Clinical trial NCT03355209
Conditions: Lennox Gastaut Syndrome
Keywords: LGS
Sponsor: Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
Start date: 2017-11-27; Completion date: 2024-05-23
Enrollment: 296 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a two-part, multicenter, double-blind, parallel-group, placebo controlled study to evaluate the effect of ZX008 when used as adjunctive therapy for the treatment of uncontrolled seizures in children and adults with Lennox-Gastaut syndrome (LGS).

Detailed description:

Arms: arm 1: Part 1: ZX008 is supplied as an oral solution. Subjects will be randomized to receive 1 of 2 doses of ZX008 0.2 mg/kg/day or 0.8 mg/kg/day. arm 2: Part 1: Matching ZX008 placebo is supplied as an oral solution. arm 3: Part 2: ZX008 is supplied as an oral solution. Study medication will be administered twice a day (BID) in equally divided doses.
Interventions: intervention 1: ZX008 0.2 or 0.8 mg/kg/day intervention 2: Matching Placebo
Intervention descriptions: intervention 1: ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride. The product is sugar free and is intended to be compatible with a Ketogenic Diet. intervention 2: Placebo will be administered twice a day (BID) in equally divided doses.

Protocol documents:
SAP_004.pdf: 
16.1.9 
Documentation of Statistical Methods 
The document listed below is provided in this section. 
Statistical Analysis Plan (Study ZX008-1601 Part 2) dated 12-October-2022 
Statistical Analysis Plan for Cardiovascular Endpoints (Study ZX008-1601 Part 2) 
dated 22-February-2023 
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application and any extensions or variations thereof.


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This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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PUBLIC COPY 
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application and any extensions or variations thereof.


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PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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PUBLIC COPY 
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application and any extensions or variations thereof.


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PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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application and any extensions or variations thereof.


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This document cannot be used to support any marketing authorization 
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PUBLIC COPY 
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application and any extensions or variations thereof.


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This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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This document cannot be used to support any marketing authorization 
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	@	AB$CDEFG?$O>BI$=	@	>%J%#K	LM;<% =	>=?
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	@	AB$CDEFG?$H?>BI$=	@	>%J%#K	LM;<% =	>=?
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application and any extensions or variations thereof.


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PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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1,,	2145
I 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


	
			
	
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	
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 !"#$%&%
'#
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I 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


	
			
	
		
	
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''$,./01EFGH79@>7B6789:6<=>?@>A87B14()*%% 
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1EFGH79@>7B6789:6<=>?@>A87B14
I 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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I 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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SAP_006.pdf: 
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SAP Text Version 3.0 04-Feb-2022 
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Statistical Analysis Plan for Interventional Studies 
Text Only  
SAP Text Version Number: 3.0 
SAP Text Date: (DD-Mmm-YYYY): 04-Feb-2022 
Sponsor Name: Zogenix International Limited 
Protocol Number: ZX008-1601 
Protocol Title: A Two-Part Study of ZX008 in Children and Adults with Lennox-Gastaut Syndrome 
(LGS); Part 1: A Randomized, Double-blind, Placebo-controlled Trial of Two Fixed Doses of ZX008 
(Fenfluramine Hydrochloride) Oral Solution as Adjunctive Therapy for Seizures in Children and 
Adults with LGS, Followed by Part 2: An Open-label Extension to Assess Long-Term Safety of 
ZX008 in Children and Adults with LGS 
Protocol Version and Date: (DD-Mmm-YYYY):  
13-Jan-2017 Version 1.1
10-Jan-2018 (Amendment 1 Rest of World)
20-Jun-2019 (Amendment 2.0)
29 July 2019 (Amendment 2.1)
02-Jul-2020 (Amendment 3.1)
29-Jul-2020 (Amendment 3.2_Japan)
Syneos Health Project Code: 1009529A 
Authors: 
 Principal Biostatistician 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Zogenix International 
Limited. Acceptance of this document constitutes agreement by the recipient that no information 
contained herein will be published or disclosed without prior written authorization from an official of 
Zogenix International Limited. However, this document may be disclosed to appropriate Institutional 
Review Board and Ethics Committees or duly authorized representatives of a national regulatory 
authority under the condition that they are requested to keep it confidential. In the event of an 
actual or suspected breach of this obligation, Syneos Health should be notified promptly. 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601 
 
This document is confidential. 
SAP Text Version 3.0 04-Feb-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 2 of 160 
Revision History 
Version 
# 
Date 
(dd-mmm-
yyyy) 
Document 
Owner 
Revision Summary 
0.1 
08-Feb-2019
Initial Release Version (unsigned) 
0.2 
24-May-2019
Proposed Updates: Separating Part 1 
SAP from Part 2 SAP. 
Requested revisions from Draft 1. 
0.3 
20-Jun-2019
Proposed Updates: Separation of Part 1 
analyses into  Cohort A and Cohort B. 
0.4 
08-Jul-2019
Proposed Updates: 4th Draft. 
0.5 
29-Jul-2019
Proposed Updates prior to Finalization 
Version 1.0 
1.0 
05-Aug-2019
Finalization Version 1.0 
1.1 
20-Dec-2019
Proposed Updates: Updates to the 
Additional Secondary Objectives 
specified for Part 1, Cohort A in the 
protocol, and to the associated 
Additional Secondary Efficacy 
Endpoints 
2.0 
06-Jan-2020
Proposed Updates and Finalization of 
SAP shells 
2.0 
08-Jan-2020
Signoff 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601 
 
This document is confidential. 
SAP Text Version 3.0 04-Feb-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
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Version 
# 
Date 
(dd-mmm-
yyyy) 
Document 
Owner 
Revision Summary 
2.1 
10-Dec-2021
Proposed Updates: Incorporating 
changes from Part 1 Note to File dated 
31-Jun-2021 that described changes in
the SAP after Version 2.0.
Incorporated changes to indicate the 
Part 1 analysis of Cohort B will now 
occur after all subjects have completed 
Part 1 instead of after all have 
completed Part 2. 
Incorporated changes for analysis of 
Cohort B results after dry run.  
Made corrections and added clarifying 
text in several places throughout the 
document. 
3.0 
28-Jan-2022
Proposed Updates: Removal of selected 
per protocol outputs for Cohort B 
Editorial changes to text and shell 
document. 
Preparation for Signoff 
3.0 
04-Feb-2022
Final Edits 
Signoff 
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Statistical Analysis Plan for Interventional Studies
Sponsor: Zogenix International Limited; Protocol No.: ZX008-1601 
This document is confidential.
SAP Text Version 3.0 04-Feb-2022
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I confirm that I have reviewed this document and agree with the content.
APPROVALS
Syneos Health
Lead Biostatistician 
Principal Biostatistician
Date (dd-Mmm-yyyy)
Senior Reviewing Biostatistician
 
Principal Biostatistician
Date (dd-Mmm-yyyy)
Zogenix International Limited 
Date (dd-Mmm-yyyy)
 Statistician on Behalf of 
Zogenix International Limited
Date (dd-Mmm-yyyy)
	



Electronically
s
d by:
Reason: I am the
author
Date: Feb 9, 2022
14:11 EST
Electronically
signed by:
ason: I am the
reviewer
Date: Feb 9, 2022
14:27 EST
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Statistical Analysis Plan for Interventional Studies
Sponsor: Zogenix International Limited; Protocol No.: ZX008-1601 
This document is confidential.
SAP Text Version 3.0 04-Feb-2022
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
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TABLE OF CONTENTS
GLOSSARY OF ABBREVIATIONS................................................................9
PURPOSE ....................................................................................................12
Responsibilities ...............................................................................................................12
Timing of Analyses..........................................................................................................12
Unblinding Plan................................................................................................................13
PART 1 OBJECTIVES..................................................................................13
Primary Objective ............................................................................................................13
Key Secondary Objective................................................................................................13
Additional Secondary Objectives...................................................................................14
Safety Objectives.............................................................................................................15
Pharmacokinetic Objectives ...........................................................................................15
Exploratory Objectives....................................................................................................15
BRIEF DESCRIPTION..................................................................................16
Subject Selection.............................................................................................................17
Determination of Sample Size.........................................................................................17
Treatment Assignment & Blinding .................................................................................18
Administration of Study Medication...............................................................................18
ENDPOINTS.................................................................................................26
Primary Efficacy Endpoint ..............................................................................................26
Key Secondary Efficacy Endpoints................................................................................26
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Statistical Analysis Plan for Interventional Studies
Sponsor: Zogenix International Limited; Protocol No.: ZX008-1601 
This document is confidential.
SAP Text Version 3.0 04-Feb-2022
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
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Additional Secondary Efficacy Endpoints.....................................................................27
Safety Endpoints..............................................................................................................28
Exploratory Endpoints.....................................................................................................28
ANALYSIS SETS .........................................................................................28
Enrolled Population.........................................................................................................29
Safety (SAF) Population ..................................................................................................29
Modified Intent-to-Treat (mITT) Population....................................................................29
Per Protocol (PP) Population..........................................................................................29
Protocol Deviations .........................................................................................................29
General Aspects for Statistical Analysis .......................................................................30
General Methods.......................................................................................................30
Definitions..................................................................................................................30
Missing Data..............................................................................................................31
Visit Windows...................................................................................................................32
Pooling of Centers...........................................................................................................34
Subgroups........................................................................................................................34
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION ...............................................................................................34
Subject Disposition and Withdrawals............................................................................34
Demographic and Other Baseline Characteristics........................................................35
Medical History, Neurologic History, and Concomitant Diseases...............................36
Medication ........................................................................................................................36
Prior and Concomitant Antiepileptic Treatments .......................................................37
EFFICACY....................................................................................................38
Multiplicity Strategy and Testing Hierarchy ..................................................................38
Primary Efficacy Endpoint and Analysis .......................................................................39
Primary Efficacy Endpoint Definition .........................................................................39
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Statistical Analysis Plan for Interventional Studies
Sponsor: Zogenix International Limited; Protocol No.: ZX008-1601 
This document is confidential.
SAP Text Version 3.0 04-Feb-2022
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Sensitivity Analysis of Cluster Imputation .................................................................................41
Part 1 Primary Efficacy Endpoint Analyses ...............................................................42
Sensitivity Analyses of Part 1 Primary Efficacy Endpoint ..........................................45
Key Secondary Efficacy Endpoints and Analyses........................................................48
50% Reduction in Seizures Resulting in Drops .........................................................48
Clinical Global Impression – Improvement (CGI-I) Rating, as assessed by the 
Principal Investigator ..................................................................................................................49
Additional Efficacy Endpoints and Analyses ................................................................50
Countable Motor Seizures Definition and Analysis....................................................50
Additional Seizure Counts .........................................................................................50
Seizure-Free Days ....................................................................................................52
Duration of the Longest Interval Between Seizures Resulting in Drops ....................53
Clinical Global Impression – Improvement Rating, as assessed by the 
Parent/Caregiver ........................................................................................................................54
Incidence of Status Epilepticus..................................................................................54
Rescue Medication Usage.........................................................................................56
Incidence of Medical Services to Treat Seizures.......................................................56
Vineland Adaptive Behavior Scale (VABS)................................................................56
Quality of Life in Childhood Epilepsy (QOLCE) Scale ...............................................57
Zarit Caregiver Burden Inventory ..............................................................................58
Patient/Caregiver Assessment using HADS Scale....................................................59
New Seizure Types ...................................................................................................60
SAFETY........................................................................................................61
Extent of Exposure ..........................................................................................................61
Treatment Compliance (Diary)........................................................................................61
Adverse Events................................................................................................................62
Overview of Adverse Events .....................................................................................63
Treatment-Emergent Adverse Events .......................................................................63
Adverse Events of Special Interest (AESI) ................................................................64
Physical Examination......................................................................................................65
Neurologic Examination..................................................................................................65
Vital Signs, Weight, and BMI...........................................................................................65
Electrocardiogram ...........................................................................................................66
Doppler Echocardiography.............................................................................................66
Tanner Staging.................................................................................................................66
Laboratory Parameters....................................................................................................67
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Statistical Analysis Plan for Interventional Studies
Sponsor: Zogenix International Limited; Protocol No.: ZX008-1601 
This document is confidential.
SAP Text Version 3.0 04-Feb-2022
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
Page 8 of 160
Columbia-Suicide Severity Rating Scale .......................................................................69
Brief Rating Inventory of Executive Function (BRIEF) .................................................70
INTERIM ANALYSES...................................................................................71
CHANGE FROM PLANNED ANALYSES.....................................................72
PROGRAMMING CONSIDERATIONS.........................................................76
General Considerations...................................................................................................76
Table, Listing, and Figure Format ..................................................................................76
General......................................................................................................................76
Headers.....................................................................................................................77
Display Titles.............................................................................................................77
Column Headers .......................................................................................................77
Body of the Data Display...........................................................................................78
Footnotes ..................................................................................................................80
QUALITY CONTROL....................................................................................80
INDEX OF TABLES, FIGURES, AND LISTINGS .........................................82
REFERENCES ........................................................................................... 158
APPENDICES............................................................................................. 159
Appendix 1 – Seizure Types.......................................................................................... 159
Seizure Classification – Primary Endpoint .................................................................. 159
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Statistical Analysis Plan for Interventional Studies
Sponsor: Zogenix International Limited; Protocol No.: ZX008-1601 
This document is confidential.
SAP Text Version 3.0 04-Feb-2022
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
Page 9 of 160
GLOSSARY OF ABBREVIATIONS
Abbreviation
Description
AE
adverse events
AED
antiepileptic drugs 
AESI
adverse event of special interest
ALB
albumin 
ALT; SGPT
alanine aminotransferase
ANCOVA
analysis of covariance
AP
alkaline phosphatase 
AS
atonic seizures 
AST; SGOT
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical 
BMI
body mass index
BRI 
Behavioral Regulation Index
BRIEF
Behavior Rating Inventory of Executive Function 
BUN
blood urea nitrogen
Ca
calcium 
CBD
cannabidiol
CDSF
change in drop seizure frequency
CGI-I
Clinical Global Impression – Improvement
CI
confidence interval 
CL
chloride 
CMH
Cochran-Mantel-Haenszel 
CO2
carbon dioxide 
CS
clonic seizures 
C-SSRS
Columbia-Suicide Severity Rating Scale 
DCR
Data Change Request
DSD
Daily Seizure Diary 
DSF
drop seizure frequency
ECG
electrocardiogram 
ECHO
echocardiogram 
eCRF
electronic Case Report Form 
EMI
Emergent Metacognition Index
ESC
Epilepsy Study Consortium
ET
Early Termination
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
This document is confidential. 
SAP Text Version 3.0 04-Feb-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 10 of 160 
 
Abbreviation 
Description 
FI 
Flexibility Index  
FS 
focal seizures  
FSH 
Follicle Stimulating Hormone  
GEC 
Global Executive Composite 
GGT 
gamma-glutamyl transferase  
GH 
Growth hormone  
GTC 
generalized tonic-clonic seizures 
HS 
hemiclonic seizures 
ICH 
International Conference on Harmonisation  
IGF-1 
insulin-like growth factor-1  
ILAE 
International League Against Epilepsy 
IMP 
Investigational Medicinal Product 
INR 
International normalized ratio  
ISCI 
Inhibitory Self-Control Index  
IWR  
Interactive Web Response system 
K  
potassium  
kg 
kilogram 
LDH 
lactate dehydrogenase  
LGS 
Lennox-Gastaut syndrome  
LH 
Luteinizing Hormone  
M 
Maintenance Period 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MI  
Metacognition Index  
mITT 
Modified Intent-to-Treat Population 
MS 
myoclonic seizures  
Na 
sodium 
NTF 
Note to File 
PBPK 
physiologically-based pharmacokinetic  
PCDSF 
percent change in drop seizure frequency 
PK 
pharmacokinetics  
PP 
Per Protocol Population 
PT 
Preferred Term  
PTT 
partial thromboplastin time  
Q1 
25th Percentile / 1st Quartile 
Q3 
75th Percentile / 3rd Quartile 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
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SAP Text Version 3.0 04-Feb-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
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Page 11 of 160 
 
Abbreviation 
Description 
QoL  
Quality of Life 
QOLCE 
Quality of Life in Childhood Epilepsy  
SAF 
Safety Population 
SAP 
statistical analysis plan  
SD 
standard deviation 
SE 
status epilepticus  
SOC 
System Organ Class  
SOP  
Standard Operating Procedures 
STC 
secondarily tonic-clonic 
T+M 
Titration and Maintenance Periods 
TA 
tonic/atonic seizures  
TEAE 
Treatment-emergent adverse events 
TLF 
tables, data listings, figures  
TS 
tonic seizures  
TSH 
thyroid stimulating hormone  
VABS 
Vineland Adaptive Behavior Scale  
WHO-DD 
World Health Organization Drug Dictionary  
 
 
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Statistical Analysis Plan for Interventional Studies
Sponsor: Zogenix International Limited; Protocol No.: ZX008-1601 
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Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
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PURPOSE
The purpose of this statistical analysis plan (SAP) is to ensure that the summary tables, 
figures, and data listings that will be produced for Part 1 of the trial, and the statistical 
methodologies that will be used, are complete and appropriate to allow valid 
conclusions regarding the study objectives.
RESPONSIBILITIES
Syneos Health will perform the statistical analyses and are responsible for the 
production and quality control of all tables, figures and listings with the exception of 
pharmacokinetics (PK), electrocardiogram (ECG), and echocardiogram (ECHO). 
Separate analysis plans for PK and for ECG/ECHO will be produced. 
BioMedical Systems, a division of Biomedical System/ERT, will provide analyses of ECG 
and ECHO data.
TIMING OF ANALYSES
Study 1601 is an international multicenter study being conducted in 2 parts. Up to 
approximately 80 study sites in North America, Europe, Australia, and Japan are 
planned to participate. Part 1 is a double-blind, parallel-group, placebo-controlled, 
study to assess the efficacy and safety of two doses of ZX008 when used as adjunctive 
therapy for seizures in children and adult subjects with LGS. Part 1 will include 2 
cohorts: Cohort A will include randomized subjects from North America, Europe, and 
Australia; Cohort B will include randomized subjects from Japan.
All objectives will be evaluated in Cohort A and B independently. Data from Part 1, 
Cohort A will constitute the primary analyses of the study. The primary analyses for Part 
1, Cohort A of the study, to include safety, efficacy, and PK, will be conducted once all 
Cohort A subjects have completed Part 1 of the study and the Per-Protocol (PP) 
Population and other populations have been defined, and approval for unblinding has 
been granted by Zogenix International Limited. This analysis will be completed by the
primary unblinded statistical team of Syneos Health.
Data from Part 1, Cohort B will be analyzed independently after the last subject in 
Cohort B completes Part 1 and the PP Population and other populations have been 
defined, and approval for unblinding of Cohort B has been granted by Zogenix 
International Limited.
Analysis results for Part 1 from Cohort A and B will be compared through descriptive 
statistics; that is, the results from Cohort A and B will be compared by reviewing the 
descriptive statistics calculated from each cohort. Some analyses may be performed 
using data from Cohorts A and B combined.
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Statistical Analysis Plan for Interventional Studies
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This document is confidential.
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Additional analyses for long-term safety and effectiveness data from Part 2 will be 
completed independently by cohort. The description of the analysis methodology for 
Part 2 of the study will be provided in a separate SAP.
UNBLINDING PLAN
Cohort A is expected to finish Part 1 before Cohort B. In order to prevent any bias in the 
completion of Cohort B, whether intentional or unintentional, an unblinding plan will be 
generated. The unblinding plan will identify individuals (by name or role) who will be 
unblinded and responsible for the analyses and reporting of Cohort A, Part 1. These 
unblinded individuals will have no involvement in study decisions that would have the 
potential to affect data integrity for Cohort B.
PART 1 OBJECTIVES
Cohorts A and B will be analyzed independently. Cohort A will be analyzed after the last 
subject completes Part 1. These analyses will form the main analyses to establish safety 
and efficacy of ZX008 in patients with LGS. Cohort A Part 1 will be evaluated with 
formal statistical testing as described below. Cohort B Part 1 will be analyzed after the 
last subject completes Part 1. Inferential statistics for Cohort B will be evaluated using 
the same methodology stated for Cohort A, but the inferential statistics will be 
considered as descriptive.
PRIMARY OBJECTIVE
The primary objective of Part 1 is the primary objective of the entire study.
The primary objective of Part 1 is:
x
To evaluate the effect of ZX008 0.8 mg/kg/day versus placebo as adjunctive 
therapy for the treatment of uncontrolled seizures in children and adults with 
Lennox-Gastaut syndrome (LGS) based on the change in frequency of seizures 
that result in drops (DSF) between baseline and the combined Titration and 
Maintenance Periods (T+M).
Seizures that result in drops include seizures of the following types that have been 
reviewed and confirmed for each subject as a drop seizure by the Epilepsy Study 
Consortium (ESC): generalized tonic-clonic seizures (GTC), secondarily generalized 
tonic-clonic seizures (SGTC), tonic seizures (TS), atonic seizures (AS), tonic/atonic 
seizures (TA).
KEY SECONDARY OBJECTIVE
The key secondary objectives of Part 1 are:
x
To evaluate the effect of ZX008 0.2 mg/kg/day versus placebo as adjunctive 
therapy for the treatment of uncontrolled seizures in children and adults with 
LGS based on the change in DSF between baseline and T+M.
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Statistical Analysis Plan for Interventional Studies
Sponsor: Zogenix International Limited; Protocol No.: ZX008-1601 
This document is confidential.
SAP Text Version 3.0 04-Feb-2022
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
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x
To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus 
SODFHERRQWKHSURSRUWLRQRIVXEMHFWVZKRDFKLHYHD 50% reduction from 
baseline in the frequency of seizures that result in drops.
x
To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus 
placebo on the Clinical Global Impression – Improvement (CGI-I) rating, as 
assessed by the Principal Investigator.
ADDITIONAL SECONDARY OBJECTIVES
The additional secondary objectives specified in this section have been modified from 
those given in the protocol.  Those modifications are described in detail in Section 11. 
The additional secondary endpoints specified in Section 5.3, and their corresponding 
analyses, are based on the objectives as specified in this section.
Additional secondary objectives of Part 1 of the study are:
x
To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus 
placebo on the following endpoints:
o
Change in frequency of all seizures that (typically) result in drops (i.e., 
GTC, SGTC, TS, AS, TA) between baseline and T+M whether ESC 
confirmed as drop or not.
o
Change in the frequency of all countable motor seizures between 
baseline and T+M (countable seizures include: GTC, SGTC, TS, AS, TA, 
clonic seizures [CS], focal seizures with clear observable motor signs [FS], 
and hemiclonic seizures [HS]).
o
Change in the frequency of all countable non-motor seizures between 
baseline and T+M (countable non-motor seizures include: absence, 
myoclonic, focal without clear observable motor signs, infantile spasms, 
and epileptic spasms)
o
Change in the frequency of all countable seizures (i.e., motor and 
nonmotor) between baseline and T+M
o
Change in frequency of seizures that result in drops (ESC confirmed) 
between baseline and the Maintenance Period (M)
o
Change in frequency of seizures that (typically) result in drops between 
baseline and the Maintenance Period (M)
o
Change in the frequency of all countable motor seizures between 
baseline and M
o
Change in the frequency of all countable non-motor seizures between 
baseline and M
o
Change in the frequency of all countable seizures (i.e., motor and 
nonmotor) between baseline and M
o
7KHSURSRUWLRQRIVXEMHFWVZKRDFKLHYHDZRUVHQLQJ!
UHGXFWLRQ, and “near seizure freedom” (i.e. 0 or 1 seizures)
between baseline and T+M, and baseline and M, in seizures that result in 
drops (ESC confirmed), seizures that typically result in drops, all 
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Statistical Analysis Plan for Interventional Studies
Sponsor: Zogenix International Limited; Protocol No.: ZX008-1601 
This document is confidential.
SAP Text Version 3.0 04-Feb-2022
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Page 15 of 160
countable motor seizures, all countable non-motor seizures, and all 
countable seizures
o
Number of seizure-free days, defined as 1) no seizures that result in 
drops (ESC confirmed), and 2) days with no countable motor seizures 
o
Longest interval between seizures that result in drops (ESC confirmed)
x
To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus 
placebo on the CGI-I rating, as assessed by the parent/caregiver.
SAFETY OBJECTIVES
The safety objectives of Part 1 are:
x
To evaluate the safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day versus 
placebo with regard to adverse events (AEs), laboratory parameters, physical 
examination, neurological examination, vital signs (blood pressure, heart rate, 
temperature, and respiratory rate), electrocardiograms (ECG), echocardiograms 
(ECHO), body weight, and body mass index (BMI)
x
To evaluate the change from baseline in cognition using age-appropriate versions 
of the Behavior Rating Inventory of Executive Function (BRIEF)
PHARMACOKINETIC OBJECTIVES
The pharmacokinetic (PK) objective of the study is:
x
To evaluate the PK of ZX008 0.2 and 0.8 mg/kg/day at steady state in 
VXEMHFWV\HDUVDQG\HDUVZLWK/*6XVLQJDnon-compartmental 
analysis and obtain exposure data that will be used in population 
pharmacokinetic (PopPK) analysis, the results of which will be reported 
separately.
EXPLORATORY OBJECTIVES
The exploratory objectives of the study are:
x
To compare the ZX008 0.2 and 0.8 mg/kg/day doses on primary, secondary, and 
safety endpoints.
x
To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus 
placebo on the following endpoints:
–
The change from baseline in behavior using the Vineland Adaptive 
Behavior Scale (VABS)
–
The change from baseline in quality of life (QoL) using the QOLCE
–
The change from baseline in caregiver burden using the Zarit Caregiver 
Burden Inventory 
–
The change from baseline in affective symptoms of the parent/caregiver 
using the Hospital Anxiety and Depression Scale (HADS)
–
The frequency of rescue medication usage
–
The incidence of medical services to treat seizures
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Statistical Analysis Plan for Interventional Studies
Sponsor: Zogenix International Limited; Protocol No.: ZX008-1601 
This document is confidential.
SAP Text Version 3.0 04-Feb-2022
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
Page 16 of 160
–
The incidence of status epilepticus (SE)
BRIEF DESCRIPTION
Study 1601 is an international multicenter study being conducted in two parts. Up to 
approximately 80 study sites in North America, Europe, Australia, and Japan are 
planned to participate. Part 1 is a double-blind, parallel-group, placebo-controlled, 
study to assess the efficacy and safety of two doses of ZX008 when used as adjunctive 
therapy for seizures in children and adult subjects with LGS. Part 1 will include 2 
cohorts: Cohort A will include randomized subjects from North America, Europe, and 
Australia; Cohort B will include randomized subjects from Japan. The main analyses for 
the study, including the primary and key secondary study endpoints are assessed from 
Part 1, Cohort A data. The primary analysis will be conducted when the last subject in 
Cohort A has completed Part 1. Part 2 will be an open-label, flexible-dose extension for 
subjects completing Part 1 of the study.
Part 1 consists of a 4-week Baseline, 2-week Titration, 12-week Maintenance, and 
2-week Taper or Transition Period. The 4-week Baseline Period consists of the 
establishment of initial eligibility during a screening visit to include an assessment of 
cardiac parameters (ECG and ECHO), followed by an observation period where subjects 
will be assessed for baseline seizure frequency based on recordings of daily seizure 
activity entered into a diary. Upon completion of the Baseline Period, subjects who 
qualify for the study are randomized (1:1:1) in a double-blind manner to receive 1 of 2 
doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; maximum dose: 30 mg/day [or 0.5 
mg/kg/day, maximum 20 mg/day, for subjects taking concomitant STP]) or placebo. 
Randomization is stratified by weight (< NJNJWRHQVXUHEDODQFHDFURVV
treatment arms, and at least 25% of subjects will be in each weight group. All subjects 
are titrated to their blinded randomized dose over a 2-week Titration Period. Following 
titration, subjects continue treatment at their randomly assigned dose over a 12-week 
Maintenance Period. Total treatment time from the beginning of the Titration Period 
through the end of the Maintenance Period is 14 weeks. Subjects will have ECG and 
ECHO assessments at weeks 6 and 14 during the Maintenance Period. At the end of the 
Maintenance Period (or early discontinuation), all subjects undergo a blinded 2-week 
Taper or Transition Period depending on whether they exit the study or are enrolled in 
Part 2, the long-term open-label extension, respectively. Cardiac safety follow-up visits 
are performed after study drug discontinuation for early termination, or for those 
subjects who complete the study but do not enter the open-label extension part. All 
subjects are required to have follow-ups at 3 and 6 months. Subjects enrolled in 
Germany, France and Netherlands will have an additional follow-up at 24 months. If 
there are any findings at a post-dose follow-up, a follow-up visit will be scheduled every 
3 months until resolved or stabilized. 
Part 2 is an open-label, long-term safety study of ZX008 for subjects who have 
successfully completed 14 weeks of treatment (titration + maintenance) in Part 1 and 
are candidates for continuous treatment for an extended period of time; subjects who 
have not completed the entire 14 weeks of treatment in Part 1 may be eligible to 
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Statistical Analysis Plan for Interventional Studies
Sponsor: Zogenix International Limited; Protocol No.: ZX008-1601 
This document is confidential.
SAP Text Version 3.0 04-Feb-2022
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
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Page 17 of 160
participate in Part 2 on a case-by-case basis and only following Sponsor approval. Part 2 
consists of a 12-month Open-Label Extension (OLE) Treatment Period and a 2-week 
Post-Dosing Period. Thus, subjects who were randomized to ZX008 during Part 1 and 
FRPSOHWH3DUWZLOOKDYHEHHQWUHDWHGZLWK=;IRUDWOHDVWZHHNVLQFOXGLQJ
their participation in both Part 1 and Part 2).
During Part 2, all subjects are treated initially with ZX008 0.2 mg/kg/day for 1 month to 
assess effectiveness of this dose in all study subjects. After 1 month at a dose of ZX008 
0.2 mg/kg/day, the investigator may adjust the dose for each subject based on 
effectiveness and tolerability. Dose changes should be made in increments of up to 
ZX008 0.2 mg/kg/day, to a maximum of ZX008 0.8 mg/kg/day (or ZX008 0.5 mg/kg/day 
for subjects taking concomitant STP) but not to exceed total dose of 30 mg/day (or 
20mg/kg/day for subjects taking concomitant STP). During the 12-month OLE subjects 
will have ECG and ECHO assessments at months 1, 3, 6, and 9, and at the end of study 
visit.
A follow-up ECG and ECHO will be performed at 3 and 6 months after study drug 
discontinuation for early termination and for those subjects who complete Part 2.
Subjects enrolled in Germany, France and Netherlands will have an additional follow-up 
at 24 months. If there are any findings at a post-dose follow-up, another follow-up will 
be scheduled every 3 months until resolved or stabilized. In both Part 1 and Part 2,
parents/caregivers will use a diary every day to record dosing of study drug, the number 
of seizures, type of seizures, time and duration of seizures, whether the seizure 
resulted in a drop, and use of rescue medication.
SUBJECT SELECTION
The inclusion and exclusion criteria are stated in full in Sections 4.1, 4.2, and 4.3 of the 
protocol document.
DETERMINATION OF SAMPLE SIZE
The sample size was estimated for Part 1 Cohort A under the assumption that adding 
ZX008 at 0.8 mg/kg/day to current therapy will lead to a mean decrease in drop 
seizures that is 30 percentage points greater than adding placebo to current therapy. 
For example, if adding placebo leads to a 10% decrease in seizures, then adding the 
ZX008 0.8 mg/kg/day dose would be expected to decrease seizures by at least 40%.
The variability expected in the trial was estimated from a Phase 3 trial of clobazam for 
patients with Lennox-Gastaut syndrome (Ng 2011) leading to an assumption that the 
standard deviation (SD) is 50%. Other assumptions include an allowance for 20% dropouts 
between randomization and the start of the maintenance period. Under these 
assumptions, a sample size of 63 subjects per treatment group for a nonparametric 
analysis affords 90% power to detect a difference between the ZX008 0.8 mg/kg/day 
DQGSODFHERJURXSVWKDWLVVLJQLILFDQWDWWKHŞ OHYHO$VVXPLQJDGURS-out rate 
prior to the start of the maintenance period yields a requirement for an additional 14 
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Statistical Analysis Plan for Interventional Studies
Sponsor: Zogenix International Limited; Protocol No.: ZX008-1601 
This document is confidential.
SAP Text Version 3.0 04-Feb-2022
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
Page 18 of 160
VXEMHFWVSHUJURXSIRUDWRWDORIVXEMHFWVSHUWUHDWPHQWJURXSIRUDQRQSDUDPHWULF
analysis. Similar calculations for the ZX008 0.2 mg/kg/day group lead to a total required 
VDPSOHVL]HRI7KHQXPEHURIVXEMHFWVUDQGRPL]HGLQWR3DUWCohort A is 
estimated to be approximately 250 due to the long baseline period.
The sample size of 10 to 15 subjects per treatment group in Cohort B is expected to 
provide a descriptive assessment of whether the treatment effect in Japanese subjects 
is similar to that observed in Cohort A subjects from the rest of the world.
TREATMENT ASSIGNMENT & BLINDING
Upon completion of the Baseline Period in Part 1, subjects who qualify for the study are
randomized (1:1:1) in a double-blind manner to receive 1 of 2 doses of ZX008 (0.2 
mg/kg/day, 0.8 mg/kg/day; 30mg/day maximum [0.2 mg/kg/day or 0.5 mg/kg/day; 20 
mg/day maximum for subjects taking concomitant STP]) or placebo. The randomization 
is stratified by weight (< NJ NJWRHQVXUHEDODQFHDFURVVWUHDWment arms, 
with a target of at least 25% in each weight group. Subjects are assigned a 
randomization number by the Interactive Web Response (IWR) system upon confirmation 
that the subject qualifies for enrollment in the Titration Period.
The primary biostatistical team, data management team, and clinical team will remain 
blinded to Cohort A subject treatment assignments until approval is given for the 
unblinding of the Part 1, Cohort A database and finalization of subject inclusion in the 
study populations is made. Similarly, the primary biostatistical team, data management 
team, and clinical team will remain blinded to Cohort B subject treatment assignments 
until approval is given for the unblinding of the Part 1, Cohort B database and 
finalization of inclusion in the study populations is made. 
The release of unblinded PK concentration, ECG, and ECHO data to facilitate external 
analyses will be completed only after the approval for unblinding of the Part 1 Cohort A 
and Part 1 Cohort B databases by Zogenix. 
ADMINISTRATION OF STUDY MEDICATION
Each bottle of study medication contains the appropriate concentration and volume of 
liquid to administer the assigned treatment (ZX008 0.2 mg/kg/day, ZX008 0.8 
mg/kg/day [or 0.5 mg/kg/day for subjects taking concomitant STP], or placebo). ZX008 
and placebo are identical, thus rendering the study drug and placebo indistinguishable. 
The blinding scheme instituted for this study ensures that the volume of study 
medication taken cannot be associated with the dose group, thus unblinding the study. 
This is achieved by random assignment of different concentrations of ZX008 or placebo 
(1.25 mg/mL, 2.5 mg/mL, and/or 5 mg/mL) by the IWR system. The IWR system 
instructs site personnel to the volume of oral solution to be administered based on that 
subject’s weight. (Dose is recalculated by the system based on weight once at the 
midpoint of Part 1 of the study.) During the Titration, Maintenance, and 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
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Taper/Transition Periods, the subjects and study personnel (investigators, clinical staff, 
personnel involved in data collection and analysis, the Medical Monitor, and the 
sponsor) are blinded to the treatment allocation and to the concentration of ZX008. If 
an investigator feels the blind should be broken, he/she can do so when necessary for 
treatment decisions. However, the investigator should endeavor to discuss with the 
Medical Monitor or Sponsor’s Medical Representative, if available. The blind should only 
be broken in the event the knowledge of whether the subject is on active study 
medication versus placebo is needed to determine course of medical treatment for the 
event. The subject will be discontinued from the clinical trial upon breaking of the blind 
and the decision whether the subject can enter Part 2 will rest with the Sponsor if the 
subject exited Part 1 prior to completion. 
 
Following randomization, subjects enter the Titration Period and are blindly titrated to 
their randomized dose as outlined in Table 1. 
 
Table 1: Titration Algorithm for Part 1 
Randomized Group 
Titration Step 1 
Study Days 1-4 
Titration Step 2 
Study Days 5-8 
Titration Step 3  
Study Days 9-14 
ZX008 0.2 
mg/kg/day 
ZX008 0.2 
mg/kg/day 
ZX008 0.2 
mg/kg/day 
ZX008 0.2 
mg/kg/day 
ZX008 0.8 
mg/kg/day (0.5 
mg/kg/day for 
subjects taking 
concomitant STP) 
ZX008 0.2 
mg/kg/day 
ZX008 0.4 
mg/kg/day 
ZX008 0.8 
mg/kg/day 
(0.5 mg/kg/day for 
subjects 
taking concomitant 
STP) 
Placebo 
Placebo 
Placebo 
Placebo 
 
After completion of the Titration Period, subjects enter the Maintenance Period and 
continue to receive the randomized dose of ZX008 or placebo and be treated for an 
additional 12 weeks.  
 
Subjects who complete the Maintenance Period and do not be continue into Part 2, the 
open-label extension, and subjects who discontinue from Part 1 early, will be tapered 
off of study medication as outlined in Table 2.  
 
Table 2: Taper Algorithm for Part 1 
Randomized Group 
Taper Step 1  
Day 1-4 after study 
completion or early 
termination 
Taper Step 2  
Days 5-8 after study 
completion or early 
termination 
ZX008 0.2 mg/kg/day 
Placebo 
Placebo 
ZX008 0.8 mg/kg/day (0.5 
mg/kg/day for subjects 
taking concomitant STP) 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
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Page 20 of 160 
 
Randomized Group 
Taper Step 1  
Day 1-4 after study 
completion or early 
termination 
Taper Step 2  
Days 5-8 after study 
completion or early 
termination 
Placebo 
Placebo 
Placebo 
 
Subjects who complete the Maintenance Period and will be continuing into the open-
label extension (Part 2) will be transitioned from double-blind study medication to 
open-label ZX008. All subjects entering the open-label extension (Part 2) will be 
transitioned from their blinded daily dose to the ZX008 0.2 mg/kg/day dose during the 
2-week interval between Visits 12 and 15, without breaking the blind. The IWR system 
will assign two bottles of Investigational Medicinal Product (IMP) to the subject, one for 
each step in the transition. A new bottle of IMP will be started by the subject at each 
level of the transition step.  
 
Table 3: Transition Algorithm for Part 1 
 
Dose Group in Double-
Blind Study 
Transition Step 1  
Day 1-4 after Visit 12 
Transition Step 2  
Day 5-14 after Visit 12 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.8 mg/kg/day (0.5 
mg/kg/day for subjects 
taking concomitant STP) 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
Placebo 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
 
The full list and timing of study procedures is provided in Table 4. 
 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
This document is confidential. 
SAP Text Version 3.0 04-Feb-2022 
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Page 21 of 160 
 
Table 4 – Schedule of Assessments  
Part 1 Assessments 
Study Assessments – PART 1 
Baseline Perioda 
Titration + Maintenance Period 
 
EOS/ 
ETb 
 
Post-
Dosingl 
Cardiac 
Follow-
upc 
 
Visit Number 
 
Screening 
 
Random-
ization 
 
Titration Period 
 
Maintenance Period 
1 
2 
(Phone) 
3 
 
4, 5 
(Phone) 
6 
7  
(Phone) 
8 
9  
(Phone) 
10 
11 
(Phone) 
12 
13 
14 
Study Day 
-28  
-15  
-1 
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
197 
Informed Consent (subject and 
parent/caregiver) 
X 
 
 
 
 
 
 
 
 
 
 
X  
(Part 2) 
 
 
Inclusion/Exclusion Criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Neurological History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epilepsy history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review retrospective seizure 
diary data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Medication, including 
AEDs 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination, complete 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
Optional 
Physical Examination, 
abbreviated  
 
 
 
 
 
Xm 
 
Xm 
 
Xm 
 
 
 
X 
Neurological Examination, 
complete 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Neurological Examination, 
abbreviated 
 
 
X 
 
 
Xm 
 
Xm 
 
Xm 
 
 
 
 
Vital signs 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
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Table 4 – Schedule of Assessments  
Part 1 Assessments 
Study Assessments – PART 1 
Baseline Perioda 
Titration + Maintenance Period 
 
EOS/ 
ETb 
 
Post-
Dosingl 
Cardiac 
Follow-
upc 
 
Visit Number 
 
Screening 
 
Random-
ization 
 
Titration Period 
 
Maintenance Period 
1 
2 
(Phone) 
3 
 
4, 5 
(Phone) 
6 
7  
(Phone) 
8 
9  
(Phone) 
10 
11 
(Phone) 
12 
13 
14 
Study Day 
-28  
-15  
-1 
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
197 
Weight 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Chest x-ray (France, Netherlands 
only) 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
12-lead ECG 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
Doppler ECHO 
X 
 
 
 
 
 
Xd 
 
 
 
Xd 
 
X 
Urine or Serum Pregnancy Test 
Xe 
 
Xe 
 
 
 
 
Xe 
 
 
 
Xe 
 
 
Clinical laboratory evaluation 
(hematology/ chemistry/urinalysiso, etc) 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Plasma sample for ZX008 PK 
 
 
 
 
 
 
 
Xf 
 
 
 
 
 
 
Plasma sample for background 
AEDs PK 
 
 
Xg 
 
 
Xg 
 
X 
 
Xg 
 
Xg 
 
 
Whole blood CBD/ THC Panel 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Tanner Staging (for subjects >7 to 
18 years old) 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Subject Diary 
D 
R 
C/R/D 
 
R 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/Dh 
C/R 
 
Epilepsy genotype panel 
(optional) 
 
X 
 
 
Study Medication 
 
 
D 
 
Ri 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/Dh 
C/R 
 
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Statistical Analysis Plan for Interventional Studies 
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Table 4 – Schedule of Assessments  
Part 1 Assessments 
Study Assessments – PART 1 
Baseline Perioda 
Titration + Maintenance Period 
 
EOS/ 
ETb 
 
Post-
Dosingl 
Cardiac 
Follow-
upc 
 
Visit Number 
 
Screening 
 
Random-
ization 
 
Titration Period 
 
Maintenance Period 
1 
2 
(Phone) 
3 
 
4, 5 
(Phone) 
6 
7  
(Phone) 
8 
9  
(Phone) 
10 
11 
(Phone) 
12 
13 
14 
Study Day 
-28  
-15  
-1 
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
197 
C-SSRS 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Clinical Global Impression - 
Improvement (assessed by 
parent/caregiver) 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
Clinical Global Impression - 
Improvement (assessed by 
Principal Investigator) 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
HADS (Effect of 
parent/caregiver) 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
BRIEF 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
VABS 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
QOLCE 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Zarit Burden 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Randomize subject 
 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
First Day of Study Drug 
Administrationj 
 
 
 
Xj 
 
 
 
Daily Diary Completion  
X 
 
Concomitant Medication 
 
 
 
X 
 
Adverse events 
X 
 
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Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
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Table 4 – Schedule of Assessments  
Part 1 Assessments 
Study Assessments – PART 1 
Baseline Perioda 
Titration + Maintenance Period 
 
EOS/ 
ETb 
 
Post-
Dosingl 
Cardiac 
Follow-
upc 
 
Visit Number 
 
Screening 
 
Random-
ization 
 
Titration Period 
 
Maintenance Period 
1 
2 
(Phone) 
3 
 
4, 5 
(Phone) 
6 
7  
(Phone) 
8 
9  
(Phone) 
10 
11 
(Phone) 
12 
13 
14 
Study Day 
-28  
-15  
-1 
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
197 
Adverse events of special interest 
X 
Xk 
Abbreviations: AED=antiepileptic drug; BMI=body mass index; C=Collect; CBD=cannabidiol; D=Dispense; ECG=electrocardiogram; EQ-5D-5L=standardized measure of health status; EOS=end 
of study; ET=early termination; HADS=Hospital Anxiety and Depression Scale; BRIEF=Behavior Rating Inventory of Executive Function; QoL=quality of life; R=Review; VABS=Vineland 
Adaptive Behavior Scale 
a: 
The Baseline Period is comprised of the initial screening for the study and the assessment of baseline seizure activity recorded daily in the diary. The procedures to be completed at the 
Screening visit may be completed in a single day or split so that they are completed over the 2-day period. 
b: 
Subjects who are discontinued early and those who complete the study and choose not to enroll in the separate open-label extension will be tapered off study medication over an up to 2-week 
period. 
c: 
The safety follow-up visit will be conducted for subjects who either terminate early from Part 1, or who complete Part 1 but do not enter Part 2. Standard follow-up visits should occur 3 and 6 
months after the last dose. For subjects enrolled in Germany, France and Netherlands, follow-ups will also occur 24 months after the last dose. If there are any findings at the last post-dose 
follow-up, a follow-up visit will be repeated every 3 months until resolved or stabilized. 
d: 
The Visit 8 ECHO must be performed any time between Study Day 40 and Study Day 54. The Visit 12 ECHO must be performed any time between Study Day 90 and Study Day 113; if a 
subject discontinues early from the study, the ECHO should be scheduled as soon as practical. If the Study Day 43 ECHO was completed < 30 days prior to early termination, the Visit 12 
ECHO will not be performed provided the parent/guardian agrees to bring the subject to the clinic for the cardiac follow-up visit. 
e: 
Females of child-bearing potential 
f: 
Plasma sample for pharmacokinetic assessment will be conducted prior to the dose at Visit 8 and 1, 2, and 4-6 hours after dose administration. 
g: 
Plasma sample for assessment of background AED(s) will be conducted prior to the dose of AED(s) at Visits 3, 8 and 12 (Visits 6 and 10 only if clinically indicated). AED plasma sample may 
be collected after the morning dose of AEDs are taken, if preferable, as long as the time of last dose is accurately recorded. 
h: 
Study drug/diary dispensed for the Transition Period for subjects entering the open-label extension and for the Taper Period for subjects exiting the study. 
i: 
Site personnel will review study medication dosing procedure (titration) with parent/caregiver. 
j: 
Study drug administration begins in the morning of Study Day 1. Study Day 1 is considered the first day of dosing, even though subjects may receive an in-clinic dose on Study Day -1. If the 
first dose is taken in the clinic, it will be recorded in the eCRF, but not the subject diary; the next dose on the morning of Study Day 1 will be the first entry in the subject’s diary. 
k: 
Only adverse events related to cardiac safety will be collected at this visit. 
l: 
Visit 13 may be conducted as a phone call, provided diaries and study medication are returned by this time. 
m: 
An abbreviated physical and/or neurological examination to be conducted as appropriate based on last exam and reported AEs. 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
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Table 4 – Schedule of Assessments  
Part 1 Assessments 
Study Assessments – PART 1 
Baseline Perioda 
Titration + Maintenance Period 
 
EOS/ 
ETb 
 
Post-
Dosingl 
Cardiac 
Follow-
upc 
 
Visit Number 
 
Screening 
 
Random-
ization 
 
Titration Period 
 
Maintenance Period 
1 
2 
(Phone) 
3 
 
4, 5 
(Phone) 
6 
7  
(Phone) 
8 
9  
(Phone) 
10 
11 
(Phone) 
12 
13 
14 
Study Day 
-28  
-15  
-1 
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
197 
n: 
Randomization should not occur prior to receiving approval from the Epilepsy Study Consortium and ERT ECHO results. 
o: 
Urine for urinalysis may be collected at home, the night before the clinic visit, as long as collection procedures are followed to maintain sample stability. 
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The targeted study day and allowable windows for visits in Part 1 are reproduced from 
the protocol below. Early termination visits will be mapped to a visit based on these 
windows.
Table 5: Visit windows for Part 1 Visits
Visit / Procedure
Time window (relative to 
scheduled visit / 
procedure)
Visit 1 (Clinic; Study Day -29 to -28 or -28 to -
Not Applicable
Visit 2 (Phone; Study -15)
± 3 days
Visit 3 (Clinic; Study Day -1; Randomization
± 4 days a
Visits 4, 5 (Phone: Study Days 4, 8)
± 3 days
Visit 6 (Clinic; Study Day 15)
± 4 days
9LVLW3KRQH6WXG\'D\
± 4 days
Visit 8 (Clinic; Study Day 43)
± 4 days
9LVLW3KRQH6WXG\'D\
± 4 days
Visit 10 &OLQLF6WXG\'D\
± 4 days
Visit 11 (Phone: Study Day 85)
± 4 days
Visit 12 (Clinic: Study Day 99)
± 4 days
Visit 13 (Clinic; Study Day 113; post dosing)
± 4 days
Visit 14 (ECHO clinic; 3-24 months after last dose)b
+ 30 days
$(' DQWLHSLOHSWLFGUXJV(&+2 HFKRFDUGLRJUDP
a In cases where the screening period is extended beyond 28 days, the immediate 28 
days before the Randomization visit will be used to calculate the baseline seizure 
frequency
b All subjects are required to have follow-ups at 3 and 6 months post-treatment. 
Subjects enrolled in Germany, France and Netherlands will have an additional 24-month
follow-up.
ENDPOINTS
PRIMARY EFFICACY ENDPOINT
Percent change from baseline in DSF in T+M in the ZX008 0.8 mg/kg/day group 
compared to the placebo group. Seizures that result in drops are GTC, SGTC, TS, AS, 
and TA confirmed for each subject as a drop seizure by the ESC.
KEY SECONDARY EFFICACY ENDPOINTS
The key secondary endpoints are: 
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x
Change from baseline in DSF in T+M in the ZX008 0.2 mg/kg/day group compared 
to the placebo group.
x
3URSRUWLRQRIVXEMHFWVZKRDFKLHYHDUHGXFWLRQIURPEDVHOLQHLQDSF
comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently 
versus placebo.
x
Proportion of subjects who achieve improvement (minimally, much, or very 
much improved) in the Clinical Global Impression – Improvement as assessed by 
the Principal Investigator, comparing the ZX008 0.8 mg/kg/day and 0.2 
mg/kg/day groups independently versus placebo.
ADDITIONAL SECONDARY EFFICACY ENDPOINTS
The additional secondary endpoints are: 
ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups compared independently versus 
placebo on the
x
Change from baseline during T+M in frequency of all seizures that (typically) 
result in drops (i.e., GTC, SGTC, TS, AS, TA) whether ESC confirmed as drop or 
not.
x
Change from baseline during T+M in frequency of all countable motor seizures
(GTC, SGTC, TS, AS, TA, CS, FS, and HS).
x
Change from baseline during T+M in frequency of all countable non-motor
seizures (absence, myoclonic, focal without clear observable motor signs, 
infantile spasms, and epileptic spasms).
x
Change from baseline during T+M in the frequency of all countable seizures (i.e., 
motor and non-motor).
x
Change from baseline during M in DSF.
x
Change from baseline during M in the frequency of seizures that typically result 
in drops.
x
Change from baseline during M in the frequency of all countable motor seizures.
x
Change from baseline during M in the frequency of all countable non-motor 
seizures.
x
Change from baseline during M in the frequency of all countable seizures (i.e., 
motor and non-motor).
x
Proportion of subjects who achieve a worsening from baseline (ie, 
reduction), or >    RUUHGXFWLRQEHWZHHQEDVHOLQH
and T+M, and baseline and M, in seizures that result in drops (ESC confirmed), 
seizures that typically result in drops, all countable motor seizures, all countable 
non-motor seizures, and all countable seizures.
x
Number of seizure-free days in the baseline, M, and T+M periods, defined as 1)
days with no seizures that results in drops (ESC confirmed), and 2) days with no 
countable motor seizures
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x
The longest interval (days) between seizures that result in drops (ESC 
confirmed) comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups 
independently versus placebo
x
Clinical Global Impression – Improvement as assessed by the parent/caregiver
SAFETY ENDPOINTS
The safety endpoints for Part 1 of the study are: 
x
AEs
x
Laboratory safety (hematology, chemistry, urinalysis)
x
Vital signs (blood pressure, heart rate, temperature, and respiratory rate)
x
Body weight and BMI
x
Physical examination
x
Neurological examination
x
BRIEF to measure changes in cognition of the subject
x
Columbia Suicidality Severity Rating Scale (C-SSRS)
x
12-lead ECGs
x
Doppler ECHOs
x
Chest x-ray (for subjects enrolled in France and Netherlands only)
x
EEG (for subjects enrolled in Italy only)
EXPLORATORY ENDPOINTS
The exploratory endpoints for Part 1 of the study are:
x
The change from baseline in behavior using the VABS
x
The change from baseline in QoL using the QOLCE
x
The change from baseline in caregiver burden using the Zarit Caregiver Burden 
Inventory
x
The change from baseline in affective symptoms of parent/caregiver using the 
HADS scale
x
Incidence of SE in the M and T+M period.
x
Incidence of rescue medication usage in the T+M and M periods
x
Number of days rescue medication used in the T+M and M periods
x
Incidence in use of medical services to treat seizures in the M and T+M periods
ANALYSIS SETS
Separate analysis datasets will be produced for Cohort A and Cohort B. Cohort A will 
include subjects from North America, Europe, and Australia; Cohort B will include 
subjects from Japan.
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ENROLLED POPULATION
The Enrolled Population is defined as all subjects who signed the informed consent 
form. 
SAFETY (SAF) POPULATION
All Part 1 safety analyses will be performed on the SAF Population, defined as all 
randomized subjects who receive at least one dose of ZX008 or placebo.
MODIFIED INTENT-TO-TREAT (MITT) POPULATION
The mITT Population is defined as all randomized subjects who receive at least one 
dose of ZX008 or placebo and for whom at least one week of diary data are available. 
Subjects will be analyzed according to the treatment group to which they were 
randomized. The primary comparison of ZX008 0.8 mg/kg/day to placebo, as well as key 
secondary analyses, will be performed on the mITT Population.
PER PROTOCOL (PP) POPULATION
The PP Population is defined as all randomized subjects who receive at least one dose 
of ZX008 or placebo, who complete at least 4 weeks of diary data in the maintenance 
period, and who have no major protocol deviations that would have a significant impact 
on clinical outcome of Part 1 data, and who have met the inclusion criteria for baseline
drop seizure count. Protocol deviations that occurred during Part 1 will be reviewed and 
the list of deviations warranting exclusion from the PP Population will be finalized prior 
to study unblinding.
PROTOCOL DEVIATIONS
Major protocol deviations will be summarized overall and by treatment group based on 
the SAF Population. Major protocol deviations are those that have the potential to
impact subject safety and/or affect data integrity and/or the efficacy conclusions.
Major protocol deviations will be grouped into categories and may include categories 
such as:
x
Violation of inclusion/exclusion criteria
x
Violation of randomization inclusion criteria
x
Non-compliance regarding intake of IMP
x
Inappropriate intake of concomitant medication
x
Subject not discontinued as per protocol
x
Other non-compliance
Multiple deviations can occur in the same subject and thus a subject can be counted in 
more than 1 deviation category.
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For each study part and cohort, major protocol deviations will be presented in a subject 
data listing for the Enrolled Population, sorted by treatment, site, subject, and type. 
Deviations will be reviewed prior to the database lock of Part 1 data for each cohort to 
determine which deviations will be classified as leading to exclusion from the PP 
Population.
During the determination of the PP Population for Part 1 Cohort A, the decision was 
made to exclude from the PP Population those subjects who had a baseline ESC-
confirmed drop seizure count value of < 6 per 28 days as well as subjects who had less 
than 4 weeks (28 days) of DSD data collected during the Maintenance Period.
GENERAL ASPECTS FOR STATISTICAL ANALYSIS
General Methods
All statistical analyses will be performed using SAS statistical software (Version 9.4 or 
later).
Part 1 summaries will be presented by treatment group (Placebo, ZX008 0.2 mg/kg/day, 
ZX008 0.8 mg/kg/day). 
Continuous data will be summarized using descriptive statistics including means, 
standard deviations, medians, lower and upper quartiles, minimum and maximum 
values. Categorical variables will be summarized with frequencies and percentages. 
Confidence intervals will be calculated for key parameters or estimates as warranted.
Two-sided statistical significance tHVWLQJŞ FRPSDULQJHDFKDFWLYHWUHDWPHQWWR
placebo will be performed for the primary and secondary endpoints as described below, 
unless otherwise noted.
All relevant collected subject data will be included in listings. All subjects entered into 
the database will be included in data listings.
Unless otherwise specified in the subsequent sections, in the event of multiple 
assessments at a given planned time point, the latest collected value will be used for 
the summarization.
Definitions
First Dose Date: First Dose Date of Investigational Drug: If the first diary date on the 
day after randomization indicates that investigational drug was taken on this day, then 
the first dose date (Study Day 1) will be the date after randomization. In all other 
situations where it is known that the subject took at least one dose of medication, the 
first dose date will be assumed to be 1 day after the date of randomization.
Study Day: Study day will be calculated relative to the First Dose Date in the Titration 
Period. For any date on or after the date of first dose, study day will be calculated as 
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assessment date – first dose date + 1. For any date prior to the date of first dose, study 
day will be calculated as assessment date – first dose date. There will be no Study Day 
0.
Baseline Value: For non-seizure frequency assessments, the Part 1 baseline value will 
be the last non-missing assessment collected on or prior to the first date of dosing in 
Part 1. Unscheduled assessments prior to First Dose Date will be considered for 
selection of the baseline value. Baseline values for seizure frequency endpoints will be 
determined from the immediate 28 days prior to study day 1 (ie, the First Dose Date) 
using methods described below.
Missing Data 
The term missing date refers to a completely missing date or to an incomplete 
date/partial date where parts are not available, eg, missing month/day/year. 
Missing Adverse Event Start and End Dates
Missing start and end date will be imputed conservatively, ie, missing values will be 
imputed in such a way that the duration of the AE is considered with the longest 
possible duration and such that, whenever the AE may potentially start after first date 
of study medication, the AE will be handled as a treatment-emergent adverse event 
(TEAE).
The missing Start date and End date of an AE will be imputed for the purpose of 
calculating treatment emergent status and assigning events to treatment periods using 
definitions given in the following table.
Adverse event
Partial 
/Missing 
Start date
Missing day – If adverse event day is missing but month and year is 
present then impute the 1st of the month unless month is same as 
month of first dose of study drug in Part 1 then impute first dose date 
in Part 1.
Missing day and month – If adverse event day and month are both 
missing but year is present then impute 1st January unless year is the 
same as first dose date in Part 1 then impute first dose date in Part 1.
Completely missing – impute first dose date in Part 1 unless the end 
date suggests it could have started prior to this in which case impute 
the 1st January of the same year as the end date.
When imputing a start date, ensure that the new imputed date is 
sensible ie, is prior to the end date of the AE.
Partial 
/Missing End 
date
Missing day – If AE end day is missing but month and year are present 
then impute the last day of the month unless month is same as month 
of last dose of study drug then impute last dose date.
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Missing day and month – If AE has missing day and month but year is 
present then impute 31st December unless year is the same as first 
dose date then impute last dose date.
Completely Missing – need to look at whether the AE is still ongoing 
before imputing a date and also when it started in relation to study 
drug. If the ongoing flag is missing then assume that AE is still present 
(ie, do not impute a date). If the AE has stopped and start date is prior 
to first dose date then impute the 1st dose date. If the AE started on 
or after the first dose date then impute the last dose date.
Data Handling for Seizure Diaries
Seizures are recorded in the Daily Seizure Diary (DSD). On each day, subjects are asked 
a question of whether there is a seizure to report that day. Subjects may either answer
“Yes” and continue to complete more details about the seizure, or answer “No, this day 
has been seizure free”. There will be no explicit imputation of intermittent missing data 
for seizure diaries. Missing DSD data will be handled as follows:
x
If no seizures are entered in the DSD and the response to the question, is there a 
seizure to report that day, is “No, this day has been seizure free” then that day 
will have the seizure count set to 0. 
x
If seizures are entered in the DSD and the response to the question, is there a 
seizure to report that day, is “No this day has been seizure free” the seizures 
entered in the DSD will supersede the seizure freedom affirmation.
x
If no seizures are entered in the DSD and there is no response to the question, is 
there a seizure to report that day, that day will be considered to have missing 
diary data.
x
If no seizures are entered in the DSD and it is indicated that there were seizures 
that day, that day will be considered to have missing diary data.
VISIT WINDOWS
The following rules will be used to window data into treatment periods for by-treatment 
period tabulations. For all by-visit tabulations, the nominal visit as recorded on the 
electronic Case Report Form (eCRF) will be used.
The following are the definitions for associating dates with the treatment periods of 
Part 1.
Baseline Period
The Baseline Period will be the 28 days immediately prior to 
the date of the Study Day 1.
Double Blind 
Treatment Period
The Double-Blind Treatment Period start date is the date of 
first full daily dose (ie, Study Day 1). The Double-Blind 
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Treatment Period end date is the last date the subject was 
on study treatment in Part 1. 
The Double-Blind Treatment Period consists of 16 weeks 
from first treatment start date, which includes 2 weeks of 
Titration Period, 12 weeks of Maintenance Period and 2 
weeks of Taper/Transition Period. The end date for efficacy 
analyses is the last day of Maintenance treatment or Visit 
12; the end date for safety analyses is the last day of 
Taper/Transition, which would be considered the date at 
Visit 15. 
 
For subjects who discontinue early from the study, the 
Double-Blind Treatment Period end date for efficacy 
analyses will be the date at the Early Termination Visit 
(Visit 12); the end date for safety analyses would be the 
date of Visit 13. If a taper is not conducted, the end date 
for both analyses would be Visit 12. 
Titration Period 
The Titration Period begins on the first full day of treatment 
(Study Day 1) and extends through Visit 6 (when the subject 
has reached their randomization dose). The Titration Period 
applies to all subjects including placebo recipients. If a 
subject withdraws from the study prior to treatment in the 
Maintenance Period, all safety assessments and events up to 
and including the date of study withdrawal will be tabulated 
in the Titration Period. 
Maintenance 
Period 
The Maintenance Period covers the 12 weeks following the 
end of the Titration Period. It begins on the date of Visit 6 + 
1 day and extends through the End of Study/Early 
Termination Visit (Visit 12). 
Titration + 
Maintenance 
Period (T+M) 
The T+M Period combines the Titration and Maintenance 
periods, beginning on the date of first treatment (Study Day 
1) and extending through the End of Study/End of 
Treatment Visit (Visit 12).  
Taper/Transition 
Period 
The Taper/Transition Period consists of 2 weeks starting 
from End of Study/Early Termination Visit (Visit 12) + 1 day 
through Visit 13 (Taper) or Visit 15 (Transition to Part 2). 
For subjects who are not entering into the Part 2 of the 
study, subjects will gradually be tapered off of study 
medication. 
For subjects who are entering Part 2, subjects will enter the 
Transition Period where all subjects will be on a dose of 
ZX008 0.2 mg/kg/day at the end of this period. 
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POOLING OF CENTERS
Analysis will be pooled by cohort (A vs. B).
SUBGROUPS
The following subgroups may be utilized for some efficacy analyses and/or AE
summarizations:
Age: 2– < 6 years, 6–< 12 years, 12 - < 18, 2-<18 years, – 35 years
Sex: Male, Female
Baseline Weight: < NJYVNJ
Number of Concomitant $QWLHSLOHSWLF0HGLFDWLRQV8VHG  4 medications
Number of Prior Antiepileptic Medications Used: 0-3, 4-- 10 medications
Baseline Frequency of Seizures that Result in Drops (events/28 days): based on observed 
tertiles
Usage of a specific concomitant medication(s) (top 3 concomitant AEDs to be 
determined by data review) (Yes / No)
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND
MEDICATION
SUBJECT DISPOSITION AND WITHDRAWALS
The Part 1 subject disposition will be presented per treatment group and overall for 
Cohort A and B independently. 
For describing the Part 1 subject disposition, the following will be summarized by 
number and percentage:
x
Subjects enrolled (only overall)
x
Subjects enrolled but not randomized (ie, screen failures) and reason for not-
randomized (only overall)
x
Subjects randomized
x
Number of randomized subjects discontinued the trial per trial period (overall 
Double-Blind Treatment Period, Titration Period, Maintenance Period, 
Taper/Transition Period).
x
Reasons for discontinuation
x
Part 1 completers
-
Completers continuing into Part 2 
-
Completers who discontinued prior to Visit 12 
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Part 1 trial completers include: 1.) subjects who did not discontinue prior to the Visit 
12, and 2.) subjects who completed at least through Visit 8 and enrolled into the Part 2 
open label extension.
For subjects enrolled but not randomized to treatment in Part 1, and for the tallies 
listed under each reason for not being randomized, the denominator used to calculate 
the percentage will be the number of enrolled subjects. For all other calculations in the 
Part 1 disposition table, the denominator will be the number of subjects randomized. 
All subject disposition data will be listed using the Enrolled Population and sorted by 
randomized treatment and site.
The number and percentage of subjects in the following populations will be summarized 
by treatment group and overall for Cohort A and B independently:
x
Enrolled Population
x
Randomized (Intent-to-Treat) Population
x
mITT Population
x
PP Population
x
SAF Population
Allocation to each analysis population will be presented by subject in a listing, by
Cohort A and B.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Part 1 subject demographics and baseline characteristics will be summarized 
descriptively per treatment group and overall, for the SAF and mITT Populations for 
Cohort A and B. 
The following demographic characteristics will be summarized:
x
Age [Years]
x
Categorized age as: 2 - < \HDUV- < \HDUV 12 - < 18 years, 2 - < 18 
years, – 35 years
x
Sex
x
Race
x
Ethnicity
x
Height [m]
x
Weight [kg]
x
BMI [kg/m2]
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x
Geography: (Cohort A) North America, Europe, Australia; (Cohort B) Japan only
All subject demographics data will be listed for the Enrolled Population, by Cohort A 
and B.
For Cohort B, a summary table will be added for the mITT Population that will 
summarize the number and percentage of subjects who experienced at least one seizure 
event of each type during the baseline period. For the seizure types that are typical 
drop seizures, the number and percentage of subjects where that seizure type was or 
was not classified as ESC confirmed drop seizures will be summarized.  
MEDICAL HISTORY, NEUROLOGIC HISTORY, AND CONCOMITANT DISEASES
Medical history and neurologic history will be summarized and sorted alphabetically, by 
primary System Organ Class (SOC) and Preferred Term (PT) coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) Version 20.1 or later. The number and 
percentage of subjects will be displayed for each SOC and PT within treatment group.
Medical history will be presented for the SAF population, separated by Cohort A and B. 
All medical history data of subjects will be listed for the Enrolled Population, by Cohort 
A and B.
MEDICATION
Medication (collected on the prior antiepileptic medications, prior medications, and 
concomitant medications eCRF page) will be coded using the World Health Organization 
Drug Dictionary (WHO-DD) Format B3 Version Sep RUODWHU
The following algorithm will be used to define prior and concomitant in Part 1.
Prior medications will be those with a stop date prior to first dose of study drug
administration in Part 1. Summaries of prior medications only include medications that 
stopped during the period from 30 days prior to the screening date to the day before 
first date of study treatment.
Concomitant medications in Part 1 will be defined as those medications that were 
initiated after first study drug administration in Part 1 (but excluding medications that 
started on or after the first dose of study medication in Part 2) or those medications 
that were ongoing at the date of first study drug administration in Part 1.
The medication will be assumed to be prior medication if it cannot be definitively 
shown that the medication did not start or continue during the Part 1 treatment period.
If the start date or stop date of a medication is partially missing, the date will be 
compared as far as possible with the date of the start of administration of study drug. 
The following approach will be taken:
x
If the start date of medication is complete and occurs on or after the day of the 
first full dose, the medication will be assumed concomitant. If the start date 
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occurs prior to the first full dose date but the end date is on or after the first 
dose date or the medication is recorded as ongoing, the medication will be 
considered concomitant.
x
If the start day is missing but the start month and year are complete, a 
medication will only be excluded as being concomitant if the start month/year is 
before the month/year of study drug administration and if the stop date (either 
full date, month and year if missing day, or year if missing month and day) is 
before study drug administration.
x
If the start day and month are missing but the start year is complete, a 
medication will only be excluded as concomitant if the start year is before the 
year of study drug administration and if the stop date (either full date, month 
and year if missing day, or year if missing month and day) is before study drug 
administration.
x
If the start date is completely missing and the stop date is prior to first dose or 
completely missing, the medication will be assumed to be a prior medication.
A medication may be counted as concomitant in Part 1 and in Part 2. By definition, a 
prior medication cannot be counted as concomitant in Part 1. Medication will be 
summarized and sorted alphabetically separately for prior and concomitant medication 
by Anatomical Therapeutic Chemical (ATC) categories (Level 2: pharmacological or 
therapeutic subgroup and Level 3: chemical or therapeutic or pharmacological 
subgroup) and WHO-DD drug code. For each medication, the number and percentage of 
subjects will be displayed by treatment group and overall. 
Part 1 medication summary tables will be presented for the SAF Population.
Prior and concomitant medications/treatments will be listed for the Enrolled 
Population.
Prior and Concomitant Antiepileptic Treatments 
Medication (collected on the prior antiepileptic medications, prior medications, and 
concomitant medications eCRF page) will be coded using the World Health Organization 
Drug Dictionary (WHO-DD) Format B3 Version Sep RUODWHUAntiepileptic 
medications will be identified using any drug entered on the prior-antiepileptic 
medication page and anti-seizure concomitant medications with indication of “Lennox-
Gastaut Syndrome,” that have an ATC2 level of ‘Antiepileptics’. Medications with a 
frequency of use specified as “as needed” (PRN) are excluded from the prior and 
concomitant antiepileptic treatments. Usages of Valproate (all forms) will be 
summarized on the prior and concomitant antiepileptic medications tables. Subjects 
may have used multiple forms of the medication. The following preferred names will be 
summarized into a combined term called “Valproate (all forms)”
x
Valproate Magnesium
x
Valproate Semisodium
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x
Valproate Sodium
x
Valproate Sodium;Valproic Acid
x
Valproic Acid
Prior and concomitant antiepileptic medications will be defined and analyzed for the 
SAF Population similar to concomitant medications as described in 6HFWLRQ. In 
addition, the number of prior antiepileptic medications and the number of concomitant 
antiepileptic medications will be summarized using descriptive statistics and presented 
by treatment group and overall. Only prior medications that stopped during the period 
from 30 days prior to the screening date to the day before first date of study treatment
will be summarized.
Prior and concomitant antiepileptic treatments will be listed for the Enrolled 
Population.
Note that further summaries of rescue medications recorded on the daily medication 
diary are described in the efficacy section. 
EFFICACY
The analysis of the Part 1 primary and secondary efficacy parameters will be performed 
on the mITT Population for Cohort A and B independently.
The Part 1 primary efficacy endpoint and key secondary efficacy endpoint analyses will 
be repeated on the PP Population for Cohort A and B independently, in order to assess 
the impact of major protocol deviations on the key inference. 
All primary and key secondary variables will be analyzed for data obtained for the T+M 
Period and will be repeated for data obtained during the M Period only.
MULTIPLICITY STRATEGY AND TESTING HIERARCHY
The Part 1, Cohort A efficacy analyses will employ a serial gatekeeper strategy to 
PDLQWDLQWKH7\SHHUURUUDWHDWŞ DFURVVWKHIDPLO\RIDQDO\VHVWKDWVXSSRUWWKH
primary and key secondary objectives. The strategy specifies a hierarchy of significance 
tests where each test acts as a gatekeeper to the tests below it.
Note that the serial gatekeeper strategy does not apply to Part 1 Cohort B since, as 
noted in the protocol, the relatively small sample size of Cohort B is expected to afford 
only a descriptive assessment of study endpoints in Cohort B.
The hierarchy starts with the primary analysis comparing ZX008 0.8 mg/kg/day to 
placebo on the change in number of seizures that results in drops from baseline. The 
next steps in the hierarchy entail the comparisons for the key secondary endpoints. 
x
Change from baseline in frequency of seizures that result in drops in T+M in the 
ZX008 0.2 mg/kg/day group compared to placebo.
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x
3URSRUWLRQRIVXEMHFWVZKRDFKLHYHDUHGXFWLRQIURPEDVHOLQHLQWKH
frequency of seizures that result in drops in the ZX008 0.8 mg/kg/day and 0.2 
mg/kg/day groups independently versus placebo.
x
Proportion of subjects who achieve improvement (minimally, much, or very 
much improved) in the CGI-I as assessed by the Principal Investigator comparing 
the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus 
placebo.
Below is a complete list of steps in the testing hierarchy in order:
1. Compare ZX008 0.8 mg/kg/day to placebo on the change in frequency in seizures 
that result in drops per 28 days between the Baseline and T+M periods.
2. Compare ZX008 0.8 mg/kg/day to placebo on the proportion of subjects who 
DFKLHYHDUHGXFWLRQIURPEDVHOLQHLQWKHQXPEHURIVHL]XUHVWKDWUHVXOWLQ
drops.
3. Compare ZX008 0.8 mg/kg/day to placebo on the CGI-I at Visit 12.
4. Compare ZX008 0.2 mg/kg/day to placebo on the change in frequency in seizures 
that result in drops per 28 days between the Baseline and T+M periods.
5. Compare ZX008 0.2 mg/kg/day to placebo on the proportion of subjects who 
DFKLHYHD 50% reduction from baseline in the number of seizures that result in 
drops.
6. Compare ZX008 0.2 mg/kg/day to placebo on the CGI-I at Visit 12
PRIMARY EFFICACY ENDPOINT AND ANALYSIS
Primary Efficacy Endpoint Definition
The Part 1 primary efficacy endpoint is the percentage change from Baseline in the 
frequency in seizures that result in drops per 28 days in the T+M Period. The following 
seizure types from the DSD will be included in the frequency count of seizures resulting 
in drops, if for an individual subject, the seizure as listed in the eCRF has been 
confirmed and approved by the ESC as a ‘drop seizure’:
x
AS
x
TS
x
TA
x
GTC
x
SGTC
For each subject, the frequency of drop seizures will be calculated from all available 
data collected during the Baseline and T+M Periods. Subjects in the ZX008 
0.8 mg/kg/day treatment group will be compared to those in the placebo group on the 
DSF) during T+M adjusted for the frequency during Baseline using a non-parametric 
ANCOVA model.
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Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
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The Baseline Period is the 28 days immediately preceding the date of Study Day 1. The 
T+M Period is planned for 14 weeks. However, actual durations will be computed for 
each subject based on the individual subject’s start and stop dates for each period, 
except that if the Baseline Period is longer than 28 days, the frequency for the Baseline 
Period will be calculated with data from the 28 days immediately preceding the Study 
Day 1. 
The frequency of drop seizures will be counted from the DSD records provided by the 
subject or parent/caregiver. 
Responses to the DSD question about the frequency of seizure episodes will be handled 
differently according to the following response options. 
Response 
Number of seizures 
No seizures 
0 
A single seizure 
1 
An episode of many discrete seizures 
Based on the response to the Question 12 
for frequency of episodes 
A cluster of seizures back-to-back 
This will be determined empirically 
dependent on the duration of the cluster 
event and the number of events reported 
in a discrete seizure event for subjects in 
the study.  
 
Seizure Clusters 
Seizure clusters are entered in the DSD by estimating the duration of the cluster in 
hours: minutes; seconds. For seizure clusters the number of discrete seizures that 
occurred during a cluster is not entered in the DSD. In order to estimate the number of 
seizures during a cluster, the number of seizures will be imputed using the seizure 
count and duration of seizures recorded for “an episode of many discrete seizures”. 
Specifically, episodes of discrete seizures include both an estimate of the number of 
seizures, and an estimate of the duration, categorized into 1 of 3 buckets: < 2 minutes; 
2-10 minutes; >10 minutes. 
Study-level summary statistics using seizure events reported in the T+M Period will be 
calculated for each bucket to determine the median number of seizures occurring in 
each bucket. 
The median number of seizures will then be used to impute counts for seizure clusters: 
x ‘VKRUW·FOXVWHUVLH 59 minutes) will be the median number of seizures 
reported in discrete seizure events < 2 minutes 
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x ‘medium’ clusters (ie, 1-5 hours) will be the median number of seizures reported 
in discrete seizure events 2-10 minutes 
x 
‘long’ clusters (ie, > 5 hours) will be the median number of seizures reported in 
discrete seizure events > 10 minutes. 
Sensitivity Analysis of Cluster Imputation  
A sensitivity analysis using an alternative method for imputing the count associated with 
cluster events was described in the Part 1 SAP Note to File (NTF) document dated 
31Jun2021.  This analysis will be completed for Cohort A and Cohort B. 
This analysis is an alternative method for imputation of the number of seizure events 
associated with episodes that were described in the diary as “A cluster of seizures back-
to-back.” The “A cluster of seizure back-to-back” episodes did not have a number of 
seizure events associated with it. In order to associate a number of seizure events with 
it, the following alternative method for imputation was defined.  
1.) Cluster episodes described in the diary as “A cluster of seizures back-to-back” were 
classified according to duration, as in the primary analysis.  
x 
Short: < 1 hour duration 
x 
Medium: 1 – 5 hours, inclusive 
x 
Long: > 5 hours 
2.) Seizure cluster episodes described as “An episode of many discrete seizures” that 
occurred during the Titration or Maintenance Period of Part 1 were identified, as in the 
primary analysis. These episodes were reported in the diary with information about the 
number of discrete seizures in the cluster episode and the duration of a single discrete 
seizure within the cluster episode. 
3.) The duration of a single seizure within the discrete seizure cluster episode was 
defined as:  
x 
2 minutes, if the duration of the discrete seizure was answered as “Less than 
2 minutes” 
x 
10 minutes, if the duration of the discrete seizure was answered as “2 – 10 
minutes” 
x 
15 minutes, if the duration of the discrete seizure was answered as “More 
than 10 minutes” 
4.) The total duration of the overall discrete seizure cluster episode was calculated as 
the duration from step 3 multiplied by the number of seizures reported in the discrete 
seizure cluster episode.  
5.) The total duration from step 4 was categorized into categories as:  
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x
Short:  59 minutes
x
Medium: 60 minutes – 300 minutes (ie, 1 – 5 hours, inclusive)
x
Long: > 300 minutes
6.) The median number of seizures reported within a discrete seizure cluster episode 
was determined for all discrete cluster episodes in the Short, Medium, and Long 
discrete cluster duration categories in the population.  The median value was then 
imputed into the Short, Medium, and Long duration back-to-back cluster categories. 
The frequency of drop seizures was then determined using the alternative cluster event 
imputation. The same summary statistics, nonparametric model, and parametric models 
as used for the primary endpoint were used for the cluster event sensitivity analysis. 
Calculation of seizure frequency / 28 days
For any individual subject, the frequency of drop seizures per 28 days during the 
baseline period (DSFB) will be derived as follows:
DSFB =
28 × Total number of drop seizures during the Baseline Period
Total number of days in the Baseline Period with nonmissing diary data
For each treatment group, the median and mean DSFB will be calculated.
Similarly, for each subject, the frequency of DSF per 28 days for the T+M period (DSFT+M) 
is derived as below:
DSFT+M =
28 × Total number of drop seizures during the T + M Period
Total number of days in the T + M Period with nonmissing diary data
The percentage change from baseline for any individual subject will be estimated by
PCDSFT+M  (DSFT+M - DSFB)*100/DSFB
The difference from baseline (CDSFT+M) will be estimated by CDSFT+M  DSF୘ା୑െDSF୆.
For each treatment group, descriptive statistics for DSF during baseline, T+M and M 
only, as well as the differences and % changes from baseline, will include the number of 
observations, mean, standard deviation, median, minimum and maximum, overall.
Part 1 Primary Efficacy Endpoint Analyses
T+M Period:
The primary analysis will compare the ZX008 0.8 mg/kg/day group to the placebo group 
for Cohort A using a two-VLGHGWHVWDWWKHŞ OHYHORIVLJQLILFDQFH The same 
comparison will be done for Cohort B but will be considered descriptive. 
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The primary endpoint will be analyzed using a non-parametric analysis of covariance 
(ANCOVA) model with treatment group (three levels; Placebo, ZX008 0.2 mg/kg/day, 
ZX008 PJNJGD\DQGZHLJKWVWUDWDJURXSNJNJDVIDFWRUVUDQNRI
baseline DSFB as a covariate and rank of percentage CDSFT+M as response. Treatment 
group mean differences from placebo will be estimated via least squares means from 
the analysis model along with 95% confidence intervals (CIs). Note that the treatment 
difference estimated from the model is based on rank-transformed data; thus, it cannot 
be interpreted as an estimate of the size of the difference between groups in 
percentage CDSF. Instead, the size of the difference between groups in percentage 
CDSF will be estimated using the Hodges-Lehmann method, described in Section 8.2.3. 
The null hypothesis 
 
H଴: ߤ୞଴.଼െߤ୔= 0, 
will be tested against the alternative 
H୅: ߤ୞଴.଼െߤ୔്0, 
where õZ0.8 and õP represent the ZX008 0.8 mg/kg and Placebo group location parameter, 
respectively.  
Rejection of the null hypothesis in favor of the alternative, in the presence of a 
statistically significantly smaller seizure frequency for the treatment group compared to 
the placebo group, (two-sided p-value <.05) will be regarded as evidence of a treatment 
benefit in favor of the ZX008 0.8 mg/kg group. A similar comparison of the location 
parameter for ZX008 0.2 mg/kg/day vs. placebo will be regarded as evidence of a 
treatment benefit of the ZX008 0.2 mg/kg group. This is the 3rd key secondary 
endpoint. 
Sample SAS code for the non-parametric ANCOVA described above is as follows: 
3URFUDQNGDWD WHPSWLHV PHDQRXW UDQNWHPS 
  Var bsrd csrd; 
  Rank r_bsrd r_csrd; 
Run; 
   
SURFJOPGDWD UDQNWHPS 
 
class wtgrp trtp; 
PRGHOUBFVUG UBEVUGZWJUSWUWS66 
lsmeans  trtp / pdiff stderr; 
ZKHUHWUWS UDQGRPL]HGWUHDWPHQWJURXSZLWKFRGHVLQGLFDWLQJSODFHERZX008 
0.2 mg/kg, and ZX008 0.8 mg/kg groups). 
    
UBEVUG UDQNRIEDVHOLQHDSF஻,  
      
UBFVUG UDQNRIpercentage CDSFT+M 
ZWJUS ZHLJKWgroup. 
Additional statements may be used to obtain estimates and associated 95% CIs.  
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A second analysis of the primary endpoint will be completed using a parametric analysis 
of covariance (ANCOVA) model with treatment group (three levels; Placebo, ZX008 0.2 
mg/kg/day, ZX008 PJNJGD\DQGZHLJKWJURXSNJNJDVIDFWRUVlog 
baseline DSFB as a covariate and log (CDSFT+M +1) as response. Treatment group mean 
differences from placebo will be estimated via least squares means from the analysis 
model along with 95% CIs. Since the least square means and confidence intervals will be 
on the log scale, these least square means and CIs will be exponentiated back to the 
original scale. 
The null hypothesis 
 
H଴: ݉୞଴.଼െ݉୔= 0, 
will be tested against the alternative 
H୅: ݉୞଴.଼െ݉୔്0, 
where mZ0.8 and mP represent the ZX008 0.8 mg/kg and Placebo group means (on the log 
scale), respectively.  
Sample SAS code for the parametric ANCOVA described above is as follows: 
   
SURFJOPGDWD WHPS 
 
class wtgrp trtp; 
PRGHOFGVI EGVIZWJUSWUWS66 
lsmeans  trtp / pdiff stderr; 
ZKHUHWUWS UDQGRPL]HGWUHDWPHQWJURXSZLWKFRGHVLQGLFDWLQg placebo, ZX008 
0.2 mg/kg, and ZX008 0.8 mg/kg groups). 
    
EGVI ORJDSF஻ +1),  
      
FGVI ORJ'6)T+M +1) 
ZWJUS ZHLJKWJURXS 
Additional statements may be used to obtain estimates and associated 95% confidence 
intervals. Endpoints of the CIs will be translated to the original scale using the ranks.  
M Period only:  
The primary endpoint analysis described above will be repeated using data from the 
Maintenance period only as response. For subjects who did not reach the Maintenance 
period, their Transition period data will be used to represent their M period data. 
Similar non-parametric and parametric ANCOVA models will be used. 
Treatment by baseline seizure category interaction: 
Treatment by baseline seizure category interaction: The non-parametric and parametric 
analysis for the T+M and M period described above will be repeated with baseline 
seizure frequency as a categorical variable, rather than a covariate, and will include 
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baseline seizure frequency by treatment interaction. Baseline seizure frequency per 28 
days will be categorized using tertiles.
Sensitivity Analyses of Part 1 Primary Efficacy Endpoint 
Wilcoxon Rank-sum Test 
The ZX008 0.8 mg/kg/day group will be compared to the placebo group on the 
percentage change from baseline in seizures resulting in drops using a Wilcoxon rank-
sum test. The median difference between the groups, and its 95% CI, will be estimated
using the Hodges-Lehmann estimator.
Impact of Antiepileptic Drugs (AED) 
Subjects in the study are required to be on stable background therapy. Using the mITT 
population, an additional nonparametric ANCOVA analysis will be performed to assess 
the impact on the primary analysis of changes in dose or type of concomitant AED, 
which are protocol violations that may occur during the course of the study. 
For this analysis, each subject will be classified according to the number of concomitant 
AEDs used during the T+M period. Fisher’s exact tests will be used to compare the ZX008
dose groups with the placebo group on the percentage of subjects within each group 
who have a change in concomitant AEDs. 
Per Protocol Analysis
The primary efficacy ANCOVA will be repeated on the PP Population (which excludes 
subjects with important protocol deviations that may affect the inference on efficacy 
such as a change in dose or type of concomitant AED).
No Imputation for Seizure Clusters
The primary efficacy ANCOVA will be repeated on the mITT Population with no 
imputation for seizure clusters; ie, seizure clusters will not be calculated in the 
frequency of seizures that result in drops.
Exclusion of Outliers
The distribution of the primary endpoint is inherently asymmetric since no subject can 
have more than a 100% decrease in seizures, but there is no reason a subject couldn’t 
have a 200% or even 1000% increase. In fact, there is no theoretical upper bound to the 
possible magnitude of an increase in a percentage change statistic. To assess the 
sensitivity of the primary analysis to extreme outliers in percentage change in drop 
seizure frequency, the primary analysis will be repeated excluding any PCDSF value that 
satisfies Tukey’s criterion for a “far out” outlier (7XNH\). Specifically, any PCDSF 
value that satisfies 
[ݍො.ଶହെ3(ݍො.଻ହെݍො.ଶହ),
ݍො.଻ହ+ 3(ݍො.଻ହെݍො.ଶହ)]
will be excluded where ݍො.ଶହand ݍො.଻ହare the sample lower and upper quartiles of all 
PCDSF data combined.
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Imputation for Dropouts 
Two different methods for imputation of missing values due to subject drop out will be 
incorporated into the analysis of the primary efficacy endpoint. When referring to 
frequency in the paragraphs below, it refers to the number of seizure events per 28 
days. The imputation for dropouts may be omitted if fewer than 5% of subjects drop out 
prior to Visit 12. 
S1: Worst value substituted: In this analysis, for a subject who drops out of treatment, 
if the DSF during T+M is lower than the baseline value, the baseline value will be 
substituted for the subject from the point of withdrawal to the end of the planned 
duration of T+M. However, if the seizure frequency during T+M is higher than the 
baseline value, there will be no substitution. The DSF for the planned duration of T+M 
will then be computed as a weighted mean of the value before dropout, and the 
imputed value after dropout. The weights will be the proportion of planned duration of 
T+M before and after dropout. The statistical analysis (nonparametric ANCOVA) 
described at the start of Section 8.2.2will then be performed on the resulting dataset. 
Treatment comparisons will be based on the least squares means and standard errors 
obtained from the ANCOVA. 
S2: Differential imputation method: In this analysis, subjects who drop out due to an 
AE, lack of compliance, loss to follow-up or subject choice will have their DSF for the 
remainder of the time during the planned T+M period replaced with the worse of the 
observed value or the baseline value as described for S1. However, for other withdrawal 
reasons (e.g., “lack of efficacy”) their observed DSF during T+M will be imputed for the 
remainder of the time between dropout and end of planned T+M. The DSF for the 
planned duration of T+M will then be computed as a weighted mean of the value before 
dropout and the imputed value after dropout. The weights will be the proportion of 
time before and after dropout. The statistical analysis (nonparametric ANCOVA) 
described at the start of Section 8.2.2will then be performed on the resulting dataset. 
Treatment comparisons will be based on the least squares means and standard errors 
obtained from the ANCOVA. 
Pre-Data Change Request (DCR) Analyses  
The following posthoc analyses of the DSF for Cohort A were described in the Part 1 SAP 
NTF dated 31Jun2021.  
A pre-edited version of the seizure datasets for Cohort A was requested for regulatory 
submissions, intended to represent the original instance of data prior to modifications 
made as a result of cleaning for Part 1 Cohort A database lock. Upon sponsor request, 
Syneos Health created 2 versions of pre-edited (“pre-DCR”) datasets that were used as 
sensitivity analyses.  The changes made in the DSD data are described below:  
x 
Pre-DCR 2) any edits made through the Trial Manager portal or directly on the 
device itself were removed  
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x 
Pre-DCR 3) any edits made through the Trial Manager portal or directly on the 
device itself were removed, with the exception of the seizure classification field 
(this field is not subject-reported and is subject to review/query/approval by 
the ESC)  
Using the different versions of the pre-DCR seizure dataset, the seizure frequency rates 
were reproduced with each set.  The following sensitivity analyses of seizures that 
result in drops were completed using these sets. 
x 
Summary statistics for observed rate, change from baseline, and percentage 
change from baseline in rate for the T+M period, M period, up to 2 weeks, up to 
6 weeks, up to 10 weeks, and up to 14 weeks. This analysis was completed for 
the mITT Population 
x 
Summary statistics for observed rate, change from baseline, and percentage 
change from baseline in rate for the T+M period, M period, up to 2 weeks, up to 
6 weeks, up to 10 weeks, and up to 14 weeks using the cluster sensitivity values. 
This analysis was completed for the mITT Population. 
x 
Nonparametric analysis for the T+M period and M period using the original values 
and alternative cluster imputation method. This analysis was completed for the 
mITT Population.  
x 
Imputation methods for dropouts described in Section 8.2.3of the Part 1 SAP  
x 
Wilcoxon rank-sum test, including Hodges-Lehmann confidence interval for 
differences from placebo, described in Section 8.2.3 
x 
The number and percentage of subjects who had a worsening or no change, 0% 
UHGXFWLRQUHGXFWLRQUHGXFWLRQUHGXFWLRQUHGXFWLRQ in 
seizure frequency, and near seizure freedom (ie, 0 or 1 seizures) between 
Baseline and T+M and between Baseline and M.  
x 
Cumulative response curve for percentage of subjects experiencing various % 
reductions in seizures (mITT Population) 
x 
Summary statistics for observed rate, change from baseline, and percentage 
change from baseline in rate for the T+M and M period by individual seizure 
type. This analysis was completed for the mITT Population 
x 
The number and percentage of subjects who had a worsening or no change, > 0% 
UHGXFWLRQ UHGXFWLRQ UHGXFWLRQ UHGXFWLRQUHGXFWLRQ in 
seizure frequency, and near seizure freedom by individual seizure type between 
Baseline and T+M and between Baseline and M 
For Cohort B, the need for pre-DCR analyses will be determined based on regulatory 
interactions, and any analyses to be performed will be detailed separately. 
 
ESC Confirmed Drop Seizures – Sensitivity to the Supplementary Drop Seizure File 
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After the Part 1 Cohort A database lock occurred, an updated version of the 
supplementary drop seizure file for Cohort A, which lists each seizure type per subject 
that was reconciled to be an ESC-confirmed drop seizure, was provided that contained 
corrections to the reconciliation based on findings discovered after database lock. The 
updated file was used to create a new version of the frequencies of ESC-confirmed drop 
seizures, and the same analyses used for the primary analyses of ESC-confirmed drop 
seizures were applied to this data.
Criteria for Establishing Efficacy
While several supportive and/or supplementary analyses are specified above, the main 
criterion for demonstrating efficacy will be the primary non-parametric analysis for the 
mITT population from Cohort A.
KEY SECONDARY EFFICACY ENDPOINTS AND ANALYSES
50% Reduction in Seizures Resulting in Drops
The first key secondary endpoint compares treatment groups on the percentage of 
subjects with at least a 50% reduction from baseline in seizures resulting in drops. That 
is, the percentage of subjects in the ZX008 0.8 mg/kg/day group who have a decrease 
in frequency of seizures resulting in drops of at least 50 percentage points will be 
compared to the analogous percentage in the placebo group. This the 1st key secondary 
efficacy endpoint.
The comparison of the percentage of subjects with at least a 50% decrease in DSF from 
baseline between treatment groups will be made using a logistic regression model that 
incorporates the factors treatment and weight strata and the baseline seizure 
frequency. Separate models will be fit for ZX008 0.2 mg/kg/day vs. placebo and ZX008 
0.8 mg/kg/day vs. placebo. Achievement of the 50 percentage point reduction or 
greater (yes or no) will be modeled as a function of treatment group (2 levels; ZX008 
0.8 mg/kg/day (or ZX008 0.2 mg/kg/day) and placebo) and baseline weight strata group 
(< NJNJ,IWKHPRGHOZLWKWUHDWPHQWDQGZHLJKWVWUDWDLVQRWFRQYHUJHQW
(eg, due to a 0 count in a treatment by weight strata combination, the model will be 
refit using treatment only and the baseline seizure frequency. If the model still does not 
converge, no odds ratio and p-value from the logistic regression will be reported.
The model estimated odds ratio (including a 95% CI) and p-value for comparison of 
ZX008 0.8 mg/kg/day to placebo and ZX008 0.2 mg/kg/day to placebo will be provided. 
A supplementary Fisher’s exact test comparing treatment groups will be provided. 
Similarly, the number and percentage of subjects who have a worsening or no change, 
 UHGXFWLRQ UHGXFWLRQ UHGXFWLRQ UHGXFWLRQUHGXFWLRn in 
seizure frequency and near seizure-freedom will be tabulated for each treatment. Near 
seizure-freedom will be defined as having 0 or 1 seizures leading to a drop in the T+M 
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period. These are additional secondary endpoints. For Cohort B, an additional 
exploratory analysis of the number and percentage of subjects who have a > 25% 
worsening from baseline will be included. This had been added by Zogenix as a posthoc 
analysis in the report of Cohort A results.
For the Pre-DCR datasets for Cohort A, the following sensitivity analyses of the change 
in seizures that result in drops were added.
•
The number and percentage of subjects who had a worsening or no change, 0% 
UHGXFWLRQ UHGXFWLRQ UHGXFWLRQ UHGXFWLRQUHGXFWLRQ
and near seizure freedom in the frequency of each individual seizure type 
between Baseline and T+M and between Baseline and M will be summarized by 
treatment group. This analysis was completed for the mITT Population.
Clinical Global Impression – Improvement (CGI-I) Rating, as assessed by 
the Principal Investigator 
The Principal Investigator will rate their global impression of the subject’s condition at 
each clinic visit after randomization: at the end of the Titration period Visit 6 (Day 15), 
during the Maintenance periRGDW9LVLW'D\DQG9LVLW'D\DQGDW9LVLW
(End of Study / Early Termination).
The CGI-I scale measures the change in the subject’s clinical status from a specific point 
in time, i.e., the Baseline Period. The CGI-I rating scale permits a global evaluation of 
the subject’s improvement over time. The severity of a subject’s condition is rated on a 
-SRLQWVFDOHUDQJLQJIURPYHU\PXFKLPSURYHGWRYHU\PXFKZRUVHDVIROORZV
 YHU\PXFKLPSURYHG
 PXFKLPSURYHG
 PLQLPDOO\improved
 QRFKDQJH
 PLQLPDOO\ZRUVH
 PXFKZRUVH
 YHU\PXFKZRUVH
Descriptive statistics for the CGI-I score, and the number and percentage of subjects 
who showed improvement (i.e., had a score of 3 or lower) will be presented for each for 
each treatment group at each assessment time point. Each assessment time point will 
include a comparison of the percentage of subjects with improvement between each 
ZX008 group and the placebo group using the Cochran-Mantel-Haenszel test (CMH) 
stratified by weight strata, and also a frequency distribution of the number and 
percentage of subjects rated in each category in the scale. A graphic showing the 
percentage of subjects rated in each category will be presented.
The number and percentage of subjects who showed clinically meaningful improvement 
(ie, had a score of 2 or lower) and a comparison of the percentage of subjects with 
clinically meaningful improvement between each ZX008 group and the placebo group 
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will be presented for each treatment group at each assessment time point as an 
exploratory analysis.
Individual subject CGI-I data will be listed.
ADDITIONAL EFFICACY ENDPOINTS AND ANALYSES
Countable Motor Seizures Definition and Analysis
The change in the frequency of countable motor seizures per 28 days between the 
Baseline and T+M periods will be calculated using the same methodology described for 
the primary endpoint. Countable motor seizures include: 
x
GTC
x
SGTC
x
TS
x
AS
x
TA
x
clonic seizures [CS]
x
hemiclonic seizures [HS]
x
focal seizures [FS] with clear observable motor signs
The change in the frequency of countable motor seizures per 28 days between the 
Baseline and M period will also be calculated.
The same non-parametric and parametric ANCOVA models described for the primary 
endpoint will be used for the analyses of countable motor seizures (change in the 
frequency between Baseline and T+M periods). The mITT Population will be used for this 
analysis. The difference between ZX008 0.8 mg/kg/day and placebo in the change 
between Baseline and T+M is a secondary endpoint. The analyses will be repeated for 
the change in frequency between the Baseline and M periods. The analysis of the 
change between Baseline and the M period is one of the additional secondary endpoints.
The number and percentage of subjects who had a worsening or no change, 0% 
UHGXFWLRQ UHGXFWLRQ UHGXFWLRQ UHGXFWLRQDQGUHGXFWLRQLQWKH
frequency of countable motor seizures between Baseline and T+M and between Baseline 
and M will be summarized by treatment group and overall. For Cohort B, the number 
and percentage of subjects who had a > 25% worsening will be determined. Except for 
the latter, which is exploratory, these analyses are part of the additional secondary 
endpoints.
Additional Seizure Counts 
The other efficacy endpoints of change in the frequency per 28 days between Baseline 
and T+M Period and between Baseline and M Period of: 
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x 
Seizures that Typically Result in Drops (i.e., GTC, SGTC, TS, AS, TA regardless of 
whether ESC confirmed as drop or not)  
x 
All Countable Non-Motor Seizures  
x 
All Countable Seizures  
x 
All Countable Seizures That Did Not Result in Drops (ESC Confirmed) – Added as 
posthoc analysis for Cohort A. It will also be included in the analysis of Cohort B. 
Each of these endpoints will be calculated using the same method as the primary 
endpoint. The same non-parametric ANCOVA, parametric ANCOVA, and logistic 
regressions used for the primary efficacy endpoint will be used. The mITT 
Population and PP Populations will be used for these analyses.  
Refer to Appendix 1 for the seizure types that are included in each of these 
endpoints.  
Pre-DCR Sensitivity Analyses of Seizures that Typically Result in Drops  
Analyses of Typical Drop Seizure endpoints for Cohort A, Part 1 using the Pre-DCR 
versions of the dataset were added and described in the Part 1 SAP NTF dated 
31Jun2021.  The following summaries were included. For Cohort B, the need for 
pre-DCR analyses will be determined based on regulatory interactions, and any 
analyses to be performed will be detailed separately.  
• Summary statistics for observed rate, change from baseline, and percentage 
change from baseline in rate for the T+M period, M period, up to 2 weeks, up to 6 
weeks, up to 10 weeks, and up to 14 weeks. This analysis was completed for the 
mITT Population. 
• Summary statistics for observed rate, change from baseline, and percentage 
change from baseline in rate for the T+M period, M period, up to 2 weeks, up to 6 
weeks, up to 10 weeks, and up to 14 weeks using the cluster sensitivity values. This 
analysis was completed for the mITT Population. 
• Nonparametric analysis for the T+M period and M period using the original values 
and alternative cluster imputation method. This analysis was completed for the 
mITT Population  
• Wilcoxon rank-sum test, including Hodges-Lehmann confidence interval for 
differences from Placebo, described in section 8.2.3 of the Part 1 SAP 
• The number and percentage of subjects who had a worsening or no change, 0% 
UHGXFWLRQ UHGXFWLRQ UHGXFWLRQ UHGXFWLRQUHGXFWLRQ in 
seizure frequency, and near seizure freedom (ie, 0 or 1 seizures) between Baseline 
and T+M and between Baseline and M. This analysis is completed for the mITT 
Population. 
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•
Cumulative response curve for percentage of subjects experiencing various % 
reductions in seizures (mITT Population)
•
Summary statistics for observed rate, change from baseline, and percentage 
change from baseline in rate for the T+M and M period by individual seizure type. 
This analysis was completed for the mITT Population
•
The number and percentage of subjects who had a worsening or no change, 0%
UHGXFWLRQ UHGXFWLRQ UHGXFWLRQ UHGXFWLRQUHGXFWLRQDQG
near seizure freedom in the frequency of each individual seizure type between 
Baseline and T+M and between Baseline and M will be summarized by treatment 
group. This analysis is completed for the mITT Population.
All Countable Seizures That Did Not Result in Drops (ESC Confirmed)
The SAP v2.0 08Jan2020 described increasingly broad groupings of seizure types for 
efficacy analyses, from the primary endpoint (drop seizures only) to all countable 
(motor + non-motor) seizures; however, it did not describe a seizure grouping that does 
not include drop seizures as defined for the primary endpoint. The calculation of the 
change in the frequency of all countable seizures that did not result in drops (ESC 
confirmed; ie, non-drop seizures) between Baseline and the T+M Period and M Period 
will be completed similarly to the method described for the primary endpoint. All 
countable seizures recorded from the diary that did not meet the criteria of drop 
seizures as defined in the primary endpoint analysis, ie, are CS, HS, FS with or without 
observable signs, myoclonic, absence/atypical absence, infantile spasms, epileptic 
spasms, other, or are seizures of the following classifications that were approved for 
each subject as non-drop seizure types by the ESC: GTC, SGTC, TS, AS, or TA seizures, 
will be included. The analysis of this parameter will also be included in the analysis of 
Part 1, Cohort B. In addition, the number and percentage of subjects who had a 
worsening or no changeUHGXFWLRQ UHGXFWLRQ 50% UHGXFWLRQ 
reduction, 100% reduction in frequency and near seizure freedom for non-drop seizures 
between Baseline and T+M and between Baseline and M will be summarized. For Cohort 
B, the number and percentage of subjects who had a > 25% worsening will also be 
determined.
Seizure-Free Days
Seizure-free days will be taken from the DSD data.
A seizure-free day with no seizures leading to drops will be defined as a day for which 
diary data are available and with no ESC-confirmed drop seizures. A day without 
countable motor seizures will be defined as a day for which diary data are available and 
with no countable motor seizures. The total number of drop seizure-free days and 
countable motor seizure-free days will be summarized for the entire T+M period and 
similarly for the Baseline Period.
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Seizure-IUHHGD\VSHUGD\VDWEDVHOLQH QXPEHURIVHL]XUHIUHHGD\VGXULQJ
baseline)*28/ (number of days during baseline with non-missing diary data)
Seizure-free days per 28 days durLQJ703HULRG QXPEHURIVHL]XUHIUHHGD\VGXULQJ
T+M Period)*28/ (number of days during T+M Period with non-missing diary data)
Statistical comparison of the ZX008 groups and placebo group on the number of drop 
seizure-free days per 28 days and countable motor seizure-free days per 28 days during 
T+M using the baseline as covariate will be done with a similar non-parametric ANCOVA 
model as described for the primary analysis.
Duration of the Longest Interval Between Seizures Resulting in Drops
The duration of the longest interval between seizures resulting in drops (in days) will be 
analyzed using nonparametric methods. 
For each subject, the duration of the longest interval between seizures resulting in 
drops (ie, ESC confirmed) will be calculated over the entire T+M period. This will be 
derived as the maximum of the number of consecutive days between seizures resulting 
in drops. The length of the intervals between seizures resulting in drops will be 
calculated as below, after which the duration of the longest interval between 
convulsive seizures will be derived. 
If a subject has a missing diary day within an otherwise seizure-free interval, that day is 
counted towards the duration of the seizure free interval. However, if a subject has two 
consecutive days of missing diary data, the current seizure-free interval will end on the 
first date of missing diary data, and a new one begun on the next date that diary data 
are available, and no seizure occurs. [In that case, for purpose of calculation of this 
variable, all intervening days, after the 2nd day, with missing diary data, will be 
assumed to have a seizure with drops occurrence, until the first available date with 
non-missing diary data.]
/HW'DWH 'D\EHWKHILUVWGD\RIWUHDWPHQW,IDVHL]XUHUHVXOting in a drop occurs 
on five days having dates as Date1, Date2, Date3, Date4, and Date5, where 
'DWH!'DWH!'DWH!'DWH!'DWH'DWHDQGOHW/'7 /DVWGDWHRIWUHDWPHQWLQWKH
PDLQWHQDQFHSHULRGZKHUH/'7'DWHWKHQWKHWLPHLQWHUYDOEHWZHHQFRQYXOVLYe 
seizures will be calculated as follows:
, 'DWH- Date1 
, 'DWH- Date2 
, 'DWH– Date3,
, 'DWH– Date4.
For completeness, we calculate the time to the first seizure as
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, 'DWH– Date0, 
and the time from the last seizure to end of treatment as
, /'7– Date5.
+HUHWKHGXUDWLRQRIWKHORQJHVWLQWHUYDO 0D[LPXP,,,,,,
If the subject does not experience a seizure during treatment, then the last available 
diary date will be used to compute the duration of the longest interval as follows:
7KHORQJHVWLQWHUYDO ODVWDYDLODEOHGLDU\GDWH– Date0
The median time of the longest interval between seizures resulting in drops (in days) 
will be presented. Additional summary statistics will be presented, including mean, 
minimum, PD[LPXPDQGWKHWKDQGWKSHUFHQWLOHVCIs on the difference in 
medians between groups (Hodges-Lehman estimator).
The Wilcoxon rank sum test will be used to test for differences between each ZX008
group and the placebo group, and the p-value from this test will be presented. A 
boxplot summarizing the duration of the longest interval between seizures will be 
provided.
Clinical Global Impression – Improvement Rating, as assessed by the 
Parent/Caregiver 
CGI-I ratings assessed by the parent/caregiver will be summarized and analyzed using 
the same methods used for CGI-I ratings recorded by the Principal Investigator as above.
Incidence of Status Epilepticus 
The incidence of SE will be evaluated based on: 1.) seizures entered as serious adverse 
events (SAEs), and 2.) seizures lasting longer than 10 minutes from the DSD. A single 
seizure meeting more than one of these criteria will be counted once. 
The number and percentage of subjects with SE during the Baseline and T+M Periods
recorded as an AE will be presented by treatment group. Statistical comparisons of the 
difference in incidence will be tested using a Fisher’s Exact Test.
From the diary data, change from Baseline in the number of seizures with duration > 10 
minutes per 28 days for the T+M Period will be reported. A nonparametric ANCOVA will 
be completed to compare ZX008 groups vs. placebo. As well, the number of unique days 
where SE was reported (normalized per 28 days) will be summarized and analyzed using 
the nonparametric ANCOVA.
All seizures recorded in the AE database as SE should also be included in the DSD. An 
edit check will be performed to identify the overlap between seizures identified as AE 
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of SE and seizures entered into the diary as seizures > 10 min. The “calculated” number 
and percentage of subjects experiencing SE will be presented by treatment group, 
defined as individuals who experience either an AE of SE, medical treatment for SE, or a 
seizure lasting longer than 10 minutes. Each subject will be represented once regardless 
of incidence. Statistical comparisons of the differences in incidence between treatment 
and placebo groups will be based on Fisher’s exact test. 
A second calculation will present the number of incidences of SE, according to the 
above definition, by treatment group normalized to per 28 days. In this analysis, a 
single subject may have more than one episode of SE, but an episode of SE recorded as 
both an AE and as a seizure longer than 10 minutes will be counted as a single episode. 
Statistical comparisons of the differences between treatment and placebo groups will 
be based on a Fisher’s Exact Test. A difference in percentages between baseline and 
the T+M period will be calculated and summarized within each treatment group. 
Sensitivity Analysis of Status Epilepticus 
The following analysis was added as a posthoc analysis for Cohort A, Part 1. This was 
included in the Part 1 SAP NTF dated 31Jun2021. This analysis will be completed for 
Cohort B. 
A sensitivity analysis of SE cases determined from the DSD was conducted, based on 
seizure types officially recognized as SE by the International League Against Epilepsy 
(ILAE). Seizure events with duration > 10 minutes that were of one of the following 
types were identified. 
x 
Absence/atypical absence 
x 
Focal with clear observable motor signs 
x 
Focal without clear observable motor signs 
x 
GTC 
x 
SGTC 
 
Such events were further divided in order of increasing risk/emergency, ie, into those 
events that required 
x 
No Rescue Medications  
x 
1 Rescue Medications  
x 
> 1 Rescue Medications  
 
The number of events of each type was counted in the Baseline Period, T+M Period, and 
M Period as well as the rate (events/ 28 days) was determined.  The number of subjects 
with at least one event was summarized and the incidence rate between the ZX008 
groups and the placebo group was compared using a Fisher’s Exact Test. 
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Rescue Medication Usage
Use of rescue medication is recorded on the daily diary. In the event of prolonged 
seizures or SE, rescue medication is administered according to each subject’s 
personalized regimen consisting of one or more medications. If the first rescue 
administration does not control the seizures, a second or even third round might be 
administered. The second and third round might use different medications or different 
doses than the first round of rescue medications.
Rescue medication will be summarized by treatment group and comparisons of ZX008 
treatment vs. placebo performed for the following:
x
The number of days rescue medication was taken (normalized to 28 days) will be 
summarized separately for the Baseline and T+M periods by the mean (SD) as 
well as the median, minimum and maximum values. Multiple medications taken 
on the same day will be counted once for that day. The ZX008 groups will be 
compared to the placebo group using a non-parametric ANCOVA analogous to 
that described in the primary efficacy endpoint section. Specifically, the rank 
ANCOVA will use the ranks of rescue medication frequency during T+M or M 
period as the response and will incorporate treatment group as a factor and the 
ranks of rescue medication frequency during Baseline as a covariate.
x
The number of medications used per episode will be summarized using similar 
descriptive statistics as above. Rescue medications related to an episode of SE 
are considered to be all rescue administered on the day of the SE (or seizure 
lasting >10 min). If more than one episode of SE or a seizure lasting >10 min 
occurred in a single day, the rescue medication for that episode is all rescue 
administered after the seizure until the start time of the next prolonged seizure.
Incidence of Medical Services to Treat Seizures
Data on hospitalization and healthcare resource use to treat seizures will be captured in 
the CRF and will be used to calculate incidence. 
Details of the hospitalizations, including reasons for hospitalization and use of resources 
during the study will be summarized. 
Vineland Adaptive Behavior Scale (VABS) 
The VABS is a parent/caregiver completed assessment that looks at the personal and 
social skills of individuals from birth through adulthood (Sparrow, S. S. & Cicchetti, D. 
V. (1989)). Because adaptive behavior refers to an individual's typical performance of 
the day-to-day activities required for personal and social sufficiency, these scales assess 
what a person actually does, rather than what he or she is able to do. The VABS assesses 
adaptive behavior in 4 domains:
x
Communication
x
Daily living skills
x
Socialization
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x
Motor skills
In Part 1, the VABS is collected at Visit 3 (Randomization), Visit 8 (Day 43), and Visit 12 
(End of Study/Early Termination). 
As noted in the Part 1 SAP NTF dated 21Jun2021, the Vineland Adaptive Behavior Scale 
data was not analyzed due to issues with the collection on the eDiary device. The 
questionnaire was not administered in a way that allowed for determination of the 
domain scores.
Quality of Life in Childhood Epilepsy (QOLCE) Scale 
The parent/caregiver will complete the QOLCE. This assessment looks at how epilepsy 
affects day-to-day functioning of their child in various life areas, including physical 
activities, well-being, cognition, social activities, behavior and general health (Sabaz et 
DO7DODUVND). There is also one question on overall quality of life, 
administered as part of the QOLCE.
The QOLCE is collected at Visit 3 (Randomization) and at Visit 12 (End of Study/Early 
Termination). 
The QOLCE scores items with a possible 5-point response. To calculate subscale scores, 
the 5-point item scores will first be reverse coded as necessary so that scores of 5 
represent the best possible response and 1 represents the worst possible response. 
[Details of the reverse coding are provided in the shells for the TLFs]. Item scores will 
then be transformed to a 0-100 scale as follows: 1 -> 0, 2 -> 25, 3 -> 50, 4 -!-> 
100. After transformation, a score for each subject for each subscale is calculated by 
averaging that subject’s responses to each item in the subscale. A value of 0 represents 
the lowest or poorest score and 100 reflects the highest level of functioning. The 16 
subscale scores per subject are then averaged to obtain an overall quality of life score 
for each subject. 
Summary descriptive statistics including the n, mean, standard deviation, median, 
minimum, and maximum will be generated for the index score at each scheduled 
collection time point.
A higher subscale and overall quality of life score indicate a better response. 
Table 6: Subscale of QOLCE:
Domain
Subscale
Item
Section 3: Physical
Physical Restrictions
3.1 a-j
Section 3: Physical
Energy/Fatigue
3.2 a,b
Section 4: Well-being
Depression
4.1 a,d,e,l
Section 4: Well-being
Anxiety
4.1 b,g,j,n,o,p
Section 4: Well-being
Control/helplessness
4.1 c,f,h,i
Section 4: Well-being
Self-esteem
4.1 k,m,q,r,s
Section 5: Cognition
Attention/Concentration
5.1 a,d,e,f,g
Section 5: Cognition
Memory
5.1 j,k,l,m,n,o
Section 5: Cognition
Language
5.1 p,q,r,s,t,u,v,w
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Section 5: Cognition
Other Cognitive
5.1 b,c,h
Section 6: Social Activities
Social Interactions
6.1 c,f,h
Section 6: Social Activities
Social Activities
6.1 a, e, 6.2 
Section 6: Social Activities
Stigma Item
6.1 i
6HFWLRQ%HKDYLRU
Behavior
D
c,f,g,h,i,j,k,l,m,o,q,r,s,t
Section 8: General Health
General Health
8.1
Section 2 (USA Version) or 
Section 9 (Australia Version): 
Quality of Life
Quality of Life Item
2.1 or 9.1
Overall Quality of Life *
Average of 16 subscale scores*
*An Overall Quality of Life Score will be computed by adding each subscale score for each 
individual and then dividing by 16. 
For each treatment group and at each schedule visit, the descriptive statistics will be 
presented for each QOLCE subscale and for the overall quality of life score. 
In addition, the change from baseline in the overall QOLCE will be calculated for each 
subject by subtracting the Part 1 baseline score from the score measured at each 
scheduled postbaseline visit. The change from baseline for each treatment group will be 
summarized by summary statistics. Treatment groups will be compared using pairwise 
Wilcoxon Rank-sum tests. 
Individual subject data for the domains will be listed.
Zarit Caregiver Burden Inventory 
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Patient/Caregiver Assessment using HADS Scale 
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New Seizure Types 
The analysis of New Seizure Types was added in the Part 1 SAP NTF dated 31Jun2021. 
In Cohort A, a posthoc analysis of the emergence of new seizure types was to be 
performed. The summary of this variable will be based on the Seizure History eCRF (a 
form that lists both previous and current seizure types experienced by each subject), 
seizures reported on the DSD prior the start of study treatment, and seizures reported 
during the T+M Period of Part 1. Each subject’s unique seizure types experienced prior 
to study treatment will be determined from the following types:   
Seizure Types 
GTC
SGTC
TS
AS
TA
CS
HS L Body
HS R Body
HS with Independent L and R
FS with clear observable signs
FS without clear observable signs
Myoclonic
Absence/atypical absence
Infantile Spasms
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Epileptic Spasms
Other
Subjects with emergence of at least one new seizure type during the T+M Period will be 
summarized by randomized treatment group.  A new seizure type is defined as a seizure 
type recorded in the DSD that was not recorded in the Seizure History eCRF as occurring 
before the first study drug dose date and that also did not occur during the Baseline 
Period.
SAFETY
All Part 1 safety analyses will be performed for the SAF Population, as defined in 
Section 6.2. Results will be reported by treatment group for the 16-week treatment 
period, unless noted otherwise.
EXTENT OF EXPOSURE
Part 1 treatment exposure data will be summarized for the SAF Population.
Duration of total exposure during Part 1 (ie, time on treatment (in days)) will be 
calculated per subject as the number of days with IMP intake during the trial and will be 
summarized using n, mean, standard error, median, minimum, Q1, Q3 and maximum. 
This will be calculated as:
Date of last IMP intake in Part 1 – Date of first full daily IMP intake in Part 1 + 1
Time on treatment will be summarized by the Part 1 treatment group.
TREATMENT COMPLIANCE (DIARY)
Study medication is to be administered twice daily, and self-reported compliance is 
recorded in the daily diary as full (both doses), partial (less than full daily dose) or 
missed (both doses) each day. From this, compliance will be calculated by assuming 
that a missed dose  0% of dose consumed, partial  RIGRVHFRQVXPHGDQGIXOO  
100% of dose consumed. For each subject, a daily diary compliance score will be thus 
obtained. 
Compliance will also be determined based on the actual quantity taken, determined 
using the weight of the dispensed drug kit and weight of the returned drug kit. The 
expected quantity taken will be determined using the assigned dosage in mg/kg/day 
and the number of days they were assigned at that dosage. If a kit was not returned, 
the compliance for the period will be missing.
For Part 1, compliance will be summarized for the SAF and mITT Populations over the 
course of T+M period and M period only per recorded visit dates, reported by treatment 
group.
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ADVERSE EVENTS
An AE is defined as any unfavorable and unintended sign (including an abnormal, 
clinically significant laboratory finding), symptom, or disease temporally associated
with the use of a medicinal (investigational) product, whether or not considered related
to the medicinal (investigational) product. For Part 1, the period of observation for AEs
extends from the time the subject gives informed consent until the end of the
Titration/Transition Period (Visit 13 or 15).
A TEAE in Part 1 is defined as any AE that based on start date information occurs after
the first intake of study treatment in Part 1, but not on or after the first dose of study 
treatment in Part 2. For subjects who participate in Part 2, the Part 1 TEAE will include 
events with onset up to the day prior to the date of first dosing in Part 2. A Part 1 TEAE 
will be further classified into the Titration Period, Maintenance Period, and 
Transition/Taper Period. The Titration Period will include all events with onset from the 
date of the first dose in Part 1 to date of the Visit 6. The Maintenance Period will 
include all events with onset from the day after Visit 6 through the date of Visit 12. The 
Transition/Taper Period will include all events with onset starting with the day after 
Visit 12 through Visit 15. 
For Part 1, tables will present TEAE data by assigned treatment group received in 
Part 1. AEs occurring after enrollment and prior to the first administration of study 
treatment in Part 1 are defined as non-treatment emergent AEs (non-TEAEs).
AEs are categorized by the Investigator as related or unrelated to study drug. If the AE 
is thought to be definitely, probably or possibly related to study drug then it is to be 
categorized as related. Possibly or definitely unrelated is categorized as unrelated. Any 
TEAE with missing relationship will be considered as “related.”
The severity of AEs (for both non-serious and serious AEs) will be assessed by the 
Investigator as follows:
Severity Definition of Adverse Events:
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 additional 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 
participant.
Severe - A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
Any AE with missing severity will be imputed as “severe.”
The original terms used by the investigators in the eCRFs to identify AEs will be coded 
using the MedDRA Version 20.1 or later.
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Overview of Adverse Events
For Cohort A and B, separately, the number and percentage of subjects with at least 
one of the following events will be summarized in an overall summary table: 
x
TEAE 
x
Treatment-related TEAE
x
Treatment-emergent SAE
x
Treatment-related treatment-emergent SAE
x
Severe TEAEs
x
Severe treatment-related TEAE
x
Adverse events of special interest
x
TEAEs leading to premature discontinuation of study treatment
x
TEAEs leading to premature discontinuation from the study
x
Death
This overall summary table will be presented for the full Part 1 period, Titration Period, 
Maintenance Period, Titration + Maintenance Period, and Taper/Transition Period.
For the full Part 1 period, Titration Period, and Titration + Maintenance Period, the 
denominator for the calculation of percentage will be the number of subjects in the SAF 
Population for the treatment group. For the Maintenance Period, the denominator for 
the calculation of the percentage will be the number of subjects for the treatment 
group with Part 1 last dose strictly greater than the date of Visit 6. For the 
Taper/Transition Period, the denominator for the calculation of the percentage will be 
the number of subjects for the treatment group with last dose strictly greater than the 
date of Visit 12.
Treatment-Emergent Adverse Events
For Cohort A and B, separately, the following summaries will display the number and 
percentage of subjects with an adverse event as well as the corresponding number of 
events by SOC and PT (sorted alphabetically):
x
All TEAEs
x
Treatment-emergent SAEs
x
TEAEs by Maximum Severity
x
Study Drug-Related TEAEs
x
All TEAEs leading to premature discontinuation from the study
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These summaries will present the TEAEs presented for the full Part 1 period, Titration 
Period, Maintenance Period, T+M Period, and Taper/Transition Period.
Summaries of TEAEs and study drug-related TEAEs will be summarized for the following 
subgroups: 
x
Age: 2– < 6 years (Cohort A only), 6–< 12 years (Cohort A only), 12 - < 18 (Cohort 
A only), 2 - < 18 years (Cohort B only) – 35 years (Cohort A and B)
x
Sex (Cohort A only)
x
Concomitant usage of most commonly used concomitant antiepileptic 
medications (eg, valproate or other medications of interest; to be determined)
x
Number of concomitant AEDs (Cohort A only)
An additional summary table will summarize the number and percentage of subjects in 
each treatment group who experience an AE that occurs in at least 5% in Cohort A (at 
least 10% of subjects for Cohort B) of subjects in any treatment group. For AEs occurring 
in at least 5% of subjects in Cohort A (at least 10% of subjects for Cohort B), another 
table will present the mean and median time to onset and the median duration of the 
onset. The summaries will be presented by preferred term in decreasing order of 
incidence. For subjects who have multiple occurrences of the same event during the 
study, the first event will be used in the summary. For unresolved events, the duration 
will be calculated using the last date of follow-up in Part 1.
Another summary of the most commonly occurring adverse events  10% incidence 
overall or in any treatment group) in Part 1 will be provided by treatment group, first 
showing the number of subjects, number of events (noting that a subject may have 
multiple occurrences of the same event), and the number of resolved events.  
No inferential statistical methods (ie, methods that yield p-values) will be used to 
compare treatment groups on the frequency or severity of AEs.
The following listings will be produced for all enrolled subjects: 
x
All AEs; events considered to be TEAEs will be identified in the listing
x
SAEs
x
AEs that lead to premature discontinuation from the study
x
Deaths
Adverse Events of Special Interest (AESI)
As per International Conference on Harmonisation (ICH) guidance (E2F Development 
Safety Update Report [2011]), the sponsor has identified the following AESIs for the 
study:
Table 7 – Adverse Events of Special Interest:
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Metabolic/Endocrine
1.ElevateGSURODFWLQOHYHO[DERYHWKHXSSHUOLPLWRIQRUPDO8/1
2.Hypoglycemia – <3.0 mmol/l or 54 mg/dl, whether that level is associated with 
symptoms or not
Neuropsychiatric  
1.Suicidal thoughts, ideation or gestures
For Part 1 AEs, the AESIs will be identified on the eCRF.
For Part 1, AESIs will be summarized by treatment group and by SOC and PT.
All AESIs will be listed separately.
PHYSICAL EXAMINATION 
A complete physical examination will be performed at Visit 1 (Screening), Visit 3 
(Randomization) prior to first dose of study medication, and at the Visit 12 (End of 
Study/Early Termination). An abbreviated physical exam is performed at Visit 6 (Day 
15), 9LVLW'D\DQG9LVLW'D\$FRPSOHWHRUDEEUHYLDWHGSK\VLFDOH[DP
may be performed at the Cardiac follow-up visit for subjects who do not enter the 
open-label extension study if clinically warranted. Clinically significant findings at 
screening will be reported on the medical history page. New clinically significant 
findings starting with after the first dose in Part 1 will be reported as AEs.
A summary of subjects with clinically significant physical examination findings at each 
visit will be provided for the T+M Period. 
All physical examination results will be presented in a subject data listing.
NEUROLOGIC EXAMINATION 
In Part 1, a complete neurological examination will be performed at Visit 1 (Screening) 
and Visit 12 (End of Study/Early Termination). An abbreviated neurological examination 
will be performed at Visit 3 (Randomization) and at Visit 6 (Day 15), Visit 8 (Day 43), 
DQG9LVLW'D\Clinically significant findings at screening will be reported on the 
medical history page. New clinically significant findings starting with after the first dose 
in Part 1 will be reported as adverse events.
A summary of subjects with clinically significant neurologic examination findings at each 
visit will be provided for the T+M Period.
All neurological examination results will be presented in a subject data listing.
VITAL SIGNS, WEIGHT, AND BMI 
Vital signs and weight and BMI data will be documented for subjects at Visit 1
(Screening), Visit 3 (Randomization) prior to first dose of study medication, at the end 
of the Titration Period at Visit 6 (Day 15), during the Maintenance Period at Visit 8 (Day 
DQG9LVLW'D\DQGDW9LVLW(QGRI6WXG\(DUO\7HUPLQDWLRQ The 
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Statistical Analysis Plan for Interventional Studies
Sponsor: Zogenix International Limited; Protocol No.: ZX008-1601 
This document is confidential.
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Page 66 of 160
measurements will include blood pressure, heart rate, temperature, respiratory rate, 
weight, and BMI.
For each vital sign and weight and BMI, observed values and change from baseline to 
each on-study evaluation will be summarized.
For weight, the occurrence of DWOHDVWDJDLQUHGXFWLRQRU10% gain/reduction 
from baseline will be summarized by visit and at any time during the T+M Period. For 
VXEMHFWVZLWKDQRFFXUUHQFHRIDUHGXFWLRQLQZHLJKWWKHQXPEHUZKRDFKLHYHGD
recovery to their baseline weight, the duration of time to recovery, and whether that 
recovery was achieved as a result of a reduction or withdrawal of the subject’s study 
medication, will be summarized. Recovery will be defined as achieving a weight after 
the  UHGXFWLRQWKDWLVDW least 99% of the baseline weight and having a weight at 
Visit 12 that is at least 99% of the baseline weight. The number of days until weight 
recovery will be determined using the date of the first date when the weight loss was 
observed and the first date when the subject’s weight had recovered to, and 
maintained for the duration of the study period, at least 99% of the baseline weight. For 
Cohort B, the summary will also be presented by subgroups of subjects 2 to < 18 and 
 18 years of age.
For VXEMHFWVZLWKDWOHDVWDUHGXFWLRQLQERG\ZHLJKWDVSDJKHWWLSORWVKRZLQJWKH
subject’s weight values by study day will be presented by actual treatment group. For 
Cohort B, the plot will also be presented by subgroups of subjects 2 to < 18 and 
 18 years of age.
Vital signs, weight, height, and BMI data will be presented in a data listing. In addition, 
change and percentage change from baseline in weight and BMI will be presented in a 
data listing.
For each subject with a clinically meaningful abnormality in vital signs (to be supplied 
by Zogenix International), a listing will be produced organized by parameter that lists 
each subject, age, sex, day of most abnormal value, and the most abnormal value. The
listing will also include subjects with at OHDVWDUHGXFWLRQLQZHLJKW or clinically 
meaningful abnormality in BMI.
ELECTROCARDIOGRAM 
Analysis of ECGs will be included in a separate report from ERT (formerly Biomedical 
Systems).
DOPPLER ECHOCARDIOGRAPHY 
Results of ECHOs will be presented in a separate report from ERT (formerly Biomedical 
Systems). 
TANNER STAGING 
,Q3DUW7DQQHU6WDJLQJZLOOEHDVVHVVHGIRUVXEMHFWV!WR\HDUVROGGXULQJWKH
study at Visit 3 (Randomization) and Visit 12 (End of Study/Early Termination). 
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Conceptually, pubertal maturation can be described in terms of sequence, timing, and 
tempo. Puberty consists of a series of predictable events, and the sequence of changes 
in secondary sexual characteristics has been categorized by several groups. The onset 
and progress of pubertal changes will be recorded on a 5-point scale for boys and girls 
separately. Boys are rated for genital development and pubic hair growth through stage 
I to stage V. Girls are rated for breast development and pubic hair growth through stage 
I to stage V.
The number and percentage of subjects in each Tanner Stage will be presented for all 
visits by treatment group separately for boys and girls overall and broken out for the 
following age groups:
!\HDUVWR\HDUV
!\HDUVWR\HDUV
> \HDUVWR\HDUV
All Tanner staging data will be presented in the subject data listing.
LABORATORY PARAMETERS 
Laboratory safety parameters will be analyzed by a central laboratory using standard 
validated methods.
All laboratory safety data will be collected as per the schedule of assessments given in 
Table 4.
The following continuous laboratory parameters will be analyzed:
x
Hematology: hemoglobin, hematocrit, erythrocytes, erythrocyte mean 
corpuscular volume, leukocytes, neutrophils, lymphocytes, monocytes, 
eosinophils, basophils and platelets
x
Blood Biochemistry: albumin (ALB), alkaline phosphatase (AP), alanine 
aminotransferase (ALT; SGPT), aspartate aminotransferase (AST; SGOT), blood 
urea nitrogen (BUN), calcium (Ca), carbon dioxide (CO2), chloride (Cl), 
creatinine, creatine kinase, gamma-glutamyl transferase (GGT), globulin, 
glucose, lactate dehydrogenase (LDH), phosphorus, potassium (K), sodium (Na), 
thyroid function, thyroid stimulating hormone (TSH), total bilirubin, direct 
bilirubin, total cholesterol, total protein, triglycerides, uric acid.
x
Tests of growth and precocious puberty: Growth hormone (GH), insulin-like 
growth factor-1 (IGF-1, low sensitivity), prolactin, Luteinizing Hormone (LH), 
Follicle Stimulating Hormone (FSH), testosterone, estradiol
x
Coagulation: Prothrombin time, International normalized ratio (INR), activated 
partial thromboplastin time (PTT)
x
Whole blood cannabidiol
x
Urinalysis: analysis for pH, glucose, ketones, nitrite, protein, bilirubin, 
urobilinogen, leukocyte esterase, and occult blood. Microscopic analysis will be 
performed for blood, all cell types, and casts.
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Statistical Analysis Plan for Interventional Studies 
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x 
Pregnancy test: Urine or serum pregnancy testing will be performed in female 
subjects of childbearing potential. 
x 
Urine or serum THC panel 
Observed continuous laboratory data will be descriptively summarized by type of 
laboratory test/parameter change from baseline. For Cohort B, tests of growth and 
precocious puberty will be summarized by age groups and/or sex groups. 
Categorical laboratory parameters will be summarized by presenting the number and % 
of subjects by visit and by treatment arm. 
For each laboratory parameter for which upper or low limits of normal are defined, shift 
tables will be created comparing the baseline status with the status at each 
postbaseline visit. Status will be classified as: 
x 
below lower limit of normal and clinically significant 
x 
below lower limit of normal, 
x 
within normal limits, 
x 
above upper limit of normal,  
x 
above upper limit of normal and clinically significant. 
Listings of the most extreme values for a subject recorded during Part 1 will be created 
for each parameter for which normal limits are defined. These will show the lowest 
recorded value and the highest recorded value noted for the subject. A listing of 
subjects with markedly abnormal laboratory results will be provided, and additional 
explorations of the data may be conducted as warranted. 
Additionally, summaries of abnormal lab results by parameter will be provided to 
investigate changes in platelet count and prolactin in detail. The summaries include: 
x 
6XEMHFWVZLWKGHFUHDVH 25% from baseline) in platelets count with normal 
platelet count at baseline 
x 
6XEMHFWVZLWKGHFUHDVH 25% from baseline) in platelets count relative to 
baseline (whether normal or abnormal) platelet count 
x 
6XEMHFWVZLWKGHFUHDVH 25% from baseline) in platelets count with normal 
platelet count at baseline, by valproate use 
x 
6XEMHFWVZLWKGHFUHDVH 25% from baseline) in platelets count with normal 
platelet count at baseline, by preVHQFHDEVHQFHRILQIHFWLRQHYHQWSULRUWR
days of the lab assessment 
x 
6XEMHFWVZLWKLQFUHDVH 25% from baseline) in prolactin with normal baseline 
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x
6XEMHFWVZLWKLQFUHDVH 25% from baseline) in prolactin with normal baseline, 
and had seizure event within 48 hours prior to prolactin
COLUMBIA-SUICIDE SEVERITY RATING SCALE 
During Part 1, the Columbia-Suicide Severity Rating Scale (C-SSRS) data will be collected 
at Visit 1 (Screening), at Visit 3 (Randomization), at the end of the Titration Period at 
Visit 6 (Day 15), during the Maintenance PHULRGDW9LVLW'D\DQG9LVLW'D\
and at Visit 12 (End of Study/Early Termination). 
6XEMHFWVZKRDUH\RXQJHUWKDQ\HDUVof age, or who are judged by the investigator not 
to have the mental capacity to understand the questions as specified on the C-SSRS, will 
not complete the rating. The investigator should use his/her judgment to substitute 
intellectually appropriate questions to probe the tendency for self-harm.
An electronic tablet will be used to collect C-SSRS data and will only ask about a 
subject’s capability to complete C-SSRS during the Baseline visit. If the site records that 
the subject is incapable of answering the questions, the C-SSRS will be removed from 
their list of required questionnaires for the remainder of the study.
The following outcomes are C-SSRS categories for 
 and have binary 
responses (yes/no):
Category
Outcome Description
1
2
3
4
5
 is assessed as a “yes” answer at any time during the T+M Period to any 
one of the five questions (1-5) above. In Part 1, the number and percentage of subjects 
with 
 at baseline and the number and the number and percentage of 
subjects with 
 at least once during the T+M Period will be presented.
The denominator will be the number of subjects completing the C-SSRS at least once 
during the period. 
The following outcomes are C-SSRS categories for 
 and have binary 
responses (yes/no):
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Sponsor: Zogenix International Limited; Protocol No.: ZX008-1601 
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SAP Text Version 3.0 04-Feb-2022
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Category
Outcome Description
6

8
9
10
 is assessed as a “yes” answer at any time during the T+M period to any 
one of the five questions (6-10) above. In Part 1, the number and percentage of 
subjects who had 
at least once at baseline and the number and 
percentage of subjects who had
at least once during the T+M Period
will be presented. The denominator will be the number of subjects completing the 
C-SSRS at least once during the period. 
An overall composite will be provided similar to the 
 
endpoints but will instead count a subject if any of the C-SSRS questions 1 through 10 
are marked as ‘yes’ at baseline and at any time during the T+M Period for Part 1.
For Part 1, the number and percentage of subjects having reported experiencing a 
 event (Question 11) at baseline and the 
number and percentage of subjects have reported such an event at any time during the 
T+M Period will be provided.
A shift table of the subject’s baseline categorization (No 
 
) vs. the subject’s most severe postbaseline 
categorization during will be provided for the Safety Population.  
 
 will not be included in subjects with 
A listing of subjects with 
 
at any time during the T+M period will be provided.
BRIEF RATING INVENTORY OF EXECUTIVE FUNCTION (BRIEF) 
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INTERIM ANALYSES
No formal interim analysis is planned for this study. However, the analysis of the Part 1 
Cohort A will occur prior to the completion of Part 1 Cohort B. The unblinding of Part 1 
Cohort A will not occur until data cleaning is completed and all decisions regarding 
protocol deviations warranting exclusion from the PP Population have been made for 
the Cohort A subjects. The review of deviations and exclusion from the PP Population 
for Cohort B subjects will occur independently. An unblinded team from Zogenix 
International and Syneos Health will be assigned to complete the unblinding of Part 1 
Cohort A. The unblinded team will not participate in any decision-making regarding the 
Cohort B subjects’ Part 1 data. Access to aggregated data (ie, group-level tables or 
figures) does not constitute unblinding and for the purpose of data cleaning these 
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subjects will be considered blinded. A separate unblinding plan will be developed to 
further define this process.
CHANGE FROM PLANNED ANALYSES 
There have been several changes to the Additional Secondary Objectives specified for 
Part 1 in the protocol, and consequently to the associated Additional Secondary Efficacy 
Endpoints. These mainly fell into the following categories:
x
Addition of new objectives
x
Clarification of seizure types involved
x
Specification of when seizure types needed ESC confirmation
x
Clarification of the treatment period involved.
The following is a list of the Additional Secondary Objectives as specified in the 
protocol and as specified in the SAP to summarize changes:
Protocol Versions 2.1 and later
Statistical Analysis Plan Version 2.0
To evaluate the effect of ZX008 0.2 and 
0.8 mg/kg/day (independently) versus 
placebo on the following endpoints:
To evaluate the effect of ZX008 0.2 and 
0.8 mg/kg/day (independently) versus 
placebo on the following endpoints:
Added:
x Change in frequency of all seizures that 
(typically) result in drops (i.e., GTC, 
SGTC, TS, AS, TA) between baseline and 
the combined T+M whether ESC 
confirmed as drop or not.
x Change in the frequency of all 
countable motor seizures between 
baseline and T+M (countable seizures 
include: generalized tonic-clonic 
seizures [GTC], tonic seizures [TS], 
clonic seizures [CS], atonic seizures 
[AS], tonic/atonic seizures [TA], clearly 
recognizable focal seizures [FS], and 
myoclonic seizures [MS] that result in a 
drop).
Modified to:
x Change in the frequency of all 
countable motor seizures between 
baseline and T+M (countable seizures 
include: GTC, SGTC, TS, AS, TA, clonic 
seizures [CS], focal seizures with clear 
observable motor signs [FS], and 
hemiclonic seizures [HS]).
x Change in the frequency of all 
countable seizures (ie, motor and 
nonmotor) between baseline and T+M
x Change in the frequency of all 
countable seizures (i.e., motor and non-
motor) between baseline and T+M
x Change in frequency of seizures that 
result in drops between baseline and 
the Maintenance Period (M)
Modified to:
x Change in frequency of seizures that 
result in drops (ESC confirmed) between 
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Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
This document is confidential. 
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baseline and the Maintenance Period 
(M) 
 
Added: 
x Change in frequency of seizures that 
(typically) result in drops between 
baseline and the Maintenance Period 
(M) 
x Change in the frequency of countable 
motor seizures that do not result in 
drops between baseline and M 
 
Deleted and replaced with: 
x Change in the frequency of all 
countable motor seizures between 
baseline and M 
x Change in the frequency of all 
countable non-motor seizures between 
baseline and M 
x Change in the frequency of all 
countable seizures (i.e., motor and non-
motor) between baseline and M 
x The proportion of subjects who have a 
ZRUVHQLQJRUQRFKDQJHLH
reduction), >    
100% reduction, and “near seizure 
freedom” (ie, 0 or 1 seizures) between 
baseline and T+M, and baseline and M, 
in all countable motor seizures (GTC, 
TS, AS, TA, FS, MS with a drop); in 
countable motor seizures that do not 
result in drops; in all countable 
seizures; in all countable seizures that 
do not result in drops; and in all 
seizures that result in drops 
Modified to: 
x The proportion of subjects who achieve 
a worsening, > 0 - <   50%, 
 UHGXFWLRQ, and “near 
seizure freedom” (ie, 0 or 1 seizures) 
between baseline and T+M, and baseline 
and M, in seizures that result in drops 
(ESC confirmed), seizures that typically 
result in drops, all countable motor 
seizures, all countable non-motor 
seizures, and all countable seizures  
x Number of seizure-free days, defined as 
1) days with no countable seizures and 
2) days with no seizures that result in 
drops 
Modified to: 
x Number of seizure-free days, defined as 
1) no seizures that result in drops (ESC 
confirmed), and 2) days with no 
countable motor seizures  
x Longest interval between seizures that 
result in drops  
Modified to: 
x Longest interval between seizures that 
result in drops (ESC confirmed) 
x To evaluate the effect of ZX008 0.2 and 
0.8 mg/kg/day (independently) versus 
placebo on the Clinical Global 
x To evaluate the effect of ZX008 0.2 and 
0.8 mg/kg/day (independently) versus 
placebo on the Clinical Global 
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Impression – Improvement rating, as 
assessed by the parent/caregiver 
Impression – Improvement (CGI-I) rating, 
as assessed by the parent/caregiver. 
 
Below is a list of the Additional Secondary Efficacy Endpoints as specified in the 
protocol: 
Protocol Version 2.1 
Statistical Analysis Plan Version 2.0 
 
Added: 
x Change from baseline during T+M in 
frequency of all seizures that (typically) 
result in drops (i.e., GTC, SGTC, TS, AS, 
TA) whether ESC confirmed as drop or 
not. 
x Change from baseline in the frequency 
of all countable motor seizures in T+M 
Countable seizures include: 
generalized tonic-clonic seizures 
[GTC], tonic seizures [TS], clonic 
seizures [CS], atonic seizures [AS], 
tonic/atonic seizures [TA], clearly 
recognizable focal seizures [FS], 
and myoclonic seizures [MS] that 
result in a drop 
Modified to: 
x Change from baseline during T+M in 
frequency of all countable motor 
seizures (GTC, SGTC, TS, AS, TA, CS, FS, 
and HS). 
x Change from baseline in the frequency 
of countable seizures that result in 
drops 
Modified to: 
x Change from baseline during T+M in the 
frequency of all countable seizures 
(i.e., motor and non-motor). 
x Change from baseline in the frequency 
of seizures that result in drops between 
baseline and the Maintenance Period 
(M) 
 
x Change from baseline during M in the 
frequency of seizures that result in 
drops. 
x Change from baseline in the frequency 
of countable seizures that do not result 
in drops 
Deleted;  
This was added as a post-hoc analysis for 
the Part 1 analysis of Cohort A, and will 
be included in the Part 1 analysis of 
Cohort B as noted in the SAP version 3.0. 
 
Added: 
x Change from baseline during T+M in 
frequency of all countable non-motor 
seizures (absence, myoclonic, focal 
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This document is confidential. 
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without clear observable motor signs, 
infantile spasms, and epileptic spasms). 
x Change from baseline during M in the 
frequency of seizures that typically 
result in drops. 
x Change from baseline during M in the 
frequency of all countable motor 
seizures. 
x Change from baseline during M in the 
frequency of all countable non-motor 
seizures. 
x Change from baseline during M in the 
frequency of all countable seizures 
(i.e., motor and non-motor). 
x Proportion of subjects who achieve a 
ZRUVHQLQJIURPEDVHOLQHLH
reduction), or  !  50%, 
 UHGXFWLRQDQG´QHDU
seizure freedom” (ie, 0 or 1 seizures) 
between baseline and T+M, and baseline 
and M, in all countable motor seizures; 
in countable motor seizures that do not 
result in drops; in all countable 
seizures; in all countable seizures that 
do not result in drops; and in all 
seizures that result in drops 
Modified to: 
x Proportion of subjects who achieve a 
worsening from baseline (ie, 
reduction), or >   50%, 
 RUUHGXFWLRQEHWZHHQ
baseline and T+M, and baseline and M, 
in seizures that result in drops (ESC 
confirmed), seizures that typically 
result in drops, all countable motor 
seizures, all countable non-motor 
seizures, and all countable seizures. 
x Number of seizure-free days in the 
baseline, M, and T+M period, defined as 
1) days with no countable seizures and 
2) days with no seizures that result in 
drops 
Modified to: 
x Number of seizure-free days in the 
baseline, M and T+M period, defined as 
1) days with no seizures that results in 
drops (ESC confirmed), and 2) days with 
no countable motor seizures 
x The longest interval (days) between 
seizures that result in drops comparing 
the ZX008 0.8 mg/kg/day and 0.2 
mg/kg/day groups independently versus 
placebo 
Modified to: 
x The longest interval (days) between 
seizures that result in drops (ESC 
confirmed) comparing the ZX008 0.8 
mg/kg/day and 0.2 mg/kg/day groups 
independently versus placebo 
x Clinical Global Impression – 
Improvement as assessed by the 
parent/caregiver 
x Clinical Global Impression – 
Improvement as assessed by the 
parent/caregiver 
 
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Statistical Analysis Plan for Interventional Studies
Sponsor: Zogenix International Limited; Protocol No.: ZX008-1601 
This document is confidential.
SAP Text Version 3.0 04-Feb-2022
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Filing requirements: TMF
Page 76 of 160
Changes and additions to the analyses described in the Part 1 SAP version 2.0 were 
described in the Part 1 SAP NTF dated 31Jun2021. They have been added to the Version 
3.0 Part 1 SAP.
PROGRAMMING CONSIDERATIONS
All tables, data listings, figures (TLFs), and statistical analyses will be generated using 
SAS® for Windows, Release 9.4 (SAS® Institute Inc., Cary, NC, USA). Computer-
generated table, listing and figure output will adhere to the following specifications.
GENERAL CONSIDERATIONS
x
One SAS program can create several outputs. / A separate SAS program will be 
created for each output.
x
One output file can contain several outputs. / Each output will be stored in a 
separate file.
x
Output files will be delivered in Word format / pdf format.
x
Numbering of TLFs will follow ICH E3 guidance.
TABLE, LISTING, AND FIGURE FORMAT
General
x
All TLFs will be produced in landscape format, unless otherwise specified.
x
All TLFs will be produced using the Courier New font, size 8 
x
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides.
x
Headers and footers for figures will be in Courier New font, size 8.
x
Legends will be used for all figures with more than 1 variable, group, or item 
displayed.
x
TLFs will be in black and white (no color), unless otherwise specified
x
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. On 
some occasions, superscripts 1, 2, or 3 may be used (see below).
x
Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 
not be used. Hexadecimal-derived characters will be used, where possible, if they 
DUHDSSURSULDWHWRKHOSGLVSOD\PDWKV\PEROVHJ&HUWDLQVXEVFULSWVDQG
superscripts (e.g., cm2, Cmax) will be employed on a case-by-case basis.
x
Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, as appropriate.
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Statistical Analysis Plan for Interventional Studies
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This document is confidential.
SAP Text Version 3.0 04-Feb-2022
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Headers
x
All output should have the following header at the top left of each page:
<Sponsor Name> Protocol XXX (Syneos Health study number xxx)              
Draft/Final Run <date>
x
All output should have Page n of N at the top or bottom right corner of each page. 
TLFs should be internally paginated in relation to the total length (i.e., the page 
number should appear sequentially as page n of N, where N is the total number of 
pages in the table).
x
The date output was generated should appear along with the program name as a 
footer on each page.
Display Titles
x
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
ICH E3 numbering is strongly recommended but sponsor preferences should be 
obtained prior to final determination (see also template &´7DEOHRI&RQWHQWV
for Tables Listings and Figures in Statistical Analysis Plan”). A decimal system (x.y 
and x.y.z) should be used to identify TLFs with related contents. The title is 
centered. The analysis set should be identified on the line immediately following 
the title. The title and table designation are single spaced. A solid line spanning the 
margins will separate the display titles from the
x
Column headers. There will be 1 blank line between the last title and the solid line.
Table x.y.z
First Line of Title
Second Line of Title if Needed
ITT Analysis Set
Column Headers
x
Column headings should be displayed immediately below the solid line described 
above in initial upper-case characters. 
x
In the case of efficacy tables, the variable (or characteristic) column will be on the 
far left followed by the treatment group columns and total column (if applicable). 
P-values may be presented under the total column or in separate p-value column (if 
applicable). Within-treatment comparisons may have p-values presented in a row 
beneath the summary statistics for that treatment.
x
For numeric variables, include “unit” in column or row heading when appropriate.
x
Analysis set sizes will be presented for each treatment group in the column heading 
DV1 [[RULQWKHURZKHDGLQJVLIDSSOLFDEOH7KLV is distinct from the ‘n’ used for 
the descriptive statistics representing the number of subjects in the analysis set.
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SAP Text Version 3.0 04-Feb-2022
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x
The order of treatments in the tables and listings will be Placebo first in the case of 
placebo controlled studies and Active comparators first in the case of active 
comparator trials, followed by a total column (if applicable).
Body of the Data Display
12.2.5.1.
General Conventions
Data in columns of a table or listing should be formatted as follows:
•
alphanumeric values are left-justified;
•
numbers in table cells are center aligned.
12.2.5.2.
Table Conventions
x
Units will be included where available
x
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category should be presented in the WDEOHHYHQLIQ IRU
all treatment groups in a given category that is between the minimum and maximum 
level for that parameter. For example, the frequency distribution for symptom 
severity would appear as:
Severity 
Rating
N
severe
0
moderate
8
mild
3
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%).
x
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation 
from the Study, etc.), then only those categories for which there is at least 1 
subject represented in 1 or more groups should be included.
x
An Unknown or Missing category should be added to any parameter for which 
information is not available for 1 or more subjects. 
x
Unless otherwise specified, the estimated mean and median for a set of values 
should be printed out to 1 more significant digit than the original values, and 
standard deviations should be printed out to 2 more significant digits than the 
original values. The minimum and maximum should report the same significant digits 
as the original values. For example, for systolic blood pressure:
N
  XX
Mean
XXX.X
Std Dev
     X.XX
Median
XXX.X
Minimum
XXX
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Statistical Analysis Plan for Interventional Studies 
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Page 79 of 160 
 
Maximum 
XXX 
x 
P-values should be output in the format: “0.xxxx”, where xxxx is the value rounded 
to 4 decimal places. Any p-value less than 0.0001 will be presented as <0.0001. If 
the p-value is returned as >0.9999 then present as >0.9999 
x 
Percentage values should be printed to one decimal place, in parentheses with no 
VSDFHVRQHVSDFHDIWHUWKHFRXQWHJ8QOHVVRWKHUZLVH
noted, for all percentages, the number of subjects in the analysis set for the 
treatment group who have an observation will be the denominator. Percentages 
after zero counts should not be displayed and percentages equating to 100% should 
be presented as 100%, without any decimal places.  
x 
Tabular display of data for medical history, prior / concomitant medications, and all 
tabular displays of adverse event data should be presented by the body system, 
treatment class, or SOC, assuming all terms are coded. Within the body system, drug 
class and SOC, medical history (by preferred term), medications (by preferred 
name), and adverse events (by preferred term) should be displayed. SOC terms are 
sorted alphabetically. Preferred tems are sorted in order of incidence within SOC 
terms. 
x 
The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis set 
presented. However, careful consideration is required in many instances due to the 
complicated nature of selecting the denominator, usually the appropriate number of 
subjects exposed. Describe details of this in footnotes or programming notes. 
x 
For categorical summaries (number and percentage of subjects) where a subject can 
be included in more than one category, describe in a footnote or programming note 
if the subject should be included in the summary statistics for all relevant categories 
or just 1 category and the criteria for selecting the criteria. 
Where a category with a subheading (such as system organ class) has to be split over 
more than one page, output the subheading followed by “(cont)” at the top of each 
subsequent page. The overall summary statistics for the subheading should only be 
output on the first relevant page. 
•    For each table, a reference to the source listing(s) will be provided in the footer.  
Listing Conventions 
x 
Listings will be sorted for presentation in order of subject num, visit/collection day, 
and visit/collection time. 
x 
Missing data should be represented on subject listings as either a hyphen (“-”) with 
a corresponding footnote (“-  XQNQRZQRUQRWHYDOXDWHGµRUDV´1$µZLWKWKH
IRRWQRWH´1$ QRWDSSOLFDEOHµZKLFKHYHULVDSSURSULDWH 
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Statistical Analysis Plan for Interventional Studies
Sponsor: Zogenix International Limited; Protocol No.: ZX008-1601 
This document is confidential.
SAP Text Version 3.0 04-Feb-2022
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
Page 80 of 160
x
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on subject listings as dashes (--JUL2000). 
Dates that are missing because they are not applicable for the subject are output as 
“N/A”, unless otherwise specified.
x
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study.
x
Units will be included where available
12.2.5.3.
Figure Conventions
x
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis 
and endpoint (e.g., treatment mean change from Baseline) values will be displayed 
on the Y-axis.
Footnotes
x
A solid line spanning the margins will separate the body of the data display from the 
footnotes. 
x
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display.
x
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, 
etc. if a reference footnote. Each new footnote should start on a new line where 
possible.
x
Subject specific footnotes should be avoided, where possible.
x
Footnotes will be used sparingly and must add value to the table, figure, or data 
listing. If more than six lines of footnotes are planned, then a cover page may be 
used to display footnotes, and only those essential to comprehension of the data will 
be repeated on each page. 
x
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, date the program was run, 
and the listing source (i.e., ‘Program : myprogram.sas    Listing source: 16.x.y.z’).
QUALITY CONTROL
SAS programs are developed to produce output such as analysis data sets, summary tables, 
data listings, figures or statistical analyses. Syneos Health SOP 03.010 and 03.013 provide 
an overview of the development of such SAS programs.
Syneos Health SOP 03.009 describes the quality control procedures that are performed 
for all SAS programs and output. Quality control is defined here as the operational 
techniques and activities undertaken to verify that the SAS programs produce the output 
by checking for their logic, efficiency and commenting and by review of the produced 
output.
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This document is confidential. 
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Sponsor: Zogenix International Limited; Protocol No.: ZX008-1601 
This document is confidential.
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Filing requirements: TMF
Page 82 of 160
INDEX OF TABLES, FIGURES, AND LISTINGS
The data analyses from Cohort B subjects in Japan will not be performed during the initial, principal analysis of the trial but 
will be conducted later. In general, the same analyses that apply to Cohort A subjects in North America, Europe and Australia
will be applied to Cohort B subjects in Japan except for those where the smaller sample size in Cohort B makes the analysis 
untenable. In particular, subset analyses will generally not be applied to Cohort B data.
Table/ 
Figure/ 
Listing
Number
Table Header
Description of Modification from Version 
2.0 SAP
14.1
Demographic data and other baseline characteristics
14.1.1
Subject disposition
Table
14.1.1.1.1
Overall Subject Disposition in Part 1 (Cohort A – North 
America, Europe, Australia) – All Enrolled Subjects
Table
14.1.1.1.2
Overall Subject Disposition in Part 1 (Cohort B - Japan) –
All Enrolled Subjects
Table
14.1.1.2.1
Major Protocol Deviations in Part 1 (Cohort A – North 
America, Europe, Australia) – Safety Population
Table
14.1.1.2.2
Major Protocol Deviations in Part 1 (Cohort B - Japan) –
Safety Population
Table 
14.1.1.3.1
Study Populations in Part 1 (Cohort A – North America, 
Europe, Australia)
Table 
14.1.1.3.2
Study Populations in Part 1 (Cohort B - Japan)
14.1.2
Demographic and other baseline characteristics
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Filing requirements: TMF 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table 
14.1.2.1.1 
Demographic and Baseline Characteristics (Cohort A – 
North America, Europe, Australia)  – Safety Population 
 
Table 
14.1.2.1.2 
Demographic and Baseline Characteristics (Cohort B - 
Japan)  – Safety Population 
 
Table 
14.1.2.2.1 
Demographic and Baseline Characteristics (Cohort A – 
North America, Europe, Australia)  – mITT Population 
 
Table 
14.1.2.2.2 
Demographic and Baseline Characteristics (Cohort B - 
Japan) – mITT Population 
 
Table 
14.1.2.3.1 
Demographic and Baseline Characteristics by Baseline 
Weight Stratum (Cohort A – North America, Europe, 
Australia) – Safety Population 
Adhoc Table request 
Table  
14.1.2.4.1 
Seizure Types Reported on the Seizure Diary During the 
Baseline Period (Cohort B – Japan) – Safety Population 
New Table  
  
14.1.3 
Medical history 
 
Table 
14.1.3.1.1 
Medical and Neurologic History (Cohort A – North 
America, Europe, Australia) – Safety Population 
Title Change; Neurologic History included 
in this table. 
Table 
14.1.3.1.2 
Medical and Neurologic History (Cohort B – Japan) – 
Safety Population 
Title Change; Neurologic History included 
in this table. 
  
14.1.4 
Prior and concomitant medication/treatment 
 
Table 
14.1.4.1.1 
Medications and Therapies/Treatments Stopped during or 
up to 30 Days prior to Screening (Cohort A – North 
America, Europe, Australia) – Safety Population 
Title Changed. Only medications that had 
stopped during screening or up to and 
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Statistical Analysis Plan for Interventional Studies 
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Filing requirements: TMF 
Page 84 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
including 30 days prior to the screening 
were included. 
Table 
14.1.4.1.2 
Medications and Therapies/Treatments Stopped during or 
up to 30 Days prior to Screening (Cohort B – Japan) – 
Safety Population 
Title Changed. Only medications that had 
stopped during screening or up to and 
including 30 days prior to the screening 
were included. 
Table 
14.1.4.2.1 
Concomitant Medications and Therapies/Treatments in Part 
1 (Cohort A – North America, Europe, Australia) – Safety 
Population 
 
Table 
14.1.4.2.2 
Concomitant Medications and Therapies/Treatments in Part 
1 (Cohort B – Japan) – Safety Population 
 
Table 
14.1.4.3.1 
Prior Antiepileptic Treatment (Cohort A – North America, 
Europe, Australia) – Safety Population 
 
Table 
14.1.4.3.2 
Prior Antiepileptic Treatment (Cohort B – Japan) – Safety 
Population 
 
Table 
14.1.4.4.1.1 
Concomitant Antiepileptic Treatment in Part 1 (Cohort A – 
North America, Europe, Australia) – Safety Population 
 
Table 
14.1.4.4.1.2 
Concomitant Antiepileptic Treatment in Part 1 (Cohort B – 
Japan) - Safety Population 
 
Table 
14.1.4.4.2.1 
Rescue Medications in Part 1 (Cohort A – North America, 
Europe, Australia) – Safety Population 
Title Change from Concomitant Rescue 
Medications 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
 
This document is confidential. 
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Filing requirements: TMF 
Page 85 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table 
14.1.4.4.2.2 
Rescue Medications in Part 1 (Cohort B – Japan) - Safety 
Population 
Title Change from Concomitant Rescue 
Medications 
  
14.1.5 
Treatment Exposure and compliance 
 
Table 
14.1.5.1.1 
Duration of IMP Treatment Exposure in Part 1 (Cohort A – 
North America, Europe, Australia) – Safety Population 
 
Table 
14.1.5.1.2 
Duration of Study Drug Treatment Exposure in Part 1 
(Cohort B – Japan) – Safety Population 
Title Adjustment 
Table 
14.1.5.2.1.1 
Compliance to IMP intake in Part 1 (Cohort A – North 
America, Europe, Australia) - mITT Population  
 
Table 
14.1.5.2.1.2 
Compliance to Study Drug Intake in Part 1 (Cohort B – 
Japan) - mITT Population  
Title Adjustment 
Table 
14.1.5.2.2.1 
Compliance to IMP intake in Part 1 (Cohort A – North 
America, Europe, Australia) - Safety Population  
This table was described in the shells but 
was not included in the table of contents. 
Table 
14.1.5.2.2.2 
Compliance to Study Drug Intake in Part 1 (Cohort B – 
Japan) - Safety Population  
This table was described in the shells but 
was not included in the table of contents. 
Title Adjustment 
Table 
14.1.5.2.3.1 
Compliance to IMP Intake in Part 1 based on Bottle Weight 
(Cohort A – North America, Europe, Australia) - mITT 
Population  
 
Table 
14.1.5.2.3.2 
Compliance to Study Drug Intake in Part 1 Based on Bottle 
Weight (Cohort B – Japan) - mITT Population  
Title Adjustment 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
 
This document is confidential. 
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Filing requirements: TMF 
Page 86 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table 
14.1.5.2.4.1 
Compliance to IMP Intake in Part 1 based on Bottle Weight 
(Cohort A – North America, Europe, Australia) - Safety 
Population  
This table was described in the shells but 
was not included in the table of contents. 
Table 
14.1.5.2.4.2 
Compliance to Study Drug Intake in Part 1 Based on Bottle 
Weight (Cohort B – Japan) - Safety Population  
This table was described in the shells but 
was not included in the table of contents. 
Title Adjustment 
  
14.2 
Efficacy, pharmacokinetics, and pharmacodynamics 
 
  
14.2.1 
Efficacy – ZX008 0.8 and 0.2 mg/kg/day vs Placebo  
Seizures resulting in drops 
 
Table 
14.2.1.1.1.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Summary Statistics 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
 
Table 
14.2.1.1.1.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Summary Statistics (Cohort A – North America, Europe, 
Australia) – mITT Population 
New Table using Supplementary Seizure 
File updated post-Part 1 Database Lock.  
Table 
14.2.1.1.1.1b 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Summary Statistics 
(Cohort A – North America, Europe, Australia) (Pre-DCR 
Seizure Event Dataset Version 2) – mITT Population 
New Table using Pre-DCR dataset Version 
2 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
 
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Filing requirements: TMF 
Page 87 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table 
14.2.1.1.1.1c 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Summary Statistics 
(Cohort A – North America, Europe, Australia) (Pre-DCR 
Seizure Event Dataset Version 3) – mITT Population 
New Table using Pre-DCR dataset Version 
3 
Table 
14.2.1.1.1.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Summary Statistics 
(Cohort B – Japan) – mITT Population 
Table number clarified in shells. 
Table 
14.2.1.1.1.3 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Summary Statistics 
(Cluster Event Sensitivity Analysis) (Cohort A – North 
America, Europe, Australia) – mITT Population 
Post-hoc table addition. The shell used is 
the same as 14.2.1.1.1.1.  The different 
methodology of imputing the number of 
seizure events associated with Cluster 
events was added. 
Table 
14.2.1.1.1.3s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Summary Statistics (Cluster Event Sensitivity Analysis) 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
New Table using Supplementary Seizure 
File updated post-Part 1 Database Lock 
Table 
14.2.1.1.1.4 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Summary Statistics 
(Cluster Event Sensitivity Analysis) (Cohort B – Japan) – 
mITT Population 
Post-hoc table addition. The shell used is 
the same as 14.2.1.1.1.1.  The different 
methodology of imputing the number of 
seizure events associated with Cluster 
events was added. 
Table 
14.2.1.1.2.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Summary Statistics 
 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
 
This document is confidential. 
SAP Text Version 3.0 04-Feb-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 88 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
(Cohort A – North America, Europe, Australia) – PP 
Population 
Table 
14.2.1.1.2.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Summary Statistics (Cohort A – North America, Europe, 
Australia) – PP Population 
New Table using Supplementary Seizure 
File updated post-Part 1 Database Lock 
Table 
14.2.1.1.2.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Summary Statistics 
(Cohort B – Japan) – PP Population 
 
Table  
14.2.1.2.1.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed)  per 28 days during Part 1: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia) – 
mITT Population 
Table Number Update  
Table  
14.2.1.2.1.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed)  per 28 days during Part 1: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) – mITT Population 
New Table using Supplementary Seizure 
File updated post-Part 1 Database Lock 
Table  
14.2.1.2.1.1b 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed)  per 28 days during Part 1: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia) 
(Pre-DCR Seizure Event Dataset Version 2)  – mITT 
Population 
New Table using Pre-DCR dataset Version 
2 
Table  
14.2.1.2.1.1c 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed)  per 28 days during Part 1: Nonparametric 
New Table using Pre-DCR dataset Version 
3 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
 
This document is confidential. 
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Filing requirements: TMF 
Page 89 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Analysis (Cohort A – North America, Europe, Australia) 
(Pre-DCR Seizure Event Dataset Version 3)  – mITT 
Population 
Table  
14.2.1.2.1.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed)  per 28 days during Part 1: Nonparametric 
Analysis (Cohort B – Japan) – mITT Population 
Planned table per SAP.  This Table number 
was added to the Table of Contents.  
Table  
14.2.1.2.1.3 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis with Categorized Baseline Seizure Frequency and 
Baseline Seizure Frequency by Treatment Interaction  
(Cohort A – North America, Europe, Australia)- MITT 
Population 
Table was described in the SAP, but shell 
had not been produced. This was added to 
the shells. 
Table  
14.2.1.2.1.3s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis with Categorized Baseline Seizure 
Frequency and Baseline Seizure Frequency by Treatment 
Interaction  (Cohort A – North America, Europe, 
Australia)- MITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.2.1.4 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis with Categorized Baseline Seizure Frequency and 
Baseline Seizure Frequency by Treatment Interaction  
(Cohort B – Japan)- MITT Population 
Table was described in the SAP, but shell 
had not been produced. This was added to 
the shells. 
Table  
14.2.1.2.2.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed)  per 28 days during Part 1: Nonparametric 
Table Number Update  
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Statistical Analysis Plan for Interventional Studies 
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This document is confidential. 
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Filing requirements: TMF 
Page 90 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Analysis (Cohort A – North America, Europe, Australia) – 
PP Population 
Table  
14.2.1.2.2.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed)  per 28 days during Part 1: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) – PP Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.2.2.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed)  per 28 days during Part 1: Nonparametric 
Analysis (Cohort B – Japan) – PP Population 
Planned table per SAP.  This Table number 
was added to the Table of Contents.  
Table  
14.2.1.3.1.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed)  per 28 days during Part 1: Parametric Analysis 
(Cohort A – North America, Europe, Australia)  – mITT 
Population 
Table Number Update  
Table  
14.2.1.3.1.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed)  per 28 days during Part 1: 
Parametric Analysis (Cohort A – North America, Europe, 
Australia)  – mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.3.1.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed)  per 28 days during Part 1: Parametric Analysis 
(Cohort B – Japan)  – mITT Population 
Planned table per SAP.  This Table number 
was added to the Table of Contents.  
Table  
14.2.1.3.1.3 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed)  per 28 days during Part 1: Parametric Analysis 
with Categorized Baseline Seizure Frequency and Baseline 
Table was described in the SAP, but shell 
had not been produced. This was added to 
the shells. 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
 
This document is confidential. 
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Filing requirements: TMF 
Page 91 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Seizure Frequency by Treatment Interaction (Cohort A – 
North America, Europe, Australia)  – mITT Population 
Table  
14.2.1.3.1.3s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed)  per 28 days during Part 1: 
Parametric Analysis with Categorized Baseline Seizure 
Frequency and Baseline Seizure Frequency by Treatment 
Interaction (Cohort A – North America, Europe, Australia)  
– mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.3.1.4 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed)  per 28 days during Part 1: Parametric Analysis 
with Categorized Baseline Seizure Frequency and Baseline 
Seizure Frequency by Treatment Interaction (Cohort B – 
Japan)  – mITT Population 
Table was described in the SAP, but shell 
had not been produced. This was added to 
the shells. 
Table  
14.2.1.3.2.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed)  per 28 days during Part 1: Parametric Analysis 
(Cohort A – North America, Europe, Australia)  – PP 
Population 
Table Number Update  
Table  
14.2.1.3.2.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed)  per 28 days during Part 1: 
Parametric Analysis (Cohort A – North America, Europe, 
Australia) – PP Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.4.1.1 
Percent Improvement in Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: Logistic 
 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
 
This document is confidential. 
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Filing requirements: TMF 
Page 92 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Regression (Cohort A – North America, Europe, Australia)  
– mITT Population 
Table  
14.2.1.4.1.1s 
Sensitivity Analysis of Percent Improvement in Frequency 
of Seizures Resulting in Drops (ESC Confirmed) per 28 
days during Part 1: Logistic Regression (Cohort A – North 
America, Europe, Australia)  – mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.4.1.1b 
Percent Improvement in Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, Australia) 
(Pre-DCR Seizure Event Dataset Version 2) – mITT 
Population 
New Table using Pre-DCR dataset Version 
2 
Table  
14.2.1.4.1.1c 
Percent Improvement in Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, Australia) 
(Pre-DCR Seizure Event Dataset Version 3) – mITT 
Population 
New Table using Pre-DCR dataset Version 
3 
Table  
14.2.1.4.1.2 
Percent Improvement in Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: Logistic 
Regression (Cohort B – Japan)  – mITT Population 
 
Table  
14.2.1.4.2.1 
Percent Improvement in Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, Australia)  
– PP Population 
 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
 
This document is confidential. 
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Filing requirements: TMF 
Page 93 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table  
14.2.1.4.2.1s 
Sensitivity Analysis of Percent Improvement in Frequency 
of Seizures Resulting in Drops (ESC Confirmed) per 28 
days during Part 1: Logistic Regression (Cohort A – North 
America, Europe, Australia)  – PP Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.4.2.2 
Percent Improvement in Frequency of Seizures resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: Logistic 
Regression (Cohort B – Japan)  – PP Population 
 
Figure  
14.2.1.5.1.1 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures Resulting 
in Drops (ESC Confirmed) during Part 1 (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
Figure  
14.2.1.5.1.1s 
Sensitivity Analysis of Cumulative Response Curve for 
Percent of Subjects Experiencing Various % Reductions in 
Seizures Resulting in Drops (ESC Confirmed) during Part 
1 (Cohort A – North America, Europe, Australia) – mITT 
Population 
New Figure using Supplemental Seizure 
File updated post-Part 1 Database Lock 
Figure  
14.2.1.5.1.1b 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures Resulting 
in Drops (ESC Confirmed) during Part 1 (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2) – mITT Population 
New Figure using Pre-DCR dataset Version 
2 
Figure  
14.2.1.5.1.1c 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures Resulting 
in Drops (ESC Confirmed) during Part 1 (Cohort A – North 
New Figure using Pre-DCR dataset Version 
3 
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Page 94 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 3) – mITT Population 
Figure  
14.2.1.5.1.2 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures Resulting 
in Drops (ESC Confirmed) during Part 1 (Cohort B - 
Japan) – mITT Population 
 
Table  
14.2.1.6.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1 by Age Subgroup: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
 
Table  
14.2.1.6.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1 by Age 
Subgroup: Nonparametric Analysis (Cohort A – North 
America, Europe, Australia) - mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.6.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1 by Sex: 
Nonparametric Analysis – (Cohort A – North America, 
Europe, Australia) - mITT Population 
 
Table  
14.2.1.6.2s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1 by Sex: 
Nonparametric Analysis – (Cohort A – North America, 
Europe, Australia) - mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.6.3 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1 by Weight Subgroup: 
 
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Page 95 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Nonparametric Analysis – (Cohort A – North America, 
Europe, Australia) - mITT Population 
Table  
14.2.1.6.3s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1 by 
Weight Subgroup: Nonparametric Analysis – (Cohort A – 
North America, Europe, Australia) - mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.6.4 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1 by Number of 
Concomitant Antiepileptic Medications Used: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
 
Table  
14.2.1.6.4s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1 by 
Number of Concomitant Antiepileptic Medications Used: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.6.5 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed)  per 28 days during Part 1 by Number of Prior 
Antiepileptic Medications Used: Nonparametric Analysis 
(Cohort A – North America, Europe, Australia) - mITT 
Population 
 
Table  
14.2.1.6.5s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed)  per 28 days during Part 1 by 
Number of Prior Antiepileptic Medications Used: 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
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Statistical Analysis Plan for Interventional Studies 
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Page 96 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
Table  
14.2.1.6.6 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed)  per 28 days during Part 1 by Baseline 
Frequency of Seizures that Result in Drops: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia) - 
mITT Population 
 
Table  
14.2.1.6.6s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed)  per 28 days during Part 1 by 
Baseline Frequency of Seizures that Result in Drops: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.6.7 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed)  per 28 days during Part 1 by Race Group: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
New Table requested. 
Table  
14.2.1.6.8 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed)  per 28 days during Part 1 by Geographic 
Region: Nonparametric Analysis (Cohort A – North 
America, Europe, Australia) mITT Population 
New Table requested. 
Table  
14.2.1.6.9 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed)  per 28 Days During Part 1 by Age Group: 
Nonparametric Analysis (Cohort B – Japan) - mITT 
Population 
New Table requested. 
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Page 97 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table  
14.2.1.6.10 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed)  per 28 Days During Part 1 by Sex: 
Nonparametric Analysis (Cohort B – Japan) - mITT 
Population 
New Table requested. 
Table 
14.2.1.7.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity Analysis 1 (Worst Value Substituted 
for Dropouts) (Cohort A – North America, Europe, 
Australia) – mITT Population 
 
Table 
14.2.1.7.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis – Sensitivity Analysis 1 (Worst 
Value Substituted for Dropouts) (Cohort A – North 
America, Europe, Australia) – mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table 
14.2.1.7.1b 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity Analysis 1 (Worst Value Substituted 
for Dropouts) (Cohort A – North America, Europe, 
Australia) (Pre-DCR Seizure Event Dataset Version 2) – 
mITT Population 
New Table using Pre-DCR dataset Version 
2 
Table 
14.2.1.7.1c 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity Analysis 1 (Worst Value Substituted 
for Dropouts) (Cohort A – North America, Europe, 
New Table using Pre-DCR dataset Version 
3 
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Statistical Analysis Plan for Interventional Studies 
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Page 98 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Australia) (Pre-DCR Seizure Event Dataset Version 3) – 
mITT Population 
Table 
14.2.1.7.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity Analysis 1 (Worst Value Substituted 
for Dropouts) (Cohort B – Japan) – mITT Population 
 
Table 
14.2.1.7.3 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity Analysis 2 (Differential Imputation 
Method for Dropouts) (Cohort A – North America, Europe, 
Australia)  – mITT Population 
Correction of Table Title for Cohort A 
Table 
14.2.1.7.3s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis – Sensitivity Analysis 2 
(Differential Imputation Method for Dropouts) (Cohort A – 
North America, Europe, Australia)  – mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table 
14.2.1.7.3b 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity Analysis 2 (Differential Imputation 
Method for  Dropouts) (Cohort A – North America, 
Europe, Australia) (Pre-DCR Seizure Event Dataset 
Version 2)  – mITT Population 
New Table using Pre-DCR dataset Version 
2 
Table 
14.2.1.7.3c 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity Analysis 2 (Differential Imputation 
New Table using Pre-DCR dataset Version 
3 
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Statistical Analysis Plan for Interventional Studies 
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Page 99 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Method for  Dropouts) (Cohort A – North America, 
Europe, Australia) (Pre-DCR Seizure Event Dataset 
Version 3)  – mITT Population 
Table 
14.2.1.7.4 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity Analysis 2 (Differential Imputation 
Method for  Dropouts)  (Cohort B – Japan)  – mITT 
Population 
Correction of Table Title for Cohort B 
Table 
14.2.1.8.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Wilcoxon Analysis – 
Sensitivity to Analysis Method (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
Table 
14.2.1.8.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Wilcoxon Analysis – Sensitivity to Analysis Method 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table 
14.2.1.8.1b 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Wilcoxon Analysis – 
Sensitivity to Analysis Method (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2) – mITT Population 
New Table using Pre-DCR dataset Version 
2 
Table 
14.2.1.8.1c 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Wilcoxon Analysis – 
Sensitivity to Analysis Method (Cohort A – North 
New Table using Pre-DCR dataset Version 
3 
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Statistical Analysis Plan for Interventional Studies 
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This document is confidential. 
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Filing requirements: TMF 
Page 100 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 3) – mITT Population 
Table 
14.2.1.8.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Wilcoxon Analysis – 
Sensitivity to Analysis Method (Cohort B – Japan) – mITT 
Population 
 
Table 
14.2.1.9.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Outliers (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
Table 
14.2.1.9.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis – Sensitivity to Outliers (Cohort A 
– North America, Europe, Australia) – mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table 
14.2.1.9.1b 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Outliers (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2) – mITT Population 
New Table using Pre-DCR dataset Version 
2 
Table 
14.2.1.9.1c 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Outliers (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 3) – mITT Population 
New Table using Pre-DCR dataset Version 
3 
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Statistical Analysis Plan for Interventional Studies 
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Filing requirements: TMF 
Page 101 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table 
14.2.1.9.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Outliers (Cohort B – Japan) – 
mITT Population 
 
Table 
14.2.1.10.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Seizure Clusters (Cohort A – 
North America, Europe, Australia) – mITT Population 
 
Table 
14.2.1.10.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis – Sensitivity to Seizure Clusters 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table 
14.2.1.10.1b 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Seizure Clusters (Cohort A – 
North America, Europe, Australia) (Pre-DCR Seizure 
Event Dataset Version 2) – mITT Population 
New Table using Pre-DCR dataset Version 
2 
Table 
14.2.1.10.1c 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Seizure Clusters (Cohort A – 
North America, Europe, Australia) (Pre-DCR Seizure 
Event Dataset Version 3) – mITT Population 
New Table using Pre-DCR dataset Version 
3 
Table 
14.2.1.10.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
 
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Statistical Analysis Plan for Interventional Studies 
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Page 102 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Analysis – Sensitivity to Seizure Clusters (Cohort B – 
Japan) – mITT Population 
Table 
14.2.1.10.3 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis (Cluster Event Sensitivity Analysis) (Cohort A – 
North America, Europe, Australia) – mITT Population 
Sensitivity Analysis to assess the impact of 
imputation of number of events associated 
with cluster events. 
Table 
14.2.1.10.3s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis (Cluster Event Sensitivity 
Analysis) (Cohort A – North America, Europe, Australia) – 
mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table 
14.2.1.10.3b 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis (Cluster Event Sensitivity Analysis) (Cohort A – 
North America, Europe, Australia) (Pre-DCR Seizure 
Event Dataset Version 2) – mITT Population 
New Table using Pre-DCR dataset Version 
2 
Table 
14.2.1.10.3c 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis (Cluster Event Sensitivity Analysis) (Cohort A – 
North America, Europe, Australia) (Pre-DCR Seizure 
Event Dataset Version 3) – mITT Population 
New Table using Pre-DCR dataset Version 
3 
Table 
14.2.1.10.4 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Sensitivity Analysis to assess the impact of 
imputation of number of events associated 
with cluster events. 
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Statistical Analysis Plan for Interventional Studies 
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Filing requirements: TMF 
Page 103 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Analysis (Cluster Event Sensitivity Analysis)  (Cohort B – 
Japan) – mITT Population 
  
14.2.2 
Efficacy – Clinical Global Impression – Improvement 
rating by Investigator 
 
Table  
14.2.2.1.1.1 
Clinical Global Impression – Improvement (CGI-I) Rating 
by Investigator in Part 1 (Cohort A – North America, 
Europe, Australia) – mITT Population 
Table Title adjustment to align with shell. 
Table  
14.2.2.1.1.2 
Clinical Global Impression – Improvement (CGI-I) Rating 
by Investigator in Part 1 (Cohort B – Japan) – mITT 
Population 
Table Title adjustment to align with shell. 
Table  
14.2.2.1.2.1 
Clinical Global Impression – Improvement (CGI-I) Rating 
by Investigator in Part 1 (Cohort A – North America, 
Europe, Australia) – PP Population 
Table Title adjustment to align with shell. 
Table  
14.2.2.1.3.1 
Clinical Global Impression – Improvement (CGI-I) Rating 
by Investigator in Part 1 by Age Subgroup (Cohort A – 
North America, Europe, Australia) – mITT Population 
Table Title adjustment to align with shell. 
Table  
14.2.2.1.3.2 
Clinical Global Impression – Improvement (CGI-I) Rating 
by Investigator in Part 1 by Sex (Cohort A – North 
America, Europe, Australia) – mITT Population 
Table Title adjustment to align with shell. 
Table  
14.2.2.1.3.3 
Clinical Global Impression – Improvement (CGI-I) Rating 
by Investigator in Part 1 by Weight Subgroup (Cohort A – 
North America, Europe, Australia) – mITT Population 
Table Title adjustment to align with shell. 
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Statistical Analysis Plan for Interventional Studies 
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This document is confidential. 
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Filing requirements: TMF 
Page 104 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table  
14.2.2.1.3.4 
Clinical Global Impression – Improvement (CGI-I) Rating 
by Investigator in Part 1 by Number of Concomitant 
Antiepileptic Medications Used (Cohort A – North 
America, Europe, Australia) – mITT Population 
Table Title adjustment to align with shell. 
Table  
14.2.2.1.3.5 
Clinical Global Impression – Improvement (CGI-I) Rating 
by Investigator in Part 1 by Number of Prior Antiepileptic 
Medications Used (Cohort A – North America, Europe, 
Australia) – mITT Population 
Table Title adjustment to align with shell. 
Table  
14.2.2.1.3.6 
Clinical Global Impression – Improvement (CGI-I) Rating 
by Investigator in Part 1 by Baseline Frequency of Seizures 
that Result in Drops (Cohort A – North America, Europe, 
Australia) – mITT Population 
Table Title adjustment to align with shell. 
Table  
14.2.2.1.3.6s 
Sensitivity Analysis of Clinical Global Impression – 
Improvement (CGI-I) Rating by Investigator in Part 1 by 
Baseline Frequency of Seizures that Result in Drops 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.2.1.3.7 
Clinical Global Impression – Improvement (CGI-I) Rating 
by Investigator in Part 1 by Age Group (Cohort B – Japan) 
- mITT Population 
New Table  
Table  
14.2.2.1.3.8 
Clinical Global Impression – Improvement (CGI-I) Rating 
by Investigator in Part 1 by Sex (Cohort B – Japan) - mITT 
Population 
New Table  
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Statistical Analysis Plan for Interventional Studies 
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Filing requirements: TMF 
Page 105 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Figure 
14.2.2.2.1 
Distribution of Clinical Global Impression – Improvement  
(CGI-I) Rating by Investigator in Part 1 (Cohort A – North 
America, Europe, Australia)– mITT Population 
Figure Title adjustment to align with shell. 
Figure 
14.2.2.2.2 
Distribution of Clinical Global Impression – Improvement 
(CGI-I) Rating by Investigator in Part 1 (Cohort B – Japan)  
– mITT Population 
Figure Title adjustment to align with shell. 
 
14.2.3 
Countable Motor Seizures  
 
Table 
14.2.3.1.1.1 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Summary Statistics (Cohort A – North America, 
Europe, Australia) – mITT Population 
 
Table 
14.2.3.1.1.2 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Summary Statistics (Cohort B – Japan)  – mITT 
Population 
 
Table 
14.2.3.1.2.1 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Summary Statistics (Cohort A – North America, 
Europe, Australia) – PP Population 
 
Table  
14.2.3.2.1.1 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Nonparametric Analysis (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
Table  
14.2.3.2.1.2 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Nonparametric Analysis (Cohort B – Japan)  – 
mITT Population 
 
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Statistical Analysis Plan for Interventional Studies 
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Filing requirements: TMF 
Page 106 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table  
14.2.3.2.2.1 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Nonparametric Analysis (Cohort A – North 
America, Europe, Australia) – PP Population 
 
 
 
 
 
Table  
14.2.3.3.1.1 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Parametric Analysis (Cohort A – North America, 
Europe, Australia)– mITT Population 
 
Table  
14.2.3.3.1.2 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Parametric Analysis (Cohort B – Japan)  – mITT 
Population 
 
Table  
14.2.3.3.2.1 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Parametric Analysis (Cohort A – North America, 
Europe, Australia) – PP Population 
 
 
 
 
 
Table  
14.2.3.4.1.1 
Percent Improvement in Frequency of Countable Motor 
Seizures per 28 days during Part 1: Logistic Regression 
(Cohort A – North America, Europe, Australia)– mITT 
Population 
 
Table  
14.2.3.4.1.2 
Percent Improvement in Frequency of Countable Motor 
Seizures per 28 days during Part 1: Logistic Regression 
(Cohort B – Japan) – mITT Population 
 
Table  
14.2.3.4.2.1 
Percent Improvement in Frequency of Countable Motor 
Seizures per 28 days during Part 1: Logistic Regression 
 
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Statistical Analysis Plan for Interventional Studies 
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Page 107 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
(Cohort A – North America, Europe, Australia)– PP 
Population 
Figure  
14.2.3.5.1.1 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Countable Motor 
Seizures during Part 1 (Cohort A – North America, Europe, 
Australia)– mITT Population 
 
Figure  
14.2.3.5.1.2 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Countable Motor 
Seizures during Part 1 (Cohort B – Japan)– mITT 
Population 
 
 
14.2.4.1 
Efficacy – Typical Drop Seizures 
 
Table  
14.2.4.1.1.1.1 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Summary Statistics (Cohort A – 
North America, Europe, Australia) – mITT Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.1.1.1s 
Sensitivity Analysis of Frequency of Seizures that 
Typically Result in Drops per 28 days during Part 1: 
Summary Statistics (Cohort A – North America, Europe, 
Australia) – mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.4.1.1.1.1b 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Summary Statistics (Cohort A – 
North America, Europe, Australia) (Pre-DCR Seizure 
Event Dataset Version 2) – mITT Population 
New Table using Pre-DCR dataset Version 
2 
Table  
14.2.4.1.1.1.1c 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Summary Statistics (Cohort A – 
New Table using Pre-DCR dataset Version 
3 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
 
This document is confidential. 
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Filing requirements: TMF 
Page 108 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
North America, Europe, Australia) (Pre-DCR Seizure 
Event Dataset Version 3) – mITT Population 
Table  
14.2.4.1.1.1.2 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Summary Statistics (Cohort B – 
Japan) – mITT Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.1.2.1 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Summary Statistics (Cohort A – 
North America, Europe, Australia) – PP Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.1.2.1b 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Summary Statistics (Cohort A – 
North America, Europe, Australia)  (Pre-DCR Seizure 
Event Dataset Version 2) – PP Population 
New Table using Pre-DCR dataset Version 
2 
Table  
14.2.4.1.1.2.1c 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Summary Statistics (Cohort A – 
North America, Europe, Australia) (Pre-DCR Seizure 
Event Dataset Version 3) – PP Population 
New Table using Pre-DCR dataset Version 
3 
 
 
 
 
Table  
14.2.4.1.2.1.1 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) – mITT Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.2.1.1b 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Nonparametric Analysis (Cohort A – 
New Table using Pre-DCR dataset Version 
2 
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Statistical Analysis Plan for Interventional Studies 
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Filing requirements: TMF 
Page 109 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
North America, Europe, Australia) (Pre-DCR Seizure 
Event Dataset Version 2) – mITT Population 
Table  
14.2.4.1.2.1.1c 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) (Pre-DCR Seizure 
Event Dataset Version 3) – mITT Population 
New Table using Pre-DCR dataset Version 
3 
Table  
14.2.4.1.2.1.2 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Nonparametric Analysis (Cohort B – 
Japan) – mITT Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.2.2.1 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) – PP Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.2.2.1b 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) (Pre-DCR Seizure 
Event Dataset Version 2)– PP Population  
New Table using Pre-DCR dataset Version 
2 
Table  
14.2.4.1.2.2.1c 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) (Pre-DCR Seizure 
Event Dataset Version 3) – PP Population  
New Table using Pre-DCR dataset Version 
3 
 
 
 
 
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Statistical Analysis Plan for Interventional Studies 
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Filing requirements: TMF 
Page 110 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table  
14.2.4.1.3.1.1 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Parametric Analysis (Cohort A – 
North America, Europe, Australia) – mITT Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.3.1.1b 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Parametric Analysis (Cohort A – 
North America, Europe, Australia) (Pre-DCR Seizure 
Event Dataset Version 2) – mITT Population   
New Table using Pre-DCR dataset Version 
2 
Table  
14.2.4.1.3.1.1c 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Parametric Analysis (Cohort A – 
North America, Europe, Australia) (Pre-DCR Seizure 
Event Dataset Version 3) – mITT Population   
New Table using Pre-DCR dataset Version 
3 
Table  
14.2.4.1.3.1.2 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Parametric Analysis (Cohort B – 
Japan) – mITT Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.3.2.1 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Parametric Analysis (Cohort A – 
North America, Europe, Australia) – PP Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.3.2.1b 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Parametric Analysis (Cohort A – 
North America, Europe, Australia) (Pre-DCR Seizure 
Event Dataset Version 2)– PP Population  
New Table using Pre-DCR dataset Version 
2 
Table  
14.2.4.1.3.2.1c 
Frequency of Seizures that Typically Result in Drops per 
28 days during Part 1: Parametric Analysis (Cohort A – 
New Table using Pre-DCR dataset Version 
3 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
 
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Filing requirements: TMF 
Page 111 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
North America, Europe, Australia) (Pre-DCR Seizure 
Event Dataset Version 3)– PP Population  
Table  
14.2.4.1.4.1.1 
Percent Improvement in Frequency of Seizures that 
Typically Result in Drops per 28 days during Part 1: 
Logistic Regression (Cohort A – North America, Europe, 
Australia)– mITT Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.4.1.1b 
Percent Improvement in Frequency of Seizures that 
Typically Result in Drops per 28 days during Part 1: 
Logistic Regression (Cohort A – North America, Europe, 
Australia)– mITT Population (Pre-DCR Seizure Event 
Dataset Version 2) 
New Table using Pre-DCR dataset Version 
2 
Table  
14.2.4.1.4.1.1c 
Percent Improvement in Frequency of Seizures that 
Typically Result in Drops per 28 days during Part 1: 
Logistic Regression (Cohort A – North America, Europe, 
Australia)– mITT Population (Pre-DCR Seizure Event 
Dataset Version 3) 
New Table using Pre-DCR dataset Version 
3 
Table  
14.2.4.1.4.1.2 
Percent Improvement in Frequency of Seizures that 
Typically Result in Drops per 28 days during Part 1: 
Logistic Regression (Cohort B – Japan)– mITT Population 
Title update made at the request of Zogenix 
Figure  
14.2.4.1.5.1.1 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures that 
Typically Result in Drops during Part 1 (Cohort A – North 
America, Europe, Australia)– mITT Population 
Title update made at the request of Zogenix 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
 
This document is confidential. 
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Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 112 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Figure  
14.2.4.1.5.1.1b 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures that 
Typically Result in Drops during Part 1 (Cohort A – North 
America, Europe, Australia)– mITT Population (Pre-DCR 
Seizure Event Dataset Version 2) 
New Figure using Pre-DCR dataset Version 
2 
Figure  
14.2.4.1.5.1.1c 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures that 
Typically Result in Drops during Part 1 (Cohort A – North 
America, Europe, Australia)– mITT Population (Pre-DCR 
Seizure Event Dataset Version 3) 
New Figure using Pre-DCR dataset Version 
3 
Figure  
14.2.4.1.5.1.2 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures that 
Typically Result in Drops during Part 1 (Cohort B – 
Japan)– mITT Population 
 
Table  
14.2.4.1.6.1.1b 
Change in Seizures that Typically Result per 28 days in 
Drops from Baseline during Part 1: Wilcoxon Analysis - 
Sensitivity to Analysis Method) (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2) - mITT Population  
New Figure using Pre-DCR dataset Version 
2 
Table  
14.2.4.1.6.1.1c 
Change in Seizures that Typically Result per 28 days in 
Drops from Baseline during Part 1: Wilcoxon Analysis - 
Sensitivity to Analysis Method) (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 3) - mITT Population  
New Figure using Pre-DCR dataset Version 
3 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
 
This document is confidential. 
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Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 113 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
 
14.2.4.2 
Efficacy – Countable Non-Motor Seizures 
 
Table  
14.2.4.2.1.1.1 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
Table  
14.2.4.2.1.1.2 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Summary Statistics (Cohort B – Japan) – 
mITT Population 
 
Table  
14.2.4.2.1.2.1 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) – PP Population 
 
Table  
14.2.4.2.2.1.1 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Nonparametric Analysis (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
Table  
14.2.4.2.2.1.2 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Nonparametric Analysis (Cohort B – Japan) 
– mITT Population 
 
Table  
14.2.4.2.2.2.1 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Nonparametric Analysis (Cohort A – North 
America, Europe, Australia) – PP Population 
 
Table  
14.2.4.2.3.1.1 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Parametric Analysis (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
 
This document is confidential. 
SAP Text Version 3.0 04-Feb-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 114 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table  
14.2.4.2.3.1.2 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Parametric Analysis (Cohort B – Japan) – 
mITT Population 
 
Table  
14.2.4.2.3.2.1 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Parametric Analysis (Cohort A – North 
America, Europe, Australia) – PP Population 
 
Table  
14.2.4.2.4.1.1 
Percent Improvement in Frequency of Countable Non-
Motor Seizures per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, 
Australia)– mITT Population 
 
Table  
14.2.4.2.4.1.2 
Percent Improvement in Frequency of Countable Non-
Motor Seizures per 28 days during Part 1: Logistic 
Regression (Cohort B – Japan)– mITT Population 
 
Figure  
14.2.4.2.5.1.1 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Countable Non-
Motor Seizures during Part 1 (Cohort A – North America, 
Europe, Australia)– mITT Population 
 
Figure  
14.2.4.2.5.1.2 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Countable Non-
Motor Seizures during Part 1 (Cohort B – Japan)– mITT 
Population 
 
 
14.2.4.3 
Efficacy – All Countable Seizures (Motor + Non-Motor) 
 
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Statistical Analysis Plan for Interventional Studies 
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This document is confidential. 
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Filing requirements: TMF 
Page 115 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table  
14.2.4.3.1.1.1 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Summary Statistics (Cohort A – 
North America, Europe, Australia) – mITT Population 
 
Table  
14.2.4.3.1.1.2 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Summary Statistics (Cohort B – 
Japan) – mITT Population 
 
Table  
14.2.4.3.1.2.1 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Summary Statistics (Cohort A – 
North America, Europe, Australia) – PP Population 
 
Table  
14.2.4.3.1.2.2 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Summary Statistics (Cohort B – 
Japan) – PP Population 
 
Table  
14.2.4.3.2.1.1 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Nonparametric Analysis (Cohort 
A – North America, Europe, Australia) – mITT Population 
 
Table  
14.2.4.3.2.1.2 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Nonparametric Analysis (Cohort 
B – Japan) – mITT Population 
 
Table  
14.2.4.3.2.2.1 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Nonparametric Analysis (Cohort 
A – North America, Europe, Australia) – PP Population 
 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
 
This document is confidential. 
SAP Text Version 3.0 04-Feb-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 116 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table  
14.2.4.3.3.1.1 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Parametric Analysis (Cohort A – 
North America, Europe, Australia) – mITT Population 
 
Table  
14.2.4.3.3.1.2 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Parametric Analysis (Cohort B – 
Japan) – mITT Population 
 
Table  
14.2.4.3.3.2.1 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Parametric Analysis (Cohort A – 
North America, Europe, Australia) – PP Population 
 
Table  
14.2.4.3.4.1.1 
Percent Improvement in Frequency of All Countable 
Seizures (Motor + Non-Motor) per 28 days during Part 1: 
Logistic Regression (Cohort A – North America, Europe, 
Australia)– mITT Population 
 
Table  
14.2.4.3.4.1.2 
Percent Improvement in Frequency of All Countable 
Seizures (Motor + Non-Motor) per 28 days during Part 1: 
Logistic Regression (Cohort B – Japan)  
Title correction  
Figure  
14.2.4.3.5.1.1 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in All Countable 
Seizures (Motor + Non-Motor)  during Part 1 (Cohort A – 
North America, Europe, Australia)– mITT Population 
Title correction  
Figure  
14.2.4.3.5.1.2 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in All Countable 
Seizures (Motor + Non-Motor) during Part 1 (Cohort B – 
Japan)– mITT Population 
Title correction  
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
 
This document is confidential. 
SAP Text Version 3.0 04-Feb-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 117 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table 
14.2.4.4.1.1 
Change from Baseline in Seizure Frequency by Types 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) - mITT Population 
Table Number Correction; This table was 
also updated to summarize the seizure types 
that were typically associated with drop 
seizures that were classified as ESC 
Confirmed Drop Seizures. 
Table 
14.2.4.4.1.1s 
Sensitivity Analysis of Change from Baseline in Seizure 
Frequency by Types during Part 1: Summary Statistics 
(Cohort A – North America, Europe, Australia) - mITT 
Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock; The 
only sections affected by the update are the 
summary of seizure types that were 
typically associated with drop seizures that 
were classified as ESC Confirmed Drop 
Seizures. 
Table 
14.2.4.4.1.1b 
Change from Baseline in Seizure Frequency by Types 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2) - mITT Population 
New Table using Pre-DCR dataset Version 
2. The only sections affected by the DCR 
update are the summary of seizure types 
that were typically associated with drop 
seizures that were classified as ESC 
Confirmed Drop Seizures. 
Table 
14.2.4.4.1.1c 
Change from Baseline in Seizure Frequency by Types 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 3) - mITT Population 
New Table using Pre-DCR dataset Version 
3. The only sections affected by the DCR 
update are the summary of seizure types 
that were typically associated with drop 
seizures that were classified as ESC 
Confirmed Drop Seizures. 
PUBLIC COPY 
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application and any extensions or variations thereof.


 
Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
 
This document is confidential. 
SAP Text Version 3.0 04-Feb-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 118 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table 
14.2.4.4.1.2 
Change from Baseline in Seizure Frequency by Types 
during Part 1: Summary Statistics (Cohort B – Japan)  - 
mITT Population 
Table Number Correction 
Table 
14.2.4.4.2.1 
Percent Improvement in Seizure Frequency by Types 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia)  – mITT Population 
Table Number Correction 
Table 
14.2.4.4.2.1s 
Sensitivity Analysis of Percent Improvement in Seizure 
Frequency by Types during Part 1: Summary Statistics 
(Cohort A – North America, Europe, Australia)  – mITT 
Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock; The 
only sections affected by the update are the 
summary of seizure types that were 
typically associated with drop seizures that 
were classified as ESC Confirmed Drop 
Seizures. 
Table 
14.2.4.4.2.1b 
Percent Improvement in Seizure Frequency by Types 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2) – mITT Population 
New Table using Pre-DCR dataset Version 
2. The only sections affected by the DCR 
update are the summary of seizure types 
that were typically associated with drop 
seizures that were classified as ESC 
Confirmed Drop Seizures. 
Table 
14.2.4.4.2.1c 
Percent Improvement in Seizure Frequency by Types 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 3) – mITT Population 
New Table using Pre-DCR dataset Version 
3. The only sections affected by the DCR 
update are the summary of seizure types 
that were typically associated with drop 
seizures that were classified as ESC 
Confirmed Drop Seizures. 
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application and any extensions or variations thereof.


 
Statistical Analysis Plan for Interventional Studies 
Sponsor: Zogenix International Limited;  Protocol No.: ZX008-1601  
 
 
 
This document is confidential. 
SAP Text Version 3.0 04-Feb-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 119 of 160 
 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table 
14.2.4.4.2.2 
Percent Improvement in Seizure Frequency by Types 
during Part 1: Summary Statistics (Cohort B – Japan) – 
mITT Population 
Table Number Correction 
 
14.2.4.5 
All Countable Seizures that Did Not Result in Drops 
(ESC Confirmed) 
 
Table 
14.2.4.5.1.1.1 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Summary Statistics (Cohort A – North America, Europe, 
Australia) - mITT Population 
New defined analysis after initial Cohort A 
analysis 
Table 
14.2.4.5.1.1.2 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Summary Statistics (Cohort B – Japan) - mITT Population 
New defined analysis after initial Cohort A 
analysis 
Table 
14.2.4.5.1.2.1 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Summary Statistics (Cohort A – North America, Europe, 
Australia) - PP Population 
New defined analysis after initial Cohort A 
analysis 
Table 
14.2.4.5.2.1.1 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
New defined analysis after initial Cohort A 
analysis  
Table 
14.2.4.5.2.1.2 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis (Cohort B – Japan) - mITT 
Population 
New defined analysis after initial Cohort A 
analysis 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table 
14.2.4.5.2.2.1 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - PP Population 
New defined analysis after initial Cohort A 
analysis 
Table 
14.2.4.5.3.1.1 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Parametric Analysis (Cohort A – North America, Europe, 
Australia) - mITT Population 
New defined analysis after initial Cohort A 
analysis 
Table 
14.2.4.5.3.1.2 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Parametric Analysis (Cohort B – Japan) - mITT Population 
New defined analysis after initial Cohort A 
analysis 
Table 
14.2.4.5.3.2.1 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Parametric Analysis (Cohort A – North America, Europe, 
Australia) - PP Population 
New defined analysis after initial Cohort A 
analysis 
Table 
14.2.4.5.4.1.1 
Percent Improvement in Frequency of All Countable 
Seizures that did not Result in Drops (ESC Confirmed) per 
28 days during Part 1: Logistic Regression (Cohort A – 
North America, Europe, Australia) - mITT Population 
New defined analysis after initial Cohort A 
analysis 
Table 
14.2.4.5.4.1.2 
Percent Improvement in Frequency of All Countable 
Seizures that did not Result in Drops (ESC Confirmed) per 
28 days during Part 1: Logistic Regression (Cohort B – 
Japan) - mITT Population 
New defined analysis after initial Cohort A 
analysis 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Figure 
14.2.4.5.5.1.1 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in All Countable 
Seizures that did not Result in Drops (ESC Confirmed) 
during Part 1 (Cohort A – North America, Europe, 
Australia) - mITT Population 
New defined analysis after initial Cohort A 
analysis 
Figure 
14.2.4.5.5.1.2 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in All Countable 
Seizures that did not Result in Drops (ESC Confirmed) 
during Part 1 (Cohort B – Japan) - mITT Population 
New defined analysis after initial Cohort A 
analysis 
 
14.2.4.6 
New Seizure Types 
 
Table 
14.2.4.6.1.1 
 
New Seizure Types During Part 1 (Cohort A – North 
America, Europe, Australia) - mITT Population 
New Post-hoc defined analysis 
Table 
14.2.4.6.1.2 
 
New Seizure Types During Part 1 (Cohort B – Japan) - 
mITT Population 
New defined analysis 
 
14.2.4.7 
Seizures Resulting in Drops (Caregiver Determination) 
 
Table  
14.2.4.7.1.1.1 
Frequency of Seizures Resulting in Drops (Caregiver 
Determination) per 28 days during Part 1: Summary 
Statistics (Cohort A – North America, Europe, Australia) – 
mITT Population 
New Post-hoc defined endpoint 
Table 
14.2.4.7.2.1.1 
Frequency of Seizures Resulting in Drops (Caregiver 
Determination) per 28 days during Part 1: Nonparametric 
New Post-hoc defined endpoint 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Analysis (Cohort A – North America, Europe, Australia) – 
mITT Population 
Table 
14.2.4.7.4.1.1 
Percent Improvement in Frequency of Seizures Resulting in 
Drops (Caregiver Determination) per 28 days during Part 1: 
Logistic Regression (Cohort A – North America, Europe, 
Australia)– mITT Population 
New Post-hoc defined endpoint 
Figure 
14.2.4.7.5.1.1 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures Resulting 
in Drops (Caregiver Determination) during Part 1 (Cohort 
A – North America, Europe, Australia)– mITT Population 
New Post-hoc defined endpoint 
 
14.2.5 
Efficacy – Seizure-free Days 
 
Table 
14.2.5.1.1 
Number of Seizure Free Days per 28 Days during Part 1: 
Nonparametric Analysis: (Cohort A – North America, 
Europe, Australia) -  mITT Population 
 
Table 
14.2.5.1.2 
Number of Countable Motor Seizure-Free Days per 28 
Days during Part 1: Nonparametric Analysis (Cohort B – 
Japan) -  mITT Population 
New Table title for Cohort B 
Table 
14.2.5.2.1 
Number of Drop Seizure Free Days per 28 Days (ESC 
Confirmed) during Part 1: Nonparametric Analysis: 
(Cohort A – North America, Europe, Australia) -  mITT 
Population 
 
Table 
14.2.5.2.1s 
Sensitivity Analysis of Number of Drop Seizure Free Days 
per 28 Days (ESC Confirmed) during Part 1: 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Nonparametric Analysis: (Cohort A – North America, 
Europe, Australia) -  mITT Population 
Table 
14.2.5.2.2 
Number of Drop Seizure Free Days per 28 Days (ESC 
Confirmed) during Part 1: Nonparametric Analysis (Cohort 
B – Japan) -  mITT Population 
 
  
14.2.6 
Efficacy – Duration of the Longest Interval between 
Seizures Resulting in Drops 
 
Table 
14.2.6.1 
Duration of Longest Interval between Seizures Resulting in 
Drops (ESC Confirmed) during Part 1 (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
Table 
14.2.6.1s 
Sensitivity Analysis of Duration of Longest Interval 
between Seizures Resulting in Drops (ESC Confirmed) 
during Part 1 (Cohort A – North America, Europe, 
Australia) – mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table 
14.2.6.2 
Duration of Longest Interval between Seizures during 
Titration and Maintenance Resulting in Drops (ESC 
Confirmed) in Part 1 (Cohort B – Japan)– mITT Population 
Adjusted title 
Figure 
14.2.6.3 
Boxplot of the Duration of Longest Interval between 
Seizures Resulting in Drops (ESC Confirmed) during Part 
1 (Cohort A – North America, Europe, Australia)– mITT 
Population 
 
Figure 
14.2.6.3s 
Sensitivity Analysis of Boxplot of the Duration of Longest 
Interval between Seizures Resulting in Drops (ESC 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Confirmed) during Part 1 (Cohort A – North America, 
Europe, Australia)– mITT Population 
Figure 
14.2.6.4 
Boxplot of the Duration of Longest Interval between 
Seizures during Titration and Maintenance Resulting in 
Drops (ESC Confirmed) during Part 1  (Cohort B – Japan)– 
mITT Population 
Adjusted title 
  
14.2.7 
Efficacy – Clinical Global Impression – Improvement 
rating by Parent/Caregiver  
 
Table 
14.2.7.1.1 
Clinical Global Impression – Improvement Rating by 
Parent/Caregiver in Part 1 (Cohort A – North America, 
Europe, Australia) – mITT Population 
 
Table 
14.2.7.1.2 
Clinical Global Impression – Improvement Rating by 
Parent/Caregiver in Part 1 (Cohort B – Japan) – mITT 
Population 
 
Figure 
14.2.7.2.1 
Distribution of Clinical Global Impression – Improvement 
Rating by Parent/Caregiver in Part 1 (Cohort A – North 
America, Europe, Australia)– mITT Population 
 
Figure 
14.2.7.2.2 
Distribution of Clinical Global Impression – Improvement 
Rating by Parent/Caregiver in Part 1 (Cohort B – Japan) – 
mITT Population 
 
  
14.2.8 
Efficacy – Incidence of Status Epilepticus 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table 
14.2.8.1.1 
Number of Episodes of Status Epilepticus (SE) per 28 days 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) - mITT Population 
 
Table 
14.2.8.1.2 
Number of Episodes of Status Epilepticus (SE) per 28 days 
during Part 1: Summary Statistics (Cohort B – Japan) - 
mITT Population 
 
Table 
14.2.8.1.3 
Sensitivity Analysis of Number of Episodes of Status 
Epilepticus (SE) per 28 days during Part 1: Summary 
Statistics (Cohort A – North America, Europe, Australia) - 
mITT Population 
New Analysis of Status Epilepticus using 
the diary events that were generalized 
tonic/clonic, secondarily generalized 
tonic/clonic, focal with clear observable 
signs, focal without clear observable sings, 
or absence/atypical absence.  These events 
were further separated into those events that 
required 0 rescue medications, 1 rescue 
medication, or > 1 rescue medications 
associated with the seizure event. 
Table 
14.2.8.1.4 
Sensitivity Analysis of Number of Episodes of Status 
Epilepticus (SE) per 28 days during Part 1: Summary 
Statistics (Cohort B – Japan) - mITT Population 
New Analysis of Status Epilepticus using 
the diary events that were generalized 
tonic/clonic, secondarily generalized 
tonic/clonic, focal with clear observable 
signs, focal without clear observable sings, 
or absence/atypical absence.  These events 
were further separated into those events that 
required 0 rescue medications, 1 rescue 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
medication, or > 1 rescue medications 
associated with the seizure event. 
Table 
14.2.8.2.1 
Number of Days where Episodes of Status Epilepticus (SE) 
Occurred per 28 Days during Part 1: Summary Statistics 
and Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
 
Table 
14.2.8.2.2 
Number of Days When Episodes of Status Epilepticus (SE) 
Occurred per 28 Days during Part 1: Summary Statistics 
and Nonparametric Analysis (Cohort B – Japan) - mITT 
Population 
Minor Table Title Update. 
  
14.2.9 
Efficacy – Rescue Medication 
 
Table 
14.2.9.1.1 
Days with Rescue Medication Usage in Part 1: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) – mITT Population 
 
Table 
14.2.9.1.2 
Days with Rescue Medication Usage in Part 1: 
Nonparametric Analysis (Cohort B – Japan) – mITT 
Population 
 
Table 
14.2.9.2.1 
Number of Rescue Medications Used per Status Epilepticus 
Episode in Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) – mITT Population 
 
Table 
14.2.9.2.2 
Number of Rescue Medications Used per Status Epilepticus 
Episode in Part 1: Nonparametric Analysis (Cohort B – 
Japan) - mITT Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table 
14.2.9.3.1 
Categorical Analysis of Change from Baseline in the 
Number of Days with Rescue Medication Usage in Part 1 
(Cohort A – North America, Europe, Australia) – mITT 
Population   
 
Table 
14.2.9.3.2 
Categorical Analysis of Change from Baseline in the 
Number of Days with Rescue Medication Usage in Part 1 
(Cohort B – Japan) – mITT Population   
 
  
14.2.10 
Efficacy – Hospitalization and Resource Utilization for 
Treatment of Seizures  
 
Table 
14.2.10.1.1 
Hospitalization and Other Healthcare Resource Utilization 
during the Study: Summary statistics (Cohort A – North 
America, Europe, Australia) – mITT Population 
Table Title updated. 
Table 
14.2.10.1.2 
Hospitalization and Other Healthcare Resource Utilization 
during the Study: Summary Statistics (Cohort B – Japan) – 
mITT Population 
Table Title updated. 
  
14.2.12 
Exploratory Efficacy – Quality of Life in Childhood 
Epilepsy Scale 
 
Table 
14.2.12.1.1 
Quality of Life in Childhood Epilepsy (QOLCE) in Part 1: 
Summary Statistics and Nonparametric Analysis (Cohort A 
– North America, Europe, Australia) – mITT population 
 
Table 
14.2.12.1.2 
Quality of Life in Childhood Epilepsy (QOLCE) in Part 1: 
Summary Statistics and Nonparametric Analysis (Cohort B 
– Japan) – mITT population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
 
14.2.13 
Exploratory Efficacy – Zarit Caregiver Burden 
Inventory 
 
Table  
14.2.13.1.1 
Zarit Caregiver Burden Inventory during Part 1: Normal; 
Borderline Abnormal; and Abnormal Categories (Cohort A 
– North America, Europe, Australia) – mITT population 
 
Table  
14.2.13.1.2 
Zarit Caregiver Burden Inventory during Part 1: Normal; 
Borderline Abnormal; and Abnormal Categories (Cohort B 
– Japan) – mITT population 
 
Table  
14.2.13.2.1 
Zarit Caregiver Burden Inventory Index Score during Part 
1: Summary Descriptive Statistics (Cohort A – North 
America, Europe, Australia)– mITT population 
Title updated; Added Burden. 
Table  
14.2.13.2.2 
Zarit Caregiver Burden Inventory Index Score during Part 
1: Summary Descriptive Statistics (Cohort B – Japan) – 
mITT population 
Title updated; Added Burden. 
 
14.2.14 
Exploratory Efficacy – Parent /Caregiver Ratings using 
HADS Scale 
 
Table  
14.2.14.1.1 
Parent/Caregiver Ratings Based on Hospital Anxiety and 
Depression Scale (HADS) during Part 1: Normal; 
Borderline Abnormal, and Abnormal Categories (Cohort A 
– North America, Europe, Australia) – mITT population 
 
Table  
14.2.14.1.2 
Parent/Caregiver Ratings Based on Hospital Anxiety and 
Depression Scale (HADS) during Part 1: Normal; 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Borderline Abnormal, and Abnormal Categories (Cohort B 
– Japan)– mITT population 
Table  
14.2.14.2.1 
Parent/Caregiver Ratings Based on Hospital Anxiety and 
Depression Scale (HADS) during Part 1: Summary 
Descriptive Statistics (Cohort A – North America, Europe, 
Australia) -mITT population 
 
Table  
14.2.14.2.2 
Parent/Caregiver Ratings Based on Hospital Anxiety and 
Depression Scale (HADS) during Part 1: Summary 
Descriptive Statistics (Cohort B – Japan) – mITT 
population 
 
  
14.3 
Safety 
 
  
14.3.1 
Summary of adverse events 
 
Table 
14.3.1.1.1.1 
Overview of Number of Subjects with TEAE during Part 1 
(Cohort A – North America, Europe, Australia)– Safety 
Population 
 
Table 
14.3.1.1.1.2 
Overview of Number of Subjects with TEAE during Part 1 
(Cohort B – Japan) – Safety Population 
 
Table 
14.3.1.2.1.1 
Treatment-Emergent Adverse Events in Part 1 by MedDRA 
System Organ Class and Preferred Term (Cohort A – North 
America, Europe, Australia)– Safety Population  
 
Table 
14.3.1.2.1.2 
Treatment-Emergent Adverse Events in Part 1 by MedDRA 
System Organ Class and Preferred Term (Cohort B – 
Japan) – Safety Population  
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table  
14.3.1.2.2.1 
Treatment-Emergent Adverse Events in Part 1 by MedDRA 
System Organ Class and Preferred Term by Age Group 
(Cohort A – North America, Europe, Australia)– Safety 
Population  
 
Table  
14.3.1.2.2.2 
Treatment-Emergent Adverse Events in Part 1 by MedDRA 
System Organ Class and Preferred Term by Age Group 
(Cohort B – Japan) – Safety Population 
 
Table  
14.3.1.2.3.1 
Treatment-Emergent Adverse Events in Part 1 by MedDRA 
System Organ Class and Preferred Term by Sex (Cohort A 
– North America, Europe, Australia)– Safety Population  
 
Table  
14.3.1.2.4.1 
Treatment-Emergent Adverse Events in Part 1 by MedDRA 
System Organ Class and Preferred Term by Usage of Most 
Commonly Used Anti-Epileptic Medications (Cohort A – 
North America, Europe, Australia)– Safety Population  
 
Table  
14.3.1.2.4.2 
Treatment-Emergent Adverse Events in Part 1 by MedDRA 
System Organ Class and Preferred Term by Usage of Most 
Commonly Used Anti-Epileptic Medications (Cohort B – 
Japan)– Safety Population  
 
Table 
14.3.1.3.1.1 
TEAEs Leading to Study Discontinuation in Part 1 by 
MedDRA System Organ Class and Preferred Term (Cohort 
A – North America, Europe, Australia)– Safety Population  
 
Table 
14.3.1.3.1.2 
Treatment-Emergent Adverse Events Leading to Study 
Discontinuation in Part 1 by MedDRA System Organ Class 
and Preferred Term (Cohort B – Japan) – Safety Population  
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table 
14.3.1.4.1.1 
Serious TEAEs in Part 1 by MedDRA System Organ Class 
and Preferred Term (Cohort A – North America, Europe, 
Australia) – Safety Population 
 
Table 
14.3.1.4.1.2 
Treatment-Emergent Serious Adverse Events in Part 1 by 
MedDRA System Organ Class and Preferred Term (Cohort 
B – Japan) – Safety Population 
 
Table 
14.3.1.5.1.1 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term (Cohort A – North 
America, Europe, Australia)– Safety Population 
 
Table 
14.3.1.5.1.2 
Treatment-Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term (Cohort B – Japan)– 
Safety Population 
 
Table 
14.3.1.5.2.1 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term by Age Group (Cohort A 
– North America, Europe, Australia)– Safety Population 
 
Table 
14.3.1.5.2.2 
Treatment-Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term by Age Group (Cohort B 
– Japan)– Safety Population 
 
Table 
14.3.1.5.3.1 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term by Sex (Cohort A – North 
America, Europe, Australia) – Safety Population 
 
Table 
14.3.1.5.4.1 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term by Usage of Most 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Common Concomitant Antiepileptic Medications (Cohort 
A – North America, Europe, Australia) – Safety Population 
Table 
14.3.1.6.1.1 
TEAEs in Part 1 by MedDRA System Organ Class and 
Preferred Term, and Maximum Severity (Cohort A – North 
America, Europe, Australia)– Safety Population 
 
Table 
14.3.1.6.1.2 
TEAEs in Part 1 by MedDRA System Organ Class and 
Preferred Term, and Maximum Severity (Cohort B – 
Japan)– Safety Population 
 
Table 
14.3.1.7.1.1 
Treatment-Emergent Adverse Events in Part 1 occurring in 
RISubjects by MedDRA System Organ Class and 
Preferred Term (Cohort A – North America, Europe, 
Australia) –  Safety Population  
 
Table 
14.3.1.7.1.2 
Treatment-Emergent Adverse Events in Part 1 Occurring in 
10% of Subjects in Any Treatment Group by MedDRA 
Preferred Term (Cohort B – Japan) –  Safety Population  
Use 10% as the cutoff for Cohort B because 
the total sample size for Cohort B is smaller 
than Cohort A, leading the 5% cut to show 
almost all events. 
Table 
14.3.1.8.1.1 
Overview of Treatment-Emergent Adverse Events of 
Special Interest during Part 1 (Cohort A – North America, 
Europe, Australia)– Safety Population 
 
Table 
14.3.1.8.1.2 
Overview of Treatment-Emergent Adverse Events of 
Special Interest during Part 1 (Cohort B – Japan) – Safety 
Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table 
14.3.1.9.1.1 
Treatment-Emergent Adverse Events of Special Interest 
(AESI) by SOC and PT (Cohort A – North America, 
Europe, Australia) – Safety Population 
 
Table 
14.3.1.9.1.2 
Treatment-Emergent Adverse Events of Special Interest 
(AESI) by SOC and PT (Cohort B – Japan) – Safety 
Population 
 
Table  
14.3.1.10.1.1.9 
Treatment-Emergent Adverse Events that Occurred in at 
Least 5% of Subjects During the Part 1 Titration + 
Maintenance Period by System Organ Class and Preferred 
Term with Number of Events and Number of Resolved 
Events (Cohort A – North America, Europe, Australia) -
Safety Population 
New Post-hoc AE Table request. Table 
number adjusted to align with Part 2 SAP. 
Table 
14.3.1.10.1.1.10 
Treatment-Emergent Adverse Events that Occurred in at 
Least 5% of Subjects During the Part 1 Titration + 
Maintenance Period by System Organ Class and Preferred 
Term with Mean Onset and Mean Duration (Cohort A – 
North America, Europe, Australia) - Safety Population 
New Post-hoc AE Table request. Table 
number adjusted to align with Part 2 SAP. 
Table 
14.3.1.10.1.1.11 
Treatment-Emergent Adverse Events During the Part 1 
Titration + Maintenance Period that Occurred in at Least 
2% of Subjects in Either ZX008 Treatment Group and With 
Higher Percentage Than the Placebo Group by System 
Organ Class and Preferred Term (Cohort A – North 
America, Europe, Australia) - Safety Population 
New Post-hoc AE Table request. Table 
number adjusted to align with Part 2 SAP. 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table  
14.3.1.10.1.2.9 
Treatment-Emergent Adverse Events that Occurred in at 
Least 10% of Subjects in Any Treatment Group During the 
Part 1 Titration + Maintenance Period by Preferred Term 
with Number of Events and Number of Resolved Events 
(Cohort B – Japan) -Safety Population 
New AE Table request. Table number 
adjusted to align with Part 2 SAP. 
Table 
14.3.1.10.1.2.10 
Treatment-Emergent Adverse Events that Occurred in at 
Least 10% of Subjects in Any Treatment Group During the 
Part 1 Titration + Maintenance Period by Preferred Term 
with Mean Onset and Mean Duration (Cohort B – Japan) - 
Safety Population 
New AE Table request. Table number 
adjusted to align with Part 2 SAP. 
 
14.3.2 
Listings of Deaths, Other Serious and Significant 
Adverse Events 
 
Table 
14.3.2.1.1 
Listing of Deaths (Cohort A – North America, Europe, 
Australia)   
 
Table 
14.3.2.1.2 
Listing of Deaths (Cohort B – Japan)  
 
Table 
14.3.2.2.1 
Listing of SAEs (Cohort A – North America, Europe, 
Australia)   
 
Table 
14.3.2.2.2 
Listing of SAEs (Cohort B – Japan)   
 
Table 
14.3.2.3.1 
Listing of Discontinuations Due to AE (Cohort A – North 
America, Europe, Australia)   
 
Table 
14.3.2.3.2 
Listing of Discontinuations Due to AE (Cohort B – Japan)   
 
  
14.3.4 
Summary of Laboratory Data 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table 
14.3.4.1.1.1 
Laboratory Parameters in Part 1 – Hematology: Summary 
Statistics (Cohort A – North America, Europe, Australia) - 
Safety Population 
 
Table 
14.3.4.1.1.2 
Laboratory Parameters in Part 1 – Hematology: Summary 
Statistics (Cohort B – Japan) – Safety Population 
 
Table 
14.3.4.1.2.1 
Shift Tables for Laboratory Parameters in Part 1 – 
Hematology (Cohort A – North America, Europe, 
Australia) – Safety Population 
 
Table 
14.3.4.1.2.2 
Shift Tables for Laboratory Parameters in Part 1 – 
Hematology (Cohort B – Japan) – Safety Population 
 
Table 
14.3.4.2.1.1 
Laboratory Parameters in Part 1 – Biochemistry: Summary 
Statistics (Cohort A – North America, Europe, Australia)  – 
Safety Population 
 
Table 
14.3.4.2.1.2 
Laboratory Parameters in Part 1 – Biochemistry: Summary 
Statistics (Cohort B – Japan)  – Safety Population 
 
Table 
14.3.4.2.2.1 
Shift Tables for Laboratory Parameters in Part 1 – 
Biochemistry (Cohort A – North America, Europe, 
Australia) – Safety Population 
 
Table 
14.3.4.2.2.2 
Shift Tables for Laboratory Parameters in Part 1 – 
Biochemistry (Cohort B – Japan) – Safety Population 
 
Table 
14.3.4.3.1.1 
Laboratory Parameters in Part 1 – Urinalysis (Quantitative 
Parameters) : Summary Statistics (Cohort A – North 
America, Europe, Australia) – Safety Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table 
14.3.4.3.1.2 
Laboratory Parameters in Part 1 – Urinalysis (Quantitative 
Parameters) : Summary Statistics (Cohort B – Japan) – 
Safety Population 
 
Table 
14.3.4.3.2.1 
Laboratory Parameters in Part 1 – Urinalysis (Categorical 
Parameters): Summary Statistics (Cohort A – North 
America, Europe, Australia) – Safety Population 
 
Table 
14.3.4.3.2.2 
Laboratory Parameters in Part 1 – Urinalysis (Categorical 
Parameters): Summary Statistics (Cohort B – Japan) – 
Safety Population 
 
Table 
14.3.4.3.3.1 
Shift Tables for Laboratory Parameters in Part 1 – 
Urinalysis (Quantitative Parameters) (Cohort A – North 
America, Europe, Australia) – Safety Population 
 
Table 
14.3.4.3.3.2 
Shift Tables for Laboratory Parameters in Part 1 – 
Urinalysis (Quantitative Parameters) (Cohort B – Japan) – 
Safety Population 
 
Table 
14.3.4.3.4.1 
Shift Tables for Laboratory Parameters in Part 1 – 
Urinalysis (Categorical Parameters) (Cohort A – North 
America, Europe, Australia) – Safety Population 
 
Table 
14.3.4.3.4.2 
Shift Tables for Laboratory Parameters in Part 1 – 
Urinalysis (Categorical Parameters) (Cohort B – Japan)  – 
Safety Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table 
14.3.4.4.1.1 
Laboratory Parameters in Part 1 – Tests of Precocious 
Puberty and Thyroid Function: Summary Statistics (Cohort 
A – North America, Europe, Australia) – Safety Population 
 
Table 
14.3.4.4.1.2 
Laboratory Parameters in Part 1 – Tests of Precocious 
Puberty and Thyroid Function: Summary Statistics (Cohort 
B – Japan) – Safety Population 
 
Table 
14.3.4.4.2.1 
Shift Tables for Laboratory Parameters in Part 1 – Tests of 
Precocious Puberty and Thyroid Function (Cohort A – 
North America, Europe, Australia) – Safety Population 
 
Table 
14.3.4.4.2.2 
Shift Tables for Laboratory Parameters in Part 1 – Tests of 
Precocious Puberty and Thyroid Function (Cohort B – 
Japan) – Safety Population 
 
Table 
14.3.4.5.1 
Laboratory Parameters in Part 1 : Epilepsy Genotype Panel 
(Cohort A – North America, Europe, Australia) – Safety 
Population 
 
Table 
14.3.4.5.2 
Laboratory Parameters in Part 1 : Epilepsy Genotype Panel 
(Cohort B – Japan) – Safety Population 
 
Table  
14.3.4.6.1.1 
Number of Subjects with Decrease in Platelets Count 
During Part 1 with Normal Platelet Count at Baseline 
(Cohort A – North America, Europe, Australia) – Safety 
Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table  
14.3.4.6.1.2 
Number of Subjects with Decrease in Platelets Count 
During Part 1 with Normal Platelet Count at Baseline 
(Cohort B – Japan) – Safety Population 
 
Table  
14.3.4.6.2.1 
Number of Subjects with Decrease in Platelets Count 
During Part 1 Relative to Baseline (whether Normal or 
Abnormal) Platelet Count (Cohort A – North America, 
Europe, Australia) – Safety Population 
 
Table  
14.3.4.6.2.2 
Number of Subjects with Decrease in Platelets Count 
During Part 1 Relative to Baseline (whether Normal or 
Abnormal) Platelet Count (Cohort B – Japan) – Safety 
Population 
 
Table  
14.3.4.6.3.1 
Number of Subjects with Decrease in Platelets Count 
During Part 1 with Normal Platelet Count at Baseline by 
Valproate Use (Cohort A – North America, Europe, 
Australia)– Safety Population 
 
Table  
14.3.4.6.3.2 
Number of Subjects with Decrease in Platelets Count 
During Part 1 with Normal Platelet Count at Baseline by 
Valproate Use (Cohort B – Japan) – Safety Population 
 
Table  
14.3.4.6.4.1 
Number of Subjects with Decrease in Platelets Count 
During Part 1 with Normal Platelet Count at Baseline by 
Presence/Absence of Infection Event (Cohort A – North 
America, Europe, Australia) – Safety Population 
 
Table  
14.3.4.6.4.2 
Number of Subjects with Decrease in Platelets Count 
During Part 1 with Normal Platelet Count at Baseline by 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Presence/Absence of Infection Event (Cohort B – Japan) – 
Safety Population 
Table  
14.3.4.7.1.1 
Number of Subjects with Normal Prolactin at Baseline who 
had a Prolactin Increase during Part 1 at each Visit Week 
(Cohort A – North America, Europe, Australia)– Safety 
Population 
 
Table  
14.3.4.7.1.2 
Number of Subjects with Normal Prolactin at Baseline who 
had a Prolactin Increase during Part 1 at each Visit Week 
(Cohort B – Japan) – Safety Population 
 
Table  
14.3.4.7.2.1 
Number of Subjects with Normal Prolactin at Baseline who 
had a Prolactin Increase during Part 1 with Seizure Event 
within 48 hours prior to Prolactin Increase at each Visit 
Week (Cohort A – North America, Europe, Australia) -
Safety Population 
 
Table  
14.3.4.7.2.2 
Number of Subjects with Normal Prolactin at Baseline who 
had a Prolactin Increase during Part 1 with Seizure Event 
within 48 hours prior to Prolactin Increase at each Visit 
Week (Cohort B – Japan) -Safety Population 
 
 
14.4.1 
Vital Signs, Weight and BMI 
 
Table  
14.4.1.1.1.1 
Vital Sign Parameters in Part 1 (Cohort A – North 
America, Europe, Australia) – Safety Population 
 
Table  
14.4.1.1.1.2 
Vital Sign Parameters in Part 1 (Cohort B – Japan) – Safety 
Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table  
14.4.1.2.1.1 
Body Weight and BMI in Part 1 (Cohort A – North 
America, Europe, Australia) – Safety Population 
 
Table  
14.4.1.2.1.2 
Body Weight, Height, and BMI in Part 1 (Cohort B – 
Japan) – Safety Population 
Minor Title Update 
Table  
14.4.1.2.2.1 
Weight Summary (Lost/Gain >=7% or >=10%) during Part 
1 (Cohort A – North America, Europe, Australia) – Safety 
Population 
 
Table  
14.4.1.2.2.2 
Weight Summary (Lost/Gain >=7% or >=10%) during Part 
1 (Cohort B – Japan) – Safety Population 
 
Table  
14.4.1.2.2.3 
Weight Summary (Lost/Gain >=7% or >=10%) during Part 
1 by Age Group and Treatment Group (Cohort B – Japan) – 
Safety Population 
 
Figure 
14.4.1.3.1.1 
Spaghetti Plot of Weight by Study Day during Part 1 for 
Subjects who had a >= 7% Decrease from Baseline in Body 
Weight (Cohort A – North America, Europe, Australia) - 
Safety Population  
 
Figure 
14.4.1.3.1.2 
Spaghetti Plot of Weight by Study Day during Part 1 for 
Subjects who had a >= 7% Decrease from Baseline in Body 
Weight by Age Group and Treatment Group (Cohort B – 
Japan) - Safety Population  
 
  
14.4.4 
Tanner Staging 
 
Table 
14.4.4.1.1.1 
Tanner Staging in Part 1 by Age Group for Boys (Cohort A 
– North America, Europe, Australia) –  Safety Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table 
14.4.4.1.1.2 
Tanner Staging in Part 1 by Age Group for Boys (Cohort B 
– Japan)  –  Safety Population 
 
Table 
14.4.4.2.1.1 
Tanner Staging in Part 1 by Age Group for Girls (Cohort A 
– North America, Europe, Australia) –  Safety Population 
 
Table 
14.4.4.2.1.2 
Tanner Staging in Part 1 by Age Group for Girls (Cohort B 
– Japan) –  Safety Population 
 
  
14.4.5 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Table 
14.4.5.1.1 
Number of Subjects with 
 
Based on the C-SSRS during Part 1 (Cohort A – 
North America, Europe, Australia) – Safety Population 
 
Table 
14.4.5.1.2 
Number of Subjects with 
 
Based on the C-SSRS during Part 1 (Cohort B – 
Japan) – Safety Population 
 
Table 
14.4.5.2.1 
Columbia Suicide Severity-Rating Scale (C-SSRS)- Shift 
Table of Changes in C-SSRS Categories During Part 1 
(Cohort A – North America, Europe, Australia) - Safety 
Population 
 
Table 
14.4.5.2.2 
Columbia Suicide Severity-Rating Scale (C-SSRS)- Shift 
Table of Changes in C-SSRS Categories During Part 1 
(Cohort B – Japan) - Safety Population 
 
  
14.4.6 
Brief Rating Inventory of Executive Function- (BRIEF) 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Table 
14.4.6.1.1 
Brief Rating Inventory of Executive Function Preschool 
Version (BRIEF-P) in Part 1: Scoring Summary Table by 
Treatment Group (Cohort A – North America, Europe, 
Australia)– Safety Population  
 
Table 
14.4.6.1.2 
Brief Rating Inventory of Executive Function Preschool 
Version (BRIEF-P) in Part 1: Scoring Summary Table by 
Treatment Group (Cohort B – Japan) – Safety Population  
 
Figure 
14.4.6.1.3 
Brief Rating Inventory of Executive Function Preschool 
Version (BRIEF-P) in Part 1: Mean Change from Baseline 
by Treatment Group (Cohort B – Japan) – Safety 
Population  
New Figure added for Cohort B 
Table 
14.4.6.2.1 
Brief Rating Inventory of Executive Function (BRIEF) in 
Part 1: Scoring Summary Table by Treatment Group 
(Cohort A – North America, Europe, Australia) – Safety 
Population 
 
Table 
14.4.6.2.2 
Brief Rating Inventory of Executive Function (BRIEF) in 
Part 1: Scoring Summary Table by Treatment Group 
(Cohort B – Japan) – Safety Population 
 
Figure 
14.4.6.2.3 
Brief Rating Inventory of Executive Function (BRIEF) in 
Part 1: Mean Change from Baseline by Treatment Group 
(Cohort B – Japan) – Safety Population  
New Figure added for Cohort B 
Table 
14.4.6.3.1 
Brief Rating Inventory of Executive Function (BRIEF-A) 
in Part 1: Scoring Summary Table by Treatment Group 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
(Cohort A – North America, Europe, Australia)–  Safety 
Population 
Table 
14.4.6.3.2 
Brief Rating Inventory of Executive Function (BRIEF-A) 
in Part 1: Scoring Summary Table by Treatment Group 
(Cohort B – Japan) - Safety Population 
 
Figure 
14.4.6.3.3 
Brief Rating Inventory of Executive Function (BRIEF-A) 
in Part 1: Mean Change from Baseline by Treatment Group 
(Cohort B – Japan) – Safety Population  
New Figure added for Cohort B 
 
14.4.7 
Clinically Relevant Physical Examination   
 
Table 
14.4.7.1.1 
Clinically Relevant Physical Examination Findings in Part 
1 (Cohort A – North America, Europe, Australia)–  Safety 
Population 
 
Table 
14.4.7.1.2 
Clinically Relevant Physical Examination Findings in Part 
1 (Cohort B – Japan) - Safety Population 
 
 
14.4.8 
Clinically Relevant Neurologic Examination   
 
Table 
14.4.8.1.1 
Clinically Relevant Neurologic Examination Findings in 
Part 1 (Cohort A – North America, Europe, Australia)–  
Safety Population 
 
Table 
14.4.8.1.2 
Clinically Relevant Neurologic Examination Findings in 
Part 1  (Cohort B – Japan) - Safety Population 
 
  
16.2 
Subject data listing 
 
  
16.2.1  
Subject disposition and discontinuation 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Listing 
16.2.1.1.1 
Subject Completion/Discontinuation in Part 1 (Cohort A - 
North America, Europe, Australia)   
 
Listing 
16.2.1.1.2 
Subject Completion/Discontinuation in Part 1 (Cohort B - 
Japan)   
 
  
16.2.2 
Protocol deviations 
 
Listing 
16.2.2.1.1 
Major Protocol Deviations in Part 1 (Cohort A - North 
America, Europe, Australia)   
 
Listing 
16.2.2.1.2 
Major Protocol Deviations in Part 1 (Cohort B - Japan) 
 
  
16.2.3 
Subjects excluded from analysis 
 
Listing 
16.2.3.1.1 
Subjects Excluded from the Per Protocol Population  
(Cohort A - North America, Europe, Australia)   
 
Listing 
16.2.3.1.2 
Subjects Excluded from the Per Protocol Population  
(Cohort B - Japan)   
 
Listing 
16.2.3.2.1 
Subject Allocation to Trial Populations (Cohort A - North 
America, Europe, Australia)   
 
Listing 
16.2.3.2.2 
Subject Allocation to Trial Populations (Cohort B - Japan)   
 
  
16.2.4  
Demographic data and other baseline characteristics 
 
Listing 
16.2.4.1.1.1 
Demographic data (Cohort A - North America, Europe, 
Australia) 
 
Listing 
16.2.4.1.1.2 
Demographic data (Cohort B - Japan) 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Listing 
16.2.4.1.2.1 
Informed Consent / Informed Assent in Part 1 (Cohort A - 
North America, Europe, Australia)   
 
Listing 
16.2.4.1.2.2 
Informed Consent / Informed Assent in Part 1 (Cohort B - 
Japan)   
 
Listing 
16.2.4.1.4.1 
% Change from Baseline in Weight and BMI (Cohort A - 
North America, Europe, Australia) 
 
Listing 
16.2.4.1.4.2 
% Change from Baseline in Weight and BMI (Cohort B - 
Japan)   
 
Listing 
16.2.4.2.1.1 
Medical History and Neurologic History (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.4.2.1.2 
Medical History and Neurologic History (Cohort B - Japan)  
Listing 
16.2.4.2.3.1 
Seizure history (Cohort A - North America, Europe, 
Australia) 
 
Listing 
16.2.4.2.3.2 
Seizure history (Cohort B - Japan) 
 
Listing 
16.2.4.3.1.1 
Medications and Therapies/Treatments Stopped during or 
up to 30 days prior to Screening (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.4.3.1.2 
Medications and Therapies/Treatments Stopped During or 
Up to 30 Days Prior to Screening (Cohort B - Japan) 
Title Adjustment 
Listing 
16.2.4.3.2.1 
Concomitant Medications and Therapies/Treatments 
(Cohort A - North America, Europe, Australia) 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Listing 
16.2.4.3.2.2 
Concomitant Medications and Therapies/Treatments 
(Cohort B - Japan) 
 
Listing 
16.2.4.4.1.1 
Prior Antiepileptic Drugs (AEDs)(Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.4.4.1.2 
Prior Antiepileptic Drugs (AEDs)(Cohort B - Japan) 
 
Listing 
16.2.4.4.2.1 
Concomitant Antiepileptic Drugs (AEDs) (Cohort A - 
North America, Europe, Australia) 
 
Listing 
16.2.4.4.2.2 
Concomitant Antiepileptic Drugs (AEDs) (Cohort B - 
Japan) 
 
Listing 
16.2.4.5.1.1 
Rescue Medications (Cohort A - North America, Europe, 
Australia) 
 
Listing 
16.2.4.5.1.2 
Rescue Medications (Cohort B - Japan) 
 
  
16.2.5 
Treatment exposure and compliance 
 
Listing 
16.2.5.1.1 
IMP Intake per Day during Treatment (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.5.1.2 
IMP Intake per Day during Treatment (Cohort B - Japan) 
 
Listing 
16.2.5.2.1 
IMP Intake – Self Reported % Compliance (Cohort A - 
North America, Europe, Australia) 
 
Listing 
16.2.5.2.2 
IMP Intake – Self Reported % Compliance (Cohort B - 
Japan) 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Listing 
16.2.5.3.1 
Drug Accountability (Cohort A - North America, Europe, 
Australia) 
 
Listing 
16.2.5.3.2 
Drug Accountability (Cohort B - Japan) 
 
Listing  
16.2.5.4.1 
Background Antiepileptic Drugs (AEDs) Pharmacokinetic 
Concentrations (Cohort A - North America, Europe, 
Australia) 
 
Listing  
16.2.5.4.2 
Background Antiepileptic Drugs (AEDs) Pharmacokinetic 
Concentrations (Cohort B - Japan) 
 
  
16.2.6 
Efficacy data 
 
Listing 
16.2.6.1.1.1 
Recorded Seizures – Duration and Number of Occurrences 
per Subject (Diary data) (Cohort A - North America, 
Europe, Australia) 
 
Listing 
16.2.6.1.1.2 
Recorded Seizures – Duration and Number of Occurrences 
per Subject (Diary data) (Cohort B - Japan) 
 
Listing 
16.2.6.1.2.1 
Change in Seizure Frequency Resulting in Drops (ESC 
Confirmed) from Baseline during Part 1 (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.6.1.2.1s 
Sensitivity Analysis of Change in Seizure Frequency 
Resulting in Drops (ESC Confirmed) from Baseline during 
Part 1 (Cohort A - North America, Europe, Australia) 
New Listing using Supplemental Seizure 
File updated post-Part 1 Database Lock 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Listing 
16.2.6.1.2.1c 
Change in Seizure Frequency Resulting in Drops (ESC 
Confirmed) from Baseline during Part 1 (Cluster 
Sensitivity) (Cohort A - North America, Europe, Australia) 
New Listing due to request for Cluster 
Sensitivity 
Listing 
16.2.6.1.2.1cs 
Sensitivity Analysis of Change in Seizure Frequency 
Resulting in Drops (ESC Confirmed) from Baseline during 
Part 1 (Cluster Sensitivity) (Cohort A - North America, 
Europe, Australia) 
New Listing using Supplemental Seizure 
File updated post-Part 1 Database Lock 
Listing 
16.2.6.1.2.1b 
Change in Seizure Frequency Resulting in Drops (ESC 
Confirmed) from Baseline during Part 1 (Cohort A - North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2) 
New Listing using Pre-DCR dataset Version 
2 
Listing 
16.2.6.1.2.1c3 
Change in Seizure Frequency Resulting in Drops (ESC 
Confirmed) from Baseline during Part 1 (Cohort A - North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 3) 
New Listing using Pre-DCR dataset Version 
3 
Listing 
16.2.6.1.2.2 
Change in Seizure Frequency Resulting in Drops (ESC 
Confirmed) from Baseline during Part 1 (Cohort B - Japan) 
 
Listing 
16.2.6.2.1.1 
Clinical Global Impression – Improvement Rating as 
Assessed by the Investigator (Cohort A - North America, 
Europe, Australia) 
Subject – Parent/Caregiver values separated 
from Investigator listing. 
Listing 
16.2.6.2.1.2 
Clinical Global Impression – Improvement Rating as 
Assessed by the Investigator (Cohort B - Japan) 
Subject – Parent/Caregiver values separated 
from Investigator listing. 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Listing 
16.2.6.2.2.1 
Clinical Global Impression – Improvement Rating as 
Assessed by the Subject or Parent/Caregiver (Cohort A - 
North America, Europe, Australia) 
Subject – Parent/Caregiver values separated 
from Investigator listing. 
Listing 
16.2.6.2.2.2 
Clinical Global Impression – Improvement Rating as 
Assessed by the Subject or Parent/Caregiver (Cohort B - 
Japan) 
Subject – Parent/Caregiver values separated 
from Investigator listing. 
Listing 
16.2.6.3.1 
Change in Countable Motor Seizures from Baseline during 
Part 1 (Cohort A - North America, Europe, Australia) 
 
Listing 
16.2.6.3.2 
Change in Countable Motor Seizures from Baseline during 
Part 1 (Cohort B - Japan) 
 
Listing  
16.2.6.4.1 
Duration of Longest Interval between Seizures during 
Titration and Maintenance Resulting in Drops (ESC 
Confirmed) in Part 1 (Cohort A - North America, Europe, 
Australia) 
 
Listing  
16.2.6.4.1s 
Sensitivity Analysis of Duration of Longest Interval 
between Seizures during Titration and Maintenance 
Resulting in Drops (ESC Confirmed) in Part 1 (Cohort A - 
North America, Europe, Australia) 
New Listing using Supplemental Seizure 
File updated post-Part 1 Database Lock 
Listing  
16.2.6.4.2 
Duration of Longest Interval between Seizures during 
Titration and Maintenance Resulting in Drops (ESC 
Confirmed)  in Part 1 (Cohort B – Japan) 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Listing  
16.2.6.5.1 
Change in Seizures that Typically Result in Drops from 
Baseline during Part 1  (Cohort A - North America, 
Europe, Australia) 
 
Listing  
16.2.6.5.1b 
Change in Seizures that Typically Result in Drops from 
Baseline during Part 1  (Cohort A - North America, 
Europe, Australia) (Pre-DCR Version 2) 
 
Listing  
16.2.6.5.1c 
Change in Seizures that Typically Result in Drops from 
Baseline during Part 1  (Cohort A - North America, 
Europe, Australia) (Pre-DCR Version 3) 
 
Listing  
16.2.6.5.2 
Change in Seizures that Typically Result in Drops from 
Baseline during Part 1  (Cohort B - Japan) 
 
Listing  
16.2.6.6.1 
Change in Countable Non-Motor Seizures from Baseline 
during Part 1 (Cohort A - North America, Europe, 
Australia) 
 
Listing  
16.2.6.6.2 
Change in Countable Non-Motor Seizures from Baseline 
during Part 1 (Cohort B - Japan) 
 
Listing  
16.2.6.7.1 
Change in All Countable Seizures (Motor + Non-Motor) 
from Baseline during Part 1 (Cohort A - North America, 
Europe, Australia) 
 
Listing  
16.2.6.7.2 
Change in All Countable Seizures (Motor + Non-Motor) 
from Baseline during Part 1 (Cohort B - Japan) 
 
Listing 
16.2.6.13.1 
Change in Rescue Medication Usage from Baseline during 
Part 1  (Cohort A - North America, Europe, Australia) 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Listing 
16.2.6.13.2 
Change in Rescue Medication Usage from Baseline during 
Part 1  (Cohort B - Japan) 
 
Listing  
16.2.6.14.1 
Seizure Free Days during Part 1 (Cohort A - North 
America, Europe, Australia) 
 
Listing  
16.2.6.14.2 
Countable Motor Seizure Free Days during Part 1 (Cohort 
B - Japan) 
Modification of Title. 
Listing  
16.2.6.14.3 
Drop Seizure Free Days (ESC Confirmed) during Part 1 
(Cohort A - North America, Europe, Australia) 
 
Listing  
16.2.6.14.3s 
Sensitivity Analysis of Drop Seizure Free Days (ESC 
Confirmed) during Part 1 (Cohort A - North America, 
Europe, Australia) 
 
Listing  
16.2.6.14.4 
Drop Seizure Free Days (ESC Confirmed) during Part 1 
(Cohort B - Japan) 
 
Listing 
16.2.6.15.1 
Hospitalizations and Medical Services (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.6.15.2 
Hospitalizations and Medical Services (Cohort B - Japan) 
 
Listing 
16.2.6.16.1 
Vineland Adaptive Behavior Scale (VABS) (Cohort A - 
North America, Europe, Australia) 
 
Listing 
16.2.6.16.2 
Vineland Adaptive Behavior Scale (VABS) (Cohort B - 
Japan) 
 
Listing 
16.2.6.17.1 
Quality of Life in Childhood Epilepsy (QOLCE) Scale 
(Cohort A - North America, Europe, Australia) 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Listing 
16.2.6.17.2 
Quality of Life in Childhood Epilepsy (QOLCE) Scale 
(Cohort B - Japan) 
 
Listing 
16.2.6.18.1 
Zarit Caregiver Burden Inventory (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.6.18.2 
Zarit Caregiver Burden Inventory (Cohort B - Japan) 
 
Listing 
16.2.6.19.1 
Parent/Caregiver Ratings using HADS Scale (Cohort A - 
North America, Europe, Australia) 
 
Listing 
16.2.6.19.2 
Parent/Caregiver Ratings Using HADS Scale (Cohort B - 
Japan) 
Title Adjustment 
Listing  
16.2.6.20.1 
Change in All Countable Seizures that did not Result in 
Drops (ESC Confirmed) from Baseline during Part 1 
(Cohort A - North America, Europe, Australia) 
New post-hoc defined endpoint 
Listing  
16.2.6.20.2 
Change in All Countable Seizures that did not Result in 
Drops (ESC Confirmed) from Baseline during Part 1 
(Cohort B - Japan) 
New post-hoc defined endpoint 
Listing  
16.2.6.21.1 
Change in Seizure Frequency Resulting in Drops 
(Caregiver Determination) from Baseline during Part 1 
(Cohort A - North America, Europe, Australia) 
New post-hoc defined endpoint 
  
16.2.7  
Adverse events 
 
Listing 
16.2.7.1.1 
Adverse Events (Cohort A - North America, Europe, 
Australia) 
 
Listing 
16.2.7.1.2 
Adverse Events (Cohort B - Japan) 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Listing 
16.2.7.2.1 
Adverse Events of Special Interest (AESI) (Cohort A - 
North America, Europe, Australia) 
 
Listing 
16.2.7.2.2 
Adverse Events of Special Interest (AESI) (Cohort B - 
Japan) 
 
  
16.2.8 
Laboratory data 
 
Listing 
16.2.8.1.1.1 
Laboratory Data Hematology Parameters (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.8.1.1.2 
Laboratory Data Hematology Parameters (Cohort B - 
Japan) 
 
Listing 
16.2.8.1.2.1 
Extreme Value Laboratory Parameters – Hematology 
(Cohort A - North America, Europe, Australia) 
 
Listing 
16.2.8.1.2.2 
Critical or Notable Value Laboratory Parameters – 
Hematology (Cohort B - Japan) 
Title Adjustment 
Listing 
16.2.8.2.1.1 
Laboratory Data Biochemistry Parameters (Cohort A - 
North America, Europe, Australia) 
 
Listing 
16.2.8.2.1.2 
Laboratory Data Biochemistry Parameters (Cohort B - 
Japan) 
 
Listing 
16.2.8.2.2.1 
Extreme Value Laboratory Parameters – Biochemistry 
(Cohort A - North America, Europe, Australia) 
 
Listing 
16.2.8.2.2.2 
Critical or Notable Value Laboratory Parameters – 
Biochemistry (Cohort B - Japan) 
Title Adjustment 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Listing 
16.2.8.3.1.1 
Laboratory Data Coagulation Parameters (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.8.3.1.2 
Laboratory Data Coagulation Parameters (Cohort B - 
Japan) 
 
Listing 
16.2.8.4.1.1 
Laboratory Data Urinalysis Parameters (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.8.4.1.2 
Laboratory Data Urinalysis Parameters (Cohort B - Japan) 
 
Listing 
16.2.8.4.2.1 
Extreme Value Urinalysis Data (Cohort A - North America, 
Europe, Australia) 
 
Listing 
16.2.8.4.2.2 
Critical or Notable Value Urinalysis Data (Cohort B - 
Japan) 
Title Adjustment 
Listing 
16.2.8.5.1 
Tests of Growth, Precocious Puberty and Thyroid Function 
(Cohort A - North America, Europe, Australia) 
 
Listing 
16.2.8.5.2 
Tests of Growth, Precocious Puberty and Thyroid Function 
(Cohort B - Japan) 
 
Listing 
16.2.8.6.1 
Urine and Serum Pregnancy tests  (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.8.6.2 
Urine and Serum Pregnancy tests  (Cohort B - Japan) 
 
Listing 
16.2.8.7.1 
Urine and Serum THC panel (Cohort A - North America, 
Europe, Australia) 
 
Listing 
16.2.8.7.2 
Urine and Serum THC panel (Cohort B - Japan) 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Listing 
16.2.8.8.1 
Laboratory Data: Listing of Test Comments from Lab 
Vendor for All Laboratory Parameters (Cohort A - North 
America, Europe, Australia) 
New Listing added. 
Listing 
16.2.8.8.2 
Laboratory Data: Listing of Test Comments from 
Laboratory Vendor for All Laboratory Parameters (Cohort 
B – Japan)  
New Listing added. 
Title Adjustment. 
  
16.2.9 
Other Safety Data 
 
Listing 
16.2.9.1.1.1 
Vital Signs  (Cohort A - North America, Europe, Australia) 
 
Listing 
16.2.9.1.1.2 
Vital Signs  (Cohort B - Japan) 
 
Listing 
16.2.9.1.2.1 
Abnormal Vital Signs Data (Cohort A - North America, 
Europe, Australia) 
 
Listing 
16.2.9.1.2.2 
Abnormal Vital Signs Data (Cohort B - Japan) 
 
Listing 
16.2.9.2.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) (Cohort 
A - North America, Europe, Australia) 
 
Listing 
16.2.9.2.2 
Columbia-Suicide Severity Rating Scale (C-SSRS) (Cohort 
B - Japan) 
 
Listing 
16.2.9.3.1.1 
Behavior Rating Inventory of Executive Function – 
Preschool Version (BRIEF-P) – Individual Questions 
(Cohort A - North America, Europe, Australia) 
 
Listing 
16.2.9.3.1.2 
Behavior Rating Inventory of Executive Function – 
Preschool Version (BRIEF-P) – Individual Questions 
(Cohort B - Japan) 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Listing 
16.2.9.3.2.1 
Behavior Rating Inventory of Executive Function – 
Preschool Version (BRIEF-P) – Summary Scales and 
Indexes (Cohort A - North America, Europe, Australia) 
 
Listing 
16.2.9.3.2.2 
Behavior Rating Inventory of Executive Function – 
Preschool Version (BRIEF-P) – Summary Scales and 
Indexes (Cohort B - Japan) 
 
Listing 
16.2.9.3.3.1 
Behavior Rating Inventory of Executive Function (BRIEF) 
– Individual Questions (Cohort A - North America, Europe, 
Australia) 
 
Listing 
16.2.9.3.3.2 
Behavior Rating Inventory of Executive Function (BRIEF) 
– Individual Questions (Cohort B - Japan) 
 
Listing 
16.2.9.3.4.1 
Behavior Rating Inventory of Executive Function (BRIEF) 
– Summary Scales and Indexes (Cohort A - North America, 
Europe, Australia) 
 
Listing 
16.2.9.3.4.2 
Behavior Rating Inventory of Executive Function (BRIEF) 
– Summary Scales and Indexes (Cohort B - Japan) 
 
Listing 
16.2.9.3.5.1 
Behavior Rating Inventory of Executive Function Adult 
Version (BRIEF-A) – Individual Questions (Cohort A - 
North America, Europe, Australia) 
 
Listing 
16.2.9.3.5.2 
Behavior Rating Inventory of Executive Function Adult 
Version (BRIEF-A) – Individual Questions (Cohort B - 
Japan) 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification from Version 
2.0 SAP 
Listing 
16.2.9.3.6.1 
Behavior Rating Inventory of Executive Function Adult 
Version (BRIEF-A) – Summary Scales and Indexes 
(Cohort A - North America, Europe, Australia) 
 
Listing 
16.2.9.3.6.2 
Behavior Rating Inventory of Executive Function Adult 
Version (BRIEF-A) – Summary Scales and Indexes 
(Cohort B - Japan) 
 
Listing 
16.2.9.4.1 
Tanner Staging (Cohort A - North America, Europe, 
Australia) 
 
Listing 
16.2.9.4.2 
Tanner Staging (Cohort B - Japan) 
 
Listing 
16.2.9.5.1 
Physical Examination and Neurologic Examination (Cohort 
A - North America, Europe, Australia) 
 
Listing 
16.2.9.5.2 
Physical Examination and Neurologic Examination (Cohort 
B - Japan) 
 
Listing 
16.2.9.7.1 
Epilepsy Genotype panel (Cohort A - North America, 
Europe, Australia) 
 
Listing 
16.2.9.7.2 
Epilepsy Genotype panel (Cohort B - Japan) 
 
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REFERENCES
ICH Topic E2F: Development Safety Update Report, 2011.
Devinsky O, Patel AD, Cross JH, et al. Effect of cannabidiol on drop seizures in the 
Lennox–Gastaut syndrome. N Engl J Med. –
Kim KR, Lee E, Namkoong K, Lee YM, Lee JS, and Kim HD, “Caregiver's burden and 
quality of life in mitochondrial diVHDVHµ3HGLDWULF1HXURORJ\YROQRSS–

Ng Y, Conry J, Drummond R, Stolle J, Weinberg M for the OV-1012 Study Investigators. 
Randomized, phase III study results of clobazam in Lennox–Gastaut syndrome. Neurology 
–1481.
RDEELW3(GUHDFW-text Methodology of frontal and executive function 
react-text: 2931. East Sussex, UK: Psychology Press.
Sabaz, M., Cairns, D. R., Lawson, J. A., Nheu, N., Bleasel, A. F., & Bye, A. M. (2000). 
Validation of a new quality of life measure for children with epilepsy. Epilepsia, 41(6), 
–
Sparrow, S. S., & Cicchetti, D. V. (1989). The Vineland Adaptive Behavior Scales. In C. 
S. Newmark (Ed.), Major psychological assessment instruments, Vol. 2, pp. 199-231). 
Needham Heights, MA, US: Allyn & Bacon.
7DODUVND'7KHXVHIXOQHVVRI4XDOLW\RI/LIH&KLOGKRRG(SLOHSV\42/&(
questionnaire in evaluating the quality of life of children with epilepsy. Advances in 
Medical Sciences, 52 Suppl 1, 191–193.
Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated 
with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-
controlled phase 3 trial. Lancet. 2018;391:1085–96.
7XNH\-: Exploratory Data Analysis. Addison-Wesley.
Westphal-Guitti C, Alonso NB, Migliorini RCVP et al., “Quality of life and burden in 
caregivers of patients with epilepsy,” The Journal of Neuroscience Nursing, vol. 39, no. 
6, pp. 354–
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APPENDICES
APPENDIX 1 – SEIZURE TYPES 
1. All Seizures
2. Countable 
Motor Seizures
3. Countable Non-
Motor Seizures
4. Drop Seizures
(ESC confirmed or 
Typical)
Generalized Tonic-Clonic
Generalized 
Tonic-Clonic
Generalized 
Tonic-Clonic
Secondarily Generalized 
Tonic-Clonic
Secondarily 
Generalized 
Tonic-Clonic
Secondarily 
Generalized 
Tonic-Clonic
Tonic
Tonic
Tonic
Atonic
Atonic
Atonic
Tonic/Atonic
Tonic/Atonic
Tonic/Atonic
Clonic
Clonic
Hemiclonic
Hemiclonic
Focal with clear 
observable signs
Focal with clear 
observable signs
Focal without clear 
observable signs
Focal without clear 
observable signs
Myoclonic
Myoclonic
Absence/atypical absence
Absence/atypical 
absence
Infantile Spasms
Infantile Spasms
Epileptic Spasms
Epileptic Spasms
Other
Other
SEIZURE CLASSIFICATION – PRIMARY ENDPOINT
The primary endpoint for Study 1601 is defined as the change from baseline in seizures 
that result in drops. Seizures that result in drops include those of type: atonic, tonic, 
tonic/atonic, and tonic clonic (ie, generalized tonic clonic, and secondarily generalized 
tonic clonic). The seizures that result in drops are similar to those as defined in the 
Epidiolex Phase 3 clinical studies GWPCARE3 and GWPCARE4, which were atonic, tonic, 
or tonic clonic (Devinsky 2018, Thiele 2018).
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In the Statistical Analysis Plan (SAP) version 1.0 dated 5 August 2019, seizures resulting 
in drops were defined as those of the five types listed above and specified in the DSD as 
seizures that result in a fall based on a “Yes” response to Question 9 in the DSD. During 
study conduct a large number of data clarifications were raised for Question 9 leading 
to the conclusion that there was uncertainty amongst caregivers in how to properly 
answer the question. Based on this uncertainty, the definition of seizures that result in 
drops was changed to those of the five pre-specified types that have been reviewed and 
approved for each subject as a “drop seizure” by the Epilepsy Study Consortium (ESC). 
Approval is based on the seizures for each subject submitted to the ESC on the Seizure 
Identification Form during the Baseline Visit and logged in the eCRF on the Seizure 
History Form. 
Thus, in version 1.1 of the SAP, drop seizures for the primary analysis will be those of 
the pre-specified type that have been approved for an individual subject as Drop by the 
ESC as indicated on the Seizure History eCRF under variable DROP_ and captured in the 
DSD. 
Under this definition, classifying a particular seizure in the diary as a drop seizure 
requires determining whether the type of seizure in question has been identified in the 
Seizure History eCRF as a drop seizure for that subject. This can typically be done by 
matching a seizure type identifier in the diary to its counterpart in the Seizure History 
eCRF. Specifically, each seizure type entered into the Seizure History eCRF is identified 
by a “Record Position” number. These seizure types are then referred to by subjects or 
caregivers when recording seizures into the electronic Seizure Diary where they are 
labeled with a “Seizure Unique ID”. For most subjects, there is a direct correspondence 
between the Seizure Unique ID in the DSD and the Record Position number on the 
Seizure History eCRF. However, for some subjects the correspondence is imperfect and 
aligning seizure types between the diary and the Seizure History eCRF requires an 
examination of text fields. In order to ensure that drop seizures are properly classified, 
a manual reconciliation between the Record Position number and the Seizure Unique ID 
was performed. The reconciliation resulted in a list of ESC-approved drop seizures for 
each subject from which the seizures entered in the DSD would be compared against in 
order to identify seizures for the primary endpoint. In order to facilitate seizure 
selection the list generated from the reconciliation was entered into a separate 
database and transferred to the study database via data transfer specifications. 
The procedures for the reconciliation are described in an addendum to the Data 
Management Plan. 
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SAP_007.pdf: 
16.1.9 
Documentation of Statistical Methods 
The document listed below is provided in this section. 
Statistical Analysis Plan (Protocol ZX008-1601) Version 2.0 dated 08-January-2020 
Statistical Analysis Plan for Cardiovascular Endpoints (Protocol ZX008-1601) Version 1.1 dated 23-January -2020
Statistical Analysis Plan (Protocol ZX008-1601) Addendum Note to File dated 31-June-2021 
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Statistical Analysis Plan 
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Syneos Health #1009529A 
Statistical Analysis Plan 
This document is proprietary and confidential to Syneos Health 
03.007A.03 
Syneos Health 
Page 1 of 110 
Document Type: 
Template 
Document ID: 
03.007A.03 
Issue Date:   
02 MAY 2016 
Effective Date:    30 MAY 2016 
Sponsor Name:  
Zogenix International Limited 
Protocol Number and Title: 
ZX008-1601: A Two-Part Study of ZX008 in Children 
and Adults with Lennox-Gastaut Syndrome (LGS); 
Part 1: A Randomized, Double-blind, Placebo-
controlled Trial of Two Fixed Doses of ZX008 
(Fenfluramine Hydrochloride) Oral Solution as 
Adjunctive Therapy for Seizures in Children and 
Adults with LGS, Followed by Part 2: An Open-label 
Extension to Assess Long-Term Safety of ZX008 in 
Children and Adults with LGS 
Protocol Version and Date: 
13-Jan-2017 Version 1.1
10-Jan-2018 (Amendment 1 Rest of World)
20-Jun-2019 (Amendment 2.0)
29 July 2019 (Amendment 2.1) 
Syneos Health Project Code: 
1009529A 
Author(s): 
 Principal Biostatistician 
SAP Version: 
2.0 
SAP Version Date: 
08-Jan-2020
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Zogenix. Acceptance of this 
document constitutes agreement by the recipient that no information contained herein will be published or 
disclosed without prior written authorization from an official of Zogenix. However, this document may be 
disclosed to appropriate Institutional Review Board and Ethics Committees or duly authorized 
representatives of a national regulatory authority under the condition that they are requested to keep it 
confidential. In the event of an actual or suspected breach of this obligation, Syneos Health should be 
notified promptly. 
S 
l> 
yneos. 
Heallti 
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Revision History 
Version 
# 
Date 
(dd-mmm-
yyyy) 
Document 
Owner 
Revision Summary 
0.1 
08-Feb-2019
Initial Release Version 
0.2 
24-May-2019
Separating Part 1 SAP from Part 2 SAP. 
Requested revisions from Draft 1. 
0.3 
20-Jun-2019
Separation of Part 1 analyses into  
Cohort A and Cohort B. 
0.4 
08-Jul-2019
4th Draft. 
0.5 
29-Jul-2019
Finalization Version 1.0 
1.0 
05-Aug-2019
Finalization Version 1.0 
1.1 
20-Dec-2019
Updates to the Additional Secondary 
Objectives specified for Part 1, Cohort 
A in the protocol, and to the associated 
Additional Secondary Efficacy 
Endpoints 
2.0 
06-Jan-2020
Finalization of SAP shells 
2.0 
08-Jan-2020
Signoff 
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10 Jan 2020
Statistical Analysis Plan 
Version 2.0 
Zopnlx lnternatlona! Limited Protocol ZX1601 
Syneos Health #1009529A 
I confirm that I have reviewed this document and agree with the content. 
Lead Bfostatistician 
Principal Biostatistician 
APPROVALS 
Health 
Date (dd-Mrnm-yyyy) 
Senior Reviewing Bfostatistfcian 
Date (dd-Mrnm-yyyy) 
 
 
z, enix International Limited 
Statistician on Behalf of 
Zogenix International Limited 
Jan-10-2020 
Date (dd-Mrnm-yyyy) 
Date (dd-Mmm-yyyy) 
03.007A.03 
Thfs document is proprietary and confidential to Syneos Health 
Syneos Health 
Page 3 of 109 
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TABLE OF CONTENTS 
 
GLOSSARY OF ABBREVIATIONS ................................................................. 8 
 
PURPOSE ...................................................................................................... 11 
 
Responsibilities ................................................................................................................. 11 
 
Timing of Analyses ............................................................................................................ 11 
 
Unblinding Plan .................................................................................................................. 12 
 
PART 1 OBJECTIVES ................................................................................... 12 
 
Primary Objective .............................................................................................................. 12 
 
Key Secondary Objective .................................................................................................. 12 
 
Additional Secondary Objectives ..................................................................................... 13 
 
Safety Objectives ............................................................................................................... 14 
 
Pharmacokinetic Objectives ............................................................................................. 14 
 
Exploratory Objectives ...................................................................................................... 14 
 
BRIEF DESCRIPTION ................................................................................... 15 
 
Subject Selection ............................................................................................................... 16 
 
Determination of Sample Size .......................................................................................... 16 
 
Treatment Assignment & Blinding ................................................................................... 17 
 
Administration of Study Medication ................................................................................ 17 
 
ENDPOINTS .................................................................................................. 25 
 
Primary Efficacy Endpoint ................................................................................................ 25 
 
Key Secondary Efficacy Endpoints ................................................................................. 25 
l. 
2. 
2.1. 
2.2. 
2.3. 
3. 
3.1. 
3.2. 
3.3. 
3.4. 
3.5. 
3.6. 
4. 
4.1. 
4.2. 
4.3. 
4.4. 
5. 
5.1. 
5.2. 
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Additional Secondary Efficacy Endpoints ...................................................................... 26 
 
Safety Endpoints ................................................................................................................ 27 
 
Exploratory Endpoints ...................................................................................................... 27 
 
ANALYSIS SETS ........................................................................................... 27 
Enrolled Population ........................................................................................................... 28 
 
Safety (SAF) Population .................................................................................................... 28 
 
Modified Intent-to-Treat (mITT) Population ..................................................................... 28 
 
Per Protocol (PP) Population ............................................................................................ 28 
Protocol Deviations ........................................................................................................... 28 
General Aspects for Statistical Analysis ......................................................................... 29 
 
General Methods ......................................................................................................... 29 
 
Definitions .................................................................................................................... 29 
 
Missing Data................................................................................................................ 30 
 
Visit Windows ..................................................................................................................... 31 
Pooling of Centers ............................................................................................................. 32 
Subgroups .......................................................................................................................... 32 
 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION................................................................................................. 33 
 
Subject Disposition and Withdrawals .............................................................................. 33 
 
Demographic and Other Baseline Characteristics ......................................................... 34 
Medical History, Neurologic History, and Concomitant Diseases ................................ 34 
 
Medication .......................................................................................................................... 35 
Prior and Concomitant Antiepileptic Treatments ......................................................... 36 
 
EFFICACY ..................................................................................................... 36 
Multiplicity Strategy and Testing Hierarchy .................................................................... 36 
 
Primary Efficacy Endpoint and Analysis ......................................................................... 37 
Primary Efficacy Endpoint Definition ........................................................................... 37 
Part 1 Primary Efficacy Endpoint Analyses ................................................................. 39 
5.3. 
5.4. 
5.5. 
6. 
6.1. 
6.2. 
6.3. 
6.4. 
6.5. 
6.6. 
6.6.1. 
6.6.2. 
6.6.3. 
6.7. 
6.8. 
6.9. 
7. 
7.1. 
7.2. 
7.3. 
7.4. 
7.4.1. 
8. 
8.1. 
8.2. 
8.2.1. 
8.2.2. 
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Sensitivity Analyses of Part 1 Primary Efficacy Endpoint ........................................... 41 
 
Key Secondary Analysis of the Primary Efficacy Endpoint ......................................... 43 
Key Secondary Efficacy Endpoints and Analyses ......................................................... 44 
 
Clinical Global Impression – Improvement (CGI-I) Rating, as assessed by the 
Principal Investigator .................................................................................................................... 44 
 
Additional Efficacy Endpoints and Analyses ................................................................. 44 
 
Countable Motor Seizures Definition and Analysis ..................................................... 44 
 
Additional Seizure Counts ........................................................................................... 45 
 
Seizure-Free Days ...................................................................................................... 46 
 
Duration of the Longest Interval between Seizures Resulting in Drops...................... 46 
 
Clinical Global Impression – Improvement Rating, as assessed by the Subject or 
Parent/Caregiver .......................................................................................................................... 47 
 
Incidence of Status Epilepticus ................................................................................... 47 
 
Rescue Medication Usage .......................................................................................... 48 
 
Incidence of Medical Services to Treat Seizures ........................................................ 49 
 
Vineland Adaptive Behavior Scale (VABS) ................................................................. 49 
 
Quality of Life in Childhood Epilepsy (QOLCE) Scale ................................................ 50 
 
Zarit Caregiver Burden Inventory ................................................................................ 51 
 
Patient/Caregiver Assessment using HADS Scale ..................................................... 52 
 
SAFETY ......................................................................................................... 53 
Extent of Exposure ............................................................................................................ 53 
Treatment Compliance (Diary) .......................................................................................... 53 
Adverse Events .................................................................................................................. 53 
 
Overview of Adverse Events ....................................................................................... 54 
 
Treatment Emergent Adverse Events ......................................................................... 55 
 
Adverse Events of Special Interest (AESI) ................................................................. 56 
 
Physical Examination ........................................................................................................ 56 
Neurologic Examination .................................................................................................... 57 
Vital Signs, Weight, and BMI ............................................................................................ 57 
 
Electrocardiogram ............................................................................................................. 58 
Doppler Echocardiography ............................................................................................... 58 
Tanner Staging ................................................................................................................... 58 
Laboratory Parameters ..................................................................................................... 58 
Columbia-Suicide Severity Rating Scale ......................................................................... 60 
Brief Rating Inventory of Executive Function (BRIEF) .................................................. 62 
8.2.3. 
8.2.4. 
8.3. 
8.3.1. 
8.4. 
8.4.1 . 
8.4.2. 
8.4.3. 
8.4.4. 
8.4.5. 
8.4.6. 
8.4.7. 
8.4.8. 
8.4.9. 
8.4.10. 
8.4.11. 
8.4.12. 
9. 
9.1. 
9.2. 
9.3. 
9.3.1. 
9.3.2. 
9.3.3. 
9.4. 
9.5. 
9.6. 
9.7. 
9.8. 
9.9. 
9.10. 
9.11. 
9.12. 
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 INTERIM ANALYSES .................................................................................... 63 
 CHANGE FROM PLANNED ANALYSES ..................................................... 63 
 PROGRAMMING CONSIDERATIONS .......................................................... 67 
 
General Considerations .................................................................................................... 67 
 
Table, Listing, and Figure Format .................................................................................... 67 
 
General ........................................................................................................................ 67 
 
Headers ....................................................................................................................... 68 
Display Titles ............................................................................................................... 68 
 
Column Headers ......................................................................................................... 68 
Body of the Data Display ............................................................................................. 69 
Footnotes .................................................................................................................... 71 
 QUALITY CONTROL ..................................................................................... 71 
 INDEX OF TABLES, FIGURES, AND LISTINGS .......................................... 72 
 REFERENCES ............................................................................................. 108 
 APPENDICES .............................................................................................. 109 
 
Appendix 1 – Seizure Types ........................................................................................... 109 
 
Seizure Classification – Primary Endpoint ................................................................... 109 
10. 
11. 
12. 
12.1. 
12.2. 
12.2.1. 
12.2.2. 
12.2.3. 
12.2.4. 
12.2.5. 
12.2.6. 
13. 
14. 
15. 
16. 
16.1. 
16.2. 
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GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
adverse events 
AED 
Antiepileptic Drugs 
AESI 
adverse event of special interest 
ALB 
albumin 
ALT;SGPT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AP 
alkaline phosphatase 
AS 
atonic seizures 
AST; SGOT 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
BRI 
Behavioral Regulation Index 
BRIEF 
Behavior Rating Inventory of Executive Function 
BUN 
blood urea nitrogen 
Ca 
calcium 
CBD 
cannabidiol 
CGI-I 
Clinical Global Impression – Improvement 
CI 
confidence interval 
CL 
chloride 
CMH 
Cochran-Mantel-Haenszel 
CO2 
carbon dioxide 
CS 
clonic seizures 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSD 
Daily Seizure Diary 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
eCRF 
electronic Case Report Form 
EMI 
Emergent Metacognition Index 
ESC 
Epilepsy Study Consortium 
ET 
Early Termination 
FI 
Flexibility Index 
FS 
focal seizures 
FSH 
Follicle Stimulating Hormone 
1. 
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Abbreviation 
Description 
GEC 
Global Executive Composite 
GGT 
gamma-glutamyl transferase 
GH 
Growth hormone 
GTC 
generalized tonic-clonic seizures 
HS 
hemiclonic seizures 
ICH 
International Conference on Harmonisation 
IGF-1 
insulin-like growth factor-1 
IMP 
Investigational Medicinal Product 
INR 
International normalized ratio 
ISCI 
Inhibitory Self-Control Index 
IWR 
Interactive Web Response system 
K 
potassium 
kg 
kilogram 
LDH 
lactate dehydrogenase 
LGS 
Lennox-Gastaut syndrome 
LH 
Luteinizing Hormone 
M 
Maintenance Period 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MI 
Metacognition Index 
mITT 
Modified Intent-to-Treat Population 
MS 
myoclonic seizures 
MS 
myoclonic seizures 
Na 
sodium 
PBPK 
physiologically-based pharmacokinetic 
PK 
pharmacokinetics 
PP 
Per Protocol Population 
PT 
Preferred Term 
PT 
Prothrombin time (PT) 
PTT 
partial thromboplastin time 
Q1 
25th Percentile / 1st Quartile 
Q3 
75th Percentile / 3rd Quartile 
QoL 
Quality of Life 
QOLCE 
Quality of Life in Childhood Epilepsy 
SAF 
Safety Population 
SAP 
statistical analysis plan 
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Abbreviation 
Description 
SD 
standard deviation 
SE 
status epilepticus 
SE 
status epilepticus 
SOC 
System Organ Class 
SOP 
Standard Operating Procedures 
STC 
secondarily tonic-clonic 
T+M 
Titration and Maintenance Periods 
T+M 
Titration and Maintenance Periods 
TA 
tonic/atonic seizures 
TEAE 
Treatment-emergent adverse events 
TLF 
tables, data listings, figures 
TS 
tonic seizures 
TSH 
thyroid stimulating hormone 
VABS 
Vineland Adaptive Behavior Scale 
WHO-DD 
World Health Organization Drug Dictionary 
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PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the summary tables, 
figures, and data listings that will be produced for Part 1 of the trial, and the statistical 
methodologies that will be used, are complete and appropriate to allow valid conclusions 
regarding the study objectives. 
RESPONSIBILITIES 
Syneos Health will perform the statistical analyses and are responsible for the production 
and quality control of all tables, figures and listings with the exception of 
pharmacokinetics (PK), electrocardiogram (ECG), and echocardiogram (ECHO).  
Separate analysis plans for PK and for ECG/ECHO will be produced. 
BioMedical Systems, a division of Biomedical System/ERT, will provide analyses of 
electrocardiogram (ECG) and echocardiogram (ECHO) data. 
 
TIMING OF ANALYSES 
Study 1601 is an international multicenter study being conducted in two parts. Up to 
approximately 80 study sites in North America, Europe, Australia, and Japan are 
planned to participate. Part 1 is a double-blind, parallel-group, placebo-controlled, 
study to assess the efficacy and safety of two doses of ZX008 when used as adjunctive 
therapy for seizures in children and adult subjects with LGS. Part 1 will include 2 
cohorts: Cohort A will include randomized subjects from North America, Europe, and 
Australia; Cohort B will include randomized subjects from Japan. 
All objectives will be evaluated in Cohort A and B independently. Data from Part 1, Cohort 
A will constitute the primary analyses of the study. The primary analyses for Part 1, 
Cohort A of the study, to include safety, efficacy, and pharmacokinetics, will be 
conducted once all Cohort A subjects have completed Part 1 of the study and the per-
protocol population and other populations have been defined, and approval for unblinding 
has been granted by Zogenix International Limited. This analysis will be completed by the 
primary unblinded statistical team of Syneos Health. 
Data from Part 1, Cohort B will be analyzed independently after the last subject in Cohort 
B completes Part 2 and the per-protocol population and other populations have been 
defined, and approval for unblinding of Cohort B has been granted by Zogenix 
International Limited. 
Analysis results for Part 1 from Cohort A and B will be compared through descriptive 
statistics and if reasonable, some analyses may be performed using data from Cohorts A 
and B combined. 
2. 
2. 1. 
2.2. 
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Additional analyses for long-term safety and effectiveness will be completed 
independently by Cohort once all subjects from each cohort have completed Part 2 of the 
study. The description of methodology of analysis for Part 2 of the study will be provided 
in a separate SAP. 
 
UNBLINDING PLAN 
Cohort A is expected to finish Part 1 before Cohort 2. In order to prevent any bias in the 
completion of Cohort B, whether intentional or unintentional, an unblinding plan will be 
generated. The unblinding plan will identify individuals (by name or role) who will be 
unblinded and responsible for the analyses and reporting of Cohort A, Part 1. These 
unblinded individuals will have no involvement in study decisions that would have the 
potential to affect data integrity for Cohort B. 
 
PART 1 OBJECTIVES 
Cohorts A and B will be analyzed independently. Cohort A will be analyzed after the last 
subject completes Part 1. These analyses will form the main analyses to establish safety 
and efficacy of ZX008 in patients with LGS. Cohort A Part 1 will be evaluated with 
formal statistical testing as described below. Cohort B will be analyzed after the last 
subject completes Part 2. Inferential statistics for Cohort B will be evaluated using the 
same methodology stated for Cohort A, but the inferential statistics will be considered 
as descriptive. 
 
PRIMARY OBJECTIVE 
The primary objective of Part 1, Cohort A is the primary objective of the entire study. 
The primary objective of Part 1 is: 
•
To evaluate the effect of ZX008 0.8 mg/kg/day versus placebo as adjunctive
therapy for the treatment of uncontrolled seizures in children and adults with
Lennox-Gastaut syndrome (LGS) based on the change in frequency of seizures
that result in drops (DSF) between baseline and the combined Titration and
Maintenance Periods (T+M).
Seizures that result in drops include seizures of the following types that have been 
reviewed and confirmed for each subject as a drop seizure by the Epilepsy Study 
Consortium (ESC): generalized tonic-clonic seizures [GTC], secondarily generalized 
tonic-clonic seizures [SGTC], tonic seizures [TS], atonic seizures [AS], tonic/atonic 
seizures [TA]. 
 
KEY SECONDARY OBJECTIVE 
The key secondary objectives of Part 1, Cohort A are: 
•
To evaluate the effect of ZX008 0.2 mg/kg/day versus placebo as adjunctive
therapy for the treatment of uncontrolled seizures in children and adults with
2.3. 
3. 
3.1. 
3.2. 
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LGS based on the change in DSF baseline and Titration and Maintenance Periods 
(T+M). 
•
To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus
placebo on the proportion of subjects who achieve a ≥ 50% reduction from
baseline in the frequency of seizures that result in drops.
•
To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus
placebo on the Clinical Global Impression – Improvement (CGI-I) rating, as
assessed by the principal investigator.
 
ADDITIONAL SECONDARY OBJECTIVES 
Additional secondary objectives of Part 1, Cohort A of the study are: 
•
To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus
placebo on the following endpoints:
o
Change in frequency of all seizures that (typically) result in drops (i.e.,
GTC, SGTC, TS, AS, TA) between baseline and the combined T+M whether
ESC confirmed as drop or not.
o
Change in the frequency of all countable motor seizures between
baseline and T+M (countable seizures include: GTC, SGTC, TS, AS, TA,
clonic seizures [CS], focal seizures with clear observable motor signs [FS],
and hemiclonic seizures [HS]).
o
Change in the frequency of all countable non-motor seizures between
baseline and T+M (countable non-motor seizures include: absence,
myoclonic, focal without clear observable motor signs, infantile spasms,
and epileptic spasms)
o
Change in the frequency of all countable seizures (i.e., motor and non-
motor) between baseline and T+M
o
Change in frequency of seizures that result in drops (ESC confirmed)
between baseline and the Maintenance Period (M)
o
Change in frequency of seizures that (typically) result in drops between
baseline and the Maintenance Period (M)
o
Change in the frequency of all countable motor seizures between
baseline and M
o
Change in the frequency of all countable non-motor seizures between
baseline and M
o
Change in the frequency of all countable seizures (i.e., motor and non-
motor) between baseline and M
o
The proportion of subjects who achieve a worsening, >0 - <25%, ≥25%,
≥50%, ≥75%, 100% reduction, and “near seizure freedom” (i.e. 0 or 1
seizures) between baseline and T+M, and baseline and M, in seizures that
result in drops (ESC confirmed), seizures that typically result in drops, all
countable motor seizures, all countable non-motor seizures, and all
countable seizures
o
Number of seizure-free days, defined as 1) no seizures that result in
drops (ESC confirmed), and 2) days with no countable motor seizures
3.3. 
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o
Longest interval between seizures that result in drops (ESC confirmed)
•
To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus
placebo on the Clinical Global Impression – Improvement (CGI-I) rating, as
assessed by the parent/caregiver.
 
SAFETY OBJECTIVES 
The safety objectives of Part 1, Cohort A are: 
•
To evaluate the safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day versus
placebo with regard to adverse events (AEs), laboratory parameters, physical
examination, neurological examination, vital signs (blood pressure, heart rate,
temperature, and respiratory rate), electrocardiograms (ECG), echocardiograms
(ECHO), body weight, and body mass index (BMI)
•
To evaluate the change from baseline in cognition using age-appropriate versions
of the Behavior Rating Inventory of Executive Function (BRIEF)
 
PHARMACOKINETIC OBJECTIVES 
The pharmacokinetic (PK) objective of the study is: 
•
To evaluate the PK of ZX008 0.2 and 0.8 mg/kg/day at steady state in
subjects < 18 years and ≥18 years with LGS using a non-compartmental
analysis and obtain exposure data that will be used in population
pharmacokinetic (PopPK) analysis, the results of which will be reported
separately.
 
EXPLORATORY OBJECTIVES 
The exploratory objectives of the study are: 
•
To compare the ZX008 0.2 and 0.8 mg/kg/day doses on primary, secondary, and
safety endpoints.
•
To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus
placebo on the following endpoints:
–
The change from baseline in behavior using the Vineland Adaptive
Behavior Scale (VABS)
–
The change from baseline in quality of life (QoL) using the QOLCE
–
The change from baseline in caregiver burden using the Zarit Caregiver
Burden Inventory
–
The change from baseline in affective symptoms of the parent/caregiver
using the Hospital Anxiety and Depression Scale (HADS)
–
The frequency of rescue medication usage
–
The incidence of medical services to treat seizures
–
The incidence of status epilepticus.
3.4. 
3.5. 
3.6. 
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BRIEF DESCRIPTION 
Study 1601 is an international multicenter study being conducted in two parts. Up to 
approximately 80 study sites in North America, Europe, Australia, and Japan are 
planned to participate. Part 1 is a double-blind, parallel-group, placebo-controlled, 
study to assess the efficacy and safety of two doses of ZX008 when used as adjunctive 
therapy for seizures in children and adult subjects with LGS. Part 1 will include 2 
cohorts: Cohort A will include randomized subjects from North America, Europe, and 
Australia; Cohort B will include randomized subjects from Japan. The main analyses for 
the study, including the primary and key secondary study endpoints are assessed from 
Part 1, Cohort A data. The primary analysis will be conducted when the last subject in 
Cohort A has completed Part 1. Part 2 will be an open-label, flexible-dose extension for 
subjects completing Part 1 of the study. 
Part 1 consists of a 4-week baseline, 2-week titration, 12-week maintenance, and 2-
week taper or transition period. The 4-week Baseline Period consists of the 
establishment of initial eligibility during a screening visit to include an assessment of 
cardiac parameters (ECG and ECHO), followed by an observation period where subjects 
will be assessed for baseline seizure frequency based on recordings of daily seizure 
activity entered into a diary. Upon completion of the Baseline Period, subjects who 
qualify for the study are randomized (1:1:1) in a double-blind manner to receive 1 of 2 
doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; maximum dose: 30 mg/day [or 0.5 
mg/kg/day, maximum 20 mg/day, for subjects taking concomitant STP]) or placebo. 
Randomization is stratified by weight (<37.5 kg, ≥ 37.5 kg) to ensure balance across 
treatment arms, and at least 25% of subjects will be in each weight group. All subjects 
are titrated to their blinded randomized dose over a 2-week Titration Period. Following 
titration, subjects continue treatment at their randomly assigned dose over a 12-week 
Maintenance Period. Total treatment time from the beginning of the Titration Period 
through the end of the Maintenance Period is 14 weeks. Subjects will have ECG and 
ECHO assessments at weeks 6 and 14 during the Maintenance Period. At the end of the 
Maintenance Period (or early discontinuation), all subjects undergo a blinded 2-week 
taper or transition period (Post-Dosing Follow-Up) depending on whether they exit the 
study or are enrolled in Part 2, the long-term open-label extension, respectively. 
Cardiac safety follow-up visits are performed after study drug discontinuation for early 
termination, or for those subjects who complete the study but do not enter the open-
label extension part. All subjects are required to have follow-ups at 3 and 6 months. 
Subjects enrolled in Germany, France and Netherlands will have an additional follow-up 
at 24 months. If there are any findings at a post-dose follow-up, a follow-up visit will be 
scheduled every 3 months until resolved or stabilized.  
Part 2 is an open-label, long-term safety study of ZX008 for subjects who have 
successfully completed 14 weeks of treatment (titration + maintenance) in Part 1 and 
are candidates for continuous treatment for an extended period of time; subjects who 
have not completed the entire 14 weeks of treatment in Part 1 may be eligible to 
participate in Part 2 on a case-by-case basis and only following sponsor approval. Part 2 
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consists of a 12-month Open-Label Extension (OLE) Treatment Period and a 2-week 
Post-Dosing Period. Thus, subjects who were randomized to ZX008 during Part 1 and 
complete Part 2 will have been treated with ZX0008 for at least 70 weeks (including 
their participation in both Part 1 and Part 2). 
During Part 2 all subjects are treated initially with 0.2 mg/kg/day for 1 month to assess 
effectiveness of this dose in all study subjects. After 1 month at a dose of 0.2 
mg/kg/day, the investigator may adjust the dose for each subject based on 
effectiveness and tolerability. Dose changes should be made in increments of 0.2 
mg/kg/day, to a maximum of 0.8 mg/kg/day (or 0.5 mg/kg/day for subjects taking 
concomitant STP) but not to exceed total dose of 30 mg/day (or 20mg/kg/day for 
subjects taking concomitant STP). During the 12-month OLE subjects will have ECG and 
ECHO assessments at months 1, 3, 6, and 9, and at the end of study visit. 
A follow-up ECG and ECHO will be performed at 3 and 6 months after study drug 
discontinuation for early termination and for those subjects who complete Part 2. 
Subjects enrolled in Germany, France and Netherlands will have an additional follow-up 
at 24 months. If there are any findings at a post-dose follow-up, another follow-up will 
scheduled every 3 months until resolved or stabilized. In both Part 1 and Part 2 
parents/caregivers will use a diary every day to record the number of seizures, type of 
seizures, time and duration of seizures, whether the seizure resulted in a drop, dosing 
of study drug, and use of rescue medication. 
SUBJECT SELECTION 
The inclusion and exclusion criteria are stated in full in the protocol document in 
sections 4.1, 4.2, and 4.3. 
 
DETERMINATION OF SAMPLE SIZE 
The sample size for Part 1 Cohort A was estimated under the assumption that adding 
ZX008 at 0.8 mg/kg/day to current therapy will lead to a mean decrease in drop 
seizures that is 30 percentage points greater than adding placebo to current therapy. 
For example, if adding placebo leads to a 10% decrease in seizures, then adding the high 
dose of ZX008 would be expected to decrease seizures by at least 40%. 
The variability expected in the trial was estimated from a Phase 3 trial of clobazam for 
patients with Lennox-Gastaut syndrome (Ng 2011) leading to an assumption that the 
standard deviation (SD) is 50%. Other assumptions include an allowance for 20% dropouts 
between randomization and the start of the maintenance period. Under these 
assumptions, a sample size of 63 subjects per treatment group for a nonparametric 
analysis affords 90% power to detect a difference between the ZX008 0.8 mg/kg/day 
and placebo groups that is significant at the α=0.05 level. Assuming a 20% drop-out rate 
prior to the start of the maintenance period yields a requirement for an additional 14 
subjects per group for a total of 79 subjects per treatment group for a nonparametric 
analysis. Similar calculations for the 0.2 mg/kg/day ZX008 group lead to a total required 
4. 1. 
4.2. 
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sample size of 237. The number of subjects randomized into Part 1 Cohort A is 
estimated to be approximately 250 due to the long baseline period. 
 
TREATMENT ASSIGNMENT & BLINDING 
Upon completion of the Baseline Period in Part 1, subjects who qualified for the study 
were randomized (1:1:1) in a double-blind manner to receive 1 of 2 doses of ZX008 (0.2 
mg/kg/day, 0.8 mg/kg/day; 30mg/day maximum [0.2 mg/kg/day or 0.5 mg/kg/day; 20 
mg/day maximum for subjects taking concomitant STP]) or placebo. The randomization 
was stratified by weight (<37.5 kg, ≥37.5 kg) to ensure balance across treatment arms, 
with a target of at least 25% in each weight group. Subjects were assigned a 
randomization number by the IWR system upon confirmation that the subject qualified 
for enrollment in the Titration Period. 
The primary biostatistical team, data management team, and clinical team will remain 
blinded to subject treatment assignments until approval is given for the unblinding of 
the Part 1, Cohort A database and finalization of inclusion in the study populations is 
made.  
The release of unblinded pharmacokinetic concentration data, ECG and ECHO data to 
facilitate external analyses will be completed only after the approval for unblinding of 
the Part 1 database by Zogenix.  
 
ADMINISTRATION OF STUDY MEDICATION 
Each bottle of study medication contains the appropriate concentration and volume of 
liquid to administer the assigned treatment (ZX008 0.2 mg/kg/day, ZX008 0.8 
mg/kg/day [or 0.5 mg/kg/day for subjects taking concomitant STP], or placebo). ZX008 
and placebo are identical, thus rendering the study drug and placebo indistinguishable.  
The blinding scheme instituted for this study ensures that the volume of study 
medication taken cannot be associated with the dose group, thus unblinding the study. 
This is achieved by random assignment of different concentrations of ZX008 or placebo 
(1.25 mg/mL, 2.5 mg/mL, and/or 5 mg/mL) by the IWR system. The IWR system 
instructs site personnel to the volume of oral solution to be administered based on that 
subject’s weight. (Dose is recalculated by the system based on weight once at the 
midpoint of Part 1 of the study.) During the Titration, Maintenance, and 
Taper/Transition Periods, the subjects and study personnel (investigators, clinical staff, 
personnel involved in data collection and analysis, the Medical Monitor, and the 
sponsor) are blinded to the treatment allocation and to the concentration of ZX008. If 
an investigator feels the blind should be broken, he/she can do so when necessary for 
treatment decisions. However, the investigator should endeavor to discuss with the 
Medical Monitor or Sponsor’s Medical Representative, if available. The blind should only 
be broken in the event the knowledge of whether the subject is on active study 
medication versus placebo is needed to determine course of medical treatment for the 
event. The subject will be discontinued from the clinical trial upon breaking of the blind 
4 .3. 
4.4. 
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and the decision whether the subject can enter Part 2 will rest with the Sponsor if the 
subject exited Part 1 prior to completion. 
Following randomization subjects enter the Titration Period and are blindly titrated to 
their randomized dose as outlined in Table 1. 
Table 1: Titration Algorithm for Part 1 
Randomized Group 
Titration Step 1 
Study Days 1-4 
Titration Step 2 
Study Days 5-8 
Titration Step 3  
Study Days 9-14 
ZX008 0.2 
mg/kg/day 
ZX008 0.2 
mg/kg/day 
ZX008 0.2 
mg/kg/day 
ZX008 0.2 
mg/kg/day 
ZX008 0.8 
mg/kg/day  (0.5 
mg/kg/day for 
subjects taking 
concomitant STP) 
ZX008 0.2 
mg/kg/day 
ZX008 0.4 
mg/kg/day 
ZX008 0.8 
mg/kg/day 
(0.5 mg/kg/day for 
subjects 
taking concomitant 
STP) 
Placebo 
Placebo 
Placebo 
Placebo 
After completion of the Titration Period, subjects enter the Maintenance Period and 
continue to receive the randomized dose of ZX008 or placebo and be treated for an 
additional 12 weeks.  
Subjects who complete the Maintenance Period and do not be continue into Part 2, the 
open-label extension, and subjects who discontinue from Part 1 early, will be tapered 
off of study medication as outlined in Table 2.  
Table 2: Taper Algorithm for Part 1 
Randomized Group 
Taper Step 1 
Day 1-4 after study 
completion or early 
termination 
Taper Step 2 
Days 5-8 after study 
completion or early 
termination 
ZX008 0.2 mg/kg/day 
Placebo 
Placebo 
ZX008 0.8 mg/kg/day  (0.5 
mg/kg/day for subjects 
taking concomitant STP) 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
Placebo 
Placebo 
Placebo 
Subjects who complete the Maintenance Period and will be continuing into the open-
label extension (Part 2) will be transitioned from double-blind study medication to 
open-label ZX008. All subjects entering the open-label extension (Part 2) will be 
transitioned from their blinded daily dose to the 0.2 mg/kg/day dose during the 2-week 
interval between Visits 12 and 15, without breaking the blind. The IWR system will 
assign two bottles of Investigational Medicinal Product (IMP) to the subject, one for 
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each step in the transition. A new bottle of IMP will be started by the subject at each 
level of the transition step.  
Table 3: Transition Algorithm for Part 1 
Dose Group in Double-
Blind Study 
Transition Step 1  
Day 1-4 after Visit 12 
Transition Step 2  
Day 5-14 after Visit 12 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.8 mg/kg/day  (0.5 
mg/kg/day for subjects 
taking concomitant STP) 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
Placebo 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
The full list and timing of study procedures is provided in Table 4. 
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Table 4 – Schedule of Assessments 
Part 1 Assessments 
Study Assessments – PART 1 
Baseline Perioda 
Titration + Maintenance Period 
EOS/ 
ETb 
Post-
Dosingl 
Cardiac 
Follow-
upc 
Visit Number 
Screening 
Random-
ization 
Titration Period 
Maintenance Period 
1 
2 
(Phone)
3 
4, 5 
(Phone)
6 
7 
(Phone)
8 
9 
(Phone)
10 
11 
(Phone) 
12 
13 
14 
Study Day 
-28
-15
-1
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
197 
Informed Consent (subject and 
parent/caregiver) 
X 
X 
(Part 2) 
Inclusion/Exclusion Criteria 
X 
X 
Demographics 
X 
Medical/Neurological History 
X 
Epilepsy history 
X 
Review retrospective seizure 
diary data 
X 
Prior Medication, including 
AEDs 
X 
X 
Physical Examination, complete 
X 
X 
X 
Optional 
Physical Examination, 
abbreviated  
Xm 
Xm 
Xm 
X 
Neurological Examination, 
complete 
X 
X 
Neurological Examination, 
abbreviated 
X 
Xm 
Xm 
Xm 
Vital signs 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
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Table 4 – Schedule of Assessments 
Part 1 Assessments 
Study Assessments – PART 1 
Baseline Perioda 
Titration + Maintenance Period 
EOS/ 
ETb 
Post-
Dosingl 
Cardiac 
Follow-
upc 
Visit Number 
Screening 
Random-
ization 
Titration Period 
Maintenance Period 
1 
2 
(Phone)
3 
4, 5 
(Phone)
6 
7 
(Phone)
8 
9 
(Phone)
10 
11 
(Phone) 
12 
13 
14 
Study Day 
-28
-15
-1
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
197 
Height 
X 
X 
Chest x-ray (France, Netherlands 
only) 
X 
X 
X 
12-lead ECG
X 
X 
X 
X 
X 
Doppler ECHO 
X 
Xd 
Xd 
X 
Urine or Serum Pregnancy Test 
Xe 
Xe 
Xe 
Xe 
Clinical laboratory evaluation 
(hematology/ chemistry/urinalysiso, etc) 
X 
X 
X 
X 
Plasma sample for ZX008 PK 
Xf 
Plasma sample for background 
AEDs PK 
Xg 
Xg 
X 
Xg 
Xg 
Whole blood CBD/ THC Panel 
X 
X 
X 
X 
Tanner Staging (for subjects >7 to 
18 years old) 
X 
X 
Subject Diary 
D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/Dh 
C/R 
Epilepsy genotype panel 
(optional) 
X 
Study Medication 
D 
Ri 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/Dh 
C/R 
C-SSRS 
X 
X 
X 
X 
X 
X 
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Table 4 – Schedule of Assessments 
Part 1 Assessments 
Study Assessments – PART 1 
Baseline Perioda 
Titration + Maintenance Period 
EOS/ 
ETb 
Post-
Dosingl 
Cardiac 
Follow-
upc 
Visit Number 
Screening 
Random-
ization 
Titration Period 
Maintenance Period 
1 
2 
(Phone)
3 
4, 5 
(Phone)
6 
7 
(Phone)
8 
9 
(Phone)
10 
11 
(Phone) 
12 
13 
14 
Study Day 
-28
-15
-1
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
197 
Clinical Global Impression - 
Improvement (assessed by 
parent/caregiver) 
X 
X 
X 
X 
Clinical Global Impression - 
Improvement (assessed by 
Principal Investigator) 
X 
X 
X 
X 
HADS (Effect of 
parent/caregiver) 
X 
X 
BRIEF 
X 
X 
VABS 
X 
X 
X 
QOLCE 
X 
X 
Zarit Burden 
X 
X 
X 
Randomize subject 
Xn 
First Day of Study Drug 
Administrationj
Xj 
Daily Diary Completion 
X 
Concomitant Medication 
X 
Adverse events 
X 
Adverse events of special interest 
X 
Xk 
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Table 4 – Schedule of Assessments 
Part 1 Assessments 
Study Assessments – PART 1 
Baseline Perioda 
Titration + Maintenance Period 
EOS/ 
ETb 
Post-
Dosingl 
Cardiac 
Follow-
upc 
Visit Number 
Screening 
Random-
ization 
Titration Period 
Maintenance Period 
1 
2 
(Phone)
3 
4, 5 
(Phone)
6 
7 
(Phone)
8 
9 
(Phone)
10 
11 
(Phone) 
12 
13 
14 
Study Day 
-28
-15
-1
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
197 
Abbreviations: AED=antiepileptic drug; BMI=body mass index; C=Collect; CBD=cannabidiol; D=Dispense; ECG=electrocardiogram; EQ-5D-5L=standardized measure of health status; EOS=end 
of study; ET=early termination; HADS=Hospital Anxiety and Depression Scale; BRIEF=Behavior Rating Inventory of Executive Function; QoL=quality of life; R=Review; VABS=Vineland 
Adaptive Behavior Scale 
a: 
The Baseline Period is comprised of the initial screening for the study and the assessment of baseline seizure activity recorded daily in the diary. The procedures to be completed at the 
Screening visit may be completed in a single day or split so that they are completed over the 2-day period. 
b: 
Subjects who are discontinued early and those who complete the study and choose not to enroll in the separate open-label extension will be tapered off study medication over an up to 2-week 
period. 
c: 
The safety follow-up visit will be conducted for subjects who either terminate early from Part 1, or who complete Part 1 but do not enter Part 2. Standard follow-up visits should occur 3 and 6 
months after the last dose. For subjects enrolled in Germany, France and Netherlands, follow-ups will also occur 24 months after the last dose. If there are any findings at the last post-dose 
follow-up, a follow-up visit will be repeated every 3 months until resolved or stabilized. 
d: 
The Visit 8 ECHO must be performed any time between Study Day 40 and Study Day 54. The Visit 12 ECHO must be performed any time between Study Day 90 and Study Day 113; if a 
subject discontinues early from the study, the ECHO should be scheduled as soon as practical. If the Study Day 43 ECHO was completed < 30 days prior to early termination, the Visit 12 
ECHO will not be performed provided the parent/guardian agrees to bring the subject to the clinic for the cardiac follow-up visit. 
e: 
Females of child-bearing potential 
f: 
Plasma sample for pharmacokinetic assessment will be conducted prior to the dose at Visit 8 and 1, 2, and 4-6 hours after dose administration. 
g: 
Plasma sample for assessment of background AED(s) will be conducted prior to the dose of AED(s) at Visits 3, 8 and 12 (Visits 6 and 10 only if clinically indicated). AED plasma sample may 
be collected after the morning dose of AEDs are taken, if preferable, as long as the time of last dose is accurately recorded. 
h: 
Study drug/diary dispensed for the Transition Period for subjects entering the open-label extension and for the Taper Period for subjects exiting the study. 
i: 
Site personnel will review study medication dosing procedure (titration) with parent/caregiver. 
j: 
Study drug administration begins in the morning of Study Day 1. Study Day 1 is considered the first day of dosing, even though subjects may receive an in-clinic dose on Study Day -1. If the 
first dose is taken in the clinic, it will be recorded in the eCRF, but not the subject diary; the next dose on the morning of Study Day 1 will be the first entry in the subject’s diary. 
k: 
Only adverse events related to cardiac safety will be collected at this visit. 
l: 
Visit 13 may be conducted as a phone call, provided diaries and study medication are returned by this time. 
m: 
An abbreviated physical and/or neurological examination to be conducted as appropriate based on last exam and reported AEs. 
n: 
Randomization should not occur prior to receiving approval from the Epilepsy Study Consortium and ERT ECHO results. 
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Table 4 – Schedule of Assessments 
Part 1 Assessments 
Study Assessments – PART 1 
Baseline Perioda 
Titration + Maintenance Period 
EOS/ 
ETb 
Post-
Dosingl 
Cardiac 
Follow-
upc 
Visit Number 
Screening 
Random-
ization 
Titration Period 
Maintenance Period 
1 
2 
(Phone)
3 
4, 5 
(Phone)
6 
7 
(Phone)
8 
9 
(Phone)
10 
11 
(Phone) 
12 
13 
14 
Study Day 
-28
-15
-1
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
197 
o: 
Urine for urinalysis may be collected at home, the night before the clinic visit, as long as collection procedures are followed to maintain sample stability. 
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The targeted study day and allowable windows for visits in Part 1 are reproduced from 
the protocol below. Early termination visits will be mapped to a visit based on these 
windows. 
Table 5: Visit windows for Part 1 Visits 
Visit / Procedure 
Time window (relative to 
scheduled visit / 
procedure) 
Visit 1 (Clinic; Study Day -29 to -28 or -28 to -27): 
Not Applicable 
Visit 2 (Phone; Study -15) 
± 3 days 
Visit 3 (Clinic; Study Day -1; Randomization 
± 4 days a 
Visits 4, 5 (Phone: Study Days 4, 8) 
± 3 days 
Visit 6 (Clinic; Study Day 15) 
± 4 days 
Visit 7 (Phone; Study Day 29) 
± 4 days 
Visit 8 (Clinic; Study Day 43) 
± 4 days 
Visit 9 (Phone: Study Day 57) 
± 4 days 
Visit 10 (Clinic; Study Day 71) 
± 4 days 
Visit 11 (Phone: Study Day 85) 
± 4 days 
Visit 12 (Clinic: Study Day 99) 
± 4 days 
Visit 13 (Clinic; Study Day 113; post dosing) 
± 4 days 
Visit 14 (ECHO clinic; 3-24 months after last dose)b 
+ 30 days
AED=antiepileptic drug (s); ECHO=echocardiogram;. 
a In cases where the screening period is extended beyond 28 days, the immediate 28 
days before the Randomization visit will be used to calculate the baseline seizure 
frequency 
b All subjects are required to have follow-ups at 3 and 6 months post-treatment. 
Subjects enrolled in Germany, France and Netherlands will have an additional 24-month 
follow-up. 
 
ENDPOINTS 
PRIMARY EFFICACY ENDPOINT 
Percent change from baseline in the frequency of seizures that result in drops (DSF) 
in the combined Titration and Maintenance Periods (T+M) in the ZX008 0.8 
mg/kg/day group compared to the placebo group. Seizures that results in drops are 
GTC, SGTC, TS, AS, and TA confirmed for each subject as a drop seizure by the ESC. 
 
KEY SECONDARY EFFICACY ENDPOINTS 
The key secondary endpoints are: 
5. 
5.1. 
5.2. 
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•
Change from baseline in DSF in T+M in the ZX008 0.2 mg/kg/day group compared
to the placebo group.
•
Proportion of subjects who achieve a ≥50% reduction from baseline in the
frequency of seizures that result in drops comparing the ZX008 0.8 mg/kg/day
and 0.2 mg/kg/day groups independently versus placebo.
•
Proportion of subjects who achieve improvement (minimally, much or very much
improved) in the Clinical Global Impression – Improvement as assessed by the
Principal Investigator comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day
groups independently versus placebo.
 
ADDITIONAL SECONDARY EFFICACY ENDPOINTS 
The additional secondary endpoints are: 
ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups compared independently versus 
placebo on the 
•
Change from baseline during T+M in frequency of all seizures that (typically)
result in drops (i.e., GTC, SGTC, TS, AS, TA) whether ESC confirmed as drop or
not.
•
Change from baseline during T+M in frequency of all countable motor seizures
(GTC, SGTC, TS, AS, TA, CS, FS, and HS).
•
Change from baseline during T+M in frequency of all countable non-motor
seizures (absence, myoclonic, focal without clear observable motor signs,
infantile spasms, and epileptic spasms).
•
Change from baseline during T+M in the frequency of all countable seizures (i.e.,
motor and non-motor).
•
Change from baseline during M in the frequency of seizures that result in drops.
•
Change from baseline during M in the frequency of seizures that typically result
in drops.
•
Change from baseline during M in the frequency of all countable motor seizures.
•
Change from baseline during M in the frequency of all countable non-motor
seizures.
•
Change from baseline during M in the frequency of all countable seizures (i.e.,
motor and non-motor).
•
Proportion of subjects who achieve a worsening from baseline (i.e. ≤ 0%
reduction), or >0%, ≥25%, ≥50%, ≥75%, or 100% reduction between baseline and
T+M, and baseline and M, in seizures that result in drops (ESC confirmed),
seizures that typically result in drops, all countable motor seizures, all countable
non-motor seizures, and all countable seizures.
•
Number of seizure-free days in the baseline, M and T+M period, defined as 1)
days with no seizures that results in drops (ESC confirmed), and  2) days with no
countable motor seizures
•
The longest interval (days) between seizures that result in drops (ESC
confirmed) comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups
independently versus placebo
5.3. 
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•
Clinical Global Impression – Improvement as assessed by the parent/caregiver
 
SAFETY ENDPOINTS 
The safety endpoints for Part 1 of the study are: 
•
AEs
•
Laboratory safety (hematology, chemistry, urinalysis)
•
Vital signs (blood pressure, heart rate, temperature, and respiratory rate)
•
Body weight and BMI
•
Physical examination
•
Neurological examination
•
BRIEF to measure changes in cognition of the subject
•
Columbia Suicidality Severity Rating Scale (C-SSRS)
•
12-lead ECGs
•
Doppler ECHOs
•
Chest x-ray (for subjects enrolled in France and Netherlands only)
•
EEG (for subjects enrolled in Italy only)
 
EXPLORATORY ENDPOINTS 
The exploratory endpoints for Part 1 of the study are: 
•
The change from baseline in behavior using the Vineland Adaptive Behavior Scale
(VABS)
•
The change from baseline in quality of life (QoL) using the Quality of Life in
Childhood Epilepsy (QOLCE)
•
The change from baseline in caregiver burden using the Zarit Caregiver Burden
Inventory
•
The change from baseline in affective symptoms of parent/caregiver using the
HADS scale
•
Incidence of status epilepticus in the M and T+M period.
•
Incidence of rescue medication usage in the T+M and M periods
•
Number of days rescue medication used in the T+M and M periods
•
Incidence in use of medical services to treat seizures in the M and T+M periods
ANALYSIS SETS 
Separate analysis data sets will be produced for Cohort A and Cohort B. Cohort A will 
include subjects from North America, Europe, and Australia; Cohort B will include 
subjects from Japan. 
5.4. 
5.5. 
6. 
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ENROLLED POPULATION 
The enrolled population is defined as all subjects who signed the informed consent 
form. This population will be used for listings. 
 
SAFETY (SAF) POPULATION 
All Part 1 safety analyses will be performed on the SAF Population defined as all 
randomized subjects who receive at least one dose of ZX008 or placebo. 
 
MODIFIED INTENT-TO-TREAT (MITT) POPULATION 
The mITT Population is defined as all randomized subjects who receive at least one 
dose of ZX008 or placebo and for whom at least one week of diary data are available. 
Subjects will be analyzed according to the treatment group to which they were 
randomized. The primary comparison of ZX008 0.8 mg/kg/day to placebo, as well as key 
secondary analyses, will be performed on the mITT Population. 
 
PER PROTOCOL (PP) POPULATION 
The PP Population is defined as all randomized subjects who receive at least one dose 
of ZX008 or placebo, who complete at least 4 weeks of diary data in the maintenance 
period, and who have no major protocol deviations that would have a significant impact 
on clinical outcome of Part 1 data, and who have met the inclusion criteria for baseline 
drop seizure count. Protocol deviations that occurred during Part 1 will be reviewed and 
the list of deviations warranting exclusion from the PP Population will be finalized prior 
to study unblinding.  
 
PROTOCOL DEVIATIONS 
Major protocol deviations will be summarized overall and by site based on the SAF 
population. Major protocol deviations are those that have the potential to impact 
subject safety and/or affect data integrity and/or the efficacy conclusions. Major 
protocol deviations will be grouped into categories and may include categories such as: 
•
Violation of inclusion/exclusion criteria
•
Violation of randomization inclusion criteria
•
Non-compliance regarding intake of IMP
•
Inappropriate intake of concomitant medication
•
Subject not discontinued as per protocol
•
Other non-compliance
Multiple deviations can occur in the same subject and thus a subject can be counted in 
more than 1 deviation category. 
Major and minor protocol deviations will be presented in a subject data listing for the 
enrolled population, sorted by treatment, site, subject, and study part.  
6. 1. 
6.2. 
6.3. 
6.4. 
6.5. 
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Deviations will be reviewed prior to the database lock of Part 1 data to determine which 
deviations will be classified as leading to exclusion from the PP set. 
 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
 
General Methods 
All statistical analyses will be performed using SAS statistical software (Version 9.4 or 
later). 
Part 1 summaries will be presented by treatment group (Placebo, ZX008 0.2 mg/kg/day, 
ZX008 0.8 mg/kg/day).  
Continuous data will be summarized using descriptive statistics including means, 
standard deviations, medians, lower and upper quartiles, minimum and maximum 
values. Categorical variables will be summarized with frequencies and percentages. 
Confidence intervals will be calculated for key parameters or estimates as warranted. 
Two-sided statistical significance testing (α= 0.05) comparing each active treatment to 
placebo will be performed for the primary and secondary endpoints as described below, 
unless otherwise noted. 
All relevant collected subject data will be included in listings. All subjects entered into 
the database will be included in data listings. 
Unless otherwise specified in the subsequent sections, in the event of multiple 
assessments at a given planned time point, the latest collected value will be used for 
the summarization. 
 
Definitions 
First Dose Date: First Dose Date of Investigational Drug: If the first diary date on the 
day after randomization indicates that investigational drug was taken on this day, then 
the first dose date will be the date after randomization (Study Day 1). In all other 
situations where it is known that the subject took at least one dose of medication, the 
first dose date will be assumed to be 1 day after the date of randomization. 
Study Day: Study day will be calculated relative to the First Dose Date in the Titration 
Period. For any date on or after the date of first dose, study day will be calculated as 
assessment date – first dose date + 1. For any date prior to the date of first dose, study 
day will be calculated as assessment date – first dose date. There will be no Study Day 
0. 
Baseline Value: For non-seizure frequency assessments, the Part 1 baseline value will 
be the last non-missing assessment collected on or prior to the first date of dosing in 
Part 1. Unscheduled assessments prior to First Dose Date will be considered for 
selection of the baseline value. Baseline values for seizure frequency endpoints will be 
6.6. 
6.6.1. 
6.6.2. 
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determined from the immediate 28 days prior to study day 1 (i.e. the First Dose Date) 
using methods described below.  
 
Missing Data 
The term missing date refers to a completely missing date or to an incomplete 
date/partial date where parts are not available, e.g. missing month/day/year. 
Missing Adverse Event Start and End Dates 
Missing start and end date will be imputed conservatively, i.e. missing values will be 
imputed in such a way that the duration of the AE is considered with the longest 
possible duration and such that, whenever the AE may potentially start after first date 
of study medication, the AE will be handled as a treatment-emergent adverse event 
(TEAE). 
The missing Start date and End date of an AE will be imputed for the purpose of 
calculating treatment emergent status and assigning events to treatment periods using 
definitions given in the following table. 
Adverse event 
Partial  
/Missing 
Start date 
Missing day – If Adverse event day is missing but month and year is 
present then Impute the 1st of the month unless month is same as 
month of first dose of study drug in Part 1 then impute first dose date 
in Part 1.  
Missing day and month – If adverse event day and month are both 
missing but year is present then impute 1st January unless year is the 
same as first dose date in Part 1 then impute first dose date in Part 1. 
Completely missing – impute first dose date in Part 1 unless the end 
date suggests it could have started prior to this in which case impute 
the 1st January of the same year as the end date.  
When imputing a start date, ensure that the new imputed date is 
sensible i.e., is prior to the end date of the AE. 
Partial 
/Missing End 
date 
Missing day – If AE end day is missing but month and year are present 
then Impute the last day of the month unless month is same as month 
of last dose of study drug then impute last dose date.  
Missing day and month – If AE has missing day and month but year is 
present then impute 31st December unless year is the same as first 
dose date then impute last dose date.  
Completely Missing – need to look at whether the AE is still ongoing 
before imputing a date and also when it started in relation to study 
drug. If the ongoing flag is missing then assume that AE is still present 
6.6.3. 
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(i.e. do not impute a date). If the AE has stopped and start date is 
prior to first dose date then impute the 1st dose date. If the AE started 
on or after the first dose date then impute the last dose date.  
Data Handling for Seizure Diaries 
Seizures are recorded in the Daily Seizure Diary (DSD). On each day, subjects are asked 
a question of whether there is a seizure to report that day. Subjects may either answer 
“Yes” and continue to complete more details about the seizure, or answer “No, this day 
has been seizure free”. There will be no explicit imputation of intermittent missing data 
for seizure diaries. Missing seizure diary data will be handled as follows: 
•
If no seizures are entered in the DSD and the response to the question, is there a
seizure to report that day, is “No, this day has been seizure free” then that day
will have the seizure count set to 0.
•
If seizures are entered in the DSD and the response to the question, is there a
seizure to report that day, is “No this day has been seizure free” the seizures
entered in the DSD will supersede the seizure freedom affirmation.
•
If no seizures are entered in the DSD and there is no response to the question, is
there a seizure to report that day, that day will be considered to have missing
diary data.
•
If no seizures are entered in the DSD and it is indicated that there were seizures
that day, that day will be considered to have missing diary data.
 
VISIT WINDOWS 
The following rules will be used to window data into treatment periods for by treatment 
period tabulations. For all by-visit tabulations, the nominal visit as recorded on the 
electronic Case Report Form (eCRF) will be used. 
The following are the definitions for associating dates with the treatment periods of 
Part 1. 
Baseline Period 
The Baseline Treatment period will be the 28 days 
immediately prior to the date of the Study Day 1. 
Double Blind 
Treatment Period 
The Double-Blind Treatment Period start date is the date of 
first full daily dose (i.e. Study Day 1). The Double-Blind 
Treatment Period end date is the last date the subject was 
on study treatment in Part 1. 
The Double-Blind Treatment Period consists of 16 weeks 
from first treatment start date, which includes 2 weeks of 
Titration period, 12 weeks of Maintenance period and 2 
weeks of Taper/Transition period. The end date for efficacy 
analyses is the last day of Maintenance treatment, or Visit 
12; the end date for safety analyses is the last day of 
6.7. 
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Taper/Transition, which would be considered the date at 
Visit 15. 
For subjects who discontinue early from the study, the 
double-blind treatment period end date for efficacy 
analyses will be the date at the early termination visit (Visit 
12); the end date for safety analyses would be the date of 
Visit 13. If a taper is not conducted, the end date for both 
analyses would be Visit 12. 
Titration Period 
The Titration Period begins on the first full day of treatment 
(Study Day 1) and extends through Visit 6 (when the subject 
has reached their randomization dose). The Titration Period 
applies to all subjects including placebo recipients. If a 
subject withdraws from the study prior to treatment in the 
maintenance period, all safety assessments and events up to 
and including the date of study withdrawal will be tabulated 
in the titration period. 
Maintenance 
Period 
The Maintenance Period covers the 12 weeks following the 
end of the titration period. It begins on the date of Visit 6 + 
1 day and extends through the end of study/early 
termination visit (Visit 12). 
Titration + 
Maintenance 
Period (T+M) 
The T+M period combines the Titration and Maintenance 
periods, beginning on the date of first treatment (Study Day 
1) and extending through the end of study/end of treatment
visit (Visit 12).
Taper/Transition 
Period 
The Taper/Transition period consists of 2 weeks starting 
from end of study/early termination visit (Visit 12) + 1 day 
through Visit 13 (Taper) or Visit 15 (Transition to Part 2). 
For subjects who are not entering into the Part 2 of the 
study, subjects will gradually be tapered off of study 
medication. 
For subjects who are entering Part 2, subjects will enter the 
transition phase where all subjects will be on a dose of 0.2 
mg/kg/day at the end of this phase. 
 
POOLING OF CENTERS 
Analysis will be pooled overall and by cohort (A vs. B). 
 
SUBGROUPS 
The following subgroups will be utilized for some efficacy analyses and adverse event 
summarizations: 
6.8. 
6.9. 
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Age: 2– <6 years, 6–<12 years, 12 - <18, 2-<18 years, ≥ 18 – 35 years. 
Sex: Male, Female 
Baseline Weight: <37.5 kg vs. ≥ 37.5 kg 
Number of concomitant Antiepileptic Medications Used: ≤2, 3, ≥4 medications 
Number of prior Antiepileptic Medications Used: 0-3, 4-6, 7-9, ≥10 medications 
Baseline Frequency of Seizures that Result in Drops (events/28 days): based on observed 
tertiles 
Usage of a specific concomitant medication(s) (top 3 concomitant AEDs to be 
determined by data review) (Yes / No) 
 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
 
SUBJECT DISPOSITION AND WITHDRAWALS 
The Part 1 subject disposition will be presented per treatment group and overall for 
Cohort A and B independently.  
For describing the Part 1 subject disposition, the following will be summarized by 
number and percentage: 
•
Subjects enrolled (only overall)
•
Subjects enrolled but not randomized and reason for not-randomized (only
overall)
•
Subjects randomized
•
Subjects in SAF
•
Subjects in mITT
•
Subjects in PP
•
Subjects assigned to SAF, mITT, PP and discontinued the study and reason.
•
Number of subjects in the trial per trial period/phase (Titration Phase,
Maintenance Phase, Taper Period for those not entering Part 2, and Follow-up
Period) will be presented for SAF and mITT sets.
•
Trial completers
-
Trial completers continuing into Part 2
-
Trial completers not continuing into Part 2 and reason for not continuing
Part 1 trial completers include: 1.) subjects who did not discontinue prior to the Visit 
12, and 2.) subjects who completed at least through Visit 8 and enrolled into the Part 2 
open label extension. 
7. 
7. 1. 
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For subjects enrolled but not randomized to treatment in Part 1, and for the tallies 
listed under each reason for not being randomized, the denominator used to calculate 
the percentage will be the number of enrolled subjects. For all other calculations in the 
Part 1 disposition table, the denominator will be the number of subjects randomized.  
All subject disposition data will be listed using the enrolled population and sorted by 
treatment and site. 
 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Part 1 subject demographics and baseline characteristics will be summarized 
descriptively per treatment group and overall, for the SAF and mITT populations for 
Cohort A and B.  
The following demographic characteristics will be summarized: 
•
Age [Years]
•
Categorized age as: 2 - <6 years, ≥ 6 - <12 years; ≥12 - <18 years, ≥ 18 – 35 years.
•
Sex
•
Race
•
Ethnicity
•
Height [m]
•
Weight [kg]
•
BMI [kg/m2]
•
Geography: North America, Europe, Australia, Japan (Cohort B analysis only)
All subject demographics data will be listed for the enrolled population. 
 
MEDICAL HISTORY, NEUROLOGIC HISTORY, AND CONCOMITANT DISEASES 
Medical history and neurologic history will be summarized and sorted alphabetically, by 
primary System Organ Class and Preferred Term coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) Version 20.1 or later. The number and percentage of 
subjects will be displayed for each System Organ Class (SOC) and Preferred Term (PT) 
within treatment group. 
Medical history will be presented for the SAF population, separated by Cohort A and B. 
All medical history data of subjects will be listed for the enrolled population, by Cohort 
A and B. 
7.2. 
7.3. 
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MEDICATION 
Medication (collected on the prior antiepileptic medications, prior medications, and 
concomitant medications eCRF page) will be coded using the World Health Organization 
Drug Dictionary (WHO-DD) Format B3 Version Sep2017 or later.  
The following algorithm will be used to define prior and concomitant in Part 1. 
Prior medications will be those with a stop date prior to first dose administration in Part 
1. 
Concomitant medications in Part 1 will be defined as those medications that were 
initiated after study drug administration in Part 1 (but excluding medications that 
started on or after the first dose of study medication in Part 2) or those medications 
that were ongoing at the date of first study drug administration in Part 1. 
The medication will be assumed to be prior medication if it cannot be definitively 
shown that the medication did not start or continue during the Part 1 treatment period. 
If the start date or stop date of a medication is partially missing, the date will be 
compared as far as possible with the date of the start of administration of study drug. 
The following approach will be taken: 
•
If the start date of medication is complete and occurs on or after the day of the
first full dose, the medication will be assumed concomitant. If the start date
occurs prior to the first full dose date but the end date is on or after the first
dose date or the medication is recorded as ongoing, the medication will be
considered concomitant.
•
If the start day is missing but the start month and year are complete, a
medication will only be excluded as being concomitant if the start month/year is
before the month/year of study drug administration and if the stop date (either
full date, month and year if missing day, or year if missing month and day) is
before study drug administration.
•
If the start day and month are missing but the start year is complete, a
medication will only be excluded as concomitant if the start year is before the
year of study drug administration and if the stop date (either full date, month
and year if missing day, or year if missing month and day) is before study drug
administration.
•
If the start date is completely missing and the stop date is prior to first dose or
completely missing, the medication will be assumed to be a prior medication.
A medication may be counted as concomitant in Part 1 and in Part 2. By definition, a 
prior medication cannot be counted as concomitant in Part 1. Medication will be 
summarized and sorted alphabetically separately for prior and concomitant medication 
by Anatomical Therapeutic Chemical (ATC) categories (Level 2: pharmacological or 
therapeutic subgroup and Level 3: chemical or therapeutic or pharmacological 
subgroup) and WHO-DD drug code. For each medication the number and percentage of 
subjects will be displayed.  
7.4. 
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Part 1 medication summary tables will be presented for the SAF population. 
All prior and concomitant medications/treatments will be listed for the enrolled 
population. 
 
Prior and Concomitant Antiepileptic Treatments 
Medication (collected on the prior antiepileptic medications, prior medications, and 
concomitant medications eCRF page) will be coded using the World Health Organization 
Drug Dictionary (WHO-DD) Format B3 Version Sep2017 or later. Anti-epileptic 
medications will be identified using any drug entered on the prior-antiepileptic 
medication page and anti-seizure concomitant medications with indication of “Lennox-
Gestaut Syndrome”.  
Prior and concomitant antiepileptic medications will be defined and analyzed for the 
SAF and OLE similar to concomitant medications as described in Section 7.4. 
All prior and concomitant antiepileptic treatments will be listed for the enrolled 
population. 
Note that further summaries of rescue medications recorded on the daily medication 
diary are described in the efficacy section.  
 
EFFICACY 
The analysis of the Part 1 primary and secondary efficacy parameters will be performed 
on the mITT population for Cohort A and B independently, except where noted. 
The Part 1 primary efficacy endpoint and key secondary efficacy analyses will be 
repeated on the PP Population for Cohort A and B independently, in order to assess the 
impact of major protocol deviations on the key inference.  
All primary and key secondary variables will be analyzed for data obtained for the T+M 
period, and will be repeated for data obtained during the M period only. 
 
MULTIPLICITY STRATEGY AND TESTING HIERARCHY 
The Part 1, Cohort A efficacy analyses will employ a serial gatekeeper strategy to 
maintain the Type 1 error rate at α=0.05 across the family of analyses that support the 
primary and key secondary objectives. The strategy specifies a hierarchy of significance 
tests where each test acts as a gatekeeper to the tests below it. 
The hierarchy starts with the primary analysis comparing ZX008 0.8 mg/kg/day to 
placebo on the change in number of seizures that results in drops from baseline. The 
next steps in the hierarchy entail the comparisons for the key secondary endpoints.  
•
Change from baseline in frequency of seizures that result in drops in T+M in the
ZX008 0.2 mg/kg/day group compared to placebo.
7.4.1 . 
8. 
8.1 . 
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•
Proportion of subjects who achieve a ≥50% reduction from baseline in the
frequency of seizures that result in drops in the ZX008 0.8 mg/kg/day and 0.2
mg/kg/day groups independently versus placebo.
•
Proportion of subjects who achieve improvement (minimally, much, or very
much improved) in the Clinical Global Impression – Improvement (CGI-I) as
assessed by the Principal Investigator comparing the ZX008 0.8 mg/kg/day and
0.2 mg/kg/day groups independently versus placebo.
Below is a complete list of steps in the testing hierarchy in order: 
1. Compare ZX008 0.8 mg/kg/day to placebo on the change in frequency in seizures
that result in drops per 28 days between the Baseline and T+M periods.
2. Compare ZX008 0.8 mg/kg/day to placebo on the proportion of subjects who
achieve a ≥ 50% reduction from baseline in the number of seizures that result in
drops.
3. Compare ZX008 0.8 mg/kg/day to placebo on the CGI-I at Visit 12.
4. Compare ZX008 0.2 mg/kg/day to placebo on the change in frequency in seizures
that result in drops per 28 days between the Baseline and T+M periods.
5. Compare ZX008 0.2 mg/kg/day to placebo on the proportion of subjects who
achieve a ≥ 50% reduction from baseline in the number of seizures that result in
drops.
6. Compare ZX008 0.2 mg/kg/day to placebo on the CGI-I at Visit 12
 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS
 
Primary Efficacy Endpoint Definition 
The Part 1 primary efficacy endpoint is the percent change from baseline in the 
frequency in seizures that result in drops per 28 days in the T+M period. The following 
seizure types from the DSD will be included in the frequency count of seizures resulting 
in drops, if for an individual subject, the seizure as listed in the eCRF has been 
confirmed and approved by the Epilepsy Study Consortium (ESC) as a ‘drop seizure’: 
•
atonic seizures [AS]
•
tonic seizures [TS]
•
tonic/atonic seizures [TA]
•
generalized tonic-clonic seizures [GTC]
•
secondarily generalized tonic-clonic [SGTC]
For each subject, the frequency of drop seizures will be calculated from all available 
data collected during the Baseline and T+M Periods. Subjects in the ZX008 
0.8 mg/kg/day treatment group will be compared to those in the placebo on the 
frequency of drop seizures (DSF) during T+M adjusted for the frequency during Baseline 
using a non-parametric ANCOVA model. 
The baseline period is the 28 days immediately preceding the date of Study Day 1. The 
T+M period is planned for 14 weeks. However, actual durations will be computed for 
8,2. 
8.2.1. 
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each subject based on the individual subject’s start and stop dates for each period, 
except that if the baseline period is longer than 28 days, the frequency for the baseline 
period will be calculated with data from the 28 days immediately preceding the Study 
Day 1. 
The frequency of drop seizures will be counted from the daily diary records provided by 
the Subject or Parent/Caregiver. 
Responses to the DSD question about the frequency of seizure episodes will be handled 
differently according to the following response options. 
Response 
Number of seizures 
No seizures 
0 
A single seizure 
1 
An episode of many discrete seizures 
Based on the response to the Question 12 
for frequency of episodes 
A cluster of seizures back to back 
This will be determined empirically 
dependent on the duration of the cluster 
event and the number of events reported 
in a discrete seizure event for subjects in 
the study.  
Seizure Clusters 
Seizure clusters are entered in the DSD by estimating the duration of the cluster in 
hours: minutes; seconds. For seizure clusters the number of discrete seizures that 
occurred during a cluster is not entered in the DSD. In order to estimate the number of 
seizures during a cluster, the number of seizures will be imputed using the seizure 
count and duration of seizures recorded for “an episode of many discrete seizures”. 
Specifically, episodes of discrete seizures include both an estimate of the number of 
seizures, and an estimate of the duration, categorized into 1 of 3 buckets: <2 minutes; 
2-10 minutes; >10 minutes.
Study-level summary statistics using seizure events reported in the T+M period will be 
calculated for each bucket to determine the median number of seizures occurring in 
each bucket. 
The median number of seizures will then be used to impute counts for seizure clusters: 
•
‘short’ clusters (i.e., ≤59 minutes) will be the median number of seizures
reported in discrete seizure events <2 minutes
•
‘medium’ clusters (i.e., 1-5 hours) will be the median number of seizures
reported in discrete seizure events 2-10 minutes
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•
‘long’ clusters (i.e., >5 hours) will be the median number of seizures reported in
discrete seizure events >10 minutes.
For any individual subject, the frequency of drop seizures per 28 days during the 
baseline period (DSFB) will be derived as follows: 
DSFB =
28 ×  Total number of drop seizures during the Baseline Period
Total number of days in the Baseline Period with nonmissing diary data
For each treatment group, the median and mean DSFB will be calculated. 
Similarly, for each subject, the frequency of DSF per 28 days for the T+M period (DSFT+M) 
is derived as below: 
DSFT+M =
28 ×  Total number of drop seizures during the T + M Period
Total number of days in the T + M Period with nonmissing diary data
The percentage change from baseline for any individual subject will be estimated by 
PCDSFT+M = (DSFT+M - DSFB)*100/DSFB
The difference from baseline (CDSFT+M) will be estimated by CDSFT+M = DSFT+M −DSFB. 
For each treatment group, descriptive statistics for DSF during baseline, T+M and M 
only, as well as the differences and % changes from baseline, will include the number of 
observations, mean, standard deviation, median, minimum and maximum, overall. 
 
Part 1 Primary Efficacy Endpoint Analyses 
T+M Period: 
The primary analysis will compare the ZX008 0.8 mg/kg/day group to the placebo group 
for Cohort A using a two-sided test at the α=0.05 level of significance. 
The primary endpoint will be analyzed using a non-parametric analysis of covariance 
(ANCOVA) model with treatment group (three levels; Placebo, 0.2 mg/kg/day, 0.8 
mg/kg/day) and weight strata group (< 37.5 kg, ≥ 37.5 kg) as factors, rank of baseline 
DSFB as a covariate and rank of percent CDSFT+M as response. Treatment group mean 
differences from placebo will be estimated via least squares means from the analysis 
model along with 95% confidence intervals.  
The null hypothesis 
H0: 𝜇𝜇Z0.8 −𝜇𝜇P = 0, 
will be tested against the alternative 
HA: 𝜇𝜇Z0.8 −𝜇𝜇P ≠0, 
where µZ0.8 and µP represent the ZX008 0.8 mg/kg and Placebo group location parameter, 
respectively.  
8.2.2. 
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Rejection of the null hypothesis in favor of the alternative, in the presence of a 
statistically significantly smaller seizure frequency for the treatment group compared to 
the placebo group, (two-sided p-value <.05) will be regarded as evidence of a treatment 
benefit in favor of the 0.8 mg/kg group. A similar comparison of the location parameter 
for Z008 0.2 mg/kg/day vs. placebo will be regarded as evidence of a treatment benefit 
of the 0.2 mg/kg group. This is the 3rd key secondary endpoint. 
Sample SAS code for the non-parametric ANCOVA described above is as follows: 
Proc rank data=temp ties=mean out=ranktemp; 
  Var bsrd csrd; 
  Rank r_bsrd r_csrd; 
Run; 
proc glm data=ranktemp; 
class wtgrp trtp; 
model r_csrd = r_bsrd wtgrp trtp  / SS3; 
lsmeans  trtp / pdiff stderr; 
where trtp = randomized treatment group (with codes 1, 2, 3 indicating placebo, 0.2 
mg/kg, and 0.8 mg/kg groups). 
r_bsrd = rank of baseline DSF𝐵𝐵,  
r_csrd = rank of percent CDSFT+M 
wtgrp = weight group. 
Additional statements may be used to obtain estimates and associated 95% confidence 
intervals.  
A second analysis of the primary endpoint will be completed using a parametric analysis 
of covariance (ANCOVA) model with treatment group (three levels; Placebo, 0.2 
mg/kg/day, 0.8 mg/kg/day) and weight group (<37.5 kg, ≥37.5 kg) as factors, log 
baseline DSFB as a covariate and log (CDSFT+M +1) as response. Treatment group mean 
differences from placebo will be estimated via least squares means from the analysis 
model along with 95% confidence intervals. Since the least square means and 
confidence intervals will be on the log scale, these least square means and confidence 
intervals will be exponentiated back to the original scale. 
The null hypothesis 
H0: 𝑚𝑚Z0.8 −𝑚𝑚P = 0, 
will be tested against the alternative 
HA: 𝑚𝑚Z0.8 −𝑚𝑚P ≠0, 
where mZ0.8 and mP represent the ZX008 0.8 mg/kg and Placebo group means (on the log 
scale), respectively.  
Sample SAS code for the parametric ANCOVA described above is as follows: 
--
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proc glm data=temp; 
class wtgrp trtp; 
model cdsf = bdsf wtgrp trtp  / SS3; 
lsmeans  trtp / pdiff stderr; 
where trtp = randomized treatment group (with codes 1, 2, 3 indicating placebo, 0.2 
mg/kg, and 0.8 mg/kg groups). 
bdsf = log(DSF𝐵𝐵 +1),  
cdsf = log(DSFT+M +1) 
wtgrp = weight group. 
Additional statements may be used to obtain estimates and associated 95% confidence 
intervals. Endpoints of the confidence interval (CIs) will be translated to the original 
scale using the ranks.  
M Period only: 
The primary endpoint analysis described above will be repeated using data from the 
Maintenance period only as response. For subjects who did not reach the Maintenance 
period, their Transition period data will be used to represent their M period data. 
Similar non-parametric and parametric ANCOVA models will be used. 
Treatment by baseline seizure category interaction: 
Treatment by baseline seizure category interaction: The non-parametric and parametric 
analysis for the T+M and M period described above will be repeated with baseline 
seizure frequency as a categorical variable, rather than a covariate, and will include 
baseline seizure frequency by treatment interaction. Baseline seizure frequency per 28 
days will be categorized using tertiles. 
 
Sensitivity Analyses of Part 1 Primary Efficacy Endpoint 
Wilcoxon Rank-sum Test 
The ZX008 0.8 mg/kg/day group will be compared to the placebo group on the percent 
change from baseline in seizures resulting in drops using a Wilcoxon rank-sum test. The 
median difference between the groups, and its 95% confidence interval, will be 
estimated using the Hodges-Lehmann estimator. 
Impact of Antiepileptic Drugs (AED) 
Subjects in the study are required to be on stable background therapy. Using the MITT 
population, an additional nonparametric ANCOVA analysis will be performed to assess 
the impact on the primary analysis of changes in dose or type of concomitant AED, 
which are protocol violations that may occur during the course of the study.  
For this analysis, each subject will be classified according to the number of concomitant 
AEDs used during the T+M period. Fisher’s exact tests will be used to compare the 
8.2.3. 
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active dose groups with the placebo group on the percentage of subjects within each 
group who have a change in concomitant AEDs.  
Per protocol Analysis 
The primary efficacy ANCOVA will be repeated on the per protocol population (which 
excludes subjects with important protocol deviations that may affect the inference on 
efficacy such as a change in dose or type of concomitant AED). 
No Imputation for Seizure Clusters 
The primary efficacy ANCOVA will be repeated on the mITT population with no 
imputation for seizure clusters; i.e., seizure clusters will not be calculated in the 
frequency of seizures that result in drops. 
Exclusion of Outliers 
The distribution of the primary endpoint is inherently asymmetric since no subject can 
have more than a 100% decrease in seizures, but there is no reason a subject couldn’t 
have a 200% or even 1000% increase. In fact, there is no theoretical upper bound to the 
possible magnitude of an increase in a percent change statistic. To assess the sensitivity 
of the primary analysis to extreme outliers in percent change in drop seizure frequency, 
the primary analysis will be repeated excluding any PCDSF value that satisfies Tukey’s 
criterion for a “far out” outlier (Tukey, 1977). Specifically, any PCDSF value that 
satisfies  
[𝑞𝑞ො.25 −3(𝑞𝑞ො.75 −𝑞𝑞ො.25),
𝑞𝑞ො.75 + 3(𝑞𝑞ො.75 −𝑞𝑞ො.25)] 
will be excluded where 𝑞𝑞ො.25 and 𝑞𝑞ො.75 are the sample lower and upper quartiles of the all 
PCDSF data combined. 
Imputation for Dropouts 
Two different methods for imputation of missing values due to subject drop out will be 
incorporated into the analysis of the primary efficacy endpoint. When referring to 
frequency in the paragraphs below, it refers to the number of seizure events per 28 
days. 
S1: Worst value substituted: In this analysis, for a subject who drops out of treatment, 
if the drop seizure frequency during T+M is lower than the baseline value, the baseline 
value will be substituted for the subject from the point of withdrawal to the end of the 
planned duration of T+M. However, if the seizure frequency during T+M is higher than 
the baseline value, there will be no substitution. The DSF for the planned duration of 
T+M will then be computed as a weighted mean of the value before dropout, and the 
imputed value after dropout. The weights will be the proportion of planned duration of 
T+M before and after dropout. The statistical analysis (nonparametric ANCOVA) 
described at the start of section 8.2.2 will then be performed on the resulting dataset. 
Treatment comparisons will be based on the least squares means and standard errors 
obtained from the ANCOVA. 
S2: Differential imputation method: In this analysis, subjects who dropout due to an 
adverse event, lack of compliance, loss to follow-up or subject choice will have their 
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convulsive seizure frequency for the remainder of the time during the planned T+M 
period replaced with the worse of the observed value or the baseline value as described 
for S1. However, for other withdrawal reasons (e.g., “lack of efficacy”) their observed 
DSF during T+M will be imputed for the remainder of the time between dropout and end 
of planned T+M. The DSF for the planned duration of T+M will then be computed as a 
weighted mean of the value before dropout and the imputed value after dropout. The 
weights will be the proportion of time before and after dropout. The statistical analysis 
(nonparametric ANCOVA) described at the start of section 8.2.2 will then be performed 
on the resulting dataset. Treatment comparisons will be based on the least squares 
means and standard errors obtained from the ANCOVA. 
Criteria for Establishing Efficacy 
While several supportive and/or supplementary analyses are specified above, the main 
criterion for demonstrating efficacy will be the primary non-parametric analysis for the 
mITT population from Cohort A.  
 
Key Secondary Analysis of the Primary Efficacy Endpoint 
The first key secondary endpoint compares treatment groups on the percentage of 
subjects with at least a 50% reduction from baseline in seizures resulting in drops. That 
is, the proportion of subjects in the ZX008 0.8 mg/kg/day group who have a decrease in 
frequency of seizures resulting in drops of at least 50 percentage points will be 
compared to the analogous proportion in the placebo group. This the 1st key secondary 
efficacy endpoint. 
The comparison of the percentage of subjects with at least a 50 percent drop from 
baseline between treatment groups will be made using a logistic regression model that 
incorporates the factors treatment and weight strata and the baseline seizure 
frequency. Separate models will be fit for ZX008 0.2 mg/kg/day vs. placebo and ZX008 
0.8 mg/kg/day vs. placebo. Achievement of the 50 percentage point reduction or 
greater, yes or no) will be modeled as a function of treatment group (2 levels; ZX008 
0.8 mg/kg/day (or ZX008 0.2 mg/kg/day) and placebo) and baseline weight strata group 
(<37.5 kg, ≥ 37.5 kg). If the model with treatment and weight strata is not convergent 
(e.g. due to a 0 count in a treatment by weight strata combination, the model will be 
refit using treatment only and the baseline seizure frequency. If the model still does not 
converge, no odds ratio and p-value from the logistic regression will be reported. 
The model estimated odds ratio (including a 95% confidence interval) and p-value for 
comparison of ZX008 0.8 mg/kg/day to placebo and ZX008 0.2 mg/kg/day to placebo 
will be provided. A supplementary Fisher’s exact test comparing treatment groups will 
be provided.  
Similarly, the number and percentage of subjects who have a worsening, ≥0% reduction, 
≥25% reduction, ≥50% reduction, ≥75% reduction, 100% reduction, and near seizure-
freedom will be tabulated for each treatment. Near seizure-freedom will be defined as 
having 0 or 1 seizures leading to a drop in the T+M period. These are additional 
secondary endpoints. 
8.2.4. 
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KEY SECONDARY EFFICACY ENDPOINTS AND ANALYSES 
 
Clinical Global Impression – Improvement (CGI-I) Rating, as assessed by 
the Principal Investigator  
The Principal Investigator will rate their global impression of the subject’s condition at 
each clinic visit after randomization: at the end of the Titration period Visit 6 (Day 15), 
during the Maintenance period at Visit 8 (Day 43) and Visit 10 (Day 71), and at Visit 12 
(End of Study / Early Termination). 
The CGI-I scale measures the change in the subject’s clinical status from a specific point 
in time, i.e., the Baseline Period. The CGI-I rating scale permits a global evaluation of 
the subject’s improvement over time. The severity of a subject’s condition is rated on a 
7-point scale ranging from 1 (very much improved) to 7 (very much worse) as follows:
1=very much improved 
2=much improved 
3=minimally improved 
4= no change 
5=minimally worse 
6=much worse 
7=very much worse 
The mean (SD) CGI-I score, and the number and percentage of subjects who showed 
improvement (i.e., had a score of 3 or lower), and the number and percentage who did 
not improve (i.e., had a score of 4 or higher) will be presented for each for each 
treatment group at each assessment time point. Each assessment time point will include 
a comparison between each active treatment and the placebo group using the Cochran-
Mantel-Haenszel test (CMH) stratified by weight strata, and a frequency distribution of 
the number and percentage of subjects in each category in the scale. A graphic showing 
the percentage of respondents in each category will be presented. 
The number and percentage of subjects who showed clinically meaningful improvement 
(i.e., had a score of 2 or lower), and the number and percentage who did not have 
clinically meaningful improvement (i.e., had a score of 3 or higher) will be presented 
for each treatment group at each assessment time point as an exploratory analysis. 
Individual subject CGI data will be listed. 
 
ADDITIONAL EFFICACY ENDPOINTS AND ANALYSES 
Countable Motor Seizures Definition and Analysis 
The change in the frequency of countable motor seizures per 28 days between the 
Baseline and T+M periods will be calculated using the same methodology described for 
the primary endpoint. Countable motor seizures include:  
8,3, 
8,3.1. 
8.4. 
8.4. 1. 
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•
generalized tonic-clonic seizures [GTC]
•
secondarily generalized tonic-clonic [SGTC]
•
tonic seizures [TS]
•
atonic seizures [AS]
•
tonic/atonic seizures [TA]
•
clonic seizures [CS]
•
hemiclonic seizures [HS]
•
focal seizures [FS] with clear observable motor signs
A change in the frequency of countable motor seizures per 28 days between the 
Baseline and M period will also be calculated. 
The same non-parametric and parametric ANCOVA models described for the primary 
endpoint will be used for the analyses of countable motor seizures (change in the 
frequency between Baseline and T+M periods). The mITT population will be used for this 
analysis. The difference between 0.8 mg/kg/day and placebo in the change between 
Baseline and T+M is a secondary endpoint. The analyses will be repeated for the change 
in frequency between the Baseline and M periods. The analysis of the change between 
Baseline and the M period is one of the additional secondary endpoints. 
The number and percentage of subjects who had a worsening, 0% reduction, ≥25% 
reduction, ≥50% reduction, ≥75% reduction, and 100% reduction in the frequency of 
countable motor seizures between Baseline and T+M and between Baseline and M will 
be summarized by treatment group and overall. These analyses are part of the 
additional secondary endpoints. 
 
Additional Seizure Counts 
The other efficacy endpoints of change in the frequency per 28 days between Baseline 
and T+M peropd and between Baseline and M period of:  
•
All Typical Drop Seizures (i.e., GTC, SGTC, TS, AS, TA regardless of ESC
confirmed as drop or not)
•
All Countable Non-Motor Seizures
•
All Countable Seizures
Each of these endpoints will be calculated using the same method as the primary 
endpoint. The same non-parametric ANCOVA, parametric ANCOVA, and logistic 
regressions used for the primary efficacy endpoint will be used. The mITT 
population and PP populations will be used for these analyses. 
Refer to Appendix 1 for the seizure types that are included in each of these 
endpoints.  
8.4.2. 
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Seizure-Free Days 
Seizure free days will be taken from the parent/caregiver diary data. 
A seizure free day with no seizures leading to drops will be defined as a day for which 
diary data are available and with no ESC-defined drop seizures. A day without countable 
motor seizures will be defined as a day for which diary data are available and with no 
countable motor seizures. The total number of countable seizure-free days and drop 
seizure-free days will be summed for the entire T+M period and similarly for the 
baseline period. 
Seizure-free days per 28 days at baseline = (number of seizure free days during 
baseline)*28/ (number of days during baseline with non-missing diary data) 
Seizure-free days per 28 days during T+M Period = (number of seizure free days during 
T+M Period)*28/ (number of days during T+M Period with non-missing diary data) 
Statistical comparison of treatment groups and placebo on the number of seizure free 
days per 28 days and drop seizure-free days per 28 days during T+M using the baseline 
as covariate will be done with a similar non-parametric ANCOVA model as described for 
the primary analysis. 
 
Duration of the Longest Interval between Seizures Resulting in Drops 
The duration of longest interval between seizures resulting in drops (in days) will be 
analyzed using nonparametric methods.  
For each subject, the duration of the longest interval between seizures resulting in 
drops (i.e., ESC confirmed) will be calculated over the entire T+M period. This will be 
derived as the maximum of the number of consecutive days between seizures resulting 
in drops. The length of the intervals between seizures resulting in drops will be 
calculated as below, after which the duration of the longest interval between 
convulsive seizures will be derived.  
If a subject has a missing diary day within an otherwise seizure-free interval, that day is 
counted towards the duration of the seizure free interval. However, if a subject has two 
consecutive days of missing diary data, the current seizure-free interval will end on the 
first date of missing diary data, and a new one begun on the next date that diary data 
are available and no seizure occurs. [In that case, for purpose of calculation of this 
variable, all intervening days, after the 2nd day, with missing diary data, will be 
assumed to have a seizure with drops occurrence, until the first available date with 
non-missing diary data.] 
Let Date0 (=Day1) be the first day of treatment. If a seizure resulting in a drop occurs 
on five days having dates as Date1, Date2, Date3, Date4, and Date5, where 
Date5>Date4>Date3>Date2>Date1≥Date0, and let LDT = Last date of treatment in the 
maintenance period, where LDT ≥ Date5, then the time interval between convulsive 
seizures will be calculated as follows: 
8.4.3. 
8.4.4. 
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I1=Date2 - Date1  
I2=Date3 - Date2  
I3=Date4 – Date3, 
I4=Date5 – Date4. 
For completeness, we calculate the time to the first seizure as 
I0=Date1 – Date0,  
and the time from the last seizure to end of treatment as 
I5 = LDT – Date5. 
Here the duration of the longest interval =Maximum (I0, I1, I2, I3, I4, I5). 
If the subject does not experience a seizure during treatment, then the last available 
diary date will be used to compute the duration of the longest interval as follows: 
The longest interval=last available diary date – Date0 
The median time of the longest interval between seizures resulting in drops (in days) 
will be presented. Additional summary statistics will be presented, including mean, 
minimum, maximum, and the 25th and 75th percentiles, 95% confidence intervals on 
the difference in medians between groups (Hodges-Lehman estimator). 
The Wilcoxon rank sum test will be used to test for differences between each treatment 
arm and placebo, and the p-value from this test will be presented. A boxplot 
summarizing the duration of the longest interval between seizures will be provided. 
 
Clinical Global Impression – Improvement Rating, as assessed by the 
Parent/Caregiver  
CGI-I score data assessed by the parent/caregiver will be summarized and analyzed 
using the same methods used for CGI-I score data recorded by Principal Investigator as 
above. 
 
Incidence of Status Epilepticus 
The incidence of status epilepticus (SE) will be evaluated based on: 1.) those entered as 
serious adverse events, and 2.) Seizures lasting longer than 10 minutes from the seizure 
diary. A single seizure meeting more than one of these criteria will be counted once.  
8,4,5, 
8.4.6. 
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The number and percentage of subjects with SE during the baseline and T+M period 
recorded as an AE will be presented by treatment group. Statistical comparisons of the 
difference in incidence will be tested using a Fisher’s Exact Test.  
From the diary data, change from baseline in the number of seizures with duration > 10 
minutes per 28 days for the baseline and T+M period will be reported. A nonparametric 
ANCOVA will be completed to compare active groups vs. placebo. As well, the number 
of unique days where status epilepticus was reported (normalized per 28 days) will be 
summarized and analyzed using the nonparametric ANCOVA. 
All seizures recorded in the AE database as status epilepticus should also be included in 
the seizure diary. An edit check will be performed to identify the overlap between 
seizures identified as AE of SE and seizures entered into the diary as seizures > 10 min. 
The “calculated” number and percentage of subjects experiencing SE will be presented 
by treatment group, defined as individuals who experience either an AE of SE, medical 
treatment for SE, or a seizure lasting longer than 10 minutes. Each subject will be 
represented once regardless of incidence. Statistical comparisons of the differences in 
incidence between treatment and placebo groups will be based on Fisher’s exact test. 
A second calculation will present the number of incidences of SE, according to the 
above definition, by treatment group normalized to per 28 days. In this analysis, a 
single subject may have more than one episode of SE, but an episode of SE recorded as 
both an AE and as a seizure longer than 10 minutes will be counted as a single episode. 
Statistical comparisons of the differences between treatment and placebo groups will 
be based on a Fisher’s Exact Test. A difference in percentages between baseline and 
the T+M period will be calculated and summarized within each treatment group. 
 
Rescue Medication Usage 
Use of rescue medication is recorded on the daily diary. In the event of prolonged 
seizures or status epilepticus, rescue medication is administered according to each 
subject’s personalized regimen consisting of one or more medications. If the first rescue 
administration does not control the seizures, a second or even third round might be 
administered. They second and third round might use different medications or different 
doses than the first round of rescue meds. 
Rescue medication will be summarized by treatment group and comparisons of active 
treatment vs. Placebo for the following: 
•
The number of days rescue medication was taken (normalized to 28 days) will be
summarized separately for the Baseline and T+M periods by the mean (SD) as
well as the median, minimum and maximum values. Multiple medications taken
on the same day will be counted once for that day. The ZX008 group will be
compared to the placebo group using a non-parametric ANCOVA analogous to
that described in the primary efficacy endpoint section. Specifically, the rank
ANCOVA will use the ranks of rescue medication frequency during T+M or M
period as the response, and will incorporate treatment group as a factor and the
ranks of rescue medication frequency during Baseline as a covariate.
8.4.7. 
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•
The number of medications used per episode will be summarized using similar
descriptive statistics as above. Rescue medications related to an episode of SE
are considered to be all rescue administered on the day of the SE (or seizure
lasting >10 min). If more than one episode of SE or a seizure lasting >10 min
occurred in a single day, the rescue medication for that episode is all rescue
administered after the seizure until the start time of the next prolonged seizure.
 
Incidence of Medical Services to Treat Seizures 
Data on hospitalization and healthcare resource use to treat seizures will be captured in 
the CRF and will be used to calculate incidence.  
Details of the hospitalizations, including reasons for hospitalization and use of resources 
will be summarized. The number and percentage of subjects who utilized medical 
center care to treat a seizure will be presented by treatment group for the T+M period. 
The mean, median, min and max describe the number of events or procedures per 
subject for those subjects who had at least one event or procedure. 
Statistical comparisons of the incidence of use of medical services between active and 
placebo groups will be provided using Fisher’s exact test. 
 
Vineland Adaptive Behavior Scale (VABS) 
The VABS is a parent/caregiver completed assessment that looks at the personal and 
social skills of individuals from birth through adulthood (Sparrow, S. S. & Cicchetti, D. 
V. (1989)). Because adaptive behavior refers to an individual's typical performance of
the day-to-day activities required for personal and social sufficiency, these scales assess
what a person actually does, rather than what he or she is able to do. The VABS assesses
adaptive behavior in 4 domains:
•
Communication
•
Daily living skills
•
Socialization
•
Motor skills
In Part 1, the VABS is collected at Visit 3 (Randomization), Visit 8 (Day 43), and Visit 12 
(End of Study/Early Termination).  
At each assessment, the standardized domain scores will be determined. 
For each domain, the change from baseline for each subject will be calculated by 
subtracting the domain score measured at Baseline from the analogous score measured 
at Visit 8 (Day 43) and Visit 12 (End of Study /Early Termination). Observed values and 
change from baseline will be summarized by descriptive statistics. The difference 
between treatment groups will be assessed using pairwise Wilcoxon rank-sum tests on 
the change from baseline. 
8,4,8, 
8.4.9. 
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The individual item outcomes and standardized domain scores will be presented in the 
subject data listing. 
 Quality of Life in Childhood Epilepsy (QOLCE) Scale 
The parent/caregiver will complete the QOLCE. This assessment looks at how epilepsy 
affects day-to-day functioning of their child in various life areas, including physical 
activities, well-being, cognition, social activities, behavior and general health (Sabaz et 
al., 2000; Talarska 2007). There is also one question on overall quality of life, 
administered as part of the QOLCE. 
The QOLCE is collected at Visit 3 (Randomization) and at Visit 12 (End of Study/Early 
Termination).  
The QOLCE scores items with a possible 5-point response. To calculate subscale scores, 
the 5-point item scores will first be reverse coded as necessary so that scores of 5 
represent the best possible response and 1 represents the worst possible response. 
[Details of the reverse coding are provided in the shells for the TLFs]. Item scores will 
then be transformed to a 0-100 scale as follows: 1 -> 0, 2 -> 25, 3 -> 50, 4 ->75, 5 -> 
100. After transformation, a score for each subject for each subscale is calculated by
averaging that subject’s responses to each item in the subscale. A value of 0 represents
the lowest or poorest score and 100 reflects the highest level of functioning. The 16
subscale scores per subject are then averaged to obtain an overall quality of life score
for each subject.
Summary descriptive statistics including the n, mean, standard deviation, median, 
minimum, and maximum will be generated for the index score at each scheduled 
collection time point. 
A higher subscale and overall quality of life score, indicates a better response. 
Table 6: Subscale of QOLCE: 
Domain 
Subscale 
Item 
Section 3: Physical 
Physical Restrictions 
3.1 a-j 
Section 3: Physical 
Energy/Fatigue 
3.2 a,b 
Section 4: Well-being 
Depression 
4.1 a,d,e,l 
Section 4: Well-being 
Anxiety 
4.1 b,g,j,n,o,p 
Section 4: Well-being 
Control/helplessness 
4.1 c,f,h,i 
Section 4: Well-being 
Self-esteem 
4.1 k,m,q,r,s 
Section 5: Cognition 
Attention/Concentration 
5.1 a,d,e,f,g 
Section 5: Cognition 
Memory 
5.1 j,k,l,m,n,o 
Section 5: Cognition 
Language 
5.1 p,q,r,s,t,u,v,w 
Section 5: Cognition 
Other Cognitive 
5.1 b,c,h 
Section 6: Social Activities 
Social Interactions 
6.1 c,f,h 
Section 6: Social Activities 
Social Activities 
6.1 a, e, 6.2 
Section 6: Social Activities 
Stigma Item 
6.1 i 
Section 7: Behavior 
Behavior 
7.1 a, 
c,f,g,h,i,j,k,l,m,o,q,r,s,t 
Section 8: General Health 
General Health 
8.1 
8.4.10. 
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Section 2 (USA Version) or 
Section 9 (Australia Version): 
Quality of Life 
Quality of Life Item 
2.1 or 9.1 
Overall Quality of Life * 
Average of 16 subscale scores* 
*An Overall Quality of Life Score will be computed by adding each subscale score for each
individual and then dividing by 16.
For each treatment group and at each schedule visit, the descriptive statistics will be 
presented for each QOLCE subscale and for the overall quality of life score.  
In addition, the change from baseline in the overall QOLCE will be calculated for each 
subject by subtracting the Part 1 baseline score from the score measured at each 
scheduled post-baseline visit. The change from baseline for each treatment group will 
be summarized by summary statistics. Treatment groups will be compared using 
pairwise Wilcoxon Rank-sum tests.  
Individual subject data for the domains will be listed. 
 
Zarit Caregiver Burden Inventory  
 
8.4.11. 
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Patient/Caregiver Assessment using HADS Scale 
8.4.12. 
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SAFETY 
All Part 1 safety analyses will be performed for the Safety population (SAF), as defined 
in Section 6.2 . Results will be reported by treatment group for the 16-week treatment 
period, unless noted otherwise. 
 
EXTENT OF EXPOSURE 
Part 1 treatment exposure data will be summarized for the SAF population. 
Duration of total exposure during Part 1 (i.e., time on treatment (in days)) will be 
calculated per subject as the number of days with IMP intake during the trial and will be 
summarized using n, mean, standard error, median, minimum, Q1, Q3 and maximum.  
This will be calculated for non-placebo subjects as: 
Date of last IMP intake in Part 1 – Date of first full daily IMP intake in Part 1 + 1 
Time on treatment will be summarized by the Part 1 treatment group. 
 
TREATMENT COMPLIANCE (DIARY) 
Study medication is to be administered twice daily, and self-reported compliance is 
recorded in the eDiary as full (both doses), partial (less than full daily dose) or missed 
(both doses) each day. From this, compliance will be calculated by assuming that a 
missed dose=0% of dose consumed, partial=50% of dose consumed, and full=100% of dose 
consumed. For each subject, a daily diary compliance score will be thus obtained.  
A compliance will also be determined based on the actual quantity taken, determined 
using the weight of the dispensed drug kit and weight of the returned drug kit. The 
expected quantity taken will be determined using the assigned dosage in mg/kg/day 
and the number of days they were assigned at that dosage. If a kit was not returned, 
the compliance for the period will be missing. 
For Part 1, compliance will be summarized for the SAF and mITT populations over the 
course of T+M period and M period only per recorded visit dates, reported by treatment 
group. 
 
ADVERSE EVENTS 
An AE is defined as any unfavorable and unintended sign (including an abnormal, 
clinically significant laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not considered related 
to the medicinal (investigational) product. For Part 1, the period of observation for 
adverse events extends from the time the subject gives informed consent until the end 
of the titration/transition period (Visit 13 or 15).  
9. 
9.1. 
9.2. 
9.3. 
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A treatment-emergent adverse event (TEAE) in Part 1 is defined as any AE that based on 
start date information occurs after the first intake of study treatment in Part 1, but not 
on or after the first dose of study treatment in Part 2. For subjects who participate in 
Part 2, the Part 1 TEAE will include events with onset up to the day prior to the date of 
first dosing in Part 2. A Part 1 TEAE will be further classified into the Titration Period, 
Maintenance Period, and Transition/Taper Period. The Titration Period will include all 
events with onset from the date of the first dose in Part 1 to date of the Visit 6. The 
Maintenance period will include all events with onset from the day after Visit 6 through 
the date of Visit 12. The Transition/Taper period will include all events with onset 
starting with the day after Visit 12 through Visit 15.  
For Part 1, tables will present TEAE data by assigned treatment group received in Part 
1. AEs occurring after enrollment and prior to the first administration of study
treatment in Part 1 are defined as non-treatment emergent AEs (non-TEAEs).
AEs are categorized as related or unrelated. If the AE is thought to be definitely, 
probably or possibly related to study drug then it is to be categorized as related. 
Possibly or definitely unrelated is categorized as unrelated. Any TEAE with missing 
relationship will be considered as “related.” 
The severity of AEs (for both nonserious and serious AEs) will be assessed by the 
investigator as follows: 
Severity Definition of Adverse Events: 
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 additional 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 
participant. 
Severe - A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
Any AE with missing severity will be imputed as “severe.” 
The original terms used by the investigators in the eCRFs to identify AEs will be coded 
using the MedDRA Version 20.1 or later. 
 
Overview of Adverse Events 
The number and percent of subjects with at least one of the following events will be 
summarized in an overall summary table:  
•
TEAE
•
Related TEAE
•
Serious TEAE
9.3.1. 
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•
Related serious TEAE
•
Severe TEAEs
•
Severe related TEAE
•
Adverse events of special interest
•
TEAEs leading to premature discontinuation of study treatment
•
TEAEs leading to premature discontinuation from the study
•
Death
This overall summary table will be presented for the full Part 1 period, Titration Period, 
Maintenance Period, Titration + Maintenance Period, and Taper/Transition Period. 
For the full Part 1 period, Titration Period, and Titration + Maintenance Period, the 
denominator for the calculation of percentage will be the number of subjects in the SAF 
for the treatment group. For the Maintenance Period, the denominator for the 
calculation of the percentage will be the number of subjects for the treatment group 
with Part 1 last dose strictly greater than the date of Visit 6. For the Taper/Transition 
Period, the denominator for the calculation of the percentage will be the number of 
subjects for the treatment group with last dose strictly greater than the date of Visit 
12. 
 
Treatment Emergent Adverse Events 
The following summaries will display the number and percentage of subjects with an 
adverse event as well as the corresponding number of events by system organ class 
(SOC) and preferred term (sorted alphabetically): 
•
All TEAEs
•
Serious TEAEs
•
TEAEs by Maximum Severity
•
Study Drug Related TEAEs
•
All TEAEs leading to premature discontinuation from the study
These summaries will present the TEAEs presented for the full Part 1 period, Titration 
Period, Maintenance Period, Titration + Maintenance Period, and Taper/Transition 
Period. 
Summaries of TEAEs and Study Drug Related TEAEs will be summarized for the following 
subgroups:  
•
Age: 2– <6 years, 6–<12 years, 12 - <18, ≥ 18 – 35 years.
•
Sex
9.3.2. 
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•
Concomitant usage of most commonly used concomitant Anti-epileptic
medications (e.g. Valproate or other medications of interest; to be determined)
•
# of con AEDs
One additional summary table will summarize the number and percent of subjects in 
each treatment group who experience an AE that occurs in at least 5% of subjects in any 
treatment group. For AEs occurring in at least 5% of subjects, the mean and median 
time to onset and the median duration of the onset will be presented. The summary will 
be presented by preferred term in decreasing order of incidence. 
No inferential statistical methods (i.e., methods that yield p-values) will be used to 
compare treatment groups on the frequency or severity of AEs. 
The following listings will be produced for all enrolled subjects: 
•
All AEs, events considered to be TEAE will be identified in the listing
•
Serious AEs
•
AEs that lead to premature discontinuation from the study
•
Deaths
 
Adverse Events of Special Interest (AESI) 
As per International Conference on Harmonisation (ICH) guidance (E2F Development 
Safety Update Report [2011]), the sponsor has identified the following AESIs for the 
ZX008 in the table below- 
Table 7 – Adverse Events of Special Interest: 
Metabolic/Endocrine 
1.Elevated prolactin level ≥2x above the upper limit of normal (ULN)
2.Hypoglycemia – <3.0 mmol/l or 54 mg/dl, whether that level is associated with
symptoms or not
Neuropsychiatric  
1.Suicidal thoughts, ideation or gestures
Standardized MedDRA Queries (SMQs) will be employed as applicable to identify each 
AESI category or manually assigned through review. For Part 1 AEs, this will be 
completed and documented prior to study unblinding.  
For Part 1, adverse events of special interest will be summarized by treatment group 
and by system organ class and preferred term. 
All AESIs will be listed separately. 
 
PHYSICAL EXAMINATION 
A complete physical examination will be performed at Screening Visit (Visit 1), Visit 3 
(Randomization) prior to first dose of study medication, and at the Visit 12 (End of 
9.3.3. 
9.4. 
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Study/Early Termination). An abbreviated physical exam is performed at Visit 6 (Day 
15), Visit 8 (Day 43), and Visit 10 (Day 71). A complete or abbreviated physical exam 
may be performed at the Cardiac follow-up visit for subjects who do not enter the 
open-label extension study if clinically warranted. Clinically significant findings at 
screening will be reported on the medical history page. New clinically significant 
findings starting with after the first dose in Part 1 will be reported as adverse events. 
A summary of subjects with clinically significant physical examination findings at each 
visit will be provided for the T+M period.  
All physical examination results will be presented in a subject data listing. 
 
NEUROLOGIC EXAMINATION  
In Part 1, a complete neurological examination will be performed at Visit 1 (Screening) 
and Visit 12 (End of Study / Early Termination). An abbreviated neurological 
examination will be performed at Visit 3 (Randomization) and at Visit 6 (Day 15), Visit 8 
(Day 43), and Visit 10 (Day 71). Clinically significant findings at screening will be 
reported on the medical history page. New clinically significant findings starting with 
after the first dose in Part 1 will be reported as adverse events. 
A summary of subjects with clinically significant neurologic examination findings at each 
visit will be provided for the T+M period.  
All neurological examination results will be presented in a subject data listing. 
 
VITAL SIGNS, WEIGHT, AND BMI  
Vital signs data will be documented for subjects during study at screening visit (Visit 1), 
Visit 3 (Randomization) prior to first dose of study medication, at the end of the 
titration period at Visit 6 (Day 15), during the maintenance period at Visit 8 (Day 43) 
and Visit 10 (Day 71), and at Visit 12 (End of Study / Early Termination). The 
measurements will include blood pressure, heart rate, temperature, respiratory rate, 
weight, and BMI. 
For each vital sign, observed values and change from baseline to each on-study 
evaluation will be summarized. 
For weight and BMI, the occurrence of at least a ≥ 7% gain/reduction or ≥ 10% 
gain/reduction from baseline will be summarized by visit and at any time during the 
T+M treatment period. For subjects with an occurrence of a ≥ 7% reduction in weight or 
BMI, the number who achieved a recovery to their baseline weight, and the duration of 
time to recovery, will be summarized, and whether that recovery was achieved as a 
result of a reduction or withdrawal of the subject’s study medication. Recovery will be 
defined as achieving a weight after the >= 7% reduction, that is at least 99% of the 
baseline weight and having a weight at Visit 12 that is at least 99% of the baseline 
weight. The number of days until weight recovery will be determined using the date of 
the first date where the weight loss was observed and the first date where the subject’s 
weight had recovered to, and maintained for the duration of the study period, at least 
99% of the baseline weight.  
9,5. 
9.6. 
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For subjects with at least a 7% reduction in body weight, a spaghetti plot of showing the 
subject’s weight values by study day will be presented by actual treatment group. 
Vital signs, Weight and BMI data will be presented in a data listing. 
For each subject with a clinically meaningful abnormality in vital signs, (to be supplied 
by Zogenix International), a table will be produced organized by parameter that lists 
each subject, age, sex, day of most abnormal value, the most abnormal value, and the 
reference range, and first date of a normal value (occurring after the abnormality). 
A listing of subjects with at least a 7% reduction in weight/BMI and clinically meaningful 
abnormal values will be created. 
 
ELECTROCARDIOGRAM 
Analysis of Echocardiograms will be included in a separate report from ERT (formerly 
Biomedical Systems). 
 
DOPPLER ECHOCARDIOGRAPHY 
Results of ECHOs will be presented in a separate report from ERT (formerly Biomedical 
Systems).  
 
TANNER STAGING 
In Part 1, Tanner Staging will be assessed for subjects > 7 to 18 years old during the 
study at Visit 3 (Randomization) and Visit 12 (End of study / Early Termination).  
Conceptually, pubertal maturation can be described in terms of sequence, timing, and 
tempo. Puberty consists of a series of predictable events, and the sequence of changes 
in secondary sexual characteristics has been categorized by several groups. The onset 
and progress of pubertal changes will be recorded on a 5-point scale for boys and girls 
separately. Boys are rated for genital development and pubic hair growth through stage 
I to stage V. Girls are rated for breast development and pubic hair growth through stage 
I to stage V. 
The number and percentage of subjects in each Tanner Stage will be presented for all 
visits by treatment group separately for boys and girls overall and broken out for the 
following age groups: 
> 7 years to ≤11 years,
> 11 years to ≤ 15 years,
> 15 years to ≤ 18 years.
All Tanner staging data will be presented in the subject data listing.
 
LABORATORY PARAMETERS
Laboratory safety parameters will be analyzed by a central laboratory using standard 
validated methods. 
All laboratory safety data will be collected as per the schedule of assessments given in 
Table 4. 
9.7. 
9,8. 
9.9. 
9,10. 
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The following continuous laboratory parameters will be analyzed: 
•
Hematology: hemoglobin, hematocrit, erythrocytes, erythrocyte mean
corpuscular volume, leukocytes, neutrophils, lymphocytes, monocytes,
eosinophils, basophils and platelets
•
Blood Biochemistry: albumin (ALB), alkaline phosphatase (AP), alanine
aminotransferase (ALT; SGPT), aspartate aminotransferase (AST; SGOT), blood
urea nitrogen (BUN), calcium (Ca), carbon dioxide (CO2), chloride (Cl),
creatinine, creatine kinase, gamma-glutamyl transferase (GGT), globulin,
glucose, lactate dehydrogenase (LDH), phosphorus, potassium (K), sodium (Na),
thyroid function, thyroid stimulating hormone (TSH), total bilirubin, direct
bilirubin, total cholesterol, total protein, triglycerides, uric acid.
•
Tests of growth and precocious puberty: Growth hormone (GH), insulin-like
growth factor-1 (IGF-1, low sensitivity), prolactin, Luteinizing Hormone (LH),
Follicle Stimulating Hormone (FSH), testosterone, estradiol
•
Coagulation: Prothrombin time (PT), International normalized ratio (INR),
activated partial thromboplastin time (PTT)
•
Whole blood cannabidiol
•
Urinalysis: analysis for pH, glucose, ketones, nitrite, protein, bilirubin,
urobilinogen, leukocyte esterase, and occult blood. Microscopic analysis will be
performed for blood, all cell types, and casts.
•
Pregnancy test: Urine or serum pregnancy testing will be performed in female
subjects of childbearing potential.
•
Urine or serum THC panel
Observed continuous laboratory data will be descriptively summarized by type of 
laboratory test/parameter change from baseline. 
Categorical laboratory parameters will be summarized by presenting the number and % 
of subjects by visit and by treatment arm. 
For each laboratory parameter, shift tables will be created comparing the baseline 
status with the status at each post-baseline visit. Status will be classified as: 
•
below lower limit of normal and clinically significant
•
below lower limit of normal,
•
within normal limits,
•
above upper limit of normal,
•
above upper limit of normal and clinically significant.
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Listings of the most extreme values for a subject recorded in Part 1 and Part 2 will be 
created for each parameter. These will show the lowest recorded value and the highest 
recorded value noted for the subject. A listing of subjects with markedly abnormal 
laboratory results will be provided, and additional explorations of the data may be 
conducted as warranted. 
Additionally, summaries of abnormal lab results by parameter will be provided to 
investigate changes in platelet count and prolactin in detail. The summaries include: 
•
Subjects with decrease (≥25% from baseline) in Platelets count with normal
platelet count at baseline
•
Subjects with decrease (≥25% from baseline) in Platelets count relative to
baseline (whether normal or abnormal) platelet count
•
Subjects with decrease (≥25% from baseline) in Platelets count with normal
platelet count at baseline, by valproate use
•
Subjects with decrease (≥25% from baseline) in Platelets count with normal
platelet count at baseline, by presence/absence of infection event prior to 7
days of the lab assessment
•
Subjects with increase (≥25% from baseline) in prolactin with normal baseline
•
Subjects with increase (≥25% from baseline) in prolactin with normal baseline,
and had seizure event within 48 hours prior to prolactin
COLUMBIA-SUICIDE SEVERITY RATING SCALE 
During Part 1, the Columbia-Suicide Severity Rating Scale (C-SSRS) data will be collected 
as per at screening visit (Visit 1), at randomization (Visit 3), at the end of the Titration 
period at Visit 6 (Day 15), during the Maintenance period at Visit 8 (Day 43) and Visit 10 
(Day 71), and at Visit 12 (End of study/Early Termination).  
Subjects who are younger than 7 years chronologically, or who are judged by the 
investigator not to have the mental capacity to understand the questions as specified on 
the C-SSRS, will not complete the rating. The investigator should use his/her judgment 
to substitute intellectually appropriate questions to probe the tendency for self-harm. 
An electronic tablet will be used to collect C-SSRS data and will only ask about a 
subject’s capability to complete C-SSRS during the Baseline visit. If the site records that 
the subject is incapable of answering the questions, the C-SSRS will be removed from 
their list of required questionnaires for the remainder of the study. 
All individual subject C-SSRS data will be listed. 
 
 The following outcomes are C-SSRS categories for 
 and have binary 
responses (yes/no): 
9.11. 
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Category Outcome Description 
1 
2 
3 
4 
5 
 is assessed as a “yes” answer at any time during the T+M period to any 
one of the five questions (1-5) above. In Part 1, the number and percentage of subjects 
with 
 will be presented, as well as the number and percentage having a 
“yes” response to each category (1-5) at least once during the T+M period. The 
denominator will be the number of subjects completing the C-SSRS at least once during 
the T+M Treatment period.  
 
The following outcomes are C-SSRS categories for 
 and have binary 
responses (yes/no): 
Category Outcome Description 
6 
7 
8 
9 
10 
 is assessed as a “yes” answer at any time during the T+M period to any 
one of the five questions (6-10) above. In Part 1, the number and percentage of 
subjects who had 
, as well as the number and percentage having a 
“yes” response to each category (6-10) at least once during the T+M period. The 
denominator will be the number of subjects completing the C-SSRS at least once during 
the T+M period.  
: 
An overall composite will be provided similar to the 
 
endpoints, but will instead count a subject if any of the C-SSRS questions 1 through 10 
are marked as ‘yes’ anything during the T+M period for Part 1. 
 
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For Part 1, the number and percentage of subjects having reported anytime during the 
T+M period experiencing a 
 event 
(Question 11) will be provided. 
 
BRIEF RATING INVENTORY OF EXECUTIVE FUNCTION (BRIEF) 
9.12. 
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INTERIM ANALYSES 
No formal interim analysis is planned for this study. However, the analysis of the Part 1 
Cohort A will occur prior to the completion of Part 1 Cohort B. The unblinding of Part 1 
Cohort A will not occur until data cleaning is completed and all decisions regarding 
protocol deviations warranting exclusion from the per protocol population have been 
made for the Cohort A subjects. The review of deviations and exclusion from the per 
protocol population for Cohort B subjects will occur independently. An unblinded team 
from Zogenix International and Syneos Health will be assigned to complete the 
unblinding of Part 1 Cohort A. The unblinded team will not participate in any decision-
making regarding the Cohort B subjects’ Part 1 data. Access to aggregated data (i.e. 
group-level tables or figures) does not constitute unblinding and for the purpose of data 
cleaning these subjects will be considered blinded. A separate unblinding plan will be 
developed to further define this process. 
CHANGE FROM PLANNED ANALYSES 
There have been several changes to the Additional Secondary Objectives specified for 
Part 1, Cohort A in the protocol, and consequently to the associated Additional 
Secondary Efficacy Endpoints. These mainly fell into the following categories: 
•
Addition of new objectives
•
Clarification of seizure types involved
•
Specification of when seizure types needed ESC confirmation
•
Clarification of the treatment period involved.
The following is a list of the Additional Secondary Objectives as specified in the 
protocol and as specified in the SAP to summarize changes: 
Protocol Version 2.1 
Statistical Analysis Plan Version 1.1 
To evaluate the effect of ZX008 0.2 and 
0.8 mg/kg/day (independently) versus 
placebo on the following endpoints: 
To evaluate the effect of ZX008 0.2 and 
0.8 mg/kg/day (independently) versus 
placebo on the following endpoints: 
Added: 
• Change in frequency of all seizures that
(typically) result in drops (i.e., GTC,
SGTC, TS, AS, TA) between baseline and
the combined T+M whether ESC
confirmed as drop or not.
• Change in the frequency of all
countable motor seizures between
baseline and T+M (countable seizures
include: generalized tonic-clonic
seizures [GTC], tonic seizures  [TS],
clonic seizures [CS], atonic seizures
Modified to: 
• Change in the frequency of all
countable motor seizures between
baseline and T+M (countable seizures
include: GTC, SGTC, TS, AS, TA, clonic
10. 
11. 
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[AS], tonic/atonic seizures [TA], clearly 
recognizable focal seizures [FS], and 
myoclonic seizures [MS] that result in a 
drop). 
seizures [CS], focal seizures with clear 
observable motor signs [FS], and 
hemiclonic seizures [HS]). 
• Change in the frequency of all
countable seizures (ie, motor and
nonmotor) between baseline and T+M
• Change in the frequency of all
countable seizures (i.e., motor and non-
motor) between baseline and T+M
• Change in frequency of seizures that
result in drops between baseline and
the Maintenance Period (M)
Modified to: 
• Change in frequency of seizures that
result in drops (ESC confirmed) between
baseline and the Maintenance Period
(M)
Added: 
• Change in frequency of seizures that
(typically) result in drops between
baseline and the Maintenance Period
(M)
• Change in the frequency of countable
motor seizures that do not result in
drops between baseline and M
Deleted and replaced with: 
• Change in the frequency of all
countable motor seizures between
baseline and M
• Change in the frequency of all
countable non-motor seizures between
baseline and M
• Change in the frequency of all
countable seizures (i.e., motor and non-
motor) between baseline and M
• The proportion of subjects who have a
worsening or no change (ie, ≤ 0%
reduction), >0%, ≥25%, ≥50%, ≥75%,
100% reduction, and “near seizure
freedom” (ie, 0 or 1 seizures) between
baseline and T+M, and baseline and M,
in all countable motor seizures (GTC,
TS, AS, TA, FS, MS with a drop); in
countable motor seizures that do not
result in drops; in all countable
seizures; in all countable seizures that
do not result in drops; and in all
seizures that result in drops
Modified to: 
• The proportion of subjects who achieve
a worsening, >0 - <25%, ≥25%, ≥50%,
≥75%, 100% reduction, and “near seizure
freedom” (i.e. 0 or 1 seizures) between
baseline and T+M, and baseline and M,
in seizures that result in drops (ESC
confirmed), seizures that typically
result in drops, all countable motor
seizures, all countable non-motor
seizures, and all countable seizures
• Number of seizure-free days, defined as
1) days with no countable seizures and
Modified to: 
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2) days with no seizures that result in
drops
• Number of seizure-free days, defined as
1) no seizures that result in drops (ESC
confirmed), and 2) days with no
countable motor seizures
• Longest interval between seizures that
result in drops
Modified to: 
• Longest interval between seizures that
result in drops (ESC confirmed)
• To evaluate the effect of ZX008 0.2 and
0.8 mg/kg/day (independently) versus
placebo on the Clinical Global
Impression – Improvement rating, as
assessed by the parent/caregiver
• To evaluate the effect of ZX008 0.2 and
0.8 mg/kg/day (independently) versus
placebo on the Clinical Global
Impression – Improvement (CGI-I) rating,
as assessed by the parent/caregiver.
Below is a list of the Additional Secondary Efficacy Endpoints as specified in the 
protocol: 
Protocol Version 2.1 
Statistical Analysis Plan Version 1.1 
Added: 
• Change from baseline during T+M in
frequency of all seizures that (typically)
result in drops (i.e., GTC, SGTC, TS, AS,
TA) whether ESC confirmed as drop or
not.
• Change from baseline in the frequency
of all countable motor seizures in T+M
• Countable seizures include:
generalized tonic-clonic seizures
[GTC], tonic seizures [TS], clonic
seizures [CS], atonic seizures [AS],
tonic/atonic seizures [TA], clearly
recognizable focal seizures [FS], and
myoclonic seizures [MS] that result in
a drop
Modified to: 
• Change from baseline during T+M in
frequency of all countable motor
seizures (GTC, SGTC, TS, AS, TA, CS, FS,
and HS).
• Change from baseline in the frequency
of countable seizures that result in
drops
Modified to: 
• Change from baseline during T+M in the
frequency of all countable seizures
(i.e., motor and non-motor).
• Change from baseline in the frequency
of seizures that result in drops between
baseline and the Maintenance Period
(M)
• Change from baseline during M in the
frequency of seizures that result in
drops.
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• Change from baseline in the frequency
of countable seizures that do not result
in drops
Deleted 
Added: 
• Change from baseline during T+M in
frequency of all countable non-motor
seizures (absence, myoclonic, focal
without clear observable motor signs,
infantile spasms, and epileptic spasms).
• Change from baseline during M in the
frequency of seizures that typically
result in drops.
• Change from baseline during M in the
frequency of all countable motor
seizures.
• Change from baseline during M in the
frequency of all countable non-motor
seizures.
• Change from baseline during M in the
frequency of all countable seizures
(i.e., motor and non-motor).
• Proportion of subjects who achieve a
worsening from baseline (ie, ≤ 0%
reduction), or >0% , ≥25%, ≥50%, ≥75%,
100% reduction, and “near seizure
freedom” (ie, 0 or 1 seizures) between
baseline and T+M, and baseline and M,
in all countable motor seizures; in
countable motor seizures that do not
result in drops; in all countable
seizures; in all countable seizures that
do not result in drops; and in all
seizures that result in drops
Modified to: 
• Proportion of subjects who achieve a
worsening from baseline (i.e. ≤ 0%
reduction), or >0%, ≥25%, ≥50%, ≥75%,
or 100% reduction between baseline and
T+M, and baseline and M, in seizures
that result in drops (ESC confirmed),
seizures that typically result in drops,
all countable motor seizures, all
countable non-motor seizures, and all
countable seizures.
• Number of seizure-free days in the
baseline, M, and T+M period, defined as
1) days with no countable seizures and
2) days with no seizures that result in
drops
Modified to: 
• Number of seizure-free days in the
baseline, M and T+M period, defined as
1) days with no seizures that results in
drops (ESC confirmed), and 2) days with
no countable motor seizures
• The longest interval (days) between
seizures that result in drops comparing
Modified to: 
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the ZX008 0.8 mg/kg/day and 0.2 
mg/kg/day groups independently versus 
placebo 
• The longest interval (days) between
seizures that result in drops (ESC
confirmed) comparing the ZX008 0.8
mg/kg/day and 0.2 mg/kg/day groups
independently versus placebo
• Clinical Global Impression –
Improvement as assessed by the
parent/caregiver
• Clinical Global Impression –
Improvement as assessed by the
parent/caregiver
PROGRAMMING CONSIDERATIONS 
All tables, data listings, figures (TLFs), and statistical analyses will be generated using 
SAS® for Windows, Release 9.4 (SAS® Institute Inc., Cary, NC, USA). Computer-
generated table, listing and figure output will adhere to the following specifications. 
 
GENERAL CONSIDERATIONS 
•
One SAS program can create several outputs. / A separate SAS program will be
created for each output.
•
One output file can contain several outputs. / Each output will be stored in a
separate file.
•
Output files will be delivered in Word format / pdf format.
•
Numbering of TLFs will follow ICH E3 guidance.
 
TABLE, LISTING, AND FIGURE FORMAT 
 
General 
•
All TLFs will be produced in landscape format, unless otherwise specified.
•
All TLFs will be produced using the Courier New font, size 8
•
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides.
•
Headers and footers for figures will be in Courier New font, size 8.
•
Legends will be used for all figures with more than 1 variable, group, or item
displayed.
•
TLFs will be in black and white (no color), unless otherwise specified
•
Specialized text styles, such as bolding, italics, borders, shading, and superscripted
and subscripted text, will not be used in the TLFs, unless otherwise specified. On
some occasions, superscripts 1, 2, or 3 may be used (see below).
•
Only standard keyboard characters will be used in the TLFs. Special characters, such
as non-printable control characters, printer-specific, or font-specific characters, will
not be used. Hexadecimal-derived characters will be used, where possible, if they
12. 
12.1 . 
12.2. 
12.2.1. 
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are appropriate to help display math symbols (e.g., μ). Certain subscripts and 
superscripts (e.g., cm2, Cmax) will be employed on a case-by-case basis. 
•
Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, as appropriate.
Headers 
•
All output should have the following header at the top left of each page:
<Sponsor Name> Protocol XXX (Syneos Health study number xxx)
Draft/Final Run <date>
•
All output should have Page n of N at the top or bottom right corner of each page.
TLFs should be internally paginated in relation to the total length (i.e., the page
number should appear sequentially as page n of N, where N is the total number of
pages in the table).
•
The date output was generated should appear along with the program name as a
footer on each page.
Display Titles 
•
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1).
ICH E3 numbering is strongly recommended but sponsor preferences should be
obtained prior to final determination (see also template 03.007C “Table of Contents
for Tables Listings and Figures in Statistical Analysis Plan”). A decimal system (x.y
and x.y.z) should be used to identify TLFs with related contents. The title is
centered. The analysis set should be identified on the line immediately following
the title. The title and table designation are single spaced. A solid line spanning the
margins will separate the display titles from the
•
Column headers. There will be 1 blank line between the last title and the solid line.
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
ITT Analysis Set 
Column Headers 
•
Column headings should be displayed immediately below the solid line described
above in initial upper-case characters.
•
In the case of efficacy tables, the variable (or characteristic) column will be on the
far left followed by the treatment group columns and total column (if applicable).
P-values may be presented under the total column or in separate p-value column (if
applicable). Within-treatment comparisons may have p-values presented in a row
beneath the summary statistics for that treatment.
•
For numeric variables, include “unit” in column or row heading when appropriate.
12.2.2. 
12.2.3. 
12.2.4. 
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•
Analysis set sizes will be presented for each treatment group in the column heading
as (N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ used for
the descriptive statistics representing the number of subjects in the analysis set.
•
The order of treatments in the tables and listings will be Placebo first in the case of
placebo controlled studies and Active comparators first in the case of active
comparator trials, followed by a total column (if applicable).
 
Body of the Data Display 
12.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
•
alphanumeric values are left-justified;
•
numbers in table cells are center aligned.
12.2.5.2. Table Conventions 
•
Units will be included where available
•
If the categories of a parameter are ordered, then all categories between the
maximum and minimum category should be presented in the table, even if n=0 for
all treatment groups in a given category that is between the minimum and maximum
level for that parameter. For example, the frequency distribution for symptom
severity would appear as:
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%). 
•
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation
from the Study, etc.), then only those categories for which there is at least 1
subject represented in 1 or more groups should be included.
•
An Unknown or Missing category should be added to any parameter for which
information is not available for 1 or more subjects.
•
Unless otherwise specified, the estimated mean and median for a set of values
should be printed out to 1 more significant digit than the original values, and
standard deviations should be printed out to 2 more significant digits than the
original values. The minimum and maximum should report the same significant digits
as the original values. For example, for systolic blood pressure:
N 
  XX 
Mean 
XXX.X
Std Dev 
X.XX
12.2.5. 
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Median 
XXX.X
Minimum 
XXX
Maximum 
XXX
•
P-values should be output in the format: “0.xxxx”, where xxxx is the value rounded
to 4 decimal places. Any p-value less than 0.0001 will be presented as <0.0001. If
the p-value is returned as >0.9999 then present as >0.9999
•
Percentage values should be printed to one decimal place, in parentheses with no
spaces, one space after the count (e.g., 7 (12.8%), 13 (5.4%)). Unless otherwise
noted, for all percentages, the number of subjects in the analysis set for the
treatment group who have an observation will be the denominator. Percentages
after zero counts should not be displayed and percentages equating to 100% should
be presented as 100%, without any decimal places.
•
Tabular display of data for medical history, prior / concomitant medications, and all
tabular displays of adverse event data should be presented by the body system,
treatment class, or SOC with the highest occurrence in decreasing order, assuming
all terms are coded. Within the body system, drug class and SOC, medical history (by
preferred term), medications (by preferred name), and adverse events (by preferred
term) should be displayed in decreasing order. If incidence for more than 1 term is
identical, they should then be sorted alphabetically.
•
The percentage of subjects is normally calculated as a proportion of the number of
subjects assessed in the relevant treatment group (or overall) for the analysis set
presented. However, careful consideration is required in many instances due to the
complicated nature of selecting the denominator, usually the appropriate number of
subjects exposed. Describe details of this in footnotes or programming notes.
•
For categorical summaries (number and percentage of subjects) where a subject can
be included in more than one category, describe in a footnote or programming note
if the subject should be included in the summary statistics for all relevant categories
or just 1 category and the criteria for selecting the criteria.
Where a category with a subheading (such as system organ class) has to be split over
more than one page, output the subheading followed by “(cont)” at the top of each
subsequent page. The overall summary statistics for the subheading should only be
output on the first relevant page.
•
For each table, a reference to the source listing(s) will be provided in the footer.
Listing Conventions 
•
Listings will be sorted for presentation in order of treatment groups as above,
subject number, visit/collection day, and visit/collection time.
•
Missing data should be represented on subject listings 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.
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•
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing
portions of dates should be represented on subject listings as dashes (--JUL2000).
Dates that are missing because they are not applicable for the subject are output as
“N/A”, unless otherwise specified.
•
All observed time values must be presented using a 24-hour clock HH:MM or
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was
measured as part of the study.
•
Units will be included where available
12.2.5.3. Figure Conventions 
•
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis
and endpoint (e.g., treatment mean change from Baseline) values will be displayed
on the Y-axis.
 
Footnotes 
•
A solid line spanning the margins will separate the body of the data display from the
footnotes.
•
All footnotes will be left justified with single-line spacing immediately below the
solid line underneath the data display.
•
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3,
etc. if a reference footnote. Each new footnote should start on a new line where
possible.
•
Subject specific footnotes should be avoided, where possible.
•
Footnotes will be used sparingly and must add value to the table, figure, or data
listing. If more than six lines of footnotes are planned, then a cover page may be
used to display footnotes, and only those essential to comprehension of the data will
be repeated on each page.
•
The last line of the footnote section will be a standard source line that indicates the
name of the program used to produce the data display, date the program was run,
and the listing source (i.e., ‘Program : myprogram.sas    Listing source: 16.x.y.z’).
QUALITY CONTROL 
SAS programs are developed to produce output such as analysis data sets, summary tables, 
data listings, figures or statistical analyses. Syneos Health SOP 03.010 and 03.013 provide 
an overview of the development of such SAS programs. 
Syneos Health SOP 03.009 describes the quality control procedures that are performed 
for all SAS programs and output. Quality control is defined here as the operational 
techniques and activities undertaken to verify that the SAS programs produce the output 
by checking for their logic, efficiency and commenting and by review of the produced 
output. 
12.2.6 .. 
13. 
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INDEX OF TABLES, FIGURES, AND LISTINGS 
The data analyses from Cohort B subjects in Japan will not be performed during the 
initial, principal analysis of the trial but will be conducted later. In general, the same 
analyses that apply to Cohort A subjects in North America, Europe and Australia will be 
applied to Cohort B subjects in Japan except for those where the smaller sample size in 
Cohort B makes the analysis untenable. In particular, subset analyses will not be applied 
to Cohort B data.  
Table/ 
Figure/ 
Listing 
Number 
Table Header 
14.1 
Demographic data and other baseline characteristics 
14.1.1 
Subject disposition 
Table 
14.1.1.1.1 
Overall subject disposition in Part 1 (Cohort A – North 
America, Europe, Australia) – All Enrolled Subjects 
Table 
14.1.1.1.2 
Overall subject disposition in Part 1 (Cohort B - Japan) 
– All Enrolled Subjects
Table 
14.1.1.2.1 
Major protocol deviations in Part 1 (Cohort A – North 
America, Europe, Australia) – Safety Population 
Table 
14.1.1.2.2 
Major protocol deviations in Part 1 (Cohort B - Japan) – 
Safety Population 
Table 
14.1.1.3.1 
Study Populations in Part 1 (Cohort A – North America, 
Europe, Australia) 
Table 
14.1.1.3.2 
Study Populations in Part 1 (Cohort B - Japan) 
14.1.2 
 Demographic and other baseline characteristics 
Table 
14.1.2.1.1 
Demographic and Baseline Characteristics (Cohort A – 
North America, Europe, Australia)– Safety Population 
Table 
14.1.2.1.2 
Demographic and Baseline Characteristics (Cohort B - 
Japan) – Safety Population 
Table 
14.1.2.2.1 
Demographic and Baseline Characteristics (Cohort A – 
North America, Europe, Australia) – mITT Population 
Table 
14.1.2.2.2 
Demographic and Baseline Characteristics (Cohort B - 
Japan) – mITT Population 
14.1.3 
Medical history 
Table 
14.1.3.1.1 
Medical History (Cohort A – North America, Europe, 
Australia) – Safety Population 
14. 
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Table 
14.1.3.1.2 
Medical History (Cohort B – Japan) – Safety Population 
Table 
14.1.3.2.1 
Neurologic History (Cohort A – North America, Europe, 
Australia) – Safety Population 
Table 
14.1.3.2.2 
Neurologic History (Cohort B – Japan) – Safety 
Population 
14.1.4 
Prior and Concomitant Medication/Treatment 
Table 
14.1.4.1.1 
Prior Pedications and Therapies/Treatments (Cohort A 
– North America, Europe, Australia) – Safety Population
Table 
14.1.4.1.2 
Prior Medications and Therapies/Treatments (Cohort B 
– Japan) – Safety Population
Table 
14.1.4.2.1 
Concomitant Medications and Therapies/Treatments in 
Part 1 (Cohort A – North America, Europe, Australia) – 
Safety Population 
Table 
14.1.4.2.2 
Concomitant Medications and Therapies/Treatments in 
Part 1 (Cohort B – Japan) – Safety Population 
Table 
14.1.4.3.1 
Prior Antiepileptic Treatment (Cohort A – North 
America, Europe, Australia) – Safety Population 
Table 
14.1.4.3.2 
Prior Antiepileptic Treatment (Cohort B – Japan) – 
Safety Population 
Table 
14.1.4.4.1.1 
Concomitant Antiepileptic Treatment in Part 1 (Cohort 
A – North America, Europe, Australia) – Safety 
Population 
Table 
14.1.4.4.1.2 
Concomitant Antiepileptic Treatment in Part 1 (Cohort 
B – Japan) - Safety Population 
Table 
14.1.4.4.2.1 
Concomitant Rescue Medications in Part 1 (Cohort A – 
North America, Europe, Australia) – Safety Population 
Table 
14.1.4.4.2.2 
Concomitant Rescue Medications in Part 1 (Cohort B – 
Japan) - Safety Population 
14.1.5 
Treatment Exposure and compliance 
Table 
14.1.5.1.1 
Duration of IMP Treatment Exposure in Part 1 (Cohort A 
– North America, Europe, Australia) – Safety Population
Table 
14.1.5.1.2 
Duration of IMP Treatment Exposure in Part 1 (Cohort B 
– Japan) – Safety Population
Table 
14.1.5.2.1.1 
Compliance to IMP Intake in Part 1 (Cohort A – North 
America, Europe, Australia) - mITT Population  
Table 
14.1.5.2.1.2 
Compliance to IMP Intake in Part 1 (Cohort B – Japan) - 
mITT Population  
Table 
14.1.5.2.3.1 
Compliance to IMP Intake in Part 1 based on Bottle 
Weight (Cohort A – North America, Europe, Australia) - 
mITT Population  
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Table 
14.1.5.2.3.2 
Compliance to IMP Intake in Part 1 based on Bottle 
Weight (Cohort B – Japan) - mITT Population  
14.2 
Efficacy, pharmacokinetics, and pharmacodynamics 
14.2.1 
Efficacy – ZX008 0.8 and 0.2 mg/kg/day vs Placebo 
Seizures resulting in drops (ESC Confirmed) 
Table 
14.2.1.1.1.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Summary 
Statistics (Cohort A – North America, Europe, Australia) 
– mITT Population
Table 
14.2.1.1.1.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Summary 
Statistics (Cohort B – Japan) – mITT Population 
Table 
14.2.1.1.2.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Summary 
Statistics (Cohort A – North America, Europe, Australia) 
– PP Population
Table 
14.2.1.1.2.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Summary 
Statistics (Cohort B – Japan) – PP Population 
Table 
14.2.1.2.1.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia) – 
mITT Population 
Table 
14.2.1.2.1.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis (Cohort B – Japan) – mITT Population 
Table 
14.2.1.2.2.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia) – 
PP Population 
Table 
14.2.1.2.2.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis (Cohort B – Japan) – PP Population 
Table 
14.2.1.3.1.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Parametric 
Analysis (Cohort A – North America, Europe, Australia)  
– mITT Population
Table 
14.2.1.3.1.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Parametric 
Analysis (Cohort B – Japan)  – mITT Population 
Table 
14.2.1.3.2.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Parametric 
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Analysis (Cohort A – North America, Europe, Australia) 
– PP Population
Table 
14.2.1.3.2.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Parametric 
Analysis (Cohort B – Japan)  – PP Population 
Table 
14.2.1.4.1.1 
Percent Improvement in Frequency of Seizures 
Resulting in Drops (ESC Confirmed) per 28 days during 
Part 1: Logistic Regression (Cohort A – North America, 
Europe, Australia) – mITT Population 
Table 
14.2.1.4.1.2 
Percent Improvement in Frequency of Seizures 
Resulting in Drops (ESC Confirmed) per 28 days during 
Part 1: Logistic Regression (Cohort B – Japan) – mITT 
Population 
Table 
14.2.1.4.2.1 
Percent Improvement in Frequency of Seizures 
Resulting in Drops (ESC Confirmed) per 28 days during 
Part 1: Logistic Regression (Cohort A – North America, 
Europe, Australia) – PP Population 
Table 
14.2.1.4.2.2 
Percent Improvement in Frequency of Seizures 
Resulting in Drops (ESC Confirmed) per 28 days during 
Part 1: Logistic Regression (Cohort B – Japan) – PP 
Population 
Figure 
14.2.1.5.1.1 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures Resulting 
in Drops (ESC Confirmed) during Part 1 (Cohort A – 
North America, Europe, Australia) – mITT Population 
Figure 
14.2.1.5.1.2 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures Resulting 
in Drops (ESC Confirmed) during Part 1 (Cohort B - 
Japan) – mITT Population 
Table 
14.2.1.6.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1 by Age Subgroup: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
Table 
14.2.1.6.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1 by Sex: 
Nonparametric Analysis – (Cohort A – North America, 
Europe, Australia) mITT Population 
Table 
14.2.1.6.3 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1 by Weight 
Subgroup: Nonparametric Analysis – (Cohort A – North 
America, Europe, Australia) mITT Population 
Table 
14.2.1.6.4 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1 by Number of 
Concomitant Antiepileptic Medications Used: 
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Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) mITT Population 
Table 
14.2.1.6.5 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1 by Number of 
Prior Antiepileptic Medications Used: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia) 
mITT Population 
Table 
14.2.1.6.6 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1 by Baseline 
Frequency of Seizures that Result in Drops: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
Table 
14.2.1.7.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Missing Data Analysis 1 (Worst 
Value Substituted for Dropouts) (Cohort A – North 
America, Europe, Australia) – mITT Population 
Table 
14.2.1.7.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Missing Data Analysis 1 (Worst 
Value Substituted for Dropouts) (Cohort B – Japan) – 
mITT Population 
Table 
14.2.1.7.3 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Missing Data Analysis 2 
(Differential Imputation Method for Dropouts) (Cohort 
A – North America, Europe, Australia) – mITT 
Population 
Table 
14.2.1.7.4 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Missing Data Analysis 2 
(Differential Imputation Method for Dropouts) (Cohort 
B – Japan) – mITT Population 
Table 
14.2.1.8.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Wilcoxon 
Analysis – Sensitivity to Analysis Method (Cohort A – 
North America, Europe, Australia) – mITT Population 
Table 
14.2.1.8.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Wilcoxon 
Analysis – Sensitivity to Analysis Method (Cohort B – 
Japan) – mITT Population 
Table 
14.2.1.9.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Outliers (Cohort A – North 
America, Europe, Australia) – mITT Population 
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Table 
14.2.1.9.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Outliers (Cohort B – Japan) – 
mITT Population 
Table 
14.2.1.10.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Seizure Clusters (Cohort A – 
North America, Europe, Australia) – mITT Population 
Table 
14.2.1.10.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Seizure Clusters (Cohort B – 
Japan) – mITT Population 
14.2.2 
Efficacy – Clinical Global Impression – Improvement 
rating by Parent/Caregiver and Investigator 
Table 
14.2.2.1.1.1 
Clinical Global Impression – Improvement Rating by 
Investigator in Part 1 (Cohort A – North America, 
Europe, Australia) – mITT Population 
Table 
14.2.2.1.1.2 
Clinical Global Impression – Improvement Rating by 
Investigator in Part 1 (Cohort B – Japan) – mITT 
Population 
Table 
14.2.2.1.2.1 
Clinical Global Impression – Improvement Rating by 
Investigator in Part 1 (Cohort A – North America, 
Europe, Australia) – PP Population 
Table 
14.2.2.1.2.2 
Clinical Global Impression – Improvement Rating by 
Investigator in Part 1 (Cohort B – Japan) – PP 
Population 
Table 
14.2.2.1.3.1 
Clinical Global Impression – Improvement Rating by 
Investigator in Part 1 by Age Subgroup (Cohort A – 
North America, Europe, Australia) – mITT Population 
Table 
14.2.2.1.3.2 
Clinical Global Impression – Improvement Rating by 
Investigator in Part 1 by Sex (Cohort A – North America, 
Europe, Australia) – mITT Population 
Table 
14.2.2.1.3.3 
Clinical Global Impression – Improvement Rating by 
Investigator in Part 1 by Weight Subgroup (Cohort A – 
North America, Europe, Australia) – mITT Population 
Table 
14.2.2.1.3.4 
Clinical Global Impression – Improvement Rating by 
Investigator in Part 1 by Number of Concomitant 
Antiepileptic Medications Used (Cohort A – North 
America, Europe, Australia) – mITT Population 
Table 
14.2.2.1.3.5 
Clinical Global Impression – Improvement Rating by 
Investigator in Part 1 by Number of Prior Antiepileptic 
Medications Used (Cohort A – North America, Europe, 
Australia) – mITT Population 
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Table 
14.2.2.1.3.6 
Clinical Global Impression – Improvement Rating by 
Investigator in Part 1 by Baseline Frequency of Seizures 
that Result in Drops (Cohort A – North America, Europe, 
Australia) – mITT Population 
Figure 
14.2.2.2.1 
Distribution of Clinical Global Impression – 
Improvement Rating by Investigator in Part 1 (Cohort A 
– North America, Europe, Australia)– mITT Population
Figure 
14.2.2.2.2 
Distribution of Clinical Global Impression – 
Improvement Rating by Investigator in Part 1 (Cohort B 
– Japan) – mITT Population
14.2.3 
Countable Motor Seizures 
Table 
14.2.3.1.1.1 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) – mITT Population 
Table 
14.2.3.1.1.2 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Summary Statistics (Cohort B – Japan) – 
mITT Population 
Table 
14.2.3.1.2.1 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) – PP Population 
Table 
14.2.3.1.2.2 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Summary Statistics (Cohort B – Japan) – 
PP Population 
Table 
14.2.3.2.1.1 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) – mITT Population 
Table 
14.2.3.2.1.2 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Nonparametric Analysis (Cohort B – 
Japan) – mITT Population 
Table 
14.2.3.2.2.1 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) – PP Population 
Table 
14.2.3.2.2.2 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Nonparametric Analysis (Cohort B – 
Japan) – PP Population 
Table 
14.2.3.3.1.1 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Parametric Analysis (Cohort A – North 
America, Europe, Australia)– mITT Population 
Table 
14.2.3.3.1.2 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Parametric Analysis (Cohort B – Japan) – 
mITT Population 
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Table 
14.2.3.3.2.1 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Parametric Analysis (Cohort A – North 
America, Europe, Australia) – PP Population 
Table 
14.2.3.3.2.2 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Parametric Analysis (Cohort B – Japan) – 
PP Population 
Table 
14.2.3.4.1.1 
Percent Improvement in Frequency of Countable Motor 
Seizures per 28 days during Part 1: Logistic Regression 
(Cohort A – North America, Europe, Australia)– mITT 
Population 
Table 
14.2.3.4.1.2 
Percent Improvement in Frequency of Countable Motor 
Seizures per 28 days during Part 1: Logistic Regression 
(Cohort B – Japan) – mITT Population 
Figure 
14.2.3.5.1.1 
Cumulative Response Curve for Percent of Subjects 
Experiencing various % Reductions in Countable Motor 
Seizures during Part 1 (Cohort A – North America, 
Europe, Australia)– mITT Population 
Figure 
14.2.3.5.1.2 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Countable Motor 
Seizures during Part 1 (Cohort B – Japan)– mITT 
Population 
14.2.4.1 
Efficacy – Typical Drop Seizures 
Table 
14.2.4.1.1.1.1 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Summary Statistics (Cohort A – North America, 
Europe, Australia) – mITT Population 
Table 
14.2.4.1.1.1.2 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Summary Statistics (Cohort B – Japan) – mITT 
Population 
Table 
14.2.4.1.1.2.1 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Summary Statistics (Cohort A – North America, 
Europe, Australia) – PP Population 
Table 
14.2.4.1.1.2.2 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Summary Statistics (Cohort B – Japan) – PP 
Population 
Table 
14.2.4.1.2.1.1 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Nonparametric Analysis (Cohort A – North 
America, Europe, Australia) – mITT Population 
Table 
14.2.4.1.2.1.2 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Nonparametric Analysis (Cohort B – Japan) – 
mITT Population 
Table 
14.2.4.1.2.2.1 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Nonparametric Analysis (Cohort A – North 
America, Europe, Australia) – PP Population 
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Table 
14.2.4.1.2.2.2 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Nonparametric Analysis (Cohort B – Japan) – PP 
Population 
Table 
14.2.4.1.3.1.1 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Parametric Analysis (Cohort A – North America, 
Europe, Australia) – mITT Population 
Table 
14.2.4.1.3.1.2 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Parametric Analysis (Cohort B – Japan) – mITT 
Population 
Table 
14.2.4.1.3.2.1 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Parametric Analysis (Cohort A – North America, 
Europe, Australia) – PP Population 
Table 
14.2.4.1.3.2.2 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Parametric Analysis (Cohort B – Japan) – PP 
Population 
Table 
14.2.4.1.4.1.1 
Percent Improvement in Frequency of Typical Drop 
Seizures per 28 days during Part 1: Logistic Regression 
(Cohort A – North America, Europe, Australia)– mITT 
Population 
Table 
14.2.4.1.4.1.2 
Percent Improvement in Frequency of Typical Drop 
Seizures per 28 days during Part 1: Logistic Regression 
(Cohort B – Japan)– mITT Population 
Figure 
14.2.4.1.5.1.1 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Typical Drop 
Seizures during Part 1 (Cohort A – North America, 
Europe, Australia)– mITT Population 
Figure 
14.2.4.1.5.1.2 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Typical Drop 
Seizures during Part 1 (Cohort B – Japan)– mITT 
Population 
14.2.4.2 
Efficacy – Countable Non-Motor Seizures 
Table 
14.2.4.2.1.1.1 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Summary Statistics (Cohort A – 
North America, Europe, Australia) – mITT Population 
Table 
14.2.4.2.1.1.2 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Summary Statistics (Cohort B – 
Japan) – mITT Population 
Table 
14.2.4.2.1.2.1 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Summary Statistics (Cohort A – 
North America, Europe, Australia) – PP Population 
Table 
14.2.4.2.1.2.2 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Summary Statistics (Cohort B – 
Japan) – PP Population 
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Table 
14.2.4.2.2.1.1 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) – mITT Population 
Table 
14.2.4.2.2.1.2 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Nonparametric Analysis (Cohort B – 
Japan) – mITT Population 
Table 
14.2.4.2.2.2.1 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) – PP Population 
Table 
14.2.4.2.2.2.2 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Nonparametric Analysis (Cohort B – 
Japan) – PP Population 
Table 
14.2.4.2.3.1.1 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Parametric Analysis (Cohort A – 
North America, Europe, Australia) – mITT Population 
Table 
14.2.4.2.3.1.2 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Parametric Analysis (Cohort B – 
Japan) – mITT Population 
Table 
14.2.4.2.3.2.1 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Parametric Analysis (Cohort A – 
North America, Europe, Australia) – PP Population 
Table 
14.2.4.2.3.2.2 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Parametric Analysis (Cohort B – 
Japan) – PP Population 
Table 
14.2.4.2.4.1.1 
Percent Improvement in Frequency of Countable Non-
Motor Seizures per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, 
Australia)– mITT Population 
Table 
14.2.4.2.4.1.2 
Percent Improvement in Frequency of Countable Non-
Motor Seizures per 28 days during Part 1: Logistic 
Regression (Cohort B – Japan)– mITT Population 
Figure 
14.2.4.2.5.1.1 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Countable Non-
Motor Seizures during Part 1 (Cohort A – North 
America, Europe, Australia)– mITT Population 
Figure 
14.2.4.2.5.1.2 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Countable Non-
Motor Seizures during Part 1 (Cohort B – Japan)– mITT 
Population 
14.2.4.3 
Efficacy – All Countable Seizures (Motor + Non-Motor) 
Table 
14.2.4.3.1.1.1 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Summary Statistics 
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(Cohort A – North America, Europe, Australia) – mITT 
Population 
Table 
14.2.4.3.1.1.2 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Summary Statistics 
(Cohort B – Japan) – mITT Population 
Table 
14.2.4.3.1.2.1 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Summary Statistics 
(Cohort A – North America, Europe, Australia) – PP 
Population 
Table 
14.2.4.3.1.2.2 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Summary Statistics 
(Cohort B – Japan) – PP Population 
Table 
14.2.4.3.2.1.1 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia) – 
mITT Population 
Table 
14.2.4.3.2.1.2 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Nonparametric 
Analysis (Cohort B – Japan) – mITT Population 
Table 
14.2.4.3.2.2.1 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia) – 
PP Population 
Table 
14.2.4.3.2.2.2 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Nonparametric 
Analysis (Cohort B – Japan) – PP Population 
Table 
14.2.4.3.3.1.1 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Parametric Analysis 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
Table 
14.2.4.3.3.1.2 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Parametric Analysis 
(Cohort B – Japan) – mITT Population 
Table 
14.2.4.3.3.2.1 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Parametric Analysis 
(Cohort A – North America, Europe, Australia) – PP 
Population 
Table 
14.2.4.3.3.2.2 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Parametric Analysis 
(Cohort B – Japan) – PP Population 
Table 
14.2.4.3.4.1.1 
Percent Improvement in Frequency of All Countable 
Seizures (Motor and Non-Motor) per 28 days during Part 
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Page 83 of 110 
1: Logistic Regression (Cohort A – North America, 
Europe, Australia)– mITT Population 
Table 
14.2.4.3.4.1.2 
Percent Improvement in Frequency of All Countable 
Seizures (Motor and Non-Motor) per 28 days during Part 
1: Logistic Regression (Cohort B – Japan)– mITT 
Population 
Figure 
14.2.4.3.5.1.1 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in All Countable 
Seizures (Motor and Non-Motor) during Part 1 (Cohort A 
– North America, Europe, Australia)– mITT Population
Figure 
14.2.4.3.5.1.2 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in All Countable 
Seizures (Motor and Non-Motor) during Part 1 (Cohort B 
– Japan)– mITT Population
Table 
14.2.4.4.1.1 
Change from Baseline in Seizure Frequency by Type 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) - mITT Population 
Table 
14.2.4.4.1.2 
Change from Baseline in Seizure Frequency by Type 
during Part 1: Summary Statistics (Cohort B – Japan) - 
mITT Population 
Table 
14.2.4.4.2.1 
Percent Improvement in Seizure Frequency by Type 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) – mITT Population 
Table 
14.2.4.4.2.2 
Percent Improvement in Seizure Frequency by Type 
during Part 1: Summary Statistics (Cohort B – Japan) – 
mITT Population 
14.2.5 
Efficacy – Seizure-free Days 
Table 
14.2.5.1.1 
Number of Seizure Free Days during Part 1: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
Table 
14.2.5.1.2 
Number of Seizure Free days during Part 1: 
Nonparametric Analysis (Cohort B – Japan) - mITT 
Population 
Table 
14.2.5.2.1 
Number of Drop Seizure Free Days (ESC Confirmed) 
during Part 1: Nonparametric Analysis: (Cohort A – 
North America, Europe, Australia) -  mITT Population 
Table 
14.2.5.2.2 
Number of Drop Seizure Free Days (ESC Confirmed) 
during Part 1: Nonparametric Analysis: (Cohort B – 
Japan) -  mITT Population 
14.2.6 
Efficacy – Duration of the Longest Interval between 
Seizures Resulting in Drops 
Table 
14.2.6.1 
Duration of Longest Interval between Seizures 
Resulting in Drops (ESC Confirmed) during Part 1 
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(Cohort A – North America, Europe, Australia)– mITT 
Population 
Table 
14.2.6.2 
Duration of Longest Interval between Seizures 
Resulting in Drops (ESC Confirmed) during Part 1 
(Cohort B – Japan)– mITT Population 
Figure 
14.2.6.3 
Boxplot of the Duration of Longest Interval between 
Seizures Resulting in Drops (ESC Confirmed) during Part 
1 (Cohort A – North America, Europe, Australia)– mITT 
Population 
Figure 
14.2.6.4 
Boxplot of the Duration of Longest Interval between 
Seizures Resulting in Drops (ESC Confirmed) during Part 
1 (Cohort B – Japan)– mITT Population 
14.2.7 
Efficacy – Clinical Global Impression – Improvement 
rating by Parent/Caregiver  
Table 
14.2.7.1.1 
Clinical Global Impression – Improvement Rating by 
Parent/Caregiver in Part 1 (Cohort A – North America, 
Europe, Australia) – mITT Population 
Table 
14.2.7.1.2 
Clinical Global Impression – Improvement Rating by 
Parent/Caregiver in Part 1 (Cohort B – Japan) – mITT 
Population 
Figure 
14.2.7.2.1 
Distribution of Clinical Global Impression – 
Improvement Rating by Parent/Caregiver in Part 1 
(Cohort A – North America, Europe, Australia)– mITT 
Population 
Figure 
14.2.7.2.2 
Distribution of Clinical Global Impression – 
Improvement Rating by Parent/Caregiver in Part 1 
(Cohort B – Japan) – mITT Population 
14.2.8 
Efficacy – Incidence of Status Epilepticus 
Table 
14.2.8.1.1 
Number of Episodes of Status Epilepticus (SE) per 28 
days during Part 1: Summary Statistics (Cohort A – 
North America, Europe, Australia) - mITT Population 
Table 
14.2.8.1.2 
Number of Episodes of Status Epilepticus (SE) per 28 
days during Part 1: Summary Statistics (Cohort B – 
Japan) - mITT Population 
Table 
14.2.8.2.1 
Number of Days where Episodes of Status Epilepticus 
(SE) occurred per 28 days during Part 1: Summary 
Statistics and Nonparametric Analysis (Cohort A – North 
America, Europe, Australia) - mITT Population 
Table 
14.2.8.2.2 
Number of Days where Episodes of Status Epilepticus 
(SE) occurred per 28 days during Part 1: Summary 
Statistics and Nonparametric Analysis (Cohort B – 
Japan) - mITT Population 
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14.2.9 
Efficacy – Rescue Medication 
Table 
14.2.9.1.1 
Days with Rescue Medication Usage in Part 1: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) – mITT Population 
Table 
14.2.9.1.2 
Days with Rescue Medication Usage in Part 1: 
Nonparametric Analysis (Cohort B – Japan) – mITT 
Population 
Table 
14.2.9.2.1 
Number of Rescue Medications Used per Status 
Epilepticus Episode in Part 1: Nonparametric Analysis 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
Table 
14.2.9.2.2 
Number of Rescue Medications Used per Status 
Epilepticus Episode in Part 1: Nonparametric Analysis 
(Cohort B – Japan) - mITT Population 
Table 
14.2.9.3.1 
Categorical Analysis of Change from Baseline in the 
Number of Days with Rescue Medication Usage in Part 1 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
Table 
14.2.9.3.2 
Categorical Analysis of Change from Baseline in the 
Number of Days with Rescue Medication Usage in Part 1 
(Cohort B – Japan) – mITT Population 
14.2.10 
Efficacy – Hospitalization and Resource Utilization 
for Treatment of Seizures  
Table 
14.2.10.1.1 
Hospitalization and Other Healthcare Resource 
Utilization to Treat Seizure during Part 1: Summary 
statistics (Cohort A – North America, Europe, Australia) 
– mITT Population
Table 
14.2.10.1.2 
Hospitalization and Other Healthcare Resource 
Utilization to Treat Seizure during Part 1: Summary 
statistics (Cohort B – Japan) – mITT Population 
14.2.11 
Exploratory Efficacy – Vineland Adaptive Behavior 
Scale (VABS) 
Table 
14.2.11.1.1 
Vineland Adaptive Behavior Scale (VABS) in Part 1: 
Summary Statistics and Nonparametric Analysis (Cohort 
A – North America, Europe, Australia) – mITT 
Population 
Table 
14.2.11.1.2 
Vineland Adaptive Behavior Scale (VABS) in Part 1: 
Summary Statistics and Nonparametric Analysis (Cohort 
B – Japan) – mITT Population 
14.2.12 
Exploratory Efficacy – Quality of Life in Childhood 
Epilepsy Scale 
Table 
14.2.12.1.1 
Quality of Life in Childhood Epilepsy (QOLCE) in Part 1: 
Summary Statistics and Nonparametric Analysis (Cohort 
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A – North America, Europe, Australia) – mITT 
population 
Table 
14.2.12.1.2 
Quality of Life in Childhood Epilepsy (QOLCE) in Part 1: 
Summary Statistics and Nonparametric Analysis (Cohort 
B – Japan) – mITT population 
14.2.13 
Exploratory Efficacy – Zarit Caregiver Burden 
Inventory 
Table 
14.2.13.1.1 
Zarit Caregiver Burden Inventory during Part 1: 
Normal; Borderline Abnormal; and Abnormal Categories 
(Cohort A – North America, Europe, Australia) – mITT 
population 
Table 
14.2.13.1.2 
Zarit Caregiver Burden Inventory during Part 1: 
Normal; Borderline Abnormal; and Abnormal Categories 
(Cohort B – Japan) – mITT population 
Table 
14.2.13.2.1 
Zarit Caregiver Inventory Index Score during Part 1: 
Summary Descriptive Statistics (Cohort A – North 
America, Europe, Australia)– mITT population 
Table 
14.2.13.2.2 
Zarit Caregiver Inventory Index Score during Part 1: 
Summary Descriptive Statistics (Cohort B – Japan) – 
mITT population 
14.2.14 
Exploratory Efficacy – Parent /Caregiver Ratings 
using HADS Scale 
Table 
14.2.14.1.1 
Parent/Caregiver Ratings Based on Hospital Anxiety 
and Depression Scale (HADS) during Part 1: Normal; 
Borderline Abnormal, and Abnormal Categories (Cohort 
A – North America, Europe, Australia) – mITT 
population 
Table 
14.2.14.1.2 
Parent/Caregiver Ratings Based on Hospital Anxiety 
and Depression Scale (HADS) during Part 1: Normal; 
Borderline Abnormal, and Abnormal Categories (Cohort 
B – Japan)– mITT population 
Table 
14.2.14.2.1 
Parent/Caregiver Ratings Based on Hospital Anxiety 
and Depression Scale (HADS) during Part 1: Summary 
Descriptive Statistics (Cohort A – North America, 
Europe, Australia) -mITT population 
Table 
14.2.14.2.2 
Parent/Caregiver Ratings Based on Hospital Anxiety 
and Depression Scale (HADS) during Part 1: Summary 
Descriptive Statistics (Cohort B – Japan) – mITT 
population 
14.3 
Safety 
14.3.1 
Summary of adverse events 
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Table 
14.3.1.1.1.1 
Overview of Number of Subjects with TEAE during Part 
1 (Cohort A – North America, Europe, Australia)– Safety 
Population 
Table 
14.3.1.1.1.2 
Overview of Number of Subjects with TEAE during Part 
1 (Cohort B – Japan) – Safety Population 
Table 
14.3.1.2.1.1 
Treatment-Emergent Adverse Events in Part 1 by 
MedDRA System Organ Class and Preferred Term 
(Cohort A – North America, Europe, Australia)– Safety 
Population  
Table 
14.3.1.2.1.2 
Treatment-Emergent Adverse Events in Part 1 by 
MedDRA System Organ Class and Preferred Term 
(Cohort B – Japan) – Safety Population  
Table 
14.3.1.2.2.1 
Treatment-Emergent Adverse Events in Part 1 by 
MedDRA System Organ Class and Preferred Term by Age 
Group (Cohort A – North America, Europe, Australia)– 
Safety Population  
Table 
14.3.1.2.2.2 
Treatment-Emergent Adverse Events in Part 1 by 
MedDRA System Organ Class and Preferred Term by Age 
Group (Cohort B – Japan) – Safety Population 
Table 
14.3.1.2.3.1 
Treatment-Emergent Adverse Events in Part 1 by 
MedDRA System Organ Class and Preferred Term by Sex 
(Cohort A – North America, Europe, Australia)– Safety 
Population  
Table 
14.3.1.2.3.2 
Treatment-Emergent Adverse Events in Part 1 by 
MedDRA System Organ Class and Preferred Term by Sex 
(Cohort B – Japan)– Safety Population  
Table 
14.3.1.2.4.1 
Treatment-Emergent Adverse Events in Part 1 by 
MedDRA System Organ Class and Preferred Term by 
Most Commonly Used Antiepileptic Medications (Cohort 
A – North America, Europe, Australia)– Safety 
Population  
Table 
14.3.1.2.4.2 
Treatment-Emergent Adverse Events in Part 1 by 
MedDRA System Organ Class and Preferred Term by 
Most Commonly Used Antiepileptic Medications (Cohort 
B – Japan)– Safety Population  
Table 
14.3.1.2.5.1 
Treatment-Emergent Adverse Events in Part 1 by 
MedDRA System Organ Class and Preferred Term by 
Number of Antiepileptic Medications Used (Cohort A – 
North America, Europe, Australia)– Safety Population  
Table 
14.3.1.2.5.2 
Treatment-Emergent Adverse Events in Part 1 by 
MedDRA System Organ Class and Preferred Term by 
Number of Antiepileptic Medications Used (Cohort B – 
Japan)– Safety Population  
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Table 
14.3.1.3.1.1 
TEAEs Leading to Study Discontinuation in Part 1 by 
MedDRA System Organ Class and Preferred Term 
(Cohort A – North America, Europe, Australia)– Safety 
Population  
Table 
14.3.1.3.1.2 
TEAEs Leading to Study Discontinuation in Part 1 by 
MedDRA System Organ Class and Preferred Term 
(Cohort B – Japan) – Safety Population  
Table 
14.3.1.4.1.1 
Serious TEAEs in Part 1 by MedDRA System Organ Class 
and Preferred Term (Cohort A – North America, Europe, 
Australia) – Safety Population 
Table 
14.3.1.4.1.2 
Serious TEAEs in Part 1 by MedDRA System Organ Class 
and Preferred Term (Cohort B – Japan) – Safety 
Population 
Table 
14.3.1.5.1.1 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term (Cohort A – North 
America, Europe, Australia)– Safety Population 
Table 
14.3.1.5.1.2 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term (Cohort B – Japan)– 
Safety Population 
Table 
14.3.1.5.2.1 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term by Age Group (Cohort 
A – North America, Europe, Australia)– Safety 
Population 
Table 
14.3.1.5.2.2 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term by Age Group (Cohort 
B – Japan)– Safety Population 
Table 
14.3.1.5.3.1 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term by Sex (Cohort A – 
North America, Europe, Australia) – Safety Population 
Table 
14.3.1.5.3.2 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term by Sex (Cohort B – 
Japan) – Safety Population 
Table 
14.3.1.5.4.1 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term by Most Commonly 
Used Antiepileptic Medications (Cohort A – North 
America, Europe, Australia) – Safety Population 
Table 
14.3.1.5.4.2 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term by Most Commonly 
Used Antiepileptic Medications (Cohort B – Japan) – 
Safety Population 
Table 
14.3.1.5.5.1 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term by Number of 
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Antiepileptic Medications Used (Cohort A – North 
America, Europe, Australia)– Safety Population  
Table 
14.3.1.5.5.2 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term by Number of 
Antiepileptic Medications Used (Cohort B – Japan)– 
Safety Population  
Table 
14.3.1.6.1.1 
TEAEs in Part 1 by MedDRA System Organ Class and 
Preferred Term, and Maximum Severity (Cohort A – 
North America, Europe, Australia)– Safety Population 
Table 
14.3.1.6.1.2 
TEAEs in Part 1 by MedDRA System Organ Class and 
Preferred Term, and Maximum Severity (Cohort B – 
Japan)– Safety Population 
Table 
14.3.1.7.1.1 
Treatment-Emergent Adverse Events in Part 1 
Occurring in ≥ 5% of Subjects by MedDRA System Organ 
Class and Preferred Term (Cohort A – North America, 
Europe, Australia) – Safety Population  
Table 
14.3.1.7.1.2 
Treatment-Emergent Adverse Events in Part 1 
Occurring in ≥ 5% of Subjects by MedDRA System Organ 
Class and Preferred Term (Cohort B – Japan) – Safety 
Population  
Table 
14.3.1.8.1.1 
Overview of Treatment-Emergent Adverse Events of 
Special Interest during Part 1 (Cohort A – North 
America, Europe, Australia)– Safety Population 
Table 
14.3.1.8.1.2 
Overview of Treatment-Emergent Adverse Events of 
Special Interest during Part 1 (Cohort B – Japan) – 
Safety Population 
Table 
14.3.1.9.1.1 
Treatment-Emergent Adverse Events of Special Interest 
(AESI) by MedDRA System Organ Class and Preferred 
Term (Cohort A – North America, Europe, Australia) – 
Safety Population 
Table 
14.3.1.9.1.2 
Treatment-Emergent Adverse Events of Special Interest 
(AESI) by MedDRA System Organ Class and Preferred 
Term (Cohort B – Japan) – Safety Population 
14.3.2 
Listings of Deaths, Other Serious and Significant 
Adverse Events 
Table 
14.3.2.1 
Listing of Deaths (Cohort A – North America, Europe, 
Australia) 
Table 
14.3.2.1 
Listing of Deaths (Cohort B – Japan) 
Table 
14.3.2.2.1 
Listing of SAEs (Cohort A – North America, Europe, 
Australia) 
Table 
14.3.2.2.2 
Listing of SAEs (Cohort B – Japan) 
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Table 
14.3.2.3.1 
Listing of Discontinuations Due to AE (Cohort A – North 
America, Europe, Australia) 
Table 
14.3.2.3.2 
Listing of Discontinuations Due to AE (Cohort B – Japan) 
14.3.4 
Summary of Laboratory Data 
Table 
14.3.4.1.1.1 
Laboratory Parameters in Part 1 – Hematology: 
Summary Statistics (Cohort A – North America, Europe, 
Australia) - Safety Population 
Table 
14.3.4.1.1.2 
Laboratory Parameters in Part 1 – Hematology: 
Summary Statistics (Cohort B – Japan) – Safety 
Population 
Table 
14.3.4.1.2.1 
Shift tables for Laboratory Parameters in Part 1 – 
Hematology (Cohort A – North America, Europe, 
Australia) – Safety Population 
Table 
14.3.4.1.2.2 
Shift tables for Laboratory Parameters in Part 1 – 
Hematology (Cohort B – Japan) – Safety Population 
Table 
14.3.4.2.1.1 
Laboratory Parameters in Part 1 – Biochemistry: 
Summary Statistics (Cohort A – North America, Europe, 
Australia) – Safety Population 
Table 
14.3.4.2.1.2 
Laboratory Parameters in Part 1 – Biochemistry: 
Summary Statistics (Cohort B – Japan) – Safety 
Population 
Table 
14.3.4.2.2.1 
Shift tables for Laboratory Parameters in Part 1 – 
Biochemistry (Cohort A – North America, Europe, 
Australia) – Safety Population 
Table 
14.3.4.2.2.2 
Shift tables for Laboratory Parameters in Part 1 – 
Biochemistry (Cohort B – Japan) – Safety Population 
Table 
14.3.4.3.1.1 
Laboratory Parameters in Part 1 – Urinalysis 
(Quantitative Parameters) : Summary Statistics (Cohort 
A – North America, Europe, Australia) – Safety 
Population 
Table 
14.3.4.3.1.2 
Laboratory Parameters in Part 1 – Urinalysis 
(Quantitative Parameters) : Summary Statistics (Cohort 
B – Japan) – Safety Population 
Table 
14.3.4.3.2.1 
Laboratory Parameters in Part 1 – Urinalysis 
(Categorical Parameters): Summary Statistics (Cohort A 
– North America, Europe, Australia) – Safety Population
Table 
14.3.4.3.2.2 
Laboratory Parameters in Part 1 – Urinalysis 
(Categorical Parameters): Summary Statistics (Cohort B 
– Japan) – Safety Population
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Table 
14.3.4.3.3.1 
Shift Tables for Laboratory Parameters in Part 1 – 
Urinalysis (Quantitative Parameters) (Cohort A – North 
America, Europe, Australia) – Safety Population 
Table 
14.3.4.3.3.2 
Shift Tables for Laboratory Parameters in Part 1 – 
Urinalysis (Quantitative Parameters) (Cohort B – Japan) 
– Safety Population
Table 
14.3.4.3.4.1 
Shift Tables for Laboratory Parameters in Part 1 – 
Urinalysis (Categorical Parameters) (Cohort A – North 
America, Europe, Australia) – Safety Population 
Table 
14.3.4.3.4.2 
Shift Tables for Laboratory Parameters in Part 1 – 
Urinalysis (Categorical Parameters) (Cohort B – Japan) 
Safety Population 
Table 
14.3.4.4.1.1 
Laboratory Parameters in Part 1 – Tests of Precocious 
Puberty and Thyroid Function: Summary Statistics 
(Cohort A – North America, Europe, Australia) – Safety 
Population 
Table 
14.3.4.4.1.2 
Laboratory Parameters in Part 1 – Tests of Precocious 
Puberty and Thyroid Function: Summary Statistics 
(Cohort B – Japan) – Safety Population 
Table 
14.3.4.4.2.1 
Shift Tables for Laboratory Parameters in Part 1 – Tests 
of Precocious Puberty and Thyroid Function (Cohort A – 
North America, Europe, Australia) – Safety Population 
Table 
14.3.4.4.2.2 
Shift Tables for Laboratory Parameters in Part 1 – Tests 
of Precocious Puberty and Thyroid Function (Cohort B – 
Japan) – Safety Population 
Table 
14.3.4.5.1 
Laboratory Parameters in Part 1 : Epilepsy Genotype 
Panel (Cohort A – North America, Europe, Australia) – 
Safety Population 
Table 
14.3.4.5.2 
Laboratory Parameters in Part 1 : Epilepsy Genotype 
Panel (Cohort B – Japan) – Safety Population 
Table 
14.3.4.6.1.1 
Number of Subjects with Decrease in Platelets Count 
During Part 1 with Normal Platelet Count at Baseline 
(Cohort A – North America, Europe, Australia) – Safety 
Population 
Table 
14.3.4.6.1.2 
Number of Subjects with Decrease in Platelets Count 
During Part 1 with Normal Platelet Count at Baseline 
(Cohort B – Japan) – Safety Population 
Table 
14.3.4.6.2.1 
Number of Subjects with Decrease in Platelets Count 
During Part 1 Relative to Baseline (whether Normal or 
Abnormal) Platelet Count (Cohort A – North America, 
Europe, Australia) – Safety Population 
Table 
14.3.4.6.2.2 
Number of Subjects with Decrease in Platelets Count 
During Part 1 Relative to Baseline (whether Normal or 
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Abnormal) Platelet Count (Cohort B – Japan) – Safety 
Population 
Table 
14.3.4.6.3.1 
Number of Subjects with Decrease in Platelets Count 
During Part 1 with Normal Platelet Count at Baseline 
by Valproate Use (Cohort A – North America, Europe, 
Australia)– Safety Population 
Table 
14.3.4.6.3.2 
Number of Subjects with Decrease in Platelets Count 
During Part 1 with Normal Platelet Count at Baseline 
by Valproate Use (Cohort B – Japan) – Safety Population 
Table 
14.3.4.6.4.1 
Number of Subjects with Decrease in Platelets Count 
During Part 1 with Normal Platelet Count at Baseline 
by Presence/Absence of Infection Event (Cohort A – 
North America, Europe, Australia) – Safety Population 
Table 
14.3.4.6.4.2 
Number of Subjects with Decrease in Platelets Count 
During Part 1 with Normal Platelet Count at Baseline 
by Presence/Absence of Infection Event (Cohort B – 
Japan) – Safety Population 
Table 
14.3.4.7.1.1 
Number of Subjects with Normal Prolactin at Baseline 
who had a Prolactin Increase during Part 1 at each Visit 
Week – Safety Population (Cohort A – North America, 
Europe, Australia) – Safety Population 
Table 
14.3.4.7.1.2 
Number of subjects with Normal Prolactin at Baseline 
who had a Prolactin Increase during Part 1 at each Visit 
Week – Safety Population (Cohort B – Japan) – Safety 
Population 
Table 
14.3.4.7.2.1 
Number of subjects with Normal Prolactin at Baseline 
who had a Prolactin Increase during Part 1 with Seizure 
Event within 48 hours prior to Prolactin Increase at 
each Visit Week (Cohort A – North America, Europe, 
Australia) -Safety Population 
Table 
14.3.4.7.2.2 
Number of subjects with Normal Prolactin at Baseline 
who had a Prolactin Increase during Part 1 with Seizure 
Event within 48 hours prior to Prolactin Increase at 
each Visit Week (Cohort B – Japan) -Safety Population 
14.4.1 
Vital Signs, Weight and BMI 
Table 
14.4.1.1.1.1 
Vital signs Parameters in Part 1 (Cohort A – North 
America, Europe, Australia) – Safety Population 
Table 
14.4.1.1.1.2 
Vital signs Parameters in Part 1 (Cohort B – Japan) – 
Safety Population 
Table 
14.4.1.2.1.1 
Body Weight and BMI in Part 1 (Cohort A – North 
America, Europe, Australia) – Safety Population 
Table 
14.4.1.2.1.2 
Body Weight and BMI in Part 1 (Cohort B – Japan) – 
Safety Population 
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Table 
14.4.1.2.2.1 
Weight Summary (Lost/Gain >=7% or >=10%) during Part 
1 (Cohort A – North America, Europe, Australia) – 
Safety Population 
Table 
14.4.1.2.2.2 
Weight Summary (Lost/Gain >=7% or >=10%) during Part 
1 (Cohort B – Japan) – Safety Population 
Figure 
14.4.1.3.1.1 
Spaghetti Plot of Weight by Study Day during Part 1 for 
Subjects who had a >= 7% Decrease from Baseline in 
Body Weight (Cohort A – North America, Europe, 
Australia) - Safety Population  
Figure 
14.4.1.3.1.2 
Spaghetti Plot of Weight by Study Day during Part 1 for 
Subjects who had a >= 7% decrease from Baseline in 
Body Weight from Baseline (Cohort B – Japan) - Safety 
Population  
14.4.4 
Tanner Staging 
Table 
14.4.4.1.1.1 
Tanner Staging in Part 1 by Age Group for Boys (Cohort 
A – North America, Europe, Australia) – Safety 
Population 
Table 
14.4.4.1.1.2 
Tanner Staging in Part 1 by Age Group for Boys (Cohort 
B – Japan) – Safety Population 
Table 
14.4.4.2.1.1 
Tanner Staging in Part 1 by Age Group for Girls (Cohort 
A – North America, Europe, Australia) – Safety 
Population 
Table 
14.4.4.2.1.2 
Tanner Staging in Part 1 by Age Group for Girls (Cohort 
B – Japan) – Safety Population 
14.4.5 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Table 
14.4.5.1.1 
Number of Subjects with 
 
 
 Based on the C-SSRS during Part 1 (Cohort A – 
North America, Europe, Australia) – Safety Population 
Table 
14.4.5.1.2 
Number of Subjects with 
 
 
 Based on the C-SSRS during Part 1 (Cohort B – 
Japan) – Safety Population 
Table 
14.4.5.2.1 
Columbia Suicide Severity-Rating Scale (C-SSRS)- Shift 
Table of Changes in C-SSRS Categories During Part 1 
(Cohort A – North America, Europe, Australia) - Safety 
Population 
Table 
14.4.5.2.2 
Columbia Suicide Severity-Rating Scale (C-SSRS)- Shift 
Table of Changes in C-SSRS Categories During Part 1 
(Cohort B – Japan) - Safety Population 
14.4.6 
Brief Rating Inventory of Executive Function- (BRIEF) 
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Table 
14.4.6.1.1 
Brief Rating Inventory of Executive Function Preschool 
Version (BRIEF-P) in Part 1: Scoring Summary Table by 
Treatment Group (Cohort A – North America, Europe, 
Australia)– Safety Population  
Table 
14.4.6.1.2 
Brief Rating Inventory of Executive Function Preschool 
Version (BRIEF-P) in Part 1: Scoring Summary Table by 
Treatment group (Cohort B – Japan) – Safety Population 
Table 
14.4.6.2.1 
Brief Rating Inventory of Executive Function (BRIEF) in 
Part 1: Scoring Summary Table by Treatment Group 
(Cohort A – North America, Europe, Australia) – Safety 
Population 
Table 
14.4.6.2.2 
Brief Rating Inventory of Executive Function (BRIEF) in 
Part 1: Scoring Summary Table by Treatment Group 
(Cohort B – Japan) – Safety Population 
Table 
14.4.6.3.1 
BRIEF-A in Part 1: Scoring Summary Table by 
Treatment Group (Cohort A – North America, Europe, 
Australia)– Safety Population 
Table 
14.4.6.3.2 
BRIEF-A in Part 1: Scoring Summary Table by 
Treatment Group (Cohort B – Japan) - Safety 
Population 
14.4.7 
Clinically Relevant Physical Examination  
Table 
14.4.7.1.1 
Clinically Relevant Physical Examination Findings in 
Part 1 (Cohort A – North America, Europe, Australia)–  
Safety Population 
Table 
14.4.7.1.2 
Clinically Relevant Physical Examination Findings in 
Part 1 (Cohort B – Japan) - Safety Population 
14.4.8 
Clinically Relevant Neurologic Examination  
Table 
14.4.8.1.1 
Clinically Relevant Neurologic Examination Findings in 
Part 1 (Cohort A – North America, Europe, Australia)– 
Safety Population 
Table 
14.4.8.1.2 
Clinically Relevant Neurologic Examination Findings in 
Part 1 (Cohort B – Japan) - Safety Population 
16.1.9.2 
Statistical Output 
Output 
16.1.9.2.1.2.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia) – 
mITT Population 
Output 
16.2.9.2.1.2.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia) – 
PP Population 
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Syneos Health #1009529A 
This document is proprietary and confidential to Syneos Health 
03.007A.03  
  Syneos Health 
Page 95 of 110 
Output 
16.2.9.2.1.3.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Parametric 
Analysis (Cohort A – North America, Europe, Australia) – 
mITT Population 
Output 
16.2.9.2.1.3.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Parametric 
Analysis (Cohort A – North America, Europe, Australia) – 
PP Population 
Output 
16.2.9.2.1.4.1.1 
Percent Improvement in Frequency of Seizures 
resulting in Drops (ESC Confirmed) per 28 days during 
Part 1: Logistic Regression (Cohort A – North America, 
Europe, Australia) – mITT Population 
Output 
16.2.9.2.1.4.1.2 
Percent Improvement in Frequency of Seizures 
resulting in Drops (ESC Confirmed) per 28 days during 
Part 1: Logistic Regression (Cohort B – Japan) – mITT 
Population 
Output 
16.2.9.2.1.4.2.1 
Percent Improvement in Frequency of Seizures 
resulting in Drops (ESC Confirmed)  per 28 days during 
Part 1: Logistic Regression (Cohort A – North America, 
Europe, Australia) – PP Population 
Output 
16.2.9.2.1.4.2.2 
Percent Improvement in Frequency of Seizures 
resulting in Drops  (ESC Confirmed) per 28 days during 
Part 1: Logistic Regression (Cohort B – Japan) – PP 
Population 
Output 
16.2.9.2.1.6.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1 by Age Subgroup: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
Output 
16.2.9.2.1.6.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1 by Sex: 
Nonparametric Analysis – (Cohort A – North America, 
Europe, Australia) mITT Population 
Output 
16.2.9.2.1.6.3 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1 by Weight 
Subgroup: Nonparametric Analysis – (Cohort A – North 
America, Europe, Australia) mITT Population 
Output 
16.2.9.2.1.6.4 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1 by Number of 
Concomitant Antiepileptic Medications Used: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) mITT Population 
Output 
16.2.9.2.1.6.5 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1 by Number of 
Prior Antiepileptic Medications Used: Nonparametric 
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This document is proprietary and confidential to Syneos Health 
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Analysis (Cohort A – North America, Europe, Australia) 
mITT Population 
Output 
16.2.9.2.1.6.6 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed)  per 28 days during Part 1 by Baseline 
Frequency of Seizures that Result in Drops: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
Output 
16.2.9.2.1.7.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Missing Data Analysis 1 (Worst 
Value Substituted for Dropouts) (Cohort A – North 
America, Europe, Australia) – mITT Population 
Output 
16.2.9.2.1.7.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Missing Data Analysis 1 (Worst 
Value Substituted for Dropouts) (Cohort B – Japan) – 
mITT Population 
Output 
16.2.9.2.1.7.3 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Missing Data Analysis 2 
(Differential Imputation Method for Dropouts) (Cohort 
A – North America, Europe, Australia) – mITT 
Population 
Output 
16.2.9.2.1.7.4 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Missing Data Analysis 2 
(Differential Imputation Method for Dropouts) (Cohort 
B – Japan) – mITT Population 
Output 
16.2.9.2.1.9.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Outliers (Cohort A – North 
America, Europe, Australia) – mITT Population 
Output 
16.2.9.2.1.9.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Outliers (Cohort B – Japan) – 
mITT Population 
Output 
16.2.9.2.1.10.1 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Seizure Clusters (Cohort A – 
North America, Europe, Australia) – mITT Population 
Output 
16.2.9.2.1.10.2 
Frequency of Seizures Resulting in Drops (ESC 
Confirmed) per 28 days during Part 1: Nonparametric 
Analysis – Sensitivity to Seizure Clusters (Cohort B – 
Japan) – mITT Population 
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Zogenix International Limited Protocol  ZX1601 
Syneos Health #1009529A 
This document is proprietary and confidential to Syneos Health 
03.007A.03  
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Page 97 of 110 
Output 
16.2.9.2.3.2.1.1 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) – mITT Population 
Output 
16.2.9.2.3.2.1.2 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Nonparametric Analysis (Cohort B – 
Japan) – mITT Population 
Output 
16.2.9.2.3.2.2.1 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) – PP Population 
Output 
16.2.9.2.3.2.2.2 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Nonparametric Analysis (Cohort B – 
Japan) – PP Population 
Output 
16.2.9.2.3.3.1.1 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Parametric Analysis (Cohort A – North 
America, Europe, Australia)– mITT Population 
Output 
16.2.9.2.3.3.1.2 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Parametric Analysis (Cohort B – Japan) – 
mITT Population 
Output 
16.2.9.2.3.3.2.1 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Parametric Analysis (Cohort A – North 
America, Europe, Australia) – PP Population 
Output 
16.2.9.2.3.3.2.2 
Frequency of Countable Motor Seizures per 28 days 
during Part 1: Parametric Analysis (Cohort B – Japan) – 
PP Population 
Output 
16.2.9.2.3.4.1.1 
Percent Improvement in Frequency of Countable Motor 
Seizures per 28 days during Part 1: Logistic Regression 
(Cohort A – North America, Europe, Australia)– mITT 
Population 
Output 
16.2.9.2.3.4.1.2 
Percent Improvement in Frequency of Countable Motor 
Seizures per 28 days during Part 1: Logistic Regression 
(Cohort B – Japan) – mITT Population 
Output 
16.2.9.2.3.2.6.1 
Frequency of Countable Motor Seizures per 28 days 
during Part 1 by Age Subgroup: Nonparametric Analysis 
(Cohort A – North America, Europe, Australia) - mITT 
Population 
Output 
16.2.9.2.3.2.6.2 
Frequency of Countable Motor Seizures per 28 days 
during Part 1 by Sex: Nonparametric Analysis (Cohort A 
– North America, Europe, Australia)– mITT Population
Output 
16.2.9.2.3.2.6.3 
Frequency of Countable Motor Seizures per 28 days 
during Part 1 by Weight Subgroup: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia)– 
mITT Population 
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Statistical Analysis Plan 
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Zogenix International Limited Protocol  ZX1601 
Syneos Health #1009529A 
This document is proprietary and confidential to Syneos Health 
03.007A.03  
  Syneos Health 
Page 98 of 110 
Output 
16.2.9.2.3.2.6.4 
Frequency of Countable Motor Seizures per 28 days 
during Part 1 by Number of Concomitant Antiepileptic 
Medications Used: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia)– mITT Population 
Output 
16.2.9.2.3.2.6.5 
Frequency of Countable Motor Seizures per 28 days 
during Part 1 by Number of Prior Antiepileptic 
Medications Used: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) – mITT Population 
Output 
16.2.9.2.3.2.6.6 
Frequency of Countable Motor Seizures per 28 days 
during Part 1 by Baseline Frequency of Seizures that 
Result in Drops: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) – mITT Population 
14.2.4.1 
Efficacy – Typical Drop Seizures 
Output 
16.1.9.2.4.1.2.1.1 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Nonparametric Analysis (Cohort A – North 
America, Europe, Australia) – mITT Population 
Output 
16.1.9.2.4.1.2.1.2 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Nonparametric Analysis (Cohort B – Japan) – 
mITT Population 
Output 
16.1.9.2.4.1.2.2.1 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Nonparametric Analysis (Cohort A – North 
America, Europe, Australia) – PP Population 
Output 
16.1.9.2.4.1.2.2.2 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Nonparametric Analysis (Cohort B – Japan) – PP 
Population 
Output 
16.1.9.2.4.1.3.1.1 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Parametric Analysis (Cohort A – North America, 
Europe, Australia) – mITT Population 
Output 
16.1.9.2.4.1.3.1.2 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Parametric Analysis (Cohort B – Japan) – mITT 
Population 
Output 
16.1.9.2.4.1.3.2.1 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Parametric Analysis (Cohort A – North America, 
Europe, Australia) – PP Population 
Output 
16.1.9.2.4.1.3.2.2 
Frequency of Typical Drop Seizures per 28 days during 
Part 1: Parametric Analysis (Cohort B – Japan) – PP 
Population 
Output 
16.1.9.2.4.1.4.1.1 
Percent Improvement in Frequency of Typical Drop 
Seizures per 28 days during Part 1: Logistic Regression 
(Cohort A – North America, Europe, Australia)– mITT 
Population 
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application and any extensions or variations thereof.


Statistical Analysis Plan 
Version 2.0 
Zogenix International Limited Protocol  ZX1601 
Syneos Health #1009529A 
This document is proprietary and confidential to Syneos Health 
03.007A.03  
  Syneos Health 
Page 99 of 110 
Output 
16.1.9.2.4.1.4.1.2 
Percent Improvement in Frequency of Typical Drop 
Seizures per 28 days during Part 1: Logistic Regression 
(Cohort B – Japan)– mITT Population 
14.2.4.2 
Efficacy – Countable Non-Motor Seizures 
Output 
16.1.9.2.4.2.2.1.1 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) – mITT Population 
Output 
16.1.9.2.4.2.2.1.2 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Nonparametric Analysis (Cohort B – 
Japan) – mITT Population 
Output 
16.1.9.2.4.2.2.2.1 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) – PP Population 
Output 
16.1.9.2.4.2.2.2.2 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Nonparametric Analysis (Cohort B – 
Japan) – PP Population 
Output 
16.1.9.2.4.2.3.1.1 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Parametric Analysis (Cohort A – 
North America, Europe, Australia) – mITT Population 
Output 
16.1.9.2.4.2.3.1.2 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Parametric Analysis (Cohort B – 
Japan) – mITT Population 
Output 
16.1.9.2.4.2.3.2.1 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Parametric Analysis (Cohort A – 
North America, Europe, Australia) – PP Population 
Output 
16.1.9.2.4.2.3.2.2 
Frequency of Countable Non-Motor Seizures per 28 
days during Part 1: Parametric Analysis (Cohort B – 
Japan) – PP Population 
Output 
16.1.9.2.4.2.4.1.1 
Percent Improvement in Frequency of Countable Non-
Motor Seizures per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, 
Australia)– mITT Population 
Output 
16.1.9.2.4.2.4.1.2 
Percent Improvement in Frequency of Countable Non-
Motor Seizures per 28 days during Part 1: Logistic 
Regression (Cohort B – Japan)– mITT Population 
14.2.4.3 
Efficacy – All Countable Seizures (Motor + Non-Motor) 
Output 
16.1.9.2.4.3.2.1.1 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia) – 
mITT Population 
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Statistical Analysis Plan 
Version 2.0 
Zogenix International Limited Protocol  ZX1601 
Syneos Health #1009529A 
This document is proprietary and confidential to Syneos Health 
03.007A.03  
  Syneos Health 
Page 100 of 110 
Output 
16.1.9.2.4.3.2.1.2 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Nonparametric 
Analysis (Cohort B – Japan) – mITT Population 
Output 
16.1.9.2.4.3.2.2.1 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia) – 
PP Population 
Output 
16.1.9.2.4.3.2.2.2 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Nonparametric 
Analysis (Cohort B – Japan) – PP Population 
Output 
16.1.9.2.4.3.3.1.1 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Parametric Analysis 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
Output 
16.1.9.2.4.3.3.1.2 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Parametric Analysis 
(Cohort B – Japan) – mITT Population 
Output 
16.1.9.2.4.3.3.2.1 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Parametric Analysis 
(Cohort A – North America, Europe, Australia) – PP 
Population 
Output 
16.1.9.2.4.3.3.2.2 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Parametric Analysis 
(Cohort B – Japan) – PP Population 
Output 
16.1.9.2.4.3.4.1.1 
Percent Improvement in Frequency of All Countable 
Seizures (Motor and Non-Motor) per 28 days during Part 
1: Logistic Regression (Cohort A – North America, 
Europe, Australia)– mITT Population 
Output 
16.1.9.2.4.3.4.1.2 
Percent Improvement in Frequency of All Countable 
Seizures (Motor and Non-Motor) per 28 days during Part 
1: Logistic Regression (Cohort B – Japan)– mITT 
Population 
Output 
16.2.9.2.5.1.1 
Number of seizure free days during Part 1: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
Output 
16.2.9.2.5.1.2 
Number of seizure free days during Part 1: 
Nonparametric Analysis (Cohort B – Japan) - mITT 
Population 
16.2 
Subject data listing 
16.2.1 
Subject disposition and discontinuation 
Listing 
16.2.1.1.1 
Subject Completion/Discontinuation in Part 1 (Cohort A 
- North America, Europe, Australia)
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Zogenix International Limited Protocol  ZX1601 
Syneos Health #1009529A 
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Page 101 of 110 
Listing 
16.2.1.1.2 
Subject Completion/Discontinuation in Part 1 (Cohort B 
- Japan)
16.2.2 
Protocol deviations 
Listing 
16.2.2.1.1 
Major Protocol Deviations in Part 1 (Cohort A - North 
America, Europe, Australia) 
Listing 
16.2.2.1.2 
Major Protocol Deviations in Part 1 (Cohort B - Japan) 
16.2.3 
Subjects excluded from analysis 
Listing 
16.2.3.1.1 
Subjects Excluded from the Per Protocol Population 
(Cohort A - North America, Europe, Australia) 
Listing 
16.2.3.1.2 
Subjects Excluded from the Per Protocol Population 
(Cohort B - Japan) 
Listing 
16.2.3.2.1 
Subject Allocation to Trial Populations (Cohort A - 
North America, Europe, Australia) 
Listing 
16.2.3.2.2 
Subject Allocation to Trial Populations (Cohort B - 
Japan) 
16.2.4 
Demographic data and other baseline characteristics 
Listing 
16.2.4.1.1.1 
Demographic Data (Cohort A - North America, Europe, 
Australia) 
Listing 
16.2.4.1.1.2 
Demographic Data (Cohort B - Japan) 
Listing 
16.2.4.1.2.1 
Informed Consent / Informed Assent in Part 1 (Cohort A 
- North America, Europe, Australia)
Listing 
16.2.4.1.2.2 
Informed Consent / Informed Assent in Part 1 (Cohort B 
- Japan)
Listing 
16.2.4.1.4.1 
% Change from Baseline in Weight and BMI (Cohort A - 
North America, Europe, Australia) 
Listing 
16.2.4.1.4.2 
% Change from Baseline in Weight and BMI (Cohort B - 
Japan) 
Listing 
16.2.4.2.1.1 
Medical History and Neurologic History (Cohort A - 
North America, Europe, Australia) 
Listing 
16.2.4.2.1.2 
Medical History and Neurologic History (Cohort B - 
Japan) 
Listing 
16.2.4.2.3.1 
Seizure history (Cohort A - North America, Europe, 
Australia) 
Listing 
16.2.4.2.3.2 
Seizure history (Cohort B - Japan) 
Listing 
16.2.4.3.1.1 
Prior Medications and Therapies/Treatments (Cohort A 
- North America, Europe, Australia)
Listing 
16.2.4.3.1.2 
Prior Medications and Therapies/Treatments (Cohort B 
- Japan)
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Zogenix International Limited Protocol  ZX1601 
Syneos Health #1009529A 
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Page 102 of 110 
Listing 
16.2.4.3.2.1 
Concomitant Medications and Therapies/Treatments 
(Cohort A - North America, Europe, Australia) 
Listing 
16.2.4.3.2.2 
Concomitant Medications and Therapies/Treatments 
(Cohort B - Japan) 
Listing 
16.2.4.4.1.1 
Prior Antiepileptic Drugs (AEDs)(Cohort A - North 
America, Europe, Australia) 
Listing 
16.2.4.4.1.2 
Prior Antiepileptic Drugs (AEDs)(Cohort B - Japan) 
Listing 
16.2.4.4.2.1 
Concomitant Antiepileptic Drugs (AEDs) (Cohort A - 
North America, Europe, Australia) 
Listing 
16.2.4.4.2.2 
Concomitant Antiepileptic Drugs (AEDs) (Cohort B - 
Japan) 
Listing 
16.2.4.5.1.1 
Rescue Medications (Cohort A - North America, Europe, 
Australia) 
Listing 
16.2.4.5.1.2 
Rescue Medications (Cohort B - Japan) 
16.2.5 
Treatment exposure and compliance 
Listing 
16.2.5.1.1 
IMP Intake per Day during Treatment (Cohort A - North 
America, Europe, Australia) 
Listing 
16.2.5.1.2 
IMP Intake per Day during Treatment (Cohort B - 
Japan) 
Listing 
16.2.5.2.1 
IMP Intake – Self Reported % Compliance (Cohort A - 
North America, Europe, Australia) 
Listing 
16.2.5.2.2 
IMP Intake – Self Reported % Compliance (Cohort B - 
North America, Europe, Australia) 
Listing 
16.2.5.3.1 
Drug Accountability (Cohort A - North America, Europe, 
Australia) 
Listing 
16.2.5.3.2 
Drug Accountability (Cohort B - Japan) 
16.2.6 
Efficacy data 
Listing 
16.2.6.1.1.1 
Recorded Seizures – Duration and Number of 
Occurrences per Subject (Diary data) (Cohort A - North 
America, Europe, Australia) 
Listing 
16.2.6.1.1.2 
Recorded Seizures – Duration and Number of 
Occurrences per Subject (Diary data) (Cohort B - 
Japan) 
Listing 
16.2.6.1.2.1 
Change in Seizure Frequency Resulting in Drops (ESC 
Confirmed) from Baseline during Part 1 (Cohort A - 
North America, Europe, Australia) 
Listing 
16.2.6.1.2.2 
Change in Seizure Frequency Resulting in Drops  (ESC 
Confirmed) from Baseline during Part 1 (Cohort B - 
Japan) 
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Listing 
16.2.6.2.1 
Clinical Global Impression – Improvement Rating as 
Assessed by the Investigator and Subject or 
Parent/Caregiver (Cohort A - North America, Europe, 
Australia) 
Listing 
16.2.6.2.2 
Clinical Global Impression – Improvement Rating as 
Assessed by the Investigator and Subject or 
Parent/Caregiver (Cohort B - Japan) 
Listing 
16.2.6.3.1 
Change in Countable Motor Seizures from Baseline 
during Part 1 (Cohort A - North America, Europe, 
Australia) 
Listing 
16.2.6.3.2 
Change in Countable Motor Seizures from Baseline 
during Part 1 (Cohort B - Japan) 
Listing 
16.2.6.4.1 
Duration of Longest Interval between Seizures during 
Titration and Maintenance Resulting in Drops (ESC 
Confirmed)  in Part 1 (Cohort A - North America, 
Europe, Australia) 
Listing 
16.2.6.4.2 
Duration of Longest Interval between Seizures during 
Titration and Maintenance Resulting in Drops (ESC 
Confirmed)  in Part 1 (Cohort B – Japan) 
Listing 
16.2.6.5.1 
Change in Typical Drop Seizures from Baseline during 
Part 1 (Cohort A - North America, Europe, Australia) 
Listing 
16.2.6.5.2 
Change in Typical Drop Seizures from Baseline during 
Part 1 (Cohort B - Japan) 
Listing 
16.2.6.6.1 
Change in Countable Non-Motor Seizures from Baseline 
during Part 1 (Cohort A - North America, Europe, 
Australia) 
Listing 
16.2.6.6.2 
Change in Countable Non-Motor Seizures during Part 1 
(Cohort B - Japan) 
Listing 
16.2.6.7.1 
Change in All Countable Seizures (Motor + Non-Motor) 
from Baseline during Part 1 (Cohort A - North America, 
Europe, Australia) 
Listing 
16.2.6.7.2 
Change in All Countable Seizures (Motor + Non-Motor) 
from Baseline during Part 1 (Cohort B - Japan) 
Listing 
16.2.6.13.1 
Change in Rescue Medication Usage from Baseline 
during Part 1 (Cohort A - North America, Europe, 
Australia) 
Listing 
16.2.6.13.2 
Change in Rescue Medication Usage from Baseline 
during Part 1 (Cohort B - Japan) 
Listing 
16.2.6.14.1 
Seizure Free Days during Part 1 (Cohort A - North 
America, Europe, Australia) 
Listing 
16.2.6.14.2 
Seizure Free Days during Part 1 (Cohort B - Japan) 
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Listing 
16.2.6.14.3 
Drop Seizure Free Days (ESC Confirmed) during Part 1 
(Cohort A - North America, Europe, Australia) 
Listing 
16.2.6.14.4 
Drop Seizure Free Days (ESC Confirmed) during Part 1 
(Cohort B - Japan) 
Listing 
16.2.6.15.1 
Hospitalizations and Medical Services (Cohort A - North 
America, Europe, Australia) 
Listing 
16.2.6.15.2 
Hospitalizations and Medical Services (Cohort B - 
Japan) 
Listing 
16.2.6.16.1 
Vineland Adaptive Behavior Scale (Cohort A - North 
America, Europe, Australia)  
Listing 
16.2.6.16.2 
Vineland Adaptive Behavior Scale (Cohort B - Japan) 
Listing 
16.2.6.17.1 
Quality of Life in Childhood Epilepsy (QOLCE) Scale 
(Cohort A - North America, Europe, Australia) 
Listing 
16.2.6.17.2 
Quality of Life in Childhood Epilepsy (QOLCE) Scale 
(Cohort B - Japan) 
Listing 
16.2.6.18.1 
Zarit Caregiver Burden Inventory (Cohort A - North 
America, Europe, Australia) 
Listing 
16.2.6.18.2 
Zarit Caregiver Burden Inventory (Cohort B - Japan) 
Listing 
16.2.6.19.1 
Parent/Caregiver Ratings using HADS Scale(Cohort A - 
North America, Europe, Australia) 
Listing 
16.2.6.19.2 
Parent/Caregiver Ratings using HADS Scale (Cohort B - 
Japan) 
16.2.7 
Adverse events 
Listing 
16.2.7.1.1 
Adverse Events (Cohort A - North America, Europe, 
Australia) 
Listing 
16.2.7.1.2 
Adverse Events (Cohort B - Japan) 
Listing 
16.2.7.2.1 
Adverse Events of Special Interests (AESI) (Cohort A - 
North America, Europe, Australia) 
Listing 
16.2.7.2.2 
Adverse Events of Special Interests (AESI) (Cohort B - 
Japan) 
16.2.8 
Laboratory data 
Listing 
16.2.8.1.1.1 
Laboratory Data Hematology Parameters (Cohort A - 
North America, Europe, Australia) 
Listing 
16.2.8.1.1.2 
Laboratory Data Hematology Parameters (Cohort B - 
Japan) 
Listing 
16.2.8.1.2.1 
Extreme Value Laboratory Parameters – Hematology 
(Cohort A - North America, Europe, Australia) 
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Listing 
16.2.8.1.2.2 
Extreme Value Laboratory Parameters – Hematology 
(Cohort B - Japan) 
Listing 
16.2.8.2.1.1 
Laboratory Data Biochemistry Parameters (Cohort A - 
North America, Europe, Australia) 
Listing 
16.2.8.2.1.2 
Laboratory Data Biochemistry Parameters (Cohort B - 
Japan) 
Listing 
16.2.8.2.2.1 
Extreme Value Laboratory Parameters – Biochemistry 
(Cohort A - North America, Europe, Australia) 
Listing 
16.2.8.2.2.2 
Extreme Value Laboratory Parameters – Biochemistry 
(Cohort B - Japan) 
Listing 
16.2.8.3.1.1 
Laboratory Data Coagulation Parameters (Cohort A - 
North America, Europe, Australia) 
Listing 
16.2.8.3.1.2 
Laboratory Data Coagulation Parameters (Cohort B - 
Japan) 
Listing 
16.2.8.4.1.1 
Laboratory Data Urinalysis Parameters (Cohort A - 
North America, Europe, Australia) 
Listing 
16.2.8.4.1.2 
Laboratory Data Urinalysis Parameters (Cohort B - 
Japan) 
Listing 
16.2.8.4.2.1 
Extreme Value Urinalysis Data (Cohort A - North 
America, Europe, Australia) 
Listing 
16.2.8.4.2.2 
Extreme Value Urinalysis Data (Cohort B - Japan) 
Listing 
16.2.8.5.1 
Tests of Growth, Precocious Puberty and Thyroid 
Function (Cohort A - North America, Europe, Australia) 
Listing 
16.2.8.5.2 
Tests of growth, Precocious Puberty and Thyroid 
Function (Cohort B - Japan) 
Listing 
16.2.8.6.1 
Urine and Serum Pregnancy Tests (Cohort A - North 
America, Europe, Australia) 
Listing 
16.2.8.6.2 
Urine and Serum Pregnancy Tests (Cohort B - Japan) 
Listing 
16.2.8.7.1 
Urine and Serum THC panel (Cohort A - North America, 
Europe, Australia) 
Listing 
16.2.8.7.2 
Urine and Serum THC panel (Cohort B - Japan) 
16.2.9 
Other Safety Data 
Listing 
16.2.9.1.1.1 
Vital signs (Cohort A - North America, Europe, 
Australia) 
Listing 
16.2.9.1.1.2 
Vital signs (Cohort B - Japan) 
Listing 
16.2.9.1.2.1 
Abnormal Vital Signs Data (Cohort A - North America, 
Europe, Australia) 
Listing 
16.2.9.1.2.2 
Abnormal Vital Signs Data (Cohort B - Japan) 
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Listing 
16.2.9.2.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
(Cohort A - North America, Europe, Australia) 
Listing 
16.2.9.2.2 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
(Cohort B - Japan) 
Listing 
16.2.9.3.1.1 
Behavior Rating Inventory of Executive Function – 
Preschool Version (BRIEF-P) – Individual Questions 
(Cohort A - North America, Europe, Australia) 
Listing 
16.2.9.3.1.2 
Behavior Rating Inventory of Executive Function – 
Preschool Version (BRIEF-P) – Individual Questions 
(Cohort B - Japan) 
Listing 
16.2.9.3.2.1 
Behavior Rating Inventory of Executive Function – 
Preschool Version (BRIEF-P) – Summary Scales and 
Indexes (Cohort A - North America, Europe, Australia) 
Listing 
16.2.9.3.2.2 
Behavior Rating Inventory of Executive Function – 
Preschool Version (BRIEF-P) – Summary Scales and 
Indexes (Cohort B - Japan) 
Listing 
16.2.9.3.3.1 
Behavior Rating Inventory of Executive Function 
(BRIEF) – Individual questions (Cohort A - North 
America, Europe, Australia) 
Listing 
16.2.9.3.3.2 
Behavior Rating Inventory of Executive Function 
(BRIEF) – Individual questions (Cohort B - Japan) 
Listing 
16.2.9.3.4.1 
Behavior Rating Inventory of Executive Function 
(BRIEF) – Summary scales and indexes (Cohort A - North 
America, Europe, Australia) 
Listing 
16.2.9.3.4.2 
Behavior Rating Inventory of Executive Function 
(BRIEF) – Summary scales and indexes (Cohort B - 
Japan) 
Listing 
16.2.9.3.5.1 
Behavior Rating Inventory of Executive Function Adult 
Version (BRIEF-A) – Individual questions (Cohort A - 
North America, Europe, Australia) 
Listing 
16.2.9.3.5.2 
Behavior Rating Inventory of Executive Function Adult 
Version (BRIEF-A) – Individual questions (Cohort B - 
Japan) 
Listing 
16.2.9.3.6.1 
Behavior Rating Inventory of Executive Function Adult 
Version (BRIEF-A) – Summary scales and indexes 
(Cohort A - North America, Europe, Australia) 
Listing 
16.2.9.3.6.2 
Behavior Rating Inventory of Executive Function Adult 
Version (BRIEF-A) – Summary scales and indexes 
(Cohort B - Japan) 
Listing 
16.2.9.4.1 
Tanner Staging (Cohort A - North America, Europe, 
Australia) 
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Listing 
16.2.9.4.2 
Tanner Staging (Cohort B - Japan) 
Listing 
16.2.9.5.1.1 
Physical Examination (Cohort A - North America, 
Europe, Australia) 
Listing 
16.2.9.5.1.2 
Physical Examination (Cohort B - Japan) 
Listing 
16.2.9.5.2.1 
Clinically Relevant Physical Examination Findings 
(Cohort A - North America, Europe, Australia) 
Listing 
16.2.9.5.2.2 
Clinically Relevant Physical Examination Findings 
(Cohort B - Japan) 
Listing 
16.2.9.6.1.1 
Neurological Examination (Cohort A - North America, 
Europe, Australia) 
Listing 
16.2.9.6.1.2 
Neurological Examination (Cohort B - Japan) 
Listing 
16.2.9.6.2.1 
Clinically Relevant Neurological Examination Findings 
(Cohort A - North America, Europe, Australia) 
Listing 
16.2.9.6.2.2 
Clinically Relevant Neurological Examination Findings 
(Cohort B - Japan) 
Listing 
16.2.9.7.1 
Epilepsy Genotype Panel (Cohort A - North America, 
Europe, Australia) 
Listing 
16.2.9.7.2 
Epilepsy Genotype Panel (Cohort B - Japan) 
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REFERENCES 
ICH Topic E2F: Development Safety Update Report, 2011. 
Devinsky O, Patel AD, Cross JH, et al. Effect of cannabidiol on drop seizures in the 
Lennox–Gastaut syndrome. N Engl J Med. 2018;378:1888–97. 
Kim KR, Lee E, Namkoong K, Lee YM, Lee JS, and Kim HD, “Caregiver's burden and 
quality of life in mitochondrial disease,” Pediatric Neurology, vol. 42, no. 4, pp. 271–
276, 2010. 
Ng Y, Conry J, Drummond R, Stolle J, Weinberg M for the OV-1012 Study Investigators. 
Randomized, phase III study results of clobazam in Lennox–Gastaut syndrome. Neurology 
2011; 77:1473–1481. 
Rabbit, P. (Ed.). (1997). /react-text Methodology of frontal and executive function 
react-text: 2931. East Sussex, UK: Psychology Press. 
Sabaz, M., Cairns, D. R., Lawson, J. A., Nheu, N., Bleasel, A. F., & Bye, A. M. (2000). 
Validation of a new quality of life measure for children with epilepsy. Epilepsia, 41(6), 
765–774. 
Sparrow, S. S., & Cicchetti, D. V. (1989). The Vineland Adaptive Behavior Scales. In C. 
S. Newmark (Ed.), Major psychological assessment instruments, Vol. 2, pp. 199-231).
Needham Heights, MA, US: Allyn & Bacon.
Talarska, D. (2007). The usefulness of Quality of Life Childhood Epilepsy (QOLCE) 
questionnaire in evaluating the quality of life of children with epilepsy. Advances in 
Medical Sciences, 52 Suppl 1, 191–193. 
Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated 
with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-
controlled phase 3 trial. Lancet. 2018;391:1085–96. 
Tukey, JW (1977). Exploratory Data Analysis. Addison-Wesley. 
Westphal-Guitti C, Alonso NB, Migliorini RCVP et al., “Quality of life and burden in 
caregivers of patients with epilepsy,” The Journal of Neuroscience Nursing, vol. 39, no. 
6, pp. 354–360, 2007. 
15. 
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APPENDICES 
APPENDIX 1 – SEIZURE TYPES 
1. All Seizures
2. Countable
Motor Seizures
3. Countable Non-
Motor Seizures
4. Drop Seizures
(ESC confirmed or
Typical) 
Generalized Tonic-Clonic 
Generalized 
Tonic-Clonic 
Generalized 
Tonic-Clonic 
Secondarily Generalized 
Tonic-Clonic 
Secondarily 
Generalized 
Tonic-Clonic 
Secondarily 
Generalized 
Tonic-Clonic 
Tonic 
Tonic 
Tonic 
Atonic 
Atonic 
Atonic 
Tonic/Atonic 
Tonic/Atonic 
Tonic/Atonic 
Clonic 
Clonic 
Hemiclonic 
Hemiclonic 
Focal with clear 
observable signs 
Focal with clear 
observable signs 
Focal without clear 
observable signs 
Focal without clear 
observable signs 
Myoclonic 
Myoclonic 
Absence/atypical absence 
Absence/atypical 
absence 
Infantile Spasms 
Infantile Spasms 
Epileptic Spasms 
Epileptic Spasms 
Other 
Other 
 
SEIZURE CLASSIFICATION – PRIMARY ENDPOINT 
The primary endpoint for Study 1601 is defined as the change from baseline in seizures 
that result in drops. Seizures that result in drops include those of type: atonic, tonic, 
tonic/atonic, and tonic clonic (ie, generalized tonic clonic, and secondarily generalized 
tonic clonic). The seizures that result in drops are similar to those as defined in the 
Epidiolex Phase 3 clinical studies GWPCARE3 and GWPCARE4, which were atonic, tonic, 
or tonic clonic (Devinsky 2018, Thiele 2018). 
16. 
16.1. 
16.2. 
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In the Statistical Analysis Plan (SAP) version 1.0 dated 5 August 2019, seizures resulting 
in drops were defined as those of the five types listed above and specified in the DSD as 
seizures that result in a fall based on a “Yes” response to Question 9 in the DSD. During 
study conduct a large number of data clarifications were raised for Question 9 leading 
to the conclusion that there was uncertainty amongst caregivers in how to properly 
answer the question. Based on this uncertainty, the definition of seizures that result in 
drops was changed to those of the five pre-specified types that have been reviewed and 
approved for each subject as a “drop seizure” by the Epilepsy Study Consortium (ESC). 
Approval is based on the seizures for each subject submitted to the ESC on the Seizure 
Identification Form during the Baseline Visit and logged in the eCRF on the Seizure 
History Form. 
Thus, in version 1.1 of the SAP, drop seizures for the primary analysis will be those of 
the pre-specified type that have been approved for an individual subject as Drop by the 
ESC as indicated on the Seizure History eCRF under variable DROP_ and captured in the 
seizure diary. 
Under this definition, classifying a particular seizure in the diary as a drop seizure 
requires determining whether the type of seizure in question has been identified in the 
Seizure History eCRF as a drop seizure for that subject. This can typically be done by 
matching a seizure type identifier in the diary to its counterpart in the Seizure History 
eCRF. Specifically, each seizure type entered into the Seizure History eCRF is identified 
by a “Record Position” number. These seizure types are then referred to by subjects or 
caregivers when recording seizures into the electronic Seizure Diary where they are 
labeled with a “Seizure Unique ID”. For most subjects, there is a direct correspondence 
between the Seizure Unique ID in the seizure diary and the Record Position number on 
the Seizure History eCRF. However, for some subjects the correspondence is imperfect 
and aligning seizure types between the diary and the Seizure History eCRF requires an 
examination of text fields. In order to ensure that drop seizures are properly classified, 
a manual reconciliation between the Record Position number and the Seizure Unique ID 
was performed. The reconciliation resulted in a list of ESC-approved drop seizures for 
each subject from which the seizures entered in the DSD would be compared against in 
order to identify seizures for the primary endpoint. In order to facilitate seizure 
selection the list generated from the reconciliation was entered into a separate 
database and transferred to the study database via data transfer specifications. 
The procedures for the reconciliation are described in an addendum to the Data 
Management Plan. 
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Zogenix ZX008-1601 
SAP 
Page 1 of 30 
ERT 
CONFIDENTIAL 
January 23, 2020 
 
 
Statistical Analysis Plan for 
Cardiovascular Endpoints 
 
Study Title: 
 
A Two-Part Study of ZX008 in Children and 
Adults with Lennox-Gastaut Syndrome (LGS); 
Part 1: A Randomized, Double-blind, Placebo-
controlled Trial of Two Fixed Doses of ZX008 
(Fenfluramine Hydrochloride) Oral Solution as 
Adjunctive Therapy for Seizures in Children and 
Adults with LGS, Followed by Part 2: An Open-
label Extension to Assess Long-Term Safety of 
ZX008 in Children and Adults with LGS 
 
 
 
Investigational 
Product: 
 
ZX008 
 
 
 
Sponsor Study No.: 
 
ZX008-1601 
 
 
 
 
 
 
SAP Status: 
 
Final Version 1.1 
 
 
 
 
 
 
Date of SAP: 
 
January 23, 2020 
 
 
 
 
 
 
SAP Prepared by: 
 
ERT (Formerly Biomedical Systems) 
 
 
 
 
 
 
Sponsor: 
 
Zogenix International Limited 
A subsidiary of Zogenix, Inc. 
5858 Horton Street, Suite 455 
Emeryville, CA 94608 USA 
 
 
 
 
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Z o g e ni x Z X 0 0 8- 1 6 0 1 
S A P 
P a g e 2 of 3 0 
E R T 
C O N FI D E N TI A L 
J a n u ar y 2 3, 2 0 2 0  
 
S A P A p pr o v al 
 
  
 
  
… … … … … … … … … … … … … … … … … … … … … … … … 
 … … … … … … … …. 
 D at e 
St ati sti ci a n 
  
 
 
  
 
  
… … … … … … … … … … … … … … … … … … … … … … … …. 
 … … … … … … … …. 
 D at e 
 
  
 
 
  
… … … … … … … … … … … … … … … … … … … … … … … …. 
 … … … … … … … …. 
S e ni or Pri n ci p al I m a gi n g St ati sti ci a n 
 
 D at e 
 
  
Z o g e ni x I n t e r n a ti o n al Li mi t e d 
 
 
 
 
 
… … … … … … … … … … … … … … … … … … … … … … … …. 
 
… … … … … … … …. 
 
D at e 
 
 
 
 
… … … … … … … … … … … … … … … … … … … … … … … …. 
 
… … … … … … … ….  
 
D at e 
 
 
 
 
 
… … … … … … … … … … … … … … … … … … … … … … … …. 
 
… … … … … … … …. 
 
D at e 
 
 
 
 
 
 
… … … … … … … … …  
… … … … … … … … … …. 
 
… … … … … … … …. 
 
D at e 
… … … … … … … … … … … … … … … … … … … … …
… …
…
… … … … … … … … … … … … … … … … … …
… … … … … … … … … … … … … … … … … … … … …
… … … … … … … … … … … … … … … … … … … … …
… …
…
… … … … … … … … … … … … … … … … … … …
… … … … … … … … …  
… … … … … … …
… … … … … … … … … … … … … … … … … … … … …
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n 
a p pli c ati o n a n d a n y e xt e n si o n s or v ari ati o n s t h er e of.


Zogenix ZX008-1601 
SAP 
Page 3 of 30 
ERT 
CONFIDENTIAL 
January 23, 2020 
 
Table of Contents 
1 
INTRODUCTION .................................................................................... 7 
2 
STUDY DESIGN AND CARDIOVASCULAR ANALYSIS OBJECTIVES ......... 10 
2.1 
General Design and Plan ................................................................... 10 
2.2 
Objectives ...................................................................................... 10 
2.2.1 Cardiovascular Safety Objectives ..................................................... 11 
2.3 
Endpoints ....................................................................................... 11 
2.3.1 Echocardiograms ........................................................................... 11 
2.3.1.1 
Main Focus for Echocardiograms .............................................................................................. 11 
2.3.1.2 
Other Echocardiographic Analyses ............................................................................................ 11 
2.3.1.3 
Heat Maps .................................................................................................................................. 12 
2.3.2 ECG ............................................................................................. 12 
2.3.2.1 
Main Focus of ECG Analysis ..................................................................................................... 12 
2.3.2.2 
Other ECG Analyses .................................................................................................................. 12 
2.3.2.3 
Listing for Abnormalities ........................................................................................................... 16 
2.4 
Study Population ............................................................................. 16 
2.4.1 Sample Size .................................................................................. 17 
2.5 
Randomization and Treatments ......................................................... 17 
3 
CARDIAC SAFETY DATA COLLECTION AND ANALYSIS ......................... 18 
3.1 
ECG Assessment ............................................................................. 18 
3.1.1 Equipment .................................................................................... 18 
3.1.2 Transfer of ECGs ........................................................................... 18 
3.1.3 Collection of ECGs.......................................................................... 18 
3.1.4 Definition of Baseline ..................................................................... 18 
3.1.5 Variables Measured ........................................................................ 18 
3.1.6 Clinical Analysis of ECGs ................................................................. 19 
3.1.7 Non-Digital ECG Evaluation ............................................................. 19 
3.2 
Echocardiographic Analysis ............................................................... 19 
3.2.1 Equipment .................................................................................... 19 
3.2.2 Transfer of Echocardiograms ........................................................... 19 
3.2.3 Collection of Echocardiograms ......................................................... 19 
3.2.4 Definition of Baseline ..................................................................... 20 
3.2.5 Variables Measured ........................................................................ 20 
3.2.6 Clinical Analysis of ECHOs ............................................................... 20 
3.2.7 Alert Criteria ................................................................................. 20 
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4 
STATISTICAL ANALYSIS ...................................................................... 22 
4.1 
General Principles and Considerations ................................................ 22 
4.2 
Analysis Set .................................................................................... 22 
4.2.1 Handling of Missing Data ................................................................ 22 
4.3 
Interim Analysis .............................................................................. 22 
4.4 
Multiplicity Adjustments ................................................................... 22 
4.5 
Primary Analyses ............................................................................. 23 
4.5.1 Electrocardiogram .......................................................................... 23 
4.5.2 Echocardiogram ............................................................................. 23 
4.6 
Secondary Analyses ......................................................................... 23 
4.7 
Additional Analysis ........................................................................... 23 
4.8 
Categorical Analysis ......................................................................... 23 
5 
TABLES, FIGURES, AND LISTINGS ....................................................... 24 
6 
REFERENCES ....................................................................................... 29 
 
 
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Abbreviations and Definitions of Terms 
ΔHR 
Change from baseline in Heart Rate 
ΔPR 
Change from baseline in the PR-interval 
ΔQRS 
Change from baseline in the QRS duration 
ΔQTcF 
Change from baseline in the QTcF interval 
ΔΔHR 
Change from baseline and placebo in Heart Rate 
ΔΔPR 
Change from baseline and placebo in the PR-interval 
ΔΔQRS 
Change from baseline and placebo in the QRS duration 
ΔΔQTcF Change from baseline and placebo in the QTcF interval 
ACI 
Abnormal Clinically Insignificant 
ANOVA 
Analysis of Variance 
APCS 
Abnormal Potentially Clinically Significant 
bpm 
Beats per minute 
CAMI 
Computer Assisted Measurement of Intervals 
Cmax 
Maximum Plasma Concentration 
CI 
Confidence Interval 
DSF 
Drop Seizure Frequency 
ECHO 
Echocardiograms 
ECG  
Electrocardiogram 
GSMB 
Global Superimposed Median Beat 
kg 
Kilogram 
HR 
Heart Rate 
LGS 
Lennox-Gastaut Syndrome 
mg 
Milligram 
mm 
Millimeter(s) 
mmHg 
Millimeters of Mercury 
ms 
Millisecond(s) 
PASP 
Pulmonary Artery Systolic Pressure 
PR 
Interval between the start of the P wave and start of the Q wave 
QRS 
QRS waves complex on the electrocardiogram tracing  
QT 
Interval between the start of the Q wave and the end of the T wave  
QTc 
Corrected QT duration 
QTcF 
QT interval corrected using Fridericia’s formula 
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RR 
The time interval between consecutive heart beats. 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
STP 
Stiripentol 
TdP 
Torsade de Pointes 
VHD 
Valvular heart disease 
ZX008 
Fenfluramine Hydrochloride 
 
 
 
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1 Introduction 
 
Study ZX008-1601 is investigating ZX008, an oral solution of fenfluramine 
hydrochloride, for the treatment of seizures associated with Lennox-
Gastautsyndrome.Lennox-Gastaut syndrome is a rare epileptic encephalopathy. The 
onset of Lennox-Gastaut syndrome occurs most commonly before age 11, with a 
peak between 3 and 5 years of age (Arzimanoglou 2009; Hancock 2013). Patients 
with Lennox-Gastaut syndrome account for 5 to 10% of children with seizures 
(Panayiotopoulos 2005).The most common seizure types are generalized tonic-
clonic seizures, tonic seizures, atonic seizures, and tonic/atonic seizures, all of 
which most often can result in “drop attacks.” Other seizure types that occur in 
some Lennox-Gastaut syndrome patients include atypical absences, nonconvulsive 
seizures, focal seizures, and myoclonic seizures. Nearly all patients have treatment-
resistant, lifelong epilepsy. Patients with Lennox-Gastaut syndrome have a poor 
prognosis: 5% of children die, 80 to 90% continue having seizures into adulthood, 
and nearly all have cognitive and behavioral problems (Panayiotopoulos 2005). 
Children and adults with Lennox-Gastaut syndrome have an enormous impact on 
their families and efforts to improve the quality of life for these subjects are 
complex. 
Fenfluramine is a serotonin releasing agent and increases the availability of 
extracellular serotonin by binding to the serotonin transporter protein and by being 
taken into the nerve terminal, where it disrupts vesicles, causing a release of 
serotonin into the extracellular space. It reverses the serotonin transporter function 
to promote serotonin release rather than uptake. In vivo and in vitro studies 
conducted by Zogenix suggest that fenfluramine reduces seizures by acting as an 
agonist at the 5-HT1D and 5-HT2C receptors and by acting as a positive allosteric 
modulator on the sigma-1 receptor; studies have shown positive allosteric 
modulators of sigma-1 reduce seizures in animal models. Fenfluramine may also 
exert antiseizure activity through the 5-HT1A and 5-HT2A receptors and possibly 
other yet to be identified mechanisms. 
When fenfluramine was marketed for treatment of obesity at doses of 60-120 
mg/day, reports of cardiac valvular disease emerged (Connolly, 1997). The FDA 
issued an advisory request for information from similar cases and eventually 
requested voluntary withdrawal of fenfluramine and dexfenfluramine from the 
market in 1997.  
Valvular heart disease (VHD) and pulmonary arterial hypertension (PAH) are 
important potential risks to monitor with ZX008 treatment based on the previously 
reported cardiotoxicity associated with fenfluramine treatment for adult obesity, 
commonly in combination with phentermine, at doses of 60 to 120 mg/day: ie, 2 to 
4 times higher than the proposed maximum daily dose for Dravet syndrome and 
Lennox-Gastaut syndrome. The ZX008 clinical development program includes a 
prospectively-defined, long-term longitudinal cardiovascular study of the function 
and structure of the heart valves, focusing on signs of VHD and PAH. Safety 
assessment in the ZX008 clinical program includes serial color Doppler ECHOs to 
monitor for VHD (valvulopathy) and PAH. Study 1603, a thorough QT study in 
healthy adult subjects was also conducted. 
In addition to Lennox-Gastaut syndrome, Zogenixis investigating ZX008 for the 
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treatment of seiures associated with Dravet syndrome.  Zogenix has reported 
safety and efficacy data from 2 adequate and well controlled studies in patients 
with Dravet syndrome, Study 1 and Study 1504 Cohort 2, and 1 interim analysis 
from the open-label extension study (Study 1503). Study 1 compared 2 doses of 
ZX008, 0.2 mg/kg/day and 0.8 mg/kg/day (up to a maximum of 30 mg/day), to 
placebo in subjects receiving standard of care anti-epileptic treatments excluding 
stiripentol (STP). Study 1504 Cohort 2 compared a dose of ZX008 0.5 mg/kg/day 
(up to a maximum of 20 mg/day) to placebo in subjects receiving standard of care 
anti-epileptic treatments where administration of STP (in combination with 
clobazam [CLB] and/or valproate [VPA]; ie, the STP regimen) was mandatory. 
Both studies met the primary efficacy endpoint and all key secondary efficacy 
endpoints. In both studies, a highly statistically significant reduction in monthly 
convulsive seizure frequency was achieved in subjects randomized to receive ZX008 
in addition to their standard of care antiepilepsy treatments compared to placebo. 
Results from both Phase 3 studies demonstrated that ZX008 was 
 and well 
tolerated at doses up to 30 mg/day administered in the ZX008 clinical program. 
A prospectively-defined cardiovascular monitoring program that employed color 
Doppler echocardiography (ECHO) was implemented in the ZX008 clinical program 
(all Dravet syndrome and Lennox-Gastaut syndrome [LGS] trials) to monitor for 
valvular heart disease (VHD) or pulmonary artery hypertension (PAH); this ECHO 
program was designed with input from FDA and from cardiology experts.  
No VHD, as measured by valve function and observations of valve structure, or 
PAH, as measured by pulmonary pressure, has developed in any subject in the 
reported Dravet syndrome trials, nor in fact has any VHD or PAH developed in any 
subject in the program as of July 2019. Normal nonpathologic trace and mild mitral 
regurgitation and trace aortic regurgitation were observed in very low rates 
consistent what has been reported in literature with no subjects progressing to 
VHD; most of these findings were transient and fluctuated between absent and 
trace regurgitation during the study. The point prevalence of trace mitral and aortic 
regurgitation were equal to or lower than the incidence rates reported in normal 
healthy developing children (Webb 2015). 
This Statistical Analysis Plan (SAP) for Cardiovascular Endpoints outlines the 
planned analyses to support the assessment of electrocardiographic (ECG) and 
echocardiographic data for Part 1 of the trial. The planned analyses identified in this 
SAP may be included in regulatory submissions, and exploratory analyses not 
defined in this SAP may be performed to support a more thorough understanding of 
the safety data. All post-hoc or unplanned analyses performed not identified in this 
SAP will be documented. 
 
Documents used to develop this SAP are: 
x 
Study Protocol ZX008-1601 (29July 2019, Amendment 2.1). 
x 
Syneos Health-ZogenixZX008-1601Statistical Analysis Plan (Final Version 
1.0, 5August 2019). 
x 
ZX008 Investigational Brochure (Version 7.0, July 2019). 
 
The description of methodology of analysis for Part 2 of the study will be provided 
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in a separate SAP as necessary. 
 
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2 Study Design and Cardiovascular Analysis Objectives 
2.1 General Design and Plan 
Study ZX008-1601 is an international multicenter study being conducted in two 
parts. Up to approximately 80 study sites in North America, Europe, Australia, and 
Japan are planned to participate. Part 1 is a double-blind, parallel-group, placebo-
controlled, study to assess the efficacy and safety of two doses of ZX008 when 
used as adjunctive therapy for seizures in children and adult subjects with Lennox-
GastautSyndrome(LGS). Part 1 will include 2 cohorts: Cohort A will include 
randomized subjects from North America, Europe, and Australia; Cohort B will 
include randomized subjects from Japan.Part 2 is an open-label extension to assess 
long-term safety of ZX008. 
Each subject in Part 1 is assigned to one of 2 treatments (0.2 mg/kg or 0.8 mg/kg) 
or placebo groups. Treatments were assigned on a 1:1:1 basis.  
Data from Part 1, Cohort A for cardiovascular endpoints will be analyzed.All other 
study results for these subjects (demographics, efficacy, safety, PK) will be 
presented in the Clinical Study Report for ZX008-Study 1601 Part 1. 
Electrocardiograms (ECGs) and echocardiograms (ECHOs) are being analyzed by 
ERT (formerly Biomedical Systems (St. Louis, MO)). 
All ECGs will be reviewed and interpreted by a board-certified cardiologist.  
Echocardiograms will be reviewed by two, board-certified cardiologists. In the case 
of a discrepancy between the readers, the echocardiogram was sent to 
adjudicatorsfor final reading. At the initiation of the ZX008 Program, the 
International (Pediatric) Cardiology Advisory Board (ICAB) was set-up to oversee 
the vendor’s ECHO readings. ICAB members were chosen solely based on their 
academic credentials and experience, with the Chair being chosen based upon 
his/her seniority and respect in the field of echocardiography.When there is a 
differing interpretation of findings in an ECHO of any subject between the vendor 
and ICAB (either in the alert level of valvular regurgitation or presence or absence 
of pulmonary hypertension), the following process will occur: a telephone 
conference call will be held with the vendor ERT cardiology readers and ICAB reader 
and ICAB Chair (if the Chair was reader, then only he/she will be on call) to discuss 
the ECHO findings and try to come to an agreement on interpretation; if agreement 
cannot be reached then ICAB Chair will read the ECHO and his/her reading will 
become the official reading.  This one ECHO report will then be sent to the IDSMC. 
2.2 Objectives 
The primary objective of ZX008-1601 Part 1is to demonstrate that ZX008 0.8 
mg/kg/day is superior to placebo as adjunctive therapy in the treatment of 
uncontrolled seizuresin children and adults with Lennox-Gastaut syndrome (LGS) 
based on the change in frequency of seizures that result in drops (drop seizure 
frequency,DSF) between baseline and the combined Titration and Maintenance 
Periods (T+M). 
 
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2.2.1 Cardiovascular Safety Objectives 
The primary cardiovascular safety objective of this analysis is to evaluate the effect 
of ZX008 on the heart as demonstrated by ECHO. 
Variables included in the analysis are listed below. These will be compared between 
Placebo and the 0.2 mg/kg and 0.8 mg/kg groups independently. 
2.3 Endpoints 
2.3.1 Echocardiograms 
2.3.1.1 Main Focus for Echocardiograms 
The main focus for the echocardiographic analysis is the regurgitation score for the 
mitral and aortic valves at each time-point with the main focus being the 
development of clinically meaningful (pathologic) changes in valve regurgitation 
(definitions and thresholds defined below). 
x 
Number of subjects who meet the FDA case definition of drug associated 
valvulopathy-aortic regurgitation ≥ mild and/or mitral regurgitation ≥ 
moderate 
x 
Number of subjects with ≥ trace mitral or aortic regurgitation at least one 
time post-baseline 
x 
Number of subjects with ≥ trace mitral or aortic regurgitation at end of study 
x 
Number of subjects within each mitral or aortic regurgitation score by visit  
x 
Number of subjects with clinically confirmed Valvular heart disease (VHD) 
 
2.3.1.2 Other Echocardiographic Analyses 
Other, secondary endpoints include: 
● Number of subjects within each tricuspid or pulmonic regurgitation score by 
visit 
● Number of subjects with normal ortrace tricuspid or pulmonic regurgitation at 
baseline and ≥ mild tricuspid or pulmonic regurgitation at end of study 
x 
Pulmonary Artery Systolic Pressure (PASP) 
o Mean change from baseline at end of study 
o Mean maximum change from baseline at anytime during therapy 
o Number of subjects with change from baseline at anytime during 
therapy shows: 
 
> 10 mmHg 
 
>15 mmHg 
 
>20 mmHg 
o Number of subjects at anytime during therapy shows 
 
PASP>35 mmHg 
● Right ventricular outflow tract(RVOT) (will be used only as confirmatory 
variables for pulmonary hypertension) 
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o Mean Change from Baseline in RVOT (mmHg) by visit 
o Number of patients with Baseline ≥100 msec and at EOS/ET RVOT 
<100 msec 
o Number of patients with any RVOT measurement < 100 msec post-
baseline 
Summary of the number of ECHOs per subject will also be presented. 
2.3.1.3 Heat Maps 
Heat maps will be constructed for all valve scores to visualize longitudinal changes, 
if any, in regurgitation measures in individual subjects over time. An example of a 
heat map is shown below. 
 
 
Subject ID 
Visit 
1 
Visit 
8 
Visit 12 
EOS/ET 
Visit 14 
Follow-up 
1001-001 
 
 
 
 
1001-002 
 
 
 
 
1001-003 
 
 
 
 
1001-004 
 
 
 
 
1001-005 
 
 
 
 
Note: different colors represent the valve scores such as No ECHO, Absent, Absent, Mild, 
Moderate, and Severe.  
Heat maps will be constructed for all valve scores by age groups (≤18, >18 years). 
 
2.3.2 ECG 
2.3.2.1 Main Focus of ECG Analysis 
The primary endpoint will be the mean change between measurements of QT 
interval corrected using Fridericia’sformula(QTcF) for ZX008  (0.2 mg/kg and 0.8 
mg/kg) and placebo after baseline adjustment, (ΔΔQTcF) 
2.3.2.2 Other ECG Analyses 
The secondary endpoints: 
x 
Mean QTcF duration including changesfrom baseline (∆QTcF)  
x 
Mean QRS duration (including changes from baseline (∆QRS) and from 
placebo and baseline (∆∆QRS)) 
x 
Mean PR interval measurements (including changes from baseline (∆PR) and 
from placebo and baseline (∆∆PR)) 
x 
Mean Heart rate (including changes from baseline (∆HR) and from placebo 
and baseline (∆∆HR)) 
x 
Categorical analyses for each variable and subgroup listed below: 
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o QTcF (number and percentage of subjects, by regimen and visit) 
Age 
Gender 
Values 
2 to < 12 years 
Males and Females 
< 320 ms 
≥ 320 ms to ≤ 450 ms 
> 450 ms to ≤480 ms 
> 480 ms 
12 to <18years 
Males  
< 320 ms 
≥ 320 ms to ≤ 450 ms 
> 450 ms to 500 ms 
> 500 ms 
12 to <18years 
Females 
< 320 ms 
≥ 320 ms to ≤ 470 ms 
> 470ms to ≤ 500 ms 
> 500 ms 
18 to 35 years 
Males  
< 320 ms 
 
 
≥ 320 ms to ≤ 450 ms 
 
 
> 450 ms to 500 ms 
 
 
> 500 ms 
18 to 35 years 
Females 
< 320 ms 
 
 
≥ 320 ms to ≤ 470 ms 
 
 
> 470ms to ≤ 500 ms 
 
 
> 500 ms 
 
o For all ages QTcF changes from baseline (ΔQTcF, number 
andpercentage of subjects, by dose) 
x 
≤ 30 ms 
x 
> 30 ms to ≤ 60 ms 
x 
> 60 ms 
o QRS (number and percentage of subjects, by regimen and visit) 
Age 
Gender 
Values 
2 to <6 years 
Males and Females 
≤ 90 ms 
> 90ms to ≤ 100 ms 
>100 ms 
6 to < 12 years 
Males and Females 
≤ 100 ms 
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> 100 ms to ≤ 110 ms 
>110 ms 
12 to <18 years 
Males and Females 
≤110ms 
>110 ms to ≤ 120ms 
>120 ms 
18 to 35 years 
Males and Females 
≤120 ms 
>120 ms 
 
 
o PR (number and percentage of subjects, by regimen and visit) 
Age 
Gender 
Values 
2 to < 6 years 
Males and Females 
≤ 90 ms 
> 90 ms to ≤ 150 ms 
> 150 ms 
6 to < 12 years 
Males and Females 
≤ 100 ms 
> 100 ms to ≤ 170 ms 
> 170 ms 
12 to <18 years 
Males and Females 
≤ 110 ms 
> 110 ms to ≤ 180 ms 
> 180 ms 
18 to 35 years 
Males and Females 
≤ 120 ms 
> 120 ms to ≤ 220 ms 
> 220 ms 
 
o Heart rate (number and percentage of subjects, by regimen and visit) 
Age 
Gender 
Values 
2 to <6 years 
Males and Females 
< 80 bpm 
≥80 bpm to ≤140bpm 
> 140 bpm to ≤ 180 bpm 
> 180 bpm 
Increase or decrease from 
baseline >10 bpm 
Increase or decrease from 
baseline > 20 bpm 
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6 to < 12 years 
Males and Females 
< 60 bpm 
≥60 bpm to ≤120bpm 
> 120 bpm to ≤ 150 bpm 
> 150 bpm 
Increase or decrease from 
baseline >10 bpm 
Increase or decrease from 
baseline > 20 bpm 
12 to <18years 
Males and Females 
< 50 bpm 
≥50 bpm to ≤100bpm 
> 100 bpm to ≤ 150 bpm 
> 150 bpm 
Increase or decrease from 
baseline >10 bpm 
Increase or decrease from 
baseline > 20 bpm 
18-35 years 
Males and Females 
< 50 bpm 
≥50 bpm to ≤100bpm 
> 100 bpm to ≤ 150 bpm 
> 150 bpm 
Increase or decrease from 
baseline >10 bpm 
Increase or decrease from 
baseline > 20 bpm 
 
 
 
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x 
Overall characterization of normal and abnormal ECGs and the number and 
percentage of subjects with normal and abnormal ECGs. ECGs will be 
characterized as Normal, Abnormal Clinically Insignificant (ACI), or Abnormal 
Potentially Clinically Significant (APCS). The number and percentage of ECGs 
within each category will be calculated by regimen and visit. 
x 
Events for specific arrhythmias: Torsade de Pointes (TdP), ventricular 
tachycardia/fibrillation, atrial fibrillation/flutter, supraventricular tachycardia, 
etc., including associations between specific ECG findings and selected 
clinical adverse events of interest will be explored as appropriate (events that 
may signal pro-arrhythmia: syncope, palpitations, dizziness, tachycardia, 
etc.). 
2.3.2.3 Listing for Abnormalities 
Listings for ECG abnormalities by regimen and visitwill be provided for the 
following: 
x 
Heart Rates 
o Sinus Tachycardia 
o Sinus Bradycardia 
x 
PR-Interval 
o First degree AV-Block 
o Short PR interval 
x 
Heart Blocks 
o Second degree AV-Block (Type 1) 
o Second degree AV-Block (Type 2) 
o Third-degree (complete) AV-Block 
o  
x 
QRS Duration 
o LBBB 
o RBBB 
x 
QT-Interval 
x 
Other abnormalities seen by the over-reading cardiologist, including changes 
in the T-wave morphology, MI, etc. 
 
2.4 Study Population 
Study ZX008-1601 includes male and female subjects, ages 2 to 35 years who met 
the inclusion and exclusion criteria in the protocol. 
 
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2.4.1 Sample Size 
The sample size for Part 1 Cohort A was estimated under the assumption that 
adding ZX008 at 0.8 mg/kg/day to current therapy will lead to a mean decrease in 
drop seizures that is 30 percentage points greater than adding placebo to current 
therapy. For example, if adding placebo leads to a 10% decrease in seizures, then 
adding the high dose of ZX008 would be expected to decrease seizures by at least 
40%.The variability expected in the trial was estimated from a Phase 3 trial of 
clobazam for patients with Lennox-Gastaut syndrome (Ng 2011) leading to an 
assumption that the standard deviation (SD) is 50%. Other assumptions include an 
allowance for 20% dropouts between randomization and the start of the 
maintenance period. Under these assumptions, a sample size of 63 subjects per 
treatment group for a nonparametric analysis affords 90% power to detect a 
difference between the ZX008 0.8 mg/kg/day and placebo groups that is significant 
at the α=0.05 level. Assuming a 20% drop-out rate prior to the start of the 
maintenance period yields a requirement for an additional 14 subjects per group for 
a total of 79 subjects per treatment group for a nonparametric analysis. Similar 
calculations for the 0.2 mg/kg/day ZX008 group lead to a total required sample size 
of 237. The number of subjects randomized into Part 1 Cohort A is estimated to be 
approximately 250 due to the long baseline period. 
No formal sample size calculations were conducted related to cardiac safety for 
Study 1601. 
2.5  Randomization and Treatments 
Upon completion of the Baseline Period in Part 1, subjects who qualified for the 
study were randomized (1:1:1) in a double-blind manner to receive 1 of 2 doses of 
ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; 30mg/day maximum [0.2 mg/kg/day or 
0.5 mg/kg/day; 20 mg/day maximum for subjects taking concomitant STP]) or 
placebo. The randomization was stratified by weight (<37.5 kg, ≥37.5 kg) to 
ensure balance across treatment arms, with a target of at least 25% in each weight 
group. Subjects were assigned a randomization number by the IWR system upon 
confirmation that the subject qualified for enrollment in the Titration Period. 
 
 
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3 Cardiac Safety Data Collection and Analysis 
3.1 ECG Assessment 
3.1.1 Equipment 
Twelve-Lead Electrocardiograms were collected on a Mortara ELI-150c ECG machine 
(Milwaukee, WI) located at each clinical site. 
 
3.1.2 Transfer of ECGs 
Electrocardiograms were digitally transferred to ERT for analysis. 
 
3.1.3 Collection of ECGs 
The clinical ECG database will be derived from 12-lead ECGs collected from the ELI-
150c ECG machines. 
Single, 12-lead ECGs were collected in Part 1 at: 
x 
Screening (Visit 1) 
x 
Randomization (Visit 3) 
x 
Maintenance Period (Study Day 43, Visit 8) 
x 
EOS/ET (Visit12) 
x 
Follow-up (Visit 14) 
x 
Unscheduled 
 
ECGs were collected after the subjects had been in supine position resting for ≥5 
minutes.  
The time of the ECG was not controlled. 
 
3.1.4 Definition of Baseline 
The baseline for this study will be the data collected from the ECG taken at 
Randomization (Visit 3). 
 
3.1.5 Variables Measured 
At the central laboratory, using CAMI software, the cardiac technician will annotate 
the Global Superimposed Median Beat (GSMB).  
The following variables will be measured or calculated on each ECG: 
x 
QRS duration 
x 
PR interval 
x 
Heart rate (10 second average) 
x 
QT  
o The QT interval will be measured from the earliest detection of 
depolarization in any lead (peak of the Q or R wave) to the latest 
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detection of repolarization in any lead (end of the T-wave). 
 
x 
QTcF 
The RR interval will be reported, from which the corrected QT interval (QTc) using 
Fridericia’sformula (QTcF) will be calculated. 
Fridericia’s correction:  
3
/
1
RR
QT
QTcF  
 
where QT, RR, and QTcF are expressed in seconds. 
For convenience, QT, RR, PR, QRS, andQTcFwill be shown in milliseconds (ms) in 
the tables, figures and listings. 
 
3.1.6 Clinical Analysis of ECGs 
The over-reading cardiologist will give a clinical interpretation for each ECG at each 
time point. These will be presented in the data listing provided at the end of the 
study. Each ECG will be classified as Normal, Abnormal Clinically Insignificant (ACI), 
or Abnormal Potentially Clinically Significant (APCS). 
 
3.1.7 Non-Digital ECG Evaluation 
Data not acquired using the ECG equipment provided by ERT will not be eligible for 
centralized reading, nor will it be included in the database.  
 
3.2 Echocardiographic Analysis 
3.2.1 Equipment 
Site-owned equipment was used for the collection of echocardiograms. 
Prior to being qualified for subject enrollment, all echocardiographers were required 
to participate in a WebEx PowerPoint training presentation and transfer test data to 
ERT. The WebEx session consisted of reviewing protocol specific views, study 
related forms and the process of uploading the images through web portal. 
Each echocardiographer who had not been previously certified for a Zogenix study 
was required to submit a certification ECHO. The certification ECHOwas performed 
on a non-study participant. The participating ECHO facility was informed during the 
training session that they would not be able to perform ECHOs on true study 
subjects until they received a “passed” Certification ECHO Evaluation Form. 
Previously certified echocardiographers were exempt. 
 
3.2.2 Transfer of Echocardiograms 
Echocardiograms were either digitally transferred or copied to CD and sent via 
courier to ERT for analysis. 
 
3.2.3 Collection of Echocardiograms 
ECHOs in Part 1 were performed at: 
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x 
Screening (Visit 1) 
x 
Maintenance Period (Visit 8; between Study Day 40 and 54) 
x 
EOS/ET (Visit 12;between Study Day 90 and Study Day 113) 
x 
Follow-up (Visit 14) 
x 
Unscheduled 
 
The time of theECHO was not controlled. 
 
3.2.4 Definition of Baseline 
The baseline for this study will be the data collected from the ECHOtaken at 
Screening. 
 
3.2.5 Variables Measured 
Echocardiograms were evaluated by two cardiologists using DigiView software. 
Details of the assessment and adjudication process are available in the ECHO 
operations manual for these studies. 
In addition to assessing each valve (Mitral, Aortic, Tricuspid, and Pulmonary) for 
regurgitation PASP was measured or calculated on each ECHO for pulmonary 
hypertension. 
 
3.2.6 Clinical Analysis of ECHOs 
Each ECHO was read independently by two physicians. A third physician was 
assigned as an adjudicator. The adjudicator read the ECHO if any of the following 
discrepancies occurred between the first and second reader: 
x 
Aortic valve findings were not identical 
x 
Mitral valve findings were not identical 
x 
Left Ventricular Fractional Shortening difference between the two physicians 
was >5% 
x 
Left Ventricular Ejection Fraction difference between the two physicians was 
>10% 
x 
PASP difference between the two physicians was >10 mmHg 
x 
Clinical significance of the comparison to previous echo’sbetween the two 
readers was not identical 
 
3.2.7 Alert Criteria 
Echocardiographic alert criteria included: 
x 
≥ Mild valve regurgitation (aortic or mitral) 
x 
≥ moderate valve regurgitation (tricuspid or pulmonic) 
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x 
Mean mitral valve gradient ≥ 4 mmHg 
x 
Mean aortic valve gradient ≥ 15 mmHg 
x 
Mean tricuspid valve gradient ≥ 4 mmHg 
x 
Peak pulmonic valve gradient ≥ 21 mmHg 
x 
Tricuspid regurgitation jet velocity > 2.8 meters/s with orwithout any 
findings OR  
x 
One of the following findings in the absence of being able to measure 
tricuspid regurgitation jet velocity: 
o Change in right ventricle/left ventricle basal diameter ratio > 1.0 
o Right ventricular outflow tract flow acceleration time < 100 ms 
o Dilation of the inferior cava vein (diameter > 21mm and <50% 
inspiratory collapse) and/or right atrial dilatation 
o Change in the geometry of the interventricular septum in systole 
(flattening) with left ventricular eccentricity index >1.1 in systole 
and/or in diastole 
o Early diastolic pulmonary regurgitation velocity > 2.2 m/s 
o Tricuspid Annular Plane Systolic Excursion below 18 mm or below Z-
score – 2 
 
 
 
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4 Statistical Analysis 
The statistical analyses of the cardiac safety data are designed to assess the 
potential cardiotoxicity of ZX008when administered for up to 14 weeks as 
adjunctive treatment for children and adults with LGS.  
4.1 General Principles and Considerations 
This section describes the algorithms and conventions that will generally apply to 
program analyses and to the formatting of the data, as required to perform the 
proposed summary tabulations and to create the individual subject data listings. 
Unless otherwise indicated, these specifications will apply to all analyses. For details 
on the tables and figures that will be created, please refer to Section 5, Tables, 
Figures, and Listings. 
The statistical analysis will be reported using summary tables, figures, and data 
listings. 
ECG and ECHO variables at each time point will be obtained. Changes from baseline 
will be calculated and compared for the 0.2 and 0.8 mg/kg/day treatment groups to 
placebo. The primary outcome is the assessment for the development of valvular 
heart disease and pulmonary arterial hypertension. 
Continuous variables will be summarized using descriptive statistics (i.e., total 
number, mean, standard deviation [SD], minimum, maximum, and 95% CI). 
Results will be presented to one or two decimal places for means and SD, as 
appropriate. 
Categorical variables will be presented as category counts and percentages. 
Percentages will be presented to onedecimal place. 
All dates will be displayed in DDMMMYYYY format (e.g.,15DEC2012).  
All analyses will be carried out using SAS Version 9.4 or higher.  
4.2 Analysis Set 
ECG and ECHO data will be analyzed using the Safety Population, including all 
randomized subjects who received at least one dose of study medication. The 
analyses will be based on the actual treatment taken. 
No comparisons between sites will beconducted. 
 
4.2.1 Handling of Missing Data 
All data available will be used for the analysis. Missing data points will not exclude 
the rest of the subject’s data from analysis, and missing data will not be imputed. 
4.3 Interim Analysis 
No interim analysis is planned for this study.  
4.4 Multiplicity Adjustments 
No adjustments for multiplicity will be made for the cardiovascular endpoints. 
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4.5 Primary Analyses 
4.5.1 Electrocardiogram 
The primary ECG objective is to evaluate the effect of ZX008 0.8 mg/kg/day (max 
30 mg/day) on QTcF.  
The primary analysis of the QTcF isthemean baseline- and placebo-adjusted 
difference at each time-point and will be performed using an analysis of variance 
(ANOVA) model with an effect for treatment for each post-dose time point. The 
upper bound of the one-sided 95% CI (or, equivalently, two-sided 90% CI) of the 
mean placebo- and baseline-adjusted difference for QTcF (ΔΔQTcF) will be 
calculated from the least square mean differences of the ANOVA for each time 
point.  
The general formula to calculate the ΔΔQTcF at the ith timepoint is: 
Mean ΔΔQTcFi = Mean ΔQTcFifor the active group - Mean ΔQTcFifor the 
placebo group, based on the ANOVA model, where i = at ith timepoint and 
ΔQTcFti =QTcFtion Day 1 –QtcFti at Baseline (i.e., Day -1), where ti = at 
ithtime point for subject t 
 
 
4.5.2 Echocardiogram 
The primary ECHO objective is to evaluate the effect of ZX008 0.8 mg/kg/day (max 
30 mg/day) on the mitral and aortic valves, and in particular evaluating for the 
development of VHD and PAH.  
The number and percentage of subjects with each category of valvular regurgitation 
will be calculated by regimen and visit for each valve (Mitral, Aortic, Tricuspid, and 
Pulmonary), based on age (where appropriate), i.e. < 18 years of age and > 18 
years of age, and for all subjects. 
PASP will be analyzed for mean, mean maximum change from baseline at each time 
point, as well as changes in PASP compared to baseline using 5, 10 and 15 mmHg 
differences. Abnormal values will be categorized by regimen and visit. 
4.6 Secondary Analyses 
Analyses conducted with 0.8 mg/kg/day (max 30 mg/day) ZX008 will be conducted 
with 0.2 mg/kg/day ZX008. Central tendency analyses will be conducted to include 
per-visit data and changes from baseline for the ECG and ECHOvalues for all 
subjects. The variables for analysis are listed in sections 2.3.1.2 and 2.3.2.2. 
4.7 Additional Analysis 
Additional analysis may be used, as appropriate. 
4.8 Categorical Analysis 
Categorical data will be reported as both numbers and percentages and will include 
changes from baseline in both ECG and ECHO variables as detailed in section 2.3.  
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5 Tables, Figures, and Listings 
 
Table 1.1.1  Means, Mean Differences from Baseline and Upper Bound of One-Sided 
95% CI from ANOVA for ECG Data - QTcF, Safety Population - Males and Females, 
2 to <12 Years – Cohort A 
Table 1.1.2  Means, Mean Differences from Baseline and Upper Bound of One-Sided 
95% CI from ANOVA for ECG Data - QTcF, Safety Population - Males, 12 to 
<18Years – Cohort A 
Table 1.1.3  Means, Mean Differences from Baseline and Upper Bound of One-Sided 
95% CI from ANOVA for ECG Data - QTcF, Safety Population - Males, 18 to 35 
Years – Cohort A 
Table 1.1.4  Means, Mean Differences from Baseline and Upper Bound of One-Sided 
95% CI from ANOVA for ECG Data - QTcF, Safety Population - Females, 12 to 
<18Years – Cohort A 
Table 1.1.5  Means, Mean Differences from Baseline and Upper Bound of One-Sided 
95% CI from ANOVA for ECG Data - QTcF, Safety Population - Females, 18 to 35 
Years – Cohort A 
Table 1.2.1  Means, Mean Differences from Baseline and Upper Bound of One-Sided 
95% CI from ANOVA for ECG Data - Heart Rate, Safety Population - Males and 
Females, 2 to < 6 Years – Cohort A 
Table 1.2.2  Means, Mean Differences from Baseline and Upper Bound of One-Sided 
95% CI from ANOVA for ECG Data - Heart Rate, Safety Population - Males and 
Females, 6 to < 12 Years – Cohort A 
Table 1.2.3  Means, Mean Differences from Baseline and Upper Bound of One-Sided 
95% CI from ANOVA for ECG Data - Heart Rate, Safety Population - Males and 
Females, 12 to <18Years – Cohort A 
Table 1.2.4  Means, Mean Differences from Baseline and Upper Bound of One-Sided 
95% CI from ANOVA for ECG Data - Heart Rate, Safety Population - Males and 
Females, 18 to 35 Years – Cohort A 
 
Table 1.3.1  Means, Mean Differences from Baseline and Upper Bound of One-Sided 
95% CI from ANOVA for ECG Data - QRS Duration, Safety Population - Males and 
Females, 2 to < 6 Years – Cohort A 
Table 1.3.2  Means, Mean Differences from Baseline and Upper Bound of One-Sided 
95% CI from ANOVA for ECG Data - QRS Duration, Safety Population - Males and 
Females, 6 to < 12 Years – Cohort A 
Table 1.3.3 Means, Mean Differences from Baseline and Upper Bound of One-Sided 
95% CI from ANOVA for ECG Data - QRS Duration, Safety Population - Males and 
Females, 12 to <18 Years – Cohort A 
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Table 1.3.4  Means, Mean Differences from Baseline and Upper Bound of One-Sided 
95% CI from ANOVA for ECG Data - QRS Duration, Safety Population - Males and 
Females, 18 to 35 Years – Cohort A 
Table 1.4.1  Means, Mean Differences from Baseline and Upper Bound of One-Sided 
95% CI from ANOVA for ECG Data - PR-Interval, Safety Population - Males and 
Females, 2 to < 6 Years – Cohort A 
Table 1.4.2  Means, Mean Differences from Baseline and Upper Bound of One-Sided 
95% CI from ANOVA for ECG Data - PR-Interval, Safety Population - Males and 
Females, 6 to < 12 Years – Cohort A 
Table 1.4.3  Means, Mean Differences from Baseline and Upper Bound of One-Sided 
95% CI from ANOVA for ECG Data - PR-Interval, Safety Population - Males and 
Females, 12 to <18 Years – Cohort A 
Table 1.4.4  Means, Mean Differences from Baseline and Upper Bound of One-Sided 
95% CI from ANOVA for ECG Data - PR-Interval, Safety Population - Males and 
Females, 18 to 35 Years – Cohort A 
Table 1.5  
Means and Mean Differences from Baseline for ECHO Data - PASP, 
Safety Population – Cohort A 
Table 2.1.1  Categorical Summary of ECG Data - QTcF, Safety Population - Males 
and Females, 2 to <12 Years – Cohort A 
Table 2.1.2  Categorical Summary of ECG Data - QTcF, Safety Population - Males, 
12 to <18 Years – Cohort A 
Table 2.1.3  Categorical Summary of ECG Data - QTcF, Safety Population - Males, 
18 to 35 Years – Cohort A 
Table 2.1.4  Categorical Summary of ECG Data - QTcF, Safety Population -     
Females, 12 to <18Years – Cohort A 
Table 2.1.5 Categorical Summary of ECG Data - QTcF, Safety Population -     
Females, 18 to 35 Years – Cohort A 
Table 2.1.6  Categorical Summary for ECG Data - QTcF Change from Baseline,    
Safety Population - Males and Females, 2 to <12 Years – Cohort A 
Table 2.1.7  Categorical Summary for ECG Data - QTcF Change from Baseline,    
Safety Population - Males, 12 to <18Years – Cohort A 
Table 2.1.8  Categorical Summary for ECG Data - QTcF Change from Baseline,    
Safety Population - Males, 18 to 35 Years – Cohort A 
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Table 2.1.9  Categorical Summary for ECG Data - QTcF Change from Baseline,    
Safety Population - Females, 12 to <18 Years – Cohort A 
Table 2.1.10  
Categorical Summary for ECG Data - QTcF Change from 
Baseline,    Safety Population - Females, 18 to 35 Years – Cohort A 
Table 2.2.1  Categorical Summary of ECG Data - Heart Rate, Safety Population - 
Males and Females, 2 to <6 Years – Cohort A 
Table 2.2.2  Categorical Summary of ECG Data - Heart Rate, Safety Population - 
Males and Females, 6 to < 12 Years – Cohort A 
Table 2.2.3  Categorical Summary of ECG Data - Heart Rate, Safety Population - 
Males and Females, 12 to <18Years – Cohort A 
Table 2.2.4  Categorical Summary of ECG Data - Heart Rate, Safety Population - 
Males and Females, 18 to 35 Years – Cohort A 
Table 2.2.5  Categorical Summary of ECG Data - Heart Rate Change from Baseline, 
Safety Population - Males and Females, 2 to <6 Years – Cohort A 
Table 2.2.6  Categorical Summary of ECG Data - Heart Rate Change from Baseline, 
Safety Population - Males and Females, 6 to < 12 Years – Cohort A 
Table 2.2.7  Categorical Summary of ECG Data - Heart Rate Change from Baseline, 
Safety Population - Males and Females, 12 to <18 Years – Cohort A 
Table 2.2.8  Categorical Summary of ECG Data - Heart Rate Change from Baseline, 
Safety Population - Males and Females, 18 to 35 Years – Cohort A 
Table 2.3.1  Categorical Summary of ECG Data - QRS Duration, Safety Population - 
Males and Females, 2 to < 6 Years – Cohort A 
Table 2.3.2  Categorical Summary of ECG Data - QRS Duration, Safety Population - 
Males and Females, 6 to < 12 Years – Cohort A 
Table 2.3.3  Categorical Summary of ECG Data - QRS Duration, Safety Population - 
Males and Females, 12 to <18 Years – Cohort A 
Table 2.3.4  Categorical Summary of ECG Data - QRS Duration, Safety Population - 
Males and Females, 18 to 35 Years – Cohort A 
Table 2.4.1  Categorical Summary of ECG Data - PR-Interval, Safety Population - 
Males and Females, 2 to < 6 Years – Cohort A 
Table 2.4.2  Categorical Summary of ECG Data - PR-Interval, Safety Population - 
Males and Females, 6 to < 12 Years – Cohort A 
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Table 2.4.3  Categorical Summary of ECG Data - PR-Interval, Safety Population - 
Males and Females, 12 to <18 Years – Cohort A 
Table 2.4.4  Categorical Summary of ECG Data - PR-Interval, Safety Population - 
Males and Females, 18 to 35 Years – Cohort A 
Table 2.5.1 Categorical Summary for ECHO Data - Any PASP Findings > 35 mmHg 
Post-Baseline, Safety Population – Cohort A 
Table 2.5.2 Categorical Summary for ECHO Data –Any PASP Change from 
Baseline> 10, >15, >20 mmHg, Safety Population – Cohort A 
Table 2.6.1 Results to Support Heat Maps of Mitral Valve Results, Safety 
Population –Cohort A 
Table 2.6.1.1 
Results to Support Heat Maps of Mitral Valve Results, Safety 
Population – 2 to <18 Years – Cohort A 
Table 2.6.1.2 
Results to Support Heat Maps of Mitral Valve Results, Safety 
Population – 18 to 35 Years – Cohort A 
Table 2.6.2 Results to Support Heat Maps of Aortic Valve Results, Safety 
Population – Cohort A 
Table 2.6.2.1 
Results to Support Heat Maps of Aortic Valve Results, Safety 
Population – 2 to <18 Years – Cohort A 
Table 2.6.2.2 
Results to Support Heat Maps of Aortic Valve Results, Safety 
Population – 18 to 35 Years – Cohort A 
Table 2.6.3 Results to Support Heat Maps of Tricuspid Valve Results, Safety 
Population – Cohort A 
Table 2.6.3.1 
Results to Support Heat Maps of Tricuspid Valve Results, Safety 
Population – 2 to <18 Years – Cohort A 
Table 2.6.3.2 
Results to Support Heat Maps of Tricuspid Valve Results, Safety 
Population – 18 to 35 Years – Cohort A 
Table 2.6.4 Results to Support Heat Maps of Pulmonic Valve Results, Safety 
Population –Cohort A 
Table 2.6.4.1 
Results to Support Heat Maps of Pulmonic Valve Results, Safety 
Population – 2 to <18 Years – Cohort A 
Table 2.6.4.2 
Results to Support Heat Maps of Pulmonic Valve Results, Safety 
Population – 18 to 35 Years – Cohort A 
Table 3 
ECG Classification by Dosing and Visit, Safety Population – Cohort A 
Table 4.1 
Echo Findings: Point Prevalenceof Valvular Regurgitation - Mitral Valve, 
Safety Population – Cohort A 
Table 4.1.1 Echo Findings: Point Prevalenceof Valvular Regurgitation - Mitral Valve, 
Safety Population – 2 to <18 Years – Cohort A 
Table 4.1.2 Echo Findings: Point Prevalenceof Valvular Regurgitation - Mitral Valve, 
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Safety Population – 18 to 35 Years – Cohort A 
Table 4.2 
Echo Findings: Point Prevalenceof Valvular Regurgitation - Aortic 
Valve, Safety Population – Cohort A 
Table 4.2.1 Echo Findings: Point Prevalenceof Valvular Regurgitation - Aortic 
Valve, Safety Population – 2 to <18 Years – Cohort A 
Table 4.2.2 Echo Findings: Point Prevalenceof Valvular Regurgitation - Aortic 
Valve, Safety Population – 18 to 35 Years – Cohort A 
Table 4.3 
Echo Findings: Point Prevalenceof Valvular Regurgitation - Tricuspid 
Valve, Safety Population – Cohort A 
Table 4.3.1 Echo Findings: Point Prevalenceof Valvular Regurgitation - Tricuspid 
Valve, Safety Population – 2 to <18 Years – Cohort A 
Table 4.3.2 Echo Findings: Point Prevalenceof Valvular Regurgitation - Tricuspid 
Valve, Safety Population – 18 to 35 Years – Cohort A 
Table 4.4 
Echo Findings: Point Prevalenceof Valvular Regurgitation - Pulmonic 
Valve, Safety Population – Cohort A 
Table 4.4.1 Echo Findings: Point Prevalenceof Valvular Regurgitation - Pulmonic 
Valve, Safety Population – 2 to <18 Years – Cohort A 
Table 4.4.2 Echo Findings: Point Prevalenceof Valvular Regurgitation - Pulmonic 
Valve, Safety Population – 18 to 35 Years – Cohort A 
 
Figure 5.1 
Plot of Mean (SE) QTcF Change from Baseline by Visit, Safety 
Population - Males and Females, 2 to <12 Years – Cohort A 
Figure 5.2 
Plot of Mean (SE) QTcF Change from Baseline by Visit, Safety 
Population - Males, 12 to <18Years – Cohort A 
Figure 5.3 
Plot of Mean (SE) QTcF Change from Baseline by Visit, Safety 
Population - Males, 18 to 35 Years – Cohort A 
Figure 5.4 
Plot of Mean (SE) QTcF Change from Baseline by Visit, Safety 
Population - Females, 12 to <18 Years – Cohort A 
Figure 5.5 
Plot of Mean (SE) QTcF Change from Baseline by Visit, Safety 
Population - Females, 18 to 35 Years – Cohort A 
Figure 6 
Dot Plot of PASP by Visit, Safety Population – Cohort A  
Figure 7 
Dot Plot of Maximum Treatment Emergent Pulmonary Artery Systolic 
Pressure, Safety Population – Cohort A 
Listing 1.1 
Raw ECG Data by Subject and Visit, Safety Population – Cohort A 
Listing 1.2 
ECG Comments, Safety Population – Cohort A 
Listing 2.1 
Raw Echo Data by Subject and Visit, Safety Population – Cohort A  
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Listing 2.2 
Echo Data at Screening and Rescreening by Subject and Visit, Safety 
Population – Subjects with Rescreening ECHO Data - Cohort A  
 
6 References 
 
 
Arzimanoglou A, French J, Blume WT, Cross JH, et al. Lennox-Gastaut syndrome: a 
consensus approach on diagnosis, assessment, management, and trial 
methodology. Lancet Neurol 2009;8(1):82-93. 
 
Connolly HM, Crary JL, McGoon MD, Hensrud DD et al. Valvular heart disease 
associated with fenfluramine-phentermine. New Engl J Med 1997;337(9):581-8. 
Erratum in: N Engl J Med 1997 Dec 11;337(24):1783. 
 
Fridericia LS (1920), Die SystolendauerimElektrocardiogrammbeinormalenMenchen 
und beiHerzkranken. Acta Med Scan 53; 469-486. 
 
Hancock EC, Cross JH. Treatment of Lennox-Gastaut syndrome. Cochrane Database 
of Systematic Reviews 2013, Issue 2. Art. No.: CD003277. DOI: 
10.1002/14651858.CD003277.pub3. 
 
 
Hurst, DL. Epidemiology of severe myoclonic epilepsy of infancy. 
Epilepsia1990;31:397-400. 
 
Nashef L, So EL, Ryvlin P, Tomson T. Unifying the definitions of sudden unexpected 
death in epilepsy. Epilepsia. 2012; 53:227-233. 
 
Panayiotopoulos C. Epileptic encephalopathies in infancy and early childhood in 
which the epileptiform abnormalities may contribute to progressive dysfunction. In 
Panayiotopoulos C (Ed) The epilepsies: seizures, syndromes and management. 
Oxfordshire, UK: Bladon Medical Publishing, 2005:137–206. 
 
Shorvon S, Tomson T. Sudden unexpected death in epilepsy. Lancet 2011;378: 
2028–38. 
Webb RH, Gentles TL, Stirling JW et al. Valvular Regurgitation Using Portable 
Echocardiography in a Healthy Student Population: Implications for Rheumatic 
Heart Disease Screening. J Ame Soc Echocardiography. 2015; Aug 28:981-988. 
ZX008 Investigator’s Brochure. Edition 6. 8 March 2018. Zogenix International 
Limited. 
 
ZX008-1601:A Two-Part Study of ZX008 in Children and Adults with Lennox-
Gastaut Syndrome (LGS); Part 1: A Randomized, Double-blind, Placebo-controlled 
Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as 
Adjunctive Therapy for Seizures in Children and Adults with LGS, Followed by Part 
2: An Open-label Extension to Assess Long-Term Safety of ZX008 in Children and 
Adults with LGS. 29 July 2019 (Protocol Amendment 2.1). 
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Note to File: SAP Addendum 
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018  
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Project /Protocol No. 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601 
Date: 
31-June-2021  
RE:  
 
Post-Hoc Analyses for Study ZX008-1601 Cohort A – Part 1 
 
APPROVALS 
Syneos Health 
 
 
 
 
Lead Biostatistician  
 
Principal Biostatistician 
 
 
 
 
 
Date (dd-Mmm-yyyy) 
Senior Reviewing Biostatistician 
Date (dd-Mmm-yyyy) 
 
 
 
Electronically signed by:
Reason: I am the author
Date: Jul 1, 2021 17:20
EDT
E
tronically signed by:
Reason: I am the
approver
Date: Jul 1, 2021 21:42
EDT
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Zogenix International Limited  
 
 
 
 
 
Date (dd-Mmm-yyyy) 
 
 
 
 Statistician on Behalf of Zogenix 
International Limited 
 
Date (dd-Mmm-yyyy) 
 
 
 
  
 
 
Date (dd-Mmm-yyyy) 
 
 
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1. Glossary of Abbreviations  
Abbreviation 
Description 
GTC 
generalized tonic-clonic seizures 
SGTC 
Secondarily Generalized Tonic-Clonic seizures 
ESC 
Epilepsy Study Consortium 
ANCOVA 
Analysis of Covariance 
ILAE 
International League Against Epilepsy 
mITT 
modified Intent-to-Treat 
PP 
Per Protocol  
DCR 
Data Change Request  
T+M 
Titration + Maintenance  
M 
Maintenance  
SAP 
Statistical Analysis Plan 
VABS 
Vineland Adaptive Behavior Scale  
 
2. Purpose  
The purpose of this SAP addendum is to document the analyses completed in Part 1 Cohort A that were 
modified from the Statistical Analysis Plan (SAP) or were not described in the SAP Version 2.0 dated 
08JAN2020.  An updated table of contents of analyses of the tables, listings, and figures is provided in 
this addendum. 
3. Medication Analyses  
Medications were collected on the “Prior Antiepiletic Drugs”, “Concomitant Medications”,  or “Rescue 
Medications” eCRF pages. Medication start and stop dates were only collected on the Concomitant 
Medications eCRF pages. Prior medications (ie, non-antiepileptic and non-concomitant drugs) were 
derived from the Concomitant Medications eCRF page and therefore only included medications that 
were stopped during the period from 30 days prior to the screening date to the day before first date of 
study treatment. This was incorporated into Cohort A outputs Table 14.1.4.1.1 and Listing 16.2.4.3.1.1.  
This will also be incorporated into Table 14.1.4.1.2 and Listing 16.2.4.3.1.2 for Cohort B.  
4. New Efficacy Analyses  
4.1 
New Seizure Types  
A post-hoc analysis of the emergence of new seizure types will be performed. The summary of this 
variable will be based on the Seizure History eCRF (a form that lists both previous and current seizure 
types experienced by each subject), seizures reported on the seizure diary prior the start of study 
treatment, and seizures reported during the Titration and Maintenance (T+M) Period of Part 1.  Each 
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subject’s unique seizure types experienced prior to study treatment will be determined from the 
following types:    
Seizures Types 
Generalized Tonic-Clonic (GTC) 
Secondarily Generalized Tonic-Clonic (SGTC) 
Tonic 
Atonic 
Tonic/Atonic 
Clonic 
Hemiclonic L Body  
Hemiclonic R Body  
Hemiclonic with Independent L and R  
Focal with clear observable signs 
Focal without clear observable signs 
Myoclonic 
Absence/atypical absence 
Infantile Spasms 
Epileptic Spasms 
Other 
Subjects with emergence of at least one new seizure type during the T+M Period will be summarized by 
randomized treatment group.  A new seizure type is defined as a seizure type recorded in the seizure 
diary that was not recorded in the Seizure History eCRF as occurring before the first study drug dose 
date and that also did not occur during the Baseline Period.  
4.2 
All Countable Seizures that did not Result in Drops (ESC Confirmed)  
The SAP v2.0 08Jan2020 describes increasingly broad groupings of seizure types for efficacy analyses, 
from the primary endpoint (drop seizures only) to all countable (motor + non-motor) seizures, however 
it does not describe a seizure grouping that does not include drop seizures. The calculation of the 
change in the frequency of all countable seizures that did not result in drops (ESC Confirmed) between 
baseline and the T+M period will be completed similarly to the method described for the primary 
endpoint. All approved seizures recorded from the diary, which were of a type not listed as an ESC 
Confirmed Drop seizure, will be included. Similarly, a change in the frequency between baseline and the 
M period will be determined.  
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The same non-parametric and parametric Analysis of Covariance (ANCOVA) models described for the 
primary endpoint will be used for the analyses of all countable seizures that did not result in drops. The 
mITT and PP population will be used for this analysis.  
The number and percentage of subjects who had a worsening, 0% reduction, ≥25% reduction, ≥50% 
reduction, ≥75% reduction, 100% reduction, and near seizure freedom  in the frequency of all countable 
seizures that did not result in a drop (ESC Confirmed) between Baseline and T+M and between Baseline 
and M will be summarized by treatment group and overall.  
4.3 
Sensitivity Analysis of Cluster Imputation  
This analysis is an alternative method for imputation of the number of seizure events associated with 
episodes that were described in the diary as “A cluster of seizures back to back”. Refer to section 8.2.1 
of the Part 1 SAP for the primary analysis. The “A cluster of seizure back to back” episodes did not have a 
number of seizure events associated with them. In order to associate a number of seizure events 
associated with them, the following alternative method for imputation was defined.  
1.) Cluster cluster episodes described in the diary as “A cluster of seizures back to back” were classified 
according to duration, as in the primary analysis.  
x 
Short: < 1 hour duration 
x 
Medium: 1 – 5 hours, inclusive 
x 
Long: > 5 hours 
2.) Seizure cluster episodes described as “An episode of many discrete seizures’ that occurred during the 
Titration or Maintenance Period of Part 1 were identified, as in the primary analysis.  These episodes 
were reported in the diary with information about the number of discrete seizures in the cluster episode 
and the duration of a single discrete seizure within the cluster episode. 
3.) The duration of a single seizure within the discrete seizure cluster episode was defined as:  
x 
2 minutes, if the duration of the discrete seizure was answered as “Less than 2 minutes” 
x 
10 minutes, if the duration of the discrete seizure was answered as “2 – 10 minutes” 
x 
15 minutes, if the duration of the discrete seizure was answered as “More than 10 minutes” 
4.) The total duration of the overall discrete seizure cluster episode was calculated as the duration from 
step 3 multiplied by the number of seizures reported in the discrete seizure cluster episode.  
5.) The total duration from step 4 was categorized into categories as:  
x 
Short: <= 59 minutes 
x 
Medium: 60 minutes – 300 minutes (i.e. 1 – 5 hours, inclusive) 
x 
Long: > 300 minutes 
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6.) The median number of seizures reported within a discrete seizure cluster episode was determined 
for all discrete cluster episodes in the Short, Medium, and Long discrete cluster duration categories in 
the population.  The median value was then imputed into the Short, Medium, and Long duration back-
to-back cluster categories.  
The frequency of ESC Confirmed Drop seizures was then determined using the alternative cluster event 
imputation. The summary statistics, nonparametric model, and parametric models as used for the 
primary endpoint, were used for the cluster event sensitivity analysis.  
4.4 
Pre-Data Change Request (DCR) Analyses  
A pre-edited version of the seizure datasets was requested for regulatory submissions, intended to 
represent the original instance of data prior to modifications made as a result of cleaning for Part 1 
Cohort A database lock. Upon sponsor request, Signant Health created 3 versions of pre-edited (“pre-
DCR”) datasets:  
x 
2) any edits made through the Trial Manager portal or directly on the device itself were 
removed,  
x 
3) any edits made through the Trial Manager portal or directly on the device itself were 
removed, with the exception of the seizure classification field (this field is not subject-reported 
and is subject to review/query/approval by the Epilepsy Study Consortium).  
Using the three different versions of the pre-DCR seizure dataset, the seizure frequency rates were 
reproduced with each set.  The following sensitivity analyses were completed using these sets. 
ESC Confirmed Drop Seizures  
x 
Summary statistics for observed rate, change from baseline, and percentage change from 
baseline in rate for the T+M period, M period, up to 2 weeks, up to 6 weeks, up to 10 weeks, 
and up to 14 weeks. This analysis was completed for the mITT Population 
x 
Summary statistics for observed rate, change from baseline, and percentage change from 
baseline in rate for the T+M period, M period, up to 2 weeks, up to 6 weeks, up to 10 weeks, 
and up to 14 weeks using the cluster sensitivity values. This analysis was completed for the 
mITTPopulation. 
x 
Nonparametric analysis for the T+M period and M period using the original values and 
alternative cluster imputation method. This analysis was completed for the mITTPopulation.  
x 
Imputation methods for dropouts described in section 8.2.3 of the Part 1 SAP  
x 
Wilcoxon rank-sum test, including Hodges-Lehmann confidence interval for differences from 
Placebo, described in section 8.2.3 of the Part 1 SAP 
x 
The number and percentage of subjects who had a worsening, 0% reduction, ≥25% reduction, 
≥50% reduction, ≥75% reduction, 100% reduction, and near seizure freedom  in the frequency of 
all countable seizures that did not result in a drop (ESC Confirmed) between Baseline and T+M 
and between Baseline and M will be summarized by treatment group and overall.  
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x 
Cumulative response curve for percent of subjects experiencing various % reductions in seizures 
(mITT Population) 
x 
Summary statistics for observed rate, change from baseline, and percentage change from 
baseline in rate for the T+M and M period by individual seizure type. This analysis was 
completed for the mITT Population 
x 
The number and percentage of subjects who had a worsening, 0% reduction, ≥25% reduction, 
≥50% reduction, ≥75% reduction, 100% reduction, and near seizure freedom  in the frequency of 
of each individual seizure type between Baseline and T+M and between Baseline and M will be 
summarized by treatment group and overall. This analysis was completed for the mITT 
Population. 
Seizures that Typically Result in Drops  
x 
Summary statistics for observed rate, change from baseline, and percentage change from 
baseline in rate for the T+M period, M period, up to 2 weeks, up to 6 weeks, up to 10 weeks, 
and up to 14 weeks. This analysis was completed for the mITTPopulation. 
x 
Summary statistics for observed rate, change from baseline, and percentage change from 
baseline in rate for the T+M period, M period, up to 2 weeks, up to 6 weeks, up to 10 weeks, 
and up to 14 weeks using the cluster sensitivity values. This analysis was completed for the 
mITTPopulation. 
x 
Nonparametric analysis for the T+M period and M period using the original values and 
alternative cluster imputation method. This analysis was completed for the mITTPopulation  
x 
Wilcoxon rank-sum test, including Hodges-Lehmann confidence interval for differences from 
Placebo, described in section 8.2.3 of the Part 1 SAP 
x 
The number and percentage of subjects who had a worsening, 0% reduction, ≥25% reduction, 
≥50% reduction, ≥75% reduction, 100% reduction, and near seizure freedom  in the frequency of 
of seizures that typically result in drops between Baseline and T+M and between Baseline and M 
will be summarized by treatment group and overall. This analysis was completed for the mITT 
Population. 
x 
Cumulative response curve for percent of subjects experiencing various % reductions in seizures 
(mITT Population) 
x 
Summary statistics for observed rate, change from baseline, and percentage change from 
baseline in rate for the T+M and M period by individual seizure type. This analysis was 
completed for the mITT Population 
x 
The number and percentage of subjects who had a worsening, 0% reduction, ≥25% reduction, 
≥50% reduction, ≥75% reduction, 100% reduction, and near seizure freedom  in the frequency of 
of each individual seizure type between Baseline and T+M and between Baseline and M will be 
summarized by treatment group and overall. This analysis was completed for the mITT 
Population. 
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4.5 
ESC Confirmed Drop Seizures – Sensitivity to the Supplementary Drop Seizure File 
After the Part 1 Cohort A database lock occurred, an updated version of the supplementary drop seizure 
file, which lists each seizure type per subject that was reconciled to be an ESC Confirmed Drop seizure, 
was provided that contained corrections to the reconciliation based on findings discovered after 
database lock. The updated file was used to create a new version of the frequencies of ESC Confirmed 
drop seizures, and the same analyses used for the primary analyses of ESC Confirmed Drop seizures 
were applied to this data. The analysis outputs were used to confirm that no changes to study 
conclusions were changed as a result of the above-mentioned findings; they were not used to replace 
original data. 
4.6 
Sensitivity Analysis of Status Epilepticus  
A sensitivity analysis of status epilepticus cases determined from the seizure diary was conducted, based 
on seizure types officially recognized as status epilepticus by the International League Against Epilepsy 
(ILAE). Seizure events with duration > 10 minutes that were of one of the following types were 
identified. 
x 
Absence or atypical absence 
x 
Absence/atypical absence 
x 
Focal with clear observable motor signs 
x 
Focal with clear observable signs 
x 
Focal without clear observable motor signs 
x 
Generalized tonic-clonic 
x 
Secondarily generalized tonic-clonic 
Such events were further divided in order of increasing risk/emergency, ie, into those events that 
required 
x 
No Rescue Medications  
x 
1 Rescue Medications  
x 
> 1 Rescue Medications  
The number of events of each type was counted in the Baseline Period, T+M Period, and M Period as 
well as the rate (events/ 28 days) was determined.  The number of subjects with at least one event was 
summarized and the incidence rate between the active treatment group and the placebo group was 
compared using a Fisher’s Exact Test.  
4.7 
Vineland Adaptive Behavior Scale (VABS)  
The planned analyses of the Vineland Adaptive Behavior Scale were not completed due to issues with 
the collection of the questionnaire on the eDiary device.  The questionnaire was not administered in a 
way that allowed for determination of the domain scores. 
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5. Table of Contents of Outputs for Part 1 
The following shows the current table of contents of the outputs for Part 1. Note that tables, figures or listings with an “s”, “b”, or “c” will have 
structure identical to the corresponding table, listing, figure without the extra letter.  The extra letter indicates whether the output was a 
sensitivity analysis, Pre-DCR Version 2, or Pre-DCR Version 3 output, respectively.  
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
 
14.1 
Demographic data and other baseline characteristics 
 
  
14.1.1 
Subject disposition 
 
Table 
14.1.1.1.1 
Overall Subject Disposition in Part 1 (Cohort A – North 
America, Europe, Australia) – All Enrolled Subjects 
 
Table 
14.1.1.1.2 
Overall Subject Disposition in Part 1 (Cohort B - Japan) – All 
Enrolled Subjects 
 
Table 
14.1.1.2.1 
Major Protocol Deviations in Part 1 (Cohort A – North 
America, Europe, Australia) – Safety Population 
 
Table 
14.1.1.2.2 
Major Protocol Deviations in Part 1 (Cohort B - Japan) – 
Safety Population 
 
Table  
14.1.1.3.1 
Study Populations in Part 1 (Cohort A – North America, 
Europe, Australia) 
 
Table  
14.1.1.3.2 
Study Populations in Part 1 (Cohort B - Japan) 
 
  
14.1.2 
 Demographic and other baseline characteristics 
 
Table 
14.1.2.1.1 
Demographic and Baseline Characteristics (Cohort A – 
North America, Europe, Australia)  – Safety Population 
 
 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.1.2.1.2 
Demographic and Baseline Characteristics (Cohort B - 
Japan)  – Safety Population 
 
Table 
14.1.2.2.1 
Demographic and Baseline Characteristics (Cohort A – 
North America, Europe, Australia)  – mITT Population 
 
Table 
14.1.2.2.2 
Demographic and Baseline Characteristics (Cohort B - 
Japan) – mITT Population 
 
  
14.1.3 
Medical history 
 
Table 
14.1.3.1.1 
Medical and Neurologic History (Cohort A – North 
America, Europe, Australia) – Safety Population 
Title Change; Neurologic History included in 
this table. 
Table 
14.1.3.1.2 
Medical and Neurologic History (Cohort B – Japan) – Safety 
Population 
Title Change; Neurologic History included in 
this table. 
  
14.1.4 
Prior and concomitant medication/treatment 
 
Table 
14.1.4.1.1 
Medications and Therapies/Treatments Stopped during or 
up to 30 Days prior to Screening (Cohort A – North 
America, Europe, Australia) – Safety Population 
Title Changed. Only medications that had 
stopped during screening or up to and 
including 30 days prior to the screening 
were included. 
Table 
14.1.4.1.2 
Medications and Therapies/Treatments Stopped during or 
up to 30 Days prior to Screening (Cohort B – Japan) – 
Safety Population 
Title Changed. Only medications that had 
stopped during screening or up to and 
including 30 days prior to the screening 
were included. 
Table 
14.1.4.2.1 
Concomitant Medications and Therapies/Treatments in 
Part 1 (Cohort A – North America, Europe, Australia)  – 
Safety Population 
 
Table 
14.1.4.2.2 
Concomitant Medications and Therapies/Treatments in 
Part 1 (Cohort B – Japan)  – Safety Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.1.4.3.1 
Prior Antiepileptic Treatment (Cohort A – North America, 
Europe, Australia) – Safety Population 
 
Table 
14.1.4.3.2 
Prior Antiepileptic Treatment (Cohort B – Japan) – Safety 
Population 
 
Table 
14.1.4.4.1.1 
Concomitant Antiepileptic Treatment in Part 1 (Cohort A – 
North America, Europe, Australia) – Safety Population 
 
Table 
14.1.4.4.1.2 
Concomitant Antiepileptic Treatment in Part 1 (Cohort B – 
Japan) - Safety Population 
 
Table 
14.1.4.4.2.1 
Rescue Medications in Part 1 (Cohort A – North America, 
Europe, Australia) – Safety Population 
Title Change from Concomitant Rescue 
Medications 
Table 
14.1.4.4.2.2 
Rescue Medications in Part 1 (Cohort B – Japan) - Safety 
Population 
Title Change from Concomitant Rescue 
Medications 
  
14.1.5 
Treatment Exposure and compliance 
 
Table 
14.1.5.1.1 
Duration of IMP Treatment Exposure in Part 1 (Cohort A – 
North America, Europe, Australia) – Safety Population 
 
Table 
14.1.5.1.2 
Duration of IMP Treatment Exposure in Part 1 (Cohort B – 
Japan) – Safety Population 
 
Table 
14.1.5.2.1.1 
Compliance to IMP intake in Part 1 (Cohort A – North 
America, Europe, Australia) - mITT Population  
 
Table 
14.1.5.2.1.2 
Compliance to IMP intake in Part 1 (Cohort B – Japan) - 
mITT Population  
 
Table 
14.1.5.2.2.1 
Compliance to IMP intake in Part 1 (Cohort A – North 
America, Europe, Australia) - Safety Population  
This table was described in the shells, but 
was not included in the table of contents. 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.1.5.2.2.2 
Compliance to IMP intake in Part 1 (Cohort B – Japan) - 
Safety Population  
This table was described in the shells, but 
was not included in the table of contents. 
Table 
14.1.5.2.3.1 
Compliance to IMP Intake in Part 1 based on Bottle Weight 
(Cohort A – North America, Europe, Australia) - mITT 
Population  
 
Table 
14.1.5.2.3.2 
Compliance to IMP Intake in Part 1 based on Bottle Weight 
(Cohort B – Japan) - mITT Population  
 
Table 
14.1.5.2.4.1 
Compliance to IMP Intake in Part 1 based on Bottle Weight 
(Cohort A – North America, Europe, Australia) - Safety 
Population  
This table was described in the shells, but 
was not included in the table of contents. 
Table 
14.1.5.2.4.2 
Compliance to IMP Intake in Part 1 based on Bottle Weight 
(Cohort B – Japan) - Safety Population  
This table was described in the shells, but 
was not included in the table of contents. 
  
14.2 
Efficacy, pharmacokinetics, and pharmacodynamics 
 
  
14.2.1 
Efficacy – ZX008 0.8 and 0.2 mg/kg/day vs Placebo  
Seizures resulting in drops 
 
Table 
14.2.1.1.1.1 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Summary Statistics (Cohort A – 
North America, Europe, Australia) – mITT Population 
 
Table 
14.2.1.1.1.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Summary Statistics (Cohort A – North America, Europe, 
Australia) – mITT Population 
New Table using Supplementary Seizure 
File updated post-Part 1 Database Lock.  
Table 
14.2.1.1.1.1b 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Summary Statistics (Cohort A – 
New Table using Pre-DCR dataset Version 2 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
North America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2) – mITT Population 
Table 
14.2.1.1.1.1c 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Summary Statistics (Cohort A – 
North America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 3) – mITT Population 
New Table using Pre-DCR dataset Version 3 
Table 
14.2.1.1.1.2 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Summary Statistics (Cohort B – 
Japan) – mITT Population 
Table number clarified in shells. 
Table 
14.2.1.1.1.3 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Summary Statistics (Cluster 
Event Sensitivity Analysis) (Cohort A – North America, 
Europe, Australia) – mITT Population 
Post-hoc table addition. The shell used is 
the same as 14.2.1.1.1.1.  The different 
methodology of imputing the number of 
seizure events associated with Cluster 
events was added. 
Table 
14.2.1.1.1.3s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Summary Statistics (Cluster Event Sensitivity Analysis) 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
New Table using Supplementary Seizure 
File updated post-Part 1 Database Lock 
Table 
14.2.1.1.1.4 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Summary Statistics (Cluster 
Event Sensitivity Analysis) (Cohort B – Japan) – mITT 
Population 
Post-hoc table addition. The shell used is 
the same as 14.2.1.1.1.1.  The different 
methodology of imputing the number of 
seizure events associated with Cluster 
events was added. 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.2.1.1.2.1 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Summary Statistics (Cohort A – 
North America, Europe, Australia) – PP Population 
 
Table 
14.2.1.1.2.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Summary Statistics (Cohort A – North America, Europe, 
Australia) – PP Population 
New Table using Supplementary Seizure 
File updated post-Part 1 Database Lock 
Table 
14.2.1.1.2.2 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Summary Statistics (Cohort B – 
Japan) – PP Population 
 
Table  
14.2.1.2.1.1 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1: Nonparametric Analysis (Cohort 
A – North America, Europe, Australia) – mITT Population 
Table Number Update  
Table  
14.2.1.2.1.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed)  per 28 days during Part 1: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) – mITT Population 
New Table using Supplementary Seizure 
File updated post-Part 1 Database Lock 
Table  
14.2.1.2.1.1b 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1: Nonparametric Analysis (Cohort 
A – North America, Europe, Australia) (Pre-DCR Seizure 
Event Dataset Version 2)  – mITT Population 
New Table using Pre-DCR dataset Version 2 
Table  
14.2.1.2.1.1c 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1: Nonparametric Analysis (Cohort 
A – North America, Europe, Australia) (Pre-DCR Seizure 
Event Dataset Version 3)  – mITT Population 
New Table using Pre-DCR dataset Version 3 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.2.1.2.1.2 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1: Nonparametric Analysis (Cohort 
B – Japan) – mITT Population 
Planned table per SAP.  This Table number 
was added to the Table of Contents.  
Table  
14.2.1.2.1.3 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis with 
Categorized Baseline Seizure Frequency and Baseline 
Seizure Frequency by Treatment Interaction  (Cohort A – 
North America, Europe, Australia)- MITT Population 
Table was described in the SAP, but shell 
had not been produced. This was added to 
the shells. 
Table  
14.2.1.2.1.3s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis with Categorized Baseline Seizure 
Frequency and Baseline Seizure Frequency by Treatment 
Interaction  (Cohort A – North America, Europe, Australia)- 
MITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.2.1.4 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis with 
Categorized Baseline Seizure Frequency and Baseline 
Seizure Frequency by Treatment Interaction  (Cohort B – 
Japan)- MITT Population 
Table was described in the SAP, but shell 
had not been produced. This was added to 
the shells. 
Table  
14.2.1.2.2.1 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1: Nonparametric Analysis (Cohort 
A – North America, Europe, Australia) – PP Population 
Table Number Update  
Table  
14.2.1.2.2.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed)  per 28 days during Part 1: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) – PP Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.2.1.2.2.2 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1: Nonparametric Analysis (Cohort 
B – Japan) – PP Population 
Planned table per SAP.  This Table number 
was added to the Table of Contents.  
Table  
14.2.1.3.1.1 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1: Parametric Analysis (Cohort A – 
North America, Europe, Australia)  – mITT Population 
Table Number Update  
Table  
14.2.1.3.1.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed)  per 28 days during Part 1: 
Parametric Analysis (Cohort A – North America, Europe, 
Australia)  – mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.3.1.2 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1: Parametric Analysis (Cohort B – 
Japan)  – mITT Population 
Planned table per SAP.  This Table number 
was added to the Table of Contents.  
Table  
14.2.1.3.1.3 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1: Parametric Analysis with 
Categorized Baseline Seizure Frequency and Baseline 
Seizure Frequency by Treatment Interaction (Cohort A – 
North America, Europe, Australia)  – mITT Population 
Table was described in the SAP, but shell 
had not been produced. This was added to 
the shells. 
Table  
14.2.1.3.1.3s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed)  per 28 days during Part 1: 
Parametric Analysis with Categorized Baseline Seizure 
Frequency and Baseline Seizure Frequency by Treatment 
Interaction (Cohort A – North America, Europe, Australia)  
– mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
PUBLIC COPY 
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application and any extensions or variations thereof.


Note to File 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 17 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.2.1.3.1.4 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1: Parametric Analysis with 
Categorized Baseline Seizure Frequency and Baseline 
Seizure Frequency by Treatment Interaction (Cohort B – 
Japan)  – mITT Population 
Table was described in the SAP, but shell 
had not been produced. This was added to 
the shells. 
Table  
14.2.1.3.2.1 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1: Parametric Analysis (Cohort A – 
North America, Europe, Australia)  – PP Population 
Table Number Update  
Table  
14.2.1.3.2.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed)  per 28 days during Part 1: 
Parametric Analysis (Cohort A – North America, Europe, 
Australia) – PP Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.3.2.2 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1: Parametric Analysis (Cohort B – 
Japan)  – PP Population 
Added to the Table of Contents 
Table  
14.2.1.4.1.1 
Percent Improvement in Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, Australia)  
– mITT Population 
 
Table  
14.2.1.4.1.1s 
Sensitivity Analysis of Percent Improvement in Frequency 
of Seizures Resulting in Drops (ESC Confirmed) per 28 days 
during Part 1: Logistic Regression (Cohort A – North 
America, Europe, Australia)  – mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.4.1.1b 
Percent Improvement in Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, Australia) 
New Table using Pre-DCR dataset Version 2 
PUBLIC COPY 
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Note to File 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 18 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
(Pre-DCR Seizure Event Dataset Version 2) – mITT 
Population 
Table  
14.2.1.4.1.1c 
Percent Improvement in Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, Australia) 
(Pre-DCR Seizure Event Dataset Version 3) – mITT 
Population 
New Table using Pre-DCR dataset Version 3 
Table  
14.2.1.4.1.2 
Percent Improvement in Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: Logistic 
Regression (Cohort B – Japan)  – mITT Population 
 
Table  
14.2.1.4.2.1 
Percent Improvement in Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, Australia)  
– PP Population 
 
Table  
14.2.1.4.2.1s 
Sensitivity Analysis of Percent Improvement in Frequency 
of Seizures Resulting in Drops (ESC Confirmed) per 28 days 
during Part 1: Logistic Regression (Cohort A – North 
America, Europe, Australia)  – PP Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.4.2.2 
Percent Improvement in Frequency of Seizures resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: Logistic 
Regression (Cohort B – Japan)  – mITT Population 
 
Figure  
14.2.1.5.1.1 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures Resulting in 
Drops (ESC Confirmed) during Part 1 (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
PUBLIC COPY 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 19 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Figure  
14.2.1.5.1.1s 
Sensitivity Analysis of Cumulative Response Curve for 
Percent of Subjects Experiencing Various % Reductions in 
Seizures Resulting in Drops (ESC Confirmed) during Part 1 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
New Figure using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Figure  
14.2.1.5.1.1b 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures Resulting in 
Drops (ESC Confirmed) during Part 1 (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2) – mITT Population 
New Figure using Pre-DCR dataset Version 
2 
Figure  
14.2.1.5.1.1c 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures Resulting in 
Drops (ESC Confirmed) during Part 1 (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 3) – mITT Population 
New Figure using Pre-DCR dataset Version 
3 
Figure  
14.2.1.5.1.2 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures Resulting in 
Drops (ESC Confirmed) during Part 1 (Cohort B - Japan) – 
mITT Population 
 
Table  
14.2.1.6.1 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1 by Age Subgroup: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia) - 
mITT Population 
 
Table  
14.2.1.6.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1 by Age 
Subgroup: Nonparametric Analysis (Cohort A – North 
America, Europe, Australia) - mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Note to File 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 20 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.2.1.6.2 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1 by Sex: Nonparametric Analysis – 
(Cohort A – North America, Europe, Australia) - mITT 
Population 
 
Table  
14.2.1.6.2s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1 by Sex: 
Nonparametric Analysis – (Cohort A – North America, 
Europe, Australia) - mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.6.3 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1 by Weight Subgroup: 
Nonparametric Analysis – (Cohort A – North America, 
Europe, Australia) - mITT Population 
 
Table  
14.2.1.6.3s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1 by 
Weight Subgroup: Nonparametric Analysis – (Cohort A – 
North America, Europe, Australia) - mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.6.4 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1 by Number of Concomitant 
Antiepileptic Medications Used: Nonparametric Analysis 
(Cohort A – North America, Europe, Australia) - mITT 
Population 
 
Table  
14.2.1.6.4s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1 by 
Number of Concomitant Antiepileptic Medications Used: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
PUBLIC COPY 
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application and any extensions or variations thereof.


Note to File 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 21 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.2.1.6.5 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1 by Number of Prior Antiepileptic 
Medications Used: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) - mITT Population 
 
Table  
14.2.1.6.5s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed)  per 28 days during Part 1 by 
Number of Prior Antiepileptic Medications Used: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.6.6 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1 by Baseline Frequency of 
Seizures that Result in Drops: Nonparametric Analysis 
(Cohort A – North America, Europe, Australia) - mITT 
Population 
 
Table  
14.2.1.6.6s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed)  per 28 days during Part 1 by 
Baseline Frequency of Seizures that Result in Drops: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.1.6.7 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1 by Race Group: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia) - 
mITT Population 
New Table requested. 
Table  
14.2.1.6.8 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1 by Geographic Region: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) mITT Population 
New Table requested. 
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Note to File 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 22 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.2.1.7.1 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity Analysis 1 (Worst Value Substituted for 
Dropouts) (Cohort A – North America, Europe, Australia) – 
mITT Population 
 
Table 
14.2.1.7.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis – Sensitivity Analysis 1 (Worst 
Value Substituted for Dropouts) (Cohort A – North 
America, Europe, Australia) – mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table 
14.2.1.7.1b 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity Analysis 1 (Worst Value Substituted for 
Dropouts) (Cohort A – North America, Europe, Australia) 
(Pre-DCR Seizure Event Dataset Version 2) – mITT 
Population 
New Table using Pre-DCR dataset Version 2 
Table 
14.2.1.7.1c 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity Analysis 1 (Worst Value Substituted for 
Dropouts) (Cohort A – North America, Europe, Australia) 
(Pre-DCR Seizure Event Dataset Version 3) – mITT 
Population 
New Table using Pre-DCR dataset Version 3 
Table 
14.2.1.7.2 
Frequency of Seizures Resulting in Drops  (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity Analysis 1 (Worst Value Substituted for 
Dropouts) (Cohort B – Japan)– mITT Population 
Correction of Table Title for Cohort B 
PUBLIC COPY 
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application and any extensions or variations thereof.


Note to File 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 23 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.2.1.7.3 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity Analysis 2 (Differential Imputation Method for 
Dropouts) (Cohort A – North America, Europe, Australia)  – 
mITT Population 
Correction of Table Title for Cohort A 
Table 
14.2.1.7.3s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis – Sensitivity Analysis 2 
(Differential Imputation Method for Dropouts) (Cohort A – 
North America, Europe, Australia)  – mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table 
14.2.1.7.3b 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity Analysis 2 (Differential Imputation Method for  
Dropouts) (Cohort A – North America, Europe, Australia) 
(Pre-DCR Seizure Event Dataset Version 2)  – mITT 
Population 
New Table using Pre-DCR dataset Version 2 
Table 
14.2.1.7.3c 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity Analysis 2 (Differential Imputation Method for  
Dropouts) (Cohort A – North America, Europe, Australia) 
(Pre-DCR Seizure Event Dataset Version 3)  – mITT 
Population 
New Table using Pre-DCR dataset Version 3 
Table 
14.2.1.7.4 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity Analysis 2 (Differential Imputation Method for  
Dropouts)  (Cohort B – Japan)  – mITT Population 
Correction of Table Title for Cohort B 
PUBLIC COPY 
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application and any extensions or variations thereof.


Note to File 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 24 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.2.1.8.1 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Wilcoxon Analysis – Sensitivity 
to Analysis Method (Cohort A – North America, Europe, 
Australia) – mITT Population 
 
Table 
14.2.1.8.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: Wilcoxon 
Analysis – Sensitivity to Analysis Method (Cohort A – North 
America, Europe, Australia) – mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table 
14.2.1.8.1b 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Wilcoxon Analysis – Sensitivity 
to Analysis Method (Cohort A – North America, Europe, 
Australia) (Pre-DCR Seizure Event Dataset Version 2) – 
mITT Population 
New Table using Pre-DCR dataset Version 2 
Table 
14.2.1.8.1c 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Wilcoxon Analysis – Sensitivity 
to Analysis Method (Cohort A – North America, Europe, 
Australia) (Pre-DCR Seizure Event Dataset Version 3) – 
mITT Population 
New Table using Pre-DCR dataset Version 3 
Table 
14.2.1.8.2 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Wilcoxon Analysis – Sensitivity 
to Analysis Method (Cohort B – Japan) – mITT Population 
 
Table 
14.2.1.9.1 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Outliers (Cohort A – North America, Europe, 
Australia) – mITT Population 
 
PUBLIC COPY 
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Note to File 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 25 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.2.1.9.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis – Sensitivity to Outliers (Cohort A 
– North America, Europe, Australia) – mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table 
14.2.1.9.1b 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Outliers (Cohort A – North America, Europe, 
Australia) (Pre-DCR Seizure Event Dataset Version 2) – 
mITT Population 
New Table using Pre-DCR dataset Version 2 
Table 
14.2.1.9.1c 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Outliers (Cohort A – North America, Europe, 
Australia) (Pre-DCR Seizure Event Dataset Version 3) – 
mITT Population 
New Table using Pre-DCR dataset Version 3 
Table 
14.2.1.9.2 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Outliers (Cohort B – Japan) – mITT Population 
 
Table 
14.2.1.10.1 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Seizure Clusters (Cohort A – North America, 
Europe, Australia) – mITT Population 
 
Table 
14.2.1.10.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis – Sensitivity to Seizure Clusters 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
PUBLIC COPY 
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application and any extensions or variations thereof.


Note to File 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 26 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.2.1.10.1b 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Seizure Clusters (Cohort A – North America, 
Europe, Australia) (Pre-DCR Seizure Event Dataset Version 
2) – mITT Population 
New Table using Pre-DCR dataset Version 2 
Table 
14.2.1.10.1c 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Seizure Clusters (Cohort A – North America, 
Europe, Australia) (Pre-DCR Seizure Event Dataset Version 
3) – mITT Population 
New Table using Pre-DCR dataset Version 3 
Table 
14.2.1.10.2 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Seizure Clusters (Cohort B – Japan) – mITT 
Population 
 
Table 
14.2.1.10.3 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis (Cluster 
Event Sensitivity Analysis) (Cohort A – North America, 
Europe, Australia) – mITT Population 
Sensitivity Analysis to assess the impact of 
imputation of number of events associated 
with cluster events. 
Table 
14.2.1.10.3s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis (Cluster Event Sensitivity Analysis) 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table 
14.2.1.10.3b 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis (Cluster 
Event Sensitivity Analysis) (Cohort A – North America, 
New Table using Pre-DCR dataset Version 2 
PUBLIC COPY 
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application and any extensions or variations thereof.


Note to File 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 27 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Europe, Australia) (Pre-DCR Seizure Event Dataset Version 
2) – mITT Population 
Table 
14.2.1.10.3c 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis (Cluster 
Event Sensitivity Analysis) (Cohort A – North America, 
Europe, Australia) (Pre-DCR Seizure Event Dataset Version 
3) – mITT Population 
New Table using Pre-DCR dataset Version 3 
Table 
14.2.1.10.4 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis (Cluster 
Event Sensitivity Analysis)  (Cohort B – Japan) – mITT 
Population 
Sensitivity Analysis to assess the impact of 
imputation of number of events associated 
with cluster events. 
  
14.2.2 
Efficacy – Clinical Global Impression – Improvement 
rating by Parent/Caregiver and Investigator 
 
Table  
14.2.2.1.1.1 
Clinical Global Impression – Improvement (CGI-I) Rating by 
Investigator in Part 1 (Cohort A – North America, Europe, 
Australia) – mITT Population 
Table Title adjustment to align with shell. 
Table  
14.2.2.1.1.2 
Clinical Global Impression – Improvement (CGI-I) Rating by 
Investigator in Part 1 (Cohort B – Japan) – mITT Population 
Table Title adjustment to align with shell. 
Table  
14.2.2.1.2.1 
Clinical Global Impression – Improvement (CGI-I) Rating by 
Investigator in Part 1 (Cohort A – North America, Europe, 
Australia) – PP Population 
Table Title adjustment to align with shell. 
Table  
14.2.2.1.2.2 
Clinical Global Impression – Improvement (CGI-I) Rating by 
Investigator in Part 1 (Cohort B – Japan) – PP Population 
Table Title adjustment to align with shell. 
Table  
14.2.2.1.3.1 
Clinical Global Impression – Improvement (CGI-I) Rating by 
Investigator in Part 1 by Age Subgroup (Cohort A – North 
America, Europe, Australia) – mITT Population 
Table Title adjustment to align with shell. 
PUBLIC COPY 
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Note to File 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 28 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.2.2.1.3.2 
Clinical Global Impression – Improvement (CGI-I) Rating by 
Investigator in Part 1 by Sex (Cohort A – North America, 
Europe, Australia) – mITT Population 
Table Title adjustment to align with shell. 
Table  
14.2.2.1.3.3 
Clinical Global Impression – Improvement (CGI-I) Rating by 
Investigator in Part 1 by Weight Subgroup (Cohort A – 
North America, Europe, Australia) – mITT Population 
Table Title adjustment to align with shell. 
Table  
14.2.2.1.3.4 
Clinical Global Impression – Improvement (CGI-I) Rating by 
Investigator in Part 1 by Number of Concomitant 
Antiepileptic Medications Used (Cohort A – North America, 
Europe, Australia) – mITT Population 
Table Title adjustment to align with shell. 
Table  
14.2.2.1.3.5 
Clinical Global Impression – Improvement (CGI-I) Rating by 
Investigator in Part 1 by Number of Prior Antiepileptic 
Medications Used (Cohort A – North America, Europe, 
Australia) – mITT Population 
Table Title adjustment to align with shell. 
Table  
14.2.2.1.3.6 
Clinical Global Impression – Improvement (CGI-I) Rating by 
Investigator in Part 1 by Baseline Frequency of Seizures 
that Result in Drops (Cohort A – North America, Europe, 
Australia) – mITT Population 
Table Title adjustment to align with shell. 
Table  
14.2.2.1.3.6s 
Sensitivity Analysis of Clinical Global Impression – 
Improvement (CGI-I) Rating by Investigator in Part 1 by 
Baseline Frequency of Seizures that Result in Drops 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Figure 
14.2.2.2.1 
Distribution of Clinical Global Impression – Improvement  
(CGI-I) Rating by Investigator in Part 1 (Cohort A – North 
America, Europe, Australia)– mITT Population 
Figure Title adjustment to align with shell. 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 29 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Figure 
14.2.2.2.2 
Distribution of Clinical Global Impression – Improvement 
(CGI-I) Rating by Investigator in Part 1 (Cohort B – Japan)  – 
mITT Population 
Figure Title adjustment to align with shell. 
 
14.2.3 
Countable Motor Seizures  
 
Table 
14.2.3.1.1.1 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Summary Statistics (Cohort A – North America, 
Europe, Australia) – mITT Population 
 
Table 
14.2.3.1.1.2 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Summary Statistics (Cohort B – Japan)  – mITT 
Population 
 
Table 
14.2.3.1.2.1 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Summary Statistics (Cohort A – North America, 
Europe, Australia) – PP Population 
 
Table 
14.2.3.1.2.2 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Summary Statistics (Cohort B – Japan) – PP 
Population 
 
Table  
14.2.3.2.1.1 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Nonparametric Analysis (Cohort A – North America, 
Europe, Australia)  – mITT Population 
 
Table  
14.2.3.2.1.2 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Nonparametric Analysis (Cohort B – Japan)  – mITT 
Population 
 
Table  
14.2.3.2.2.1 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) – PP Population 
 
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Note to File 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 30 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.2.3.2.2.2 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Nonparametric Analysis (Cohort B – Japan)  – PP 
Population 
 
Table  
14.2.3.3.1.1 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Parametric Analysis (Cohort A – North America, 
Europe, Australia)– mITT Population 
 
Table  
14.2.3.3.1.2 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Parametric Analysis (Cohort B – Japan)  – mITT 
Population 
 
Table  
14.2.3.3.2.1 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Parametric Analysis (Cohort A – North America, 
Europe, Australia) – PP Population 
 
Table  
14.2.3.3.2.2 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Parametric Analysis (Cohort B – Japan) – PP 
Population 
 
Table  
14.2.3.4.1.1 
Percent Improvement in Frequency of Countable Motor 
Seizures per 28 days during Part 1: Logistic Regression 
(Cohort A – North America, Europe, Australia)– mITT 
Population 
 
Table  
14.2.3.4.1.2 
Percent Improvement in Frequency of Countable Motor 
Seizures per 28 days during Part 1: Logistic Regression 
(Cohort B – Japan) – mITT Population 
 
Figure  
14.2.3.5.1.1 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Countable Motor 
Seizures during Part 1 (Cohort A – North America, Europe, 
Australia)– mITT Population 
 
PUBLIC COPY 
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Note to File 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 31 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Figure  
14.2.3.5.1.2 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Countable Motor 
Seizures during Part 1 (Cohort B – Japan)– mITT Population 
 
 
14.2.4.1 
Efficacy – Typical Drop Seizures 
 
Table  
14.2.4.1.1.1.1 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) – mITT Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.1.1.1s 
Sensitivity Analysis of Frequency of Seizures that Typically 
Result in Drops per 28 days during Part 1: Summary 
Statistics (Cohort A – North America, Europe, Australia) – 
mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table  
14.2.4.1.1.1.1b 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2) – mITT Population 
New Table using Pre-DCR dataset Version 2 
Table  
14.2.4.1.1.1.1c 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 3) – mITT Population 
New Table using Pre-DCR dataset Version 3 
Table  
14.2.4.1.1.1.2 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Summary Statistics (Cohort B – Japan) – 
mITT Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.1.2.1 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) – PP Population 
Title update made at the request of Zogenix 
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Note to File 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 32 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.2.4.1.1.2.1b 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia)  (Pre-DCR Seizure Event 
Dataset Version 2) – PP Population 
New Table using Pre-DCR dataset Version 2 
Table  
14.2.4.1.1.2.1c 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 3) – PP Population 
New Table using Pre-DCR dataset Version 3 
Table  
14.2.4.1.1.2.2 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Summary Statistics (Cohort B – Japan) – 
PP Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.1.2.2b 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Summary Statistics (Cohort B – Japan) 
(Pre-DCR Seizure Event Dataset Version 2) – PP Population 
New Table using Pre-DCR dataset Version 2 
Table  
14.2.4.1.1.2.2c 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Summary Statistics (Cohort B – Japan) 
(Pre-DCR Seizure Event Dataset Version 3) – PP Population  
New Table using Pre-DCR dataset Version 3 
Table  
14.2.4.1.2.1.1 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) – mITT Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.2.1.1b 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2) – mITT Population 
New Table using Pre-DCR dataset Version 2 
Table  
14.2.4.1.2.1.1c 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Nonparametric Analysis (Cohort A – 
New Table using Pre-DCR dataset Version 3 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 33 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
North America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 3) – mITT Population 
Table  
14.2.4.1.2.1.2 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Nonparametric Analysis (Cohort B – 
Japan) – mITT Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.2.2.1 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) – PP Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.2.2.1b 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2)– PP Population  
New Table using Pre-DCR dataset Version 2 
Table  
14.2.4.1.2.2.1c 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 3) – PP Population  
New Table using Pre-DCR dataset Version 3 
Table  
14.2.4.1.2.2.2 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Nonparametric Analysis (Cohort B – 
Japan) – PP Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.3.1.1 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Parametric Analysis (Cohort A – North 
America, Europe, Australia) – mITT Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.3.1.1b 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Parametric Analysis (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2) – mITT Population   
New Table using Pre-DCR dataset Version 2 
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Note to File 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 34 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.2.4.1.3.1.2 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Parametric Analysis (Cohort B – Japan) 
– mITT Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.3.2.1 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Parametric Analysis (Cohort A – North 
America, Europe, Australia) – PP Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.3.2.1b 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Parametric Analysis (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2)– PP Population  
New Table using Pre-DCR dataset Version 2 
Table  
14.2.4.1.3.2.2 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Parametric Analysis (Cohort B – Japan) 
– PP Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.4.1.1 
Percent Improvement in Frequency of Seizures that 
Typically Result in Drops per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, Australia)– 
mITT Population 
Title update made at the request of Zogenix 
Table  
14.2.4.1.4.1.1b 
Percent Improvement in Frequency of Seizures that 
Typically Result in Drops per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, Australia)– 
mITT Population (Pre-DCR Seizure Event Dataset Version 2) 
New Table using Pre-DCR dataset Version 2 
Table  
14.2.4.1.4.1.1c 
Percent Improvement in Frequency of Seizures that 
Typically Result in Drops per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, Australia)– 
mITT Population (Pre-DCR Seizure Event Dataset Version 3) 
New Table using Pre-DCR dataset Version 3 
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Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 35 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.2.4.1.4.1.2 
Percent Improvement in Frequency of Seizures that 
Typically Result in Drops per 28 days during Part 1: Logistic 
Regression (Cohort B – Japan)– mITT Population 
Title update made at the request of Zogenix 
Figure  
14.2.4.1.5.1.1 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures that 
Typically Result in Drops during Part 1 (Cohort A – North 
America, Europe, Australia)– mITT Population 
Title update made at the request of Zogenix 
Figure  
14.2.4.1.5.1.1b 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures that 
Typically Result in Drops during Part 1 (Cohort A – North 
America, Europe, Australia)– mITT Population (Pre-DCR 
Seizure Event Dataset Version 2) 
New Figure using Pre-DCR dataset Version 
2 
Figure  
14.2.4.1.5.1.1c 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures that 
Typically Result in Drops during Part 1 (Cohort A – North 
America, Europe, Australia)– mITT Population (Pre-DCR 
Seizure Event Dataset Version 3) 
New Figure using Pre-DCR dataset Version 
3 
Figure  
14.2.4.1.5.1.2 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures that 
Typically Result in Drops during Part 1 (Cohort B – Japan)– 
mITT Population 
 
Table  
14.2.4.1.6.1.1b 
Change in Seizures that Typically Result per 28 days in 
Drops from Baseline during Part 1: Wilcoxon Analysis - 
Sensitivity to Analysis Method) (Cohort A – North America, 
Europe, Australia) (Pre-DCR Seizure Event Dataset Version 
2) - mITT Population  
New Figure using Pre-DCR dataset Version 
2 
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Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 36 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.2.4.1.6.1.1c 
Change in Seizures that Typically Result per 28 days in 
Drops from Baseline during Part 1: Wilcoxon Analysis - 
Sensitivity to Analysis Method) (Cohort A – North America, 
Europe, Australia) (Pre-DCR Seizure Event Dataset Version 
3) - mITT Population  
New Figure using Pre-DCR dataset Version 
3 
 
14.2.4.2 
Efficacy – Countable Non-Motor Seizures 
 
Table  
14.2.4.2.1.1.1 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
Table  
14.2.4.2.1.1.2 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Summary Statistics (Cohort B – Japan) – 
mITT Population 
 
Table  
14.2.4.2.1.2.1 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) – PP Population 
 
Table  
14.2.4.2.1.2.2 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Summary Statistics (Cohort B – Japan) – PP 
Population 
 
Table  
14.2.4.2.2.1.1 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Nonparametric Analysis (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
Table  
14.2.4.2.2.1.2 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Nonparametric Analysis (Cohort B – Japan) – 
mITT Population 
 
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Note to File 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 37 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.2.4.2.2.2.1 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Nonparametric Analysis (Cohort A – North 
America, Europe, Australia) – PP Population 
 
Table  
14.2.4.2.2.2.2 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Nonparametric Analysis (Cohort B – Japan) – 
PP Population 
 
Table  
14.2.4.2.3.1.1 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Parametric Analysis (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
Table  
14.2.4.2.3.1.2 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Parametric Analysis (Cohort B – Japan) – 
mITT Population 
 
Table  
14.2.4.2.3.2.1 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Parametric Analysis (Cohort A – North 
America, Europe, Australia) – PP Population 
 
Table  
14.2.4.2.3.2.2 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Parametric Analysis (Cohort B – Japan) – PP 
Population 
 
Table  
14.2.4.2.4.1.1 
Percent Improvement in Frequency of Countable Non-
Motor Seizures per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, Australia)– 
mITT Population 
 
Table  
14.2.4.2.4.1.2 
Percent Improvement in Frequency of Countable Non-
Motor Seizures per 28 days during Part 1: Logistic 
Regression (Cohort B – Japan)– mITT Population 
 
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application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 38 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Figure  
14.2.4.2.5.1.1 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Countable Non-
Motor Seizures during Part 1 (Cohort A – North America, 
Europe, Australia)– mITT Population 
 
Figure  
14.2.4.2.5.1.2 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Countable Non-
Motor Seizures during Part 1 (Cohort B – Japan)– mITT 
Population 
 
 
14.2.4.3 
Efficacy – All Countable Seizures (Motor + Non-Motor) 
 
Table  
14.2.4.3.1.1.1 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Summary Statistics (Cohort A – 
North America, Europe, Australia) – mITT Population 
 
Table  
14.2.4.3.1.1.2 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Summary Statistics (Cohort B – 
Japan) – mITT Population 
 
Table  
14.2.4.3.1.2.1 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Summary Statistics (Cohort A – 
North America, Europe, Australia) – PP Population 
 
Table  
14.2.4.3.1.2.2 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Summary Statistics (Cohort B – 
Japan) – PP Population 
 
Table  
14.2.4.3.2.1.1 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Nonparametric Analysis (Cohort 
A – North America, Europe, Australia) – mITT Population 
 
PUBLIC COPY 
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application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 39 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.2.4.3.2.1.2 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Nonparametric Analysis (Cohort 
B – Japan) – mITT Population 
 
Table  
14.2.4.3.2.2.1 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Nonparametric Analysis (Cohort 
A – North America, Europe, Australia) – PP Population 
 
Table  
14.2.4.3.2.2.2 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Nonparametric Analysis (Cohort 
B – Japan) – PP Population 
 
Table  
14.2.4.3.3.1.1 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Parametric Analysis (Cohort A – 
North America, Europe, Australia) – mITT Population 
 
Table  
14.2.4.3.3.1.2 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Parametric Analysis (Cohort B – 
Japan) – mITT Population 
 
Table  
14.2.4.3.3.2.1 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Parametric Analysis (Cohort A – 
North America, Europe, Australia) – PP Population 
 
Table  
14.2.4.3.3.2.2 
Frequency of All Countable Seizures (Motor + Non-Motor) 
per 28 days during Part 1: Parametric Analysis (Cohort B – 
Japan) – PP Population 
 
Table  
14.2.4.3.4.1.1 
Percent Improvement in Frequency of All Countable 
Seizures (Motor + Non-Motor) per 28 days during Part 1: 
Logistic Regression (Cohort A – North America, Europe, 
Australia)– mITT Population 
 
PUBLIC COPY 
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Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 40 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.2.4.3.4.1.2 
Percent Improvement in Frequency of All Countable 
Seizures (Motor + Non-Motor) per 28 days during Part 1: 
Logistic Regression (Cohort B – Japan)  
Title correction  
Figure  
14.2.4.3.5.1.1 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in All Countable 
Seizures (Motor + Non-Motor)  during Part 1 (Cohort A – 
North America, Europe, Australia)– mITT Population 
Title correction  
Figure  
14.2.4.3.5.1.2 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in All Countable Motor 
Seizures (Motor + Non-Motor) during Part 1 (Cohort B – 
Japan)– mITT Population 
Title correction  
Table 
14.2.4.4.1.1 
Change from Baseline in Seizure Frequency by Types 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) - mITT Population 
Table Number Correction; This table was 
also updated to summarize the seizure 
types that were typically associated with 
drop seizures that were classified as ESC 
Confirmed Drop Seizures. 
Table 
14.2.4.4.1.1s 
Sensitivity Analysis of Change from Baseline in Seizure 
Frequency by Types during Part 1: Summary Statistics 
(Cohort A – North America, Europe, Australia) - mITT 
Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock; The 
only sections affected by the update are 
the summary of seizure types that were 
typically associated with drop seizures that 
were classified as ESC Confirmed Drop 
Seizures. 
Table 
14.2.4.4.1.1b 
Change from Baseline in Seizure Frequency by Types 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2) - mITT Population 
New Table using Pre-DCR dataset Version 2. 
The only sections affected by the DCR 
update are the summary of seizure types 
that were typically associated with drop 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
seizures that were classified as ESC 
Confirmed Drop Seizures. 
Table 
14.2.4.4.1.1c 
Change from Baseline in Seizure Frequency by Types 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 3) - mITT Population 
New Table using Pre-DCR dataset Version 3. 
The only sections affected by the DCR 
update are the summary of seizure types 
that were typically associated with drop 
seizures that were classified as ESC 
Confirmed Drop Seizures. 
Table 
14.2.4.4.1.2 
Change from Baseline in Seizure Frequency by Types 
during Part 1: Summary Statistics (Cohort B – Japan)  - 
mITT Population 
Table Number Correction 
Table 
14.2.4.4.2.1 
Percent Improvement in Seizure Frequency by Types 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia)  – mITT Population 
Table Number Correction 
Table 
14.2.4.4.2.1s 
Sensitivity Analysis of Percent Improvement in Seizure 
Frequency by Types during Part 1: Summary Statistics 
(Cohort A – North America, Europe, Australia)  – mITT 
Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock; The 
only sections affected by the update are 
the summary of seizure types that were 
typically associated with drop seizures that 
were classified as ESC Confirmed Drop 
Seizures. 
Table 
14.2.4.4.2.1b 
Percent Improvement in Seizure Frequency by Types 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2) – mITT Population 
New Table using Pre-DCR dataset Version 2. 
The only sections affected by the DCR 
update are the summary of seizure types 
that were typically associated with drop 
seizures that were classified as ESC 
Confirmed Drop Seizures. 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.2.4.4.2.1c 
Percent Improvement in Seizure Frequency by Types 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 3) – mITT Population 
New Table using Pre-DCR dataset Version 3. 
The only sections affected by the DCR 
update are the summary of seizure types 
that were typically associated with drop 
seizures that were classified as ESC 
Confirmed Drop Seizures. 
Table 
14.2.4.4.2.2 
Percent Improvement in Seizure Frequency by Types 
during Part 1: Summary Statistics (Cohort B – Japan) – 
mITT Population 
Table Number Correction 
 
14.2.4.5 
All Countable Seizures that Did Not Result in Drops (ESC 
Confirmed) 
 
Table 
14.2.4.5.1.1.1 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Summary Statistics (Cohort A – North America, Europe, 
Australia) - mITT Population 
New Post-hoc defined endpoint 
Table 
14.2.4.5.1.1.2 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Summary Statistics (Cohort B – Japan) - mITT Population 
New Post-hoc defined endpoint 
Table 
14.2.4.5.1.2.1 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Summary Statistics (Cohort A – North America, Europe, 
Australia) - PP Population 
New Post-hoc defined endpoint 
Table 
14.2.4.5.1.2.2 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Summary Statistics (Cohort B – Japan) - PP Population 
New Post-hoc defined endpoint 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.2.4.5.2.1.1 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
New Post-hoc defined endpoint 
Table 
14.2.4.5.2.1.2 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis (Cohort B – Japan) - mITT 
Population 
New Post-hoc defined endpoint 
Table 
14.2.4.5.2.2.1 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - PP Population 
New Post-hoc defined endpoint 
Table 
14.2.4.5.2.2.2 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis (Cohort B – Japan) - PP Population 
New Post-hoc defined endpoint 
Table 
14.2.4.5.3.1.1 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Parametric Analysis (Cohort A – North America, Europe, 
Australia) - mITT Population 
New Post-hoc defined endpoint 
Table 
14.2.4.5.3.1.2 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Parametric Analysis (Cohort B – Japan) - mITT Population 
New Post-hoc defined endpoint 
Table 
14.2.4.5.3.2.1 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Parametric Analysis (Cohort A – North America, Europe, 
Australia) - PP Population 
New Post-hoc defined endpoint 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.2.4.5.3.2.2 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Parametric Analysis (Cohort B – Japan) - PP Population 
New Post-hoc defined endpoint 
Table 
14.2.4.5.4.1.1 
 
Percent Improvement in Frequency of All Countable 
Seizures that did not Result in Drops (ESC Confirmed) per 
28 days during Part 1: Logistic Regression (Cohort A – 
North America, Europe, Australia) - mITT Population 
New Post-hoc defined endpoint 
Table 
14.2.4.5.4.1.2 
 
Percent Improvement in Frequency of All Countable 
Seizures that did not Result in Drops (ESC Confirmed) per 
28 days during Part 1: Logistic Regression (Cohort B – 
Japan) - mITT Population 
New Post-hoc defined endpoint 
Figure 
14.2.4.5.5.1.1 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in All Countable 
Seizures that did not Result in  Drops (ESC Confirmed) 
during Part 1 (Cohort A – North America, Europe, 
Australia) - mITT Population 
New Post-hoc defined endpoint 
Figure 
14.2.4.5.5.1.2 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in All Countable 
Seizures that did not Result in  Drops (ESC Confirmed) 
during Part 1 (Cohort B – Japan) - mITT Population 
New Post-hoc defined endpoint 
 
14.2.4.6 
New Seizure Types 
 
Table 
14.2.4.6.1.1 
 
New Seizure Types During Part 1 (Cohort A – North 
America, Europe, Australia) - mITT Population 
New Post-hoc defined endpoint 
Table 
14.2.4.6.1.2 
 
New Seizure Types During Part 1 (Cohort B – Japan) - mITT 
Population 
New Post-hoc defined endpoint 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.2.4.7.1.1.1 
Frequency of Seizures Resulting in Drops (Caregiver 
Determination) per 28 days during Part 1: Summary 
Statistics (Cohort A – North America, Europe, Australia) – 
mITT Population 
New Post-hoc defined endpoint 
Table 
14.2.4.7.2.1.1 
Frequency of Seizures Resulting in Drops (Caregiver 
Determination) per 28 days during Part 1: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia) – 
mITT Population 
New Post-hoc defined endpoint 
Table  
 
14.2.4.7.4.1.1 
 
Percent Improvement in Frequency of Seizures Resulting in 
Drops (Caregiver Determination) per 28 days during Part 1: 
Logistic Regression (Cohort A – North America, Europe, 
Australia)– mITT Population 
New Post-hoc defined endpoint 
Figure  
 
14.2.4.7.5.1.1 
Cumulative Response Curve for Percent of Subjects 
Experiencing Various % Reductions in Seizures Resulting in 
Drops (Caregiver Determination) during Part 1 (Cohort A – 
North America, Europe, Australia)– mITT Population 
New Post-hoc defined endpoint 
 
14.2.5 
Efficacy – Seizure-free Days 
 
Table 
14.2.5.1.1 
Number of Seizure Free Days per 28 Days during Part 1: 
Nonparametric Analysis: (Cohort A – North America, 
Europe, Australia) -  mITT Population 
 
Table 
14.2.5.1.2 
Number of Seizure Free Days per 28 Days during Part 1: 
Nonparametric Analysis (Cohort B – Japan) -  mITT 
Population 
 
Table 
14.2.5.2.1 
Number of Drop Seizure Free Days per 28 Days (ESC 
Confirmed) during Part 1: Nonparametric Analysis: (Cohort 
A – North America, Europe, Australia) -  mITT Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.2.5.2.1s 
Sensitivity Analysis of Number of Drop Seizure Free Days 
per 28 Days (ESC Confirmed) during Part 1: Nonparametric 
Analysis: (Cohort A – North America, Europe, Australia) -  
mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table 
14.2.5.2.2 
Number of Drop Seizure Free Days per 28 Days (ESC 
Confirmed) during Part 1: Nonparametric Analysis (Cohort 
B – Japan) -  mITT Population 
 
  
14.2.6 
Efficacy – Duration of the Longest Interval between 
Seizures Resulting in Drops 
 
Table 
14.2.6.1 
Duration of Longest Interval between Seizures Resulting in 
Drops (ESC Confirmed) during Part 1 (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
Table 
14.2.6.1s 
Sensitivity Analysis of Duration of Longest Interval 
between Seizures Resulting in Drops (ESC Confirmed) 
during Part 1 (Cohort A – North America, Europe, 
Australia) – mITT Population 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Table 
14.2.6.2 
Duration of Longest Interval between Seizures Resulting in 
Drops (ESC Confirmed) during Part 1 (Cohort B – Japan)– 
mITT Population 
 
Figure 
14.2.6.3 
Boxplot of the Duration of Longest Interval between 
Seizures Resulting in Drops (ESC Confirmed) during Part 1 
(Cohort A – North America, Europe, Australia)– mITT 
Population 
 
Figure 
14.2.6.3s 
Sensitivity Analysis of Boxplot of the Duration of Longest 
Interval between Seizures Resulting in Drops (ESC 
New Table using Supplemental Seizure File 
updated post-Part 1 Database Lock 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Confirmed) during Part 1 (Cohort A – North America, 
Europe, Australia)– mITT Population 
Figure 
14.2.6.4 
Boxplot of the Duration of Longest Interval between 
Seizures Resulting in Drops (ESC Confirmed) during Part 1  
(Cohort B – Japan)– mITT Population 
 
  
14.2.7 
Efficacy – Clinical Global Impression – Improvement 
rating by Parent/Caregiver  
 
Table 
14.2.7.1.1 
Clinical Global Impression – Improvement Rating by 
Parent/Caregiver in Part 1 (Cohort A – North America, 
Europe, Australia)  – mITT Population 
 
Table 
14.2.7.1.2 
Clinical Global Impression – Improvement Rating by 
Parent/Caregiver in Part 1 (Cohort B – Japan)  – mITT 
Population 
 
Figure 
14.2.7.2.1 
Distribution of Clinical Global Impression – Improvement 
Rating by Parent/Caregiver in Part 1 (Cohort A – North 
America, Europe, Australia)– mITT Population 
 
Figure 
14.2.7.2.2 
Distribution of Clinical Global Impression – Improvement 
Rating by Parent/Caregiver in Part 1 (Cohort B – Japan)  – 
mITT Population 
 
  
14.2.8 
Efficacy – Incidence of Status Epilepticus 
 
Table 
14.2.8.1.1 
Number of Episodes of Status Epilepticus (SE) per 28 days 
during Part 1: Summary Statistics (Cohort A – North 
America, Europe, Australia) - mITT Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.2.8.1.2 
Number of Episodes of Status Epilepticus (SE) per 28 days 
during Part 1: Summary Statistics (Cohort B – Japan) - mITT 
Population 
 
Table 
14.2.8.1.3 
Sensitivity Analysis of Number of Episodes of Status 
Epilepticus (SE) per 28 days during Part 1: Summary 
Statistics (Cohort A – North America, Europe, Australia) - 
mITT Population 
New Analysis of Status Epilepticus using the 
diary events that were generalized 
tonic/clonic, secondarily generalized 
tonic/clonic, focal with clear observable 
signs, focal without clear observable sings, 
or absence/atypical absence.  These events 
were further separated into those events 
that required 0 rescue medications, 1 
rescue medication, or > 1 rescue 
medications associated with the seizure 
event. 
Table 
14.2.8.1.4 
Sensitivity Analysis of Number of Episodes of Status 
Epilepticus (SE) per 28 days during Part 1: Summary 
Statistics (Cohort A – North America, Europe, Australia) - 
mITT Population 
New Analysis of Status Epilepticus using the 
diary events that were generalized 
tonic/clonic, secondarily generalized 
tonic/clonic, focal with clear observable 
signs, focal without clear observable sings, 
or absence/atypical absence.  These events 
were further separated into those events 
that required 0 rescue medications, 1 
rescue medication, or > 1 rescue 
medications associated with the seizure 
event. 
Table 
14.2.8.2.1 
Number of Days where Episodes of Status Epilepticus (SE) 
Occurred per 28 Days during Part 1: Summary Statistics 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
and Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
Table 
14.2.8.2.2 
Number of Days where Episodes of Status Epilepticus (SE) 
Occurred per 28 Days during Part 1: Summary Statistics 
and Nonparametric Analysis (Cohort B – Japan) - mITT 
Population 
 
  
14.2.9 
Efficacy – Rescue Medication 
 
Table 
14.2.9.1.1 
Days with Rescue Medication Usage in Part 1: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) – mITT Population 
 
Table 
14.2.9.1.2 
Days with Rescue Medication Usage in Part 1: 
Nonparametric Analysis (Cohort B – Japan) – mITT 
Population 
 
Table 
14.2.9.2.1 
Number of Rescue Medications Used per Status 
Epilepticus Episode in Part 1: Nonparametric Analysis 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
 
Table 
14.2.9.2.2 
Number of Rescue Medications Used per Status 
Epilepticus Episode in Part 1: Nonparametric Analysis 
(Cohort B – Japan) - mITT Population 
 
Table 
14.2.9.3.1 
Categorical Analysis of Change from Baseline in the 
Number of Days with Rescue Medication Usage in Part 1 
(Cohort A – North America, Europe, Australia) – mITT 
Population   
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.2.9.3.2 
Categorical Analysis of Change from Baseline in the 
Number of Days with Rescue Medication Usage in Part 1 
(Cohort B – Japan) – mITT Population   
 
  
14.2.10 
Efficacy – Hospitalization and Resource Utilization for 
Treatment of Seizures  
 
Table 
14.2.10.1.1 
Hospitalization and Other Healthcare Resource Utilization 
to Treat Seizure during Study: Summary statistics (Cohort 
A – North America, Europe, Australia) – mITT Population 
Table Title updated. 
Table 
14.2.10.1.2 
Hospitalization and Other Healthcare Resource Utilization 
to Treat Seizure during Study: Summary statistics (Cohort 
B – Japan) – mITT Population 
Table Title updated. 
  
14.2.12 
Exploratory Efficacy – Quality of Life in Childhood 
Epilepsy Scale 
 
Table 
14.2.12.1.1 
Quality of Life in Childhood Epilepsy (QOLCE) in Part 1: 
Summary Statistics and Nonparametric Analysis (Cohort A 
– North America, Europe, Australia) – mITT population 
 
Table 
14.2.12.1.2 
Quality of Life in Childhood Epilepsy (QOLCE) in Part 1: 
Summary Statistics and Nonparametric Analysis (Cohort B 
– Japan) – mITT population 
 
 
14.2.13 
Exploratory Efficacy – Zarit Caregiver Burden Inventory 
 
Table  
14.2.13.1.1 
Zarit Caregiver Burden Inventory during Part 1: Normal; 
Borderline Abnormal; and Abnormal Categories (Cohort A 
– North America, Europe, Australia) – mITT population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.2.13.1.2 
Zarit Caregiver Burden Inventory during Part 1: Normal; 
Borderline Abnormal; and Abnormal Categories (Cohort B 
– Japan) – mITT population 
 
Table  
14.2.13.2.1 
Zarit Caregiver Inventory Index Score during Part 1: 
Summary Descriptive Statistics (Cohort A – North America, 
Europe, Australia)– mITT population 
 
Table  
14.2.13.2.2 
Zarit Caregiver Inventory Index Score during Part 1: 
Summary Descriptive Statistics (Cohort B – Japan) – mITT 
population 
 
 
14.2.14 
Exploratory Efficacy – Parent /Caregiver Ratings using 
HADS Scale 
 
Table  
14.2.14.1.1 
Parent/Caregiver Ratings Based on Hospital Anxiety and 
Depression Scale (HADS) during Part 1: Normal; Borderline 
Abnormal, and Abnormal Categories (Cohort A – North 
America, Europe, Australia) – mITT population 
 
Table  
14.2.14.1.2 
Parent/Caregiver Ratings Based on Hospital Anxiety and 
Depression Scale (HADS) during Part 1: Normal; Borderline 
Abnormal, and Abnormal Categories (Cohort B – Japan)– 
mITT population 
 
Table  
14.2.14.2.1 
Parent/Caregiver Ratings Based on Hospital Anxiety and 
Depression Scale (HADS) during Part 1: Summary 
Descriptive Statistics (Cohort A – North America, Europe, 
Australia) -mITT population 
 
Table  
14.2.14.2.2 
Parent/Caregiver Ratings Based on Hospital Anxiety and 
Depression Scale (HADS) during Part 1: Summary 
Descriptive Statistics (Cohort B – Japan) – mITT population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
  
14.3 
Safety 
 
  
14.3.1 
Summary of adverse events 
 
Table 
14.3.1.1.1.1 
Overview of Number of Subjects with TEAE during Part 1 
(Cohort A – North America, Europe, Australia)– Safety 
Population 
 
Table 
14.3.1.1.1.2 
Overview of Number of Subjects with TEAE during Part 1 
(Cohort B – Japan) – Safety Population 
 
Table 
14.3.1.2.1.1 
Treatment-Emergent Adverse Events in Part 1 by MedDRA 
System Organ Class and Preferred Term (Cohort A – North 
America, Europe, Australia)– Safety Population  
 
Table 
14.3.1.2.1.2 
Treatment-Emergent Adverse Events in Part 1 by MedDRA 
System Organ Class and Preferred Term (Cohort B – Japan) 
– Safety Population  
 
Table  
14.3.1.2.2.1 
Treatment-Emergent Adverse Events in Part 1 by MedDRA 
System Organ Class and Preferred Term by Age Group 
(Cohort A – North America, Europe, Australia)– Safety 
Population  
 
Table  
14.3.1.2.2.2 
Treatment-Emergent Adverse Events in Part 1 by MedDRA 
System Organ Class and Preferred Term by Age Group 
(Cohort B – Japan) – Safety Population 
 
Table  
14.3.1.2.3.1 
Treatment-Emergent Adverse Events in Part 1 by MedDRA 
System Organ Class and Preferred Term by Sex (Cohort A – 
North America, Europe, Australia)– Safety Population  
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.3.1.2.3.2 
Treatment-Emergent Adverse Events in Part 1 by MedDRA 
System Organ Class and Preferred Term by Sex (Cohort B – 
Japan)– Safety Population  
 
Table  
14.3.1.2.4.1 
Treatment-Emergent Adverse Events in Part 1 by MedDRA 
System Organ Class and Preferred Term by Usage of Most 
Commonly Used Anti-Epileptic Medications (Cohort A – 
North America, Europe, Australia)– Safety Population  
 
Table  
14.3.1.2.4.2 
Treatment-Emergent Adverse Events in Part 1 by MedDRA 
System Organ Class and Preferred Term by Usage of Most 
Commonly Used Anti-Epileptic Medications (Cohort B – 
Japan)– Safety Population  
 
Table 
14.3.1.3.1.1 
TEAEs Leading to Study Discontinuation in Part 1 by 
MedDRA System Organ Class and Preferred Term (Cohort 
A – North America, Europe, Australia)– Safety Population  
 
Table 
14.3.1.3.1.2 
TEAEs Leading to Study Discontinuation in Part 1 by 
MedDRA System Organ Class and Preferred Term (Cohort 
B – Japan) – Safety Population  
 
Table 
14.3.1.4.1.1 
Serious TEAEs in Part 1 by MedDRA System Organ Class 
and Preferred Term (Cohort A – North America, Europe, 
Australia) – Safety Population 
 
Table 
14.3.1.4.1.2 
Serious TEAEs in Part 1 by MedDRA System Organ Class 
and Preferred Term (Cohort B – Japan) – Safety Population 
 
Table 
14.3.1.5.1.1 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term (Cohort A – North 
America, Europe, Australia)– Safety Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.3.1.5.1.2 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term (Cohort B – Japan)– Safety 
Population 
 
Table 
14.3.1.5.2.1 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term by Age Group (Cohort A – 
North America, Europe, Australia)– Safety Population 
 
Table 
14.3.1.5.2.2 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term by Age Group (Cohort B – 
Japan)– Safety Population 
 
Table 
14.3.1.5.3.1 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term by Sex (Cohort A – North 
America, Europe, Australia) – Safety Population 
 
Table 
14.3.1.5.3.2 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term by Sex (Cohort B – Japan) 
– Safety Population 
 
Table 
14.3.1.5.4.1 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term by Usage of Most 
Common Concomitant Antiepileptic Medications (Cohort A 
– North America, Europe, Australia) – Safety Population 
 
Table 
14.3.1.5.4.2 
Treatment Related TEAEs in Part 1 by MedDRA System 
Organ Class and Preferred Term by Usage of Most 
Common Concomitant Antiepileptic Medications (Cohort B 
– Japan) – Safety Population 
 
Table 
14.3.1.6.1.1 
TEAEs in Part 1 by MedDRA System Organ Class and 
Preferred Term, and Maximum Severity (Cohort A – North 
America, Europe, Australia)– Safety Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.3.1.6.1.2 
TEAEs in Part 1 by MedDRA System Organ Class and 
Preferred Term, and Maximum Severity (Cohort B – 
Japan)– Safety Population 
 
Table 
14.3.1.7.1.1 
Treatment-Emergent Adverse Events in Part 1 occurring in 
≥ 5% of subjects by MedDRA System Organ Class and 
Preferred Term (Cohort A – North America, Europe, 
Australia) –  Safety Population  
 
Table 
14.3.1.7.1.2 
Treatment-Emergent Adverse Events in Part 1 occurring in 
≥ 5% of subjects by MedDRA System Organ Class and 
Preferred Term (Cohort B – Japan) –  Safety Population  
 
Table 
14.3.1.8.1.1 
Overview of Treatment-Emergent Adverse Events of 
Special Interest during Part 1 (Cohort A – North America, 
Europe, Australia)– Safety Population 
 
Table 
14.3.1.8.1.2 
Overview of Treatment-Emergent Adverse Events of 
Special Interest during Part 1 (Cohort B – Japan) – Safety 
Population 
 
Table 
14.3.1.9.1.1 
Treatment-Emergent Adverse Events of Special Interest 
(AESI) by SOC and PT (Cohort A – North America, Europe, 
Australia) – Safety Population 
 
Table 
14.3.1.9.1.2 
Treatment-Emergent Adverse Events of Special Interest 
(AESI) by SOC and PT (Cohort B – Japan) – Safety 
Population 
 
Table  
14.3.1.10.1.1.9 
Treatment-Emergent Adverse Events that Occurred in at 
Least 5% of Subjects During the Part 1 Titration + 
Maintenance Period by System Organ Class and Preferred 
Term with Number of Events and Number of Resolved 
New Post-hoc AE Table request. Table 
number adjusted to align with Part 2 SAP. 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Events (Cohort A – North America, Europe, Australia) -
Safety Population 
Table 
14.3.1.10.1.1.10 
Treatment-Emergent Adverse Events that Occurred in at 
Least 5% of Subjects During the Part 1 Titration + 
Maintenance Period by System Organ Class and Preferred 
Term with Mean Onset and Mean Duration (Cohort A – 
North America, Europe, Australia) - Safety Population 
New Post-hoc AE Table request. Table 
number adjusted to align with Part 2 SAP. 
Table 
14.3.1.10.1.1.11 
Treatment-Emergent Adverse Events During the Part 1 
Titration + Maintenance Period that Occurred in at Least 
2% of Subjects in Either ZX008 Treatment Group and With 
Higher Percentage Than the Placebo Group by System 
Organ Class and Preferred Term (Cohort A – North 
America, Europe, Australia) - Safety Population 
New Post-hoc AE Table request. Table 
number adjusted to align with Part 2 SAP. 
Table  
14.3.1.10.1.2.9 
Treatment-Emergent Adverse Events that Occurred in at 
Least 5% of Subjects During the Part 1 Titration + 
Maintenance Period by System Organ Class and Preferred 
Term with Number of Events and Number of Resolved 
Events (Cohort B – Japan) -Safety Population 
New Post-hoc AE Table request. Table 
number adjusted to align with Part 2 SAP. 
Table 
14.3.1.10.1.2.10 
Treatment-Emergent Adverse Events that Occurred in at 
Least 5% of Subjects During the Part 1 Titration + 
Maintenance Period by System Organ Class and Preferred 
Term with Mean Onset and Mean Duration (Cohort B – 
Japan) - Safety Population 
New Post-hoc AE Table request. Table 
number adjusted to align with Part 2 SAP. 
Table 
14.3.1.10.1.2.11 
Treatment-Emergent Adverse Events During the Part 1 
Titration + Maintenance Period that Occurred in at Least 
2% of Subjects in Either ZX008 Treatment Group and With 
Higher Percentage Than the Placebo Group by System 
New Post-hoc AE Table request. Table 
number adjusted to align with Part 2 SAP. 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Organ Class and Preferred Term (Cohort B – Japan) - Safety 
Population 
 
14.3.2 
Listings of Deaths, Other Serious and Significant Adverse 
Events 
 
Table 
14.3.2.1 
Listing of Deaths (Cohort A – North America, Europe, 
Australia)   
 
Table 
14.3.2.2.1 
Listing of SAEs (Cohort A – North America, Europe, 
Australia)   
 
Table 
14.3.2.2.2 
Listing of SAEs (Cohort B – Japan)   
 
Table 
14.3.2.3.1 
Listing of Discontinuations Due to AE (Cohort A – North 
America, Europe, Australia)   
 
Table 
14.3.2.3.2 
Listing of Discontinuations Due to AE (Cohort B – Japan)   
 
  
14.3.4 
Summary of Laboratory Data 
 
Table 
14.3.4.1.1.1 
Laboratory Parameters in Part 1 – Hematology: Summary 
Statistics (Cohort A – North America, Europe, Australia) - 
Safety Population 
 
Table 
14.3.4.1.1.2 
Laboratory Parameters in Part 1 – Hematology: Summary 
Statistics (Cohort B – Japan) – Safety Population 
 
Table 
14.3.4.1.2.1 
Shift tables for Laboratory Parameters in Part 1 – 
Hematology (Cohort A – North America, Europe, Australia) 
– Safety Population 
 
Table 
14.3.4.1.2.2 
Shift tables for Laboratory Parameters in Part 1 – 
Hematology (Cohort B – Japan) – Safety Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.3.4.2.1.1 
Laboratory Parameters in Part 1 – Biochemistry: Summary 
Statistics (Cohort A – North America, Europe, Australia)  – 
Safety Population 
 
Table 
14.3.4.2.1.2 
Laboratory Parameters in Part 1 – Biochemistry: Summary 
Statistics (Cohort B – Japan)  – Safety Population 
 
Table 
14.3.4.2.2.1 
Shift tables for Laboratory Parameters in Part 1 – 
Biochemistry (Cohort A – North America, Europe, 
Australia) – Safety Population 
 
Table 
14.3.4.2.2.2 
Shift tables for Laboratory Parameters in Part 1 – 
Biochemistry (Cohort B – Japan) – Safety Population 
 
Table 
14.3.4.3.1.1 
Laboratory Parameters in Part 1 – Urinalysis (Quantitative 
Parameters) : Summary Statistics (Cohort A – North 
America, Europe, Australia) – Safety Population 
 
Table 
14.3.4.3.1.2 
Laboratory Parameters in Part 1 – Urinalysis (Quantitative 
Parameters) : Summary Statistics (Cohort B – Japan) – 
Safety Population 
 
Table 
14.3.4.3.2.1 
Laboratory parameters in Part 1 – Urinalysis (Categorical 
Parameters): Summary Statistics (Cohort A – North 
America, Europe, Australia) – Safety Population 
 
Table 
14.3.4.3.2.2 
Laboratory parameters in Part 1 – Urinalysis (Categorical 
Parameters): Summary Statistics (Cohort B – Japan) – 
Safety Population 
 
Table 
14.3.4.3.3.1 
Shift Tables for Laboratory Parameters in Part 1 – 
Urinalysis (Quantitative Parameters) (Cohort A – North 
America, Europe, Australia) – Safety Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.3.4.3.3.2 
Shift Tables for Laboratory Parameters in Part 1 – 
Urinalysis (Quantitative Parameters) (Cohort B – Japan) – 
Safety Population 
 
Table 
14.3.4.3.4.1 
Shift Tables for Laboratory Parameters in Part 1 – 
Urinalysis (Categorical Parameters) (Cohort A – North 
America, Europe, Australia) – Safety Population 
 
Table 
14.3.4.3.4.2 
Shift Tables for Laboratory Parameters in Part 1 – 
Urinalysis (Categorical Parameters) (Cohort B – Japan)  – 
Safety Population 
 
Table 
14.3.4.4.1.1 
Laboratory Parameters in Part 1 – Tests of Precocious 
Puberty and Thyroid Function: Summary Statistics (Cohort 
A – North America, Europe, Australia) – Safety Population 
 
Table 
14.3.4.4.1.2 
Laboratory Parameters in Part 1 – Tests of Precocious 
Puberty and Thyroid Function: Summary Statistics (Cohort 
B – Japan) – Safety Population 
 
Table 
14.3.4.4.2.1 
Shift Tables for Laboratory Parameters in Part 1 – Tests of 
Precocious Puberty and Thyroid Function (Cohort A – 
North America, Europe, Australia) – Safety Population 
 
Table 
14.3.4.4.2.2 
Shift Tables for Laboratory Parameters in Part 1 – Tests of 
Precocious Puberty and Thyroid Function (Cohort B – 
Japan) – Safety Population 
 
Table 
14.3.4.5.1 
Laboratory Parameters in Part 1 : Epilepsy Genotype Panel 
(Cohort A – North America, Europe, Australia) – Safety 
Population 
 
Table 
14.3.4.5.2 
Laboratory Parameters in Part 1 : Epilepsy Genotype Panel 
(Cohort B – Japan) – Safety Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.3.4.6.1.1 
Number of Subjects with Decrease in Platelets Count 
During Part 1 with Normal Platelet Count at Baseline 
(Cohort A – North America, Europe, Australia) – Safety 
Population 
 
Table  
14.3.4.6.1.2 
Number of Subjects with Decrease in Platelets Count 
During Part 1 with Normal Platelet Count at Baseline 
(Cohort B – Japan) – Safety Population 
 
Table  
14.3.4.6.2.1 
Number of Subjects with Decrease in Platelets Count 
During Part 1 Relative to Baseline (whether Normal or 
Abnormal) Platelet Count (Cohort A – North America, 
Europe, Australia) – Safety Population 
 
Table  
14.3.4.6.2.2 
Number of Subjects with Decrease in Platelets Count 
During Part 1 Relative to Baseline (whether Normal or 
Abnormal) Platelet Count (Cohort B – Japan) – Safety 
Population 
 
Table  
14.3.4.6.3.1 
Number of Subjects with Decrease in Platelets Count 
During Part 1 with Normal Platelet Count at Baseline by 
Valproate Use (Cohort A – North America, Europe, 
Australia)– Safety Population 
 
Table  
14.3.4.6.3.2 
Number of Subjects with Decrease in Platelets Count 
During Part 1 with Normal Platelet Count at Baseline by 
Valproate Use (Cohort B – Japan) – Safety Population 
 
Table  
14.3.4.6.4.1 
Number of Subjects with Decrease in Platelets Count 
During Part 1 with Normal Platelet Count at Baseline by 
Presence/Absence of Infection Event (Cohort A – North 
America, Europe, Australia) – Safety Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.3.4.6.4.2 
Number of Subjects with Decrease in Platelets Count 
During Part 1 with Normal Platelet Count at Baseline by 
Presence/Absence of Infection Event (Cohort B – Japan) – 
Safety Population 
 
Table  
14.3.4.7.1.1 
Number of Subjects with Normal Prolactin at Baseline who 
had a Prolactin Increase during Part 1 at each Visit Week 
(Cohort A – North America, Europe, Australia)– Safety 
Population 
 
Table  
14.3.4.7.1.2 
Number of Subjects with Normal Prolactin at Baseline who 
had a Prolactin Increase during Part 1 at each Visit Week 
(Cohort B – Japan) – Safety Population 
 
Table  
14.3.4.7.2.1 
Number of Subjects with Normal Prolactin at Baseline who 
had a Prolactin Increase during Part 1 with Seizure Event 
within 48 hours prior to Prolactin Increase at each Visit 
Week (Cohort A – North America, Europe, Australia) -
Safety Population 
 
Table  
14.3.4.7.2.2 
Number of Subjects with Normal Prolactin at Baseline who 
had a Prolactin Increase during Part 1 with Seizure Event 
within 48 hours prior to Prolactin Increase at each Visit 
Week (Cohort B – Japan) -Safety Population 
 
 
14.4.1 
Vital Signs, Weight and BMI 
 
Table  
14.4.1.1.1.1 
Vital Sign Parameters in Part 1 (Cohort A – North America, 
Europe, Australia) – Safety Population 
 
Table  
14.4.1.1.1.2 
Vital Sign Parameters in Part 1 (Cohort B – Japan) – Safety 
Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table  
14.4.1.2.1.1 
Body Weight and BMI in Part 1 (Cohort A – North America, 
Europe, Australia) – Safety Population 
 
Table  
14.4.1.2.1.2 
Body Weight and BMI in Part 1 (Cohort B – Japan) – Safety 
Population 
 
Table  
14.4.1.2.2.1 
Weight Summary (Lost/Gain >=7% or >=10%) during Part 1 
(Cohort A – North America, Europe, Australia) – Safety 
Population 
 
Table  
14.4.1.2.2.2 
Weight Summary (Lost/Gain >=7% or >=10%) during Part 1 
(Cohort B – Japan) – Safety Population 
 
Figure 
14.4.1.3.1.1 
Spaghetti Plot of Weight by Study Day during Part 1 for 
Subjects who had a >= 7% Decrease from Baseline in Body 
Weight (Cohort A – North America, Europe, Australia) - 
Safety Population  
 
Figure 
14.4.1.3.1.2 
Spaghetti Plot of Weight by Study Day during Part 1 for 
Subjects who had a >= 7% Decrease from Baseline in Body 
Weight (Cohort B – Japan) - Safety Population  
 
  
14.4.4 
Tanner Staging 
 
Table 
14.4.4.1.1.1 
Tanner Staging in Part 1 by Age Group for Boys (Cohort A – 
North America, Europe, Australia) –  Safety Population 
 
Table 
14.4.4.1.1.2 
Tanner Staging in Part 1 by Age Group for Boys (Cohort B – 
Japan)  –  Safety Population 
 
Table 
14.4.4.2.1.1 
Tanner Staging in Part 1 by Age Group for Girls (Cohort A – 
North America, Europe, Australia) –  Safety Population 
 
Table 
14.4.4.2.1.2 
Tanner Staging in Part 1 by Age Group for Girls (Cohort B – 
Japan) –  Safety Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
  
14.4.5 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Table 
14.4.5.1.1 
Number of Subjects with
 
 
Based on the C-SSRS during Part 1 (Cohort A – North 
America, Europe, Australia) – Safety Population 
 
Table 
14.4.5.1.2 
Number of Subjects with
 
 
ased on the C-SSRS during Part 1 (Cohort B – 
Japan) – Safety Population 
 
Table 
14.4.5.2.1 
Columbia Suicide Severity-Rating Scale (C-SSRS)- Shift 
Table of Changes in C-SSRS Categories During Part 1 
(Cohort A – North America, Europe, Australia) - Safety 
Population 
 
Table 
14.4.5.2.2 
Columbia Suicide Severity-Rating Scale (C-SSRS)- Shift 
Table of Changes in C-SSRS Categories During Part 1 
(Cohort B – Japan) - Safety Population 
 
  
14.4.6 
Brief Rating Inventory of Executive Function- (BRIEF) 
 
Table 
14.4.6.1.1 
Brief Rating Inventory of Executive Function Preschool 
Version (BRIEF-P) in Part 1: Scoring Summary Table by 
Treatment Group (Cohort A – North America, Europe, 
Australia)– Safety Population  
 
Table 
14.4.6.1.2 
Brief Rating Inventory of Executive Function Preschool 
Version (BRIEF-P) in Part 1: Scoring Summary Table by 
Treatment Group (Cohort B – Japan) – Safety Population  
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Table 
14.4.6.2.1 
Brief Rating Inventory of Executive Function (BRIEF) in Part 
1: Scoring Summary Table by Treatment Group (Cohort A – 
North America, Europe, Australia) – Safety Population 
 
Table 
14.4.6.2.2 
Brief Rating Inventory of Executive Function (BRIEF) in Part 
1: Scoring Summary Table by Treatment Group (Cohort B – 
Japan) – Safety Population 
 
Table 
14.4.6.3.1 
Brief Rating Inventory of Executive Function (BRIEF-A) in 
Part 1: Scoring Summary Table by Treatment Group 
(Cohort A – North America, Europe, Australia)–  Safety 
Population 
 
Table 
14.4.6.3.2 
Brief Rating Inventory of Executive Function (BRIEF-A) in 
Part 1: Scoring Summary Table by Treatment Group 
(Cohort B – Japan) - Safety Population 
 
 
14.4.7 
Clinically Relevant Physical Examination   
 
Table 
14.4.7.1.1 
Clinically Relevant Physical Examination Findings in Part 1 
(Cohort A – North America, Europe, Australia)–  Safety 
Population 
 
Table 
14.4.7.1.2 
Clinically Relevant Physical Examination Findings in Part 1 
(Cohort B – Japan) - Safety Population 
 
 
14.4.8 
Clinically Relevant Neurologic Examination   
 
Table 
14.4.8.1.1 
Clinically Relevant Neurologic Examination Findings in Part 
1 (Cohort A – North America, Europe, Australia)–  Safety 
Population 
 
Table 
14.4.8.1.2 
Clinically Relevant Neurologic Examination Findings in Part 
1  (Cohort B – Japan) - Safety Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
 
16.1.9.2 
Statistical Output 
 
Output  
16.1.9.2.1.2.1.1 
Frequency of Seizures Resulting in Drops per 28 days 
during Part 1: Nonparametric Analysis (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
Output  
16.1.9.2.1.2.1.1 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis (Cohort 
A – North America, Europe, Australia) – mITT Population 
 
Output  
16.1.9.2.1.2.1.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) – mITT Population 
 
Output  
16.1.9.2.1.2.1.2 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis (Cohort 
B – Japan) – mITT Population 
 
Output  
16.1.9.2.1.2.1.3 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis with 
Categorized Baseline Seizure Frequency and Baseline 
Seizure Frequency by Treatment Interaction  (Cohort A – 
North America, Europe, Australia)- MITT Population 
 
Output  
16.1.9.2.1.2.1.3s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis with Categorized Baseline Seizure 
Frequency and Baseline Seizure Frequency by Treatment 
Interaction  (Cohort A – North America, Europe, Australia)- 
MITT Population 
 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Output  
16.1.9.2.1.2.1.4 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis with 
Categorized Baseline Seizure Frequency and Baseline 
Seizure Frequency by Treatment Interaction  (Cohort B – 
Japan)- MITT Population 
 
Output 
16.1.9.2.1.2.2.1 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis (Cohort 
A – North America, Europe, Australia) – PP Population 
 
Output 
16.1.9.2.1.2.2.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) – PP Population 
 
Output 
16.1.9.2.1.2.2.2 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis (Cohort 
B – Japan) – PP Population 
 
Output 
16.1.9.2.1.3.1.1 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Parametric Analysis (Cohort A – 
North America, Europe, Australia) – mITT Population 
 
Output 
16.1.9.2.1.3.1.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Parametric Analysis (Cohort A – North America, Europe, 
Australia) – mITT Population 
 
Output 
16.1.9.2.1.3.1.2 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Parametric Analysis (Cohort A – 
North America, Europe, Australia) – mITT Population 
 
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application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 67 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Output 
16.1.9.2.1.3.1.3 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1: Parametric Analysis with 
Categorized Baseline Seizure Frequency and Baseline 
Seizure Frequency by Treatment Interaction (Cohort A – 
North America, Europe, Australia)  – mITT Population 
 
Output 
16.1.9.2.1.3.1.3s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed)  per 28 days during Part 1: 
Parametric Analysis with Categorized Baseline Seizure 
Frequency and Baseline Seizure Frequency by Treatment 
Interaction (Cohort A – North America, Europe, Australia)  
– mITT Population 
 
Output 
16.1.9.2.1.3.1.4 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1: Parametric Analysis with 
Categorized Baseline Seizure Frequency and Baseline 
Seizure Frequency by Treatment Interaction (Cohort B – 
Japan)  – mITT Population 
 
Output 
16.1.9.2.1.3.2.1 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Parametric Analysis (Cohort A – 
North America, Europe, Australia) – PP Population 
 
Output 
16.1.9.2.1.3.2.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed)  per 28 days during Part 1: 
Parametric Analysis (Cohort A – North America, Europe, 
Australia) – PP Population 
 
Output 
16.1.9.2.1.3.2.2 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Parametric Analysis (Cohort B – 
Japan) – PP Population 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 68 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Output 
16.1.9.2.1.4.1.1 
Percent Improvement in Frequency of Seizures resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, Australia) – 
mITT Population 
 
Output 
16.1.9.2.1.4.1.1s 
Sensitivity Analysis of Percent Improvement in Frequency 
of Seizures resulting in Drops (ESC Confirmed) per 28 days 
during Part 1: Logistic Regression (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
Output 
16.1.9.2.1.4.1.1b 
Percent Improvement in Frequency of Seizures resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, Australia) 
(Pre-DCR Seizure Event Dataset Version 2) – mITT 
Population 
 
Output 
16.1.9.2.1.4.1.1c 
Percent Improvement in Frequency of Seizures resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, Australia) 
(Pre-DCR Seizure Event Dataset Version 3) – mITT 
Population 
 
Output 
16.1.9.2.1.4.1.2 
Percent Improvement in Frequency of Seizures resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: Logistic 
Regression (Cohort B – Japan) – mITT Population 
 
Output 
16.1.9.2.1.4.2.1 
Percent Improvement in Frequency of Seizures resulting in 
Drops (ESC Confirmed)  per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, Australia) – 
PP Population 
 
Output 
16.1.9.2.1.4.2.1s 
Sensitivity Analysis of Percent Improvement in Frequency 
of Seizures resulting in Drops (ESC Confirmed)  per 28 days 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 69 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
during Part 1: Logistic Regression (Cohort A – North 
America, Europe, Australia) – PP Population 
Output 
16.1.9.2.1.4.2.2 
Percent Improvement in Frequency of Seizures resulting in 
Drops  (ESC Confirmed) per 28 days during Part 1: Logistic 
Regression (Cohort B – Japan) – PP Population 
 
Output 
16.1.9.2.1.6.1 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1 by Age Subgroup: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia) - 
mITT Population 
 
Output 
16.1.9.2.1.6.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1 by Age 
Subgroup: Nonparametric Analysis (Cohort A – North 
America, Europe, Australia) - mITT Population 
 
Output 
16.1.9.2.1.6.2 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1 by Sex: Nonparametric Analysis – 
(Cohort A – North America, Europe, Australia) - mITT 
Population 
 
Output 
16.1.9.2.1.6.2s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1 by Sex: 
Nonparametric Analysis – (Cohort A – North America, 
Europe, Australia) - mITT Population 
 
Output 
16.1.9.2.1.6.3 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1 by Weight Subgroup: 
Nonparametric Analysis – (Cohort A – North America, 
Europe, Australia) - mITT Population 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 70 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Output 
16.1.9.2.1.6.3s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1 by 
Weight Subgroup: Nonparametric Analysis – (Cohort A – 
North America, Europe, Australia) - mITT Population 
 
Output 
16.1.9.2.1.6.4 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1 by Number of Concomitant 
Antiepileptic Medications Used: Nonparametric Analysis 
(Cohort A – North America, Europe, Australia) - mITT 
Population 
 
Output 
16.1.9.2.1.6.4s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1 by 
Number of Concomitant Antiepileptic Medications Used: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
 
Output 
16.1.9.2.1.6.5 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1 by Number of Prior Antiepileptic 
Medications Used: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) - mITT Population 
 
Output 
16.1.9.2.1.6.5s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1 by 
Number of Prior Antiepileptic Medications Used: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
 
Output 
16.1.9.2.1.6.6 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1 by Baseline Frequency of 
Seizures that Result in Drops: Nonparametric Analysis 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 71 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
(Cohort A – North America, Europe, Australia) - mITT 
Population 
Output 
16.1.9.2.1.6.6s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed)  per 28 days during Part 1 by 
Baseline Frequency of Seizures that Result in Drops: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
 
Output 
16.1.9.2.1.6.7 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1 by Race Group: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia) - 
mITT Population 
 
Output 
16.1.9.2.1.6.8 
Frequency of Seizures Resulting in Drops (ESC Confirmed)  
per 28 days during Part 1 by Geographic Region: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) mITT Population 
 
Output 
16.1.9.2.1.7.1 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Missing Data Analysis 1 (Worst Value 
Substituted for Dropouts) (Cohort A – North America, 
Europe, Australia) – mITT Population 
 
Output 
16.1.9.2.1.7.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis – Sensitivity to Missing Data 
Analysis 1 (Worst Value Substituted for Dropouts) (Cohort 
A – North America, Europe, Australia) – mITT Population 
 
Output 
16.1.9.2.1.7.1b 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 72 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Sensitivity to Missing Data Analysis 1 (Worst Value 
Substituted for Dropouts) (Cohort A – North America, 
Europe, Australia) (Pre-DCR Seizure Event Dataset Version 
2) – mITT Population 
Output 
16.1.9.2.1.7.1c 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Missing Data Analysis 1 (Worst Value 
Substituted for Dropouts) (Cohort A – North America, 
Europe, Australia) (Pre-DCR Seizure Event Dataset Version 
3) – mITT Population 
 
Output 
16.1.9.2.1.7.2 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Missing Data Analysis 1 (Worst Value 
Substituted for Dropouts) (Cohort B – Japan) – mITT 
Population 
 
Output 
16.1.9.2.1.7.3 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Missing Data Analysis 2 (Differential 
Imputation Method for Dropouts) (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
Output 
16.1.9.2.1.7.3s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis – Sensitivity to Missing Data 
Analysis 2 (Differential Imputation Method for Dropouts) 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 73 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Output 
16.1.9.2.1.7.3b 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis – Sensitivity to Missing Data 
Analysis 2 (Differential Imputation Method for Dropouts) 
(Cohort A – North America, Europe, Australia) – mITT 
Population (Pre-DCR Seizure Event Dataset Version 2)  – 
mITT Population 
 
Output 
16.1.9.2.1.7.3c 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis – Sensitivity to Missing Data 
Analysis 2 (Differential Imputation Method for Dropouts) 
(Cohort A – North America, Europe, Australia) – mITT 
Population (Pre-DCR Seizure Event Dataset Version 3)  – 
mITT Population 
 
Output 
16.1.9.2.1.7.4 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Missing Data Analysis 2 (Differential 
Imputation Method for Dropouts) (Cohort B – Japan) – 
mITT Population 
 
Output 
16.1.9.2.1.9.1 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Outliers (Cohort A – North America, Europe, 
Australia) – mITT Population 
 
Output 
16.1.9.2.1.9.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis – Sensitivity to Outliers (Cohort A 
– North America, Europe, Australia) – mITT Population 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 74 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Output 
16.1.9.2.1.9.1b 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Outliers (Cohort A – North America, Europe, 
Australia) (Pre-DCR Seizure Event Dataset Version 2) – 
mITT Population 
 
Output 
16.1.9.2.1.9.1c 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Outliers (Cohort A – North America, Europe, 
Australia) (Pre-DCR Seizure Event Dataset Version 3) – 
mITT Population 
 
Output 
16.1.9.2.1.9.2 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Outliers (Cohort B – Japan) – mITT Population 
 
Output 
16.1.9.2.1.10.1 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Seizure Clusters (Cohort A – North America, 
Europe, Australia) – mITT Population 
 
Output 
16.1.9.2.1.10.1s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis – Sensitivity to Seizure Clusters 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
 
Output 
16.1.9.2.1.10.1b 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Seizure Clusters (Cohort A – North America, 
Europe, Australia) (Pre-DCR Seizure Event Dataset Version 
2) – mITT Population 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 75 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Output 
16.1.9.2.1.10.1c 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Seizure Clusters (Cohort A – North America, 
Europe, Australia) (Pre-DCR Seizure Event Dataset Version 
3) – mITT Population 
 
Output 
16.1.9.2.1.10.2 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis – 
Sensitivity to Seizure Clusters (Cohort B – Japan) – mITT 
Population 
 
Output 
16.1.9.2.1.10.3 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis (Cluster 
Event Sensitivity Analysis) (Cohort A – North America, 
Europe, Australia) – mITT Population 
 
Output 
16.1.9.2.1.10.3s 
Sensitivity Analysis of Frequency of Seizures Resulting in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis (Cluster Event Sensitivity Analysis) 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
 
Output 
16.1.9.2.1.10.3b 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis (Cluster 
Event Sensitivity Analysis) (Cohort A – North America, 
Europe, Australia) (Pre-DCR Seizure Event Dataset Version 
2)  – mITT Population 
 
Output 
16.1.9.2.1.10.3c 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis (Cluster 
Event Sensitivity Analysis) (Cohort A – North America, 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 76 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Europe, Australia) (Pre-DCR Seizure Event Dataset Version 
3)  – mITT Population 
Output 
16.1.9.2.1.10.4 
Frequency of Seizures Resulting in Drops (ESC Confirmed) 
per 28 days during Part 1: Nonparametric Analysis (Cluster 
Event Sensitivity Analysis) (Cohort B – Japan) – mITT 
Population 
 
Output  
16.1.9.2.3.2.1.1 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) – mITT Population 
 
Output  
16.1.9.2.3.2.1.2 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Nonparametric Analysis (Cohort B – Japan) – mITT 
Population 
 
Output  
16.1.9.2.3.2.2.1 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) – PP Population 
 
Output  
16.1.9.2.3.2.2.2 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Nonparametric Analysis (Cohort B – Japan) – PP 
Population 
 
Output  
16.1.9.2.3.3.1.1 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Parametric Analysis (Cohort A – North America, 
Europe, Australia)– mITT Population 
 
Output  
16.1.9.2.3.3.1.2 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Parametric Analysis (Cohort B – Japan) – mITT 
Population 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 77 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Output  
16.1.9.2.3.3.2.1 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Parametric Analysis (Cohort A – North America, 
Europe, Australia) – PP Population 
 
Output  
16.1.9.2.3.3.2.2 
Frequency of Countable Motor Seizures per 28 days during 
Part 1: Parametric Analysis (Cohort B – Japan) – PP 
Population 
 
Output 
16.1.9.2.3.4.1.1 
Percent Improvement in Frequency of Countable Motor 
Seizures per 28 days during Part 1: Logistic Regression 
(Cohort A – North America, Europe, Australia)– mITT 
Population 
 
Output 
16.1.9.2.3.4.1.2 
Percent Improvement in Frequency of Countable Motor 
Seizures per 28 days during Part 1: Logistic Regression 
(Cohort B – Japan) – mITT Population 
 
 
14.2.4.1 
Efficacy – Typical Drop Seizures 
 
Output 
16.1.9.2.4.1.2.1.1 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) – mITT Population 
 
Output 
16.1.9.2.4.1.2.1.1c 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 3) – mITT Population 
 
Output 
16.1.9.2.4.1.2.1.2 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Nonparametric Analysis (Cohort B – 
Japan) – mITT Population 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 78 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Output 
16.1.9.2.4.1.2.2.1 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) – PP Population 
 
Output 
16.1.9.2.4.1.2.2.1b 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2) – PP Population 
 
Output 
16.1.9.2.4.1.2.2.1c 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Nonparametric Analysis (Cohort A – 
North America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 3) – PP Population 
 
Output 
16.1.9.2.4.1.2.2.2 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Nonparametric Analysis (Cohort B – 
Japan) – PP Population 
 
Output 
16.1.9.2.4.1.3.1.1 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Parametric Analysis (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
Output 
16.1.9.2.4.1.3.1.1a 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Parametric Analysis (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
Output 
16.1.9.2.4.1.3.1.1b 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Parametric Analysis (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2) – mITT Population 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 79 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Output 
16.1.9.2.4.1.3.1.2 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Parametric Analysis (Cohort B – Japan) 
– mITT Population 
 
Output 
16.1.9.2.4.1.3.2.1 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Parametric Analysis (Cohort A – North 
America, Europe, Australia) – PP Population 
 
Output 
16.1.9.2.4.1.3.2.1b 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Parametric Analysis (Cohort A – North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2) – PP Population 
 
Output 
16.1.9.2.4.1.3.2.2 
Frequency of Seizures that Typically Result in Drops per 28 
days during Part 1: Parametric Analysis (Cohort B – Japan) 
– PP Population 
 
Output 
16.1.9.2.4.1.4.1.1 
Percent Improvement in Frequency of Seizures that 
Typically Result in Drops per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, Australia)– 
mITT Population 
 
Output  
16.1.9.2.4.1.4.1.1b 
Percent Improvement in Frequency of Seizures that 
Typically Result in Drops per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, Australia)– 
mITT Population (Pre-DCR Seizure Event Dataset Version 2) 
 
Output 
16.1.9.2.4.1.4.1.1c 
Percent Improvement in Frequency of Seizures that 
Typically Result in Drops per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, Australia)– 
mITT Population (Pre-DCR Seizure Event Dataset Version 3) 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 80 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Output 
16.1.9.2.4.1.4.1.2 
Percent Improvement in Frequency of Seizures that 
Typically Result in Drops per 28 days during Part 1: Logistic 
Regression (Cohort B – Japan)– mITT Population 
 
 
14.2.4.2 
Efficacy – Countable Non-Motor Seizures 
 
Output 
16.1.9.2.4.2.2.1.1 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Nonparametric Analysis (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
Output 
16.1.9.2.4.2.2.1.2 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Nonparametric Analysis (Cohort B – Japan) – 
mITT Population 
 
Output 
16.1.9.2.4.2.2.2.1 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Nonparametric Analysis (Cohort A – North 
America, Europe, Australia) – PP Population 
 
Output 
16.1.9.2.4.2.2.2.2 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Nonparametric Analysis (Cohort B – Japan) – 
PP Population 
 
Output 
16.1.9.2.4.2.3.1.1 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Parametric Analysis (Cohort A – North 
America, Europe, Australia) – mITT Population 
 
Output 
16.1.9.2.4.2.3.1.2 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Parametric Analysis (Cohort B – Japan) – 
mITT Population 
 
Output 
16.1.9.2.4.2.3.2.1 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Parametric Analysis (Cohort A – North 
America, Europe, Australia) – PP Population 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 81 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Output 
16.1.9.2.4.2.3.2.2 
Frequency of Countable Non-Motor Seizures per 28 days 
during Part 1: Parametric Analysis (Cohort B – Japan) – PP 
Population 
 
Output 
16.1.9.2.4.2.4.1.1 
Percent Improvement in Frequency of Countable Non-
Motor Seizures per 28 days during Part 1: Logistic 
Regression (Cohort A – North America, Europe, Australia)– 
mITT Population 
 
Output 
16.1.9.2.4.2.4.1.2 
Percent Improvement in Frequency of Countable Non-
Motor Seizures per 28 days during Part 1: Logistic 
Regression (Cohort B – Japan)– mITT Population 
 
 
14.2.4.3 
Efficacy – All Countable Seizures (Motor + Non-Motor)  
 
Output 
16.1.9.2.4.3.2.1.1 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Nonparametric Analysis 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
 
Output 
16.1.9.2.4.3.2.1.2 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Nonparametric Analysis 
(Cohort B – Japan) – mITT Population 
 
Output 
16.1.9.2.4.3.2.2.1 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Nonparametric Analysis 
(Cohort A – North America, Europe, Australia) – PP 
Population 
 
Output 
16.1.9.2.4.3.2.2.2 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Nonparametric Analysis 
(Cohort B – Japan) – PP Population 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 82 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Output 
16.1.9.2.4.3.3.1.1 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Parametric Analysis 
(Cohort A – North America, Europe, Australia) – mITT 
Population 
 
Output 
16.1.9.2.4.3.3.1.2 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Parametric Analysis 
(Cohort B – Japan) – mITT Population 
 
Output 
16.1.9.2.4.3.3.2.1 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Parametric Analysis 
(Cohort A – North America, Europe, Australia) – PP 
Population 
 
Output 
16.1.9.2.4.3.3.2.2 
Frequency of All Countable Seizures (Motor and Non-
Motor) per 28 days during Part 1: Parametric Analysis 
(Cohort B – Japan) – PP Population 
 
Output 
16.1.9.2.4.3.4.1.1 
Percent Improvement in Frequency of All Countable 
Seizures (Motor and Non-Motor) per 28 days during Part 
1: Logistic Regression (Cohort A – North America, Europe, 
Australia)– mITT Population 
 
Output 
16.1.9.2.4.3.4.1.2 
Percent Improvement in Frequency of All Countable 
Seizures (Motor and Non-Motor) per 28 days during Part 
1: Logistic Regression (Cohort B – Japan)– mITT Population 
 
 
14.2.4.5 
All Countable Seizures that Did Not Result in Drops (ESC 
Confirmed) 
 
Output 
16.1.9.2.4.5.2.1.1 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
 
PUBLIC COPY 
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application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 83 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - mITT Population 
Output 
16.1.9.2.4.5.2.1.2 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis (Cohort B – Japan) - mITT 
Population 
 
Output 
16.1.9.2.4.5.2.2.1 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis (Cohort A – North America, 
Europe, Australia) - PP Population 
 
Output 
16.1.9.2.4.5.2.2.2 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Nonparametric Analysis (Cohort B – Japan) - PP Population 
 
Output 
16.1.9.2.4.5.3.1.1 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Parametric Analysis (Cohort A – North America, Europe, 
Australia) - mITT Population 
 
Output 
16.1.9.2.4.5.3.1.2 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Parametric Analysis (Cohort B – Japan) - mITT Population 
 
Output 
16.1.9.2.4.5.3.2.1 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Parametric Analysis (Cohort A – North America, Europe, 
Australia) - PP Population 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 84 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Output 
16.1.9.2.4.5.3.2.2 
 
Frequency of All Countable Seizures that did not Result in 
Drops (ESC Confirmed) per 28 days during Part 1: 
Parametric Analysis (Cohort B – Japan) - PP Population 
 
Output 
16.1.9.2.4.5.4.1.1 
 
Percent Improvement in Frequency of All Countable 
Seizures that did not Result in Drops (ESC Confirmed) per 
28 days during Part 1: Logistic Regression (Cohort A – 
North America, Europe, Australia) - mITT Population 
 
Output 
16.1.9.2.4.5.4.1.2 
 
Percent Improvement in Frequency of All Countable 
Seizures that did not Result in Drops (ESC Confirmed) per 
28 days during Part 1: Logistic Regression (Cohort B – 
Japan) - mITT Population 
 
Output 
16.1.9.2.4.7.2.1.1 
Frequency of Seizures Resulting in Drops (Caregiver 
Determination) per 28 days during Part 1: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia) – 
mITT Population 
New Post-hoc defined endpoint 
Output 
16.1.9.2.4.7.4.1.1 
 
Percent Improvement in Frequency of Seizures Resulting in 
Drops (Caregiver Determination) per 28 days during Part 1: 
Logistic Regression (Cohort A – North America, Europe, 
Australia)– mITT Population 
New Post-hoc defined endpoint 
 
14.2.5 
Efficacy – Seizure-free Days 
 
Output  
16.1.9.2.5.1.1 
Number of seizure free days during Part 1: Nonparametric 
Analysis (Cohort A – North America, Europe, Australia) - 
mITT Population 
 
Output 
16.1.9.2.5.1.2 
Number of seizure free days during Part 1: Nonparametric 
Analysis (Cohort B – Japan) - mITT Population 
 
PUBLIC COPY 
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application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 85 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Output 
16.1.9.2.5.2.1 
Number of Drop Seizure Free Days per 28 Days (ESC 
Confirmed) during Part 1: Nonparametric Analysis: (Cohort 
A – North America, Europe, Australia) -  mITT Population 
 
Output 
16.1.9.2.5.2.1s 
Sensitivity Analysis of Number of Drop Seizure Free Days 
per 28 Days (ESC Confirmed) during Part 1: Nonparametric 
Analysis: (Cohort A – North America, Europe, Australia) -  
mITT Population 
 
Output 
16.1.9.2.5.2.2 
Number of Drop Seizure Free Days per 28 Days (ESC 
Confirmed) during Part 1: Nonparametric Analysis (Cohort 
B – Japan) -  mITT Population 
 
  
16.2 
Subject data listing 
 
  
16.2.1  
Subject disposition and discontinuation 
 
Listing 
16.2.1.1.1 
Subject Completion/Discontinuation in Part 1 (Cohort A - 
North America, Europe, Australia)   
 
Listing 
16.2.1.1.2 
Subject Completion/Discontinuation in Part 1 (Cohort B - 
Japan)   
 
  
16.2.2 
Protocol deviations 
 
Listing 
16.2.2.1.1 
Major Protocol Deviations in Part 1 (Cohort A - North 
America, Europe, Australia)   
 
Listing 
16.2.2.1.2 
Major Protocol Deviations in Part 1 (Cohort B - Japan) 
 
  
16.2.3 
Subjects excluded from analysis 
 
Listing 
16.2.3.1.1 
Subjects Excluded from the Per Protocol Population  
(Cohort A - North America, Europe, Australia)   
 
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Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 86 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Listing 
16.2.3.1.2 
Subjects Excluded from the Per Protocol Population  
(Cohort B - Japan)   
 
Listing 
16.2.3.2.1 
Subject Allocation to Trial Populations (Cohort A - North 
America, Europe, Australia)   
 
Listing 
16.2.3.2.2 
Subject Allocation to Trial Populations (Cohort B - Japan)   
 
  
16.2.4  
Demographic data and other baseline characteristics 
 
Listing 
16.2.4.1.1.1 
Demographic data (Cohort A - North America, Europe, 
Australia) 
 
Listing 
16.2.4.1.1.2 
Demographic data (Cohort B - Japan) 
 
Listing 
16.2.4.1.2.1 
Informed Consent / Informed Assent in Part 1 (Cohort A - 
North America, Europe, Australia)   
 
Listing 
16.2.4.1.2.2 
Informed Consent / Informed Assent in Part 1 (Cohort B - 
Japan)   
 
Listing 
16.2.4.1.4.1 
% Change from Baseline in Weight and BMI (Cohort A - 
North America, Europe, Australia) 
 
Listing 
16.2.4.1.4.2 
% Change from Baseline in Weight and BMI (Cohort B - 
Japan)   
 
Listing 
16.2.4.2.1.1 
Medical History and Neurologic History (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.4.2.1.2 
Medical History and Neurologic History (Cohort B - Japan) 
 
Listing 
16.2.4.2.3.1 
Seizure history (Cohort A - North America, Europe, 
Australia) 
 
Listing 
16.2.4.2.3.2 
Seizure history (Cohort B - Japan) 
 
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Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 87 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Listing 
16.2.4.3.1.1 
Medications and Therapies/Treatments Stopped during or 
up to 30 days prior to Screening (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.4.3.1.2 
Medications and Therapies/Treatments Stopped during or 
up to 30 days prior to Screening  (Cohort B - Japan) 
 
Listing 
16.2.4.3.2.1 
Concomitant Medications and Therapies/Treatments 
(Cohort A - North America, Europe, Australia) 
 
Listing 
16.2.4.3.2.2 
Concomitant Medications and Therapies/Treatments 
(Cohort B - Japan) 
 
Listing 
16.2.4.4.1.1 
Prior Antiepileptic Drugs (AEDs)(Cohort A - North America, 
Europe, Australia) 
 
Listing 
16.2.4.4.1.2 
Prior Antiepileptic Drugs (AEDs)(Cohort B - Japan) 
 
Listing 
16.2.4.4.2.1 
Concomitant Antiepileptic Drugs (AEDs) (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.4.4.2.2 
Concomitant Antiepileptic Drugs (AEDs) (Cohort B - Japan) 
 
Listing 
16.2.4.5.1.1 
Rescue Medications (Cohort A - North America, Europe, 
Australia) 
 
Listing 
16.2.4.5.1.2 
Rescue Medications (Cohort B - Japan) 
 
  
16.2.5 
Treatment exposure and compliance 
 
Listing 
16.2.5.1.1 
IMP Intake per Day during Treatment (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.5.1.2 
IMP Intake per Day during Treatment (Cohort B - Japan) 
 
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application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 88 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Listing 
16.2.5.2.1 
IMP Intake – Self Reported % Compliance (Cohort A - 
North America, Europe, Australia) 
 
Listing 
16.2.5.2.2 
IMP Intake – Self Reported % Compliance (Cohort B - 
Japan) 
 
Listing 
16.2.5.3.1 
Drug Accountability (Cohort A - North America, Europe, 
Australia) 
 
Listing 
16.2.5.3.2 
Drug Accountability (Cohort B - Japan) 
 
Listing  
16.2.5.4.1 
Background Antiepileptic Drugs (AEDs) Pharmacokinetic 
Concentrations (Cohort A - North America, Europe, 
Australia) 
 
Listing  
16.2.5.4.2 
Background Antiepileptic Drugs (AEDs) Pharmacokinetic 
Concentrations (Cohort B - Japan) 
 
  
16.2.6 
Efficacy data 
 
Listing 
16.2.6.1.1.1 
Recorded Seizures – Duration and Number of Occurrences 
per Subject (Diary data) (Cohort A - North America, 
Europe, Australia) 
 
Listing 
16.2.6.1.1.2 
Recorded Seizures – Duration and Number of Occurrences 
per Subject (Diary data) (Cohort B - Japan) 
 
Listing 
16.2.6.1.2.1 
Change in Seizure Frequency Resulting in Drops (ESC 
Confirmed) from Baseline during Part 1 (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.6.1.2.1s 
Sensitivity Analysis of Change in Seizure Frequency 
Resulting in Drops (ESC Confirmed) from Baseline during 
Part 1 (Cohort A - North America, Europe, Australia) 
New Listing using Supplemental Seizure File 
updated post-Part 1 Database Lock 
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application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 89 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Listing 
16.2.6.1.2.1c 
Change in Seizure Frequency Resulting in Drops (ESC 
Confirmed) from Baseline during Part 1 (Cluster Sensitivity) 
(Cohort A - North America, Europe, Australia) 
New Listing due to request for Cluster 
Sensitivity 
Listing 
16.2.6.1.2.1cs 
Sensitivity Analysis of Change in Seizure Frequency 
Resulting in Drops (ESC Confirmed) from Baseline during 
Part 1 (Cluster Sensitivity) (Cohort A - North America, 
Europe, Australia) 
New Listing using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Listing 
16.2.6.1.2.1b 
Change in Seizure Frequency Resulting in Drops (ESC 
Confirmed) from Baseline during Part 1 (Cohort A - North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 2) 
New Listing using Pre-DCR dataset Version 
2 
Listing 
16.2.6.1.2.1c3 
Change in Seizure Frequency Resulting in Drops (ESC 
Confirmed) from Baseline during Part 1 (Cohort A - North 
America, Europe, Australia) (Pre-DCR Seizure Event 
Dataset Version 3) 
New Listing using Pre-DCR dataset Version 
3 
Listing 
16.2.6.1.2.2 
Change in Seizure Frequency Resulting in Drops (ESC 
Confirmed) from Baseline during Part 1 (Cohort B - Japan) 
 
Listing 
16.2.6.2.1 
Clinical Global Impression – Improvement Rating as 
Assessed by the Investigator and Subject or 
Parent/Caregiver (Cohort A - North America, Europe, 
Australia) 
 
Listing 
16.2.6.2.2 
Clinical Global Impression – Improvement Rating as 
Assessed by the Investigator and Subject or 
Parent/Caregiver (Cohort B - Japan) 
 
Listing 
16.2.6.3.1 
Change in Countable Motor Seizures from Baseline during 
Part 1 (Cohort A - North America, Europe, Australia) 
 
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application and any extensions or variations thereof.


Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 90 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Listing 
16.2.6.3.2 
Change in Countable Motor Seizures from Baseline during 
Part 1 (Cohort B - Japan) 
 
Listing  
16.2.6.4.1 
Duration of Longest Interval between Seizures during 
Titration and Maintenance Resulting in Drops (ESC 
Confirmed) in Part 1 (Cohort A - North America, Europe, 
Australia) 
 
Listing  
16.2.6.4.1s 
Sensitivity Analysis of Duration of Longest Interval 
between Seizures during Titration and Maintenance 
Resulting in Drops (ESC Confirmed) in Part 1 (Cohort A - 
North America, Europe, Australia) 
New Listing using Supplemental Seizure File 
updated post-Part 1 Database Lock 
Listing  
16.2.6.4.2 
Duration of Longest Interval between Seizures during 
Titration and Maintenance Resulting in Drops (ESC 
Confirmed)  in Part 1 (Cohort B – Japan) 
 
Listing  
16.2.6.5.1 
Change in Seizures that Typically Result in Drops from 
Baseline during Part 1  (Cohort A - North America, Europe, 
Australia) 
 
Listing  
16.2.6.5.1b 
Change in Seizures that Typically Result in Drops from 
Baseline during Part 1  (Cohort A - North America, Europe, 
Australia) (Pre-DCR Version 2) 
 
Listing  
16.2.6.5.1c 
Change in Seizures that Typically Result in Drops from 
Baseline during Part 1  (Cohort A - North America, Europe, 
Australia) (Pre-DCR Version 3) 
 
Listing  
16.2.6.5.2 
Change in Seizures that Typically Result in Drops from 
Baseline during Part 1  (Cohort B - Japan) 
 
Listing  
16.2.6.6.1 
Change in Countable Non-Motor Seizures from Baseline 
during Part 1 (Cohort A - North America, Europe, Australia) 
 
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Note to File 
Zogenix Limited International, Inc.; Protocol No.: ZX008-1601  
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 91 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Listing  
16.2.6.6.2 
Change in Countable Non-Motor Seizures from Baseline 
during Part 1 (Cohort B - Japan) 
 
Listing  
16.2.6.7.1 
Change in All Countable Seizures (Motor + Non-Motor) 
from Baseline during Part 1 (Cohort A - North America, 
Europe, Australia) 
 
Listing  
16.2.6.7.2 
Change in All Countable Seizures (Motor + Non-Motor) 
from Baseline during Part 1 (Cohort B - Japan) 
 
Listing 
16.2.6.13.1 
Change in Rescue Medication Usage from Baseline during 
Part 1  (Cohort A - North America, Europe, Australia) 
 
Listing 
16.2.6.13.2 
Change in Rescue Medication Usage from Baseline during 
Part 1  (Cohort B - Japan) 
 
Listing  
16.2.6.14.1 
Seizure Free Days during Part 1 (Cohort A - North America, 
Europe, Australia) 
 
Listing  
16.2.6.14.2 
Seizure Free Days during Part 1 (Cohort B - Japan) 
 
Listing  
16.2.6.14.3 
Drop Seizure Free Days (ESC Confirmed) during Part 1 
(Cohort A - North America, Europe, Australia) 
 
Listing  
16.2.6.14.3s 
Sensitivity Analysis of Drop Seizure Free Days (ESC 
Confirmed) during Part 1 (Cohort A - North America, 
Europe, Australia) 
 
Listing  
16.2.6.14.4 
Drop Seizure Free Days (ESC Confirmed) during Part 1 
(Cohort B - Japan) 
 
Listing 
16.2.6.15.1 
Hospitalizations and Medical Services (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.6.15.2 
Hospitalizations and Medical Services (Cohort B - Japan) 
 
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Note to File 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 92 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Listing 
16.2.6.17.1 
Quality of Life in Childhood Epilepsy (QOLCE) Scale (Cohort 
A - North America, Europe, Australia) 
 
Listing 
16.2.6.17.2 
Quality of Life in Childhood Epilepsy (QOLCE) Scale (Cohort 
B - Japan) 
 
Listing 
16.2.6.18.1 
Zarit Caregiver Burden Inventory (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.6.18.2 
Zarit Caregiver Burden Inventory (Cohort B - Japan) 
 
Listing 
16.2.6.19.1 
Parent/Caregiver Ratings using HADS Scale (Cohort A - 
North America, Europe, Australia) 
 
Listing 
16.2.6.19.2 
Parent/Caregiver Ratings using HADS Scale (Cohort B - 
Japan) 
 
Listing  
16.2.6.20.1 
Change in All Countable Seizures that did not Result in 
Drops (ESC Confirmed) from Baseline during Part 1 (Cohort 
A - North America, Europe, Australia) 
New post-hoc defined endpoint 
Listing  
16.2.6.20.2 
Change in All Countable Seizures that did not Result in 
Drops (ESC Confirmed) from Baseline during Part 1 (Cohort 
B - Japan) 
New post-hoc defined endpoint 
Listing  
16.2.6.21.1 
Change in Seizure Frequency Resulting in Drops (Caregiver 
Determination) from Baseline during Part 1 (Cohort A - 
North America, Europe, Australia) 
New post-hoc defined endpoint 
Listing  
16.2.6.21.2 
Change in Seizure Frequency Resulting in Drops (Caregiver 
Determination) from Baseline during Part 1 (Cohort B - 
Japan) 
New post-hoc defined endpoint 
  
16.2.7  
Adverse events 
 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 93 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Listing 
16.2.7.1.1 
Adverse Events (Cohort A - North America, Europe, 
Australia) 
 
Listing 
16.2.7.1.2 
Adverse Events (Cohort B - Japan) 
 
Listing 
16.2.7.2.1 
Adverse Events of Special Interest (AESI) (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.7.2.2 
Adverse Events of Special Interest (AESI) (Cohort B - Japan) 
 
  
16.2.8 
Laboratory data 
 
Listing 
16.2.8.1.1.1 
Laboratory Data Hematology Parameters (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.8.1.1.2 
Laboratory Data Hematology Parameters (Cohort B - 
Japan) 
 
Listing 
16.2.8.1.2.1 
Extreme Value Laboratory Parameters – Hematology 
(Cohort A - North America, Europe, Australia) 
 
Listing 
16.2.8.1.2.2 
Extreme Value Laboratory Parameters – Hematology 
(Cohort B - Japan) 
 
Listing 
16.2.8.2.1.1 
Laboratory Data Biochemistry Parameters (Cohort A - 
North America, Europe, Australia) 
 
Listing 
16.2.8.2.1.2 
Laboratory Data Biochemistry Parameters (Cohort B - 
Japan) 
 
Listing 
16.2.8.2.2.1 
Extreme Value Laboratory Parameters – Biochemistry 
(Cohort A - North America, Europe, Australia) 
 
Listing 
16.2.8.2.2.2 
Extreme Value Laboratory Parameters – Biochemistry 
(Cohort B - Japan) 
 
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This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 94 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Listing 
16.2.8.3.1.1 
Laboratory Data Coagulation Parameters (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.8.3.1.2 
Laboratory Data Coagulation Parameters (Cohort B - 
Japan) 
 
Listing 
16.2.8.4.1.1 
Laboratory Data Urinalysis Parameters (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.8.4.1.2 
Laboratory Data Urinalysis Parameters (Cohort B - Japan) 
 
Listing 
16.2.8.4.2.1 
Extreme Value Urinalysis Data (Cohort A - North America, 
Europe, Australia) 
 
Listing 
16.2.8.4.2.2 
Extreme Value Urinalysis Data (Cohort B - Japan) 
 
Listing 
16.2.8.5.1 
Tests of Growth, Precocious Puberty and Thyroid Function 
(Cohort A - North America, Europe, Australia) 
 
Listing 
16.2.8.5.2 
Tests of Growth, Precocious Puberty and Thyroid Function 
(Cohort B - Japan) 
 
Listing 
16.2.8.6.1 
Urine and Serum Pregnancy tests  (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.8.6.2 
Urine and Serum Pregnancy tests  (Cohort B - Japan) 
 
Listing 
16.2.8.7.1 
Urine and Serum THC panel (Cohort A - North America, 
Europe, Australia) 
 
Listing 
16.2.8.7.2 
Urine and Serum THC panel (Cohort B - Japan) 
 
Listing 
16.2.8.8.1 
Laboratory Data: Listing of Test Comments from Lab 
Vendor for All Laboratory Parameters (Cohort A - North 
America, Europe, Australia) 
New Listing added. 
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Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 95 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Listing 
16.2.8.8.2 
Laboratory Data: Listing of Test Comments from Lab 
Vendor for All Laboratory Parameters (Cohort B – Japan)  
New Listing added. 
  
16.2.9 
Other Safety Data 
 
Listing 
16.2.9.1.1.1 
Vital Signs  (Cohort A - North America, Europe, Australia) 
 
Listing 
16.2.9.1.1.2 
Vital Signs  (Cohort B - Japan) 
 
Listing 
16.2.9.1.2.1 
Abnormal Vital Signs Data (Cohort A - North America, 
Europe, Australia) 
 
Listing 
16.2.9.1.2.2 
Abnormal Vital Signs Data (Cohort B - Japan) 
 
Listing 
16.2.9.2.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) (Cohort A - 
North America, Europe, Australia) 
 
Listing 
16.2.9.2.2 
Columbia-Suicide Severity Rating Scale (C-SSRS) (Cohort B - 
Japan) 
 
Listing 
16.2.9.3.1.1 
Behavior Rating Inventory of Executive Function – 
Preschool Version (BRIEF-P) – Individual Questions (Cohort 
A - North America, Europe, Australia) 
 
Listing 
16.2.9.3.1.2 
Behavior Rating Inventory of Executive Function – 
Preschool Version (BRIEF-P) – Individual Questions (Cohort 
B - Japan) 
 
Listing 
16.2.9.3.2.1 
Behavior Rating Inventory of Executive Function – 
Preschool Version (BRIEF-P) – Summary Scales and Indexes 
(Cohort A - North America, Europe, Australia) 
 
Listing 
16.2.9.3.2.2 
Behavior Rating Inventory of Executive Function – 
Preschool Version (BRIEF-P) – Summary Scales and Indexes 
(Cohort B - Japan) 
 
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Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 96 of 97 
Version Date: 31JUN2021 
Filing requirement: TMF/PMF 
Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Listing 
16.2.9.3.3.1 
Behavior Rating Inventory of Executive Function (BRIEF) – 
Individual Questions (Cohort A - North America, Europe, 
Australia) 
 
Listing 
16.2.9.3.3.2 
Behavior Rating Inventory of Executive Function (BRIEF) – 
Individual Questions (Cohort B - Japan) 
 
Listing 
16.2.9.3.4.1 
Behavior Rating Inventory of Executive Function (BRIEF) – 
Summary Scales and Indexes (Cohort A - North America, 
Europe, Australia) 
 
Listing 
16.2.9.3.4.2 
Behavior Rating Inventory of Executive Function (BRIEF) – 
Summary Scales and Indexes (Cohort B - Japan) 
 
Listing 
16.2.9.3.5.1 
Behavior Rating Inventory of Executive Function Adult 
Version (BRIEF-A) – Individual Questions (Cohort A - North 
America, Europe, Australia) 
 
Listing 
16.2.9.3.5.2 
Behavior Rating Inventory of Executive Function Adult 
Version (BRIEF-A) – Individual Questions (Cohort B - Japan) 
 
Listing 
16.2.9.3.6.1 
Behavior Rating Inventory of Executive Function Adult 
Version (BRIEF-A) – Summary Scales and Indexes (Cohort A 
- North America, Europe, Australia) 
 
Listing 
16.2.9.3.6.2 
Behavior Rating Inventory of Executive Function Adult 
Version (BRIEF-A) – Summary Scales and Indexes (Cohort B 
- Japan) 
 
Listing 
16.2.9.4.1 
Tanner Staging (Cohort A - North America, Europe, 
Australia) 
 
Listing 
16.2.9.4.2 
Tanner Staging (Cohort B - Japan) 
 
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Version Date: 31JUN2021 
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Table/ 
Figure/ 
Listing 
 
Number 
 
Table Header 
Description of Modification(s) 
Listing 
16.2.9.5.1 
Physical Examination and Neurologic Examination (Cohort 
A - North America, Europe, Australia) 
 
Listing 
16.2.9.5.2 
Physical Examination and Neurologic Examination (Cohort 
B - Japan) 
 
Listing 
16.2.9.7.1 
Epilepsy Genotype panel (Cohort A - North America, 
Europe, Australia) 
 
Listing 
16.2.9.7.2 
Epilepsy Genotype panel (Cohort B - Japan) 
 
 
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Prot_000.pdf: 
Confidential 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Two-Part Study of ZX008 in Children and Adults with 
Lennox-Gastaut Syndrome (LGS); Part 1: A Randomized, 
Double-blind, Placebo-controlled Trial of Two Fixed Doses 
of ZX008 (Fenfluramine Hydrochloride) Oral Solution as 
Adjunctive Therapy for Seizures in Children and Adults with 
LGS, Followed by Part 2: An Open-label Extension to 
Assess Long-Term Safety of ZX008 in Children and Adults 
with LGS 
Study Number: 
ZX008-1601 
Study Product: 
Fenfluramine Hydrochloride Oral Solution; ZX008 
IND Number: 
132604 
EudraCT Number: 
2017-002628-26 
Sponsor: 
Zogenix International Limited  
A wholly owned subsidiary of UCB Biosciences, Inc. 
4000 Paramount Pkwy, 
Morrisville, NC 27560, USA 
Sponsor's Medical 
Contact: 
Program Physician 
UCB Biosciences Inc 
Date and Version of 
Study Protocol: 
25 July 2022 (PA 4.0 Japan) 
29 July 2020 (PA 3.2 Japan) 
29 October 2018 (PA 1.6.1 Japan) 
Based on 10 January 2018 (Amendment 1.0 ROW)  
This protocol includes information and data that contain trade secrets and privileged or confidential information, 
which is the property of the sponsor. This information must not be made public without written permission from the 
sponsor. These restrictions on disclosure will apply equally to all future information supplied to you. This material 
may be disclosed to and used by your personnel and associates as may be necessary to conduct the clinical study. 
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ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 2 of 198 
LIST OF PERSONNEL AND ORGANIZATIONS RESPONSIBLE FOR 
CONDUCT OF STUDY 
A list of personnel and organizations responsible for the conduct of the study will be 
supplied to study sites as part of the Investigator Study File. This list will be updated by 
the sponsor or the sponsor's agent and provided to study sites as needed. 
 
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ZX008 (Fenfluramine Hydrochloride) 
ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 3 of 198 
TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ............................................................................................... 1 
LIST OF PERSONNEL AND ORGANIZATIONS RESPONSIBLE FOR CONDUCT OF 
STUDY ........................................................................................................................... 2 
TABLE OF CONTENTS ............................................................................................................. 3 
SIGNATURE OF SPONSOR .................................................................................................... 11 
SIGNATURE OF COORDINATING INVESTIGATOR ......................................................... 12 
SIGNATURE(S) OF THE PRINCIPAL INVESTIGATOR ...................................................... 13 
LIST OF ABBREVIATIONS .................................................................................................... 14 
STUDY SYNOPSIS ................................................................................................................... 16 
1. 
INTRODUCTION ........................................................................................................ 34 
1.1 BACKGROUND INFORMATION ON INDICATION STUDIED ........ 34 
1.1.1 Existing Treatment for LGS ................................................................... 34 
1.2 BACKGROUND INFORMATION ON STUDY PRODUCT ................. 35 
1.3 CLINICAL DATA .................................................................................... 35 
1.4 PHARMACOKINETICS, PRECLINICAL DATA, AND CLINICAL 
PHARMACOLOGY .......................................................................................... 38 
1.4.1 Pharmacokinetics ................................................................................... 38 
1.4.2 Preclinical Data ...................................................................................... 39 
1.4.3 Clinical Pharmacology ........................................................................... 39 
1.5 BACKGROUND INFORMATION ON REFERENCE PRODUCT ....... 40 
1.6 RATIONALE FOR CURRENT STUDY ................................................. 40 
1.7 RISK-BENEFIT ASSESSMENT ............................................................. 42 
2. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 43 
2.1 PART 1 ...................................................................................................... 43 
2.1.1 PRIMARY OBJECTIVE ....................................................................... 43 
2.1.2 KEY SECONDARY OBJECTIVES ...................................................... 43 
2.1.3 ADDITIONAL SECONDARY OBJECTIVES ..................................... 43 
2.1.4 SAFETY OBJECTIVE .......................................................................... 44 
2.1.5 PHARMACOKINETIC OBJECTIVE ................................................... 44 
2.1.6 EXPLORATORY OBJECTIVES .......................................................... 45 
2.2 PART 2 ...................................................................................................... 45 
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2.2.1 PRIMARY OBJECTIVE ....................................................................... 45 
2.2.2 SECONDARY OBJECTIVES ............................................................... 45 
2.2.3 EXPLORATORY OBJECTIVES .......................................................... 46 
2.3 STUDY ENDPOINTS .............................................................................. 46 
2.3.1 Efficacy Endpoints ................................................................................. 46 
2.3.2 Safety Endpoints .................................................................................... 47 
2.3.3 Exploratory Endpoints ........................................................................... 47 
3. 
INVESTIGATIONAL PLAN ....................................................................................... 48 
3.1 OVERALL STUDY DESIGN AND PLAN ..................................... 48 
3.2 NUMBER OF SUBJECTS ....................................................................... 49 
3.3 STUDY DURATION ............................................................................... 49 
3.4 NUMBER OF STUDY CENTERS .......................................................... 50 
3.5 RATIONALE FOR STUDY DESIGN AND CHOICE OF TREATMENT 
GROUPS ............................................................................................................ 51 
3.6 RATIONALE FOR STUDY DESIGN AND CHOICE OF TREATMENT 
GROUPS ............................................................................................................ 51 
3.7 PREMATURE TERMINATION OF STUDY ......................................... 52 
3.8 STUDY MONITORING PROCEDURES ................................................ 52 
3.8.1 Independent Data Safety Monitoring Committee .................................. 52 
3.8.2 International Cardiac Advisory Board (ICAB) ...................................... 53 
4. 
SELECTION OF STUDY POPULATION .................................................................. 54 
4.1 PART 1 ...................................................................................................... 54 
4.1.1 INCLUSION CRITERIA ....................................................................... 54 
4.1.2 EXCLUSION CRITERIA ...................................................................... 55 
4.2 RANDOMIZATION INCLUSION CRITERIA ....................................... 56 
4.3 PART 2 ...................................................................................................... 57 
4.4 SUBJECTS OF REPRODUCTIVE POTENTIAL ................................... 58 
4.4.1 Sperm and Egg Donation ....................................................................... 59 
4.4.2 Pregnancy ............................................................................................... 59 
4.5 REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT .... 59 
4.6 TERMINATION OF THE CLINICAL STUDY ...................................... 61 
4.7 REPLACEMENT OF SUBJECTS ........................................................... 61 
5. 
INVESTIGATIONAL MEDICINAL PRODUCT INFORMATION .......................... 62 
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5.1 IDENTITY OF INVESTIGATIONAL MEDICINAL PRODUCT .......... 62 
5.1.1 Labeling and Packaging ........................................................................ 62 
5.2 DESCRIPTION OF REFERENCE TREATMENT, COMPARATOR, 
AND/OR PLACEBO ......................................................................................... 63 
5.2.1 Labeling and Packaging ........................................................................ 63 
5.3 SHIPMENT AND STORAGE .................................................................. 63 
5.4 IMP ACCOUNTABILITY ....................................................................... 63 
5.5 TREATMENT ADMINISTRATION ....................................................... 64 
5.5.1 Part 1: Randomization ........................................................................ 64 
5.5.1.1 Blinding ........................................................................................... 64 
5.5.2 Part 1: Titration Period ....................................................................... 65 
5.5.3 Part 1: Maintenance Period .................................................................... 66 
5.5.4 Part 1: Taper Period (for subjects not entering Part 2)........................... 66 
5.5.5 Part 1: Transition Period ........................................................................ 67 
5.5.6 Part 2: OLE Treatment Period................................................................ 68 
5.5.7 Taper Period ........................................................................................... 69 
5.6 PRIOR AND CONCOMITANT MEDICATION .................................... 70 
5.6.1 Vagal Nerve Stimulation ........................................................................ 71 
5.6.2 Ketogenic Diet ....................................................................................... 71 
5.6.3 Rescue Medication for Seizures ............................................................. 71 
5.6.4 Prohibited Concomitant Medications ..................................................... 71 
5.7 TREATMENT COMPLIANCE................................................................ 72 
6. 
VISIT SCHEDULE ...................................................................................................... 73 
6.1 
Part 1 ............................................................................................................................. 73 
6.1.1 BASELINE PERIOD (STUDY DAY -28 TO STUDY DAY -1) ......... 73 
6.1.1.1. Screening, Clinic Visit 1 (Study Day -28) ......................................... 73 
6.1.1.2. Phone Visit 2 (Study Day -15) ........................................................... 75 
6.1.1.3. Clinic Visit 3 (Study Day -1): Randomization ................................... 75 
6.1.2 TITRATION AND MAINTENANCE PERIODS ................................. 77 
6.1.2.1 Titration Period Study Day 1 .............................................................. 77 
6.1.2.2 Phone Visits 4 and 5 (Titration Period Study Days 4 and 8) .............. 77 
6.1.2.3 Clinic Visit 6 (Titration Period Study Day 15) ................................... 77 
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6.1.2.4 Phone Visit 7 (Maintenance Period Study Day 29) ............................ 77 
6.1.2.5 Clinic Visit 8 (Maintenance Period Study Day 43) ............................ 78 
6.1.2.6 Phone Visit 9 (Maintenance Period Study Day 57) ............................ 78 
6.1.2.7 Clinic Visit 10 (Maintenance Period Study Day 71) .......................... 79 
6.1.2.8 Phone Visit 11 (Maintenance Period Study Day 85) .......................... 79 
6.1.2.9 Clinic Visit 12 (Maintenance Period Study Day 99): End of 
Study/Early Termination.................................................................................... 79 
6.1.3 POST-DOSE VISIT (CLINIC VISIT 13; STUDY DAY 113) .............. 81 
6.1.4 CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 14; 3 and 6 months 
after last dose) .................................................................................................... 81 
6.2 
Part 2 ............................................................................................................................. 82 
6.2.1 
Clinic Visit 15 (OLE Study Day 1) .............................................................................. 83 
6.2.2 
Clinic/Phone Visit 16 (OLE Study Day 15) ................................................................. 84 
6.2.3 
Clinic Visits 17-21 (OLE Months, 1, 2, 3, 6, and 9) .................................................... 85 
6.2.4 
Clinic Visit 22 (OLE Month 12) ................................................................................... 86 
6.2.5 
Clinic Visits 23-41 (OLE Months 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 
57, 60, 63, 66, 69) ......................................................................................................... 87 
6.2.6 
Clinic Visit 42:  End of Study/Early Termination ........................................................ 88 
6.2.7 
POST-DOSE VISIT (CLINIC Visit 43; 14 DAYS AFTER LAST DOSE OF IMP) .. 90 
6.2.8 
CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 44, 45; 3 AND 6 MONTHS AFTER 
LAST DOSE OF IMP) ................................................................................................. 90 
6.3 
STUDY CONDUCT DURING COVID-19 ................................................................. 91 
6.4 
ESTIMATED BLOOD VOLUME COLLECTION ..................................................... 91 
7. 
EFFICACY, SAFETY, AND PHARMACOKINETIC ASSESSMENTS ................... 94 
7.1 EFFICACY/EFFECTIVENESS ASSESSMENTS ................................... 94 
7.1.1 Seizure Assessments .............................................................................. 94 
7.1.2 Clinical Global Impression - Improvement ............................................ 95 
7.1.3 Vineland Adaptive Behavior Scale (VABS) .......................................... 96 
7.1.4 QOLCE .................................................................................................. 96 
7.1.5 Parent/Caregiver Affective Symptoms .................................................. 96 
7.2 SAFETY ASSESSMENTS ....................................................................... 97 
7.2.1 Demographics, Medical/Neurological/Epilepsy History, and Pre-Study 
Medication ......................................................................................................... 97 
7.2.2 Adverse Events ....................................................................................... 97 
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7.2.3 Physical Examinations ........................................................................... 97 
7.2.4 Neurological Examinations .................................................................... 97 
7.2.5 Vital Signs (Including Height and Weight) ........................................... 98 
7.2.6 Laboratory Measurements ...................................................................... 98 
7.2.7 Plasma Sample for Concomitant Antiepileptic Drug(s) ......................... 99 
7.2.8 Electrocardiograms ................................................................................ 99 
7.2.9 Doppler Echocardiography .................................................................... 99 
7.2.10 Behavior Rating Inventory of Executive Function (BRIEF) ............... 99 
7.2.11 Tanner Staging ................................................................................... 100 
7.2.12 Columbia-Suicide Severity Rating Scale ........................................... 100 
7.3 PHARMACOKINETIC ASSESSMENTS ............................................. 100 
7.4 EPILEPSY GENOTYPE PANEL ........................................................... 100 
7.5 APPROPRIATENESS OF MEASUREMENTS .................................... 101 
8. 
ADVERSE EVENTS.................................................................................................. 102 
8.1 DEFINITIONS ........................................................................................ 102 
8.1.1 Adverse Events ..................................................................................... 102 
8.1.2 Serious Adverse Events ........................................................................ 103 
8.1.3 Adverse Events of Special Interest ...................................................... 104 
8.2 SEVERITY OF ADVERSE EVENTS .................................................... 104 
8.3 CAUSALITY OF ADVERSE EVENTS ................................................ 105 
8.4 OBSERVATION PERIOD FOR ADVERSE EVENT REPORTING ... 105 
8.5 ADVERSE EVENT REPORTING ......................................................... 106 
8.5.1 Adverse Events ................................................................................... 106 
8.6 SERIOUS ADVERSE EVENTS REPORTING .................................... 106 
8.6.1 Requirements for Immediate Reporting of Serious Adverse Events ... 107 
8.7 REPORTING OF SERIOUS ADVERSE EVENTS BY INVESTIGATOR 
TO IEC/IRB ..................................................................................................... 107 
8.8 REPORTING OF EVENTS OTHER THAN SERIOUS ADVERSE 
EVENTS BY INVESTIGATOR TO SPONSOR ............................................ 108 
8.9 FOLLOW-UP OF ADVERSE EVENTS ................................................ 108 
8.9.1 Follow-up of Echocardiogram Findings .............................................. 108 
8.10 PREGNANCY ..................................................................................... 110 
9. 
DATA HANDLING PROCEDURES ........................................................................ 110 
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9.1 RECORDING OF DATA ....................................................................... 110 
9.2 DATA QUALITY ASSURANCE .......................................................... 111 
9.3 RECORD RETENTION ......................................................................... 111 
10. 
STATISTICS .............................................................................................................. 112 
10.1 STATISTICAL ANALYSIS: PART 1 ................................................. 112 
10.1.1 DETERMINATION OF SAMPLE SIZE .......................................... 112 
10.1.2 ANALYSIS POPULATIONS ............................................................ 112 
10.1.2.1 Safety (SAF) Population ................................................................. 112 
10.1.2.2 Modified Intent-to-Treat (mITT) Population .................................. 113 
10.1.2.3 Per Protocol (PP) Population .......................................................... 113 
10.1.3 SUBJECT COHORTS ....................................................................... 113 
10.1.3.1 Cohort A .......................................................................................... 113 
10.1.3.2 Cohort B .......................................................................................... 113 
10.1.4 TREATMENT GROUPS ................................................................... 113 
10.1.5 TREATMENT PERIODS .................................................................. 113 
10.1.6 STATISTICAL ANALYSES AND METHODS............................... 114 
10.1.6.1 Efficacy Analyses............................................................................ 114 
10.1.6.2 Safety Analyses ............................................................................... 115 
10.1.6.3 Pharmacokinetic Analyses .............................................................. 116 
10.2 STATISTICAL ANALYSIS: PART 2 ................................................. 116 
10.2.1 ANALYSIS POPULATIONS ............................................................ 116 
10.2.1.1 OLE Population ............................................................................... 116 
10.2.1.2 OLE mITT Population .................................................................... 116 
10.2.2 TREATMENT GROUPS ................................................................... 116 
10.2.3 TREATMENT PERIODS .................................................................. 116 
10.2.4 STATISTICAL ANALYSES AND METHODS............................... 117 
10.2.4.1 Safety Analyses ............................................................................... 117 
10.2.4.2 Effectiveness Analyses.................................................................... 117 
10.2.5 ANALYSES PROVIDED TO AN INDEPENDENT DATA AND 
SAFETY MONITORING COMMITTEE ....................................................... 117 
11. 
ETHICAL & REGULATORY CONSIDERATIONS................................................ 117 
11.1 ETHICAL CONSIDERATIONS .......................................................... 117 
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11.2 INFORMED CONSENT ...................................................................... 118 
11.3 REGULATORY CONSIDERATIONS AND INDEPENDENT ETHICS 
COMMITTEE/INSTITUTIONAL REVIEW BOARD................................... 119 
11.4 PROTOCOL COMPLIANCE ............................................................... 120 
12. 
ADMINISTRATIVE ASPECTS ................................................................................ 120 
12.1 CLINICAL TRIAL AGREEMENT ...................................................... 120 
12.2 FINANCIAL DISCLOSURE BY INVESTIGATOR ........................... 120 
12.3 CLINICAL STUDY REGISTRATION AND RESULTS DISCLOSURE
 
121 
12.4 STUDY FILES AND MATERIALS .................................................... 121 
12.5 INITIATION OF THE STUDY ............................................................ 121 
12.6 SUBJECT REIMBURSEMENT ........................................................... 122 
12.7 LIABILITY AND INSURANCE ......................................................... 122 
12.8 SUBJECT IDENTIFICATION AND CONFIDENTIALITY .............. 122 
12.9 MONITORING OF THE STUDY ........................................................ 123 
12.10 PROTOCOL AMENDMENTS .......................................................... 123 
12.11 AUDITS AND INSPECTIONS .......................................................... 124 
12.12 CLINICAL STUDY REPORT ........................................................... 124 
12.13 USE OF DATA AND PUBLICATIONS ........................................... 124 
13. 
REFERENCE LIST .................................................................................................... 126 
14. 
APPENDICES ............................................................................................................ 129 
APPENDIX 1 – LIST OF PROHIBITED CONCOMITANT MEDICATIONS ..................... 129 
APPENDIX 2 – COLUMBIA – SUICIDE SEVERITY RATING SCALE ............................ 131 
APPENDIX 3 – BEHAVIOR RATING INVENTORY OF EXECUTIVE FUNCTION ....... 136 
APPENDIX 4 – VINELAND ADAPTIVE BEHAVIOR SCALE .......................................... 146 
APPENDIX 5 – TANNER STAGING ..................................................................................... 164 
APPENDIX 6 – QOLCE QUALITY OF LIFE ........................................................................ 167 
APPENDIX 7 – HOSPITAL ANXIETY AND DEPRESSION SCALE ................................. 179 
APPENDIX 8 – ZARIT CAREGIVER BURDEN INVENTORY .......................................... 182 
APPENDIX 9 – MAXIMUM ALLOWABLE BLOOD DRAW VOLUMES ........................ 184 
APPENDIX 10 – STUDY CONDUCT DURING COVID-19 ................................................ 185 
APPENDIX 11 - SUMMARY OF PROTOCOL AMENDMENT 4.0 .................................... 188 
 
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LIST OF TABLES 
Table 1. 
Schedule of Assessments: Part 1 ....................................................................... 29 
Table 2. 
Schedule of Assessments: Part 2 Cohort B only................................................ 31 
Table 3               Post Hoc Estimates of Fenfluramine and Norfenfluramine Steady-State 
Pharmacokinetic Parameters in Subjects with Dravet Syndrome in Study 1 (Geometric Mean 
[CV%]) .......................................................................................................................................... 38 
Table 4: 
Investigational Medicinal Product – ZX008 ...................................................... 62 
Table 5: 
Titration Algorithm for Part 1 ............................................................................ 66 
Table 6: 
Taper Algorithm for Part 1 ................................................................................ 67 
Table 7: 
Transition Algorithm for Part 1 ......................................................................... 67 
Table 8.  
Taper Algorithm for Part 2 ................................................................................ 69 
Table 9: 
Time Windows for Assessments in Part 1 ......................................................... 73 
Table 10: 
Schedule of Post-Treatment Cardiac Follow-up for Part 1 ................................ 82 
Table 11: 
Time Windows for Assessments in Part 2 ......................................................... 83 
Table 12. 
Schedule of Post-Treatment Cardiac Follow-up for Part 2 ................................ 91 
Table 13: 
Maximum Estimated Blood Volume Collection for Part 1* ............................. 92 
Table 14. 
Maximum Estimated Blood Volume Collection for Part 2* ............................. 92 
Table 15: 
Priorities for Blood Sample Collections ............................................................ 93 
Table 16: 
Adverse Events of Special Interest .................................................................. 104 
Table 17: 
Severity Definition of Adverse Events ............................................................ 105 
Table 18: 
Clinical Measures Enacted Upon Increasing Severity of ECHO Findings ..... 108 
 
 
 TABLE OF FIGURES 
 
Figure 1; Study Schema ................................................................................................................ 50 
 
 
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SIGNATURE OF SPONSOR 
Study Number: 
ZX008-1601 
PA 4.0(Japan) 
25 July 2022 
Study Title: 
A Two-Part Study of ZX008 in Children and 
Adults with Lennox-Gastaut Syndrome 
(LGS); Part 1: A Randomized, Double-blind, 
Placebo-controlled Trial of Two Fixed Doses 
of ZX008 (Fenfluramine Hydrochloride) Oral 
Solution as Adjunctive Therapy for Seizures 
in Children and Adults with LGS, Followed 
by Part 2: An Open-label extension to Assess 
Long-Term Safety of ZX008 in Children and 
Adults with LGS 
Sponsor’s Responsible Officer: 
 
  
Zogenix International Limited  
A wholly owned subsidiary of UCB 
Biosciences, Inc. 
4000 Paramount Pkwy, 
, 
Morrisville, NC 27560, USA 
 
 
Signature 
 
On behalf of 
:  
UCB Biosciences Inc. 
 
Date (Day/Month/Year) 
 
 
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SIGNATURE OF COORDINATING INVESTIGATOR 
Study Number: 
ZX008-1601  
PA 4.0 (Japan) 
25 July 2022 
 
Study Title: 
A Two-Part Study of ZX008 in Children and 
Adults with Lennox-Gastaut Syndrome 
(LGS); Part 1: A Randomized, Double-blind, 
Placebo-controlled Trial of Two Fixed Doses 
of ZX008 (Fenfluramine Hydrochloride) Oral 
Solution as Adjunctive Therapy for Seizures 
in Children and Adults with LGS, Followed 
by Part 2: An Open-label extension to Assess 
Long-Term Safety of ZX008 in Children and 
Adults with LGS 
Coordinating Investigator: 
 
Children’s Hospital Colorado 
Anschutz Medical Campus 
Aurora, CO   80045 
 
 
 
Signature 
Date (Day/Month/Year) 
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SIGNATURE(S) OF THE PRINCIPAL INVESTIGATOR 
Study Number: 
ZX008-1601  
PA 4.0 (Japan) 
25July 2022 
Study Title: 
A Two-Part Study of ZX008 in Children and 
Adults with Lennox-Gastaut Syndrome (LGS); 
Part 1: A Randomized, Double-blind, Placebo-
controlled Trial of Two Fixed Doses of ZX008 
(Fenfluramine Hydrochloride) Oral Solution as 
Adjunctive Therapy for Seizures in Children and 
Adults with LGS, Followed by Part 2: An Open-
label Extension to Assess Long-Term Safety of 
ZX008 in Children and Adults with LGS 
I have read this study protocol, including all appendices. By signing this study 
protocol, I agree to conduct the clinical study, following approval by an Independent 
Ethics Committee (IEC)/Institutional Review Board (IRB), in accordance with the 
study protocol, the current International Conference on Harmonization (ICH) 
Guideline for Good Clinical Practice (GCP), and applicable regulatory requirements. I 
will ensure that all personnel involved in the study under my direction will be informed 
about the contents of this study protocol and will receive all necessary instructions for 
performing the study according to the study protocol. 
Name and affiliation to be filled out by the investigator 
Principal Investigator  
(Name & Affiliation): 
 
 
 
 
 
 
Signature 
Date (Day/Month/Year) 
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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AE 
Adverse Event 
AED 
Antiepileptic drug 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of covariance 
AS 
Atonic seizure 
AUC 
Area under the concentration-time curve 
AUC0-t 
Area under the concentration-time curve from time zero to time=t 
BID 
bis in die; two times per day 
BMI 
Body Mass Index 
BRIEF 
Behavior Rating Inventory of Executive Function 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
Cavg•ss 
Average plasma concentration 
CBD 
Cannabidiol 
CFR 
Code of Federal Regulations 
CGI 
Clinical Global Impression 
Cmax 
Maximum observed concentration determined directly from the 
concentration-time profile 
CRF 
Case report form 
CS 
Clonic seizures 
Cyp 
Cytochrome p450 
dL 
Deciliter 
DS 
Dravet syndrome 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
electronic Case Report Form 
EEG 
electroencephalogram 
EOS 
End Of Study 
EPAR 
European Public Assessment Report 
ET 
Early Termination 
FS 
Focal seizure 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GH 
Growth Hormone 
GMP 
Good Manufacturing Practices 
GTC 
Generalized tonic-clonic seizure 
HADS 
Hospital Anxiety and Depression Scale 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
IDSMC 
Independent Data and Safety Monitoring Committee 
IEC 
Independent Ethics Committee 
IGF-1 
Insulin-like Growth Factor-1 
ILAE 
International League Against Epilepsy 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
ICAB 
International Cardiology Advisory Board 
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ABBREVIATION 
DEFINITION 
IRB 
Institutional Review Board 
IU 
International Unit 
IWR 
Interactive Web Response (System) 
KD 
Ketogenic diet 
kg 
Kilogram 
Leiter-3 
Leiter International Performance Scale-Revised 
LGS 
Lennox-Gastaut syndrome 
LH 
Luteinizing Hormone 
M 
Maintenance period 
MCDS 
Mean change in number of seizures that results in drops 
MCSF 
Mean Convulsive Seizure Frequency 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mg/kg/day 
Milligram per kilogram per day 
Min 
Minutes 
mITT 
Modified Intent-to-Treat 
mL 
Milliliter 
MS 
Myoclonic seizure 
OLE 
Open-label extension 
PopPK model 
Population Pharmacokinetic model 
PK 
Pharmacokinetics 
PP 
Per Protocol 
QoL 
Quality of Life 
QOLCE 
Quality of Life in Childhood Epilepsy 
QTcF 
corrected QT interval using Fredericia method 
SAE 
Serious Adverse Event 
SAF 
safety population 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Status epilepticus 
SMEI 
Severe Myoclonic Epilepsy Of Infancy 
STP 
Stiripentol 
SUDEP 
Sudden Unexpected Death in Epilepsy 
T+M 
Titration plus Maintenance Periods 
t1/2 
Terminal half-life 
TA 
Tonic/atonic seizure 
THC 
Tetrahydrocannabinol 
Tmax 
Time to maximum concentration 
TS 
Tonic seizure 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
USA 
United States of America 
USP 
United States Pharmacopeia 
VABS 
Vineland Adaptive Behavior Scale 
VNS 
Vagal Nerve Stimulator/Stimulation 
ZX008 
Fenfluramine Hydrochloride Oral Solution 
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STUDY SYNOPSIS 
Study Title: A Two-Part Study of ZX008 in Children and Adults with Lennox-Gastaut 
Syndrome (LGS); Part 1: A Randomized, Double-blind, Placebo-controlled Trial of Two 
Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as Adjunctive Therapy 
for Seizures in Children and Adults with LGS, Followed by Part 2: An Open-label Extension 
to Assess Long-Term Safety of ZX008 in Children and Adults with LGS 
Study Number: ZX008-1601 
Study Product: Fenfluramine Hydrochloride Oral Solution, ZX008 
Type of Study: 
Part 1: Efficacy and safety study 
Part 2: Long-term safety study 
Indication Studied:  
Adjunctive therapy for seizures in Lennox-
Gastaut syndrome (LGS) 
Phase of Development: Phase III  
Countries: North America, Europe, Japan, and 
Australia 
Sponsor: Zogenix International Limited  
Coordinating Investigator:  
Estimated Duration of Individual Subject Participation: 
The duration of participation in the study for an individual subject in the double-blind study (Part 1) is 
expected to be up to 20 weeks. The duration of participation in the open-label extension (Part 2) is up 
to 72 months or until ZX008 is approved in a subject’s country of residence and listed on a patient’s 
health plan formulary, whichever occurs first. The total participation time is up to approximately 77 
months.  Regardless of whether subjects end participation early, do not continue with the open-label 
extension, or roll over to the open-label extension, all subjects who do not transition to commercial 
drug will have a follow-up visit 3 to 6 months after the last dose of study medication for final safety 
monitoring.  
Objectives: 
The primary objective of Part 1 is the primary objective of the entire study. 
Part 1 
The primary objective of Part 1 is: 
x To evaluate the effect of ZX008 0.8 mg/kg/day versus placebo as adjunctive therapy for the 
treatment of uncontrolled seizures in children and adults with Lennox-Gastaut syndrome (LGS) 
based on the change in frequency of seizures that result in drops between baseline and the 
combined Titration and Maintenance Periods (T+M) 
The key secondary objectives of Part 1 are: 
x To evaluate the effect of ZX008 0.2 mg/kg/day versus placebo as adjunctive therapy for the 
treatment of uncontrolled seizures in children and adults with LGS based on the change in 
frequency of seizures that result in drops between baseline and T+M 
x To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo on the 
proportion of subjects who achieve a ≥50% reduction from baseline in the frequency of seizures 
that result in drops 
x To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo on the 
Clinical Global Impression – Improvement rating, as assessed by the Principal Investigator 
 
See Statistical Methods (Section 10.1.5.1) for hierarchical testing procedure. 
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Additional secondary efficacy objectives of Part 1 are: 
x To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo on the 
following endpoints: 
- Change in the frequency of all countable motor seizures between baseline and T+M 
(countable seizures include: generalized tonic-clonic seizures [GTC], tonic seizures [TS], 
clonic seizures [CS], atonic seizures [AS], tonic/atonic seizures [TA], clearly recognizable 
focal seizures [FS], and myoclonic seizures [MS] that result in a drop)  
- Change in the frequency of all countable seizures (ie, motor and non-motor) between baseline 
and T+M 
- Change in frequency of seizures that result in drops between baseline and the Maintenance 
Period (M) 
- Change in the frequency of countable motor seizures that do not result in drops between 
baseline and M 
- The proportion of subjects who achieve a worsening or no change (i.e ≤ 0% reduction), >0%,  
≥25%, ≥50%, ≥75%, 100% reduction, and “near seizure freedom” (ie, 0 or 1 seizures) 
between baseline and T+M, and baseline and M, in all countable motor seizures (GTC, TS, 
AS, TA, FS, MS with a drop); in countable motor seizures that do not result in drops; and in 
all seizures that result in drops  
- Number of seizure-free days, defined as 1) days with no countable seizures and 2) days with 
no seizures that result in drops 
- Longest interval between seizures that result in drops 
x To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo on the 
following endpoints: 
- Clinical Global Impression – Improvement rating, as assessed by the parent/caregiver 
The safety objectives of Part 1 are: 
x To evaluate the safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day versus placebo with 
regard to adverse events (AEs), laboratory parameters, physical examination, neurological 
examination, vital signs (blood pressure, heart rate, temperature, and respiratory rate), 
electrocardiograms (ECG), echocardiograms (ECHO), body weight, and BMI  
x To evaluate the change from baseline in cognition using age-appropriate Behavior Rating 
Inventory of Executive Function (BRIEF) 
The pharmacokinetic (PK) objective of Part 1 is: 
x To evaluate the PK of ZX008 0.2 and 0.8 mg/kg/day at steady state in subjects <18 years and 
≥18 years with LGS using a non-compartmental analysis; and obtain exposure data that will be 
used in population pharmacokinetic (PopPK) analysis, the results of which will be reported 
separately.. 
The exploratory objectives of Part 1 are: 
x To compare the ZX008 0.2 and 0.8 mg/kg/day doses on primary, secondary and safety endpoints 
x To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo on the 
following endpoints: 
- The frequency of rescue medication usage 
- The incidence of medical services used to treat seizures 
- The incidence of status epilepticus 
- The change from baseline in behavior using the Vineland Adaptive Behavior Scale (VABS) 
(Cohort A) 
- The change from baseline in QoL using the Quality of Life in Childhood Epilepsy (QOLCE) 
Assessment 
- The change from baseline in caregiver burden using the Zarit Caregiver Burden Inventory 
- The change from baseline in affective symptoms of the parent/caregiver using the Hospital 
Anxiety and Depression Scale (HADS) 
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Page 18 of 198 
 
 
Part 2 
The primary objective of Part 2 is:  
x 
To assess the long-term safety and tolerability of ZX008 in children and adults with LGS with 
regard to adverse events (AEs), laboratory parameters, physical examination, neurological 
examination, suicidality, cognition (BRIEF), vital signs (blood pressure, heart rate, 
temperature, and respiratory rate), electrocardiograms (ECG), echocardiograms (ECHO), body 
weight, and BMI. 
The secondary objectives of Part 2 are: 
x To assess the effect of ZX008 relative to the baseline on the following effectiveness measures: 
- The change in the frequency of seizures that result in drops 
- The change in the frequency of all countable motor seizures (GTC, TS, CS, AS, TA, FS, MS 
with a drop) 
- The change in the frequency of all countable seizures 
- The proportion of subjects who achieve a worsening or no change (ie, ≤0% reduction),>0%, 
≥25%, ≥50%, ≥75%, 100% reduction, and “near seizure freedom” (ie 0 or 1 seizures) in 
frequency of all countable seizures that result in drops, countable motor seizures that do not 
result in drops, all countable motor seizures, all countable seizures, and all countable seizures 
that do not result in drops 
- Number of seizure-free days, defined as 1) days with no countable seizures and 2) days with 
no seizures that result in drops 
- Longest interval between seizures that result in drops 
 
x To evaluate the effect of ZX008 on the following endpoints: 
- Clinical Global Impression – Improvement rating, as assessed by the Principal Investigator 
- Clinical Global Impression – Improvement rating, as assessed by the parent/caregiver 
The exploratory objectives of Part 2 are: 
x To determine the incidence of the following on subjects receiving ZX008: 
- The incidence of medical services used to treat seizures 
- The incidence of status epilepticus 
- The use of rescue medication 
x To assess the effect of ZX008 on the following measures: 
- The change from baseline in QoL using the QOLCE 
- The change from baseline in caregiver burden using the Zarit Caregiver Burden Inventory 
- The change from baseline in affective symptoms of the parent/caregiver using the Hospital 
Anxiety and Depression Scale (HADS) 
 
Methodology: 
This is an international multicenter study being conducted in two parts.  Up to approximately 80 study 
sites in North America, Europe, Japan, and Australia are initially planned to participate.  Part 1 is a 
double-blind, parallel-group, placebo-controlled, study to assess the efficacy and safety of two doses 
of ZX008 when used as adjunctive therapy for seizures in children and adult subjects with LGS. The 
study will include 2 cohorts: Cohort A will include randomized subjects from North America, Europe, 
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and Australia; Cohort B will include randomized subjects from Japan only. The primary study 
endpoint is assessed from Part 1 Cohort A data. The primary analysis will be conducted when the last 
subject in Cohort A has completed Part 1. Cohort B will be analyzed independently with  an interim 
analysis occurring after the last subject in Cohort B completes 12 months in Part 2 and a final analysis 
when the last subject in Cohort B completes Part 2. Part 2 will be an open-label, flexible-dose 
extension for subjects completing Part 1 of the study. 
 
Part 1 will consist of a 4-week baseline, 2-week titration, 12-week maintenance, and 2-week taper or 
transition period.  The 4-week Baseline Period will consist of the establishment of initial eligibility 
during a screening visit to include an assessment of cardiac parameters (ECG and ECHO), followed by 
an observation period where subjects will be assessed for baseline seizure frequency based on 
recordings of daily seizure activity entered into a diary.  Upon completion of the Baseline Period, 
subjects who qualify for the study will be randomized (1:1:1) in a double-blind manner to receive 1 of 
2 doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; maximum dose: 30 mg/day [or 0.5 mg/kg/day, 
maximum 20 mg/day, for subjects taking concomitant stiripentol (STP)]) or placebo.  Randomization 
will be stratified by weight (<37.5 kilograms [kg], ≥37.5 kg) to ensure balance across treatment arms, 
and at least 25% of subjects will be in each weight group. All subjects will be titrated to their blinded 
randomized dose over a 2-week Titration Period. Following titration, subjects will continue treatment 
at their randomly assigned dose over a 12-week Maintenance Period. Total treatment time from the 
beginning of the Titration Period through the end of the Maintenance Period is 14 weeks.  Subjects 
will have ECG and ECHO assessments at weeks 6 and 14 during the Maintenance Period.  At the end 
of the Maintenance Period (or early discontinuation), all subjects will undergo a blinded 2-week taper 
or transition period (Post-Dosing Follow-Up) depending on whether they exit the study or are enrolled 
in Part 2, the long-term open-label extension, respectively. A follow-up ECG and ECHO will be 
performed 3-6 months after study drug discontinuation for early termination, or for those subjects who 
complete the study but do not enter the open-label extension part.  If there are any findings at the 3-
month post-dose follow-up, a second follow-up will be repeated at 6 months and then every 3 months 
until resolved or stabilized. 
 
Part 2 is an open-label, long-term safety study of ZX008 for subjects who have successfully completed 
14 weeks of treatment (titration + maintenance) in Part 1 and are candidates for continuous treatment 
for an extended period of time; subjects who have not completed the entire 14 weeks of treatment in 
Part 1 may be eligible to participate in Part 2 on a case-by-case basis and only following sponsor 
approval. Part 2 will consist of a 12-month Open-Label Extension (OLE) Treatment Period and a 2-
week Post-Dosing Period. Thus, subjects who complete 12 months of OLE in Part 2 will have been 
treated with ZX008 for at least 70 weeks (including their participation in both Part 1 and Part 2). If 
marketing approval is not yet received after the end of the OLE Treatment Period, treatment may be 
extended on an annual basis in order to provide continuity of treatment for subjects who are enrolled 
in Part 2 of the study until ZX008 is approved in the subject’s country of residence and listed on a 
patient’s health plan formulary. Up to -5 annual extensions can be applied, for a total treatment time of 
up to  72 months in the OLE. Continuation will be based on review of safety/tolerability and 
effectiveness, and be offered for subjects who continue to meet eligibility requirements, comply with 
investigator’s instructions, and for whom the investigator judges benefit outweighs risk. 
 
During Part 2 all subjects will be treated initially with 0.2 mg/kg/day for 1 month to assess 
effectiveness of this dose in all study subjects and determine the minimally effective dose. After 1 
month at a dose of 0.2 mg/kg/day, the investigator may adjust the dose for each subject based on 
effectiveness and tolerability. Dose changes should be made in maximum increments of 0.2 
mg/kg/day, to a maximum of 0.8 mg/kg/day (or 0.5 mg/kg/day for subjects taking concomitant STP) 
but not to exceed total dose of 30 mg/day (or 20 mg/day for sujects taking concomitant STP).  During 
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the 12-month OLE subjects will have ECG and ECHO assessments at months 1, 3, 6, and 9, and at the 
end of study visit. In the event the OLE is extended, subjects will continue to have ECG (if clinically 
indicated) and ECHO assessments every 6 months until the end of their participation in the study. 
 
A follow-up ECG and ECHO will be performed at 3 and 6 months after study drug discontinuation for 
early termination and for those subjects who complete Part 2. If there are any findings at a post-dose 
follow-up, another follow-up will scheduled every 3 months until resolved or stabilized. Subjects who 
transition to commercially available ZX008 will not return for these follow-ups, but must have an 
ECHO within 3 to 6 months of the transition date and will have follow-up ECHOs within required 
timeframs while on commercial drug supply. 
 
In both Part 1 and the first 12 months of Part 2, parents/caregivers will use a diary every day to record 
the number of seizures, type of seizures, time and duration of seizures, whether the seizure resulted in 
a drop, dosing of study drug, and use of rescue medication. Seizures that result in a drop are defined as 
seizures involving the entire body, trunk, or head that led to a fall, injury, slumping in a chair, or the 
subject’s head hitting a surface or that could have led to a fall or injury, depending on the patient’s 
position at the time of the seizure.  
 
A schedule of assessments for Part 1 is provided in Table 1 and for Part 2 in Table 2. 
 
External Individuals and Committees:  The ZX008 clinical program will employ an Independent 
Data and Safety Monitoring Committee (IDSMC) that will be responsible for safety oversight. A 
separate International Cardiology Advisory Board (ICAB) advises the Sponsor on matters of cardiac 
safety of the ZX008 clinical trials.  ECGs and Doppler ECHOs will be centrally read and interpreted 
under blinded conditions using pre-specified criteria, and if necessary, with review by the ICAB. 
Number of Subjects: 
Approximately 340 subjects will be screened and approximately 250 subjects will be randomized into 
Part 1 Cohort A, and at least 30 and up to 50 subjects will be randomized into Part 1 Cohort B. The 
number of screened subjects may exceed 340 depending on the screen fail rate.  Only subjects that 
participated in Part 1 are eligible for participation in Part 2. Each clinical site will not randomize more 
than a maximum of 15 subjects into Part 1 without prior consent from the sponsor. 
Selection Criteria for Part 1 
Inclusion Criteria: All subjects must meet all of the following inclusion criteria to be enrolled into 
the study: 
1. Subject is male or non-pregnant, non-lactating female, age 2 to 35 years, inclusive as of the 
day of the Screening Visit.  Female subjects of childbearing potential must not be pregnant or 
breast-feeding. Female subjects of childbearing potential must have a negative urine or serum 
pregnancy test at screening. Subjects of childbearing or child-fathering potential must be 
willing to use medically acceptable forms of birth control (see Section 4.4), which includes 
abstinence, while being treated on this study and for 90 days after the last dose of study drug. 
2. Subject must have a diagnosis of Lennox-Gastaut syndrome, where seizures that result in 
drops are not completely controlled by current antiepileptic treatments. (Subjects without a 
formal diagnosis may still be enrolled after review and consultation between the Investigator 
and Sponsor, and in some cases, the Epilepsy Study Consortium.  Final decisions on 
enrollment are at the discretion of the sponsor if all other criteria are met.) 
3. Subjects must meet all of the following 4 criteria for Lennox-Gastaut syndrome, as defined in 
this protocol: 
a. Onset of seizures at 11 years of age or younger. 
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b. Multiple seizure types (must include TS or TA), including countable motor seizures 
that result in drops. Countable motor seizure types eligible for inclusion are: GTC, TS, 
CS, AS, FS with observable motor symptoms, and MS with a drop.  
c. Abnormal cognitive development. 
d. Evidence of EEG in the medical history that shows abnormal background activity 
accompanied by slow spike and wave pattern <2.5 Hz. (Acceptable evidence includes 
a copy of the EEG trace, EEG report, or physician note that appropriately describes 
the EEG findings.) 
4. Subject must have had at least 8 drop seizures in the last 4 weeks prior to Screening (minimum 
of 4 drop seizures in the first two weeks and 4 in the last two weeks before Screening), by 
parent/guardian report to investigator or investigator medical notes 
5. Receiving at least 1 concomitant AED and up to 4 concomitant AEDs, inclusive. KD and 
VNS are permitted but do not count towards the total number of AEDs.  Rescue medications 
for seizures are not counted towards the total number of AEDs. 
6. All medications or interventions for epilepsy (including KD and VNS) must be stable for at 
least 4 weeks prior to screening and are expected to remain stable throughout the study. 
7. Subject has been informed of the nature of the study and informed consent has been obtained 
from the legally responsible parent/guardian. 
8. Subject has provided assent in accordance with Institutional Review Board (IRB)/Ethics 
Committee requirements, if capable. 
9. Subject’s parent/caregiver is willing and able to be compliant with diary completion, visit 
schedule and study drug accountability. 
 
Exclusion Criteria: Subjects who meet any of the following exclusion criteria will not be enrolled 
into the study: 
1. Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study 
medication. 
2. Subject’s etiology of seizures is a degenerative neurological disease.  
3. Subject has a history of hemiclonic seizures in the first year of life. 
4. Subject only has drop seizures in clusters, where individual seizures cannot be counted 
reliably. 
5. Subject has pulmonary arterial hypertension. 
6. Subject has current or past history of cardiovascular or cerebrovascular disease, such as 
cardiac valvulopathy, myocardial infarction or stroke, or clinically significant structural 
cardiac abnormality, including but not limited to mitral valve prolapse, atrial or ventricular 
septal defects, patent ductus arteriosis (note: Patent Foramen Ovale or a bicuspid valve are not 
considered exclusionary). 
7. Subject has current or recent history of Anorexia Nervosa, bulimia, or depression within the 
prior year that required medical treatment or psychological treatment for a duration greater 
than 1 month. 
8. Subject has a current or past history of glaucoma. 
9. Subject has had an anoxic episode requiring resuscitation within 6 months of the Screening 
Visit. 
10. Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild hepatic 
impairment (elevated liver enzymes < 3x ULN and/or elevated bilirubin <2x ULN) may be 
entered into the study after review and approval by the Medical Monitor in conjunction with 
the sponsor, in consideration of comorbidities and concomitant medications. 
11. Subject has severe renal impairment (estimated glomerlular filtration rate <30mL/min/1.73m2) 
12. Subject is receiving concomitant therapy with any of the following: centrally-acting anorectic 
agents; monoamine-oxidase inhibitors; any centrally-acting compound with clinically 
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appreciable amount of serotonin agonist or antagonist properties, including serotonin reuptake 
inhibition; other centrally-acting noradrenergic agonists, including atomoxetine; or 
cyproheptadine (see Appendix 1 for a list of prohibited medications). (Note: Short-term 
medication requirements for prohibted medications will be handled on a per case basis by the 
Medical Monitor.) 
13. Subject has positive result on urine or serum tetrahydrocannabinol (THC) Panel or whole 
blood cannabidiol (CBD) at the Screening Visit. 
14. Subject is taking felbamate for less than 1 year prior to screening and/or does not have stable 
liver function and hematology laboratory tests, and/or the dose has not been stable for at least 
60 days prior to the Screening Visit. 
15. Subject is known to be human immunodeficiency virus (HIV) positive. 
16. Subject is known to have active viral hepatitis (B or C)  
17. Subject is currently receiving an investigational product. 
18. Subject has participated in another clinical trial within the past 30 days (calculated from that 
study’s last scheduled visit). Participation in non-treatment trials will be reviewed by the 
medical monitor.  
19. Subject is at imminent risk of self-harm or harm to others, in the investigator’s opinion, based 
on clinical interview and responses provided on the Columbia-Suicide Severity Rating Scale 
(C-SSRS).  Subjects must be excluded if they report suicidal behavior in the past 6 months as 
measured by the C-SSRS at Screening or Baseline, which includes suicidal ideation with 
intent and plan (Item #5). If a subject reports suicidal ideation on Item 4 without specific plan, 
and the investigator feels that the subject is appropriate for the study considering the potential 
risks, the investigator must document appropriateness for inclusion, and discuss with the 
parent/caregiver to be alert to mood or behavioral changes, especially around times of dose 
adjustment. 
20. Subject is unwilling or unable to comply with scheduled visits, drug administration plan, 
laboratory tests, other study procedures, and study restrictions.  
21. Subject is institutionalized in a general nursing home (ie, in a facility that does not provide 
skilled epilepsy care). 
22. Subject does not have a reliable caregiver who can provide seizure diary information 
throughout the study. 
23. Subject has a clinically significant condition, including chronic obstructive pulmonary disease, 
interstitial lung disease, or portal hypertension, or has had clinically relevant symptoms or a 
clinically significant illness in the 4 weeks prior to the Screening Visit, other than epilepsy, 
that would negatively impact study participation, collection of study data, or pose a risk to the 
subject. 
Randomization Inclusion Criteria: Subjects must meet all of the inclusion criteria and none of the 
exclusion criteria above and meet the following criteria in order to be randomized: 
1. Subject has been approved for study inclusion by the Epilepsy Study Consortium. 
2. Subject does not have an exclusionary cardiovascular or cardiopulmonary abnormality based 
on ECHO, ECG or physical examination and is approved for entry by the central cardiac 
reader.  Exclusionary abnormalities include, but are not limited to: 
a. Trace or greater mitral or aortic valve regurgitation in subjects ≤18 years of age 
b. Mild or greater mitral or aortic valve regurgitation in subjects >18 years of age 
c. Possible signs of pulmonary hypertension with abnormal or greater than upper range 
of normal values 
d. Evidence of left ventricular dysfunction (systolic or diastolic) 
3. Subject demonstrates a stable baseline with ≥ 2 seizures per week resulting in drops during the 
4-week Baseline Period. 
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4. Subject’s parent/caregiver has been compliant with diary completion during the Baseline 
Period, in the opinion of the Investigator and Sponsor. 
 
Selection Criteria for Part 2 
To be included in Part 2: 
1. Subjects must continue to meet the Selection Criteria for Part 1 (except for criteria related to 
seizure frequency).  If a subject entering Part 2 does not meet Randomization Criteria 2 
regarding cardiovascular abnormalities, Section 8.9.1 Follow-up of Cardiovascular Findings 
will be applied to determine eligibility to continue into Part 2. 
2. All subjects must have satisfactorily completed Part 1 of the study in the opinion of the 
investigator and the sponsor. 
3. Review of inclusion and exclusion criteria and written informed parental or guardian consent 
and assent of minors (if the subject is capable of providing assent) for Part 2 must be obtained 
before a subject can start any of the Part 2 Visit 15 procedures. 
4. Subjects must, in the medical opinion of the Investigator, be candidates for continued 
treatment for an extended period of time with ZX008. Candidates for continuous treatment 
should not meet Discontinuation criteria listed in Section 4.5 and should not meet the 
following criteria: 
a. Clinically meaningful worsening of seizures, judged by Investigator or 
subject/caregiver such that treatment outside of the protocol and other than ZX008 is 
assumed to be in the subject’s best interest. A clinically meaningful worsening is an 
increase in frequency, severity or duration of existing seizures, or (in some cases) 
emergence of a new seizure type. Frequent or increased use of rescue medication may 
be considered indicative of worsening. 
b. Clinically significant clinical laboratory findings (e.g. elevated ALT levels, decrease 
in platelet count, etc. that are CTCAE Grade 3 or higher) in subjects with no prior 
relevant history, that were not present during Baseline, are confirmed by a repeat test 
within a week, and not attributable to other concomitant medications. 
c. Weight loss >15% during the T+M period that has not stabilized and is considered, in 
the opinion of the Investigator, detrimental to continuing treatment with ZX008.  
5. Those subjects who do not complete the 12-week Maintenance Period of Part 1 may, on a 
case-by-case basis, be eligible for entrance after consideration of the circumstances of the 
early termination and the potential benefit-risk of continued participation in a ZX008 trial. The 
decision whether to permit participation in Part 2 for subjects who do not complete Part 1 
resides solely with the sponsor, who will require a formal request for early Part 2 continuation 
to be made by the site investigator as well as an evaluation of risk/benefit. The sponsor may 
also consult with the ICAB and/or the IDSMC, and take into consideration evidence of the 
following for approval: 
a. The subject is experiencing a worsening in condition that is not likely to be related to 
Part 1 treatment, in the opinion of the Investigator 
b. The subject has progressed at least half-way through Part 1 (i.e. Visit 8) 
c. The subject has been compliant with assessments and requirements of Part 1 
d. The subject does not exhibit other contraindications to initiating open-label treatment 
 
 Study Product, Dose, and Mode of Administration: 
ZX008 is supplied as an oral solution in concentrations of 1.25, 2.5, and 5 mg/mL. Subjects will be 
randomized to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; maximum dose: 
30 mg/day) or placebo.  Study medication will be administered twice a day (BID) in equally divided 
doses. (Note that subjects taking concomitant STP will be randomized to 0.5 mg/kg/day, maximum 
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dose 20 mg/day, or equivalent volume of placebo.  Subjects randomized to 0.5 mg/kg/day will be 
included in analyses with the subjects randomized to 0.8 mg/kg/day not taking STP.) 
Reference Product, Dose, and Mode of Administration: 
Matching ZX008 placebo is supplied as an oral solution.  
Duration of Treatment: 
In Part 1 all subjects will receive ZX008 or matching placebo for up to approximately 16 weeks 
(Titration Period=2 weeks; Maintenance Period=12 weeks; Taper/Transition Period=2 weeks). At the 
end of the 12-week Maintenance Period, eligible subjects may enroll into Part 2, the open-label 
extension, after completing a 2-week transition period with blinded study medication.  Subjects who 
enroll in Part 2 will have the option to receive ZX008 for up to 72 months (plus a 2-week taper at the 
end of the open-label extension), or until ZX008 is approved in the subject’s country of residence and 
listed on a patient’s health plan formulary, whichever comes first.  Subjects who do not enroll in the 
open-label extension will undergo a taper off of study medication (doses will be administered in a 
blinded fashion similar to the titration, ie, doses will be decreased in 4-day increments). Follow-up 
cardiovascular safety assessments, including ECG and ECHO, will be performed following the last 
dose of study medication for all subjects that do not transition to commercial drug, regardless of 
whether they complete the entire study or terminate early, unless the subject was known to be taking 
placebo (ie, blind was broken). These follow-ups will occur 3 months following the last dose of study 
medication for any subject taking the medication for 2-13 weeks, and 3 and 6 months following the 
last dose for any subject taking the medication for >13 weeks. If there are any findings at a post-dose 
follow-up, another follow-up will scheduled every 3 months until resolved or stabilized. Subjects who 
transition to commercially available ZX008 will not return for a follow-up after EOS/ET or a cardiac 
follow up after last dose but must have had an ECHO within 3 to 6 months before the transition date 
and will have follow-up ECHOs within required timeframe while on commercial drug supply. 
Criteria for Evaluation: 
Efficacy: 
The efficacy endpoints for Part 1 of the study are: 
Primary Endpoint: 
Percent change from baseline in the frequency of seizures that result in drops in the combined 
Titration and Maintenance Periods (T+M) in the ZX008 0.8 mg/kg/day group compared to the placebo 
group.  
Key Secondary Endpoints: 
x 
Change from baseline in the frequency of seizures that result in drops in T+M in the ZX008 
0.2 mg/kg/day group compared to the placebo group.  
x 
Proportion of subjects who achieve a ≥50% reduction from baseline in the frequency of 
seizures that result in drops comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups 
independently versus placebo 
x 
Proportion of subjects who achieve clinically-meaningful improvement (much or very much 
improved) in the Clinical Global Impression – Improvement as assessed by Principal 
Investigator comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently 
versus placebo. 
Additional Secondary Endpoints: 
x 
Change from baseline in the frequency of all countable motor seizures in T+M in the ZX008 
0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo 
o Countable motor seizures include: generalized tonic-clonic seizures [GTC], tonic 
seizures [TS], clonic seizures [CS], atonic seizures [AS], tonic/atonic seizures [TA], 
clearly recognizable focal seizures [FS], and myoclonic seizures [MS] that result in a 
drop 
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x 
Change from baseline in the frequency of countable seizures that result in drops 
x 
Change from baseline in the frequency of seizures that result in drops between baseline and 
the Maintenance Period (M) 
x 
Change from baseline in frequency of countable seizures that do not result in drops 
x 
Proportion of subjects who achieve a worsening from baseline (ie <= 0% reduction), or >0%,  
≥25%, ≥50%, ≥75%, 100% reduction, and “near seizure freedom” (ie 0 or 1 seizures) between 
baseline and T+M, and baseline and M, in all countable motor seizures; in countable motor 
seizures that do not result in drops; in all countable seizures; in all countable seizures that do 
not result in drops; and in all seizures that result in drops 
x 
Number of seizure-free days in the baseline, M and T+M period defined as 1) days with no 
countable seizures and 2) days with no seizures that result in drops 
x 
The longest interval (days) between seizures that result in drops comparing the ZX008 
0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo 
x 
Clinical Global Impression – Improvement as assessed by the parent/caregiver 
The efficacy endpoints for Part 2 of the study are: 
x 
The change from baseline in the frequency of seizures that result in drops.  
x 
The change from baseline in the frequency of all countable motor seizures (GTC, TS, CS, AS, 
TA, FS, MS with a drop) 
x 
The change from baseline in the frequency of all countable seizures 
x 
The proportion of subjects who achieve a worsening from baseline (ie <= 0% reduction), or 
>0%,   ≥ 25%, ≥ 50%, ≥ 75%, 100% reduction, and “near seizure freedom” (ie 0 or 1 seizures) 
from baseline in frequency of all countable seizures that result in drops, countable motor 
seizures that do not result in drops, all countable motor seizures, all countable seizures, and all 
countable seizures that do not result in drops 
x 
Number of seizure-free days, defined as 1) days with no countable seizures and 2) days with 
no seizures that result in drops 
x 
Clinical Global Impression – Improvement rating, as assessed by the Investigator. 
x 
Clinical Global Impression – Improvement rating, as assessed by the parent/caregiver. 
 
Safety: 
The safety endpoints for Part1 and Part 2 of the study are: 
x 
AEs 
x 
Laboratory safety (hematology, chemistry, urinalysis) 
x 
Vital signs (blood pressure, heart rate, temperature, and respiratory rate) 
x 
Physical examination 
x 
Neurological examination 
x 
BRIEF to measure changes in cognition of the subject 
x 
Columbia Suicidality Severity Rating Scale (C-SSRS) 
x 
12-lead ECGs 
x 
Doppler ECHOs 
x 
Body weight and BMI 
 
Exploratory: 
The exploratory endpoints for Part 1 and Part 2 of the study are: 
x 
Incidence of status epilepticus 
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x 
Incidence of rescue medication usage 
x 
Number of days rescue medication used 
x 
Incidence in use of medical services to treat seizures 
x 
The change from baseline in behavior using the Vineland Adaptive Behavior Scale (VABS) 
(Part 1 Cohort A only) 
x 
The change from baseline in quality of life using the QOLCE 
x 
The change from baseline in caregiver burden using the Zarit Caregiver Burden Inventory 
x 
The change from baseline in affective symptoms of parent/caregiver using the HADS scale 
 
Pharmacokinetics: 
Steady-state plasma fenfluramine and norfenfluramine PK parameters (maximum and minimum 
plasma concentration (Cmin ss, Cmax ss) and area under the concentration time curve from time zero 
to time=t and time=24 hours (AUC0-t, AUC0-24) after administration of ZX008 derived using a 
population pharmacokinetic model. 
Sample Size Determination: 
The sample size for Part 1 Cohort A was estimated under the assumption that adding ZX008 at 0.8 
mg/kg/day to current therapy will lead to a mean decrease in the frequency of drop seizures that is 30 
percentage points lower than adding placebo to current therapy. The variability expected in the trial 
was estimated from the confidence intervals reported in a Phase 3 trial of clobazam for patients with 
Lennox-Gastaut syndrome (Ng, 2011) leading to an assumption that the SD is 50%. Under these 
assumptions, and using a Wilcoxon rank-sum test to approximate the primary analysis, a sample size 
of 63 subjects per treatment group affords 90% power to detect a difference between groups that is 
significant at the α=0.05 level. Assuming a 20% drop-out rate prior to the start of the maintenance 
period yields a requirement for an additional 16 subjects per group for a total of 79 subjects per 
treatment group.  Similar calculations for the 0.2 mg/kg/day ZX008 group lead to a total required 
sample size of 237. The number of subjects randomized into Part 1 Cohort A is estimated to be 
approximately 250 due to the long baseline period. The sample size of 10 to 15 subjects per treatment 
group in Cohort B is expected to provide a descriptive assessment of whether the treatment effect in 
Japanese subjects is similar to that observed in Cohort A subjects from the rest of the world. 
Statistical Methods: 
Part 1 
The primary analyses of the study will be performed on data from Part 1 Cohort A after the last 
subject enrolled in Cohort A has completed the last study visit of Part 1. Data from Part 1, Cohort B 
will be analyzed independently after the last subject in Cohort B completes Part 1. An interim analysis 
of Part 2 will be performed after all Cohort B subjects complete 12 months in Part 2.  A secondary 
analysis will be conducted after the last Cohort B subject has enrolled and completed the last study 
visit of Part 2. Analysis results for Part 1 from Cohort A and Cohort B may be compared through 
descriptive statistics, and if reasonable, some analyses may be performed using data from Cohort A 
and Cohort B combined. Subjects randomized to 0.5 mg/kg/day (ie, those taking concomitant STP) 
will be grouped with subjects randomized to 0.8 mg/kg/day for all efficacy analyses.  
Efficacy 
Primary Efficacy Analysis:  The primary efficacy endpoint for Part 1 is the percent change in 
frequency of seizures that result in drops (DSF: drop seizure frequency) per 28 days between the T+M 
and Baseline periods in Cohort A. The DCF will be calculated from all available data collected during 
the Baseline and treatment periods without imputation. The percent change in DSF will be calculated 
as the change in DSF between T+M and Baseline / DSF during Baselineu 100. Both the mean and 
median percent change in DCF frequency will be presented. The primary endpoint will be assessed 
using an non-parametric rank analysis of covariance (ANCOVA) with treatment and weight groups 
(<37.5 kg, ≥37.5 kg) as factors, and with Baseline MCDS as a covariate rank baseline DSF as a 
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covariate, and rank percent change in DSF from baseline as the response variable.  The primary 
analysis will compare the ZX008 0.8 mg/kg/day group to the placebo group at the alpha=0.05 level of 
significance. The difference between the ZX008 0.8 mg/kg/day and placebo groups in percent change 
in DSF, and its 95% confidence interval, will be estimated using the Hodges-Lehmann method. As a 
sensitivity analysis, the primary endpoint will also be analyzed using a parametric ANCOVA that 
incorporates treatment group and weight group as factors, log baseline DSF as a covariate; and log 
DSF during T+M as the response variable. Another sensitivity analysis will use a Wilcoxon rank-sum 
test to compare the ZX008 0.8 mg/kg/day group to the placebo group. Part 1 Cohort B will be 
analyzed using analogous methods.  
A key secondary analysis will compare the ZX008 0.2 mg/kg/day group to the placebo group on 
percent change in DSF using the same method as the primary analysis. Other key secondary analyses 
will compare the ZX008 0.8 and 0.2 mg/kg/day groups to the placebo group on the proportion of 
subjects who achieve a ≥50% reduction from baseline in DSF. The analyses will utilize independent 
logistic regression models that incorporate the same factors and covariate as the primary analysis. Two 
other key secondary analyses will compare both ZX008 dose groups (independently) to placebo on the 
proportion of subjects assessed by the Principal Investigator as minimally, much, or very much 
improved on the Clinical Global Impression – Improvement (CGI-I). The comparisons will employ 
separate Cochran-Mantel-Haenszel tests (CMH) stratified by weight strata. A serial gatekeeper 
strategy will be used to maintain the Type 1 error rate at α=0.05 across the family of analyses that 
support the primary and key secondary objectives. 
Safety  
All safety data will be appropriately analyzed by treatment group. The number and percentage of 
subjects with AEs will be displayed by body system and preferred term using the Medical Dictionary 
for Regulatory Activities (MedDRA). Summaries in terms of severity and relationship to study drug 
will also be provided. Adverse Events of Special Interest (AESI) and Serious AEs (SAEs) will be 
summarized separately in a similar manner. Laboratory tests, vital signs, physical examinations, 
neurological examinations, ECG, Doppler echocardiogram, C-SSRS, Tanner Staging results, etc, will 
be summarized appropriately, by treatment. All safety summaries will be based on the Safety 
Population. 
Pharmacokinetics 
Model derived plasma PK parameters (Cmax_ss, Cmin_ss, AUC0-t, AUC0-24) will be summarized 
descriptively by treatment group, when sufficient data are available. A PopPK model of 
fenfluramine, previously developed using data from healthy adults and pediatric patients with 
Dravet syndrome, will be updated to include the fenfluramine and norfenfluramine concentration-
time data collected during the Maintenance Period of Part 1. This model will be informed by all 
relevant data available at the time of data collection (both adults and pediatrics). The results from 
the PopPK modeling will be reported separately and conducted according to a separate SAP. 
Part 2 
The primary objective of Part 2 is to assess the long-term safety and tolerability of ZX008 in 
children and adults with LGS with regard to AEs, laboratory parameters, physical examination, 
neurological examination, vital signs, ECG, ECHO, body weight, and BMI. 
The number and percentage of subjects who experience treatment emergent AEs will be displayed by 
body system and preferred term using MedDRA. Summaries in terms of severity and relationship to 
study drug will also be provided. SAEs will be summarized separately in a similar manner. Laboratory 
tests, vital signs, physical examinations, neurological examinations, ECG, ECHO, cognition and body 
weight will be summarized using appropriate methods. 
Effectiveness will be assessed by the change from baseline (prior to randomization into Part 1) in DSF. 
The DSF per 28 days will be calculated as the number of seizures that result in drops divided by the 
number of days in the period and multiplied by 28. The change in DSF during the first 12 months of 
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ZX008 (Fenfluramine Hydrochloride) 
ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 28 of 198 
Part 2 OLE Treatment Period will be calculated as the difference between DSF during the OLE and the 
baseline DSF measured prior to randomization in Part 1. Both the mean and median percent change in 
DCF will be presented and the statistical significance of the percent change will be assessed using a 
Wilcoxon signed-rank test. Other secondary assessments will be compared to baseline from prior to Part
1, or by visit throughout Part 1 and the first 12 months of Part 2, as appropriate. 
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ZX008 (Fenfluramine Hydrochloride) 
ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 29 of 198 
Table 1. 
Schedule of Assessments: Part 1 
Study Assessments – PART 1 
Baseline Perioda 
Titration + Maintenance Period 
 
EOS/ 
ETb 
 
Post-
Dosingl 
Cardiac 
Follow-
upc 
 
Visit Number 
 
Screening 
 
Random-
ization 
 
Titration Period 
 
Maintenance Period 
1 
2 
(Phone) 
3 
 
4, 5 
(Phone) 
6 
7  
(Phone) 
8 
9  
(Phone) 
10 
11 
(Phone) 
12 
13  
 
14 
Study Day 
-28  
-15  
-1 
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
197 
Informed Consent (subject and 
parent/caregiver) 
X 
 
 
 
 
 
 
 
 
 
 
X  
(Part 2) 
 
 
Inclusion/Exclusion Criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Neurological History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epilepsy history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review retrospective seizure 
diary data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Medication, including AEDs 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination, complete 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
Optional 
Physical Examination, 
abbreviated  
 
 
 
 
 
Xm 
 
Xm 
 
Xm 
 
 
 
Xc 
Neurological Examination, 
complete 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Neurological Examination, 
abbreviated 
 
 
X 
 
 
Xm 
 
Xm 
 
Xm 
 
 
 
 
Vital signs 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Weight 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
12-lead ECG 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Xc 
Doppler ECHO 
X 
 
 
 
 
 
Xd 
 
 
 
Xd 
 
Xc 
Urine or Serum Pregnancy Test 
Xe 
 
Xe 
 
 
 
 
Xe 
 
 
 
Xe 
 
 
Clinical laboratory evaluation 
(hematology/ chemistry/urinalysiso, etc) 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Plasma sample for ZX008 PK 
 
 
 
 
 
 
 
Xf 
 
 
 
 
 
 
Plasma sample for background 
AEDs 
 
 
Xg 
 
 
Xg 
 
X 
 
Xg 
 
Xg 
 
 
Urine or serum THC Panel 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Whole blood CBD 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Tanner Staging (for subjects >7 to 
18 years old) 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Subject Diary 
D 
R 
C/R/D 
 
R 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/Dh 
C/R 
 
Epilepsy genotype panel 
(optional) 
 
X 
 
 
Study Medication 
 
 
D 
 
Ri 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/Dh 
C/R 
 
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ZX008 (Fenfluramine Hydrochloride) 
ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 30 of 198 
Study Assessments – PART 1 
Baseline Perioda 
Titration + Maintenance Period 
 
EOS/ 
ETb 
 
Post-
Dosingl 
Cardiac 
Follow-
upc 
 
Visit Number 
 
Screening 
 
Random-
ization 
 
Titration Period 
 
Maintenance Period 
1 
2 
(Phone) 
3 
 
4, 5 
(Phone) 
6 
7  
(Phone) 
8 
9  
(Phone) 
10 
11 
(Phone) 
12 
13  
 
14 
Study Day 
-28  
-15  
-1 
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
197 
C-SSRS 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Clinical Global Impression - 
Improvement (assessed by 
parent/caregiver) 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
Clinical Global Impression - 
Improvement (assessed by 
investigator) 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
HADS (Effect of 
parent/caregiver) 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
BRIEF 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
QOLCE 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Zarit Burden 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Randomize subject 
 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
First Day of Study Drug 
Administration 
 
 
Xj 
Xj 
 
 
 
Daily Diary Completion  
X 
 
Concomitant Medication 
 
 
 
X 
 
Adverse events 
X 
 
Adverse events of special interest 
X 
Xk 
AED=antiepileptic drug; BMI=body mass index; C=Collect; CBD=cannabidiol; D=Dispense; ECG=electrocardiogram; EOS=end of study; ET=early termination; HADS=Hospital Anxiety and Depression Scale; BRIEF=Behavior Rating Inventory of Executive 
Function; QoL=quality of life; R=Review 
a: 
The Baseline Period is comprised of the initial screening for the study and the assessment of baseline seizure activity recorded daily in the diary. The procedures to be completed at the Screening visit may be completed in a single day or split so that they are 
completed over the 2-day period. 
b: 
Subjects who are discontinued early and those who complete the study and choose not to enroll in the separate open-label extension will be tapered off study medication over an up to 2-week period. 
c: 
The safety follow-up visit will be conducted for subjects who either terminate early from Part 1, or who complete Part 1 but do not enter Part 2. Standard follow-up visits should occur 3 and 6 months after the last dose. If there are any findings at the last post-
dose follow-up, a follow-up visit will be repeated every 3 months until resolved or stabilized. 
d: 
The Visit 8 ECHO must be performed any time between Study Day 40 and Study Day 54.  The Visit 12 ECHO must be performed any time between Study Day 90 and Study Day 113; if a subject discontinues early from the study, the ECHO should be 
scheduled as soon as practical.  If the Study Day 43 ECHO was completed < 30 days prior to early termination, the Visit 12 ECHO will not be performed provided the parent/guardian agrees to bring the subject to the clinic for the cardiac follow-up visit. 
e: 
Females of child-bearing potential 
f: 
Plasma sample for pharmacokinetic assessment will be conducted prior to the dose at Visit 8 and 1, 2, and 4-6 hours after dose administration. 
g: 
Plasma sample for assessment of background AED(s) will be conducted prior to the dose of AED(s) at Visits 3, 8 and 12 (Visits 6 and 10 only if clinically indicated). Plasma sample may be collected after the morning dose of AED(s) are taken, if preferable, as 
long as the time of last dose is accurately recorded. 
h: 
Study drug/diary dispensed for the Transition Period for subjects entering the open-label extension and for the Taper Period for subjects exiting the study. 
i: 
Site personnel will review study medication dosing procedure (titration) with parent/caregiver. 
j: 
Study drug administration begins in the clinic on Study Day -1. Study Day 1 is considered the first day of dosing, even though subjects received an in-clinic dose on Study Day -1. The first dose taken in the clinic will be recorded in the eCRF, but not the 
subject diary; the next dose on the morning of Study Day 1 will be the first entry in the subject’s diary. 
k: 
Only adverse events related to cardiac safety will be collected at this visit. 
l: 
Visit 13 may be conducted as a phone call, provided diaries and study medication are returned by this time. 
m: 
An abbreviated physical and/or neurological examination to be conducted as appropriate based on last exam and reported AEs. 
n: 
Randomization should not occur prior to receiving approval from the Epilepsy Study Consortium and ERT ECHO results. 
o: 
Urine for urinalysis may be collected at home, the night before the clinic visit, as long as collection procedures are followed to maintain sample stability. 
 
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ZX008 (Fenfluramine Hydrochloride) 
ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 31 of 198 
Table 2. 
Schedule of Assessments: Part 2 Cohort B only 
 
After Visit 26/ Month 24 (or a later visit if V26/ Month 24 visit has already been performed at the time of Protocol Amendment 4.0 
approval), in clinic study visits will occur every 6 months until ZX008 is approved by the subject country of residence and listed on 
the patient health plan formulary. A phone visit will be performed between in clinic visits (with a 3-month interval).During the phone 
visits, only a review of concomitant medications, adverse events and adverse events of special interest will be performed.  
 
Last Visit Number/Study Month pre approval 
of Amendment 4.0 
Next In Clinic Visits to be Scheduled (until ZX008 approval by health authority) 
-Every 6 months- 
Visit 26 / Month 24 
Visit 28/M30 
Visit 30/M36 
Visit 32/M42 
Visit 34/M48 
Visit 36/M54 
Visit 27 / Month 27 
Visit 29/M33 
Visit 31/M39 
Visit 33/M45 
Visit 35/M51 
 
Visit 28 / Month 30 
Visit 30/M36 
Visit 32/M42 
Visit 34/M48 
Visit 36/M54 
 
Visit 29 / Month 33 
Visit 31/M39 
Visit 33/M45 
Visit 35/M51 
 
 
Visit 30 / Month 36 
Visit 32/M42 
Visit 34/M48 
Visit 36/M54 
 
 
 
 
Study Assessments – PART 2 
OLE Treatment Period** 
Post-
Dosing 
Cardiac Follow-up 
Visit Number 
Visit 15a 
 
Visit 16b 
Visits 17-21 
(Months 1, 2, 
3, 6 and 9**) 
Visit 22 
(Month 12) 
Visits 23-41 (Months 
15, 18, 21, 24, 27, 30, 
33, 36, 39, 42, 45, 48, 
51, 54, 57, 60, 63, 66, 
69) 
Visit 42c 
(EOS/ET) 
 
Visit 43 
 
Visit  44 and 45 
 
OLE Study Day 
1a 
15 
 30, 60, 90, 
180, and 270 
360 
450, 540, 630, 720, 
810, 900, 990, 1080, 
1170, 1260, 1350, 
1440, 1530, 1620, 
1710, 1800, 1890, 
1980, 2070 
2160 
2174k,q 
(3 and 6 months post 
last dose)d,k 
Clinic 
Phone 
Clinic 
Phone 
Informed Consent 
X 
 
 
 
X** 
X** 
 
 
 
 
Entry Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics 
Xa 
 
 
 
 
 
 
 
 
 
Medical/Neurological History 
Xa 
 
 
 
 
 
 
 
 
 
Epilepsy History 
Xa 
 
 
 
 
 
 
 
 
 
Physical Examination, complete 
Xa 
 
 
 
X 
 
 
X 
 
X 
Physical Examination, abbreviated 
 
Xm 
 
Xm 
 
Xm 
 
 
Xm 
X 
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ZX008 (Fenfluramine Hydrochloride) 
ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 32 of 198 
Study Assessments – PART 2 
OLE Treatment Period** 
Post-
Dosing 
Cardiac Follow-up 
Visit Number 
Visit 15a 
 
Visit 16b 
Visits 17-21 
(Months 1, 2, 
3, 6 and 9**) 
Visit 22 
(Month 12) 
Visits 23-41 (Months 
15, 18, 21, 24, 27, 30, 
33, 36, 39, 42, 45, 48, 
51, 54, 57, 60, 63, 66, 
69) 
Visit 42c 
(EOS/ET) 
 
Visit 43 
 
Visit  44 and 45 
 
Neurological Examination, complete 
Xe 
 
 
 
X 
 
 
X 
 
 
Neurological Examination, abbreviated 
 
Xm 
 
Xm 
 
Xm 
 
 
Xm 
 
Vital signs 
X 
X 
 
X 
X 
X 
 
X 
 
 
Weight 
Xa 
X 
 
X 
X 
X 
 
X 
X 
 
Height 
Xa 
 
 
 
X 
 
 
X 
 
 
12-lead ECG 
Xa 
 
 
X 
X 
Xq 
 
Xq 
 
X 
Doppler ECHO 
Xa 
 
 
Xf,g 
X 
Xg 
 
X 
 
X 
Urine or Serum Pregnancy Testh 
Xa 
 
 
Xn 
X 
X 
 
X 
 
 
Clinical laboratory evaluation  
(hematology/chemistry/urinalysisp, etc) 
Xi 
Xi 
 
Xn 
X 
Xq 
 
Xq 
 
 
Urine or serum THC Panel 
Xa 
 
 
Xn 
X 
 
 
Xs 
 
 
Whole blood CBD 
Xa 
 
 
Xn 
X 
 
 
Xs 
 
 
Plasma sample for background AEDs 
 
Xm 
 
Xn 
X 
Xq 
 
Xq 
 
 
Tanner Staging (for subjects >7 to 18 years old) 
Xa 
 
 
Xj 
X 
 
 
Xs 
 
 
C-SSRS 
Xa 
 
 
X 
X 
X 
 
X 
 
 
CGI-I (assessed by parent/caregiver) 
Xa 
 
 
X 
X 
X 
 
X 
 
 
CGI-I (assessed by investigator) 
Xa 
 
 
X 
X 
X 
 
X 
 
 
Overall change in seizure frequency 
(assessed by investigator) 
 
 
 
 
 
Xr 
 
Xr 
 
 
HADS (Effect of parent/caregiver) 
Xa 
 
 
Xo 
X 
 
 
Xs 
 
 
BRIEF 
Xa 
 
 
Xo 
X 
 
 
Xs 
 
 
QOLCE 
Xa 
 
 
Xo 
X 
 
 
Xs 
 
 
Zarit Burden 
Xa 
 
 
 
X 
 
 
Xs 
 
 
Subject Diary 
C/R/D 
C/R/D 
R 
C/R/D 
Xr 
Xr 
 
C/Rr 
C/R 
 
Study Medication 
C/R/D 
C/R 
R 
C/R/D 
C/R/D 
C/R/D 
 
C/R/D 
C/R 
 
Daily Diary Completion 
---------------------- X -------------------------------- 
 
 
Concomitant Medication 
Xa 
----------------------------------------------X-------------------------------------------------- 
 
Adverse Events 
Xa 
----------------------------------------------X-------------------------------------------------- 
 
Adverse events of special interest 
Xa 
----------------------------------------------X-------------------------------------------------- 
Xl 
 
 
 
 
AED=antiepileptic drug; BMI=body mass index; C=Collect; CBD=cannabidiol; D=Dispense; ECG=electrocardiogram; EOS=end of study; ET=early termination; HADS=Hospital Anxiety and Depression Scale; BRIEF=Behavior Rating Inventory of Executive Function; 
QoL=quality of life; R=Review; 
a: 
Use data collected at Visit 12 of Part 1. 
b: 
At the discretion of the investigator, Visit 16 may be conducted as a phone visit. 
c: 
Or early termination. 
d: 
Safety Follow-up visits will be conducted for subjects who terminate early from Part 2 and for those who complete Part 2. Standard follow-up visits should occur 3 and 6 months after the last dose. If there are any findings at a post-dose 
follow-up, a follow-up visit will be scheduled every 3 months until resolved or stabilized. 
e: 
Use Part 1 Visit 12 information unless complete neurological examination is warranted based on significant changes in subject status. 
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ZX008 (Fenfluramine Hydrochloride) 
ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 33 of 198 
Study Assessments – PART 2 
OLE Treatment Period** 
Post-
Dosing 
Cardiac Follow-up 
Visit Number 
Visit 15a 
 
Visit 16b 
Visits 17-21 
(Months 1, 2, 
3, 6 and 9**) 
Visit 22 
(Month 12) 
Visits 23-41 (Months 
15, 18, 21, 24, 27, 30, 
33, 36, 39, 42, 45, 48, 
51, 54, 57, 60, 63, 66, 
69) 
Visit 42c 
(EOS/ET) 
 
Visit 43 
 
Visit  44 and 45 
 
f: 
ECHOs will be performed at Months 1, 3, 6, and 9. 
g: 
The Months 3, 6, 9, 12, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 & 72 ECHO may be performed any time within 3 weeks prior to the study visit. If a subject discontinues early from the study, the ECHO should be 
scheduled as soon as practical. 
h: 
Females of child-bearing potential 
i: 
For Visit 15, use data collected at Part 1 Visit 12 unless clinical laboratory evaluation is warranted based on significant changes in subject status. For Visit 16, clinical laboratory evaluation is optional based on subject status. 
j: 
Visit 20 only. 
k: 
For subjects who are transitioning to commercial drug, do not initiate drug taper or conduct post-dosing and cardiac follow-up visits. 
l: 
Only adverse events related to cardiac safety will be collected at this visit. 
m: 
An abbreviated physical and/or neurological examination to be conducted as appropriate based on last exam and reported AEs. 
n: 
Visits 19, 20, and 21 (Months 3, 6, and 9) only. 
o: 
Visit 20 (Month 6) only 
p: 
Urine for urinalysis may be collected at home, the night before the clinic visit, as long as collection procedures are followed to maintain sample stability. 
q 
r: 
 
 
s: 
As clinically indicated for subjects extending Part 2 participation past 12 months. Abnormal clinically significant findings must be reported as adverse events. 
Electronic diary is to be used the first 12 months of Part 2, and should be reviewed and collected on Visit 22 (for subjects continuing in Part 2 of the study) or Visit 42 (for subjects who do not continue in Part 2 of the study past 12 months). 
After 12 months in Part 2, seizure diaries are not required. Rather, based on discussions with the parent/caregiver, clinical evaluation, and review of any documentation provided by the caregivers, investigators will assess the percent 
improvement in seizure burden on a 5-point scale: <25%, ≥25%, ≥50%, ≥75%, 100% [ie, seizure-fee] improvement. 
Only applicable for subjects ending Part 2 participation within the first 12 months. Not applicable for subjects who completed Visit 22 and extended participation in Part 2. 
 
** If marketing approval is not yet received after the end of the OLE Treatment Period, treatment may be extended on an annual basis in order to provide continuity of treatment for subjects who are enrolled in Part 2 of the study. Up to 5 
annual extensions can be applied, for a total treatment time of 72 months in the OLE. Continuation will be based on review of safety/tolerability and effectiveness, and be offered for subjects who continue to meet eligibility requirements, 
comply with investigator’s instructions, and for whom the investigator judges benefit outweighs risk. The decision to extend and informed consent should be completed before the start of the first visit of each annual extension ( i.e. Month 
12, 24, 36, 48 and  60). After approval from Investigator and Sponsor for extension and starting after Visit26/Month24 (or a later visit if Visit26/Month24 visit has already occurred at the time of Protocol Amendment 4.0 approval) , subject 
will return to the clinic every 6 months and have a phone visit 3 months after the in clinic visit for each 1-year extension, until up to Month 72. The End of Study will be Visit 42. Further extensions can then be applied as required if 
marketing approval is not yet received 
 
 
 
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ZX008 (Fenfluramine Hydrochloride) 
ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 34 of 198 
1. 
INTRODUCTION 
1.1 
BACKGROUND INFORMATION ON INDICATION STUDIED 
ZX008 (fenfluramine hydrochloride) is under clinical development for the adjunctive treatment 
of patients with Dravet syndrome and Lennox-Gastaut syndrome (LGS). Fenfluramine 
(Fintepla®) is authorized for sale in the United States for the treatment of seizures associated 
with Dravet syndrome in patients 2 years of age and older. 
LGS is a rare epileptic encephalopathy.  Onset of LGS usually occurs most commonly before 
age 11, with a peak between 3 and 5 years of age (Arzimanoglou 2009; Hancock and Cross, 
2013). Patients with LGS account for 5–10% of children with seizures (Panayiotopoulos 2005). 
The diagnosis of LGS includes clinical signs combined with typical EEG features. The clinical 
presentation of LGS is heterogeneous, however LGS is always characterized by a triad of 
symptoms: multiple seizure types, slow spike-and-wave EEG, and abnormal cognitive 
development. The most common seizure types are generalized tonic-clonic seizures, tonic 
seizures, atonic seizures, and tonic/atonic seizures, all of which most often can result in “drop 
attacks.” Other seizure types that occur in some LGS patients include atypical absences, non-
convulsive seizures, focal seizures, and myoclonic seizures. Nearly all LGS patients have 
treatment-resistant, lifelong epilepsy. Prognosis for LGS is very poor: 5% of children die, 80–
90% continue having seizures into adulthood, and nearly all have cognitive and behavioral 
problems (Panayiotopoulos 2005).  Children and adults with LGS have an enormous impact on 
their families, and efforts to improve the quality of life for these patients are complex. 
1.1.1 
Existing Treatment for LGS 
Currently, two drugs are approved in Japan for the treatment of Lennox-Gastaut syndrome: 
lamotrigine (2008) and rufinamide (2013). Nine AEDs are approved for treating Lennox-
Gastaut syndrome EU-wide and in selected EU Member States: felbamate, topiramate, 
lamotrigine, rufinamide, clonazepam, clobazam, valproate, nitrazepam, and cannabidiol 
(Epidyolex®). The same AEDs are approved in the US except valproate and nitrazepam. Other 
pharmacologic (valproate, benzodiazepines, zonisamide) and non-pharmacologic (KD, VNS, 
surgery) treatments also are prescribed based on clinical experience.  
Because patients with LGS experience a range of different seizure types, the condition is 
notoriously difficult to treat (Arzimanoglou 2009, Cross 2017) and seizures in LGS are usually 
not fully controlled (Hancock, 2013). Initial treatment for LGS is usually monotherapy with 
one of the currently approved AEDs.  If this is not successful, which is the most common case, 
a second agent is usually added; although some physicians move on to the second drug as 
monotherapy (Wheless 2007; Arzimanoglou 2009). The treatment of LGS frequently requires 
a combination of 2 or more of these compounds, but with continued suboptimal seizure 
control. The recommendation is to attempt to use drugs that have different mechanisms of 
action and the least amount of interaction with one other. After lack of response to 2 or more 
AEDs, non-pharmacological treatments such as KD, VNS, or surgery may be considered. A 
treatment that has been shown to be effective in common certain seizure types cannot be 
assumed to be effective in patients with LGS to treat that seizure type. 
Given the suboptimal treatment of seizures in the majority of LGS patients, even with 
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ZX008 (Fenfluramine Hydrochloride) 
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Confidential 
Page 35 of 198 
polytherapy, and the developmental and cognitive consequences believed to be caused, at least 
in part, by frequent childhood seizure activity, there is a medical need for a new anticonvulsant 
treatment with a novel mechanism of action that can significantly reduce seizure activity in 
LGS.  
1.2 
BACKGROUND INFORMATION ON STUDY PRODUCT 
Zogenix is developing a new formulation of fenfluramine hydrochloride, ZX008, for the 
adjunctive treatment of seizures associated with LGS. Fenfluramine is an amphetamine 
analogue that was first synthesized many years ago. It was approved in a large number of 
countries and widely prescribed as an appetite suppressant for the treatment of adult 
obesity. Brand names for fenfluramine formulations included Ponderax and Pondimin.  
Fenfluramine was also used extensively in an off-label combination with phentermine 
(“Fen-Phen”). Fenfluramine is a racemic compound and the single enantiomer D-
fenfluramine (dexfenfluramine) was also approved and marketed for the treatment of 
obesity as Adifax, Redux, and others. 
Fenfluramine was introduced in the USA in 1973. Products containing fenfluramine and D- 
fenfluramine were withdrawn from all markets between 1997 and 2000 after reports of heart 
valve disease and pulmonary hypertension (Connolly 1997; CDC 1997; Wong 1998). While 
the risk/benefit relationship for fenfluramine is thus considered unfavorable for the treatment 
of obesity in adults, establishing seizure control in LGS or any of the refractory catastrophic 
childhood epilepsies might lead to a more acceptable risk/benefit profile for fenfluramine. 
As a result of this previous extensive use of fenfluramine, there is a large body of information 
in the public domain concerning its pharmacology, toxicology and use in the treatment of 
obesity.  These data are summarized in the ZX008 Investigator Brochure (ZX008 IB). There 
is also a large body of information concerning its clinical safety profile. 
1.3 
CLINICAL DATA 
Two double-blind, placebo-controlled, randomized Phase 3 studies (Study 1 and Study 1504 
Cohort 2) of ZX008 in children and young adults with Dravet syndrome have been completed. 
Study 1 investigated two doses of ZX008 (0.2 and 0.8 mg/kg/day) or placebo and included 119 
subjects with Dravet syndrome from North America, Europe and Australia. Study 1504 Cohort 2 
included 87 subjects from North America and Europe, and compared addition of ZX008 
(0.5 mg/kg/day) or placebo in subjects who were receiving standard of care anti-epileptic 
treatments where administration of STP was mandatory.  
The primary efficacy measure in both studies was the change from baseline in the frequency of 
convulsive seizures (per 28 days) during the combined 14-week (Study 1) or 15-week (Study 
1504 Cohort 2) Titration and Maintenance periods (T+M). The primary analysis in Study 1 
compared ZX008 0.8 mg/kg/day to placebo and in Study 1504 Cohort 2 compared ZX008 0.5 
mg/kg/day to placebo. A key secondary measure in Study 1 compared the 0.2 mg/kg/day group 
to the placebo group on the same measure. Other key secondary measures in both studies 
included a comparison of the ≥ 50% Responder Rate (ie, the number of subjects with a ≥ 50% 
reduction in the frequency of convulsive seizures), and the longest seizure free interval. 
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Both Study 1 and Study 1504 Cohort 2 met the primary endpoint with a highly statistically 
significant reduction in convulsive seizures in all active treatment groups.  
In Study 1, subjects randomized to ZX008 0.8 mg/kg/day and 0.2 mg/kg/day had a median 
baseline convulsive seizure frequency of 20.7 and 17.5, respectively, compared to 27.3 for 
subjects randomized to placebo. Subjects randomized to ZX008 0.8 mg/kg/day (n= 40) achieved 
a 62.3% greater reduction in mean monthly convulsive seizure frequency (P<0.001) compared to 
those in the placebo group (n=40). In addition, subjects randomized to ZX008 0.2 mg/kg/day 
(n=39) had a 32.4% reduction compared to placebo (P = 0.021). Comparing the seizure reduction 
results for the 2 doses of ZX008 in Study 1 suggests a dose-response effect on seizures. The 
pattern of individual responses in the ZX008 0.2 mg/kg/day group supports the selection of 0.2 
mg/kg/day as the minimally effective dose. 
In Study 1504 Cohort 2, subjects randomized to ZX008 0.5 mg/kg/day had a median baseline 
convulsive seizure frequency 14.0 compared to 10.7 for subjects randomized to placebo. 
Subjects randomized to ZX008 0.5 mg/kg/day achieved a 54.0% reduction compared to placebo 
(P < 0.001).  
Controlling for multiplicity with a hierarchical testing procedure, all key secondary endpoints 
were met in both studies, for ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups (Study 1) and 
ZX008 0.5 mg/kg/day (Study 1504 Cohort 2). In Study 1, the proportion of subjects achieving a 
≥ 50% reduction from Baseline in CSF was 67.5% for the ZX008 0.8 mg/kg/day group, and 
38.5% for the 0.2 mg/kg/day group, with both groups being statistically significantly different 
from placebo (12.5%; P < 0.001 and P = 0.009, respectively). In Study 1504 Cohort 2, 53.5% of 
subjects randomized to ZX008 0.5 mg/kg/day compared to 4.5% of subjects randomized to 
placebo achieved a ≥ 50% reduction from Baseline in CSF (P <0.001).  
The proportion of subjects with a ≥ 50% reduction in monthly convulsive seizure frequency 
was also highly statistically significant for all ZX008 dose groups compared to placebo, 
with 38.5%, 53.5%, and 67.5% of subjects in the 0.2 mg/kg/day, 0.5 mg/kg/day, and 0.8 
mg/kg/day cohorts achieving ≥ 50% reduction as compared to 8.3% in placebo. 
Additionally, in Study 1, subjects randomized to ZX008 0.2 and 0.8 mg/kg/day had a 
median 15- and 25-day convulsive seizure-free interval, respectively, compared to 9.5 days 
for placebo (P = 0.035 and P < 0.001). In Study 1504 Cohort 2, subjects randomized to 
ZX008 0.5 mg/kg/day had a median 22-day convulsive seizure-free interval compared to 
13 days for placebo (P < 0.004). 
ZX008 was generally well tolerated in both Study 1 and Study 1504 Cohort 2. Though more 
subjects randomized to ZX008 than to placebo reported TEAEs during the double-blind studies, 
the percent of subjects with serious TEAEs was similar. Additionally, the adverse events 
observed in the program were either already known to be associated with fenfluramine, are 
common to many other antiepileptic drugs being prescribed to these patients, and/or are common 
to the age group and population studied. Specifically, the most common adverse events seen 
were diarrhea, fatigue, pyrexia, upper respiratory tract infection, blood glucose decreased, weight 
decreased, decreased appetite, lethargy and tremor. No valvular heart disease, pulmonary arterial 
hypertension or abnormal valve structure was observed in any subject at any time during the 
entire program.  
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In an integrated analysis of safety of the double-blind studies, 117 (95.9%) subjects in any 
ZX008 treatment group and 68 (81.0%) subjects in the combined placebo group reported at least 
1 TEAE. The most common (≥ 10%) TEAEs reported in subjects receiving any dose of ZX008 
were: blood glucose decreased, constipation, decreased appetite, diarrhea, echocardiogram 
abnormal, fall, fatigue, lethargy, nasopharyngitis, pyrexia, seizure, somnolence, status 
epilepticus, tremor, upper respiratory tract infection, vomiting, and weight decreased. All of the 
echocardiogram abnormal TEAEs were trace mitral or trace aortic valve regurgitation, which are 
normal physiological findings seen in healthy children (Webb 2015). A total of 15 (12.3%) 
subjects in any ZX008 treatment group and 11 (13.1%) subjects in the combined placebo group 
reported at least 1 serious TEAE. The most frequently reported (≥ 5%) serious AEs (SAEs) were 
status epilepticus and seizure. A total of 76 (62.3%) subjects in any ZX008 treatment group and 
22 (26.2%) subjects in the combined placebo group reported a TEAE determined by the 
Investigators to be related to the study drug, and 3 (2.5%) subjects in any ZX008 treatment group 
and 1 (1.2%) subject in the combined placebo group reported a serious TEAE determined to be 
related to the study drug. During the double-blind treatment periods, 7 (5.7%) subjects in any 
ZX008 treatment group and 1 (1.2%) subject in the combined placebo group reported a TEAE 
that lead to discontinuation from study participation. There were no deaths during the double-
blind treatment periods. 
Subjects in Study 1 and Study 1504 if eligible could participate in Study 1503, an open-label 
long-term, safety extension study that is currently ongoing. All subjects in Study 1503 started 
ZX008 at 0.2 mg/kg/day and could flexibly titrate to a maximum dose of 0.8 mg/kg/day, 
maximum 30 mg/day (if not receiving a concomitant STP regimen) or 0.5 mg/kg/day, maximum 
20 mg/day (if receiving concomitant STP regimen), based on effectiveness, safety and 
tolerability. Though primarily a safety study, subjects in Study 1503 maintained a daily seizure 
diary and continued to complete rating scales on overall effectiveness and quality of life 
measures. 
In a safety update of Study 1503 (cut-off date 14-Oct-2019, n=330 enrolled), the median percent 
change in CSF compared to baseline (core study) for the overall open-label Treatment period 
(Day 1 to End of Study [EOS]) was -66.8% (P <0.001). The reduction from baseline in monthly 
CSF observed at Month 1 of the open-label Treatment period was maintained through Month 24, 
the longest treatment duration included in the analysis. A total of 317/330 subjects reported at 
least 1 TEAE during the open-label Treatment period. The most common (≥ 10%) TEAEs 
reported during the open-label Study 1503 at the time of the cut-off date were blood glucose 
decreased, decreased appetite, diarrhea, ear infection, echocardiogram abnormal, influenza, 
nasopharyngitis, pyrexia, seizure, and upper respiratory tract infection. As in the double-blind 
studies, all of the echocardiogram abnormal TEAEs in Study 1503 were trace mitral or trace 
aortic valve regurgitation, which are not considered pathologic as stated in current guidelines on 
the use of ECHO for the assessment of valve function (Zoghbi 2017, Lancellotti 2010a, 
Lancellotti 2010b). At least 1 treatment-emergent SAE was reported by 80/330 (24.2%) subjects. 
The most frequently reported (≥ 5%) SAE was seizure, occurring in 24/330 (7.3%) of subjects. A 
total of 176/330 subjects (53.3%) experienced at least 1 TEAE that was considered to be related 
to study treatment and 8/330 subjects (2.4%) reported at least 1 SAE that was considered to be 
related to study treatment. A total of 11/330 (3.3%) subjects discontinued due to a TEAE. 
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Please reference the ZX008 IB for more detailed information on the safety and efficacy of 
ZX008. 
 
1.4 
PHARMACOKINETICS, PRECLINICAL DATA, AND CLINICAL 
PHARMACOLOGY 
1.4.1 
Pharmacokinetics 
The pharmacokinetics of fenfluramine, norfenfluramine and their respective isomers have been 
studied in mice, rats, dogs and humans. Fenfluramine and norfenfluramine were more slowly 
eliminated in humans than in other species. In vitro metabolism studies have shown 
considerable species differences in the metabolism of fenfluramine, with no single species 
having a profile similar to humans. No human-specific metabolites were detected and both rat 
and dog showed good coverage of the human fenfluramine metabolites. In humans, 
fenfluramine is metabolized primarily to norfenfluramine. Fenfluramine is partially 
metabolized by CYP1A2, CYP2B6, and CYP2D6, with additional metabolism by CYP2C9, 
CYP2C19, and CYP3A4. Norfenfluramine does not appear to be strong substrate of any 
CYP450 enzyme, but is metabolized by CYP1A2, CYP2B6, CYP2C19, and CYP2D6 in vitro. 
There is also some contribution of renal clearance to the elimination of dexfenfluramine 
(8%-16%) and nordexfenflurmaine (7%-8%) from the body. Because fenfluramine and its 
active metabolite norfenfluramine have multiple pathways of elimination, interference with a 
single pathway is unlikely to cause a significant change in fenfluramine’s clearance though the 
probability of an interaction increases if multiple elimination mechanisms are affected 
simultaneously. 
While in vitro studies showed that both fenfluramine and norfenfluramine cause weak 
inhibition of CYP2D6 and fenfluramine causes weak induction of CYP3A4 and CYP2B6, 
further analysis based on the FDA’s mechanistic static model shows that fenfluramine and its 
major metabolite norfenfluramine are unlikely to alter the pharmacokinetics of substrates of 
CYP450 enzymes in the range of ZX008 doses that will be administered in this study. 
In Study 1 and Study 1504 Cohort 2, pharmacokinetic parameters of fenfluramine and 
norfenfluramine for patients with Dravet syndrome were determined using a population 
pharmacokinetic (PopPK) model developed using PK data from both healthy volunteers and 
patients with Dravet syndrome. The Study 1 data are provided in Table 3. 
Table 3               Post Hoc Estimates of Fenfluramine and Norfenfluramine Steady-State 
Pharmacokinetic Parameters in Subjects with Dravet Syndrome in Study 1 (Geometric Mean 
[CV%]) 
Analyte: 
Fenfluramine 
Norfenfluramine 
ZX008 Dose 
0.2 mg/kg/day 
0.8 mg/kg/day 
0.2 mg/kg/day 
0.8 mg/kg/day 
Cmax (ng/mL) 
18.5 (29.1) 
68.0 (40.7) 
9.60 (52.8) 
37.8 (49.9) 
AUC0-24 (ng.hr/mL) 
375 (32.9) 
1390 (43.5) 
220 (55.5) 
872 (52.1) 
Tmax (hr) Median 
(Min, Max) 
3.00 (3.00 to 3.50) 
3.00 (3.00 to 3.50) 
4.00 (3.50 to 5.00) 
4.50 (3.50 to 5.00) 
Source: ICPD Report 00445-3, Table 5. 
Abbreviations: AUC0-24 = area under the plasma concentration-time curve from time 0 to 24 hours; BID = twice daily; 
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Cmax = peak plasma drug concentration; CV= coefficient of variation; Max = maximum; Min = minimum; Tmax = time of peak 
plasma drug concentration.  
Study 1504 Cohort 2 required STP as a concomitant medication. Although the dose of ZX008 in 
Study 1504 Cohort 2 was lower than the high dose in Study 1, fenfluramine AUC0-24 values 
were approximately 130% higher in Study 1504 Cohort 2, than the high dose in Study 1, and 
norfenfluramine AUC0-24 values were approximately 60% lower than in Study 1. However, the 
clinical results indicated that the efficacy and AE profile were similar between Study 1 and 
Study 1504, indicating that the dose adjustment studied for the concomitant use of the STP 
regimen met the intended clinical outcome. 
1.4.2 
Preclinical Data 
A 10-week GLP juvenile toxicology and toxicokinetic study in rats, which included 
fenfluramine doses of 3.5, 9 and 20 mg/kg/day by oral gavage for 10 weeks (post natal day 
(PND) 7 to 76). The data from the juvenile toxicology studies suggest that the effects of 
fenfluramine in juvenile animals (CNS-related clinical signs, effects on body weight and food 
consumption, and neurobehavioral deficits) are similar to effects previously reported in 
neonatal and adult rats (Morford, 2002; Williams, 2002). There was no evidence of CNS 
histopathology; importantly, there were also no histopathologic findings in aortic or mitral 
cardiac valves, and no adverse effects on any other tissues at necropsy.  
The NOAEL for the juvenile rats was determined to be 9 mg/kg/day. A NOAEL of 9 mg/kg/day 
corresponds to PND 76 AUC0-t of 3480 hr*ng/mL for males and 4680 hr*ng/mL for females for 
fenfluramine, and 4470 hr*ng/mL for males and 6210 hr*ng/mL for females for norfenfluramine. 
The AUC(0-t) at the NOAEL provided a safety factor (both sexes combined) of approximately 3-
fold or higher for fenfluramine and approximately 6-fold or higher for norfenfluramine. 
1.4.3 
Clinical Pharmacology 
Please see the ZX008 IB for details on clinical pharmacology. Below are the clinical 
pharmacology conclusions.  
x 
Coadministration of ZX008 with the STP regimen (STP with CLB and/or VPA) resulted 
in an increased fenfluramine and decreased norfenfluramine concentrations, and 
therefore a dose adjustment is used in the clinical trials. 
x 
STP is the predominant perpetrator of the interaction; while VPA and CLB do not have 
a significant independent impact on the PK of fenfluramine or norfenfluramine, whether 
administered with or without STP. 
x 
Coadministration of ZX008 with CBD at steady state resulted in increased fenfluramine 
concentrations but this increase was within the range of safe dosing used in Study 1504 
Cohort 2; thus, no dose adjustment is recommended when fenfluramine is 
coadministered with CBD.  
x 
In the population PK analysis, intrinsic patient factors (age, gender, race/ethnicity, and 
BMI) demonstrated no substantial impact on the clearance or exposure to fenfluramine 
or norfenfluramine when dosed on a mg/kg basis to a maximum of 30 mg/day.  
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x 
ZX008 had no effect on QTc intervals at either the therapeutic or supratherapeutic dose, 
and no relationship was observed between fenfluramine or norfenfluramine exposure 
and QTcF. 
x 
ZX008 exhibited approximately dose proportional PK over a 4-fold range of doses (15 
to 120 mg/day). 
x 
CYP450 metabolizer genotype for CYP1A2, CYP2B6, CYP2C19, CYP2D6, or 
CYP3A4 had no impact on the PK of fenfluramine or norfenfluramine. 
Further details on the preclinical data of ZX008 are available in the Investigator’s Brochure 
(ZX008 IB). The current version is available in the Investigator Study File. 
1.5 
BACKGROUND INFORMATION ON REFERENCE PRODUCT 
Not applicable. 
1.6 
RATIONALE FOR CURRENT STUDY 
There have been several published reports of fenfluramine’s successful treatment of 
refractory childhood epilepsy in the 1980s (Aicardi 1985; Aicardi 1988) and its successful 
treatment of 11 refractory pediatric epilepsy patients in Belgium (Boel 1996).   
A number of small studies and case series have been published describing the use of 
fenfluramine in epilepsy.  In 1996, a Belgian group reported on the use of fenfluramine in 11 
children (ages 18 months to 15.5 years old) with refractory or self-induced epilepsy (Boel 1996).  
Patients were treated with fenfluramine at 0.5 – 1 mg/kg/day for 3 to 8.5 years (average duration 
5 years 7 months). Seven children (64%) became seizure-free and the remaining 4 patients 
experienced ≥75% reduction in seizure frequency. 
In 2002, Casaer and Boel published a brief update of their study with fenfluramine. The study 
population was expanded to 22 patients with intractable or self-induced seizures, including the 
previously reported 11 patients (Casaer 2002). The duration of treatment was between 1 and 12 
years. In this study, of the 22 patients treated, 6 (27%) became seizure-free, 10 (45%) patients 
had a 90% reduction in seizure frequency and 6 (27%) patients were non-responders. 
Fenfluramine was also shown to be effective in multiple seizures types in Dravet syndrome (DS), 
another very drug resistant pediatric epileptic encephalopathy syndrome (Ceulemans 2012; 
Schoonjans 2015; Ceulemans 2016; Schoonjans 2017). Zogenix is currently evaluating ZX008 in 
Dravet Syndrome in two Phase 3 double-blind, randomized, placebo-controlled studies and one 
open-label extension (clinicaltrials.gov identifiers: NCT02826863, NCT02682927, and 
NCT02823145). 
Currently, a small cohort of refractory patients with Lennox-Gastaut syndrome in Belgium are 
being treated in an ongoing Phase 2 open-label, pilot, dose-finding trial of fenfluramine as an 
add-on therapy to conventional therapy (Lagae, 2017; Study S58545; clinicaltrials.gov identifier: 
NCT02655198).  
The study includes a 20-week Core period, in which subjects are titrated to ≥50% response and 
then held at that dose until the end of the 20-week period, and an Extension period, in which 
subjects are titrated to maximum efficacy and tolerability.  Subjects aged 3 to 18 years, fulfilling 
the diagnostic criteria for LGS as described by the ILAE in 1989, who have failed at least two 
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AEDs (including VNS), and have had at least 4 documented convulsive seizures (General Tonic 
Clonic, Tonic Seizures, Atonic Seizure, and Focal Seizure with a motor component) and on at 
least two AEDs at stable doses in the prior 4 weeks are eligible for this study.  After the initial 4-
week baseline period to record seizure type and frequency, treatment with fenfluramine, 0.2 
mg/kg/day, is initiated. An efficacy response (“responder”) is defined as a ≥50% reduction in 
major motor seizure frequency (GTC+TS+AS+FS).  At the 8-week visit (following 4 weeks of 
ZX008 treatment), subjects who were non-responders and have no intolerable side effects 
receive an increased dose of 0.4 mg/kg/day.  At the 12-week visit, subjects who were non-
responders and have no intolerable side effects receive an increased dose of 0.8 mg/kg/day.  At 
any visit, subjects who achieve a ≥50% reduction in major motor seizure frequency remain at 
their currently administered dose.  As this is a pilot dose-finding study, it is important to note 
that per protocol, dose escalation stops when a subject’s convulsive seizure frequency is reduced 
by ≥50% of baseline.  It is possible that a higher dose could result in even greater seizure 
reduction.  The maximum allowed dose is 30 mg/day.  
Results have been presented for the 13 LGS subjects who completed the Core study: (Lagae, 
2017). Overall, subjects had received a median of 8 years of antiepileptic treatment and were 
failing a median of 5 AEDs prior to entry. Upon study entry, patients were taking a median of 4 
concurrent anti-epileptic therapies. All subjects received ZX008 treatment for at least 20 weeks 
with the exception of 3 subjects who discontinued due to lack of efficacy; of which 2 also 
discontinued due to side effects. For subjects who completed the 20-week Core period, the 
median seizure frequency was reduced from a mean of 60 major motor seizures per month in the 
pre-ZX008 baseline period to a mean of 22 major motor seizures per month at the end of the 
Core ZX008 treatment period. At week 20, 8 of the 13 enrolled patients (62%) had at least a 50% 
reduction in major motor seizures with ZX008 treatment. Nine of the 13 patients completed the 
Core period and entered the Extension period. At the time of each of subjects’ most recent visit, 
6 of 9 patients (67%) had at least a 50% reduction in major motor seizures and 2 of 9 (22%) had 
a 75% or greater seizure reduction. In the Extension period, there was a 58% median reduction in 
seizure frequency as compared to baseline. The most common treatment emergent adverse 
events to date include decreased appetite (n=4) and decreased alertness/fatigue (n=3). Sleep 
problems, tiredness, and sleepiness were each reported in one subject. 
No clinical signs of valvulopathy or pulmonary hypertension have been observed in any patients 
in the Belgian cohort  (ZX008 IB ). 
In addition, numerous publications discuss the use of fenfluramine in over 500 children with 
neurobehavioral conditions for the treatment of mostly autism and ADHD, without any reports 
of any cardiovascular adverse events (summarized in ZX008 IB ). 
Prior to being withdrawn from the market, fenfluramine was marketed at doses of 20 mg and 
40 mg three times daily for the management of obesity in adults. The doses tested thus far in DS 
range from 0.12 to 0.9 mg/kg/day in subjects over 1 year of age to adults in the Belgian cohort, 
and 0.2 and 0.8 mg/kg/day in the Zogenix Phase 3 trials. Doses tested in pediatric studies 
evaluating autism and ADHD ranged from 0.65 mg/kg/day to 3.6 mg/kg/day, but a commonly 
used dose was 1.5 mg/kg/day. Occasionally, fixed doses of 30 to 80 mg were used.  The PK 
exposure associated with the doses in the LGS study of 0.2 mg/kg/day and 0.8 mg/kg/day, 
administered orally (in equally divided doses BID) is expected to be lower than that obtained at 
the doses used in the past for the treatment of obesity in adults and of neurobehavioral conditions 
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in children and adolescents (ZX008 IB ). The doses used in this study are based on the data from 
the DS and LGS patients being successfully treated in Belgium discussed above. 
In summary, fenfluramine has been shown to be effective in reducing the frequency of seizures 
in patients with Dravet syndrome and LGS, and its activity persists over a long duration of time 
(Ceulemans 2012, Ceulemans 2016, Schoonjans 2017, Lagae 2018). Though the mechanism 
remains to be fully elucidated, data from in vitro receptor binding, functional assays, and 
zebrafish models suggest that fenfluramine reduces seizures by acting as an agonist at the 5-
HT1D and the 5-HT2C receptors and by acting on the sigma-1 receptor. Fenfluramine may 
also exert anti-seizure activity through the 5-HT1A and the 5-HT2A receptors (ZX008 IB 
2018).  
The lack of consistent efficacy and individual tolerability and safety concerns with current 
treatments available for LGS have resulted in the continued significant unmet need for a new 
treatment with a novel mechanism of action for children and adults with LGS. 
The rationale for conducting the Part 2 open-label extension period is primarily to evaluate the 
long-term safety of ZX008 in subjects with LGS. This protocol also provides the opportunity 
for continued treatment for subjects responding to treatment from Part 1 and an opportunity for 
initial treatment with ZX008 for subjects randomized to placebo in Part 1. The study will also 
allow access to ZX008 for the treatment of LGS for eligible Japanese subjects until 
commercial product is available, as it is not approved in Japan. The period from the approval 
of this drug to its launch is positioned as a post-marketing study.  
1.7 
RISK-BENEFIT ASSESSMENT 
As described above, fenfluramine has been used successfully for up to 30 years in Belgium 
in refractory pediatric epilepsy patients, including those with LGS and DS (Boel 1996, 
Ceulemans 2012, Schoonjans 2015, Schoonjans 2017). The doses tested thus far in DS 
range from 0.12 to 0.9 mg/kg/day in subjects over 1 year of age to adults. No patients have 
developed valvulopathy or pulmonary hypertension.  
The clinical benefit of ZX008 in the Lennox-Gastaut syndrome has been evaluated in 
an open label study (Lagae 2017, 2018) as mentioned in Section 1.6.  In addition, 2 
positive, adequate and well-controlled, multi-national, randomized, double-blind, 
placebo-controlled trials of ZX008 in subjects with Dravet syndrome, Study 1 and 
Study 1504 Cohort 2, demonstrated a statistically significant and clinically 
meaningful reduction in monthly convulsive seizure frequency and was generally 
well tolerated.  There was no clinical or echocardiographic evidence of cardiac 
valvulopathy or pulmonary hypertension in any study and no patient discontinued 
participation or required a change in monitoring in the study due to cardiac factors. 
The PK exposure associated with the doses of ZX008 in the Dravet syndrome studies 
of 0.2 mg/kg/day to 0.8 mg/kg/day administered orally [in equally divided doses 
twice per day (BID)] is lower than that obtained at the doses used in the past for the 
treatment of obesity in adults and of neurobehavioral conditions in children and 
adolescents (ZX008 IB). The doses used in this study are based on the data from the 
patients being successfully treated in Belgium discussed above, Study 1, and Study 
1504 Cohort 2 data. 
The pharmacologic and toxicological profile for the active pharmaceutical ingredient, 
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fenfluramine, following oral administration is well established (see ZX008 IB ). 
The safety monitoring practices employed by this protocol are adequate to protect the subjects’ 
safety and should detect expected and unexpected treatment-emergent adverse events, and are 
the same as those currently being utilized for the global Phase 3 DS program. 
The approximate volume of blood (194.0 mL) planned for collection from each subject over the 
course of the entire study (Screening to End of Study Part 2, but not including repeat or 
additional tests ordered by the investigator) presents no undue risk to the subjects. 
The ZX008 0.2 mg/kg/day and 0.8 mg/kg/day doses are believed to be likely therapeutic doses, 
which could provide sufficient anti-epileptic effect for a sustained period of time during the 
study. 
The available information suggests that the present clinical study has an acceptable risk-benefit 
ratio. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
PART 1 
2.1.1 
PRIMARY OBJECTIVE 
The primary objective of Part 1 is the primary objective of the entire study. 
The primary objective of Part 1 is: 
x To evaluate the effect of ZX008 0.8 mg/kg/day versus placebo as adjunctive therapy for 
the treatment of uncontrolled seizures in children and adults with Lennox-Gastaut 
syndrome (LGS) based on the change in frequency of seizures that result in drops 
between baseline and the combined Titration and Maintenance Periods (T+M). 
2.1.2 
KEY SECONDARY OBJECTIVES 
The key secondary objectives of Part 1 are: 
x To evaluate the effect of ZX008 0.2 mg/kg/day versus placebo as adjunctive therapy for 
the treatment of uncontrolled seizures in children and adults with LGS based on the 
change in frequency of seizures that result in drops between baseline and T+M. 
– To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus 
placebo on the proportion of subjects who achieve a ≥50% reduction from 
baseline in the frequency of seizures that result in drops. 
– To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus 
placebo on the Clinical Global Impression – Improvement rating, as assessed by 
the principal investigator. 
See Statistical Methods (Section 10.1.5.1) for hierarchical testing procedure. 
2.1.3 
ADDITIONAL SECONDARY OBJECTIVES 
Additional secondary objectives of the study are: 
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x To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo 
on the following endpoints: 
– Change in the frequency of all countable motor seizures between baseline and T+M 
(countable seizures include: generalized tonic-clonic seizures [GTC], tonic seizures 
[TS], clonic seizures [CS], atonic seizures [AS], tonic/atonic seizures [TA], 
clearly recognizable focal seizures [FS], and myoclonic seizures [MS] that result 
in a drop). 
– Change in the frequency of all countable seizures (ie, motor and non-motor) 
between baseline and T+M 
– Change in frequency of seizures that result in drops between baseline and the 
Maintenance Period (M) 
– Change in the frequency of countable motor seizures that do not result in drops 
between baseline and M 
– The proportion of subjects who have a worsening or no change (i.e. ≤ 0% 
reduction), >0%,  ≥25%, ≥50%, ≥75%, 100% reduction, and “near seizures 
freedom” (ie 0 or 1 seizures) between baseline and T+M, and baseline and M, in 
all countable motor seizures (GTC, TS, AS, TA, FS, MS with a drop); in 
countable motor seizures that do not result in drops; in all countable seizures; in 
all countable seizures that do not result in drops; and in all seizures that result in 
drops  
–  
– Longest interval between seizures that result in drops 
– Number of seizure-free days, defined as 1) days with no countable seizures and 2) 
days with no seizures that result in drops 
x To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo 
on the Clinical Global Impression – Improvement rating, as assessed by the 
parent/caregiver. 
2.1.4 
SAFETY OBJECTIVE 
The safety objectives of Part 1 are: 
x To evaluate the safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day versus placebo 
with regard to adverse events (AEs), laboratory parameters, physical examination, 
neurological examination, vital signs (blood pressure, heart rate, temperature, and 
respiratory rate), electrocardiograms (ECG), echocardiograms (ECHO), body weight, and 
BMI 
x To evaluate the change from baseline in cognition using age-appropriate versions of the 
BRIEF 
2.1.5 
PHARMACOKINETIC OBJECTIVE 
The pharmacokinetic (PK) objective of the study is: 
x To evaluate the PK of ZX008 0.2 and 0.8 mg/kg/day at steady state in subjects < 18 
years and ≥18 years with LGS using a non-compartmental analysis; and obtain 
exposure data that will be used in population pharmacokinetic (PopPK) analysis, the 
results of which will be reported separately. 
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2.1.6 
EXPLORATORY OBJECTIVES 
The exploratory objectives of the study are: 
x To compare the ZX008 0.2 and 0.8 mg/kg/day doses on primary, secondary, and safety 
endpoints. 
x To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo 
on the following endpoints: 
– The frequency of rescue medication usage 
– The incidence of medical services to treat seizures 
– The incidence of status epilepticus 
– The change from baseline in behavior using the Vineland Adaptive Behavior 
Scale (VABS)(Cohort A) 
– The change from baseline in QoL using the QOLCE 
– The change from baseline in caregiver burden using the Zarit Caregiver Burden 
Inventory  
– The change from baseline in affective symptoms of the parent/caregiver using the 
Hospital Anxiety and Depression Scale (HADS) 
2.2 
PART 2 
2.2.1 
PRIMARY OBJECTIVE 
The primary objective of Part 2 is to assess the long-term safety and tolerability of ZX008 in 
children and adults with LGS with regard to adverse events (AEs), laboratory parameters, 
physical examination, neurological examination,  cognition (BRIEF), vital signs (blood pressure, 
heart rate, temperature, and respiratory rate), ECG, ECHO, body weight, and BMI. 
2.2.2 
SECONDARY OBJECTIVES 
The secondary objectives of Part 2 are: 
x To assess the effect of ZX008 relative to the baseline on the following effectiveness 
measures: 
- The change in the frequency of seizures that result in drops 
- The change in the frequency of all countable motor seizures (GTC, TS, CS, AS, TA, FS, 
MS with a drop) 
- The change in the frequency of all countable seizures 
- The proportion of subjects who have a worsening or no change (i.e. ≤ 0% reduction), >0 
%,  ≥25%, ≥50%, ≥75%, 100% reduction, and “near seizure freedom (ie, 0 or 1 seizures) 
in frequency of all countable seizures that result in drops, countable motor seizures that 
do not result in drops, all countable motor seizures, all countable seizures, and all 
countable seizures that do not result in drops 
- Number of seizure-free days, defined as 1) days with no countable seizures and 2) days 
with no seizures that result in drops 
- Longest interval between seizures that result in drops 
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x  To evaluate the effect of ZX008 on the following endpoints: 
- Clinical Global Impression – Improvement rating, as assessed by the principal 
investigator 
- Clinical Global Impression – Improvement rating, as assessed by the parent/caregiver 
2.2.3 
EXPLORATORY OBJECTIVES 
The exploratory objectives of Part 2 are: 
x To estimate the incidence of the following on subjects receiving ZX008: 
- The incidence medical services use to treat seizures 
- The incidence of status epilepticus 
- The use of rescue medication 
x To assess the effect of ZX008 on the following measures: 
- The change from baseline in affective symptoms of the parent/caregiver using the HADS 
- The change from baseline in QoL using the QOLCE 
- The change from baseline in caregiver burden using the Zarit Caregiver Burden 
Inventory 
2.3 
STUDY ENDPOINTS 
2.3.1 
Efficacy Endpoints 
The efficacy endpoints for Part 1 of the study are: 
Primary Endpoint: 
x Percent change from baseline in the frequency of seizures that result in drops in the 
combined Titration and Maintenance Periods (T+M) in the ZX008 0.8 mg/kg/day group 
compared to the placebo group. 
 
Key Secondary Endpoints: 
x Change from baseline in the frequency of seizures that result in drops in T+M in the 
ZX008 0.2 mg/kg/day group compared to the placebo group 
x Proportion of subjects who achieve a ≥50% reduction from baseline in the frequency of 
seizures that result in drops comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day 
groups independently versus placebo 
x 
Proportion of subjects who achieve improvement (minimally, much, or very much 
improved) in the Clinical Global Impression – Improvement as assessed by Principal 
Investigator comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups 
independently versus placebo. 
x Number, frequency, and duration of countable seizures that result in drops 
x Number, frequency, and duration of countable seizures that do not result in drops 
x Number, frequency, and duration of all countable seizures by type  
x Proportion of subjects who achieve a ≥25%, ≥50%, ≥75%, or 100% reduction from 
baseline in seizure frequency 
x Number of seizure-free days 
x Clinical Global Impression – Improvement as assessed by parent/caregiver 
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The efficacy endpoints for Part 2 of the study are: 
x The change from baseline in the frequency of seizures that result in drops.  
x The change from baseline in the frequency of all countable motor seizures (GTC, TS, CS, 
AS, TA, FS, MS with a drop) 
x The change from baseline in the frequency of all countable seizures 
x The proportion of subjects who achieve a worsening from baseline (i.e. <= 0% 
reduction), or >0%,   ≥ 25%, ≥ 50%, ≥ 75%, and 100% reduction from baseline in 
frequency of all countable seizures that result in drops, countable motor seizures that do 
not result in drops, all countable motor seizures, all countable seizures, and all countable 
seizures that do not result in drops 
x Number of seizure-free days, defined as 1) days with no countable seizures and 2) days 
with no seizures that result in drops 
x Number of instances of rescue medication use and number of doses of rescue medication 
x Longest interval between seizures that result in drops 
x Clinical Global Impression – Improvement rating, as assessed by the Principal 
Investigator. 
x Clinical Global Impression – Improvement rating, as assessed by the parent/caregiver. 
2.3.2 
Safety Endpoints 
The safety endpoints for Part1 and Part 2 of the study are: 
x AEs 
x Laboratory safety (hematology, chemistry, urinalysis) 
x Vital signs (blood pressure, heart rate, temperature, and respiratory rate) 
x Body weight and BMI 
x Physical examination 
x Neurological examination 
x BRIEF to measure changes in cognition of the subject 
x Columbia Suicidality Severity Rating Scale (C-SSRS) 
x 12-lead ECGs 
x Doppler ECHOs 
2.3.3 
Exploratory Endpoints 
The exploratory endpoints for Part 1 and Part 2 of the study are: 
x The incidence of medical services used to treat seizures 
x The incidence of status epilepticus 
x Incidence of rescue medication usage 
x Number of days rescue medication used 
x The change from baseline in behavior using the Vineland Adaptive Behavior Scale 
(VABS) (Part 1 Cohort A only) 
x The change from baseline in quality of life using the QOLCE 
x The change from baseline in caregiver burden using the Zarit Caregiver Burden Inventory 
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x The change from baseline in affective symptoms of parent/caregiver using the HADS 
scale 
3. 
INVESTIGATIONAL PLAN 
3.1 
OVERALL STUDY DESIGN AND PLAN 
This is an international multicenter study being conducted in two parts.  Up to approximately 
80 study sites in North America, Europe, Japan, and Australia are initially planned to 
participate.  Part 1 is a double-blind, parallel-group, placebo-controlled, study to assess the 
efficacy and safety of two doses of ZX008 when used as adjunctive therapy for seizures in 
children and adult subjects with LGS. Part 1 will include 2 cohorts: Cohort A will include 
randomized subjects from North America, Europe, and Australia; Cohort B will include 
randomized subjects from Japan only. The primary study endpoint is assessed from Part 1 
Cohort A data. The primary analysis will be conducted when the last subject in Cohort A has 
completed Part 1.  Part 2 will be an open-label, flexible-dose extension for subjects completing 
Part 1 of the study. 
Part 1 will consist of a 4-week baseline, 2-week titration, 12-week maintenance, and 2-week 
taper or transition period.  The 4-week Baseline Period will consist of the establishment of 
initial eligibility during a screening visit to include an assessment of cardiac parameters (ECG 
and ECHO), followed by an observation period where subjects will be assessed for baseline 
seizure frequency based on recordings of daily seizure activity entered into a diary.  Upon 
completion of the Baseline Period, subjects who qualify for the study will be randomized 
(1:1:1) in a double-blind manner to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 0.8 
mg/kg/day; maximum dose: 30 mg/day) or placebo.  Randomization will be stratified by 
weight (<37.5 kilograms [kg], ≥37.5 kg) to ensure balance across treatment arms, and at least 
25% of subjects will be in each weight group. All subjects will be titrated to their blinded 
randomized dose over a 2-week Titration Period. Following titration, subjects will continue 
treatment at their randomly assigned dose over a 12-week Maintenance Period. Total treatment 
time from the beginning of the Titration Period through the end of the Maintenance Period is 
14 weeks.  Subjects will have ECG and ECHO assessments at weeks 6 and 14 during the 
Maintenance Period.  At the end of the Maintenance Period (or early discontinuation), all 
subjects will undergo a 2-week taper or transition period (Post-Dosing Follow-Up) depending 
on whether they exit the study or are enrolled in Part 2, the long-term open-label extension, 
respectively. A follow-up ECG and ECHO will be performed after study drug discontinuation 
for early termination, or for those subjects who complete the study but do not enter the open-
label extension (Part 2), as outlined in Table 9. 
Part 2 is an open-label, long-term safety study of ZX008 for subjects who have successfully 
completed 14 weeks of treatment (titration + maintenance) in Part 1, are candidates for 
continuous treatment for an extended period of time, have met the Selection Criteria for Part 1 
(except for criteria related to seizure frequency), and signed informed consent/assent forms 
prior to the start of Part 2. Subjects who have not completed the entire 14 weeks of treatment in 
Part 1 may be eligible to participate in Part 2 on a case-by-case basis and only following 
sponsor approval. Other requirements for participation in Part 2 are described in Section 4.3. 
Part 2 will consist of a 12-month Open-Label Extension (OLE) Treatment Period and a 2-week 
Post-Dosing Period. Thus, subjects who complete 12 months of OLE in Part 2 will have been 
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treated with ZX008 for at least 70 weeks (including their participation in both Part 1 and Part 
2). If marketing approval is not yet received after the end of the OLE Treatment Period, 
treatment may be extended on an annual basis in order to provide continuity of treatment for 
subjects who are enrolled in Part 2 of the study until ZX008 is approved in the subject’s 
country of residence and listed on a patient’s health plan formulary. Up to 5 annual extensions 
can be applied, for a total treatment time of 72 months in the OLE. Continuation will be based 
on review of safety/tolerability and effectiveness, and be offered for subjects who continue to 
meet eligibility requirements, comply with investigator’s instructions, and for whom the 
investigator judges benefit outweighs risk. 
During Part 2 all subjects will be treated initially with 0.2 mg/kg/day for 1 month to assess 
effectiveness of this dose in all study subjects and determine the minimally effective dose. 
After 1 month at a dose of 0.2 mg/kg/day, the investigator may adjust the dose for each subject 
based on effectiveness and tolerability. Dose changes should be made in maximum increments 
of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day but not to exceed total dose of 30 
mg/day.  During the 12-month OLE subjects will have ECG and ECHO assessments at months 
1, 3, 6, and 9, and at the end of study visit. In the event the OLE is extended, subjects will 
continue to have ECG (if clinically indicated) and ECHO assessments every 6 months until the 
end of their participation in the study. See Section 5.5 for instructions on dosing and dose 
adjustments. 
A follow-up ECG and ECHO will be performed after study drug discontinuation for early 
termination and for those subjects who complete Part 2, as outlined in Table 11. Subjects who 
transition to commercially available ZX008 will not return for these follow-ups, but must have 
an ECHO within 3 to 6 months of the transition date and will have follow-up ECHOs within 
required timeframes while on commercial drug supply. 
In both Part 1 and the first 12 months of Part 2, parents/caregivers will use a diary every day to 
record the number of seizures, type of seizures, time and duration of seizures, whether the 
seizure resulted in a drop, dosing of study drug, and use of rescue medication.     
A schedule of assessments for Part 1 is provided in Table 1 and for Part 2 in Table 2. 
3.2 
NUMBER OF SUBJECTS 
Approximately 340 subjects will be screened to obtain 250 subjects randomized into Part 1 
Cohort A (75 subjects per treatment arm) , and at least 30 (and up to 50) subjects will be 
randomized into Part 1 Cohort B.  The number of screened subjects may exceed 340 
depending on the screen fail rate. Each clinical site will not randomize more than a maximum 
of 15 subjects without prior consent from the sponsor. 
3.3 
STUDY DURATION 
The duration of participation in the study for an individual subject is expected to be up to 
20 weeks in Part 1 to include: 
x  Baseline Period – 4 weeks 
x T+M Period - 14 weeks 
x Taper/Transition Period – 2 weeks after  
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Subjects who do not enroll in the open-label extension (Part 2) will undergo a taper off of study 
medication;  eligible subjects who enroll in the open-label extension will undergo a 2-week 
transition period  
Subjects who enroll in Part 2 will have the option to receive ZX008 for up to 72months 
(plus a 2-week taper at the end of the open-label extension), or until ZX008 is approved 
in the subject’s country of residence and listed on a patient’s health plan formulary, 
whichever occurs first 
Follow-up cardiovascular safety assessments, including ECG and ECHO, will be 
performed following the last dose of study medication for all subjects that do not 
transition to commercial drug, regardless of whether they complete the entire study or 
terminate early. These follow-ups will occur 3 months following the last dose of study 
medication for any subject taking the medication for 2-13 weeks, and 3 and 6 months 
following the last dose for any subject taking the medication for >13 weeks. If there are 
any findings at a post-dose follow-up, another follow-up will be repeated every 3 months 
until resolved or stabilized. Subjects who transition to commercially available ZX008 
will not return for a follow-up after EOS/ET or a cardiac follow up after last dose but 
must have had an ECHO within 3 to 6 months before the transition date and will have 
follow-up ECHOs within required timeframe while on commercial drug supply. 
The study schema is shown in Figure 1. 
 
Figure 1; Study Schema 
 
3.4 
NUMBER OF STUDY CENTERS 
The study expects to use up to approximately 80 research centers from North America, 
Europe, Japan, or Australia. Additional study centers within or outside of these geographic 
areas may be added if enrollment cannot be completed in a timely manner.  Sites also may be 
closed if they fail to enroll. 
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3.5 
RATIONALE FOR STUDY DESIGN AND CHOICE OF 
TREATMENT GROUPS 
It is recognized that performing clinical studies in young children or in subjects with reduced 
cognitive capacity presents particular practical and ethical issues. However, given the 
seriousness of LGS, and the possible consequences of current inadequate treatments, the 
inclusion of children with LGS and adults with LGS who may have intellectual disability in 
this study is considered justified. Eligible subjects include males and females between 2 and 
35 years of age inclusive. Because an accurate diagnosis of LGS is difficult in children 
younger than 2 years, and seizures that result in drops may not be accurately counted in this 
age group, children younger than 2 years are not included.  Although seizures persist into 
adulthood, the primary seizure types and the treatment setting may differ, thus adults older 
than 35 years have not been included in this protocol.  
Stratifying the randomization by weight is considered appropriate since the daily dosage of 
ZX008 increases with weight up to a maximum of 30 mg/day. The two strata in the study will 
be subjects who weigh less than 37.5 kg and subjects who weigh 37.5 kg or more.  The study 
design has incorporated a titration period to enable subjects randomized to the high dose group 
adequate time to acclimate to this dose. Following the Titration Period, subjects will enter a 
12-week Maintenance Period where they will continue on their randomized dose for the 
remainder of the study. The 12-week duration of the Maintenance Period is in keeping with the 
current standard study duration for evaluating the efficacy of chronic medications. Given the 
individual variability in seizure frequency and seizure type in this patient population, the 
primary endpoint, which seeks to compare an appropriate baseline of motor seizure that can 
result in a drop frequency to the motor seizure that can result in a drop frequency following 
treatment, is an appropriate primary endpoint for efficacy in this population. 
Subjects will receive investigational medicinal product (IMP; ZX008 or placebo) in addition to 
their existing antiepileptic medications at their stable doses throughout the entire Part 1. Thus, 
subjects receiving placebo will not be denied active therapy; they will continue to receive their 
existing medications at the exact same dosages. As the principal study measurement (seizures 
that result in drops) might be considered subjective, a double-blind study design will prevent 
subjective bias. Upon completion of Part 1, eligible subjects will be able to receive ZX008 in 
Part 2, the open-label extension, for up to 5 additional years of treatment. 
 
3.6 
RATIONALE FOR STUDY DESIGN AND CHOICE OF 
TREATMENT GROUPS 
Initial enrollment in Study 1601 was planned at up to 115 study sites in North America, 
Europe, Australia, and Japan. During the first 14 months of enrollment (ie, between November 
2017 and January 2019), 50% of patients were randomized. During the next 5 months of 
enrollment (ie, between February 2019 and June 2019), enrollment proceeded faster than 
projected, with the remaining 50% of patients being randomized across a total of 70 active 
sites.   
The speed of enrollment signifies the strong need for new medications for patients with LGS. 
Amending the Study 1601 protocol to split enrollment into 2 cohorts -- Cohort A (randomized 
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subjects from North America, Europe, and Australia) and Cohort B (randomized subjects from 
Japan only) -- and pre-specifying the primary analysis endpoint in the protocol and statistical 
analysis plan to include only subjects from Cohort A allows analyses to be conducted on a 
suitable number of subjects that are in accordance with the sample size estimations.  Moreover, 
this approach allows evaluation of ZX008 in a Japanese population as part of a global clinical 
study while adhering to the requirements of the sample size estimation.  The number of 
subjects in Japan will be increased from 15 to at least 30 (with the possibility to include up to 
50) in order to provide a suitable sample for comparison, acknowledging that the speed of 
enrollment in Japan could mimic that of the other countries. 
Japan has a large patient population with a high unmet medical need. Cultural differences 
between Japanese patients and Western patients are well documented in the literature.  
Moreover, due to operational challenges in clinical trial conduct, patients in Japan are typically 
not included in global studies, and when they are, it is often in very small numbers 
proportionally. Analyzing Cohorts A and B independently enables a properly powered primary 
analysis on Cohort A while providing the opportunity to increase enrollment in Japan in Cohort 
B, thus allowing for a more substantial comparison of safety and efficacy between Japanese 
patients and non-Japanese patients. 
3.7 
PREMATURE TERMINATION OF STUDY 
The sponsor can terminate the study prematurely at any time for medical, ethical, or 
administrative reasons at individual or at all study sites. The investigator will be notified in 
writing, outlining the reasons for the termination. Instructions will be provided if assessments 
beyond those described in the study protocol need to be conducted. 
The Independent Data Safety Monitoring Committee (IDSMC) may request that the study be 
terminated after review of the safety information at any time during the study.  
If the study is terminated prematurely for any reason, the investigator should promptly inform 
the subjects participating at his or her study site and should ensure that appropriate follow-up 
care is available and that End-of-Study procedures are conducted, as described in 
Section 6.1.2.9 and Section 6.2.4. 
All study materials including IMP (unless prior approval for onsite destruction is granted by 
sponsor) and completed, partially completed, and blank documentation, except documents 
needed for archiving requirements, will be returned to the sponsor. The study monitor will 
ensure that any outstanding data clarification issues and queries are resolved, and that all study 
records at the study site are complete. 
In accordance with applicable regulatory requirements, the sponsor will promptly inform the 
competent regulatory authorities of the termination and its reason(s), and the investigator or 
sponsor will promptly inform the Independent Ethics Committee (IEC)/IRB. 
3.8 
STUDY MONITORING PROCEDURES 
3.8.1 
Independent Data Safety Monitoring Committee 
The IDSMC is an independent advisory body that monitors participant safety, data quality and 
progress of the clinical trial. The IDSMC charter will outline the roles and responsibilities of 
the committee and guide its operations and frequency of meetings. The IDSMC will consist of 
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individuals external to the sponsor who have relevant clinical trial expertise and experience in 
safety assessment. 
At regularly defined intervals, the IDSMC will convene to review and monitor study progress, 
AEs and SAEs, other measures of safety such as ECGs or ECHOs, and efficacy data as dictated 
by the charter. 
The IDMSC will: 
x Be responsible for providing recommendations to the sponsor surrounding study conduct 
matters that affect safety. The IDMSC will review the data for the development of heart 
valve disease and pulmonary hypertension as they occur on a case-by-case basis and at 
regular meetings. 
x Review safety data at ad hoc time points and identify if significant safety concerns arise 
during the study. 
x Review data that may affect subject continuation. 
x Make recommendations regarding the continuation, suspension, or termination of the 
study. 
 
3.8.2 
International Cardiac Advisory Board (ICAB) 
The ICAB is an advisory body to the sponsor that assists in monitoring cardiac safety of the 
ZX008 clinical trials and provides advice to the IDMSC. The ICAB consists of individuals 
external to the sponsor who have relevant experience in cardiology, pediatric cardiology, and 
echocardiography. The ICAB will advise the sponsor and the IDSMC on the cardiac safety 
monitoring plan, including alert criteria and decision pathway for subject management relative 
to cardiac safety in the clinical studies of ZX008 when requested.  ICAB members also 
provide secondary review or adjudication of ECHOs and ECGs, as well as risk assessment, as 
needed. 
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4. 
SELECTION OF STUDY POPULATION 
The study population will be selected on the basis of the inclusion and exclusion criteria 
described in the sections below. Before evaluating these criteria and deciding on the eligibility 
of subjects to participate in the study, it is important that the investigator is familiar with the 
safety profile of ZX008 by referring to the Investigator’s Brochure, as supplied by the 
sponsor.  Subjects receiving concomitant STP are not prohibited from study participation. For 
these subjects the maximum dose will be 0.5 mg/kg/day, with a maximum 20 mg/day, or 
equivalent placebo volume. For analyses purposes these subjects will be grouped with 
subjects randomized to 0.8 mg/kg/day.  The dose of 0.5 mg/kg/day (maximum 20 mg/day) 
was selected for concomitant administration with STP based on the predicted effects of 
concomitant STP on ZX008 and the dose that best matches the exposure for the reference 
dose (ie, 0.8 mg/kg/day with a maximum of 30 mg/day, in the absence of STP). Both the 
mg/kg and maximum dose were modified to ensure the best match of exposure in young 
children (0.5 mg/kg/day) as well as to ensure that individual older patients did not have 
excursions in exposure (20 mg/day). 
4.1 
PART 1 
4.1.1 
INCLUSION CRITERIA 
Subjects meeting all of the following inclusion criteria may be enrolled into the study: 
1. Subject is male or non-pregnant, non-lactating female, age 2 to 35 years, inclusive as of 
the day of the Screening Visit.  Female subjects of childbearing potential must not be 
pregnant or breast-feeding. Female subjects of childbearing potential must have a 
negative urine or serum pregnancy test at screening. Subjects of childbearing or child-
fathering potential must be willing to use medically acceptable forms of birth control 
(see Section 4.4), which includes abstinence, while being treated on this study and for 
90 days after the last dose of study drug. 
2. Subject must have a diagnosis of Lennox-Gastaut syndrome, where seizures that result 
in drops are not completely controlled by current antiepileptic treatments. (Subjects 
without a formal diagnosis may still be enrolled at sponsor discretion if all other criteria 
are met.) 
3. Subjects must meet all of the following 4 criteria for Lennox-Gastaut syndrome, as 
defined in this protocol: 
a. Onset of seizures at 11 years of age or younger. 
b. Multiple seizure types (must include TS or TA), including countable motor 
seizures that result in drops. Countable motor seizure types eligible for inclusion 
are: GTC, TS, CS, AS, FS with observable motor symptoms, and MS that result 
in a drop.  
c. Abnormal cognitive development. 
d. Evidence of EEG in the medical history that shows abnormal background 
activity accompanied by slow spike and wave pattern <2.5 Hz. (Acceptable 
evidence includes a copy of the EEG trace, EEG report, or physician note that 
appropriately describes the EEG findings.) 
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4. Subject must have had at least 8 drop seizures in the last 4 weeks prior to Screening 
(minimum of 4 drop seizures in the first two weeks and 4 in the last two weeks before 
baseline), by parent/guardian report to investigator or investigator medical notes 
5. Receiving at least 1 concomitant AED and up to 4 concomitant AEDs, inclusive. KD 
and VNS are permitted but do not count towards the total number of AEDs.  Rescue 
medications for seizures are not counted towards the total number of AEDs. 
6. All medications or interventions for epilepsy (including KD and VNS) must be stable 
for at least 4 weeks prior to screening and are expected to remain stable throughout the 
study. 
7. Subject has been informed of the nature of the study and informed consent has been 
obtained from the legally responsible parent/guardian. 
8. Subject has provided assent in accordance with Institutional Review Board (IRB)/Ethics 
Committee requirements, if capable. 
9. Subject’s parent/caregiver is willing and able to be compliant with diary completion, 
visit schedule and study drug accountability. 
4.1.2 
EXCLUSION CRITERIA 
Subjects who meet any of the following exclusion criteria must not be enrolled into the study: 
1. Subject has a known hypersensitivity to fenfluramine or any of the excipients in the 
study medication. 
2. Subject’s etiology of seizures is a degenerative neurological disease.  
3. Subject has a history of hemiclonic seizures in the first year of life. 
4. Subject only has drop seizure clusters, where individual seizures cannot be counted 
reliably. 
5. Subject has pulmonary arterial hypertension. 
6. Subject has current or past history of cardiovascular or cerebrovascular disease, such as 
cardiac valvulopathy, myocardial infarction or stroke, or clinically significant structural 
cardiac abnormality, including but not limited to mitral valve prolapse, atrial or 
ventricular septal defects, patent ductus arteriusis (note: Patent Foramen Ovale or a 
bicuspid valve are not considered exclusionary). 
7. Subject has current or recent history of Anorexia Nervosa, bulimia, or depression within 
the prior year that required medical treatment or psychological treatment for a duration 
greater than 1 month. 
8. Subject has a current or past history of glaucoma. 
9. Subject has had an anoxic episode requiring resuscitation within 6 months of the 
Screening Visit. 
10. Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild 
hepatic impairment (elevated liver enzymes < 3x ULN and/or elevated bilirubin <2x 
ULN) may be entered into the study after review and approval by the Medical Monitor 
in conjunction with the sponsor, in consideration of comorbidities and concomitant 
medications. 
11. Subject has severe renal impairment (estimated glomerular filtration rate 
<30mL/min/1.73m2) 
12. Subject is receiving concomitant therapy with: centrally-acting anorectic agents; 
monoamine-oxidase inhibitors; any centrally-acting compound with clinically 
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appreciable amount of serotonin agonist or antagonist properties, including serotonin 
reuptake inhibition; other centrally-acting noradrenergic agonists, including 
atomoxetine; or cyproheptadine (see Appendix 1 for a list of prohibited medications). 
(Note: Short-term medication requirements for prohibted medications will be handled 
on a per case basis by the Medical Monitor.) 
13. Subject has positive result (as defined in the laboratory manual) on urine or serum 
tetrahydrocannabinol (THC) Panel or whole blood cannabidiol (CBD) at the Screening 
Visit. 
14. Subject is taking felbamate for less than 1 year prior to screening and/or does not have 
stable liver function and hematology laboratory tests, and/or the dose has not been 
stable for at least 60 days prior to the Screening Visit. 
15. Subject is known to be human immunodeficiency virus (HIV) positive. 
16. Subject is known to have active viral hepatitis (B or C).. 
17. Subject is currently receiving an investigational product. 
18. Subject has participated in another clinical trial within the past 30 days (calculated from 
that study’s last scheduled visit). Participation in non-treatment trials will be reviewed 
by the Medical Monitor. 
19. Subject is at imminent risk of self-harm or harm to others, in the investigator’s opinion, 
based on clinical interview and responses provided on the Columbia-Suicide Severity 
Rating Scale (C-SSRS).  Subjects must be excluded if they report suicidal behavior in 
the past 6 months as measured by the C-SSRS at Screening or Baseline, which includes 
suicidal ideation with intent and plan (Item #5). If a subject reports suicidal ideation on 
Item 4 without specific plan, and the investigator feels that the subject is appropriate for 
the study considering the potential risks, the investigator must document 
appropriateness for inclusion, and discuss with the parent/caregiver to be alert to mood 
or behavioral changes, especially around times of dose adjustment. 
20. Subject is unwilling or unable to comply with scheduled visits, drug administration 
plan, laboratory tests, other study procedures, and study restrictions.  
21. Subject is institutionalized in a general nursing home (ie, in a facility that does not 
provide skilled epilepsy care). 
22. Subject does not have a reliable caregiver who can provide seizure diary information 
throughout the study. 
23. Subject has a clinically significant condition, including chronic obstructive pulmonary 
disease, interstitial lung disease, or portal hypertension, or has had clinically relevant 
symptoms or a clinically significant illness in the 4 weeks prior to the Screening Visit, 
other than epilepsy, that would negatively impact study participation, collection of 
study data, or pose a risk to the subject. 
4.2 
RANDOMIZATION INCLUSION CRITERIA 
Subjects must meet all of the inclusion criteria and none of the exclusion criteria 
above and meet the following criteria in order to be randomized: 
1. Subject has been approved for study inclusion by the Epilepsy Study Consortium. 
2. Subject does not have an exclusionary cardiovascular or cardiopulmonary abnormality 
based on ECHO, ECG or physical examination and is approved for entry by the central 
cardiac reader.  Exclusionary abnormalities include, but are not limited to: 
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a. Trace or greater mitral or aortic valve regurgitation in subjects <18 years of age 
b. Mild or greater mitral or aortic valve regurgitation in subjects >18 yrs of age 
c. Possible signs of pulmonary hypertension with abnormal or greater than upper 
range of normal values 
d. Evidence of left ventricular dysfunction (systolic or diastolic) 
3. Subject demonstrates a stable baseline with ≥ 2 seizures per week resulting in 
drops during the 4-week Baseline Period. 
4. Subject’s parent/caregiver has been compliant with diary completion during 
the Baseline Period, in the opinion of the investigator and sponsor. 
4.3 
PART 2 
To be included in Part 2: 
1. Subjects must continue to meet the Selection Criteria for Part 1 (except for criteria 
related to seizure frequency). If a subject entering Part 2 does not meet Randomization 
Criteria 2 regarding cardiovascular abnormalities, Section 8.9.1 Follow-up of 
Cardiovascular Findings will be applied to determine eligibility to continue into Part 2. 
2. All subjects must have satisfactorily completed Part 1 of the study in the opinion of the 
investigator and the sponsor. 
3. Review of inclusion and exclusion criteria and written informed parental or guardian 
consent and assent of minors (if the subject is capable of providing assent) for Part 2 
must be obtained before a subject can start any of the Part 2 Visit 15 procedures. 
4. Subjects must, in the medical opinion of the Investigator, be candidates for continued 
treatment for an extended period of time with ZX008. Candidates for continuous 
treatment should not meet Discontinuation criteria listed in Section 4.5 and should not 
meet the following criteria: 
• 
Clinically meaningful worsening of seizures, judged by Investigator or 
subject/caregiver such that treatment outside of the protocol and other than 
ZX008 is assumed to be in the subject’s best interest. A clinically meaningful 
worsening is an increase in frequency, severity or duration of existing seizures, 
or (in some cases) emergence of a new seizure type. Frequent or increased use 
of rescue medication may be considered indicative of worsening. 
• 
Clinically significant clinical laboratory findings (e.g. elevated ALT levels, 
decrease in platelet count, etc. that are CTCAE Grade 3 or higher) in subjects 
with no prior relevant history, that were not present during Baseline, are 
confirmed by a repeat test within a week, and not attributable to other 
concomitant medications. 
• 
Weight loss >15% during the T+M period that has not stabilized and is 
considered, in the opinion of the Investigator, detrimental to continuing 
treatment with ZX008.  
5. Those subjects who do not complete the 12-week Maintenance Period of Part 1 may, on 
a case-by-case basis, be eligible for entrance after consideration of the circumstances of 
the early termination and the potential benefit-risk of continued participation in a 
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ZX008 trial. The decision whether to permit participation in Part 2 for subjects who do 
not complete Part 1 resides solely with the sponsor, will require a formal request for 
early Part 2 continuation to be made by the Investigator as well as an evaluation of 
risk/benefit. The Sponsor who may consult with the site investigator, the ICAB and/or 
the IDSMC, and take into consideration evidence of the following for approval: 
a. The subject is experiencing a worsening in condition that is not likely to be 
related to Part 1 treatment, in the opinion of the Investigator 
b. The subject has progressed at least half-way through Part 1 (i.e. Visit 8) 
c. The subject has been compliant with assessments and requirements of Part 1 
d. The subject does not exhibit other contraindications to initiating open-label 
treatment 
4.4 
SUBJECTS OF REPRODUCTIVE POTENTIAL 
Male subjects who are sexually active with a partner of childbearing potential must use, with 
their partner, a condom plus an approved method of highly effective contraception from the 
time of informed consent until 90 days after the last dose of study drug. 
The following methods are acceptable: 
x Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
x Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o oral 
o injectable 
o implantable intrauterine device 
o intrauterine hormone-releasing system 
x Surgical sterilization (vasectomy or bilateral tubal occlusion) 
Female subjects who are not of childbearing potential do not need to use any methods of 
contraception. A woman is considered of childbearing potential, unless they are at least 2 years 
post-menopausal or permanently sterile, or if she has not yet reached menarche. Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. 
Female subjects who are sexually active and are of childbearing potential must use, with their 
partner, an approved method of highly effective contraception from the time of informed 
consent until 90 days after the last dose of study drug. 
The following methods are acceptable: 
x Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation and a barrier method (ie, condom for male partner): 
o oral 
o intravaginal 
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o transdermal 
x Progestogen-only hormonal contraception associated with inhibition of ovulation and a 
barrier method (ie, condom for male partner):  
o oral 
o injectable 
o implantable intrauterine device 
o intrauterine hormone-releasing system 
x Surgical sterilization (vasectomy or bilateral tubal occlusion) 
Alternatively, true abstinence is acceptable when it is in line with the subject’s preferred and 
usual lifestyle. If a subject is usually not sexually active but becomes active, they, with their 
partner, they must comply with the contraceptive requirements detailed above. 
4.4.1 Sperm and Egg Donation 
Male subjects should not donate sperm and female subjects should refrain from egg donation 
for the duration of the study and for at least 90 days after the last day of study medication 
administration. 
4.4.2 Pregnancy 
Subjects will be instructed that if they/their partner become pregnant during the study this 
should be reported to the investigator. The investigator should also be notified of 
pregnancy occurring during the study but confirmed after completion of the study. In the 
event that a subject/subject’s partner is subsequently found to be pregnant after the 
volunteer is included in the study, then consent will be sought from the partner and, if 
granted, any pregnancy will be followed and the status of mother and/or child will be 
reported to the sponsor after delivery. Any subject reporting a pregnancy during the study 
will be withdrawn from the study drug by completing the taper schedule. All safety 
follow-up activities must be completed. 
4.5 
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT 
While subjects are encouraged to complete all study evaluations, subjects may voluntarily 
withdraw from the study for any reason at any time. They may be considered withdrawn if they 
fail to return for visits, or become lost to follow-up for any other reason. 
If premature withdrawal occurs for any reason, the investigator must make a genuine effort to 
determine the primary reason for a subject’s premature withdrawal from the study and record 
this information on the electronic case report form (eCRF). All subjects who withdraw from the 
study with an ongoing AE must be followed until the event is resolved or deemed stable. If a 
subject withdraws prematurely after dosing, all data to be collected prior to discharge from the 
clinical site should be collected at the time of premature discontinuation or at the scheduled 
discharge. 
For subjects who are lost to follow-up (ie, those subjects whose status is unclear because they 
failed to appear for study visits without stating an intention to withdraw), the investigator 
should show "due diligence" by documenting in the source documents the steps taken to 
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contact the subject (eg, dates of telephone calls, registered letters). 
Subjects must be discontinued from the study for the following reasons, if deemed appropriate 
by the sponsor or investigator: 
1. Development of signs or symptoms indicative of cardiac valvulopathy or regurgitation 
(mitral, aortic, tricuspid, pulmonary valves), or pulmonary hypertension for which 
IDSMC, in consultation with cardiac readers and the investigator believe the benefit 
of continued participation does not outweigh the risk. 
2. Subject is found to have entered the clinical investigation in violation of the protocol. 
3. Subject requires or starts using unacceptable or contraindicated 
concomitant medications, or currently utilized chronic daily seizure 
therapy is changed. 
4. 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. 
5. Subject is noncompliant with procedures set forth in the protocol in an ongoing 
or repeated manner. 
6. Subject experiences an AE that warrants withdrawal from the clinical investigation. 
7. Clinically significant worsening of seizures, judged by investigator or subject/caregiver 
such that treatment outside of the protocol and other than ZX008 is assumed to be in 
the subject’s best interest. Frequent or increased use of rescue medication may be 
considered indicative of worsening. 
8. An “actual suicide attempt” as classified by the Columbia-Suicide Severity Rating 
Scale (C-SSRS). 
9. It is the investigator’s opinion that it is not in the subject’s best interest to continue in 
the study. 
10. Subject is found to be pregnant while on study. Subject will be withdrawn following the 
taper schedule; all safety follow-up activities must be completed. 
Discontinuation decisions will be made at each participating site by the site investigator. 
Discontinuations due to development of cardiovascular or cardiopulmonary complications are 
to be made by the IDMSC. 
If feasible, the process of discontinuation should be discussed with the Medical Monitor. The 
decisions regarding the discontinuation of the investigational therapy, whether the study 
medication should be stopped immediately or tapered should be discussed with the Medical 
Monitor, but final decisions about the process will remain at the discretion of the site principal 
investigator. 
Subjects who are discontinued from the clinical investigation for any reason will not be 
replaced. 
Subjects may withdraw their consent to participate in the study at any time without having to 
justify the reason for doing so. The decision to withdraw consent and discontinue participation 
in the study will not prejudice the subject’s future medical treatment in any way.  
Subjects must be discontinued from receiving ZX008 and/or participating in any further study 
procedures under the following circumstances: 
x The subject or the subject’s legally authorized representative wishes to discontinue 
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participation in the study. 
x The investigator advises that the subject’s safety or well-being could be compromised by 
further participation in the study. 
x The sponsor requests that a subject discontinues participation in the study (eg, due to 
suspicion of fraud, multiple enrollments in clinical studies, lack of compliance). 
In the event that the study is terminated prematurely then the procedure for termination should 
be followed as described in Section 3.7. Concern for the interests of the subject will always 
prevail over the interests of the study. 
The reason for, and date of discontinuation from participation in the study must be recorded in 
detail in the eCRF and in the subject’s medical records (eg, AEs, lack of compliance, lost to 
follow-up, etc). If possible, the subject/subject’s legally authorized representative should 
confirm his decision in writing. 
The investigator will attempt to complete all procedures usually required at the end of the study 
at the time when the subject’s participation in the study is discontinued or as close as possible 
to that time. Specific procedures required for each Part of the study are described in Section 
6.1.2.9 and Section 6.2.4. As far as possible, a complete final examination must be performed 
on all subjects who do not complete the study according to the study protocol. 
Data collected until the time a subject discontinues participation in the study will be handled in 
the same manner as data for subjects completing the study. Where possible, further information 
will be collected if any AEs are experienced by a subject after discontinuing participation in the 
study. 
4.6 
TERMINATION OF THE CLINICAL STUDY 
If the investigator, the sponsor, the Medical Monitor, or the IDSMC becomes aware of 
conditions or events that suggest a possible hazard to subjects if the clinical study continues, 
then the clinical study may be terminated. The decision to terminate the study lies  solely with 
the sponsor. The clinical study may be terminated at the sponsor’s discretion at any time also in 
the absence of such a finding. 
Conditions that may warrant termination of the clinical study include, but are not limited to: 
x The discovery of an unexpected, relevant, or unacceptable risk to the subjects enrolled in 
the clinical study. 
x Failure to enroll subjects at the required rate. 
x A decision of the sponsor to suspend or discontinue development of ZX008. 
4.7 
REPLACEMENT OF SUBJECTS 
Enough subjects will be enrolled in Part 1 of the trial to ensure that approximately 250 
subjects are randomized into the T+M Period of Part 1 Cohort A, and at least 30 subjects 
are randomized into Part 1 Cohort B.  Randomized subjects will not be replaced. 
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5. 
INVESTIGATIONAL MEDICINAL PRODUCT INFORMATION 
ZX008/matching placebo will be administered in the current study. A brief description of the 
ZX008 product is provided below (Table 4). 
Table 4: 
Investigational Medicinal Product – ZX008 
 
Study Product 
 
Substance Code 
ZX008 
 
Active Substance (INN) 
Fenfluramine Hydrochloride 
 
Trade Name 
Not applicable 
 
Formulation (including dosage form and strength) 
Solution 1.25, 2.5, and 5 
mg/mL Route/Mode of Administration 
Oral 
 
Manufacturer 
PCI Pharma Services on behalf of Zogenix 
  
International Limited 
 
 
5.1 
IDENTITY OF INVESTIGATIONAL MEDICINAL PRODUCT 
ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 
and provided in concentrations of 1.25 mg/mL, 2.5 mg/mL, and 5 mg/mL. The excipients 
selected have been approved for use in the formulations of currently marketed drug products 
and are considered to be safe. The solution formulations will be suitably flavored, and will 
contain preservatives and a thickening agent. The product is sugar free and is intended to be 
compatible with a KD. 
The formulation for Part 1 will be provided in bottles with tamper-evident, child-resistant 
caps. The clinical trials material will be supplied in 1 bottle size with nominal fill volume 
of 120 mL. Matching placebo also will be provided.  Doses to be studied include ZX008 
0.2 mg/kg/day and ZX008 0.8 mg/kg/day divided into two daily (BID) doses, up to a 
maximum of 30 mg/day (subjects taking concomitant STP will receive 0.5 mg/kg/day, up 
to a maximum of 20 mg/day, or equivalent volume of placebo). An intermediate dose of 
0.4 mg/kg/day will be used for titration. The concentration of ZX008 oral solution received 
by subjects (1.25 mg/mL, 2.5 mg/mL, and/or 5 mg/mL) will be randomized across the 3 
available concentrations in order to ensure blinding. 
For Part 2 flexible dosing will be studied, up to 0.8 mg/kg/day divided into two daily 
doses, up to a maximum of 30 mg/day (subjects taking concomitant STP will receive up to 
0.5 mg/kg/day, up to a maximum of 20 mg/day).  ZX008 drug product will be provided in 
a concentration of 2.5 mg/mL in 1 bottle size with nominal fill volume of 120 mL. 
5.1.1 
Labeling and Packaging 
The ZX008 product will be packaged and labeled according to current International Conference 
on Harmonization (ICH), Good Manufacturing Practices (GMP), and Good Clinical Practices 
(GCP) guidelines, and national legal requirements. 
Dosing directions for the product can be found in the Pharmacy Manual for the study 
subjects and for the investigator. 
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5.2 
DESCRIPTION OF REFERENCE TREATMENT, 
COMPARATOR, AND/OR PLACEBO 
Placebo solution is identical in aspect and composition to ZX008 and is composed of identical 
ingredients used in the ZX008 formulation, except that it does not contain the active ingredient, 
fenfluramine hydrochloride.  Subjects randomized to placebo will receive concentration 
equivalent volumes of investigational product that does not include the active ingredient. 
No comparators or reference treatments will be used. 
5.2.1 
Labeling and Packaging 
Placebo solution will be packaged in an identical manner to ZX008. The matching placebo 
product will be packaged and labeled according to current ICH, GMP, and GCP guidelines, and 
national legal requirements. 
Dosing directions for the product can be found in the IMP handling instructions for the study 
subjects and for the investigator. 
5.3 
SHIPMENT AND STORAGE 
IMP will be supplied to the study sites by the sponsor or its delegate. 
All IMP will be transported, received, stored, and handled strictly in accordance with the 
container or product label, the instructions supplied to the research site and its designated 
pharmacy, the site’s standard operating procedures, and applicable regulations. IMP must be 
stored separately from normal hospital or practice inventories, in a locked facility with access 
limited to the investigator and authorized personnel. The investigator must ensure that the IMP 
is dispensed only to subjects enrolled in this study according to this study protocol. 
Appropriate storage temperature and transportation conditions will be maintained for the study 
drug from the point of manufacture up to delivery of the study drug. Study medication must be 
stored at 15-25°C (59-77°F) with excursions of 5-40°C (41-104°F) permitted; do not refrigerate 
or freeze. 
Storage and handling instructions of the IMP maintained at the subject’s home are described in 
the subject’s IMP handling instructions. 
All unused IMP will be saved by the site for final disposition according to the sponsor’s 
directive. 
5.4 
IMP ACCOUNTABILITY 
The investigator or delegate will confirm receipt of all shipments of the IMP in writing using 
the receipt form(s) provided by the sponsor or vendor. 
Assignment of ZX008 or placebo to the subject will be handled through an interactive voice 
randomization (IVR) or Interactive Web Response (IWR) platform. The investigator or 
delegate will be required to register the subject through IVR/IWR and all study medication will 
be assigned to the subject through the IVR/IWR. The IVR/IWR will also maintain a log of all 
received and dispensed medication. 
All supplies must be accounted for throughout the study using the drug accountability form 
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provided by the sponsor before the start of the study. Drug accountability is the process of 
documenting all aspects of IMP receipt, storage, use, and disposition so that a full accounting 
of each unit can be made.  This includes administration, and return and/or destruction of IMP. 
At the end of the study, the dated and signed (by the investigator or delegate, eg, pharmacist) 
original drug accountability form must be retained at the study site as verification of final 
drug accountability. 
Records for the delivery of the IMP to the study site, the inventory at the study site, the use by 
each subject (use by subject will be documented in the subject diary), and the destruction or 
return of the IMP to the sponsor must be maintained by the investigator (or delegate). The 
records will include dates, quantities, batch numbers, and unique code numbers assigned to the 
IMP and to the subjects. The investigator must maintain records documenting that subjects 
were provided with the doses of the IMP specified in this study protocol. Furthermore, the 
investigator must reconcile all IMPs received from the sponsor. The investigator must provide 
reasons for any discrepancies in drug accountability. Forms will be provided by the sponsor to 
ensure standardized and complete drug accountability. 
5.5 
TREATMENT ADMINISTRATION 
5.5.1 
Part 1: Randomization 
Upon completion of the Baseline Period in Part 1, subjects who qualify for the study will be 
randomized (1:1:1) in a double-blind manner to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 
0.8 mg/kg/day; 30mg/day maximum [0.5 mg/kg/day; 20 mg/day maximum for subjects taking 
concomitant STP]) or placebo. The randomization will be stratified by weight (<37.5 kg, ≥37.5 
kg) to ensure balance across treatment arms, with a target of at least 25% in each weight group. 
Subjects will be assigned a randomization number by the IWR system upon confirmation that 
subject qualifies for enrollment in the Titration Period. Once a randomization number is 
assigned to a subject, the site will record the subject’s initials and identification number on the 
corresponding study drug bottles. Each bottle will contain the appropriate concentration and 
volume of liquid to administer the assigned treatment (ZX008 0.2 mg/kg/day, ZX008 0.8 
mg/kg/day [or 0.5 mg/kg/day for subjects taking concomitant STP], or placebo). ZX008 and 
placebo will be identical, thus rendering the study drug and placebo indistinguishable. For each 
IMP bottle and randomization number assigned, the following information will be recorded on 
the drug accountability form: subject initials, unique bottle number, date each bottle is 
assigned, and drug used and unused during the study. 
5.5.1.1 
Blinding 
The blinding scheme instituted for this study will ensure that the volume of study medication 
taken cannot be associated with the dose group, thus unblinding the study. This is achieved by 
random assignment of different concentrations of the ZX008 oral solution (1.25 mg/mL, 
2.5 mg/mL, and/or 5 mg/mL) by the IWR system. The IWR system will instruct site personnel 
to the volume of oral solution to be administered based on that subject’s weight. (Dose will be 
recalculated by the system based on weight once at the midpoint of the study.) During the 
Titration, Maintenance, and Taper/Transition Periods, the subjects and study personnel 
(investigators, clinical staff, personnel involved in data collection and analysis, the Medical 
Monitor, and the sponsor) will be blinded to the treatment allocation and to the concentration of 
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ZX008 oral solution. If an investigator feels the blind should be broken, he/she can do so when 
necessary for treatment decisions. However, the investigator should endeavor to discuss with 
the Medical Monitor or Sponsor’s Medical Representative, if available. The blind should only 
be broken in the event the knowledge of whether the subject is on active study medication 
versus placebo is needed to determine course of medical treatment for the event. The subject 
will be discontinued from the clinical trial upon breaking of the blind and the decision whether 
the subject can enter Part 2 will rest with the Sponsor if the subject exited Part 1 prior to 
completion. 
5.5.2 
Part 1: Titration Period 
The investigator (or delegate) will dispense IMP only to subjects included in Part 1 of 
this study following the procedures set out in this study protocol. Subjects will be 
required to stay in the clinic for monitoring of adverse reactions until the investigator 
determines it is safe to leave. Those considered by the investigator to need further 
monitoring will be hospitalized until the investigator determines they can be safely 
discharged. 
Study medication will be administered as equal doses BID in the morning and in the evening 
approximately 12 hours apart. Each dose should be separated by a minimum of 8 hours and a 
maximum of 12 hours. A missed dose of study medication may be taken later up to 8 hours 
before the next scheduled dose; otherwise, the missed dose should not be given. 
If the parent/caregiver is unable to administer the full dose due to spillage (eg, dose was spilled 
during measuring, subject spit dose out during administration), he/she should attempt to give 
the full dose noting the extra amount used to fulfill the dose. If the subject vomits within the 
first 15 minutes of administration the dose may be readministered. Care must be taken not to 
overdose. If the amount spilled is not known, the parent/caregiver should not give additional 
medication to avoid potential overdose. 
Administration of the IMP will be based on the randomized dose and subject’s weight (kg) at 
Visit 3 (Part 1; Study Day -1). At Visit 8 (Part 1; Study Day 43), if the subject’s weight (kg) 
has changed ±25% of the weight at Part 1; Study Day-1, the IMP dose will be recalculated. 
Subjects should be dosed using the oral dosing syringe provided. 
In order to maintain the blind across all dose groups in Part 1 (Section 5.5.1.1) and allow step 
titration to the high dose, the dose for each subject will be titrated starting with a dose of 
ZX008 0.2 mg/kg/day (or placebo equivalent) BID. After 4 days at this dose level (Study Day 
5), subjects randomized to the ZX008 0.8 mg/kg/day (or 0.5 mg/kg/day for subjects taking 
concomitant STP) group will increase their dose to 0.4 mg/kg/day (maximum 30 mg/day or 20 
mg/day for subjects taking concomitant STP) while doses in the other two groups will remain 
constant. On Study Day 9, the dose for the 0.8 mg/kg/day group (or 0.5 mg/kg/day for 
subjects taking concomitant STP) will increase to the target dose or a maximum of 30 mg/day 
(or 20 mg/day for subjects taking concomitant STP). The titration is expected to take a total of 
14 days (Table 5). A new bottle of IMP will be started by the subject at each level of the 
titration step. See Section 5.1 for more information about the volume of ZX008 or placebo to 
be administered.  If a subject does not tolerate IMP during titration, slower titration may be 
considered after consultation with the Medical Monitor. 
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Table 5: 
Titration Algorithm for Part 1 
 
Randomized Group 
Titration Step 1 
Study Day 1-4 
Titration Step 2 
Study Days 5-8 
Titration Step 3 
Study Days 9-14 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.8 mg/kg/day 
(0.5 mg/kg/day for subjects 
taking concomitant STP) 
ZX008 0.2 mg/kg/day 
ZX008 0.4 mg/kg/day 
ZX008 0.8 mg/kg/day  
(0.5 mg/kg/day for subjects 
taking concomitant STP) 
Placebo 
Placebo 
Placebo 
Placebo 
Note: maximum daily dose of ZX008 is 30 mg (20mg for subjects taking concomitant STP) 
 
5.5.3 
Part 1: Maintenance Period 
After completion of the Titration Period, subjects will enter the Maintenance Period and 
continue to receive the randomized dose of ZX008 or placebo and be treated for an additional 
12 weeks. Study medication will continue to be administered BID in the morning and in the 
evening, approximately 12 hours apart. Each dose should be separated by a minimum of 8 
hours and a maximum of 12 hours. A missed dose of study medication may be taken later up 
to 8 hours before the next scheduled dose; otherwise, the missed dose should not be given. 
5.5.4 
Part 1: Taper Period (for subjects not entering Part 2) 
Subjects who complete the Maintenance Period and will not be continuing into Part 2, the 
open-label extension, and subjects who discontinue from Part 1 early, will be tapered off of 
study medication.  Study medication will be administered as equal doses BID in the morning 
and in the evening approximately 12 hours apart. Each dose should be separated by a minimum 
of 8 hours and a maximum of 12 hours. A missed dose of study medication may be taken later 
up to 8 hours before the next scheduled dose; otherwise, the missed dose should not be given. 
IMP should be administered using the oral dosing syringe provided. 
If the parent/caregiver is unable to administer the full dose due to spillage (eg, dose was spilled 
during measuring, subject spit dose out during administration), he/she should attempt to give 
the full dose noting the extra amount used to fulfill the dose. If the subject vomits within the 
first 15 minutes of administration the dose may be readministered. Care must be taken not to 
overdose. If the amount spilled is not known, the parent/caregiver should not give additional 
medication to avoid potential overdose. 
In order to maintain the blind across all dose groups, all subjects who do not continue into Part 
2 will participate in a blinded dose-tapering procedure over the course of 8 days. On the first 
day of the tapering period subjects in the ZX008 0.8 mg/kg/day group (or 0.5 mg/kg/day for 
subjects taking concomitant STP) will decrease to a dose of ZX008 0.4 mg/kg/day BID 
(maximum 30 mg/day or 20 mg/day for subjects taking concomitant STP). After 4 days at this 
dose level (Study Day 5), subjects in this group will decrease their dose to 0.2 mg/kg/day. 
Subjects in the ZX008 0.2 mg/kg/day group will decrease their dose to placebo on the first day 
of tapering while doses in the placebo group will remain constant throughout the tapering 
procedure. On Study Day 9, all subjects will stop taking study medication. The taper is 
expected to take a total of 8 days (Table 6). A new bottle of IMP will be started by the subject 
at each level of the taper step. 
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Table 6: 
Taper Algorithm for Part 1 
 
 
Randomized Group 
Taper Step 1 
Day 1-4 after study completion or 
early termination 
Taper Step 2 
Days 5-8 after study completion or 
early termination 
ZX008 0.2 mg/kg/day 
Placebo 
Placebo 
ZX008 0.8 mg/kg/day 
(0.5 mg/kg/day for subjects 
taking concomitant STP) 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
Placebo 
Placebo 
Placebo 
Note:  maximum daily dose of ZX008 is 30 mg. (20mg for subjects taking concomitant STP) 
 
5.5.5 
Part 1: Transition Period 
Subjects who complete the Maintenance Period and will be continuing into the open-label 
extension (Part 2) will be transitioned from double-blind study medication to open-label ZX008 
(Table 7).  
All subjects entering the open-label extension (Part 2) will be transitioned from their blinded 
daily dose to the 0.2 mg/kg dose during the 2-week interval between Visits 12 and 15, without 
breaking the blind. The IWR system will assign two bottles of IMP to the subject, one for each 
step in the transition. A new bottle of IMP will be started by the subject at each level of the 
transition step. See Section 5.1 for more information about the volume of ZX008 or placebo to 
be administered. 
Table 7: 
Transition Algorithm for Part 1 
Dose Group in Double-
Blind Study 
Transition Step 1 
Day 1-4 after Visit 12 
Transition Step 2 
Days 5-14 after Visit 12 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.8 mg/kg/day 
(0.5 mg/kg/day for subjects taking 
concomitant STP) 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
Placebo 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
Note: maximum daily dose of ZX008 is 30 mg (or 20 mg for subjects taking concomitant STP). 
 
Subjects who had been randomized to placebo increase their dose to 0.2 mg/kg/day beginning 
on Day 1 of the transition. The first dose should be taken in the clinic during Visit 12. Subjects 
will be required to stay in the clinic for monitoring of adverse reactions until the investigator 
determines it is safe to leave. Those considered by the investigator to need further monitoring 
will be hospitalized until the investigator determines they can be safely discharged. Subjects 
who had been randomized to 0.2 mg/kg/day will continue to receive that dose. Subjects who 
had been randomized to 0.8 mg/kg/day or were receiving the maximum dose of 30 mg/day (or 
subjects taking concomitant STP and randomized to 0.5 mg/kg/day; 20 mg/day maximum) 
decrease to a dose of ZX008 0.4 mg/kg/day, or a maximum of 30 mg/day (20 mg/day for 
subjects taking concomitant STP). After 4 days at this dose level (Day 5), these subjects will 
decrease their dose to 0.2 mg/kg/day. Subjects will report to the clinic on Day 14 for enrollment 
into the open-label extension. 
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Study medication will be administered as equal doses BID in the morning and in the evening 
approximately 12 hours apart. Each dose should be separated by a minimum of 8 hours and a 
maximum of 12 hours. A missed dose of study medication may be taken later up to 8 hours 
before the next scheduled dose; otherwise, the missed dose should not be given. Study 
medication should be administered using the oral dosing syringe provided. 
If the parent/caregiver is unable to administer the full dose due to spillage (eg, dose was spilled 
during measuring, subject spit dose out during administration), he/she should attempt to give the 
full dose noting the extra amount used to fulfill the dose. If the subject vomits within the first 15 
minutes of administration the dose may be readministered. Care must be taken not to overdose. If 
the amount spilled is not known, the parent/caregiver should not give additional medication to 
avoid potential overdose. 
5.5.6 
Part 2: OLE Treatment Period 
During the Part 2 OLE Treatment Period, all subjects will be treated initially with 0.2 mg/kg/day 
for 1 month to assess effectiveness of this dose in all study subjects. After 1 month at a dose of 
ZX008 0.2 mg/kg/day, the investigator may adjust the dose of each subject based on 
effectiveness and tolerability.  
Administration of the initial IMP will be based on the 0.5 mg/kg/day (maximum 30 mg/day or 20 
mg/day for subjects taking concomitant STP) dose and subject’s weight recorded for Visit 15 
(Part 2; Study Day 1). At Visits 19, 20, and 21 of Part 2 (Months 3, 6, and 9), if the subject’s 
weight has changed ± 25% of the weight  recorded for Visit 15, the IMP dose will be 
recalculated. Subjects will be dosed using the oral dosing syringe provided. 
Dose increases should not occur earlier than every 14 days at each dose level. Dose increases 
may only occur after a review of the diary and reported AEs, and if, in the investigator’s opinion, 
seizure frequency, severity, and/or duration indicates a change in medication regimen is 
warranted. Temporary dose decreases for tolerability can occur at the investigator’s discretion, in 
dose amounts and frequency appropriate for the situation. Subsequent dose rechallenge should 
occur at the investigator’s discretion in consultation with the Medical Monitor.  ZX008 dose 
adjustments outside of these parameters should be discussed with the Medical Monitor and must 
be approved by the Sponsor prior to initiation.  
If after approximately the midway point of the first 30 days on ZX008 0.2 mg/kg/day there is a 
clinically meaningful worsening in seizure type, frequency, and/or duration compared with the 
recent treatment in the core study, the investigator, in consultation with the Medical Monitor and 
approval of the sponsor, may increase the dose to 0.4 mg/kg/day (maximum 30 mg/day or 20 
mg/day for subjects taking concomitant STP). A clinically meaningful worsening would be an 
increase in frequency, severity or duration of existing seizures, or (in some cases) emergence of a 
new seizure type. The description of clinical worsening must be documented in the source notes 
and case report form (CRF). Further increase to 0.8 mg/kg/day (maximum 30 mg/day or 0.5 
mg/kg/day; maximum 20 mg/day for subjects taking concomitant STP) could also be undertaken 
for the same conditions after a minimum of 4 days on 0.4 mg/kg/day, if the condition has not 
stabilized on the 0.4 mg/kg/day dose. Dosing outside of the specified range (ie, up to 0.8 
mg/kg/day [or 0.5 mg/kg/day for subjects taking concomitant STP]) may be considered after 
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consultation between the investigator and Medical Monitor and approval of the Sponsor; 
however, excursions over 30 mg/day (or 20 mg/day for subjects taking concomitant STP) are 
prohibited. 
Study medication will be administered as equal doses BID in the morning and in the evening, 
approximately 12 hours apart. Each dose should be separated by a minimum of 8 hours and a 
maximum of 12 hours. A missed dose of study medication may be taken later up to 8 hours 
before the next scheduled dose; otherwise, the missed dose should not be given. 
If the parent/caregiver is unable to administer the full dose due to spillage (eg, dose was spilled 
during measuring, subject spit dose out during administration), he/she should attempt to give the 
full dose noting the extra amount used to fulfill the dose. If the subject vomits within the first 15 
minutes of administration the dose may be readministered. Care must be taken not to overdose. If 
the amount spilled is not known, the parent/caregiver should not give additional medication to 
avoid potential overdose. 
5.5.7 
Taper Period 
All subjects (those who complete the Part 2 OLE Treatment Period and those who discontinue 
from the study early) will be tapered off of study medication, unless they are transitioning to 
commercial drug.  
The tapering scheme is a 2-step process as described in Table 8.  
Study medication will be administered as equal doses BID in the morning and in the evening, 
approximately 12 hours apart. Each dose should be separated by a minimum of 8 hours and a 
maximum of 12 hours. A missed dose of study medication may be taken later up to 8 hours 
before the next scheduled dose; otherwise, the missed dose should not be given. IMP will be 
administered using the oral dosing syringe provided.  
Table 8.  
Taper Algorithm for Part 2 
 
 
Current Dose 
Taper Step 1  
Days 1-4 after study 
completion or early 
termination 
Taper Step 2 
Days 5-8 after study completion 
or early termination 
ZX008 0.2 mg/kg/day 
Not applicable 
Not applicable 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
Not applicable 
ZX008 0.5 mg/kg/day 
(for subjects taking 
concomitant STP) 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.6 mg/kg/day 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.8 mg/kg/day  
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
Note:  maximum daily dose of ZX008 is 30 mg (or 20 mg for subjects taking concomitant STP). 
 
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5.6 
PRIOR AND CONCOMITANT MEDICATION 
All medications taken by a subject before receiving study medication (ie, during the Screening 
and Baseline Seizure Assessment Periods in Part 1) and stopped before the first administration of 
IMP are regarded as prior therapy and must be documented in the eCRF. Significant medications 
(eg, antibiotics) taken within 30 days prior to the Screening visit should also be captured. All 
prior and concomitant AEDs will be collected in the eCRF. 
All medications taken by a subject after the first administration of IMP, including those that 
started before the first administration of IMP and are continuing, are regarded as concomitant 
medication and must be documented in the eCRF, including over-the-counter medication, herbal 
and vitamin/supplement preparations.  
Subjects are required to take at least one concomitant AED during study participation. No new 
concomitant AEDs may be introduced while in this study without discussion with the Medical 
Monitor prior to initiation. Non-study medications and therapies (this does not include KD, VNS, 
and RNS) that are considered necessary for the subject’s welfare and will not interfere with the 
response to the study medication may be given at the discretion of the investigator, informing the 
Medical Monitor as soon as possible.  
It should be noted for any subject receiving hypoglycemic agents, the investigator should 
consider diabetic medication changes in the setting of weight loss and hypoglycemia. 
Part 1 
All subjects will continue to receive their existing AED(s) with the same doses throughout the 
Part 1 Double-blind Treatment Period. Every effort should be made to ensure that the regimen of 
existing medications remains stable during Part 1; any changes must be discussed with the 
sponsor prior to implementation. If a decrease in a concomitant AED is necessary to manage an 
AE, this must be discussed with the sponsor as soon as possible after implementation if not 
before implementation. Increases in dose or number of concomitant AEDs are not permitted 
during Part 1 of the study.   
Part 2 
During at least the first 6 months of the Part 2 OLE Treatment Period, subjects will continue to 
receive their existing AEDs at the same dose and frequency as prior to starting Part 2. However, 
once the subject has been stable on a ZX008 dose for at least 6 months with good seizure control, 
investigators will be allowed as per typical clinical practice to alter one or more other 
concomitant AED doses as deemed clinically appropriate. Subjects who achieve robust seizure 
control may be considered to decrease concomitant AEDs earlier than 6 months after 
review/discussion with the Medical Monitor and approval from the Sponsor. Concomitant AEDs 
may be withdrawn completely but all subjects must remain on a minimum of 1 concomitant 
AED plus ZX008. Addition of new concomitant AEDs must be discussed with and approved by 
the Medical Monitor prior to initiation. AED doses may be lowered for safety considerations at 
any time.  All medication dose changes must be documented with a clinical explanation and 
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justification. Concomitant AED dose adjustments outside of these parameters should be 
discussed with the Medical Monitor prior to initiation.   
5.6.1 
Vagal Nerve Stimulation 
Subjects receiving treatment with a VNS may be included as long as the VNS has been in place 
for at least 6 months prior to entry into the study, the VNS battery is not due for replacement 
during the study, and stimulation parameters have been kept constant for 4 weeks prior to 
screening and must remain so throughout the study. VNS may not be the only anti-epileptic 
treatment (ie, it does not count as an AED but it does count as a treatment for LGS).  The 
subject’s use of VNS will be recorded in the eCRF. 
During at least the first 6 months of the Part 2 OLE Treatment Period, VNS stimulation 
parameters will be kept constant. However, once the subject has been stable on a ZX008 dose for 
at least 6 months with good seizure control, investigators will be allowed as per typical clinical 
practice to alter VNS stimulation parameters as deemed clinically appropriate. All VNS 
stimulation parameter changes must be documented with a clinical explanation and justification. 
VNS stimulation parameter adjustments outside of these boundaries should be discussed with the 
Medical Monitor prior to initiation.  
5.6.2 
Ketogenic Diet 
Adherence to the KD, or a modified version of KD, is permitted during the study if the dietary 
habits were initiated more than 4 weeks prior to Screening and remain stable throughout the 
study. KD may not be the only anti-epileptic treatment (ie, it does not count as an AED but 
does count as a treatment for LGS). The subject’s use of KD will be recorded in the eCRF. 
During at least the first 6 months of the Part 2 OLE Treatment Period, the KD will be adhered to. 
However, once the subject has been stable on a ZX008 dose for at least 6 months with good 
seizure control, investigators will be allowed as per typical clinical practice to alter the KD as 
deemed clinically appropriate. All KD changes must be documented with a clinical explanation 
and justification. KD adjustments outside of these parameters should be discussed with the 
Medical Monitor prior to initiation. 
5.6.3 
Rescue Medication for Seizures 
The subject's usual or prescribed regimen and frequency of rescue therapy for seizures should 
be entered into the concomitant medication sections of the eCRF and identified as a rescue 
medication by selecting the appropriate box. 
Use of rescue medication is permitted during the study and should be recorded on the eCRF 
(day, medication[s], dose[s]) and in the diary (day, timeframe associated with seizure episodes). 
Repeated administrations within the same episode should be recorded separately. 
5.6.4 
Prohibited Concomitant Medications 
Examples of concomitant medications in the classes prohibited are listed in Appendix 1 and 
summarized below.  If medical necessity requires short-term use of one or more of these 
medications during the course of the study, please contact the Medical Monitor for approval. 
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x Felbamate is prohibited as a concomitant medication unless the subject has been on 
felbamate for at least 12 months prior to screening, has stable liver function and 
hematology laboratory tests, and the dose has been stable for at least 60 days prior to 
screening and is expected to remain constant throughout the study. 
x Products that contain cannabis and/or cannabinoids are prohibited for the duration of 
pariticpation in the study. 
x Drugs that interact with central serotonin: imipramine, monoamine oxidase inhibitors, 
selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, 
vortioxetine. 
x Drugs that increase cardiovascular risk: e.g. atomoxetine. 
x Drugs intended to facilitate weight loss. 
x Ergot alkaloids and their derivatives, including pergolide and cabergoline 
x Phenylpropanolamine and other decongestants may be used for short-term use only. 
5.7 
TREATMENT COMPLIANCE 
Each subject or parent/caregiver will record the dose, dosing frequency and IMP consumption 
in the subject’s diary. Subjects will bring their used, partially used, and unused IMP to every 
study visit. Treatment compliance will be monitored by measuring the volume of IMP in 
these bottles and comparing to the dispensation log and diary records. 
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6. 
VISIT SCHEDULE 
6.1 
Part 1 
Study procedures for the Part 1 Double-blind Treatment Period will be conducted 
according to the Schedule of Assessments in Table 1. Time windows for all assessments 
in Part 1 are detailed in Table 9 
 
Table 9: 
Time Windows for Assessments in Part 1 
Visit / Procedure 
Time window (relative to scheduled visit / procedure) 
Visit 1 (Clinic; Study Day -29 to -28 or -28 to -27): 
Not applicable 
Visit 2 (Phone; Study Day -15) 
± 3 days 
Visit 3 (Clinic; Study Day -1; Randomization) 
+ 4 daysa 
Visits 4, 5 (Phone: Study Days 4, 8) 
± 3 days 
Visit 6 (Clinic; Study Day 15) 
± 4 days 
Visit 7 (Phone: Study Day 29) 
± 4 days 
Visit 8 (Clinic; Study Day 43) 
± 4 days 
Visit 9 (Phone: Study Day 57) 
± 4 days 
Visit 10 (Clinic; Study Day 71) 
± 4 days 
Visit 11 (Phone: Study Day 85) 
± 4 days 
Visit 12 (Clinic: Study Day 99) 
± 4 days 
Visit 13 (Clinic; Study Day 113; post dosing) 
± 4 days 
Visit 14 (ECHO clinic; 3-6 months after last dose) 
+ 30 days 
Blood collection for ZX008 PK 
± 15 minutes 
AED=antiepileptic drug (s); ECHO=echocardiogram; PK = pharmacokinetics 
a 
In cases where the screening period is extended beyond 28 days, the immediate 28 days before the Randomization visit 
will be used to calculate the baseline seizure frequency 
 
6.1.1 
BASELINE PERIOD (STUDY DAY -28 TO STUDY DAY -1) 
The Baseline Period of the study encompasses the screening activities that will occur on 
Study Day -28 as well as the observation period where subjects will be assessed for baseline 
seizure activity based on recordings of daily seizure activity entered into a diary. 
6.1.1.1. 
Screening, Clinic Visit 1 (Study Day -28) 
Screening is the predetermined series of procedures with which each investigator selects an 
appropriate and representative sample of subjects for enrollment into the study. Select 
screening data will be documented in the IWR and eCRF. 
Written informed parental or guardian consent and assent of minors (if the subject is capable of 
providing assent) must be obtained before a subject can start any of the screening procedures. 
The procedure(s) for obtaining written informed consent and assent of minor (if the subject is 
capable of providing assent) are described in Section 11.2. 
The Screening visit will occur on Study Day -28; however, the procedures may be split over 
2 consecutive days (eg, Study Day -29 and Study Day -28 or Study Day -28 and Study Day -27). 
Splitting the visit procedures across 2 nonsequential days requires the approval of the medical 
monitor. The following procedures will be performed for all subjects before the start of seizure 
activity observation: 
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x 
Obtain written informed consent for the study 
x 
Obtain written informed consent from parent/caregiver to collect information about 
parent/caregiver symptoms and burden via the Zarit Caregiver Burden, and HADS 
rating 
x 
Review inclusion and exclusion criteria 
x 
Review retrospective seizure diary data 
x 
Record demographic information 
x 
Record medical, neurological, and epilepsy history 
x 
Record current epilepsy status (number/type/duration seizures per month); submit 
form to Epilepsy Study Consortium 
x 
Collect past 6 months (or available duration) of parent/caregiver seizure diary data 
if available (screen shots of cell phones are acceptable, as are photocopies of paper 
diaries or print outs) and place in source file 
x 
Record prior medications 
x 
Complete physical examination, including height and weight 
x 
Complete neurological examination 
x 
12-lead electrocardiogram 
x 
Doppler ECHO (this may be obtained any time between Study Day -28 and 
Study Day -15) 
x 
Vital signs 
x 
Urine or serum pregnancy test for females of child-bearing potential 
x 
Laboratory evaluation (serum chemistry, hematology, immunoglobulin, and 
urinalysis) 
x 
Urine or serum THC panel 
x 
Whole blood CBD 
x 
C-SSRS Baseline/Screening Assessment (Appendix 2) 
x 
Instruct parent/caregiver on use of diary 
x 
Dispense diary (after above procedures have been concluded; the 28-day period for 
determining baseline seizure frequency begins when screening assessments are 
completed and the seizure diary is dispensed) 
x 
Record AEs 
x 
Record AESIs 
Only eligible subjects as specified by the inclusion and exclusion criteria who are 
independently confirmed to be eligible by the Epilepsy Study Consortium will be enrolled into 
the study. 
After enrollment into the study, each subject will be issued a “Subject Card” containing 
information about the subject’s participation in the study. The subject or parent/caregiver will be 
advised to retain this card on his person for the entire duration of the study so that the investigator 
or the sponsor can be contacted in case of emergency. 
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In certain circumstances the sponsor may allow subjects who did not meet all inclusion/exclusion 
criteria at the time of the Screening Visit to have the screening period extended, or to be re-
screened for eligibility. In all cases the investigator should consult with the Medical Monitor. 
Decisions whether to permit rescreening resides solely with the sponsor.  
The decision whether to permit extended screening or rescreening can be influenced by many 
factors individual to that subject case. Some general principles apply: 
1. If baseline seizure screening is extended or the subject is discontinued and then rescreened, 
the screening period for establishing the baseline seizure frequency will be the immediate 
4 weeks before the randomization visit. 
2. Subjects who are found to be on a prohibited medication at the screening visit may be 
weaned off of that medication provided: 
a. Decisions to withdraw a disallowed concomitant medication must be made with 
the agreement of the prescribing physician 
b. If the medication has antiepileptic properties, a wash out of at least 5 half-lives 
must be completed before collection of baseline seizure data.  
c. If a decision has been made to wean off of a medication without antiepileptic 
properties and the washout period (at least 5 half-lives) is expected to be shorter 
than 3 weeks, then the subject may remain in screening and chart seizures using 
the seizure diary. 
3. 
If screening is extended, laboratory and ECHO assessments must be at least 6 weeks 
current at the time of Randomization. Assessments older than 6 weeks will need to be 
repeated prior to Randomization. If laboratory assessments are repeated within 2 weeks of 
Randomization, samples do not need to be collected during Visit 3, provided valid results 
are obtained. 
6.1.1.2. 
Phone Visit 2 (Study Day -15) 
Site personnel will contact the subject via telephone on Study Day -15 and record the 
following: 
x AEs 
x AESI 
In addition, site personnel with review the diary entries with the parent/caregiver. Ensure diary is 
being completed daily; if diary compliance is low (i.e. <90%), re-train parent/caregiver. 
6.1.1.3. 
Clinic Visit 3 (Study Day -1): Randomization 
This period is intended to ensure that subjects meet the study entry criteria and confirm they 
have experienced ≥ 2 seizures resulting in drops per week during the 4-week Baseline Period. 
Subjects must have at least 28 days of prospective diary data at Visit 3.  
The following procedures will be performed on Study Day -1: 
x 
Review inclusion and exclusion criteria 
x 
Review current seizure activity (number/type/duration) from diary since previous 
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visit and calculate the number of seizures resulting in drops per week and over the 
4-week observation period. 
x 
Ensure approval for enrollment has granted by the Epilepsy Study Consortium and 
after ECHO review (ERT). 
x 
Record prior medications since previous visit 
x 
Complete physical examination, including weight 
x 
Abbreviated neurological examination 
x 
Vital signs 
x 
12-lead ECG 
x 
Urine or serum pregnancy test for females of child-bearing potential 
x 
Laboratory evaluation (serum chemistry, hematology, immunoglobulin, hormones, 
coagulation,, and urinalysis (urine for urinalysis may be collected at home, the 
night before the clinic visit, as long as collection procedures are followed to 
maintain sample stability)) 
x 
Collect plasma sample for AED pharmacokinetic evaluation (must document time 
of last dose) 
x 
Urine or serum THC panel 
x 
Whole blood CBD 
x 
Obtain (optional) blood sample for epilepsy genotype panel (if not obtained at this 
visit, it should be obtained by Visit 12) 
x 
Tanner Staging for subjects >7 to 18 years of age (Appendix 5) 
x 
Collect, review, and dispense diary. Ensure diary is being completed daily; if diary 
compliance is low (i.e. <90%), re-train parent/caregiver. 
x 
C-SSRS Since Last Visit Assessment (Appendix 2) 
x 
BRIEF (Appendix 3) 
x 
QOLCE (Appendix 6) 
x 
HADS (Appendix 7) 
x 
Zarit Caregiver Burden Inventory (Appendix 8) 
x 
Record AEs 
x 
Record AESI 
x 
When eligibility for the Titration Period is confirmed, obtain treatment assignment 
from the IWR 
x 
Dispense and administer study medication. Subjects will be required to stay in the 
clinic for monitoring of adverse reactions until the investigator determines it is safe 
to leave. Those considered by the investigator to need further monitoring will be 
hospitalized until the investigator determines they can be safely discharged. The 
first dose taken in the clinic will be recorded in the eCRF, but not the subject diary, 
and the next dose should be at least 8 hours later or the following morning. The 
dose on the following morning will count as Study Day 1 and be recorded in the 
subject diary. 
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6.1.2 
TITRATION AND MAINTENANCE PERIODS 
6.1.2.1 
Titration Period Study Day 1 
Subjects will take their second dose of study medication on the morning of Study Day 1. Study 
Day 1 is considered the first day of dosing, even though subjects received an in-clinic dose on 
Study Day -1. 
6.1.2.2 
Phone Visits 4 and 5 (Titration Period Study Days 4 and 8) 
Site personnel will contact the subject via telephone on Titration Period Study Days 4 and 8 
and record the following: 
x AEs 
x AESI 
x Concomitant medications 
In addition, site personnel will review study medication dosing procedure and the diary entries 
with the parent/caregiver. 
6.1.2.3 
Clinic Visit 6 (Titration Period Study Day 15) 
Subjects will report to the clinic in the morning on Titration Period Study Day 15. The 
following procedures will be performed: 
x Review current seizure activity (number/type/duration) from diary since previous visit 
x Record concomitant medications 
x Obtiain weight 
x Obtain vital signs 
x Collect, review, and dispense diary. Ensure diary is being completed daily; if diary 
compliance is low (i.e. <90%), re-train parent/caregiver. 
x C-SSRS Since Last Visit Assessment (Appendix 2) 
x Clinical Global Impression – Improvement (assessed by parent/caregiver) 
x Clinical Global Impression – Improvement (assessed by investigator) 
x Record AEs 
o Perform an abbreviated physical and/or neurological examination as appropriate 
based on last exam and reported AEs 
o Collect plasma sample for AED pharmacokinetic evaluation if clinically 
indicated (must document time of last dose) 
x Record AESI 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x Dispense study medication 
6.1.2.4 
Phone Visit 7 (Maintenance Period Study Day 29) 
Site personnel will contact the subject via telephone on Maintenance Period Study Day 29 and 
record the following: 
x AEs 
x AESI 
x Concomitant medications 
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In addition, site personnel will review the diary entries with the parent/caregiver. Ensure diary 
is being completed daily; if diary compliance is low (i.e. <90%), re-train parent/caregiver. 
6.1.2.5 
Clinic Visit 8 (Maintenance Period Study Day 43) 
x Subjects will report to the clinic in the morning on Maintenance Period Study Day 43. 
Subjects should not take their morning dose(s) of study medication. The following 
procedures will be performed: 
x Review current seizure activity (number/type/duration) from diary since previous visit 
x Record concomitant medications 
x Obtain weight (Note: if the subject’s weight is ±25% of the weight at Study Day-1, 
the IMP dose will be recalculated) 
x Obtain vital signs 
x 12-lead electrocardiogram 
x Doppler ECHO (this must be obtained any time between Study Day 40 and Study 
Day 54) 
x Urine or serum pregnancy test for females of child-bearing potential 
x Laboratory evaluation (serum chemistry, hematology, immunoglobulin hormones, and 
urinalysis (urine for urinalysis may be collected at home, the night before the clinic visit, 
as long as collection procedures are followed to maintain sample stability)) 
x Urine or serum THC panel 
x Whole blood CBD 
x Collect plasma sample for ZX008 pharmacokinetic evaluation at the following 
timepoints: within 1 hour prior to the morning dose of study medication, and 1, 2 and 4-6 
hours after the morning dose of study medication 
x Collect plasma sample for AED pharmacokinetic evaluation (must document time of last 
dose) 
x Collect, review, and dispense diary. Ensure diary is being completed daily; if diary 
compliance is low (i.e. <90%), re-train parent/caregiver. 
x C-SSRS Since Last Visit Assessment (Appendix 2) 
x Zarit Caregiver Burden Inventory (Appendix 8) 
x Clinical Global Impression – Improvement (assessed by parent/caregiver) 
x Clinical Global Impression – Improvement (assessed by investigator) 
x Perform an abbreviated physical and/or neurological examination as appropriate based on 
last exam and reported AEs 
x Record AESI 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x Dispense study medication 
6.1.2.6 
Phone Visit 9 (Maintenance Period Study Day 57) 
Site personnel will contact the subject via telephone on Maintenance Period Study Day 57 and 
record the following: 
x AEs 
x AESI 
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x Concomitant medications 
In addition, site personnel with review the diary entries with the parent/caregiver. Ensure diary 
is being completed daily; if diary compliance is low (i.e. <90%), re-train parent/caregiver. 
6.1.2.7 
Clinic Visit 10 (Maintenance Period Study Day 71) 
Subjects will report to the clinic on Maintenance Period Study Day 71. The following 
procedures will be performed: 
x Review current seizure activity (number/type/duration) from diary since previous visit 
x Record concomitant medications 
x Obtain weight 
x Obtain vital signs 
x Collect, review, and dispense diary. Ensure diary is being completed daily; if diary 
compliance is low (i.e. <90%), re-train parent/caregiver. 
x C-SSRS Since Last Visit Assessment (Appendix 2) 
x Clinical Global Impression – Improvement (assessed by parent/caregiver) 
x Clinical Global Impression – Improvement (assessed by investigator) 
x Record AEs 
x Perform an abbreviated physical and/or neurological examination as appropriate based on 
last exam and reported AEs 
x Collect plasma sample for AED pharmacokinetic evaluation if clinically indicated 
x Record AESI 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x Dispense study medication 
At Clinic Visit 10, compliant subjects who have tolerated IMP should be presented with the 
ICF for the open-label extension (Part 2). Informed consent for the open-label extension 
should be signed at Visit 12 or earlier in order to enter the open-label extension. 
6.1.2.8 
Phone Visit 11 (Maintenance Period Study Day 85) 
Site personnel will contact the subject via telephone on Maintenance Period Study Day 85 and 
record the following: 
x AEs 
x AESI 
x Concomitant Medications 
In addition, site personnel with review the diary entries with the parent/caregiver. Ensure diary 
is being completed daily; if diary compliance is low (i.e. <90%), re-train parent/caregiver. 
6.1.2.9 
Clinic Visit 12 (Maintenance Period Study Day 99): End of Study/Early 
Termination 
The End-of-Study participation in Part 1 for an individual subject occurs after he/she has 
received IMP for 12 weeks in the Maintenance Period. At the Part 1 End-of-Study visit, the 
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subject may enroll into the Part 2 OLE Treatment Period if they have completed 12 weeks of 
treatment in the Maintenance Period. Other circumstances for participation in Part 2 are 
described in Section 4.3. Informed consent for the Part 2 OLE Treatment Period should be 
signed before data collection begins on Visit 12 (if not signed earlier) in order to participate in 
Part 2. 
The End-of-Study visit may also occur if the subject withdraws participation from the study or 
the sponsor terminates the study. If the subject withdraws participation from the study, they 
may on a case-by-case basis, be eligible for entrance into the Part 2 OLE Treatment Period 
after consideration of the circumstances of the early termination and the potential benefit- risk 
of continued participation in a ZX008 trial. The decision whether to permit Part 2 participation 
resides solely with the sponsor, who may consult with the site investigator. If the sponsor 
terminates the study early, the subject may or may not be offered enrollment into Part 2, 
depending on the reason for termination. 
Subjects will visit the clinic for the End-of-Study visit if one the following events occur: 
1. The subject withdraws or is withdrawn from participation in the study. 
2. The sponsor terminates the study. 
3. The subject completes all study related visits and 
procedures. The following procedures will be performed: 
x Review current seizure activity (number/type/duration) from diary since previous visit 
x Record concomitant medications 
x Complete physical examination, including height and weight 
x Complete neurological examination 
x Obtain vital signs 
x 12-lead electrocardiogram 
x Doppler ECHO (must be performed any time between Study Day 90 and Study Day 113; 
if subject terminates early from the study, the ECHO should be scheduled as soon as 
practical). If the Study Day 43 ECHO was completed ≤30 days prior to early termination, 
the Visit 12 ECHO will not be performed provided the parent/guardian agrees to bring 
the subject to the clinic for the cardiac follow-up visit (see Table 9). 
x Urine or serum pregnancy test for females of child-bearing potential 
x Laboratory evaluation (serum chemistry, hematology, immunoglobulin, hormones, and 
urinalysis (urine for urinalysis may be collected at home, the night before the clinic visit, 
as long as collection procedures are followed to maintain sample stability)) 
x Urine or serum THC panel 
x Whole blood CBD 
x Collect plasma sample for AED pharmacokinetic evaluation (must document time of last 
dose) 
x Tanner Staging for subjects >7 to 18 years of age (Appendix 5) 
x Collect, review, and dispense diary. Ensure diary is being completed daily; if diary 
compliance is low (i.e. <90%), re-train parent/caregiver 
x C-SSRS Since Last Visit Assessment (Appendix 2) 
x Clinical Global Impression – Improvement (assessed by parent/caregiver) 
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x Clinical Global Impression – Improvement (assessed by investigator) 
x BRIEF (Appendix 3) 
x QOLCE (Appendix 6) 
x HADS (Appendix 7) 
x Zarit Caregiver Burden Inventory (Appendix 8) 
x Record AEs 
x Record AESIs 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x Dispense study medication for taper for subjects not continuing into Part 2.  
x Dispense and administer study medication for transition for subjects continuing into Part 
2. Subjects will be required to stay in the clinic for monitoring of adverse reactions until 
the investigator determines it is safe to leave. Those considered by the investigator to 
need further monitoring will be hospitalized until the investigator determines they can be 
safely discharged.   
6.1.3 POST-DOSE VISIT (CLINIC VISIT 13; STUDY DAY 113) 
For subjects entering the Part 2 OLE Treatment Period, the subject will visit the 
clinic on Day 113, which will also be Part 2 Day 1.  The procedures described in 
Section 6.2 will be followed.   
 
If the subject does not enter the Part 2 OLE Treatment Period (or discontinues from the 
study early), the subject will visit the clinic on Study Day 113 (or 14 days after the day of 
discontinuation). If necessary, Visit 13 may be conducted as a phone call, provided diaries 
and study medication are returned by this time. The following will be recorded/performed: 
x Review current seizure activity (number/type/duration) from diary since previous visit 
x AEs 
x AESIs 
x Concomitant medications 
x Collect and review diary with parent/caregiver 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
6.1.4 CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 14; 3 and 6 months after 
last dose) 
If the subject completes the study but does not enter the Part 2 OLE Treatment Period or 
discontinues from the study early, the subject will return to the clinic after study drug 
discontinuation for follow-up cardiac testing. The timing and frequency of exams are in Table 
10. Subjects on blinded medication who are found to have been on placebo are not required to 
participate in follow-up testing once the blind is broken. As the ECHO and ECG will be 
administered in a separate clinic than the pediatric neurology clinic, an asymptomatic subject 
receiving a follow-up ECHO and ECG does not require a physical examination. 
Subjects with positive findings on safety evaluations at post-dose follow-ups should have 
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repeat examinations every 3 months until the finding is resolved or stable and unlikely to 
change, with reports submitted as AEs to the ZX008 safety database. 
Table 10: 
Schedule of Post-Treatment Cardiac Follow-up for Part 1 
 
 
 
 
Parameter 
Duration of Blindeda or Fenfluramine Treatment 
 
Less than 
2 weeks 
Cumulative 
 
 
2 and 
<13 weeks 
>13 weeks 
Have had any cardiac sign or symptom 
regardless of the time on study drugb 
ECHO 
No 
Yes, 
3 months post- 
treatment 
Yes, 
3 and 6 months 
post-treatment 
Yes, 
3 and 6 months post- treatment, and every 
3 months until resolved, or stable and 
unlikely to change 
ECG 
No 
Yes, 
3 months post- 
treatment 
Yes, 
3 and 6 months 
post-treatment 
Yes, 
3 and 6 months post- treatment and every 3 
months until resolved, or stable and 
unlikely to change 
Physical 
examination 
No 
Yes, 
3 months post- 
treatment 
Yes, 
3 months post- 
treatment only 
Yes, 
3 and 6 months post- treatment, and every 
3 months until resolved, or stable and 
unlikely to change 
a If blind is broken at the end of the study and a subject revealed to have taken only placebo, no further testing is 
required. 
b    Positive sign or symptom includes any development of valve thickening or regurgitation (“trace” or greater in mitral, 
aortic; mild or greater in pulmonary, tricuspid), or sign or symptom indicative of potential pulmonary hypertension 
as adjudicated by the ICAB. 
 
6.2 
Part 2 
Review of inclusion and exclusion criteria and written informed parental or guardian consent 
and assent of minors (if the subject is capable of providing assent) for Part 2 must be obtained 
before a subject can start any of the Part 2 Visit 15 procedures.  This includes review and 
approval (or adjudication if required) of the ECG and/or ECHO findings by the central reader, 
and approval for continuation in the open-label extension (if applicable) by the IDSMC. 
Only eligible subjects as specified by the inclusion and exclusion criteria who have 
successfully completed Part 1, or have permission from the Sponsor, will be enrolled into 
Part 2. Other circumstances for participation in Part 2 are described in Section 4.3. 
Study procedures for the Part 2 OLE Treatment Period will be conducted according to 
the Schedule of Assessments in Table 2. Time windows for all assessments are detailed 
in Table 11. 
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Table 11: 
Time Windows for Assessments in Part 2 
Visit / Procedure 
Time window (relative to scheduled 
visit / procedure) 
Visit 15 (Clinic; OLE Study Day 1)  
± 4 daysa 
Visits 16 (Clinic/Phone; OLE Study Day 15) 
± 3 days 
Visits 17-41 (Clinic: OLE Study Days 30, 60, 90, 180, 270, 360, 
450, 540*, 630, 720*, 810, 900*, 990, 1080*, 1170,1260*, 1350, 
1440*,1530, 1620*, 1710, 1800*, 1890, 1980*, 2070) 
± 4 days 
Visit 42 (Clinic; OLE Study Day2160; EOS) 
± 4 days 
Visit 43 (Clinic; OLE Study Day 2174; post dosing) 
± 4 days 
Visit 44, 45 (ECHO clinic; 3 and 6 months after last dose) 
+ 30 days 
AED=antiepileptic drug (s); ECHO=echocardiogram 
a In the case of a required safety review of a Visit 12 ECHO alert, the transition period between Visit 12 and Vist 15 may be 
extended up to 14 days to allow time for adjudication. 
*If marketing approval is not yet received after the end of the OLE Treatment Period, treatment may be extended on an annual basis in order to provide continuity 
of treatment for subjects who are enrolled in Part 2 of the study. Up to 5 annual extensions can be applied, for a total treatment time of 72 months in the OLE. 
Continuation will be based on review of safety/tolerability and effectiveness, and be offered for subjects who continue to meet eligibility requirements, comply 
with investigator’s instructions, and for whom the investigator judges benefit outweighs risk. The decision to extend and informed consent should be completed 
before the start of the first visit of the extension (e.g. Month 12,  24, 36, 48 or 60). After approval from Investigator and Sponsor for extension and starting after 
Visit 26/ Month24 (or at a later visit if Visit 26/ Month 24 visit has already occured at the time of Protocol Amendment 4.0 approval), subject will return to the 
clinic every 6 months for the 1 year extension (i.e. Month 30, 36). The End of Study will be Visit 42, unless another extension is granted, in which case the subject 
will continue to return for clinic visits every 6 months and will have a phone visit 3 months after the in-clinic visit.. Further extensions can then be applied as 
required if marketing approval is not yet received. 
 
6.2.1 
Clinic Visit 15 (OLE Study Day 1) 
Part 2 Visit 15 will occur 14 days (± 4 days) after Part 1 Visit 12. The 14-day transition period 
preceding Visit 15 may be extended up to 14 days in the case of a required safety adjudication of 
a Visit 12 ECHO alert.  
The following procedures will be performed during Visit 15: 
x Ensure entry criteria for Part 2 are met 
x Vital signs 
x Record prior and concomitant medications (use core study Visit 12 information)  
x Instruct parent/caregiver on use of diary 
x Record ongoing AEs as medical history  
x Record ongoing AESI as medical history  
x Collect, review, and dispense diary (after above procedures have been concluded) 
x Dispense study medication 
Data collected from Part 1 Visit 12 may be used for the following procedures unless otherwise 
indicated: 
x Record medical, neurological, and epilepsy history 
x Complete physical examination, including height and weight (use data collected at Part 1 
Visit 12, unless there was a significant change in subject status warranting a new 
complete examination) 
x Complete neurological examination (use data collected at Part 1 Visit 12, unless there 
was a significant change in subject status warranting a new complete examination) 
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x 12-lead ECG  
x Doppler ECHO  
x Laboratory evaluation (serum chemistry, hematology, immunoglobulin, hormones, and 
urinalysis) (use Part 1 Visit 12 information, unless investigator determines new 
laboratory evaluation is warranted due to change in subject status) (if collecting urine for 
urinalysis, urine may be collected at home, the night before the clinic visit, as long as 
collection procedures are followed to maintain sample stability) 
x Pregnancy test 
x Urine or serum THC panel  
x Whole blood CBD  
x C-SSRS Since Last Visit Assessment (Appendix 2)  
x CGI-I (assessed by parent/caregiver) 
x CGI-I (assessed by investigator)  
x BRIEF (Appendix 3) 
x QOLCE (Appendix 6) 
x HADS (Appendix 7) 
x Zarit Caregiver Burden Inventory (Appendix 8) 
 
6.2.2 
Clinic/Phone Visit 16 (OLE Study Day 15) 
Part 2 Visit 16 may be performed in the clinic, or, at the discretion of the investigator, performed 
via phone. 
If Visit 16 is performed in the clinic, subjects will report to the clinic in the morning of that day. 
The following procedures will be performed: 
x Review current seizure activity (number/type/duration) from diary since previous visit  
x Record concomitant medications since previous visit 
x Obtain weight 
x Vital signs 
x Laboratory evaluation (serum chemistry, hematology, immunoglobulin, hormones, and 
urinalysis) (only if investigator determines new laboratory evaluation is warranted due to 
change in subject status since Visit 15) (if collecting urine for urinalysis, urine may be 
collected at home, the night before the clinic visit, as long as collection procedures are 
followed to maintain sample stability) 
x Collect, review, and dispense diary. Ensure diary is being completed daily; if diary 
compliance is low (i.e. <90%), re-train parent/caregiver. 
x Record AEs 
o Perform an abbreviated physical and/or neurological examination as appropriate 
based on last exam and reported AEs 
o Collect plasma sample for AED pharmacokinetic evaluation if clinically indicated 
(must document time of last dose) 
x Record AESI 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
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x Collect and review study medication 
If the visit is performed as a phone visit, site personnel will contact the subject on Study Day 15 
and record/review the following: 
x Concomitant medications 
x AEs 
x AESI 
x Study medication use 
x Diary entries 
6.2.3 
Clinic Visits 17-21 (OLE Months, 1, 2, 3, 6, and 9)  
Subjects will report to the clinic for Part 2 Clinic Visits 17 through 21. The following procedures 
will be performed: 
x Review current seizure activity (number/type/duration) from diary since previous visit  
x Record concomitant medications 
x Obtain weight (Note: if the subject’s weight is ±25% of the weight at Part 2 Day 15, 
the IMP dose will be recalculated) 
x Obtain vital signs 
x 12-lead ECG 
x Doppler ECHO (at Months 1, 3, 6, and 9) 
x Urine or serum pregnancy test for females of child-bearing potential (at Months 3, 6, and 
9) 
x Laboratory evaluation (serum chemistry, hematology, immunoglobulin, hormones, and 
urinalysis; at Months 3, 6 and 9 unless otherwise clinically indicated) (urine for urinalysis 
may be collected at home, the night before the clinic visit, as long as collection 
procedures are followed to maintain sample stability) 
x Urine or serum THC panel (at Months 3, 6 and 9) 
x Whole blood CBD (at Months 3, 6, and 9) 
x Collect plasma sample for AED PK and document time of last dose (at Months 3, 6, and 
9 unless otherwise clinically indicated) 
x Tanner Staging for subjects > 7 to 18 years of age (Month 6 only) (Appendix 5) 
x Collect, review, and dispense diary. Ensure diary is being completed daily; if diary 
compliance is low (i.e. <90%), re-train parent/caregiver. 
x C-SSRS Since Last Visit Assessment (Appendix 2) 
x CGI-I (assessed by parent/caregiver) 
x CGI-I (assessed by investigator) 
x BRIEF (Month 6 only) (Appendix 3) 
x QOLCE (Month 6 only) (Appendix 6) 
x HADS (Month 6 only) (Appendix 7) 
x Record AEs 
o Perform an abbreviated physical and/or neurological examination as appropriate 
based on last exam and reported AEs 
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o Collect plasma sample for AED pharmacokinetic evaluation if clinically 
indicated 
x Record AESI 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x Dispense study medication 
 
The next study visit should be Visit 30 (EOS), unless a 1-year extension is granted. If 
extending study participation, the decision should be made during Visit 21 (or at least prior to 
conducting Visit 22 procedures) by the Investigator and the consent from the subject or 
parent/caregiver obtained. After approval from Investigator and Sponsor for extension, 
Subject will return every 3 months for the 1 year extension (i.e. Month 12, 15, 18, 21). The 
End of Study will be Visit 30, on the 24th month of OLE, unless another 1 year extension is 
granted, in which case the subject will continue to return for clinic visits every 3 months (i.e. 
Month 24, 27, 30, 33) until the EOS Visit 30 on the 36th month of OLE. 
6.2.4 
Clinic Visit 22 (OLE Month 12) 
Subjects will report to the clinic and the following procedures will be performed: 
x Review current seizure activity (number/type/duration) from diary since previous visit  
x Record concomitant medications 
x Obtain weight (Note: if the subject’s weight is ±25% of the weight at Part 2 Day 15, 
the IMP dose will be recalculated) 
x Complete physical examination, including height and weight, and calculation of BMI 
x Complete neurological examination 
x Obtain vital signs 
x 12-lead ECG 
x Doppler ECHO (must be performed any time between Study Day 344 and Study 
Day 365). 
x Urine or serum pregnancy test for females of child-bearing potential 
x Laboratory evaluation (serum chemistry and hematology, and urinalysis) 
x Urine or serum THC panel 
x Whole blood CBD 
x Collect plasma sample for AED PK evaluation (must document time of last dose) 
x Tanner Staging for subjects > 7 to 18 years of age (Appendix 5) 
x Collect and review diary 
x C-SSRS Since Last Visit Assessment (Appendix 2) 
x CGI-I (assessed by parent/caregiver) 
x CGI-I (assessed by investigator) 
x BRIEF (Appendix 3) 
x QOLCE (Appendix 6) 
x HADS (Appendix 7) 
x Zarit Caregiver Burden Inventory (Appendix 8) 
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x Record AEs 
x Record AESI 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x Dispense study medication 
6.2.5 
Clinic Visits 23-41 (OLE Months 15, 18, 21, 24, 27, 30, 33, 36, 39, 
42, 45, 48, 51, 54, 57, 60, 63, 66, 69) 
If marketing approval is not yet received after the the end of the OLE Treatment Period, 
treatment may be extended on an annual basis in order to provide continuity of treatment for 
subjects who are enrolled in Part 2 of the study. Continuation will be based on review of 
safety/tolerability and effectiveness, and be offered for subjects who continue to meet eligibility 
requirements, comply with investigator’s instructions, and for whom the investigator judges 
benefit outweighs risk. 
From Visit 26/Month 24 (or a later visit if Visit 26/Month 24 has already occurred at the time of 
Protocol Amendment 4.0 approval), if approved for the extensions, subjects will report to the 
clinic every 6 months and will have a phone visit 3 months after each in-clinic visit for Part 2 
Clinic Visits 26 through 41.  
The following procedures will be performed during in-clinic visits: 
x Record concomitant medications 
x Obtain weight (Note: if the subject’s weight is ±25% of the weight at Part 2 Day 15, 
the IMP dose will be recalculated) 
x Obtain vital signs 
x Abbreviated physical examination, as appropriate based on last exam and reported AEs 
x Abbreviated neurological examination, as appropriate based on last exam and reported 
AEs 
x 12-lead ECG, if clinically indicated  
x Doppler ECHO 
x Urine or serum pregnancy test for females of child-bearing potential 
x Only if clinically indicated: 
o Laboratory evaluation (serum chemistry, hematology, immunoglobulin, 
hormones, and urinalysis) (urine for urinalysis may be collected at home, the 
night before the clinic visit, as long as collection procedures are followed to 
maintain sample stability) 
o Collect plasma sample for AED PK and document time of last dose 
x Seizure Assessment by Investigator 
x C-SSRS Since Last Visit Assessment (Appendix 2) 
x CGI-I (assessed by parent/caregiver) 
x CGI-I (assessed by investigator) 
x Record AEs 
x Record AESI 
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x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x Dispense study medication 
 
The following procedures will be performed during phone visits: 
x Record concomitant medications 
x Record AEs 
x Record AESI 
 
The next study visit after Visit 25/Month 21, Visit 29/Month 33, Visit 33/Month 45, Visit 
37/Month 57 or Visit 41/Month 69  should be Visit 42 (EOS), unless another 1-year extension is 
granted. If extending study participation, the decision should be made during the in-clinic visit 
preceeding the annual reconduction by the Investigator and the consent from the subject or 
parent/caregiver obtained. After approval from Investigator and Sponsor for extension and 
starting after Visit26/Month 24 (or a later visit if Visit 26/Month 24 has already occurred at the 
time of Protocol Amendment 4.0 approval), subject will return to the clinic every 6 months and 
will have a phone visit 3 months after each in-clinic visit for the 1 year extension. The End of 
Study will be Visit 42, the 72nd month of the OLE, or until ZX008 is approved in the subject’s 
country of residence and listed on a patient’s health plan formulary, whichever occurs first. 
 
6.2.6 
Clinic Visit 42:  End of Study/Early Termination 
The End-of-Study participation in Part 2 for an individual subject occurs after he/she has 
received IMP for up to 5 years in the Part 2 OLE Treatment Period, or until ZX008 is approved 
in a subject’s country of residence and listed on a patient’s health plan formulary, whichever 
occurs first. The End-of-Study visit may also occur if the subject withdraws participation from in 
Part 2 or the Sponsor terminates the study.  
Subjects will visit the clinic for the End-of-Study visit if one the following events occur: 
1. The subject withdraws or is withdrawn from participation in the study. 
2. The Sponsor terminates the study. 
3. The subject completes all study related visits and procedures (at least up to Month 12, 
but extensions may be granted for up to 72 months). 
4. ZX008 is approved in a subject’s country of residence and is listed on a patient’s 
health plan formulary 
The following procedures will be performed for subjects who did not extend Part 2 participation 
past 12 months: 
x Review current seizure activity (number/type/duration) from diary since previous visit  
x Record concomitant medications 
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x Complete physical examination, including height and weight, and calculation of BMI 
x Complete neurological examination 
x Obtain vital signs 
x 12-lead ECG 
x Doppler ECHO (must be performed within 3 weeks of the visit; if subject terminates 
early from the study, the ECHO should be scheduled as soon as practical). If the previous 
ECHO was completed ≤ 30 days prior to early termination, the Visit 30 ECHO will not 
be performed provided the parent/guardian agrees to bring the subject to the clinic for the 
cardiac follow-up visit (see Table 12). 
x Urine or serum pregnancy test for females of child-bearing potential 
x Laboratory evaluation (serum chemistry, hematology, immunoglobulin, hormones, and 
urinalysis) (urine for urinalysis may be collected at home, the night before the clinic visit, 
as long as collection procedures are followed to maintain sample stability) 
x Urine or serum THC panel 
x Whole blood CBD 
x Collect plasma sample for AED PK evaluation (must document time of last dose) 
x Tanner Staging for subjects > 7 to 18 years of age (Appendix 5) 
x Collect and review diary C-SSRS Since Last Visit Assessment (Appendix 2) 
x CGI-I (assessed by parent/caregiver) 
x CGI-I (assessed by investigator) 
x BRIEF (Appendix 3) 
x QOLCE (Appendix 6) 
x HADS (Appendix 7) 
x Zarit Caregiver Burden Inventory (Appendix 8) 
x Record AEs 
x Record AESI 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x Dispense study medication (not applicable for subjects transitioning to commercial drug) 
The following procedures will be performed for subjects who are extended Part 2 participation 
past 12 months: 
x Record concomitant medications 
x Complete physical examination, including height and weight, and calculation of BMI 
x Complete neurological examination 
x Obtain vital signs 
x Doppler ECHO (must be performed within 3 weeks of the visit; if subject terminates 
early from the study, the ECHO should be scheduled as soon as practical). If the previous 
ECHO was completed ≤ 30 days prior to early termination, the Visit 30 ECHO will not 
be performed provided the parent/guardian agrees to bring the subject to the clinic for the 
cardiac follow-up visit (see Table 12). 
x Urine or serum pregnancy test for females of child-bearing potential 
x Only if clinically indicated: 
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o Collect plasma sample for AED PK evaluation (must document time of last 
dose) 
o Laboratory evaluation (serum chemistry, hematology, immunoglobulin, 
hormones, and urinalysis) (urine for urinalysis may be collected at home, the 
night before the clinic visit, as long as collection procedures are followed to 
maintain sample stability) 
o 12-lead ECG 
x Collect and review diary C-SSRS Since Last Visit Assessment (Appendix 2) 
x CGI-I (assessed by parent/caregiver) 
x CGI-I (assessed by investigator) 
x Seizure assessment by investigator 
x Record AEs 
x Record AESI 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x Dispense study medication (not applicable for subjects transitioning to commercial drug) 
 
6.2.7 
POST-DOSE VISIT (CLINIC Visit 43; 14 DAYS AFTER LAST 
DOSE OF IMP) 
If the subject completes the study (or discontinues from the study early), and is not switching to 
commercially available drug, the subject will visit the clinic for Visit 43 (14 days after the EOS 
or day of discontinuation). Visit 43 may be conducted as a phone call if physical and 
neurological examinations are not clinically indicated, provided diaries (if applicable) and study 
medication are returned by this time. The following procedures will be performed: 
x Review current seizure activity (number/type/duration) from diary since previous visit 
x Record AEs 
x Perform an abbreviated physical and/or neurological examination as appropriate based on 
last exam and reported AEs 
x Obtain weight 
x Record AESI 
x Record concomitant medications 
x Collect and review diary with parent/caregiver 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
 
6.2.8 
CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 44, 45; 3 AND 6 
MONTHS AFTER LAST DOSE OF IMP) 
If the subject completes Part 2 or discontinues from the Part 2 early, and is not switching to 
commercially available drug, the subject will return to the clinic for follow-up cardiac testing. 
The timing and frequency of exams are in Table 12. As the ECHO and ECG will be administered 
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in a separate clinic than the pediatric neurology clinic, an asymptomatic subject receiving a 
second follow-up ECHO and ECG does not require a physical examination.  
Subjects with positive findings on safety follow-up examinations should continue to be followed 
until the finding is resolved or stable and unlikely to change.  
If the subject completes the study (or discontinues from the study early) and is switching to 
commercially available drug, the subject will complete the EOS visit and follow the drug 
administration process outlined for commercial product as advised by the subject’s physician. 
The EOS/ET and cardiac follow-up visits are not required. 
 
Table 12. 
Schedule of Post-Treatment Cardiac Follow-up for Part 2 
 
Duration of Fenfluramine Treatment 
 
 
 
Parameter 
 
Less than  
2 weeks 
Cumulative 
 
 
2 and  
≤ 13 weeks 
 
 
 
> 13 weeks 
Have had any cardiac sign or symptom 
regardless of the time on study druga 
ECHO 
No 
Yes,  
3 months post- 
treatment 
Yes,  
3 and 6 months 
post-treatment 
Yes,  
3 and 6 months post-treatment, and until 
resolved, or stable and unlikely to change 
ECG 
No 
Yes,  
3 months post- 
treatment 
Yes,  
3 and 6 months 
post-treatment 
Yes, 
3 and 6 months post-treatment and until 
resolved, or stable and unlikely to change 
Physical 
examination 
No 
Yes,  
3 months post- 
treatment 
Yes,  
3 months post- 
treatment only 
Yes, 
3 and 6 months post-treatment, and until 
resolved, or stable and unlikely to change 
a Positive sign or symptom includes any development of valve thickening or regurgitation (“trace” or greater in mitral, 
aortic; mild or greater in pulmonary, tricuspid), or sign or symptom indicative of potential pulmonary hypertension as 
adjudicated by the ICAB. 
 
6.3 
STUDY CONDUCT DURING COVID-19 
In March 2020, the World Health Organization declared a global pandemic related to an illness 
caused by a novel coronavirus known as COVID-19. Alternative procedures and allowances are 
permitted due to restrictions related to COVID-19, including delays to in-person visits and 
specific assessments, performing remote phone or video visits if in-person visits cannot be 
conducted, and arranging shipments of investigational product directly to subjects. These 
allowances are detailed in Appendix 10. Though every attempt should be made to conduct study 
visits as described in this protocol, any implementation of alternative processes should be 
properly documented, including what was done differently, and which assessments or visits were 
missed or performed via phone or video. 
6.4 
ESTIMATED BLOOD VOLUME COLLECTION 
The maximum total blood volume collected during Part 1 of the study for clinical laboratory 
testing, genotyping, and PK will be approximately 84.0 mL, as outlined in Table 13 The 
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maximum total blood volume collected during Part 2 of the study for clinical laboratory testing 
and PK will be variable as the clinical laboratory testing will be performed as clinically indicated 
for the majority of in clinic visits after Visit26/Month 24, and will be approximately 104.0 mL at 
the minimum and will equal up to 351.5 mL , as outlined in Table 14. 
Table 13: 
Maximum Estimated Blood Volume Collection for Part 1* 
PART 1 
Visit 1 
(Day -28) 
Visit 3 
(Day -1) 
Visit 8 
(Day 43) 
Visit 12 
(Day 99) 
TOTAL 
Coagulation 
  
3.0 mL 
  
  
3.0 mL 
Chemistry 
5.0 mL 
5.0 mL 
5.0 mL 
5.0 mL 
20.0 mL 
Pregnancy test (serum) 
included in 
Chemistry 
included in 
Chemistry 
included in 
Chemistry 
included in 
Chemistry 
0.0 mL 
Hormones 
  
5.0 mL 
5.0 mL 
5.0 mL 
15.0 mL 
Immunoglobulin 
2.5 mL 
2.5 mL 
2.5 mL 
2.5 mL 
10.0 mL 
Hematology 
2.0 mL 
2.0 mL 
2.0 mL 
2.0 mL 
8.0 mL 
Genotype Panel 
  
4.0 mL 
  
  
4.0 mL 
AED PK plasma sample* 
  
2.0 mL 
2.0 mL 
2.0 mL 
6.0 mL 
ZX008 PK plasma sample 
  
  
8.0 mL 
  
8.0 mL 
Volume for flushing indwelling 
catheter 
  
  
2.0 
  
2.0 mL 
Cannabidiol/THC 
2.0 mL 
2.0 mL 
2.0 mL 
2.0 mL 
8.0 mL 
TOTAL 
11.5 mL 
25.5 mL 
28.5 mL 
18.5 mL 
84.0 mL 
AED=Anti-epileptic drugs; PK=pharmacokinetics 
*Blood collection for AED pharmacokinetic evaluation may be collected on Visits 6 and 10 if clinically indicated. If 
collected during these visits, the total blood volume per subject would equal up to 88.0 mL. 
 
Table 14. 
Maximum Estimated Blood Volume Collection for Part 2* 
PART 2 
Visit 19 
(Day 90) 
Visit 20 (Day 
180) 
Visit 21 (Day 
270) 
Visit 22 (Day 
360) 
Visits 23-
42 (in 
clinic 
only) 
TOTAL 
Chemistry 
5.0 mL 
5.0 mL 
5.0 mL 
5.0 mL 
 
20.0 mL 
Pregnancy test 
(serum) 
included in 
Chemistry 
included in 
Chemistry 
included in 
Chemistry 
included in 
Chemistry 
2.5 mL 
2.5 mL 
Hormones 
5.0 mL 
5.0 mL 
5.0 mL 
5.0 mL 
 
20.0 mL 
Immunoglobulin 
2.5 mL 
2.5 mL 
2.5 mL 
2.5 mL 
 
10.0 mL 
Hematology 
2.0 mL 
2.0 mL 
2.0 mL 
2.0 mL 
 
8.0  mL 
AED PK plasma 
sample 
2.0 mL 
2.0 mL 
2.0 mL 
2.0 mL 
 
8.0 mL 
Cannabidiol/THC 
2.0 mL 
2.0 mL 
2.0 mL 
2.0 mL 
 
8.0 mL 
TOTAL 
18.5 mL 
18.5 mL 
18.5 mL 
18.5 mL 
 30 mL 
104.0 mL 
AED=Anti-epileptic drugs; PK=pharmacokinetics 
*Laboratory testing may be conducted on Visits 16-18 and 23-42 if clinically indicated. After Visit 26, in-clinic visits will 
occur every 6 months. If collected during these visits, the total blood volume per subject would equal up to 351.5mL. 
*In concordance with The Seattle Children’s Research Foundation Guidance (Appendix 9), 
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blood collection volumes for children weighing up to 15 kg will be: 
x The maximum allowable volume of blood in one draw is 22-30 mL (2.5% of total blood 
volume) 
x The maximum in a 30-day period is 44-60 mL. 
On Part 1 Day 43/Visit 8 the pharmacokinetic blood draw will be completed as the priority and 
the blood draw for chemistry and hematology will be skipped for those subjects who weigh less 
than 13.5 kg, unless medical concerns (for example, from previous tests or reported side effects) 
prioritize chemistry and/or hematology. 
If blood collection is restricted due to volume or due to inability to draw adequate volume, 
collection should be prioritized as shown in Table 15 
Table 15: 
Priorities for Blood Sample Collections 
Assessment 
Priority 
ZX008 PK sample 
Priority 1 
Clinical chemistry 
Priority 2 
Cannabidiol 
Priority 2 
AED plasma sample 
Priority 2 
LH, FSH, estradiol, testosterone, GH, 
prolactin 
Priority 3 
Hematology 
Priority 3 
IGF-1 
Priority 4 
Genotyping 
One time optional collection any time during or after Visit 3 
(Randomization) in Part 1 
Coagulation 
One time collection any time before Part 1 PK day 
 
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7. 
EFFICACY, SAFETY, AND PHARMACOKINETIC 
ASSESSMENTS 
For an overview of the study variables and measurement times, see Schedule of 
Assessments (Table 1 and Table 2). 
Variables used to measure treatment compliance with respect to administration of the IMP are 
described in Section 5.7. 
7.1 
EFFICACY/EFFECTIVENESS ASSESSMENTS 
Baseline is defined as the frequency of motor seizures resulting in drops during the 4-week 
Baseline Period prior to administration of IMP. 
Retrospective diary data (up to 6 months) will be collected, if available, for an 
exploratory evaluation of the duration of baseline data capture on interpretation of post-
treatment effect. 
For all questionnaires and rating scales, the same evaluator (at the clinical site and 
parent/caregiver) should complete the assessments for the duration of the study. Substitutions 
at the clinic with another rater that has established inter-rater reliability is acceptable on an 
infrequent basis. For the in-clinic questionnaires and rating scales completed by the 
parent/caregiver, if the same parent/caregiver cannot complete the questionnaire/rating scale at 
a visit, the questionnaire/rating scale will not be completed. For the diary, the same 
parent/caregiver will complete all entries throughout the study. 
7.1.1 
Seizure Assessments 
Seizure frequency by type and duration will be recorded daily by the parent/caregiver in 
a diary during Part 1 and up to 12 months in Part 2 (i.e., up to Visit 22). Seizure types 
include: 
A: 
Hemiclonic (note lateralization – right body, left body, or independent right 
and left) 
B: 
Focal With or Without Retained Awareness 
C: 
Secondarily Generalized Tonic Clonic (evolving to bilateral convulsive 
seizure from focal seizure) 
D: 
Generalized Tonic Clonic 
Convulsion E: 
Absence or Atypical 
Absence 
F: 
Myoclonic 
G: 
Tonic 
H: 
Atonic 
I: 
Clonic 
J: 
Tonic/Atonic (cannot differentiate) 
K: 
Infantile Spasms (if under 3 years of age) 
L: 
Epileptic Spasms (if 3 years of age and older)  
O: 
Other* 
* “Other” indicates a seizure type that cannot be classified in any of the above seizure 
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types A-L. All other seizures must be classified appropriately based on the 
Investigator’s medical opinion and Epilepsy Study Consortium approval. 
Parents/caregivers will also indicate in the diary entry whether the seizure resulted in a drop, or 
would have resulted in a drop were it not for the position (ie, in a chair).  This includes seizures 
involving the entire body, trunk, or head that led to a fall, injury, slumping in a chair, or the 
subject’s head hitting a surface or that could have led to a fall or injury, depending on the 
patient’s position at the time of the seizure. 
Efficacy/effectiveness endpoints that will be derived from the diary data include frequency of 
seizures that result in drops and seizures that do not result in drops, motor seizures, and all 
seizures, and the number/duration of seizure-free intervals. 
Seizures that evolve into status epilepticus (SE) will be captured by type and duration (>10 
minutes) as are all seizures. SE should be entered as an SAE if a prolonged seizure or series of 
seizures persists for 30 minutes or longer, regardless of administration of rescue medication, 
and is either diagnosed by a medical professional or occurs more than once in a day. SE lasting 
for less than 30 minutes should be entered as an AE, unless one of the other SAE criteria (eg, 
hospitalization) are met. If this incident involves multiple seizures close in time, the SE 
definition applies if the seizures are close together such that consciousness is not regained 
between ictal events. 
After 12 months in Part 2, seizure diaries are not required. Rather, based on discussions with 
the parent/caregiver, clinical evaluation, and review of any documentation provided by the 
caregivers, investigators will assess the percent improvement in seizure burden on a 5-point 
scale: <25%, ≥25%, ≥50%, ≥75%, 100% [ie, seizure-fee] improvement. 
7.1.2 
Clinical Global Impression - Improvement 
Both the parent/caregiver and the investigator will rate their global impression of the subject’s 
condition throughout the study according to the schedule in Table 1 and Table 2. 
The CGI scale measures the change in the subject’s clinical status from a specific point in time, 
ie, the Baseline Period. The CGI rating scale permits a global evaluation of the subject’s 
improvement over time. The severity of a patient’s condition is rated on a 7-point scale ranging 
from 1 (very much improved) to 7 (very much worse) as follows: 
1=very much improved 
2=much improved 
3=minimally improved  
4= no change 
5=minimally worse 
6=much worse 
7=very much worse 
The parent/caregiver will be asked to indicate the appropriate response that adequately 
describes how their child’s symptoms have improved or worsened relative to baseline before 
the beginning of the study (before any study drug was taken). 
The investigator (or appropriately trained designee) will be asked to indicate the appropriate 
response that adequately describes how the subject’s symptoms have improved or worsened 
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relative to baseline before the beginning of the study (before any study drug was taken). A 
paragraph describing symptoms and function at baseline will be document in the source file 
prior to rating. 
7.1.3 
Vineland Adaptive Behavior Scale (VABS) 
The VABS (Appendix 4) is a parent/caregiver completed assessment that looks at the personal 
and social skills of individuals from birth through adulthood.  Because adaptive behavior 
refers to an individual's typical performance of the day-to-day activities required for personal 
and social sufficiency, these scales assess what a person actually does, rather than what he or 
she is able to do.  The VABS assesses adaptive behavior in 4 domains: communication, daily 
living skills, socialization, motor skills, and will be conducted according to the schedule in 
Table 1.  
7.1.4 
QOLCE 
The QOLCE (Appendix 6) is a parent/caregiver completed assessment that looks at how epilepsy 
affects day-to-day functioning of their child in various life areas, including physical activities, 
well-being, cognition, social activities, behavior and general health, will be conducted according 
to the schedule in Table 1 and Table 2. The QOLCE has been validated in children aged 4 and 
older, and there are published data on the use of the QOLCE in children with epilepsy as young 
as 2 years of age (Sabaz et al., 2000; Talarska 2007).  
7.1.5 
Parent/Caregiver Affective Symptoms 
7.1.5.1 The impact on anxiety and depressive symptoms of the parent/caregiver 
responsible for a patient with LGS will be assessed according to the schedule in Table 
1 and Table 2 using 2 scales: the HADS and the Zarit Caregiver Burden Inventory. 
Parents/caregivers who do not give consent to collect this rating scale will not 
complete them. The same parent/caregiver should complete this rating throughout the 
study. If that person is not available at the visit, the scale should not be 
completed.Hospital Anxiety and Depression Scale (HADS) 
The HADS (Appendix 7) is a tool commonly used to determine the levels of anxiety and 
depression that a person is experiencing. It is a 14-item scale that generates ordinal data. Seven 
of the items relate to anxiety and 7 relate to depression. 
The HADS (Appendix 7) is a tool commonly used to determine the levels of anxiety and 
depression that a person is experiencing. It is a 14-item scale that generates ordinal data. Seven 
of the items relate to anxiety and 7 relate to depression. 
7.1.5.2 Zarit Caregiver Burden Inventory 
The impact on caregiver burden will be assessed according to the schedule in Table 1 and Table 
2 using the Zarit Caregiver Burden Inventory. Parents/caregivers who do not give consent to 
collect this rating scale will not complete them. The same parent/caregiver should complete this 
rating throughout the study. If that person is not available at the visit, the scale should not be 
completed. 
The Zarit Caregiver Burden Inventory (Appendix 8) is a 22-item inventory derived from the 
original 29-item Zarit inventory. It is the most widely used standardized, validated scale to 
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assess caregiver burden, administered previously in various neurological disorders, including 
epilepsy (Kim, 2010; Westphal-Guitti, 2007). The 22 items evaluate the effect of disease on the 
caregiver’s QOL, psychological suffering, financial difficulty, shame, guilt, and difficulty in 
social and family relationships. Scores range from 0 to 88 with higher scores indicating higher 
burden (<20: little or no burden, 21–40: mild-to-moderate burden, 41–60: moderate-to severe 
burden, 61–88: severe burden). 
7.2 
SAFETY ASSESSMENTS 
7.2.1 
Demographics, Medical/Neurological/Epilepsy History, and Pre-Study 
Medication 
Subject demographics (sex, age, height, weight, and BMI), all ongoing conditions and relevant 
medical history from the past 5 years (including all major hospitalizations and surgeries) as 
well as the subject’s current medical status will be recorded at the Screening visit. Significant 
medications taken during the 30 days prior to the Screening visit will be documented. 
Medication history will be updated as outlined in Table 1 and Table 2. 
7.2.2 
Adverse Events 
Adverse events (AEs) will be collected from the time of signing the informed consent 
form/assent form until the end of the study, including the follow-up clinic visit. Details of the 
definitions and categorization of AEs, and procedures for the reporting of AEs, are available in 
Section 9. 
Severity and causality of AEs will be evaluated according to the criteria specified in Section 8.2 
and Section 8.3, respectively. The observation period for AE reporting is specified in Section 
8.4. At the beginning of each visit at the study site, the study personnel will specifically inquire 
about any AEs that might have occurred since the last study site visit.  As described below, an 
abbreviated physical and/or neurological examination for each subject will be conducted based 
on reported AEs.All AEs will be recorded on the appropriate eCRF page. 
7.2.3 
Physical Examinations 
Complete and abbreviated physical examinations, including height and weight, will be 
conducted by the investigator or designee during the study as outlined in Table 1 and Table 2. 
A complete standard of care physical examination for each subject will be performed and will 
cover the following body systems: general appearance, skin, eyes, ears, nose, throat, heart, 
lungs, abdomen, neurological system, lymph nodes, spine, and extremities. An abbreviated 
physical examination for each subject will cover the following body systems: heart, lungs, and 
follow up of other systems as appropriate based on last exam and reported AEs. 
Any unfavorable findings not present at screening, or worsened from the baseline assessment 
and considered by the investigator as clinically significant, occurring at any point in the 
study will be documented in the eCRF as an AE. 
7.2.4 
Neurological Examinations 
Complete and abbreviated neurological examination will be conducted by the investigator or 
designee during the study as outlined in Table 1 and Table 2. A complete standard of care 
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neurological examination for each subject will be performed and will cover the following: 
cranial nerves, muscle strength and tone, reflexes, coordination, sensory function, and gait. 
An abbreviated neurological follow-up examination for each subject will evaluate any 
symptoms or systems found to be abnormal and unstable or potentially unstable that might 
evolve during study treatment, or to investigate any reported or observed AEs. 
Any unfavorable findings not present at screening, or worsened from the baseline assessment 
and considered by the investigator as clinically significant, occurring at any point in the 
study will be documented in the eCRF as an AE. 
7.2.5 
Vital Signs (Including Height and Weight) 
Height, weight, and vital signs (blood pressure, heart rate, temperature, and respiratory 
rate) will be documented for subjects during study as outlined in Table 1 and Table 2. 
7.2.6 
Laboratory Measurements 
Laboratory safety parameters will be analyzed using standard validated methods. 
The following parameters will be assessed by the laboratory as described in Table 1, 
Table 2 and Table 10: 
x Hematology: hemoglobin, hematocrit, erythrocyte mean corpuscular volume, 
leukocytes, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, neutrophils, lymphocytes, monocytes, eosinophils, basophils and 
platelets 
x Blood Biochemistry: albumin (ALB), alkaline phosphatase (ALP), alanine 
aminotransferase (ALT; SGPT), aspartate aminotransferase (AST; SGOT), bicarbonate, 
blood urea nitrogen (BUN), calcium (Ca), carbon dioxide (CO2), chloride (Cl), 
creatinine, creatine kinase, gamma-glutamyl transferase (GGT), glucose, lactate 
dehydrogenase (LDH), phosphorus, potassium (K), sodium (Na), total bilirubin, direct 
bilirubin, total cholesterol, total protein, triglycerides, uric acid, eGFR. 
x Tests of growth and precocious puberty: Growth hormone (GH), insulin-like growth 
factor-1 (IGF-1), prolactin, Luteinizing Hormone (LH), Follicle Stimulating Hormone 
(FSH), testosterone, estradiol, thyroid function (T3, T4, and thyroid stimulating 
hormone [TSH]), 
x Immunoglobulin (IgG, IgA, IgM) 
x Epilepsy genotype panel 
x Coagulation: Prothrombin time (PT)/International normalized ratio (INR), activated 
partial thromboplastin time (PTT) 
x Whole blood cannabidiol 
x Urinalysis: analysis for pH, glucose, ketones, nitrite, protein, bilirubin, urobilinogen, 
leukocyte esterase, and occult blood. Microscopic analysis will be performed for blood, 
all cell types, and casts. 
x Urine or serum pregnancy test: Urine or serum pregnancy testing will be performed in 
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female subjects of childbearing potential. 
x Urine or serum THC panel 
x The investigator will receive the laboratory report from the central laboratory. After 
reviewing the report and evaluating any results that are outside the normal range for 
clinical significance, the investigator must sign and date the laboratory report in a 
timely fashion. 
Tests resulting in abnormal laboratory values that have been classified by the investigator as 
abnormal, clinically significant should be repeated as soon as possible after receiving the 
laboratory report to rule out laboratory errors. 
At Screening, any laboratory values that deviate from the reference ranges that are not 
exclusionary and are considered by the investigator as clinically relevant must be documented 
on the medical history form of the eCRF. Any deviation outside of the reference range 
considered by the investigator as clinically significant (ie, classified as an abnormal, clinically 
significant value) at any visit after screening will be documented in the eCRF as an AE (see 
Section 9). 
7.2.7 
Plasma Sample for Concomitant Antiepileptic Drug(s) 
Plasma samples to ensure that concomitant AEDs dosing is within an acceptable range will be 
conducted during the study as outlined in Table 1 and Table 2. All samples will be analyzed at 
study end and do not constitute safety assessments. (Importantly, plasma samples for 
concomitant AEDs can be performed at any time if considered clinically indicated. In these 
instances results will be provided to the unblinded Medical Monitor and discussed with the 
Principal Investigator.) 
7.2.8 
Electrocardiograms 
Twelve-lead ECGs will be conducted during study as outlined in Table 1 and Table 2 after 
the subject has been in the supine position resting for ≥5 minutes. Heart rate, PR duration, 
QRS duration, QT duration, QTcF (Fridericia's correction formula), and the investigator’s 
overall interpretation will be recorded. 
7.2.9 
Doppler Echocardiography 
Doppler echocardiography will be conducted at a facility with experience for the subject’s age 
during study as outlined in Table 1 and Table 2. Doppler echocardiography uses ultrasound 
technology to examine the heart or blood vessels. An ECHO uses high frequency sound 
waves to create an image of the heart while the use of Doppler technology allows 
determination of the speed and direction of blood flow by utilizing the Doppler effect. 
Predetermined standard guidelines on the proper evaluation of certain measurements, as well 
as abnormality thresholds, were constructed by the sponsor’s ICAB prior to study initiation. 
These thresholds are provided in Table 9 and Table 11. A manual of proper ECHO technique 
for sites is provided in a separate document. 
7.2.10 
Behavior Rating Inventory of Executive Function (BRIEF) 
The Behavior Rating Inventory of Executive Function (BRIEF) is a parent or teacher report 
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measure designed to address the multidimensional nature of the executive function construct and 
will be used to assess the effects of ZX008 on cognition. The BRIEF assesses eight theoretically 
and statistically derived subdomains of executive function. It was designed to be used for a wide 
range of childhood disorders in order to augment traditional clinic-based assessments, and to 
provide an increased level of ecological validity for clinical assessments (Rabbit, 1997).  Age-
appropriate versions of the BRIEF .(BRIEF-P: 2 to 5 year olds; BRIEF: 6 to 18 year olds; 
BRIEF-A: 19 to 35 year olds), will be conducted according to the schedule in Table 1.  
7.2.11 
Tanner Staging 
Tanner Staging (Appendix 5) will be assessed for subjects >7 to 18 years old during the study 
as outlined in Table 1 and Table 2. Conceptually, pubertal maturation can be described in 
terms of sequence, timing, and tempo. Puberty consists of a series of predictable events, and 
the sequence of changes in secondary sexual characteristics has been categorized by several 
groups. The staging system used most frequently was published by Marshall and Tanner 
(1969, 1970) and the sequence of changes are commonly referred to as ‘Tanner stages’. 
7.2.12 
Columbia-Suicide Severity Rating Scale 
C-SSRS (Appendix 2) will be assessed during study as outlined in Table 1 and Table 2. The C-
SSRS is a validated rating scale that assesses suicidal behavior and ideation. The scale is used 
to assess and track suicide events and provides a summary measure of suicidal tendency. Age 
and intellectual development appropriate versions of the C-SSRS ( Baseline/Screening and 
Since Last Visit) will be used in this study. 
Subjects who are younger than 7 years chronologically, or who are judged by the investigator 
not to have the mental capacity to understand the questions as specified on the C-SSRS, will 
not complete the rating. The investigator should use his/her judgment to substitute 
intellectually-appropriate questions to probe the tendency for self-harm. 
7.3 
PHARMACOKINETIC ASSESSMENTS 
Blood samples for PK assessments of fenfluramine and its metabolite (norfenfluramine) will be 
obtained from all subjects via an indwelling cannula or by venipuncture. 
Blood samples for PK assessment (2 mL) will be obtained at the following time points: 
x 
Part 1 Study Day 43: within 1 hour prior to the morning dose, and 1 (± 15 min), 2 (± 15 
min), and 4-6 hours after the morning dose. 
A total of 4 PK samples will be drawn for each subject for a total of approximately 8 mL of 
blood. 
When blood draws for PK coincide with other assessments, the PK draws take precedence. 
The procedure for the collection and handling of PK samples is outlined in a separate study 
manual. 
7.4 
EPILEPSY GENOTYPE PANEL 
Optional blood samples for genetic analysis are being collected for a comprehensive analysis 
for a broad epilepsy gene panel that will be analyzed at the end of the study to investigate 
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genetic characteristics of study responders and non-responders.  Whole genome sequencing is 
not being performed. Testing is restricted to a 377 childhood epilepsy gene panel; thus, the risk 
of revealing clinically relevant or medically actionable incidental findings is low. Samples may 
be retained for up to 24 months after the end of the study.  
The field of genetics related to epileptic encephalopathies are developing rapidly, thus, in the 
event that new theories emerge on the genetics associated with LGS, the retained samples 
might be used to investigate this genotype in the study population. Results of genetic testing 
will only be provided upon written request; therefore, unless required by law individual results 
of genotyping will not be disseminated outside of the Sponsor, including to the study site.  
Genotyping samples will be double-coded (pseudonymized) so that it is impossible to trace 
back the personal identifying information from the sample number. 
7.5 
APPROPRIATENESS OF MEASUREMENTS 
All of the variables assessed are standard tests or procedures that are commonly used in studies 
of this type. 
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8. 
ADVERSE EVENTS 
8.1 
DEFINITIONS 
8.1.1 
Adverse Events 
According to ICH guidelines, an AE is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment. An AE can, therefore, be any unfavorable and 
unintended sign (including an abnormal, clinically significant laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product. The period of observation for 
adverse events extends from the time the subject gives informed consent until the end of study. 
Adverse events may include: 
x 
Exacerbation (ie, an increase in the frequency or severity) of a pre-existing condition. 
Illness present before study entry should be recorded in the medical history section of 
the eCRF and only be reported as an AE if there is an increase in the frequency or 
severity of the condition during the study. Exacerbation of seizures is considered an AE 
if there was an increase in frequency beyond the subject's typical pre-study fluctuations, 
or in the event that seizures lengthen in duration in a clinically meaningful way 
compared with baseline, or if a new seizure type emerges. 
x 
A clinical event occurring after consent but before IMP administration. 
x 
Intercurrent illnesses with an onset after administration of IMP.  
Adverse events do not include: 
x 
Medical or surgical procedures (the condition that leads to the procedure is the AE, 
eg, tonsillitis is the AE if a tonsillectomy is performed) 
x 
Situations where an untoward medical occurrence has not taken place. For example: 
x 
Planned hospitalizations due to pre-existing conditions, which have not worsened. 
x 
Hospitalizations that occur for procedures not due to an AE (eg, cosmetic surgery). 
x 
Hospitalizations for a diagnostic procedure where the hospital stay is less than 24 
hours in duration or for normal management procedures (eg, chemotherapy). 
For laboratory safety parameters, any instances of absolute values being outside the reference 
range or changes at any visit after study start that are considered by the investigator as 
clinically significant must be recorded in the eCRF as AEs. In addition, at the investigator’s 
discretion, any changes or trends over time in laboratory parameters can be recorded in the 
eCRF as AEs if such changes or trends are considered to be clinically relevant, even if the 
absolute values are within the reference range. 
Laboratory findings do not need to be reported as AEs in the following cases: 
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1. Laboratory parameters are already beyond the reference range, unless a further 
increase/decrease can be considered an exacerbation of a pre-existing 
condition. 
2. Abnormal laboratory parameters caused by mechanical or physical influences on 
the blood sample (eg, hemolysis) and flagged as such by the laboratory in the 
laboratory report. 
3. Abnormal parameters that are obviously biologically implausible (eg, values 
that are incompatible with life). 
4. An abnormal laboratory value that cannot be confirmed after a repeated analysis, 
preferably in the same laboratory (eg, the previous result could be marked as 
not valid and should not necessarily be reported as an AE). 
8.1.2 
Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose: 
1. 
Results in death – The event must be the cause of death for the SAE to meet this 
serious criterion. 
2. 
Is life-threatening – The term “life-threatening” 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 had been more severe. 
3. 
Requires in-patient hospitalization or prolongation of existing hospitalization – 
The sponsor considers “hospitalization or prolongation of existing hospitalization” for 
at least 24 hours as the defining criterion for an SAE.  Hospital admissions for planned 
surgery or for normal disease management procedures (eg, chemotherapy) are not 
considered as defining criteria for SAEs. 
4. 
Results in persistent or significant disability or incapacity. 
5. 
Is a congenital anomaly or birth defect. 
6. 
Is medically significant – A medically significant event is defined as an event that 
does not meet any of the other 5 SAE criteria, but which is judged by a physician to 
potentially jeopardize the subject or require medical or surgical intervention to prevent 
one of the above outcomes listed as an SAE criterion. Anaphylaxis that is successfully 
treated by administration of epinephrine prior to other sequelae is an example of a 
potentially medically important event. 
The most important term should be selected as the criteria for the SAE.  Medically 
significant should be used when none of the other terms apply. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are defined as SAEs that do 
not meet determination of expectedness as determined in accordance with applicable 
product information (Investigator's Brochure or other reference documentation). Upon 
receipt of a SAE report from an Investigator site, all suspected adverse reactions related to 
the IMP which occur within the clinical trial will be assessed for expectedness. Any SAE 
not listed in the reference documentation is considered a Suspected Unexpected Serious 
Adverse Reaction (SUSAR). SUSARs will be reported by the Sponsor, or its designee, in 
compliance with local legal requirements. During the course of the study, the Sponsor will 
report within required timelines all SAEs that are both unexpected and at least reasonably 
related to the IMP (SUSARs) to the Health Authorities, IECs / IRBs as appropriate and to 
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the Investigators. This study will comply with all applicable regulatory requirements and 
adhere to the full requirements of ICH Topic E2A (Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting [1994]).  
For the purpose of data collection in this study, a prolonged seizure or series of seizures 
from which the subject does not regain consciousness between ictal events, that is at least 
30 minutes in duration, is termed status epilepticus (SE). SE should be entered as an SAE if a 
prolonged seizure or series of seizures persists for 30 minutes or longer, regardless of 
administration of rescue medication, and is either diagnosed by a medical professional or 
occurs more than once in a day. SE lasting for less than 30 minutes should be entered as an 
AE, unless one of the other SAE criteria (eg, hospitalization) are met. If this incident 
involves multiple seizures close in time, the SE definition applies if the seizures are close 
together such that consciousness is not regained between ictal events. 
Adverse events that do not fall into the above categories are defined as nonserious AEs. 
8.1.3 
Adverse Events of Special Interest 
As per ICH guidance (E2F Development Safety Update Report [2011]), the sponsor has 
identified the following AESIs for the ZX008 program (Table 16). 
Table 16: 
Adverse Events of Special Interest 
 
Metabolic/Endocrine 
1. Elevated prolactin level ≥2x above the upper limit of normal (ULN) 
2. Hypoglycemia – <3.0 mmol/l or 54 mg/dl, whether that level is associated with symptoms 
or not  
Neuropsychiatric 
1. Suicidal thoughts, ideation or gestures 
8.2 
SEVERITY OF ADVERSE EVENTS 
The severity of AEs (whether nonserious or serious AEs) is to be assessed by the 
investigator as follows (Table 17). 
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Table 17: 
Severity Definition of Adverse Events 
Severity 
Definition 
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 additional 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 participant. 
Severe: 
A type of AE that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention. 
  
8.3 
CAUSALITY OF ADVERSE EVENTS 
The causal relationship of an AE to IMP must always be assessed by the investigator. All 
AEs will be classified as either related or not related to IMP. If a causality assessment is 
not provided for an AE (including an SAE), that AE will be considered as related to IMP. 
The degree of certainty with which an AE is attributed to IMP or an alternative cause (eg, 
natural history of the underlying disease, concomitant medication) will be determined by 
how well the event can be understood in terms of: 
x Known pharmacology of ZX008 
x Clinically and/or pathophysiologically plausible context 
x Reaction of a similar nature previously observed with similar products, or reported in the 
literature for similar products as being product related (eg, headache, facial flushing, 
pallor) 
x Plausibility supported by the temporal relationship (eg, the event being related by time to 
administration or termination of treatment with IMP drug withdrawal or reproduced on 
rechallenge) 
The following classifications should be used in categorization of relatedness: 
Not Related: 
Concomitant illness, accident or event with no reasonable association with 
study drug. 
Related: 
The event follows a reasonable temporal sequence from administration of 
study drug and is definitive pharmacologically; cannot to be attributed to 
concurrent disease or other factors or medications. A clinically reasonable 
response should be observed if the study drug is withdrawn or dose 
reduced. 
8.4 
OBSERVATION PERIOD FOR ADVERSE EVENT REPORTING 
The observation period for AE and SAE reporting in an individual subject will start at the time 
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of giving written informed consent for participation in the current study and finish 15 days after 
the last dose of study drug or the last visit, whichever is later. For subjects who enroll in the 
open-label extension (Part 2), ongoing AEs will be followed in that study. 
If the investigator becomes aware of an SAE that has started after the observation period has 
finished, and the event could in some way be associated with IMP (irrespective of whether or 
not it is considered by the investigator to be causally related to IMP), then this must also be 
reported to the sponsor (see Section 8.6). 
8.5 
ADVERSE EVENT REPORTING 
8.5.1 
Adverse Events 
At each clinical evaluation, the investigator (or delegate) will determine whether any AEs have 
occurred. Adverse events will be recorded in the AE page of the eCRF. If known, the medical 
diagnosis of an AE should be recorded in preference to the listing of individual signs and 
symptoms. The investigator must follow up on the course of an AE until resolution or 
stabilization. If an AE is ongoing after the end of study visit, the AE will continue to be 
followed up until resolution or stabilization. 
If, during the study period, a subject presents with a pre-existing condition that was not noted at 
the time of study entry, the condition should be retrospectively recorded in the Medical History 
section of the eCRF. 
8.6 
SERIOUS ADVERSE EVENTS REPORTING 
This study will comply with all applicable regulatory requirements and adhere to the full 
requirements of ICH Topic E2A (Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting [1994]). 
In the event of a SAE the investigator or delegate must:  
1. Enter all relevant information in the AE page of the eCRF 
2. Inform the safety group and/or the Medical Monitor of the SAE via email or fax 
within 24 hours of becoming aware of the SAE. 
3. Follow the initial notification with a completed SAE report form. The SAE form must 
be emailed or faxed to iHC within 24 hours of becoming aware of the SAE.  
All SAEs that occur during the course of the study, beginning the day Informed Consent 
is signed, whether or not causally related to IMP must be reported immediately via fax or 
email (within 24 hours of the investigator becoming aware of the event) to the 
sponsor/designee or the Medical Monitor.  
Adverse events occurring in the period between the time the subject gave written informed 
consent and the first exposure to IMP that meet one or more of the seriousness criteria for AEs 
must be reported to the sponsor/designee and the Medical Monitor in the same manner as 
other SAEs and will be included in the clinical study database. 
Any SAE that occurs 15 days after the last dose of study drug or the last visit, whichever is later 
that is considered to be causally related to IMP must be reported immediately (ie, within 24 
hours of the investigator becoming aware of the event) to the sponsor/designee and the 
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Medical Monitor. 
Contact details and guidance for reporting SAEs will be provided to study site before the study 
starts. 
8.6.1 
Requirements for Immediate Reporting of Serious Adverse Events 
The minimum reporting requirements for immediate reporting of SAEs include: 
1. Identifiable subject 
2. Suspected drug product 
3. Event description 
4. Identifiable reporting 
source In addition, the investigator 
must: 
1. Report all SAEs to the relevant IRB/IEC within the timeframe specified by 
the IRB/IEC. 
2. Submit follow-up reports to the sponsor Global Clinical Safety and 
Pharmacovigilance/designee and the Medical Monitor until the SAE has 
resolved, or, in the case of permanent impairment, until stabilized. 
3. Ensure that the AE term(s) and causality assessment for all SAEs is entered in 
the eCRF. 
If the minimum requirements for reporting are fulfilled, the investigator should not wait to 
receive additional information to fully document the event before notifying the 
sponsor/designee. 
When submitting SAE reports to the sponsor/designee, subjects should be identified only by 
their subject number and study number. The investigator should not include the subject’s name 
and address. 
SAE update reports can be submitted to the sponsor/designee any time that additional relevant 
information becomes available. In cases of death, the investigator should supply the 
sponsor/designee and the IEC/IRB (as applicable, see Section 8.7) with any additional 
requested information as it becomes available (eg, autopsy reports and detailed medical 
reports). Once an SAE is reported to the sponsor/designee’s Safety Group, a Safety Specialist 
may contact the investigator with follow-up questions. 
The procedure to be followed if an ongoing AE becomes an SAE after the end of the 
observation period for AEs is described in Section 8.9. 
8.7 
REPORTING OF SERIOUS ADVERSE EVENTS BY INVESTIGATOR 
TO IEC/IRB 
The timeframe within an IEC/IRB must be notified of a death or an unexpected SAE 
considered at least possibly related to the IMP is stipulated by each individual IEC/IRB. The 
investigator is responsible for complying with the requirements for IEC/IRB notification. The 
investigator will notify the relevant IEC/IRB within the applicable timeframe by forwarding the 
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safety report (eg, MedWatch/CIOMS form) completed by the sponsor/designee for the 
notifiable event. 
8.8 
REPORTING OF EVENTS OTHER THAN SERIOUS ADVERSE 
EVENTS BY INVESTIGATOR TO SPONSOR 
Even if none of the criteria for an SAE are fulfilled, any of the following events must be 
reported by the investigator to the Medical Monitor within 72 hours from the time the 
investigator is notified. 
1. Hypersensitivity reactions 
2. Pulmonary hypertension 
3. Cardiac symptoms requiring intervention, or valvulopathy, if 
identified outside of study-related monitoring 
8.9 
FOLLOW-UP OF ADVERSE EVENTS 
Every effort should be made to follow-up subjects who continue to experience an AE or an 
SAE on completion of the study or until the AE resolves. All follow-up information (and 
attempted follow-up contacts) should be documented in the subject’s medical records. Details 
of the subject’s progress should also be submitted to the sponsor/designee’s Global Clinical 
Safety and Pharmacovigilance and the Medical Monitor. 
Subjects who are discontinued from the study or complete the study and have been found to have 
any signs of valvulopathy or pulmonary hypertension on ECHO will be followed until the 
condition has resolved or stabilized where no further changes are likely, for a minimum of 
6 months from the last dose of study medication, unless it is determined after unblinding that the 
subject did not receive ZX008. 
8.9.1 
Follow-up of Echocardiogram Findings 
All ECHOs will be evaluated by a central reader, in consultation with the ICAB, if 
warranted. Findings related to pulmonary hypertension or valvulopathy on any of the four 
valves (aortic, mitral, pulmonary, tricuspid) will be reported to the investigator with grades of 
normal, trace, mild, moderate or severe. If the ECHO result has progressed in severity since 
the last reading then new oversight measures will be enacted as described below in Table 18 
which describes the severity of ECHO findings with the level of increasing oversight if the 
subject is to remain in the study. 
Table 18: 
Clinical Measures Enacted Upon Increasing Severity of ECHO Findings 
 
Severity 
Valve 
Aortic 
Mitral 
Pulmonary 
Tricuspid 
Trace (≤18 years) 
Level 2 
Level 2 
Level 1 
Level 1 
Trace (>18 years) 
Level 1 
Level 1 
Level 1 
Level 1 
Mild (≤18 years) 
Level 2 
Level 2 
Level 1 
Level 1 
Mild (>18 years) 
Level 2 
Level 1 
Level 1 
Level 1 
Moderate 
Level 3 
Level 3 
Level 3 
Level 3 
Severe 
Level 3 
Level 3 
Level 3 
Level 3 
 
Level 1:   Continue per protocol 
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Level 2: 
1. If there is a desire to continue study medication: 
a. The investigator will evaluate the efficacy to date based on study diaries 
and consult with the parent/guardian, and determine whether study 
treatment was associated with significant, meaningful benefit in number, 
severity and/or duration of seizures and/or on the impact on daily 
functioning. 
b. The investigator will consider whether the subject has had reasonable trials 
(dose and duration) of other available anticonvulsants (eg, valproic acid, 
clobazam, or topiramate), alone or in combination, and not maintained the 
level of seizure control achieved with study medication. 
2. If the investigator feels consideration of continued treatment is warranted considering 
benefit and potential risk, and the parent/guardian feels strongly that the subject be 
maintained on the study medication when understanding the risks, the parent/guardian 
must sign a new consent which describes the additional risks and the subject should 
provide assent if appropriate. 
a. If both of these conditions are not met, the subject is discontinued 
from treatment. 
3. The investigator prepares a case history and rationale for continuation to be submitted 
to the IDSMC for review, including consideration of effects on seizures and 
comorbidities. 
4. The cardiac reviewers (from the central reader, and potentially ICAB) prepare an 
evaluation of the cardiopulmonary risks and proposed monitoring plan if applicable, 
for submission to the IDSMC. 
5. IDMSC will review the submissions from the Investigator and cardiac central reader 
and unblind the subject treatment if warranted. 
6. IDSMC makes a determination of appropriate path, including the possible outcomes: 
a. Discontinue study medication 
b. Increase frequency of ECHO and ECG monitoring 
c. Add additional ECG and/or ECHO measures to be monitored 
d. Reduce the dose of study medication 
Level 3: 
1. The investigator will evaluate efficacy to date based on study diaries and consult 
with the parent/guardian, and determine whether the achieved benefit justifies the 
consideration of continuing study treatment by the IDSMC. MINIMAL efficacy 
criteria for IDSMC consideration: 
a. Seizures must be more than 75% improved (number of motor seizures per 28 
days) on treatment over baseline, and improvement must be consistent. 
b. The number, type, duration, and distribution of seizures at baseline should be of 
a severity, which justifies the risks of cardiopulmonary complications, 
considering the subject’s age and overall health. 
c. Subject has had reasonable trials (dose and duration) of other available 
anticonvulsants (eg, valproic acid, clobazam, topiramate), alone or in 
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combination, and not maintained the level of seizure control achieved with 
study medication. 
2. If the investigator feels consideration of continued treatment is warranted 
considering benefit and potential risks, and the parent/guardian feels strongly that 
the child be maintained on the study medication when understanding the risks, the 
parent/guardian must sign a new consent, which describes the additional risks and 
the child should provide assent if possible. 
a. If both of these conditions are not met, the subject is discontinued 
from treatment. 
3. The investigator prepares a case history and rationale for continuation to be submitted 
to the IDSMC for review, which includes effects of study medication on seizures and 
comorbidities related to LGS. 
4. The cardiac reviewers (from the central reader, and potentially ICAB) prepare an 
evaluation of the cardiopulmonary risks and proposed monitoring plan if applicable, 
for submission to the IDSMC. 
5. IDMSC will review the submissions from the Investigator and cardiac central reader 
and unblind the subject treatment if warranted. 
6. IDSMC makes a determination of appropriate path, including these possible 
outcomes: 
a. Discontinue study medication 
b. Increase frequency of ECHO and ECG monitoring 
c. Add additional ECG and/or ECHO measures to be monitored 
8.10 
PREGNANCY 
This study is open to female and male subjects. Whenever possible, a pregnancy in a female 
subjects or the female partner of a male subject exposed to IMP should be followed to term so 
as to assess any potential occurrence of congenital anomalies or birth defects. Any follow-up 
information, including premature termination and the status of the mother and child after 
delivery, should be reported by the investigator to the sponsor/designee using a pregnancy 
reporting/outcome form. 
9. 
DATA HANDLING PROCEDURES 
9.1 
RECORDING OF DATA 
The investigator (or delegate) will maintain individual records for each subject. These records 
should include dates when a subject visited the study site, study-required information and data, 
and other notes as appropriate. These records constitute source data. 
An eCRF and a subject diary will be provided by the sponsor (or delegate) for each subject 
enrolled into the study. Study site staff will enter data directly into the validated electronic data 
capture (EDC) system by completing the eCRF via a secure internet connection. The 
investigator is responsible for ensuring accurate and proper completion of the eCRF and subject 
diary for recording data according to the instructions given in the eCRF and subject diary. 
All entries in the eCRF must be backed up by the relevant source data at the study site. All 
source data will be kept according to all applicable regulatory requirements (see Section 12.8). 
Source data must follow good documentation practices, be completed legibly for each subject 
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enrolled into the study and signed by the investigator (or delegate). 
Data entry in the eCRF and subject diary must be completed in a timely manner so that they 
always reflect the latest observations on the subjects enrolled in the study. 
The subject’s diary will be completed by the parent/caregiver at home. Data entries will be 
reviewed by the investigator for completion and consistency. 
9.2 
DATA QUALITY ASSURANCE 
An initiation meeting will be held before starting the study, during which the study design, 
procedures to be followed, and measures for ensuring standardized performance will be 
explained by a delegate from the sponsor, and a common understanding of the requirements of 
the study will be reached with the investigator and other relevant personnel at the study site. 
Data generated throughout the study will be monitored and the data entered in the eCRFs will 
be checked against the subject records for completeness and accuracy. The sponsor’s study 
monitor will perform this function. 
The computer system used for study data handling will be fully FDA 21 CFR Part 11 
compliant. All creation, modification or deletion of electronic study records will be 
documented through an automated Audit Trail. Following completion of eCRF pages and entry 
of the data into a database, the data will be checked electronically for consistency and 
plausibility. Data queries will be generated for questionable data and response clarification will 
be sought from the investigator. These data queries must be resolved in a timely manner by the 
investigator (or delegate). 
9.3 
RECORD RETENTION 
A study document binder will be provided by the sponsor for the investigator at each site for all 
requisite study documents (constituting the “Investigator Study File”). 
Following completion of the study, the investigator will retain copies of the approved study 
protocol, ICF, relevant source documents, and all other supporting documentation related to the 
study according to applicable regulatory requirements. 
The investigator is responsible for archiving the Investigator Study File, the subject’s records, 
and the source data according to applicable regulatory requirements. These documents have to 
be archived for at least 15 years or at least 2 years after the last approval of a marketing 
application in an ICH region, but should be retained for longer if required by regulatory 
requirements or by agreement with the sponsor. 
If the investigator can no longer maintain the archive of study records (eg, due to retirement or 
relocation), the sponsor must be informed in writing about any change in responsibility for 
record retention, including the name of the new responsible party, contact information, and 
location of the study records. Records may not be destroyed without prior written consent from 
the sponsor. 
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10. 
STATISTICS 
10.1 
STATISTICAL ANALYSIS: PART 1 
The primary analyses of the study will be performed on data from Part 1 Cohort A after the last  
subject enrolled in Cohort A has completed the last study visit of Part 1. Data from Part 1, 
Cohort B will be analyzed independently after the last subject in Cohort B completes Part 1. 
An interim analysis of Part 2 will be performed after all Cohort B subjects complete 12 months 
in Part 2.  A secondary analysis will be conducted after the last Cohort B subject has enrolled 
and completed the last study visit of Part 2.  Analysis results for Part 1 from Cohort A and 
Cohort B will be compared through descriptive statistics, and if reasonable, some analysis may 
be performed using data from Cohort A and Cohort B combined. Subjects randomized to 0.5 
mg/kg/day (ie, those taking concomitant STP) will be grouped with subjects randomized to 
0.8 mg/kg/day for all efficacy analyses. 
10.1.1 
DETERMINATION OF SAMPLE SIZE 
The sample size for Part 1 Cohort A was estimated under the assumption that adding ZX008 at 
0.8 mg/kg/day to current therapy will lead to a mean decrease in drop seizures that is 30 
percentage points greater than adding placebo to current therapy. For example, if adding placebo 
leads to a 10% decrease in seizures, then adding the high dose of ZX008 would be expected to 
decrease seizures by at least 40%. 
The variability expected in the trial was estimated from a Phase 3 trial of clobazam for patients 
with Lennox-Gastaut syndrome (Ng 2011) leading to an assumption that the SD is 50%. Other 
assumptions include an allowance for 20% dropouts between randomization and the start of the 
maintenance period.  
Under these assumptions, and using a Wilcoxon rank-sum test to approximate the primary 
comparison between the ZX008 0.8 mg/kg/day and placebo groups, a sample size of 63 subjects 
per treatment group affords 90% power to detect a difference between groups that is significant 
at the α=0.05 level. Assuming a 20% drop-out rate prior to the start of the maintenance period 
yields a requirement for an additional 16 subjects per group for a total of 79 subjects per 
treatment group.  Similar calculations for the 0.2 mg/kg/day ZX008 group lead to a total required 
sample size of 237. The number of subjects randomized into Part 1 Cohort A is estimated to be 
approximately 250 due to the long baseline period. 
The sample size of 10 to 15 subjects per treatment group in Cohort B is expected to provide a 
descriptive assessment of whether the treatment effect in Japanese subjects is similar that 
observed in Cohort A subjects from the rest of the world. 
10.1.2 
ANALYSIS POPULATIONS 
10.1.2.1 
Safety (SAF) Population 
All Part 1 safety analyses will be performed on the SAF Population defined as all randomized 
subjects who receive at least one dose of ZX008 or placebo.  
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10.1.2.2 
Modified Intent-to-Treat (mITT) Population 
The mITT Population is defined as all randomized subjects who receive at least one dose of 
ZX008 or placebo and for whom at least one week of diary data are available. Subjects will be 
analyzed according to the treatment group to which they were randomized. The primary 
comparison of ZDX008 0.8 mg/kg/day to placebo, who complete at least 4 weeks of diary 
data in the maintenance period, as well as key secondary analyses, will be performed on the 
mITT Population. 
10.1.2.3 
Per Protocol (PP) Population 
The PP Population is defined as all randomized subjects who receive at least one dose of 
ZX008 or placebo, and have no major protocol deviations that would have a significant 
impact on clinical outcome.  
10.1.3 
SUBJECT COHORTS 
10.1.3.1 
Cohort A 
Cohort A comprises all randomized subjects from North America, Europe, and Australia 
10.1.3.2 
Cohort B 
Cohort B comprises all randomized subjects from Japan only. 
10.1.4 
TREATMENT GROUPS 
Subjects will be randomly assigned to one of three treatment groups: ZX008 0.8 mg/kg/day, 
ZX008 0.2 mg/kg/day, or placebo. 
10.1.5 
TREATMENT PERIODS 
Baseline Period 
The Baseline Period covers the 28 days immediately prior to randomization. The baseline 
frequency of seizures that lead to drops will be calculated from data collected during this period. 
Titration Period 
The Titration Period covers the first 14 days of treatment while subjects are titrated to their 
randomized dose. It begins on the first full day of treatment (Study Day 1) and extends 
through Study Day 15 regardless of the exact day on which a subject reaches his or her 
assigned dose. The Titration Period applies to all subjects including placebo recipients. 
Maintenance Period 
The Maintenance Period covers the 12 weeks following the end of the titration period. It begins 
on Study Day 16 and extends through Study Day 99. 
Titration +Maintenance (T+M) Period 
The T+M period combines the Titration and Maintenance periods, beginning on Study Day 1 
and extending through Study Day 99. The T+M period is considered the treatment period. 
Taper/Transition Period 
The Taper/Transition Period begins immediately at the end of T+M period and extends to Visit 
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13, 2 weeks later; ie, from Study Day 99 through Study Day 113.  
10.1.6 
STATISTICAL ANALYSES AND METHODS 
All efficacy, safety, and PK data will be summarized by cohort. Continuous data will be 
summarized using descriptive statistics including means, standard deviations, medians, lower 
and upper quartiles, and ranges. Categorical variables will be summarized with frequencies and 
percentages. Confidence intervals will be calculated for key parameters or estimates as 
warranted. 
A complete description of the statistical analyses and methods will be available in a SAP, 
which will be finalized before the database is locked. 
10.1.6.1 
Efficacy Analyses 
Primary Efficacy Analysis 
The primary efficacy endpoint for Part 1 is the percent change in frequency of seizures that 
result in drops (DSF: drop seizure frequency) per 28 days between the combined Titration and 
Maintenance (T+M) and Baseline periods in Cohort A. The DSF will be calculated from all 
available data collected during the Baseline and T+M Periods without imputation. The percent 
change from baseline DSF will be calculated as the the change in DSF between T+M and 
Baseline / DSF during Baselineu 100. Both the mean and median percent change in DSF Both 
the mean and median percent change in DSF will be presented. 
The primary endpoint will be assessed using a nonparametric, rank analysis of covariance 
(ANCOVA) with treatment group (ZX008 0.8 mg/kg/day, ZX008 0.2 mg/kg/day or placebo) 
and weight group (<37.5 kg, ≥37.5 kg) as factors;rank baseline DSF as a covariate; and rank 
percent change in DSF from baseline as the response variable. The primary analysis will 
compare the ZX008 0.8 mg/kg/day group to the placebo group at the α=0.05 level of 
significance. The difference between the ZX008 0.8 mg/kg/day group and the placebo group in 
percent change in DSF, and its 95% confidence interval, will be estimated using the Hodges-
Lehmann method. 
As a sensitivity analysis, the primary endpoint will also be analyzed using a parametric 
ANCOVA that incorporates treatment group and weight group as factors; log baseline DSF as a 
covariate; and log DSF during T+M as the response variable. Significance will be assessed by a 
model contrast that compares the ZX008 0.8 mg/kg/day group to the placebo group. The size of 
the treatment effect will be estimated by exponentiating the difference between the ZX008 0.8 
mg/kg/day group and the placebo group derived from the model. Another sensitivity analysis 
will compare the ZX008 0.8 mg/kg/day group to the placebo group using a Wilcoxon rank-sum 
test. 
Key Secondary Analyses 
The first key secondary endpoint for the ZX008 0.8 mg/kg/day group – the proportion of 
subjects who achieve a ≥50% reduction from baseline in the frequency of seizures that result in 
drops – is derived directly from the primary endpoint, but is widely considered a benchmark for 
clinical meaningfulness of a medical intervention for seizures. The comparison will be made 
using a logistic regression model that incorporates the same factors and covariate as the 
ANCOVA used in the primary analysis. The second key secondary endpoint – the proportion of 
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subjects assessed by the Investigator as minimally, much, or very much improved on the CGI-I 
will be analyzed using a Cochran-Mantel-Haenszel test (CMH) stratified by weight strata. 
The percent change from baseline DSF in the ZX008 0.2 mg/kg/day group will be compared to 
the placebo group using the same methods employed for the primary analysis. In particular, the 
same ANCOVA model will be used. Nonparametric methods will be used if normality 
assumptions do not hold. Analyses of other key secondary endpoints involving the ZX008 0.2 
mg/kg/day group will employ similar methods as those used to compare ZX008 0.8 mg/kg/day 
to placebo. 
Multiplicity Strategy and Testing Hierarchy 
The efficacy analyses will employ a serial gatekeeper strategy to maintain the Type 1 error rate 
at α=0.05 across the family of analyses that support the primary and key secondary objectives. 
The strategy specifies a hierarchy of significance tests where each test acts as a gatekeeper to 
the tests below it. 
The hierarchy starts with the primary analysis comparing ZX008 0.8 mg/kg/day to placebo 
on the percent change from baseline in DSF. The next two steps in the hierarchy also entail 
comparisons of ZX008 0.8 mg/kg/day to placebo on two key secondary endpoints. The last 
three steps in the hierarchy all involve comparisons of ZX008 0.2 mg/kg/day to placebo. 
Below is a complete list of steps in the testing hierarchy in order: 
1. 
Compare ZX008 0.8 mg/kg/day to placebo on the percent change in DSF from 
baseline in DSF. 
2. 
Compare ZX008 0.8 mg/kg/day to placebo on the proportion of subjects who 
achieve a ≥50% reduction from baseline in DSF. 
3. 
Compare ZX008 0.8 mg/kg/day to placebo on the change from baseline in the 
number of all countable motor seizures. 
4. 
Compare ZX008 0.2 mg/kg/day to placebo on the percent change from baseline in 
DSF. 
5. 
Compare ZX008 0.2 mg/kg/day to placebo on the proportion of subjects who 
achieve a ≥50% reduction from baseline in the DSF. 
6. 
Compare ZX008 0.2 mg/kg/day to placebo on the CGI-I at Visit 12. 
Part 1 Cohort B 
Efficacy analyses for Part 1 Cohort B will use the same methods as described for Part 1 Cohort 
A. Some subsets analyses may not be feasible in Cohort B due to its smaller sample size. 
10.1.6.2 
Safety Analyses 
Summaries of safety data will be presented by treatment – ZX008 0.8 mg/kg/day, ZX008 
0.2 mg/kg/day or placebo – for the T+M period. The number and percentage of subjects in 
each treatment group with AEs will be displayed by body system and preferred term using the 
Medical Dictionary for Regulatory Activities (MedDRA). Summaries of AEs by severity and 
relationship to study drug will also be presented. A separate summary will be provided for all 
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serious AEs (SAEs). If warranted, selected summaries will be repeated broken out by weight 
group, ie, for subjects who weigh <37.5 kg and those who weigh ≥37.5 kg. 
Laboratory tests, vital signs, physical examinations, neurological examinations, ECG, Doppler 
echocardiogram, C-SSRS, Tanner Staging results, etc, will be summarized appropriately, by 
treatment. All safety summaries will be based on the SAF Population. 
10.1.6.3 
Pharmacokinetic Analyses 
Model-derived plasma PK parameters of fenfluramine and norfenfluramine (Cmax_ss, 
Cmin_ss, , AUC0-t, AUC0-24) will be summarized descriptively by treatment group when 
sufficient data are available. A population PK model, previously developed using data 
from healthy adults and pediatric patients with Dravet syndrome, will updated to include 
the fenfluramine and norfenflurmaine concentration-time data collected during the 
Maintenance Period. This model will be informed by all relevant data available at the time 
of data collection (both adults and pediatrics). The results from the PopPK modeling will 
be reported separately and conducted according to a separate SAP. 
10.2 
STATISTICAL ANALYSIS: PART 2 
Safety and effectiveness will be assessed  in the subjects who continue into Part 2 of the study in 
which all subjects receive open-label ZX008. 
10.2.1 
ANALYSIS POPULATIONS 
10.2.1.1 
OLE Population 
Safety analyses for Part 2 will be performed on the OLE Safety Population defined as all 
subjects who receive at least one dose of ZX008 during the open label extension. 
10.2.1.2 
OLE mITT Population 
The OLE mITT Population is defined as all randomized subjects who receive at least one dose 
of ZX008 and have valid seizure data during the open label extension. 
10.2.2 
TREATMENT GROUPS 
All subjects in Part 2 will receive ZX008 and will be considered a single treatment group. 
Selected data summaries may be broken out by the treatment received during Part 1 and/or 
average dose received during Part 2. 
10.2.3 
TREATMENT PERIODS 
Open-Label Extension (OLE) Treatment Period 
The OLE Treatment Period covers the duration during which subjects receive open label 
treatment with ZX008. 
OLE Taper Period 
The OLE Taper Period begins immediately after the OLE Treatment period and extends for 2 
weeks. 
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10.2.4 
STATISTICAL ANALYSES AND METHODS 
10.2.4.1 
Safety Analyses 
The number and percentage of subjects who experience treatment emergent AEs will be 
displayed by body system and preferred term using MedDRA. Summaries in terms of severity 
and relationship to study drug will also be provided. SAEs will be summarized separately in a 
similar manner. Laboratory tests, vital signs, physical examinations, neurological 
examinations, ECG, ECHO, cognition and body weight will be summarized using appropriate 
methods. 
10.2.4.2 
Effectiveness Analyses 
Effectiveness will be assessed by the change from baseline (prior to randomization into Part 1) 
in DSF. The DSF per 28 days will be calculated as the number of seizures recorded divided by 
the number of days in the period and multiplied by 28. The change in DSF during the OLE 
Treatment Period will be calculated as the difference between DSF during the OLE and the 
baseline DSF measuredprior to randomization in Part 1. The percent change in DSF is the 
change in DSF between OLE and Baseline / DSF during Baseline x 100. Both the mean and 
median percent change in DSF will be presented and the statistical significance of the percent 
change will be assessed using a Wilcoxon signed-rank test.  Other secondary assessments will 
be compared to baseline from prior to Part 1, or by visit throughout Part 1 and Part 2, as 
appropriate. 
For subjects continuing in Part 2 past Visit 22, effectiveness will be assessed by investigator 
rating of overall change in seizure frequency (<25%, ≥25%, ≥50%, or ≥75%, 100% (seizure-
free) improvement compared to last visit). 
10.2.5 
ANALYSES PROVIDED TO AN INDEPENDENT DATA AND SAFETY 
MONITORING COMMITTEE 
A safety oversight monitoring plan will be in place with an IDSMC evaluating data from the 
subjects. Details will be provided in the IDSMC charter. The IDSMC’s primary responsibility 
is to ensure that study subjects are not exposed to unanticipated harm that could have been 
prevented by timely review and intervention. The IDSMC is established to review safety data 
at predefined time points, and to recommend to the sponsor whether to continue, modify, or 
terminate the study as necessary. The IDSMC is composed of expert permanent members who 
cover relevant specialties. The IDSMC members may request assistance from a number of 
additional and ad hoc members if needed. 
11. 
ETHICAL & REGULATORY CONSIDERATIONS 
11.1 
ETHICAL CONSIDERATIONS 
The procedures set out in this study protocol are designed to ensure that the sponsor and the 
investigator abide by the principles of the current ICH GCP guideline on the conduct, 
evaluation and documentation of this study, as described in ICH Topic E6 Guideline. ICH GCP 
is an international ethical and scientific quality standard for designing, conducting, recording, 
and reporting studies that involve the participation of human subjects. Compliance with this 
standard provides public assurance that the rights, safety, and well-being of study subjects are 
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protected and consistent with the principles of the Declaration of Helsinki, and that the clinical 
study data are credible. 
The study will also be carried out according to all applicable international and national 
regulatory requirements. 
The sponsor and the investigator must inform each other (eg, during a study initiation visit, via 
e-mail, etc) that all ethical and legal requirements have been met before the first subject is 
enrolled into the study. 
11.2 
INFORMED CONSENT 
The investigator is responsible for obtaining a subject’s written informed consent to participate 
in the study. 
A Subject Information Sheet and a master ICF will be prepared by the sponsor according to the 
provisions of ICH GCP and local legal requirements. 
All subjects will be informed that the study will be registered in the public database at 
ClinicalTrials.gov in accordance with the FDA Amendments Act of 2007 (Section 12.3). 
Before undergoing screening procedures for possible enrollment into the study, subjects must 
be informed, in an understandable form, about the nature, scope, and possible consequences of 
the study. This information must be given orally to subjects by a physician or medically 
qualified person (according to applicable regulatory requirements) who is well informed about 
the nature, scope, and possible consequences of the study. Written information about the study 
will also be provided in a Subject Information Sheet. The date on which this oral and written 
information on the study was provided to the subject, and by whom it was provided, must be 
documented in the ICF. 
As specified in ICH GCP Section 4.8 and the US 21CFR Section 50.25, the informed consent 
discussion must emphasize that participation in the study is voluntary and that subjects have the 
right to withdraw their consent at any time without giving a reason and without any 
disadvantage for their subsequent care. 
Subjects must be given ample time and opportunity to inquire about details of the study and to 
consider their participation in the study. If, after reading the Subject Information Sheet and the 
ICF, consent is given to participate in the study, then the ICF must be signed and personally 
dated by the subject and the person conducting the informed consent discussion (and an 
impartial witness, if required). The subject will be provided with a copy of the signed ICF. 
Verification of the signed ICF will be recorded in the subject’s eCRF. The original signed ICF 
will be filed with the subject’s records and/or in the Investigator Study File. 
The Subject Information Sheet and ICF have to be approved by the IEC/IRB before they can be 
used in the study. 
The Subject Information Sheet and ICF must be revised whenever important new information 
becomes available that may be relevant to the subject’s consent. Any revision of these 
documents must be approved by the IEC/IRB before they can be used in the study. Subjects 
must be informed in a timely manner if new information becomes available that may be 
relevant to their willingness to continue participation in the study. The communication of this 
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information should be documented by having all parties concerned sign and personally date the 
revised ICF. 
Subject or Subject’s Legally Acceptable Representative Unable to Read 
If a subject is unable to read, or if a legally acceptable representative is unable to read, an 
impartial witness should be present during the entire informed consent discussion. After the 
ICF and any other written information provided to the subject, parent or guardian has been read 
and explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the ICF, 
the witness should also sign and personally date the ICF. By signing the ICF, the witness attests 
that the information in the ICF and any other written information was accurately explained to, 
and apparently understood by, the subject or the subject’s legally acceptable representative, and 
that informed consent was freely given by the subject or the subject’s legally acceptable 
representative. 
Assent for Subjects Under the Age of Consent (Pediatric Subjects) 
All subjects are under the age of consent (ie, pediatric subjects under 18 years of age); the 
written informed consent of a legally acceptable representative is required. Pediatric subjects 
who can understand the nature, scope, and possible consequences of the study must also give 
their assent, orally and/or in writing via the assent document, as appropriate. After the ICF and 
any other written information to be provided to subjects has been read and explained to the 
subject and the subject’s legally acceptable representative, and after the subject and the legally 
acceptable representative have orally consented to the subject’s participation in the study and, if 
capable of doing so, the subject has signed and personally dated the assent document, the 
legally acceptable representative should sign and personally date the ICF. By signing the ICF, 
the legally acceptable representative attests that the information in the ICF and any other 
written information was accurately explained to, and apparently understood by, the subject, and 
that assent was freely given by the subject. 
11.3 
REGULATORY CONSIDERATIONS AND INDEPENDENT 
ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD 
The sponsor (or delegate) will submit the appropriate documents to all applicable competent 
regulatory authorities and IEC/IRBs, and will await all relevant approval before enrolling any 
subjects into the study. Written approval should mention the study protocol by study title, study 
number, and version date. 
This study will be conducted under Investigational New Drug (IND) Application and 
documented in accordance with the applicable regulatory guidelines and requirements. 
The sponsor (delegate) will ensure that the investigators conduct the study as 
stipulated in this study protocol and in accordance with all applicable regulatory 
requirements. The sponsor (delegate) is obliged to obtain evidence of the 
investigator’s qualification to perform the clinical study. Therefore, the investigator 
has to provide a signed and dated copy of his or her professional curriculum vitae 
(prepared no more than 2 years beforehand and preferably written in English) before 
the start of the study, including information on his or her experience in conducting 
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clinical studies according to ICH GCP and other applicable regulatory requirements. 
Written notification of the identity and occupation of the members of the IEC/IRB is also 
required by the sponsor (delegate). Should the IEC/IRB be unwilling to provide this 
information, a letter stating that the committee was constituted in accordance with applicable 
regulatory requirements should be provided. 
11.4 
PROTOCOL COMPLIANCE 
The investigator must conduct the study in compliance with this study protocol as agreed to by 
the sponsor and, if required, by any competent regulatory authority, and which has been 
approved by, or given a favorable opinion by, the IEC/IRB. 
The investigator should not implement any deviation from, or changes to, the study protocol 
without agreement by the sponsor (delegate) and prior review and documented approval or 
favorable opinion from the IEC/IRB of an amendment to the study protocol. Exceptions include 
only cases of medical emergency to address immediate hazards to study subjects, or when the 
changes involve only logistic or administrative aspects of the study. 
In the event of a medical emergency, the investigator at each site may institute any medical 
procedures deemed appropriate to address an immediate hazard to a subject without prior 
IEC/IRB approval or favorable opinion. As soon as possible, the implemented deviation or 
change, the reason(s) for it, and, if appropriate, the proposed study protocol amendment(s) 
should be submitted to: 
x The sponsor (delegate) for agreement. 
x The IEC/IRB for review and approval or favorable opinion (if required). 
x The applicable competent regulatory authority (if required). 
Details of the procedure for implementing study protocol amendments are available in 
Section 12.10. 
At the earliest opportunity, the investigator (or delegate) must inform the sponsor (delegate) 
about any notable protocol deviations and explain any deviation from the approved study 
protocol in the eCRF and/or in the Protocol Deviation Log, if applicable. 
12. 
ADMINISTRATIVE ASPECTS 
12.1 
CLINICAL TRIAL AGREEMENT 
This study will be conducted under a Clinical Trial Agreement between the sponsor (or 
delegate) and the respective institutions representing the study sites. Any financial support 
given to the study sites will be detailed in the Clinical Trial Agreement. The Clinical Trial 
Agreement, which must be signed before the start of any study related procedures, will clearly 
delineate the responsibilities and obligations of the investigator and the sponsor (delegate), and 
will form the contractual basis upon which the study will be conducted. 
12.2 
FINANCIAL DISCLOSURE BY INVESTIGATOR 
Prior to study initiation, the investigator and any subinvestigator(s) to be directly involved in 
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the treatment or evaluation of study subjects at each study site will disclose to the sponsor 
(delegate) any relevant financial or proprietary interests in either the study product or the 
sponsor company. The appropriate disclosure form(s) will be provided by the sponsor 
(delegate) for this purpose. Any relevant updates to the financial disclosure information that 
occur during the conduct of the study, or during one year after completion of the study, will be 
provided by the investigator and subinvestigator(s) to the sponsor (delegate). All financial 
disclosure information provided by the investigator and subinvestigator(s) will be submitted to 
appropriate competent authorities according to the applicable regulatory requirements. 
12.3 
CLINICAL STUDY REGISTRATION AND RESULTS DISCLOSURE 
The sponsor will provide the relevant study protocol information in a public database 
(ClinicalTrials.gov) before or at commencement of the study, as required by the 2007 FDA 
Amendments Act. The sponsor (delegate) may also provide study information for inclusion in 
national registries according to local regulatory requirements. 
If a potential subject contacts the sponsor regarding participation in the study, the investigator 
agrees that the sponsor (delegate) may forward the relevant study site and contact details to the 
subject. Based on the inclusion and exclusion criteria for the study, the investigator will assess 
the suitability of the subject for enrollment into the study. Results of this study will be 
disclosed according to the relevant regulatory requirements. All publications in peer-reviewed 
medical journals resulting from this study will be listed in the original study protocol 
registration record on ClinicalTrials.gov. 
12.4 
STUDY FILES AND MATERIALS 
Before the start of any study related procedures, all essential documents specified by ICH GCP 
and other applicable regulations must be available in the relevant files maintained by the 
sponsor (or delegate) and the investigator. An Investigator Study File prepared by the sponsor 
(or delegate), containing all applicable documents for use at the study site, will be made 
available to the investigator before the start of the study. A list of personnel and organizations 
responsible for conduct of the study as well as the list of investigators will be included in the 
Investigator Study File. The respective files will be kept and updated by the sponsor (or 
delegate) and the investigator, as applicable. 
All study documentation and materials maintained in the Investigator Study File at the study 
site must be available for inspection by the sponsor’s study monitor (or delegate) to determine 
that all required documentation is present and correct (see Section 12.9). 
The study may be audited or inspected by qualified delegates from the sponsor or a competent 
regulatory authority (see Section 12.11). 
12.5 
INITIATION OF THE STUDY 
Before the start of the study at each study site, the sponsor’s study monitor (or delegate) will 
ensure adequacy of the facilities and discuss responsibilities regarding study protocol 
adherence with the investigator and other personnel involved in the study. 
The investigator may not enroll any subjects into the study before the sponsor has received 
written approval or a favorable opinion from the IEC/IRB for conducting the study and a 
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formal meeting has been conducted by the sponsor’s study monitor (or delegate) to initiate the 
study (study initiation visit).  
12.6 
SUBJECT REIMBURSEMENT 
Where relevant, subjects will be reimbursed for reasonable travel costs associated with 
participation in this study, after presentation of receipts for the travel in question, at a rate to be 
approved by the IEC/IRB. Subjects will not be paid for participating in the study. 
12.7 
LIABILITY AND INSURANCE 
The civil liability of the involved parties with respect to financial loss due to personal injury 
and other damage that may arise as a result of this study being conducted are governed by the 
applicable legal requirement(s). 
The sponsor will provide insurance to the investigator if required by the applicable regulatory 
and legal requirement(s). 
If required by local law, subjects taking part in this study will be insured against any injury 
caused by the study in accordance with the applicable regulatory and legal requirement(s). 
12.8 
SUBJECT IDENTIFICATION AND CONFIDENTIALITY 
All study documents, including the study protocol and eCRFs, are the confidential property of 
the sponsor and should be treated as such. 
All subjects screened for the study will be documented in a screening log in compliance with 
the requirements of individual study sites. Subjects not enrolled into the study will be 
documented as such in the screening log together with the reason for not having been enrolled. 
The investigator will maintain a personal list of subject names and subject numbers (Subject 
Identification List) for participants in the study to enable records to be identified at a later date. 
These records should be retained in a confidential manner for the duration stipulated by 
applicable regulatory requirements. All subject names will be kept in confidence and will not 
be revealed to the sponsor. Subject names must be made unreadable on any documents made 
available to the sponsor. 
Subjects participating in the study will be identified in the eCRF by the subject number allotted 
to them during the study. 
The ICF will include a statement that all study findings, irrespective of the medium on which 
they are stored, will be handled in strictest confidence in accordance with applicable data 
protection laws (eg, the European Data Protection Directive [95/46/EC] and the USA Health 
Insurance Portability and Accountability Act [HIPAA]), and will be evaluated by the sponsor 
and/or a competent regulatory authority in an anonymized form. The subjects are also to be 
informed that their medical records may be audited or inspected by qualified delegates from the 
sponsor or a competent regulatory authority. The subject’s written consent authorizing direct 
access to his medical records, and computer processing and publishing of his anonymous 
personal data, must be obtained prior to participation in the study. 
A subject’s identity will be disclosed by the investigator only in case of emergency (ie, to 
address any immediate health hazard). 
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12.9 
MONITORING OF THE STUDY 
The investigator at each site will allow the sponsor’s study monitor (or delegate) reasonable 
access to the eCRFs and direct access to related source documents for monitoring purposes as 
frequently as the sponsor deems necessary. These documents include records of tests performed 
as a requirement for participating in the study as well as other medical records required to 
confirm information contained in the eCRF, such as past history and secondary diagnoses. 
 
Before each monitoring visit, the investigator (or delegate) should record all data generated 
since the last monitoring visit in the eCRF. The investigator and other relevant personnel at 
each study site will be expected to cooperate with the sponsor’s study monitor to assist in 
providing any missing information. 
The study monitor will require access to the Investigator Study File to ensure completeness of 
all documentation required for the study. The study monitor will ensure that the investigator at 
each site has been provided with adequate means for organization and filing of study 
documentation (see Section 12.4). 
The date on which the study monitor (or delegate) visits the study site will be recorded in the 
Site Visit Log. During monitoring visits, the study site’s coordinator (if applicable) and the 
investigator should be available, the source documentation should be accessible, and a suitable 
environment should be provided for the study monitor to review study related documentation. 
The main objectives of monitoring visits conducted by the study monitor include: 
x Resolution of any problems. 
x Examination of all study documentation for completion, adherence to the study protocol, 
and possible AEs. 
x Clarification of inconsistencies or missing data. 
x Verification of study data against source documents. 
x Checks that investigator obligations have been fulfilled. 
x Review of ICFs and dates of consent. 
x Inspection of IMP with respect to storage, labeling, and documentation. 
x Drug accountability 
After each subject’s visit to the study site, the investigator (or delegate) will ensure that all data 
have been entered into the eCRF correctly and in a timely manner, after which the investigator 
will sign the eCRF. 
12.10 
PROTOCOL AMENDMENTS 
A “substantial” amendment of a study protocol is any written description of change(s) to, or 
formal clarification of, a study protocol that may have a significant impact on the safety or 
physical or mental integrity of subjects, the scientific value of the study, the conduct or 
management of the study, or the quality or safety of any IMP used in the study. The IEC/IRB 
must approve all substantial protocol amendments prior to their implementation. If required by 
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applicable local regulatory requirements, the local regulatory authority must also approve all 
substantial protocol amendments prior to their implementation. 
A “non-substantial” amendment of a study protocol includes minor corrections or clarifications 
that have no significant impact on the way the study is to be conducted and has no effect on the 
safety of participating subjects (eg, change in study monitor, contact details, etc). If required by 
applicable local regulatory requirements, the IEC/IRB, and/or the local regulatory authority 
should be notified of all non-substantial protocol amendments. The substantial and non- 
substantial protocol amendments will be integrated into an updated study protocol at the 
discretion of the sponsor if the changes to the original study protocol are numerous, or if 
required by applicable regulatory requirements. 
12.11 
AUDITS AND INSPECTIONS 
The study may be audited or inspected by qualified delegates from the sponsor or a competent 
regulatory authority. 
In the event of an audit by the sponsor, the investigator must make all study related 
documentation available to the auditor(s). Regulatory authorities may request access to all 
study related documentation, including source documents, for inspection and copying in 
keeping with applicable regulations. The sponsor will immediately notify the investigator (or 
vice versa) of an upcoming audit or inspection. 
If an audit or inspection occurs, the investigator and relevant personnel at the study site must 
allocate sufficient time to discuss the findings and any relevant issues. 
12.12 
CLINICAL STUDY REPORT 
After completion of the study, a clinical study report covering clinical and statistical aspects of 
the study will be prepared by the sponsor (or delegate) in consultation with the coordinating 
investigator. As required by the applicable regulatory requirements, the clinical study report 
will be signed by the sponsor’s responsible medical officer as well as the coordinating 
investigator (if applicable). 
Progress reports and/or a summary of the clinical study report will be provided to the IEC/IRB 
and competent regulatory authorities in accordance with applicable requirements. 
12.13 
USE OF DATA AND PUBLICATIONS 
The rights and obligations of investigators and the sponsor concerning any formal presentation 
or publication of data collected as a direct or indirect result of this study will be addressed 
specifically in the Clinical Trial Agreement for the study (see Section 12.1). 
For multicenter studies, the first publication must be based upon all data obtained from all 
analyses, as stipulated in the study protocol by the biostatistician and not by the investigators. 
Investigators participating in multicenter studies must agree not to present data gathered 
individually or by a subgroup of study sites before the full, initial publication is available or 
5 years after the last clinical study visit, whichever is later, unless this has been agreed to by all 
other investigators and by the sponsor. 
The sponsor must receive a copy of any intended communications in advance of the proposed 
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submission date. This is to allow the sponsor time to review the communication for accuracy 
(thus avoiding potential discrepancies with submissions to regulatory authorities), to verify that 
confidential and/or proprietary information is not inadvertently divulged, to provide any 
relevant supplementary information, and to allow establishment of co-authorship (as 
appropriate). The authorship of communications arising from pooled data will include 
investigators from study sites that contributed data as well as relevant personnel from the 
sponsor. Ownership of all data will remain with the sponsor. 
 
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the effectiveness and tolerability of low-dose ZX008 (fenfluramine HCl) in Lennox-Gastaut 
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Marshall WA, Tanner JM. Variations in the pattern of pubetal changes in boys. Arch Dis Child 
1970; 45:13. 
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 
1969;44(235):291-303. 
Morford, L. L., Inman-Wood, S. L., Gudelsky, G. A., Williams, M. T. and Vorhees, C. V. 
(2002), Impaired spatial and sequential learning in rats treated neonatally with d-fenfluramine. 
European Journal of Neuroscience, 16: 491–500. doi:10.1046/j.1460-9568.2002.02100.x 
Ng Y, Conry J, Drummond R, Stolle J, Weinberg M for the OV-1012 Study 
Investigators. Randomized, phase III study results of clobazam in Lennox–Gastaut 
syndrome. Neurology 2011; 77:1473–1481. 
Panayiotopoulos C. Epileptic encephalopathies in infancy and early childhood in which the 
epileptiform abnormalities may contribute to progressive dysfunction. In Panayiotopoulos C (Ed) 
The epilepsies: seizures, syndromes and management. Oxfordshire, UK: Bladon Medical 
Publishing, 2005:137–206. 
Rabbit, P. (Ed.). (1997). /react-text Methodology of frontal and executive function react-text: 
2931 . East Sussex, UK: Psychology Press. 
Sabaz, M., Cairns, D. R., Lawson, J. A., Nheu, N., Bleasel, A. F., & Bye, A. M. (2000). 
Validation of a new quality of life measure for children with epilepsy. Epilepsia, 41(6), 765–774. 
Schoonjans A, Marchau F, Paelinck B, Gunning B, Verhoeven JS, Gammaitoni AR, Galer BS, 
Lagae L, Ceulemans B. Low-Dose Fenfluramine Provides Significant and Long-Term Seizure 
Reduction in Dravet Syndrome: Update and Follow-Up of the Prospective Study. American 
Epilepsy Society Annual Meeting 2017: Abstract 3.264. 
Schoonjans A-S, Lagae L, Ceulemans B. Low-dose fenfluramine in the treatment of neurologic 
disorders: experience in Dravet syndrome. Therapeutic Advances in Neurological Disorders. 
2015;8(6):328-338. doi:10.1177/1756285615607726. 
Talarska, D. (2007). The usefulness of Quality of Life Childhood Epilepsy (QOLCE) 
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questionnaire in evaluating the quality of life of children with epilepsy. Advances in Medical 
Sciences, 52 Suppl 1, 191–193. 
Webb RH, Gentles TL, Stirling JW, et al. Valvular regurgitation using portable 
echocardiography in a healthy student population: implications for rheumatic heart disease 
screening. J Am Soc Echocardiogr. 2015;28:981 988. 
Westphal-Guitti C, Alonso NB, Migliorini RCVP et al., “Quality of life and burden in caregivers 
of patients with epilepsy,” The Journal of Neuroscience Nursing, vol. 39, no. 6, pp. 354–360, 
2007. 
Wheless JW, Clarke DF, Arzimanoglou A, et al. Treatment of pediatric epilepsy: European 
expert opinion, 2007. Epileptic Disord 2007;9:353–412. 
Williams, M. T., Morford, L. L., McCrea, A. E., Wood, S. L., & Vorhees, C. V. (2002). 
Administration of d,l-fenfluramine to rats produces learning deficits in the Cincinnati water maze 
but not the Morris water maze: relationship to adrenal cortical output. Neurotoxicology and 
Teratology, 24(6), 783–796. 
Wong J, Reddy SS, Klein AL. Anorectic drugs and valvular heart disease: a biological and 
clinical perspective.  Cleveland Clinical Journal of Medicine 1998; 65:35-41. 
ZX008 Investigator’s Brochure Version 8, 2020. 
 
 
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14. 
APPENDICES 
APPENDIX 1 – LIST OF PROHIBITED CONCOMITANT 
MEDICATIONS 
The below table lists examples of medications in the classes prohibited under the exclusion 
criteria defined in the protocol, but it is not an exhaustive list. Please consult the medical monitor 
in your region if a participant is on a medication that falls into any prohibited classifications but 
is not listed in the below table. 
ADHD Medications 
Atomoxetine  
Amphetamine and derivates 
Methamphetamine 
Guanfacine  
Methylphenidate  
Lisdexamfetamine 
Bupropion  
Dexmethylphenidate  
Dextroamphetamine  
Clonidine  
 
Anti-arrhythmics 
Antibiotics 
Anti-nausea 
Anti-pyretic 
Mexiletine 
Linezolid 
Metoclopramide 
Phenacetin 
Propafenone 
 
Ondansetron 
 
Anticonvulsants 
Felbamate** 
Retigabine/ezogabine 
THC and derivatives 
 
Epidiolex 
Cannabidiol products 
 
 
Antidepressants (SSRIs, SNRIs, NRIs) 
Amitriptyline 
Clomipramine 
Fluvoxamine 
Paroxetine 
Bupropion 
Desipramine 
Imipramine 
Sertraline 
Buspirone 
Duloxetine 
Nefazodone 
Trazodone 
Citalopram 
Fluoxetine 
Nortriptyline 
Vortioxetine 
Antihistamines 
Astemizole 
Hydroxyzine  
Chlorphenamine  
 
Cyproheptadine 
 
Diphenhydramine  
 
Anti-migraine 
Almotriptan 
Eletriptan 
Naratriptan 
Sumatriptan 
Cafergot 
Ergotamine tartrate 
Rizatriptan 
Zolmitriptan 
Antipsychotics/Neuroleptics (serotonin agonists/ antagonists, noradrenergic agonists/antagonists) 
Amisulpride 
Guanfacine 
Paliperidone 
Risperidone 
Amphetamine 
Haloperidol 
Perospirone 
Sulpiride 
Aripiprazole 
Levomepromazine 
Perphenazine 
Ziprasidone 
Asenapine 
Lurasidone 
Promethazine 
Zuclopenthixol 
Clozapine 
Methylphenidate 
Propanolol 
 
Clonidine 
Olanzapine 
Quetiapine 
 
Anti-viral 
Beta Blocker 
Chemotherapy 
Cough 
Suppressant 
Interferon 
Alprenolol 
Dasatinib 
Dextromethorphan 
Ritonavir 
Bufuralol 
 
 
Telaprevir 
 
 
 
Centrally-acting anorectic agents 
Lorcaserin 
Phentermine 
Naltrexone-
bupropion  
Phentermine-
topiramate 
Diethylpropion 
Benzphetamine 
Phendimetrazine 
Decongestants (allowed for short-term use only) 
Statins 
Phenylpropanolamine 
 
Cerivastatin 
 
Ergot Alkaloids, their derivatives, and Antiparkinson agents 
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Pergolide  
Cabergoline  
Ergotamine Tartrate 
 
Monoamine-oxidase inhibitors 
Isocarboxazid  
Selegiline 
Tranylcypromine 
Phenelzine  
Opioids 
Alfentanil 
Levacetylmethadol (LAAM) 
Meperidine 
Oxycodone 
Codeine 
Fentanyl 
Methadone 
Tramadol 
 
*Felbamate is prohibited as a concomitant medication unless the subject has been on felbamate for at 
least 12 months prior to screening, has stable liver function and hematology laboratory tests, the dose 
has been stable for at least 60 days prior to screening and is expected to remain constant throughout the 
study. 
 
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APPENDIX 5 – TANNER STAGING 
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APPENDIX 6 – QOLCE QUALITY OF LIFE 
 
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APPENDIX 7 – HOSPITAL ANXIETY AND DEPRESSION SCALE 
Hospital Anxiety and Depression Scale (HADS) 
 
Tick the box beside the reply that is closest to how you have been feeling in the past   week. 
Don’t take too long over you replies: your immediate is  best. 
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D 
A 
 
D 
A 
 
 
I feel tense or 'wound up': 
I feel as if I am slowed down: 
 
3 
Most of the time 
3 
Nearly all the time 
 
2 
A lot of the time 
2 
Very often 
 
1 
From time to time, occasionally 
1 
Sometimes 
 
0 
Not at all 
0 
Not at all 
 
 
 
 
 
I still enjoy the things I used to 
enjoy: 
I get a sort of frightened feeling like 
'butterflies' in the stomach: 
0 
 
Definitely as much 
0 
Not at all 
1 
 
Not quite so much 
1 
Occasionally 
2 
 
Only a little 
2 
Quite Often 
3 
 
Hardly at all 
3 
Very Often 
 
 
 
 
 
I get a sort of frightened feeling as if 
something awful is about to  
happen: 
I have lost interest in my  appearance: 
 
3 
Very definitely and quite badly 
3 
Definitely 
 
2 
Yes, but not too badly 
2 
I don't take as much care as I should 
 
1 
A little, but it doesn't worry me 
1 
I may not take quite as much care 
 
0 
Not at all 
0 
I take just as much care as ever 
 
 
 
 
 
I can laugh and see the funny side 
of things: 
I feel restless as I have to be on the 
move: 
0 
 
As much as I always could 
3 
Very much indeed 
1 
 
Not quite so much now 
2 
Quite a lot 
2 
 
Definitely not so much now 
1 
Not very much 
3 
 
Not at all 
0 
Not at all 
 
 
Worrying thoughts go through my 
mind: 
I look forward with enjoyment to 
things: 
 
3 
A great deal of the time 
0 
As much as I ever did 
 
2 
A lot of the time 
1 
Rather less than I used to 
 
1 
From time to time, but not too often 
2 
Definitely less than I used to 
 
0 
Only occasionally 
3 
Hardly at all 
 
 
 
 
 
I feel cheerful: 
I get sudden feelings of panic: 
3 
 
Not at all 
3 
Very often indeed 
2 
 
Not often 
2 
Quite often 
1 
 
Sometimes 
1 
Not very often 
0 
 
Most of the time 
0 
Not at all 
 
 
 
 
 
I can sit at ease and feel relaxed: 
I can enjoy a good book or radio or TV 
program: 
 
0 
Definitely 
0 
Often 
 
1 
Usually 
1 
Sometimes 
 
2 
Not Often 
2 
Not often 
 
3 
Not at all 
3 
Very seldom 
Please check you have answered all the questions 
 
Scoring: 
Total score: Depression (D)   
 
0-7 
= Normal 
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8-10 = Borderline abnormal (borderline case) 11-21 = Abnormal (case) 
 
 
 
 
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APPENDIX 8 – ZARIT CAREGIVER BURDEN INVENTORY 
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APPENDIX 9 – MAXIMUM ALLOWABLE BLOOD DRAW VOLUMES 
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APPENDIX 10 – STUDY CONDUCT DURING COVID-19 
In March 2020, the World Health Organization declared a global pandemic related to an illness caused by 
a novel coronavirus known as COVID-19.  As a result, public health initiatives, such as laws, regulations 
and policies were enacted at country and institutional levels to protect the health of the general public. 
These initiatives and policies have affected the ability of study sites to conduct the trial per protocol and 
the ability of the sponsor and/or delegate to conduct trial oversight and monitoring visits.  
In an effort to support the rights, safety and welfare of subjects and ensure as little impact on the integrity 
of the research as possible the following alternative processes have been implemented due to restrictions 
related to COVID-19. Though every attempt should be made to conduct study visits per protocol, any 
implementation of alternative processes should be properly documented. If there are no impacts or 
accomodations for COVID-19 at a study site, these allowances must not be followed. 
1. Allowance of Delays to In-person Study Visits 
If sites are unable to conduct study visits, or subjects are unable to travel to the study site due to 
COVID-19 circumstances, an in-person visit may be delayed up to 6 weeks from the protocol-defined 
visit due date. Data will need to be entered per normal procedures in the EDC, with a description 
indicating COVID-19 as the cause for delay in response to queries. If a subject is unable to travel to 
the study site within this expanded 6-week window, a telephone or video telemedicine visit should be 
attempted, as described below. If a telephone or video telemedicine visit cannot be conducted in the 
6-week window, the visit should be considered missed and the next scheduled visit conducted.  
2. Allowance of Remote Telemedicine/Telephone/Video Visits:  
Visits 1-5 should be conducted in person. For Visits 6, 8, 10, 15-21, remote visits via telephone or 
video are acceptable when subjects are unable to travel to the site for in-person visits due to COVID-
19 circumstances. The following information should be collected and recorded in the source 
documentation and in the EDC where applicable. Log pages (e.g. AEs, concomitant medication 
changes) will be entered normally as they are not associated with specific visits; assessment forms 
located within a particular visit page will also be entered normally, however, queries will be fired to 
capture specific information explaining the basis for missing or alternatively collected (ie. remote) 
data. Detailed instruction for EDC entry may be found in the CRF Completion Guidelines (CCGs). 
x Date and time of the telephone/video visit 
x Any changes in health status  
x AEs/SAE assessment 
x Concomitant medication query 
x Review seizure and medication diary with parent/caregiver for compliance and any 
abnormalities in seizure activity 
x Scales and Questionnaires, when applicable and if feasible 
o C-SSRS 
o CGI-I (by Investigator and Parent/Caregiver) 
o BRIEF 
o Tanner Staging 
o QOLCE 
o Zarit Caregiver Burden 
o HADS  
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3. End-of-Study/Early Termination (EOS/ET) and Follow-up Visits:  
Cardiac follow-up visits (Visits 14, 24, or 25) must be conducted in-person. 
 
EOS/ET for subjects tapering off ZX008: 
For the EOS/ET visit (Visit 12 or 22) and Post-Dosing Follow-up visit (Visit 13 or 23), every attempt 
should be made to conduct these visits in-person. For subjects tapering off study-drug that are unable 
to come to the study site, the EOS/ET and Post-Dosing Follow-up visits may be conducted via 
telephone or video. However, subjects should return to the study site in person, as soon as feasible to 
conduct any safety assessments that were unable to be evaluated remotely. If an in-person visit cannot 
be scheduled within 6 months of the EOS/ET and/or Post-Dosing Follow-up visit windows to conduct 
the required safety assessments, these assessments will be considered as missed. 
 
EOS/ET for subjects transitioning to another Extension Study: 
For subjects transitioning into another ZX008 extension study that are unable to attend the EOS/ET 
visit due to restrictions to traveling to the study site, delays in the start-up of the extension study, or 
other COVID-related delays, the EOS/ET visit may be delayed until an in-person visit is conducted. 
Therefore, subjects may remain on study for longer than the planned duration of participation. If the 
delay is over 6 weeks, medical monitor review and approval is required. If approval to extend beyond 
6 weeks is granted,  telephone or video visits should be conducted at least every 12 weeks until the in-
person EOS/ET transitional visit to the other extension study is performed. The telephone or video 
visits will collect the following data, at minimum: 
x Date and time of the telephone/video visit 
x Any changes in health status  
x AEs/SAE assessment 
x Concomitant medication query 
x Review seizure and medication diary with parent/caregiver for compliance and any 
abnormalities in seizure activity 
4. Allowance of delays to ECHO, ECG, Chest X-Ray, EEG and clinical lab assessments when in-
person study visits are missed or delayed 
If it is not possible to obtain the above assessments as described below, a documented 
risk/benefit discussion with the medical monitor is required to determine a course of action, 
which may include approval to delay further for a pre-specified duration, subject withdrawal, 
or other actions. The risk/benefit analysis will take into account AEs, previous assessment 
findings, duration of delay, clinical improvement while on study drug (seizure and non-seizure 
outcomes), and region-specific risk of attending in-person visits to complete the assessments. 
 
Doppler ECHO:   
If subjects are unable to travel to the study site due to COVID-19 circumstances, ECHOs may be 
delayed up to an additional 3 months from the protocol-designated ECHO due date (for a total of 6 
months from the time of the last ECHO) for subjects that exhibited the following on their previous, 
most recent ECHO: absent aortic regurgitation, absent or trace mitral regurgitation, and PASP <30 
mmHg. 
All subjects with regurgitation ≥ trace aortic regurgitation, ≥mild mitral regurgitation, or PASP ≥30 
mmHg may have ECHO delayed from the protocol-designated ECHO due date by up to 6 weeks 
only.  
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In those cases where an ECHO cannot be performed in the specified time period at the study-
authorized facility by a certified sonographer, the Sponsor may approve administration of the ECHO 
at an alternative facility to minimize need for travel. If the ECHO cannot be performed, a benefit 
risk/benefit analysis must be conducted as described above. 
If a delayed ECHO was conducted within 30 days of a scheduled Cardiac Follow-up Visit and there 
were no findings meeting Level 2 criteria (see Protocol Table 17), the Cardiac Follow-up Visit may 
be cancelled. If Level 2 or greater findings were observed, then the Cardiac Follow-up Visit should be 
rescheduled 3 months from the date of the delayed ECHO.  
ECG, Chest X-ray and EEG:   
If clinically indicated and where applicable, delays in these assessments may be implemented based 
on the investigators’ clinical discretion, weighing the risk/benefit of the clinical necessity of the 
assessment versus the risk of an in-person visit. All decisions should be documented appropriately in 
the source documentation. If not conducted at the study site, ECG, chest X-ray and EEG can be 
performed at any qualified local facility with results sent to the Principal Investigator for safety 
overread and documentation.  
If the ECG (or in the case of certain country-specific regulations: Chest X-ray or EEG) was 
conducted within 30 days of a scheduled Cardiac Follow-up Visit, these assessments do not need to 
be repeated at the Cardiac Follow-up Visit provided there were no significant findings that require 
additional follow-up.  
Clinical Laboratory Assessments: 
If clinically indicated and where applicable, delays in these assessments may be implemented based 
on the investigators’ clinical discretion, weighing the risk/benefit of the clinical necessity of the 
assessment versus the risk of an in-person visit. All decisions should be documented appropriately in 
the source documentation. If not conducted at the study site, clinical laboratory assessments can be 
performed at any qualified local facility with results sent to the Principal Investigator for safety 
overread and documentation.  
5. Alternative Dispensation for Study Drug 
Shipments of investigational product may be sent by courier from site pharmacy to the subject’s home 
via Sponsor-approved processes if the subject cannot or will not attend the dispensation visit(s). This 
shipment of drug should be arranged for patients who are due in the clinic for a drug dispensation 
visit. Other alternative dispensation, such as curbside pickup, may be implemented provided they are 
approved by the Sponsor and appropriate safeguards are taken to ensure compliance with existing 
regulatory requirements for maintaining investigational product accountability. Detailed instructions 
for drug handling, storage, accountability, etc. are described in the Pharmacy Manual.  
 
 
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ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 188 of 198 
APPENDIX 11 - SUMMARY OF PROTOCOL AMENDMENT 4.0 
Rationale for Protocol Amendment 4.0 
The protocol is being amended to simplify the visit schedule and reduce burden on the remaining 
participating subjects and their caregivers in Japan. The reduced in-clinic visit schedule (in-clinic 
visits every six months) will provide longitudinal safety data in an open-label setting which will 
inform the ongoing monitoring of Safety and Efficacy for Lennox-Gastaut syndrome subjects 
receiving fenfluramine as an Investigational Product. The reduction in in-clinic visit frequency is 
also considered to reduce risk for subjects in terms of exposure to COVID19 during a period 
when the global pandemic still poses considerable uncertainty. The assessment of cardiac 
function by ECHO performed every six months is aligned with the Sponsor’s Global Safety 
Surveillance for fenfluramine which has now achieved approval in the US and Europe for the 
indication of Dravet’s Syndrome. Information on seizure data and study drug administration will 
continue to be reported by the parents/caregivers which will enable the Investigator to monitor 
the subject appropriately and assess benefit-risk despite the decrease in visit schedule. A phone 
visit will be performed in between in-clinic visits to collect adverse events, concomitant 
medications and any change in the health status of the subject. Further detail is presented in the 
Summary of Change section.  
This amendment also extends the subject’s study participation for up to 5 years in Part 2, to 
allow subjects to remain on treatment until ZX008 becomes commercially available in the 
subject’s country of residence. 
 
List of Specific Changes 
Additions are marked in red and deletions are marked in strikethrough. Minor editorial and 
nonsubstantive changes, such as the correction of typing or formatting errors, updated use of 
abbreviations, updating headers and footers, tables of contents, list of abbreviations, signature 
pages, etc., are not listed. The list of specific changes below is grouped by rationale and not 
necessarily presented in the order in which they appear in the protocol. 
 
1. Update of Sponsor Information (address, sponsor’s representative and medical contact) 
to reflect the acquisition of Zogenix International Limited by UCB Biosciences Inc.  
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ZX008 (Fenfluramine Hydrochloride) 
ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 189 of 198 
 
 
2. Update to extend the subject’s study participation in Part 2 to up to 5 years (5 annual 
extensions, 72 months) 
Updates were made to the protocol language in study synopsis, sections  3.1, 3.3, 3.5, 6.2. Table 
2: Schedule of Assessments: Part 2 Cohort B only- and Table 11 have also been updated to add 
study visits to accommodate protocol extension to up to 5 years, Month 72 (see. next section for 
detailed modifications) 
Study Synopsis/ Study duration 
 
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ZX008 (Fenfluramine Hydrochloride) 
ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 190 of 198 
 
Study synopsis/Methodology  
 
Section 3.1:  
 
Section 3.3:  
 
Section 3.5:  
 
Section 6.2.5:  
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ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 191 of 198 
 
Section 6.2.6:  
 
 
3. Update to reduce the in-clinic study visit schedule to every 6 months.  
From Visit 26/Month 24 (or a later visit if Visit 26/Month 24 has already occurred at the time of 
Protocol Amendment 4.0 approval), subjects will perform in-clinic visits every 6 months. Study 
visits have been added to accommodate the addition of the annual extensions for up to 5 years. 
Phone visits will be performed between in-clinic visits (3 months after the last in-clinic visit).   
Updates were made to Table 2 and Table 11, as well as Sections 6.2 in order to increase the 
number of visits (phone or in-clinic visits) up to 72 months. Visit numbers have been updated 
accordingly.  
 
Study Synopsis/ Methodology 
 
 
Table 2: Schedule of Assessments: Part 2 Cohort B only 
 
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ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 192 of 198 
 
 
 
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ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 193 of 198 
 
 
Table 11: Time Windows for Assessments in Part 2:  
 
Section 6.2.5:  
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ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 194 of 198 
 
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ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 195 of 198 
 
 
4. Updates to the blood volume collected during the study.  
The range of blood volume collected during Part 2 has been updated to reflect the reduced visit 
schedule from V26/Month24 (or a later visit if V26/Month24 has already occurred at the time of 
PA4.0 approval).   
 
Section 6.4:  
 
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ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 196 of 198 
 
 
 
5. Update to clarify the timing of analysis of 1601 Cohort A and Cohort B 
Clarification has been made to reflect the timing of data analysis performed for Cohort A and 
Cohort B.   
Updates have been made to study synopsis and sections 10.1 
Study Synopsis/ Methodology:  
 
Study Synopsis/ Statistical Methods:  
 
 
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ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 197 of 198 
 
 
Section 10.1:  
 
 
6. Addition of language to define the study status between drug approval and launch in 
Japan 
Language has  been added in section 1.6. 
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ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
Page 198 of 198 
 
 
7. Clarification on the dispensation of study drug to subjects transitioning to commercial 
drug 
Updates has been made to section 6.2.6:  
 
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SAP_005.pdf: 
16.1.9 
Documentation of Statistical Methods 
The document listed below is provided in this section. 
Statistical Analysis Plan (Study ZX008-1601 Part 2) dated 12-October-2022 
Statistical Analysis Plan for Cardiovascular Endpoints (Study ZX008-1601 Part 2) 
dated 22-February-2023 
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PUBLIC COPY 
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
• 
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kg,~ 37.5 kg) to ensure balance across tre 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
for subjects taking concomitant STP) dose and subject's weight at Visit 15 (Part 2; Study Day 1). At Visits 
s 3, 6, and 9), if the subject's weight has changed ± 25% of the weight 
occur after a review of the diary and reported AEs, and if, in the Investigator's opinion, seizure 
rability can occur at the Investigator's discretion, in dose amounts and frequency 
appropriate for the situation. Subsequent dose rechallenge should occur at the Investigator's discretion 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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Part 2 summaries may be presented by the subject's Part 1 treatment group (Placebo, ZX00B 0.2 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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PUBLIC COPY 
This document cannot be used to support any marketing authorization 
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
ject's weight and 
Assigned dose level (mg/kg), if the subject's weig 
30 (mg)/ weight (kg), if the subject's weight (kg) * assigned dose (mg/kg) was> 30 mg 
bject was on concomitant STP and the subject's weight (kg) * 
tion of the full day's 
A partial dose will be considered as 25% of the subject's daily dosage. 
The mean daily dose will be calculated as the sum of each day's dosage in mg/kg/day divided by the 
be a subject's initial dosage at the end of Visit 22 at Month 12. The subject will be 
) + .... +(Dose 
+ ... +Days 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
• 
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• 
• 
=l, 2, ... , n) 
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s 
• 
• 
• 
• 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


	
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
mg/kg/day, 0.8 mg/kg/day), the subject's weight 
=2, 3, ... , 6) years in Part 2 if they 
investigator has documented the subject's last Part 2 study drug date. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
seizure to report that day, is "No, this day has been seizure free" then that day will have the seizure 
is "No this day has been seizure free" the seizures entered in the DSD will supersede the seizure 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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 !"#$%#&#&'(%)*+,#)'-*.//0123/2
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
• 
• 
• 
• 
• 
• 
• 
• 
• 
, < 15 years,~ 15 years 
18 years,~ 18-
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


	
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


	
				
 !"#$%#&#&'(%)*+,#)'-*.//0123/2
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
• 
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• 
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• 
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• 
< 18 years,;?: 18-
< 18 years,;?: 18-
with the ATC2 level code of "Antiepileptics". 
6 years,;?: 6 
6 years,;?: 6 
12 years;;?: 
18 years,;?: 18 -
;?: 
12 years;;?: 
18 years,;?: 18 -
< 15 years,;?: 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


	
				
 !"#$%#&#&'(%)*+,#)'-*.//0123/2
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
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PUBLIC COPY 
This document cannot be used to support any marketing authorization 
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
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This document cannot be used to support any marketing authorization 
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"related." 
Any AE with missing severity will be imputed as "severe." 
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
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PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
scores will be determined based on the subject's age at the date o 
For weight, the occurrence of at least a~ 7% gain/reduction or~ 10% gain/reduction from 
For subjects with an occurrence of a 7% reduction in weight 
18 years of age. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
• 
• 
7 years to sll years, 
> 11 years to s 15 years, 
> 15 years to s 18 years . 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


	
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
• 
• 
• 
• 
• 
• 
• 
• 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


	
				
 !"#$%#&#&'(%)*+,#)'-*.//0123/2
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
SSRS data and will only ask about a subject's capability to 
is assessed as a "yes" answer at any time during the 
is assessed as a "yes" answer at any time during the 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


	
				
 !"#$%#&#&'(%)*+,#)'-*.//0123/2
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
questions 1 through 10 are marked as 'yes' 
experiencing a
event (Question 11) will be provided 
A shift table of the subject's Part 1 baseline categorization {No
 vs. the subject's most se 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


	
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


	
				
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
confirmed and approved by the Epilepsy Study Consortium (ESC) as a 'drop seizure' 
• 
• 
• 
• 
• 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


	
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
question "Enter the 
in the episode". 
data reported for "episodes of many discrete 
seizures" of other subjects in the 
") 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


	
				
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*
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
seizures will be imputed using the seizure count and duration of seizures recorded for "an episode of 
zures". 
• 
'short' clusters (i.e., 
59 minutes) will be 
• 
'medium' clusters (i.e., 1 
• 
'long' clusters (i.e., > 
iary as "A cluster of seizures back to back" 
"episodes 
duration" 
. The "A cluster of 
Cluster episodes described in the diary as "A cluster of seizures back 
back" w 
• 
• 
• 
2.) Seizure cluster episodes described as "An episode of many discrete seizures" 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
• 
2 minutes, if the duration of the discrete seizure was answered as "Less than 2 minutes" 
• 
crete seizure was answered as "2 - 10 minutes" 
• 
15 minutes, if the duration of the discrete seizure was answered as "More than 10 minutes" 
• 
• 
• 
28 x Total number of drop seizures during the Part 1 baseline period 
DSFsi = Total number of days in the Part 1 study baseline period with nonmissing diary data 
28 x Total number of drop seizures during the Part 1 T + M period 
DSFTM = Total number of days in the Part 1 T + M period with nonmissing diary data 
28 x Total number of drop seizures during the final week of Part 1 T + M 
DSFFwl = Total number of days with nonmissing diary data during the final week of Part 1 T + M 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
28 x Total number of drop seizures during the days in the Part 1 transition period 
DSFrRA = Total number of days with nonmissing diary data during the Part 1 transition period 
, i=1, 2, 3, ... , 12, is de 
28 x Total number of drop seizures in the ith interval 
DSFoLE,; = Total number of days in the ith interval with nonmissing diary data 
28 x Total number of drop seizures from Day 1 of OLE to Cohort A EOS 
DSFEi = Total number of days from Day 1 to Cohort A EOS with nonmissing diary data 
28 x Total number of drop seizures from Day 31 of OLE to Cohort A EOS 
DSFEi = Total number of days from Day 31 to Cohort A EOS with nonmissing diary data 
28 x Total number of drop seizures from Day 1 of OLE to Visit 22 
DSF =------------------------
BEl 
Total number of days from Day 1 to Visit 22 
28 x Total number of drop seizures from Day 31 of OLE to Visit 22 
DSFEi = 
Total number of days from Day 1 to Visit 22 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
H_O:µ µ 
H_A: µ µ ;eQ, 
.!: 18 years 
• 
• 
• 
• 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
, <! 25% reduction, <! 50% reduction, <! 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
:2:so%, :2:75%, 100% I 
:2: 
here LDT :2: Dates, then the time interval 
point scale: <25%, :2:25%, 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


	
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
be calculated. In addition, the number of subjects who had at least a ~25% improvement -
the number who had either a ~25%, ~50%, ~75%, or 100% improvement, -
ar tallies will present the number of subjects with at least a ~50% 
improvement and the number with at least a ~75% improvement. 
will rate their global impression of the subject's condition at each clinic visit 
I scale measures the change in the subject's clinical status from a speci 
I rating scale permits a global evaluation of the subject's improvement 
over time. The severity of a subject's condition is rated on a 7 
• 
• 
• 
• 
• 
• 
• 
• 
• 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
• 
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PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
• 
• 
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rescue medication may be administered according to each subject's personalized regimen consisting of 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
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subject's 
PUBLIC COPY 
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application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
• 
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,SO% 
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reduction, and "near seizure freedom" (i.e., O 
• 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
,SO% 
reduction), >0%, :.!:25%, :.!:50%, :.!:75%, 100% 
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• 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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ee E, Namkoong K, Lee YM, Lee JS, and Kim HD, "Caregiver's burden and quality of life in 
mitochondrial disease," Pediatric Neurology, vol. 42, no. 4, pp. 271-
Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut 
drome (GWPCARE4}: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 
C, Alonso NB, Migliorini RCVP et al., "Quality of life and burden in caregivers of patients 
with epilepsy," The Journal of Neuroscience Nursing, vol. 39, no. 6, pp. 354-
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
PUBLIC COPY 
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
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This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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				
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
PUBLIC COPY 
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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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DocuSign Envelope ID: 16929825-935F-487B-9858-7F797EB7B0BC 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
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I 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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PUBLIC COPY 
This document cannot be used to support any marketing authorization 
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PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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I 
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application and any extensions or variations thereof.


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This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


	
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PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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I 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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I 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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I 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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	
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PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


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PUBLIC COPY 
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application and any extensions or variations thereof.


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This document cannot be used to support any marketing authorization 
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