the time of death that did not contribute to the subject’s 
death, the outcome should be considered not resolved, without a resolution date recorded. 
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (e.g., the drug was interrupted, 
reduced, or withdrawn), the action taken with the investigational product should be recorded as 
“dose not changed” or “not applicable” (if the subject never received the investigational 
product).  The investigational product action of “withdrawn” should not be selected solely as a 
result of the subject’s death.  
8.2.7. 
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The sponsor is responsible for notifying the relevant regulatory authorities in the United States 
(US) and the CRO is responsible for notifying the relevant regulatory authorities in rest of world 
of related, unexpected SAEs. 
In addition, the sponsor or the CRO is responsible for notifying active sites and central 
institutional review boards (IRBs) of all related, unexpected SAEs occurring during all 
interventional studies across the GNX program.  
The 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. 
8.3. 
Adverse Events of Special Interest 
8.3.1. 
Reference Safety Information 
The following represent the Adverse Events of Special Interest: 
 Rash 
 Adverse Events that would be classified under reproductive system and breast disorders 
system organ class


 
 
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9. 
DATA MANAGEMENT AND STATISTICAL METHODS 
9.1. 
Data Collection 
The 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 subject is screened, it is expected that site personnel 
will complete the eCRF entry within approximately 7 business days of the subject’s visit. 
The subject’s parent/caregiver/LAR must enter the information required by the protocol in the 
eDiary. A study monitor will review all seizure diary entries in accordance with the monitoring 
plan for completeness and accuracy.  Discrepancies will be addressed by the subjects’ 
parent/caregiver/LAR and qualified site personnel. When a data discrepancy warrants correction, 
the correction will be made by the subjects’ parent/caregiver/LAR and authorized site personnel.  
Data collection procedures will be discussed with the site at the site initiation visit and/or at the 
investigator’s meeting.  Once the subject’s parent/caregiver/LAR signs informed consent, it is 
expected that all eDiary 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 
subject disposition, demographics, and baseline characteristics; investigational product exposure; 
and prior and concomitant medications.  The SAP will also include a description of how missing 
data will be addressed. 


 
 
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To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock. 
All statistical analyses will be performed using SAS® (SAS Institute, Cary, NC 27513).  
9.4. 
Data Monitoring Committee 
The emerging study data will be reviewed on a regular basis by an independent Data Monitoring 
Committee (DMC).  The mission of the DMC will be to safeguard the interests of study 
participants and to enhance the integrity and credibility of the trial.  To enable the DMC to 
achieve their mission, the DMC will have ongoing access to unblinded efficacy and safety data 
and data regarding quality of trial conduct and will ensure the confidentiality of these data will 
be protected. A DMC charter will provide the principles and guidelines for the DMC process. 
9.5. 
Sample Size Calculation and Power Considerations 
Based on data from the 7 patients in Study 1042-0900 evaluating GNX in CDKL5 patients, the 
standard deviation for the percent change in 28-day seizure frequency for seizure types tonic 
(sustained motor activity ≥ 3 seconds), tonic-clonic, atonic/drop, epileptic spasms, or clonic 
(generalized or unilateral) is estimated to be 44.5.  Therefore, when the percent change in 28-day 
seizure frequency on GNX minus that on PBO truly is 30%, then a trial with 100 subjects 
randomized in a 1:1 manner will have 92% power to detect this effect when using an analysis of 
variance (ANOVA) that preserves a (one-sided) 2.5% false positive error rate. (If the true 
difference in the percent changes is 35%, then the study will have 97.5% power.)  The threshold 
for achieving statistical significance at the final analysis when 100 subjects have completed their 
17-week double-blind treatment period would be achieved with an estimate of the difference that 
is approximately 17.5%. (The actual analysis will use a Wilcoxon rank-sum test, which has 
approximately the same power as the ANOVA.)   
9.6. 
Study Population 
The Safety and Intent to Treat (ITT) populations comprise all randomized subjects who received 
at least one dose of investigational product. In addition to being the population for the safety and 
ITT analyses, it is the primary population for the efficacy analyses and for the concomitant AED 
level and neurosteroid level analyses. 
The Per-Protocol (PP) population consists of ITT subjects who received study drug for at least 6 
weeks, provided at least 5 weeks of post-baseline seizure data, and had no major protocol 
violations (defined prior to database lock).  A supportive analysis of the primary and secondary 
efficacy endpoints will be conducted in this population. There will be no PP population for the 
OL period of the study. 
The results of the primary, secondary and exploratory endpoints in the double-blind and open-
label phases will be summarized separately. In both phases, the results will be summarized by 
the double-blind treatment to which the subjects were randomized and, for the open-label phase 
of the study, combined over the treatment groups.    
Subject demographics, characteristics, and medical history at randomization will be summarized 
using descriptive statistics. 


 
 
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9.7. 
Efficacy Analyses 
All endpoints will be assessed descriptively, by the double-blind treatment to which the subjects 
are randomized, with point estimates and 95% confidence intervals. Only the primary endpoint 
will be assessed in an inferential manner since it is unlikely the trial will be powered to achieve 
statistical significance regarding effects on these measures. 
9.7.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the percent change in 28-day primary seizure frequency 
through the end of the 17-week, double-blind treatment phase relative to the 6-week prospective 
baseline period.  The primary seizure types include bilateral tonic (sustained motor activity ≥ 3 
seconds), generalized tonic-clonic, bilateral clonic, atonic/drop seizures or focal to bilateral 
tonic-clonic.  
The baseline, post-baseline, and arithmetic and percent changes from baseline in 28-day seizure 
frequency will be summarized using descriptive statistics. The difference between the treatment 
groups in the percent changes will be tested for statistical significance. Since the percent 
differences are anticipated to display skewness and/or outliers, the test will be performed using 
the Wilcoxon Rank-Sum statistic using a 2-sided significance level of 0.05. 
Three sensitivity analyses of the primary efficacy endpoint will be performed (1) To examine the 
primary outcome measure when a subject stops recording measurements permanently prior to the 
end of the 17-week DB phase using the imputation approach outlined in the Statistical Analysis 
Plan, (2) to explore the possibility that subjects who stop recording seizure counts tend to have 
higher counts than other subjects, and  (3) To  examine the effect of GNX compared to PBO  
among subjects with low Allo-S levels.  
9.7.2. 
Key Secondary Efficacy Endpoints 
The key Secondary endpoints are: 
 Number (%) of subjects with a ≥50% reduction from baseline in primary seizure 
frequency. 
 Clinical Global Impression of Improvement (CGI-I) at the last scheduled visit in the 17-
week DB treatment phase. 
9.7.3. 
Secondary Efficacy Endpoints 
In addition to evidence about effects of GNX on 28-day seizure frequency, the clinical trial will 
provide substantive insights about its effects on several secondary endpoints that capture 
important symptoms and activities of daily living that are meaningfully compromised by CDD.  
The seizure-related secondary endpoints, along with the primary endpoint, should be the most 
influential in the assessment of anti-epileptic efficacy.  The behavioral/neuropsychiatric 
secondary endpoints will provide information about the overall impact of GNX compared with 
PBO on the treatment of subjects with CDD.  The CGICA, CGI-C, CGI-CSID, and the CGI-I are 
all 7-point scales, and the number and percentage of subjects with each score will be 
summarized. The scores range from 1=very much improved to 7=very much worse.  






 
 
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9.7.7. 
Sensitivity Analyses 
Three sensitivity analyses of the primary efficacy endpoint will be performed for subjects who 
stop recording their seizure counts as outlined in the Statistical Analysis Plan: 
 To examine the primary outcome measure when a subject stops recording measurements 
permanently prior to the end of the 17-week DB phase using the imputation approach 
outlined in the Statistical Analysis Plan. 
 To explore the possibility that subjects who stop recording seizure counts tend to have 
higher counts than other subjects. 
 To examine the effect of GNX compared to PBO among subjects with low Allo-S levels. 
9.7.8. 
Open-Label Analyses 
All the analyses for the double-blind phase will be repeated for the open-label phase, with the 
following differences:  
 The results will be presented overall and also classified according to the double-blind 
treatment received by subjects. 
 The post-baseline seizure endpoints will be derived starting from the first dosing day of 
OLE treatment 
 The only sensitivity analysis to be performed is the analysis of the primary endpoint 
among subjects with low plasma allopregnanolone sulfate (Allo-S) levels. 
 The seizure frequencies during the titration and maintenance phases will not be Analyzed 
separately 
 The time points for the efficacy, exploratory, and quality of life endpoints will be at 
Weeks 21, 34, 52, and every 16 weeks thereafter of open-label treatment relative to the 
6-week prospective baseline phase. For the seizure endpoints, this corresponds to the first 
4, 17, 35, 51, etc. weeks from the start of the open-label phase 
 The differences between the double-blind treatment groups in the percent changes from 
baseline of the 28-day seizure frequencies will not be tested for statistical significance. 
 No PP analyses will be performed 
 If a subject prematurely discontinues from the OLE phase, the EEG comparison to 
baseline at the Final OL/Taper Visit cannot be reassigned for analysis purposes since the 
EEG is performed only at that visit in the OLE phase; hence the tabulation at that visit 
will include all the subjects, regardless of whether they discontinued.(Taper Visit 
assessments among the subjects who prematurely discontinue from the DB phase are 
reassigned if possible; if they cannot be reassigned then they are not tabulated.) 
9.8. 
Safety Analyses 
All safety analyses will be performed in the Safety Population. The results in the double-blind 
and open-label phases will be summarized separately. In both phases, the results will be 


 
 
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summarized by the double-blind treatment actually received and, for the open-label phase of the 
study, combined over the treatment groups.   
The number and percentage of days that subjects received investigational product, the highest 
percentage of the maximum allowable daily dose (1800 mg or 63 mg/kg) that subjects received, 
and the total amount of investigational product received will be summarized.  The denominator 
for the percentage of days of study drug is the number of days in the phase. For the open-label 
phase, they will be summarized over just the open-label phase as well as over the entire study 
(combined DB and OL phases) but the classification by the double-blind treatment applies only 
for the open-label phase summary. The summarization over the entire study will include the 
double-blind data only from subjects who were in the GNX group during the double-blind phase, 
regardless of whether they entered the open-label phase, and all the subjects from the open-label 
phase. 
A subject data listing will be provided with full details of the study drug dispensation. 
Safety assessments include: 
 AEs  
 Clinical laboratory tests  
 Vital signs including temperature, blood pressure, pulse rate, and weight 
 12-lead ECG 
 Physical, neurological and developmental examinations 
 Tanner staging (OL phase only) 
 Concomitant AED levels (If available) 
Detailed analysis and complete listings will be outlined in the SAP. 
9.9. 
Other Analyses 
Concomitant AED levels will be analyzed according to the SAP. 
9.10. 
Pharmacokinetic Analyses 
The PK population will include all subjects who have received at least 1 dose and who have had 
at least 1 sample collected and a valid bioanalytical result obtained. Four samples will be drawn 
between 1 and 5 hours or between 4 and 8 hours after the last dose, the remaining samples will 
be drawn without specific time constraints.   Exact date and time of sample draw and drug intake 
will be recorded in the electronic case report form (eCRF). Pharmacokinetic analyses will be 
limited to listing of concentrations because sufficient concentration-time data will not be 
available for noncompartmental analyses such as Cmax, AUC or tmax. Pharmacokinetic data 
from this study may be used for a Population PK analyses to be conducted separately from this 
study and reported separately.  


 
 
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9.11. 
Interim Analysis 
A formal interim analysis is planned, in addition to the final analysis, of treatment effect on the 
primary endpoint in accordance with the SAP. 


 
 
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10. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This study is conducted in accordance with current applicable regulations, ICH, European Union 
(EU) Directive 2001/20/EC and its updates, and local ethical and legal requirements.  
The name and address of each third-party vendor (e.g., CRO) used in this study will be 
maintained in the investigators’ and sponsor’s files, as appropriate. 
10.1. 
Sponsor’s Responsibilities 
10.1.1. 
Good Clinical Practice (GCP) Compliance 
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), and EU Directive 2001/20/EC, 
as well as all applicable national and local laws and regulations. 
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, eDiaries/seizure calendars and eCRFs in accordance with current GCP and the 
respective local and (inter)national government regulations and guidelines.  Records and data 
may additionally be reviewed by auditors or by regulatory authorities. 
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study.  The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product 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 
(1996), EU Directive 2001/20/EC, 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 subjects 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 subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study. 
A coordinating PI is appointed to review the final clinical study report for multicenter studies.  
Agreement with the final clinical study report is documented by the signed and dated signature 
of the PI (single-site study) or coordinating PI (multicenter study), in compliance with Directive 
2001/83/EC as amended by Directive 2003/63/EC and ICH Guidance E3 (1995).  
10.2.2. 
Protocol Adherence and Investigator Agreement 
The investigator and any sub-investigators must adhere to the protocol as detailed in this 
document.  The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria.  Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol. 
If the 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 investigational product, 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. eCRFs 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 review all data in accordance with the 
clinical monitoring plan.  If the data are unclear or contradictory to source data, 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. Electronic Seizure Diaries (eDiary) 
The eDiaries 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 eDiary data in accordance with the 
clinical monitoring plan.  If the data are unclear or contradictory, queries are sent for corrections 
or verification of data. 
10.2.3.3. Recording, Access, and Retention of Source Data and Study Documents 
Original source data to be reviewed during this study will include, but are not limited to, the 
subject’s medical file, the subject’s electronic or paper seizure diaries, and original clinical 
laboratory reports.  
All key data must be recorded in the subject’s medical records. 
The 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 
subject 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., subject’s medical 
file, appointment books, original laboratory reports, EEGs, ECGs, etc.).  
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (e.g., the US Food and 
Drug Administration [FDA], European Medicines Agency [EMA], United Kingdom [UK] 
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 EMA, the UK Medicines and Healthcare Products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site. 
10.2.3.5. Financial Disclosure 
The 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 investigational product; 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 
It is the responsibility of the investigator to obtain written informed consent from the subject’s 
parent/LAR for all study subjects prior to any study-related procedures, including screening 
assessments.  As the disease under consideration is a condition for which the subjects will not be 
capable of signing consent/assent for themselves, a parent/caregiver/LAR will be required to sign 
upon identification of the subject for participation.  
All consent documentation must be in accordance with applicable regulations and GCP.  Each 
subject’s parent/ LAR, as applicable, is requested to sign and date the subject’s informed consent 
form or a certified translation, if applicable, after they have received and read (or been read) the 
written subject information and received an explanation of what the study involves, including but 
not limited to the objectives, potential benefits and risk, inconveniences, and the subject’s rights 
and responsibilities.  A copy of the informed consent documentation (i.e., a complete set of 
subject information sheets and fully executed signature pages) must be given to the subject’s 
parent/ LAR, as applicable.  This document may require translation into the local language.  
Signed consent forms must remain in each subject’s study file and must be available for 
verification at any time. 
Site personnel should document providing instruction for and understanding by the parent/ LAR 
of the safe, responsible storage and administration of the oral investigational product. 
The PI provides the sponsor with a copy of the consent form that was reviewed by the IRB/EC 
and received their favorable opinion/approval.  A copy of the IRB/EC’s written favorable 
opinion/approval of these documents must be provided to the sponsor prior to the start of the 


 
 
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study unless it is agreed to and documented (abiding by regulatory guidelines and national 
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 subject 
information and consent document provided by the sponsor, the documentation supporting this 
requirement must be provided to the sponsor. 
10.3.2. 
Institutional Review Board or Ethics Committee 
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information, and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation. 
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement. 
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue. 
Investigational product supplies will not be released until the CRO has received written IRB/EC 
approval of and copies of revised documents. 
For sites outside the EU, the investigator is responsible for keeping the IRB/EC informed of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year.  This can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating PI, according to national provisions.  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 subjects will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After the subject’s parent/caregiver/LAR have consented to take part in the study, the sponsor 
and/or its representatives review the medical records and data collected during the study.  These 
records and data may, in addition, be reviewed by others, including the following: independent 
auditors who validate the data on behalf of the sponsor; third parties with whom the sponsor may 
develop, register, or market GNX; national or local regulatory authorities; and the IRB/EC that 
gave approval for the study to proceed.  The sponsor and/or its representatives accessing the 
records and data will take all reasonable precautions in accordance with applicable laws, 
regulations, and guidelines to maintain the confidentiality of subjects’ identities. 
Subjects are each assigned a unique identifying number; however, their initials and date of birth 
may also be collected and used to assist the sponsor in verifying the accuracy of the data (e.g., to 
confirm that laboratory results have been assigned to the correct subject).  


 
 
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The results of studies—containing subjects’ unique identifying numbers, relevant medical 
records, and possibly initials and dates of birth—will be recorded.  They may be transferred to, 
and used in, other countries that may not afford the same level of protection that applies within 
the countries where this study is conducted.  The purposes of any such transfer would include to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, and to answer questions asked by regulatory or health authorities. 
10.5. 
Study Results/Publication Policy 
Marinus will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative.  Additionally, Marinus adheres to external guidelines 
(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 


 
 
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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 
current standards.  Participation as an investigator does not confer any rights to authorship of 
publications. 


 
 
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11. 
REFERENCES 
Bahi-Buisson N, Nectoux J, Rosas-Vargas H, Milh M, Boddaert N, Girard B, Cances C, Ville D, 
Afenjar A, Rio M, Héron D, N’guyen Morel MA, Arzimanoglou A, Philippe C, Jonveaux P, 
Chelly J, Bienvenu T. Key clinical features to identify girls with CDKL5 mutations. Brain. 
2008;131(Pt 10):2647–61. 
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. 
Carouge D, Host L, Aunis D, Zwiller J, Anglard P. CDKL5 is a brain MeCP2 target gene 
regulated by DNA methylation. Neurobiol Dis. 2010;38(3):414-24. 
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. 
Esbensen AJ, Rojahn J, Aman MG, Ruedrich S. Reliability and validity of an assessment 
instrument for anxiety, depression, and mood among individuals with mental retardation. J 
Autism Dev Disord. 2003;33(6):617-29. 
Fehr S, Wilson M, Downs J, Williams S, Murgia A, Sartori S, Vecchi M, Ho G, Polli R, Psoni S, 
Bao X, de Klerk N, Leonard H, Christodoulou J. The CDKL5 disorder is an independent clinical 
entity associated with early-onset encephalopathy. Eur J Hum Genet. 2013;21(3):266-73.  
Fuchs C, Trazzi S, Torricella R, De Franceschi M, Amendola E, Gross C, Calzà L, Bartesaghi R, 
Ciani E. Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering 
AKT/GSK-3b signaling. Neurobiol Dis. 2014; 70:53–68. 
Ganaxolone Investigator’s Brochure. Marinus Pharmaceuticals, Inc., Dated 08-Feb-2018. 
International Conference on 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 
Kameshita I, Sekiguchi M, Hamasaki D, Sugiyama Y, Hatano N, Suetake I, Tajima S, Sueyoshi 
N. Cyclin-dependent kinase-like 5 binds and phosphorylates DNA methyltransferase 1. Biochem 
Biophys Res Commun. 2008;377(4):1162-7. 
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. 


 
 
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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. 
Lou Lou Foundation [Internet]. http://www.louloufoundation.org/about-cdkl5.html. Accessed 
20-Feb-2018. 
Mangatt M, Wong K, Anderson B, Epstein A, Hodgetts S, Leonard H, Downs J. Prevalence and 
onset of comorbidities in the CDKL5 disorder differ from Rett syndrome. Orphanet JRare Dis. 
2016; 11:39. 
Markand ON. Lennox–Gastaut syndrome (childhood epileptic encephalopathy).J Clin 
Neurophysiol. 2003;20(6):426–41. 
Müller A, Helbig I, Jansen C, Bast T, Guerrini R, Jähn J, Muhle H, Auvin S, Korenke GC, Philip 
S, Keimer R, Striano P, Wolf NI, Püst B, Thiels Ch, Fogarasi A, Waltz S, Kurlemann G, 
Kovacevic-Preradovic T, Ceulemans B, Schmitt B, Philippi H, Tarquinio D, Buerki S, von 
Stülpnagel C, Kluger G. Retrospective evaluation of low long-term efficacy of antiepileptic 
drugs and ketogenic diet in 39 patients with CDKL5-related epilepsy. Eur J Paediatr Neurol. 
2016;20(1):147-51. 
National Institutes of Health. Infantile Spasms Information Page. National Institute of 
Neurological Disorders and Stroke. May 22, 2017; https://www.ninds.nih.gov/Disorders/All-
Disorders/Infantile-Spasms-Information-Page. Accessed 20-Feb-2018. 
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):558-564. 
 


 
 
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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 
 
a. 
A strong inhibitor for CYP3A is defined as an inhibitor that increases the AUC of a substrate for CYP3A by ≥ 5-fold. 
b. 
In vivo inhibitor of P-glycoprotein. 
c. 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent.  Studies 
have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (eg, high dose, 
double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (eg, low dose, single strength). 
d. 
Withdrawn from the United States market because of safety reasons. 
e. 
A strong inducer for CYP3A is defined as an inducer that results in ≥ 80% decrease in the AUC of a substrate for CYP3A. 
f. 
In vivo inducer of P-glycoprotein.   
 
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 January 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 
Ketones 
Sodium 
Protein 
Calcium 
Glucose 
Alkaline Phosphatase 
Bilirubin 
Chloride 
Blood 
Creatinine 
Leukocyte esterase 
CO2 
Nitrite 
eGFR4 
Drug screen5 
Quantitative serum -human 
chorionic growth hormone 
(-HCG) serum pregnancy 
1ALT = alanine aminotransferase  
2AST = aspartate aminotransferase  
3BUN = blood urea nitrogen 
4eGFR = estimated glomerular filtration rate 
5Urine or plasma drug screen for THC, CBD 
 
 
 
 


 
 
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Protocol 1042- CDD-3001 
 
26 May 2020, Amendment 2.0 
12.3. 
Appendix 3:  Dosing Instructions for Oral Suspension 
GANAXOLONE 1042-CDD-3001 STUDY 
DOSING INSTRUCTIONS FOR ORAL SUSPENSION  
(DOUBLE-BLIND DOSE TITRATION, DOUBLE-BLIND AND OPEN-LABEL 
MAINTENACE 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 approximately 4 - 8 oz of 
water. 
 
Example 1: 
 
Dose Titration / Dose Maintenance / Dose Taper (Please circle phase) 
 
For a 15 kg child, please dose the following 
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 Taper (Please circle phase) 
 
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 
 
 


 
 
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Marinus Pharmaceuticals Inc. 
Protocol 1042- CDD-3001 
 
26 May 2020, Amendment 2.0 
Please take the study medication as outlined below: 
 
Dose Titration / Dose Maintenance / Dose Taper (Please circle phase) 
 
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, 2-3 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 bottle adapter and dosing syringes provided. Do not use a household spoon. The syringe should 
be replaced daily and cleaned between each dose that day by rinsing for 30 seconds using hot water and 


 
 
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Protocol 1042- CDD-3001 
 
26 May 2020, Amendment 2.0 
allowing it to air dry. The bottle adapter should stay in the bottle once it’s inserted.  It should not be 
removed. 
 
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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IND 44,020 
 
Marinus Pharmaceuticals Inc. 
Protocol 1042- CDD-3001 
 
26 May 2020, Amendment 2.0 
GANAXOLONE 1042-CDD-3001 STUDY 
DOSING INSTRUCTIONS FOR ORAL SUSPENSION  
(DOUBLE-BLIND TO OPEN-LABEL TRANSITION) 
 
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 approximately 4 - 8 oz of 
water. 
 
Study Drug Group A and B Dosing Instructions: Transition to active study medication 
 
Your child is receiving bottles to Study Drug Group A and B during the transition to active study 
medication. During the next few weeks, the dosage of Study Drug B will be increased. The dosage of 
Study Drug A will remain the same. The following items will be discussed below: 
 
 
Bottle numbers to Study Drug Group A and B 
 
The amount of Study Drug A and B to be given each day 
 
Example 1: 
 
For a 15 kg child, please dose the following 
Date___/___/___ to Date ___/___/___ 
Study Drug A 
mls 
3 times/day 
Study Drug B 
mls 
3 times/ day 
9/23/18-9/29/18; Days 1-7 
6.3 
1.8 
9/30/18-10/6/18; Days 8-14 
6.3 
3.3 
Visit 6, Week 19 
Safety visit and new set of Study Drug A 
and B bottles issued 
10/7/18-10/13/18; Days 15-21 
6.3 
4.8 
10/14/18-10/20/18; Days 22-28 
6.3 
6.3 
 
 
 
 
 
 
 
 


 
 
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IND 44,020 
 
Marinus Pharmaceuticals Inc. 
Protocol 1042- CDD-3001 
 
26 May 2020, Amendment 2.0 
Please take the study medication as outlined below: 
 
Study Drug Group Bottle A Number(s)_____________________________________________ 
 
Study Drug Group Bottle B Number(s)_____________________________________________ 
 
Date___/___/___   to Date___/___/___ 
Study Drug A 
mls 
3 times/day 
Study Drug B 
mls 
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, 2-3 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 
 
 


 
 
Confidential 
 
Page 134 of 152 
IND 44,020 
 
Marinus Pharmaceuticals Inc. 
Protocol 1042- CDD-3001 
 
26 May 2020, Amendment 2.0 
Use the bottle adapter and dosing syringes provided. Do not use a household spoon. The syringe should 
be replaced daily and cleaned between each dose that day by rinsing for 30 seconds using hot water and 
allowing it to air dry. The bottle adapter should stay in the bottle once it’s inserted.  It should not be 
removed. 
 
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:  __________________________________________________  
 


 
 
Confidential 
 
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Protocol 1042- CDD-3001 
 
26 May 2020, Amendment 2.0 
12.4. 
 Appendix 4:  Caregiver Global Impression of Change in Attention 
(CGICA) 
 
  Date: 
 
 
 
 
 
Subject No:  
 
 
 
 
 
  Rater Initials: 
 
 
 
 
Subject Initials: 
 
 
 
 
 
  Behavior that denotes attention: __________________________ 
 
 
  Rate the change in attention after the start of investigational product. Please circle 
the appropriate number. 
 
 
 
1. 
Very much improved 
2. 
Much improved 
3. 
Minimally improved 
4. 
No change 
5. 
Minimally worse 
6. 
Much worse 
7. 
Very much worse 
 
 


 
 
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IND 44,020 
 
Marinus Pharmaceuticals Inc. 
Protocol 1042- CDD-3001 
 
26 May 2020, Amendment 2.0 
12.5. 
Appendix 5:  Caregiver Global Impression of Change (CGI-C) – 
Target Behavior 
 
  Date: 
 
 
 
 
 
Subject No:  
 
 
 
 
 
  Rater Initials: 
 
 
 
 
Subject Initials: 
 
 
 
 
 
Choose one from the following domains (please circle):  sociability, communication, 
irritability,  hyperactivity 
 
   Behavior that denotes target domain: __________________________ 
 
 
  Rate the change in target domain after the start of investigational product. Please 
circle the appropriate number. 
 
 
 
1. 
Very much improved 
2. 
Much improved 
3. 
Minimally improved 
4. 
No change 
5. 
Minimally worse 
6. 
Much worse 
7. 
Very much worse 
 
 
 


 
 
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Protocol 1042- CDD-3001 
 
26 May 2020, Amendment 2.0 
12.6. 
Appendix 6:  Caregiver Global Impression of Change in Seizure 
Intensity/Duration (CGI-CSID) 
 
  Date: 
 
 
 
 
 
Subject No:  
 
 
 
 
 
  Rater Initials: 
 
 
 
 
Subject Initials: 
 
 
 
 
 
 
 
  Rate the change in seizure intensity and/or duration after the start of investigational 
product. Please circle the appropriate number. 
 
 
 
1. 
Very much improved 
2. 
Much improved 
3. 
Minimally improved 
4. 
No change 
5. 
Minimally worse 
6. 
Much worse 
7. 
Very much worse 
 
 
 


 
 
Confidential 
 
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Marinus Pharmaceuticals Inc. 
Protocol 1042- CDD-3001 
 
26 May 2020, Amendment 2.0 
12.7. 
Appendix 7:  Clinical Global Impression - Improvement (CGI-I)  
 
For the Clinician: 
 
  Date: 
 
 
 
 
 
Subject No:  
 
 
 
 
 
  Rater Initials: 
 
 
 
 
Subject Initials: 
 
 
 
 
 
 
 
  Rate the overall global impression of change after the start of investigational product 
relative to baseline (prior to investigational product). Please circle the appropriate 
number. 
 
 
 
1. 
Very much improved 
2. 
Much improved 
3. 
Minimally improved 
4. 
No change 
5. 
Minimally worse 
6. 
Much worse 
7. 
Very much worse 
 
 
 


 
 
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Marinus Pharmaceuticals Inc. 
Protocol 1042- CDD-3001 
 
26 May 2020, Amendment 2.0 
Clinical Global Impression - Improvement (CGI-I) for the Caregiver 
 
 
  Date: 
 
 
 
 
 
Subject No:  
 
 
 
 
 
  Rater Initials: 
 
 
 
 
Subject Initials: 
 
 
 
 
 
 
 
  Rate the overall global impression of change after the start of investigational product 
relative to baseline (prior to investigational product). Please circle the appropriate 
number. 
 
 
 
1. 
Very much improved 
2. 
Much improved 
3. 
Minimally improved 
4. 
No change 
5. 
Minimally worse 
6. 
Much worse 
7. 
Very much worse 
 


 
 
Confidential 
 
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Marinus Pharmaceuticals Inc. 
Protocol 1042- CDD-3001 
 
26 May 2020, Amendment 2.0 
12.8. 
Appendix 8:  Children’s Sleep Habit Questionnaire (CSHQ) 
  
Child’s Sleep Habits 
(Preschool and School-Aged) 
(Abbreviated Version) 
_______________ 
 
Coding 
 
 
 
CSHQ Abbreviated 
The following statements are about your child’s sleep habits and possible difficulties with sleep. Think about the past week in your 
child’s life when answering the questions. If last week was unusual for a specific reason (such as your child had an ear infection 
and did not sleep well or the TV set was broken), choose the most recent typical week. Answer USUALLY if some hing occurs 5 or 
more times in a week; answer SOMETIMES if it occurs 2-4 times in a week; answer RARELY if something occurs never or 1 time 
during a week. Also, please indicate whether or not the sleep habit is a problem by circling “Yes,” “No,” or “Not applicable (N/A)”. 
 
Bedtime 
Write in child’s bed ime: ___________________ 
 
3 
Usually 
(5-7) 
2 
Sometimes 
(2-4) 
1 
Rarely 
(0-1)  
 
Problem? 
1) 
Child goes to bed at the same time at night (R) 
 
 
 
Yes 
No 
N/A 
2) 
Child falls asleep within 20 minutes after going to bed (R) 
 
 
 
Yes 
No 
N/A 
3) 
Child falls asleep alone in own bed (R) 
 
 
 
Yes 
No 
N/A 
4) 
Child falls asleep in parent’s or sibling’s bed 
 
 
 
Yes 
No 
N/A 
5) 
Child needs parent in the room to fall asleep 
 
 
 
Yes 
No 
N/A 
6) 
Child struggles at bedtime  
(cries, refuses to stay in bed, etc.) 
 
 
 
Yes 
No 
N/A 
7) 
Child is afraid of sleeping in he dark 
 
 
 
Yes 
No 
N/A 
8) 
Child is afraid of sleep alone 
 
 
 
Yes 
No 
N/A 
 
Sleep Behavior 
Child’s usual amount of sleep each day: ____________ hours and ____________ minutes 
(combining nighttime sleep and naps) 
 
3 
Usually 
(5-7) 
2 
Sometimes 
(2-4) 
1 
Rarely 
(0-1) 
 
Problem? 
9) 
Child sleeps too little 
 
 
 
Yes 
No 
N/A 
10) Child sleeps the right amount (R) 
 
 
 
Yes 
No 
N/A 
11) Child sleeps about the same amount each day (R) 
 
 
 
Yes 
No 
N/A 
12) Child wets the bed at night 
 
 
 
Yes 
No 
N/A 
13) Child talks during sleep 
 
 
 
Yes 
No 
N/A 
14) Child is restless and moves a lot during sleep 
 
 
 
Yes 
No 
N/A 
15) Child sleepwalks during he night 
 
 
 
Yes 
No 
N/A 
16) Child moves to someone else’s bed during he night 
(parent, brother, sister, etc ) 
 
 
 
Yes 
No 
N/A 
17) Child grinds teeth during sleep (your dentist may have told 
you this) 
 
 
 
Yes 
No 
N/A 
18) Child snores loudly 
 
 
 
Yes 
No 
N/A 


 
 
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Protocol 1042- CDD-3001 
 
26 May 2020, Amendment 2.0 
 
_______________ 
 
Coding 
 
 
2 
CSHQ Abbreviated 
Sleep Behavior (continued) 
 
3 
Usually 
(5-7) 
2 
Sometimes 
(2-4) 
1 
Rarely 
(0-1) 
 
Problem? 
19) Child seems to stop breathing during sleep 
 
 
 
Yes 
No 
N/A 
20) Child snorts and/or gasps during sleep 
 
 
 
Yes 
No 
N/A 
21) Child has trouble sleeping away from home (visiting 
relatives, vacation) 
 
 
 
Yes 
No 
N/A 
22) Child awakens during night screaming, sweating, and 
inconsolable 
 
 
 
Yes 
No 
N/A 
23) Child awakens alarmed by a frightening dream 
 
 
 
Yes 
No 
N/A 
 
Waking During the Night 
 
3 
Usually 
(5-7) 
2 
Sometimes 
(2-4) 
1 
Rarely 
(0-1) 
 
Problem? 
24) Child awakes once during the night 
 
 
 
Yes 
No 
N/A 
25) Child awakes more than once during the night 
 
 
 
Yes 
No 
N/A 
 
Write he number of minutes a night waking usually lasts: _________________ 
 
Morning Waking/Daytime Sleepiness 
Write in the time of day child usually wakes in the morning: _______________ 
 
3 
Usually 
(5-7) 
2 
Sometimes 
(2-4) 
1 
Rarely 
(0-1) 
 
Problem? 
26) Child wakes up by him/herself (R) 
 
 
 
Yes 
No 
N/A 
27) Child wakes up in negative mood 
 
 
 
Yes 
No 
N/A 
28) Adults or siblings wake up child 
 
 
 
Yes 
No 
N/A 
29) Child has difficulty getting out of bed in the morning 
 
 
 
Yes 
No 
N/A 
30) Child takes a long time to become alert in the morning 
 
 
 
Yes 
No 
N/A 
31) Child seems tired 
 
 
 
Yes 
No 
N/A 
 
Child has appeared very sleepy or fallen asleep during the following (check all that apply): 
 
1 
Not Sleepy 
2 
Very Sleepy 
3 
Falls Asleep 
32) Watching TV 
 
 
 
33) Riding in car 
 
 
 
 


 
 
Confidential 
 
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Protocol 1042- CDD-3001 
 
26 May 2020, Amendment 2.0 
12.9. 
Appendix 9:  Anxiety, Depression, and Mood Scale (ADAMS) - 
Baseline 
Instructions 
The Anxiety Depression and Mood Scale (ADAMS) contains a list of behaviors that can be 
found among individuals with intellectual disability. Please describe the individual’s 
behavior over the last 6 months  
 
0 
behavior has not occurred, or is not a problem 
1 
behavior occurs occasionally, or is a mild problem 
2 
behavior occurs quite often, or is a moderate problem 
3 
behavior occurs a lot, or is a severe problem 
 
not a 
problem 
mild 
problem 
moderate 
problem 
severe 
problem 
1. 
Nervous  
0 
1 
2 
3 
2. 
Problems initiating communication  
0 
1 
2 
3 
3. 
Does not relax or settle down  
0 
1 
2 
3 
4. 
Has periods of over-activity  
0 
1 
2 
3 
5. 
Sleeps more than normal  
0 
1 
2 
3 
6. 
Withdraws from other people  
0 
1 
2 
3 
7. 
Tense  
0 
1 
2 
3 
8. 
Engages in ritualistic behaviors  
0 
1 
2 
3 
9. 
Depressed mood 
0 
1 
2 
3 
10. 
Sad  
0 
1 
2 
3 
11. 
Worried  
0 
1 
2 
3 
12. 
Has developed difficulty staying on task or 
 
 
 
 
completing work  
0 
1 
2 
3 
13. 
Shy  
0 
1 
2 
3 
14. 
Easily fatigued (not due to being overweight) 
0 
1 
2 
3 
15. 
Anxious  
0 
1 
2 
3 
16. 
Repeatedly checks items  
0 
1 
2 
3 
17. 
Easily distracted  
0 
1 
2 
3 
18. 
Lacks energy  
0 
1 
2 
3 
19. 
Avoids others, spends much of time alone 
0 
1 
2 
3 
20. 
Easily upset if ritualistic behaviors are interrupted  
0 
1 
2 
3 
21. 
Lacks emotional facial expressions 
0 
1 
2 
3 
22. 
Has shown difficulty in starting routine tasks 
0 
1 
2 
3 
23. 
Listless 
0 
1 
2 
3 
24. 
Experiences panic attacks 
0 
1 
2 
3 
25. 
Avoids eye contact 
0 
1 
2 
3 
26. 
Trembles when frightening situations are not present 
0 
1 
2 
3 
27. 
Avoids peers 
0 
1 
2 
3 
28. 
Tearful 
0 
1 
2 
3 
 
 
 


 
 
Confidential 
 
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IND 44,020 
 
Marinus Pharmaceuticals Inc. 
Protocol 1042- CDD-3001 
 
26 May 2020, Amendment 2.0 
12.10. 
Appendix 10:  Anxiety, Depression, and Mood Scale (ADAMS) – Post 
Baseline Visits 
Instructions 
The Anxiety Depression and Mood Scale (ADAMS) contains a list of behaviors that can be 
found among individuals with intellectual disability. Please describe the individual’s 
behavior since the last visit (post-baseline visits). 
 
4 
behavior has not occurred, or is not a problem 
5 
behavior occurs occasionally, or is a mild problem 
6 
behavior occurs quite often, or is a moderate problem 
7 
behavior occurs a lot, or is a severe problem 
 
not a 
problem 
mild 
problem 
moderate 
problem 
severe 
problem 
1. 
Nervous  
0 
1 
2 
3 
2. 
Problems initiating communication  
0 
1 
2 
3 
3. 
Does not relax or settle down  
0 
1 
2 
3 
4. 
Has periods of over-activity  
0 
1 
2 
3 
5. 
Sleeps more than normal  
0 
1 
2 
3 
6. 
Withdraws from other people  
0 
1 
2 
3 
7. 
Tense  
0 
1 
2 
3 
8. 
Engages in ritualistic behaviors  
0 
1 
2 
3 
9. 
Depressed mood 
0 
1 
2 
3 
10. 
Sad  
0 
1 
2 
3 
11. 
Worried  
0 
1 
2 
3 
12. 
Has developed difficulty staying on task or 
 
 
 
 
completing work  
0 
1 
2 
3 
13. 
Shy  
0 
1 
2 
3 
14. 
Easily fatigued (not due to being overweight) 
0 
1 
2 
3 
15. 
Anxious  
0 
1 
2 
3 
16. 
Repeatedly checks items  
0 
1 
2 
3 
17. 
Easily distracted  
0 
1 
2 
3 
18. 
Lacks energy  
0 
1 
2 
3 
19. 
Avoids others, spends much of time alone 
0 
1 
2 
3 
20. 
Easily upset if ritualistic behaviors are interrupted  
0 
1 
2 
3 
21. 
Lacks emotional facial expressions 
0 
1 
2 
3 
22. 
Has shown difficulty in starting routine tasks 
0 
1 
2 
3 
23. 
Listless 
0 
1 
2 
3 
24. 
Experiences panic attacks 
0 
1 
2 
3 
25. 
Avoids eye contact 
0 
1 
2 
3 
26. 
Trembles when frightening situations are not present 
0 
1 
2 
3 
27. 
Avoids peers 
0 
1 
2 
3 
28. 
Tearful 
0 
1 
2 
3 
 
 


 
 
Confidential 
 
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IND 44,020 
 
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Protocol 1042- CDD-3001 
 
26 May 2020, Amendment 2.0 
12.11. 
Appendix 11:  Quality of Life Inventory – Disability (QI-Disability) 
 
 
 
 
 
 
 
 
 
 
Quality of Life Inventory-Disability (QI-Disability) 
Questionnaire for children and adolescents 
Parent Version 
 
 
 
 
 
 
 
 
 
 
 
 










 
 
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Protocol 1042- CDD-3001 
 
26 May 2020, Amendment 2.0 
12.12. 
Appendix 12:  Parenting Stress Index (PSI) 
 
 


 
 
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Protocol 1042- CDD-3001 
 
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Confidential 
 
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Protocol 1042- CDD-3001 
 
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SAP_003.pdf: 
Sponsor: Marinus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Study 1042-CDD-3001 
22 August 2019 
 
Version: Final 
Confidential 
Page 1 of 49 
 
Statistical Analysis Plan 
 
Protocol No.: 1042-CDD-3001  
 
A double-blind, randomized, placebo-controlled trial of adjunctive ganaxolone treatment 
in children and young adults with cyclin-dependent kinase-like 5 (CDKL5) deficiency 
disorder (CDD) followed by long-term open-label treatment 
 
 
 
 
Sponsor: 
Marinus Pharmaceuticals, Inc. 
Version: 
Final 
Issue Date: 
22 August 2019 
 
 


Sponsor: Marinus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Study 1042-CDD-3001 
22 August 2019 
 
Version: Final 
Confidential 
Page 2 of 49 
Statistical Analysis Plan Approval 
 
Author: 
 
________________________ 
 
Date:  _____/_____/_________ 
 PhD 
 
 
 
Reviewed and approved by: 
_________________________ 
 
Date:  _____/_____/_________ 
 PhD 
 
Marinus Pharmaceuticals, Inc. 
 
Sponsor Review: 
________________________ 
 
Date:  _____/_____/_________ 
 MD 
Marinus Pharmaceuticals, Inc. 
DocuSign Envelope ID: 
29-08-2019 | 11:43 AM EDT
28-08-2019 | 12:12 PM PDT
DocuSign Envelope ID: 0B62F1E3-D0A3-4348-89F4-D591EC38913D
29-08-2019 | 2:25 PM EDT


Sponsor: Marinus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Study 1042-CDD-3001 
22 August 2019 
 
Version: Final 
Confidential 
Page 3 of 49 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................ 3 
LIST OF IN-TEXT TABLES .......................................................................................................... 6 
LIST OF IN-TEXT FIGURES ........................................................................................................ 6 
1. 
INTRODUCTION ................................................................................................................. 9 
1.1 
Study Objectives ............................................................................................................. 9 
1.1.1 
Primary Objective ........................................................................................................ 9 
1.1.2 
Secondary Objectives .................................................................................................. 9 
 
 
1.2 
Study Endpoints ............................................................................................................ 10 
1.2.1 
Primary Efficacy Endpoint ........................................................................................ 10 
1.2.2 
Secondary Efficacy Endpoints ................................................................................... 10 
 
 
1.2.4 
Safety and Tolerability Endpoints .............................................................................. 12 
1.2.5 
Open-Label Phase Endpoints ..................................................................................... 12 
1.3 
Summary of the Study Design ...................................................................................... 12 
1.3.1 
General Study Design and Plan ................................................................................. 12 
1.3.2 
Sample Size and Statistical Power Considerations .................................................... 23 
2. 
STATISTICAL METHODS ................................................................................................ 23 
2.1 
General Considerations ................................................................................................. 23 
2.1.1 
Reporting Precision ................................................................................................... 24 
2.2 
Definitions of Analysis Populations (Analysis Sets) .................................................... 24 
2.2.1 
Safety and Intention-to-Treat (ITT) Population ......................................................... 24 
2.2.2 
Per-Protocol Population (PP) ..................................................................................... 24 
2.3 
Time Windows for Analysis .......................................................................................... 25 
2.4 
Pooling of Centers ......................................................................................................... 25 
2.5 
Handling of Missing Data ............................................................................................. 25 
2.6 
Analysis Software ......................................................................................................... 25 
3. 
STUDY SUBJECTS ............................................................................................................ 25 
3.1 
Disposition of Subjects ................................................................................................. 25 
3.2 
Eligibility Criteria and Protocol Deviations .................................................................. 26 




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7.1.8 
Sensitivity Analyses ................................................................................................... 35 
7.2 
Open-Label Extension ................................................................................................... 37 
8. 
PHARMACOKINETICS .................................................................................................... 38 
9. 
SAFETY ANALYSIS .......................................................................................................... 38 
9.1 
Adverse Events.............................................................................................................. 39 
9.1.1 
Deaths, Serious and Adverse Events Leading to Early Study Drug Termination ...... 41 
9.2 
Clinical Laboratory Parameters .................................................................................... 41 
9.3 
Other Safety Endpoints ................................................................................................. 42 
9.3.1 
Vital Signs .................................................................................................................. 42 
9.3.2 
ECG ........................................................................................................................... 43 
9.3.3 
Physical, Neurological, and Developmental Examinations ....................................... 44 
9.3.4 
Tanner Staging ........................................................................................................... 44 
9.3.5 
Concomitant AED Levels .......................................................................................... 45 
10. 
INTERIM ANALYSES AND DATA AND MONITORING COMMITTEE (DMC) ......... 45 
10.1 
Termination Based on Reliable Evidence of Lack of Benefit ....................................... 45 
10.2 
Termination Based on Definitive Evidence of Benefit ................................................. 46 
10.3 
Data Monitoring Committee ......................................................................................... 47 
11. 
SUMMARY OF MAJOR CHANGES IN THE PLANNED ANALYSES ......................... 47 
12. 
PROGRAMMING SPECIFICATIONS .............................................................................. 47 
12.1 
Format of Appendix Tables/Figures/Listings ................................................................ 47 
12.2 
SAS Procedures for Seizure Analyses .......................................................................... 49 
13. 
REFERENCES .................................................................................................................... 49 
 


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LIST OF IN-TEXT TABLES 
Table 1: 
Schedule of Assessment for the 17-week, Double-blind Treatment Phase of the Study
 .................................................................................................................................... 14 
Table 2: 
Schedule of Assessments for Open-Label Phase ....................................................... 18 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
Study Design .............................................................................................................. 13 
 


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ABBREVIATIONS 
Abbreviation 
Term 
ABC-C 
Aberrant Behavior Checklist – Community Edition 
AEs 
adverse events 
AED 
anti-epilepsy drugs 
Allo-S 
Allopregnanolone Sulfate 
ALT 
alanine aminotransferase  
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase  
ATC 
Anatomical Therapeutic Chemical  
bpm 
beats per minute 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CDD 
CDKL5 Deficiency Disorder 
CDKL5 
Cyclin-Dependent Kinase Like 5  
CGICA 
Caregiver Global Impression of Change in Attention 
CGI-CSID 
Caregiver Global Impression Of Change in Seizure Intensity/Duration 
CGI-C 
Clinical Global Impression Of Change 
CGI-I 
Clinical Global Impression Of Improvement 
cm 
centimeter 
CNS 
central nervous system 
CO2 
carbon dioxide  
CRF 
case report form 
CSHQ 
Children’s Sleep Habit Questionnaire 
D/C 
discontinuation 
DB 
double-blind 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
EEG 
electroencephalogram 
eCRF 
electronic case report form 
°C 
degrees celsius 
FDA 
Food And Drug Administration 
GNX 
ganaxolone 
ITT 
intent-to-treat 
kg 
kilogram 
kg/m2 
kilogram per square meter 
LAR 
legally authorized representative 
lb 
pound 
LLN 
Lower limit of normal 


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Abbreviation 
Term 
m 
meter 
MedDRA 
Medical Dictionary For Regulatory Activities 
mg 
milligram 
mmHg 
millimeters mercury 
OL 
open label  
OLE 
open-label extension 
PBO 
placebo 
PCS 
potentially clinically significant 
PK 
pharmacokinetics 
PP 
per protocol 
PSI 
Parenting Stress Index 
PT 
Preferred Term 
QI 
Quality of Life Inventory 
SAEs 
serious adverse events 
SAP 
statistical analysis plan  
SD 
standard deviation 
SI 
Système International 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event  
ULN 
Upper limit of normal 
US 
United States 
WHO 
World Health Organization  
wks 
weeks 




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1.2 
Study Endpoints 
The primary interest in the study is the effects of GNX treatment following 17 weeks of 
DB treatment, and so the endpoints will be based upon data through the end of the 17-week 
DB treatment.  But as indicated in Section 7.1.6, they will also be examined from earlier time 
points.  
Three categories of seizures will be assessed in this study; individual seizures, clusters with 
countable seizures, and clusters with uncountable seizures.  The analyses will be performed on 
the sum of the individual seizures, the seizures within a cluster in which the seizures are 
countable, and the clusters with uncountable seizures (each cluster with uncountable seizures 
contributes 1 to the sum). 
1.2.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the percentage change from baseline in 28-day primary seizure 
frequency during the 17-week DB treatment phase.  
Baseline is defined as the 6-week prospective baseline phase.   
The primary seizure types include bilateral tonic (sustained motor activity ≥ 3 seconds), 
generalized tonic-clonic, atonic/drop, bilateral clonic, and focal to bilateral tonic-clonic. The 
seizure data is taken from the patient diaries.   
1.2.2 Secondary Efficacy Endpoints 
Derived seizure secondary efficacy endpoints will be based on data through the end of the 
17-week DB treatment phase relative to the 6-week prospective baseline phase.   
Seizure control:  
 Change from baseline in the percentage of seizure-free days during the 17-week DB 
treatment phase, based on the primary seizure types 
 Number (%) of subjects with a ≥50% reduction from baseline in primary seizure 
frequency 
 Caregiver Global Impression of Change in Seizure Intensity/Duration (CGI-CSID). 
Behavioural/Neuropsychiatric:  
 Caregiver Global Impression of Change in Attention (CGICA) score 
 Clinical Global Impression-Change (CGI-C) in parent/caregiver/LAR identified 
behavioural target - potential domains include sociability, communication, irritability, 
and hyperactivity 
 Clinical Global Impression of Improvement (CGI-I): overall improvement by both 
parent/caregiver/LAR and clinician. 




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1.2.4 Safety and Tolerability Endpoints 
Safety and tolerability endpoints include: 
 Adverse events (AEs) 
 Clinical laboratory tests  
 Vital signs including temperature, blood pressure, pulse rate, respiration rate, and 
weight  
 Physical, neurological and developmental examinations 
 12-lead Electrocardiogram (ECG) 
 Concomitant AED levels 
1.2.5 Open-Label Phase Endpoints 
Except for the changes in seizure frequency during the titration phase and during the 
maintenance phase, the same efficacy, exploratory, quality of life, and safety endpoints for the 
DB phase will also be used for the open-label phase.  In addition, the Tanner Staging, which is 
performed only at Screening in the DB phase of the study unless the subject does not enter the 
OLE phase, is another safety endpoint.  When the DB phase is completed in all the subjects, a 
cutoff date will be declared for purposes of NDA submission and all open label data collected up 
to the cutoff will be analyzed.  When the full study is completed, the open-label data will be re-
analyzed. 
The results for the open-label phase should be interpreted cautiously because there is no control 
group in that phase, and the intent-to-treat principle may be compromised since several subjects 
may not enter the phase and, among those entering, several may withdraw from the study prior to 
its completion.  In addition, there is no blinding during the open-label phase. 
1.3 
Summary of the Study Design  
1.3.1 General Study Design and Plan 
This is a phase 3 global, DB, randomized, PBO-controlled trial of adjunctive GNX treatment in 
children and young adults with CDD.  The trial consists of a 6-week prospective baseline period 
to collect seizure data, followed by a 17-week DB treatment phase, which is then followed by a 
long-term open-label phase.   
The double blind phase includes 6 weeks prospective baseline, 4 weeks of titration followed by 
13 weeks of dose maintenance.  After meeting the eligibility criteria, children and young adults 


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aged 2-21 years (inclusive) with CDD will be randomly assigned to receive GNX or PBO 
(1:1 ratio) for 17 weeks in addition to their standard anti-seizure treatment.  Recruitment will 
stop after approximately 100 children and young adults have been enrolled.  Participants will be 
titrated to 63 mg/kg/day (max 1800 mg/day) over 4 weeks, and then maintained at that dose for 
another 13 weeks.  Subjects who are not able to tolerate 63 mg/kg/day (or 1800 mg/day 
maximum) may be maintained on a lower dose after discussion with the Sponsor.  A minimum 
dose of 33 mg/kg/day or 900 mg/day is required during the DB phase.   
After completing the initial 17-week, DB, PBO-controlled phase, all subjects will be treated with 
GNX in the open-label phase of the study.  GNX subjects will continue GNX treatment and PBO 
subjects will titrate onto GNX.  To maintain the blind, subjects initially randomized to GNX will 
undergo a false titration (increasing PBO doses) for 4 weeks, while PBO subjects will titrate up 
to 63 mg/kg/day GNX (1800 mg/day maximum) during the same time phase (Figure 1).  The 
open-label phase is estimated to take an additional 3 years.  It will continue until the sponsor 
terminates the program or GNX has been approved and marketed the investigational product in 
the subjects’ respective country. 
Participants who complete the study or discontinue investigational product treatment before the 
end of the study will undergo a 2-week taper phase after which he/she will return to the site 
2 weeks postdose for a safety follow up visit.  Subjects who discontinue investigational product 
treatment before the completion of the DB phase will continue to be followed per protocol and at 
minimum maintain daily seizure diary entry until the DB phase is completed.  These subjects 
will also return to the site 2 weeks after the taper for safety follow-up assessments. 
Figure 1. Study Design 
 
Participants will be required to complete a daily seizure calendar noting seizure type and 
frequency in an electronic seizure diary calendar to determine GNX’s effect on drug resistant 
seizures.   
The Schedule of Events for the 17-week pre-randomization and double-treatment phase is 
presented in Table 1.  The Schedule of Events for the OLE is presented in Table 2.


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Table 1: 
Schedule of Assessment for the 17-week, Double-blind Treatment Phase of the Study 
Screen/Baseline 
DB Titration + Maintenance 
Final DB Visit  
WEEK 
-14 
-6 
(Screening) 
0 
Baseline 
(Randomization) 
3  
days 
1, 2, 3, 4 
5 
9 
11, 13 
17 
Visit Windows 
 
 
+6 daysn 
± 1 day 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
Historical 
Seizure 
frequency 
Visit 1 
Visit 2 
Phone 
Follow-up 
Phone  
Follow-up 
Visit 3 
Visit 4 
Phone  
Follow-up 
Visit 5 
Screening and Diagnosis 
Informed Consenta 
 Xb 
X 
 
Demographics & 
Medical History 
 
X 
 Xc 
Historical Seizure 
Calendar Review 
 
X 
 
Inclusion/Exclusion 
Criteria 
 
X 
X 
Genetic testingd 
 
X 
 
Seizure Identification 
and Diagnostic Review 
Form (Epilepsy Study 
Consortium) 
 
X 
X 
Safety Assessments 
Vital signs (BP, HR, 
RR, and body 
temperature) 
 
 Xe 
X 
 
 
X 
X 
 
 Xf 
Physical/Neurological/ 
Developmental Exam 
 
X 
 
 
X 
 
X 
Physical/Neurological/ 
Developmental Exam 
Follow-up 
 
 
X 
 
 
X 
 
 


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Table 1: 
Schedule of Assessment for the 17-week, Double-blind Treatment Phase of the Study 
Screen/Baseline 
DB Titration + Maintenance 
Final DB Visit  
WEEK 
-14 
-6 
(Screening) 
0 
Baseline 
(Randomization) 
3  
days 
1, 2, 3, 4 
5 
9 
11, 13 
17 
Visit Windows 
 
 
+6 daysn 
± 1 day 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
Historical 
Seizure 
frequency 
Visit 1 
Visit 2 
Phone 
Follow-up 
Phone  
Follow-up 
Visit 3 
Visit 4 
Phone  
Follow-up 
Visit 5 
ECG 
 
X 
X 
 
 
X 
 
 
X 
Clinical Laboratory 
Testsg 
 
X 
X 
 
 
X 
X 
 
X 
Urinalysis 
 
Xh 
Xh 
 
 
 
X 
Drug screeni 
 
X 
 
 
 
 
Pregnancy Test 
(WCBP)j 
 
X 
X 
 
 
 
Tanner Staging 
 
X 
 
 
 
 
Investigational Product 
PK 
 
 
 
 
 
 Xk 
 Xk 
 
X 
Concomitant AED 
Review and levels if per 
standard of carel 
 
X 
X 
 
 
X 
X 
 
X 
Neurosteroid levels 
 
X 
 
 
 
 
 
 
X 
Adverse Event 
 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy Assessments 
Seizure eDiary review 
X 
X 
X 
X 
X 
X 
X 
X 
Caregiver Global 
Impression of Change 
in Attention (CGICA) 
 
Xm  
 
 
 
X 
X 
 
X 
Caregiver Global 
Xm 
 
 
 
X 
X 
 
X 




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Table 1: 
Schedule of Assessment for the 17-week, Double-blind Treatment Phase of the Study 
Screen/Baseline 
DB Titration + Maintenance 
Final DB Visit  
WEEK 
-14 
-6 
(Screening) 
0 
Baseline 
(Randomization) 
3  
days 
1, 2, 3, 4 
5 
9 
11, 13 
17 
Visit Windows 
 
 
+6 daysn 
± 1 day 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
Historical 
Seizure 
frequency 
Visit 1 
Visit 2 
Phone 
Follow-up 
Phone  
Follow-up 
Visit 3 
Visit 4 
Phone  
Follow-up 
Visit 5 
 
 
 
 
 
 
 
 
 
 
Dispense Investigational 
Product 
 
 
X 
 
 
X 
X 
 
X 
AED = antiepileptic drug; BP = blood pressure; CBD = cannabidiol; D/C = discontinuation; DB = double-blind; ECG = electrocardiogram; EEG = electroencephalogram; HR = 
heart rate; LAR = legally authorized representative; PK = pharmacokinetic; RR = respiratory rate; THC = tetrahydrocannabinol; WCBP = women of childbearing potential. 
a. 
Written informed consent/assent must be obtained from subject, parent or LAR before any study assessments are performed. 
b. 
Written informed consent/assent from subject, parent or LAR needed if 8-week historical control is not available and need to chart prospectively. 
c. 
Review of medical history only.  
d. 
Genetic testing to be performed to confirm pathogenic or likely pathogenic CDKL5 variant. 
e. 
In addition, height and weight will be measured.  If weight unable to be collected at Visit 1, may be collected at Visit 2. 
f. 
In addition, weight will be measured. 
g. 
Chemistry & Hematology (Section 12.2).  
h. 
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. 
i. 
A drug screen (urine or plasma) will be performed to test for THC and CBD at screening. A negative drug test at screening meets the protocol eligibility criteria. If the screening drug test is 
positive, a plasma drug screen will be performed to test for THC and CBD at baseline. A positive drug test at baseline will exclude the subject from the study. 
j. 
Serum pregnancy test is required for all girls/women of childbearing potential.  
k. 
Population PK will be conducted at these visits (Visit 3: between 1-5 hours since last IP dosing, Visit 4: between 4-8 hours since the last IP dosing).  
l. 
Concomitant AEDs or their dose must be stable for 1 month prior to screening and cannot be changed at any time prior to Visit 5 but may be adjusted during the open-label phase of the study. 
m. During the Screening visit, the investigator and parent/caregiver/LAR will decide on a specific behavior that the patient exhibits that denotes assessment measured.  This behavior will be used at 
subsequent visits to assess change after the initiation of investigational product. 
n. 
Visit 2 to occur minimum of 6 weeks (42 days) after Visit 1 and maximum of 6 weeks + 6 days (48 days) 


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Table 2: 
Schedule of Assessments for Open-Label Phase 
Final DB 
Visit/ First 
OL Visit 
Titration 
(4 weeks blinded) 
Open-Label Maintenance 
(Visits will be every 16 weeks with a telephone 
follow up in-between after 52 weeks) 
Final 
OL Visit 
or  
Taper 
Safety  
Follow-
up 
post 
WEEK 
17 
3 Days 
Post 
Visit 5 
18 
19 
20 
21 
28 
34 
43 
52 
60 
68 
and 
X 
visit 
X/ 
or 
early 
D/C 
2 
weeks 
post 
last 
d
Visit Windows 
 
± 1 
± 3 days 
± 3 
days 
± 3 
days 
± 3 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7  
days 
± 3 
days 
Visit 5 
Phone 
follow-up 
Phone 
follow-up 
Visit 6 Phone 
follow-
up 
Visit 7 Phone 
follow-
up 
Visit 8 Phone 
follow-
up 
Visit 9 Phone 
follow-
up 
Visit 10 
and 
Visit X 
Visit X Visit X 
Safety Assessments 
Vital signs (BP, HR, 
RR, and body 
temperature)a 
X a 
 
 
X 
 
X 
 
X a b 
 
X a b 
 
X a 
X a b 
X 
Physical/Neurological/ 
Developmental Exam 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Physical/Neurological/ 
Developmental Exam 
Follow-up 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Clinical 
Laboratory
Testsc 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
Xe 
 
 
X 
Xe 
Pregnancy Test 
(WCBP)d 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Tanner Staginge 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 


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Table 2: 
Schedule of Assessments for Open-Label Phase 
Final DB 
Visit/ First 
OL Visit 
Titration 
(4 weeks blinded) 
Open-Label Maintenance 
(Visits will be every 16 weeks with a telephone 
follow up in-between after 52 weeks) 
Final 
OL Visit 
or  
Taper 
Safety  
Follow-
up 
post 
WEEK 
17 
3 Days 
Post 
Visit 5 
18 
19 
20 
21 
28 
34 
43 
52 
60 
68 
and 
X 
visit 
X/ 
or 
early 
D/C 
2 
weeks 
post 
last 
d
Visit Windows 
 
± 1 
± 3 days 
± 3 
days 
± 3 
days 
± 3 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7  
days 
± 3 
days 
Visit 5 
Phone 
follow-up 
Phone 
follow-up 
Visit 6 Phone 
follow-
up 
Visit 7 Phone 
follow-
up 
Visit 8 Phone 
follow-
up 
Visit 9 Phone 
follow-
up 
Visit 10 
and 
Visit X 
Visit X Visit X 
Investigational 
Product PK 
X 
 
 
X 
 
Xf 
 
X 
 
Xf 
 
X 
X 
X 
Concomitant AED 
Review and levels if 
per standard of care 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Neurosteroid Levels 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy Assessments 
Seizure eDiary 
review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Caregiver Global 
Impression of 
Change in Attention 
(CGICA) 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 


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Table 2: 
Schedule of Assessments for Open-Label Phase 
Final DB 
Visit/ First 
OL Visit 
Titration 
(4 weeks blinded) 
Open-Label Maintenance 
(Visits will be every 16 weeks with a telephone 
follow up in-between after 52 weeks) 
Final 
OL Visit 
or  
Taper 
Safety  
Follow-
up 
post 
WEEK 
17 
3 Days 
Post 
Visit 5 
18 
19 
20 
21 
28 
34 
43 
52 
60 
68 
and 
X 
visit 
X/ 
or 
early 
D/C 
2 
weeks 
post 
last 
d
Visit Windows 
 
± 1 
± 3 days 
± 3 
days 
± 3 
days 
± 3 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7  
days 
± 3 
days 
Visit 5 
Phone 
follow-up 
Phone 
follow-up 
Visit 6 Phone 
follow-
up 
Visit 7 Phone 
follow-
up 
Visit 8 Phone 
follow-
up 
Visit 9 Phone 
follow-
up 
Visit 10 
and 
Visit X 
Visit X Visit X 
Caregiver Global 
Impression of 
Change (CGI-C) in 
parent/caregiver 
identified behavioral 
target 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Clinical Global 
Impression of 
Improvement (CGI-I) 
by parent/ caregiver 
& clinician) 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Caregiver Global 
Impression of 
Change in Seizure 
Intensity/Duration 
Severity (CGI-CSID) 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 




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Table 2: 
Schedule of Assessments for Open-Label Phase 
Final DB 
Visit/ First 
OL Visit 
Titration 
(4 weeks blinded) 
Open-Label Maintenance 
(Visits will be every 16 weeks with a telephone 
follow up in-between after 52 weeks) 
Final 
OL Visit 
or  
Taper 
Safety  
Follow-
up 
post 
WEEK 
17 
3 Days 
Post 
Visit 5 
18 
19 
20 
21 
28 
34 
43 
52 
60 
68 
and 
X 
visit 
X/ 
or 
early 
D/C 
2 
weeks 
post 
last 
d
Visit Windows 
 
± 1 
± 3 days 
± 3 
days 
± 3 
days 
± 3 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7  
days 
± 3 
days 
Visit 5 
Phone 
follow-up 
Phone 
follow-up 
Visit 6 Phone 
follow-
up 
Visit 7 Phone 
follow-
up 
Visit 8 Phone 
follow-
up 
Visit 9 Phone 
follow-
up 
Visit 10 
and 
Visit X 
Visit X Visit X 
AED = antiepileptic drug; BP = blood pressure; DB = double-blind; D/C = discontinuation; ECG = electrocardiogram; EEG = electroencephalogram; HR = heart rate; PK = 
pharmacokinetic; OL = open-label; RR = respiratory rate; WCBP = women of childbearing potential.  
a. 
In addition, weight will be measured at every visit, except the safety follow-up visit. 
b. 
In addition, height will be measured.  Height will be measured annually after Visit 9 (Week 52), except the safety follow-up visit. 
c. 
Chemistry & Hematology (Section 12.2). 
d. 
Serum pregnancy test is required for all girls/women of childbearing potential. 
e. 
Conduct annually and at the final open-label visit. 
f. 
Population PK will be conducted at these visits: Visit 7: between 1-5 hours since last IP dosing and Visit 9: between 1-5 hours since last IP dosing 
 
 


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1.3.2 Sample Size and Statistical Power Considerations 
Based on data from the 7 patients in Study 1042-0900 evaluating GNX in CDKL5 patients, the 
standard deviation for the percent change in 28-day seizure frequency for seizure types tonic 
(sustained motor activity ≥ 3 seconds), tonic-clonic, atonic/drop, epileptic spasms, or clonic 
(generalized or unilateral) is estimated to be 44.5.  Therefore, when the percent change in 28-day 
seizure frequency on GNX minus that on PBO truly is 30%, then a trial with 100 subjects 
randomized in a 1:1 manner will have 92% power to detect this effect when using an ANOVA 
that preserves a (one-sided) 2.5% false positive error rate. If the true difference in the percent 
changes is 35%, then the study will have 97.5% power.  
The threshold for achieving statistical significance at the final analysis when 100 subjects have 
completed their 17-week DB treatment phase would be an estimate of the difference that is 
approximately 17.5%. (The actual analysis will use a Wilcoxon rank-sum test, which has 
approximately the same power as the ANOVA.) 
2. STATISTICAL METHODS 
2.1 
General Considerations 
In general, non-categorical variables will be summarized by number of subjects, mean, standard 
deviation (SD), median, 25th and 75th percentiles, minimum, and maximum values.  Categorical 
variables will be summarized by counts and percentage of subjects in each category.  
Except where noted, separate tables and data listings will be prepared for the DB and OLE 
phases of the study.  Only events occurring before entry into the OLE phase will be included in 
the DB phase outputs, and except where indicated, only pre-treatment events and events 
occurring after entry into the OLE phase will included in the OLE phase outputs.  The tables for 
the DB phase will show the results for each DB treatment group, and, where noted, combined 
over the groups as well.  The tables for the OLE phase will show the results for each DB 
treatment group (all subjects will be receiving GNX in the OLE phase) and combined over them.  
For the efficacy endpoints, the results will be derived according to the randomized treatment 
group; for the other endpoints, they will be derived according to the treatment actually received. 
Source data for the summary tables and statistical analyses will be presented as subject data 
listings, which include data collected on the electronic case report forms (eCRFs) as well as any 
derived efficacy variables for all enrolled subjects. 
Baseline seizure activity will be determined by 6 weeks of prospective recording in subject daily 
seizure calendars, which are provided after signing informed consent.  Within the DB phase of 
the study, post-baseline seizure activity will be determined by the days following the first day 
after the first DB treatment.  (The first day of DB treatment is included in neither the baseline 
nor DB phase since seizures could occur both before and after the initiation of treatment.)  
Within the OLE phase, post-baseline seizure activity will be determined by the first day of OLE 
treatment. 


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Baselines for non-seizure efficacy and safety assessments are defined as the last non-missing 
value of the assessment before the first dose of treatment.  
The OLE phase will use the same baseline as the DB phase. 
The study day for all assessments that are performed on or after the first day of treatment will be 
calculated as: 
Study Day = date of the assessment  date of first treatment + 1.  
For assessments performed before the first day of treatment, the study day calculation is: 
Study day = date of the assessment – date of first treatment. 
2.1.1 Reporting Precision 
Summary statistics will be presented to the following degree of precision, unless otherwise 
specified: 
Statistics 
Degree of Precision 
Mean, Median, Quartiles, Confidence limit 
boundaries 
One decimal place more than the raw data. 
Standard deviation 
Two decimal places more than the raw data. 
Minimum, Maximum 
The same as the raw data. 
p-value 
Rounded to 4 decimal places and therefore presented as 0.xxxx; 
p-values smaller than 0.0001 as ‘< 0.0001’; p-values greater 
than 0.9999 as ‘> 0.9999’. 
Percentage 
One decimal place.  A percentage of 100% will be reported as 
100%.  Percentages of zero will be reported as 0. 
For weight and height, one decimal place will be used for summary statistics.  Fractional 
numeric values will be presented with a zero to the left of the decimal point (for example, 
0.12 - 0.30). 
2.2 
Definitions of Analysis Populations (Analysis Sets) 
2.2.1 Safety and Intention-to-Treat (ITT) Population  
This population comprises all randomized subjects who received at least one dose of study drug. 
In addition to being the population for the safety analyses, it is the primary population for the 
efficacy and neurosteroid level analyses.  
2.2.2 Per-Protocol Population (PP) 
This population consists of ITT subjects who received study drug for at least 6 weeks, provided 
at least 5 weeks of post-baseline seizure data, and had no major protocol violations.  There will 
be no PP population for the OLE phase of the study. 


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2.3 
Time Windows for Analysis 
For by-visit safety or efficacy summaries, only scheduled visits will be analyzed. But if subjects 
prematurely discontinue from the study and complete assessments at the Taper Visit, then that 
visit may be reassigned to another visit for analysis purposes, as described in subsequent 
sections, including Section 7.1.1. 
2.4 
Pooling of Centers  
Data of all sites will be pooled together for analysis. 
2.5 
Handling of Missing Data 
Missing data will not be replaced except as noted. Missing efficacy data will be imputed in a 
sensitivity analysis as described in Section 7.1.7.   
2.6 
Analysis Software 
All summaries and statistical analyses will be generated using SAS® version 9.4 or later. 
3. STUDY SUBJECTS 
3.1 
Disposition of Subjects 
A data listing of Screening failures for the DB phase of the study will be provided.  
Disposition will be summarized within the DB treatment groups and overall among all subjects 
within both the DB and extension phases of the study. 
The disposition will include the following: 
 Subjects screened (DB phase only) 
 Screen failures (DB phase only) 
 Subjects enrolled (randomized) 
 Subjects in the Safety Population  
 Subjects in the ITT Population  
 Subjects in the PP Population  
 Ongoing subjects (OLE phase only) 
 Subjects who completed the phase 
 Subjects who discontinued study drug before the end of the phase (DB phase only) 
 Reasons for study drug discontinuation before the end of the phase (DB phase only) 


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 Subjects who discontinued study before the end of the phase  
 Reasons for study discontinuation before the end of the phase (OLE phase only) 
 
Subjects completing the DB phase of the study are those who completed the 17-week DB 
treatment phase, regardless of whether they entered the OLE.  A listing of dispositions will be 
provided for all randomized subjects. 
3.2 
Eligibility Criteria and Protocol Deviations 
The clinical team will identify deviations and the deviations will be recorded into the database 
and provided in a data listing.  
A data listing of subjects who violate any of the inclusion/exclusion characteristics will be 
provided as well as a data listing of subjects with other protocol violations. 
4. DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographic data (age, gender, race, height, weight and body mass index (BMI), country, and 
ethnicity) and the Tanner staging collected prior to the first dose; and the number of prior 
medications taken and stopped prior to the first dose will be summarized using descriptive 
statistics in the safety population and, if it differs substantially from the safety population, the PP 
population as well. (The safety population is also the ITT population.) The statistics will be 
shown within each DB treatment group and combined over them.  
Height (in cm) = Height (in inches) * 2.54 
Weight (in kg) = Weight (in lbs) * 0.4536 
BMI (kg/m2) = Weight (kg)/[Height(m)2] 
 
Baseline values of the efficacy and safety parameters will be summarized in the respective 
tables. 
 
5. MEDICAL HISTORY AND GENETIC TESTING 
Medical history will be coded with the Medical Dictionary for Regulatory Activities (MedDRA) 
Terminology version 16.0 or higher.  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) by treatment and overall in the safety population and, if it differs 
substantially from the safety population, the PP population as well. 


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The number and percent of subject replies to each question of the genetic testing done at 
Screening will be summarized by treatment and overall in the safety population and, if it differs 
substantially from the safety population, the PP population as well. 
6. PRIOR AND CONCOMITANT MEDICATIONS AND THERAPIES 
Prior medications are defined as medications/therapies that started and stopped prior to the first 
dose of DB study drug.  Concomitant medications/therapies are defined as medications/therapies 
(other than the study drug) administered on or after the first dose of the DB study, regardless of 
when the medications/therapies started.    The summary of concomitant medications/therapies for 
the main 17-week DB treatment phase of the study will not include concomitant 
medications/therapies that start after that phase; i.e., they will not include any starting on or after 
the first dosing day of the OLE phase. 
The summary of concomitant medications/therapies for the OLE phase will include all 
medications/therapies, other than study drug, administered on or after the first dosing day of the 
phase.  (There will be no summary of prior medications/therapies for the OLE phase.)  
All investigator terms for medications recorded on the CRF will be coded using the World 
Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) drug dictionary (Version 
WHO Drug Dictionary, March 2014).  The number (percentage) of subjects who took prior and 
concomitant medications will be summarized by treatment and overall in the safety population 
and, if it differs substantially from the safety population, the PP population as well, by ATC 
Classification and WHO Drug PT.  The tables of prior and concomitant medications will be 
provided separately for non-AED and AED medications, as will subject data listings of them.  
The number (percentage) of subjects who received prior and concomitant therapies will be 
summarized by treatment and overall in the safety population and, if it differs substantially from 
the safety population, the PP population as well. The therapies will also be in a subject data 
listing. 
To define prior or concomitant medications/therapies, the following table describes how missing 
date information will be handled; however the actual dates, not the imputed ones, will display in 
the listing. 
Partial Missing Start or Stop Date 
Imputed Start Date 
Imputed Stop Date 
Missing year, month, and day 
First dose date 
 
Missing month and day, and the year  
is present 
First dose date if the year is the same as 
the year of first dose date, else first dose 
date of the OLE if the year is the same as 
the year of the first OLE dose date, else 
January 1 of the start year. 
December 31 of that year 


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Missing day, but year and month are 
present 
First dose date if the year and month are 
the same as the year and month of first 
dose date, else first dose date of the OLE if 
the year and month are the same as the 
year and month of the first OLE dose date, 
else the 1st of the start month. 
Last day of that month 
Missing month, but year and day are 
present 
Assume day is also missing and impute as 
above 
Missing month imputed as 
December 
If an imputed start date is later than the stop date, then the stop date (after any needed 
imputations) will be used instead for the imputed start date. 
7. EFFICACY ANALYSES 
In addition to the descriptive statistics mentioned in Section 2.1, the baseline, post-baseline, and 
relevant changes from baseline for the seizure endpoints will also be summarized with 95% 
distribution-free confidence intervals for the median and Hodges-Lehmann point estimates and 
asymptotic 95% confidence limits for the location shifts.  Section 12.2 contains SAS code for 
obtaining the distribution-free confidence limits for the median and the Hodges-Lehmann 
estimates and confidence intervals. 
The baseline, post-baseline, and changes from baseline for the other non-categorical endpoints 
will be summarized with 95% confidence intervals for the means and differences in means 
between the treatment groups in addition to the other descriptive statistics. 
7.1 
Double-Blind Phase 
All efficacy analyses will be conducted in the ITT population.  A supportive analysis of the 
primary and secondary efficacy endpoints also will be conducted in the PP population.   
The estimand that is most clinically relevant as well as estimable in a manner that protects the 
integrity of randomization is the outcome measure (e.g., the percent change in 28-day seizure 
frequency), where ALL randomized subjects would be included in this analysis throughout the 
study period.  Hence, all available data will be used, even if they were collected after the subject 
stopped taking study medication, regardless of whether the subject took rescue medication.  
Section 7.1.1 details the handling of missing data.  
For the analyses of seizures, the baseline phase consists of 6 weeks before the first day of 
treatment and the DB phase starts the day following the first day of DB treatment until the final 
visit for subjects who do not enter the OLE and up to the day before the first dose of OLE 
treatment for those who do.  The first day of treatment is not in either phase since the seizures 
could occur both before and after the first treatment. 
Tests of significance between the 2 treatment groups will be performed for the primary endpoint 
with a 2-sided significance level of 0.05. 


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Seizure diary compliance for the baseline and the post-baseline DB phase intervals will be 
calculated as: 
100 x (Number of Days with Available Seizure Diary) / (Last Available Seizure Diary Date – 
First Day of the Phase + 1).  
Seizure diary compliance between visits will be calculated as: 
100 x (Number of days with available seizure data between visits) / Number of days between 
visits), with the days between visits defined as the day of the prior visit up to the day before the 
current visit. 
The compliances will be summarized with descriptive statistics and the percentage of subjects at 
least 80% compliant. 
7.1.1 Handling of Missing Data 
The primary analysis will use all available data. Careful educating and monitoring of the study 
sites will attempt to limit the amount of missing data to nearly zero, but despite these efforts, 
some missing data may still arise. Thus a sensitivity analysis, in which the missing data will be 
replaced, will be performed on the primary efficacy endpoint; see Section 7.1.8. 
When an item from a secondary or efficacy endpoint is missing, then so will any subscales or 
totals that include it. 
When subjects prematurely discontinue from the study they are asked to complete the non-
seizure assessments at the Taper Visit. For analysis purposes, their data from the Taper Visit will 
be reassigned to the first visit at which the assessment is scheduled subsequent to the 
discontinuation and the scheduled day is within 32 days of the Taper visit. For example if a 
subject completed Visit 3 and then prematurely discontinued and completed assessments at the 
Taper Visit on Study Day 100, then the Taper visit would be reassigned to Visit 5 (Week 17) for 
analysis purposes since Visit 5 is scheduled for Study Day 120, 20 days after the assessments 
were actually completed. (Although the first visit after Visit 3 is Visit 4 (Week 9), that visit is 
scheduled on Study Day 64, which is not within 32 days of Study Day 100.) But if the Taper 
Visit assessments were completed on Study Day 28 then the Taper visit would not be reassigned 
to a regular study visit since Study Day 28 is not within the 32-day window of any scheduled 
visit. Taper Visit assessments that are not reassigned will not be included in the tabulations but 
will be included in the data listings.  
  
7.1.2 Primary Efficacy Endpoint 
The primary efficacy endpoint is the percent change from baseline in 28-day primary seizure 
frequency during the 17-week DB treatment phase. Primary seizure types include bilateral tonic, 
generalized tonic-clonic, atonic/drop, bilateral clonic, or focal to bilateral tonic-clonic seizures.  
Post-baseline 28-day seizure frequency will be calculated as the total number of seizures in the 
17-week DB treatment phase divided by the number of days with seizure data in the phase, 
multiplied by 28.  Baseline 28-day seizure frequency will be calculated as the total number of 
seizures in the baseline phase divided by the number of days with seizure data in the phase, 


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multiplied by 28.  The calculation for percent change from baseline in 28-day seizure frequency 
will be done as follows for each subject: 
 
The baseline and post-baseline values and the changes and percent changes from baseline in 28-
day seizure frequency will be summarized using descriptive statistics.  
The difference between the treatment groups in the percent changes from baseline will be tested 
for statistical significance.  Since the percent differences are anticipated to display skewness 
and/or outliers, the tests will be performed using the Wilcoxon Rank-Sum statistic.  
7.1.3 Secondary Efficacy Endpoints 
All secondary efficacy endpoints will compare GNX and PBO at the end of the 17-week DB 
treatment phase relative to the 6-week prospective baseline phase. If any endpoint value at 
baseline is zero, then any percentage changes from baseline for that endpoint will be missing. 
All secondary analyses will be done primarily in the ITT population and secondarily in the PP 
population.  
7.1.3.1 Change from baseline in the Percentage of Seizure-Free Days Based on the Primary 
Seizure Types 
The percentages of seizure-free days will be based on the primary seizure types.  Post-baseline 
percentage of seizure-free days will be calculated as the number of days in the 17-week DB 
treatment phase with zero seizures divided by the number of days with seizure data in the phase, 
multiplied by 100.  The baseline percentage of seizure-free days will be calculated as the number 
of days in the 6-week baseline phase with zero seizures divided by the number of days with 
seizure data in the baseline phase, multiplied by 100. 
The baseline and post-baseline values and the arithmetic changes from baseline will be 
summarized using descriptive statistics.   
7.1.3.2 Percentage of Subjects Experiencing ≥ 50% Reduction from Baseline in 28-day 
Seizure Frequency Based on the Primary Seizure Types 
The number and percentage of subjects experiencing a reduction (improvement) of at least 50% 
from baseline in the 28-day seizure frequency of the primary seizure types will be summarized.   
In addition, a cumulative responder curve figure will be provided, in which the X-axis represents 
amount of improvement in increments of 5%, and the Y-axis represents the percentage of 
subjects improving by at least the amount on the X-axis.  The treatment groups will be presented 
separately within the figure. 












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minimal in occurrence) prior to the end of the 17-week DB phase: for those missing days, the 
corresponding median PBO data will be imputed (irrespective of treatment arm) as follows: 
 Partition the subjects in the PBO arm into quartiles, where the quartile equals 
Floor[Rank*4/(n+1)], where Floor[.] is the integer floor function, Rank is the rank of the 28-
day seizure frequency in the PBO arm based on all available PBO measurements during the 
6-week baseline phase (tied scores receive tied ranks), and n is the number of subjects in the 
PBO arm.  
 Assign each subject for whom imputation is needed into the quartile that covers the 28-day 
seizure frequency based on that subject’s available measurements during the 6-week baseline 
phase. If a frequency is lower than the lower bound of the lowest quartile (which could 
happen only in the GNX arm), then assign that subject to the lowest frequency quartile; 
likewise if a frequency is higher than the upper bound of the highest quartile, then assign that 
subject to the highest frequency quartile. If a frequency falls between two quartiles (which, 
again, could happen only in the GNX arm), then based on the distances between the 
frequency and the upper and lower bounds of the lower and higher quartiles, respectively, 
assign the subject to the closer quartile (in case of a tie, assign to the lower quartile). 
 Within each quartile, compute the median 28-day seizure frequency in the PBO arm based on 
all available PBO measurements during the 17-week DB treatment phase.  Label that ‘X’, 
and define ‘A’ to be ‘X’/28, (i.e., the daily average on placebo during the 17-week DB 
phase). 
 For any days (whether they be on the PBO or GNX arm) with missing counts due to a subject 
stopping recording measurements permanently, impute ‘A’ from the corresponding quartile 
on that day. 
 
The second sensitivity analysis will explore the possibility that subjects who stop recording their 
seizure counts tend to have higher seizure counts than the other subjects. The imputation method 
described in the 3rd and 4th bullets above, except that quartiles are not used, will be modified to 
use the median of the 5 highest counts (equivalent to the 3rd highest count) among all the PBO 
subjects with data. 
The third sensitivity analysis is to examine the effect of GNX compared to PBO among subjects 
with low Allo-S levels. The open-label phase 2 study 1042-0900 enrolled 30 subjects who were 
treated for up to six months.  In these subjects with various pediatric epilepsies, including 11 
with PCDH19 genetic epilepsy and 7 with CDKL5 Deficiency Disorder, Allo-S levels and 28-
day seizure rates were assessed.  A GNX responder was specified, by post-hoc definition, as 
having at least a 25% reduction in 28-day seizure rate.  In the PCDH19 cohort, responders (n=6) 
and non-responders (n=5) had plasma Allo-S concentrations of 501 ± 430 pg mL-1 and 9,829 ± 
6,638 pg mL-1, respectively (mean ± SD).  When performing a retrospective separation of the 
PCDH19 cohort according to their Allo-S levels, the 7 subjects with Allo-S levels below 2,500 
pg mL-1 had a 53.9% reduction in seizure rates while the 4 subjects with Allo-S levels above 
2,500 pg mL-1 had a 247% increase.    


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All 7 of the subjects with CDKL5 Deficiency Disorder in the 1042-0900 study had low Allo-S 
levels (below 1000 pg/mL), and their median 28-day seizure reduction was 31%. 
The PCDH19 cohort results were based on only 11 subjects and were from an uncontrolled 
study.  Even if low Allo-S levels are indeed associated with increased efficacy of GNX relative 
to PBO among patients with PCDH19 seizures, this effect modification by baseline Allo-S levels 
will not necessarily hold among subjects with CDKL5 seizures; it does nevertheless suggest that 
among patients suffering with CDKL5 seizures the benefit of GNX compared to PBO could be 
greater in patients with low Allo-S levels. As a result, most important sensitivity analysis for the 
effect of GNX on the primary efficacy endpoint of change in 28-day frequency of the primary 
seizure types will be in those subjects with low Allo-S levels at baseline. Based upon insights 
from the Study 1042-0900 clinical trial data, subjects in this trial will be considered to have low 
Allo-S levels if they have a baseline Allo-S level of less than or equal to 2500 pg/mL (Pinna Lab 
method).  
7.2 
Open-Label Extension 
All of the analyses for the DB phase will be repeated for the OLE phase, with the following 
differences: 
 The results will be presented overall and also classified according to the DB treatment 
received by the subjects  
 The post-baseline seizure endpoints will be derived starting from the first dosing day 
of OLE treatment 
 The only sensitivity analysis to be performed is the analysis of the primary endpoint 
among subjects with low Allo-S levels 
 The seizure frequencies during the titration and maintenance phases will not be 
analyzed separately 
 The time points for the efficacy, exploratory, and quality of life endpoints will be at 
Weeks 21, 34, 52, and every 16 weeks thereafter of open-label treatment relative to 
the 6-week prospective baseline phase. For the seizure endpoints, this corresponds to 
the first 4, 17, 35, 51, etc. weeks from the start of the OLE phase 
 The differences between the DB treatment groups in the percent changes from 
baseline of the 28-day seizure frequencies will not be tested for statistical significance 
 No PP analyses will be performed 
 If a subject prematurely discontinues from the OLE phase, the EEG comparison to 
baseline at the Final OL/Taper Visit cannot be reassigned for analysis purposes since 
the EEG is performed only at that visit in the OLE phase; hence the tabulation at that 
visit will include all the subjects, regardless of whether they discontinued. (Taper 
Visit assessments among the subjects who prematurely discontinue from the DB 
phase are reassigned if possible; if they cannot be reassigned then they are not 
tabulated.) 


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8. PHARMACOKINETICS 
A listing of the pharmacokinetic collection times will be provided, but the analyses will be 
described in a separate report.  
9. SAFETY ANALYSIS 
All safety analyses will be performed in the Safety Population.  The results in the DB and OLE 
phases will be summarized separately.  In both phases, the results will be summarized by the DB 
treatment actually received and, for the OLE phase of the study, combined over the treatment 
groups.   
The number and percentage of days that subjects received study drug, the highest percentage of 
the maximum allowable daily dose (1800 mg or 63 mg/kg) that subjects received, and the total 
amount of study drug received will be summarized. The denominator for the percentage of days 
of study drug is the number of days in the phase. If the subject stops taking drug during the phase 
then the last day that drug was taken will be used for the last day of the phase, and if the subject 
is ongoing in the phase then the last known treatment date will be used. For the OLE phase, the 
number and percentage of days that subjects received study drug will be summarized over just 
the OLE phase as well as over the entire study (combined DB and OLE phases) but the 
classification by the DB treatment applies only for the OLE phase summary. The summarization 
over the entire study will include the DB data only from subjects who were in the GNX group 
during the DB phase, regardless of whether they entered the OLE, and all the subjects from the 
OLE phase 
A subject data listing will be provided with full details of the study drug dispensation. 
Safety assessments include: 
 AEs  
 Clinical laboratory tests  
 Vital signs including temperature, blood pressure, pulse rate, and weight 
 12-lead ECG 
 Physical, neurological and developmental examinations 
 Tanner staging (OLE phase only) 
 Concomitant AED levels 
Baseline is defined as the last non-missing value obtained before the first DB treatment.   
Assessments performed at multiple post-baseline time points will be summarized at each time 
point for which they are scheduled, but the listings will also include any assessments performed 
at unscheduled time points. Assessments performed at the Taper Visit for prematurely 
discontinued subjects will be reassigned as described in Section 7.1.1; if the assessments are not 


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reassigned, they will not be included in the tabulations but will be included in the data listings. 
Subjects who prematurely discontinue from the study are also asked to complete assessments at 
the Safety Follow-up Post-Taper Visit, but these will not be reassigned. 
9.1 
Adverse Events 
Adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT) 
using the MedDRA®, version 16.0 or higher.  The verbatim term will be included in the AE 
listings.  Except where indicated, the summary tables will include only TEAEs.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings. 
A treatment-emergent adverse event (TEAE) is defined as an AE that starts or worsens on or 
after the first dosing day of study drug.  The AE analyses for the main 17-week DB treatment 
phase of the study will include AEs that start or worsen during that phase and will not include 
AEs that start or worsen during the OLE phase; ie, they will not include any AEs starting or 
worsening on or after the first dosing day of the OLE phase.  
For the OLE phase of the study, the AEs will be summarized over just the OLE phase as well as 
over the entire study (combined DB and OLE phases) but the classification by the DB treatment 
applies only for the OLE phase summary.  The summarization over the entire study will include 
AEs in the DB phase only from subjects who were in the GNX group during the DB phase, 
regardless of whether they entered the OLE, and all the subjects from the OLE phase; i.e., it will 
include only the AEs following GNX exposure. The summarizations over just the OLE phase 
will include TEAEs that start or worsen after the first day of the OLE phase; the summarizations 
over the entire study will include TEAEs that start or worsen on or after the first dosing day of 
GNX. 
The TEAEs will be summarized as the number of events and the number and percentage of 
subjects with TEAEs.  Subjects who report the same PT on multiple occasions will be counted 
once for the PT:  under the highest severity (severe > moderate > mild) when summarized by 
severity and under the closest relationship (related > unrelated) to study drug when summarized 
by relationship.  TEAEs with missing relationships will be considered as related. 
If a subject reports multiple PTs for a SOC, the subject will be counted only once for that SOC.  
For the counting of events, all the PTs will be included in the counts, even when subjects have 
multiple PTs.  
Pre-treatment emergent AEs by will be summarized by SOC and PT (only for the DB period 
summary). 
TEAEs will be summarized as below.  
 An overview table of TEAEs, including number of events and number (%) of subjects 
with  
o TEAEs 


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o serious TEAEs (Treatment-emergent SAEs) 
o treatment related TEAEs 
o TEAEs by severity  
o TEAEs leading to study drug discontinuation 
o TEAEs leading to dose reduction or temporary study drug discontinuation 
o TEAEs leading to death 
 TEAEs by SOC and PT 
 TEAE by SOC, PT, and Severity 
 Study drug related TEAEs by SOC, PT 
 Treatment-emergent SAEs by SOC and PT 
 TEAEs leading to study drug discontinuation by SOC and PT 
 TEAEs leading to dose reduction or temporary study drug discontinuation by SOC 
and PT 
 TEAEs of special interest: rashes and the reproductive system and breast disorders 
system organ class 
 TEAEs by PT 
All AE tables will be sorted by SOC and PT in decreasing frequency of the number of subjects in 
the GNX group in the DB summaries and the combined groups in the OLE summaries; in case of 
tied frequencies, the sorting will be alphabetical. 
For purposes of determining treatment emergent events, missing start and stop dates will be 
imputed as shown in the following table; however the actual dates, not the imputed ones, will 
display in the data listing. 
Partial Missing Start or Stop 
Date 
Imputed Start Date 
Imputed Stop Date 
Missing month, day, and year 
First dose date 
 
Missing month and day, and the 
year is present 
 
First dose date if the year is the same as the 
year of first dose date, else first dose date 
of the OLE if the year is the same as the 
year of the first OLE dose date, else 
January 1 of the AE start year. 
December 31 of that year 
Missing day, but year and month 
are present 
 
First dose date if the year and month are the 
same as the year and month of first dose 
date, else first dose date of the OLE if the 
year and month are the same as the year 
and month of the first OLE dose date, else 
the 1st of the AE start month. 
Last day of that month 
Missing month, but year and day 
are present 
Assume day is also missing and impute as 
above 
Missing month imputed as 
December 


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If an imputed start date is later than the stop date, then the stop date (after any needed 
imputations) will be used instead for the imputed start date. 
9.1.1 Deaths, Serious and Adverse Events Leading to Early Study Drug Termination 
The listings of deaths, SAEs, AEs leading to study drug discontinuation, and AEs of special 
interest will be provided.  
9.2 
Clinical Laboratory Parameters 
Laboratory assessments include hematology, clinical chemistry, and urinalysis: 
 Hematology: Hemoglobin, Hematocrit, Erythrocytes, Leukocytes + differential, 
Thrombocytes (platelet count). 
 Clinical Chemistry:  Total Bilirubin, Aspartate Aminotransferase (AST), Alanine 
Aminotransferase (ALT), Blood Urea Nitrogen (BUN), Glucose, Potassium, Sodium, 
Calcium, Alkaline Phosphatase, Chloride, Creatinine, Carbon Dioxide (CO2), eGFR. 
 Urinalysis: pH, Color, Clarity, Specific Gravity, Urobilinogen, Ketones, Protein, 
Glucose, Bilirubin, Blood, Leukocyte esterase, Nitrite 
All laboratory parameters will be presented in SI units.  Quantitative results (including actual 
value, and change from baseline) will be summarized using descriptive statistics by baseline and 
post-baseline visit for each laboratory test group above.  Laboratory test results will be assigned 
an LNH classification according to whether the value was below (L), within (N), or above (H) 
the normal reference range (some urinalysis labs are assigned only normal and abnormal 
classifications).  Values outside the normal range are also classified as to whether they were 
potentially clinically significant (PCS).  The number and percentage of subjects in each category 
will be summarized by baseline and post-baseline visit for each lab test.  In addition, shift tables 
cross-tabulating the baseline and post-baseline LNH classifications, by visit, will be provided.  
The PCS criteria are: 
Clinical Chemistry  
Hematology  
Urinalysis 
Total Bilirubin  ≥ 1.5x 
ULN 
Hemoglobin  < 0.85x LLN or 
>1.25x ULN 
pH  ≤ 4  or >9 
AST (SGOT)  ≥ 3x 
ULN  
Hematocrit < 0.85x LLN or >1.25x 
ULN 
Color N/A 
ALT (SGPT)  ≥ 3x 
ULN  
Erythrocytes < 0.85x LLN or 
>1.25x ULN 
Clarity N/A 
BUN  ≥ 1.5x ULN 
Leukocytes + differential (total) < 
0.50x LLN or >1.50x ULN 
Specific Gravity < 1.001 or > 
1.035 
Glucose < 0.8x LLN or 
>1.5x ULN  
Thrombocytes (platelet count) < 
0.50x LLN or >1.50x ULN 
Urobilinogen > 4.0 mg/dL 
Potassium  < 0.9x LLN 
or >1.1x ULN 
 
Ketones 
positive 
value 
if 
negative pre-Rx or ≥2 unit 
increase from pre-Rx 


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Sodium < 0.95x LLN 
or >1.05x ULN 
 
Protein positive value if negative 
pre-Rx or ≥2 unit increase from 
pre-Rx 
Calcium < 0.9x LLN 
or >1.1x ULN 
 
Glucose 
positive 
value 
if 
negative pre-Rx or ≥2 unit 
increase from pre-Rx 
Alkaline 
Phosphatase  
≥ 1.5x ULN 
 
Bilirubin 
positive 
value 
if 
negative pre-Rx or ≥2 unit 
increase from pre-Rx 
Chloride < 0.9x LLN 
or >1.1x ULN 
 
Blood positive value if negative 
pre-Rx or ≥2 unit increase from 
pre-Rx 
Creatinine  ≥ 1.5x 
ULN  
 
Leukocyte 
esterase 
positive 
value if negative pre-Rx or ≥2 
unit increase from pre-Rx  
CO2 < 0.8x LLN or 
>1.2x ULN 
 
Nitrite positive value if negative 
pre-Rx or ≥2 unit increase from 
pre-Rx 
eGFRc < 0.8 x LLN 
(LLN=90, 
regardless 
of calculation method) 
 
 
 
All laboratory data will be included in the listings.  A pregnancy listing will be provided 
separately.  
9.3 
Other Safety Endpoints 
9.3.1 Vital Signs 
Vital signs include weight (kg), height (cm), temperature (°C), systolic and diastolic blood 
pressure (mmHg), respiration rate (breaths per minute), and pulse rate (bpm). 
Quantitative results (including actual value, and change from baseline to each post-baseline visit) 
will be summarized using descriptive statistics by baseline and post-baseline visit for each 
parameter.  
Vital sign test results will be assigned an LNH classification according to whether the value was 
below (L), within (N), or above (H) the normal reference range.  Values outside the normal range 
will also be classified as to whether they were potentially clinically significant (PCS).  Vital 
signs normal ranges are: 
Age 
SBP (mm Hg) 
DBP (mm Hg) 
Pulse 
(beats/min) 
Respiration Rate 
(breaths/min) 
1 – 3 yrs 
90-105 
55-70 
80-125 
20-30 


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> 3 – 6 yrs 
95-110 
60-75 
70-115 
20-25 
> 6 – 12 yrs 
100-120 
60-75 
60-100 
14-22 
> 12 yrs 
100-120 
70-80 
60-100 
12-18 
 
The subjects’ age categories will be determined by their age at the time of the vital signs 
collection. Since only the birth years of the subjects are available, the month and day of birth will 
be assumed July 1st. The subjects’ age at the time of the collection will then be derived as: 
Floor((Collection Date – Birth Date  + 1) / 365.25). 
 
PCS abnormalities are defined as:  
 
SBP:  
High:  ≥1.5 x ULN; or a ≥ 20 mmHg increase from baseline if clinically significant at baseline 
Low: ≤0.75 x LLN; or a ≥ 20 mmHg decrease from baseline if clinically significant at baseline 
 
DBP: 
High:  ≥1.3 x ULN; or a ≥ 15 mmHg increase from baseline if clinically significant at baseline 
Low: ≤0.70 x LLN; or a ≥ 15 mmHg decrease from baseline if clinically significant at baseline 
 
Pulse:  
High:  ≥1.20x ULN; or a ≥ 15 bpm increase from baseline if clinically significant at baseline  
Low: ≤0.80x LLN; or a ≥ 15 bpm decrease from baseline if clinically significant at baseline 
 
Respiratory Rate 
Low: ≤0.80 x LLN  
High  ≥1.25 x ULN 
The number and percentage of subjects with abnormalities will be summarized by baseline and 
post-baseline time point for each parameter.    
A subject listings of vital signs, including out of the normal range and PCS flags, will be 
provided.  
9.3.2 ECG 
The 12-lead ECG parameters including value and change from baseline will be summarized 
using descriptive statistics by baseline and post-baseline visit.  Except for QTc, the parameters 
will be assigned an LNH classification according to whether the value was below (L), within 
(N), or above (H) the normal reference range.  Values outside the normal range, and the QTc 
parameters, will also be classified as to whether they were potentially clinically significant 
(PCS).   
ECG normal ranges and PCS criteria are: 


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HR:   
 
Same as in Vital Signs   
PR interval:  
PCS: < 0.9xLLN or >1.1 x ULN   
QRS:  
 
PCS: >1.1x ULN 
QTc B/FN interval:  PCS: ≥ 470 msec (females), ≥ 450 msec (males), or increase ≥ 60 msec 
from baseline 
 
PR, QRS Normal Ranges: 
 
Age 
PR Interval 
(sec) 
QRS Duration 
(sec) 
1–3 yr 
0.10–0.14  
<= 0.07 
4–5 yr 
0.11–0.15  
<= 0.08 
6–8 yr 
0.12–0.16  
<= 0.08 
9–11 yr 
0.12–0.17  
<= 0.09 
12–16 yr 
0.12–0.17  
<= 0.10 
>16 yr 
0.12–0.20  
<= 0.10 
 
Overall ECG results were interpreted as normal, abnormal (not clinically significant) or 
abnormal (clinically significant).  The number and percentage of subjects in each category will 
be summarized by baseline and post-baseline visit, and shift tables cross-tabulating the baseline 
and post-baseline ECG interpretations, by visit, will be provided. 
A subject listing of the ECG parameters and overall interpretation, including out of the normal 
range and PCS flags, will be provided.   
9.3.3 Physical, Neurological, and Developmental Examinations 
Physical examination results are interpreted as normal, abnormal (not clinically significant) or 
abnormal (clinically significant).  Neurological examination results were interpreted as normal or 
abnormal.  The number and percentage of subjects in each category for these examinations will 
be summarized.  The developmental examination consists of several questions and the number 
and percentage of subject replies to each question will be summarized.  Listings for all the 
examinations will be provided.  
9.3.4 Tanner Staging 
This endpoint is a safety endpoint for only the OLE period of the study.  
The Tanner scale (also known as the Tanner stages) is a scale of physical development in 
children, adolescents and adults.  The scale defines physical measurements of development based 
on external primary and secondary sex characteristics.  Subjects will be evaluated and rated as 


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Tanner I, Tanner II, Tanner III, Tanner IV and Tanner V.  Tanner staging will occur at Screening 
(Visit 1), Visit 9 (Week 52) and will continue to be assessed annually for the duration of the 
subject’s participation in the open-label phase and at the final OLE visit. 
The number and percentage of subjects of each category will be summarized by Screening and 
OLE visit, and a listing will be provided.  
9.3.5 Concomitant AED Levels 
Concomitant AED levels are not mandatory but will be collected per sites’ standard of care.  A 
subject listing, including date and time of last AED dose and date and time of AED PK sample, 
will be provided. 
10. INTERIM ANALYSES AND DATA AND MONITORING COMMITTEE 
(DMC)  
Up to two formal interim analyses are planned, in addition to the final analysis, of treatment 
effect on the primary endpoint. They will be conducted when 50 subjects and 75 subjects are at 
least 17 weeks post randomization. The interim analyses will include only those subjects, and 
will be based on use of O’Brien-Fleming monitoring boundaries regarding benefit and lack of 
benefit. If the trial is not terminated at the interim analyses, the sample size at the final analysis 
will be approximately 100 participants. 
(Note that while the boundaries discussed in the remainder of this section will be illustrated for 
the setting in which 50 (75) subjects would be at least 17 weeks post randomization at the 
interim analysis, these boundaries will be computed based on the actual number ‘X’ of subjects 
at the times of the interim analyses.) 
In addition, two supportive analyses will be performed, for informational purposes only, at each 
interim analysis: 
 For those subjects who stop recording measurements permanently (anticipated to be 
minimal in occurrence) prior to the end of the 17-week DB phase, the imputation 
procedure for the first sensitivity analysis described in Section 7.1.8 will be applied. 
 All randomized subjects who are at least 4 weeks post randomization at the time of the 
interim analyses will be included. 
10.1 Termination Based on Reliable Evidence of Lack of Benefit 
An O’Brien-Fleming boundary that rules out benefit will be used, protecting an experimental 
(one-sided) 0.025 false negative error rate, under an assumed maximum sample size of 100 
participants, and under the alternative hypothesis that the percent change in 28-day seizure 
frequency on ganaxolone minus that on placebo truly is 0.5618 times the standard deviation for 
the percent change in 28-day seizure frequency; when that standard deviation is 44.5, this 
alternative hypothesis for the percent change in 28-day seizure frequency on ganaxolone minus 


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that on placebo would be 25%.  (This reduction is the effect the trial has 80% power to detect at 
the final analysis when 100 subjects have completed their 17-week DB treatment phase.)   
If the standard deviation for the percent change in 28-day seizure frequency is 44.5, then the 
estimate of the percent change in 28-day seizure frequency on ganaxolone minus that on placebo 
that would be at the boundary for early termination due to lack of benefit at 50 subjects would be 
approximately an estimated 10% increase, and at 75 subjects would be approximately an 
estimated 1% decrease.    
The proposed boundary for termination based on reliable evidence of lack of benefit is somewhat 
conservative, in part due to the recognition that statistical significance might not be required for 
this trial to be sufficiently favorable to justify regulatory approval.  
10.2 Termination Based on Definitive Evidence of Benefit 
An O’Brien-Fleming boundary for definitive evidence of benefit will be used, protecting an 
experimental (one-sided) 0.005 false positive error rate, under an assumed maximum sample size 
of 100 participants, and under the null hypothesis of no effect on the percent change in 28-day 
seizure frequency on ganaxolone minus that on placebo. 
This boundary for termination based on definitive evidence of benefit would be crossed only if 
the statistical strength of evidence is midway between that of one and two trials, (i.e., one in 200 
under the null hypothesis), even when adjustment is made for multiplicity due to interim 
monitoring.  It is proposed that two interim ‘efficacy’ analyses be performed, specifically at the 
times when 50% and 75% of the 100 subjects have completed the 17 week double blind period.  
The Z-values at the interim analyses conducted at the times of 50% and 75% information are:  
2.64  (100/50)½ = 3.73     (at 50 subjects) 
and  
2.64  (100/75)½ =  3.03     (at 75 subjects) 
 
The (one-sided) nominal p-value corresponding to the Z-value of 3.73 is 0.0001; and 
corresponding to the Z-value of 3.03 is 0.0012. 
If the standard deviation for the percent change in 28-day seizure frequency is 44.5, then the 
estimate of the percent change in 28-day seizure frequency on ganaxolone minus that on placebo 
that would be at the boundary for early termination due to definitive evidence of benefit at 50 
subjects would be an estimated 47% decrease, and at 75 subjects would be an estimated 32% 
decrease.     
Nearly all of the experimental (one-sided) 0.025 false positive error rate will be spent at the time 
of the final analysis of the primary endpoint, conducted when all 100 study participants have 
completed their double-blind period, because the interim analyses were conducted using an 
O’Brien-Fleming boundary that, during the interim analyses, preserved the (one-sided) 0.005 
false positive error rate.  To be specific, at least 0.0250 - 0.0013 = 0.0237 of the (one-sided) false 


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positive error remains for this final analysis.  Hence, the two-sided p-value at the final analysis 
will be approximately 0.048. 
10.3 Data Monitoring Committee  
The emerging study data will be reviewed on a regular basis by an independent Data Monitoring 
Committee (DMC).  The mission of the DMC will be to safeguard the interests of study 
participants and to enhance the integrity and credibility of the trial.  To enable the DMC to 
achieve their mission, the DMC will have ongoing access to efficacy and safety data and data 
regarding quality of trial conduct, and will ensure the confidentiality of these data will be 
preserved.  A DMC Charter will provide the principles and guidelines for the DMC process. 
11. SUMMARY OF MAJOR CHANGES IN THE PLANNED ANALYSES 
Any major changes in the planned analyses will appear in updated versions of this SAP. In the 
event of discrepancies between the SAP and the protocol, the SAP will take precedence. 
12. PROGRAMMING SPECIFICATIONS 
12.1 Format of Appendix Tables/Figures/Listings 
1. Unless otherwise specified, all computer-generated tables, figures and listings (TFL) will be 
produced (via SAS ODS) into RTF output, which can be imported in table format via 
Microsoft Word.  The TFLs should be in landscape mode with required margins: at least 1.5 
inches on top (the binding margin, or left for portrait output) and 1 inch on left, right, and 
bottom.  All output should have the following headers on each page: 
 Two-line header at the upper left margin: 
Marinus, Inc. 
Study No 1042-CDD-3001 
 Header with page number at the upper right margin: 
PAGE: X of N 
TFLs should be internally paginated in relation to total length (ie, page number should 
appear sequentially as page X of N, where N is the total number of pages within a table 
or listing). 
 Footer with the date the output was generated: 
ddMMMyyyy: hh:mm 
2. Each TFL should be identified by in a sequential numeric order, and the TFL number should 
be centered above the title.  The title is centered in initial capital characters and should 
include the population type analyzed (eg, Safety Population).  The title and designation are 
single-spaced but are separated from the TFL by at least a double space. 
 


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Table xx.x.x.x 
 
First Line of Title 
Second Line of Title (if needed) 
Population Type Analyzed 
 
3. Column headings for tables and listings should be in initial upper-case characters. 
4. Footnotes should be single spaced but separated by at least a double space from the bottom 
line of the TFL.  The notes are left justified, with each note starting on a new line.  Following 
the last footnote insert a single space.  Tables and listings should then display the source 
listing number and all outputs should display the source SAS program name.  For example, 
the set of footnotes for a table: 
Note: [1] Footnote 1 
[2]Footnote 2 
 
Source Data: Listing X  
Program: Program name.sas 
5. All data listings should be sorted by treatment group (PBO first) with a page break between 
them, subject number, parameter (where appropriate), and study visit date/time where 
appropriate.  If data for a subject and/or parameter is displayed on multiple lines, then display 
the subject number and/or parameter on only the first line.  However, if the data for a subject 
or parameter is split between pages, then the subject number and parameter should be 
displayed on the page following the split. 
6. For tables that summarize categorical (discrete) data, all categories between the maximum 
and minimum category should be presented in the table, even if there is a zero count for a 
particular category.  A Missing category should be added to any variables to indicate missing 
information, if appropriate, but the percentages should be based on the number of subjects 
with non-missing categories.  
7. If the categories are not ordered (eg, Medical History, Reasons for Discontinuation from the 
Study, etc.), then only those categories for which there is at least 1 subject represented in 1 or 
more groups should be included. 
8. All fractional numeric values should be printed with a zero to the left of the decimal point 
(eg, 0.12, 0.3). 
9. Missing descriptive statistics or p-values due to non-estimability in tables, as well as missing 
data in subject listings should be represented as either a hyphen (“-“) with a corresponding 
footnote (“ - = unknown or not evaluated”), or as “N/A” with the footnote “N/A = not 
applicable” whichever is appropriate.  
10. Date values in the listings should be in the format ddMMMyyyy.  If part of the date is 
unknown then leave it out; eg, APR2019.  (In the unlikely event that the date and year are 
available but the month is not, insert a hyphen between the date and year.) 
11. Any data listing for which there were no events should be produced, stating, “There were no 
events” 
In addition, Section 2.1.1 contains information on reporting precision. 


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12.2 SAS Procedures for Seizure Analyses 
The following code will provide the 95% distribution-free confidence interval of the median: 
proc univariate data=dataset(where=(specify analysis population, 
endpoint, study phase, and time point) ciquandf; 
  class trtp;  *trtp is the name of the randomized treatment 
variable; 
  var pchg;  *pchg is the name of the percent change variable; 
run; 
The following code will provide the Wilcoxon rank-sum test along with the Hodges-Lehmann 
estimate and its asymptotic 95% confidence interval: 
proc npar1way data=dataset (where=(specify analysis population, 
endpoint, study phase, and time point) wilcoxon 
HL(refclass=’formatted value of PBO group’); 
  class trtp;  *trtp is the name of the randomized treatment 
variable; 
  var pchg;  *pchg is the name of the percent change variable; 
run; 
 
13. REFERENCES 
Rothmann MD, Zhang JJ, Lu L, Fleming TR(2012). Testing in a prespecified subgroup and the 
intent-to-treat population. Drug Info Journ 46: 175-179