Conditions: Dravet Syndrome
Keywords: seizure tonic clonic epilepsy myoclonic encephalopathy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 375
Healthy volunteers: no

Brief summary:
This is an international, multicenter, open-label, long-term safety study of ZX008 in subjects with Dravet syndrome.

Detailed description:
This is an international, multicenter, open-label, long-term safety study of ZX008 in pediatric and young adult subjects with Dravet syndrome who participated in one of the core studies (ZX008-1501 and ZX008-1502) and are candidates for continuous treatment for an extended period of time. This trial will consist of a 36-month Open-Label Extension (OLE) Treatment Period and a 2-week Post-Dosing Period.

Arms:
arm 1: ZX008 is supplied as an oral solution in a concentration of 2.5 mg/mL. Subjects will be titrated to an effective dose beginning with 0.2 mg/kg/day (maximum: 30 mg/day).

Interventions: intervention 1: ZX008 (Fenfluramine Hydrochloride)
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
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. 
Confidential
Clinical Study Protocol
Study Title:
An Open-Label Extension Trial to Assess the Long-Term Safety of 
ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive 
Therapy in Children and Young Adults with Dravet Syndrome 
Study Number:
ZX008-1503 
Study Product:
Fenfluramine Hydrochloride Oral Solution; ZX008 
IND Number:
125797 
EudraCT:
2016-002804-14 
Sponsor:
Zogenix International Limited
A wholly owned subsidiary of Zogenix, Inc.  
5959 Horton Street, 
 
Emeryville, CA 94608 USA 
Sponsor's Medical 
Contact 
Zogenix, Inc.
Date/Version of 
Study Protocol: 
03 August 2020 (amendment 5.0: ROW)
02 February 2018 (amendment 4.0: ROW) 
05 May 2017 (amendment 3.0: ROW) 
01 November 2016 (amendment 2.0: ROW) 
13 September 2016 (amendment 1.2.1: ROW) 
31 May 2016 (amendment 1.2: ROW) 
07 March 2016 (original)
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 2 of 194  
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.
PUBLIC COPY 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 3 of 194  
TABLE OF CONTENTS
TABLE OF CONTENTS ........................................................................................ 3
LIST OF TABLES................................................................................................. 10
SIGNATURE OF SPONSOR ...............................................................................11
SIGNATURES OF CO-COORDINATING INVESTIGATORS .....................12
SIGNATURE(S) OF PRINCIPAL INVESTIGATOR(S)..................................15
LIST OF ABBREVIATIONS ...............................................................................16
STUDY SYNOPSIS ...............................................................................................18
1.
INTRODUCTION ............................................................................30
1.1
BACKGROUND INFORMATION ON INDICATION STUDIED ............... 30
1.1.1
Existing Treatment for Dravet Syndrome ........................................................ 31
1.2
BACKGROUND INFORMATION ON STUDY PRODUCT ........................ 33
1.3
CLINICAL DATA .............................................................................................. 33
1.4
PRECLINICAL DATA ...................................................................................... 35
1.5
PHARMACOKINETICS ................................................................................... 36
1.6
CLINICAL PHARMACOLOGY ...................................................................... 37
1.7
BACKGROUND INFORMATION ON REFERENCE PRODUCT ............. 38
1.8
RATIONALE FOR CURRENT STUDY .......................................................... 38
1.9
RATIONALE FOR INCLUDING DE NOVO SUBJECTS ............................ 38
1.10
RISK-BENEFIT ASSESSMENT ...................................................................... 39
2.
STUDY OBJECTIVES AND ENDPOINTS ..................................41
2.1
PRIMARY OBJECTIVE ................................................................................... 41
2.2
SECONDARY OBJECTIVES ........................................................................... 41
2.3
EXPLORATORY OBJECTIVES ..................................................................... 42
2.4
STUDY ENDPOINTS ......................................................................................... 42
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 4 of 194  
2.4.1
Effectiveness Endpoints ...................................................................................... 42
2.4.2
Safety Endpoints ................................................................................................. 42
2.4.3
Exploratory Endpoints ....................................................................................... 43
3.
INVESTIGATIONAL PLAN..........................................................44
3.1
OVERALL STUDY DESIGN AND PLAN ...................................................... 44
3.2
NUMBER OF SUBJECTS ................................................................................. 46
3.3
STUDY DURATION .......................................................................................... 46
3.4
NUMBER OF STUDY CENTERS .................................................................... 46
3.5
RATIONALE FOR STUDY DESIGN AND CHOICE OF 
TREATMENT GROUPS ................................................................................... 46
3.6
PREMATURE TERMINATION OF STUDY ................................................. 46
3.7
STUDY MONITORING PROCEDURES ........................................................ 47
3.7.1
Independent Data and Safety Monitoring Committee (IDSMC) ................... 47
3.7.2
International Pediatric Cardiac Advisory Board (IPCAB) ............................ 48
4.
SELECTION OF STUDY POPULATION....................................49
4.1
INCLUSION CRITERIA ................................................................................... 49
4.2
EXCLUSION CRITERIA .................................................................................. 50
4.3
SUBJECTS OF REPRODUCTIVE POTENTIAL .......................................... 52
4.3.1
Sperm and Egg Donation ................................................................................... 53
4.3.2
Pregnancy ............................................................................................................ 53
4.4
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT .......... 53
4.5
TERMINATION OF THE CLINICAL STUDY ............................................. 56
4.6
REPLACEMENT OF SUBJECTS .................................................................... 56
5.
INVESTIGATIONAL MEDICINAL PRODUCT 
INFORMATION...............................................................................57
5.1
IDENTITY OF INVESTIGATIONAL MEDICINAL PRODUCT ............... 57
5.1.1
Labeling and Packaging ..................................................................................... 57
5.2
DESCRIPTION OF REFERENCE TREATMENT, COMPARATOR, 
AND/OR PLACEBO .......................................................................................... 58
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 5 of 194  
5.3
IMP ACCOUNTABILITY ................................................................................. 58
5.4
TREATMENT ADMINISTRATION ............................................................... 58
5.4.1
OLE Treatment Period ....................................................................................... 58
5.4.2
Taper Period ........................................................................................................ 60
5.4.2.1
Taper Period for Subjects not Receiving Concomitant STP .............................. 60
5.4.2.2
Taper Period for Subjects from Core Study ZX008-1504 Cohort 1 
Regimen 3 and Cohort 2 Receiving Concomitant STP ...................................... 60
5.5
BLINDING .......................................................................................................... 61
5.6
PRIOR AND CONCOMITANT MEDICATION ............................................ 61
5.6.1
Vagal Nerve Stimulation .................................................................................... 62
5.6.2
Ketogenic Diet ..................................................................................................... 62
5.6.3
Rescue Medication for Seizures ......................................................................... 62
5.6.4
Prohibited Concomitant Medication and Food ................................................ 62
5.7
TREATMENT COMPLIANCE ........................................................................ 63
6.
VISIT SCHEDULE ..........................................................................64
6.1
OLE TREATMENT PERIOD ........................................................................... 64
6.1.1
Screening Visit for de novo Subjects ................................................................. 65
6.1.2
Clinic Visit 1 (Study Day 1; Transition from Core Study) .............................. 66
6.1.2.1
Clinic Visit 1 for Subjects from Core Studies ZX008-1501 or ZX008-
1502 ....................................................................................................................... 66
6.1.2.2
Clinic Visit 1 for Subjects from Core Study ZX008-1504 ................................... 68
6.1.3
Clinic/Phone Visit 2 (Study Day 15) .................................................................. 69
6.1.4
Clinic Visits 3-15 (Months, 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33) ............. 70
6.1.5
Clinic Visit 16 (Month 36): End of Study/Early Termination ........................ 71
6.2
POST-DOSE VISIT (CLINIC VISIT 17; STUDY DAY 1099) ...................... 72
6.3
CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 18, 19; 3 AND 6 
MONTHS) AFTER LAST DOSE OF IMP ...................................................... 73
6.4
ESTIMATED BLOOD VOLUME COLLECTION ........................................ 74
6.5
STUDY CONDUCT DURING COVD-19 ........................................................ 74
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 6 of 194  
7.
EFFECTIVENESS, SAFETY, AND PHARMACOKINETIC 
ASSESSMENTS................................................................................75
7.1
EFFECTIVENESS ASSESSMENTS ................................................................ 75
7.1.1
Seizure Assessments ............................................................................................ 75
7.1.2
Clinical Global Impression - Improvement ...................................................... 76
7.1.3
Quality of Life in Childhood Epilepsy Scale ..................................................... 76
7.1.4
Pediatric Quality of Life Inventory (PedsQL) .................................................. 77
7.1.5
Parent/Caregiver Quality of Life ....................................................................... 77
7.1.6
Study Medication Palatability Assessment ....................................................... 77
7.2
EXPLORATORY ASSESSMENTS .................................................................. 78
7.2.1
Sleep Quality and Meal Time Behavior Questions .......................................... 78
7.2.2
Karolinska Sleepiness Scale ............................................................................... 79
7.2.3
Healthcare Utilization Questions ....................................................................... 79
7.3
SAFETY ASSESSMENTS ................................................................................. 79
7.3.1
Demographics, Medical/Neurological/Epilepsy History, and Pre-
Study Medication ................................................................................................ 79
7.3.2
Physical Examinations ........................................................................................ 79
7.3.3
Neurological Examinations ................................................................................ 80
7.3.4
Vital Signs ............................................................................................................ 80
7.3.5
Laboratory Measurements ................................................................................. 80
7.3.6
Plasma Sample for Concomitant Antiepileptic Drug(s) .................................. 81
7.3.7
Electrocardiograms ............................................................................................. 81
7.3.8
Doppler Echocardiography ................................................................................ 81
7.3.9
Tanner Staging .................................................................................................... 82
7.3.10
Columbia-Suicide Severity Rating Scale .......................................................... 82
7.3.11
Adverse Events .................................................................................................... 82
7.3.12
Behavior Rating Inventory of Executive Function (BRIEF) .......................... 83
7.4
APPROPRIATENESS OF MEASUREMENTS .............................................. 83
8.
ADVERSE EVENTS ........................................................................84
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 7 of 194  
8.1
DEFINITIONS .................................................................................................... 84
8.1.1
Adverse Events .................................................................................................... 84
8.1.2
Serious Adverse Events ...................................................................................... 85
8.1.3
Adverse Events of Special Interest .................................................................... 86
8.1.4
Adverse Events Requiring Hospitalization ....................................................... 87
8.2
SEVERITY OF ADVERSE EVENTS .............................................................. 87
8.3
CAUSALITY OF ADVERSE EVENTS ........................................................... 88
8.4
OBSERVATION PERIOD FOR ADVERSE EVENT REPORTING ........... 88
8.5
ADVERSE EVENT REPORTING ................................................................... 89
8.5.1
Adverse Events .................................................................................................... 89
8.6
SERIOUS ADVERSE EVENTS REPORTING ............................................... 89
8.6.1
Requirements for Immediate Reporting of Serious Adverse Events ............. 90
8.7
REPORTING OF SERIOUS ADVERSE EVENTS BY 
INVESTIGATOR TO IEC/IRB ........................................................................ 91
8.8
REPORTING OF EVENTS OTHER THAN SERIOUS ADVERSE 
EVENTS BY INVESTIGATOR TO SPONSOR ............................................. 91
8.9
FOLLOW-UP OF ADVERSE EVENTS .......................................................... 91
8.9.1
Follow-up of Echocardiogram Findings ........................................................... 92
8.10
PREGNANCY ..................................................................................................... 94
9.
DATA HANDLING PROCEDURES .............................................95
9.1
RECORDING OF DATA ................................................................................... 95
9.2
DATA QUALITY ASSURANCE ...................................................................... 95
9.3
RECORD RETENTION .................................................................................... 96
10.
STATISTICS.....................................................................................97
10.1
DETERMINATION OF SAMPLE SIZE ......................................................... 97
10.2
ANALYSIS POPULATIONS ............................................................................ 97
10.2.1
Safety (SAF) Population ..................................................................................... 97
10.2.2
Modified Intent-to-Treat (mITT) Population................................................... 97
10.2.3
Per Protocol (PP) Population ............................................................................. 97
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 8 of 194  
10.3
TREATMENT GROUPS ................................................................................... 97
10.4
TREATMENT PERIODS .................................................................................. 97
10.5
STATISTICAL ANALYSES AND METHODS .............................................. 99
10.5.1
Safety Analyses .................................................................................................... 99
10.5.2
Effectiveness Analyses ........................................................................................ 99
10.5.2.1
Key Effectiveness Analysis ................................................................................... 99
10.5.2.2
Other Secondary Analyses ................................................................................. 100
10.6
ANALYSES PROVIDED TO AN INDEPENDENT DATA AND 
SAFETY MONITORING COMMITTEE ..................................................... 101
11.
ETHICAL & REGULATORY CONSIDERATIONS................102
11.1
ETHICAL CONSIDERATIONS ..................................................................... 102
11.2
INFORMED CONSENT .................................................................................. 102
11.3
REGULATORY CONSIDERATIONS AND INDEPENDENT 
ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD ................ 104
11.4
PROTOCOL COMPLIANCE ......................................................................... 104
12.
ADMINISTRATIVE ASPECTS ...................................................106
12.1
CLINICAL TRIAL AGREEMENT ................................................................ 106
12.2
FINANCIAL DISCLOSURE BY INVESTIGATOR .................................... 106
12.3
CLINICAL STUDY REGISTRATION AND RESULTS 
DISCLOSURE ................................................................................................... 106
12.4
STUDY FILES AND MATERIALS ................................................................ 106
12.5
INITIATION OF THE STUDY ....................................................................... 107
12.6
SUBJECT REIMBURSEMENT ..................................................................... 107
12.7
LIABILITY AND INSURANCE ..................................................................... 107
12.8
SUBJECT IDENTIFICATION AND CONFIDENTIALITY ...................... 108
12.9
MONITORING OF THE STUDY .................................................................. 108
12.10
PROTOCOL AMENDMENTS ....................................................................... 109
12.11
AUDITS AND INSPECTIONS ........................................................................ 110
12.12
CLINICAL STUDY REPORT ........................................................................ 110
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 9 of 194  
12.13
USE OF DATA AND PUBLICATIONS ......................................................... 111
13.
REFERENCE LIST........................................................................112
14.
APPENDICES.................................................................................117
14.1
APPENDIX 1 – LIST OF PROHIBITED CONCOMITANT 
MEDICATIONS ............................................................................................... 117
14.2
APPENDIX 2 – COLUMBIA – SUICIDE SEVERITY RATING 
SCALE ............................................................................................................... 118
14.3
APPENDIX 3 – BEHAVIOR RATING INVENTORY OF 
EXECUTIVE FUNCTION – PRESCHOOL VERSION .............................. 124
14.4
APPENDIX 4 – QUALITY OF LIFE IN CHILDHOOD EPILEPSY 
SCALE ............................................................................................................... 134
14.5
APPENDIX 5 – TANNER STAGING ............................................................. 147
14.6
APPENDIX 6 – PEDSQL ................................................................................. 149
14.7
APPENDIX 7 – EQ-5D-5L QUESTIONNAIRE ............................................ 160
14.8
APPENDIX 8 – HOSPITAL ANXIETY AND DEPRESSION SCALE ...... 162
14.9
APPENDIX 9 – MAXIMUM ALLOWABLE BLOOD DRAW 
VOLUMES ........................................................................................................ 163
14.10
APPENDIX 10 – KAROLINSKA SLEEPINESS SCALE ............................ 165
14.11
APPENDIX 11 - STUDY CONDUCT DURING COVID-19 ........................ 166
SUMMARY OF PROTOCOL AMENDMENT 5.0 ............................................................... 170
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 10 of 194  
LIST OF TABLES
TABLE 1.
SCHEDULE OF ASSESSMENTS FOR SUBJECTS FROM CORE STUDIES 
ZX008-1501 AND ZX008-1502, AND DE NOVO SUBJECTS** ............................ 26
TABLE 2.
SCHEDULE OF ASSESSMENTS FOR SUBJECTS FROM CORE STUDY 
ZX008-1504 ................................................................................................................. 28
TABLE 3
POST HOC ESTIMATES OF FENFLURAMINE AND 
NORFENFLURAMINE STEADY-STATE PHARMACOKINETIC 
PARAMETERS IN SUBJECTS WITH DRAVET SYNDROME IN STUDY 1 
(GEOMETRIC MEAN [CV%]) ................................................................................... 37
TABLE 4.
INVESTIGATIONAL MEDICINAL PRODUCT – ZX008 ....................................... 57
TABLE 5. 
TAPER ALGORITHM FOR SUBJECTS FROM CORE STUDIES ZX008-
1501, ZX008-1502, AND ZX008-1504 COHORT 1/REGIMENS 1&2NOT 
RECEIVING CONCOMITANT STP .......................................................................... 60
TABLE 6. 
TAPER ALGORITHM FOR SUBJECTS RECEIVING CONCOMITANT STP....... 61
TABLE 7.
TIME WINDOWS FOR ASSESSMENTS .................................................................. 64
TABLE 8.
SCHEDULE OF POST-TREATMENT CARDIAC FOLLOW-UP ............................ 73
TABLE 9.
ESTIMATED BLOOD VOLUME COLLECTIONA................................................... 74
TABLE 10.
ADVERSE EVENTS OF SPECIAL INTEREST ........................................................ 87
TABLE 11. 
SEVERITY DEFINITION OF ADVERSE EVENTSA ............................................... 87
TABLE 12.
CLINICAL MEASURES ENACTED UPON INCREASING SEVERITY OF 
ECHO FINDINGS........................................................................................................ 92
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 15 of 194  
SIGNATURE(S) OF PRINCIPAL INVESTIGATOR(S)
Study Number: ZX008-1503 
Study Title: An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 
(Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and Young 
Adults with Dravet Syndrome 
___________________________________________________________________________ 
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 and 
affiliation:_____________________________________________________________ 
_____________________________________________________________________ 
(Signature) (Date [DD/MMM/YYYY]) 
  
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 16 of 194  
LIST OF ABBREVIATIONS
ABBREVATION
DEFINITION
ADHD
attention deficit hyperactivity disorder
AE
adverse event
AED
antiepileptic drug
AESI
adverse event of special interest
ANCOVA
analysis of covariance
BID
bis in die; two times per day
BMI
body mass index
BRIEF
Behavior Rating Inventory for Executive Function
CBD
cannabidiol
CFR
Code of Federal Regulations
CGI-I
Clinical Global Impression - Improvement
CRF
case report form
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450
dL
deciliter
DS
Dravet syndrome
ECG
electrocardiogram
ECHO
echocardiogram
EOS
end of study
EQ-5D-5L
standardized measure of health status
ET
early termination
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GH
growth hormone
GMP
Good Manufacturing Practices
GP
general practitioner
HADS
Hospital Anxiety and Depression Scale
HR
heart rate
ICF
informed consent form
ICH
International Conference on Harmonization
IDSMC
Independent Data and Safety Monitoring Committee
IEC
Independent Ethics Committee
IGF-1
insulin-like growth factor-1
IMP
investigational medicinal product
IPCAB
International Pediatric Cardiology Advisory Board
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 17 of 194  
ABBREVATION
DEFINITION
IRB
Institutional Review Board
IVR
interactive voice response (system)
IWR
interactive web response (system)
KD
ketogenic diet
kg
kilogram
LH
luteinizing hormone
LLN
lower limit of normal
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
OLE
open-label extension
PedsQL
Pediatric Quality of Life Inventory
PDN
Postnatal day
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
SD
standard deviation
SE
status epilepticus
SMEI
severe myoclonic epilepsy of infancy
STP
stiripentol
SUDEP
sudden unexpected death in epilepsy
THC
tetrahydrocannabinol
TSH
thyroid stimulating hormone
ULN
upper limit of normal
USA
United States of America
USP
United States Pharmacopeia
VNS
vagal nerve stimulator/stimulation
ZX008
fenfluramine hydrochloride oral solution
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 18 of 194  
STUDY SYNOPSIS
Study Title: An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine 
Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and Young Adults with Dravet 
Syndrome
Study Number: ZX008-1503
Study Product: Fenfluramine Hydrochloride, ZX008
Type of Study:
Safety and effectiveness study
Indication Studied: 
Adjunct therapy in Dravet syndrome
Phase of Development: Phase III 
Countries: North America, Europe, Australia
Sponsor: Zogenix International Limited
Co-Coordinating Investigators:
 Pediatric Epilepsy Center
University of California, San Francisco
San Francisco, CA USA
Leuven University, Department of 
Development and Regeneration,
Section Pediatric Neurology
  Leuven, Belgium
Service de Neuromètabolisme
CHU Paris - Hȏpital Necker-Enfants 
Malades
  Paris, France
Estimated Duration of Individual Subject Participation:
The duration of the study for an individual subject is expected to be up to approximately 36 months. 
Objectives:
The primary objective of the study is:  
•
To assess the long-term safety and tolerability of ZX008. 
The secondary objectives of the study are: 
• To assess the effect of ZX008 relative to the pre-ZX008 baseline on the following effectiveness 
measures:
- The change in the frequency of convulsive seizures from Visit 3 to Visit 8 (ie, Day 31 to 
Day 365) and for the entire Year 1 treatment period (ie, Visit 1/Day 1 to Visit 8/Day 365) 
- The proportion of subjects who achieve a ≥40%, ≥50%, and ≥75% reduction in convulsive 
seizure frequency 
- The longest convulsive seizure-free interval
- The percentage of convulsive seizure-free days
- The non-convulsive seizure frequency
- The convulsive + non-convulsive seizure frequency. 
• To estimate the incidence of the following on subjects receiving ZX008: 
- Use of rescue medication
- Hospitalization to treat seizures 
- Status epilepticus (SE)
• To assess the effect of ZX008 relative to the pre-ZX008 baseline on the following quality of life 
(QoL) measures:
- Quality of Life in Childhood Epilepsy (QOLCE) score 
- Pediatric Quality of Life Inventory™ (PedsQL) score 
- PedsQL Family Impact module score  
- QoL of the parent/caregiver using the standardized measure of health status (EQ-5D-5L) scale
- Affective symptoms of the parent/caregiver using the Hospital Anxiety and Depression Scale 
(HADS)
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 19 of 194  
• To assess the effect of ZX008 on the following QoL measures:
- Clinical Global Impression – Improvement (CGI-I) rating, as assessed by the principal 
investigator 
- CGI-I rating, as assessed by the parent/caregiver
The exploratory objectives of the study are: 
• To assess the effect of ZX008 on the following QoL measures for subjects who participated in the 
core study ZX008-1504: 
- Sleep quality and mealtime behavior, as assessed by the parent/caregiver
- Karolinska Sleep Scale
- Health and social care resource use (These measures include planned and unplanned hospital 
visits, use of ambulances, general practitioner [GP] visits, speech and language therapy 
utilization, occupational and physical therapy utilization).
Methodology: This is an international, multicenter, open-label, long-term safety study of ZX008 in 
pediatric and young adult subjects with Dravet syndrome (DS).  Subjects eligible for participation are 
those who have successfully completed 14 weeks of treatment in 1 of the 3 core studies ZX008-1501, 
ZX008-1502, or ZX008-1504 Cohort 2, or successfully completed core study ZX008-1504 Cohort 1 
and are candidates for continuous treatment for an extended period of time. In addition, subjects who 
are >18 to ≤35 years of age at the time of screening, and who meet all other eligibility criteria may be 
eligible for participation after discussion with the Medical Monitor and sponsor about the potential 
risks and benefits for receiving ZX008.  Participation for these subjects will be at the discretion of the 
sponsor. 
This trial will consist of an up to 36-month Open-Label Extension (OLE) Treatment Period and a 
2-week Post-Dosing Period. Thus, subjects who complete this trial will have been treated with ZX008 
for a minimum of up to 3 years (including their participation in both the core study and this study). 
Subjects who did not participate in one of the core studies will undergo a screening period up to 28 
days to confirm eligibility prior to receiving their first dose in the OLE Treatment Period.
During the 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 0.2 mg/kg/day, the 
investigator may adjust the dose of each subject based on effectiveness and tolerability. For subjects
who are not receiving concomitant stiripentol (STP), including de novo subjects and those who 
participated in core studies ZX008-1501, Z008-1502, and dose regimen 1 or 2 from Cohort 1 of 
ZX008-1504, dose changes should be made in 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. For subjects who are receiving concomitant 
STP, including de novo subjects and those who participated in core study ZX008-1504 Cohort 1, dose 
regimen 3 and Cohort 2, the first dose change will be to 0.4 mg/kg/day and the final dose change will 
be to 0.5 mg/kg/day, but not to exceed 20 mg/day. 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 
adverse events (AEs), and if, in the investigator’s opinion, seizure frequency, severity, or duration 
indicates a change in medication regimen is warranted. Dose decreases for tolerability can occur at the 
investigator’s discretion, in dose amounts and frequency appropriate for the situation. ZX008 dose 
adjustments outside of these parameters should be discussed with the Medical Monitor prior to 
initiation.
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 20 of 194  
In addition, if a subject has been stable on the same dose of ZX008 for 6 months or longer, 
investigators may adjust the doses of one or more of the other concomitant anti-epileptic drugs (AEDs) 
as per typical clinical practice. Concomitant AEDs may be withdrawn completely but all subjects must 
remain on a minimum of 1 concomitant AED plus ZX008. No new concomitant AEDs or anti-epileptic 
treatments may be introduced while in this study. All medication dose changes must be documented 
with a clinical explanation and justification. Concomitant AED dose adjustments outside of these 
parameters should be discussed with the Medical Monitor prior to initiation if possible.  
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, may increase the 
dose to 0.4 mg/kg/day (maximum 30 mg/day for subjects who are not receiving concomitant STP; 
20 mg/day for subjects who are receiving concomitant STP). A clinically meaningful worsening would 
be an increase in frequency, severity or duration of existing seizures, or 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) for subjects who are not 
receiving concomitant STP, and to 0.5 mg/kg/day (maximum 20 mg/day) for subjects who are 
receiving 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, 0.2 to 0.8 mg/kg/day) may be considered after consultation between the 
investigator and Medical Monitor. 
A follow-up electrocardiogram (ECG) and echocardiogram (ECHO) will be performed at 3 and 
6 months after study drug discontinuation for early termination and for those subjects who complete the 
study. Caregivers will use a diary daily to record the number/type of seizures, dosing, and use of rescue 
medication. A schedule of assessments is provided in Table 1 for subjects from core studies 
ZX008-1501 and ZX008-1502 and those who did not participate in one of the core studies (de novo 
subjects), and in Table 2 for subjects from core study ZX008-1504.  
After at least 1 year of treatment in Study 1503 subjects who participated in one of the core studies will 
transition to a separate extension study (Study 1900) once that study is approved and the study site is 
initiated. Continuation in a separate extension protocol will be based on benefit/risk and continued 
eligibility criteria being met. De novo subjects must have participated in this trial for at least 3 months 
with at least 1 ECHO completed and continue to meet eligibility requirements to be eligible to 
transition to a separate extension protocol. Alternatively, subjects will transition to commercial product 
once it is available. For subjects who are entering the separate extension trial or who transition to 
commercially available drug, post-dosing and cardiac safety follow-up visits are not required in this 
trial. Subjects who transition to commercially available drug must have an ECHO within 3-6 months 
before starting commercial drug and will have follow-up ECHOs within the required timeframe while 
on commercial drug.
External 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 
Pediatric Cardiology Advisory Board (IPCAB) will monitor the cardiac safety of the ZX008 clinical 
trials. ECGs and Doppler ECHOs will be centrally read (Biomedical Systems, Inc.) and interpreted 
under blinded conditions using pre-specified criteria, and if necessary, with review by the IPCAB. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 21 of 194  
Number of Subjects: Up to approximately 340 subjects from the core studies and up to 50 subjects 
who did not participate in the core studies may be enrolled. 
Inclusion Criteria: All subjects must meet all of the following inclusion criteria to be enrolled into the 
study: 
1.
Subject is aged 2 to 18 years inclusive, as of the day of the core study Screening Visit.  
2.
Subject has satisfactorily completed the core study in the opinion of the investigator and the 
Sponsor. NOTE: Those subjects who do not complete the 12-week Maintenance Period of the 
core study 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 OLE study participation resides solely with 
the Sponsor, who may consult with the site investigator, the IPCAB and/or the IDSMC. 
3.
Subject is male or non-pregnant, non-lactating female. Female subjects of childbearing 
potential must not be pregnant or breast-feeding. Female subjects of childbearing potential 
must have a negative urine pregnancy test. Subjects of childbearing or child-fathering potential 
must be willing to use medically acceptable forms of birth control, which includes abstinence, 
while being treated on this study and for 90 days after the last dose of study drug. 
4.
Subject has documented medical history to support a clinical diagnosis of DS, where 
convulsive seizures are not completely controlled by current antiepileptic drugs. 
5.
Subject has been informed of the nature of the study and informed consent has been obtained 
from the legally responsible parent/guardian. 
6.
Subject has provided assent in accordance with Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) requirements, if capable.
7.
Subject’s caregiver is willing and able to be compliant with diary completion, visit schedule 
and study drug accountability. 
8.
Subject’s parent/caregiver has been compliant with diary completion during the core study, in 
the opinion of the investigator (eg, at least 90% compliant).
9.
Subjects entering from study ZX008-1504 must be receiving a therapeutically relevant and 
stable dose of clobazam (CLB) and/or valproic acid (VPA), and STP (Cohort 1 dose regimen 3 
and Cohort 2 only) for at least 4 weeks prior to screening and are expected to remain stable 
throughout the study. 
10. Subjects who are >18 to ≤35 years of age at the time of screening and did not participate in one 
of the core studies must meet criteria 3 to 7 above and the following criteria below in order to 
be considered for participation. Participation is at the discretion of the Sponsor: 
a.
Onset of seizures in the first year of life in an otherwise healthy infant.
b.
A history of seizures that are either generalized tonic-clonic or unilateral clonic
or bilateral clonic, and are prolonged.
c.
Initial development is normal.
d.
History of normal brain MRI without cortical brainmalformation.
e.
Lack of alternative diagnosis.
f.
Meets one of the following 3 confirmatory diagnostic criteria:
i. Emergence of another seizure type, including myoclonic, generalized
tonic-clonic, tonic, atonic, absence and/or focal has developed after the
first seizure type.
ii.
Prolonged exposure to warm temperatures induces seizures and/or 
seizures are associated with fevers due to illness or vaccines, hot baths,
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 22 of 194  
high levels of activity and sudden temperature changes and/or seizures 
are induced by strong naturaland/or fluorescent lighting, as well as 
certain visualpatterns.
iii.
Genetic test results consistent with a diagnosis of Dravet syndrome
(pathogenic, likely pathogenic, variant of unknown significance, or
inconclusive but unlikely to support an alternative diagnosis.)
g.
Subject has been approved for study inclusion by the Epilepsy Study Consortium.
h.
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:
i.
Mild or greater mitral or aortic valve regurgitation in subjects >18 yrs of age 
ii.
Possible signs of pulmonary hypertension with abnormal or greater than upper 
limit of normal values 
iii.
Evidence of diastolic dysfunction
i.
Subject must have had ≥4 convulsive seizures (tonic, tonic-atonic, tonic-clonic, 
clonic) per 4-week period for past 12 weeks prior to screening, by parent/guardian 
report to investigator or investigator medical notes.
j.
All medications or interventions for epilepsy (including ketogenic diet [KD] and 
vagal nerve stimulation [VNS]) must be stable for at least 4 weeks prior to 
screening and are expected to remain stable throughout the study.
11. Subject’s parent/caregiver is willing and able to be compliant with diary completion, visit 
schedule and study drug accountability.
Exclusion Criteria: All subjects must meet none of the following exclusion criteria to be enrolled into 
the study:
1.
Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study 
medication.
2.
Subject has current or past history of cardiovascular or cerebrovascular disease, myocardial 
infarction or stroke.
3.
Subject from one of the core studies with current cardiac valvulopathy or pulmonary 
hypertension that the investigator, parent, IPCAB, IDSMC, or Sponsor deems clinically 
significant and warrants discontinuation of study medication.
4.
For de novo subjects: possible signs of pulmonary hypertension with abnormal or greater than 
upper limit of normal values. 
5.
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.
6.
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 as measured by the 
C-SSRS Since Last Visit, 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.
7.
Subject has a current or past history of glaucoma.
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her
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 23 of 194  
8.
Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild hepatic 
impairment (elevated liver enzymes < 3x upper limit of normal [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.
9.
Subject is receiving concomitant therapy with: centrally-acting anorectic agents; monoamine-
oxidase inhibitors; any centrally-acting compound with clinically appreciable amount of 
serotonin agonist or antagonist properties, including serotonin reuptake inhibition; 
atomoxetine, or other centrally-acting noradrenergic agonist; cyproheptadine, and/or 
cytochrome P450 (CYP) 2D6/3A4/2B6 inhibitors/substrates (Appendix 1). (Note: Short-term 
medication requirements will be handled on a per case basis by the Medical Monitor.)
10. Subject is currently taking carbamazepine, oxcarbazepine, eslicarbazepine, phenobarbital, or 
phenytoin, or has taken any of these within the past 30 days, as maintenance therapy.
11. For subjects entering from core studies ZX008-1501, ZX008-1502, or ZX008-1504 
(Cohort 1/dose regimens 1 &2): Subject is currently receiving or has received stiripentol in the 
past 21 days prior to core study Visit 1.
12. Subject is unwilling to refrain from large or daily servings of grapefruits and/or Seville 
oranges, and their juices beginning with the Visit 1 and throughout the study.
13. Subject has positive result on urine tetrahydrocannabinol (THC) Panel or whole blood 
cannabidiol (CBD) at Visit 1.
14. Subject is unwilling or unable to comply with scheduled visits, drug administration plan, 
laboratory tests, other study procedures, and study restrictions. 
15. Subject has a clinically significant condition, or has had clinically relevant symptoms or a 
clinically significant illness at Visit 1, other than epilepsy, that would negatively impact study 
participation, collection of study data, or pose a risk to the subject, including chronic obstructive 
pulmonary disease, interstitial lung disease, or portal hypertension.
16. Subject has participated in another clinical trial within the past 30 days (ie, the last visit of the 
previous study was in the past 30 days), with the exception of one of the core studies.
Study Product, Dose, and Mode of Administration:
•
ZX008 is supplied as an oral solution in a concentration of 2.5 mg/mL. Subjects will be titrated 
to an effective dose beginning with 0.2 mg/kg/day (maximum 30 mg/day for subjects who are not 
receiving concomitant STP; maximum 20 mg/day for subjects who are receiving concomitant STP). 
Study medication will be administered twice a day (BID) in equally divided doses with food.
Reference Product, Dose, and Mode of Administration:
Not applicable. 
Duration of Treatment:
All subjects will receive ZX008 for up to approximately 36 months. All subjects, including those who 
prematurely discontinue from the study, will undergo an up to 2-week taper of study medication, at the 
conclusion of the study. 
Criteria for Evaluation:
Safety: 
AEs, laboratory safety parameters (hematology, chemistry, urinalysis), vital signs (blood pressure, 
heart rate, temperature, and respiratory rate), physical examination, neurological examination, 12-lead 
ECGs, Doppler ECHOs, and body weight. The Behavior Rating Inventory for Executive Function 
(BRIEF) will be administered to track cognitive function.
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 24 of 194  
Effectiveness:
•
Number of seizures by type 
•
Convulsive seizure-free interval
•
CGI-I as assessed by parent/caregiver
•
CGI-I as assessed by principal investigator
•
QOLCE to measure changes in quality of life of the subject 
•
PedsQL to measure changes in quality of life of the subject
•
PedsQL Family Impact module to measure changes in quality of life of the parent/caregiver 
•
QoL of parent/caregiver using the EQ-5D-5L scale
•
Affective symptoms of parent/caregiver using the Hospital Anxiety and Depression Scale 
(HADS) (in parents/caregivers from core studies ZX008-1501 and ZX008-1502 only) 
•
Duration of prolonged seizures (seizure type that, during pre-ZX008 baseline, had duration 
> 2 minutes)
•
Number of episodes of SE
•
Number of instances of rescue medication use and number of doses
•
Number of inpatient hospital admissions due to seizures
Exploratory (in subjects who participated in core study ZX008-1504 only): 
•
Health and social care resource use, including GP visits, speech and language, occupational 
and physical therapy, in addition to acute hospital and institutional length of stay, loss of work, 
etc.  
•
Sleep quality
•
Mealtime behavior
•
Karolinska Sleepiness Scale to measure the effect of study medication on sleepiness
Sample Size Determination:
The sample size will be determined by the number of subjects who participate in 1 of the 3 core studies 
– Study ZX008-1501, Study ZX008-1502, or ZX008-1504 - and who volunteer for the extension study 
and meet the necessary criteria for enrollment. Approximately 100-120 subjects are expected to 
participate in each of the core trials; thus, if all participants also enroll in the extension, the total sample 
size of the extension trial would be up to approximately 340.  In addition, up to 50 additional subjects, 
who otherwise would have qualified for participation in one of the core studies, but are >18 to ≤35 
years of age may participate.
Statistical Methods:
Study Populations 
Safety Population: Safety analyses will be performed on the Safety Population defined as all subjects 
who receive at least one dose of ZX008 during the open label extension. 
Modified Intent-to-Treat (mITT) Population: The mITT Population is defined as all subjects who 
receive at least one dose of ZX008 and have valid seizure data during the open label extension. 
Safety 
The number and percentage of subjects who experience treatment emergent 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. Serious AEs 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 25 of 194  
(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
The frequency of convulsive seizures during a given treatment period will be derived from the number 
and type of events recorded in subject diaries. The seizure frequency 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 
convulsive seizure frequency during the OLE Treatment Period will be compared to the pre-ZX008 
baseline frequency measured prior to first treatment with ZX008. Both the mean and median change 
from baseline will be presented and the statistical significance of the change will be assessed using an 
analysis of covariance (ANCOVA) with baseline frequency as a covariate and age group (< 6 or ≥ 6 
years old) as a factor. Other factors may be included in the model if they are found to be informative 
during analyses of the core trials. Similar methods will be used to assess the change in frequency of 
non-convulsive seizures and the composite endpoint of non-convulsive plus convulsive seizures. The 
percentage of subjects who achieve a ≥40%, ≥50%, and ≥75% reduction in seizures will be presented 
along 95% confidence intervals for each percentage. Quality of life measures, such as the QOLCE 
assessed during the OLE Treatment Period, will be compared to the analogous baseline measure 
assessed prior to first treatment with ZX008.  Subjects who did not participate in one of the core 
studies will be excluded from analyses of effectiveness and the change over time will be described.
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 26 of 194  
Table 1. 
Schedule of Assessments for Subjects from Core Studies ZX008-1501 and ZX008-1502, and de Novo Subjects** 
Study Assessments
OLE Treatment Period
Post-Dosing
Cardiac Follow-up
Visit Number
Visit 1a
Visit 2c
Visits 3-15
(Months 1, 2, 3, 6, 9, 12, 15, 18, 
21, 24, 27, 30, and 33)
Visit 16d
(EOS/ET) 
Month 36
Visit 17o
Visit 18, 19o
Study Day
-28 to 1a
15
30, 60, 90, 180, 270, 365, 455, 
545, 635, 725. 815, 905, 995
1085
1099
3 and 6 months post last dose
Clinic
Phone
Informed Consent
X
Entry Criteria
X
Demographics
X
Medical/Neurological History
Xa
Epilepsy History
Xa,b
Physical Examination, complete
Xa
X
Xe
Physical Examination, abbreviated
X
X
Xe
Neurological Examination, complete
Xf
X
Neurological Examination, abbreviated
X
X
Vital signs
X
X
X
X
Weight, Height, BMI
Xa
X
X
X
12-lead ECG
Xa
X
X
Xe
Doppler ECHO
Xa
Xg,h
X
Xe
Urine Pregnancy Testh
X
X
X
Clinical laboratory evaluation 
(hematology/clinical chemistry/urinalysis, etc)
Xj
Xj
X
X
Urine THC Panel/Whole blood CBD
Xa
X
X
Plasma sample for background AEDs
X
X
X
Tanner Staging (for subjects >7 to ≤ 18 years)
Xa
Xk
X
Xk
C-SSRS
Xa
X
X
CGI-I (assessed by parent/caregiver)
Xa
X
X
CGI-I (assessed by principal investigator)
Xa
X
X
QOLCE
Xa
X
X
EQ-5D-5L (QoL of parent/caregiver)
Xa
X
X
HADS (Affect of parent/caregiver)
Xa
X
X
BRIEF
Xa
X
X
continued 
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th


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 27 of 194  
Table 1. 
Schedule of Assessments for Subjects from Core Studies ZX008-1501 and ZX008-1502, and de Novo Subjects** 
(continued)
Study Assessments
OLE Treatment Period
Post-Dosing
Cardiac Follow-up
Visit Number
Visit 1a
Visit 2c
Visits 3-15
(Months 1, 2, 3, 6, 9, 12, 15, 
18, 21, 24, 27, 30, and 33)
Visit 16c
(EOS/ET) 
Month 36
Visit 17o
Visit 18, 19o
Study Day
-28 to 1a
15
30, 60, 90, 180, 270, 365, 455, 
545, 635, 725. 815, 905, 995
1085
1099
3 and 6 months post last dose
Clinic
Phone
PedsQL n
Xa
X
X
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Xl
Subject Diary
D
C/R/D
R
C/R/D
C/R
C/R
Study Medication
Db
C/R/D
R
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--------------------------------------------------
Xm
AED=antiepileptic drug; BMI=body mass index; BRIEF=Behavior Rating Inventory of Executive Function; C=Collect; CBD=cannabidiol; CGI-I=Clinical Global Impression-Improvement; D=Dispense; ECG=electrocardiogram; EOS=end of 
study; ET=early termination; EQ-5D-5L=standardized measure of health status; HADS=Hospital Anxiety and Depression Scale; PedsQL=Pediatric Quality of Life Inventory; QoL=quality of life; QOLCE=Quality of Life in Childhood 
Epilepsy; R=Review
NOTE:  If a subject has a birthday during the study that makes a previously unrequired assessment now required (eg, Tanner staging in a male subject who turns 8 years old during the study), this assessment(s) should be 
initiated at visits subsequent to the birthday.
** de Novo subjects are subjects who did not participate in one of the core studies and may or may not be currently taking STP.
a:
For subjects enrolling from one of the core studies use data collected at Visit 12 and Visit 13 of Study ZX008-1501 or ZX008-1502. 
For de novo subjects, a screening period up to 28 days is required. During this period, informed consent is required prior to any study-related procedures.  All results to determine eligibility must be reviewed prior to receiving the first 
dose of study study medication at Visit 1.  
For all subjects, clinical laboratory results and all ECHO/ECG results must be available and meet eligibility criteria prior to receiving the first dose of study medication at Visit 1.
b:
De Novo subjects must meet entry criteria 3 to 7, and 10, including having had ≥4 convulsive seizures (tonic, tonic-atonic, tonic-clonic, clonic) per 4-week period for past 12 weeks prior to screening, by parent/guardian report to 
investigator or investigator medical notes.
c:
At the discretion of the investigator, Visit 2 may be conducted as a phone visit.
d:
Or early termination.
e;
Follow-up ECG, ECHO, and physical examination will be performed 3 and 6 months after study completion or early termination (see Section 6.3).
f:
For subjects enrolling from one of the core studies, use core study Visit 12 information unless complete neurological examination is warranted based on significant changes in subject status.
g:
ECHOs will be performed at Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, and 33.
h:
The Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, and 33 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 (see 
Table 7).
i:
Females of child-bearing potential
j:
For subjects enrolling from one of the core studies, use data collected at Visit 12 of ZX008-1501 or ZX008-1502 for Visit 1 unless clinical laboratory evaluation is warranted based on significant changes in subject status. Visit 2 
clinical laboratory evaluation is optional based on subject status for all cohorts.
k:
Visits 6, 15, and 27 only.
l:
Visits 3 and 4 (Months 1 and 2) only.
m:
Only adverse events related to cardiac safety will be collected at this visit (see Table 7).
n:
o:
Not to be completed for de novo subjects >18 years old.
For subjects who are entering the separate extension trial or who transition to commercially available drug, post-dosing and cardiac safety follow-up visits are not required in this trial.
C
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th


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 28 of 194  
Table 2. 
Schedule of Assessments for Subjects from Core Study ZX008-1504 
Study Assessments
OLE Treatment Period
Post-Dosing
Cardiac Follow-up
Visit Number
Visit 1a
Visit 2b
Visits 3-15
(Months 1, 2, 3, 6, 9, 12, 15, 18, 
21, 24, 27, 30, and 33)
Visit 16c
(EOS/ET) 
Month 36
Visit 17m
Visit 18, 19m
Study Day
1a
15
30, 60, 90, 180, 270, 365, 455, 
545, 635, 725. 815, 905, 995
1085
1099
3 and 6 months post last dose
Clinic
Phone
Informed Consent
X
Entry Criteria
X
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X
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Physical Examination, complete
Xa
X
Xd
Physical Examination, abbreviated
X
X
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Xe
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X
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X
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X
X
Xd
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Xd
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X
X
X
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(hematology/clinical chemistry/urinalysis, etc)
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Xi
X
X
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X
X
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X
X
X
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Xa
Xj
X
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X
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X
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CGI-I (assessed by principal investigator)
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X
X
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X
X
BRIEF
Xa
X
X
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Xa
X
X
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 29 of 194  
Table 2. 
Schedule of Assessments for Subjects from Core Study ZX008-1504 (continued)
Study Assessments
OLE Treatment Period
Post-Dosing
Cardiac Follow-up
Visit Number
Visit 1a
Visit 2b
Visits 3-15
(Months 1, 2, 3, 6, 9, 12, 15, 
18, 21, 24, 27, 30, and 33)
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(EOS/ET) 
Month 36
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1a
15
30, 60, 90, 180, 270, 365, 455, 
545, 635, 725. 815, 905, 995
1085
1099
3 and 6 months post last dose
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Phone
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Xa
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X
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Xa
X
X
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X
X
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R
C/R/D
C/R/D
C/R
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Concomitant Medications
Xa
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Adverse Events
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EOS=end of study; ET=early termination; EQ-5D-5L=standardized measure of health status; HADS=Hospital Anxiety and Depression Scale; PedsQL=Pediatric Quality of Life Inventory; QoL=quality of life; QOLCE=Quality of 
Life in Childhood Epilepsy; R=Review
NOTE:  If a subject has a birthday during the study that makes a previously unrequired assessment now required (eg, Tanner staging in a male subject who turns 8 years old during the study), this assessment(s) should be initiated 
at visits subsequent to the birthday.
a:
For subjects from the core Study ZX008-1504 Cohort 1, use data collected at the last visit of the transition period; for subjects from core Study ZX008-1504 Cohort 2 use data collected at the Visit 12 and Visit 13.
For de novo subjects, a screening period up to 28 days is required. During this period, informed consent is required prior to any study-related procedures.  All results to determine eligibility must be reviewed prior to 
receiving the first dose of study drug at Visit 1.  
For subjects from ZX008-1504 Cohort 2 and de novo subjects, clinical laboratory, ECHO, and ECG results must be available and meet eligibility criteria prior to receiving the first dose of study drug at Visit 1.
b:
At the discretion of the investigator, Visit 2 may be conducted as a phone visit.
c:
Or early termination.
d:
Follow-up ECG, ECHO, and physical examination will be performed 3 and 6 months after study completion or early termination (see Section 6.3).
e;
Unless complete neurological examination is warranted based on significant changes in subject status, use data collected at the last visit of the transition period of Study ZX008-1504 Cohort 1 and for subjects from Study 
ZX008-1504 Cohort 2, use data collected at the Visit 12.
f:
ECHOs will be performed at Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, and 33.
g:
The Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, and 33 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 (see Table 7).
h:
Females of child-bearing potential
i:
Unless clinical laboratory evaluation is warranted based on significant changes in subject status, use data collected at the last visit of the transition period of Study ZX008-1504 Cohort 1; for subjects from Study ZX008-
1504 Cohort 2, use data collected at the Visit 12. For Visit 2, clinical laboratory evaluation is optional based on subject status.
j:
Visits 6, 15, and 27.
k:
Visits 3 and 4 (Months 1 and 2) only.
l:
m:
Only adverse events related to cardiac safety will be collected at this visit (see Table 7).
For subjects who are entering the separate extension trial or who transition to commercially available drug, post-dosing and cardiac safety follow-up visits are not required in this trial. 
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ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 30 of 194  
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 (DS) and Lennox-Gastaut syndrome. 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 
Dravet syndrome, previously known as severe myoclonic epilepsy of infancy (SMEI), is a rare 
and severe form of epilepsy first described by Charlotte Dravet in 1978 (Dravet 1978). The 
International League Against Epilepsy (ILAE) considers Dravet syndrome a developmental and 
epileptic encephalopathy, “a condition in which the epileptic activity itself may directly 
contribute additional cognitive and behavioral impairments over those expected from the 
underlying etiology alone and that suppression of epileptic activity might minimize this 
additional impairment” (Scheffer 2017). 
Dravet syndrome is estimated to affect 1 out of every 15,700 live births in the US and less than 
1 in 20,000 persons in the European Union (Wu 2015; EMA 2014). Dravet syndrome is 
responsible for 7% of the severe epilepsies starting before the age of 3 years (Ceulemans 2004). 
The diagnosis of Dravet syndrome is based on clinical signs and symptoms, though the 
presence of a mutation in the SCN1A gene is considered a likely, though not definitive, marker 
for the disorder (Dravet 2011; Fujiwara 2006). Dravet syndrome is usually not diagnosed until 
at least 1 year of age (Cooper 2016) and is characterized by medically intractable seizures along 
with motor and neurodevelopmental comorbidities. Onset of the first seizure typically occurs in 
the first year of life (usually at 5 to 8 months of age) in otherwise healthy infants and most 
often consists of prolonged, unilateral or generalized, clonic seizures provoked by fever 
(Orphanet 2014; Ceulemans 2004; Dravet 2011). These patients will have poor response or 
worsening seizures to standard antiepileptic drugs, in particular, sodium channel antagonist 
medications (Dravet 2011).  
After the first year, other types of seizures often begin to occur with high frequency and include 
(1) convulsive seizures consisting of generalized clonic seizures, generalized tonic-clonic 
(GTC) seizures or alternating unilateral clonic seizures (in the youngest patients, they often 
evolve into status epilepticus [SE]); (2) myoclonic seizures (appearing between the ages of 1 
and 5 years); (3) atypical absences (appearing at different ages between 4 months and 6 years 
or later); (4) focal seizures with or without secondary generalization (appearing between the 
ages 4 months and 4 years); or (5) rarely, tonic seizures (TS) (Dravet 2011). Individuals with 
Dravet syndrome are at higher risk for SE that often results in injury and hospitalization 
(Ceulemans 2004). A high incidence for SUDEP (sudden expected death in epilepsy) exists in 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 31 of 194  
Dravet syndrome with the major risk factor being the frequency of generalized tonic-clonic 
seizures (Harden 2017).  
Dravet syndrome is highly treatment-resistant and affects infants, children, adolescents, and 
adults. In general, convulsive seizure semiology is similar in patients across ages, although 
seizures tend to become less frequent and less severe in patients with Dravet syndrome as they 
enter adulthood (Lagae 2018). Generalized convulsive seizures, mostly reported as generalized 
tonic-clonic seizures persist into adulthood, often with a focal onset. These seizures are less 
frequent than in childhood and are mostly nocturnal. Some of these major convulsive seizures 
may have less typical aspects, for example, bilateral or asymmetric tonic posturing, followed in 
some cases by a tonic vibratory state or clonic movements (Oguni, 2001; Akiyama 2009). 
Throughout the lives of patients with Dravet syndrome, frequent and disabling seizures are 
associated with significant neurobehavioral, cognitive, developmental, and motor 
comorbidities,
1.1.1
Existing Treatment for Dravet Syndrome 
Currently no treatment algorithm exists for Dravet syndrome as recommended by the ILAE 
(International League Against Epilepsy) or any other similar medical entity. The main 
treatment goal in Dravet syndrome aims to reduce the frequency, duration, and severity of 
seizures with the ultimate goal of complete or near-complete seizure-freedom (Wirrell 2017). 
Attaining seizure-freedom or near seizure-freedom may be particularly important during the 
early developmental years. However, even with currently available AED polypharmacy, 
seizure-freedom or near seizure-freedom is rarely achieved (Dravet 2000; Dravet 2005, 
Dravet 2011, Chiron 2011). Commonly prescribed anticonvulsant medications, the sodium 
channel antagonists such as phenytoin and carbamazepine, exacerbate seizures in Dravet 
syndrome and are thus not useful (Wirrell 2016). Treatment for Dravet syndrome involves 
finding the best combination of medicines to treat seizures with tolerable side effects, 
preventing SE, and reducing comorbidity and mortality risk. Elimination or significant 
reduction of prolonged convulsive seizures and SE should represent the highest priority in 
treatment (Wirrell 2017).
Stiripentol and cannabidiol are the only 2 treatments approved for seizures associated with 
Dravet syndrome. 
Other therapies, topiramate (TPM), levetiracetam (LEV), and bromide may provide efficacy as 
adjunctive therapy for some patients (Chiron 2011). Published uncontrolled studies with LEV 
(Striano 2007), verapamil (Iannetti 2009), ketogenic diet (KD) (Caraballo 2011a; Caraballo 
2011b), deep brain stimulation (Andrade 2010), and vagal nerve stimulation (VNS) (Zamponi 
2011) show infrequent clinically meaningful improvement. Carbamazepine, oxcarbazepine, 
lamotrigine, phenytoin, vigabatrin, and high doses of intravenous (IV) phenobarbital should be 
avoided because they often exacerbate seizures (Sazgar 2005; Wirrell 2016; de Lange 2018). 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 32 of 194  
Rescue medications (clonazepam, diazepam, lorazepam, and midazolam, etc) are often used to 
stop prolonged seizures that may evolve to SE and require emergency intervention.  
Due to the severe and refractory nature of seizures associated with Dravet syndrome and given 
the risks of premature death from SUDEP, cognitive deficits, and other neurological 
consequences, there remains an urgent unmet medical need for the treatment of convulsive 
seizures associated with Dravet syndrome. The frequent and disabling seizures of different 
types, and the associated significant neurobehavioral, cognitive, developmental, and motor 
comorbidities that characterize Dravet syndrome, have a major negative impact on the patient's 
quality of life, as well as on their families. The neurobehavioral, cognitive, developmental, and 
motor comorbidities are at least partly caused by the poor control of seizures resulting in 
ongoing damage to the brain (Wolff 2006; Ragona 2011; Nabbout 2013; Wirrell 2016). A high 
incidence for SUDEP exists in Dravet syndrome with the major risk factor being the frequency 
of generalized tonic-clonic GTC seizures. 
Dravet syndrome drains a family emotionally, physically, and financially. Parents/caregivers 
suffer emotional exhaustion and anxiety related to the “fear of the next seizure” and “will this 
be the seizure that kills my child” (Campbell 2018). Patients with the highest seizure frequency 
tend to have more comorbidities and a lower quality of life (Lagae 2017). A 2006 study 
identified the challenges faced by parents caring for children with Dravet syndrome, reporting 
that the combination of persistent, severe seizures, together with developmental, behavioral, 
and sleep issues result in a high caregiver stress load with little ability to find respite and relief 
(Nolan 2006). The comorbid conditions, high mortality, disorder management requirements, 
and difficulties with family adaptation result in constant distress (Skluzacek 2011). In addition, 
Dravet syndrome is associated with extensive healthcare costs due to increased medical care 
use and intensive caregiver supervision as well as indirect burdens such as losses of 
productivity, family time, and leisure (Whittington 2018). The unremitting seizure episodes 
account for a high degree of healthcare resource utilization including hospitalizations, 
emergency room visits, and emergency transport services (Strzelczyk 2014). Aras and 
coworkers report 4 or more emergency room admissions in > 10% of children and up to 30 
admissions per year for some (Aras 2015). The impacts of Dravet syndrome typically not 
considered by healthcare professionals when making treatment decisions include the child’s 
expressive and receptive communications with family members, disruption of daily activities, 
and caregivers’ social interactions (Villas 2017; Nabbout 2013). 
A more effective treatment for Dravet syndrome that will abolish or significantly reduce 
seizure activity in a higher proportion of patients and provide periods of seizure freedom is 
urgently needed. Moreover, such outcomes could also lessen chronic brain injury and 
neuroinflammation due to unremitting seizures and thus potentially also improve Dravet 
syndromes’ associated comorbidities. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 33 of 194  
1.2
BACKGROUND INFORMATION ON STUDY PRODUCT
Zogenix is developing a new formulation of fenfluramine hydrochloride, ZX008, for the 
adjunctive treatment of DS. Fenfluramine 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, Pondimin and others. 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 as Adifax, Redux, and others.  
Fenfluramine was introduced in the USA in 1973. Products containing fenfluramine and 
D-fenfluramine were withdrawn from the USA market in 1997 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 DS or any of the catastrophic childhood 
epilepsies might lead to a more acceptable risk/benefit profile for fenfluramine, especially if 
lower doses can be used successfully. 
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 (ZX008 IB). There is also a large body of information concerning its clinical safety 
profile.
1.3
CLINICAL DATA
Zogenix has conducted 2 positive, adequate and well-controlled, multi-national, randomized, 
double-blind, placebo-controlled trials of ZX008 in subjects with Dravet syndrome aged 2 to 18 
years, Study 1 and Study 1504 Cohort 2. Study 1 compared 2 doses of ZX008, 0.8 mg/kg/day
and 0.2 mg/kg/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 to
placebo in subjects who were receiving stable 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. These subjects were randomized to receive ZX008 or placebo in 
addition to their current standard of care treatments. The dose of 0.5 mg/kg/day was selected to 
account for the anticipated drug interaction when ZX008 was administered in combination with 
STP.  
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) Treatment period. Key secondary objectives in both studies included a 
comparison of subjects who experienced at least a 50% reduction in monthly convulsive 
seizure frequency (also known as the ≥ 50% Responder Rate), and the median longest seizure 
free interval between convulsive seizures.  
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ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 34 of 194  
Both Study 1 and Study 1504 Cohort 2 met the primary efficacy endpoint and all key secondary 
efficacy endpoints. In Study 1, subjects randomized to ZX008 0.8 mg/kg/day achieved a 
reduction in mean monthly (28 days) baseline-adjusted CSF of 62.3% compared to placebo 
(P < 0.001) and subjects randomized to ZX008 0.2 mg/kg/day achieved a 32.4% reduction 
compared to placebo (P = 0.021). In Study 1504 Cohort 2, in which all subjects were taking 
STP, 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).  
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.  
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).  
Fifteen (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 3 (2.5%) subjects in any
ZX008 treatment group and 1 (1.2%) subject in the combined placebo group reported a serious 
TEAE determined by Investigators to be related to the study drug. In Study 1, two subjects, 
both of whom were in the ZX008 0.8 mg/kg/day group, reported SAEs that were considered by 
the Investigator to be related to study drug: SAEs of lethargy, and diarrhea leading to 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 35 of 194  
hospitalization in a 
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leading to hospitalization, drowsiness, reduced appetite, and weight loss in a 
who was discontinued from the study (The recorded weight loss was less than 1 kg.) In Study 
1504 Cohort 2, two subjects reported SAEs that were considered by the Investigator to be 
related to study drug: 2 episodes of seizure cluster, and seizure leading to hospitalization in a 
 in the placebo group; lethargy in a 
 in the ZX008 0.5 mg/kg/day 
group who was discontinued from the study. 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 this study, Study 1503, an 
open-label long-term, safety extension study. 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. 
Please reference the ZX008 IB for more detailed information on the safety and efficacy of 
ZX008. 
1.4
PRECLINICAL DATA
The pharmacokinetics (PK) of fenfluramine, norfenfluramine and their respective isomers has 
been studied in mice, rats, dogs and humans. The PK in humans differs from that of other 
species, with a longer duration of exposure to both the parent and the metabolite. In vitro 
metabolism studies have shown that there are large species differences in PK and metabolism 
of fenfluramine after oral administration. A 10-week GLP juvenile toxicology and toxicokinetic 
study in rats, which included fenfluramine hydrochloride doses of 3.5, 9 and 20 mg/kg/day by 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 36 of 194  
oral gavage for 10 weeks (Days 7 to 76 postpartum).  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 (ZX008 IB). There was no evidence of 
CNS-related histopathology findings.; 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 in this study, 9 mg/kg/day, provided a safety 
factor (both sexes combined) of approximately 3-fold or higher for fenfluramine and 
approximately 6-fold or higher for norfenfluramine. 
Further preclinical data on ZX008 are available in the Investigator’s Brochure (ZX008 IB). 
1.5
PHARMACOKINETICS 
Fenfluramine is metabolized to norfenfluramine. CYP1A2, CYP2B6 and CYP2D6 appear to be 
the predominant CYP (cytochrome P450) enzymes that metabolize fenfluramine to 
norfenfluramine. CYP2C9, CYP2C19 and CYP3A4 also appear to be involved, but to a lesser 
degree. 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 Food and Drug Administration’s (FDA’s) mechanistic static 
model shows that fenfluramine and its major metabolite norfenfluramine are unlikely to alter 
the PK of substrates of these CYP450 enzymes in the range of ZX008 doses that will be 
administered in this study. 
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 and are 
provided in the Table 3 below. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 37 of 194  
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)
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(Min, Max)
3.00 (3.00 to 3.50)
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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; 
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.
1.6
CLINICAL PHARMACOLOGY 
Please see the ZX008 IB for details on clinical pharmacology. Below are the clinical 
pharmacology conclusions.  
•
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.
•
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.
•
Coadministration of ZX008 with CBD at steady state resulted in increased fenfluramine 
concentrations but this increase was within the range of 
 dosing used in Study 1504 
Cohort 2; thus, no dose adjustment is recommended when fenfluramine is coadministered 
with CBD. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 38 of 194  
•
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. 
•
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.
•
ZX008 exhibited approximately dose proportional PK over a 4-fold range of doses (15 to 
120 mg/day). 
•
CYP450 metabolizer genotype for CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP3A4 
had no impact on the PK of fenfluramine or norfenfluramine. 
1.7
BACKGROUND INFORMATION ON REFERENCE PRODUCT
Not applicable.
1.8
RATIONALE FOR CURRENT STUDY
The rationale for conducting this open-label extension study is primarily to evaluate the long-
term safety of ZX008 in DS. This protocol also provides the opportunity for continued 
treatment for subjects responding to treatment from the Phase 3 double-blind studies, and an 
opportunity for initial treatment with ZX008 for subjects randomized to placebo in those 
studies. 
1.9
RATIONALE FOR INCLUDING DE NOVO SUBJECTS
Subjects who are >18 to ≤35 years of age at the time of screening, and who meet all other 
eligibility criteria may be eligible for participation after discussion with the Medical Monitor 
and sponsor about the potential risks and benefits for receiving ZX008.  Participation for these 
subjects will be at the discretion of the sponsor.   
Epileptic seizures tend to become less frequent and less severe after childhood; however, the 
mortality rate remains high.  One study on the long-term outcome of 24 adult patients with DS 
reported 5 (20.8%) deaths, at a mean age of 24.8 years, one by status epilepticus, three by 
sudden unexpected death in epilepsy (SUDEP), and one of unknown cause (Genton 2011). 
Fever sensitivity (temperature variations) persists throughout the clinical course of DS, but its 
impact on seizure frequency and severity is milder than in infancy. Generalized convulsive 
seizures, mostly reported as generalized tonic-clonic seizures persist, often with a focal onset 
but are less frequent than in childhood and mostly nocturnal. Some of these major convulsive 
seizures have less typical aspects, for example, bilateral or asymmetric tonic posturing, 
followed in some cases by a tonic vibratory state or clonic movements (Oguni 2001; 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 39 of 194  
Akiyama 2010). Other seizures like myoclonic seizures, atypical absences, and complex partial 
seizures are less common in adulthood.  Motor abnormalities are also common in adulthood, as 
is intellectual disability. Dependency in adulthood is nearly constant. 
Including subjects >18 to ≤35 years of age provides the opportunity to investigate the impact of 
ZX008 on DS outcomes as subjects transition to adulthood.
1.10
RISK-BENEFIT ASSESSMENT
Fenfluramine has been used successfully for up to 30 years in Belgium in refractory pediatric 
epilepsy patients, including those with DS (Boel 1996, Ceulemans 2012, Ceulemans 2016, 
Schoonjans 2016, Schoonjans 2017). The efficacy and safety of this therapeutic approach has 
been reported to be overwhelmingly favorable. Of the 15 DS treated patients, 10 (67%) were 
reported as seizure-free, with the average time of seizure-freedom being 6 years (range 1-19 
years). Twelve patients (87%) had a greater than 90% reduction in seizure frequency and 14 
patients (93%) with greater than 70% reduction in seizure frequency. No patients experienced 
emergence of clinical valvulopathy or pulmonary hypertension. 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. Fenfluramine has 
also been administered to over 500 children with neurobehavioral conditions, including autism 
and ADHD with good safety and tolerability. Doses tested in these pediatric studies 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. 
In addition, ZX008 demonstrated a statistically significant and clinically meaningful reduction 
in monthly convulsive seizure frequency in Study 1 and Study 1504 Cohort 2 and was 
generally well tolerated.  There was no clinical or echocardiographic evidence of cardiac 
valvulopathy or pulmonary hypertension 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 DS studies of 0.2 mg/kg/day to 0.8 mg/kg/day administered orally [in 
equally divided doses twice per day (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 
in children and adolescents (ZX008 IB). The doses used in this study are based on the data 
from the DS patients being successfully treated in Belgium discussed above and supported by 
results from Study 1 and Study 1504 Cohort 2. 
Interim results from this open-label study show that the effects observed during the double-
blind studies were durable and long-lasting; the reduction in convulsive seizures for subjects in 
Study 1503 was maintained throughout study participation of up to 3 years at the time of the 
interim analysis, with no evidence for developing tolerance. The pharmacologic and 
toxicological profile for the active pharmaceutical ingredient, fenfluramine, following oral 
administration is well established (ZX008 IB).
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 40 of 194  
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. Subjects 
will be enrolled into this study from the core studies where they had been transitioned to the 
lowest dose of ZX008 (0.2 mg/kg/day; maximum 30 mg/day or 20 mg/day for subjects from 
ZX008-1504 Cohort 1 dose regimen 3 or Cohort 2) and will remain on this dose for the first 
month of this study. After this time, the dose of ZX008 may be adjusted based on effectiveness 
and tolerability. For subjects that participated in core studies ZX008-1501, ZX008-1502, and 
dose regimen 1 or 2 from Cohort 1 of ZX008-1504 dose increases may be made in increments 
of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day (maximum dose 30 mg/day), and these 
increases should not occur earlier than every 14 days at each dose level. For subjects that 
participated in core study ZX008-1504 Cohort 1 dose regimen 3 and Cohort 2 and are receiving 
concomitant STP the first dose change will be to 0.4 mg/kg/day and the final dose change will 
be to 0.5 mg/kg/day, but not to exceed 20 mg/day. Dose increases may only occur after a 
review of the diary and reported adverse events (AEs), and if, in the investigator’s opinion, 
seizure frequency, severity, and/or duration indicates a change in medication regimen is 
warranted. Dose decreases for tolerability can occur at the investigator’s discretion, in dose 
amounts and frequency appropriate for the situation. Dose adjustments outside of these 
parameters must be discussed with the Medical Monitor prior to initiation.  
It is acknowledged that the initial dose of ZX008 in this study, 0.2 mg/kg/day, may or may not 
be effective or may be less effective than 0.8 mg/kg/day (or 0.5 mg/kg/day for subjects taking 
concomitant STP) for some subjects and some subjects may experience a worsening of their 
seizure condition after transitioning to the lower dose. However, there is benefit in identifying a 
minimally effective dose for all subjects in the study since the cardiotoxicity of fenfluramine 
appears to be dose-related in adults. The dosing instructions of this protocol permit dose 
adjustment during the first month of fixed dosing at 0.2 mg/kg/day if a clinically meaningful 
worsening occurs, such as an increase in frequency, severity or duration of existing seizures, or 
emergence of a new seizure type. 
The approximate volume of blood (240 mL) planned for collection from each subject over the 
course of the entire study (approximately 3 years, 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, 0.4 mg/kg/day, 0.6 mg/kg/day, 0.8 mg/kg/day, and 0.5 mg/kg/day 
(in subjects taking concomitant STP) doses are believed to be therapeutic doses, which could 
provide sufficient anti-epileptic support for a sustained period of time during the study.  
The available information suggests that the present clinical study has an acceptable risk-benefit 
ratio.
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 41 of 194  
2.
STUDY OBJECTIVES AND ENDPOINTS
2.1
PRIMARY OBJECTIVE
The primary objective of the study is: 
•
To assess the long-term safety and tolerability of ZX008. 
2.2
SECONDARY OBJECTIVES 
The secondary objectives of the study are: 
• To assess the effect of ZX008 relative to the pre-ZX008 baseline on the following 
effectiveness measures:
- The change in the frequency of convulsive seizures from Visit 3 to Visit 8 (ie, Day 31 
to Day 365) and for the entire Year 1 treatment period (ie, Visit 1/Day 1 to Visit 8/ 
Day 365) 
- The proportion of subjects who achieve a ≥ 40%, ≥ 50%, and ≥ 75% reduction in 
convulsive seizure frequency 
- The longest convulsive seizure-free interval
- The percentage of convulsive seizure-free days
- The non-convulsive seizure frequency 
- The convulsive + non-convulsive seizure frequency
• To estimate the incidence of the following on subjects receiving ZX008: 
- Use of rescue medication
- Hospitalization to treat seizures
- Status epilepticus (SE)
• To assess the effect of ZX008 relative to the pre-ZX008 baseline on the following QoL 
measures:
- Quality of Life in Childhood Epilepsy (QOLCE) score 
- Pediatric Quality of Life Inventory™ (PedsQL score) 
- PedsQL Family Impact module score 
- QoL of the parent/caregiver using the standardized measure of health status 
(EQ-5D-5L scale
- Affective symptoms of the parent/caregiver using the Hospital Anxiety and Depression 
Scale (HADS)
• To assess the effect of ZX008 on the following QoL measures: 
- Clinical Global Impression – Improvement (CGI-I) rating, as assessed by the principal 
investigator 
- CGI-I rating, as assessed by the parent/caregiver 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 42 of 194  
2.3
EXPLORATORY OBJECTIVES
The exploratory objectives for subjects who participated in core study ZX008-1504 are: 
• To assess the effect of ZX008 on the following QoL measures: 
- Sleep quality and mealtime behavior, as assessed by the parent/caregiver 
- Karolinska Sleep Scale
- Health and social care resource use (These measures include planned and unplanned 
hospital visits, use of ambulances, General Practitioner (GP) visits, speech and 
language therapy utilization, occupational and physical therapy utilization) 
2.4
STUDY ENDPOINTS
2.4.1
Effectiveness Endpoints
The effectiveness endpoints of the study are: 
•
Number of seizures by type 
•
Convulsive seizure-free interval
•
CGI-I as assessed by parent/caregiver
•
CGI-I as assessed by principal investigator 
•
QOLCE to measure changes in quality of life of the subject
•
PedsQL to measure changes in quality of life of the subject 
•
PedsQL Family Impact module to measure changes in quality of life of the 
parent/caregiver
•
QoL of parent/caregiver using the EQ-5D-5L scale
•
Affective symptoms of parent/caregiver using the HADS (in parents/caregivers from 
core studies ZX008-1501 and ZX008-1502 only) 
•
Duration of prolonged seizures (seizure type that, during pre-Z008 baseline, had 
duration > 2 minutes) 
•
Number of episodes of SE
•
Number of instances of rescue medication use and number of doses 
•
Number of inpatient hospital admissions due to seizures 
2.4.2
Safety Endpoints
The safety endpoints of the study are: 
•
AEs
•
Laboratory safety (hematology, chemistry, urinalysis) 
•
Vital signs (blood pressure, heart rate, temperature, and respiratory rate)
•
Physical examination
•
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 43 of 194  
•
12-lead electrocardiogram (ECGs) 
•
Doppler echocardiogram (ECHOs) 
•
Body weight 
•
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cognition 
2.4.3
Exploratory Endpoints 
For subjects who participated in core study ZX008-1504 only, the exploratory endpoints of this 
study are: 
•
Health and social care resource use, including GP visits, speech and language, 
occupational and physical therapy, in addition to acute hospital and institutional length 
of stay, loss of work, etc. 
•
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•
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•
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 44 of 194  
3.
INVESTIGATIONAL PLAN
3.1
OVERALL STUDY DESIGN AND PLAN
This is an international, multicenter, open-label, long-term safety study of ZX008 in pediatric 
and young adult subjects with DS. Subjects eligible for participation are those who have 
successfully completed 14 weeks of treatment in core studies ZX008-1501 or ZX008-1502, and 
15 weeks of treatment in core study ZX008-1504 Cohort 2, or successfully completed core 
study ZX008-1504 Cohort 1, and are candidates for continuous treatment for an extended 
period of time. In addition, subjects who are >18 to ≤35 years of age at the time of screening, 
and who meet all other eligibility criteria may be eligible for participation after discussion with 
the Medical Monitor and sponsor about the potential risks and benefits for receiving ZX008.  
Participation for these subjects will be at the discretion of the sponsor.  
This trial will consist of an up to 36-month open-label extension (OLE) Treatment Period and a 
2-week Post-Dosing Period. Thus, subjects who complete this trial will have been treated with 
ZX008 for a minimum of up to 3 years (including their participation in both the core study and 
this study). Subjects who did not participate in one of the core studies will undergo a screening 
period up to 28 days to confirm eligibility prior to receiving their first dose in the OLE 
Treatment Period
During the 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 
0.2 mg/kg/day, the investigator may adjust the dose of each subject based on effectiveness and 
tolerability. For subjects who are not receiving concomitant STP, including de novo subjects 
and those who participated in core studies ZX008-1501, ZX008-1502, and dose regimen 1 or 2 
from Cohort 1 of ZX008-1504, dose changes should be made in 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. For subjects who
are receiving concomitant STP, including de novo subjects and those who participated in core 
study ZX008-1504 Cohort 1 dose regimen 3 and Cohort 2, and the first dose change will be to 
0.4 mg/kg/day and the final dose change will be to 0.5 mg/kg/day, but not to exceed 20 mg/day.  
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. Dose decreases for tolerability can occur at the investigator’s discretion, in dose 
amounts and frequency appropriate for the situation. ZX008 dose adjustments outside of these 
parameters should be discussed with the Medical Monitor prior to initiation.  
In addition, if a subject has been stable on the same dose of ZX008 for 6 months or longer, 
investigators may adjust the doses of one or more of the other concomitant AEDs as per typical 
clinical practice. Concomitant AEDs may be withdrawn completely but all subjects must 
remain on a minimum of 1 concomitant AED plus ZX008. No new concomitant AEDs or 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 45 of 194  
antiepileptic treatments may be introduced while in this study. All medication dose changes 
must be documented with a clinical explanation and justification. Concomitant AED dose 
adjustments outside of these parameters should be discussed with the Medical Monitor 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, 
may increase the dose to 0.4 mg/kg/day (maximum 30 mg/day for subjects who are not 
receiving concomitant STP; 20 mg/day for subjects who are receiving concomitant STP). A 
clinically meaningful worsening would be an increase in frequency, severity or duration of 
existing seizures, or emergence of a new seizure type. The description of the 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 for subjects who are not receiving concomitant STP and to 
0.5 m/kg/day (maximum 20 mg/day) for subjects who are receiving 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, 0.2 to 0.8 mg/kg/day or 0.5 mg/kg/day for subjects who are receiving concomitant STP) 
may be considered after consultation between the investigator and Medical Monitor. 
A follow-up ECG and ECHO will be performed 3 and 6 months after study drug 
discontinuation for early termination and for those subjects who complete the study. 
Caregivers will use a diary daily to record the number/type of seizures, dosing, and use of 
rescue medication. A schedule of assessments is provided in Table 1 and Table 2. 
After at least 1 year of treatment in Study 1503 subjects who participated in one of the core 
studies will transition to a separate extension study (Study 1900) once that study is approved 
and the study site is initiated. Continuation in a separate extension protocol will be based on 
benefit/risk and continued eligibility criteria being met. De novo subjects must have 
participated in this trial for at least 3 months with at least 1 ECHO completed and continue to 
meet eligibility requirements to be eligible to transition to a separate extension protocol. 
Alternatively, subjects will transition to commercial product once it is available. For subjects 
who are entering the separate extension trial or who transition to commercially available drug, 
post-dosing and cardiac safety follow-up visits are not required in this trial. Subjects who 
transition to commercially available drug must have an ECHO within 3-6 months before
starting commercial drug and will have follow-up ECHOs within the required timeframe while 
on commercial drug.  
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 46 of 194  
3.2
NUMBER OF SUBJECTS
Up to approximately 340 subjects from the core studies and up to 50 subjects who did not 
participate in the core studies may be enrolled. 
3.3
STUDY DURATION
The duration of participation in the study for an individual subject is expected to be up to 158 
weeks, plus follow-up safety visit 3 and 6 months after the last dose: 
•
OLE Treatment Period - 36 months (156 weeks)
•
Post-Dosing Visit - 2 weeks after study completion or early termination
•
Cardiac Follow-up (ECG and ECHO) - 3 and 6 months after study drug discontinuation 
for early termination and for those subjects who complete the study; not applicable to 
subjects who transition to commercial product. 
3.4
NUMBER OF STUDY CENTERS
The study expects to use up to approximately 75 research centers in North America, Europe, 
Australia and Japan.  
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 DS, and the possible consequences of current inadequate treatments, the use of 
children with DS in this study is considered justified. The study design has incorporated an 
initial 1-month of treatment at the lowest dose (ZX008 0.2 mg/kg/day) after which time the 
investigator may adjust the dose based on effectiveness and tolerability. After the first month, 
dose increases will be made incrementally every 14 days to ensure adequate time to acclimate
to the new dose. Dose decreases for tolerability can occur at the investigator’s discretion, in 
dose amounts and frequency appropriate for the situation. The duration of the study, up to 36 
months, will allow for collection of appropriate data to characterize the safety profile of 
ZX008. 
3.6
PREMATURE TERMINATION OF STUDY
The Sponsor can terminate the study prematurely at any time for medical or ethical reasons at 
individual study sites or at all study sites. The investigator will be notified in writing, outlining 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 47 of 194  
the reasons for the termination. Instructions will be provided if assessments beyond those 
described in the study protocol need to be conducted.  
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 alternative 
therapy is available and that End-of-Study procedures are conducted, as described in 
Section 6.1.5 and Section 6.2. 
All study materials including investigational medicinal product (IMP) 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)/Institutional Review 
Board (IRB). 
3.7
STUDY MONITORING PROCEDURES
3.7.1
Independent Data and Safety Monitoring Committee (IDSMC)
The Independent Data and Safety Monitoring Committee (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 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:
•
Be responsible for providing recommendations to the Sponsor surrounding study 
conduct matters that affect safety
•
Review safety data at ad hoc time points and identify if significant safety concerns arise 
during the study 
•
Review PK data and any other data that may affect subject continuation
•
Make recommendations regarding the continuation, suspension, or termination of the 
study 
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3.7.2
International Pediatric Cardiac Advisory Board (IPCAB) 
The International Pediatric Cardiac Advisory Board (IPCAB) is an advisory body to the 
Sponsor that monitors cardiac safety of the ZX008 clinical trials and provides advice to the 
IDSMC. The IPCAB charter outlines the roles and responsibilities of the committee and guide 
its operations, and review of individual subject cases. The IPCAB consists of individuals 
external to the Sponsor who have relevant experience in cardiology, pediatric cardiology, and 
echocardiography. The IPCAB 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.  
All ECHO examinations performed throughout the trial will be sent to an experienced pediatric 
cardiologist central reader (Biomedical Systems, Inc.). If the central reader classifies a subject 
as having met a pre-defined threshold value indicative of potential cardiac valvulopathy or 
pulmonary hypertension, or any other unexpected cardiac adverse event, the case will then be 
sent for secondary adjudication by one or more members of the IPCAB according to the 
procedures outlined in the IPCAB manual. In addition, member of the IPCAB will perform 
audits of ECHOs deemed normal by the central cardiac reader. 
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ZX008, Fenfluramine Hydrochloride
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Confidential
Page 49 of 194  
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.  
4.1
INCLUSION CRITERIA
Subjects meeting all of the following inclusion criteria may be enrolled into the study: 
1. Subject is aged 2 to 18 years inclusive, as of the day of the core study Screening Visit.  
2. Subject has satisfactorily completed the core study in the opinion of the investigator and 
the Sponsor. 
NOTE: Those subjects who do not complete the 12-week Maintenance Period of the 
core study 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 open-label extension 
study participation resides solely with the Sponsor, who may consult with the site 
investigator, the IPCAB and/or the IDSMC. 
3. Subject is male or non-pregnant, non-lactating female. Female subjects of childbearing 
potential must not be pregnant or breast-feeding. Female subjects of childbearing 
potential must have a negative urine pregnancy test. Subjects of childbearing or child-
fathering potential must be willing to use medically acceptable forms of birth control, 
which includes abstinence, while being treated on this study and for 90 days after the 
last dose of study drug. 
4. Subject has documented medical history to support a clinical diagnosis of DS, where 
convulsive seizures are not completely controlled by current antiepileptic drugs. 
5. Subject has been informed of the nature of the study and informed consent has been 
obtained from the legally responsible parent/guardian. 
6. Subject has provided assent in accordance with IRB/IEC requirements, if capable.
7. Subject’s caregiver is willing and able to be compliant with diary completion, visit 
schedule and study drug accountability. 
8. Subject’s parent/caregiver has been compliant with diary completion during the core 
study, in the opinion of the investigator (eg, at least 90% compliant). 
9. Subjects entering from study ZX008-1504 must be receiving a therapeutically relevant 
and stable dose of CLB and/or VPA, and STP (Cohort 1 dose regimen 3 and Cohort 2 
only) for at least 4 weeks prior to screening and are expected to remain stable 
throughout the study. 
10. Subjects who are >18 to ≤35 years of age at the time of screening and did not 
participate in one of the core studies must meet criteria 3 to 7 above and the following 
criteria below in order to be considered for participation. Participation is at the 
discretion of the Sponsor: 
a. Onset of seizures in the first year of life in an otherwise healthy infant.
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Confidential
Page 50 of 194  
b. A history of seizures that are either generalized tonic-clonic or unilateral
clonic or bilateral clonic, and are prolonged.
c. Initial development is normal.
d. History of normal brain MRI without cortical brainmalformation.
e. Lack of alternative diagnosis.
f.
Meets one of the following 3 confirmatory diagnostic criteria:
i. Emergence of another seizure type, including myoclonic,
generalized tonic-clonic, tonic, atonic, absence and/or focal has
developed after the first seizure type.
ii. Prolonged exposure to warm temperatures induces seizures and/or 
seizures are associated with fevers due to illness or vaccines, hot
baths, high levels of activity and sudden temperature changes 
and/or seizures are induced by strong naturaland/or fluorescent 
lighting, as well as certain visualpatterns.
iii. Genetic test results consistent with a diagnosis of Dravet syndrome
(pathogenic, likely pathogenic, variant of unknown significance, or
inconclusive but unlikely to support an alternative diagnosis.)
g. Subject has been approved for study inclusion by the Epilepsy Study 
Consortium.
h. 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:
i. Mild or greater mitral or aortic valve regurgitation in subjects >18 yrs of 
age
ii. Possible signs of pulmonary hypertension with abnormal or greater than 
upper limit of normal values 
iii. Evidence of diastolic dysfunction
i.
Subject must have had ≥4 convulsive seizures (tonic, tonic-atonic, tonic-
clonic, clonic) per 4-week period for past 12 weeks prior to screening, by 
parent/guardian report to investigator or investigator medical notes.
j.
All medications or interventions for epilepsy (including ketogenic diet [KD] 
and vagal nerve stimulation [VNS]) must be stable for at least 4 weeks prior 
to screening and are expected to remain stable throughout the study.
11. Subject’s parent/caregiver is willing and able to be compliant with diary 
completion, visit schedule and study drug accountability.
4.2
EXCLUSION CRITERIA
Subjects meeting any of the following exclusion criteria must not be enrolled into the study:
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 51 of 194  
1. Subject has a known hypersensitivity to fenfluramine or any of the excipients in the 
study medication. 
2. Subject has current or past history of cardiovascular or cerebrovascular disease, 
myocardial infarction or stroke.
3. Subject from one of the core studies with current cardiac valvulopathy or pulmonary 
hypertension that the investigator, parent, IPCAB, IDSMC, or Sponsor deems clinically 
significant and warrants discontinuation of study medication. 
4. For de novo subjects: possible signs of pulmonary hypertension with abnormal or 
greater than upper limit of normal values 
5. 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. 
6. 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 as 
measured by the C-SSRS Since Last Visit, 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. 
7. Subject has a current or past history of glaucoma. 
8. Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild 
hepatic impairment (elevated liver enzymes < 3x upper limited of normal [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.
9. Subject is receiving concomitant therapy with: centrally-acting anorectic agents; 
monoamine-oxidase inhibitors; any centrally-acting compound with clinically 
appreciable amount of serotonin agonist or antagonist properties, including serotonin 
reuptake inhibition; atomoxetine, or other centrally-acting noradrenergic agonist; 
cyproheptadine, and/or cytochrome P450 (CYP) 2D6/3A4/2B6 inhibitors/substrates 
(Appendix 1). (Note: Short-term medication requirements will be handled on a per case 
basis by the Medical Monitor.) 
10. Subject is currently taking carbamazepine, oxcarbazepine, eslicarbazepine, 
phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as 
maintenance therapy.
11. For subjects entering from core studies ZX008-1501, ZX008-1502, or ZX008-1504 
(Cohort 1/dose regimens 1 &2):  Subject is currently receiving or has received STP in 
the past 21 days prior to core study Visit 1. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 52 of 194  
12. Subject is unwilling to refrain from large or daily servings of grapefruits and/or Seville 
oranges, and their juices beginning with Visit 1 and throughout the study. 
13. Subject has positive result on urine tetrahydrocannabinol (THC) Panel or whole blood 
cannabidiol (CBD) at Visit 1.
14. Subject is unwilling or unable to comply with scheduled visits, drug administration 
plan, laboratory tests, other study procedures, and study restrictions. 
15.  Subject has a clinically significant condition, or has had clinically relevant symptoms 
or a clinically significant illness in the 4 weeks prior to Visit 1, other than epilepsy, that 
would negatively impact study participation, collection of study data, or pose a risk to 
the subject, including chronic obstructive pulmonary disease, interstitial lung disease, or portal 
hypertension. 
16. Subject has participated in another clinical trial within the past 30 days (ie, the last visit 
of the previous study was in the past 30 days), with the exception of the core studies. 
4.3
SUBJECTS OF REPRODUCTIVE POTENTIAL
Male subjects who are sexually active with a partner of child-bearing 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: 
•
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation:  
−
oral 
−
intravaginal  
−
transdermal 
•
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−
oral 
−
injectable 
−
implantable intrauterine device
−
intrauterine hormone-releasing system
•
Surgical sterilization (vasectomy or bilateral tubal occlusion)
Female subjects who are not of child-bearing 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. Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy. 
Female subjects who are sexually active and are of child-bearing potential must use, with their 
partner, an approved method of highly effective contraception from the time of informed 
consent until 90 days following the last dose of study drug. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 53 of 194  
The following methods are acceptable: 
•
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation and a barrier method (ie, condom for male partner): 
−
oral 
−
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−
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barrier method (ie, condom for male partner):  
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•
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.
4.3.1
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.
4.3.2
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 subject 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 and 
should complete the taper schedule. 
4.4
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.  
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 54 of 194  
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 CRF. 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 
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 the IPCAB, the central cardiac reader, 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 the use of an unacceptable or contraindicated 
concomitant medication. 
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 C-SSRS. 
9. It is the investigator’s opinion that it is not in the subject’s best interest to continue in the 
study. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 55 of 194  
10. Subject is found to be pregnant while on study.  
Discontinuation decisions will be made at each participating site by the site investigator, except 
that discontinuations due to development of cardiovascular or cardiopulmonary complications 
are to be made by the IDMSC with input from the IPCAB and the investigator.  
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 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: 
•
The subject or the subject’s legally authorized representative wishes to discontinue 
participation in the study 
•
The investigator advises that the subject’s safety or well-being could be compromised 
by further participation in the study 
•
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, etc)
The IDSMC may request that the study be terminated after review of the safety information at
any time during the study. The IDSMC 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.  
In the event that the study is terminated prematurely then the procedure for termination should 
be followed as described in Section 3.6. 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 CRF and in the subject’s medical records (eg, AEs, lack of compliance, lost to 
follow-up, etc). If possible, the subject/subject’s legal 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 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 56 of 194  
to that time. Specific procedures required are described in Section 6.1.5 and Section 6.2. 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. 
4.5
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 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: 
•
The discovery of an unexpected, relevant, or unacceptable risk to the subjects enrolled 
in the clinical study
•
Failure to enroll subjects at the required rate
•
A decision of the Sponsor to suspend or discontinue development of ZX008  
4.6
REPLACEMENT OF SUBJECTS
Enrolled subjects will not be replaced. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 57 of 194  
5.
INVESTIGATIONAL MEDICINAL PRODUCT INFORMATION
ZX008 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 2.5 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 a concentration of 2.5 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 formulation 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 ketogenic diet (KD). 
The formulation will be provided in bottles with tamper-evident, child-resistant caps. 
Doses to be studied include 0.2 mg/kg/day, 0.4 mg/kg/day, 0.6 mg/kg/day, and 0.8 mg/kg/day 
divided into two daily doses, up to a maximum of 30 mg/day. 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 fulfil the dose. 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. 
5.1.1
Labeling and Packaging 
The ZX008 product will be packaged and labeled according to current ICH, Good 
Manufacturing Practices (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. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 58 of 194  
5.2
DESCRIPTION OF REFERENCE TREATMENT, COMPARATOR, 
AND/OR PLACEBO
No comparators, reference treatments, or placebo will be used in this study. 
5.3
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 bottles to the subject will be handled through an interactive voice 
response (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 
provided by the Sponsor before the start of the study. 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.
5.4
TREATMENT ADMINISTRATION
5.4.1
OLE Treatment Period
The investigator (or delegate) will dispense IMP only to subjects included in this study 
following the procedures set out in this study protocol. 
Study medication will be administered as equal doses BID in the morning and in the evening, 
approximately 12 hours apart, with food. 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. 
Administration of the initial IMP will be based on the 0.2 mg/kg/day (maximum 30 mg/day or 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 59 of 194  
20 mg/day for subjects taking concomitant STP) dose and subject’s weight at Visit 1 (Study 
Day 1). At Visits 5 to 15 (Months 3 to 33), if the subject’s weight has changed ± 25% of the 
weight from the previous dose calculation, the IMP dose will be recalculated. Subjects will be 
dosed using the oral dosing syringe provided. 
During the 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.  
Dose changes should be made in increments of 0.2 mg/kg/day, as follows: 
•
Subjects who are not receiving concomitant STP: may increase to a maximum of 
0.8 mg/kg/day but not to exceed total dose of 30 mg/day 
•
Subjects who are receiving concomitant STP: the first dose change will be to 
0.4 mg/kg/day and the final dose change will be to 0.5 mg/kg/day, but not to exceed 
20 mg/day  
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. Dose decreases for tolerability can occur at the investigator’s discretion, in dose 
amounts and frequency appropriate for the situation. ZX008 dose adjustments outside of these 
parameters should be discussed with the Medical Monitor 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, 
may increase the dose to 0.4 mg/kg/day (maximum 30 mg/day for subjects who are not 
receiving concomitant STP; 20 mg/day for subjects who are receiving concomitant STP). A 
clinically meaningful worsening would be an increase in frequency, severity or duration of 
existing seizures, or 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) for subjects who are not receiving concomitant STP, and 
to 0.5 mg/kg/day (maximum: 20 mg/day) for subjects who are receiving 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; however, the maximal dose 
determined for subjects on concomitant STP must not be exceeded. Dosing outside of the 
specified range (ie, 0.2 to 0.8 mg/kg/day or 0.5 mg/kg/day for subjects taking concomitant 
STP) may be considered after consultation between the investigator and Medical Monitor. 
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ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
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5.4.2
Taper Period
All subjects (those who complete the OLE Treatment Period or those who discontinue from the 
study early and are not transitioning to another ZX008 extension study or treatment with
commercial drug) will be tapered off of study medication.  
5.4.2.1
Taper Period for Subjects not Receiving Concomitant STP
The tapering scheme is a 2-step process for subjects who are not receiving concomitant STP, 
including subjects from core studies ZX008-1501 and ZX008-1502, and from study ZX008-
1504 Cohort 1/Regimens 1&2. This is described in Table 5.  
Study medication will be administered as equal doses BID in the morning and in the evening, 
approximately 12 hours apart, with food. 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 5.  
Taper Algorithm for Subjects from Core Studies ZX008-1501, ZX008-1502, 
and ZX008-1504 Cohort 1/Regimens 1&2Not Receiving Concomitant STP 
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
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ZX008 0.4 mg/kg/day
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ZX008 0.6 mg/kg/day
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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.
5.4.2.2
Taper Period for Subjects from Core Study ZX008-1504 Cohort 1 Regimen 3 and 
Cohort 2 Receiving Concomitant STP
The tapering scheme is a 3-step process for subjects receiving concomitant STP, including 
subjects from core study ZX008-1504 Cohort 1 Regimen 3 and Cohort 2, and is described in 
Table 6.  
Study medication will be administered as equal doses BID in the morning and in the evening, 
approximately 12 hours apart, with food. 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. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 61 of 194  
Table 6.  
Taper Algorithm for Subjects Receiving Concomitant STP
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
Taper Step 3
Days 9-14 after study 
completion or early 
termination
ZX008 0.2 mg/kg/day
Not applicable
Not applicable
Not applicable
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day
Not applicable
Not applicable
ZX008 0.5 mg/kg/day
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day
Not applicable
Note:  maximum daily dose of ZX008 is 20 mg.
5.5
BLINDING
This is an open-label study.  
5.6
PRIOR AND CONCOMITANT MEDICATION
All prior and concomitant medication will be collected in the CRF.
All medications taken by a subject after the first administration of IMP are regarded as 
concomitant medication and must be documented in the CRF, including over-the-counter 
medication, herbal and vitamin/supplement preparations.  
Subjects are required to take at least one concomitant AED throughout the study. During at 
least the first 6 months of the study, subjects will continue to receive their existing AEDs at the 
same dose as prior to initiating this study. 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. Concomitant AEDs may be withdrawn completely but all subjects must 
remain on a minimum of 1 concomitant AED plus ZX008. No new concomitant AEDs may be 
introduced while in this study. All medication dose changes must be documented with a clinical 
explanation and justification. Concomitant AED dose adjustments outside of these parameters 
should be discussed with the Medical Monitor prior to initiation.  
Non-study medications and therapies 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.  
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 62 of 194  
5.6.1
Vagal Nerve Stimulation
Subjects receiving treatment with vagal nerve stimulation (VNS) may be included as long as 
the VNS has been in place for at least 6 months prior to entry into the core study, or for de novo 
subjects prior to first dose in the OLE, and stimulation parameters have been kept constant for 
4 weeks prior to core study Visit 1. During at least the first 6 months of the study, 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. The subject’s use 
of VNS will be recorded in the CRF. 
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 entry into the core study, or for de novo 
subjects 4 weeks prior to first dose in the OLE. During at least the first 6 months of the study, 
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. The subject’s use of KD will be 
recorded in the CRF.
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 prior and/or concomitant medication sections of the CRF.   
Use of rescue medication is permitted during the study and should be recorded on the CRF
(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 Medication and Food 
Alcohol in all forms (wine, beer, liquors) and amounts is prohibited during the study. The 
following concomitant medications/foods are prohibited during the clinical trial:
•
AEDs: Phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, retigabine/ezogabine 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 63 of 194  
• STP: Subjects who are not receiving concomitant STP, including de novo subjects and 
those from core studies ZX008-1501, ZX008-1502, and ZX008-1504 Cohort 1/Dose 
Regimens 1&2 only, must be off STP for a minimum of 21 days prior to the core study 
or OLE Screening visit. 
•
Felbamate is prohibited as a concomitant medication unless the subject has been on 
felbamate for at least 18 months prior to the core study or OLE Screening visit, has 
stable liver function and hematology laboratory tests, and the dose is expected to remain 
constant throughout the study. 
•
Drugs that interact with central serotonin: imipramine, monoamine oxidase inhibitors, 
selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, 
vortioxetine 
•
Drugs that increase cardiovascular risk: atomoxetine
•
Drugs intended to facilitate weight loss
•
Other: any form of marijuana, THC and derivatives (including Epidiolex®) 
•
Drugs/foods that potentially interact with ZX008 via the CYP2D6, CYP3A4, and/or 
CYP2B6 pathways: A list of medications/foods that are to be avoided as ongoing 
medications or for chronic use if initiated during the study from the time of signing the 
informed consent form (ICF) until the end-of-study visit (or early termination) is 
provided in Appendix 1. 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. 
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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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 64 of 194  
6.
VISIT SCHEDULE
Study procedures will be conducted according to the Schedule of Assessments in Table 1 and 
Table 2. Time windows for all assessments are detailed in Table 7. For details on alternative 
procedures and allowances regarding study conduct during COVD-19 refer to Appendix 11. 
Table 7. 
Time Windows for Assessments
Visit / Procedure
Time window (relative to scheduled visit / procedure)
Visit 1 (Clinic; Study Day 1) 
Not applicable (this is the same visit as Visit 13 from the 
core study)
Visits 2 (Clinic/Phone; Study Day 15)
± 3 days
Visits 3-15 (Clinic: Study Days 30, 60, 90, 180, 
270, 365, 455, 545, 635, 725, 815, 905, 995)
± 4 days
Visit 16 (Clinic; Study Day 1085)
± 4 days
Visit 17 (Clinic; Study Day 1099; post dosing)
± 4 days
Visit 18, 19 (ECHO clinic; 3 and 6 months after 
last dose)
+ 30 days
Blood collection for AED concentration
Prior to morning dose of AED medication
AED=antiepileptic drug (s); ECHO=echocardiogram
6.1
OLE TREATMENT PERIOD
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 this study, including 
collection of HADs, EQ-5D-5L, and PedQL Family Impact Module ratings of parent/caregiver 
symptoms and quality of life, must be obtained before a subject can start any of the Visit 1
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. For subjects from the core studies it 
is assumed that consent for this study will have been obtained prior to completion of 
procedures at
•
ZX008-1501 and ZX008-1502 Visit 12/End of Study 
•
The last visit of the transition period of ZX008-1504 Cohort 1 
•
ZX008-1504 Cohort 2 Visit 12/End of Study 
For de novo subjects, consent for this study must be obtained prior to any study-related 
procedures. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 65 of 194  
Only eligible subjects as specified by the inclusion and exclusion criteria who have 
successfully completed the core study, or who are >18 to ≤35 years of age at the time of 
screening and who meet all other eligibility criteria, will be enrolled into study ZX008-1503. 
6.1.1
Screening Visit for de novo Subjects
For de novo subjects a screening period up to 28 days is required to determine eligibility prior 
to dosing. Clinical laboratory results and all ECHO/ECG results must be available and meet 
eligibility criteria prior to receiving the first dose of study medication at Visit 1. The following 
procedures will be performed during this screening period for all de novo subjects before the 
first dose of study medication: 
•
Obtain written informed consent for the study 
•
Obtain written informed consent from parent/caregiver to collect PedsQL Family 
Impact, HADS, and EQ-5D-5L ratings of parent/caregiver symptoms and quality of life 
•
Review inclusion and exclusion criteria 
•
Record demographic information 
•
Record medical, neurological, and epilepsy history 
•
Record current epilepsy status (number/type/duration seizures per month) 
•
Collect past 3 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 
•
Record prior medications 
•
Complete physical examination, including height, weight, and calculation of BMI 
•
Complete neurological examination 
•
12-lead electrocardiogram
•
Doppler ECHO (this must be obtained and results provided prior to starting ZX008) 
•
Vital signs
•
Urine pregnancy test for females of child-bearing potential 
•
Laboratory evaluation (serum chemistry, hematology, urinalysis, etc) 
•
Urine THC panel
•
Whole blood CBD 
•
Obtain blood sample for epilepsy genotype panel 
•
C-SSRS Baseline/Screening Assessment (Appendix 2) 
•
CGI-I (assessed by parent/caregiver)
•
CGI-I (assessed by investigator)  
•
BRIEF (Appendix 3) 
•
QOLCE (Appendix 4) 
•
Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
•
Affective symptoms of parent/caregiver using the HADS scale (Appendix 8) 
•
Instruct parent/caregiver on use of diary 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 66 of 194  
•
Dispense diary (after above procedures have been concluded) 
•
Record AEs
Review inclusion/exclusion criteria, including echocardiogram, ECG, clinical laboratory 
results, and approval from the Epilepsy Study Consortium.  Only eligible subjects as specified 
by the inclusion and exclusion criteria with an independently confirmed diagnosis of DS by the 
Epilepsy Study Consortium, and approved by the sponsor, will be enrolled into the study and 
receive study medication. 
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. 
In certain circumstances the sponsor may allow subjects who did not meet all 
inclusion/exclusion criteria during the Screening period 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. 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. 
If a decision has been made to wean off of a medication without antiepileptic properties and the 
wash-out period (at least 5 half-lives) is expected to be shorter than 5 weeks, then the subject 
may remain in screening and chart seizures using the seizure diary.
6.1.2
Clinic Visit 1 (Study Day 1; Transition from Core Study) 
6.1.2.1
Clinic Visit 1 for Subjects from Core Studies ZX008-1501 or ZX008-1502 
The following procedures will be performed during Visit 1 (Visit 13 of ZX008-1501 and 
ZX008-1502): 
•
Record demographic information
•
Vital signs
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 67 of 194  
•
Record prior and concomitant medications (use core study Visit 13 information)  
•
Urine pregnancy test for females of child-bearing potential 
•
Tanner Staging for subjects >7 to ≤18 years of age (Appendix 5) 
•
Instruct parent/caregiver on use of diary 
•
Record ongoing AEs as medical history (use core study Visit 13 information) 
•
Record ongoing adverse events of special interest (AESIs) as medical history (use core 
study Visit 13 information) 
•
Dispense diary (after above procedures have been concluded) 
•
Dispense study medication
Data collected from Visit 12/End of Study for the core study may be used for the following 
procedures unless otherwise indicated: 
•
Record medical, neurological, and epilepsy history 
•
Complete physical examination, including height, weight, and calculation of body mass 
index (BMI) 
•
Complete neurological examination (use data collected at core study Visit 12, unless 
there was a significant change in subject status warranting a new complete examination)
•
12-lead ECG 
•
Doppler ECHO  
•
Laboratory evaluation (serum chemistry, hematology, urinalysis, etc) (use core study 
Visit 12 information, unless investigator determines new laboratory evaluation is 
warranted due to change in subject status) 
•
Urine THC panel  
•
Whole blood CBD  
•
Tanner Staging for subjects > 7 to ≤18 years of age (Appendix 5) 
•
C-SSRS Children’s Since Last Visit Assessment (Appendix 2)  
•
CGI-I (assessed by parent/caregiver)
•
CGI-I (assessed by investigator)  
•
BRIEF (Appendix 3) 
•
QOLCE (Appendix 4) 
•
PedsQL (Appendix 6) (only for subjects from the core studies) 
•
Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
Affective symptoms of parent/caregiver using the HADS scale (Appendix 8). After enrollment 
into the study, each subject will be issued a new “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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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 68 of 194  
6.1.2.2
Clinic Visit 1 for Subjects from Core Study ZX008-1504 
The following procedures will be performed during Visit 1(the last transition period of 
ZX008 1504 Cohort 1 and Visit 12 of ZX008-1504 Cohort 2): 
•
Record demographic information 
•
Vital signs
•
Urine pregnancy test for females of child-bearing potential 
Data collected from the last transition period of Cohort 1 and Visit 12/End of Study for 
Cohort 2 procedures may be used unless otherwise indicated: 
•
Record medical, neurological, and epilepsy history 
•
Record prior and concomitant medications  
•
Complete physical examination, including height, weight, and calculation of BMI  
•
Complete neurological examination (use core study Visit 12 information for subjects 
who participated in Cohort 2, and use core study information from the last transition 
period visit for subjects who participated in Cohort 1, unless there was a significant 
change in subject status warranting a new complete examination) 
•
12-lead ECG 
•
Doppler ECHO 
•
Laboratory evaluation (serum chemistry, hematology, urinalysis, etc) (use data collected 
at core study Visit 12 for subjects who participated in Cohort 2, and use core study 
information from the last transition period visit for subjects who participated in 
Cohort 1, unless investigator determines new laboratory evaluation is warranted due to 
change in subject status)
•
Urine THC panel 
•
Whole blood CBD  
•
Tanner Staging for subjects > 7 to ≤18 years of age (Appendix 5) 
•
C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
•
CGI-I (assessed by parent/caregiver) 
•
CGI-I (assessed by investigator)  
•
BRIEF (Appendix 3) 
•
QOLCE (Appendix 4) 
•
PedsQL (Appendix 6) (only for subjects from the core studies) 
•
Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
•
Healthcare utilization questions 
•
Karolinska Sleepiness Scale (Appendix 10) 
•
Sleep quality and meal time behavior questions  
•
Instruct parent/caregiver on use of diary 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 69 of 194  
•
Record ongoing AEs as medical history 
•
Record ongoing AESIs as medical history 
•
Dispense diary (after above procedures have been concluded) 
•
Dispense study medication 
After enrollment into the study, each subject will be issued a new “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.
6.1.3
Clinic/Phone Visit 2 (Study Day 15) 
Visit 2 is to be performed in the clinic. At the discretion of the investigator, this visit may be
performed via phone. 
If Visit 2 is performed in the clinic, subjects will report to the clinic in the morning of that day. 
Subjects should not take their morning dose(s) of AED medication prior to reporting to the 
clinic. The following procedures will be performed:
•
Review current seizure activity (number/type/duration) from diary since previous visit  
•
Record concomitant medications since previous visit 
•
Abbreviated physical examination, including height and weight, and calculation of BMI 
•
Abbreviated neurological examination
•
Vital signs
•
Laboratory evaluation (serum chemistry, hematology, urinalysis, etc) (only if 
investigator determines new laboratory evaluation is warranted due to change in subject 
status since Visit 1)
•
Collect plasma sample for AED PK evaluation prior to the morning dose of study 
medication(s)
•
Collect and review diary with parent/caregiver
•
Dispense diary
•
Record AEs
•
Record AESI
•
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver
•
Dispense 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: 
•
Concomitant medications
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 70 of 194  
•
AEs
•
AESI
•
Study medication use 
•
Diary entries
6.1.4
Clinic Visits 3-15 (Months, 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33)  
Subjects will report to the clinic in the morning of Clinic Visits 3 through 15. Subjects should 
not take their morning dose(s) of AED prior to reporting to the clinic. The following procedures 
will be performed: 
•
Review current seizure activity (number/type/duration) from diary since previous visit  
•
Record concomitant medications
•
Abbreviated physical examination, including height and weight, and calculation of BMI 
•
Abbreviated neurological examination 
•
Obtain vital signs
•
12-lead ECG
•
Doppler ECHO (at Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33) 
•
Urine pregnancy test for females of child-bearing potential 
•
Laboratory evaluation (serum chemistry and hematology, and urinalysis)
•
Urine THC panel
•
Whole blood CBD 
•
Collect plasma sample for AED PK evaluation prior to the morning dose of study 
medication(s)
•
Tanner Staging for subjects > 7 to ≤18 years of age (Visits 6, 15, and 27 only) 
(Appendix 5) 
•
Collect and review diary with parent/caregiver
•
Dispense diary
•
C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
•
CGI-I (assessed by parent/caregiver)
•
CGI-I (assessed by investigator) 
•
BRIEF (Appendix 3) 
•
QOLCE (Appendix 4) 
•
PedsQL (Appendix 6) (only for subjects from the core studies) 
•
Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
•
Affective symptoms of parent/caregiver using the HADS scale (Appendix 8) (for 
subjects from core studies ZX008-1501 and ZX008-1502 only) 
•
Healthcare utilization questions (for subjects from core study ZX008-1504 only)
•
Karolinska Sleepiness Scale (Appendix 10) (for subjects from core study ZX008-1504 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 71 of 194  
•
Sleep quality and mealtime behavior questions (for subjects from core study ZX008-
1504 only) 
•
Study medication palatability assessment (Visits 3 and 4 only) 
•
Record AEs
•
Record AESI
•
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver
•
Dispense study medication 
6.1.5
Clinic Visit 16 (Month 36): End of Study/Early Termination 
The End-of-Study participation for an individual subject occurs after he/she has received IMP
for 3 years in the OLE Treatment Period or if the subject is transitioning to receive ZX008 in a 
separate extension protocol when available 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 the study 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. 
4. The subject is being transitioned to another extension study or transitioning to 
commercially available drug. 
The following procedures will be performed:
•
Review current seizure activity (number/type/duration) from diary since previous visit  
•
Record concomitant medications
•
Complete physical examination, including height and weight, and calculation of BMI 
•
Complete neurological examination 
•
Obtain vital signs
•
12-lead ECG
•
Doppler ECHO (must be performed any time between Study Day 1064 and Study 
Day 1085; if subject terminates early from the study, the ECHO should be scheduled as 
soon as practical). If the Month 3, 6, 9, 12,1 5, 18, 21, 24, 27, 30, or 33 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 (Table 8).
•
Urine pregnancy test for females of child-bearing potential 
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•
Laboratory evaluation (serum chemistry and hematology, and urinalysis) 
•
Urine THC panel
•
Whole blood CBD 
•
Collect plasma sample for AED PK evaluation prior to the morning dose of study 
medication(s)
•
Tanner Staging for subjects > 7 to ≤18 years of age (Appendix 5) 
•
Collect and review diary with parent/caregiver
•
C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
•
CGI-I (assessed by parent/caregiver)
•
CGI-I (assessed by investigator) 
•
BRIEF (Appendix 3) 
•
QOLCE (Appendix 4) 
•
PedsQL (Appendix 6) (only for subjects from the core studies) 
•
Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
•
Affective symptoms of parent/caregiver using the HADS scale (Appendix 8) (for 
subjects from core studies ZX008-1501 and ZX008-1502 only) 
•
Healthcare utilization questions (for subjects from core study ZX008-1504 only)
•
Karolinska Sleepiness Scale (Appendix 10) (for subjects from core study ZX008-1504 
only) 
•
Sleep quality and mealtime behavior questions (for subjects from core study ZX008-
1504 only) 
•
Record AEs
•
Record AESI
•
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver
•
Dispense study medication (not applicable for subjects transitioning to another 
extension protocol or to commercial drug) 
6.2
POST-DOSE VISIT (CLINIC VISIT 17; STUDY DAY 1099) 
If the subject completes the study (or discontinues from the study early), and is not 
transitioning to another extension protocol or switching to commercially available drug, the 
subject will visit the clinic on Study Day 1099 (or 14 days after the day of discontinuation) 
The following procedures will be performed: 
•
Record AEs
•
Record AESI
•
Record concomitant medications
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•
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver
6.3
CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 18, 19; 3 AND 6 MONTHS) 
AFTER LAST DOSE OF IMP
If the subject completes the study or discontinues from the study early, the subject will return to 
the clinic for follow-up cardiac testing (ECHO, ECG, and in some cases, physical 
examination). The timing and frequency of exams are in Table 8. As the ECHO and ECG will 
be administered 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. 
Cardiac follow-up visits are not required for subjects who have entered another ZX008 
extension study or have transitioned to commercial drug. 
Subjects with positive findings on ECHO, ECG and/or physical examination should continue to 
be followed until the finding is resolved or stable and unlikely to change.  
If the subject is switching to commercially available drug, (subjects must have an ECHO within 
3-6 months before starting commercial 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 post dosing and cardiac follow-up visits are not required. 
Table 8. 
Schedule of Post-Treatment Cardiac Follow-up
Duration of Fenfluramine Treatment
Parameter
Less than 
2 weeks 
Cumulative
2 to 4 weeks
> 4 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 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 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
Yes, 
3 months post- 
treatment only
Yes,
3 and 6 months post-
treatment, and until 
resolved, or stable and 
unlikely to change
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aortic; mild or greater in pulmonary, tricuspid), or sign or symptom indicative of potential pulmonary hypertension as 
adjudicated by the IPCAB.
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6.4
ESTIMATED BLOOD VOLUME COLLECTION
The maximum total blood volume collected during the study for clinical laboratory testing, 
genotyping, and PK will be approximately 240.0 mL, as outlined in Table 9. 
Table 9. 
Estimated Blood Volume Collectiona
OLE Treatment Period (study day)
Assessment/ 
(Study Day)
15
30, 60, 90. 180, 270. 365, 455, 545, 635, 725, 815, 905, 995, 1085
Total 
Clinical chemistry 
--
7.5 mL at each visit
105 mL
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testosterone, GH, prolactin
--
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in Chemistry
Hematology 
--
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28 mL
IGF-1 
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3.5 mL at each visit
49 mL
Cannabidiol
--
2 mL at each visit
28 mL
AED plasma sample
1 x 2 mL
1 x 2 mL at each visit
30 mL
Approximate total blood 
volume per subject 
2.0 mL
17.0 mL at each visit
240.0 mL
FSH=follicle stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; LH-luteinizing hormone
aIn concordance with The Seattle Children’s Research Foundation Guidance (Appendix 9), 
blood collection volumes for children weighing up to 15 kg will be:
•
The maximum allowable volume of blood in one draw is 22-30 mL (2.5% of total blood 
volume) 
•
The maximum in a 30-day period is 44-60 mL 
6.5
STUDY CONDUCT DURING COVD-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 11. 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, which assessments or visits were 
missed or performed via phone or video. 
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Page 75 of 194  
7.
EFFECTIVENESS, 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
EFFECTIVENESS ASSESSMENTS
For all questionnaires and rating scales, the same evaluator (at the clinical site and 
parent/caregiver) will 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 (< 2 minutes, 2-10 minutes, > 10 minutes) will be 
recorded daily by the parent/caregiver in a diary. Seizure types include:
A: 
Hemiclonic (note lateralization – right body, left body, or independent right and left) 
B1: Focal With or Without Clear, Observable Motor Signs 
B2: Focal Without Clear, Observable Motor Signs 
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; also known as ‘drop attack’) 
K:  Infantile Spasms (if under 3 years of age) 
L:  
Epileptic Spasms (if 3 years of age and older) 
O: 
Other
Effectiveness endpoints that will be derived from the diary data include frequency of 
convulsive seizures and of all seizures, and the number/duration of seizure free intervals. 
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Page 76 of 194  
Seizures that evolve into SE will be captured by type and duration (> 10 minutes) as are all
seizures. The diagnosis of SE should be entered as an AE or SAE if a prolonged seizure or 
series of seizures persists for 30 minutes or longer, regardless of administration of rescue 
medication. 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. 
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 Clinical Global Impression (CGI) scale measures the change in the subject’s clinical status 
from a specific point in time. 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 core study (before any study drug was taken). 
The investigator will be asked to indicate the appropriate response that adequately describes 
how the subject’s symptoms have improved or worsened relative to baseline before the 
beginning of the core study (before any study drug was taken). 
7.1.3
Quality of Life in Childhood Epilepsy Scale
The QOLCE (Appendix 4), a low-burden 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 2000; Talarska 2007).  
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Page 77 of 194  
7.1.4
Pediatric Quality of Life Inventory (PedsQL)
The PedsQL (Appendix 6) is a pediatric modular measure of health-related QoL completed by 
the parent/caregiver on behalf of the subject. It consists of 4 core scales that measure physical, 
emotional, social, and school functioning. The PedsQL will be conducted according to the 
schedule in Table 1 and Table 2. The PedsQL will only be conducted in subjects who enter 
from the core studies (ie, PedQL will not be performed on de novo subjects >18 years of age). 
7.1.5
Parent/Caregiver Quality of Life  
The impact on the quality of life of the parent/caregiver responsible for a patient with DS will 
be assessed according to the schedule in Table 1 and Table 2 using 3 scales: the EQ-5D-5L, the 
HADS, and the PedsQL Family Impact Module. Parents/caregivers who do not give consent to 
collect these ratings scales will not complete them. The same parent/caregiver should complete 
these ratings throughout the study. If that person is not available at the visit, the scales should 
not be completed.  
The EQ-5D-5L (Appendix 7) is a standardized measure of health status used to provide a 
simple, generic assessment for clinical and economic appraisal. It consists of 6 questions and 
can be completed in less than 10 minutes.
The HADS (Appendix 8) 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 PedsQL Family Impact module (Appendix 6) is designed to measure the impact of 
pediatric chronic health conditions on parents and the family by measuring parent self-reported 
physical, emotional, social, and cognitive functioning, communication, worry, and family daily 
activities relationships. The PedsQL Family Impact module will not be assessed in the 
Netherlands.
The parent/caregiver will be asked to indicate the appropriate response that adequately 
describes how the care of their child with DS has impacted their quality of life using the scales 
described above.
7.1.6
Study Medication Palatability Assessment 
The palatability and overall acceptability of the IMP will be assessed indirectly by the 
parent/caregiver responsible for the patient according to the schedule in Table 1 and Table 2
using 3 questions: 
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Confidential
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QUESTION 1: Over the past month, on the basis of the reaction ⁄ facial expression of your 
child, do you think that the medicine’s taste and texture are: 
•
Acceptable to your child 
•
Not acceptable to your child 
QUESTION 2: Over the past month, please rate how much your child likes/dislikes the 
medicine’s taste using the following grading scale: 
•
5 (likes it very much) 
•
4 (likes it) 
•
3 (neither likes it or dislikes)
•
2 (dislikes it) 
•
1 (dislikes it very much)
QUESTION 3: Over the past month, do you sometimes have problems giving the medicine to 
your child due to its taste or texture? 
•
No
•
Yes 
o
How often?  

Every day in the past month 

Once to several times every week in the past month

Once or several times in the past month
7.2
EXPLORATORY ASSESSMENTS
The following exploratory assessments will be conducted for subjects who participated in core 
study ZX008-1504 only. 
7.2.1
Sleep Quality and Meal Time Behavior Questions
The parent/caregiver will be asked to indicate the appropriate response that adequately 
describes their child’s sleep quality and eating behavior since starting IMP based on the 
following questions: 
1. Since your child has started taking the study medication in this study, have you noticed that 
s/he has been waking in the middle of the night or very early in the morning more than usual? 
o
My child’s sleep is more disturbed than it was before s/he started the study medication 
o
My child’s sleep patterns are the same as they were before starting the study medication
o
My child sleeps better than s/he did before starting the study medication
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Page 79 of 194  
2. Since your child has started taking the study medication in this study, have you noticed that 
s/he has had a change in their mealtime behavior? 
o
My child has worse meal time behavior since starting the study medication
o
My child’s meal time behavior has not changed since starting the study medication 
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7.2.2
Karolinska Sleepiness Scale
The Karolinska Sleepiness Scale (Appendix 10) will be administered according to the schedule 
in Table 2. The Karolinska Sleepiness scale is a self-report scale that measures the subject’s 
drowsiness. It is a 9-point verbally anchored scale, which ranges from ‘extremely alert’ at one 
end of the scale to ‘extremely sleepy – fighting sleep’ at the other end of the scale. Within this 
study, the scale will be completed by the observer in an exploratory manner.
7.2.3
Healthcare Utilization Questions
In order to better understand the healthcare resource burden associated with the management of 
DS, caregivers will be asked which of the following hospital and community-based healthcare 
services they had interactions with over the preceding month: emergency room services, 
ambulance, planned and unplanned hospitalization, family physician services, speech and 
language therapy, occupational therapy, and physical therapy. This information will be 
captured in the CRF. 
7.3
SAFETY ASSESSMENTS
7.3.1
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 and current medications will be carried over from 
the core study. 
7.3.2
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.  
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Page 80 of 194  
Any unfavorable findings not present at Visit 12 of the core study considered by the 
investigator as clinically significant, occurring at any point in the study will be documented in 
the CRF as an AE. 
7.3.3
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 
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.  
7.3.4
Vital Signs
Vital signs including blood pressure, heart rate, temperature, and respiratory rate will be 
documented for subjects during study as outlined in Table 1 and Table 2. 
7.3.5
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 and 
Table 2, and Table 9: 
•
Hematology: hemoglobin, hematocrit, erythrocytes, erythrocyte mean 
corpuscular volume, leukocytes, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, neutrophils, lymphocytes, monocytes, 
eosinophils, basophils and platelets 
•
Blood Biochemistry: albumin (ALB), alkaline phosphatase (AP), alanine 
aminotransferase (ALT; SGPT), aspartate aminotransferase (AST; SGOT), 
bicarbonate, blood urea nitrogen (BUN), calcium (Ca), chloride (Cl), creatinine, 
creatine kinase, gamma-glutamyl transferase (GGT), globulin, glucose, lactate 
dehydrogenase (LDH), phosphorus, potassium (K), sodium (Na), thyroid 
function (T3, T4, and 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 
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Page 81 of 194  
•
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. 
•
Urine pregnancy test: Urine pregnancy testing will be performed in female 
subjects of childbearing potential. 
•
Urine THC panel
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, the investigator must 
sign and date the laboratory report.  
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.
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 will be 
documented in the CRF as an AE (Section 9).
7.3.6
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. 
7.3.7
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. 
7.3.8
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 
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guidelines on the proper evaluation of certain measurements, as well as abnormality thresholds, 
were constructed by the Sponsor’s IPCAB prior to study initiation. These thresholds are 
provided in Table 10 (Adverse Events of Special Interest). A manual of proper ECHO 
technique for sites is provided in a separate document. 
7.3.9
Tanner Staging
Tanner Staging (Appendix 5) will be assessed for subjects >7 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’.  
7.3.10
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. 
The C-SSRS version 6/23/10 (Children’s Since Last Visit) will be used in this study as 
appropriate for the age and level of intellectual development.
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.
If a subject with the intellectual capacity to complete the C-SSRS has their 7th birthday during 
the study, use of the C-SSRS should be initiated at subsequent visits. 
7.3.11
Adverse Events
For de novo subjects, adverse events 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. For 
subjects who participated in one of the core studies, adverse events that occur after signing 
informed consent for this study, but before Visit 1 will be recorded as adverse events in the 
core study and medical history in ZX008-1503. 
Details of the definitions and categorization of AEs, and procedures for the reporting of AEs, 
are available in Section 8. 
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Page 83 of 194  
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. All AEs will be 
recorded on the appropriate CRF page.  
7.3.12
Behavior Rating Inventory of Executive Function (BRIEF) 
The BRIEF is a standardized, validated rating scale to measure executive function. 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 assessed according to the schedule in Table 1 and 
Table 2. The BRIEF measures multiple aspects of executive functioning; scales include Inhibit 
(control impulses; stop behavior), Shift (move freely from one activity/situation to another; 
transition; problem-solving flexibility), Emotional Control (modulate emotional responses 
appropriately), Initiate (begin activity; generate ideas), Working Memory (hold information in 
mind for purpose of completing task), Plan/Organize/Organization of Materials (anticipate 
future events; set goals; develop steps; grasp main ideas), and Monitor (check work; assess own 
performance). 
7.4
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. For de novo subjects, the 
period of observation for adverse events extends from the time the subject gives informed 
consent until the end of study. For subjects who participated in one of the core studies, the 
period of observation for adverse events extends from Visit 1 of ZX008-1503 until the end of 
study. Adverse events that occur after signing informed consent for this study, but before 
Visit 1 will be recorded as adverse events in the core study and medical history in ZX008-1503. 
Adverse events may include: 
•
Illness present before core study entry should be recorded in the medical history 
section of the CRF along with any ongoing AEs that were present at Visit 13 of the 
core study. These events should only be reported as an AE if there is an increase in 
the frequency or severity of the condition from the core study  
•
Exacerbation of seizures is considered an AE if there was an increase in frequency 
beyond the subject's typical pre-core study fluctuations, or in the event that seizures 
lengthen in duration in a clinically meaningful way compared with core study 
baseline, or if a new seizure type emerges  
•
A clinical event occurring after consent but before IMP administration
•
Intercurrent illnesses with an onset after administration of IMP
Adverse events do not include: 
•
Medical or surgical procedures (the condition that leads to the procedure is the AE, 
eg, tonsillitis is the AE if a tonsillectomy is performed) 
•
Situations where an untoward medical occurrence has not taken place. For example:
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 85 of 194  
o
Hospitalizations that occur for procedures not due to an AE (eg, cosmetic 
surgery) 
o
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 CRF as AEs. In addition, at the investigator’s 
discretion, any changes or trends over time in laboratory parameters can be recorded in the 
CRF 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: 
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 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 86 of 194  
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, for cases in which, had 
there not been intervention, one of the other SAE outcomes would have likely 
occurred. For example, anaphylaxis successfully treated with an epinephrine injection 
would be a medically important event.
•
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 SE. A single episode of SE in a 24-
hour period, regardless of whether rescue medication was administered, should be 
entered in the AE log as well as in the seizure diary. If two or more episodes occur 
within 24 hours, each lasting 30 minutes or more, an SAE of SE should be recorded. 
Hospitalization to manage SE, regardless of the number of episodes, should be 
reported as an SAE.
Adverse events that do not fall into the above categories are defined as non-serious 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 10). 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 87 of 194  
Table 10. 
Adverse Events of Special Interest
Metabolic/Endocrine
1.
Elevated prolactin level ≥2x above the upper limit of normal (ULN)
2.
Hypoglycemia – serum blood glucose more than 20% below the glucose level on Study Day -1 value or
more than 10% below LLN (reference range 60 – 140 mg/dL)
Neuropsychiatric
1.
Suicidal thoughts, ideation or gestures
LLN = lower limit of normal; ULN = upper limit of normal
8.1.4
Adverse Events Requiring Hospitalization
If a subject is treated in a medical facility (hospital, emergency room, free-standing clinic) 
related to the occurrence of any AE, the following data will be collected to model health care 
utilization in patients with DS: AE/reason for hospitalization/clinic visit; duration of the visit in 
hours/days; admission to intensive care unit; and name/number of procedures performed, 
including but not limited to, electroencephalogram, ECG, ECHO, positive emission 
tomography (PET) scan, magnetic resonance imaging (MRI), x-ray, computed tomography 
(CT) scan, surgery, and lumbar puncture/spinal tap. 
8.2
SEVERITY OF ADVERSE EVENTS
The severity of AEs (whether non-serious or serious AEs) is to be assessed by the investigator 
as follows (Table 11 ).
Table 11.  
Severity Definition of Adverse Eventsa
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.
a
Clinical Data Interchange Standards Consortium Study Data Tabulation Model Severity Intensity Scale for 
Adverse Event Terminology
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 88 of 194  
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: 
•
Known pharmacology of ZX008 
•
Clinically and/or pathophysiologically plausible context 
•
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) 
•
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:
1. Not Related: 
Concomitant illness, accident or event with no reasonable association with 
study drug. 
2. 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 for de novo subjects will start at the time 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 participated in 
one of the core studies, the observation period for adverse events will start at Visit 1 of 1503 
and finish 15 days after the last dose of study drug or the last visit, whichever is later. Ongoing 
AEs from the core studies will be considered medical history unless there is an increase in the 
frequency or severity of the condition from the core study. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 89 of 194  
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 CRF. 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 CRF. 
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 Medical Monitor or the Sponsor of the SAE via email or telephone 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 Inventive Health Care 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 for de novo subjects and at Visit 1 for subjects from the core studies, whether or 
not causally related to IMP must be reported immediately via telephone or email (within
24 hours of the investigator becoming aware of the event) to the Sponsor or the Medical 
Monitor.  
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 90 of 194  
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 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 and the 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 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 
CRF.
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.  
When submitting SAE reports to the Sponsor, subjects should be identified only by their
subject number and study number. The investigator should not include the subject’s name and 
address.
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 91 of 194  
SAE Update reports can be submitted to the Sponsor any time that additional relevant 
information becomes available. In cases of death, the investigator should supply the Sponsor 
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’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 
safety report (eg, MedWatch/CIOMS form) completed by the Sponsor 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’s Global Clinical Safety and 
Pharmacovigilance and the Medical Monitor. In the event of a SAE, a blood sample for ZX008 
and AED PK should be collected as soon as feasible. 
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 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 92 of 194  
condition has resolved or stabilized where no further changes are likely, for a minimum of 
6 months from the last dose of study medication. 
8.9.1
 Follow-up of Echocardiogram Findings  
All ECHOs will be evaluated by a central reader from BioMedical Systems, Inc. (BMS), in 
consultation with the IPCAB, 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 Levels 1-3. Table 12 describes the severity of ECHO findings with the level 
of increasing oversight if the subject is to remain in the study. 
Table 12. 
Clinical Measures Enacted Upon Increasing Severity of ECHO Findings
Severity
Valve
Aortic
Mitral
Pulmonary
Tricuspid
Trace 
Level 1
Level 1
Level 1
Level 1
Mild (≤18 years)
Level 2
Level 1
Level 1
Level 1
Mild (>18 years)
Level 2
Level 1
Level 1
Level 1
Moderate
Level 3
Level 2
Level 2
Level 2
Severe
Level 3
Level 3
Level 3
Level 3
Level 1: Continue per protocol 
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, VPA, CLB, 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 risk and the subject should 
provide assent if appropriate. 
a.
If both of these conditions are not met, the subject is discontinued from 
treatment.
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 93 of 194  
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 Co-Chairs of the IPCAB are alerted to the request and prepare, after consultation 
with BMS, an evaluation of the cardiopulmonary risk and proposed monitoring plan if 
applicable, for submission to the IDSMC.
5. IDSMC will review the submission from the Investigator and the IPCAB and unblind the 
subject’s core study 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 convulsive 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, VPA, CLB, 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 risks, 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 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 DS. 
4. The Co-Chairs of the IPCAB are alerted to the request, and in consultation with BMS 
prepare an evaluation of the risks and proposed monitoring plan if applicable for 
submission to the IDSMC.
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 94 of 194  
5. IDSMC will review the submission from the Investigator and the IPCAB and unblind 
the subject’s core study 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 
d. Reduce the dose of study medication 
8.10
PREGNANCY
This study is open to female and male subjects. Whenever possible, a pregnancy in a female 
subject 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 using a pregnancy 
reporting/outcome form.  
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 95 of 194  
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.  
A CRF 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 CRF via a secure internet connection. The 
investigator is responsible for ensuring accurate and proper completion of the CRF and subject 
diary for recording data according to the instructions given in the CRF and subject diary.  
All entries in the CRF 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 (Section 12.8). 
Source data must be completed legibly for each subject enrolled into the study and signed by 
the investigator (or delegate).  
Data entry in the CRF 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 CRFs 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 21 Code of Federal Regulations 
(CFR) Part 11 compliant. All creation, modification or deletion of electronic study records will 
be documented through an automated Audit Trail. Following completion of CRF 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).
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 96 of 194  
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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ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 97 of 194  
10.
STATISTICS
10.1
DETERMINATION OF SAMPLE SIZE
The sample size will be determined by the number of subjects who participate in 1 of 3 core 
studies (Study ZX008-1501, Study ZX008-1502, or Study ZX008-1504) and who volunteer for 
the extension study and meet the necessary criteria for enrollment. Approximately 100-120 
subjects are expected to participate in each of the core studies; thus, if all participants also 
enroll in the extension, the total sample size of the extension study would be approximately 340. 
10.2
ANALYSIS POPULATIONS
10.2.1
Safety (SAF) Population 
Safety analyses will be performed on the Safety (SAF) Population defined as all subjects who 
receive at least one dose of ZX008 during the open label extension. 
10.2.2
Modified Intent-to-Treat (mITT) Population 
The modified Intent-to-Treat (mITT) Population is defined as all subjects who receive at least 
one dose of ZX008 and have valid seizure data during the open label extension. Effectiveness 
analyses, such as evaluating the change in the frequency of convulsive seizures, will be 
performed on the mITT Population. 
10.2.3
Per Protocol (PP) Population  
The Per Protocol (PP) Population is defined as all subjects who receive at least one dose of 
ZX008, complete the entire OLE Treatment Period of the open label extension, and have no 
major protocol deviations that would have a significant impact on clinical outcome. Key 
effectiveness analyses will be repeated on the PP Population in addition to the mITT 
Population. 
10.3
TREATMENT GROUPS
All subjects will receive ZX008 and will be considered a single treatment group.
10.4
TREATMENT PERIODS
Pre-ZX008 Baseline Period 
For subjects who receive ZX008 in Study ZX008-1501, Study ZX008-1502, or Study 
ZX008-1504 Cohort 2, the pre-ZX008 baseline period is equivalent to the core study pre-
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34


Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 98 of 194  
randomization baseline period, ie, the approximately 42-day span just prior to randomization 
and start of treatment in the core study.  
For subjects who receive placebo in Study ZX008-1501, Study ZX008-1502, or Study 
ZX008-1504 Cohort 2, the pre-ZX008 baseline period begins with the core study pre-
randomization baseline period and extends through the entire span of the core study up to the 
transition period. The pre-ZX008 baseline period for a subject ends when that subject receives 
their first treatment with ZX008.
Study ZX008-1504 Cohort 1 have a shortened (exploratory) baseline period of approximately 
12 days (after the single-dose PK assessment) and this will be used in an exploratory manner. 
For de novo subjects, the pre-ZX008 baseline period is the screening period of up to 28 days 
prior to receiving the first dose. 
The baseline frequency of convulsive seizures will be calculated from data collected during the 
entire length of the pre-ZX008 baseline period. 
Open-Label Extension Treatment Period 
The OLE Treatment Period covers the 36 months during which subjects will receive open label 
treatment with ZX008.
Post-dosing Period 
The Post-dosing Period begins immediately at the end of OLE Treatment Period and extends 
for 2 weeks.
After at least 1 year of treatment in Study 1503 subjects who participated in one of the core 
studies will transition to a separate extension study (Study 1900) once that study is approved 
and the study site is initiated. Continuation in a separate extension protocol will be based on 
benefit/risk and continued eligibility criteria being met. De novo subjects must have 
participated in this trial for at least 3 months with at least 1 ECHO completed and continue to 
meet eligibility requirements to be eligible to transition to a separate extension protocol. 
Alternatively, subjects will transition to commercial product once it is available if they have 
had an ECHO within 3-6 months before starting commercial drug. For subjects who are 
entering the separate extension trial or who transition to commercially available drug, post-
dosing and cardiac safety follow-up visits are not required in this trial. Subjects who transition 
to commercially available drug will have follow-up ECHOs within the required timeframe 
while on commercial drug.  
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 99 of 194  
10.5
STATISTICAL ANALYSES AND METHODS
All safety, effectiveness and exploratory data will be summarized. 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 statistical 
analysis plan (SAP), which will be finalized before the database is locked.
10.5.1
Safety Analyses 
Adverse events will be monitored throughout each core study and the open label extension. 
Adverse events will be considered to be treatment emergent (TEAE) if they begin between the 
first day of treatment with ZX008 and the last day of the Post-dosing period or occur prior to 
first ZX008 treatment but increase in severity after ZX008 treatment begins.
The number and percentage of subjects in each treatment group with TEAEs will be displayed 
by body system and preferred term using the Medical Dictionary for Regulatory Activities 
(MedDRA). A table will enumerate the TEAEs that occur in at least 5% of subjects. A separate 
summary will be provided for all serious AEs (SAEs). Selected summaries will be repeated 
broken out by age group, ie, for ages < 6 years and ≥ 6 years.
Hematology and chemistry laboratory results will be summarized using shift tables that tabulate 
the proportion of subjects who have lab results that change from pre-ZX008 baseline, where 
pre-ZX008 baseline values will be determined from lab results obtained prior to first treatment 
with ZX008. The shift tables will be presented for each time point where lab results are 
collected. Mean change from pre-ZX008 baseline will also be calculated for continuous 
hematology and chemistry results at all time points available.
Physical examinations, vital signs, ECG, ECHO and body weight will be summarized 
appropriately. All safety summaries will be based on the SAF Population.  
10.5.2
Effectiveness Analyses 
10.5.2.1
Key Effectiveness Analysis
The key effectiveness endpoint is the change in the convulsive seizure frequency per 28 days 
between the pre-ZX008 Baseline and OLE Treatment Period. The frequency of convulsive 
seizures during a given period will be derived from the number and type of events recorded in 
subject diaries. The seizure frequency 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 convulsive 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 100 of 194  
seizure frequency will be calculated from all available data collected during either the 
pre-ZX008 Baseline or OLE Treatment Periods.  
Both the mean and median frequency of convulsive seizures will be presented for the 
pre-ZX008 Baseline Period and the OLE Treatment Period. The significance of the change 
between periods will be assessed using an analysis of covariance (ANCOVA) model with age 
group (< 6 years, ≥ 6 years) as a factor and with pre-ZX008 baseline frequency as a covariate. 
Other factors may be included in the model if they are found to be informative during analyses 
of the core studies. 
Since the ANCOVA relies on assumptions of normality, the key effectiveness endpoint will 
also be analyzed using a nonparametric method that does not require as stringent assumptions. 
A test such as the stratified Wilcoxon signed rank test will be used to assess the change from 
baseline while stratifying by age group. 
An additional analysis will be performed to assess the sensitivity of the key effectiveness 
analysis to changes in dose or type of concomitant AED medications that may occur during the 
course of the trial. Specifically, the analysis will be repeated with a factor added to the model to 
indicate whether a subject had a change in prescribed dose or type of concomitant AED 
medication during the OLE Treatment Period. Further exploratory analyses may be conducted 
if changes in concomitant AED medication appear to have a significant impact on the 
effectiveness of ZX008. 
Only subjects from Studies ZX008-1501, ZX008-1502, and Cohort 2 of ZX008-1504 will be 
included in change from baseline analyses of effectiveness. Subjects from Study ZX008-1504 
Cohort 1 will be excluded from such analyses since they will enter the OLE Treatment Period 
without first participating in a baseline period that includes a formal assessment of pre-ZX008 
seizure frequency.
10.5.2.2
Other Secondary Analyses
Methods similar to those used for the key effectiveness analysis will also be used to assess the 
change in frequency of non-convulsive seizures and the composite endpoint of non-convulsive 
plus convulsive seizures. The proportion of subjects who achieve a ≥40% reduction from 
baseline in convulsive seizure frequency, along with its 95% CI, will be reported. A similar 
summary will be reported for the proportion of subjects who achieve a ≥50% reduction from 
baseline. The analyses will be performed using data collected over the open label OLE 
Treatment Period. 
The longest interval between convulsive seizures will be calculated for each subject over the 
entire OLE Treatment Period. The median interval will be presented. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 101 of 194  
Palatability will be assessed through descriptive statistical methods. For example, the 
percentage of parents or caregivers who consider the medicine’s taste and texture to be 
acceptable to the subject will be presented along with a 95% CI at each time point data are 
available.
QoL measures will be summarized by descriptive statistic for each time point where they are 
obtained. Where appropriate, the significance of the change from baseline will be assessed 
using mixed effects models for repeated measures.
10.6
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 (neurology, cardiology, pediatrics, and statistics). The IDSMC 
members may request assistance from a number of additional and hoc members if needed.
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 102 of 194  
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 
protected, 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 a public database at (eg, 
ClinicalTrials.gov) in accordance with the local country requirements. 
Before undergoing screening 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. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 103 of 194  
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 CRF. 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 
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 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 104 of 194  
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 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 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 105 of 194  
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: 
•
The Sponsor (delegate) for agreement
•
The IEC/IRB for review and approval or favorable opinion (if required) 
•
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 CRF and/or in the Protocol Deviation Log, if applicable. 
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ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 106 of 194  
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 
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 (eg, 
ClinicalTrials.gov) before or at commencement of the study, as required by local country 
requirements. 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 public databases (eg, 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 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 107 of 194  
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 
visit the study site to ensure adequacy of the facilities and to 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 
formal meeting has been conducted by the Sponsor’s study monitor (or delegate) to initiate the 
study (study initiation visit). This meeting will include an inventory of study supplies and a 
detailed review of the study protocol and procedures, the CRF, IMP accountability, and the 
subject diary. 
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).
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 108 of 194  
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 CRFs, 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 CRF 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), 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).
12.9
MONITORING OF THE STUDY
The investigator at each site will allow the Sponsor’s study monitor (or delegate) reasonable 
access to the CRFs 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 CRF, such as past history and secondary 
diagnoses. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 109 of 194  
Before each monitoring visit, the investigator (or delegate) should record all data generated 
since the last monitoring visit in the CRF. 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: 
•
Resolution of any problems 
•
Examination of all study documentation for completion, adherence to the study 
protocol, and possible AEs
•
Clarification of inconsistencies or missing data
•
Verification of study data against source documents 
•
Checks that investigator obligations have been fulfilled 
•
Review of ICFs and dates of consent 
•
Inspection of IMP with respect to storage, labeling, and documentation 
•
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 CRF correctly and in a timely manner, after which the investigator 
will sign the CRF.
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 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 110 of 194  
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 
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. 
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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 
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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13.
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Zoghbi WA, Adams D, Bonow RO, Enriquez-Sarano M, Foster E, Grayburn PA, et al.
Recommendations for noninvasive evaluation of native valvular regurgitation: a 
report from the American Society of Echocardiography developed in collaboration 
with the Society for Cardiovascular Magnetic Resonance. J Am Soc Echocardiogr. 
2017;30(4):303-71. 
ZX008 Investigator’s Brochure Version 8. 
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14.
APPENDICES
14.1
APPENDIX 1 – LIST OF PROHIBITED CONCOMITANT MEDICATIONS 
alfentanil
mexiletine
almotriptan
naratriptan
alprenolol
nefazodone
amitriptyline
nortriptyline
amphetamine
ondansetron
astemizole
oxcarbazepine
atomoxetine
oxycodone
bufuralol
paroxetine
bupropion
perphenazine
buspirone
phenacetin
cafergot
phenobarbital
cannabidiol
phenytoin
carbamazepine
promethazine
cerivastatin
propafenone
citalopram
retigabine/ezogabine
clomipramine
risperidone
codeine
ritonavir
cyproheptadine
rizatriptan
desipramine
selegiline
dextromethorphan
sertraline
duloxetine
sumatriptan
eletriptan
telaprevir
encainide
thc and derivatives
ergotamine tartrate
tramadol
eslicarbazepine
trazodone
felbamate
vortioxetine
fentanyl
zolmitriptan
fluoxetine
zuclopenthixol
fluvoxamine
frovatriptan
imipramine
levacetylmethadol (laam)
linezolid
meperidine
methadone
metoclopramide
PUBLIC 
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va
v
thereof. 


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14.2
 APPENDIX 2 – COLUMBIA – SUICIDE SEVERITY RATING SCALE
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14.3
APPENDIX 3 – BEHAVIOR RATING INVENTORY OF EXECUTIVE 
FUNCTION – PRESCHOOL VERSION
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th
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14.4
APPENDIX 4 – QUALITY OF LIFE IN CHILDHOOD EPILEPSY SCALE
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g 
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s 
variations thereof. 
t


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PY
PY 
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ny
ny 
ing 
marketin
rization 
authoriz
application and any extensions or variations 
ria
riations
. 
thereof.


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PUB
UB
UBLIC COPY 
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14.5
APPENDIX 5 – TANNER STAGING
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14.6
APPENDIX 6 – PEDSQL
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14.7
APPENDIX 7 – EQ-5D-5L QUESTIONNAIRE
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14.8
APPENDIX 8 – HOSPITAL ANXIETY AND DEPRESSION SCALE
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14.9
APPENDIX 9 – MAXIMUM ALLOWABLE BLOOD DRAW VOLUMES
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14.10
APPENDIX 10 – KAROLINSKA SLEEPINESS SCALE
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14.11
APPENDIX 11 - 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.  
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:
Visit 1 should be conducted in person. For Visits 2 through 15, 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). 
•
Date and time of the telephone/video visit
•
Any changes in health status 
•
AEs/SAE assessment
•
Concomitant medication query
•
Review seizure and medication diary with parent/caregiver for compliance and any 
abnormalities in seizure activity
•
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 167 of 194  
o
Tanner Staging 
3. End-of-Study/Early Termination (EOS/ET) and Follow-up Visits:  
Cardiac follow-up visits must be conducted in-person. 
EOS/ET for subjects tapering off ZX008: 
For the EOS/ET visit (Visit 16) and Post-Dosing Follow-up visit (Visits 17-19), 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, these visits will be considered as missed.
EOS/ET for subjects transitioning to Commercial drug: 
For the EOS/ET visit (Visit 16) and Post-Dosing Follow-up visit (Visit 17), 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. Subjects who transition to 
commercially available drug must have an ECHO within 3-6 months before starting commercial 
drug and will have follow-up ECHOs within the required timeframe while on commercial drug.
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 ins 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:
•
Date and time of the telephone/video visit
•
Any changes in health status  
•
AEs/SAE assessment
•
Concomitant medication query
•
Review seizure and medication diary with parent/caregiver for compliance and any 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 168 of 194  
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 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 report of drug effectiveness, 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 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 subject’s need for travel. If the ECHO cannot be 
performed, a 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, this 
assessment does not need to be repeated at the Cardiac Follow-up Visit provided there were no 
findings meeting Level 2 criteria (see Protocol Table 12) that require additional follow-up. 
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. If not conducted at the study site, results should be sent to 
the Principal Investigator for safety overread and documentation. If Level 2 or greater findings were 
observed, then the Cardiac Follow-up Visit should be re-scheduled from the date of the delayed 
ECHO.
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 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 169 of 194  
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, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 170 of 194  
SUMMARY OF PROTOCOL AMENDMENT 5.0 
Clarifications and changes were made to the protocol amendment 5.0 to include study conduct 
information for the COVID-19 pandemic, updated background information related to existing 
treatments for Dravet and additional clinical and pre-clinical study data made available in the 
updated ZX008 IB. 
List of Specific Changes
Additions are marked by underlined font and deletions are marked in strikethrough. Minor 
editorial and non-substantive 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. Note that the list of specific changes below is 
presented in the order in which they appear in the protocol. 
1. Zogenix Address Change: 
Title Page and Signature Page: 
2.  Addition of the following text regarding transition of subjects to a separate ZX008 
extension protocol or to commercial drug.  
Study Synopsis: 
Table 1: Schedule of Assessments for Subjects from Core Studies ZX008-1501 and 
ZX008-1502, and de Novo Subjects and Table 2: Schedule of Assessments for Subjects in 
Core Study ZX008-1504 
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LIC 
C
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COPY 
This document cannot be used to upp
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tion 
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ns 
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Section 3.1: Overall Study Design and Plan 
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OPY 
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ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
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rt
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ariations 
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Section 10.4: Treatment Periods 
3. Update to include Japan in list of participating centers
LIC 
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Confidential
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4.  Updated background information related to existing treatments for Dravet and additional 
clinical and pre-clinical study data made available in the updated ZX008 IB. 
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5.
Updates to the data available for Risk-Benefit Section 1.8 
6.  Reference to ZX008 IB 2016 updated to ZX008 IB. 
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7.  Provides study conduct information during the COVID-19 Pandemic 
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Confidential
Page 194 of 194  
8. Table 11 updated to Table 12. Table was amended to reflect the latest safety database, 
contained in the NDA and MAA and updated in the 120-day Safety update, the lack of 
appearance of valvular heart disease or PAH in any subject supports the removal of 
IDSMC oversight of mild mitral regurgitation in children. It further supports utilization of 
the Level 2 review for moderate mitral, pulmonic and tricuspid regurgitation in the 
absence of any indicators of PAH. 
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SAP_001.pdf: 
DocuSign Envelope ID:
STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
Zogenix International Limited
A subsidiary of Zogenix, Inc. 
5959 Horton Street, 
 
Emeryville, CA 94608 USA
An Open-Label Extension Trial to Assess the Long-Term Safety of 
ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive 
Therapy in Children and Young Adults with Dravet Syndrome
Protocol No: ZX008-1503 
Dated: 2 February 2018
Prepared by:
Syneos Health Clinical
This document contains confidential information of Zogenix International Limited. Any viewing or disclosure 
of such information that is not authorized in writing by Zogenix International Limited is strictly prohibited.
Such information may be used solely for the purpose of reviewing or performing this study.
STATISTICAL ANALYSIS PLAN
PUBLIC COPY 
l
C
l No:
COP
No: Z
P
Z
ed: 2 F
C CO
ed: 2 F
This document cannot be used to support any marketing authorization 
me
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STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 2 of 76
v3.0
04Aug2020
SIGNATURE PAGE
Zogenix International Limited
A subsidiary of Zogenix, Inc. 
5959 Horton Street, 
 
Emeryville, CA 94608 USA
An Open-Label Extension Trial to Assess the Long-Term Safety of 
ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive 
Therapy in Children and Young Adults with Dravet Syndrome
Protocol No: ZX008-1503
STATISTICAL ANALYSIS PLAN
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Approvals
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STATISTICAL ANALYSIS PLAN
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ZX008-1503
CONFIDENTIAL
Page 5 of 76
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REVISION HISTORY
Date
Revision
Initials
January 16, 2017
V0.1 based on 13 September 2016 version (Protocol 
Amendment 1.2.1 (ROW)
RS/GAS
February 21, 2018
V1.0 Based on Amendment 3
GAS
April 6, 2018
V1.1; signatures; prior to database lock for interim
GAS
July 15, 2018
V1.2; updated to include data cutoff dates, TOC for interim;
other edits
GAS
February 11, 2019
V2.0 Based on Amendment 4
GAS
April 1, 2019
V2.1 Updated TOC for TFLs to correct items missed in
previous version; updated Tables 7a-7d
GAS
July 14, 2020
V2.2: Updated to include TOC for Japan sites
MLW
July 30, 2020
Version 3.0 Signed for Japan Interim Analysis
MLW
August 4, 2020
Signoff
MLW
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dated
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ZX008-1503
CONFIDENTIAL
Page 6 of 76
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TABLE OF CONTENTS
Page
Approvals....................................................................................................................................... iii
1.
INTRODUCTION...........................................................................................................................11
2.
STUDY OBJECTIVES....................................................................................................................12
2.1
Primary Objective ..........................................................................................................................12
2.2
Secondary Objectives.....................................................................................................................12
2.3
Exploratory Objectives...................................................................................................................13
3.
STUDY DESIGN ............................................................................................................................14
3.1
Overall Study Design and Plan.......................................................................................................14
3.2
Treatments......................................................................................................................................14
3.3
Treatment Periods ..........................................................................................................................16
3.3.1
OLE Treatment Period .......................................................................................................16
3.3.2
Taper Period.......................................................................................................................16
3.4
Randomization and Blinding..........................................................................................................18
4.
SCHEDULE OF ASSESSMENTS..................................................................................................19
5.
ANALYSIS POPULATIONS..........................................................................................................23
5.1
Enrolled Population........................................................................................................................23
5.2
Safety (SAF) Population.................................................................................................................23
5.3
Modified Intent-To-Treat (mITT) Population ................................................................................23
6.
STATISTICAL METHODOLOGY ................................................................................................23
6.1
Statistical and Analytical Issues .....................................................................................................23
6.1.1
Statistical Methods.............................................................................................................23
6.1.2
Multiplicity Issues..............................................................................................................24
6.1.3
Subgroups...........................................................................................................................24
6.1.4
Definitions..........................................................................................................................24
6.1.5
Other Definitions................................................................................................................25
6.1.6
Visit Windows and Period Start/Stop Dates.......................................................................25
6.1.7
Handling of Dropouts and Missing Data ............................................................................30
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6.1.8
Conversion of time interval ................................................................................................31
6.1.9
Pooling of Investigative Sites.............................................................................................32
6.1.10
Determination of Sample Size........................................................................................32
6.2
Subject Characteristics ...................................................................................................................32
6.2.1
Subject Disposition.............................................................................................................32
6.2.2
Protocol Deviations............................................................................................................32
6.2.3
Background and Demographic Characteristics...................................................................33
6.2.4
Treatment Exposure and Compliance.................................................................................33
6.2.5
Prior and Concomitant Medications and/or Therapies (Non-medications).........................34
6.2.6
Prior and Concomitant Antiepileptic Treatment.................................................................35
6.2.7
Medical History..................................................................................................................36
6.3
Effectiveness Analyses...................................................................................................................36
6.3.1
Convulsive Seizure Frequency ...........................................................................................36
6.3.2
Other Effectiveness Analyses – Seizure Related ................................................................40
6.3.3
Other Effectiveness Analyses.............................................................................................44
6.3.4
Exploratory Analysis (in subjects from core study ZX008-1504 only) ..............................50
6.4
Safety Analysis...............................................................................................................................51
6.4.1
Adverse Events...................................................................................................................51
6.4.2
Adverse Events of Special Interest (AESI).........................................................................53
6.4.3
Physical Examination.........................................................................................................53
6.4.4
Neurological Examination..................................................................................................54
6.4.5
Vital Signs, Weight, and BMI ............................................................................................54
6.4.6
Electrocardiogram ..............................................................................................................54
6.4.7
Doppler Echocardiography.................................................................................................54
6.4.8
Tanner Staging ...................................................................................................................55
6.4.9
Laboratory Parameters........................................................................................................55
6.4.10
Columbia-Suicide Severity Rating Scale........................................................................56
6.4.11
Brief Rating Inventory of Executive Function (BRIEF, BRIEF-P, BRIEF-A)...............57
6.5
PK/PD Analysis .............................................................................................................................58
6.6
Analysis of Other Assessments ......................................................................................................58
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6.7
Interim Analysis.............................................................................................................................58
6.8
Independent Data and Safety Monitoring Committee ....................................................................59
6.9
International Pediatric Cardiac Advisory Board (IPCAB)..............................................................59
6.10
Changes to Methods Planned in the Protocol .............................................................................59
7.
REFERENCES................................................................................................................................59
8.
APPENDICES.................................................................................................................................61
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CONFIDENTIAL
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
ABBREVATION
DEFINITION
AE
Adverse Event
AED
Antiepileptic Drug
AESI
Adverse Event of Special Interest
ANCOVA
Analysis of Covariance
ATC
Anatomical Therapeutic Chemical
BID
bis in die; two times per day
BMI
Body Mass Index
BRIEF
Behavior Rating Inventory for Executive Function
C-SSRS
Columbia-Suicide Severity Rating Scale
CBD
Cannabidiol
CDISC
Clinical Data Interchange Standards Consortium
CGI
Clinical Global Impression
DS
Dravet syndrome
ECG
Electrocardiogram
ECHO
Echocardiogram
eCRF
electronic Case Report Form
EOS
End of study
EPAR
European Public Assessment Report
EQ-5D-5L
Standardized measure of health status
ET
Early Termination
FAS
Full Analysis Set
HADS
Hospital Anxiety and Depression Scale
HR
Heart Rate
IDSMC
Independent Data and Safety Monitoring Committee
IMP
Investigational Medicinal Product
IPCAB
International Pediatric Cardiology Advisory Board
IR
Incidence rate
IVR
Interactive Voice Randomization
IWR
Interactive Web Response (System)
Kg
Kilogram
Kg/ m2
Kilogram per meter square
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
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ZX008-1503
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ABBREVATION
DEFINITION
mL
Milliliter
MMRM
Mixed Effects Model for Repeated Measures
msec
Millisecond
OLE
Open Label Extension
OLED1
Open label Extension Day 1
PA
Protocol Amendment
PedsQL
Pediatric Quality of Life Inventory
PD
Pharmacodynamics
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
SDTM
Study Data Tabulation Model
SMEI
Severe Myoclonic Epilepsy Of Infancy
SOC
System Organ Class
T+M
Titration plus Maintenance Periods
TEAE
Treatment Emergent Adverse Event
THC
Tetrahydrocannabinol
TSH
Thyroid Stimulating Hormone
WHO-DD
World Health Organization Drug Dictionary
ZX008
Fenfluramine Hydrochloride Oral Solution
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ZX008-1503
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1. INTRODUCTION
ZX008 (fenfluramine hydrochloride) is under clinical development for the adjunctive treatment of patients 
with Dravet syndrome (DS). DS, also known as severe myoclonic epilepsy of infancy (SMEI), is a rare and 
severe form of epilepsy first described by Charlotte Dravet in 1978 (Dravet 1978). The condition most 
commonly appears during the first year of life as frequent febrile seizures. As the condition progresses, other 
types of seizures typically occur, including myoclonic seizures and status epilepticus (Dravet 1978). Following 
the appearance of these seizures, affected children develop several co-morbid conditions including 
psychomotor regression, ataxia, sleep disturbance, and cognitive impairment. Intellectual impairment begins to 
become apparent around age 2 years due to lack of intellectual/behavioral progression. Dravet children often 
have a lack of coordination, poor development of language, hyperactivity, and difficulty relating to others 
(Dravet 1978; Hurst 1990). DS is a highly treatment-resistant and refractory epilepsy syndrome. To date, only 
one treatment, Diacomit® (stiripentol) is approved, and only in Europe, as adjunctive therapy in patients with 
severe myoclonic epilepsy in infancy (SMEI, Dravet syndrome), and must be co-administered with clobazam 
and valproate.
Zogenix is developing a new formulation of fenfluramine hydrochloride, ZX008, for the adjunctive treatment 
of DS. Studies ZX008-1501 and 1502 are two randomized controlled trials of two fixed doses of ZX008 
(Fenfluramine HCl) as an adjunctive therapy in children and young adults with DS. Study 1501 is conducted in 
North America (Canada and the USA), and 1502 is being conducted in Europe and Australia (Australia, 
Belgium, Denmark, France, Germany, Italy, Spain, Sweden, and the United Kingdom). The objective of each 
study is to demonstrate that ZX008 0.8 mg/kg/day is superior to placebo as adjunctive therapy in the treatment 
of DS in children and young adults based on change in the frequency of convulsive seizures between baseline 
and the combined Titration and Maintenance Periods (T+M). Study ZX008-1504 is a multicenter, 2-Cohort 
trial to first assess the pharmacokinetic and safety profile of a single dose of ZX008 (Fenfluramine 
Hydrochloride) oral solution when added to standard of care (Cohort 1), followed by a randomized, double-
blind, placebo-controlled parallel group evaluation of the efficacy, safety, and tolerability of ZX008 as 
adjunctive antiepileptic therapy to stiripentol treatment in children and young adults with DS (Cohort 2).
The purpose of this Statistical Analysis Plan (SAP) is to outline the planned analyses and presentation of the 
clinical data from protocol ZX008-1503, dated 08 February2018 (amendment 4.0), an international, 
multicenter, open-label, long-term safety study of ZX008 in pediatric and young adult subjects with DS who 
have successfully completed 14 weeks of treatment in core study ZX008-1501, ZX008-1502, and ZX008-1504 
Cohort 2, or successfully completed core study ZX008-1504 Cohort 1, and are candidates for continuous 
treatment for an extended period of time. In addition, subjects who are >18 to ≤35 years of age at the time of 
screening, and who meet all other eligibility criteria may be eligible for participation after discussion with the 
Medical Monitor and sponsor about the potential risks and benefits for receiving ZX008. Participation for
these subjects will be at the discretion of the sponsor.
Amendment 3 of this clinical trial extended the initial 12-month study period to 24 months, and Amendment 4 
extended the duration to 36 months. Thus, with the implementation of Amendment 4, this clinical trial will 
consist of an up to 36-month Open-Label Extension (OLE) Treatment Period and a 2-week Post-Dosing
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ZX008-1503
CONFIDENTIAL
Page 12 of 76
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Period. Subjects who complete this trial will have been treated with ZX008 for a minimum of up to 3 years 
(including their participation in both the core study and this study). Subjects who did not participate in one of 
the core studies will undergo a screening period up to 28 days to confirm eligibility prior to receiving their first 
dose in the OLE Treatment Period. A follow-up electrocardiogram (ECG) and echocardiogram (ECHO) will
be performed at 3 and 6 months after study drug discontinuation for early termination and for those subjects 
who complete the study.
An earlier version of this Statistical Analysis Plan detailed statistical analyses performed as an interim analysis 
to support the filing of a New Drug Application (NDA) with the US Food and Drug Administration (FDA) and 
a Marketing Authorisation Application (MAA) with the European Medicines Agency (EMA), based on 
Amendment 3 of the Study Protocol. The purpose of this updated Statistical Analysis Plan is to provide details 
of the statistical presentation of the data from this study based on Amendment 4 of the protocol, for the 120-
day safety update report following filing of the New Drug Application with the US Food and Drug 
Administration.
It is planned to perform an analysis of key safety data obtained up to February 15, 2019, for all subjects who 
entered Study ZX008-1503 by December 31, 2018.The planned interim analysis will present data without 
revealing the individual treatment groups from the Core studies. The specific list of TFLs that will be 
presented in the interim analysis will be delineated in the Table of Contents for the TFL shells.
An analysis of Study ZX008-1503 to include only those subjects who entered Study ZX008-1503 from sites in 
Japan (i.e., Japanese subjects) is planned when all Japanese subjects have reached at least the Month 3 visit.. 
Selected analyses, described in the SAP for the rest of the world, will be performed for this population.
A final analysis and report of all data obtained from this study will be provided within 6 months of completion 
of the last subject’s final study visit.
The planned analyses identified in this SAP will be included in regulatory submissions and/or future 
manuscripts. Exploratory analyses not identified or defined in the SAP may be performed to support the 
clinical development program. Any post-hoc or unplanned analyses performed and not identified in this SAP 
will be documented in the CSR or final report.
2. STUDY OBJECTIVES
2.1 PRIMARY OBJECTIVE
The primary objective of the study is to assess the long-term safety and tolerability of ZX008.
2.2 SECONDARY OBJECTIVES
The secondary objectives of the study are:
•
To assess the effect of ZX008 relative to the pre-ZX008 baseline on the following effectiveness 
measures:
-
The change in the frequency of convulsive seizures.
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-
The proportion of subjects who achieve a ≥25%, ≥50%, and ≥75% reduction in convulsive 
seizure frequency.
-
The duration of the longest interval between convulsive seizures.
-
The percentage of convulsive seizure-free days.
-
The change in the frequency of non-convulsive seizures.
-
The change in the frequency of convulsive + non-convulsive seizures.
•
To estimate the incidence of the following on subjects receiving ZX008:
-
Use of rescue medication
-
Hospitalization to treat seizures
-
Status epilepticus
•
To assess the effect of ZX0008 relative to the pre-ZX0008 baseline on the following measures:
-
Quality of Life in Childhood Epilepsy (QOLCE) score
-
The Pediatric Quality of Life Inventory (PedsQL) (Version 4.0) – Parent Report
-
PedsQL Family Impact Module (Version 2.0) – Parent Report – mITT Population
-
QoL of the parent/care giver using the EQ-5D-5L scale
-
Affective symptoms of the parent/caregiver using the HADS.
•
To assess the effect of ZX0008 on the following global ratings
-
Clinical Global Impression – Improvement rating, as assessed by the principal investigator
-
Clinical Global Impression – Improvement rating, as assessed by the parent/caregiver
2.3 EXPLORATORY OBJECTIVES
Exploratory objectives of the study are the following measures that were assessed only in subjects who had 
participated in Study ZX008-1504, Cohort 2 as their feeder study. Additional exploratory analyses may be 
undertaken if warranted, as mentioned above.
•
To assess the effect of ZX008 on the following measures:
-
Sleep quality and mealtime behavior, as assessed by the parent/caregiver
-
Karolinska Sleep Scale
-
Health and social care resource use (These measures include planned and unplanned hospital 
visits, use of ambulances, GP visits, speech and language therapy utilization, occupational and 
physical therapy utilization)
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STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
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3. STUDY DESIGN
3.1 OVERALL STUDY DESIGN AND PLAN
This is an international, multicenter, open-label, long-term safety study of ZX008 in pediatric and young adult 
subjects with Dravet syndrome who have successfully completed 14 weeks of treatment in core study ZX008-
1501, ZX008-1502, and ZX008-1504 Cohort 2, or successfully completed core study ZX008-1504 Cohort 1, 
and are candidates for continuous treatment for an extended period of time. This trial will consist of a 24-
month OLE Treatment Period and a 2-week Post-Dosing Period. Thus, subjects who complete this trial will 
have been treated with ZX0008 for at least 1 year (including their participation in both the core study and this 
study).
3.2 TREATMENTS
Subjects in the double-blind studies Z008-1501, -1502, and cohort 2 of 1504 who enter Study ZX008-1503 
would have transitioned to 0.2 mg/kg during the transition period (between Visits 12 and 13), as described in 
the 1501 and 1502 Clinical Study Protocols Section 5.5.5, and 1504 Sections 5.5.6 and 5.5.7. Subjects entering 
from Cohort 1 in Study ZX008-1504 will enter a transition period at a fixed dose of ZX008 0.2 mg/kg/day for 
up to 24 additional weeks.
In Study ZX008-1503, during the 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 0.2 
mg/kg/day, the investigator may adjust the dose of each subject based on effectiveness and tolerability.
Subjects whose conditioned worsened relative to their status at the end of the double-blind feeder study could 
request permission to increase to 0.4 mg/kg/day (max 30mg) after approximately 2 weeks on the 0.2 mg/kg 
dose, Dose changes should be made in 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. Dose increases should not occur earlier than every 14 days at each dose 
level. For subjects in Study ZX008-1504 Cohort 2, the dose titration schedule is 0.2 mg/kg/day, to 0.4, to 0.5 
not to exceed 20 mg/day. 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. Dose decreases for tolerability can occur at the investigator’s discretion, in dose 
amounts and frequency appropriate for the situation. ZX008 dose adjustments outside of these parameters 
should be discussed with the Medical Monitor prior to initiation.
Effectiveness and safety data will be provided for all subjects treated with ZX008. Data will be summarized by 
subjects’ treatment group in their previous study.
The treatment groups that may be used to summarize the results of the final analysis are presented in Table 1. 
Groups 1 to 5 are the basic treatment groups.
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STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
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Table 1.
Treatment Groups in Study ZX008-1503 According to Treatment in Feeder Study
Name of Treatment 
Group
Treatment 
Group Code
AED Treatment from Feeder 
study
Feeder Study(s)
Approximate Total 
Number of subjects 
at Final Analysis
PBO-ZX008 OL
1
Placebo in feeder study along 
with any protocol-
approved background AED 
combination; no active ZX008
1501, 1502, 1504
Cohort 2
120
ZX 0.2 – ZX008 OL
2
Any protocol-approved 
background AED combination; 
plus, ZX008 0.2 mg/kg/day max 
30 mg
1501, 1502
80
ZX 0.8 – ZX008 OL
3
Any protocol-approved 
background AED combination; 
plus, ZX008 0.8 mg/kg/day max 
30 mg
1501, 1502
80
ZX 0.5 – ZX008 OL
4
Protocol-approved background 
regimen including STP + VPA 
and/or CBZ; plus ZX008 0.5 
mg/kg/day max 20 mg
1504 Cohort 2
40
PK - ZX008 OL
5
Protocol-approved background 
regimen including STP + VPA 
and/or CBZ; plus ZX008 0.5 
mg/kg/day max 20 mg
1504 Cohort 1
18
ZX DBA – ZX008 
OL
6 (Groups 2-4)
Any protocol-approved 
background regimen, plus 
ZX008 at any protocol-approved 
dose – DB Studies only
200
ZX DB – ZX008 OL
7 (Groups 1-4)
Any protocol-approved 
background regimen at any 
protocol-approved dose – DB 
Studies only
320
ZX – ZX008 OL
8 (Groups 2-5)
Any protocol-approved 
background regimen, plus 
ZX008 at any protocol-approved 
dose – All studies
218
ZX008 OL
9 (Groups 1-5)
Any protocol-approved 
background regimen at any 
protocol-approved dose – All 
studies
338
De Novo Subjects
10
N/A
N/A
TBD
PUBLIC COPY
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Zogenix International Limited
ZX008-1503
CONFIDENTIAL
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3.3 TREATMENT PERIODS
The duration of participation in the study for an individual subject is expected to be up to 158 weeks, plus a 
follow-up safety visit 3 and 6 months after the last dose.
•
OLE Treatment Period – 36 months (156 weeks)
•
Post-Dosing Visit – 2 weeks after study completion or early termination.
•
Cardiac Follow-up (ECG and ECHO) – 3 and 6 months after study drug discontinuation for early 
termination and for those subjects who complete the study.
3.3.1 OLE Treatment Period
Study medication will be administered as equal doses BID in the morning and in the evening approximately 12 
hours apart, with food. 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.
Administration of the initial IMP will be based on the 0.2 mg/kg/day (maximum 30 mg/day or 20 mg/day for 
subjects taking concomitant STP) dose and subject’s weight at Visit 1 (Study Day 1). At Visits 5 to 15 
(Months 3 to 33), if the subject’s weight has changed ± 25% of the weight from the previous dose calculation, 
the IMP dose will be recalculated. Subjects will be dosed using the oral dosing syringe provided.
During the 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.
Dose changes should be made in increments of 0.2 mg/kg/day, as follows:
•
Subjects who are not receiving concomitant STP: may increase to a maximum of 0.8 mg/kg/day but 
not to exceed total dose of 30 mg/day
•
Subjects who are receiving concomitant STP: the first dose change will be to 0.4 mg/kg/day and the 
final dose change will be to 0.5 mg/kg/day, but not to exceed 20 mg/day
Additional details on dosing are provided in the clinical study Protocol.
3.3.2 Taper Period
All subjects (those who complete the OLE Treatment Period and those who discontinue from the study early) 
will be tapered off study medication.
3.3.2.1 Taper Period for Subjects from Core Studies ZX008-1501, ZX008-1502, and ZX008-1504
Cohort 1/Regimens 1&2
The tapering scheme is a 2-step process for subjects who are not receiving concomitant STP, including 
subjects from core studies ZX008-1501 and ZX008-1502, and from study ZX008-1504 Cohort 1/Regimens 
1&2. This is described in Table 2.
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STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 17 of 76
v3.0
04Aug2020
Study medication will be administered as equal doses BID in the morning and in the evening, approximately 
12 hours apart, with food. 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 2.
Taper Algorithm for Subjects from Core Studies ZX008-1501, ZX008-1502, and ZX008-1504 
Cohort 1/Regimens 1&2 Not Receiving Concomitant STP
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 0.6 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.
Regimen 1 = CLB + VPA + ZX008 0.2 mg/kg; Regimen 2 = CLB + VPA + ZX008 0.4 mg/kg
3.3.2.2 Taper Period for Subjects from Core Study ZX008-1504 Cohort 1 Regimen 3 and Cohort 2
The tapering scheme is a 3-step process for subjects receiving concomitant STP, including subjects from core 
study ZX008-1504 Cohort 1 Regimen 3 and Cohort 2, and is described in Table 3.
Study medication will be administered as equal doses BID in the morning and in the evening, approximately 
12 hours apart, with food. 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 3.
Taper Algorithm for Subjects Receiving Concomitant STP
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
Taper Step 3 
Days 9-14 after study 
completion or early
termination
ZX008 0.2 mg/kg/day
Not applicable
Not applicable
Not applicable
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day
Not applicable
Not applicable
ZX008 0.5 mg/kg/day
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day
Not applicable
Note: maximum daily dose of ZX008 is 20 mg.
Regimen 3 = CLB + VPA + STP + ZX008 0.2 mg/kg
Seizure data from the Taper period will not be included in the planned effectiveness endpoints except where 
specified. However, all safety data obtained including data obtained through the taper period, will be included 
in the safety analyses.
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STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 18 of 76
v3.0
04Aug2020
3.4 RANDOMIZATION AND BLINDING
This is an open-label study and the doses to be administered are ZX008 0.2 mg/kg to 0.8 mg/kg up to a 
maximum of 30 mg/day. Subjects taking concomitant STP, including subjects from Study ZX008-1504, 
should not exceed 0.5 mg/kg/day; with a daily maximum of 20 mg. Assignment of subject to treatment is not 
randomized. All subjects begin the OLE treatment period with 0.2 mg/kg for one month, after which the dose 
may be adjusted in increments of 0.2 mg/kg to achieve appropriate level of effectiveness/tolerability.
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STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 19 of 76
v3.0:
04Aug2020
4. SCHEDULE OF ASSESSMENTS
Table 4.
Schedule of Assessments for Subjects from Core Studies ZX008-1501 and ZX008-1502, and de Novo Subjects**
Study Assessments
OLE Treatment Period
Post-Dosing
Cardiac Follow-up
Visit Number
Visit 1a
Visit 2c
Visits 3-15
(Months 1, 2, 3, 6, 9, 12, 15, 18,
21, 24, 27, 30, and 33)
Visit 16d
(EOS/ET)
Month 36
Visit 17
Visit 18, 19
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15
30, 60, 90, 180, 270, 365, 455,
545, 635, 725. 815, 905, 995
1085
1099
3 and 6 months post last
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Phone
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X
Entry Criteria
X
Demographics
X
Medical/Neurological History
Xa
Epilepsy History
Xa,b
Physical Examination, complete
Xa
X
Xe
Physical Examination, abbreviated
X
X
Xe
Neurological Examination, complete
Xf
X
Neurological Examination, abbreviated
X
X
Vital signs
X
X
X
X
Weight, Height, BMI
Xa
X
X
X
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Xa
X
X
Xe
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Xa
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X
Xe
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X
X
X
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Xj
Xj
X
X
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Xa
X
X
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X
X
X
Tanner Staging (for subjects >7 to ≤18 
years)
Xa
Xk
X
Xk
C-SSRS
Xa
X
X
CGI-I (assessed by parent/caregiver)
Xa
X
X
CGI-I (assessed by principal investigator)
Xa
X
X
QOLCE
Xa
X
X
EQ-5D-5L (QoL of parent/caregiver)
Xa
X
X
HADS (Affect of parent/caregiver)
Xa
X
X
BRIEF
Xa
X
X
continued
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STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 20 of 76
v3.0:
04Aug2020
Table 4.
Schedule of Assessments for Subjects from Core Studies ZX008-1501 and ZX008-1502, and de Novo Subjects** (continued)
Study Assessments
OLE Treatment Period
Post-Dosing
Cardiac Follow-up
Visit Number
Visit 1a
Visit 2c
Visits 3-15
(Months 1, 2, 3, 6, 9, 12, 15,
18, 21, 24, 27, 30, and 33)
Visit 16c
(EOS/ET)
Month 36
Visit 17
Visit 18, 19
Study Day
-28 to 1a
15
30, 60, 90, 180, 270, 365, 455,
545, 635, 725. 815, 905, 995
1085
1099
3 and 6 months post last
dose
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Xa
X
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D
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R
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R
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X
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Xa
X
Adverse Events
Xa
X
Adverse events of special interest
Xa
----------------------------------------------X--------------------------------------------------
Xm
AED=antiepileptic drug; BMI=body mass index; BRIEF=Behavior Rating Inventory of Executive Function; C=Collect; CBD=cannabidiol; CGI-I=Clinical Global Impression-Improvement; D=Dispense;
ECG=electrocardiogram; EOS=end of study; ET=early termination; EQ-5D-5L=standardized measure of health status; HADS=Hospital Anxiety and Depression Scale; PedsQL=Pediatric Quality of Life Inventory;
QoL=quality of life; QOLCE=Quality of Life in Childhood Epilepsy; R=Review
NOTE: If a subject has a birthday during the study that makes a previously unrequired assessment now required (eg, Tanner staging in a male subject who turns 8 years old during the study), this assessment(s)
should be initiated at visits subsequent to the birthday.
** de Novo subjects are subjects who did not participate in one of the core studies and may or may not be currently taking STP.
a:
For subjects enrolling from one of the core studies use data collected at Visit 12 and Visit 13 of Study ZX008-1501 or ZX008-1502.
For de novo subjects, a screening period up to 28 days is required. During this period, informed consent is required prior to any study-related procedures. All results to determine eligibility must be reviewed prior to
receiving the first dose of study medication at Visit 1.
For all subjects, clinical laboratory results and all ECHO/ECG results must be available and meet eligibility criteria prior to receiving the first dose of study medication at Visit 1.
b:
De Novo subjects must meet entry criteria 3 to 7, and 10, including having had ≥4 convulsive seizures (tonic, tonic-atonic, tonic-clonic, clonic) per 4-week period for past 12 weeks prior to screening, by
parent/guardian report to investigator or investigator medical notes.
c:
At the discretion of the investigator, Visit 2 may be conducted as a phone visit.
d:
Or early termination.
e;
Follow-up ECG, ECHO, and physical examination will be performed 3 and 6 months after study completion or early termination.
f:
For subjects enrolling from one of the core studies, use core study Visit 12 information unless complete neurological examination is warranted based on significant changes in subject status.
g:
ECHOs will be performed at Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, and 33.
h:
The Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, and 33 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 (see Table 7).
i:
Females of child-bearing potential
j:
For subjects enrolling from one of the core studies, use data collected at Visit 12 of ZX008-1501 or ZX008-1502 for Visit 1 unless clinical laboratory evaluation is warranted based on significant changes in subject
status. Visit 2 clinical laboratory evaluation is optional based on subject status for all cohorts.
k:
Months 6, 15, and 27 only.
l:
Visits 3 and 4 (Months 1 and 2) only.
m:
Only adverse events related to cardiac safety will be collected at this visit (see Table 7).
n:
Not to be completed for de novo subjects >18 years old.
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STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 21 of 76
v3.0:
04Aug2020
Table 5.
Schedule of Assessments for Subjects from Core Study ZX008-1504
Study Assessments
OLE Treatment Period
Post-Dosing
Cardiac Follow-up
Visit Number
Visit 1a
Visit 2b
Visits 3-15
(Months 1, 2, 3, 6, 9, 12, 15,
18, 21, 24, 27, 30, and 33)
Visit 16c
(EOS/ET)
Month 36
Visit 17
Visit 18, 19
Study Day
1a
15
30, 60, 90, 180, 270, 365, 455,
545, 635, 725. 815, 905, 995
1085
1099
3 and 6 months post last
dose
Clinic
Phone
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X
Entry Criteria
X
Demographics
X
Medical/Neurological History
Xa
Epilepsy History
Xa
Physical Examination, complete
Xa
X
Xd
Physical Examination, abbreviated
X
X
Xd
Neurological Examination, complete
Xe
X
Neurological Examination, abbreviated
X
X
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X
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Xa
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X
X
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X
X
X
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Xa
Xj
X
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Xa
X
X
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Xa
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Xa
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EQ-5D-5L (QoL of parent/caregiver)
Xa
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BRIEF
Xa
X
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Healthcare utilization questions
Xa
X
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continued
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Table 5.
Schedule of Assessments for Subjects from Core Study ZX008-1504 (continued)
Study Assessments
OLE Treatment Period
Post-Dosing
Cardiac Follow-up
Visit Number
Visit 1a
Visit 2b
Visits 3-15
Visit 16c
Visit 17
Visit 18, 19
(Months 1, 2, 3, 6, 9, 12, 15,
(EOS/ET)
18, 21, 24, 27, 30, and 33)
Month 36
Study Day
1a
15
30, 60, 90, 180, 270, 365, 455,
1085
1099
3 and 6 months post last
Clinic
Phone
545, 635, 725. 815, 905, 995
dose
Karolinska Sleep Scale
Xa
X
X
Sleep quality/mealtime behavior questions
Xa
X
X
PedsQL
Xa
X
X
Study medication palatability assessment
Xk
Subject Diary
D
C/R/D
R
C/R/D
C/R
C/R
Study Medication
Db
C/R/D
R
C/R/D
C/R/D
C/R
Daily Diary Completion
X
Concomitant Medications
Xa
X
Adverse Events
Xa
X
Adverse events of special interest
Xa
----------------------------------------------X--------------------------------------------------
Xl
AED=antiepileptic drug; BMI=body mass index; BRIEF=Behavior Rating Inventory of Executive Function; C=Collect; CBD=cannabidiol; CGI-I=Clinical Global Impression-Improvement; D=Dispense;
ECG=electrocardiogram; EOS=end of study; ET=early termination; EQ-5D-5L=standardized measure of health status; HADS=Hospital Anxiety and Depression Scale; PedsQL=Pediatric Quality of Life Inventory;
QoL=quality of life; QOLCE=Quality of Life in Childhood Epilepsy; R=Review
NOTE: If a subject has a birthday during the study that makes a previously unrequired assessment now required (e.g., Tanner staging in a male subject who turns 8 years old during the study), this assessment(s) should be
initiated at visits subsequent to the birthday.
a:
For subjects from the core Study ZX008-1504 Cohort 1, use data collected at the last visit of the transition period; for subjects from core Study ZX008-1504 Cohort 2 use data collected at the Visit 12 and Visit 13.
For de novo subjects, a screening period up to 28 days is required. During this period, informed consent is required prior to any study-related procedures. All results to determine eligibility must be reviewed prior to
receiving the first dose of study drug at Visit 1.
For subjects from ZX008-1504 Cohort 2 and de novo subjects, clinical laboratory, ECHO, and ECG results must be available and meet eligibility criteria prior to receiving the first dose of study drug at Visit 1.
b:
At the discretion of the investigator, Visit 2 may be conducted as a phone visit.
c:
Or early termination.
d:
Follow-up ECG, ECHO, and physical examination will be performed 3 and 6 months after study completion or early termination.
e;
Unless complete neurological examination is warranted based on significant changes in subject status, use data collected at the last visit of the transition period of Study ZX008-1504 Cohort 1 and for subjects from
Study ZX008-1504 Cohort 2, use data collected at the Visit 12.
f:
ECHOs will be performed at Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, and 33.
g:
The Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, and 33 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 (see Table 7).
h:
Females of child-bearing potential
i:
Unless clinical laboratory evaluation is warranted based on significant changes in subject status, use data collected at the last visit of the transition period of Study ZX008-1504 Cohort 1; for subjects from Study
ZX008-1504 Cohort 2, use data collected at the Visit 12. For Visit 2, clinical laboratory evaluation is optional based on subject status.
j:
Months 6, 15, and 27.
k:
Visits 3 and 4 (Months 1 and 2) only.
l:
Only adverse events related to cardiac safety will be collected at this visit (see Table 7).
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5. ANALYSIS POPULATIONS
5.1 ENROLLED POPULATION
The enrolled population includes all subjects who gave informed consent or assent for entry into Study 
ZX008-1503.
5.2 SAFETY (SAF) POPULATION
The SAF population is the set of all enrolled subjects who received at least one dose of ZX008 during the open 
label extension. Safety analyses will be performed on the SAF Population.
5.3 MODIFIED INTENT-TO-TREAT (MITT) POPULATION
The mITT Population is defined as all enrolled subjects who receive at least one dose of ZX008 and have at 
least one month (30 days) of valid seizure data during the open label extension. Effectiveness analyses, such as 
evaluating the change in the frequency of convulsive seizures, will be performed on the mITT Population.
6. STATISTICAL METHODOLOGY
6.1 STATISTICAL AND ANALYTICAL ISSUES
6.1.1 Statistical Methods
All data on safety, effectiveness and exploratory endpoints will be summarized. Continuous data will be 
summarized using descriptive statistics including number of subjects, means, standard deviations, medians, 
lower and upper quartiles, and ranges. Categorical variables will be summarized with frequencies and 
percentages.
Effectiveness and safety data may be summarized by treatment group in previous study as described in Section
3.2 in this SAP. The effectiveness and safety data will also be summarized by age group as described in 
Section 6.1.3, and overall.
Point and interval estimates (95% confidence intervals) will be calculated for within treatment changes from 
baseline for key parameters as warranted. These within-treatment changes from baseline comparisons should 
be interpreted with caution, as any effect of treatment may be confounded with the time-course of disease or 
other factors. The primary evidence for efficacy and safety of ZX008 is based on the treatment comparisons 
from the double-blind studies, while the data from this OLE study provides evidence of long-term safety and 
effectiveness.
Confidence intervals and/or p-values, where provided for between treatment group differences, should be 
regarded as descriptive and not for formal inferential purposes.
All descriptive statistical analyses will be performed using SAS statistical software (Version 9.3, unless 
otherwise noted). Adverse events will be coded using the most recent MedDRA version available at the time 
of analysis. Concomitant medications will be coded using the most recent version of World Health 
Organization (WHO) Drug.
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6.1.2 Multiplicity Issues
This is an open-label extension study with no formal comparisons to be made between treatment groups 
defined by subjects’ initial regimen in the previous study. Comparisons will be made within each treatment 
group comparing measurements observed during different time points in the OLE to the measurements 
obtained during the baseline period in the double-blind or PK study completed prior to this OLE.
Confidence intervals presented for descriptive purposes only will each have nominal 95% coverage 
probability.
No formal adjustment for multiplicity is made.
6.1.3 Subgroups
Effectiveness and select safety data may be further broken down by the following subgroups:
•
Age strata (based on age at informed consent at core study entry or entry de novo): 2 to <6 years, ≥6 –
18 years.
•
Region: Countries may be grouped into two regions: North America (US/Canada), Rest-of-World 
(ROW).
•
Japan: Subjects enrolled from Japan are considered as a separate subgroup.
6.1.4 Definitions
6.1.4.1 Baseline (Core)
For de novo subjects, the baseline (core) is undefined. For other subjects, the baseline (core) is defined as 
follows.
For effectiveness endpoints (excluding seizure), the baseline (core) will be defined dependent on their core 
study. For subjects from ZX008-1501, ZX008-1502, or ZX008-1504 Cohort 2, baseline (core) is the last value 
prior to randomization in the preceding double-blind study. For subjects from ZX008-1504 Cohort 1, baseline 
(core) is the last value prior to the start of PK dosing and assessments. For De Novo subjects, the baseline is 
the last value prior to dosing in ZX008-1503.
For all subjects in Study ZX008-1501, Study ZX008-1502, or Study ZX008-1504 Cohort 2, the baseline (core) 
period is equivalent to the core study pre-randomization period, i.e., the approximately 42-day span just prior 
to randomization and start of treatment in the core study. The baseline (core) seizure frequency will be based 
on the information collected from their daily diaries during the baseline period (lasting approximately 42
days).
For subjects from Study ZX008-1504 Cohort 1 the baseline (core) for efficacy rating scales (e.g. 
questionnaires) will be the last rating prior to start of dosing in the Core Study. Baseline seizure frequency for 
Study ZX008-1504 Cohort 1 will not be calculated.
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6.1.4.2 Baseline (OLE)
Baseline (OLE) value for the Open-label treatment period is defined as the last assessment on or before the 
start of the OLE period. In most cases, (though not seizure frequency) this will be the value obtained at Visit 1 
(Study Day 1) of Study ZX008-1503.
Thus, Baseline (OLE) lab, vital signs, ECG, ECHO, assessments refer to the assessments obtained on this day, 
as does Baseline (OLE) value for effectiveness endpoints with the exception of seizures.
For de novo subjects, the baseline (OLE) seizure frequency will be based on the information collected from 
their daily diaries during the baseline period (lasting approximately 28 days) prior to first dose in ZX008-1503.
6.1.4.3 Open-Label Extension (OLE) Treatment Period
The OLE Treatment Period covers the 36 months during which subjects will receive open label treatment with 
ZX008.
For each subject, OLE day 1 (OLED1) is the subject’s first day of dosing in the OLE period. Study day for 
1503 begins with OLED1.
6.1.4.4 Post-dosing Period
The Post-dosing Period begins immediately at the end of OLE Treatment Period and extends for 2 weeks.
6.1.4.5 Follow-up Period
Subjects are to return for an ECHO and ECG assessment 3 and 6 months after the end of the study. The 
follow-up period begins the day after Visit13 and ends with Visit15.
6.1.5 Other Definitions
6.1.5.1 Phase and Study Day Definitions
The analyses will require definition of 3 Phases: Pre-OLE, OLE, and Post-OLE.
•
The pre-OLE Phase comprises (1) the baseline (Core) period, (2) the Core Study (CS) period 
(including the transition period in the core study)
•
The OLE Phase starts from dosing on OLED1 and comprises (1) the OLE Treatment Period, and (2) 
the Taper Period. The last day of the OLE phase is the date of Visit 17.
•
The post-OLE phase begins one day after the date of Visit 17 in 1503 and ends with the date of Visit 
19.
Study Day 1 is the date of first dose in the OLE Study. In most cases, this will be the date of Visit 1 or the day 
after that date.
6.1.6 Visit Windows and Period Start/Stop Dates
The following definitions of phase and period will be used:
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Table 6.
Definition of Phase/Period
Phase
Period
Description
Pre-OLE Phase
Baseline (Core) 
Period
This description here applies to all subjects except the de novo subjects. This period 
refers to the period prior to the beginning of the double-blind period in the Core study. 
The Baseline (Core) period start date is the date of Visit 1 in the Core study. The 
Baseline (Core) period end date is the date of Visit 3/randomization in the Core study.
For subjects in Study ZX008-1504 (Cohort 1), the baseline period starts and ends on 
the date of Visit 1.
Pre-OLE Phase
Core Study 
Period
This description here applies to all subjects except the de novo subjects. The start date 
of this period is the date of randomization or first dose in the Core (double-blind) 
study, whichever occurs first. The end date of this period is the last date the subject 
was on study treatment.
For subjects entering Study ZX008-1503 who completed Core studies ZX008-1501, 
ZX008-1502 or ZX008-1504 Cohort 2, this will be the date of Visit 13 in the core 
study. For subjects who discontinue early from the Core study, the Core study period 
end date is the latest assessment date for that study.
For subjects entering ZX008-1503 who were in ZX008-1504 Cohort 1, this will be the 
date of the Visit 17 assessment in Study 1504 Cohort 1 (for those who completed), or 
the date of the latest assessment date (for those who discontinued ZX008-1504 Cohort 
1 prematurely but were allowed entry into 1503, if any).
Pre-OLE Phase
Baseline (OLE) 
Period – de novo 
subjects
This description here applies to the de novo subjects. This start date of this period be 
the date of screening. The end date of the period will be the last date prior to the first 
dose of study drug in Study ZX008-1503.
OLE Phase
OLE Treatment 
Period
The OLE Treatment Period consists of the 36-month period from Visit 1 of the OLE 
study through Visit 16 of the OLE study
The OLE Treatment Period start date is the date of first dose in Study ZX008-1503. 
The OLE Treatment Period end date is the date of end of study visit, Visit 16/ET. For 
subjects who discontinue early from the study, the OLE Treatment Period end date 
will be the date of the ET visit - safety measures collected at the last clinic visit will 
be used even in the event that study drug was discontinued prior to the date of the 
visit.
Note: Adverse events occurring up to Visit 17 are regarded as occurring during 
treatment. In addition, AEs occurring up to 30 days after the last dose date will be 
regarding as treatment emergent.
OLE Phase
Taper Period
The Taper period consists of 2 weeks starting from end of study/early termination 
visit (Visit 16) + 1 day.
The end date of this period is the date recorded for Visit 17.
Post-OLE 
Phase
Post-OLE Period
The start date of the post-OLE period is the date of Visit 17, + 1 day for subjects who 
complete the OLE Treatment period, or the day after the date of end of taper, for 
subjects who discontinue early.
[There is not explicit end date for the post-OLE Phase. However, if needed, this may 
be set to be 45 days after the date of Visit 19, or V17 date + 210.]]
For the purpose of statistical analysis, visit windows around the target visit dates will be implemented to 
capture effectiveness and/or safety data within similar periods. These windows are distinct from the
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ZX008-1503
CONFIDENTIAL
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permissible visit scheduling windows specified in the Visit Schedule in the protocol that are used for the 
conduct of the study.
The following rules will be used to window data into treatment periods for tabulations that are generated by 
time during the OLE Treatment period.
Table 7a. Time Intervals for Analysis Visits for Seizure Analysis*
Analysis 
Phase/Period
Scheduled Visit
Number in 
ZX008-1503
Analysis 
Visit**
Time Interval 
(label on output)
Time Interval 
(Day)
Pre-OLE
N/A
-99
Baseline (Core)*
Core Study Day -42 to Day-1 of Core Study
Pre-OLE
N/A
-9
Core Study (T+M)*
Day1 of Core Study to End of T+M in Core 
Study
Pre-OLE
N/A
-1
Core Study Final *
Week
End of T+M in Core Study – 6 days, to End of
T+M in Core Study
Pre-OLE de
novo
N/A
-99
Baseline (OLE)*
Day -28 to Day -1 of Study ZX008-1503
OLE
3
1
Month 1 (OLE)
1-30
OLE
4
2
Month 2 (OLE)
31-60
OLE
5
3
Month 3 (OLE)
61-90
OLE
6
Month 4-6 (OLE)
91-180
OLE
7
5
Month 7-9 (OLE)
181-270
OLE
8
6
Month 10-12 (OLE)
271-360
OLE
9
7
Month 13-15 (OLE)
361-450
OLE
10
8
Month 16-18 (OLE)
451-540
OLE
11
9
Month 19-21 (OLE)
541-630
OLE
12
10
Month 22-24 (OLE)
631-730
OLE
13
11
Month 25-27 (OLE)
731-820
OLE
14
12
Month 28-30 (OLE)
821-910
OLE
15
13
Month 31-33 (OLE)
911-1000
OLE
16
14
Month 34-36 (OLE)
1001-1095
OLE
NA
99
Month 01-EOS
(ENDPT1)
1 to min(Last Dose date, Visit 16 date)
OLE
NA
98
Month 02-EOS
(ENDPT2)
31 to min(Last Dose date, Visit 16 date)
Note: EOS/ET date = Visit16 date. Per protocol, Visit 17 is end of the OLE Phase. 
T+M=Titration + Maintenance in Core Study.
*Subjects in Study ZX008-1504 Cohort 1 will not have a baseline(core), For those subjects, the Core Study(T+M) represents all their 
seizure data during the transition period in the core study. Their core study final week will be the last 7 days of seizure data prior to the 
first visit in ZX008-1503. De novo subjects start Study ZX008-1503 treatment after a screening period.
**Analysis visit numbers are not the same as nominal visit numbers.
PUBLIC COPY
Wee
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ZX008-1503
CONFIDENTIAL
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Table 7b. Time Intervals for Questionnaires*
Analysis 
Phase/Period
Scheduled Visit 
Number in ZX008-
1503
Analysis 
Visit 
Number*
Time Interval 
(label on output)
Time Interval 
(Day)
Target Time 
Point (Day)
Pre-OLE
N/A
-99
Baseline (Core)
<1
Core Study Day -
42 to Day-1 of 
Core Study
Pre-OLE
1
1
Baseline (OLE)
1
1
OLE
3
3
Month 1 (OLE)
21 to 44
30
OLE
4
4
Month 2 (OLE)
45 to 74
60
OLE
5
5
Month 3 (OLE)
75 to 134
90
OLE
6
6
Month 6 (OLE)
135 to 224
180
OLE
7
7
Month 9 (OLE)
225 to 314
270
OLE
8
8
Month 12 (OLE)
315 to 409
365
OLE
9
9
Month 15 (OLE)
410 to 499
455
OLE
10
10
Month 18 (OLE)
500 to 589
545
OLE
11
11
Month 21 (OLE)
590 to 679
635
OLE
12
12
Month 24 (OLE)
680 to 774
730
OLE
13
13
Month 27 (OLE)
775 to 864
820
OLE
14
14
Month 30 (OLE)
865 to 954
910
OLE
15
15
Month 33 (OLE)
955 to 1044
1000
OLE
16
16
Month 36 (OLE)
1045 to 1109
1095
OLE
OLE Last Visit**
99
Last Value
Day 2 to Visit 17
date
*For multiple measurements within a time window, please use the closest to the target time point. Note that measurements occurring on 
the end date of a phase/period or start date of a new phase/period are assigned to the preceding phase/period. For example, 
measurements taken on OLE Study Day1 are assigned as Baseline (OLE).
**The last observation in the time window will be used. [This is an exception from the rule in the preceding note.]
Table 7c. Time Intervals for Analysis Visits for Laboratory Data and Vital Signs*
Analysis 
Phase/Period
Scheduled Visit 
Number in ZX008-
1503
Analysis 
Visit 
Number*
Time Interval 
(label on output)
Time Interval 
(Day)
Target Time 
Point (Day)
Pre-OLE
1
1
Baseline (OLE)
1
1
OLE
2
2
Week 2 (OLE)
2 to 20
15
OLE
3
3
Month 1 (OLE)
21 to 44
30
OLE
4
4
Month 2 (OLE)
45 to 74
60
OLE
5
5
Month 3 (OLE)
75 to 134
90
OLE
6
6
Month 6 (OLE)
135 to 224
180
OLE
7
7
Month 9 (OLE)
225 to 314
270
OLE
8
8
Month 12 (OLE)
315 to 409
365
OLE
9
9
Month 15 (OLE)
410 to 499
455
OLE
10
10
Month 18 (OLE)
500 to 589
545
OLE
11
11
Month 21 (OLE)
590 to 679
635
OLE
12
12
Month 24 (OLE)
680 to 774
730
OLE
13
13
Month 27 (OLE)
775 to 864
820
PUBLIC COPY
Mon
Y
Mon
Month
PY 
Month
Y
Mon
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Mon
PY
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STATISTICAL ANALYSIS PLAN
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ZX008-1503
CONFIDENTIAL
Page 29 of 76
v3.0:
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Analysis 
Phase/Period
Scheduled Visit
Number in ZX008-
1503
Analysis
Visit 
Number*
Time Interval 
(label on output)
Time Interval 
(Day)
Target Time 
Point (Day)
OLE
14
14
Month 30 (OLE)
865 to 954
910
OLE
15
15
Month 33 (OLE)
955 to 1044
1000
OLE
16
16
Month 36 (OLE)
1045 to 1109
1095
OLE
OLE last Visit**
99
Last Value
Day 2 to Visit 17
date
*For multiple measurements within a time window, please use the closest to the target time point. Note that measurements occurring on 
the end date of a phase/period or start date of a new phase/period are assigned to the preceding phase/period. For example, 
measurements taken on OLE Study Day1 are assigned as Baseline (OLE).
**The last observation in the time window will be used. [This is an exception from the rule in the preceding note.]
Table 7d. Time Intervals for Analysis Visits for Tanner Staging*
Analysis 
Phase/Period
Scheduled Visit
Number in ZX008-
1503
Analysis
Visit 
Number*
Time Interval 
(label on output)
Time Interval 
(Day)
Target Time 
Point (Day)
Pre-OLE
1
1
Baseline (OLE)
1
1
OLE
2
2
Week 2 (OLE)
2 to 20
15
OLE
3
3
Month 1 (OLE)
21 to 44
30
OLE
4
4
Month 2 (OLE)
45 to 74
60
OLE
5
5
Month 3 (OLE)
75 to 134
90
OLE
6
6
Month 6 (OLE)
135 to 224
180
OLE
7
7
Month 9 (OLE)
225 to 314
270
OLE
8
8
Month 12 (OLE)
315 to 409
365
OLE
9
9
Month 15 (OLE)
410 to 499
455
OLE
10
10
Month 18 (OLE)
500 to 589
545
OLE
11
11
Month 21 (OLE)
590 to 679
635
OLE
12
12
Month 24 (OLE)
680 to 774
730
OLE
13
13
Month 27 (OLE)
775 to 864
820
OLE
14
14
Month 30 (OLE)
865 to 954
910
OLE
15
15
Month 33 (OLE)
955 to 1044
1000
OLE
16
16
Month 36 (OLE)
1045 to 1109
1095
OLE
17/OLE Last Visit**
99
Last Value
Day 2 to Visit 17 
date
*For multiple measurements within a time window, please use the closest to the target time point. Note that measurements occurring on 
the end date of a phase/period or start date of a new phase/period are assigned to the preceding phase/period. For example, 
measurements taken on OLE Study Day1 are assigned as Baseline (OLE). Visits where the Tanner Stage is not scheduled for collection 
are included due to early termination visits occurring between scheduled visits.
**The last observation in the time window will be used. [This is an exception from the rule in the preceding note.]
PUBLIC COPY 
abel
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ZX008-1503
CONFIDENTIAL
Page 30 of 76
v3.0:
04Aug2020
Table 7e. Time Intervals for ECGs and ECHO*
Analysis 
Phase/Period
Scheduled Visit 
Number in 
ZX008-1503
Analysis Visit*
Time Interval 
(label on output)
Time Interval 
(Day)
Target Time 
Point (Day)
Pre-OLE
1
1
Baseline (OLE)
<1
1
OLE
3
3
Month 1 (OLE)
2 to 44
30
OLE
4
4
Month 2 (OLE)
45 to 74
60
OLE
5
5
Month 3 (OLE)
75 to 134
90
OLE
6
6
Month 6 (OLE)
135 to 224
180
OLE
7
7
Month 9 (OLE)
225 to 314
270
OLE
8
8
Month 12 (OLE)
315 to 409
365
OLE
9
9
Month 15 (OLE)
410 to 499
455
OLE
10
10
Month 18 (OLE)
500 to 589
545
OLE
11
11
Month 21 (OLE)
590 to 679
635
OLE
12
12
Month 24 (OLE)
680 to 774
730
OLE
13
13
Month 27 (OLE)
775 to 864
820
OLE
14
14
Month 30 (OLE)
865 to 954
910
OLE
15
15
Month 33 (OLE)
955 to 1044
1000
OLE
16
16
Month 36 (OLE)
1045 to 1109
1095
OLE
17/Final Visit**
99
Last Value
2 to Visit 17 date
Post-OLE
18
999
Cardiac FU 1
Visit 17 date + 1,
to Visit 18 date
Post-OLE
19
9999
Cardiac FU 2
Visit 18 date +1, to
Visit 19 date
*For multiple measurements within a time window, please use the closest to the target time point. Note that measurements occurring on 
the end date of a phase/period or start date of a new phase/period are assigned to the preceding phase/period. For example, 
measurements taken on OLE Study Day1 are assigned as Baseline (OLE).
** The last observation in the time window will be used. [This is an exception from the rule in the preceding note.]
6.1.7 Handling of Dropouts and Missing Data
6.1.7.1 Missing Data
There will be no explicit imputation of missing data for effectiveness endpoints.
6.1.7.2 Seizure Diaries
Seizures are recorded in the Daily Seizure Diary, while the End of Day Diary provides Yes/No confirmation 
that that seizures were experienced for a specific date, or that the date was seizure free.
•
If no seizures are entered in the DSD and the EDD confirms seizure freedom, the number of seizures 
for that date is zero.
•
If seizures are entered in the DSD and the EDD states seizures freedom, the seizures recorded for that 
date supersede the EDD stating seizure freedom.
•
If no seizures are entered in the DSD and there is no response in the EDD, that day will be considered 
to have missing diary data.
•
If no seizures are entered in the DSD and there is a Yes response in the EDD, that day will be 
considered to have missing diary data.
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STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 31 of 76
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Handling of missing date information for AEs:
•
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 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 IMP, the AE will be handled as a TEAE.
•
The missing start date and end date of 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.
Table 8 Data Conventions for Missing Adverse Event Start or Stop Dates
Start or End 
Date Missing
Data Convention
Partial
/Missing 
Start date
Missing day – If Adverse event day is missing but month and year are present then Impute the 
1st of the month unless month is same as month of first dose of study drug then impute first dose 
date.
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 then impute first dose date. 
Completely missing – impute first dose date 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
If the AE is “ongoing”, do not impute an end date.
The following applies to a missing end date where the AE is not “ongoing”:
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 the last dose date then impute last dose date.
Completely Missing – need to look at whether the AE is still ongoing before imputing a date and 
when it started in relation to study drug. If the ongoing flag is missing then assume that AE is 
still present (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 it started on or after first dose date then impute a date that is 
after the last dose date.
6.1.8 Conversion of Time Interval
In case a time interval was calculated in days and needs to be converted into weeks, months or years the 
following conversion factors need to be used:
1 week
= 7 days
1 month = 30.4 days
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STATISTICAL ANALYSIS PLAN
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ZX008-1503
CONFIDENTIAL
Page 32 of 76
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1 year
= 365.25 days
6.1.9 Pooling of Investigative Sites
Sites participating in this study are from Australia, Europe and North America. Due to the small numbers of 
subjects at each site, there is no plan to use site as a stratifying factor in the analyses; the primary analysis will 
use data pooled across site. The effectiveness and safety analyses may be presented by region.
6.1.10 Determination of Sample Size
The sample size justification as indicated in the study protocol is as follows: The sample size will be 
determined by the number of subjects in the three core studies (Study ZX008-1501, Study ZX008-1502, or 
Study ZX008-1504) who volunteer for the extension study and meet the necessary criteria for enrollment. 
Approximately 100-120 subjects are expected to participate in each of the core studies. Thus, if all of those 
participants also enrolled in the extension, the total sample size of the extension study would be between 300 
and 360.
It is expected that this sample size will provide adequate exposure information for this orphan drug, to inform 
the label at time of marketing authorization, and would allow detection of at least one, two or three rare events 
with reasonable likelihood. As an example, if a slightly conservative estimate of the number of subjects 
enrolled in Study ZX008-1503 is set at n=270, the table below provides probability calculations for detecting 
at least one, 2, or 3 events, assuming various values for an underlying event rate of 1, 2, 3, 4, 5, or 10%:
Table 9: Probability calculations for specified adverse event occurrence rates
Probability of detecting an adverse event in trial with n=270, with specified 
true event rate of:
Probability of observing
10%
5%
4%
3%
2%
1%
≥1 event
100.0
100.0
99.998
99.97
99.6
93.4
≥2 events
100.0
99.999
99.98
99.7
97.2
75.3
≥3 events
100.0
99.989
99.88
98.8
90.7
50.7
6.2 SUBJECT CHARACTERISTICS
Individual subject data will be listed for all subjects in the SAF population. Unless otherwise specified, all data 
summaries will be overall and by Core study treatment group as described in Section 3.2 of this SAP.
6.2.1 Subject Disposition
Subject disposition will be presented for all subjects overall, and by treatment group in Core study for the 
Enrolled and SAF populations. Disposition information that will be summarized includes number of subjects 
who started treatment in the OLE study, number who withdrew prematurely, and reasons for withdrawal.
6.2.2 Protocol Deviations
Protocol deviations will be reviewed, and those deviations that are regarded as major will be summarized. 
Major protocol deviations affecting effectiveness or safety assessment may include:
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STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
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•
Non-compliance regarding intake of IMP
•
Inappropriate intake of concomitant medication or background AEDs
•
Other non-compliance
Multiple deviations can occur in the same subject and thus a subject can be counted in more than one deviation 
category.
All protocol deviations will be presented in a subject data listing for the SAF population sorted by subject 
within study site.
6.2.3 Background and Demographic Characteristics
Subject demographics and baseline characteristics will be summarized for the SAF and mITT.
6.2.3.1 Subject Demographics/Baseline Characteristics
The following demographic characteristics will be summarized for the data at entry into 1503:
•
Age at Core Study entry [Years] / for de novo subjects, this will be the age at entry into 1503
•
Age Category( <6 years or ≥6 years)
•
Sex
•
Race
•
Ethnicity
•
Height [m]
•
Weight [kg]
•
BMI [kg/m2]
All subject demographics data will be listed for the SAF populations.
6.2.3.2 Other Baseline Characteristics
Epilepsy/seizure history will be descriptively summarized as per data type (continuous or categorical). 
All subject baseline characteristics will be listed for the SAF population.
6.2.4 Treatment Exposure and Compliance
6.2.4.1 Treatment Exposure
Treatment exposure data will be summarized for subjects’ time on treatment in Study ZX008-1503 only and 
analyzed for the SAF population.
Duration of total exposure to fenfluramine hydrochloride (i.e., time on treatment (in days)) will be calculated 
per subject as the number of days with IMP intake during the trial, as follows:
Duration of exposure = Date of last IMP intake – Date of first IMP intake + 1
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STATISTICAL ANALYSIS PLAN
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ZX008-1503
CONFIDENTIAL
Page 34 of 76
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The number of days exposed to fenfluramine hydrochloride will be summarized overall and by treatment 
group using n, mean, standard error, median, minimum, Q1, Q3 and maximum.
The actual dose of medication consumed will be calculated and summarized overall and by treatment group 
using n, mean, standard error, median, minimum, Q1, Q3 and maximum.
The shift in dosage of ZX008 will be presented at each scheduled visit starting from Visit 3 – OLE Month 1 
and going to Visit 16 – OLE Month 36 or End of Study. At the visit, the number of subjects who attended the 
visit will be provided with the dosage of ZX008 assigned to the subject at the last study drug dispense prior to 
the visit and the dosage of ZX008 assigned at the conclusion of the visit.
The duration of exposure to fenfluramine hydrochloride will be summarized in monthly periods based on the 
mean daily dosage in mg/kg/day and in mg/day. In addition, the duration of time in days based on the assigned 
dosage in mg/kg/day will be summarized. For the actual dosage summary, the periods where a subject has had 
a particular dosage assigned may not be concurrent.
6.2.4.2 Compliance to IMP Intake
Study medication is to be administered twice daily, and 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 to IMP intake 
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 compliance score will be thus obtained.
Compliance will be summarized for the SAF and mITT populations.
6.2.5 Prior and Concomitant Medications and/or Therapies (Non-medications)
Data are collected on the following CRFs:
•
Prior AEDs (Prior AED)
•
Concomitant AEDs (Con AED)
•
Prior and concomitant medications (MEDS)
•
Prior Non-medications (Prior Non-Meds)
•
Concomitant non-medications (Con Non-Med)
Rescue medications are recorded in subjects’ diary, however the CRF obtains a code list of a subject’s planned 
rescue medications. This section does not discuss details of rescue medication use.
Medication (collected on the prior/concomitant medication eCRF page) will be coded using the World Health 
Organization Drug Dictionary (WHO-DD).
The following algorithm will be used to define prior/baseline and concomitant medications/therapies:
Medications/therapies can be prior/baseline only, concomitant only, or prior/baseline and concomitant, 
depending on the start and stop dates.
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STATISTICAL ANALYSIS PLAN
Zogenix International Limited
ZX008-1503
CONFIDENTIAL
Page 35 of 76
v3.0:
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•
Any medication/therapy whose start and stop dates were before the start of study medication in Study 
ZX008-1503 will be considered as a prior/baseline medication.
•
Any medication initiated after commencement of study drug in Study ZX008-1503 will be regarded as 
being only concomitant.
•
Medications that were initiated before study drug was started in Study ZX008-1503 and ended during 
or after the study will be considered as prior/baseline and concomitant.
The medication will be assumed to be prior/baseline medication if it cannot be definitively shown that the 
medication did not start or continue during the OLE treatment period.
If the start date or stop date of a medication/therapy 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/therapy is complete and occurs on or after the day of the first dose in 
1503, the medication will be assumed concomitant only. If the start date occurs prior to the first 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/therapy will only be 
excluded as being concomitant (i.e. regarded as prior only) 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/therapy will only be 
excluded as concomitant (i.e., will be regarded as prior/baseline only) 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/therapy will be assumed a prior/baseline medication only.
Prior/baseline and concomitant medications/therapies will be summarized and sorted alphabetically, 
separately, 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/therapy, the number and percentage of subjects will be displayed.
Summary tables will be presented on the SAF population.
All prior/baseline and concomitant medications/therapies will be listed for the safety population.
6.2.6 Prior and Concomitant Antiepileptic Treatment
Treatments (collected on the prior/concomitant antiepileptic treatment eCRF page) will be coded using the 
World Health Organization Drug Dictionary (WHO-DD).
Prior and concomitant antiepileptic treatments will be defined and analyzed for the SAF population similar to 
concomitant medications as described in section 6.2.5.
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CONFIDENTIAL
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All prior and concomitant antiepileptic treatments will be listed for the SAF population.
6.2.7 Medical History
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 and current medications will be carried over from 
the core study. AEs starting during the core study will be counted as medical history if they conclude prior to 
start of 1503. Ongoing AEs will be included as such in 1503.
Medical history will be summarized and sorted alphabetically, by primary System Organ Class and Preferred 
Term coded via the most recent version of Medical Dictionary for Regulatory Activities (MedDRA). The 
number and percentage of subjects will be displayed for each System Organ Class and Preferred Term within 
treatment group.
Medical history will be presented for the SAF population.
6.3 EFFECTIVENESS ANALYSES
All effectiveness and exploratory data will be summarized overall and by treatment group in Core study as 
described in Section 3.2 of this SAP. 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. Point estimates and 95% confidence intervals will be calculated 
for key parameters as warranted. No formal comparison of treatment groups is planned.
Analyses of the key effectiveness endpoints will be performed on the mITT population, except where noted.
6.3.1 Convulsive Seizure Frequency
The key effectiveness endpoint is the change in the convulsive seizure frequency per 28 days between the pre-
ZX008 Baseline and OLE Treatment Period. To aid in assessing the effect of OL treatment after treatment 
with blinded fixed doses, CSF per 28 days will also be presented for each pre-OLE cohort for the last weekly 
measure in double-blind treatment (T+M) for the entire OLE treatment period, and separately for the first, 
second and third months of the OLE. In addition, CSF over the remainder of the OLE treatment period will be 
presented, for 3-month intervals. The next section defines variables associated with these endpoints.
6.3.1.1 Variables (Estimands)
Two key CSF-related variables will be defined:
•
(1) the difference in convulsive seizure frequency per 28 days (CSF) for the open-label Treatment 
Period (Day1 to EOS) compared to the Baseline (Core Study);
•
(2) the difference in CSF for the Month2 to EOS (Day 31 to EOS) time point compared to the Baseline 
(Core).
Additional variables associated with the assessment of CSF are:
•
Baseline (Core), Core Study (T+M), Core Study Final Week [Note: The Core Study Final Week is a 
subset of the Core Study (T+M) period.]
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•
CSF during the following time intervals: Month 1, Month 2, Month 3, Month 4-6, Month 7-9, Month 
10-12, Month 13-15, Month 15-18, Month 19-21, Month 22-24, Month 25-27, Month 28-30, Month
31-33 and Month 34-36.
The frequency of convulsive seizures during a given interval will be derived from the number and type of 
events recorded in subject diaries. For each subject, the seizure frequency per 28 days will be calculated as the 
number of seizures recorded during the period, divided by the number of days in the period and multiplied by
28. The convulsive seizure frequency will be calculated from all available data collected during the relevant 
interval.
The Baseline (Core) convulsive seizure frequency, or CSFBC, is calculated as in the Core Study using the CSF 
from the 42 days immediately preceding the Randomization visit in the Core Study. For any individual subject, 
the convulsive seizure frequency per 28 days during the baseline period (CSFBC) will be derived as follows:
ʹͺ ൈ          
CSF ൌ             
For each treatment group, the mean is obtained by averaging over the subjects in the treatment group.
The convulsive seizure frequency per 28 days for the Core Study T+M period (CSFCTM) is defined below:
ʹͺ ൈ          ൅ 
CSF ൌ         ൅    
The convulsive seizure frequency per 28 days for the Core Study Final Week of T+M (CSFCSFW) is defined 
below:
ʹͺ ൈ          
CSF	 ൌ             
Additionally for the other intervals (Month 1 through Month 36) defined in Table 7a, the convulsive seizure 
frequency per 28 days for that interval, CSFOLE, i, i=1, 2, 3, … , 14, is defined as follows:
ʹͺ ൈ       𝑡ℎ
CSFǡ  ൌ      𝑡ℎ    
The two key effectiveness measures, CSFE1 and CSFE2, will be calculated as follows:
ʹͺ ൈ       ͳ  
CSFͳ ൌ      ͳ      
ʹͺ ൈ       ͵ͳ  
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For each analysis group, the mean is obtained by averaging over the subjects in the analysis group.
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6.3.1.2 Changes from Baseline
In all seizure analyses, the Baseline (Core) value will be the baseline used. These analyses exclude the subjects 
from Study ZX008-1504 Cohort 1. For any of the variables defined in the previous section, the change from 
baseline for any individual subject will be calculated as
CCSF = Post-baseline value – CSFBC
The percentage change from baseline for any individual subject will be calculated as 
PCCSF = (Post-baseline value – CSFBC) *100 / CSFBC
The key effectiveness measures are CSFE1 and CSFE2. Summary statistics for the changes from baseline and 
the percentage changes from baseline will also be presented. A Wilcoxon signed rank test will be used to 
assess the significance of the change from baseline. Given that baseline refers to the period prior to initiation 
of double-blind treatment in the Core study, it is expected that long-term treatment with ZX008 will lead to a 
reduction in convulsive seizure frequency. If we designate the mean baseline (core) CSF by µBC, and the mean 
for CSFE1 and CSFE2 by µE1 and µE2, respectively, the key effectiveness objective is to test the null hypothesis
Ͳǣ 𝜇ͳ −𝜇 ൌͲ,
Against the alternative
ǣ 𝜇ͳ −𝜇 ≠Ͳ,
Rejection of the null hypothesis in favor of the alternative, in the presence of a statistically significantly 
smaller mean convulsive seizure frequency during OLE Treatment (two-sided p-value < 0.05) will be regarded 
as evidence of a treatment benefit.
In a similar manner, each of the changes over time will be summarized and assessed for statistical significance. 
The summary statistics and statistical testing will also be presented by age group.
A graph of the CSF for baseline (Core), Core Study (T+M), and during OLE Month 1 …36 will be generated, 
and another graph of the percentage changes from baseline may be plotted.
6.3.1.3 Treatment Group Estimates – Endpoint Analyses
The analysis of covariance (ANCOVA) analyses described in this section exclude de novo subjects. The 
convulsive seizure frequency per 28 days during the entire OLE Treatment period and the convulsive seizure 
frequency per 28 days during Month 2 to EOS, CSFE1 and CSFE2, respectively, will each be analyzed using an 
ANCOVA model with age group (<6 years, ≥6 years) and treatment group (4 levels) as factors, and CSFBC and 
CSFCTM as continuous covariates. The goal of this analysis is to estimate the seizure frequency during (1) the 
entire OLE treatment, and (2) during Month 2 to EOS, for each of the treatment groups included in the OLE, 
after adjusting for the other factors in the model. To avoid taking the logarithm of 0, a value of 1 will be added
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to a covariate and/or response prior to taking logs. From the general linear model, least squares estimates of 
treatment means and the corresponding 95% confidence intervals, will be exponentiated and a value of 1 
subtracted from the result, (to offset the addition of 1 prior to taking logs), in order to provide estimates and 
associated 95% confidence intervals on the original scale for the response variable.
Since the ANCOVA relies on assumptions of normality, the analysis will be repeated using a nonparametric 
method that does not require as stringent assumptions. A nonparametric ANCOVA will be used to analyze the 
data, with ranks of the CSFBC, and ranks of the CSFCTM as covariates and ranks of the response (CSFE1 or 
CSFE2); other terms/factors in the model will be the same as for the parametric ANCOVA.
Due to certain portions of the core studies remaining blinded, the ANCOVA analyses described in this section 
will not be submitted with the Japanese interim analysis.
6.3.1.4 Treatment Group Estimates – CSF Over Time
The general linear mixed effects model with repeated measures (i.e. MMRM) described in this section exclude 
de novo subjects. Analyses will be performed for the convulsive seizure frequency per 28 days, over time. In 
these analyses, the CSFCSFW will not be included in the model. A MMRM will be employed to estimate the 
mean convulsive seizure frequency per 28 days, over time, for each treatment group. The model will include 
CSFBC and CSFCTM as fixed covariates; time (14 levels for Month1, Month2, Month3, Month 4-6, Month 7-9, 
Month 10-12, Month 12-15, Month 16-18, Month 19-21, Month 22-24, Month 25-27, Month 28-30, Month
31-33, and Month 34-36) as a fixed effect; age stratum (2 levels) as a fixed effect; treatment group (4 levels) as 
a fixed effect; and subject as a random effect.
CSF will be log transformed prior to analysis, and a value of 1 may be added to avoid taking the logarithm of 
0.
The purpose of this modeling is to obtain least-squares adjusted means over time for the frequency of 
convulsive seizures per 28 days along with 95% confidence intervals.
While we seek to estimate the means over time, the variances and covariances are nuisance parameters and 
need to be estimated to provide associated standard errors for the treatment estimates. For the MMRM, an 
unstructured covariance matrix will be used. [If the model experiences convergence issues, a different 
covariance structure may be explored from the available choices in SAS PROC MIXED, and the covariance 
structure with the smallest AIC will be chosen.]
The model adjusted means and associated confidence limits will be plotted against time.
Furthermore, exploratory analysis will be carried out using a general linear model that includes the mean daily 
dose during OLE period (categorized as low, medium, and high) as explanatory variable, and the same factors 
used in the MMRM described above.
Due to certain portions of the core studies remaining blinded, the MMRM analyses described in this section 
will not be submitted with the Japanese interim analysis.
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6.3.1.5 Seizure Frequency by Dose
Additional analyses will be performed to examine the convulsive seizure frequency over time, reported as per 
28 days, by the actual dose administered.
Subjects will be grouped into low, medium, and high dose groups depending on their mean daily dose of 
ZX008 during the OLE Treatment period:
•
Low: 0.2 to <0.4 mg/kg
•
Medium: 0.4 to <0.6 mg/kg
•
High: >0.6 mg/kg.
The parametric ANCOVA for the endpoint analysis will be repeated using these three dose groups in place of 
the four treatment groups, excluding de novo subjects.
Similarly, a nonparametric ANCOVA will be performed using these dose groups, excluding de novo subjects.
Due to certain portions of the core studies remaining blinded, the ANCOVA analyses described in this section 
will not be submitted with the Japanese interim analysis.
6.3.1.6 Impact of Concomitant AED Medication Use on Seizure Frequency
Subjects in the study were required to be on stable background therapy for the first 6 months of treatment, after 
which background AEDs could be reduced or withdrawn so long as one background AED remained. The 
percentage of subjects who had changes in dose or type of concomitant AED medications during the first, 
second, third, fourth, fifth, and sixth months will be summarized by treatment group and overall.
6.3.2 Other Effectiveness Analyses – Seizure Related
6.3.2.1 Non-convulsive Seizure Frequency per 28 Days
Similar methods as described above will be used to assess the frequency of non-convulsive seizures per 28 
days.
6.3.2.2 Convulsive and Non-convulsive Seizure Frequency per 28 Days
The frequency of seizures (convulsive and non-convulsive) will be analyzed using methods similar for the 
analysis of convulsive seizure frequency per 28 days as described above.
6.3.2.3 Percentage of Subjects with ≥50% Reduction from Baseline
A response curve will be generated for the mITT population. This graph will plot the percentage of subjects
(y-axis) against percentage reduction in seizure frequency per 28 days in the OLE treatment period (x-axis). In 
the graph, subjects experiencing an increase in seizure frequency will be regarded as having a 0% reduction in 
seizure frequency. Hence, the ordinate for time point 0 may not necessarily be at 100%. For example, if 15% 
of subjects have no reduction in seizure frequency between baseline and OLE Treatment period, the graph will 
start on the y-axis at 85%. The graph will be generated for all subjects (excluding de novo subjects), and for 
each age stratum and each treatment group. A separate graph will be generated for de novo subjects.
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A point estimate and 95% confidence interval for the percentage of subjects achieving a ≥50% reduction from 
baseline (Core) to OLE Treatment period, and monthly periods of the OLE will be computed. This will be 
repeated for the Month 2 to EOS endpoint. The confidence interval for the proportion will be based on the 
normal approximation to the binomial distribution. The analysis will be computed for the mITT population 
excluding de novo subjects, and, separately, for the de novo subjects.
Similar methods will be used to estimate the proportion of subjects who achieve a 25%, reduction, 75% 
reduction, and 100% reduction in seizures.
6.3.2.4 Duration of the Longest Interval between Seizures
The duration of the longest interval (in days) between convulsive seizures will be analyzed.
For each subject, the longest interval between convulsive seizures will be calculated over the entire OLE 
period. This will be derived as the maximum of the number of days between consecutive convulsive seizures. 
The intervals between consecutive convulsive seizures (gaps) will be calculated as below, after which the 
longest interval between convulsive seizures will be derived.
If a subject has two consecutive days of missing diary data, the current seizure-free interval will be ended 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 convulsive seizure occurrence, until the first available date 
with non-missing diary data.]
Let Date0 (=Day1) be the first day of treatment. If convulsive seizures occur 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 OLE treatment period, where LDT ≥ Date5, then the time interval between 
convulsive seizures will be calculated as follows:
I1=Date2 - Date1 
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I4=Date5 – Date4.
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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
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The median time of the longest convulsive seizure-free interval will be presented. Additional summary 
statistics will be presented, including mean, minimum, maximum, and the 25th and 75th percentiles, 95% 
confidence intervals for the percentiles using the normal approximation to the binomial distribution. Analyses 
will be presented for the mITT population (excluding de novo subjects), de novo mITT subjects, and all mITT 
subjects.
A boxplot of the duration of the longest interval (in days) between seizures will be presented. The boxplot will 
be presented for the mITT population (excluding de novo subjects), de novo mITT subjects, and all mITT 
subjects.
A summary of the recurrences of seizures and the gap times between seizures will also be presented. [The 
duration of the longest interval between convulsive seizures is closely related to the maximum gap time.]
6.3.2.5 The Number of Convulsive Seizure-free Days
Convulsive seizure-free days will be assessed based on the parent/caregiver diary data.
A convulsive seizure-free day will be defined as a day for which no convulsive seizures have been reported. 
Refer to Section 6.1.7, Missing Data. For each subject, the total number of convulsive seizure free days per 28-
day period will be summed for the entire OLE Treatment period, the Month 3 to EOS period, and similarly for 
the baseline (Core) period.
Seizure free days per 28 days at baseline = (number of seizure free days during baseline in Core study)*28/ 
(number of days during baseline with non-missing diary data)
Seizure free days per 28 days during OLE Treatment Period = (number of seizure free days during OLE 
Treatment Period)*28/ (number of days during OLE Treatment Period with non-missing diary data)
A summary of this effectiveness endpoint will be provided over time (baseline (Core), Core Study (T+M), and 
OLE Month.
A MMRM will be employed with factors for subject (random effect), age group (2 levels), time, age 
group*time interaction as factors, and baseline (Core) and Core Study (T+M) as covariates. Least squares 
estimates for each age group, over time, will be obtained, along with associated 95% CIs.
Additional analysis will be done using the mean daily dose over time by grouping subjects into low, medium, 
and high dose groups. An MMRM will be employed, and least squares estimates of means for each age group 
will be obtained, along with associated 95% CIs. The MMRM will exclude de novo subjects.
6.3.2.6 Healthcare Utilization
6.3.2.6.1 Inpatient Hospitalizations Due to Seizures (All subjects)
Hospitalization data will be captured in the CRF.
Details of the hospitalizations, including reasons for hospitalization and use of resources will be summarized.
Summary statistics will include the number and percentage of subjects who experience at least one 
hospitalization to treat a seizure, as well as the incidence density.
6.3.2.6.2 Healthcare Utilization Questions (subjects from core study ZX008-1504 only)
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In order to better understand the healthcare resource burden associated with the management of Dravet 
syndrome, caregivers will be asked which of the following hospital and community based healthcare services 
they interacted with over the preceding month: emergency room services, ambulance, planned and unplanned 
hospitalization, family physician services, speech and language therapy, occupational therapy, and physical 
therapy. This information will be captured in the CRF.
Summary statistics will include the number and percentage of subjects who utilized these services.
6.3.2.7 Incidence of Status Epilepticus Episodes
The incidence of status epilepticus during the OLE treatment period will be evaluated based on cases captured 
as such with treatment at hospitals or other treatment centers, those entered as adverse events (including SAEs) 
into the safety database, and also as convulsive seizures lasting longer than 10 min from the seizure diary. A 
single seizure meeting more than one of these criteria will be counted once. According to the ILAE, seizures of 
this duration are to be considered SE.
The number and percentage of subjects with status epilepticus recorded as an AE will be presented by 
treatment group and overall.
In addition, from the diary data, the number and percentage of subjects having convulsive seizures with 
duration >10 min during OLE will be reported by treatment group and overall.
Additionally, the number and percentage of subjects having an SE episode or a seizure with duration > 10 
minutes will be summarized by treatment group and overall.
6.3.2.8 Duration of Prolonged Seizures
Duration of convulsive seizures at baseline and on treatment will be presented by treatment group and overall 
using categories as <2 min, 2-10 min and >10 min.
To obtain a baseline probability distribution for the three categories, we will proceed as follows: For each 
subject, we will calculate the percentage of their total number of baseline seizures that is in each category. (For 
example, if the subject had 5 seizures, with 2 in the first category and 3 in the last category, their percentage 
distribution would be 40%, 0%, and 60% in the <2, 2-10, and >10 categories. We can calculate similar 
numbers for the next subject, and so on.) We will then average these over all subjects to obtain the percentage 
of subjects’ seizures that were <2 min in duration, the percentage between 2-10 min in duration, and the 
percentage >10 min in duration. These 3 percentages should total 100%. Thus, we will obtain a distribution of 
seizure duration for baseline.
Using the seizure duration data obtained for the OLE period, we will proceed similarly, to obtain a distribution 
for the OLE period.
No formal analytic method will be used to assess the distribution of seizure duration during baseline vs. during 
the OLE treatment period. However, it is expected that the distribution may shift in such a way that a greater 
proportion of seizures during the OLE period will have shorter interval duration when compared to the 
baseline period.
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6.3.2.9 Incidence of 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. The second and third round might use different medications or different doses 
than the first round of rescue meds.
Rescue medication will be summarized:
•
The number of days rescue medication was taken (normalized to 28 days) will be summarized 
separately for the Baseline (Core), Month 1, Month 2, and Month 3 of the OLE Treatment Period by 
the mean (SD) as well as the median and range.
6.3.3 Other Effectiveness Analyses
For effectiveness rating scales administered at study visits, the overall goal is to analyze the data by visit. 
However, it is recognized that for a long-term study such as this, the time of the study visits might vary from 
pre-planned times established in the protocol. Therefore, in order to provide a common framework for the 
assessment of these measures, the time windows specified in Table 3 will be used. If multiple visits (scheduled 
or unscheduled) fall within a time window, the measurements obtained closest to the target time point will be 
used.
For each time point and parameter or subscale considered in these patient reported outcomes, an individual 
subject’s value is to be obtained for the parameter and time point. The subjects’ values are then the basis for 
obtaining treatment group means, standard deviations, etc. for the summary stats and changes form baseline.
6.3.3.1 Clinical Global Impression – Improvement Rating, as assessed by the Parent/Caregiver
The parent/caregiver will rate their global impression of the subject’s condition at each visit except Visit 2.
The CGI-I scale measures the perception in 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 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
At each assessment time point during the OLE treatment period, and at End Point (End of Study or Early 
Termination), frequency counts (and %) of scores by severity rating will be produced overall, and by treatment 
group.
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Descriptive statistics will be presented for the following dichotomized categories for each time point where 
measured, and for the last available or final (EOS/ET) assessment, and will include the number and % of 
subjects responding in the combined categories, along with an associated exact two-sided 95% CI.
(1) Very much improved or much improved, i.e., number of subjects with a score of 1 or 2; vs. others (3, 
4, 5, 6, 7)
(2) Improved, i.e., number of subjects with a score of 1, 2, or 3; vs others (4, 5, 6, 7)
This will be presented for the mITT population as a whole, by treatment group, and for de novo subjects. 
Individual subject data will be listed for CGI-I scale as assessed by the parent/caregiver.
6.3.3.2 Clinical Global Impression – Improvement Rating, as assessed by the Principal
Investigator
CGI-I score data assessed by the principal investigator will be analyzed by the same methods used for CGI-I 
score data recorded by parent/caregiver as above.
6.3.3.3 Quality of Life in Childhood Epilepsy (QOLCE) Scale
The parent/caregiver will complete the QOLCE. This assessment evaluates how epilepsy affects day-to-day 
functioning of a child with epilepsy in various life areas, including physical activities, well-being, cognition, 
social activities, behavior and general health, at baseline period (Core study) during the OLE Treatment 
period, and at EOS/ET (Visit 12). There is also one question on overall quality of life, administered as part of 
the QOLCE.
The QOLCE scores items with a possible 5-point response. [Not including “6”, “Not Applicable.”] 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. Item scores will then be 
transformed to a 0-100 scale as follows: 1 maps to 0, 2 maps to 25, 3 maps to 50, 4 maps to 75, and 5 maps to
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. The mean and standard deviation across all subjects are then calculated for each 
subscale, including the overall quality of life score. The higher the subscale and overall quality of life scores, 
the better the response.
Table 10: Subscales of the QOLCE
Domain
Subscale
Item
Section 3: Physical
Physical Restrictions
3.1 a-j
Section 3: Physical
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3.2 a,b
Section 4: Well-being
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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
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Domain
Subscale
Item
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 Item
8.1
Section 2 (USA Version) or Section 9 (Australia Version)
Quality of Life Item
2.1 or 9.1
Overall Quality of Life*
Average of 16 subscale scores*
*For each subject, an Overall Quality of Life Score will be computed by adding each subscale score for each individual and then 
dividing by 16.
Individual subject data for the domains will be listed.
For each subscale, descriptive statistics will be provided for the baseline, EOS/ET, and change from baseline 
subscale mean, overall, by treatment group and for de novo subjects.
For each treatment group at Baseline and End of Study/ET, the mean and standard deviation of the subscale 
score will be presented for each QOLCE subscale and for the Overall Quality of Life score.
In addition, the change from baseline in the Overall QOL score will be calculated for each subject by 
subtracting the baseline overall score from the overall score measured at End of Study/ET. The change from 
baseline for each treatment group will be summarized using the mean and standard deviation. Statistical 
significance of the within group change from baseline will be assessed using a Wilcoxon signed rank test.
Individual subject data for the subscales will be listed.
6.3.3.4 Quality of Life of the Parent/Caregiver using EQ-5D-5L Scale
The impact on the quality of life of the parent/caregiver responsible for a patient with DS will be assessed at 
Baseline (Core Study) and during the OLE Treatment period using the EQ-5D-5L.
The EQ-5D-5L health questionnaire is a health-related quality of life instrument with five dimensions: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has five possible 
levels: no problems, slight problems, moderate problems, severe problems and extreme problems.
The summary of results will follow the EQ-5D-5L guideline results presentation. For the “Health Profiles” 
descriptive system summary results will show the number, and percentage of subjects in each Item score (No 
Problems, Slight Problems, Moderate Problem, Severe Problem, Extreme Problems) overall and by treatment 
group, at baseline (Core), during the OLE treatment period and at EOS/ET. In addition, the item scores will be 
classified into two categories as “No Problems” and “Problems” comprised of items: slight, moderate, severe 
and extreme problems. Summary results will show number of patients and percentage with “No Problems” and 
with “Problems” overall, by treatment group and for de novo subjects, at baseline, during OLE Treatment 
period, and at EOS/ET.
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In addition, the item scores will be again be classified into two categories as “Slight/No Problems” and 
“Moderate/Severe/Extreme Problems”. Summary results will show number of patients and percentage with 
“Slight/No Problems” and with “Moderate/Severe/Extreme Problems” overall and by treatment group, at 
baseline, during OLE Treatment period, and at EOS/ET.
For the VAS measure of overall self-rated health status, descriptive statistics will be presented for the VAS 
absolute score and change from baseline showing number of subjects, mean, standard deviation, median, and 
range overall and by treatment group at baseline (Core), during OLE treatment period, and at EOS/ET. 
Statistical significance of the within group change from baseline will be assessed using a Wilcoxon signed 
ranks test.
The quality of life of parent/caregiver individual data will be listed using EQ-5D-5L scale.
6.3.3.5 Parent/Caregiver HADS Rating Scale
The HADS is a tool commonly used to determine the levels of anxiety and depression that a person is 
experiencing and is validated as a patient screening tool in the outpatient setting though it has not been 
validated specifically for caregivers. It is a 14-item scale that generates ordinal data for two dimensions: 1) 
Anxiety, and 2) Depression. Seven of the items relate to anxiety and seven relate to depression. Each item has 
four possible answers rated 0-3. All answers to the items for a dimension with their respective rating are added 
resulting in a range for each dimension from 0-21. Scores for the entire scale (emotional distress) range from 0 
to 42, with higher scores indicating more distress.
For the Anxiety and Depression dimensions, summary descriptive statistics including the mean and SD will be 
generated separately for the Anxiety and Depression dimensions at each visit. In addition, for the anxiety and 
depression scales but not the total score, each subject will be categorized at each visit based on the score cut-
offs below:
Score
Interpretation
0-7
Normal
8-10
Borderline abnormal
11-21
Abnormal
Summary statistics will include number and percentage of subjects in each of the categories above at each 
study visit.
In addition, the total score for Anxiety and total score for Depression will be calculated. Descriptive statistics 
including mean, standard deviation, median, minimum and maximum will be provided overall and for each 
treatment group, at baseline, during OLE treatment period and at EOS/ET. The change from baseline for each 
subject will be calculated by subtracting the total Anxiety and Depression score measured at Baseline from the 
analogous score measured at End of Study/ET. The change from baseline will be summarized by descriptive 
statistics as well as 95% CI for the change from baseline. A Wilcoxon signed ranks test will be used to obtain a 
p-value for change from baseline.
The individual item outcomes will be presented in the subject data listing.
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6.3.3.6 Pediatric Quality of Life Inventory (PedsQL 4.0 Generic Core) Scale
The PedsQL 4.0 is a quality of life scale that measures four functional areas (physical, emotional, social, and 
school functioning). The scale is available in age-appropriate instruments with child self-report and parent 
proxy-report formats. In this study, the age appropriate categories for the administration of the instrument were 
ages 2-4, 5-7, 8-12 and 13-18 years, and the Parent Reports were used.
There are eight items for Physical Functioning (PF), and five questions each for Emotional Functioning (EF), 
Social Functioning (SoF), and School Functioning (ScF). Each of the responses to the 23 items is initially 
scored on a 5-point Likert scale from 0 (Never) to 4 (Almost always). Scores will be linearly transformed to a 
scale of 0 to 100, where 0=100, 1=75, 2=50, 3=25 and 4=0, and higher scores mean better health related 
quality of life. If more than 50% of the items in the scale are missing, the scale scores should not be computed. 
For each subject, a mean score is calculated for each scale (PF, EF, SoF, ScF) as the sum of the scores for 
items in that scale over the number of items answered. If some of the answers on a scale are missing but 50% 
or more of the items in the scale are completed, then impute the mean of the competed items in a scale. The 
scaled results will be combined across age categories to produce a single score for each functional area.
A Psychosocial Health Summary score is computed as the sum of the items over the number of items answered 
in the Emotional, Social, and School Functioning Scales.
A Physical Health Summary score is made up of the Physical Functioning Scale Score.
The Total Score is computed as the sum of all the items over the number of items answered on all the Scales.
Descriptive statistics for all subjects and by treatment group, at baseline, during OLE treatment period and at 
EOS/ET will be provided for the Psychosocial Health Summary score, the Physical Health Summary score and 
Total score.
The change from baseline for the Total score will be calculated for each subject by subtracting the Total score 
measured at Baseline from the Total score measured at End of Study/ET. The change from baseline will be 
summarized with descriptive statistics and the within group changes from baseline will be tested from 
significance from 0 using a Wilcoxon signed ranks test.
6.3.3.7 Pediatric Quality of Life Inventory (PedsQL 2.0 Family Impact Module) Scale
The PedsQL™ Family Impact Module was designed to measure the impact of pediatric chronic health 
conditions on parents and the family. The PedsQL™ Family Impact Module measures parent self-reported 
physical, emotional, social, and cognitive functioning, communication, and worry. The Module also measures 
parent-reported family daily activities and family relationships.
There are six items for Physical Functioning (PF), five items each for Emotional Functioning (EF), Cognitive 
Functioning (CF) and Worry (W), four for Social Functioning (SoF), and three for Communication (c). There 
are additionally three questions for Daily Activities (DA) and five for Family Relationships (FR).
Each of the responses to the 36 items is initially scored on a 5-point Likert scale from 0 (Never) to 4 (Almost 
always). Scores will be linearly transformed to a scale of 0 to 100, where 0=100, 1=75, 2=50, 3=25 and 4=0, 
and higher scores mean better health related quality of life. If more than 50% of the items in the scale are 
missing, the scale scores should not be computed. For each subject a mean scale score is calculated for each 
scale (PF, EF, CF, W, SoF, C, DA, FR) as the sum of the scores for items in that scale over the number of
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items answered. If some of the answers on a scale are missing but 50% or more of the items in the scale are 
completed, then impute the mean of the competed items in a scale.
The Parent HRQL Summary Score (20 items) is computed as the sum of the items divided by the number of 
items answered in the Physical, Emotional, Social, and Cognitive Functioning scales.
The Family Functioning Summary Score (8 items) is computed as the sum of the items divided by the number 
of items answered in the Daily Activities and Family Relationships scales.
The Total Score is the sum of all 36 items divided by the number of items answered.
Descriptive statistics for baseline and EOS/ET will be provided for the summary scores. The change between 
baseline and EOS/ET in the Summary Scores and Total score will be assessed for significance using a 
Wilcoxon signed-rank test.
6.3.3.8 Study Medication Palatability Assessment
The palatability and acceptability of the IMP will be assessed indirectly by the parent/caregiver responsible for 
the patient according to the schedule in Table 1 using three questions:
QUESTION 1: Over the past month, on the basis of the reaction ⁄ facial expression of your child, do you think 
that the medicine’s taste and texture are:
•
Acceptable to your child
•
Not acceptable to your child
QUESTION 2: Over the past month, please rate how much your child likes/dislikes the medicine’s taste using 
the following grading scale:
•
5 (likes it very much)
•
4 (likes it)
•
3 (neither likes it or dislikes)
•
2 (dislikes it)
•
1 (dislikes it very much)
QUESTION 3: Over the past month, do you sometimes have problems giving the medicine to your child due 
to its taste or texture?
•
No
•
Yes
o
How often?
▪
Every day in the past month
▪
Once to several times every week in the past month
▪
Once or several times in the past month
Palatability will be assessed through descriptive statistical methods. For example, the percentage of parents or 
caregivers who consider the medicine’s taste and texture to be acceptable to the child will be presented along 
with a 95% CI at each time point data are available.
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6.3.4 Exploratory Analysis (in subjects from core study ZX008-1504 only)
The following exploratory effectiveness endpoints will be assessed for subjects from ZX008-1504 from whom 
these data are obtained.
6.3.4.1 Sleep Quality and Mealtime Behavior Questions
The parent/caregiver will be asked to indicate the appropriate response that adequately describes their child’s 
sleep quality and eating behavior since starting IMP based on the following questions:
1.
Since your child has started taking the study medication in this study, have you noticed that s/he has 
been waking in the middle of the night or very early in the morning more than usual?
o
My child’s sleep is more disturbed than it was before s/he started the study medication
o
My child’s sleep patterns are the same as they were before starting the study medication
o
My child sleeps better than s/he did before starting the study medication
2.
Since your child has started taking the study medication in this study, have you noticed that s/he has 
had a change in their mealtime behavior?
o
My child has worse mealtime behavior since starting the study medication
o
My child’s mealtime behavior has not changed since starting the study medication
o
My child has improved his/her mealtime behavior since starting the study medication
The responses will be summarized using counts and percentages.
6.3.4.2 Karolinska Sleepiness Scale
The Karolinska Sleepiness Scale will be administered according to the schedule in Table 1. The Karolinska 
Sleepiness scale is a self-report scale that measures the subject’s drowsiness. It is a 9-point verbally anchored 
scale, which ranges from ‘extremely alert’ at one end of the scale to ‘extremely sleepy – fighting sleep’ at the 
other end of the scale. Within this study, the scale will be completed by the observer. The scale scores 
(responses) are as follows:
Table 11: Karolinska Sleepiness Scale Score Description
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Scores of 1-6 may be categorized as “active” and scores of 7-9 may be categorized as “sleepy”. 
Assessments will be made at Visit1 (Baseline), and each visit from Visit 3 through Visit 16.
The categories will be summarized using counts and percentages for each time point.
The scores will be summarized using mean, standard deviation, median, minimum and maximum, for baseline 
and time point.
6.4 SAFETY ANALYSIS
Safety will be assessed through evaluation of AEs, Laboratory data (hematology, chemistry, urinalysis), vital 
signs (blood pressure, heart rate, temperature, and respiratory rate), Physical examination, Neurological 
examination, 12-lead ECGs, Doppler ECHOs, Tanner Staging, BRIEF to measure cognition, and Columbia–
Suicide Severity Rating Scale.
All safety analyses will be performed for the SAF population and will be reported for all subjects overall. 
Select analyses may be repeated by treatment group, for example, treatment-emergent adverse events initiating 
on or before Visit 2 (Week 2), Visit 3 (Month 1), and Visit 4 (Month 2).
6.4.1 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. The period of 
observation for adverse events extends from the time the subject gives informed consent until 15 days after the 
last dose of study drug or the last visit, whichever is later. For patients who continue into the open-label 
extension study, AEs from the core studies will be considered medical history unless there is an increase in the 
frequency or severity of the condition from the core study.
A TEAE is defined as any AE that based on start date information occurs after the first intake of study 
treatment. All other AEs occurring after enrollment and prior to the first administration of study treatment are 
defined as non-treatment emergent AEs (non-TEAEs).
AEs are categorized as related or not related to IMP. Per protocol, the following rule was used to assess 
causality of an AE to IMP:
•
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.
Any missing relationship/causality assessment will be considered as “related.”
The severity of AEs (whether non-serious or serious) will be assessed by the investigator as follows:
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•
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.
Per the CDISC SDTM Severity Intensity Scale for Adverse Event Terminology, any 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 most recent 
version of the MedDRA implemented by the sponsor at the end of the study.
6.4.1.1 Overview of Adverse Events:
The number and percent of patients with at least one of the following events will be summarized in an overall 
summary table:
•
TEAE
•
Serious TEAE
•
Related TEAE
•
Related serious TEAE
•
Severe TEAEs
•
Adverse events of special interest
•
Deaths
The percentage denominator for the calculation of percentage will be the number of subjects in the SAF 
population. The above summary will be provided for the OLE treatment period.
6.4.1.2 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
•
All TEAEs occurring in ≥5% of subjects
•
Serious TEAEs
•
TEAEs by Maximum Severity
•
TEAEs by prior treatment group, with onset before or up to Visit 1, Visit 2; Visit 3; Visit 4
•
Study Drug Related TEAEs
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•
Study Drug Related TEAEs occurring in ≥5% of subjects
•
All AEs that lead to premature discontinuation from the study
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.
These summaries will be provided for the OLE treatment period. 
Additionally, 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
6.4.2 Adverse Events of Special Interest (AESI)
As per ICH guidance (E2F Development Safety Update Report [2011]), the Sponsor has identified the 
following AESIs for the ZX008 program.
Table 12 Adverse Events of Special Interest:
Metabolic/Endocrine
1.
Elevated prolactin level ≥2x above the upper limit of normal (ULN)
2.
Hypoglycemia – serum blood glucose more than 20% below the glucose level on Study Day -1 value or
more than 10% below LLN (reference range 60 – 140 mg/dL)
Neuropsychiatric
1.
Suicidal thoughts, ideation or gestures
LLN = lower limit of normal; ULN = upper limit of normal
The following summary tabulations will be provided to explore the AEs of special interest:
•
AEs with decreased appetite or hypophagia
Adverse events of special interest will be summarized overall, and by treatment group, ZX008 combined and 
overall by system organ class and preferred term for the OLE treatment period.
All adverse events of special interest will be listed separately.
6.4.3 Physical Examination
A complete physical examination will be performed at Visit 1 and EOS/ET visit (Visit 16), and at the Cardiac 
follow-up visits (Visit 17 and 18). An abbreviated physical exam is performed at Day 15 (Visit 2), Visit 3 
through Visit 16 (Days 30, 60, 90, 180, 270, 365, 455, 545, 635, 725, 815, 905 and 995)
All physical examination results will be presented in a subject data listing, including the description of 
abnormalities.
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6.4.4 Neurological Examination
A complete neurological examination will be performed at baseline (OLE) Visit (Visit 1) and at EOS / ET 
(Visit 16).
All neurological examination results will be presented in a subject data listing, including the description of 
abnormalities.
6.4.5 Vital Signs, Weight, and BMI
Vital signs data including blood pressure, heart rate, temperature, respiratory rate, weight, and BMI will be 
documented for subjects during study Visits 1 through Visit 16 (EOS/ET).
The actual value and change from baseline (OLE) to each on-study evaluation time point will be summarized 
for vital signs and weight overall and by treatment group. Vital signs, weight and BMI data will be presented 
for each patient in a data listing.
A listing of subjects with Potentially Clinical Significant vital sign results will be provided. In this listing, 
those values outside the sponsor defined alert ranges will be marked and further available details about clinical 
relevance and diagnosis will be added.
Descriptive statistics will be provided for weight over time at baseline (OLE), and every 3 months during the 
OLE treatment period, for all subjects in the safety population. For the same time periods, the percent of 
subjects who lost at least 7% or 10% of their body weight during OLE when compared to baseline (OLE) will 
be summarized. Similarly, the percent of subjects who gained 7% or 10% of their body weight during OLE 
when compared to baseline (OLE) will be summarized. For subjects who lost at least 7% of their body weight, 
the number who achieved a recovery to their baseline (OLE) weight, and the duration of time to recovery, will 
be summarized. Recovery will be defined as achieving a weight, after the ≥ 7% reduction, which is at least 
99% of the baseline (OLE) weight at two separate, consecutive assessments. 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 at least two consecutive study visits, at 
least 99% of the baseline (OLE) weight. A similar analysis of 5% weight loss and weight gain will be 
conducted.
In addition, weight will be summarized by age group (2-<4; 4-<6; 6 to<12; and ≥12 years). 
A scatterplot will plot height and age for subjects at the end of the OLE period.
6.4.6 Electrocardiogram
12-Lead ECGs data will be obtained during study at baseline (Core study), baseline (OLE), Visit 1, and Visit 3 
through Visit 16 (End of Study/ET) and at Cardiac Follow-up (Visits 17 and 18).
A separate report will be provided by the ECG vendor.
6.4.7 Doppler Echocardiography
Doppler echocardiography will be conducted at a facility with experience for the subject’s age at baseline 
(Core study), baseline (OLE), Visit 1, and Visit 3 through Visit 11, at End of Study/ET (Visit 16) and at 
Cardiac Follow-up (Visits 17 and 18).
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A separate report will be provided by the ECHO vendor.
6.4.8 Tanner Staging
Tanner Staging will be assessed for subjects >7 years old during the study at baseline (Core) period, baseline 
(OLE), and at Visit 3 through Visit 15 and EOS/ET (Visit 16). 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 baseline (Core) and EOS by 
treatment group separately for boys and girls.
All Tanner staging data will be presented in the subject data listing.
6.4.9 Laboratory Parameters
Blood samples for clinical laboratory evaluation will be obtained at each study visit as indicated in the 
schedule of assessments given in Table 1. Laboratory safety parameters will be analyzed by a central 
laboratory using standard validated methods.
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
•
Epilepsy genotype panel
•
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.
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ZX008-1503
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•
Urine pregnancy test: Urine pregnancy testing will be performed in female subjects of childbearing 
potential.
•
Urine THC panel
Observed continuous laboratory data will be descriptively summarized by type of laboratory test/parameter 
overall and by treatment group. Changes from baseline will also be presented for all continuous laboratory 
parameters overall and by treatment group over time.
Categorical laboratory parameters will be summarized by presenting the number and percentage of subjects by 
visit for all subjects and by treatment group.
All laboratory values (including invalid values, reference ranges, and possible flags (low, high,)) will be 
presented in the subject data listings.
A listing of subjects with extreme laboratory results will be provided.
6.4.10 Columbia-Suicide Severity Rating Scale
The Columbia–Suicide Severity Rating Scale (C-SSRS) is an assessment tool that evaluates suicidal ideation 
(including intent), and behavior. Baseline (core study) data were collected in the screening visit (Visit 1) of the 
Core study using the C-SSRS Children’s Baseline/Screening Assessment. For the current study, baseline 
(OLE) Treatment period data and Visits 3 through Visit 15 and EOS/ET (Visit 16) data are collected using the 
C-SSRS Children’s ‘Since Last Visit Assessment.
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.
If a subject with the intellectual capacity to complete the C-SSRS reaches 7 years of age during the study, use 
of the C-SSRS should be initiated at subsequent visits.
6.4.10.1 Suicidal Ideation
The following outcomes are C-SSRS categories and have binary responses (yes/no):
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Suicidal ideation is assessed as a “yes” answer at any time during the OLE treatment period to any one of the 
five questions (1-5) above. The number and percentage of subjects with suicidal ideation will be presented, as 
well as the number and percentage having a “yes” response to each category (1-5) at least once during the 
OLE period. The denominator will be the number of subjects completing the C-SSRS at least once during the 
OLE treatment period.
6.4.10.2 Suicidal Behavior
The following outcomes are C-SSRS categories and have binary responses (yes/no):
Suicidal behavior is assessed as a “yes” answer at any time during the OLE treatment period to any one of the 
five questions (6-10) above. The number and percentage of subjects who had suicidal behavior, as well as the 
number and percentage having a “yes” response to each category (6-10) at least once during the OLE period. 
The denominator will be the number of subjects completing the C-SSRS at least once during the OLE 
treatment period.
6.4.10.3 Suicidal Ideation or Behavior
An overall composite will be provided similar to the suicidal ideation and behavior composite endpoints but 
will instead count a subject if any of the C-SSRS questions 1 through 10 is marked as “yes” any time during 
the OLE period.
6.4.10.4 Self-injurious Behavior without Suicidal Intent
Self-injurious behavior without suicidal intent is also a C-SSRS outcome (although not suicide related) and has 
a binary response (yes/no).
The number and percentage of subjects having reported anytime during the OLE treatment period experiencing 
a ‘Self-injurious behavior without suicidal intent’ event (Question 11) will be provided.
6.4.11 Brief Rating Inventory of Executive Function (BRIEF, BRIEF-P, BRIEF-A)
The Behavior Rating Inventory of Executive Function (BRIEF™) , preschool version, BRIEF-P, and adult 
version (used for subjects aged 19-35), are standardized, validated rating scales to measure executive function 
in children within the home and school environments that will be assessed by the parent according to the 
schedule in Table 1.
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The BRIEF measures multiple aspects of executive functioning; scales include Inhibit, Shift, Emotional 
Control, Initiate, Working Memory, Plan/Organize, Organization of Materials and Monitor.
The original BRIEF was the basis for the development of the BRIEF-P. The BRIEF-P Rating Form consists of 
63 items that measure various aspects of executive functioning: Inhibit Shift, Emotional Control, Working 
Memory, and Plan/Organize.
The BRIEF-A Rating Form consists of 75 items that measure various aspects of executive functioning. Nine 
overlapping scales are created.in two different indexes. For the BRIEF-A, the BRI is composed of four scales: 
Inhibit, Shift, Emotional Control, and Self-Monitor. The Metacognition Index is composed of five scales: 
Initiate, Working Memory, Plan/Organize, Task Monitor, and Organization of Materials. The BRI and MI 
combine to yield the GEC Index.
For the BRIEF, BRIEF-P, and BRIEF-A, mean scores at Baseline, End of Study/ET and mean change from 
baseline to End of Study/ET, and descriptive statistics will be presented by treatment group and overall for the 
Safety population (SAF).
6.5 PK/PD ANALYSIS
Not applicable.
6.6 ANALYSIS OF OTHER ASSESSMENTS
Not applicable
6.7 INTERIM ANALYSIS
Accumulating safety data from this study may be provided to and be reviewed by the Sponsor and its 
representatives and/or to an Independent Data and Safety Monitoring Committee (IDSMC) or regulatory 
authority as needed in order to fulfill regulatory requirements.
A planned interim analysis was conducted to support product registration. All subjects who had enrolled in the 
study on or before March 13, 2018 were included in the analysis. The data cutoff for the interim analysis was 
April 27, 2018. All CRF and vendor data obtained on or before April 27, 2018 were included, and electronic 
diary data obtained up to June 18, 2018, for subjects enrolled on or before March 13, 2018, were included.
The specific list of TFLs that were presented in the interim analysis were delineated in the Table of Contents 
for the TFL shells.
Additionally, data on all subjects were included in the Integrated Summary of Effectiveness and the Integrated 
Summary of safety for the ZX008 NDA. Within the ISS and ISE, data presentations for subjects from Study 1 
and Study ZX008-1504 Cohort 2 were designated by their double-blind treatment regimens since those data 
had been unblinded at the time of the NDA submission.
An interim cut and analysis of subjects enrolled from Japan will be completed after all subjects from Japan 
have reached the 3 Month time point in the study. The specific list of TFLs that will be presented in the interim 
analysis are delineated in the Table of Contents for the TFL shells.
A final analysis and report of all data obtained from this study will be provided within 6 months of completion 
of the last subject’s final study visit.
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6.8 INDEPENDENT DATA AND 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 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 IDSMC will:
•
Be responsible for providing recommendations to the sponsor surrounding study conduct matters that 
affect safety.
•
Review safety data at ad hoc time points and identify if significant safety concerns arise during the 
study.
•
Review pharmacokinetic data and any other data that may affect subject continuation.
•
Make recommendations regarding the continuation, suspension, or termination of the study. 
Tables, listings, and figures will be provided to the IDSMC as per IDSMC charter.
6.9 INTERNATIONAL PEDIATRIC CARDIAC ADVISORY BOARD (IPCAB)
The IPCAB is an advisory body to the sponsor that monitors cardiac safety of the ZX008 clinical trials and 
provides advice to the IDMSC. The IPCAB charter outlines the roles and responsibilities of the committee and 
guide its operations, and review of individual subject cases. The IPCAB consists of individuals external to the 
sponsor who have relevant experience in cardiology, pediatric cardiology, and echocardiography. The IPCAB 
will advise the sponsor and the IDMSC 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.
All ECHO examinations performed throughout the trial will be sent to an experienced pediatric cardiologist 
central reader (Biomedical Systems, Inc.). If the central reader classifies a subject as having met a pre-defined 
threshold value indicative of potential cardiac valvulopathy or pulmonary hypertension, or any other 
unexpected cardiac adverse event, the case will then be sent for secondary adjudication by one or more 
members of the IPCAB according to the procedures outlined in the IPCAB manual. In addition, member of the 
IPCAB will perform audits of ECHOs deemed normal by the central cardiac reader.
6.10 CHANGES TO METHODS PLANNED IN THE PROTOCOL
There were no changes in this SAP when comparing to the protocol are specified below.
7. REFERENCES
Dravet C, Bureau M, Oguni H, Fukuyama Y, Cokar O. Severe myoclonic epilepsy in infancy: 
Dravet syndrome. Adv Neurol 2005; 95: 71-102.
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Zogenix International Limited
ZX008-1503
CONFIDENTIAL
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Dravet C. Les epilepsies graves de l’enfant. Vie Med. 1978; 8:543–548.
Dravet C. Severe myoclonic epilepsy in infants and its related syndromes. Epilepsia 2000; 41:7.
EMA 2007. Stiripentol SmPC and EPAR Scientific Discussion. Available at 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000664/huma
n_med_000742.jsp&mid=WC0b01ac058001d124. Accessed 31 July 2015.
Hurst, DL. Epidemiology of severe myoclonic epilepsy of infancy. Epilepsia 1990; 31:397-400. 
ICH Topic E2F: Development Safety Update Report, 2011.
Sabaz M, Carins D, Lawson J, Nheu N et al. Validation of a New Quality of Life Measure for Children with 
Epilepsy. Epilepsia 2000; 41(6):765-774.
Sabaz M, Carins D, Lawson J, Nheu N et al. The health-related quality of life of children with refractory 
Epilepsy: A comparison of those with and without intellectual disability 2001; 42(5):621-628.
Shorvon S, Tomson T. Sudden unexpected death in epilepsy. Lancet 2011;378: 2028–38.
Talarska D. The usefulness of Quality of Life Childhood Epilepsy (QOLCE) questionnaire in evaluating the 
quality of life of children with epilepsy. Advances Med. Sci 2007; 52 suppl 1:191-193.
COPY 
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8. APPENDICES
APPENDIX 1: LIST OF PLANNED TABLES, FIGURES AND LISTINGS FOR FINAL
REPORT
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
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update
report
Included in
1503 Japan
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report, 2020
14.1
Subject Information
14.1.1
Subject disposition, protocol deviations, and study
populations
Table
14.1.1.1
Subject disposition – all enrolled subjects
Y
Y
Table
14.1.1.1.1
Subject disposition – all enrolled subjects (Japan)
Y
Table
14.1.1.2
Major protocol deviations – Safety Population
Y
Y
Table
14.1.1.2.1
Major protocol deviations – Safety Population (Japan)
Y
Table
14.1.1.3
Study Populations
Y
Table
14.1.1.3.1
Study Populations (Japan)
Y
14.1.2
Demographic and baseline characteristics
Table
14.1.2.1
Demographic and baseline Characteristics – Safety
Population
Y
Y
Table
14.1.2.1.1
Demographic and baseline Characteristics – Safety
Population (Japan)
Y
Table
14.1.2.2
Demographic and baseline Characteristics – mITT
Population
Y
Table
14.1.2.2.1
Demographic and baseline Characteristics – mITT
Population (Japan)
Y
14.1.3
Medical history
Table
14.1.3.1
Medical history – Safety Population
Table
14.1.3.1.1
Medical history – Safety Population (Japan)
Y
14.1.4
Prior/Baseline and concomitant medications and
therapies/treatments
Table
14.1.4.1
Prior/Baseline medications and therapies/treatments – Safety
Population
Table
14.1.4.2
Concomitant medications and therapies/treatments – Safety
Population
Table
14.1.4.3
Prior/Baseline antiepileptic treatment – Safety Population
Y
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Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety
update
report
Included in
1503 Japan
safety update
report, 2020
Table
14.1.4.3.1
Prior/Baseline antiepileptic treatment – Safety Population
(Japan)
Y
Table
14.1.4.4.1
Concomitant antiepileptic treatment – Safety Population
Y
Y
Table
14.1.4.4.1.1
Concomitant antiepileptic treatment – Safety Population
(Japan)
Y
Table
14.1.4.4.2
Frequency Distribution for Number of Concomitant
Antiepileptic Treatments-Safety Population
Y
Table
14.1.4.4.2.1
Frequency Distribution for Number of Concomitant
Antiepileptic Treatments-Safety Population (Japan)
Y
14.1.5
Treatment Exposure and compliance
Table
14.1.5.1
Duration of Treatment Exposure – Safety Population
Y
Y
Table
14.1.5.1.1
Duration of Treatment Exposure by Age Group – Safety
Population
Y
Table
14.1.5.1.2
Duration of Treatment Exposure by Sex – Safety Population
Y
Table
14.1.5.1.3
Duration of Treatment Exposure – Safety Population (Japan)
Y
Table
14.1.5.1.4
Duration of Treatment Exposure by Age Group – Safety
Population (Japan)
Y
Table
14.1.5.1.5
Duration of Treatment Exposure by Sex – Safety Population
(Japan)
Y
Table
14.1.5.1.6
Duration of Treatment Exposure in ZX008-1502 and
ZX008-1503 Combined (Subjects Treated in ZX008-1502
or ZX008-1503) (Japan)
Y
Table
14.1.5.1.7.1
Shift in Assigned ZX008 Dosage in ZX008-1503 by Study
Visit – Safety Population
Table
14.1.5.1.7.2
Shift in Assigned ZX008 Dosage in ZX008-1503 by Study
Visit – Safety Population (Japan)
Y
Table
14.1.5.1.8.1
Number of Subjects Receiving ZX008 According to Mean
Daily Dose and Duration of Treatment – Safety Population
Table
14.1.5.1.8.2
Number of Subjects Receiving ZX008 According to Mean
Daily Dose and Duration of Treatment – Safety Population
(Japan)
Y
Table
14.1.5.1.9.1
Number of Subjects Receiving ZX008 According to Mean
Dose (mg/day) and Duration of Treatment – Safety
Population
Table
14.1.5.1.9.2
Number of Subjects Receiving ZX008 According to Mean
Dose (mg/day) and Duration of Treatment – Safety
Population (Japan)
Y
Table
14.1.5.1.10.1
Number of Subjects Receiving ZX008 According to Actual
Dose (mg/kg) and Duration of Treatment – Safety
Population
PUBLIC COPY
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1503
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1503 Japan
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safety
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safety upd
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upd
report
ori
report
on
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Table
14.1.5.1.10.2
Number of Subjects Receiving ZX008 According to Actual
Dose (mg/kg) and Duration of Treatment – Safety
Population (Japan)
Y
Table
14.1.5.2.1
Compliance to IMP intake – Safety Population
Y
Y
Table
14.1.5.2.1.1
Compliance to IMP intake – Safety Population (Japan)
Y
Table
14.1.5.2.2
Compliance to IMP intake – mITT Population
Y
Y
Table
14.1.5.2.2.1
Compliance to IMP intake – mITT Population (Japan)
Y
14.2
Effectiveness
14.2.1
Effectiveness – Convulsive Seizure Frequency
Table
14.2.1.1.1
Convulsive seizure frequency per 28 days during OLE
Treatment Period: Summary Statistics and Tests of Changes
from Baseline
Y
Y
Table
14.2.1.1.2
Convulsive seizure frequency per 28 days during OLE
Treatment Period, by Age Group: Summary statistics and
Tests of Changes from Baseline – mITT Population
Y
Table
14.2.1.1.3
Convulsive seizure frequency per 28 days during OLE
Treatment Period Using Mean Daily Dose: Summary
Statistics and Tests of Changes from Baseline –mITT
Population
Y
Table
14.2.1.1.4
Convulsive seizure frequency per 28 days during OLE
Treatment Period Using Mean Daily Dose, , by Age Group:
Summary Statistics and Tests of Changes from Baseline –
mITT Population
Y
Table
14.2.1.1.5
Convulsive seizure frequency per 28 days during OLE
Treatment Period: Summary Statistics – 1504 Cohort 1
Subjects
Y
Table
14.2.1.1.6
Convulsive seizure frequency per 28 days during OLE
Treatment Period: Summary Statistics and Tests of Changes
from Baseline – mITT Population (Japan)
Y
Table
14.2.1.1.7
Convulsive seizure frequency per 28 days during OLE
Treatment Period, by Age Group: Summary Statistics and
Tests of Changes from Baseline – mITT Population (Japan)
Y
Table
14.2.1.1.8
Convulsive seizure frequency per 28 days during OLE
Treatment Period Using Mean Daily Dose: Summary
statistics and Tests of Changes from Baseline –mITT
Population (Japan)
Y
Table
14.2.1.1.9
Convulsive seizure frequency per 28 days during OLE
Treatment Period Using Mean Daily Dose, by Age Group:
Summary statistics and Tests of Changes from Baseline –
mITT Population (Japan)
Y
Table
14.2.1.2
Convulsive seizure frequency per 28 days - Endpoint:
Parametric analysis – mITT Population
PUBLIC COPY 
Freq
Y
Freq
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PY
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Statistics
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Statistics a
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n
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ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
ho
ho
ho
ho
Y
a
Y
a
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ng
ng
ng
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Y
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any
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28 days durin
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Table
14.2.1.3
Convulsive seizure frequency per 28 days - Endpoint:
Nonparametric analysis – mITT Population
Table
14.2.1.4
Convulsive seizure frequency per 28 days, Over Time -
Parametric analysis – mITT Population
Table
14.2.1.5
Convulsive seizure frequency per 28 days, Over Time,
Using Mean Daily Dose: Parametric Analysis – mITT
Population
Table
14.2.1.6
% of subjects with Changes in AED medications during the
first 6 months of the OLE Treatment Period – mITT
Population
Figure
14.2.1.7
Graph of means for convulsive seizure frequency per 28
days - mITT Population
Figure
14.2.1.8
Graph of model adjusted means for Convulsive seizure
frequency per 28 days – mITT Population
Figure
14.2.1.9
Graph of convulsive frequency per 28 days, Over Time,
Using Mean Daily Dose – mITT Population
14.2.2
Effectiveness – Proportion of responders for convulsive
seizure frequency
Table
14.2.2.1
Percent reduction in convulsive seizure frequency, OLE
Treatment Period– mITT population
Y
Y
Table
14.2.2.1.1
Percent reduction in convulsive seizure frequency, OLE
Treatment Period– mITT population (Japan)
Y
Figure
14.2.2.2
Cumulative response curves for percent reduction in CSF
during OLE Treatment Period – mITT population
Y
Y
Figure
14.2.2.2.1
Cumulative response curves for percent reduction in CSF
during OLE Treatment Period – mITT population
Y
14.2.3
Effectiveness – Duration of Longest interval between
convulsive seizures
Table
14.2.3.1
Duration of Longest interval between convulsive seizures
during OLE Treatment Period – mITT Population
Figure
14.2.3.2
Boxplot of distribution of duration of longest interval
between convulsive seizures during OLE Treatment Period
– mITT Population
14.2.4
Effectiveness – Summary of duration of convulsive
episodes
Table
14.2.4.1
Summary of Duration of Convulsive Seizure Episodes
during OLE Treatment Period - mITT Population
Table
14.2.4.2
Summary of Gaps between Convulsive Seizure Episodes
during OLE Treatment Period
mITT Population
14.2.5
Effectiveness – Number of convulsive seizure free days
Table
14.2.5.1
Convulsive seizure-free days – summary statistics – mITT
Population
PUBLIC COPY 
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ns
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ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
ho
ho
ho
ho
au
ng
ng
ng
ng
ng
ke
a
per
y
per 28
y
28
m
sive
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seizure
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rt
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14.2.4
pp
ap


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safety update
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Table
14.2.5.2
Convulsive seizure-free days – Parametric Analysis by Age
Group - mITT Population
Table
14.2.5.3
Convulsive seizure-free days – Parametric Analysis by
Mean Daily Dose - mITT Population
Table
14.2.5.4
Convulsive seizure-free days – summary statistics for
subjects from Study 1504 –Cohort 1
14.2.6
Effectiveness –non-convulsive and convulsive seizure
frequency
Table
14.2.6.1
Non-convulsive seizure frequency during OLE Treatment
Period – mITT Population
Table
14.2.6.2
Convulsive + non-convulsive seizure frequency during OLE
Treatment Period – mITT Population
14.2.7
Effectiveness – Incidence of rescue medication
Table
14.2.7.1
Days with Rescue medication usage during OLE Treatment
Period – mITT Population
Y
Table
14.2.7.2
Days with Rescue medication usage during OLE Treatment
Period – mITT Population (Japan)
Y
14.2.8
Effectiveness – Incidence of hospitalization to treat
seizure
Table
14.2.8.1
Hospitalization and Other Healthcare Resource Utilization
to Treat Seizure - mITT Population– mITT Population
Table
14.2.8.2
Hospitalization and Other Healthcare Resource Utilization
to Treat Seizure - mITT Population– mITT Population
(Japan)
Y
14.2.9
Effectiveness – Incidence of status epilepticus
Table
14.2.9.1
Number of episodes of status epilepticus during OLE
Treatment Period - mITT Population
Table
14.2.9.1.1
Number of episodes of status epilepticus during OLE
Treatment Period - mITT Population (Japan)
Y
Table
14.2.9.2
Duration of Seizures – mITT Population
14.2.10
Effectiveness – Clinical Global Impression of
Improvement, – Rating by Parent/Caregiver and
Investigator
Table
14.2.10.1
Clinical Global Impression of Improvement,
Parent/Caregiver Rating – mITT Population
Y
Table
14.2.10.1.1
Clinical Global Impression of Improvement,
Parent/Caregiver Rating – mITT Population (Japan)
Y
Figure
14.2.10.2
Clinical Global Impression of Improvement,
Parent/Caregiver Rating – mITT Population
Y
Figure
14.2.10.2.1
Clinical Global Impression of Improvement,
Parent/Caregiver Rating – mITT Population (Japan)
Y
C COPY 
re
Y
re frequ
Y
frequ
ation
PY
ation
Y
f
O
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OP
rescue m
P
m
PY
cation
CO
cation usa
CO
usa
ulation
C C
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CO
BLIC 
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LI
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LIC
medicat
TT Populati
BLIC
TT Populati
PUBL C
ness
UB
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BL
Inc
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spitalizat
PU
spitalizat
eat S
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n
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ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
ho
ho
ho
ho
au
ng
ng
ng
ng
ng
ket
a
nt
m
nt
ar
a
during
ny
during OLE
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dication
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during OLE
rt
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sup
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ment cannot be used to supp
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n
14.2.1
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14.2.1
nt
This documen
able
cu
able
m
Table
do
Table
oc
d
or variations thereof. 
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ria
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Treatment
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Treatment
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ten
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mITT Popu
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ppl
14.2.10.
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ap
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1503 Japan
safety update
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Table
14.2.10.3
Clinical Global Impression of Improvement, Investigator
Rating – mITT Population
Y
Table
14.2.10.3.1
Clinical Global Impression of Improvement, Investigator
Rating – mITT Population (Japan)
Y
Figure
14.2.10.4
Clinical Global Impression of Improvement, Investigator
Rating – mITT Population
Y
Figure
14.2.10.4.1
Clinical Global Impression of Improvement, Investigator
Rating – mITT Population (Japan)
Y
14.2.11
Effectiveness – Quality of Life in Childhood Epilepsy
Scale
Table
14.2.11.1
Quality of Life in Childhood Epilepsy (QOLCE) – mITT
population
14.2.12
Effectiveness – Peds QL
Table
14.2.12.1
PedsQL Pediatric Quality of Life Inventory (Version 4.0) -
Parent Report – mITT Population
Table
14.2.12.2
PedsQL Family Impact Module (Version 2.0) – Parent
Report – mITT Population
14.2.13
Effectiveness –Quality of Life of the Parent /Caregiver
using EQ-5D-5L Sale
Table
14.2.13.1
QOL of Parent/Caregiver using EQ-5D-5L –QOL of
Parent/Caregiver Based on EQ-5D-5L: Health Profile
Summary Original Response Categories – mITT Population
Table
14.2.13.2
QOL of Parent/Caregiver Based on EQ-5D-5L: Health
Profile Summary Using Dichotomized Response Categories
– mITT Population
Table
14.2.13.3
QOL of Parent/Caregiver Based on EQ-5D-5L: Overall
Health Status Using VAS (0-100) Scale - mITT Population
14.2.14
Effectiveness –Quality of Life of the Parent /Caregiver
using HADS Scale
Table
14.2.14.1
Parent/Caregiver Ratings Based on Hospital Anxiety and
Depression Scale (HADS): Normal; Borderline Abnormal;
and Abnormal Categories – mITT population
Table
14.2.14.2
Parent/Caregiver ratings Based on Hospital Anxiety and
Depression Scale (HADS): Total Score – mITT population
14.2.15
Exploratory objectives (feeder study ZX008-1504
subjects only)
Table
14.2.15.1
Study medication palatability assessment
Y
Table
14.2.15.2
Sleep quality and mealtime behavior – mITT population
Table
14.2.15.3
Karolinska sleepiness scale – mITT population
14.3
Safety
14.3.1
Summary of adverse events
COPY 
psy
Y
psy (QO
Y
(QO
Y
PY
C CO
ity
C
ity of
CO
of Life
CO
Life
TT Populati
C C
TT Populati
PUBLIC CO
Impact
LIC
Impact Mo
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TT Populat
BLIC
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ness
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ness –
B
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EQ
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L of Pare
PU
L of Pare
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t/Ca
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rt any marketing authorization 
n
cluded
ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
ho
ho
ho
ho
au
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Y
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Y
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STATISTICAL ANALYSIS PLAN
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Include in
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Included in
1503 Japan
safety update
report, 2020
Table
14.3.1.1
Overview of number of subjects with TEAE during OLE
Treatment Period – Safety Population
Y
Y
Table
14.3.1.1.1
Overview of number of subjects with TEAE during OLE
Treatment Period – Safety Population (Japan)
Y
Table
14.3.1.2.1
Treatment-Emergent Adverse Events by MedDRA System
Organ Class and Preferred Term –– Safety Population
Y
Y
Table
14.3.1.2.1.1
Treatment-Emergent Adverse Events during Open-label
Treatment Periods by Age Group (< 6 yrs, ≥6 yrs) by
MedDRA System Organ Class and Preferred Term – Safety
Population
Y
Table
14.3.1.2.1.2
Treatment-Emergent Adverse Events with Decreased
Appetite, Loss of appetite, or Hypophagia during Open-
Label Treatment Periods – Safety Population
Y
Table
14.3.1.2.2
Treatment-Emergent Adverse Events occurring in ≥5% of
subjects by MedDRA System Organ Class and Preferred
Term– Safety population
Y
Y
Table
14.3.1.2.2.1
Treatment-Emergent Adverse Events occurring in ≥5% of
subjects by MedDRA System Organ Class and Preferred
Term– Safety Population (Japan)
Y
Table
14.3.1.2.1.3
Treatment-Emergent Adverse Events by MedDRA System
Organ Class and Preferred Term –– Safety Population
(Japan)
Y
Table
14.3.1.2.1.4
Treatment-Emergent Adverse Events during Open-label
Treatment Periods by Age Group (<6 yrs, ≥6 yrs) by
MedDRA System Organ Class and Preferred Term – Safety
Population (Japan)
Y
Table
14.3.1.2.1.5
Treatment-Emergent Adverse Events with Decreased
Appetite, Loss of appetite, or Hypophagia during Open-
Label Treatment Periods – Safety Population (Japan)
Y
Table
14.3.1.3
TEAEs leading to study discontinuation by MedDRA
System Organ Class and Preferred Term – Safety Population
Y
Y
Table
14.3.1.3.1
TEAEs leading to study discontinuation by MedDRA
System Organ Class and Preferred Term – Safety Population
(Japan)
Y
Table
14.3.1.4
Serious TEAEs by MedDRA System Organ Class and
Preferred Term – Safety Population
Y
Y
Table
14.3.1.4.1
Serious TEAEs by MedDRA System Organ Class and
Preferred Term – Safety Population (Japan)
Y
Table
14.3.1.5.1
Related TEAEs MedDRA System Organ Class and
Preferred Term – Safety Population
Y
Y
Table
14.3.1.5.2
Related TEAEs occurring in at least 5% of subjects by
MedDRA System Organ Class and Preferred Term -Safety
population
Y
Y
Table
14.3.1.5.3
Related TEAEs MedDRA System Organ Class and
Preferred Term – Safety Population (Japan)
Y
PUBLIC COPY
s wit
Y
s wit
ophagia
PY
ophagia d
Y 
d
ety Popula
OPY
ety Popula
rse
CO
rse Events
COP
Events
ystem Org
CO
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ation
C C
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LIC
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IC 
Adve
MedDRA Sy
LIC
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gan Class a
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pan)
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pan)
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This document cannot be used to support any marketing authorization 
n
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ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
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Y
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Preferred T
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application and any extensions or variations thereof. 
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ap


STATISTICAL ANALYSIS PLAN
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1503 Japan
safety update
report, 2020
Table
14.3.1.5.4
Related TEAEs occurring in at least 5% of subjects by
MedDRA System Organ Class and Preferred Term -Safety
Population (Japan)
Y
Table
14.3.1.6
TEAEs by Maximum Severity, MedDRA System Organ
Class and Preferred Term – Safety Population
Y
Y
Table
14.3.1.6.1
TEAEs by Maximum Severity, MedDRA System Organ
Class and Preferred Term – Safety Population (Japan)
Y
Table
14.3.1.7
Overview of AESIs
Y
Y
Table
14.3.1.7.1
Overview of AESIs - Safety Population (Japan)
Y
Table
14.3.1.8
Adverse events of special interest (AESI) by MedDRA
System Organ Class and Preferred Term– Safety Population
Y
Y
Table
14.3.1.8.1
Adverse events of special interest (AESI) by MedDRA
System Organ Class and Preferred Term – Safety Population
(Japan)
Y
Table
14.3.1.9.1
Non-treatment Emergent Adverse Events Starting between
Visits 12 and 13 of the Feeder Study, by MedDRA System
Organ Class, Preferred Term and Prior Treatment in Feeder
Study – Safety Population
Y
Table
14.3.1.9.1.1
Non-treatment Emergent Adverse Events Starting between
Visits 12 and 13 of the Feeder Study, by MedDRA System
Organ Class, Preferred Term and Prior Treatment in Feeder
Study – Safety Population (Japan)
Y
Table
14.3.1.9.2
TEAEs starting in the 1st month of OLE by MedDRA
System Organ Class, Preferred Term and Prior Treatment in
Feeder Study – Safety Population
Y
Table
14.3.1.9.2.1
TEAEs starting in the 1st month of OLE by MedDRA
System Organ Class, Preferred Term and Prior Treatment in
Feeder Study – Safety Population (Japan)
Y
Table
14.3.1.9.3
TEAEs starting in the 2nd month of OLE by MedDRA
System Organ Class, , Preferred Term and Prior Treatment
in Feeder Study – Safety Population
Y
Table
14.3.1.9.3.1
TEAEs starting in the 2nd month of OLE by MedDRA
System Organ Class, , Preferred Term and Prior Treatment
in Feeder Study – Safety Population (Japan)
Y
Table
14.3.1.9.4
TEAEs starting in the 3rd month of OLE by MedDRA
System Organ Class, Preferred Term and Prior Treatment in
Feeder Study – Safety Population
Y
Table
14.3.1.9.4.1
TEAEs starting in the 3rd month of OLE by MedDRA
System Organ Class, Preferred Term and Prior Treatment in
Feeder Study – Safety Population (Japan)
Y
Table
14.3.1.10.1
Treatment-Emergent Adverse Events that Occurred in at
least 5% of Subjects during Double-blind Treatment Period
by MedDRA System Organ Class and Preferred Term with
Mean Time to Onset (days) and Mean Duration (days) –
Safety Population
PUBLIC COPY
ESI
Y
ESI
Term
PY
Term–
Y
–
m–
m
Y
m–
m S
Y 
S
erest (AESI
OPY
erest (AESI
eferred
OP
eferred Te
OP
Te
PY
rgent Adve
C C
rgent Adve
of the Feed
IC 
of the Feed
Preferred
LIC
Preferred T
C
T
fety Popula
BL
fety Popula
C
eatment Em
UB
eatment Em
its 12 and 1
PU
its 12 and 1
gan
P
gan Clas
PU
Clas
B
cannot be used to support any marketing authorization 
n
cluded
ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
ho
ho
ho
ho
Y
a
Y
a
ng
ting
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ng
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Y
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DRA
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DRA
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–
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rt a
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Po
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p
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rgent Advers
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Feeder Study
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This doc
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Table
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d
ication and any extensions or variations thereof. 
of
of
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t
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Y
th
s t
ns
Y
tio
Y
io
ria
pulation
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pulation
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or 
rting between
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Treatment inin
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se Events Sta
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m
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and
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p
1
ap
ap
ap
ap


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Include in
120-day
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report
Included in
1503 Japan
safety update
report, 2020
Table
14.3.1.10.1.1
Treatment-Emergent Adverse Events that Occurred in at
least 5% of Subjects during Double-blind Treatment Period
by MedDRA System Organ Class and Preferred Term with
Mean Time to Onset (days) and Mean Duration (days) –
Safety Population (Japan)
Y
Table
14.3.1.10.2
Treatment-Emergent Adverse Events that Occurred in at
least 5% of Subjects during Double-blind through Open-
label Treatment Periods by MedDRA System Organ Class
and Preferred Term, Mean Average Dose in ZX008-1503
with Mean Time to Onset (days) and Mean Duration (days)
– Safety Population
Table
14.3.1.10.2.1
Treatment-Emergent Adverse Events that Occurred in at
least 5% of Subjects during Double-blind through Open-
label Treatment Periods by MedDRA System Organ Class
and Preferred Term, Mean Average Dose in ZX008-1503
with Mean Time to Onset (days) and Mean Duration (days)
– Safety Population (Japan)
Y
14.3.2
Listings of Deaths, Other Serious and Significant
Adverse Events
Table
14.3.2.1
Listing of Deaths
Y
Y
Table
14.3.2.1.1
Listing of Deaths (Japan)
Y
Table
14.3.2.2
Listing of SAEs
Y
Y
Table
14.3.2.2.1
Listing of SAEs (Japan)
Y
Table
14.3.2.3
Listing of Discontinuations Due to AE
Y
Y
Table
14.3.2.3.1
Listing of Discontinuations Due to AE (Japan)
Y
14.3.4
Laboratory value
Table
14.3.4.1
Laboratory parameters – Hematology– Safety Population
Y
Y
Table
14.3.4.1.1
Laboratory parameters – Hematology– Safety Population
(Japan)
Y
Table
14.3.4.2
Laboratory parameters – Biochemistry– Safety Population
Y
Y
Table
14.3.4.2.1
Laboratory parameters – Biochemistry– Safety Population
(Japan)
Y
Table
14.3.4.4.1
Laboratory parameters – Urinalysis (Quantitative variables)
– Safety Population
Y
Y
Table
14.3.4.4.1.1
Laboratory parameters – Urinalysis (Quantitative variables)
– Safety Population (Japan)
Y
Table
14.3.4.4.2
Laboratory parameters – Urinalysis (Qualitative variables) –
Safety Population
Y
Y
Table
14.3.4.4.2.1
Laboratory parameters – Urinalysis (Qualitative variables) –
Safety Population (Japan)
Y
Table
14.3.4.5
Laboratory parameters – Tests of growth, precocious
puberty and thyroid function – Safety Population
Y
Y
PUBLIC COPY
s that
Y
s that
le
PY
le-
PY
-blind t
PY 
blind t
edDRA Sys
OPY
edDRA Sys
Average D
OP
Average D
(day
CO
(days)
CO
s) an
O
an
apan)
C
apan)
s,
C
s, Other
C C
Other S
C
S
s
L
s
C C
Deaths
BL
Deaths
LI
g
P
g of
U
of Death
UB
Death
UB
ting
P
ting of
PU
of S
U
S
PU
P
nnot be used to support any marketing authorization 
n
cluded
ati
cluded in
tio
in
1503
za
1503 Japan
zat
Japan
safety
riza
safety upd
za
upd
report
ori
report
on
ho
n
ho
ho
ho
ng
ho
ys)
m
ys)
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any
m Organ Cla
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t a
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Mean
ort
Mean Duratio
ort 
Duratio
m
ious
p
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pp
and Sig
p
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14.3
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ap


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120-day
safety
update
report
Included in
1503 Japan
safety update
report, 2020
Table
14.3.4.5.1
Laboratory parameters – Tests of growth, precocious
puberty and thyroid function – Safety Population (Japan)
Y
14.4.1
Vital Signs
Table
14.4.1.1
Vital signs parameters – Safety Population
Y
Y
Table
14.4.1.1.1
Vital signs parameters – Safety Population (Japan)
Y
Figure
14.4.1.2
Scatterplot of Age (X-axis) and Height (Y-axis) at End of
Study during the Open-label Treatment Period – Safety
Population
Y
Figure
14.4.1.2.1
Scatterplot of Age (X-axis) and Height (Y-axis) at End of
Study during the Open-label Treatment Period – Safety
Population (Japan)
Table
14.4.1.3
Weight during the Open-Label Study Period over Time by
Age Group (2 - <4; 4 - <6; 6 to <12; and ≥12): Summary
Statistics – Safety Population
Y
Table
14.4.1.3.1
Weight during the Open-Label Study Period over Time by
Age Group (2 - <4; 4 - <6; 6 to <12; and ≥12): Summary
Statistics – Safety Population (Japan)
Y
Table
14.4.1.4
Weight during the Open-Label Study Period over Time for
De Novo Subjects: Summary Statistics – Safety Population
Table
14.4.1.4.1
Weight during the Open-Label Study Period over Time for
De Novo Subjects: Summary Statistics – Safety Population
(Japan)
Y
Table
14.4.1.5
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the
Open-Label Study Period – Safety Population
Y
Table
14.4.1.5.1
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the
Open-Label Study Period – Safety Population (Japan)
Y
Table
14.4.1.6
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the
Open-Label Study Period by Concomitant Topiramate –
Safety Population
Y
Table
14.4.1.6.1
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the
Open-Label Study Period by Concomitant Topiramate –
Safety Population (Japan)
Y
Table
14.4.1.7
Weight Summary (Lost/Gain ≥5%) during the Open-Label
Study Period – Safety Population
Y
Table
14.4.1.7.1
Weight Summary (Lost/Gain ≥5%) during the Open-Label
Study Period – Safety Population (Japan)
Y
Table
14.4.1.8
Weight Summary (Lost/Gain ≥5%) during Open-Label
Study Period by Concomitant Topiramate – Safety
Population
Y
Table
14.4.1.8.1
Weight Summary (Lost/Gain ≥5%) during Open-Label
Study Period by Concomitant Topiramate – Safety
Population (Japan)
Y
14.4.4
Tanner Staging
PUBLIC COPY 
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Table
14.4.4.1
Tanner staging by age group for Boys– Safety Population
Y
Table
14.4.4.1.1
Tanner staging by age group for Boys– Safety Population
(Japan)
Y
Table
14.4.4.2
Tanner staging by age group for Girls– Safety Population
Y
Table
14.4.4.2.1
Tanner staging by age group for Girls– Safety Population
(Japan)
Y
14.4.5
Columbia-Suicide Severity Rating Scale (C-SSRS)
Table
14.4.5.1
Number of Subjects with Suicidal Ideation, Suicidal
Behavior, and Self-Injurious Behavior without Suicidal
Intent Based on the C-SSRS during Treatment – Safety
Population
Y
Y
Table
14.4.5.1.1
Number of Subjects with Suicidal Ideation, Suicidal
Behavior, and Self-Injurious Behavior without Suicidal
Intent Based on the C-SSRS during Treatment – Safety
Population (Japan)
Y
Table
14.4.5.2
Number of Subjects with Suicide-Related Treatment-
Emergent Events Based on the C-SSRS during Treatment –
Safety Population
Y
Table
14.4.5.2.1
Number of Subjects with Suicide-Related Treatment-
Emergent Events Based on the C-SSRS during Treatment –
Safety Population (Japan)
Y
14.4.6
Brief Rating Inventory of Executive Function-Preschool
version (BRIEF)
Table
14.4.6.1
Behavior Rating Inventory of Executive Function-Preschool
Version (BRIEF-P) – Scoring summary table – Safety
population
Y
Y
Table
14.4.6.1.1
Behavior Rating Inventory of Executive Function-Preschool
Version (BRIEF-P) – Scoring summary table –Safety
population (Japan)
Y
Table
14.4.6.2
Behavior Rating Inventory of Executive Function (BRIEF) –
Scoring summary table – Safety population
Y
Y
Table
14.4.6.2.1
Behavior Rating Inventory of Executive Function (BRIEF) –
Scoring summary table – Safety population (Japan)
Y
Table
14.4.6.3
Behavior Rating Inventory of Executive Function- Adult
Version (BRIEF-A) – Scoring summary table– Safety
population (De Novo Subjects)
Table
14.4.6.3.1
Behavior Rating Inventory of Executive Function- Adult
Version (BRIEF-A)– Scoring summary table– Safety
population (Japan) (De Novo Subjects)
Y
16.2
Subject data listing
16.2.1
Subject disposition and discontinuation
Listing
16.2.1.1
Subject completion/discontinuation
Y
Y
PUBLIC COPY 
Treat
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Listing
16.2.1.2
Subject completion/discontinuation (Japan)
Y
16.2.2
Protocol deviations
Y
Listing
16.2.2.1
Major Protocol Deviations
Y
Y
Listing
16.2.2.2
Major Protocol Deviations (Japan)
Y
16.2.3
Subjects excluded from analysis
Listing
16.2.3.1
Subjects excluded from analysis populations
Y
Y
Listing
16.2.3.1.1
Subjects excluded from analysis populations (Japan)
Y
Listing
16.2.3.2
Subject allocation to trial populations
Y
Y
Listing
16.2.3.2.1
Subject allocation to trial populations (Japan)
Y
16.2.4
Demographic data and other baseline characteristics
Listing
16.2.4.1.1
Demographic data
Y
Y
Listing
16.2.4.1.1.1
Demographic data (Japan)
Y
Listing
16.2.4.1.2
% Change from baseline in weight and BMI
Y
Y
Listing
16.2.4.1.2.1
% Change from baseline in weight and BMI (Japan)
Y
Listing
16.2.4.2
Medical history
Listing
16.2.4.3
Prior and concomitant medications and therapies/treatments
Y
Listing
16.2.4.3.1
Prior and concomitant medications and therapies/treatments
(Japan)
Y
Listing
16.2.4.4.1
Prior antiepileptic Drugs (AEDs)
Y
Y
Listing
16.2.4.4.2
Concomitant antiepileptic Drugs (AEDs)
Y
Y
Listing
16.2.4.4.3
Prior antiepileptic Drugs (AEDs) (Japan)
Y
Listing
16.2.4.4.4
Concomitant antiepileptic Drugs (AEDs) (Japan))
Y
Listing
16.2.4.5
Rescue medications
Y
Listing
16.2.4.5.1
Rescue medications (Japan)
Y
16.2.5
Treatment exposure and compliance
Listing
16.2.5.1
IMP Intake per day during Treatment
Y
Y
Listing
16.2.5.1.1
IMP Intake per day during Treatment (Japan)
Y
Listing
16.2.5.2
IMP Intake – self reported % compliance
Y
Y
Listing
16.2.5.2.1
IMP Intake – self reported % compliance (Japan)
Y
Listing
16.2.5.3
Drug Accountability and Compliance to Study Treatment by
Visit
Listing
16.2.5.3.1
Drug Accountability and Compliance to Study Treatment by
Visit (Japan)
Y
PUBLIC COPY 
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16.2.6
Effectiveness data
Listing
16.2.6.1
Convulsive seizure – duration and number of occurrences
per subject (Diary data)
Y
Y
Listing
16.2.6.1.1
Convulsive seizure – duration and number of occurrences
per subject (Diary data) (Japan)
Y
Listing
16.2.6.2
Non-Convulsive seizure – by type, duration and number of
occurrences per subject (Diary data)
Y
Listing
16.2.6.2.1
Non-Convulsive seizure – by type, duration and number of
occurrences per subject (Diary data) (Japan)
Y
Listing
16.2.6.3
Duration of the Longest interval between convulsive
seizures and convulsive seizure free days per subject
Listing
16.2.6.3.1
Duration of the Longest interval between convulsive
seizures and convulsive seizure free days per subject (Japan)
Y
Listing
16.2.6.4
Percent reduction in convulsive seizure frequency from
baseline
Y
Y
Listing
16.2.6.4.1
Percent reduction in convulsive seizure frequency from
baseline (Japan)
Y
Listing
16.2.6.5
Clinical Global Impression – Improvement rating as
assessed by the Parent/Caregiver and Investigator
Y
Y
Listing
16.2.6.5.1
Clinical Global Impression – Improvement rating as
assessed by the Parent/Caregiver and Investigator (Japan)
Y
Listing
16.2.6.6
Quality of Life in Childhood Epilepsy Scale
Listing
16.2.6.7
Quality of life of the Parent/Caregiver using EQ-5D-5L
scale
Listing
16.2.6.8
Quality of life of the Parent/Caregiver using HADS scale
Listing
16.2.6.9.1
Pediatric Quality of Life Inventory (Peds QL) - for
TODDLERS (age 2-4 years)
Listing
16.2.6.9.2
Pediatric Quality of Life Inventory (Peds QL) - for Young
Children (age 5-7 years)
Listing
16.2.6.9.3
Pediatric Quality of Life Inventory (Peds QL) - for Children
(age 8-12 years)
Listing
16.2.6.9.4
Pediatric Quality of Life Inventory (Peds QL) - for TEENS
(age 13-18 years)
Listing
16.2.6.9.5
Pediatric Quality of Life Inventory (Peds QL) – Family
Impact Module
Listing
16.2.6.10
Study medication palatability assessment
Y
Listing
16.2.6.11
Sleep quality and mealtime behavior
Listing
16.2.6.12
Karolinska sleepiness scale
Listing
16.2.6.13
Healthcare utilization questions
16.2.7
Adverse events
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Listing
16.2.7.1
Adverse events
Y
Y
Listing
16.2.7.2
Adverse events of special interests (AESI)
Y
Y
16.2.7.3
Adverse events for de novo subjects
Y (New)
16.2.8
Laboratory data
Listing
16.2.8.1.1
Laboratory Data Hematology parameters
Y
Y
Listing
16.2.8.1.1.1
Laboratory Data Hematology parameters (Japan)
Y
Listing
16.2.8.1.2
Most Abnormal Laboratory Parameters during Open-label
Treatment Period - Hematology
Y
Y
Listing
16.2.8.1.2.1
Most Abnormal Laboratory Parameters during Open-label
Treatment Period – Hematology (Japan)
Y
Listing
16.2.8.2.1
Laboratory Data Biochemistry parameters
Y
Y
Listing
16.2.8.2.1.1
Laboratory Data Biochemistry parameters (Japan)
Y
Listing
16.2.8.2.2
Most Abnormal Laboratory Parameters during Open-label
Treatment Period - Biochemistry
Y
Y
Listing
16.2.8.2.2.1
Most Abnormal Laboratory Parameters during Open-label
Treatment Period – Biochemistry (Japan)
Y
Listing
16.2.8.3
Laboratory Data Coagulation parameters
Y
Y
Listing
16.2.8.3.1
Laboratory Data Coagulation parameters (Japan)
Y
Listing
16.2.8.4.1
Laboratory Data Urinalysis parameters
Y
Y
Listing
16.2.8.4.1.1
Laboratory Data Urinalysis parameters (Japan)
Y
Listing
16.2.8.4.2
Most Abnormal Laboratory Parameters during Open-label
Treatment Period - Urinalysis
Y
Y
Listing
16.2.8.4.2.1
Most Abnormal Laboratory Parameters during Open-label
Treatment Period - Urinalysis (Japan)
Y
Listing
16.2.8.5
Tests of growth, precocious puberty and thyroid function
Y
Y
Listing
16.2.8.5.1
Tests of growth, precocious puberty and thyroid function
(Japan)
Y
Listing
16.2.8.6
Urine Pregnancy test
Y
Y
Listing
16.2.8.6.1
Urine Pregnancy test (Japan)
Y
Listing
16.2.8.7
Urine THC panel
Y
Y
Listing
16.2.8.7.1
Urine THC panel (Japan)
Y
Listing
16.2.8.8
Whole blood cannabidiol
Y
Y
Listing
16.2.8.8.1
Whole blood cannabidiol (Japan)
Y
16.2.9
Other Safety Data
Listing
16.2.9.1.1
Vital signs
Y
Y
PUBLIC COPY 
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STATISTICAL ANALYSIS PLAN
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ZX008-1503
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Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety
update
report
Included in
1503 Japan
safety update
report, 2020
Listing
16.2.9.1.1.1
Vital signs (Japan)
Y
Listing
16.2.9.1.2
Abnormal Vital Signs Data
Y
Y
Listing
16.2.9.1.2.1
Abnormal Vital Signs Data (Japan)
Y
Listing
16.2.9.1.9
Subjects with Weight Decrease >5% during Treatment
Y
Y
Listing
16.2.9.1.9.1
Subjects with Weight Decrease >5% during Treatment
(Japan)
Y
Listing
16.2.9.2
Columbia-Suicide Severity Rating Scale (C-SSRS)
Y
Y
Listing
16.2.9.2.1
Columbia-Suicide Severity Rating Scale (C-SSRS) (Japan)
Y
Listing
16.2.9.3.1
Behavior Rating Inventory of Executive Function –
Preschool Version (BRIEF-P) – Individual Responses
Y
Y
Listing
16.2.9.3.1.1
Behavior Rating Inventory of Executive Function –
Preschool Version (BRIEF-P) – Individual Responses
(Japan)
Y
Listing
16.2.9.3.2
Behavior Rating Inventory of Executive Function –
Preschool Version (BRIEF-P) – Summary Scales
Y
Y
Listing
16.2.9.3.2.1
Behavior Rating Inventory of Executive Function –
Preschool Version (BRIEF-P) – Summary Scales (Japan)
Y
Listing
16.2.9.3.3
Behavior Rating Inventory of Executive Function (BRIEF) –
Individual Responses
Y
Y
Listing
16.2.9.3.3.1
Behavior Rating Inventory of Executive Function (BRIEF) –
Individual Responses (Japan)
Y
Listing
16.2.9.3.4
Behavior Rating Inventory of Executive Function (BRIEF) –
Summary Scales
Y
Y
Listing
16.2.9.3.4.1
Behavior Rating Inventory of Executive Function (BRIEF) –
Summary Scales (Japan)
Y
Listing
16.2.9.3.5
Behavior Rating Inventory of Executive Function – Adult
Version (BRIEF-A) – Individual Responses
Y
Y
Listing
16.2.9.3.5.1
Behavior Rating Inventory of Executive Function – Adult
Version (BRIEF-A) – Individual Responses (Japan)
Y
Listing
16.2.9.3.6
Behavior Rating Inventory of Executive Function – Adult
Version (BRIEF-A) – Summary Scales
Y
Y
Listing
16.2.9.3.6.1
Behavior Rating Inventory of Executive Function – Adult
Version (BRIEF-A) – Summary Scales (Japan)
Y
Listing
16.2.9.4
Tanner Staging
Y
Y
Listing
16.2.9.4.1
Tanner Staging (Japan)
Y
Listing
16.2.9.5
Physical Examination
Y
Y
Listing
16.2.9.5.1
Physical Examination (Japan)
Y
Listing
16.2.9.6
Neurological Examination
Y
Y
Listing
16.2.9.6.1
Neurological Examination (Japan)
Y
PUBLIC COPY 
cutive Fu
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a


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


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CONFIDENTIAL
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Draft 3.0: 04Aug2020
Shells of Tables, Data Listings, and Figures for Zogenix Study ZX008-1503
Programming notes are provided, as applicable, for each table and data listing.
The data listings will be sorted by treatment group in the Core Study and subjects will be identified and sorted by subject number.
The following programming notes apply to all tables (where applicable):
General Programming notes:
-
In the Table header, Gp1, Gp2 etc should be replaced with the actual treatment group names
-
Add missing categories where appropriate
-
Percentages should be based on the number of non-missing subjects in the population in each treatment group (no percentage calculation should be performed and presented against the
missing category)
-
All listing displays for this open-label study are to be done by treatment group in the feeder study
Updated (01/15/2018)
-
This Document provides TFLs for the study for the eventual final report. However, for interim reports, a subset of TFLs will be needed, and not all columns indicated in the TFL shells will be
needed. For the NDA submission, programming will provide TFLs for only Group 9 (the “All subjects” column) in the TFLs.
Updated (14-Jul-2020)
-
Adding in separate outputs for Japan. These will be replicate tables/listings of the existing outputs.
PUBLIC COPY 
p
OP
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PY
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tables/lis


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CONFIDENTIAL
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Draft 3.0: 04Aug2020
REVISION HISTORY
PUBLIC COPY 
document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
This do
do
TIAL
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TIAL
application and any extensions or variations thereof. 
a


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ZX008-1503
CONFIDENTIAL
Page 3 of 234
Draft 3.0: 04Aug2020
Date
Revision
Initials
13December2017
Based on SAP Version 0.3 for Protocol Amendment 3.0 dated 05may2017
GAS
01January
Clarified that only Group 9 (All Subjects) column will be used in the data presentations for the interim analysis
GAS
09January2018
Revised; included TFL shells for all efficacy and safety, and prioritization for interim analysis.
GAS
18Feb2018
Added age, gender and race to the AE listing mock
GAS
21Feb2018
Clarifying language added to QOLCE and PedsQL
GAS
11May2018
Updated Listings 16.2.9.3.1 – 16.2.9.3.4 - Headings for BRIEF-P and BRIEF
GAS
12Jul2018
Updated TFLs to include “n’s” for the PROs
GAS
14JUL2020
Added Tables / listings for Japan
MLW
30JUL2020
Finalization for Japan Interim Analysis
MLW
04AUG2020
Signoff
MLW
PUBLIC COPY 
prioritizatio
PY
prioritizatio
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.9.3.4
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.9.3.4
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ZX008-1503
CONFIDENTIAL
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PUBLIC COPY 
document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
This do
do
TIAL
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TIAL
application and any extensions or variations thereof. 
a


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Treatment Groups in Study ZX008-1503
Name of Treatment Group
Treatment
Group Code
Description
AED Treatment from Feeder study
Feeder Study(s)
Approximate n
PBO-ZX008 OL
1
Placebo arms in all studies
Placebo in feeder study along with any protocol-
approved background AED combination; no active ZX008
1501, 1502, 1504
Cohort 2
120
ZX 0.2 – ZX008 OL
2
0.2 arm in DB Studies
Any protocol-approved background AED combination; plus,
ZX008 0.2 mg/kg/day max 30 mg
1501, 1502
80
ZX 0.8 – ZX008 OL
3
0.8 arm in DB studies
Any protocol-approved background AED combination; plus,
ZX008 0.8 mg/kg/day max 30 mg
1501, 1502
80
ZX 0.5 – ZX008 OL
4
Active arm in 1504 cohort 2
Protocol-approved background regimen including STP +
VPA + CBZ; plus ZX008 0.5 mg/kg/day max 20 mg
1504 Cohort 2
40
PK – ZX008 OL
5
Cohort 1 PK Study - Open label
study
1504 Cohort 1
40
Summary Treatment
Groups1
ZX DBA – ZX008 OL
6 (Groups2-4)
All Active arms in the DB studies
Any protocol-approved background regimen, plus ZX008 at
any protocol-approved dose – DB Studies only
1501, 1502, 1504
Cohort 2
200
ZX DB – ZX008 OL
7 (Groups1-4)
All subjects in randomized
double-blind (DB) studies
Any protocol-approved background regimen at any protocol-
approved dose – DB Studies only
ZX – ZX008 OL
8 (Groups2-5)
All Active arms
Any protocol-approved background regimen, plus ZX008 at
any protocol-approved dose – All studies
1501, 1502, 1504
Cohort 1, 1504
Cohort 2
240
ZX008 OL
9 (Groups1-5)
All Subjects in 1503 excluding de
novo subjects
Any protocol-approved background regimen at any protocol-
approved dose – All studies
1501, 1502, 1504
(both cohorts)
360
De Novo Subjects
10
Subjects entering 1503 who had not participated in any of the
core studies
None
35
Notes:1: Subjects in 1504 cohort 1 do not have a pre-study treatment baseline for seizures and are not included in analyses requiring baseline (Core) seizure frequency.
Analysis Summary types
Type
Treatment By Groups (Codes as above)
A
1, 2, 3, 4,5,9, 10
B
1, 8, 9, 10
C
1, 6, 7, 10
PUBLIC COPY
8 0.8 m
Y
8 0.8 m
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TLF Shells
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ZX008-1503
CONFIDENTIAL
Page 6 of 234
Draft 3.0: 04Aug2020
NOTES:
The TFL shells provided are for the final study report. For the interim analysis, please note the following:
Programming Prioritization for Interim Analysis, 2018
Provide summaries for ZX008 OL (Group 9), i.e., “All Subjects” column only
1 = High priority -
2 = Medium Priority
3 = Low Priority
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
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s d
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uth
application and any extensions or variations thereof. 
a


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Draft 3.0: 04Aug2020
LIST OF TABLES, FIGURES AND LISTINGS FOR FINAL REPORT
Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
14.1
Subject Information
14.1.1
Subject disposition, protocol deviations, and study populations
Table
14.1.1.1
Subject disposition – all enrolled subjects
Y
Y
Table
14.1.1.1.1
Subject disposition – all enrolled subjects (Japan)
Y
Table
14.1.1.2
Major protocol deviations – Safety Population
Y
Y
Table
14.1.1.2.1
Major protocol deviations – Safety Population (Japan)
Y
Table
14.1.1.3
Study Populations
Y
Table
14.1.1.3.1
Study Populations (Japan)
Y
14.1.2
Demographic and baseline characteristics
Table
14.1.2.1
Demographic and baseline Characteristics – Safety Population
Y
Y
Table
14.1.2.1.1
Demographic and baseline Characteristics – Safety Population (Japan)
Y
Table
14.1.2.2
Demographic and baseline Characteristics – mITT Population
Y
Table
14.1.2.2.1
Demographic and baseline Characteristics – mITT Population (Japan)
Y
14.1.3
Medical history
Table
14.1.3.1
Medical history – Safety Population
Table
14.1.3.1.1
Medical history – Safety Population (Japan)
Y
14.1.4
Prior/Baseline and concomitant medications and therapies/treatments
Table
14.1.4.1
Prior/Baseline medications and therapies/treatments – Safety Population
Table
14.1.4.2
Concomitant medications and therapies/treatments – Safety Population
Table
14.1.4.3
Prior/Baseline antiepileptic treatment – Safety Population
Y
PUBLIC COPY 
Y
PY
OP
on
C
on (Japan)
C C
(Japan)
C
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LI
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TIAL
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Included inin
Interi
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pp


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safety update
report
Included in 1503
Japan safety
update report,
2020
Table
14.1.4.3.1
Prior/Baseline antiepileptic treatment – Safety Population (Japan)
Y
Table
14.1.4.4.1
Concomitant antiepileptic treatment – Safety Population
Y
Y
Table
14.1.4.4.1.1
Concomitant antiepileptic treatment – Safety Population (Japan)
Y
Table
14.1.4.4.2
Frequency Distribution for Number of Concomitant Antiepileptic Treatments-Safety Population
Y
Table
14.1.4.4.2.1
Frequency Distribution for Number of Concomitant Antiepileptic Treatments-Safety Population
(Japan)
Y
14.1.5
Treatment Exposure and compliance
Table
14.1.5.1
Duration of Treatment Exposure – Safety Population
Y
Y
Table
14.1.5.1.1
Duration of Treatment Exposure by Age Group – Safety Population
Y
Table
14.1.5.1.2
Duration of Treatment Exposure by Sex – Safety Population
Y
Table
14.1.5.1.3
Duration of Treatment Exposure – Safety Population (Japan)
Y
Table
14.1.5.1.4
Duration of Treatment Exposure by Age Group – Safety Population (Japan)
Y
Table
14.1.5.1.5
Duration of Treatment Exposure by Sex – Safety Population (Japan)
Y
Table
14.1.5.1.6
Duration of Treatment Exposure in ZX008-1502 and ZX008-1503 Combined (Subjects Treated in
ZX008-1502 or ZX008-1503) (Japan)
Y
Table
14.1.5.1.7.1
Shift in Assigned ZX008 Dosage in ZX008-1503 by Study Visit – Safety Population
Table
14.1.5.1.7.2
Shift in Assigned ZX008 Dosage in ZX008-1503 by Study Visit – Safety Population (Japan)
Y
Table
14.1.5.1.8.1
Number of Subjects Receiving ZX008 According to Mean Daily Dose and Duration of Treatment –
Safety Population
Table
14.1.5.1.8.2
Number of Subjects Receiving ZX008 According to Mean Daily Dose and Duration of Treatment –
Safety Population (Japan)
Y
UBLIC COPY 
eptic
Y
eptic
iepileptic
PY
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Y
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Population
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Number of
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Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Table
14.1.5.1.9.1
Number of Subjects Receiving ZX008 According to Mean Dose (mg/day) and Duration of Treatment –
Safety Population
Table
14.1.5.1.9.2
Number of Subjects Receiving ZX008 According to Mean Dose (mg/day) and Duration of Treatment –
Safety Population (Japan)
Y
Table
14.1.5.1.10.1
Number of Subjects Receiving ZX008 According to Actual Dose (mg/kg) and Duration of Treatment –
Safety Population
Table
14.1.5.1.10.2
Number of Subjects Receiving ZX008 According to Actual Dose (mg/kg) and Duration of Treatment –
Safety Population (Japan)
Y
Table
14.1.5.2.1
Compliance to IMP intake – Safety Population
Y
Y
Table
14.1.5.2.1.1
Compliance to IMP intake – Safety Population (Japan)
Y
Table
14.1.5.2.2
Compliance to IMP intake – mITT Population
Y
Y
Table
14.1.5.2.2.1
Compliance to IMP intake – mITT Population (Japan)
Y
14.2
Effectiveness
14.2.1
Effectiveness – Convulsive Seizure Frequency
Table
14.2.1.1.1
Convulsive seizure frequency per 28 days during OLE Treatment Period: Summary Statistics and Tests
of Changes from Baseline
Y
Y
Table
14.2.1.1.2
Convulsive seizure frequency per 28 days during OLE Treatment Period, by Age Group: Summary
statistics and Tests of Changes from Baseline – mITT Population
Y
Table
14.2.1.1.3
Convulsive seizure frequency per 28 days during OLE Treatment Period Using Mean Daily Dose:
Summary Statistics and Tests of Changes from Baseline –mITT Population
Y
Table
14.2.1.1.4
Convulsive seizure frequency per 28 days during OLE Treatment Period Using Mean Daily Dose, , by
Age Group: Summary Statistics and Tests of Changes from Baseline – mITT Population
Y
Table
14.2.1.1.5
Convulsive seizure frequency per 28 days during OLE Treatment Period: Summary Statistics – 1504
Cohort 1 Subjects
Y
PUBLIC COPY 
Dose
Y
Dose (mg
Y
(mg
Y
Actual
COP
Actual Do
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app
app


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report
Included in 1503
Japan safety
update report,
2020
Table
14.2.1.1.6
Convulsive seizure frequency per 28 days during OLE Treatment Period: Summary Statistics and Tests
of Changes from Baseline – mITT Population (Japan)
Y
Table
14.2.1.1.7
Convulsive seizure frequency per 28 days during OLE Treatment Period, by Age Group: Summary
Statistics and Tests of Changes from Baseline – mITT Population (Japan)
Y
Table
14.2.1.1.8
Convulsive seizure frequency per 28 days during OLE Treatment Period Using Mean Daily Dose:
Summary statistics and Tests of Changes from Baseline –mITT Population (Japan)
Y
Table
14.2.1.1.9
Convulsive seizure frequency per 28 days during OLE Treatment Period Using Mean Daily Dose, by
Age Group: Summary statistics and Tests of Changes from Baseline – mITT Population (Japan)
Y
Table
14.2.1.2
Convulsive seizure frequency per 28 days - Endpoint: Parametric analysis – mITT Population
Table
14.2.1.3
Convulsive seizure frequency per 28 days - Endpoint: Nonparametric analysis – mITT Population
Table
14.2.1.4
Convulsive seizure frequency per 28 days, Over Time - Parametric analysis – mITT Population
Table
14.2.1.5
Convulsive seizure frequency per 28 days, Over Time, Using Mean Daily Dose: Parametric Analysis –
mITT Population
Table
14.2.1.6
% of subjects with Changes in AED medications during the first 6 months of the OLE Treatment
Period – mITT Population
Figure
14.2.1.7
Graph of means for convulsive seizure frequency per 28 days - mITT Population
Figure
14.2.1.8
Graph of model adjusted means for Convulsive seizure frequency per 28 days – mITT Population
Figure
14.2.1.9
Graph of convulsive frequency per 28 days, Over Time, Using Mean Daily Dose – mITT Population
14.2.2
Effectiveness – Proportion of responders for convulsive seizure frequency
Table
14.2.2.1
Percent reduction in convulsive seizure frequency, OLE Treatment Period– mITT population
Y
Y
Table
14.2.2.1.1
Percent reduction in convulsive seizure frequency, OLE Treatment Period– mITT population (Japan)
Y
Figure
14.2.2.2
Cumulative response curves for percent reduction in CSF during OLE Treatment Period – mITT
population
Y
Y
IC COPY 
ment
Y
ment P
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Table/ Figure/
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Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Figure
14.2.2.2.1
Cumulative response curves for percent reduction in CSF during OLE Treatment Period – mITT
population
Y
14.2.3
Effectiveness – Duration of Longest interval between convulsive seizures
Table
14.2.3.1
Duration of Longest interval between convulsive seizures during OLE Treatment Period – mITT
Population
Figure
14.2.3.2
Boxplot of distribution of duration of longest interval between convulsive seizures during OLE
Treatment Period – mITT Population
14.2.4
Effectiveness – Summary of duration of convulsive episodes
Table
14.2.4.1
Summary of Duration of Convulsive Seizure Episodes during OLE Treatment Period - mITT Population
Table
14.2.4.2
Summary of Gaps between Convulsive Seizure Episodes during OLE Treatment Period
mITT Population
14.2.5
Effectiveness – Number of convulsive seizure free days
Table
14.2.5.1
Convulsive seizure-free days – summary statistics – mITT Population
Table
14.2.5.2
Convulsive seizure-free days – Parametric Analysis by Age Group - mITT Population
Table
14.2.5.3
Convulsive seizure-free days – Parametric Analysis by Mean Daily Dose - mITT Population
Table
14.2.5.4
Convulsive seizure-free days – summary statistics for subjects from Study 1504 –Cohort 1
14.2.6
Effectiveness –non-convulsive and convulsive seizure frequency
Table
14.2.6.1
Non-convulsive seizure frequency during OLE Treatment Period – mITT Population
Table
14.2.6.2
Convulsive + non-convulsive seizure frequency during OLE Treatment Period – mITT Population
14.2.7
Effectiveness – Incidence of rescue medication
Table
14.2.7.1
Days with Rescue medication usage during OLE Treatment Period – mITT Population
Y
Table
14.2.7.2
Days with Rescue medication usage during OLE Treatment Period – mITT Population (Japan)
Y
PUBLIC COPY 
Y
between
OPY
between
Y
PY
vulsive
C
vulsive ep
C
ep
CO
ure
IC
ure Episod
IC 
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ive
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BLI
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PU
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PU
P
not be used to support any marketing authorization 
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au
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ment
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ment Period
y m
Period
m
vulsive
an
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an
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ny
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po
odes
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during OLE
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p
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up
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up
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ed
statist
d
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us
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days
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days –
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nn
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nt c
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n
w
nt
me
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me
me
me
ume
m
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h
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her
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s
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etric Analysi
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Table/ Figure/
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Number
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120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
14.2.8
Effectiveness – Incidence of hospitalization to treat seizure
Table
14.2.8.1
Hospitalization and Other Healthcare Resource Utilization to Treat Seizure - mITT Population– mITT
Population
Table
14.2.8.2
Hospitalization and Other Healthcare Resource Utilization to Treat Seizure - mITT Population– mITT
Population (Japan)
Y
14.2.9
Effectiveness – Incidence of status epilepticus
Table
14.2.9.1
Number of episodes of status epilepticus during OLE Treatment Period - mITT Population
Table
14.2.9.1.1
Number of episodes of status epilepticus during OLE Treatment Period - mITT Population (Japan)
Y
Table
14.2.9.2
Duration of Seizures – mITT Population
14.2.10
Effectiveness – Clinical Global Impression of Improvement, – Rating by Parent/Caregiver and
Investigator
Table
14.2.10.1
Clinical Global Impression of Improvement, Parent/Caregiver Rating – mITT Population
Y
Table
14.2.10.1.1
Clinical Global Impression of Improvement, Parent/Caregiver Rating – mITT Population (Japan)
Y
Figure
14.2.10.2
Clinical Global Impression of Improvement, Parent/Caregiver Rating – mITT Population
Y
Figure
14.2.10.2.1
Clinical Global Impression of Improvement, Parent/Caregiver Rating – mITT Population (Japan)
Y
Table
14.2.10.3
Clinical Global Impression of Improvement, Investigator Rating – mITT Population
Y
Table
14.2.10.3.1
Clinical Global Impression of Improvement, Investigator Rating – mITT Population (Japan)
Y
Figure
14.2.10.4
Clinical Global Impression of Improvement,, Investigator Rating – mITT Population
Y
Figure
14.2.10.4.1
Clinical Global Impression of Improvement,, Investigator Rating – mITT Population (Japan)
Y
14.2.11
Effectiveness – Quality of Life in Childhood Epilepsy Scale
Table
14.2.11.1
Quality of Life in Childhood Epilepsy (QOLCE) – mITT population
14.2.12
Effectiveness – Peds QL
PUBLIC COPY 
PY
OLE
CO
OLE Treatm
CO
Treatm
OP
uring
C C
uring OLE
C C
OLE T
C
T
C
C
pression
BL
pression o
L
o
LI
of
P
of Improv
PU
Improv
PU
P
not be used to support any marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
ti
opulation
ark
opulation–
k
–
ke
- mITT
y m
mITT Popu
m
Popu
m
ny
nt
nt Period
rt 
Period -
t a
atment
po
atment Perio
po
Perio
or
pp
mprovement
su
mprovement
up
ment,
d t
ment, Parent
d to
Parent
to
ovement,
sed
ovement, Pa
d
Pa
ed
Improveme
us
Improveme
se
on
b
on of
be
of Improv
be 
Improv
u
ression
t b
ression of
b
of Im
Im
be
Impression
not
Impression
ot
ann
lobal
an
lobal Impres
nn
Impres
ument cann
cal
c
cal Global
ca
Global Im
Im
an
Effectivene
nt 
Effectivene
t c
e
Quality
en
Quality
en
me
This docume
do
TIAL
s d
TIAL
Ef
Ef
me
me
me
ume
nd any extensions or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
her
th
mITT
s
mITT
th
th
th
th
lation
tio
lation–
io
– mITT
o
mITT
on
ria
mITT
v
mITT Populat
va
Populat
va
d -
o
- mITT
or
mITT Po
Po
r v
o
,
i
, –
o
– Rating
ion
Rating by
by
ns
/Caregiver
ens
/Caregiver R
s
R
ns
rent/Caregiv
xte
rent/Caregiv
te
nt,
nt, Parent/Ca
ex
Parent/Ca
ex
ement,
ny
ement, Pare
y 
Pare
y e
provement,
an
provement,
any
of
n
of Improvem
nd 
Improvem
d a
and
sion
a
sion of
an
of Impr
an
Impr
lication and
mpression
on 
mpression of
of
a
ss
t
ss –
ti
– Quality
tio
Quality
on
y of
c
of Life
cat
Life in
a
in Ch
t
Ch
at
plic
fectiveness
plic
fectiveness
lic
app
app


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Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Table
14.2.12.1
PedsQL Pediatric Quality of Life Inventory (Version 4.0) - Parent Report – mITT Population
Table
14.2.12.2
PedsQL Family Impact Module (Version 2.0) – Parent Report – mITT Population
14.2.13
Effectiveness –Quality of Life of the Parent /Caregiver using EQ-5D-5L Sale
Table
14.2.13.1
QOL of Parent/Caregiver using EQ-5D-5L –QOL of Parent/Caregiver Based on EQ-5D-5L: Health
Profile Summary Original Response Categories – mITT Population
Table
14.2.13.2
QOL of Parent/Caregiver Based on EQ-5D-5L: Health Profile Summary Using Dichotomized Response
Categories – mITT Population
Table
14.2.13.3
QOL of Parent/Caregiver Based on EQ-5D-5L: Overall Health Status Using VAS (0-100) Scale - mITT
Population
14.2.14
Effectiveness –Quality of Life of the Parent /Caregiver using HADS Scale
Table
14.2.14.1
Parent/Caregiver Ratings Based on Hospital Anxiety and Depression Scale (HADS): Normal; Borderline
Abnormal; and Abnormal Categories – mITT population
Table
14.2.14.2
Parent/Caregiver ratings Based on Hospital Anxiety and Depression Scale (HADS): Total Score – mITT
population
14.2.15
Exploratory objectives (feeder study ZX008-1504 subjects only)
Table
14.2.15.1
Study medication palatability assessment
Y
Table
14.2.15.2
Sleep quality and mealtime behavior – mITT population
Table
14.2.15.3
Karolinska sleepiness scale – mITT population
14.3
Safety
14.3.1
Summary of adverse events
Table
14.3.1.1
Overview of number of subjects with TEAE during OLE Treatment Period – Safety Population
Y
Y
Table
14.3.1.1.1
Overview of number of subjects with TEAE during OLE Treatment Period – Safety Population (Japan)
Y
BLIC COPY
reg
Y
reg
opulation
PY 
opulation
h
O
h Profile
OP
Profile Su
P
Su
PY
L:
C
L: Overall
C C
Overall
C
e
B
e Parent
BLI
Parent /C
LI
/C
LIC
PUB
d
U
d on
UB
on Hosp
UB
Hosp
Categories
PU
Categories
P B
d
P
d
P
support any marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
on
k
on
ti
ke
ar
d on
y
on EQ
y m
EQ-
y m
-5D
m
5D
m
mary
t a
mary Using
a
Using
an
alth
p
alth Status
po
Status U
or
regiver
su
regiver using
up
using
up
d to s
t
Anxiety
to s
Anxiety and
s
and
mITT popula
d to
mITT popula
cannot be used 
s
Hospital
ed
Hospital Anx
d
Anx
d
eder
e
eder study
e u
study Z
us
atability
be
atability asse
e
asse
be
mealtime
ot 
mealtime b
t b
leepiness
nno
leepiness sc
o
sc
o
nn
nt ca
ummary
t ca
ummary of
ca
of a
a
a
This document 
do
TIAL
s d
TIAL
ca
Overview
ent
Overview
nt
e
Ove
e
Ove
en
me
m
ions or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
her
th
th
th
th
th
ns
L:
t
L: Health
tio
Health
io
Dichotomize
ar
Dichotomize
ria
sing
o
sing VAS
or
VAS (0
r 
(0
r v
g HADS
ons
HADS Scale
ns
Scale
ns
ensio
Depression
sio
Depression
tion
n
tion
n and any exten ion
xiety
xt
xiety and
te
and Dep
e
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en
X008
y
X008-
y e
-1504
y e
1504 s
ex
ssment
any
ssment
ny
ehavior
d a
ehavior –
a
– mI
a
mI
an
ale
ale –
n
– mITT
nd
mITT po
d
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an
tion 
dverse
ion
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on
even
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atio
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lic
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ica
of num
ca
num
ca
pli


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Table Header
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120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Table
14.3.1.2.1
Treatment-Emergent Adverse Events by MedDRA System Organ Class and Preferred Term –– Safety
Population
Y
Y
Table
14.3.1.2.1.1
Treatment-Emergent Adverse Events during Open-label Treatment Periods by Age Group (< 6 yrs, ≥6
yrs) by MedDRA System Organ Class and Preferred Term – Safety Population
Y
Table
14.3.1.2.1.2
Treatment-Emergent Adverse Events with Decreased Appetite, Loss of appetite, or Hypophagia
during Open-Label Treatment Periods – Safety Population
Y
Table
14.3.1.2.2
Treatment-Emergent Adverse Events occurring in ≥5% of subjects by MedDRA System Organ Class
and Preferred Term– Safety population
Y
Y
Table
14.3.1.2.2.1
Treatment-Emergent Adverse Events occurring in ≥5% of subjects by MedDRA System Organ Class
and Preferred Term– Safety Population (Japan)
Y
Table
14.3.1.2.1.3
Treatment-Emergent Adverse Events by MedDRA System Organ Class and Preferred Term –– Safety
Population (Japan)
Y
Table
14.3.1.2.1.4
Treatment-Emergent Adverse Events during Open-label Treatment Periods by Age Group (<6 yrs, ≥6
yrs) by MedDRA System Organ Class and Preferred Term – Safety Population (Japan)
Y
Table
14.3.1.2.1.5
Treatment-Emergent Adverse Events with Decreased Appetite, Loss of appetite, or Hypophagia
during Open-Label Treatment Periods – Safety Population (Japan)
Y
Table
14.3.1.3
TEAEs leading to study discontinuation by MedDRA System Organ Class and Preferred Term – Safety
Population
Y
Y
Table
14.3.1.3.1
TEAEs leading to study discontinuation by MedDRA System Organ Class and Preferred Term – Safety
Population (Japan)
Y
Table
14.3.1.4
Serious TEAEs by MedDRA System Organ Class and Preferred Term – Safety Population
Y
Y
Table
14.3.1.4.1
Serious TEAEs by MedDRA System Organ Class and Preferred Term – Safety Population (Japan)
Y
Table
14.3.1.5.1
Related TEAEs MedDRA System Organ Class and Preferred Term – Safety Population
Y
Y
C COPY 
etite,
Y
etite, Lo
Y
Lo
tion
P
tion
Y
≥5%
CO
≥5% of
OP
of su
OP
su
OP
BLIC C
urring
C
urring in
C C
in ≥
C
≥
on (Japan)
LIC
on (Japan)
PUBL C C
ents
B
ents by
BL
by Me
BL
Me
BL
rse
P
rse Even
PU
Even
PU
port any marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
m
k
m ––
ket
–– Safety
et
Safety
ti
Age
m
Age Group
ma
Group (<
r
(<
n
ar
appetite,
ny
appetite, or
y
or
y m
cts
rt
cts by
rt
by MedD
t a
MedD
a
suppo
of
p
of subjects
ppo
subjects
ot be used to su po
DRA
DRA System
su
System
su
during
d t
during Open
t
Open
ass and Prefe
ed
ass and Prefe
to
e Events
us
Events with
s
with
ment Periods
e u
ment Periods
se
dy
dy discontinu
be
discontinu
be
annot
ng
ng to
n
to study
no
study d
on
a
on (Japan)
ann
(Japan)
This document can
do
TIAL
s d
TIAL
ot
ous
c
ous TEAEs
ca
TEAEs by
by
an
Serious
nt
Serious TEA
TEA
t c
e
Relate
en
Relate
en
me
me
me
me
or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
Y
her
th
6 yrs,
ns
yrs, ≥6
ns
≥6
s
Hypophagia
iati
Hypophagia
tio
RA
v
RA System
va
System O
ar
ns or
by
s
by MedDRA
o
MedDRA S
d any extensions or
Organ
io
Organ Class
on
Class
ns
label
en
label Treatm
en
Treatm
rred Term
xte
rred Term –
ns
Decreased
ex
Decreased
– Safety Pop
y e
Safety Pop
xt
ation
an
ation by
any
by Me
y
Me
ny
and 
scontinuatio
nd
scontinuatio
lication a d
y
o
y MedDRA
on 
MedDRA Sy
Sy
a
Es
t
Es by
tio
by MedDR
tio
MedDR
on
d TEAEs
ca
TEAEs Med
a
Med
at
applic
a
lic


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Table/ Figure/
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Number
Table Header
Included in
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Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Table
14.3.1.5.2
Related TEAEs occurring in at least 5% of subjects by MedDRA System Organ Class and Preferred
Term -Safety population
Y
Y
Table
14.3.1.5.3
Related TEAEs MedDRA System Organ Class and Preferred Term – Safety Population (Japan)
Y
Table
14.3.1.5.4
Related TEAEs occurring in at least 5% of subjects by MedDRA System Organ Class and Preferred
Term -Safety Population (Japan)
Y
Table
14.3.1.6
TEAEs by Maximum Severity, MedDRA System Organ Class and Preferred Term – Safety Population
Y
Y
Table
14.3.1.6.1
TEAEs by Maximum Severity, MedDRA System Organ Class and Preferred Term – Safety Population
(Japan)
Y
Table
14.3.1.7
Overview of AESIs
Y
Y
Table
14.3.1.7.1
Overview of AESIs - Safety Population (Japan)
Y
Table
14.3.1.8
Adverse events of special interest (AESI) by MedDRA System Organ Class and Preferred Term– Safety
Population
Y
Y
Table
14.3.1.8.1
Adverse events of special interest (AESI) by MedDRA System Organ Class and Preferred Term – Safety
Population (Japan)
Y
Table
14.3.1.9.1
Non-treatment Emergent Adverse Events Starting between Visits 12 and 13 of the Feeder Study, by
MedDRA System Organ Class, Preferred Term and Prior Treatment in Feeder Study – Safety
Population
Y
Table
14.3.1.9.1.1
Non-treatment Emergent Adverse Events Starting between Visits 12 and 13 of the Feeder Study, by
MedDRA System Organ Class, Preferred Term and Prior Treatment in Feeder Study – Safety
Population (Japan)
Y
Table
14.3.1.9.2
TEAEs starting in the 1st month of OLE by MedDRA System Organ Class, Preferred Term and Prior
Treatment in Feeder Study – Safety Population
Y
Table
14.3.1.9.2.1
TEAEs starting in the 1st month of OLE by MedDRA System Organ Class, Preferred Term and Prior
Treatment in Feeder Study – Safety Population (Japan)
Y
PUBLIC COPY 
Y
Class
OP
Class and
PY
and
PY
rgan
CO
rgan Class
CO
Class
OP
C C
on
B
on (Japan)
BLI
(Japan)
LIC
est
U
est (AESI)
UB
(AESI)
B
re
P
re
P
cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
Inclu
au
Inclu
ut
g a
referred
ket
referred
ti
ation
ma
ation (Japan)
mar
(Japan)
ar
an
y
an Class
y m
Class and
m
and
m
ferred
an
ferred Term
an
Term
ny
d Preferred
rt 
Preferred
t a
po
up
MedDRA
to s
MedDRA Sy
s
Sy
s
(AESI)
ed
(AESI) by
ed
by Me
d
Me
d
Adverse
e u
Adverse Eve
u
Eve
n Class, Prefe
be 
n Class, Prefe
us
t
n
t Emergent
not
Emergent A
ystem Organ
nno
ystem Organ
tion
a
tion (Japan)
an
(Japan)
ot
ent ca
AEs
t
AEs starting
t ca
starting
Treatment 
nt 
Treatment 
This documen
do
TIAL
s d
TIAL
ca
e
TEAEs
en
TEAEs
Tre
e
Tre
en
ume
m
n and any extensions or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
Y
her
th
s
Preferred
tio
Preferred
on
–
a
– Safety
aria
Safety Pop
a
Pop
ria
Term 
v
Term –
va
– Safet
va
Safet
va
o
ns
stem
si
stem Organ
sio
Organ
ion
dDRA
te
dDRA System
te
System
en
nts
y
nts Starting
y e
Starting b
erred Term a
ny
erred Term a
ex
Adverse
d
Adverse Even
d 
Even
Class, Prefe
and
Class, Prefe
d a
ation 
n the
on
the 1
on
1st
n
st mo
n
mo
n Feeder Stu
tio
n Feeder Stu
applicat
a
n
starting
ca
starting in
a
in th
th
atment in Fe
plic
atment in Fe
at
pl


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Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Table
14.3.1.9.3
TEAEs starting in the 2nd month of OLE by MedDRA System Organ Class, , Preferred Term and Prior
Treatment in Feeder Study – Safety Population
Y
Table
14.3.1.9.3.1
TEAEs starting in the 2nd month of OLE by MedDRA System Organ Class, , Preferred Term and Prior
Treatment in Feeder Study – Safety Population (Japan)
Y
Table
14.3.1.9.4
TEAEs starting in the 3rd month of OLE by MedDRA System Organ Class, Preferred Term and Prior
Treatment in Feeder Study – Safety Population
Y
Table
14.3.1.9.4.1
TEAEs starting in the 3rd month of OLE by MedDRA System Organ Class, Preferred Term and Prior
Treatment in Feeder Study – Safety Population (Japan)
Y
Table
14.3.1.10.1
Treatment-Emergent Adverse Events that Occurred in at least 5% of Subjects during Double-blind
Treatment Period by MedDRA System Organ Class and Preferred Term with Mean Time to Onset
(days) and Mean Duration (days) – Safety Population
Table
14.3.1.10.1.1
Treatment-Emergent Adverse Events that Occurred in at least 5% of Subjects during Double-blind
Treatment Period by MedDRA System Organ Class and Preferred Term with Mean Time to Onset
(days) and Mean Duration (days) – Safety Population (Japan)
Y
Table
14.3.1.10.2
Treatment-Emergent Adverse Events that Occurred in at least 5% of Subjects during Double-blind
through Open-label Treatment Periods by MedDRA System Organ Class and Preferred Term, Mean
Average Dose in ZX008-1503 with Mean Time to Onset (days) and Mean Duration (days) – Safety
Population
Table
14.3.1.10.2.1
Treatment-Emergent Adverse Events that Occurred in at least 5% of Subjects during Double-blind
through Open-label Treatment Periods by MedDRA System Organ Class and Preferred Term, Mean
Average Dose in ZX008-1503 with Mean Time to Onset (days) and Mean Duration (days) – Safety
Population (Japan)
Y
14.3.2
Listings of Deaths, Other Serious and Significant Adverse Events
Table
14.3.2.1
Listing of Deaths
Y
Y
Table
14.3.2.1.1
Listing of Deaths (Japan)
Y
PUBLIC COPY 
Organ
Y
Organ
Y
A
C
A System
COP
System O
P
O
n (Japan)
CO
n (Japan)
OP
Occurred
C C
Occurred
m Organ
LIC
m Organ Cl
C
Cl
Safety Po
BL
Safety Po
C C
Events
UB
Events th
B
th
DRA
PU
DRA Syste
PU
Syste
ays)
P
ays)
UB
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
Inclu
au
Inclu
ut
g a
m
k
m and
ket
and Prior
et
Prior
ti
red
m
red Term
ma
Term an
r
an
ar
Preferred
ny 
Preferred T
y m
an
r
an Class,
rt a
Class, Pre
a
Pre
a
at
p
at least
ppo
least 5%
po
5%
and
up
and Prefer
upp
Prefer
lation
su
lation
po
Occurred
to 
Occurred inin
Organ
d to
Organ Class
to
Class
Safety Popu
ed 
Safety Popu
s
Events that 
use
Events that 
ent
ent Periods
us
Periods
1503 with M
be 
1503 with M
se
ergent Adver
ot 
ergent Adver
en
n
en-label
nno
label Tre
o
Tre
Dose in ZX0
ann
Dose in ZX0
ulation
ca
ulation (Japa
a
(Japa
t
Listings
nt c
Listings of
c
of D
c
D
t c
Listing
en
Listing
nt
me
Lis
Lis
me
me
me
ume
m
ication and any extensions or variations thereof. 
ded
of
ded in
of
in
nterim
eo
nterim
Analysis?
ere
Analysis?
h
.
Y
her
th
d Prior
ns
Prior
s
erm
a
erm and
ati
and Prio
ti
Prio
tio
ferred
va
ferred Term
va
Term
ar
of
of Subjects
s o
Subjects d
ed
n
ed Term wit
ns 
Term wit
or
at
at least
sio
least 5%
io
5%
and
n
and Preferr
ns
Preferr
ation (Japan
ten
ation (Japan
io
Occurred in a
ext
Occurred in a
by
y
by MedDRA
y e
MedDRA
Mean Time to
ny 
Mean Time to
xte
se Events th
d a
se Events th
tment
nd
tment Perio
nd
Perio
08
08-1503 with
an
1503 with
n)
n)
a
eaths,
tio
eaths, Other
o
Other
on
of
c
of Deaths
cat
Deaths
ati
plic
ting
pl
ting of
plic
of Death
ic
Death
app
a
ica
p


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120-day
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report
Included in 1503
Japan safety
update report,
2020
Table
14.3.2.2
Listing of SAEs
Y
Y
Table
14.3.2.2.1
Listing of SAEs (Japan)
Y
Table
14.3.2.3
Listing of Discontinuations Due to AE
Y
Y
Table
14.3.2.3.1
Listing of Discontinuations Due to AE (Japan)
Y
14.3.4
Laboratory value
Table
14.3.4.1
Laboratory parameters – Hematology– Safety Population
Y
Y
Table
14.3.4.1.1
Laboratory parameters – Hematology– Safety Population (Japan)
Y
Table
14.3.4.2
Laboratory parameters – Biochemistry– Safety Population
Y
Y
Table
14.3.4.2.1
Laboratory parameters – Biochemistry– Safety Population (Japan)
Y
Table
14.3.4.4.1
Laboratory parameters – Urinalysis (Quantitative variables) – Safety Population
Y
Y
Table
14.3.4.4.1.1
Laboratory parameters – Urinalysis (Quantitative variables) – Safety Population (Japan)
Y
Table
14.3.4.4.2
Laboratory parameters – Urinalysis (Qualitative variables) – Safety Population
Y
Y
Table
14.3.4.4.2.1
Laboratory parameters – Urinalysis (Qualitative variables) – Safety Population (Japan)
Y
Table
14.3.4.5
Laboratory parameters – Tests of growth, precocious puberty and thyroid function – Safety
Population
Y
Y
Table
14.3.4.5.1
Laboratory parameters – Tests of growth, precocious puberty and thyroid function – Safety
Population (Japan)
Y
14.4.1
Vital Signs
Table
14.4.1.1
Vital signs parameters – Safety Population
Y
Y
Table
14.4.1.1.1
Vital signs parameters – Safety Population (Japan)
Y
Figure
14.4.1.2
Scatterplot of Age (X-axis) and Height (Y-axis) at End of Study during the Open-label Treatment
Period – Safety Population
Y
LIC COPY 
Y
ulation
COP
ulation
OP
Populatio
CO
Populatio
CO
Safety
IC
Safety Pop
C 
Pop
C C
BLIC
try
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– Safety
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Safety
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pp


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2020
Figure
14.4.1.2.1
Scatterplot of Age (X-axis) and Height (Y-axis) at End of Study during the Open-label Treatment
Period – Safety Population (Japan)
Table
14.4.1.3
Weight during the Open-Label Study Period over Time by Age Group (2 - <4; 4 - <6; 6 to <12; and
≥12): Summary Statistics – Safety Population
Y
Table
14.4.1.3.1
Weight during the Open-Label Study Period over Time by Age Group (2 - <4; 4 - <6; 6 to <12; and
≥12): Summary Statistics – Safety Population (Japan)
Y
Table
14.4.1.4
Weight during the Open-Label Study Period over Time for De Novo Subjects: Summary Statistics –
Safety Population
Table
14.4.1.4.1
Weight during the Open-Label Study Period over Time for De Novo Subjects: Summary Statistics –
Safety Population (Japan)
Y
Table
14.4.1.5
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the Open-Label Study Period – Safety Population
Y
Table
14.4.1.5.1
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the Open-Label Study Period – Safety Population
(Japan)
Y
Table
14.4.1.6
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the Open-Label Study Period by Concomitant
Topiramate – Safety Population
Y
Table
14.4.1.6.1
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the Open-Label Study Period by Concomitant
Topiramate – Safety Population (Japan)
Y
Table
14.4.1.7
Weight Summary (Lost/Gain ≥5%) during the Open-Label Study Period – Safety Population
Y
Table
14.4.1.7.1
Weight Summary (Lost/Gain ≥5%) during the Open-Label Study Period – Safety Population (Japan)
Y
Table
14.4.1.8
Weight Summary (Lost/Gain ≥5%) during Open-Label Study Period by Concomitant Topiramate –
Safety Population
Y
Table
14.4.1.8.1
Weight Summary (Lost/Gain ≥5%) during Open-Label Study Period by Concomitant Topiramate –
Safety Population (Japan)
Y
14.4.4
Tanner Staging
UBLIC COPY 
Age
Y
Age Gro
Y
Gro
Y
Time
CO
Time for
OP
for D
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and
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app
app


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2020
Table
14.4.4.1
Tanner staging by age group for Boys– Safety Population
Y
Table
14.4.4.1.1
Tanner staging by age group for Boys– Safety Population (Japan)
Y
Table
14.4.4.2
Tanner staging by age group for Girls– Safety Population
Y
Table
14.4.4.2.1
Tanner staging by age group for Girls– Safety Population (Japan)
Y
14.4.5
Columbia-Suicide Severity Rating Scale (C-SSRS)
Table
14.4.5.1
Number of Subjects with Suicidal Ideation, Suicidal Behavior, and Self-Injurious Behavior without
Suicidal Intent Based on the C-SSRS during Treatment – Safety Population
Y
Y
Table
14.4.5.1.1
Number of Subjects with Suicidal Ideation, Suicidal Behavior, and Self-Injurious Behavior without
Suicidal Intent Based on the C-SSRS during Treatment – Safety Population (Japan)
Y
Table
14.4.5.2
Number of Subjects with Suicide-Related Treatment-Emergent Events Based on the C-SSRS during
Treatment – Safety Population
Y
Table
14.4.5.2.1
Number of Subjects with Suicide-Related Treatment-Emergent Events Based on the C-SSRS during
Treatment – Safety Population (Japan)
Y
14.4.6
Brief Rating Inventory of Executive Function-Preschool version (BRIEF)
Table
14.4.6.1
Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P) – Scoring summary
table – Safety population
Y
Y
Table
14.4.6.1.1
Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P) – Scoring summary
table –Safety population (Japan)
Y
Table
14.4.6.2
Behavior Rating Inventory of Executive Function (BRIEF) – Scoring summary table – Safety population
Y
Y
Table
14.4.6.2.1
Behavior Rating Inventory of Executive Function (BRIEF) – Scoring summary table – Safety population
(Japan)
Y
Table
14.4.6.3
Behavior Rating Inventory of Executive Function- Adult Version (BRIEF-A) – Scoring summary table–
Safety population (De Novo Subjects)
PUBLIC COPY 
pan)
Y
pan)
Y
Behavior,
OP
Behavior,
atment 
CO
atment –
CO
– S
O
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OP
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C C
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C
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Related
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Behavio
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Safe
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and any extensions or variations thereof. 
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120-day
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Included in 1503
Japan safety
update report,
2020
Table
14.4.6.3.1
Behavior Rating Inventory of Executive Function- Adult Version (BRIEF-A)– Scoring summary table–
Safety population (Japan) (De Novo Subjects)
Y
16.2
Subject data listing
16.2.1
Subject disposition and discontinuation
Listing
16.2.1.1
Subject completion/discontinuation
Y
Y
Listing
16.2.1.2
Subject completion/discontinuation (Japan)
Y
16.2.2
Protocol deviations
Y
Listing
16.2.2.1
Major Protocol Deviations
Y
Y
Listing
16.2.2.2
Major Protocol Deviations (Japan)
Y
16.2.3
Subjects excluded from analysis
Listing
16.2.3.1
Subjects excluded from analysis populations
Y
Y
Listing
16.2.3.1.1
Subjects excluded from analysis populations (Japan)
Y
Listing
16.2.3.2
Subject allocation to trial populations
Y
Y
Listing
16.2.3.2.1
Subject allocation to trial populations (Japan)
Y
16.2.4
Demographic data and other baseline characteristics
Listing
16.2.4.1.1
Demographic data
Y
Y
Listing
16.2.4.1.1.1
Demographic data (Japan)
Y
Listing
16.2.4.1.2
% Change from baseline in weight and BMI
Y
Y
Listing
16.2.4.1.2.1
% Change from baseline in weight and BMI (Japan)
Y
Listing
16.2.4.2
Medical history
Listing
16.2.4.3
Prior and concomitant medications and therapies/treatments
Y
PUBLIC COPY 
Y
PY
CO
C
IC
BL
lysis
PU
lysis popul
PU
popul
UB
ysis
P
ysis
P
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
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Inclu
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su
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to
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pulations (Ja
 
(Ja
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populations
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populations
us
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Listing
16.2.4.3.1
Prior and concomitant medications and therapies/treatments (Japan)
Y
Listing
16.2.4.4.1
Prior antiepileptic Drugs (AEDs)
Y
Y
Listing
16.2.4.4.2
Concomitant antiepileptic Drugs (AEDs)
Y
Y
Listing
16.2.4.4.3
Prior antiepileptic Drugs (AEDs) (Japan)
Y
Listing
16.2.4.4.4
Concomitant antiepileptic Drugs (AEDs) (Japan))
Y
Listing
16.2.4.5
Rescue medications
Y
Listing
16.2.4.5.1
Rescue medications (Japan)
Y
16.2.5
Treatment exposure and compliance
Listing
16.2.5.1
IMP Intake per day during Treatment
Y
Y
Listing
16.2.5.1.1
IMP Intake per day during Treatment (Japan)
Y
Listing
16.2.5.2
IMP Intake – self reported % compliance
Y
Y
Listing
16.2.5.2.1
IMP Intake – self reported % compliance (Japan)
Y
Listing
16.2.5.3
Drug Accountability and Compliance to Study Treatment by Visit
Listing
16.2.5.3.1
Drug Accountability and Compliance to Study Treatment by Visit (Japan)
Y
16.2.6
Effectiveness data
Listing
16.2.6.1
Convulsive seizure – duration and number of occurrences per subject (Diary data)
Y
Y
Listing
16.2.6.1.1
Convulsive seizure – duration and number of occurrences per subject (Diary data) (Japan)
Y
Listing
16.2.6.2
Non-Convulsive seizure – by type, duration and number of occurrences per subject (Diary data)
Y
Listing
16.2.6.2.1
Non-Convulsive seizure – by type, duration and number of occurrences per subject (Diary data)
(Japan)
Y
Listing
16.2.6.3
Duration of the Longest interval between convulsive seizures and convulsive seizure free days per
subject
PUBLIC COPY 
Y
OP
CO
C C
t
B
t
LIC
tment
UB
tment (Jap
B
(Jap
BL
%
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P
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not be used
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be u
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u
be
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no
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anno
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nn
seizure –
n
– d
canno
Convulsive
ca
Convulsive
an
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Non
nt
Non-
t
-Convul
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(Japan)
t c
e
me
Dur
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Dur
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ensions or variations thereof. 
ded
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th
th
th
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subject
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app
app


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Listing
16.2.6.3.1
Duration of the Longest interval between convulsive seizures and convulsive seizure free days per
subject (Japan)
Y
Listing
16.2.6.4
Percent reduction in convulsive seizure frequency from baseline
Y
Y
Listing
16.2.6.4.1
Percent reduction in convulsive seizure frequency from baseline (Japan)
Y
Listing
16.2.6.5
Clinical Global Impression – Improvement rating as assessed by the Parent/Caregiver and
Investigator
Y
Y
Listing
16.2.6.5.1
Clinical Global Impression – Improvement rating as assessed by the Parent/Caregiver and
Investigator (Japan)
Y
Listing
16.2.6.6
Quality of Life in Childhood Epilepsy Scale
Listing
16.2.6.7
Quality of life of the Parent/Caregiver using EQ-5D-5L scale
Listing
16.2.6.8
Quality of life of the Parent/Caregiver using HADS scale
Listing
16.2.6.9.1
Pediatric Quality of Life Inventory (Peds QL) - for TODDLERS (age 2-4 years)
Listing
16.2.6.9.2
Pediatric Quality of Life Inventory (Peds QL) - for Young Children (age 5-7 years)
Listing
16.2.6.9.3
Pediatric Quality of Life Inventory (Peds QL) - for Children (age 8-12 years)
Listing
16.2.6.9.4
Pediatric Quality of Life Inventory (Peds QL) - for TEENS (age 13-18 years)
Listing
16.2.6.9.5
Pediatric Quality of Life Inventory (Peds QL) – Family Impact Module
Listing
16.2.6.10
Study medication palatability assessment
Y
Listing
16.2.6.11
Sleep quality and mealtime behavior
Listing
16.2.6.12
Karolinska sleepiness scale
Listing
16.2.6.13
Healthcare utilization questions
16.2.7
Adverse events
Listing
16.2.7.1
Adverse events
Y
Y
PUBLIC COPY
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Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Listing
16.2.7.2
Adverse events of special interests (AESI)
Y
Y
16.2.7.3
Adverse events for de novo subjects
Y (New)
16.2.8
Laboratory data
Listing
16.2.8.1.1
Laboratory Data Hematology parameters
Y
Y
Listing
16.2.8.1.1.1
Laboratory Data Hematology parameters (Japan)
Y
Listing
16.2.8.1.2
Most Abnormal Laboratory Parameters during Open-label Treatment Period - Hematology
Y
Y
Listing
16.2.8.1.2.1
Most Abnormal Laboratory Parameters during Open-label Treatment Period – Hematology (Japan)
Y
Listing
16.2.8.2.1
Laboratory Data Biochemistry parameters
Y
Y
Listing
16.2.8.2.1.1
Laboratory Data Biochemistry parameters (Japan)
Y
Listing
16.2.8.2.2
Most Abnormal Laboratory Parameters during Open-label Treatment Period - Biochemistry
Y
Y
Listing
16.2.8.2.2.1
Most Abnormal Laboratory Parameters during Open-label Treatment Period – Biochemistry (Japan)
Y
Listing
16.2.8.3
Laboratory Data Coagulation parameters
Y
Y
Listing
16.2.8.3.1
Laboratory Data Coagulation parameters (Japan)
Y
Listing
16.2.8.4.1
Laboratory Data Urinalysis parameters
Y
Y
Listing
16.2.8.4.1.1
Laboratory Data Urinalysis parameters (Japan)
Y
Listing
16.2.8.4.2
Most Abnormal Laboratory Parameters during Open-label Treatment Period - Urinalysis
Y
Y
Listing
16.2.8.4.2.1
Most Abnormal Laboratory Parameters during Open-label Treatment Period - Urinalysis (Japan)
Y
Listing
16.2.8.5
Tests of growth, precocious puberty and thyroid function
Y
Y
Listing
16.2.8.5.1
Tests of growth, precocious puberty and thyroid function (Japan)
Y
Listing
16.2.8.6
Urine Pregnancy test
Y
Y
Listing
16.2.8.6.1
Urine Pregnancy test (Japan)
Y
PUBLIC COPY 
Y
en
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Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Listing
16.2.8.7
Urine THC panel
Y
Y
Listing
16.2.8.7.1
Urine THC panel (Japan)
Y
Listing
16.2.8.8
Whole blood cannabidiol
Y
Y
Listing
16.2.8.8.1
Whole blood cannabidiol (Japan)
Y
16.2.9
Other Safety Data
Listing
16.2.9.1.1
Vital signs
Y
Y
Listing
16.2.9.1.1.1
Vital signs (Japan)
Y
Listing
16.2.9.1.2
Abnormal Vital Signs Data
Y
Y
Listing
16.2.9.1.2.1
Abnormal Vital Signs Data (Japan)
Y
Listing
16.2.9.1.9
Subjects with Weight Decrease >5% during Treatment
Y
Y
Listing
16.2.9.1.9.1
Subjects with Weight Decrease >5% during Treatment (Japan)
Y
Listing
16.2.9.2
Columbia-Suicide Severity Rating Scale (C-SSRS)
Y
Y
Listing
16.2.9.2.1
Columbia-Suicide Severity Rating Scale (C-SSRS) (Japan)
Y
Listing
16.2.9.3.1
Behavior Rating Inventory of Executive Function – Preschool Version (BRIEF-P) – Individual Responses
Y
Y
Listing
16.2.9.3.1.1
Behavior Rating Inventory of Executive Function – Preschool Version (BRIEF-P) – Individual Responses
(Japan)
Y
Listing
16.2.9.3.2
Behavior Rating Inventory of Executive Function – Preschool Version (BRIEF-P) – Summary Scales
Y
Y
Listing
16.2.9.3.2.1
Behavior Rating Inventory of Executive Function – Preschool Version (BRIEF-P) – Summary Scales
(Japan)
Y
Listing
16.2.9.3.3
Behavior Rating Inventory of Executive Function (BRIEF) – Individual Responses
Y
Y
Listing
16.2.9.3.3.1
Behavior Rating Inventory of Executive Function (BRIEF) – Individual Responses (Japan)
Y
Listing
16.2.9.3.4
Behavior Rating Inventory of Executive Function (BRIEF) – Summary Scales
Y
Y
PUBLIC COPY 
Y
OP
CO
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Table/ Figure/
Listing
Number
Table Header
Included in
Interim
Analysis?
Include in
120-day
safety update
report
Included in 1503
Japan safety
update report,
2020
Listing
16.2.9.3.4.1
Behavior Rating Inventory of Executive Function (BRIEF) – Summary Scales (Japan)
Y
Listing
16.2.9.3.5
Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) – Individual Responses
Y
Y
Listing
16.2.9.3.5.1
Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) – Individual Responses
(Japan)
Y
Listing
16.2.9.3.6
Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) – Summary Scales
Y
Y
Listing
16.2.9.3.6.1
Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) – Summary Scales (Japan)
Y
Listing
16.2.9.4
Tanner Staging
Y
Y
Listing
16.2.9.4.1
Tanner Staging (Japan)
Y
Listing
16.2.9.5
Physical Examination
Y
Y
Listing
16.2.9.5.1
Physical Examination (Japan)
Y
Listing
16.2.9.6
Neurological Examination
Y
Y
Listing
16.2.9.6.1
Neurological Examination (Japan)
Y
PY
Version
PY
Version (B
Y 
(B
PUBLIC COPY
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Part 1 of 2
Table 14.1.1.1
Subject Disposition
All Enrolled Subjects
Gp1
(N=xx)
Gp 2
(N=xx)
Gp3
(N=xx)
Gp 4
(N=xx)
Gp5
(N=xx)
ZX008 OL
(N=xx)
De Novo Subjects
(N=xx)
Enrolled
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Subjects discontinued trial
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Reasons for trial discontinuation
Reason 1
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Reason 2
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
---
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
---
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Completed Study*
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Note: Percentages for summaries where only a Total column is present use number of enrolled subjects as the denominator.
*Study is an ongoing open-label extension. Amendment 4 allows de novo subjects to be enrolled.
Programming Notes:
-
Information on this table comes from CRF pages 6, 14, 33 and 34.
-
For 120 day safety update – One column only for this table– ZX008 OL
-
For 15Feb2019 IDSMC, please add the following note:
"Note: A total of 10 de novo subjects enrolled as of the data cutoff date for this report (15FEB2019) are not included in the tables but are included in the listings. None of those subjects has withdrawn from
the study as of the data cutoff date." Add only for the IDSMC output.
For 120-day output: *Study is an ongoing open-label extension. Amendment 4 allows de novo subjects to be enrolled. A total of 10 de novo subjects enrolled as of the data cutoff date for this report
(15FEB2019) are not included in the tables, figures and listings.”
UBLIC COPY 
x
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xx
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ica
ures and listi


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Table 14.1.1.1
Subject Disposition
All Enrolled Subjects
Part 2 of 2
Gp1
(N = XX) [1]
Gp8
(N = XX) [2]
Gp9
(N = XX)
Enrolled
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Subjects discontinued trial early:
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Reasons for early trial discontinuation:
Reason 1
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Reason 2
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
---
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
---
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Completed study
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Programming Notes:
-
Information on this table comes from CRF 6, 14, 33 and 34.
Treatment Group for Part 2 of 2:
Groups 1, 6 and 7
Programming Notes: Use the shell for 14.1.1.1 for
Table 14.1.1.1.1
Subject disposition
All Enrolled Subject (Japan).
PUBLIC COPY 
x%)
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xxx.x%)
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x
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a
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Table 14.1.1.2
Major protocol deviations
Safety Population
Gp1
(N = XX) [1]
Gp8
(N = XX) [2]
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
No. (%) Subjects with at Least One MPD
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
Type of MPD
MPD 1
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
MPD 2
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
MPD 3
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
xx (xxx.x%)
MPD = Major protocol deviation
Note: Subjects may have had more than one MPD.
Programming Note: Use the shell for 14.1.1.2 for
Table 14.1.1.2.1
Major protocol deviations
Safety Population (Japan)
PUBLIC COPY 
x
xx
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xx
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ort
(xxx.x%)
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TIAL
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s or variations thereof. 
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ZX008
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ZX008 OL
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x
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Table 14.1.1.3
Study Populations
Gp1
(N=xx)
Gp2
(N=xx)
Gp3
(N=xx)
Gp4
(N=xx)
Gp5
(N=xx)
Gp9
(N=XXX)
De Novo Subjects
(N=xxx)
Enrolled (ITT) Population[1]
XX
XX
XX
XX
XX
XX
XX
Modified ITT (mITT) Population[2]
XX
XX
XX
XX
XX
XX
XX
Safety (SAF) Population [3]
XX
XX
XX
XX
XX
XX
XX
Notes:
[1] Enrolled (ITT) population: All subjects who gave informed consent or assent for entry into Study ZX008-1503.
[2] Modified ITT Population: All enrolled subjects who receive at least one dose of ZX008 and for whom at least 30 days of diary data are available. [All subjects on study from Day 30 of OLE period onward
are included in the mITT population.]
[3] Safety population: All subjects who received at least one dose of ZX008 during the open label extension.
Programming note: For [2] include any subject who has any data from Study Day 30 onward.
Programming note: Use the shell for 14.1.1.3 for
Table 14.1.1.3.1
Study Populations (Japan)
PUBLIC COPY 
Y
XX
PY
XX
PY 
OP
O
try
C
try into
C C
into Stu
C
Stu
ZX008
C
ZX008 and
C 
and
during
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during the
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national
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03
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s d
TIAL
Gp5
ng
Gp5
(N
n
(N
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e
ke
ke
ket
ke
rke
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m
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ward.


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Table 14.1.2.1
Demographic and Baseline Characteristics
Safety Population
Gp1
(N=xx)
Gp2
(N=xx)
Gp3
(N=xx)
Gp4
(N=xx)
Gp5
(N=xx)
ZX008 OL
(N=XXX)
De Novo Subjects
(N=xxx)
Age (years)
N
XX
XX
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
XX
Age Group, n (%)
<6 Years
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
6-18 Years
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
>18 Years
Sex
Male
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Female
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Race[ADSL.RACE]
White
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Black or African American
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Asian
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
American Indian or Alaska native
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Native Hawaiian or Other Pacific Islander
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Other[ADSL.RACEOTH]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
PUBLIC COPY 
Y
PY
OP
OP
OP
OP
OP
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Gp1
(N=xx)
Gp2
(N=xx)
Gp3
(N=xx)
Gp4
(N=xx)
Gp5
(N=xx)
ZX008 OL
(N=XXX)
De Novo Subjects
(N=xxx)
Not Reported
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Ethnic Group
Hispanic or Latino
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Not Hispanic or Latino
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Not Reported[*]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Unknown[*]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Baseline Height (m)
N
XX
XX
XX
XX
XX
XX
XX
Mean
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
SD
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
Median
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
Min
XXX
XXX
XXX
XXX
XXX
XXX
XXX
Max
XXX
XXX
XXX
XXX
XXX
XXX
XXX
Baseline Weight (kg)
N
XX
XX
XX
XX
XX
XX
XX
Mean
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
SD
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
Median
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
Min
XXX
XXX
XXX
XXX
XXX
XXX
XXX
Max
XXX
XXX
XXX
XXX
XXX
XXX
XXX
Baseline BMI (kg/m2)
N
XX
XX
XX
XX
XX
XX
XX
Mean
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
SD
XX.XXX
XX.XXX
XX.XXX
XX.XXX
XX.XXX
XX.XXX
XX.XXX
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(N=xx)
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th
(XX.X%)
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(XX.X%)
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XX (XX.X%)
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XX (XX.X%
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Gp1
(N=xx)
Gp2
(N=xx)
Gp3
(N=xx)
Gp4
(N=xx)
Gp5
(N=xx)
ZX008 OL
(N=XXX)
De Novo Subjects
(N=xxx)
Median
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Min
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Max
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
*Not reported, or missing: Privacy laws in some regions/countries preclude disclosure of certain personal information.
BMI=Body Mass Index, where BMI = weight (kg) / height (m2).
Note: Percentages are calculated based on the number of subjects with non-missing data in the Safety population.
Subjects do not necessarily reside in the country in which they attend clinic for the purpose of this study.
Programming note: Use the shell for Table 14.1.2.1 for
Table 14.1.2.1.1
Demographic and Baseline Characteristics
Safety Population (Japan)
Table 14.1.2.2
Demographic and Baseline Characteristics
mITT Population
Table 14.1.2.2.1
Demographic and Baseline Characteristics
mITT Population (Japan)
PUBLIC COPY 
Safety
PY
Safety pop
Y
pop
of this stud
OP
of this stud
Dem
LI
Dem
This document cannot be used to support any marketing authorization 
uth
national
zat
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03
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ation.
Table
upp
Table 14
pp
14
graphic
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Dem
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on
Gp5
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Gp5
(N=xx)
of
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ny
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Table
14.1.3.1
Medical
History
Safety Population
Gp1
Gp8
Gp9
De Novo Subjects
MedDRA [1] System Organ Class and Preferred Term
(N = XX)
(N = XX)
(N = XX)
(N = XX)
Subjects with at Least One Previous or Concurrent
Medical History
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
System Organ Class 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 2
…
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
…
[1] MedDRA : Medical Dictionary for Regulatory Activities – latest version at the time of data collection.
Programming note: Use the shell for 14.1.3.1 for
Table 14.1.3.1.1
Medical History
Safety Population (Japan)
PUBLIC COPY 
BL
n
U
n at
UB
at the
UB
the tim
B
tim
thorization 
national
zat
national L
03
03
support any marketing auth
ting
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TIAL
(XX.X%)
t an
(XX.X%)
XX
rt
XX (XX.X%)
rt a
(XX.X%)
XX
ort
XX (XX.X
ort
(XX.X
s
of
o
of data
o s
data colle
s
colle
uth
ons or variations thereof. 
ere
Gp9
s th
Gp9
(N
s
(N = X
X
ns
%)
%)
application and any extension
a
ion
ction.
sio
ction.


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Table 14.1.4.1
Prior Medications and Therapies/Treatments
Safety Population
Drug Class ATC Level 2 [1]
Preferred Term
Gp1
(N = XX)
Gp8
(N = XX)
Gp9
(N = XX)
De Novo Subjects
(N = XX)
Subjects with at Least One prior Medication
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
DRUG CLASS
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Name 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Name 2
…
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
…
[1] Medication terms are coded using the World Health Organization (WHO) Drug Dictionary – latest version.
UBLIC COPY 
Y
)
C
)
PUB
X%)
C
X%)
XX.X%)
C C
XX.X%)
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national
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national L
03
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p8
m
p8
N
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N = XX)
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XX)
XX
any
XX (XX.X
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(XX.X
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X
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X
to 
to
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or
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Table 14.1.4.2
Concomitant Medications and Therapies/Treatments
Safety Population
Drug Class ATC Level 2
Preferred Term [1]
Gp1
(N = XX)
Gp8
(N = XX)
Gp9
(N = XX)
De Novo Subjects
(N = XX)
Subjects with at Least One Concomitant Medication
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
DRUG CLASS
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Name 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Name 2
…
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
…
[1] Medication terms are coded using the World Health Organization (WHO) Drug Dictionary – latest version.
BLIC COPY 
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)
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C
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XX)
XX
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XX (XX.X%)
ny 
(XX.X%)
m
XX
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XX (X
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X
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X
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Table 14.1.4.3
Prior/Baseline Antiepileptic Treatment
Safety Population
Drug Class ATC Level 2
Preferred Term [1]
Gp1
(N = XX)
Gp8
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Subjects with at Least One prior Antiepileptic treatment
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
DRUG CLASS
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Name 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Name 2
…
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
…
[1] Medication terms are coded using the World Health Organization (WHO) Drug Dictionary – latest version.
Note: Multiple occurrences of the same Antiepileptic treatment are counted once for each subject within a drug class and preferred drug name.
Programming Note: Use the shell for 14.1.4.3 for
Table 14.1.4.3.1
Prior/Baseline Antiepileptic Treatment
Safety Population (Japan)
PUBLIC COPY 
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X%)
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X (XX.X%)
va
(XX.X%)
XX
r
XX (XX.X%)
r v
(XX.X%)
ioioion
est
s
est version
sio
version.
bject
n
bject within
nsi
within a
Prior/
y e
Prior/


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Table 14.1.4.4.1
Concomitant Antiepileptic Treatment
Safety Population
Drug Class ATC Level 2
Preferred Term [1]
Gp1
(N = XX)
Gp8
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Subjects with at Least One Concomitant antiepileptic treatment
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
DRUG CLASS
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Name 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Name 2
…
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
…
[1] Medication terms are coded using the World Health Organization (WHO) Drug Dictionary – latest version.
Note: Multiple occurrences of the same antiepileptic treatment are counted once for each subject within a drug class and preferred drug name.
Note: A concomitant antiepileptic treatment (AEDs) defined as antiepileptic treatment with a start or stop date after the first dose of study treatment. Missing or partial start or stop dates for concomitant
AEDs are handled as specified in SAP Section 6.2.5
Programming Note: Use the shell for 14.1.4.4.1 for
Table 14.1.4.4.1.1
Concomitant Antiepileptic Treatment
Safety Population (Japan)
PUBLIC COPY 
X%)
C
X%)
BL
HO)
UB
HO) Drug
UB
Drug
ounted
PU
ounted on
U
on
epileptic
PU
epileptic
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
eti
XX)
m
XX)
XX
ny
XX (XX.X%)
ny 
(XX.X%)
m
XX
an
XX (X
n
(X
X
a
X
s
tionary
to s
tionary –
s
– lat
s
lat
for
t
for each
to
each sub
o
sub
eatment
d t
eatment with
t
with
application and any extensions or variations thereof. 
a
he
on
on
on
X.X%)
ar
X.X%)
X (XX.X%)
va
(XX.X%)
XX
r
XX (XX.X%)
r v
(XX.X%)
ioioion
est
s
est version
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version.
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ject within
nsi
within a
a
e
a start or
en
start or stst


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Table 14.1.4.4.2
Frequency Distribution for Number of Concomitant Antiepileptic Drugs
Safety Population
Gp1
Gp8
Gp9
De Novo Subjects
(N = XX)
(N = XX)
(N = XX)
(N = XX)
Number of Concomitant AED
1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
2
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
3
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
4
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
5
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
6
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
---
AED=Antiepileptic Drugs.
Programming Note: Use the shell for 14.1.4.4.2 for
Table 14.1.4.4.2
Frequency Distribution for Number of Concomitant Antiepileptic Drugs
Safety Population (Japan)
PUBLIC COPY 
XX
Y
XX
XX
PY
XX (X
Y
(X
X
P
X
IC
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
tin
rke
)
X%)
an
X%)
(XX.X%)
t an
(XX.X%)
XX
r
XX (XX.X%)
rt a
(XX.X%)
XX
por
XX (XX.X%
or
(XX.X%
pp
quency
se
quency Distri
se
Distri
uth
application and any extensions or variations thereof. 
a
Gp9
h
Gp9
er
(N
t
(N =
th
= XX)
the
XX)
th
XX
n
XX
%)
o
%)
s o
Table
e
Table
bution
ext
bution for
xt
for Nu
Nu
Saf
x
Saf


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Table 14.1.5.1
Duration of Treatment Exposure
Safety Population
Time on Treatment (days)
Gp1
(N = XX)
Gp8
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
n
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
Min
XX
XX
XX
XX
Q1
XX
XX
XX
XX
Q2 (Median)
XX.X
XX.X
XX.X
XX.X
Q3
XX
XX
XX
XX
Max
XX
XX
XX
XX
SD: Standard Deviation. Q1=Lower Quartile; Q2=Median; Q3=Upper Quartile.
Note: Time on treatment (in days) will be calculated per subject as the number of days with IMP intake during the trial. This will be calculated as Date of last IMP intake – Date of first IMP intake + 1.
Programming Note: Use the shell for 14.1.5.1 for
Table 14.1.5.1.3
Duration of Treatment Exposure
Safety Population (Japan)
C COPY 
XX.X
OP
XX.X
PUBLIC 
XX
COP
XX
XX
CO
XX
C C
of
L
of days
LIC
days w
C
w
thorization 
national
zat
national L
03
03
port any marketing auth
tin
tin
ting
XX
a
XX
ke
XX.X
ma
XX.X
XX.XX
m
XX.XX
X
This document cannot be used to supp
do
TIAL
s d
TIAL
p
IMP
u
IMP intake
up
intake d
uth
or variations thereof. 
ZX008
her
ZX008 OL
r
OL
(N
he
(N =
e
= X
ere
th
XX
ri
XX
XX.X
ari
XX.X
application and any extensions o
a
XX
va
XX
XX
v
XX
o
during
ns
during the
ns 
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tri
Tabl
e
Tabl
Duration
ext
Duration
Saf
x
Saf


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Table 14.1.5.1.1
Duration of Treatment Exposure by Age Group
Safety Population
Subjects <6 years at Entry in Core Study
(N=xxx)
Subjects ≥6 years at Entry in Core Study
(N=xxx)
ALL ZX008 Treated Subjects
(N=xx)
Summary Stats
n
XX
XX
XX
Mean (days)
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
Min, Max
XX, XX
XX, XX
XX, XX
Duration of Exposure
<1 month
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
1 to <3 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
3 to <6 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
6 to <12 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
12 to <18 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
18 to <24 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
24 to <30 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
30 to <36 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
≥36 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Note: De novo subjects are not included in this update. Duration of exposure is calculated from date of first dose in this study to the last date of treatment or data cutoff date for this report, whichever is
earlier.
Programming note:
Similar to DX21 in ISS, but population here is the 1503 safety population, and the duration is from day 1 in OLE study; add rows for 24-30 and 30-36 as show in shell
You may present two tables using by group of Age Group or present as above, whichever works best for programming.
Programming note: Use the shell for 14.1.5.1 for
Table 14.1.5.1.4
Duration of Treatment Exposure by Age Group
Safety Population (Japan)
UBLIC COPY 
Y
PY
OP
O
CO
C C
X.X%)
LIC
X.X%)
C
(XX.X%)
BLIC
(XX.X%)
LIC
X
B
X (XX.X%
BL
(XX.X%
BL
XX
UB
XX (XX
UB
(XX
UB
PU
XX
PU
XX (X
U
(X
U
XX
P
XX
PU
P
to support any marketing authorization 
uth
national
zat
national L
03
03
ke
ears
a
ears at
ark
at Entry
ark
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(N=xxx)
mar
(N=xxx)
rk
ma
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present as ab


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Table 14.1.5.1.2
Duration of Treatment Exposure by Sex
Safety Population
Female Subjects
Male Subjects
ALL ZX008 Treated Subjects
Summary Stats
n
XX
XX
XX
Mean (days)
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
Min, Max
XX, XX
XX, XX
XX, XX
Duration of Exposure
<1 month
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
1 to <3 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
3 to <6 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
6 to <12 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
12 to <18 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
18 to <24 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
24 to <30 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
30 to <36 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
≥36 months
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Note: Duration of exposure is calculated from date of first dose in this study to the last date of treatment or data cutoff date for this report, whichever is earlier
Programming note:
Similar to DX22 in ISS, but add rows for 24-30, 30-36;
Programming note: Use the shell for 14.1.5.2 for
Table 14.1.5.1.5
Duration of Treatment Exposure by Sex
Safety Population (Japan)
LIC COPY
X
Y 
X
Y
PY
OP
O
CO
CO
CO
CO
CO
C C
)
L
)
C
PUBLIC
X%)
BL
X%)
LIC
X.X%)
BL
X.X%)
BL
(XX.X%)
UB
(XX.X%)
UB
XX
P
XX (XX.X%
PU
(XX.X%
U
PU
XX
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XX (XX
PU
(XX
PU
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P
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P
to support any marketing authorization 
uth
national
zat
national L
03
03
ke
ALL
ark
ALL Z
rk
ar
ma
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m
XX
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XX.X
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t a
XX
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su
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se
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X008
s
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X (XX.X%)
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(XX.X%)
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s 
XX
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the last
y e
last date
y e
date


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Table 14.1.5.1.6
Duration of Treatment Exposure in ZX008-1502 and ZX008-1503 Combined
Subjects Treated in ZX008-1502 and ZX008-1503 Combined (Japan)
Time on Treatment (days)
Gp1
(N = XX)
Gp2
(N = XX)
Gp3
(N = XX)
Gp4
(N = XX)
All Subjects
(N = XX)
n
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Min
XX
XX
XX
XX
XX
Q1
XX
XX
XX
XX
XX
Q2 (Median)
XX.X
XX.X
XX.X
XX.X
XX.X
Q3
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
SD: Standard Deviation. Q1=Lower Quartile; Q2 = Median; Q3=Upper Quartile
Note: Time on treatment (in days) will be calculated per subject as the number of days with IMP intake during the trial. This will be calculated as Date of last IMP intake in ZX008-1502 or ZX008-1503 – Date
of first IMP intake in ZX008-1503 + 1. The duration includes the transition period in ZX008-1502.
BLIC COPY 
C
of
L
of days
LIC
days w
C
w
PUBL
period in ZX
BL
period in ZX
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
Gp3
etin
Gp3
(N
ket
(N =
et
= XX)
et
XX)
ting
ke
X
a
X
XX.X
t a
XX.X
XX
rt a
XX
XX
rt
XX
p
IMP
u
IMP intake 
up
intake 
08
08-
s
-1502.
su
1502.
uth
application and any extensions or variations thereof. 
a
ere
XX
n
XX
th
XX.X
on
XX.X
XX.XX
tio
XX.XX
XX
i
XX
o
during
ns
during the
s 
the trtr


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Draft 3.0: 04Aug2020
Table 14.1.5.1.7.1
Shift in Assigned ZX008 Dosage in ZX008-1503 by Study Visit
Safety Population
Subject dosage (mg/kg) assigned at Visit
Visit
Last Assigned Dose
Prior to Visit
Number
of
Subjects
0.2 mg/kg/day
0.3 mg/kg/day
0.4 mg/kg/day
0.5 mg/kg/day
0.6 mg/kg/day
0.8 mg/kg/day
Visit 2 – Day 15
Subjects attending Visit
0.2 mg/kg/day
XXX
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.3 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.4 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.5 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.6 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.8 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
Visit 3 – Month 1
Subjects attending Visit
0.2 mg/kg/day
xxx
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.3 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.4 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.5 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.6 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
0.8 mg/kg/day
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
Note: For each visit after Visit 1, the number of subjects who attended the visit is presented. The assigned dosage of ZX008 that the subject was on prior to that visit is provided in the row and the assigned
dosage at the conclusion of the visit is provided in the columns. Percentages are based on the number of subjects who attended the visit.
Programming Notes: This table was MAA34 in the ISS package. Continue for other scheduled visits in 1503 through Month 36. Use the Table 14.1.5.1.7.1 shell for
Table 14.1.5.1.7.2
Shift in Assigned ZX008 Dosage in ZX008-1503 by Study Visit
Safety Population (Japan)
PUBLIC COPY 
X
O
X (XX.X%)
OPY
(XX.X%)
XXX
CO
XXX (XX.X
CO
(XX.X
XXX
CO
XXX (X
CO
(X
XX
C
XX
%)
L
%)
X.X%)
BL
X.X%)
XXX
P
XXX (XX
P
(XX
thorization 
national
zat
national L
03
03
nnot be used to support any marketing auth
tin
o
kg)
e
kg) assigned
etin
assigned
/kg/day
ma
/kg/day
rke
XXX
t an
XXX (XX.
an
(XX.
m
XXX
t a
XXX
X%)
po
X%)
X
(XX.X%)
ppo
(XX.X%)
XX
u
XX (XX.X%)
upp
(XX.X%)
XXX
su
XXX (XX.X%
sup
(XX.X%
%)
d
%)
XX.X%)
sed
XX.X%)
X
u
X (XX.X%)
use
(XX.X%)
XXX
e u
XXX (XX.X%
u
(XX.X%
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be
XXX (XX
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XXX
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cts
cts who
no
who atte
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This document can
do
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s d
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the columns
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the columns
n the
c
the ISS
ca
ISS pa
a
pa
uth
and any extensions or variations thereof. 
ere
d 
at
h
at Visit
he
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0.5
io
0.5 mg/kg/d
ion
mg/kg/d
th
X%)
a
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tio
XX.X%)
va
XX.X%)
XX
o
XX (XX.X%)
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(XX.X%)
XXX
o
XXX (XX.X%
or
(XX.X%
XXX
s 
XXX (X
o
(X
%)
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s
XXX
XXX
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XXX (XX.X%)
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e
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nded the
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nded the
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s. Percentage
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s. Percentage
ckage.
on
ckage. Contin
n 
Contin


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Draft 3.0: 04Aug2020
Table 14.1.5.8.1
Number of Subjects Receiving ZX008 According to Mean Daily Dose and Duration of Treatment
Safety Population
Number of Subjects[2] Receiving ZX008
Duration
(Months)
Mean Dose (mg/kg)[1]
Any Dose
>0 to 0.2 (n)
>0.2 to 0.4 (n)
>0.4 to 0.6 (n)
>0.6 to 0.8 (n)
Total(N)
(%)
≤1
XX
XX
XX
XX
XX
XX.X
>1 to ≤2
XX
XX
XX
XX
XX
XX.X
>2 to ≤3
XX
XX
XX
XX
XX
XX.X
>3 to ≤4
XX
XX
XX
XX
XX
XX.X
>4 to ≤5
XX
XX
XX
XX
XX
XX.X
>5 to ≤6
XX
XX
XX
XX
XX
XX.X
>6 to ≤7
XX
XX
XX
XX
XX
XX.X
>7 to ≤8
XX
XX
XX
XX
XX
XX.X
>8 to ≤9
XX
XX
XX
XX
XX
XX.X
>9 to ≤10
XX
XX
XX
XX
XX
XX.X
>10 to ≤11
XX
XX
XX
XX
XX
XX.X
>11 to ≤12
XX
XX
XX
XX
XX
XX.X
>12 to ≤18
XX
XX
XX
XX
XX
XX.X
>18 to ≤24
XX
XX
XX
XX
XX
XX.X
>24 to ≤30
XX
XX
XX
XX
XX
XX.X
>30 to ≤36
XX
XX
XX
XX
XX
XX.X
>36 to ≤42
XX
XX
XX
XX
XX
XX.X
>42 to ≤48
XX
XX
XX
XX
XX
XX.X
Total (Any Duration)
XX
XX
XX
XX
XX
XX.X
%
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
(%): (n/N) * 100  n: Number in each dosage group. N: total number for the month
[1] The mean daily dose is calculated over a subject’s entire treatment period in the trial.
[2] The tabulated frequency in a given cell is the number of subjects whose exposure duration is in that row, and whose mean daily dose over the entire treatment period falls in the specified column. The
duration endpoints, in days, are 30, 60, 90, 120, … , 330, 360; for example, a subject exposed for 70 days will be counted in the >2 to ≤3 months row. The mean daily dose is then calculated for each subject
for dose categorization. For example, if the above subject had a mean daily dose of 0.7 mg/kg during 70 days of exposure, that subject will be counted in the >0.6 to 0.8 mg/kg column.
Programming Note: This table is calculated by first categorizing subjects on the basis of the interval of exposure for each (e.g., a subject exposed for 6 and a half months would be counted in the >6 to ≤7
row. The mean daily dose is then calculated for each subject for dose categorization (e.g., a subject with a mean daily dose of 0.5 mg/kg would be counted in the >0.4 to 0.6 column). Subjects are
enumerated in only 1 cell of the matrix (i.e., this is a mutually exclusive display). Mean doses in the >4 to ≤5 row refer to mean doses over 0-5 months, not month 4-5.
PUBLIC COPY 
XX
Y
XX
XX
PY
XX
Y
XX
PY
XX
PY
OP
CO
CO
C C
C C
C C
C C
C C
C
LIC
XX
UB
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BL
XX
UB
XX
UB
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PU
XX
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thorization 
national
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03
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be used to support any marketing auth
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Programming Note: Use the same shell for Table 14.1.5.1.8.1 shell for
Table 14.1.5.8.2
Number of Subjects Receiving ZX008 According to Mean Daily Dose and Duration of Treatment
Safety Population (Japan)
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
of
of Treatmen
g a
Treatmen
uth
application and any extensions or variations thereof. 
a
t


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Table 14.1.5.1.9.1
Number of Subjects Receiving ZX008 According to Mean Dose (mg/day) and Duration of Treatment
Safety Population
Number of Subjects[2] Receiving ZX008
Duration
(Months)
Mean Dose (mg/day) [1]
Any Dose
< 5 (n)
5 - <10 (n)
10 - < 20 (n)
20 – 30 (n)
Total(N)
(%)
≤1
XX
XX
XX
XX
XX
XX.X
>1 to ≤2
XX
XX
XX
XX
XX
XX.X
>2 to ≤3
XX
XX
XX
XX
XX
XX.X
>3 to ≤4
XX
XX
XX
XX
XX
XX.X
>4 to ≤5
XX
XX
XX
XX
XX
XX.X
>5 to ≤6
XX
XX
XX
XX
XX
XX.X
>6 to ≤7
XX
XX
XX
XX
XX
XX.X
>7 to ≤8
XX
XX
XX
XX
XX
XX.X
>8 to ≤9
XX
XX
XX
XX
XX
XX.X
>9 to ≤10
XX
XX
XX
XX
XX
XX.X
>10 to ≤11
XX
XX
XX
XX
XX
XX.X
>11 to ≤12
XX
XX
XX
XX
XX
XX.X
>12 to ≤18
XX
XX
XX
XX
XX
XX.X
>18 to ≤24
XX
XX
XX
XX
XX
XX.X
>24 to ≤30
XX
XX
XX
XX
XX
XX.X
>30 to ≤36
XX
XX
XX
XX
XX
XX.X
>36 to ≤42
XX
XX
XX
XX
XX
XX.X
>42 to ≤48
XX
XX
XX
XX
XX
XX.X
Total (Any Duration)
XX
XX
XX
XX
XX
XX.X
%
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
(%): (n/N) * 100  n: Number in each dosage group. N: total number for the month
[1] The mean daily dose is calculated over a subject’s entire treatment period in the trial.
[2] The tabulated frequency in a given cell is the number of subjects whose exposure duration is in that row, and whose mean daily dose over the entire treatment period falls in the specified column. The
duration endpoints, in days, are 30, 60, 90, 120, … , 330, 360. For example, a subject exposed for 70 days will be counted in the >2 to <=3 months row. The mean daily dose, in mg/day, is then calculated for
each subject for dose categorization.
Programming Note: See MAA Table 14.1.5.3_120_mg_day.
Use the same shell for Table 14.1.5.1.9.1. shell for
Table 14.1.5.1.9.2
Number of Subjects Receiving ZX008 According to Mean Dose (mg/day) and Duration of Treatment
Safety Population (Japan)
PUBLIC COPY 
XX
Y
XX
XX
PY
XX
Y
XX
PY
XX
PY
OP
CO
CO
C C
C C
C C
C C
C C
C
LIC
XX
UB
XX
BL
XX
UB
XX
UB
XX
PU
XX
PU
X
P
X
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thorization 
national
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national L
03
03
be used to support any marketing auth
of
of Treatmen
au
Treatmen
X008
ti
X008
ting
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20
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k
– 30
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30 (n)
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XX
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XX
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XX
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XX
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XX
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be
b
number
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no
tire treatme
not
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Table 14.1.5.1.10.1
Number of Subjects Receiving ZX008 According to Actual Daily Dose (mg/kg) and Duration of Treatment
Safety Population
Number of Subjects[2] Receiving ZX008
Duration
(Months)
Actual Daily Dose (mg/kg) [1]
Any Dose
>0 to 0.2 (n)
>0.2 to 0.4 (n)
>0.4 to 0.6 (n)
>0.6 to 0.8 (n)
Total(N)
(%)
≤1
XX
XX
XX
XX
XX
XX.X
>1 to ≤2
XX
XX
XX
XX
XX
XX.X
>2 to ≤3
XX
XX
XX
XX
XX
XX.X
>3 to ≤4
XX
XX
XX
XX
XX
XX.X
>4 to ≤5
XX
XX
XX
XX
XX
XX.X
>5 to ≤6
XX
XX
XX
XX
XX
XX.X
>6 to ≤7
XX
XX
XX
XX
XX
XX.X
>7 to ≤8
XX
XX
XX
XX
XX
XX.X
>8 to ≤9
XX
XX
XX
XX
XX
XX.X
>9 to ≤10
XX
XX
XX
XX
XX
XX.X
>10 to ≤11
XX
XX
XX
XX
XX
XX.X
>11 to ≤12
XX
XX
XX
XX
XX
XX.X
>12 to ≤18
XX
XX
XX
XX
XX
XX.X
>18 to ≤24
XX
XX
XX
XX
XX
XX.X
>24 to ≤30
XX
XX
XX
XX
XX
XX.X
>30 to ≤36
XX
XX
XX
XX
XX
XX.X
>36 to ≤42
XX
XX
XX
XX
XX
XX.X
>42 to ≤48
XX
XX
XX
XX
XX
XX.X
Total (Any Duration)
XX
XX
XX
XX
XX
XX.X
%
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
(%): (n/N) * 100  n: Number in each dosage group. N: total number for the month
[1] The actual dosage in mg/day assigned by the investigator over the course of the study..
[2] The times on a particular dosate may not be concurrent. The tabulated frequency in a given cell is the number of subjects whose exposure duration is in that row, and whose assigned dosage over the
entire treatment period falls in the specified column. The duration endpoints, in days, are 30, 60, 90, 120, … , 330, 360;
Programming Note: Use the same shell for Table 14.1.5.1.10.1. shell for
Table 14.1.5.1.10.2
Number of Subjects Receiving ZX008 According to Actual Dose (mg/day) and Duration of Treatment
Safety Population (Japan)
PUBLIC COPY 
XX
Y
XX
XX
PY
XX
Y
XX
PY
XX
PY
OP
CO
CO
C C
C C
C C
C C
C C
C
LIC
XX
UB
XX
BL
XX
UB
XX
UB
XX
PU
XX
PU
X
P
X
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thorization 
national
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national L
03
03
used to support any marketing auth
n of
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of Treatm
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ti
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>0.6 to
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1.5.1.10.1.
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ca
Num


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Table 14.1.5.2.1
Compliance to IMP intake
Safety Population
Gp1
Gp8
ZX008 OL
De Novo Subjects
(N = XX)
(N = xx)
(N = XX)
(N = XX)
Overall compliance % during OLE Treatment Period
N
XX
XX
XX
XX
Mean
XX.XX
XX.XX
XX.XX
XX.XX
SD
XX.XXX
XX.XXX
XX.XXX
XX.XXX
Median
XX.XX
XX.XX
XX.XX
XX.XX
Min
XX.X
XX.X
XX.X
XX.X
Max
XX.X
XX.X
XX.X
XX.X
Compliance category
<80%
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
80-<90%
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
90-<100%
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
100-<110%
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
>110%
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
XXX (XX.X%)
IMP = Investigational medicinal product; OL=Open-label; OLE=Open-label Extension.
Note: Percentages are calculated based on the number of subjects with non-missing data in the Safety population.
Programming Note: For each day, based on the response to the daily diary, a missed dose=0% of dose consumed, partial=50% of dose consumed, and full=100% of dose consumed. For each subject, a daily
compliance score will be thus obtained. The total score for the subject during the study will then be divided by the number of days on study and multiplied by 100.
PUBLIC COPY 
XX.XX
Y
XX.XX
XX.XXX
PY
XX.XXX
XX.X
PY
XX.X
%)
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%)
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(XX.X%)
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(XX.X%)
XX
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thorization 
national
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national L
03
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ed to support any marketing auth
ZX008
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ZX008
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(XX.X%)
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(XX.X%)
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(XX.X%)
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Programming note: use table shell for 14.1.5.2.1 for the production of
Table 14.1.5.2.1.1
Compliance to IMP intake
Safety Population (Japan)
Table 14.1.5.2.2
Compliance to IMP intake
mITT Population
Table 14.1.5.2.2.1
Compliance to IMP intake
mITT Population (Japan)
PY 
14.1.
Y
14.1.
liance
PY
liance to
Y
to IM
Y
IM
PUBLIC COP
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OPY
TT Popula
thorization 
national
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03
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This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
intake
any
intake
n (Japan)
t an
n (Japan)
uth
application and any extensions or variations thereof. 
a


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Table 14.2.1.1.1
Convulsive seizure frequency per 28 days during Baseline (Core), Double-blind and OLE Treatment Period:
Summary statistics and Tests of Changes from Baseline
mITT Population
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
All treatments
combined*
(N = XX)
De Novo Subjects
(N = XX) **
Baseline[1]
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study (T+M) [2]
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study (T+M) Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study (T+M) % Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study Final Week of T+M [3]
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
PUBLIC COPY 
Y
PY
PY
PY
PY
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XX.X
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PU
PU
PU
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cannot be used to support any marketing authorization 
uth
national
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national L
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lilililic
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TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 51 of 234
Draft 3.0: 04Aug2020
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
All treatments
combined*
(N = XX)
De Novo Subjects
(N = XX) **
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study Final Week of T+M Change
from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study Final Week of T+M % Change
from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Month1 (OLE)
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Month1 (OLE) Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Month1 (OLE) % Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
PUBLIC COPY 
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TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 52 of 234
Draft 3.0: 04Aug2020
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
All treatments
combined*
(N = XX)
De Novo Subjects
(N = XX) **
Month2 (OLE)
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Month2 (OLE) Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Month2 (OLE) % Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
……
Repeat for Month3, Month4-6, Month7-9,
Month10-12, Month13-15, Month16-18,
Month19-21, Month22-24, Month 25-27,
Month 28-30, Month 31-33, Month 34-36
ENDPOINT1: Overall OLE Treatment
Period
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
ENDPOINT1: Overall OLE Treatment
Period Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
PUBLIC COPY
XX
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XX
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pplp


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 53 of 234
Draft 3.0: 04Aug2020
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
All treatments
combined*
(N = XX)
De Novo Subjects
(N = XX) **
ENDPOINT1: Overall OLE Treatment
Period % Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
ENDPOINT2: Month02-EOS
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
ENDPOINT2: Month02-EOS Change from
Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
ENDPOINT2: Month02-EOS % Change
from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
*Includes subjects randomizedto placebo and all doses of ZX008 during DB.
** For De Novo subjects, the baseline period is the 28 days prior to dosing in ZX008-1503. Change from baseline for this group is calculated relative to this baseline period.
T+M = Titration + Maintenance; OLE = Open-label extension; SD = Standard deviation; Chg = Change; EOS = End of study
Data from core study includes subjects on Placebo as well as ZX008.
[1] Baseline=Baseline prior to double-blind treatment in the core study or 28 days prior to dosing in ZX008-1503 for De Novo Subjects. Subjects in 1504-C1 do not have a Baseline(Core).
[2] Core Study (T+M) is the entire Titration+Maintenance Period during the Core study; does not include the transition period.
PUBLIC COPY 
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TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 54 of 234
Draft 3.0: 04Aug2020
[3] Core Study Final Week of T+M is the last 7 days of the T+M period.
[4]P-value for within group % change from baseline is based on Wilcoxon signed rank test that the % change from baseline is statistically significantly different from 0.
Programming note:
P-values are only calculated for the OLE Period, starting from Month1 onward. The p-value will be obtained for the percentage change from baseline, not the change from baseline. Please see SAP section
6.1.6. It does does matter whether we attach the p-value to the change stats or the percent change stats; Zogenix wantsthe p-value from the analysis of the percentage changes from baseline. Use the
round function to get the percentage change to 3 or 4 decimal places before calculating pccs25yn, pccs50yn, pccs75yn and especially pccs00yn.]
Code to get p-value for percentage change at each time point:: calculate the percentage change from baseline:
For example:
Data temp;
Set data1;
if base ne . and twval ne .;
chng = base – twval;
pctchng=(base – twval)/base;
run;
ods trace on;
ods output TestsForLocation=univout;
proc univariate data=anal;
var pctchng;
run;
ods trace off;
data dpout;
set univout;
where Test='Signed Rank' and Testlab='S';
pout=pValue; **be sure to write “<0.001” if the p-value is <0.001;
keep pctchng Test pout;
run;
Programming Note: Use the same 14.2.1.1.1 shell for
Table 14.2 1.1.6
Convulsive seizure frequency per 28 days during Baseline (Core), Double-blind and OLE Treatment Period:
Summary statistics and Tests of Changes from Baseline
mITT Population (Japan)
PUBLIC COPY 
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seizur


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Draft 3.0: 04Aug2020
Programming Note: Use the shell for 14.2.1.1.1 to produce:
Table 14.2.1.1.2
Convulsive seizure frequency per 28 days during OLE Treatment Period, by Age Group:
Summary statistics and Tests of Changes from Baseline
mITT Population
Table 14.2.1.1.7
Convulsive seizure frequency per 28 days during OLE Treatment Period, by Age Group:
Summary statistics and Tests of Changes from Baseline
mITT Population (Japan)
Programming Note: Add Header, top left, prior to the table proper, “Age Group: <6 years” or “Age Group: >= 6 years”
PUBLIC COPY 
Popu
Y
Popu
Table
OPY
Table 14
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14
per
CO
per 28
CO
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day
statistics
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statistics a
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<6 yea
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This document cannot be used to support any marketing authorization 
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03
03
do
TIAL
s d
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s
yea


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Table 14.2.1.1.3
Convulsive seizure frequency per 28 days during OLE Treatment Period Using Mean Daily Dose: Summary Statistics and Tests of Changes from Baseline
mITT Population
ZX008 Low Mean Daily Dose*
(>0 - <0.4 mg/kg)
(N = XX)
ZX008 Medium Mean Daily
Dose*
(0.4 – 0.6 mg/kg)
(N = XX)
ZX008 High Mean Daily Dose*
(>0.6 mg/kg)
(N = XX)
Any ZX008 OL Dose*
(N = XX)
Baseline[1]
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study (T+M) [2]
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study (T+M) Change from Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study (T+M) % Change from Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study Final Week of T+M [3]
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
PUBLIC COPY 
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XX.X
PY
XX.X
PY
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03
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(>0.6 mg/
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lic
pl
pp


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ZX008 Low Mean Daily Dose*
(>0 - <0.4 mg/kg)
(N = XX)
ZX008 Medium Mean Daily
Dose*
(0.4 – 0.6 mg/kg)
(N = XX)
ZX008 High Mean Daily Dose*
(>0.6 mg/kg)
(N = XX)
Any ZX008 OL Dose*
(N = XX)
Core Study Final Week of T+M Change from
Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Core Study Final Week of T+M % Change from
Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Month 1 (OLE)
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Month 1 (OLE) Change from Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
Month 1 (OLE) % Change from Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
PUBLIC COPY 
Y
OP
O
CO
C C
C C
C C
C C
C C
C 
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UB
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X.X, XX
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P
ent cannot be used to support any marketing authorization 
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national
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national L
03
03
gh
gh Mean
au
Mean Dai
au
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cation and any extensions or variations thereof. 
ly
o
ly Dose*
of
Dose*
kg)
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kg)
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r
XX)
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XX
th
XX
th
XX.X
s t
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lic
p c


TLF Shells
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CONFIDENTIAL
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ZX008 Low Mean Daily Dose*
(>0 - <0.4 mg/kg)
(N = XX)
ZX008 Medium Mean Daily
Dose*
(0.4 – 0.6 mg/kg)
(N = XX)
ZX008 High Mean Daily Dose*
(>0.6 mg/kg)
(N = XX)
Any ZX008 OL Dose*
(N = XX)
Month 2 (OLE)
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Month 2 (OLE) Change from Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Month2 (OLE) % Change from Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
……
Repeat for Month3, Month6, Month9, Month12,
Month15, Month18, Month21, Month24
ENDPOINT1: Overall OLE Treatment Period
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
ENDPOINT1: Overall OLE Treatment Period
Change from Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
PUBLIC COPY 
Y
XX.
PY
XX.
PY
OP
CO
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C C
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X, XX.X
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XX.X
UB
X.XXX
PU
X.XXX
PU
P
ment cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
gh
gh Mean
au
Mean Dai
au
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(>0.6 mg/k
g a
(>0.6 mg/k
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(N =
g
= X
g
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ly
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ly Dose*
of
Dose*
kg)
e
kg)
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r
XX)
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TLF Shells
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CONFIDENTIAL
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Draft 3.0: 04Aug2020
ZX008 Low Mean Daily Dose*
(>0 - <0.4 mg/kg)
(N = XX)
ZX008 Medium Mean Daily
Dose*
(0.4 – 0.6 mg/kg)
(N = XX)
ZX008 High Mean Daily Dose*
(>0.6 mg/kg)
(N = XX)
Any ZX008 OL Dose*
(N = XX)
ENDPOINT1: Overall OLE Treatment Period %
Change from Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
ENDPOINT2: Month02-EOS
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
ENDPOINT2: Month02-EOS Change from
Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
ENDPOINT2: Month02-EOS % Change from
Baseline
N
XX
XX
XX
XX
Mean (SD)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
Median
XX.X
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
T+M = Titration + Maintenance; OLE = Open-label extension; SD = Standard deviation; Chg = Change; EOS = End of study
Data from core study includes subjects on Placebo as well as ZX008
*Note: The calculated (weight adjusted) daily doses over the entire OLE period were averaged to get a mean dialy dose, which was then categorized as follows: > 0 – <0.4 mg/kg = Low; 0.4 – 0.6 mg/kg =
Medium; >0.6 mg/kg = High
UBLIC COPY
XX
Y
XX
X.
Y 
X.
Y
PY
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P
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support any marketing authorization 
uth
national
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national L
03
03
gh
gh Mean
au
Mean Dai
au
Dai
(>0.6 mg/k
g a
(>0.6 mg/k
(N
ng
(N =
g
= X
g
X
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ting
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ons or variations thereof. 
ly
o
ly Dose*
of
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kg)
e
kg)
XX)
r
XX)
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XX
t
XX
s t
XX.X
ns
XX.X (
ns
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th


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
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Draft 3.0: 04Aug2020
[1] Baseline=For subjects who participated in a doube-blind study, the Baseline prior to double-blind treatment in the core study. Subjects in 1504-C1 do not have a Baseline(Core), and are not included in
this table. For De Novo subjects, the baseline period is the 28 days prior to dosing in ZX008-1503. Change from baseline for this group is calculated relative to this baseline period.
[2] Core Study is the entire Titration+Maintenance Period during the Core study; does not include the transition period.
[3] Core Study Final Week of T+M is the last 7 days of the T+M period.
[4]P-value for within group change from baseline is based on Wilcoxon signed rank test that the change from baseline is statistically significantly different from 0.
Programming note: Need to use exposure data to determine mean daily dose during OLE for each subject, and categorize each subject as having had Low, Medium or High dose of ZX008 as follows:
0 – <0.4 mg/kg = Low;
0.4 – 0.6 mg/kg = Medium;
>0.6 mg/kg = High
Programming note: Use the shell for Table 14.2.1.1.3 for
Table 14.2.1.1.8
Convulsive seizure frequency per 28 days during OLE Treatment Period Using Mean Daily Dose: Summary Statistics and Tests of Changes from Baseline
mITT Population (Japan)
PUBLIC COPY 
>0.6
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Table 14.2.1.1.4
Convulsive seizure frequency per 28 days during OLE Treatment Period Using Mean Daily Dose, by Age Group: Summary Statistics and Tests of Changes from Baseline
mITT Population
Programming Note: Repeat 14.2.1.1.3 for Age groups <6, and ≥6.
Add Header, top left, prior to the table proper, “Age Group: <6 years” or “Age Group: >= 6 years”.
Programming Note: Use the same shell fo produce
Table 14.2.1.1.9
Convulsive seizure frequency per 28 days during OLE Treatment Period Using Mean Daily Dose, by Age Group: Summary Statistics and Tests of Changes from Baseline
mITT Population (Japan)
PUBLIC COPY 
Tab
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Table 14.2.1.1.5
Convulsive seizure frequency per 28 days during OLE Treatment Period: Summary Statistics
Subjects from 1504 Cohort 1
ZX008 OL[1]
(N = XX)
Core Study Day 2 through End of PK Follow-up Period *
N
XX
Mean (SD)
XX.X (XX.XX)
Median
XX.X
Min, Max
XX.X, XX.X
Core Study Transition Period**
N
XX
Mean (SD)
XX.X (XX.XX)
Median
XX.X
Min, Max
XX.X, XX.X
Month1 (OLE)
N
XX
Mean (SD)
XX.X (XX.XX)
Median
XX.X
Min, Max
XX.X, XX.X
Month2 (OLE)
N
XX
Mean (SD)
XX.X (XX.XX)
Median
XX.X
Min, Max
XX.X, XX.X
……
Repeat for Month3, Month6, Month9, Month12, Month15, Month18, Month21, Month24, Month 27, Month 30, Month 33, Month 36
ENDPOINT1: Overall OLE Treatment Period
N
XX
Mean (SD)
XX.X (XX.XX)
Median
XX.X
Min, Max
XX.X, XX.X
PUBLIC COPY 
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ZX008 OL[1]
(N = XX)
ENDPOINT2: Month02-EOS
N
XX
Mean (SD)
XX.X (XX.XX)
Median
XX.X
Min, Max
XX.X, XX.X
Notes:
[1]Subjects were on open-label ZX008 0.2 mg/kg during the entire 6 months of the Transition Period. Starting from Day 1 in the OLE Period, their dose was set at 0.2 mg/kg for the first month, and
subsequently adjusted by the PI to achieve optimal dose for effectiveness/tolerability.
*For most subjects this ends on Day 15; for some subjects the PK Period ends on Day 14 or Day 16.
**Transition Period starts 1 day after end of PK Follow-up Period and ends 1 day prior to OLE Visit 1 Day 1.
PUBLIC COPY
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Table 14.2.1.2
Convulsive seizure frequency per 28 days - ENDPOINT: Parametric Analysis
mITT Population
PBO-ZX008 OL
ZX 0.2 – ZX008 OL
ZX 0.5 – ZX008 OL
ZX 0.8 – ZX008 OL
ZX008 OL
Statistics
(N = XX)
(N = XX)
(N = XX)
(N = XX)
(N = XX)
ENDPOINT1: OLE TREATMENT PERIOD ANALYSIS
Baseline (Core) Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Core Study Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
OLE Period Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
OLE Period: Parametric Model Summary[1]
Results on log scale[2]
Least Squares Mean (SE) [2]
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
95% CI for Least Squares Mean [2]
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
PUBLIC COPY 
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XX
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Original scale
Least Squares Mean[3]
XX.X
XX.X
XX.X
XX.X
95% CI[3]
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
ENDPOINT2: MONTH2 TO EOS ANALYSIS
Baseline (Core) Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Core Study Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Month2 to EOS Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Month2 to EOS: Parametric Model Summary[1]
Results on log scale[2]
Least Squares Mean (SE) [2]
95% CI for Least Squares Mean [2]
XX.X (XX.XX)
(XX.X,XX.X)
XX.X (XX.XX)
(XX.X,XX.X)
XX.X (XX.XX)
(XX.X,XX.X)
XX.X (XX.XX)
(XX.X,XX.X)
Original scale
Least Squares Mean[3]
XX.X
XX.X
XX.X
XX.X
95% CI[3]
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
PUBLIC COPY 
X.X
LI
X.X
XX.XX
BLI
XX.XX
XX.X
BL
XX.X
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mITT = Modified intent-to-treat population; CI = Confidence Interval; SD = Standard Deviation; SE = Standard Error.
Note: this table excludes de Novo subjects.
[1] Baseline and overall OLE values were log transformed prior to analysis. To avoid taking log of 0, a value of 1 was added to each subject’s convulsive seizure frequency value (with the exception of the
Baseline (Core) value) before log transformation.
[2] Results are based on an ANCOVA model with treatment group (four levels excluding group that contained all subjects enrolled in 1503 – regardless of feeder study) and age group (< 6 years, ≥6 years) as
factors, log baseline convulsive seizure frequency as a covariate, CSF during Core Study as another covariate, and log convulsive seizure frequency (overall OLE period, or Month2 to EOS) as response.
[3]Values obtained from the ANCOVA model were exponentiated to get the corresponding values on the original scale.
Programming note: Use PROC MEANS for summary stats, and PROC GLM for parametric model analysis.
PUBLIC COPY 
sis.
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sis.
This document cannot be used to support any marketing authorization 
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national
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Table 14.2.1.3
Convulsive seizure frequency per 28 days - ENDPOINT: Nonparametric Analysis
mITT Population
PBO-ZX008 OL
ZX 0.2 – ZX008 OL
ZX 0.5 – ZX008 OL
ZX 0.8 – ZX008 OL
ZX008 OL
Statistics
(N = XX)
(N = XX)
(N = XX)
(N = XX)
(N = XX)
ENDPOINT1: OLE TREATMENT PERIOD ANALYSIS
Baseline (Core) Ranks[1]: Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Core Study Ranks[1]: Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
OLE Period Ranks[1]: Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
OLE Period: Nonparametric Model Summary[1]
Results on rank scale
Least Squares Mean (SE) [2]
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
95% CI for Least Squares Mean [2]
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
PUBLIC COPY 
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C
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XX
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XX
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XX
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Statistics
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
MONTH2 to EOS ANALYSIS
Baseline (Core) Ranks[1]: Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Core Study Ranks[1]: Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Month2 to EOS Ranks[1]: Summary Statistics
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Month2 to EOS Analysis: Nonparametric Model Summary[1]
Results on rank scale
Least Squares Mean (SE) [2]
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
95% CI for Least Squares Mean [2]
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
mITT = Modified intent-to-treat population; CI = Confidence Interval; SD = Standard Deviation; SE = Standard Error.
Note: this table excludes de Novo subjects.
[1] Baseline, Core Study, Month3 to EOS and overall OLE values were rank transformed prior to analysis.
PUBLIC COPY 
X
C
X
XX.X
IC
XX.X
XX.XX
LIC
XX.XX
XX.
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XX.
This document cannot be used to support any marketing authorization 
national
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[2]The results are on the rank scale. Results are based on an ANCOVA model with treatment group (four levels excluding group that contained all subjects enrolled in 1503 – regardless of feeder study) and
age group (< 6 years, ≥6 years) as factors, rank of baseline convulsive seizure frequency as a covariate, rank of Core Study CSF as another covariate, and rank of convulsive seizure frequency (overall OLE
period, or Month2 to EOS) as response.
Programming note: Rank the baseline and OLE period convulsive seizure frequency, then use PROC MEANS for summary stats, and PROC GLM for parametric model analysis. See stats manual.
PUBLIC COPY 
thorization 
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Table 14.2.1.4
Convulsive seizure frequency per 28 days, Over Time – Parametric Analysis
mITT Population
PBO-ZX008 OL
ZX 0.2 – ZX008 OL
ZX 0.5 – ZX008 OL
ZX 0.8 – ZX008 OL
ZX008 OL
Statistics
(N = XX)
(N = XX)
(N = XX)
(N = XX)
(N = XX)
SUMMARY STATISTICS
Baseline (Core)
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Core Study
N
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
RESULTS FROM GENERAL LINEAR MODEL
Month1: Parametric Model Summary
Results on log scale[1]
Least Squares Mean (SE) [1]
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
95% CI for Least Squares Mean [1]
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
Original scale
Least Squares Mean[2]
XX.X
XX.X
XX.X
XX.X
95% CI[2]
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
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…. (Repeat for months 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33,
and 36
mITT = Modified intent-to-treat population; CI = Confidence Interval; SD = Standard Deviation; SE = Standard Error.
Note: this table excludes de Novo subjects.
[1] Baseline and overall OLE values were log transformed prior to analysis. To avoid taking log of 0, a value of 1 was added to each subject’s convulsive seizure frequency value (the response variable) for
each timepoint in the OLE period before taking the natural logarithm.
[2] Results are based on a general linear model with fixed effects for treatment group (four levels excluding group that contained all subjects enrolled in 1503 – regardless of feeder study) and age group (< 6
years, ≥6 years), time (Months 1, 2, 3, 6, 9, 12, 15, 18, 21,and 24) and log baseline convulsive seizure frequency as a covariate; and random effects for subject (repeated over time). The dependent variable is
log convulsive seizure frequency (overall OLE period) as response.
[3] Values obtained from the ANCOVA model were exponentiated to get the corresponding values on the original scale.
Programming note: Use PROC MEANS for summary stats
For MMRM model, use PROC MIXED. Before calling the PROC, please add 1 to the Month1, Month2, … Month24 CSF values, then take the natural log (log to base e) of these values to be used in the model.
PROC MMRM for parametric model analysis. The LSMeans are the LSMeans for the time*treatment interaction terms. See stats manual.
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Programming Notes: Use the shell for 14.2.1.4 for
Table 14.2.1.5
Convulsive seizure frequency per 28 days, Over Time – Parametric Analysis Using Mean Daily Dose
mITT Population
In place of treatment groups, categorize subjects into three treatments depending on their mean daily dose during the OLE Treatment period as Low, Medium, and High. See SAP.
Categories for Low, Medium, High depending on the following doses of ZX008
<0.4 mg/kg = Low
0.4-0.6 mg/kg = Medium
>0.6 mg/kg = High
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Table 14.2.1.6
% of Subjects with Changes in AED medications during 1st 6 months of OLE Treatment Period
mITT Population
OLE Period
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
Any Change in AED medication during the 1st 6 months
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
Month 1
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
Month 2
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
Month 3
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
Month 4
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
Month 5
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
Month 6
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
XX (XX%)
mITT = Modified intent-to-treat population ; Months are defined in 30 day increments. Month1=Day1-Day30, Month2=Day31-Day60, and so on.
Programming Note: we need to determine what a change in AED medication is
PUBLIC COPY 
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Figure 14.2.1.7
Graph of means for convulsive seizure frequency per 28 days during OLE Treatment Period
mITT Population
mITT = Modified intent-to-treat population
Programming Note: This plots the means from Table 14.2.1.1.1
45
40
ZX008 OL
35
30
25
20
15
10
5
0
Study Period
Convulsive seizure frequency per 28 days
PUBLIC COPY 
PUBLIC COPY
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Figure 14.2.1.8
Graph of model adjusted means for Convulsive seizure frequency per 28 days – mITT Population
Programming note: Forest plots for the model adjusted means and CIs
Programming note: Repeat Figure 14.2.1.7 using the following 3 treatment groups: Low, Medium, and High to produce
Figure 14.2.1.9
Graph of convulsive frequency per 28 days, Over Time, Using Mean Daily Dose
mITT Population
PUBLIC COPY 
and
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Table 14.2.2.1
Percent Reduction in Convulsive Seizure Frequency, OLE Treatment Period
mITT Population
Distribution of Percentage
Change from Baseline(Core) in
De Novo
Time Period
convulsive Seizure
Frequency[1]
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL #
(N = XXX)
Subjects
(N = XXX)
OLE Period
≥25%: n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95%CI*
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
≥50%: n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95%CI*
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
≥75%: n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95%CI*
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
=100%: n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95%CI*
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
Month 1
≥25%: n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95%CI*
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
≥50%: n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95%CI*
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
≥75%: n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95%CI*
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
=100%: n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95%CI*
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
XX.X%, XX.X%
mITT = Modified Intent-to treat; CI = Confidence Interval; *Exact Clopper-Pearson CI. # Excludes the De Novo subjects.
PUBLIC COPY 
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[1]Baseline=Baseline prior to double-blind treatment in the core study. Subjects in 1504-C1 do not have a Baseline(Core), and are not included in this table.
Programming Note: …. Repeat for months 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, and 36. Use the Table 14.2.2.1 shell for
Table 14.2.2.1.1
Percent Reduction in Convulsive Seizure Frequency, OLE Treatment Period
mITT Population (Japan)
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aut
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application and any extensions or variations thereof. 
a
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Figure 14.2.2.2
Cumulative Response Curves for Percent Reduction in CSF during OLE Treatment Period
mITT Population
Example graph: From PROC LIFETEST.
Example graph above: use rgkmtest_strpntl.sas
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ent Period
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and any extensions or variations 


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Programming Note: Use the Figure 14.2.2.2 shell for
Footnote: mITT = Modified intent-to-treat population.
Figure 14.2.2.2.1
Cumulative Response Curves for Percent Reduction in CSF during OLE Treatment Period
mITT Population (Japan).
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a
d
e
d


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Table 14.2.3.1
Duration of the Longest interval (days) between convulsive seizures
mITT Population
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
n
XX
XX
XX
XX
XX
XX
mean
XX.x
XX.x
XX.x
XX.x
XX.x
XX.x
SD
XX.xx
XX.xx
XX.xx
XX.xx
XX.xx
XX.xx
Min
XX
XX
XX
XX
XX
XX
25th Percentile
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
75th Percentile
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Max
XX
XX
XX
XX
XX
XX
mITT = Modified Intent-to-treat; CI = Confidence Interval;
Note: Percentages are calculated based on the number of subjects with non-missing data in the modified ITT population.
C COPY 
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XX.X
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Figure 14.2.3.2
Boxplot of Distribution of Duration of Longest Interval between Convulsive Seizures during OLE Treatment Period
mITT Population
Programming notes:
Footnote: mITT = Modified intent-to-treat population
Example only: Separate boxplot for each group.
For interim analysis, if done, use only one box, for Group 9 (ZX008 OL, All Subjects)
PY 
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thorization 
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Table 14.2.4.1
Summary of Duration of Convulsive Seizure Episodes during OLE Treatment Period
mITT Population
Convulsive Seizure
Duration
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Total no. with at least one episode[1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Total no. of episodes
XXX
XXX
XXX
XXX
XXX
XXX
< 2-minute duration
No. of subjects
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
No. of episodes
XXX
XXX
XXX
XXX
XXX
XXX
2 – 10-minute duration
No. of subjects
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
No. of episodes
XXX
XXX
XXX
XXX
XXX
XXX
>10 minutes duration
XX (XX.X%)
No. of subjects
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XXX
No. of episodes
XXX
XXX
XXX
XXX
XXX
Clusters of Convulsive Seizures
No. of subjects
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XXX
No. of episodes
XXX
XXX
XXX
XXX
XXX
mITT = Modified Intent-to-treat; % = n/N*100 where n is number in category and N is number in cohort(except Total Recurring Seizures)
[1] % = ((Number in Cohort)/(Grand Total))*100.
PUBLIC COPY 
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num


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Table 14.2.4.2
Summary of Gaps between Convulsive Seizure Episodes during OLE Treatment Period
mITT Population
Duration by Number of Days* between
Convulsive Seizure Episodes
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
1 Recurrence
n
XX
XX
XX
XX
XX
XX
Min
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
2 Recurrences
XX
XX
XX
XX
XX
XX
n
XX
XX
XX
XX
XX
XX
Min
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
3 Recurrences
XX
XX
XX
XX
XX
XX
n
XX
XX
XX
XX
XX
XX
Min
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
4 Recurrences
XX
XX
XX
XX
XX
XX
n
XX
XX
XX
XX
XX
XX
Min
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
>= 5 Recurrences
XX
XX
XX
XX
XX
XX
n
XX
XX
XX
XX
XX
XX
Min
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
mITT = Modified Intent-to-treat; % = n/N*100 where n is number in category and N is number in cohort(except Total Recurring Seizures)
*A Recurrence day is a day on which a subject has a seizure, given that the subject has had a seizure on another day previously.
PUBLIC COPY 
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Programming Note: Use shell for Table 14.2.1.1.1 to produce
Table 14.2.5.1
Convulsive seizure-free days – summary statistics
mITT Population
Note: Percentage of convulsive seizure free days will be calculated as the total of seizure free days / total number of days with non-missing diary data*100.
PUBLIC COPY 
thorization 
national
zat
national L
03
03
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TIAL
on
k
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application and any extensions or variations thereof. 
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th
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the
data*10


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Table 14.2.5.2
Convulsive seizure-free days - Parametric Analysis - MMRM by Age Group
mITT Population
Statistics
Age < 6 years
(N = XX)
Age >= 6 years
(N = XX)
ZX008 OL
(N = XX)
SUMMARY STATISTICS
Baseline (Core)
N
XX
XX
XX
Mean
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
Min
XX
XX
XX
Max
XX
XX
XX
Core Study
N
XX
XX
XX
Mean
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
Min
XX
XX
XX
Max
XX
XX
XX
Month 1 (Original Scale) Summary Statistics
N
XX
XX
XX
Mean
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
Min
XX
XX
XX
Max
XX
XX
XX
RESULTS FROM MMRM MODEL
Results on log scale[1]
Least Squares Mean (SE) [1]
XX.X (XX.XX)
XX.X (XX.XX)
95% CI for Least Squares Mean [1]
(XX.X,XX.X)
(XX.X,XX.X)
PUBLIC COPY 
X.X
CO
X.X
XX.XX
CO
XX.XX
XX.X
C C
XX.X
XX
C 
XX
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ex
XX
XX
e
XX


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Original scale
Least Squares Mean[2]
XX.X
XX.X
95% CI[2]
(XX.X,XX.X)
(XX.X,XX.X)
…. (Repeat for months 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, and 36.
mITT = Modified intent-to-treat population; CI = Confidence Interval; SD = Standard Deviation; SE = Standard Error. MMRM = Mixed Model Repeated Measures.
[1] Baseline and overall OLE values were log transformed prior to analysis. Results are scaled to the number of seizure free days per 28 days. To avoid taking log of 0, a value of 1 was added to each subject’s
convulsive seizure frequency value (the response variable) for each timepoint in the OLE period before taking the natural logarithm.
[2]Results are based on a MMRM with fixed effects for age group (< 6 years, ≥6 years), time (Months 1, 2, 3, 6, 9, 12, 15, 18, 21,and 24), and log baseline convulsive seizure-free days and log T+M seizure
free days as covariates; and random effects for subject (repeated over time). The dependent variable is log convulsive seizure-ree fdays / 28 days frequency.
[3]Values obtained from the MMRM model were exponentiated to get the corresponding values on the original scale.
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Table 14.2.5.3
Convulsive seizure-free days - Parametric Analysis - MMRM by Mean Daily Dose
mITT Population
Statistics
ZX008 Low Mean Daily Dose*
(>0 - <0.4 mg/kg)
(N = XX)
ZX008 Medium Mean Daily Dose*
(0.4 – 0.6 mg/kg)
(N = XX)
ZX008 High Mean Daily Dose*
(>0.6 mg/kg)
(N = XX)
Any ZX008 OL Dose*
(N = XX)
SUMMARY STATISTICS
Baseline (Core)
N
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
Max
XX
XX
XX
XX
Core Study
N
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
Max
XX
XX
XX
XX
Month 1 (Original Scale) Summary Statistics
N
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
Max
XX
XX
XX
XX
RESULTS FROM MMRM MODEL
Results on log scale[1]
Least Squares Mean (SE) [1]
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
95% CI for Least Squares Mean [1]
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
PUBLIC COPY 
XX
PU
XX
XX.X
PU
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an
XX.X


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Original scale
Least Squares Mean[2]
XX.X
XX.X
XX.X
XX.X
95% CI[2]
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
…. (Repeat for months2, 3, 6, 9, 12, 15, 18, 21
and 24
mITT = Modified intent-to-treat population; CI = Confidence Interval; SD = Standard Deviation; SE = Standard Error. MMRM = Mixed Model Repeated Measures.
*Note: The calculated (weight adjusted) daily doses over the entire OLE period were averaged to get a mean dialy dose, which was then categorized as follows: > 0 – <0.4 mg/kg = Low; 0.4 – 0.6 mg/kg =
Medium; >0.6 mg/kg = High.
[1] Baseline and overall OLE values were log transformed prior to analysis. Results are scaled to the number of seizure free days per 28 days. To avoid taking log of 0, a value of 1 was added to each subject’s
convulsive seizure frequency value (the response variable) for each timepoint in the OLE period before taking the natural logarithm.
[2]Results are based on a MMRM with fixed effects for mean daily dose (3 levels), time (Months 1, 2, 3, 6, 9, 12, 15, 18, 21,and 24), and log baseline convulsive seizure-free days and log T+M seizure free
days as covariates; and random effects for subject (repeated over time). The dependent variable is log convulsive seizure-ree fdays / 28 days frequency.
[3]Values obtained from the MMRM model were exponentiated to get the corresponding values on the original scale.
PUBLIC COPY 
numbe
Y
numbe
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nths
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nths 1,
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1, 2,
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2, 3
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scale.


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Programming Notes: Use shell for Table 14.2.1.5.1 to produce
Table 14.2.5.4
Convulsive seizure-free days – summary statistics for subjects from Study 1504 –Cohort 1
Treatment group is Group 5.
Time periods do not include a Baseline(Core), as cohort 1 subjects did not have the extended baseline period that those in cohort 2 and 1501, 1502 subjects had.
PUBLIC COPY
eline
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eline peri
Y 
peri
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national
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03
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cohort 2
at
2 and
t
and


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Table 14.2.6.1
Non-convulsive seizure frequency during OLE Treatment Period
mITT Population
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = xx)
Non-convulsive seizure frequency (All types)
Baseline *
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX, xx
XX, xx
XX, xx
XX, XX
XX, XX
XX, XX
OLE Treatment Period
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX, xx
XX, xx
XX, xx
XX, XX
XX, XX
XX, XX
Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX, xx
XX, xx
XX, xx
XX, XX
XX, XX
XX, XX
P_value**
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
% Change from Baseline
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX, xx
XX, xx
XX, xx
XX, XX
XX, XX
XX, XX
PUBLIC COPY 
Y
PY
PY
PY
PY
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Least Squares Mean (SE)***
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
95% CI for Least Squares Mean***
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
(XX.X,XX.X)
mITT = Modified Intent-to-treat; CI = Confidence Interval; ANCOVA = Analysis of Covariance;
SE = Standard Error.
* Note: The baseline for De Novo subjects is based on the 28 day period prior to dosing in the ZX008-1503 study.
**P-value from the Wilcoxon signed ranks test of the change from baseline being significantly different from 0.
*** Note: Results are based on an ANCOVA model on change from baseline in non-convulsive seizure frequency, with baseline non-convulsive seizure frequency and age as covariates and treatment as a
fixed effect. The model excludes the de novo subjects.
Programming note: Use the table shell for Table 14.2.6.1 to produce the following tables.
Table 14.2.6.1.1
Non-convulsive seizure frequency during OLE Treatment Period
mITT Population (Japan)
Table 14.2.6.2
Convulsive + non-convulsive seizure frequency during OLE Treatment Period
mITT Population
Table 14.2.6.2.1
Convulsive + non-convulsive seizure frequency during OLE Treatment Period
mITT Population (Japan)
PUBLIC COPY 
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mITT Pop


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Table 14.2.7.1
Days with Rescue Medication Usage during the OLE Treatment Period
mITT Population
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Number (%) of Subjects with at Least One rescue
medication used during OLE Treatment Period
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
NUMBER OF DAYS RESCUE MEDICATION USED DURING
OLE, BY OLE TREATMENT PERIOD
Number of days rescue medication used per 28 days OLE
Month1 [1]
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.XX (XX.XXX)
XX.XX (XX.XXX)
XX.XX (XX.XXX)
XX.XX (XX.XXX)
XX.XX (XX.XXX)
XX.XX (XX.XXX)
Median
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
…
Repeat for OLE Months 2 and 3, Month 4-6, Month 9-12,
Month 13-15, Month 16-18, Month 19-21, Month 21-24..
etc, Month 33-36.
Number of days rescue medication used per 28 days
during OLE Treatment Period [1]
N
XX
XX
XX
XX
XX
XX
Mean (SD)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX, xx
XX, XX
XX, xx
XX, XX
XX, XX
XX, XX
mITT = Modified Intent-to-treat
[1]This is normalized to 28 days.
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Programming note:“Rescue medications” are those marked in the diary as such. Need to identify these and note usage during the baseline and treatment periods.
Programming note: Use the Table 14.2.7.1 shell fo produce
Table 14.2.7.2
Days with Rescue Medication Usage during the OLE Treatment Period
mITT Population (Japan)
PUBLIC COPY 
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TIAL
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Table 14.2.8.1
Hospitalization and Other Healthcare Resource Utilization to Treat Seizure
mITT Population
Event or Procedure
PBO-ZX008 OL
(N = XX)
ZX 0.2 - ZX008 OL
(N = XX)
ZX 0.5 - ZX008 OL
(N = XX)
ZX 0.8 - ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
No. (%) of Subjects with at least one hospital admission
to treat seizures
XX (%)
XX (%)
XX (%)
XX (%)
XX (%)
XX (%)
Number of Hospital Admissions to treat seizures
No. of subjects (%)
XX (%)
XX (%)
XX (%)
XX (%)
XX (%)
XX (%)
Number of occurrences for subjects with at least one
Mean (SD)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max
Xx, xx
Xx, xx
Xx, xx
Xx, xx
Xx, xx
Xx, xx
Occurrences per 100 subject years [1]
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
EEG
No. of subjects (%)
XX (%)
XX (%)
XX (%)
XX (%)
XX (%)
XX (%)
Number of occurrences for subjects with at least one
Mean (SD)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
XX.X (xx.xx)
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min, Max
XX, xx
XX, XX
XX, xx
XX, XX
XX, XX
XX, XX
Occurrences per 100 subject years [1]
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
xxx.xx
Repeat for the following
ECG
ECHO
PET Scans
MRI
X Ray
CT Scan
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Surgery
Lumber Puncture / Spinal Tap
Other
mITT = Intent-to-treat;
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.
[1] Occurrence rate is based on the total number of occurrences during the study divided by the total number of subject years of followup for subjects in the column. Multiple occurrences for the same
subject are included.
PUBLIC COPY 
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Programming note: Use the same Table 14.2.8.1 shell to produce
Table 14.2.8.2
Hospitalization and Other Healthcare Resource Utilization to Treat Seizure
mITT Population (Japan)
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
national
zat
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TIAL
s d
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zure
ng
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uth
application and any extensions or variations thereof. 
a


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Table 14.2.9.1
Number of episodes of status epilepticus (SE)
mITT Population
PBO-ZX008 OL
(N = XX)
ZX 0.2 - ZX008 OL
(N = XX)
ZX 0.5 - ZX008 OL
(N = XX)
ZX 0.8 - ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Subjects with at Least One episode of status epilepticus
reported as AE[1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Number of seizures reported greater than 10 min[2]
No. of subjects
XX
XX
XX
XX
XX
XX
Mean per subject
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Std. Error
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
Total unique events: SE as an AE, plus seizures >10 min
No. (%) of Subjects with at least one event
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Age group <6 years
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95% Exact CI
(xx.x%,xx.x%)
(xx.x%,xx.x%)
(xx.x%,xx.x%)
(xx.x%,xx.x%)
(xx.x%,xx.x%)
(xx.x%,xx.x%)
Age group ≥6 years
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95% Exact CI
(xx.x%,xx.x%)
(xx.x%,xx.x%)
(xx.x%,xx.x%)
(xx.x%,xx.x%)
(xx.x%,xx.x%)
(xx.x%,xx.x%)
Total unique events: SE as an AE, plus seizures >10 min
Unique events
1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
2
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
3
……….
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
mITT = Intent-to-treat;
PUBLIC COPY 
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XX.X
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[1] Any AE with Status Epilepticus or presumed Epilepticus
[2] This includes all single seizures >10 minutes in duration as recorded in the subject’s seizure diary. For each subject, the number of episodes is calculated; then the number per subject for each treatment
group is obtained by summing across subjects in each group and dividing by number of subjects in that treatment group who had single seizures > 10 min.
Programming note: Use the same Table 14.2.9.1 shell for
Table 14.2.9.1.1
Number of episodes of status epilepticus (SE)
mITT Population (Japan)
PUBLIC COPY 
thorization 
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des is
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Table 14.2.9.2
Duration of Seizures
mITT Population
Percentage of seizures by duration
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Baseline
<2 min
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
NA
2-10 min
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
NA
>10 min
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
NA
OLE Treatment Period
<2 min
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
2-10 min
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
>10 min
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
mITT = modified Intent-to-treat; 95% CI are based on the exact (Clopper-Pearson) method. NA = Not Applicable.
Programming notes:
To calculate the probability of a seizure <2 min. for a given treatment group: for each subject, calculate the proportion of seizures < 2 min. For example, if the subject has a total of 5 seizures with 2 being <2
min in duration, their proportion is 2/5. Add these proportions for all subjects in the treatment group, and divide the total by the number of subjects to get the treatment group proportion of subjects with
seizure duration <2 min. Then multiply the result by 100 to get the percentage.
Repeat for the other treatment groups. Repeat for seizure durations 2-10 min., and for >10 min.
BLIC COPY 
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Table 14.2.10.1
Clinical Global Impression of Improvement, Parent/Caregiver Rating
mITT Population
Categorical Description
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
OLE Month 1 (Visit 3)
Summary Statistics
n [1]
Xx
Xx
xx
Xx
xx
xx
Mean (SE)
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max
Xx, xx
Xx, xx
Xx, xx
Xx, xx
Xx, xx
Xx, xx
Number (%) of subjects responding at visit, by response
category
1=Very much improved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
2=Much improved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
3=Minimally improved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
4=No change
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
5=Minimally worse
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
6=Much worse
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
7=Very much worse
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Much/very much Improved (1, 2): n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95% CI*
(xx.x, xx.x)
xx.x, xx.x)
(xx.x, xx.x)
xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
Minimally/much/very much Improved(1,2,3): n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95% CI*
(xx.x, xx.x)
xx.x, xx.x)
(xx.x, xx.x)
xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
Repeat for:
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
PUBLIC COPY 
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XX
%)
si
%)
X.X%)
nsi
X.X%)
(XX.X%)
ens
(XX.X%)
XX
t
XX (XX.X%)
ten
(XX.X%)
XX
xt
XX (XX.X
xte
(XX.X
XX
e
XX
XX.X%)
d a
XX.X%)
xx.x,
nd
xx.x, xx.x)
nd
xx.x)


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OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
Summary Statistics
n [1]
Xx
Xx
xx
Xx
xx
xx
Mean (SE)
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max
Xx, xx
Xx, xx
Xx, xx
Xx, xx
Xx, xx
Xx, xx
Number (%) of subjects at visit, by response category
1=Very much improved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
2=Much improved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
3=Minimally improved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
4=No change
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
5=Minimally worse
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
6=Much worse
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
7=Very much worse
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Much/very much improved (1, 2): n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95% CI*
(xx.x, xx.x)
xx.x, xx.x)
(xx.x, xx.x)
xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
Minimally/much/very much Improved(1,2,3): n (%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
95% CI*
(xx.x, xx.x)
xx.x, xx.x)
(xx.x, xx.x)
xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
mITT = Modified Intent-to-treat; CI = Confidence Interval; SE = Standard Error; N= Number of subjects in population.
[1]n=number of subjects at time point; this is used as the denominator when calculating the percent of subjects responding in each CGI category and the percent who show improvement or much/very
much improvement.
*Exact Clopper-Pearson two-sided confidence interval for the percentage of subjects with that response.
,
PUBLIC COPY 
XX
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XX (XX
CO
(XX
XX
C 
XX
%)
B
%)
XX.X%)
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XX.X%)
X
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X (XX.X%)
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XX
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fo


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Programming note:
n – use the total for nonmissing responses
Here we are doing no comparisons, the 95% CI is for the percentage or proportion for that group (for interim, it’s ZX008 OL) at that time point. Include all visits out through EOS visit.
Use the Table 14.2.10.1 shell for
Table 14.2.10.1.1
Clinical Global Impression of Improvement, Parent/Caregiver Rating
mITT Population (Japan)
PUBLIC COPY 
thorization 
national
zat
national L
03
03
marketing auth
me
ti
me point.
ting
point.
This document cannot be used to support any ma
do
TIAL
s d
TIAL
In
g
In
t/Caregiver
ma
t/Caregiver
y
uth
application and any extensions or variations thereof. 
a
clude
er
clude all
ere
all visit
e
visit
Rating
on
Rating


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Treatment Group=ZX008 0L
Programming Note:
Include all visits where the data is collected.
Use Labels
OLE Month 1 (Visit 3)
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
Figure 14.2.10.2
Clinical Global Impression of Improvement, Parent/Caregiver Rating
mITT Population
40
35
30
25
20
15
10
5
0
Month 1
Month 6
Month 12
EOS/ET
Minimally Improved
Much Worse
Much Improved
Minimally Worse
Very Much Improved
No Change
Percentage of Subjects, by Category
UBLIC COPY 
IC CO
P BL
PY
PUB
UBL
keting authorization 
national
zat
national L
03
03
uth
nnot be used to support any marke
pport
t be
ed t
s
an
t any
e us
used
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ot be used to support any m
This document cann
do
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TIAL
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marke
k
nnot be used to support any market
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a
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nd any extensions or variations thereof. 
s
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s or
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y e
d any extensions or variatio
application an
a
ions th
o
nd any extensions or variations the
M
Much
s t
Much Impro
s t
Impro
Minima
ons
Minima


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OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/ET.
Note EOS/ET = Last Available Data Point during OLE. [For interim we are plotting for ZX008 OL.]
For interim analysis, only the ZX008 OL group (ie all subjects) is plotted.
Use the Figure 14.2.10.2 shell for
Figure 14.2.10.2.1
Clinical Global Impression of Improvement, Parent/Caregiver Rating
mITT Population (Japan)
PUBLIC COPY 
X008
C C
X008 OL.]
C
OL.]
inical
UB
inical Glob
UB
Glob
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
Figur
su
Figur
Impression
to s
Impression
m
uth
ions or variations thereof. 
e 14.2.10.2.1
on
14.2.10.2.1
sio
f Improvem
sio
Improvem
application and any extens
a
ITT Populati
ns
ITT Populati


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CONFIDENTIAL
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Programming note: Use shell for Table 14.2.10.1 shell to produce the following.
Table 14.2.10.3
Clinical Global Impression of Improvement, Investigator Rating
mITT Population
Table 14.2.10.3.1
Clinical Global Impression of Improvement, Investigator Rating
mITT Population (Japan)
Programming note: Use shell for Figure 14.2..10.2 shell to produce the following.
Figure 14.2.10.4
Clinical Global Impression of Improvement, Investigator Rating
mITT Population
Figure 14.2.10.4.1
Clinical Global Impression of Improvement, Investigator Rating
mITT Population (Japan)
PUBLIC COPY 
m
Y
m
opulatio
Y
opulatio
Figu
O
Figu
Impressio
C CO
Impressio
Clinical
UB
Clinical Gl
B
Gl
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
r
k
r Rating
ket
Rating
Investigato
y m
Investigato
pan)
ny
pan)
14.2.10.4
rt 
14.2.10.4
of
p
of Improvem
por
Improvem
mITT
pp
mITT Popula
ppo
Popula
Figure
sup
Figure
al
o
al Impressio
o s
Impressio
m
ns or variations thereof. 
Rating
tio
Rating
ent,
or
ent, Investig
or v
Investig
sion
tion
tion
14.2.10.4.1
ons
14.2.10.4.1
of
si
of Improve
sio
Improve
application and any extens
a
TT Populatio
nsi
TT Populatio


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Table 14.2.11.1
Quality of Life in Childhood Epilepsy (QOLCE)
mITT Population
Domain
Subscale
Visit
Statistics
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XXX)
De Novo Subjects
(N = XX)
Physical
Physical
Restriction
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
PUBLIC COPY 
Y
X
C
X (XX.X)
CO
(XX.X)
OP
CO
X
C
X
C C
X
C
X
IC
LI
LI
LI
LI
LI
BL
Mean
PU
Mean (SD)
PU
(SD)
UB
PU
P
t be used to support any marketing authorization 
uth
national
zat
national L
03
03
ZX
rk
ZX 0.5
rke
0.5 –
e
– ZX
e
ZX
(N
k
(N
ket
ma
ma
ma
ma
ma
m
XX
ny
XX
ny
XX
t a
XX (X
a
(X
t a
ort
po
po
po
po
po
(XX.X)
up
(XX.X)
pp
up
XX
s
XX
s
XX
to
XX (X
(X
to 
d t
ed
ed
ed
ed
ed
This document cannot b
do
TIAL
s d
TIAL
n
9)
n
9)
Visit
an
Visit 10)
ann
10)
1
c
1 (Visit
can
(Visit 11)
an
11)
th
t
th 24
t c
24 (Visit
c
(Visit 1
Month
nt
Month 27
nt
27 (Vi
(Vi
LE
LE Month
en
Month 30
n
30
OLE
m
OLE Month
me
Month
OLE
um
OLE EO
m
EO
cu
cu
cu
cu
t b
ed
tensions or variations thereof. 
008
t
008 OL
th
OL
N = XX)
ns
N = XX)
Z
the
he
he
he
n
tio
at
ari
XX.X)
v
XX.X)
a
v
XX
or
XX
or
XX
s 
XX (XX
(XX
s o
ns
oioioion
io
X.X)
n
X.X)
si
n
ny exte
te
pplication and any
2)
i
2)
sit
a
sit 13)
ati
13)
(Visit
ca
(Visit 14)
cat
14)
33
li
33 (Visit
lic
(Visit 15)
c
15)
S/EOT
ppl
S/EOT (Visit
pl
(Visit
app
app
n a
ny


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EOS/EOT
REPEAT
FOR
Physical
Physical
Restrictions
Physical
Energy/Fatig
ue
Well-being
Depression
Well-being
Anxiety
Well-being
Control/help
lessness
Well-being
Self-esteem
Cognition
Attention/Co
ncentration
Cognition
Memory
Cognition
Language
Cognition
Other
Cognitive
Social
Activities
Social
Interactions
Social
Activities
Social
Activities
Social
Activities
Stigma Item
Behavior
Behavior
General
Health
General
Health Item
Quality of
Life
Quality of
life Item
UBLIC COPY 
Y
PY
OP
C
C
LI
BL
PUB
UB
PU
o support any marketing authorization 
uth
national
zat
national L
03
03
ut
au
g
ti
ke
ma
ma
ma
ma
ma
y
ny
t a
o
po
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annot be used to 
o
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ed
se
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t b
t b
t b
t b
t b
n
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do
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TIAL
an
t c
me
m
cu
cu
cu
cu
nsions or variations thereof. 
o
he
he
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her
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th
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ati
iririria
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on
io
and any extensio
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a
nd
pplication an
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n a
tio
ca
pli
app
app


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Overall
Quality of
Life
Overall
Quality of
Life
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
P-value*
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
mITT = Modified intent-to-treat; SD= Standard Deviation; N=Nmber of subjects with resposnes for that visit/time point.
*P-value is based on the Wilcoxon signed ranks test that the within-group change from baseline is different from 0.
Programming notes:
Note: For the interim, only the last column is analyzed and reported.
Note: For the final, to conserve space may use the domain and subscale as headers and start table using the Vist column
Note: Use question list for above tables as given below:
OPY 
Y
x
O
x
PUBLIC COPY
PY
OP
LI
ny marketing authorization 
uth
national
zat
national L
03
03
ut
au
XX
ti
XX (XX.X)
ting
(XX.X)
ng
ti
XX
e
XX
ke
X
rk
ma
ma
ma
ma
ma
XX
y
XX
m
XX
n
XX (XX.X)
ny
(XX.X)
y
ment cannot be used to support any
0.xxx
an
0.xxx
any
t a
not b
ed
po
ation;
nn
ation; N=Nm
n
N=Nm
est
a
est that
an
that the
n
the
umn
en
umn is
en
is anal
nt
anal
pace
m
pace may
me
may us
e
us
This docum
do
TIAL
s d
TIAL
ove tables as
um
ove tables as
ariations thereof. 
XX
f
XX
XX
e
XX
re
he
he
he
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he
th
X (XX.X)
ns
(XX.X)
s t
ns
XX
o
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io
XX
t
XX
ati
ri
lication and any extensions or varia
ririria
ari
ar
ar
ar
nd
ny
io
ar
ber
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ber of
an
of subje
n
subje
within
n a
within-
a
-grou
a
grou
yzed
a
yzed and
ati
and rep
ti
rep
the
ic
the domain
ica
domain
appl
a
s given below
plic
s given below


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Domains and Subscales 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
Section 2 (USA Version) or Section 9 (Australia Version)
Quality of lifeitem
2.1 or 9.1
For each treatment group at Baseline and End of Study/ET, the mean (SD) score 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 baseline overall score from the overall score measured at each visit. The change from baseline for each treatment group will be
summarized by the mean (SD) and assiessed for significance using Wilcoxon signed-rank tests.
Revised 5/30/2017
Programming Note: see below for reverse coding and transformation of scores
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. Item
scores will then be transformed to a 0-100 scale as follows: 1-0, 2-25, 3-50, 4-75, 5-100.
LIC COPY 
es
Y
es
m
Y
m
Y
on/Concen
OPY
on/Concen
PY
emory
COP
emory
OP
Language
CO
Language
CO
Other
C C
Other
C
C 
So
C
So
PUBLIC
LIC
BL
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PU
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pport any marketing authorization 
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national
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national L
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ng
.1 a
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.1 a-
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3.2 
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4.1 
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4.1 a,
k
a,
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4.
a
4.
a
m
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ation
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ation
ny
a
rt
ognitive
po
ognitive
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upp
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Interaction
ed to supp
ocial
su
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sup
Activiti
up
Stigma
o s
Stigma Ite
Ite
su
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Behav
to 
Behav
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to
Ge
t
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se
n (SD)
e u
n (SD) score
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score
ing the base
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using Wilcox
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using Wilcox
nt 
g and
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an
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tem scores
nt c
tem scores
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do
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TIAL
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e
-100 scale a
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100 scale a
or variations thereof. 
re
er
the
d,e,l
ns
d,e,l
s t
1 b,g,j,n,o,p
ons
b,g,j,n,o,p
ns
4.1
ti
4.1 c,f,h,i
tio
c,f,h,i
on
4.1 
at
4.1 k,m
t
k,m
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5.1
a
5.1
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or
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s
tensions o
s
ns
m
i
m
on
or
n
or
sio
neral
en
neral Health
ens
Health
ns
and any exten
Quality
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Quality of
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xt
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ny 
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ati
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ZX008-1503
CONFIDENTIAL
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Draft 3.0: 04Aug2020
Item/Question No.
Reverse coded items*
Scale
Comments
3.1
c, d, e, f, g, h, I, j
1-5
3.2
b
1-5
4.1
b, d, f, k, l, m, q
1-5
5.1
i
1-5
6.1
b, d, g
1-5
6.2
1-5
1=0; 2=25, 3=50, 4=75, 5=100
6.3**
6.3
1-5
Recode 1 to 4; 2 to 3; 3 to 2; 4 to 1. Do not
recode “5”
6.4**
6.4
1-5
Recode 1 to 4; 2 to 3; 3 to 2; 4 to 1. Do not
recode “5”
7.1
e, i, l, m, n, o, s, t,v
1-5
8.1
8.1
1-5
9.1
9.1
1-5
Usual coding: 1=0,  2=25, 3=50, 4=75, 5=100.
*Reverse coded items.
For these, please code as follows: 1=100, 2=75, 3=50, 4=25, 5=0
**For 6.3 and 6.4, the (reverse coded)scores will be as follows:
1=75, 2=50 3=25, 4=0, 5=.
For 6.2, score as follows:
1=0,  2=25, 3=50, 4=75, 5=100.
OPY 
Y
C COP
1
C
1-
C
-5
CO
5
BLIC COP
C
1
C 
1
C C
C
LIC
PUBL
BL
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t any marketing authorization 
uth
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ng
eti
ke
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ma
m
ny
support a
t a
po
1
s
1-
s
-5
s
5
upp
This document cannot be used to su
do
TIAL
s d
TIAL
1
o s
1-
o s
-5
s
5
su
to
to
to
to
d to
, 5=0
be
5=0
ollows:
not
ollows:
3=50,
ca
3=50, 4=7
a
4=7
or variations thereof. 
of.
eo
he
th
ns
1=0;
ti
1=0; 2=25,
tio
2=25, 3
io
Recode
ria
Recode
rec
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rec
at
ari
ons or va
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application and any extension
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on
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en
5,
o
5, 5=100.
n 
5=100.


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Table 14.2.12.1
Pediatric Quality of Life Inventory (Peds QL)- (Version 4.0) – Parent Report
mITT Population
Functioning Area
Visit
Statistics
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XXX)
De Novo Subjects
(N = XXX)
Physical
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
P-value*
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
PUBLIC COPY 
XX
Y
XX
Y
XX
PY
XX (
Y
(
PY
OP
CO
CO
CO
CO
CO
X.X)
C
X.X)
C C
IC
XX
BL
XX
LI
XX
UB
XX (X
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(X
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U
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ed to support any marketing authorization 
uth
national
zat
national L
03
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eport
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eport
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a
– ZX008
ar
ZX008 O
(N = XX)
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(N = XX)
rk
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.X)
any
ny
ny
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XX
or
XX
ort
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(XX.X
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cument cannot be used
)
a
)
t 11)
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11)
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t
Visit 12)
t c
12)
27
27 (Visit
nt
(Visit 13)
t 
13)
th
th 30
e
30 (Visit
en
(Visit 1
Month
m
Month 33
me
33 (Vi
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(Vi
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EOS/EOT
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L
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(XX.X)
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or
X)
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or
or
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or
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XX
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XX
ns
XX
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io
(XX.X)
ion
0.xx
s
0.xx
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pplication and any exte
14)
c
14)
sit
l
sit 15)
lic
15)
Visit
pp
Visit 16)
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16)
app
a
te
te
te
pp ca
nd
xte


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EOS/EOT
REPEAT FOR
Emotional
Social
School
Physical Health
Summary[1]
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
P-value*
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
COPY
XX
PY
XX (XX.
Y 
(XX.
Y
PY
OP
CO
CO
CO
UBLIC CO
CO
CO
C C
XX
LIC
XX
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XX
BL
XX (XX.X)
BLI
(XX.X)
LIC
0.x
B
0.x
BL
PUB
UB
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rt any marketing authorization 
uth
national
zat
national L
03
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etitititi
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ny
any
ny
ny
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XX
rt
XX
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port
XX
o
XX (XX.X)
ort
(XX.X)
to support
po
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p
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pp
X
p
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up
s
This document cannot be used to s
do
TIAL
s d
TIAL
s
13)
ca
13)
Visit
t
Visit 14)
t ca
14)
3 (Visit
nt
(Visit 15)
t 
15)
EOT (Visit 16
en
EOT (Visit 16
OT
m
OT
to
cu
a
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or variations thereof. 
f
eo
re
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th
s t
ns
ns
ns
ns
ns
X
i
X (XX.X)
iat
(XX.X)
ati
ria
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or v
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ons or v
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(XX.X)
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sion
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0.xxx
tension
sio
application and any exte
a
)
pp ca
nd
xte


TLF Shells
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Psychosocial Health
Summary[2]
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
P-value*
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
Total Score[3]
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
PUBLIC COPY
X
Y
X (X
Y
(X
0.xxx
PY 
0.xxx
Y
PY
P
CO
not be used to support any marketing authorization 
uth
national
zat
national L
03
03
XX
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XX
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Mea
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um
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m
1 C
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f
XX.X)
re
XX.X)
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XX
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XX
th
XX (XX
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(XX
th
s t
ns
ns
ns
ns
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XX.X)
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0.xxx
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0.xxx
ati
ria
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d
pplication and 
d
nd
nd
nd
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(SD)
n
(SD)
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Mean
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BL
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lic
pp c


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CONFIDENTIAL
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Mean (SD)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
P-value*
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
0.xxx
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
mITT = Modified intent-to-treat; SD = Standard Deviation; N=Number of subjects in population; n=number of subjects with responses for that visit/time point. EOS/ET=Last available measurement in OLE
Treatment Period.
*Higher scores indicate better functioning
[1] The Physical Health Summary score is equal to the Physical Functioning Scale Score.
[2] Computed as the sum of the items over the number of items answered in the Emotional, Social, and School Functioning Scales.
[3]Computed as the sum of all the items over the number of items answered on all the Scales.
[4]P-value is based on the Wilcoxon signed ranks test that the within-group change from baseline is different from 0.
Programming note: Please see ZX008-1503 SAP section 6.3.3.7 for scoring instructions.
PUBLIC COPY 
P
CO
PU
P
of
P
of su
P
su
d to support any marketing authorization 
uth
national
zat
national L
03
03
XX
a
XX (XX.X)
aut
(XX.X)
ut
0.xxx
a
0.xxx
au
g
s
ny
tin
to
This document cannot be used 
do
TIAL
s d
TIAL
d
ects
ed
ects in
ed
in popu
d 
popu
ctioning
e u
ctioning Scale
u
Scale
s answered
be
answered i
of items answ
ot b
of items answ
at
n
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not
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ot
within
ection
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ection 6.3.3
nn
6.3.3
any extensions or variations thereof. 
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eo
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lation;
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lation; n=nu
en
n=nu
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the Emotio
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wered on all t
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chan
7 for
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for scoring
an
scoring


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Draft 3.0: 04Aug2020
Table 14.2.12.2
PedsQL Family Impact Module (Version 2.0) – Parent Report
mITT Population
Functioning Area
Visit
Statistics
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo
Subjects
(N = XX)
Physical Functioning
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
REPEAT FOR
Emotional
Functioning
COPY 
XX
Y
XX (
Y
(
Y
PY 
PY
OP
O
CO
PUBLIC CO
XX
C
XX
C C
XX
LIC
XX (XX.X)
LIC
(XX.X)
C
LIC
BL
PU
PU
port any marketing authorization 
uth
national
zat
national L
03
03
–
k
– ZX008
ke
ZX008 OL
e
OL
(N = XX)
ark
(N = XX)
eti
ma
m
y m
y
ny
XX
t
XX
an
XX
r
XX (XX.X)
rt a
(XX.X)
t a
ort
used to suppo
XX
o
XX
po
XX
p
XX
pp
up
u
su
nt cannot be u
16)
c
16)
a
cument c
u
u
t c
nt 
en
me
This docu
do
TIAL
s d
TIAL
cu
or variations thereof. 
ZX
th
ZX 0.8
th
0.8 –
he
s
ns
XX
ti
XX
on
XX
a
XX (XX.X)
ati
(XX.X)
tio
iat
XX
XX
ri
v
XX
a
XX
va
v
ensions or v
r v
or
(XX.X)
s
(XX.X)
o
s 
on
pplication and any exten
d
en
on
tio
at
ca
ic
applic
a
c
pp c


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Social Functioning
Cognitive
Functioning
Communication
Worry
Daily Activities
Family Relationships
Parent HRQL[1]
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
P-value[4]
x.xxxx
x.xxxx
x.xxxx
x.xxxx
x.xxxx
x.xxxx
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
Family
Functioning[2]
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
PUBLIC COPY 
XX
Y
XX (X
Y 
(X
Y
PY
OP
O
CO
XX
C
XX
C C
XX
LIC
XX (XX.X)
LIC
(XX.X)
C
x.xxx
LI
x.xxx
LIC
BL
PU
ment cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
ut
au
ng
ng
ng
ng
ng
tin
et
ke
ark
ma
m
y
ny
XX
t
XX
an
XX
or
XX (XX.X)
ort 
(XX.X)
t a
or
XX
o
XX
po
XX
p
XX
pp
up
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)
16)
c
16)
su
a
u
u
(Visit
nt
(Visit 1)
nt c
1)
t c
en
ume
me
cum
LE
c
LE Month
cum
Month 1
m
1
This docu
do
TIAL
s d
TIAL
um
cu
plication and any extensions or variations thereof. 
f
eo
ere
he
th
s
ns
XX
ti
XX
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XX
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XX (XX.X)
iati
(XX.X)
ati
ia
XX
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ari
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XX
a
XX
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r v
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r v
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or
(XX.X)
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(XX.X)
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x.xxxx
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d
en
n
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ca
Mea
a
Mea
ca
ca
ca
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lic
(Visit
pp
(Visit 3)
ppl
3)
appl
a pl
pp


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Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
P-value[4]
x.xxxx
x.xxxx
x.xxxx
x.xxxx
x.xxxx
x.xxxx
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
Total Score[3]
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 (Visit 3)
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
OLE Month 1 Chg BL
n
XX
XX
XX
XX
XX
XX
Mean (SE)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
P-value[4]
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
n
XX
XX
XX
XX
XX
XX
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TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 118 of 234
Draft 3.0: 04Aug2020
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
mITT = Modified intent-to-treat; SD = Standard Deviation.
Notes:
EOS/ET=Last available measurement in OLE Treatment Period.
[1] Computed as the sum of the items divided by the number of items answered in the Physical, Emotional, Social, and Cognitive Functioning scales.
[2] Computed as the sum of the items divided by the number of items answered in the Daily Activities and Family Relationships scales.
[3] Computed as the sum of all 36 items divided by the number of items answered.
[4]P-value is based on the Wilcoxon signed ranks test that the within-group change from baseline is different from 0.
Programming note:
For each subject, be sure to calculate a scale score for each functioning area. Please see SAP for rules.
[1] Computed as the sum of the items divided by the number of items answered in the Physical, Emotional, Social, and Cognitive Functioning scales.
[2] Computed as the sum of the items divided by the number of items answered in the Daily Activities and Family Relationships scales.
[3] Computed as the sum of all 36 items divided by the number of items answered.
Please see SAP section 6.3.3.15 for full instructions.
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TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 119 of 234
Draft 3.0: 04Aug2020
Table 14.2.13.1
QOL of Parent/Caregiver Based on EQ-5D-5L – Health Profile Summary Original Response Categories
mITT Population
Parameter
Visit
Category
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Mobility
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
No problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Slight problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate problem
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Severe problem
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Extreme problem
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
Self-care
Baseline
n
XX
XX
XX
XX
XX
XX
No problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Slight problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate problem
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Severe problem
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Extreme problem
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Continue for
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
PUBLIC COPY 
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TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 120 of 234
Draft 3.0: 04Aug2020
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
Repeat summary for the domains:
Usual activities
Pain/discomfort
Anxiety/depression
Mobility
Self-care
Usual activities
Pain/discomfort
mITT = Modified Intent-to-treat;
Notes:
EOS/ET=Last available measurement in OLE Treatment Period.
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
national
zat
national L
03
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do
TIAL
s d
TIAL
us
uth
application and any extensions or variations thereof. 
a
ex


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 121 of 234
Draft 3.0: 04Aug2020
Table 14.2.13.2:
QOL of Parent/Caregiver Based on EQ-5D-5L – Health Profile Summary Using Dichotomized Response Categories - mITT Population
mITT Population
Parameter
Visit
Category
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008
OL
(N = XX)
ZX 0.5 – ZX008
OL
(N = XX)
ZX 0.8 – ZX008
OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Mobility
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
No problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
No/slight problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate/severe/extreme
problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
Self-care
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
No problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
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TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 122 of 234
Draft 3.0: 04Aug2020
Parameter
Visit
Category
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008
OL
(N = XX)
ZX 0.5 – ZX008
OL
(N = XX)
ZX 0.8 – ZX008
OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
No/slight problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate/severe/extreme
problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
Usual
activities
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
No problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
No/slight problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate/severe/extreme
problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Continue for
PUBLIC COPY 
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TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 123 of 234
Draft 3.0: 04Aug2020
Parameter
Visit
Category
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008
OL
(N = XX)
ZX 0.5 – ZX008
OL
(N = XX)
ZX 0.8 – ZX008
OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
Pain/discomf
ort
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
No problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
No/slight problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate/severe/extreme
problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Continue for
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
PUBLIC COPY 
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Parameter
Visit
Category
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008
OL
(N = XX)
ZX 0.5 – ZX008
OL
(N = XX)
ZX 0.8 – ZX008
OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
Anxiety/depr
ession
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
XX
No problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
No/slight problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate/severe/extreme
problems
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
C COPY 
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Parameter
Visit
Category
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008
OL
(N = XX)
ZX 0.5 – ZX008
OL
(N = XX)
ZX 0.8 – ZX008
OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
mITT = Modified Intent-to-treat;
Notes:
EOS/ET=Last available measurement in OLE Treatment Period.
Programming note: This table repeats Table 14.2.13.1, with responses categorized into two levels.
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Table 14.2.13.3
QOL of Parent/Caregiver Based on EQ-5D-5L – Overall Health Status Using VAS (0-100) Scale
mITT Population
Overall Health Status
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Visit
Visit Value
Change
from
baseline
Visit Value
Change
from
baseline
Visit
Value
Change
from
baseline
Visit Value
Change
from
baseline
Visit Value
Change
from
baseline
Visit
Value
Change
from
baseline
OLE Baseline (Visit 1)
n
Xx
Xx
Xx
Xx
Xx
Xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Min
Xx
Xx
Xx
Xx
Xx
Xx
Max
Xx
Xx
Xx
Xx
Xx
Xx
OLE Month 1 (Visit 3)
n
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Min
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Max
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
P-value [1]
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
…. Repeat for all visits
OLE
EOS/EOT
(Month
36) Visit 16)
n
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Min
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
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Max
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
P-value [1]
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
EOS/EOT
n
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Xx.x
Min
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Max
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
P-value [1]
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
Notes:
EOS/ET=Last available measurement in OLE Treatment Period.
[1] P-value is based on the Wilcoxon signed ranks test that the within-group change from baseline is different from 0.
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Table 14.2.14.1
QOL of Parent/Caregiver Based on Hospital Anxiety and Depression Scale (HADS): Normal, Borderline Abnormal and Abnormal Categories
mITT Population
Parameter
Visit
Category
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008 OL
(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Anxiety
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
Normal
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Borderline abnormal
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Abnormal
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
End of study visit
Depression
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
Normal
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Borderline abnormal
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Abnormal
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Visit 8 (during
Maintenance period)
…
End of study visit
Total (Emotional
Distress)
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
Normal
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Borderline abnormal
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Abnormal
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
End of study visit
mITT = Intent-to-treat; Note: This table includes those subjects from 1501 and 1502, and excludes subjects from 1504; the HADS was not assessed in subjects from 1504.
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Table 14.2.14.2
QOL of Parent/Caregiver Based on Hospital Anxiety and Depression Scale (HADS): Summary Descriptive Statistics
mITT Population
Scale
Visit
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008
OL(N = XX)
ZX 0.8 – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Anxiety
OLE Baseline (Visit 1)
n
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
End of study visit
n
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
Change from Baseline
n
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
95% CI
(xxx.x, xxx.x)
(xxx.x, xxx.x)
(xxx.x, xxx.x)
(xxx.x, xxx.x)
(xxx.x, xxx.x)
P-value[1]
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
Repeat for Depression and
Total (Emotional Distress)
Scores
mITT = Intent-to-treat; SE = Standard Error. CI = Confidence Interval.
Note: The 95% confidence interval is based on the t-distribution.
[1] p-value from Wilcoxon signed-rank test.
PUBLIC COPY 
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XX
ca
X
XX
e
XX
XX
x
XX
X
ca
applica
a
Confidence
ica
Confidence
on the t
plic
on the t-dis
c
dis
st.
p
st.


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Table 14.2.15.1
Study Medication Palatability Assessment
mITT Population
Visit
Response
PBO-ZX008 OL
(N = XX)
ZX 0.2 – ZX008
OL
(N = XX)
ZX 0.5 – ZX008
OL
(N = XX)
ZX 0.8 – ZX008
OL (N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
Item/Question
OLE Month 1 (Visit 3)**
n=xxx
n=xxx
n=xxx
n=xxx
n=xxx
n=xxx
1.
Medication Taste and
Texture
Acceptable
Not acceptable
Missing response
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
2.
Rating of Medication
Taste
5 (likes very much)
4 (likes it)
3 (neutral)
2 (dislikes)
1 (dislikes very much)
Missing Response
% liking it (4, 5)
95% CI*
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
3.
Problems administering
medication due to taste or
texture?
No
Yes
Every day
Once or more every week
Once or more during the
month
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
OLE Month 2 (Visit 4)**
n=xxx
n=xxx
n=xxx
n=xxx
n=xxx
n=xxx
1.
Medication Taste and
Texture
Acceptable
Not acceptable
Missing response
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
2.
Rating of Medication
Taste
5 (likes very much)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
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XX.XX%)
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XX (XX
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Missing
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Missing rere
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m
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pplication and any extensions or variations thereof. 
X 0.8
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he
ZX00
OL (N = X
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OL (N = X
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XX.XX%)
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XX.XX%)
X
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(XX.XX%
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X.XX%)
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(XX.XX%)
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(XX.XX%)
XX
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XX (XX.
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XX.X
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XX (XX.X
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XX (X
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X.X%)
(XX.X%)
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(XX.X%)
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(XX.X%)
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4 (likes it)
3 (neutral)
2 (dislikes)
1 (dislikes very much)
Missing Response
% liking it (4, 5)
95% CI*
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX.X, XX.X
3.
Problems administering
medication due to taste or
texture?
No
Yes
Every day
Once or more every week
Once or more during the
month
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
mITT = modified Intent-to-treat.
*Exact Clopper-Pearson Confidence interval
** Study Medication Palatability Assessment was performed at Visits 3 and 4 only.
proc format;
value likfmt 1='Very much improved'
5=likes very much
4=likes it
3=neutral
2=dislikes
1=dislikes very much
.=Missing Response;
value likynfmt
0='No: Neutral or dislikes it'
1='Yes: Likes it ';
run;
data effdat;
set alleff;
if mittfl="Y";
PUBLIC COPY 
Y
XX.X%)
Y
XX.X%)
X
P
X (XX.X%)
PY
(XX.X%)
XX
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XX (XX.X
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if anl01fl="Y";
if aval ne .;
likeityn=(aval ge 4.0);
run;
proc sort data=effdat out=effdat;
by paramcd avisitn;
%macro exci_(type,param, paramfmt);
ods trace on;
ods output Binomial=bin_&type;
proc sort data=effdat; by paramcd avisitn descending &param;
proc freq data=effdat order=data;
tables &param / out=outp&type exact binomial; **outp11 has percentages for table;
by paramcd avisitn;
format aval &param. &paramfmt.. ;
run;
data bin_&type;
set bin_&type;
if Name1 in ('XL_BIN', 'XU_BIN');
cValue1=cValue1*100.0; *****convert endpoint values from proportions to percentages;
nValue1=nvalue1*100.0;
run;
%mend;
%exci_(lkt, likeityn, likynfmt);
PUBLIC COPY 
rtions
P
rtions
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
percentage
ed 
percentage
uth
application and any extensions or variations thereof. 
a
s;
t
s;


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Table 14.2.15.2
Sleep quality and mealtime behavior
mITT Population
Visit/Question
Response Category
PBO-ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
PK – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
OLE Baseline (Visit 1)
n=xxx
n=xxx
n=xxx
n=xxx
n=xxx
1.
Child waking in night or
very early in morning more
than usual?
More disturbed than before
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
Sleep pattern is same as before
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
Sleeps better than before
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
Missing response
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
2.
Change in mealtime
behavior since taking study
medication?
Worsened mealtime behavior
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
No change in mealtime behavior
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
Improved in mealtime behavior
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
Missing Response
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
XX (XX.XX%)
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
mITT = modified Intent-to-treat. Only subjects in feeder study 1504 were given this assessment. N=Total number of subjects in the population. n=number of subjects answering.
Notes:
EOS/ET=Last available measurement in OLE Treatment Period.
OPY 
Y
X%)
OP
X%)
COPY
PY
XX%)
COP
XX%)
OP
XX.XX%)
CO
XX.XX%)
CO
PUBLIC C
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03
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any marketing auth
PK
ti
PK –
tin
– ZX008
ting
ZX008
(N = X
tin
(N = X
ng
n
ket
rk
%)
%)
X
k
X
rk
rk
rk
ark
X%)
m
X%)
a
X.XX%)
m
X.XX%)
ma
XX.XX%)
y m
XX.XX%)
m
X (XX.XX%
any
(XX.XX%
ny
t any
XX
a
XX (XX.X
an
(XX.X
port any
XX
t a
XX (XX
a
(XX
t a
XX
rt 
XX (
rt
o
This document cannot be used to suppor
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TIAL
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or
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p
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us
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ects
nt
ects in
t c
in feede
c
feede
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e
in OLE
en
OLE Trea
en
Trea
uth
ariations thereof. 
OL
e
OL
XX)
h
XX)
re
re
re
re
=xxx
th
=xxx
he
X (XX.XX%
ns t
(XX.XX%
s t
XX
n
XX (XX.X
ns
(XX.X
ns
XX
ion
XX (XX
n
(XX
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t
XX
io
XX (
tio
at
%)
%)
X
at
at
at
at
X%)
a
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r varia
ria
X.XX%)
va
X.XX%)
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r va
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application and any extensions or v
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r v
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r study
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on
1504
tment
cat
tment Period
at
Period


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Table 14.2.15.3
Karolinska sleepiness scale: Frequency Distribution
mITT Population
PBO-ZX008 OL
(N = XX)
ZX 0.5 – ZX008 OL
(N = XX)
PK – ZX008 OL
(N = XX)
ZX008 OL
(N = XX)
De Novo Subjects
(N = XX)
OLE Baseline (Visit 1)
n=xxx
n=xxx
n=xxx
n=xxx
n=xxx
Score/Description
1.
Extremely alert
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
2.
Very alert
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
3.
Alert
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
4.
Rather alert
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
5.
Neither alert nor sleepy
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
6.
Some signs of sleepiness
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
7.
Sleepy, but no effort to keep awake
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
8.
Sleepy, some effort to keep awake
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
9.
Very sleepy, great effort to keep awake, fighting sleep
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Active (1-6)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Sleepy (7-9)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Continue for
OLE Month 2 (Visit 4)
OLE Month 3 (Visit 5)
OLE Month 6 (Visit 6)
OLE Month 9 (Visit 7)
OLE Month 12 (Visit 8)
OLE Month 15 (Visit 9)
OLE Month 18 (Visit 10)
OLE Month 21 (Visit 11)
OLE Month 24 (Visit 12)
OLE Month 27 (Visit 13)
OLE Month 30 (Visit 14)
OLE Month 33 (Visit 15)
OLE EOS/EOT (Visit 16)
EOS/EOT
COPY 
%)
P
%)
Y
X.X%)
OP
X.X%)
PY
X
C
X (XX.X%)
CO
(XX.X%)
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XX (XX.X
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XX
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(XX.X%)
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XX (XX.X%)
su
(XX.X%)
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XX
to
XX (X
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(X
to
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ed
se
se
This document cannot be use
do
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s d
TIAL
se
se
cu
se
uth
r variations thereof. 
PK
h
PK –
he
– ZX008
her
ZX008 O
(N = XX
the
(N = XX
ere
n
th
s
n
on
%)
a
%)
tio
XX.X%)
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XX.X%)
at
X (XX.X%)
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(XX.X%)
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XX
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XX (XX.X%
va
(XX.X%
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sions or v
XX
r 
XX (XX
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(XX
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mITT = modified Intent-to-treat. Only subjects in feeder study 1504 were given this assessment. N=nmber of subjects eligible for assessment (subjects from 1504 who entered 1503). N=number answering at
visit.
Notes:
EOS/ET=Last available measurement in OLE Treatment Period.
PUBLIC COPY 
thorization 
national
zat
national L
03
03
auth
ut
au
This document cannot be used to support any marketing a
do
TIAL
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t (subjects
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(subjects frfr
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application and any extensions or variations thereof. 
a
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of.
om 1504 w
. 
w


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Table 14.3.1.1
Overview of number of subjects with TEAE during OLE Treatment Period
Safety Population
De Novo
Gp1
Gp 2
Gp3
Gp 4
Gp5
ZX008 OL
Subjects
Number of Subjects with…
(N=xx)
(N=xx)
(N=xx)
(N=xx)
(N=xx)
(N=xx)
(N=xx)
Treatment-Emergent Adverse Events
At least one TEAE
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
At Least one Serious TEAE
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
At Least one Fatal TEAE
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
At Least one Related TEAE
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
At Least one Related Serious TEAE
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
At Least one TEAE Leading to Discontinuation of Study Treatment
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
TEAE = Treatment-Emergent Adverse Event.
Note: Percentages are calculated based on the number of subjects in the Safety population in each treatment group.
Note: Adverse events are classified as treatment-emergent if they started on or after the date of first dose of study treatment.
Adverse events with partial or missing start dates are classified as treatment-emergent, unless the non-missing components of
the start date confirm otherwise.
Programming note: Use the Table 14.3.1.1 shell to produce
Table 14.3.1.1.1
Overview of number of subjects with TEAE during OLE Treatment Period
Safety Population (Japan)
LIC COPY
XX
P
XX (XX.X%
PY 
(XX.X%
XX
OP
XX (X
P
(X
PUBLIC
P
X%)
C
X%)
X
L
X (XX.X%)
LIC
(XX.X%)
XX
UBL
XX (XX
BL
(XX
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
d
ting
XX
XX (XX.X%)
m
(XX.X%)
rk
XX
ny
XX (X
y
(X
X%)
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X%)
X
p
X (XX.X%)
po
(XX.X%)
XX
upp
XX (XX.
pp
(XX.
%)
o
%)
X
Safety
se
Safety popul
se
popul
ted
u
ted on
us
on or
s
or afaf
reatment
e u
reatment-
u
-em
em
duce
no
duce
uth
application and any extensions or variations thereof. 
a
en
ere
Gp
th
Gp 4
th
4
(N=xx)
s th
(N=xx)
XX
on
XX (
s t
X.X%)
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X.X%)
XX
v
XX (XX.X%)
va
(XX.X%)
XX
or 
XX (XX
(XX
X%)
n
X%)
X (XX.X%)
ion
(XX.X%)
ation
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in each
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Table 14.3.1.2.1
Treatment-Emergent Adverse Events by MedDRA System Organ Class and Preferred Term
Safety Population
MedDRA System Organ Class and Preferred Term
Gp1
(N=xx)
Gp 2
(N=xx)
Gp3
(N=xx)
Gp 4
(N=xx)
Gp5
(N=xx)
ZX008 OL
(N=xx)
De Novo
Subjects
(N=xx)
Subjects with any TEAE
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
System Organ Class 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 2
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
.
TEAE = Treatment-Emergent Adverse Event.
Note: Percentages are calculated based on the number of subjects in the Safety population.
Note: Adverse events are classified as treatment-emergent if they started on or after the date of first dose of study treatment. Adverse events with partial or missing start dates are classified as treatment-
emergent, unless the non-missing components of the start date confirm otherwise.
Note: A subject with more than one TEAE with the same preferred term is counted once for that term. A subject with more than one TEAE under a system organ class is counted once for that class.
Programming note: Use the Table 14.3.1.2.1 shell to produce same shell for 14.3.1.2.1.3 (Japan).
Table 14.3.1.2.1.3
Treatment-Emergent Adverse Events by MedDRA System Organ Class and Preferred Term
Safety Population (Japan)
OPY 
XX
Y
XX
Y
XX
Y
XX
Y
PY
PUBLIC COP
OP
OP
OP
OP
COP
O
ulation.
C C
ulation.
fter
IC
fter the
IC
the da
C 
da
rwise.
BLIC
rwise.
ounted
BL
ounted o
L
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hell
PU
hell for
PU
for 14
U
14
thorization 
national
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national L
03
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t any marketing auth
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ed Term
au
Term
Gp
ke
Gp 4
ke
4
(N=xx)
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(N=xx)
ting
ng
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XX
ma
XX (XX
a
(XX
a
m
y m
%)
n
%)
y m
y m
y m
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(XX.X%)
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do
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pp
of first dose
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dose
for
s
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mergent
use
mergent Adv
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uth
ariations thereof. 
Gp5
e
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X.X%)
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X.X%)
ns
on
XX
a
XX (XX.X%)
atio
(XX.X%)
tio
XX
ria
XX (XX.X
a
(XX.X
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XX
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application and any extensions or vari
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Table 14.3.1.2.1.1
Treatment-Emergent Adverse Events during Open-label Treatment Periods by Age Group (<6 yrs, ≥6 yrs), MedDRA System Organ Class and Preferred Term
Safety Population
Programming note: Similar to Table SADS21 in ISS, but population is 1503 Safety, and only use AEs occurring during 1503. One column only, ALL subjects in ZX008 OL. Alternatively, this is just the above
Table, 14.3.1.2.1, by Age Group.
Programming Note: Use the shell for 14.3.1.2.1.1 to produce same format for 14.3.1.2.1.4.
Table 14.3.1.2.1.4
Treatment-Emergent Adverse Events during Open-label Treatment Periods by Age Group (< 6 yrs, ≥6 yrs), MedDRA System Organ Class and Preferred Term
Safety Population (Japan)
PY
14.3
Y
14.3
ods
PY
ods by
PY
by Ag
Y 
Ag
PUBLIC COP
ety Popula
OPY
ety Popula
thorization 
national
zat
national L
03
03
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do
TIAL
s d
TIAL
System
au
System Org
au
Org
mn
et
mn only,
etin
only, ALL
n
ALL
roup
n
roup (<
ny
(< 6
y
6 yr
y
yr
on (Japan)
an
on (Japan)
uth
application and any extensions or variations thereof. 
a
an
o
an Cl
of
Class
of
ass an
. 
an
subjects
her
subjects in
r
in Z
, ≥6
i
≥6 yrs),
riat
yrs), Me
t
Me


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Table 14.3.1.2.1.2
Treatment-emergent Adverse Events with Decreased Appetite or Hypophagia during Open-Label Treatment Period
Safety Population
Placebo
(N = xxx )
ZX008 0.2 mg
(N = XXX)
ZX008 0.5 mg
(N = XXX)
ZX008 0.8 mg
(N = XXX)
ZX008 OL
(N = XXX)
De Novo Subjects
(N = XXX)
Decreased Appetite
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Had adverse event unresolved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Duration of event for subjects who had event
resolved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
n
XX
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX
XX
XX
XX
XX
XX
Min, Max
XX
XX
XX
XX
XX
XX
Hypophagia
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Had adverse event unresolved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Duration of event for subjects who had event
resolved
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
n
XX
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX
XX
XX
XX
XX
XX
Min, Max
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
TEAE = Treatment-Emergent Adverse Event.
Note: Events considered are all TEAEs occurring during OLE. Adverse events are classified as treatment-emergent if they started on or after the date of first dose of study treatment. Adverse events with
partial or missing start dates are classified as treatment-emergent, unless the non-missing components of the start date confirm otherwise.
Programmin note: Please see annotations in ISS for SST16
Programming notes:If subjects has multiple events with the same preferred term, count the worst case (if one event is unresolved, count the unresolved one).
Programming Note: Use the same shell for 14.3.1.2.1.5 (Japan).
PUBLIC COPY 
%)
PY
%)
Y
XX
O
XX
PY
XX.X
CO
XX.X
OP
XX.XX
CO
XX.XX
CO
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C
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C
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%)
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UB
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thorization 
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Label
g
Label Treat
g 
Treat
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a
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ZX
e
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ket
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XX.X%)
ma
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X (XX.X%)
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XX
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XX (XX.X%
ny 
(XX.X%
y
X
n
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an
t a
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pp
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XX
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XX (XX.X%
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XX (XX.X
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to
XX (X
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be
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(N = XXX
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cat
.2.1.5 (Japan


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Programming Note: Use the shell for Table 14.3.1.2.1) for the following Tables:
Table 14.3.1.2.2
Treatment-Emergent Adverse Events occurring in at least 5% of the subjects by MedDRA System Organ Class and PT
Safety Population
For the interim: Since we are only tabulating for “All subjects”,
Add the footnote: “Events listed are those for which the % of subjects having that AE is ≥5.0% of subjects.”
Table 14.3.1.3
TEAEs leading to study discontinuation by MedDRA System Organ Class and Preferred Term
Safety Population
Table 14.3.1.3.1
TEAEs leading to study discontinuation by MedDRA System Organ Class and Preferred Term
Safety Population (Japan)
Table 14.3.1.4
Serious TEAEs by MedDRA System Organ Class and Preferred Term
Safety Population
Table 14.3.1.4.1
Serious TEAEs by MedDRA System Organ Class and Preferred Term
Safety Population (Japan)
Table 14.3.1.5.1
Related TEAEs MedDRA System Organ Class and Preferred Term
Safety Population
Table 14.3.1.5.2
Related TEAEs occurring in at least 5% of subjects by MedDRA System Organ Class and Preferred Term
Safety population
Table 14.3.1.5.3
Related TEAEs MedDRA System Organ Class and Preferred Term
Safety Population (Japan)
Table 14.3.1.5.4
Related TEAEs occurring in at least 5% of subjects by MedDRA System Organ Class and Preferred Term
Safety population (Japan)
PUBLIC COPY
Med
Y
Med
fety
PY
fety Popu
PY 
Popu
Table
OP
Table
nuation
CO
nuation b
O
b
Safet
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Safet
EAEs
LIC
EAEs by
IC
by M
C
M
Serious
PU
Serious
thorization 
national
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03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
System
ing
System Orga
g
Orga
tem
y
tem Organ
y m
Organ C
m
C
on
on
.3.1.3.1
rt a
.3.1.3.1
MedDRA
ort
MedDRA Syst
t
Syst
Population (J
po
Population (J
Table
pp
Table 14.3
p
14.3
DRA
up
DRA System
upp
System
Safety
sup
Safety
EAEs
d t
EAEs by
d to
by Med
to
Med
Related
us
Related
ated
o
ated TEAEs
ot
TEAEs
uth
application and any extensions or variations thereof. 
a
an
an Class
re
Class and
e
and
ass
at
ass and
atio
and Pref
io
Pref
em
r
em Organ
r va
Organ Cl
a
Cl
apan)
or
apan)
1.4
1.4
Organ
ns
Organ Class
s 
Class
Population
ons
Population
Table
si
Table 14.3.1
sio
14.3.1
DRA
n
DRA System
ens
System
Safety Pop
ten
Safety Pop
TEAEs
y e
TEAEs MedD
y e
MedD
occurring
d 
occurring inin
Rela
c
Rela


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For the interim: Since we are only tabulating for “All subjects”,
Add the footnote: “Events listed are those for which the % of subjects having that AE is ≥5.0% of subjects.”
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
uth
application and any extensions or variations thereof. 
a


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Table 14.3.1.6
TEAEs by Maximum Severity, MedDRA System Organ Class and Preferred Term
Safety Population
MedDRA System Organ Class and Preferred
Term
Maximum
Severity
Gp1
(N=xx)
Gp 2
(N=xx)
Gp3
(N=xx)
Gp 4
(N=xx)
Gp5
(N=xx)
Gp 9
(N=xx)
De Novo
Subjects
(N=xx)
Subjects with any TEAE
Mild
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Severe
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
System Organ Class 1
Mild
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Severe
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 1
Mild
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Severe
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 2
Mild
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
.
Severe
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
…..
System Organ Class 2
Mild
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Severe
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 1
Mild
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Severe
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 2
Mild
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Moderate
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Severe
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
…..
PUBLIC COPY 
X.X%)
Y
X.X%)
Y
XX
O
XX (XX.X%
OPY
(XX.X%
PY
XX
CO
XX (XX.
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OP
XX
CO
XX (
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LIC
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(XX.X%)
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LIC
XX
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XX (XX.X%
BL
(XX.X%
BL
UB
XX
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XX (
U
(
U
PU
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thorization 
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not be used to support any marketing auth
m
Gp
ket
Gp 4
t
4
(N=x
ke
(N=x
ting
rk
a
X%)
m
X%)
X
a
ma
XX.X%)
m
XX.X%)
m
XX
XX (XX.X%)
ny 
(XX.X%)
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XX
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XX (XX
n
(XX
an
t
%)
%)
XX
a
XX
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XX
XX (XX.X%)
pp
(XX.X%)
pp
XX
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XX (XX.X%
up
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XX
su
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(XX.X%)
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TEAE = Treatment-Emergent Adverse Event.
Note: Adverse events are classified as treatment-emergent if they started on or after the date of first dose of study treatment. Adverse events with partial or missing start dates are classified as treatment-
emergent, unless the non-missing components of the start date confirm otherwise.
Note: A subject with more than one TEAE with the same preferred term is counted once at the maximum severity for that term. A subject with more than one TEAE under a system organ class is counted
once at the maximum severity for that class
Note: TEAEs with missing severity are considered severe in this summary
Programming Note: Use Table 14.3.1.6 shell for
Table 14.3.1.6.1
TEAEs by Maximum Severity, MedDRA System Organ Class and Preferred Term
Safety Population (Japan)
Programming Note: use shell from Table 14.3.1.1 to produce the following tables.
Table 14.3.1.7
Overview of number of subjects with Treatment-Emergent Adverse Events of Special Interest
Safety Population
Table 14.3.1.7.1
Overview of number of subjects with Treatment-Emergent Adverse Events of Special Interest
Safety Population (Japan)
Add footnote: AESI=Adverse event of sepcial interest.
Programming Note: use shell from Table 14.3.1.2.1 for
Table 14.3.1.8
Treatment Emergent Adverse events of special interest (TE AESI) by MedDRA System Organ Class and Preferred Term
Safety Population
Table 14.3.1.8.1
Treatment Emergent Adverse events of special interest (TE AESI) by MedDRA System Organ Class and Preferred Term
Safety Population (Japan)
Please change footnote from TEAE to TE AESI=Treatment emergent adverse event of special interest.
PUBLIC COPY
RA
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of
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subjects
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Table 14.3.1.9.1
Non-treatment Emergent Adverse Events Starting between Visits 12 and 13 of the Feeder Study, by MedDRA System Organ Class, Preferred Term and Prior Treatment in Feeder Study
Safety Population
MedDRA System Organ Class and Preferred Term
Gp1
(N=xx)
Gp 2
(N=xx)
Gp3
(N=xx)
Gp 4
(N=xx)
Gp5
(N=xx)
Gp 9
(N=xx)
Subjects with Any Non-TEAE Starting
Between Visits 12 and 13 of Feeder Study
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
System Organ Class 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 2
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
.
.
TEAE = Treatment-Emergent Adverse Event.
Note: Percentages are calculated based on the number of subjects in the Safety population.
Note: Adverse events in this table have a start date preceding the start of treatment in Study 1503, hence were classified as “non-treatment-emergent”.
Adverse events are classified as treatment-emergent if they started on or after the date of first dose of study treatment. Adverse events with partial or missing start dates are classified as treatment-
emergent, unless the non-missing components of the start date confirm otherwise.
Note: A subject with more than one non-TEAE with the same preferred term is counted once for that term. A subject with more than one Non-TEAE under a system organ class is counted once for that class.
Programming Note: Include only events whose start date is between Day -30 (inclusive) and Day -1 (inclusive), counting study days from beginning of OLE Treatment period, not core. There will be no De
Novo Column for this table.
Use the Table 14.3.1.9.1 shell for
Table 14.3.1.9.1.1
Non-treatment Emergent Adverse Events Starting between Visits 12 and 13 of the Feeder Study, by MedDRA System Organ Class, Preferred Term and Prior Treatment in Feeder Study
Safety Population (Japan)
PUBLIC COPY 
LIC
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Table 14.3.1.9.2
TEAEs starting in the 1st month of OLE by System Organ Class, Preferred, Term and Prior Treatment in Feeder Study
Safety Population
MedDRA System Organ Class and Preferred Term
Gp1
(N=xx)
Gp 2
(N=xx)
Gp3
(N=xx)
Gp 4
(N=xx)
Gp5
(N=xx)
De Novo Subjects
(N=xx)
Subjects with any TEAE starting in the first month.
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
System Organ Class 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 1
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Preferred Term 2
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
TEAE = Treatment-Emergent Adverse Event.
Note: A subject with more than one TEAE with the same preferred term is counted once for that term. A subject with more than one
TEAE under a system organ class is counted once for that class.
Programming note:
Include only events starting on or after Day 1 up to Day 30 (counting from beginning of OLE Treatment period, NOT Core).
Use same Table 14.3.1.9.2 shell for
Table 14.3.1.9.2.1
TEAEs starting in the 1st month of OLE by System Organ Class, Preferred, Term and Prior Treatment in Feeder Study
Safety Population (Japan)
PUBLIC COPY 
)
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)
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once
C
once for
C C
for th
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thorization 
national
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03
03
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do
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a
in Feed
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Programing note: Use the 14.3.1.9.1 shell to produce the following tables. Include only events starting on or after Study Day31 up to Day 60 (counting from beginning of OLE Treatment period, NOT Core)
Table 14.3.1.9.3
TEAEs starting in the 2nd month of OLE by System Organ Class, Preferred Term and Prior Treatment in Feeder Study
Safety Population
Table 14.3.1.9.3.1
TEAEs starting in the 2nd month of OLE by System Organ Class, Preferred Term and Prior Treatment in Feeder Study
Safety Population (Japan)
Programing note: Use the Table 14.3.1.9.1 shell for the following tables. Include only events starting on or after Study Day61 up to day 90(counting from beginning of OLE Treatment period, NOT Core)
Table 14.3.1.9.4
TEAEs starting in the 3rdmonth of OLE by System Organ Class, Preferred Term and Prior Treatment in Feeder Study
Safety Population
Table 14.3.1.9.4 .1
TEAEs starting in the 3rdmonth of OLE by System Organ Class, Preferred Term and Prior Treatment in Feeder Study
Safety Population (Japan)
PUBLIC COPY 
pulat
Y
pulat
starting
COP
starting o
P
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OLE
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OLE by
LIC
by Sy
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thorization 
national
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national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
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Table 14.3.1.10.1
Treatment-Emergent Adverse Events that Occurred in at least 5% of Subjects during Double-blind Treatment Period by MedDRA System Organ Class and Preferred Term
with Mean Time to Onset (days) and Mean Duration (days)
Safety Population
Placebo
(N=xx)
n (%)/
Mean Onset/
ZX008 0.2 mg/kg/day
(N=xx)
n (%)/
Mean Onset/
ZX008 0.5 mg/kg/day
(N=xx)
n (%)/
Mean Onset/
ZX008 0.8 mg/kg/day
(N=xx)
n (%)/
Mean Onset/
Any DB ZX008
(N=xx)
n(%)
Mean Onset/
TEAE = Treatment-Emergent Adverse Event.
TEAE = Treatment-Emergent Adverse Event.
Note: Percentages are calculated based on the number of subjects in each treatment group.
Note: Mean Onset and Mean Duration are measured in days. The onset day is the study day at the adverse event onset. The duration is the number of days from onset to resolution or from onset to last
follow-up day if the event was ongoing.
Note: Adverse events are classified as treatment-emergent if they started on or after the date of first dose of study treatment. Adverse events with partial or missing start dates are classified as treatment-
emergent, unless the non-missing components of the start date confirm otherwise.
Note: In subjects with more than one occurrence of the same event, the time to onset and duration is based on the earliest occurring event.
Note: Time to onset is the number of days since first treatment with either ZX008 or placebo. The duration of an event is limited to the period of the double-blind study.
Note: A subject with more than one TEAE with the same preferred term is counted once for that term. A subject with more than one TEAE under a system organ class is counted once for that class.
Programing note: Use shell for 14.3.1.10.1 for 14.3.1.10.1.1
Table 14.3.1.10.1.1
Treatment-Emergent Adverse Events that Occurred in at least 5% of Subjects during Double-blind Treatment Period by MedDRA System Organ Class and Preferred Term
with Mean Time to Onset (days) and Mean Duration (days)
Safety Population (Japan)
MedDRA System Organ Class and Preferred Term
Mean Duration
Mean Duration
Mean Duration
Mean Duration
Mean Duration
Subjects with any TEAE starting in the first month.
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
System Organ Class 1
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
Preferred Term 1
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
Preferred Term 2
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
PUBLIC COPY 
ch
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(XX.X%)
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Onset/
on
Onset/
ZX0
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ZX0
t the
ns
the adverse
ns
adverse
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e date
xte
date of firs
te
of firs
nset
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nset and
ex
and dur
x
dur
08
08 or
y
or placeb
y e
placeb
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ny
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y
once
ts
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ts that
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Duration
(XX.X%)
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(XX.X%) /
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/ x
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XX
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XX (XX.X
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XX
r v
XX (XX
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(XX
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x.x
XX
r
XX
s


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Table 14.3.1.10.2
Treatment-Emergent Adverse Events that Occurred in at least 5% of Subjects during Double-blind through Open-label Treatment Periods by MedDRA System Organ Class and Preferred Term, Mean Average
Dose in ZX008-1503 with Mean Time to Onset (days) and Mean Duration (days)
Safety Population
ZX008
0 - < 0.2 mg/kg [1]
(N=xx)
n (%)/
ZX008
0.2 - < 0.4 mg/kg
(N=xx)
n (%)/
ZX008
0.4 - < 0.6 mg/kg
n (%)/
ZX008
0.6 - < 0.8 mg/kg
(N=xx)
n (%)/
Any OLE ZX008
(N=xx)
n(%)
Mean Onset/
Mean Onset/
Mean Onset/
Mean Onset/
Mean Onset/
MedDRA System Organ Class and Preferred Term
Mean Duration
Mean Duration
Mean Duration
Mean Duration
Mean Duration
Subjects with any TEAE starting in the first month.
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
System Organ Class 1
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
Preferred Term 1
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
Preferred Term 2
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
XX (XX.X%) / xx.x /xx.x
.
.
TEAE = Treatment-Emergent Adverse Event.
Note: Percentages are calculated based on the number of subjects in each treatment group.
Note: Mean Onset and Mean Duration are measured in days. The onset day is the study day at the adverse event onset. The duration is the number of days from onset to resolution or from onset to last
follow-up day if the event was ongoing.
Note: Adverse events are classified as treatment-emergent if they started on or after the date of first dose of study treatment. Adverse events with partial or missing start dates are classified as treatment-
emergent, unless the non-missing components of the start date confirm otherwise.
Note: In subjects with more than one occurrence of the same event, the time to onset and duration is based on the earliest occurring event.
Note: Onset day is measured from the first date of ZX008 treatment to onset. Duration for the TEAEs in the placebo group start after the subject starts ZX008 treatment in the OLE.
[1] For subjects treated with Placebo in the core study, TEAEs are counted only after the subject started ZX008 treatment.
Programming note: Use the shell for Table 14.3.1.10.2.1.
Table 14.3.1.10.2.1
Treatment-Emergent Adverse Events that Occurred in at least 5% of Subjects during Double-blind through Open-label Treatment Periods by MedDRA System Organ Class and Preferred Term, Mean Average
Dose in ZX008-1503 with Mean Time to Onset (days) and Mean Duration (days)
Safety Population (Japan)
PUBLIC COPY 
PU
Y
Durati
Y
Durati
XX.X%)
OPY
XX.X%) /
PY
/ x
P
x
Y
XX
C
XX (XX.X
CO
(XX.X
XX
C C
XX (X
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(X
x
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x
XX
C 
XX
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national
zat
national L
03
03
be used to support any marketing auth
to
y MedDRA Sy
au
MedDRA Sy
(days)
g
(days)
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ZX008
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eatment
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do
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be 
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1.10.2.1.
an
1.10.2.1.
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Occurred inin
uth
application and any extensions or variations thereof. 
a
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g/kg
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ean Duration
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a
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only
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at least
ion
least 5%
n
5%


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Programming Notes: Use the Listing 16.2.7.1 shell for the following tables.
Table 14.3.2.1
Listing of Deaths
Table 14.3.2.1.1
Listing of Deaths (Japan)
Table 14.3.2.2
Listing of SAEs
Table 14.3.2.2.1
Listing of SAEs (Japan)
Table 14.3.2.3
Listing of Discontinuations Due to AE
Table 14.3.2.3.1
Listing of Discontinuations Due to AE (Japan)
PUBLIC COPY 
ng
Y
ng o
Y
o
Table
OPY
Table 14
PY
14
Listing
CO
Listing
P
Listin
IC
Listin
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
2.2.1
a
2.2.1
AEs
rt
AEs (Japan)
rt a
(Japan)
Table
ppo
Table 14.3.2
po
14.3.2
of
u
of Discontin
upp
Discontin
Ta
Ta
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to
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to
of Dis
o 
Dis
uth
sions or variations thereof. 
.3.3
ations
s
ations Due
s o
Due t
o
t
ble
i
ble 14.3.2.3.
ion
14.3.2.3.
application and any extens
a
ontinuation
nsi
ontinuation


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Laboratory Data
Please see below (also in SAP) for time windows
Time Intervals for Analysis Visits for Laboratory Data and Vital Signs
Analysis
Phase/Period
Scheduled Visit Number
in ZX008-1503
Analysis Visit
Number*
Time Interval
(label on output)
Time Interval
(Day)
Target Time Point
(Day)
Pre-OLE
1
1
Baseline (OLE)
1
1
OLE
2
2
Week 2 (OLE)
2 to 20
15
OLE
3
3
Month 1 (OLE)
21 to 44
30
OLE
4
4
Month 2 (OLE)
45 to 74
60
OLE
5
5
Month 3 (OLE)
75 to 134
90
OLE
6
6
Month 6 (OLE)
135 to 224
180
OLE
7
7
Month 9 (OLE)
225 to 314
270
OLE
8
8
Month 12 (OLE)
315 to 409
365
OLE
9
9
Month 15 (OLE)
410 to 499
455
OLE
10
10
Month 18 (OLE)
500 to 589
545
OLE
11
11
Month 21 (OLE)
590 to 679
635
OLE
12
12
Month 24 (OLE)
680 to 774
730
OLE
13
13
Month 27 (OLE)
775 to 864
820
OLE
14
14
Month 30 (OLE)
865 to 954
910
OLE
15
15
Month 33 (OLE)
955 to 1044
1000
OLE
16
16
Month 36 (OLE)
1045 to 1109
1095
OLE
OLE last Visit**
99
Last Value
Day 2 to Visit 17
date
Programming Notes:
*For multiple measurements within a time window, please use the closest to the target time point. Note that measurements occurring on the end date of a phase/period or start date of a new phase/period
are assigned to the preceding phase/period. For example, measurements taken on OLE Study Day1 are assigned as Baseline (OLE).
**The last observation in the time window will be used. [This is an exception from the rule in the preceding note.]
LIC COPY 
Y
PY
PY
PY
PY
PY
E)
CO
E)
OP
(OLE)
CO
(OLE)
CO
6
C
6 (OLE)
C C
(OLE)
C
nth
IC
nth 9
IC
9 (OLE
C 
(OLE
C
Month
LIC
Month 12
IC
12 (
C
(
IC
PUBL
Month
BL
Month
BLI
Mon
UB
Mon
B
M
U
M
UB
PU
P
support any marketing authorization 
uth
national
zat
national L
03
03
Target
ark
Target
rk
ma
ma
ma
ma
ma
m
to
n
to 20
ny
20
ny
21
a
21 to
an
to 44
an
44
any
45
rt a
45 to
a
to 74
a
74
t a
75
rt
75 to
to
rt
13
13
o
p
pp
LE)
LE)
pp
pp
pp
sed to supp
(OLE)
s
(OLE)
sup
18
o
18 (OLE)
to s
(OLE)
s
nth
t
nth 21
to
21 (OLE)
to
(OLE)
to
Month
d t
Month 24
d t
24 (O
t
(O
d t
Month
ed
Month 27
d
27
ed
use
Month
se
Month
annot be use
Mo
s
Mo
us
u
be
be
be
ot be
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do
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s d
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can
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. For exampl
t ca
. For exampl
w
n
w will
nt
will be
t c
be use
c
use
ns or variations thereof. 
Time
s
Time Point
s t
Point
(Day)
ons
(Day)
s t
on
1
o
1
tio
at
ria
ar
ar
ar
ar
ar
134
r
134
va
5 to
o
to 224
or
224
r
225
s
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to 314
o
314
o
315
ns
315 to
s 
to 4
s
xtensions
410
n
410 t
ns
i
50
50
ion
sisisisio
si
LE)
e
LE)
ns
(OLE)
xte
(OLE)
ten
ext
30
e
30 (OLE)
ext
(OLE)
d any exte
nth
nth 33
e
33 (OLE)
ex
(OLE)
ex
Month
y
Month 36
y e
36 (O
e
(O
y e
Last
any
Last Va
y
Va
ny
application and a
a
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on 
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t
d. [This
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[This is
o
is an
an


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Laboratory Test: Parameter (units)
Table 14.3.4.1
Laboratory parameters – Hematology
Safety Population
ZX008 OL
(N=xxx)
De Novo Subjects
(N=xxx)
Visit
Visit Values
Change from Baseline
Visit Values
Change from Baseline
Baseline (OLE)
N
XX
XX
Mean
XX.X
XX.X
SD
XX.XX
XX.XX
Median
XX.X
XX.X
Min
XX
XX
Max
XX
XX
Week 2 (OLE)
N
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
Max
XX
XX
XX
XX
Repeat for other time periods:
Month 2 (OLE), 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, and
Last Value (OLE)
PUBLIC COPY 
Y
OP
OP
OP
OP
CO
X
C
X
C C
XX
BLI
XX
LIC
XX
B
XX
BL
PU
P
ot be used to support any marketing authorization 
uth
national
zat
national L
03
03
ke
ke
ke
ke
aseline
ma
aseline
a
m
ny
a
rt
po
up
up
up
up
up
s
to
d
XX
se
XX
se
u
b
t cannot be
be
b
ot
no
an
ment c
21,
e
21, 24,
en
24, 27,
n
27, 3
This docum
do
TIAL
s d
TIAL
t c
m
ny extensions or variations thereof. 
th
ns
ioioioio
tio
at
ar
v
or
s
on
s
en
en
en
en
en
xt
XX.X
y
XX.X
y e
d any
XX.XX
any
XX.XX
plication and any
XX
a
XX
d a
nd
a
0,
c
0, 33,
cat
33, 36,
at
36, and
t
and
application
a
on
plic


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Laboratory Test: Parameter (units)
Table 14.3.4.1
Laboratory parameters – Hematology
Safety Population
Visit [1]
Gp1
(N = XX)
Gp2
(N = XX)
Gp3
(N = XX)
Gp4
(N = XX)
Gp5
(N = XX)
Gp9
(N = XX)
De Novo Subjects
(N =XX)
Baseline (OLE)
N
XX
XX
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
XX
Week 2 (OLE)
Observed
N
XX
XX
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
XX
CFB
N
XX
XX
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
XX
…
Repeat for all time
points
PUBLIC COPY 
Y
PY
PY
PY
PY
PY
X
C
X
OP
XX
C
XX
CO
XX
C C
XX
C
C
LIC
BL
UB
UB
UB
UB
UB
U
PU
P
nnot be used to support any marketing authorization 
uth
national
zat
national L
03
03
ke
a
m
XX
y
XX
y m
XX.X
any
XX.X
ny
XX.XX
an
XX.XX
an
XX.
a
XX.
t a
rt
po
pp
pp
pp
pp
pp
up
su
XX
to
XX
s
XX.X
to
XX.X
to
XX.X
t
XX.X
d t
ed
se
us
us
us
us
us
e u
be
XX
ot b
XX
t b
XX.X
ot
XX.X
ot
XX.X
no
XX.X
no
ment cann
nn
an
ca
ca
ca
ca
ca
t c
n
This docum
do
TIAL
s d
TIAL
m
um
and any extensions or variations thereof. 
Gp5
s t
Gp5
(N
n
(N =
s
= XX)
s t
XX)
th
ns
on
tio
aiaiaiat
ria
ria
ria
ria
ria
X
a
XX
r
XX
v
XX
or
XX
or
o
s
n
io
sisisisisi
X
t
X
ns
XX.X
xt
XX.X
te
XX
ext
XX
xt
XX
e
XX
ex
y e
ny
an
a
d a
X
a
X
nd
an
XX.X
a
XX.X
ation an
XX
n
XX
a
XX
on
XX
on
tio
applicat
a
ati
ic
licicic
plic


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CONFIDENTIAL
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CFB = Change from Baseline.
Note: Time windows are specified in the Statistical Analysis Plan. For multiple measurements within a time window, the closest to the target time point was used. Measurements occurring on the end date
of an interval or start date of a new interval are assigned to the preceding interval: For example, measurements taken on OLE Study Day1 are assigned as Baseline(OLE). However, for the Last value (OLE) ,
the last observation in the time window is used.
[1] Laboratory tests were performed at all visits
Programming Note:
-
Repeat for all other laboratory parameters.
-
Use correct number of decimal places for summary statistics depending on the raw data recorded for each parameter. Please do not use more than 3 decimal places unless there are 2 significant
digits or fewer. Two decimal places are preferred.
-
Include correct units for the lab tests in the titles.
Programming Notes: Use the table shell for 14.3.4.1 for the following tables.
Table 14.3.4.1.1
Laboratory parameters – Hematology
Safety Population (Japan)
Table 14.3.4.2 Laboratory parameters –Biochemistry
Safety Population
Table 14.3.4.2.1 – Laboratory parameters – Biochemistry
Safety Population (Japan)
Table 14.3.4.4.1
Laboratory Parameters - Urinalysis (Quantitative Parameters)
Safety Population
Table 14.3.4.4.1.1
Urinalysis (Quantitative Parameters)
Safety Population (Japan)
PUBLIC COPY 
Labor
IC
Labor
Tab
UB
Tab
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
t time
a
time point
au
point
1 are
g
1 are assigne
g a
assigne
meter.
ma
meter. Pleas
a
Pleas
Table
pp
Table 14.3.4
ppo
14.3.4
ory
u
ory paramet
upp
paramet
Safety Popu
sup
Safety Popu
4.3.4.2
to s
4.3.4.2 Labo
s
Labo
Table
ed
Table 14.3.4
ed
14.3.4
uth
any extensions or variations thereof. 
was
of
was used.
of.
used. M
ed
e
ed as
eo
as Baselin
eof
Baselin
e
o
e do
on
do not
ons
not use
s
use
1.1
1.1
ers
s
ers –
s
– Hemato
s o
Hemato
lation (Japan
ns
lation (Japan
ratory
sio
ratory param
io
param
Safety
ns
Safety Popu
s
Popu
.2.1
xt
.2.1 –
te
– Labora
te
Labora
application and a
a
Safety
xt
Safety
Laboratory
an
Laboratory


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CONFIDENTIAL
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Table 14.3.4.4.2
Laboratory parameters - Urinalysis (Categorical)
Safety Population
Laboratory Test: Parameter [Example Table below for illustrative purpose only]
Programming Note: For interims and 120-day, please use only last column ZX008 OL
Gp1
(N=39)
Gp2
(N=40)
Gp3
(N=5)
Gp4
(N=43)
Gp5
(N=14)
Gp9
(N=141)
De Novo Subjects(
(N=XXX)
Baseline (OLE)
n
34
36
3
38
0
111
111
NEGATIVE
34 (100.0%)
36 (100.0%)
3 (100.0%)
38 (100.0%)
0 (0.0%)
111 (100.0%)
111 (100.0%)
Week 2 (OLE)
n
2
2
0
1
0
5
5
NEGATIVE
2 (100.0%)
2 (100.0%)
0 (0.0%)
1 (100.0%)
0 (0.0%)
5 (100.0%)
5 (100.0%)
Month 1 (OLE)
n
29
31
2
34
10
106
106
NEGATIVE
29 (100.0%)
31 (100.0%)
2 (100.0%)
34 (100.0%)
10 (100.0%)
106 (100.0%)
106 (100.0%)
Month 2 (OLE)
n
26
30
2
33
10
101
101
NEGATIVE
26 (100.0%)
30 (100.0%)
2 (100.0%)
33 (100.0%)
10 (100.0%)
101 (100.0%)
101 (100.0%)
………
Repeat for all visits
Last Value (OLE)
n
26
30
2
33
10
101
101
NEGATIVE
26 (100.0%)
30 (100.0%)
2 (100.0%)
33 (100.0%)
10 (100.0%)
101 (100.0%)
101 (100.0%)
Note: Time windows are specified in the Statistical Analysis Plan. For multiple measurements within a time window, the closest to the target time point was used. Measurements occurring on the end date
of an interval or start date of a new interval are assigned to the preceding interval: For example, measurements taken on OLE Study Day1 are assigned as Baseline(OLE). However, for the Last value (OLE) ,
the last observation in the time window is used.
PUBLIC COPY 
Y
3
P
3
3
CO
3 (10
O
(10
0.0%)
BL
0.0%)
3
U
3
31
P
31
thorization 
national
zat
national L
03
03
ment cannot be used to support any marketing auth
e
Gp4
ma
Gp4
(N=43)
y m
(N=43)
a
y m
0%)
or
0%)
0
pp
0
0
up
0 (0.0
up
(0.0
00.0%)
ed
00.0%)
30
u
30
30
e
30 (1
(1
26
ca
26
26
t c
26 (100.0%
t ca
(100.0%
um
d in the
me
in the Stati
e
Stati
new interv
um
new interv
This docu
do
TIAL
s d
TIAL
ime window
cu
ime window
uth
application and any extensions or variations thereof. 
a
ca
ns
tio
38
ar
38
38
va
38 (100.0
va
(100.0
0%)
o
0%)
2
ns
2
2
en
2 (100
en
(100
00.0%)
ny
00.0%)
)
stical
lic
stical Analys
ica
Analys
l are
pli
are assigne
plic
assigne
is used.
pp
is used.


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 155 of 234
Draft 3.0: 04Aug2020
Programming Note: Use the Table 14.3.4.4.2 shell to produce the following table.
Table 14.3.4.4.2.1
Laboratory parameters - Urinalysis (Categorical)
Safety Population (Japan)
Table 14.3.4.5.1
Laboratory parameters – Tests of growth, precocious puberty and thyroid function
Safety Population (Japan)
PY 
wth,
Y
wth,
PUBLIC COPY
pr
Y
pr
y Populati
PY
y Populati
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
ous
ny
ous puberty
ny 
puberty
n (Japan)
any
n (Japan)
application and any extensions or variations thereof. 
a
and
at
and thyroid
atio
thyroid


TLF Shells
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CONFIDENTIAL
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Draft 3.0: 04Aug2020
Programming Note: Use Table 14.3.4.1 shell for the following tables.
Table 14.3.4.5
Laboratory parameters – Tests of growth, precocious puberty and thyroid function
Safety Population
Table 14.3.4.5.1
Laboratory parameters – Tests of growth, precocious puberty and thyroid function
Safety Population (Japan)
For interims and 120-day, please use only last column
For IDMC uses all columns
Programming Note: Use shell for Table 14.3.4.1 Include correct units in the titles for the Vital sign parameter
Table 14.4.1.1
Vital Signs
Safety Population
Table 14.4.1.1.1
Vital Signs
Safety Population (Japan)
PUBLIC COPY
wth,
Y
wth, p
Y
p
Populatio
PY 
Populatio
tles
L
tles for
LIC
for the
IC
the
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uth
national
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03
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nd
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thyroid f
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application and any extensions or variations thereof. 
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sio
Table 14.4.1
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14.4.1
Vital
ns
Vital Sig
Sig
Safety
en
Safety P


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Programming Note:
Use shell for Figure 1b in ISS for the the following figures.
Figure 14.4.1.2
Scatterplot of Age (X-axis) and Height (Y-axis) at End of Study during the Open-label Treatment Period
Safety Population
Figure 14.4.1.2.1
Scatterplot of Age (X-axis) and Height (Y-axis) at End of Study during the Open-label Treatment Period
Safety Population (Japan)
Y-axis: ADVS.AVAL where PARAMCD=HEIGHT and AVISIT=EOS/ET and SAFFL=’Y’
X-axis: ADSL.AGEEOS
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an
Study during
any
during
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do
TIAL
s d
TIAL
tion (Japan)
t a
tion (Japan)
application and any extensions or variations thereof. 
a
l Treatment
s t
Treatment
the
r
the Open
ria
Open-
a
-la
a
la


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Table 14.4.1.3
Weight during the Open-Label Study Period over Time by Age Group (2 - <4; 4 - <6; 6 to <12; and ≥12): Summary Statistics
Safety Population
Age Group: 2-<4 years/ 4 -<6 years/ 6 - <12 years/>=12 years
Visit [1]
Gp1
(N = XX)
Gp2
(N = XX)
Gp3
(N = XX)
Gp4
(N = XX)
Gp5
(N = XX)
Gp9
(N = XX)
Baseline (OLE)
N
XX
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
Week 2 (OLE)
Observed
N
XX
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
CFB
N
XX
XX
XX
XX
XX
XX
Mean
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
SD
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Median
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
Min
XX
XX
XX
XX
XX
XX
Max
XX
XX
XX
XX
XX
XX
…
PUBLIC COPY 
Y
PY
PY
PY
PY
PY
OP
X.XX
C
X.XX
CO
XX.X
C C
XX.X
C
XX
C
XX
C
X
C
X
LIC
BL
B
UB
UB
UB
UB
U
PU
P
cannot be used to support any marketing authorization 
uth
national
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national L
03
03
nd
n
nd ≥12):
ng
≥12): Sum
g
Sum
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a
y m
ny
XX
an
XX
an
XX.X
a
XX.X
t a
X
rt
o
pp
pp
pp
pp
pp
upp
pp
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p
su
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XX
t
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us
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TIAL
m
um
and any extensions or variations thereof. 
mmary
eo
mmary Statis
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Statis
Gp5
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Gp5
(N
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(N = X
ns
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ria
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Repeat for all time
points
Note: If a test is repeated at any given visit, the last non-missing result is used in the summary.
Note: this table excludes the De Novo Subjects.
Programming note: Use the Table 14.4.1.3 shell for
Table 14.4.1.3.1
Weight during the Open-Label Study Period over Time by Age Group (2 - <4; 4 - <6; 6 to <12; and ≥12): Summary Statistics
Safety Population (Japan)
PUBLIC COPY 
pulat
Y
pulat
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
ut
ut
ut
ut
g a
ng
4;4; 4
m
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m
<6; 6
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application and any extensions or variations thereof. 
a
of
eo
<12;
io
<12; and
on
and ≥1
n
≥1


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Table 14.4.1.4
Weight Over Time during the Open-Label Study Period for De Novo Subjects: Summary Statistics
Safety Population – De Novo Subjects
Visit [1]
De Novo Subjects
(N = XX)
Baseline (OLE)
N
XX
Mean
XX.X
SD
XX.XX
Median
XX.X
Min
XX
Max
XX
Week 2 (OLE)
Observed
N
XX
Mean
XX.X
SD
XX.XX
Median
XX.X
Min
XX
Max
XX
CFB
N
XX
Mean
XX.X
SD
XX.XX
Median
XX.X
Min
XX
Max
XX
…
Repeat for all time points
Note: If a test is repeated at any given visit, the last non-missing result is used in the summary.
PUBLIC COPY 
Y
PY
OP
CO
C
C C
IC
LI
BL
UB
PU
P
thorization 
national
zat
national L
03
03
ment cannot be used to support any marketing auth
ry
g
ry Statistics
a
Statistics
ects
ke
ects
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k
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tin
rk
ar
XX
m
XX
ma
XX.X
m
XX.X
m
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ation and any extensions or variations thereof. 
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X.XX
ia
X.XX
at
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ari
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XX
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the last
plic
last non
ic
non


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Programming note: Use the Table 14.4.1.4 shell for
Table 14.4.1.4.1
Weight Over Time during the Open-Label Study Period for De Novo Subjects: Summary Statistics
Safety Population – De Novo Subjects – Japan
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
mmary
ng
mmary Statist
g 
Statist
uth
application and any extensions or variations thereof. 
a
cs
e
cs


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Table 14.4.1.5
Weight Summary (Lost/Gain ≥7% or ≥10%) during the Open-Label Study Period
Safety Population
Placebo/
ZX 008 OL
(N = XX)
ZX008 0.2 mg/
ZX 008 OL
(N = XX)
ZX008 0.5 mg/
ZX008 OL
(N = XX)
ZX008 0.8 mg/
ZX 008 OL
(N = XX)
All Subjects
(N = XX)
De Novo Subjects
(N = XX)
Baseline (OLE) n
xx
xx
xx
xx
xx
xx
At Any Visit in OLE, n
xx
xx
xx
xx
xx
xx
Lost >=7% of weight [1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Recovered lost weight [2]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Days until Recovery
Mean
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
SD
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
Median
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
Min
XXX
XXX
XXX
XXX
XXX
XXX
Max
XXX
XXX
XXX
XXX
XXX
XXX
Lost >=10% of weight [1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Gain >=7% of weight [1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Gain >=10% of weight [1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Month 1 (OLE), n
xx
xx
xx
xx
xx
xx
Lost >=7% of weight [1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Recovered lost weight [2]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Days until Recovery
Mean
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
SD
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
XXX.XX
Median
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
XXX.X
Min
XXX
XXX
XXX
XXX
XXX
XXX
Max
XXX
XXX
XXX
XXX
XXX
XXX
Lost >=10% of weight [1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Gain >=7% of weight [1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
PUBLIC COPY 
%)
C
%)
XXX.X
C C
XXX.X
XXX.XX
LIC
XXX.XX
XX
LI
XX
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
od
od
ZX008
keti
ZX008 0
ZX
e
ZX
tin
ar
ar
ar
xx
an
xx
XX
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an
(XX.X%
XX
rt 
XX (XX
a
(XX
X
XXX
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XXX
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to
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XX (XX.X%
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(XX.X%
XX
ed
XX (XX
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(XX
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XX
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(XX.X%)
ot
(XX.X%)
XXX.X
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XXX.X
XX
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uth
application and any extensions or variations thereof. 
a
8
h
8 mg/
the
mg/
008
t
008 OL
th
OL
(N
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(N =
s
= XX)
s t
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X%)
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X%)
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XXX.XX
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X.X%)
(XX.X%)
ext
(XX.X%)
xx
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xx
XX
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XX (X
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X.XX
XXX.X
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XXX
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XXX
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XX (


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Gain >=10% of weight [1]
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Note: Time windows are specified in the statistical analysis plan. In the event of 2 or more assessments in the interval, the assessment completed closest to the target time point are assessed. For the last
assessment, the last non-missing value observed.
[1] Percentages are based on the number of subjects with a baseline weight and a weight at the visit meeting the criteria noted in the row.
[2] A subject recovered, if they had a weight recorded after the visit being summarized that was within 1% of the baseline body weight at 2 consecutive visits. Percentages are based on the number of
subjects who had the 7%/10% weight loss and had a value meeting the criteria noted in the row.
Programming Notes: Use the Table 14.4.1.5 shell for the following tables.
Table 14.4.1.5.1
Weight Summary (Lost/Gain ≥7% or ≥10%) during the Open-Label Study Period
Safety Population (Japan)
Table 14.4.1.6
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the Open-Label Study Period by Concomitant Topiramate
Safety Population
Table 14.4.1.6.1
Weight Summary (Lost/Gain ≥7%, or ≥10%) during the Open-Label Study Period by Concomitant Topiramate
Safety Population (Japan)
Programming notes: Repeat Table 14.4.1.5 for 14.4.1.6 and 14.4.1.6.1 by subset by (a) subjects on concomitant topiramate, and (b) subjects not on concomitant topiramate.
Programming note: Use the Table 14.4.1.5 shell but only present for 5% to produce the following tables.
Table 14.4.1.7
Weight Summary (Lost/Gain ≥5%) during the Open-Label Study Period
Safety Population
Table 14.4.1.7.1
Weight Summary (Lost/Gain ≥5%) during the Open-Label Study Period
Safety Population (Japan)
PUBLIC COPY 
Table
OP
Table 1
P
1
ain
CO
ain ≥7%
CO
≥7% o
O
o
Safety
CO
Safety
P
n
B
n ≥7%,
BLI
≥7%, o
LI
o
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03
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%)
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ompleted clo
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be
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uth
application and any extensions or variations thereof. 
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consecutive
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ns
4.4.1.6
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Populatio
Table
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Table 14.
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produce the
y
the
Weight
and
Weight


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Table 14.4.1.8
Weight Summary (Lost/Gain ≥5%) during the Open-Label Study Period by Concomitant Topiramate
Safety Population
Table 14.4.1.8.1
Weight Summary (Lost/Gain ≥5%) during the Open-Label Study Period by Concomitant Topiramate
Safety Population (Japan)
PUBLIC COPY 
thorization 
national
zat
national L
03
03
keting auth
t Topiramate
au
Topiramate
This document cannot be used to support any marke
do
TIAL
s d
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Concomitan
ket
Concomitan
uth
hereof. 
application and any extensions or variations the
a
t
t
t Topiramate
the
Topiramate


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Table 14.4.4.1
Tanner Staging by Age Group for Boys
Safety Population
Age Group
Visit [1]
Tanner
Stage
Gp1
(N = XX)
Gp2
(N = XX)
Gp3
(N = XX)
Gp4
(N = XX)
Gp5
(N = XX)
Gp9
(N = XX)
<7years
Baseline (OLE)(Day 1)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Visit 6 (Month 6)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Visit 12 (Month 24)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Final Visit/EOS
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
>7years to <=11
Baseline (OLE)(Day1)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
PUBLIC COPY 
X%)
Y
X%)
XX.X%)
PY
XX.X%)
XX
O
XX (XX.X%)
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Stage III
Stage IV
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Visit 6 (Month 6)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Visit 12 (MNonth 24)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Final Visit/EOS
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
>11years to <=15
Baseline (OLE) (Day 1)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Visit 6 (Month 6)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
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Visit 12
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Final Visit/EOS
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
>15years to <=18
Baseline (OLE) (Day 1)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Visit 6 (Month 6)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Visit 12 (Month 24)
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Final Visit/EOS
Stage I
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage II
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage III
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Stage IV
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
PUBLIC COPY 
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Stage V
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
[1] Per protocol amendment 3.0, Tanner Staging was to be completed at Baseline (Visit 1), and Months 6, 15, 27 and 36.
Programming Note: use shell from Table 14.4.4.1 for
Table 14.4.4.1.1
Tanner Staging by Age Group for Boys
Safety Population (Japan)
Table 14.4.4.1.2
Tanner Staging by Age Group for Girls
Safety Population
Table 14.4.4.1.2.1
Tanner Staging by Age Group for Girls
Safety Population (Japan)
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Table 14.4.5.1
Number of Subjects with Suicidal Ideation, Suicidal Behavior and Self Injurious Behavior Without Suicidal Intent
Based on the (C-SSRS) during Treatment
Safety Population
Period
Gp1
(N = XX)
Gp2
(N = XX)
Gp3
(N = XX)
Gp4
(N = XX)
Gp5
(N = XX)
Gp9
(N = XX)
De Novo
Subjects
(N = XX)
Baseline (Visit 1 of OLE) [1]
No.of Subjects Completing CSSRS
No.of Subjects with Any Suicidal Ideation
No.of Subjects with Any Suicidal Behavior
No.of Subjects without Suicidal Ideation or Suicidal Behavior
No. of Subjects with ‘Self-injurious behavior without suicidal
intent’
OLE Period [2]
No.of Subjects Completing CSSRS
No.of Subjects with Any Suicidal Ideation
No.of Subjects with Any Suicidal Behavior
No.of Subjects without Suicidal Ideation or Suicidal Behavior
No. of Subjects with ‘Self-injurious behavior without suicidal
intent’
C-SSRS: Columbia Suicide Severity-Rating Scale
[1] Counts are based on response at Visit 1 of the OLE Period.
[2] Counts are based on responses during the OLE period.
Note: each subject is counted only once, using the most severe C-SSRS response category during treatment. No event=0; suicidal ideation=1, 2, 3, 4, 5; suicidal behavior=6, 7, 8, 9, 10. See SAP Section 6.4.10.
N=number of subjects with baseline AND post-baseline C-SSRS assessment. Cell frequencies are to be divided by the total N in the relevant treatment group and multiplied by 100 to get the cell %.
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TLF Shells
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Programming note: Use the Table 14.4.5.1 shell for:
Table 14.4.5.1.1
Number of Subjects with Suicidal Ideation, Suicidal Behavior and Self Injurious Behavior Without Suicidal Intent
Based on the (C-SSRS) during Treatment
Safety Population (Japan)
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Table 14.4.5.2
Number of Subjects with Suicide-Related Treatment-Emergent Events Based on the (C-SSRS) during Treatment
Safety Population
-----Most Severe Post Baseline Potentially Suicide-Related Category----
BASELINE (OLE)
No suicidal ideation or
behavior
Suicidal ideation
Suicidal behavior
Total
Gp1 (N=xxx)
No suicidal ideation or behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal ideation
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Gp2 (N=xxx)
No suicidal ideation or behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal ideation
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Gp3 (N=xxx)
No suicidal ideation or behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal ideation
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Gp4 (N=xxx)
No suicidal ideation or behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal ideation
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Gp5 (N=xxx)
No suicidal ideation or behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal ideation
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
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Suicidal behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Gp9 (N=xxx)
No suicidal ideation or behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal ideation
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
De Novo Subjects (N=xxx)
No suicidal ideation or behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal ideation
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
Suicidal behavior
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
XX (XX.X%)
C-SSRS: Columbia Suicide Severity-Rating Scale
Programming Notes: Use the 14.4.5.2.shell for
Table 14.4.5.2.1
Number of Subjects with Suicide-Related Treatment-Emergent Events Based on the (C-SSRS) during Treatment
Safety Population (Japan)
PY 
Y
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Table 14.4.6.1
Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P) – Scoring summary table
Safety Population
Scale/Index
Visit
Statistics
Gp1
(N = XX)
Gp2
(N = XX)
Gp3
(N = XX)
Gp4
(N = XX)
Gp5
(N = XX)
Gp9
(N = XX)
SCALES
Inhibit
OLE Baseline
n
Mean (SE)
OLE Month 1
n
Mean (SE)
OLE Month 1 Chg BL
n
Mean (SE)
OLE Month 2
n
Mean (SE)
OLE Month 2 Chg BL
n
Mean (SE)
OLE Month 3
n
Mean (SE)
OLE Month 3 Chg BL
n
Mean (SE)
OLE Month 6
n
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Gp4
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(N =
e
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Mean (SE)
OLE Month 6 Chg BL
n
Mean (SE)
OLE Month 9
n
Mean (SE)
OLE Month 9 Chg BL
n
Mean (SE)
OLE Month12
n
Mean (SE)
OLE Month 12 Chg BL
n
Mean (SE)
… Repeat for OLE
Months 15, 18, 21,
24, 27, 30, 33, 36
OLE Last Visit
n
Mean (SE)
OLE Last Visit Chg BL
n
Mean (SE)
….
[REPEAT for
Shift
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Emotional Control
(EC)
Working Memory
(WM)
Plan/Organize
(PO)]
INDEXES
Inhibitory Self-
Control Index
(ISCI) (Inhibit +
EC)[1]
OLE Baseline
n
Mean (SE)
OLE Month 1
n
Mean (SE)
OLE Month 1 Chg BL
n
Mean (SE)
OLE Month 2
n
Mean (SE)
OLE Month 2 Chg BL
n
Mean (SE)
OLE Month 3
n
Mean (SE)
OLE Month 3 Chg BL
n
Mean (SE)
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OLE Month 6
n
Mean (SE)
OLE Month 6 Chg BL
n
Mean (SE)
OLE Month 9
n
Mean (SE)
OLE Month 9 Chg BL
n
Mean (SE)
OLE Month12
n
Mean (SE)
OLE Month 12 Chg BL
n
Mean (SE)
… Repeat for OLE
Months 15, 18, 21,
24, 27, 30, 33, 36
OLE Last Visit
n
Mean (SE)
OLE Last VisitChg BL
n
Mean (SE)
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90% CI for
change from
BL[5]
(xxx.x, xxx.x)
(xxx.x, xxx.x)
(xxx.x, xxx.x)
(xxx.x, xxx.x)
(xxx.x, xxx.x)
(xxx.x, xxx.x)
…..
REPEAT FOR
Flexibility Index
(FI) (Shift + EC)[2]
Emergent
Metacognition
Index (EMI) (WM +
PO)[3]
Global Executive
Composite (GEC)
(Inhibit + Shift + EC
+ WM + PO) [4]
The BRIEF-P questionnaire was administered to preschool age children. N=# subjects in analysis population; n=number of subjects assessed at time point.
mITT = Modified Intent-to-Treat; SE=Standard Error; Chg. BL=Change from Baseline; EOS/ET=End-of-Study/Early Termination or Last available measurement.
Notes:
[1] ISCI: Computed as the sum of the scale raw scores obtained for Inhibit and Emotional Control.
[2] FI: Computed as the sum of the raw scale scores obtained for Shift and Emotional Control
[3] EMI: Computed as the sum of the raw scale scores for Working Memory and Plan/Organize.
[4] GEC: Inhibit + Shift + EC + WM + PO
[5] Based on T distribution. Endpoints of the interval are Mean ± T*SE, where T is obtained as the 95% percentile from the Student’s T distribution with n-1 degrees of freedom
Programming notes:
1.
The rater’s responses are scored as follows: 1=Never, 2=Sometimes, and 3=Often
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Scales of the BRIEF-P
Scale
No. of items
Items
Scoring Instructions (for each individual)*
Inhibit
16
3, 8, 13, 18, 23, 28, 33, 38, 43, 48, 52, 54, 56, 58, 60, 62
Add up scores for items on the scale
Shift
10
5, 10, 15, 20, 25, 30, 35, 40, 45, 50
Add up scores for items on the scale
Emotional Control
10
1, 6, 11, 16, 21, 26, 31, 36, 41, 46
Add up scores for items on the scale
Working Memory
17
2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 51, 53, 55, 57, 59, 61, 63
Add up scores for items on the scale
Plan/Organize
10
4, 9, 14, 19, 24, 29, 34, 39, 44, 49
Add up scores for items on the scale
Validity scales
Inconsistency
10 pairs
(1, 11), (3, 33), (5, 45), (10, 20), (11, 26), (16, 21), (18, 52), (33, 38), (43,
52), (48, 54)
For each item in a pair, obtain the score for each item, and
subtract the scores, keeping the absolute difference. Sum the 10
absolute differences to get the Inconsistency score.
Classification[1]:
0-6: Acceptable
7  Acceptable
≥8: Inconsistent
Negativity
10
30, 44, 46, 47, 53, 55, 56, 57, 59, 63
Count the number of items with a score of 3. That is the
negativity score.
Classification[1]:
0-2 Acceptable
3 Acceptable
≥4 Elevated
2. *Missing data handling for the BRIEF-P[2]
1. First obtain the number of missing responses for the entire questionnaire of 63 items.
2. If the total number of unanswered items is >12, do not compute any of the (five) scale raw scores (I, S, EC, WM, PO) for the BRIEF-P, as per the authors, the “protocol should be considered invalid”.
In that case, all the scale raw scores will be missing, and the index scores will be missing as well.
3. If more than 2 (of the 63) items on the BRIEF-P have missing responses for a Scale (any of the 5 listed above), then a scale raw score should not be calculated. However, for any scale with 2 or fewer
missing responses, impute a score of “1” for the missing item
References:
[1] Gioia GA, Espy KA, Isquith PK. BRIEF-P: Behavior Rating Inventory of Executive Function-Preschool Version. Professional Manual. 2003 Edition. Pages 15-16.
[2] Gioia GA, Espy KA, Isquith PK. BRIEF-P: Behavior Rating Inventory of Executive Function-Preschool Version. Professional Manual. 2003 Edition. Page 7.”Missing Responses”.
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Programming Notes: Use the sheel for 14.4.6.1 for the following tables.
Table 14.4.6.1.1
Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P) – Scoring summary table
Safety Population (Japan)
Table 14.4.6.2
Behavior Rating Inventory of Executive Function- (BRIEF)
Safety Population
For 14.4.6.2 and 14.4.6.2.1,
Scales are:
Inhibit
Shift
Emotional Control (EC)
Initiate
Working Memory (WM)
Plan/Organize (PO)
Organization of Materials (OM)
Monitor
Table 14.4.6.2.1
Behavior Rating Inventory of Executive Function- (BRIEF)
Safety Population (Japan)
For Indexes Part, where we use the 90% CI for the EOS/ET measurement, the following are used, along with relevant footnotes;
Behavioral Regulation Index (BRI)[1]
Metacognition Index (MI)[2]
Global Executive Composite (GEC) [3]
For the following line, include [4] as footnote
90% CI for change from BL[4]
PUBLIC COPY 
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Footnotes
The BRIEF questionnaire was administered to school age children. N=# subjects in analysis population; n=number of subjects assessed at time point.
mITT = Modified Intent-to-Treat; SE=Standard Error; Chg. BL=Change from Baseline; EOS/ET=End-of-Study/Early Termination or Last available measurement
Notes:
[1] Computed as the sum of the scale raw scores obtained for Inhibit, Shift, and Emotional Control.
[2] Computed as the sum of the raw scale scores obtained for Initiate, Working Memory, Plan/Organize, Organization of Materials, and Monitor.
[3]Computed as the sum of the raw scale scores for BRI and MI.
[4]Based on T distribution. Endpoints of the interval are Mean ± T*SE, where T is obtained as the 95% percentile from the Student’s T distribution with n-1 degrees of freedom
Programming notes:
1.
The rater’s responses are scored as follows: 1=Never, 2=Sometimes, and 3=Often
Scales of the BRIEF
Scale
Item
Total No. of Items for Parent Form
Inhibit
38, 41, 43, 44, 49, 54, 55, 56, 59, 65, 73, 78, 79, 81, 82
15
Shift
5, 6, 8, 12, 13, 23, 30, 39, 80, 84, 85
11
Emotional Control
1, 7, 20, 25, 26, 45,50, 62, 64, 70
10
Initiate
3, 10, 16, 47, 48, 61, 66, 71
8
Working Memory
2, 9, 17, 19, 24, 27, 32, 33, 37, 57, 83
11
Plan/Organize
11, 15, 18, 22, 28, 35, 36, 40, 46, 51, 53, 58, 76, 77, 86
15
Organization of Materials
4, 29, 67, 68, 69, 72, 74, 75
8
Monitor
14, 21, 31, 34, 42, 52, 60, 63
8
Total No. of Items
86
Validity scales
Scoring Instructions for Validity Scales
Inconsistency
(7,25), (11, 22), (27, 17), (33, 32), (38, 59), (41, 65), (42, 63), (44, 54), (53, 60), (55, 44)
For each item in a pair, obtain the score for each
item, and subtract the scores, keeping the
absolute difference. Sum the 10 absolute
differences to get the Inconsistency score.
Classification[1]:
0-6: Acceptable
7-8: Questionable
PUBLIC COPY 
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≥9: Inconsistent
Negativity
8, 13, 23, 30, 62, 71, 80, 83, 85
Count how many of the 9 items in the scale have a
score of 3. That is the negativity score.
Classification[1]:
0-4 Acceptable
5-6 Elevated
≥7 Highly Elevated
To calculate the Behavioral Regulation Index (BRI) raw score, sum the scale raw scores obtained for Inhibit, Shift, and Emotional Control scales.
To calculate the Metacognition Index (Ml) raw score, sum the raw scale scores obtained for Initiate, Working Memory, Plan/Organize, Organization of Materials, and Monitor scales.
To calculate the Global Executive Composite (GEC) raw score, sum the raw scores for BRI and MI.
Missing data handling (For items 1-72 only; items 73-86 are additional clinical items)
1.
If the total number of unanswered items is >14, do not compute any of the (eight) scale raw scores (INH, S, EC, INI, WM, PO, OM, m) for the BRIEF, as per the authors, the “protocol should be
considered invalid”. In that case, all the scale raw scores will be missing, and the index scores will be missing as well.
2.
If more than 2 (of the first 72) items have missing responses for a Scale (any of the 8 listed above), then a scale raw score should not be calculated. However, for any scale with 2 or fewer missing
responses, impute a score of “1” for the missing item.
3.
IMPORTANT: When calculating index scores, please first obtain the scale raw scores, and then the index scores are derived from the scale raw scores. Do not simply add up the scores for the
individual questions.
References:
[1] Gioia GA, Espy KA, Isquith PK. BRIEF-P: Behavior Rating Inventory of Executive Function-Preschool Version. Professional Manual. 2003 Edition. Pages 15-16, Tables 2 and 4.
[2] Gioia GA, Espy KA, Isquith PK. BRIEF-P: Behavior Rating Inventory of Executive Function-Preschool Version. Professional Manual. 2003 Edition. Page 7.”Missing Responses”.
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Programming Notes: Use the sheel for 14.4.6.1 for the following tables.
Table 14.4.6.3
Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) – Scoring summary table
Safety Population (De Novo Subjects)
Table 14.4.6.3.1
Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) – Scoring summary table
Safety Population (De Novo Subjects) (Japan)
Scales are:
Inhibit
Shift
Emotional Control (EC)
Self Monitor
Initiate
Working Memory (WM)
Plan/Organize (PO)
Organization of Materials (OM)
For Indexes Part, where we use the 90% CI for the EOS/ET measurement, the following are used, along with relevant footnotes;
Behavioral Regulation Index (BRI)[1]
Metacognition Index (MI)[2]
Global Executive Composite (GEC) [3]
For the following line, include [4] as footnote
90% CI for change from BL[4]
[1] Computed as the sum of the scale raw scores obtained for Inhibit, Shift, Emotional Control, and Self Monitor.
[2] Computed as the sum of the raw scale scores obtained for Initiate, Working Memory, Plan/Organize, Organization of Materials, and 
Monitor.
[3] Computed as the sum of the raw scale scores for BRI and MI.
[4] Confidence interval of the mean change from baseline based on the t distribution.
PUBLIC COPY 
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Scales of the BRIEF-A
Scale
No. of items
Items
Scoring Instructions (for each individual)*
Inhibit
8
5, 16, 29, 36, 43, 55, 58, 73
Add up scores for items on the scale
Shift
6
8, 22, 32, 44, 61, 67
Add up scores for items on the scale
Emotional
Control
10
1, 12, 19, 28, 33, 42, 51, 57, 69, 72
Add up scores for items on the scale
Self-Monitor
6
13, 23, 37, 50, 64, 70,
Add up scores for items on the scale
Initiate
8
6, 14, 20, 25, 45, 49, 53, 62
Add up scores for items on the scale
Working
Memory
8
4, 11, 17, 26, 35, 46, 56, 68
Add up scores for items on the scale
Plan/Organize
10
9, 15, 21, 34, 39, 47, 54, 63, 66, 71
Add up scores for items on the scale
Task Monitor
6
2, 18, 24, 41, 52, 75
Add up scores for items on the scale
Organization of
Materials
8
3, 7, 30, 31, 40, 60, 65, 74
Add up scores for items on the scale
Validity scales
Infrequency
10, 27, 38, 48, 59
Number of question responses where:(Question 10 = 3),
(Question 27 = 1), (Question 38 = 3), (Question 48 = 1),
Question 59 = 1)
Number of questions meeting conditions: 0-2 is Acceptable.
>= 3 is Infrequent.
Inconsistency
10 pairs
(2, 41), (25, 49), (28, 42), (33, 72), (34, 63), (44, 61), (46, 56), (51, 75), (60,
74), (64, 70).
For each item in a pair, obtain the score for each item, and
subtract the scores, keeping the absolute difference. Sum the 10
absolute differences to get the Inconsistency score.
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Classification[1]:
0-7: Acceptable
≥8: Inconsistent
Negativity
10
1, 8, 19, 21, 22, 23, 29, 36, 39, 40
Count the number of items with a score of 3. That is the
negativity score.
Classification[1]:
0-5 Acceptable
≥6 Elevated
2. *Missing data handling for the BRIEF-A
1. If the total number of unanswered items is >= 1 in the Shift, Self-Monitor, and Task Monitor, the raw domain score is invalidated and won’t be calculated.
2. If the total number of unanswered items is >= 2 in the Inhibit, Emotional Control, Initiate, Working Memory, Plan/Organize, and Organization of Materials, the raw domain score is invalidated and
won’t be calculated. However, for any scale with 1 missing responses, impute a score of “1” for the missing item.
3. IMPORTANT: When calculating index scores, please first obtain the scale raw scores, and then the index scores are derived from the scale raw scores. Do not simply add up the scores for the individual
questions.
PUBLIC COPY 
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LISTINGS
All listing displays for this open-label study are to be done by country and study site. Then by subject number.
Programming Note: May keep the by Treatment group, but treatment group = ZX008 OL for all subjects in this open-label study.
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
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Listing 16.2.1.1
Subject completion/discontinuation
Subject
Identifier
Country
Site/
Investigator
Withdrawal/
Completion
Date/Day#
Completed
as Scheduled
Reason for Premature Discontinuation*
XXXX
TEXT
XXX/TEXT
DDMMMYYYY/XX
Yes/No
Adverse Event/Serious Adverse Event
Death
Investigator Decision
Lack of Efficacy
Lost to follow-up
Protocol Violation
Sponsor Decision
Voluntary Withdrawal
Inclusion/Exclusion Criteria not met
Other reason: TEXT
# Relative to first dose of study treatment.
* If more than one reason is given for premature discontinuation, the first reason listed is the primary reason.
Note to Programmers: Please put the primary reason first in the list. Use the same shell for
Listing 16.2.1.2
Subject completion/discontinuation (Japan)
PUBLIC COPY 
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Treatment group: xxx
Subject
Identifier
Country
Listing 16.2.2.1
Major Protocol Deviations
Site/
Investigator
Type
Major Protocol Deviation
XXXX
Inclusion/Exclusion
Compliance <80% or >120%
TEXT
TEXT
TEXT*
XXXX
TEXT
XXXX
.
.
.
Programming Note: Please put the primary reason first in the list. Use the same shell for
Listing 16.2.2.2
Major Protocol Deviations (Japan)
PUBLIC COPY 
U
se
P
se the
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the
thorization 
national
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Listing 16.2.3.1
Subjects Excluded from Analysis Populations
Subject Identifier
Deviation/Reason
Analysis Population(s) Excluded from
XXXX
TEXT
XXXX
XXXX
.
.
.
Programming note: For inclusion/exclusion criteria not met use the wording of the criteria not met from the CRF.
Use the 16.2.3.1 shell for:
Listing 16.2.3.1.1
Subjects Excluded from Analysis Populations (Japan)
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Treatment group: xxx
Country: xxxx
Listing 16.2.3.2
Subject allocation to trial Populations
Subject Identifier
Site
Core Study
Enrolled population
Safety Population
mITT Population
XXXXX
VS01, VS02, 1504-C1,
1504-C2
Yes
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.
.
mITT = Modified Intent-to-Treat.
Note: Blank core study indicates de novo subject.
Programming note: Use the 16.2.3.2 shell for:
Listing 16.2.3.2.1
Subject allocation to trial Populations (Japan)
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pp
up
su
o s
uth
or variations thereof. 
fety
t
fety Populatio
th
Populatio
er
t
Yes/No
ons
Yes/No
ns
io
tioioioio
ia
ar
va
r
ions o
s
on
application and any extensio
a
io
Subject
y e
Subject al
e
al


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Listing 16.2.4.1.1
Demographic Data
Date of
Baseline
Baseline
Baseline
Subject
Visit 1
Informed Consent/Assent
Date of
Age*
Weight*
Height*
BMI*
Identifier
Country
Date
Parent
Child
Birth
(years)
Sex
Race
Ethnic Group
(kg)
(m)
(kg/m2)
XXXX
TEXT
DDMMMYYYY
DDMMMYYYY
DDMMMYYYY
DDMMMYYYY
XX
Male
Female
Caucasian
Black/African
American
Asian
Pacific Islander
Etc.
Latino
NonLatino
XXX
XXX
XX.X
XXXX
XXXX
.
.
.
* Age at Visit 1.
Programming note: Informed consent/assent date should be the initial consent obtained at Visit 1 of 1503 (or Visit 13 of the core study)
Use the shell for 16.2.4.1.1 for
Listing 16.2.4.1.1.1
Demographic Data (Japan)
PUBLIC COPY 
MYYYY
PY
MYYYY
Y
C C
Y
LIC
BL
UB
PU
PU
P
thorization 
national
zat
national L
03
03
to support any marketing auth
tin
rk
rk
rk
rk
ark
ex
m
ex
R
a
m
y
Male
y 
Male
Fe
y
Fe
y
ort
ny
up
su
o
This document cannot be used to s
do
TIAL
s d
TIAL
be
o s
o
to
d
e
us
e u
uld
n
uld be
no
be the
o
the inin
uth
nsions or variations thereof. 
er
he
s t
ace
o
ace
ns
on
male
ari
male
Cauca
at
Cauca
Bla
a
Bla
ati
or
ia
s
on
on
on
on
on
application and any extensio
a
ny
io
ns
en
xte
ex
ex
ex
ex
y ex
e
itial
nd
itial consent
nd
consent


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Treatment group: xxx
Listing 16.2.4.1.2
% Change from baseline in weight and BMI
Weight
BMI
Subject
Identifier
Visit
Date/Day
Result
(kg)
Base
Flag
Change
from
Baseline
% change
from
Baseline *
Result
(kg/m2)
Base
Flag
Change
from
Baseline
% change
from
Baseline *
1501-0101-02
Visit 1 - Day 1
ddmonyyyy/hh:mm
45.9
Y
17.17
Y
Visit 3 - Month 1 (Clinic)
ddmonyyyy/hh:mm
45
-0.9
-1.96
16.77
-0.4
-2.33
Visit 4 - Month 2 (Clinic)
ddmonyyyy/hh:mm
44.59
-1.31
-2.85
16.77
-0.4
-2.33
….
Visit 12 - Month 24 (Clinic)
45
-0.9
-1.96 *
16.85
-0.32
-1.86
……
BMI = Body mass index; * Indicates a decrease from baseline in weight or BMI >= 7%.
Programming note: Use the shell for 16.2.4.1.2 for
Listing 16.2.4.1.2.1
% Change from baseline in weight and BMI (Japan)
PUBLIC COPY 
P
Y
PY
Y
45
C
45
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
ed
ine
m
ine
%
rk
% change
ark
change
from
ar
from
Bas
a
Bas
ke
m
-
n
-0.9
ny
0.9
-1
MI
MI >=
ed
>= 7%.
ed
7%.
tin
uth
application and any extensions or variations thereof. 
a
te
eline
on
eline *
on
*
th
ion
-
ria
-1.96
ria
1.96
.31
v
.31
-2
r
2
-
o
-0.9
o
0.9
%
a
% Ch
Ch
ere


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Treatment group: xxx
Listing 16.2.4.2
Medical History
Subject Identifier
Previous or Concurrent Medical History Term/
Medical Condition/Surgical Procedure
Onset
Date/Day#
Stop
Date/Day#
Ongoing at
Screening
XXXX
TEXT
DDMMMYYYY/XX
Ongoing
DDMMMYYYY/XX
DDMMMYYYY/XX
Stopped
XXXX
TEXT
XXXX
.
.
.
# Relative to first dose of study treatment.
PUBLIC COPY 
UB
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
o s
Stop
e
Stop
MYYYY/XX
y m
MYYYY/XX
MMMYYYY/XX
ny 
MMMYYYY/XX
a
tin
uth
application and any extensions or variations thereof. 
a
io
p
Date/Day#
ns t
Date/Day#
DD
DD
ns
er


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Treatment group: xxx
Listing 16.2.4.3
Prior and concomitant medications and therapies/treatments
Subject
Identifier
Medication/
ATC Classification [1]
Dose
Unit
Route
Frequency*
Indication
Start
Date/Day#
Stop
Date/Day#
XXXX
TEXT
TEXT
XXXX
TEXT
B1M1
TEXT
DDMMMYYYY/XX
DDMMMYYYY/XX
& TEXT
BID
Ongoing
PRN
Q4H
Q6H
Q12H
Q24H
QID
QM
# Relative to first dose of study treatment.
* B1M1 = Twice per month, BID = Twice per day, PRN = As needed, Q4H = Every four hours, Q6H = Every Six hours, Q12H = Every Twelve hours, Q24H = Every Twenty-four hours, QID = Four times a day, QM
= Every Month.
& Prior medication.
[1] WHO Drug Dictionary (latest version).
Programming note: Use the shell for 16.2.4.3 for
Listing 16.2.4.3.1
Prior and concomitant medications and therapies/treatments (Japan)
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
be
y*
k
y*
Ind
Ind
tin
M1
m
M1
rk
BID
m
BID
PRN
y 
PRN
Q4H
ny
Q4H
Q
s needed,
ot 
needed, Q4
Q4
4.3
t
4.3 for
t c
for
t c
uth
application and any extensions or variations thereof. 
a
ny
ication
th
ication
er
er
er
TEXT
ns
TEXT
t
Q6H
a
Q6H
Q12H
va
Q12H
Q24H
or v
Q24H
QID
o
QID
4H
d
4H =
d
= Every
d a
Every fo
a
fo


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Listing 16.2.4.4.1
Prior antiepileptic Drugs (AEDs)
Subject
Identifier
Medication
/ATC Classification [1]
Type of
treatment
Route
Dose
Frequency*
Start
Date/Day#
Stop
Date/Day#
XXXX
TEXT
Non-medication
TEXT
TEXT
B1M1
BID
PRN
Q4H
Q6H
Q12H
Q24H
QID
QM
DDMMMYYYY/XX
DDMMMYYYY/XX
Ongoing
& TEXT
Risk medication
* B1M1 = Twice per month, BID = Twice per day, PRN = As needed, Q4H = Every four hours, Q6H = Every Six hours, Q12H = Every Twelve hours, Q24H = Every Twenty-four hours, QID = Four times a day, QM
= Every Month. Qd or QD=Daily, or Everyday, or once a day.
# Relative to first dose of study treatment.
& Prior medication.
[1] WHO Drug Dictionary
Programming note: Use the shell for 16.2.4.4.1 for the following listings.
Listing 16.2.4.4.2
Concomitant antiepileptic Drugs (AEDs)
PUBLIC COPY 
ion
B
ion
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
b
TEXT
ar
TEXT
eeded,
t b
eeded, Q4H
b
Q4H
day.
no
day.
6.2.4.4.1
nt
6.2.4.4.1 for
t
for
ke ng
uth
application and any extensions or variations thereof. 
a
an
Frequency*
the
Frequency*
B1M
B1M
= Every
d an
Every four
an
four
the
at
the followin
atio
followin
th re


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Listing 16.2.4.4.3
Prior antiepileptic Drugs (AEDs) (Japan)
Liisting 16.2.4.4
Concomitant antiepileptic Drugs (AEDs) (Japan)
Listing 16.2.4.5
Rescue medications
Liisting 16.2.4.5.1
Rescue medications (Japan)
PY 
ng
Y
ng 16.2
Y
16.2
PUBLIC COPY
e
P
e medicatio
PY
medicatio
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
s (Japan)
any
(Japan)
uth
application and any extensions or variations thereof. 
a


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Country:
Listing 16.2.5.1
IMP Intake per day during Treatment
Subject Identifier
Date+Time
Study Day#
Epoch
Dose Taken? (None/Partial/Full)
XXXX
XXXX
.
.
.
# Relative to first dose of study treatment.
[1] Study date and time is the time the dose was entered into diary
[2] Study medication was administered twice daily, and compliance was recorded each time in the eDiary as full, partial or none.
Programming note: Use the shell for 16.2.5.1 for
Listing 16.2.5.1.1
IMP Intake per day during Treatment (Japan)
COPY 
Y
PY
OP
CO
PUBLIC C
C
orded
BL
orded eac
BL
eac
thorization 
national
zat
national L
03
03
ort any marketing auth
Dose
rke
Dose Ta
e
Ta
ng
rk
rk
rk
rk
ark
a
m
y
ny
a
rt
This document cannot be used to suppo
do
TIAL
s d
TIAL
o
pp
me
s
me in
s
in the
su
the e
u
e
IM
IM
uth
r variations thereof. 
ken?
th
ken? (None/
th
(None/
re
s t
ns
on
t
at
at
ati
at
ia
ar
va
application and any extensions or 
a
or
o
Diary
io
Diary as
on
as full,
n
full,
MP
MP Intake
ex
Intake pe
x
pe


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Treatment group: xxx
Subject Identifier: <subject no.> Age: < >  Sex:<x>
Listing 16.2.5.2
IMP Intake – self reported % compliance
Study Week
Day1
Day2
Day3
Day4
Day5
Day6
Day7
Compliance %
1
2
3
4
Month1
Xxx.xx%
5
6
7
8
Month2
xxx.x%
…
…..
Note: Study medication was administered twice daily, and compliance was recorded each time in the eDiary as full, partial or none. (See Listing 16.2.5.1) From this, compliance was calculated by assuming
that a missed dose=0% of dose consumed, partial=50%, full=100%.
Programming Note: from daily diary record.
Programming note: Use the shell for 16.2.5.2 for
Listing 16.2.5.2.1
IMP Intake – self reported % compliance (Japan)
C COPY 
Y
PY
OP
CO
C
PUBLIC 
C
LIC
LIC
LIC
LIC
LIC
BL
UB
PU
P
thorization 
national
zat
national L
03
03
upport any marketing auth
Day6
rke
Day6
ke
rk
a
m
y
ny
a
rt
o
po
sed to supp
pp
up
su
o
d to
d
ed
e used
se
us
This document cannot be 
do
TIAL
s d
TIAL
e
ompliance
t be
ompliance w
ull=100%.
ot 
ull=100%.
or
c
or
uth
or variations thereof. 
D
th
s t
ns
on
ati
iaiaia
ria
ar
va
or
xtensions o
ns
on
io
sioioio
ns
ten
application and any ext
a
xt
ex
y
s recorded e
any
recorded e


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Listing 16.2.5.3
Drug Accountability and Compliance to Study Treatment by Visit
Treatment group: xxx
Subject Identifier
Visit
Bottle
Number
Amount
Of volume
Dispensed
Date/Day#
Dispensed
Amount of Volume Returned
Date/Day#
Returned
XXXX
V1, etc.
XXXXXX
XXXXXX
NA
XXX
XXX
TEXT
NA
DDMMMYYYY/XX
DDMMMYYYY/XX
NA
NA
DDMMMYYYY/XX
XXXX
XXXX
.
.
.
# Relative to first dose of study treatment.
Programming Notes: Use 28 days, keep in ADEC. Use the shell for 16.2.5.3 for
Listing 16.2.5.3.1
Drug Accountability and Compliance to Study Treatment by Visit (Japan)
PUBLIC COPY 
MMMY
Y
MMMY
DDMMMY
PY
DDMMMY
NA
OP
NA
Y
CO
CO
CO
CO
CO
C C
IC
BL
UB
PU
P
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
s
Am
Am
ket
ark
ma
X
n
X
Y/XX
an
Y/XX
y m
or
po
pp
su
su
su
sup
su
s
to
d
ed
ell
t
ell for
t b
for 16.2.5
b
16.2.5
uth
application and any extensions or variations thereof. 
a
ex
mount
n
mount of
ns
of Volu
s
Volu
he
on
NA
atio
NA
DDM
a
DDM
tio
ria
r v
or
s
ns
io
s
en
te
te
te
te
.3.3 for
a
for
Drug
nd
Drug Acco
d
Acco


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Listing 16.2.6.1
Convulsive seizure – duration and number of occurrences per subject (Diary data)
Randomized Treatment: XXX
Subject
Identifier
Period
Seizure
Date/Study Day**
Time of Seizure
Single/
Cluster/Discrete
Type of
convulsive seizure
Duration of
seizure
Approximate
duration of
cluster
Number of seizures
XXXX
<Baseline(Core)>
Yyyy-mm-dd
<Single, or Cluster>
Type 1
<2 min
1
<Core Study(T+M)>
Yyyy-mm-dd
Type 2
2-10 min
2
<OLE Treatment>
Yyyy-mm-dd
Type 3
>10min
3*
…
4
…
XXXX
XXXX
.
.
.
*Note: Clusters of seizures could be recorded by duration, by number of seizures, or both. When reported by duration only, the number of seizures was set equal to 3 for analysis.
**With reference to start of OLE Study
Programming note: Present the subject identifier (grayed out) on all lines after the first line for a subject.
Convulsive seizures:
A: HEMICLONIC (Note lateralization: R body, L body, or independent R and L)
B1: FOCAL WITH CLEAR OBSERVABLE MOTOR SIGNS (i.e. automatisms,dystonic posturing, focal tonic stiffening)
C: SECONDARILY GENERALIZED TONIC CLONIC (evolving to bilateral convulsive seizure from focal seizure)
D: GENERALIZED TONIC CLONIC CONVULSION
G: TONIC
I: CLONIC (Note bilateral: symmetric R and L)
J: TONIC/ATONIC (cannot differentiate) - ‘drop attacks’ should be placed here
PUBLIC COPY 
ngle,
PY
ngle, or
Y
or
Y
CO
CO
CO
C
C C
LIC
BL
UB
PU
PU
PU
PU
PU
P
thorization 
national
zat
national L
03
03
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do
TIAL
s d
TIAL
data)
g
data)
Type
a
Type of
ark
of
convulsiv
ma
convulsiv
ke
m
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er>
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ot
on all
t 
all l
ody,
ca
ody, or
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or indep
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ca
SIGNS (i.e.
ONIC
t
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t c
(evolvi
ULSION
ent
ULSION
etric
m
etric R
m
R and
me
and L)
e
L)
erentiate)
um
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m
-
uth
n and any extensions or variations thereof. 
e
o
e seizure
ons
seizure
Dur
t
Dur
th
s t
on
ype
ia
ype 1
iat
1
tio
Type
aria
Type 2
ria
2
Type
var
Type 3
r
3
v
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o
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on
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te
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or both.
y 
both.
nes
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after the
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pendent
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a
R an
a
an
application
a
automatisms
on 
automatisms
ng to bilater
tion
ng to bilater
drop
pl
drop attacks
pli
attacks


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Use the shell fo 16.2.6.1 for
Listing 16.2.6.1.1
Convulsive seizure – duration and number of occurrences per subject (Diary data) (Japan)
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
y
t
y data)
ting
data) (Japa
ng
(Japa
uth
application and any extensions or variations thereof. 
a
n)
e
n)


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Listing 16.2.6.2
Non-Convulsive seizure – by type, duration and number of occurrences per subject (Diary data)
Treatment group: XXX
Subject
Identifier
Period
Seizure Date/Study
Day**
Single/ Cluster
Type of non-
convulsive seizure
Duration of seizure
Approximate
duration of cluster
Number of
seizures
XXXX
Baseline(Core)
Yyyy-mm-dd
<Single, or Cluster>
Type 1
<2 min
1
Core Study(T+M)
Yyyy-mm-dd
Single, or Cluster>
Type 2
2-10 min
2
OLE Treatment
Yyyy-mm-dd
Single, or Cluster>
Type 3
>10min
3*
…
4
…
XXXX
XXXX
.
.
.
*Imputed – the number of seizures in the cluster was not stated. It was imputed as 3.
**With reference to start of OLE Study.
Programming note: Present the subject identifier (grayed out) on all lines after the first line for a subject.
Non-convulsive Seizures:
B2: FOCAL WITHOUT CLEAR OBSERVABLE MOTOR SIGNS (i.e. autonomicchanges like color change or pupillary dilation, and no motor signs)
E: ABSENCE OR ATYPICAL ABSENCE
F: MYOCLONIC
H: ATONIC – not resulting in a drop
K: INFANTILE SPASMS (if under 3 years of age)
L: EPILEPTIC SPASMS (if 3 years of age and older)
PUBLIC COPY 
r>
P
r>
C
C
LIC
BL
UB
UB
UB
UB
UB
PU
P
thorization 
national
zat
national L
03
03
to support any marketing auth
Diary
g a
Diary data)
g a
data)
-
ve
a
ve seizure
ark
seizure
ke
a
Type
y
Type 1
y m
1
m
Type
ny
Type 2
y 
2
n
Type
any
Type
n
an
…
a
…
a
or
p
up
su
o s
This document cannot be used to
do
TIAL
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TIAL
to
d
e
use
s
as
as imputed
us
imputed
out)
ot
out) on
ot
on all
t b
all lin
b
lin
TOR
c
TOR SIGNS
ca
SIGNS (
years
m
years of
me
of age)
e
age)
s of
u
of age
um
age and
m
and
uth
nsions or variations thereof. 
Duration
s t
Duration
th
ns
ns
ns
ns
<
on
3
r v
o
s o
s
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io
application and any extens
a
ns
en
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es
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es after
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after the
a
the
.e.
o
.e. autonom
on 
autonom
older)
pli
older)


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M: NON CONVULSIVE STATUS (greater than 30 min)
O: OTHER
Programming Note: Use the 16.2.6.2 shell for
Listing 16.2.6.2.1
Non-Convulsive seizure – by type, duration and number of occurrences per subject (Diary data) (Japan)
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
ect
et
ect (Diary
etin
(Diary da
n
da
uth
application and any extensions or variations thereof. 
a
ta)
h
ta) (Japan)
her
(Japan)


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Listing 16.2.6.3
Duration of the Longest interval between convulsive seizures and convulsive seizure free days per subject
Treatment group: XXX
Subject
Identifier
Period
Number of Days with a Seizure
Occurrence
Longest interval between convulsive
seizures
Convulsive seizure free days
XXXX
Baseline(Core)
Core Study(T+M)
OLE Treatment
Xxx
Xxx
xxx
xx
Xxx
xxx
XX
Xxx
xxx
XXXX
XXXX
.
.
.
Programming Note: Present the subject identifier (grayed out) on all lines after the first line for a subject. Use the 16.2.6.3 shell for
Listing 16.2.6.3.1
Duration of the Longest interval between convulsive seizures and convulsive seizure free days per subject (Japan)
PUBLIC COPY 
OP
CO
C
C
LIC
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UB
PU
PU
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03
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do
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s d
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days
g a
days per
g a
per sub
a
sub
nterval
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nterval betw
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Xxx
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se
after the
se
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ot
the Longest
ot b
Longest
uth
application and any extensions or variations thereof. 
a
ject
of
ject
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t
een convulsiv
th
convulsiv
th
ns
on
ar
va
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s
on
sio
ns
en
rst
e
rst line
ext
line for
xt
for a
interval
d a
interval betw
a
betw


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Listing 16.2.6.4
Percent reduction in convulsive seizure frequency from baseline
Treatment group: XXX
Subject ID
mITT Population?
Period
CSF per 28 Days
% Change from
Baseline(Core)
>=25%? (Y/N)
>=50%? (Y/N)
>=75% (Y/N)
=100%? (Y/N)
XXXX
Y
Baseline (Core)
xxx.x
Core Study (T+M)
xxx.x
xxx.x
Y
N
Y
N
Month1-EOT
xxx.x
xxx.x
Y
Y
N
N
Month2-EOT
xxx.x
xxx.x
Y
N
N
N
XXXX
Y
Baseline (Core)
xxx.x
Core Study (T+M)
xxx.x
xxx.x
Y
Y
Y
N
Month1-EOT
xxx.x
xxx.x
Y
Y
Y
N
Month2-EOT
xxx.x
xxx.x
Y
Y
Y
N
XXXX
Y
Baseline (Core)
xxx.x
Core Study (T+M)
xxx.x
xxx.x
Y
Y
Y
N
Month1-EOT
xxx.x
xxx.x
Y
Y
Y
N
XXXX
Y
Month2-EOT
xxx.x
xxx.x
Y
Y
Y
Y
Programming Note: Present the subject identifier (grayed out) on all lines after the first line for a subject.
Use the 16.2.6.4 shell for
Listing 16.2.6.4.1
Percent reduction in convulsive seizure frequency from baseline (Japan)
PUBLIC COPY 
Y
PY
PY
PY 
PY
PY
PY
PY
PY
x
C
x
OP
xx.x
C
xx.x
CO
xxx.x
C C
xxx.x
C
C
xx
C
xx
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LI
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UB
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PU
OT
UB
UB
UB
UB
PU
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>=25%
rke
>=25%
ket
ar
a
ma
x
y
x
m
xx.x
ny
xx.x
y
ny
an
xxx.
a
xxx.
t a
x
rt
o
p
pp
x
pp
pp
pp
pp
xx.x
s
xx.x
sup
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to
xxx.x
to
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ed
se
se
se
se
) on
b
on all
be
all lines
e
lines
uth
tensions or variations thereof. 
? (Y/N)
s th
(Y/N)
he
he
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Y
ns
Y
o
Y
ion
Y
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x.x
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xx
ns
on
sisisisio
si
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en
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a
xte
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after
n
after the
ny
the firs
y
firs
Percent
nd
Percent re
re


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Listing 16.2.6.5
Clinical Global Impression – Improvement rating as assessed by the Parent/Caregiver and Investigator
Subject
Identifier
Age/sex
Assessment Date
Clinic Visit
Analysis Visit
CGI score by parent/caregiver
CGI score by Investigator
XXXX
Visit 1,
Visit 3,
Visit 4,
Visit 5,
Visit 6,
Visit 7,
Visit 8,
….
Very much improved
Much improved
Minimally improved
No change
Minimally worse
Much worse
Very much worse
Very much improved
Much improved
Minimally improved
No change
Minimally worse
Much worse
Very much worse
Visit 12
XXXX
…
…
…
XXXX
.
.
.
Note: CGI = Clinical Global Impression
Programming note: Present the subject identifier (grayed out) on all lines after the first line for a subject. Use the shell for 16.2.6.5 for
Listing 16.2.6.5.1
Clinical Global Impression – Improvement rating as assessed by the Parent/Caregiver and Investigator (Japan)
PUBLIC COPY 
5,
PY
5,
sit
P
sit 6,
OPY
6,
Visit
OP
Visit 7,
OP
7,
Visit
CO
Visit
C
C
LIC
BL
UB
PU
P
thorization 
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03
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do
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s d
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be
d Investigat
g a
Investigat
parent/care
keti
parent/care
ng
ke
much
ar
much impro
ark
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uch
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uch improve
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Minimally
No
ny
No cha
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ny
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uth
application and any extensions or variations thereof. 
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th
ved
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nimally
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worse
Very
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es after
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bal
n
bal Impressi
n a
Impressi


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Treatment group: ZX008 OL
Listing 16.2.6.6
Quality of life in Childhood Epilepsy Scale
Subject
Identifier
Age/Sex
Visit
Response
(Raw Score)
Transformed
Score
XXXX
Baseline
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
PUBLIC COPY 
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
n
an
ca
t
en
me
um
um
um
um
cum
u
uth
nnot be used to support any marketin
plication and any extensions or variations thereof. 
t
at
ica
ppli
pli
app
app
ation and any extensions or variations ther


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Draft 3.0: 04Aug2020
XXXXX
XXXXX
XXXXX
XXXXX
XXXX
PARCAT1=’QOLCE’
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
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ut
used to support any marketing aut
application and any extensions or variations thereof
a
extensions or variations thereof. 


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Listing 16.2.6.7
Quality of life of the Parent/Caregiver using EQ-5D-5L scale
Subject
Identifier
Age/Sex
Visit
Assessment
Date/Day #
Was the assessment
done
Response
XXXX
Baseline
End of study visit
DDMMMYYYY/XX
Yes
No
XXXXXX
XXXXXX
XXXXXX
XXXXXX
XXXXXX
XX
XXXX
…
…
…
XXXX
.
.
.
PUBLIC COPY 
ting authorization 
uth
national
zat
national L
03
03
tin
This document cannot be used to support a
do
TIAL
s d
TIAL
ot
…
t
…
any marketi
thereof. 
her
application and any extensions o
a
d a
s or variations th


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Listing 16.2.6.8
Quality of life of the Parent/Caregiver using HADS scale
Subject
Identifier
Visit [1]
Was the assessment done
Response
XXXX
Baseline Visit 1
XXXXX
XXXXX
XXXXX
Visit 3
XXXXX
XXXXX
Visit 4
XXXXX
XXXXX
XXXXX
Visit 5
XXXXX
XXXXX
XXXXX
---
XXXXX
XXXXX
XXXXX
Visit 12
XXXXX
XXXXX
XXXX
…
…
XXXX
[1] repeated for Visit 1 and each clinical visit from Visit 3 through Visit 16
Programming note:  This table for ZX008 – 1501 and ZX008-1502 subjects only. Do not include ZX008-1504 Cohort 2
PUBLIC COPY 
ing authorization 
national
zat
national L
03
03
g
uth
This documen
do
TIAL
s d
TIAL
…
a
…
nical
me
nical visit
men
visit fro
n
fro
for
m
for ZX008
me
ZX008 –
en
ent cannot be use
sed to support any marketing
thereof. 
th re
applicat
a
m Visit
ca
Visit 3
a
3 thro
a
thro
1501
pli
1501 and
plic
and ZX
c
ZX
at
ation and an
any extensions or variations th


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Treatment Group: ZX008 OL
Listing 16.2.6.9.1
Pediatric Quality of Life Inventory (Peds QL)- for TODDLERS (age 2-4 years)
Subject
Identifier
Visit [1]
Response
XXXX
Baseline
AVALC
XXXXX
Visit 1
XXXXX
XXXXX
Visit 3
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
---
XXXXX
XXXXX
…
…
Visit 12
XXXX
…
…
XXXX
.
.
.
[1] Repeated for Visit 1 and Visit 3 through Visit 16
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
national
zat
national L
03
03
do
TIAL
s d
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)
g
)
Visit
cu
Visit 3
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um
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application and any extensions or variations thereof. 
a
gh
p
gh Visit
ppl
Visit 16
pl
16
pli
nd any extensions or variations ther


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Programming Notes: Use Listing shell 16.2.6.9 for below listings:
Listing 16.2.6.9.2
Pediatric Quality of Life Inventory (Peds QL) - for Young Children (age 5-7 years)
Listing 16.2.6.9.3
Pediatric Quality of Life Inventory (Peds QL) - for Children (age 8-12 years)
Listing 16.2.6.9.4
Pediatric Quality of Life Inventory (Peds QL) - for TEENS (age 13-18 years)
Listing 16.2.6.9.5
Pediatric Quality of Life Inventory (Peds QL) – Family Impact Module
PUBLIC COPY 
ng
Y
ng 16.2
Y
16.2
ntory
PY
ntory (Ped
PY
(Ped
Listi
CO
Listi
y
C
y of
C C
of Life
C C
Life In
C
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thorization 
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03
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do
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s d
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(age
ket
(age 5
eti
5-
et
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eti
7 year
ti
year
ldren
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ldren (age
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QL)
a
QL) -
a
- for
any
for TEEN
ny
TEEN
g 16.2.6.9.5
ort 
16.2.6.9.5
ntory
po
ntory (Peds
por
(Peds Q
uth
application and any extensions or variations thereof. 
a
rs)
h
rs)
12
o
12 years)
ons
years)
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ria
(age 13
ia
13-
a
-18
a
18
QL)
o
QL) –
or
– Family
or 
Family


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Treatment Group: ZX008 OL
Listing 16.2.6.10
Study Medication Palatability Assessment
Subject
Identifier
Age/Sex
Visit
Was the assessment
done
Question
Response
XXXX
Visit 3
Yes
No
1 – Over the past month, on the basis of the reaction ⁄ facial expression of your child, do
you think that the medicine’s taste and texture are acceptable/not acceptable to your
child?
XXXXXX
2 – Over the past month, please rate [1]how much your child likes/dislikes the medicine’s
taste
XXXXXX
3 - Over the past month, do you sometimes have problems giving the medicine to your
child due to its taste or texture?
XX
XXXX
…
…
XXXX
.
.
.
[1]Rating scale: 5=likes it very much; 4=likes it; 3=neither likes or dislikes it; 2=dislikes it; 1=dislikes it very much
PUBLIC COPY 
th
Y
th
Over
PY
Over the
PY
the
taste
OP
taste
PY
3
CO
3 -
CO
- Ov
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thorization 
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national L
03
03
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tin
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n
m
n the
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the basis
ma
basis
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1=


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Treatment Group: ZX008 OL
Listing 16.2.6.11
Sleep quality and mealtime behavior
Subject
Identifier
Age/Sex
Visit
Date of
Assessment /Day #
Sleep Quality Question Response
Mealtime Behavior Question Response
XXXX
xxx/x
Visit 3
DDMMMYYYY/XXX
More Disturbed
Same
Better
Worse Behavior
Not Changed
Improved Behavior
XXXX
…
XXXX
.
.
.
Note: This scale is collected only for subjects from core study ZX008-1504.
# Relative to first dose of study treatment.
UBLIC COPY 
PY
OP
CO
C
C
LIC
BL
BL
PUBL
BL
BL
BL
UB
PU
P
thorization 
national
zat
national L
03
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tin
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a
ny
a
rt
o
pp
up
This document cannot be used to su
do
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o
to
d 
sed
e
4.
u
4.
uth
ons or variations thereof. 
Mealtime
he
Mealtime B
er
s t
s
W
s
W
ns
ia
ar
va
r
o
s 
xtension
on
sio
ns
ten
application and any ext
a
xt


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Treatment Group: ZX008 OL
Listing 16.2.6.12
Karolinska sleepiness scale
Subject
Identifier
Age/Sex
Visit
Date of
Assessment /Day #
XXXX
xxx/x
Visit 3
DDMMMYYYY/XXX
XXXX
…
XXXX
.
.
.
Note: This scale is collected only for subjects from core study ZX008-1504.
# Relative to first dose of study treatment.
[1] Values 1 – 6 are categorized as Alert. Values 7 – 9 are categorized as sleepy.
PUBLIC
BL
BL
UB
PU
P BLIC COPY 
thorization 
national
zat
national L
03
03
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to
d
…
d
…
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ed
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any extensions or variations thereof. 
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ny
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application
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008
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008-
a
-1504.
an
1504.
categorized
on 
categorized
ns or variations ther


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Listing 16.2.7.1
Adverse Events
Adverse Event
Age/
(System Organ
Start
stop
Action
Other
Subject
Gender/
Class/
Date/
Date/
Related to study
Taken with Study
Action
Identifier
Race
Preferred Term)
Day#
Day#
Drug
Severity
treatment
Taken
Outcome
Serious
XXXX
Xx/
& TEXT (SOC/PT)
DDMMMYYYY DDMMMYYYY Yes
Mild
Dose not changed
None
Not resolved
Yes:
X/
/XX
x
/XX
No
Moderate
Severe
Dose Increased
Dose reduced
Drug Interrupted
Drug Withdrawal
NA
withdrawn
from study
Treated with
Medication
Other: TEXT
Resolved
Resolved
w/sequelae
Resolving
Unknown
Fatal
Death
Life-
Threatening
Hospitalization
Disability/Permanent Damage
Congenital Anomaly/Birth defect
Medically significant
No
XXXX
XXXX
.
.
.
# Relative to first dose of study treatment.
& Treatment-emergent adverse event.
NA = Not applicable
PUBLIC COPY 
Moderat
Y
Moderat
Severe
PY
Severe
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
nn
ng
Othe
ti
Othe
Study
rk
Study
A
e
A
nt
nt
a
ose
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ose not
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not chan
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chan
Dose
ny
Dose Incre
y 
Incre
Dose
any
Dose r
y
r
Dru
a
Dru
uth
ns thereof. 
re
ction
th
ction
Taken
s t
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ariations
ns
ged
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ged
Non
o
Non
ased
iat
ased
application and any extensions or var
a
an
duced
ria
duced
g
v
g Interrupte
var
Interrupte
Drug
r v
Drug Withdr
va
Withdr
NA
or
NA


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Programming note:
Use the shell for 16.2.7.1 for the following listings:
Listing 16.2.7.1.1 Adverse events (Japan)
Listing 16.2.7.2 Adverse events of special interests (AESI)
Listing 16.2.7.2.1 Adverse events of special interests (AESI) (Japan)
Note: Please record only Adverse event of special interest as per definition provided in Protocol
PUBLIC COPY 
thorization 
national
zat
national L
03
03
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do
TIAL
s d
TIAL
uth
application and any extensions or variations thereof. 
a


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Draft 3.0: 04Aug2020
Listing 16.2.8.1.1
Laboratory Data: Hematology parameters
Subject
Identifier
Visit
Sample Date/Day# and
Parameter
Value*
Reference
Range
Unit
XXXX
Screening (Visit 1)
DDMMMYYYY/XX
Haemoglobin
XX.X H
XX.X-XX.X
TEXT
Visit 2
ND: TEXT
Haematocrit
XX.X L
Visit 3
…
XX.X
Visit 4
…
Visit 5
Visit 6
…
Visit 12
XXXX
XXXX
.
.
.
ND = Not Done.
# Relative to first dose of study treatment.
* H = Above reference range, L = Below reference range
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
national
zat
national L
03
03
do
TIAL
s d
TIAL
be
ence
tin
ence
ange
ket
ange
ng
XX.X
ark
XX.X-XX
k
XX
ke
X
y
X
…
n
…
e
uth
application and any extensions or variations thereof. 
a
ny
re
.X
n
.X
th


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Page 218 of 234
Draft 3.0: 04Aug2020
Programming Notes: Use the shell for 16.2.8.1.1 for the following listings:
Listing 16.2.8.1.1.1
Laboratory Data: Hematology parameters (Japan)
Listing 16.2.8.2.1
Laboratory Data: Biochemistry parameters
Listing 16.2.8.2.1.1
Laboratory Data: Biochemistry parameters (Japan)
Listing 16.2.8.3
Laboratory Data: Coagulation parameters
Listing 16.2.8.3.1
Laboratory Data: Coagulation parameters (Japan)
Listing 16.2.8.4.1
Laboratory Data: Urinalysis parameters
Listing 16.2.8.4.1.1
Laboratory Data: Urinalysis parameters(Japan)
For Listing 16.2.8.4 and 16.2.8.4.1, Urinalysis – add column “Result” (as 5th column) with result “Normal” or “Abnormal”.
Listing 16.2.8.5
Tests of growth, precocious puberty and Thyroid Function
Listing 16.2.8.5.1
Tests of growth, precocious puberty and Thyroid Function (Japan)
PUBLIC COPY 
Listing
PY
Listing 16.
Y
16.
ry
O
ry Data:
OP
Data: Co
P
Co
L
C
L
oratory
IC
oratory Da
C 
Da
thorization 
national
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national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
meters
y m
meters (Japan
m
(Japan
8.3
a
8.3
gulation
t a
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a
para
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ting 16.2.8.3
po
16.2.8.3
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pp
Coagulatio
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aboratory
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a
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lumn)
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Programming Notes: Please use STLB11 from ISS but only include Baseline (OLE) through End of Study in OLE for the following listngs.
Listing 16.2.8.1.2
Most Abnormal Laboratory Parameters during Open-label Treatment Period - Hematology
Listing 16.2.8.1.2 .1
Most Abnormal Laboratory Parameters during Open-label Treatment Period - Hematology (Japan)
Programming Notes: Use shell for ISS STLB12 but only include Baseline (OLE) through End of Study in OLE for the following listings.
Listing 16.2.8.2.2
Most Abnormal Laboratory Parameters during Open-label Study Periods – Biochemistry
Listing 16.2.8.2.2.1
Most Abnormal Laboratory Parameters during Open-label Study Periods – Biochemistry (Japan)
Programming Notes: Please use shell for ISS Listing STLB13 but only include Baseline (OLE) through End of Study in OLE for the following listings.
Listing 16.2.8.4.2
Most Abnormal Laboratory Parameters during Open-label Study Periods -- Urinalysis
Listing 16.2.8.4.2.1
Most Abnormal Laboratory Parameters during Open-label Study Periods -- Urinalysis (Japan)
Use shell from 16.2.8.2.2 – add column “Result” (as 5th column) with result.
PUBLIC COPY 
dy
P
dy in
PY
in OLE
PY
OLE f
Y
f
L
C
L
atory
C
atory Param
C C
Param
aboratory
UBL
aboratory
clude
P
clude
thorization 
national
zat
national L
03
03
not be used to support any marketing auth
eriod
ket
eriod -
et
- Hema
ti
Hema
ment
m
ment Period
ma
Period
the
a
the followin
any
followin
ing
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ing 16.2.8.2.
por
16.2.8.2.
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during O
o
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sup
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rameters
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rameters du
u
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aseline (OLE
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Abnormal La
La
Most
ot
Most Abnorm
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This document cann
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TIAL
s d
TIAL
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nd any extensions or variations thereof. 
atology
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Hematology
ons
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ria
listings.
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o
2
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label St
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and
n) with result


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Listing 16.2.8.6
Urine Pregnancy Test
Subject Identifier
Was Pregnancy test performed
Date of Urine pregnancy test / (Visit)
Result
XXXX
NA(female of non-child bearing potential)
Not Done
Done
DDMMMYYYY/ Visit X
Negative
Positive
XXXX
XXXX
.
.
.
# Relative to first dose of study treatment.
PUBLIC COPY 
PU
thorization 
national
zat
national L
03
03
to support any marketing auth
ng
This document cannot be used to
do
TIAL
s d
TIAL
d to
g
uth
nsions or variations thereof. 
re
application and any extens
a
ns
Result
eo
Result
N
o


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Programming Notes: Use the shell for 16.2.8.6 for the following:
Listing 16.2.8.6.1
Urine Pregnancy Test (Japan)
Listing 16.2.8.7
Urine THC panel
Listing 16.2.8.7.1
Urine THC panel (Japan)
Listing 16.2.8.8
Whole blood cannabidiol
Listing 16.2.8.8.1
Whole blood cannabidiol (Japan)
PUBLIC COPY 
p
Listing
PY
Listing 16.
Y
16.
Whole
OP
Whole bloo
OP
bloo
L
C
L
Whol
C 
Whol
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
8.8
a
8.8
annabidiol
t a
annabidiol
ting
p
ting 16.2.8.8
po
16.2.8.8
blood
pp
blood canna
pp
canna
uth
application and any extensions or variations thereof. 
a
1
o
1
bidiol
s o
bidiol (Japan
o
(Japan


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Listing 16.2.9.1.1
Vital Signs
Treatment group: xxx
Subject
Identifier
Age/Sex
Visit
Visit
Date/Day#
Systolic
Blood
Pressure
(mmHg)
Diastolic
Blood Pressure
(mmHg)
Heart
Rate
(bpm)
Respira-
tory
(Breaths/
min)
Body
Weight
(kg)
Body
Height
(cm)
BMI
(kg/m^2)
Temper-
ature
(C)
XXXX
XX/X
Screening (Visit 1)
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
…..
DDMMMYYYY/XX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
NA
NA
NA
NA
XXX
NA
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
Visit 16
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXX
XXXX
XXXX
.
NA = Not Applicable.
# Relative to first dose of study treatment.
PUBLIC COPY 
Y
XX
BL
XX
XXX
UB
XXX
X
U
X
XX
P
XX
XXX
OP
XXX
XXX
CO
XXX
X
C
X
PY
P
IC
thorization 
national
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national L
03
03
ot be used to support any marketing auth
pm)
pm)
Respira
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Respira
to
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to
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ket
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ryry
Breaths/
ons
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application a
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a
on a


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ZX008-1503
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Programming Note; Use shell for 16.2.9.1.1or the following listings.
Listing 16.2.9.1.1.1
Vital signs (Japan)
Listing 16.2.9.1.2
Abnormal Vital signs data (Japan)
Listing 16.2.9.1.2.1
Abnormal Vital signs data (Japan)
Programming Note : The lows and highs for determination of abnormality will be supplied by Zogenix. Abnormal weight range: subjects with weight decrease of >=7% or increase of >=7%. For these
subjects, include the baseline, treatment value, change from baseline, their age and sex.
PUBLIC COPY 
al
Y
al sign
Y
sign
Listing
OPY
Listing 16.
PY
16.
ormal
COP
ormal Vita
OP
Vita
pplied
C C
pplied by
C
by Z
C
Z
and sex.
IC
and sex.
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
Japan)
y
Japan)
.1.2.1
an
.1.2.1
igns
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data (Ja
a
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genix.
p
genix. Abnorm
po
Abnorm
application and any extensions or variations thereof. 
a
pan)
v
pan)
mal
o
mal weight
or 
weight r


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Listing 16.2.9.1.9
Subjects with Weight Decrease >5% during Treatment
Treatment Group: xxx
Did Subject have
a TEAE of
Change
%Change
Subject
decreased
Weight
Baseline
From
From
Identifier
Age
Sex
appetite? (Yes/No)*
Visit
Visit Date/Day
(kg)
flag
Baseline
Baseline
ZX008-1504-1001-43
13
M
No
Xxxx
16JAN2017/-109
62.69
Y
Xxxx
29MAY2017/25
60.33
-2.36
-3.76
Xxxx
27JUN2017/54
38.83
-23.86
-38.06#
Xxxx
24JUL2017/81
57.79
-4.9
-7.82
ZX008-1504-1001-45
9
M
No
Xxxx
27JAN2017/-116
22.77
Y
Xxxx
20JUN2017/29
21.5
-1.27
-5.58#
Xxxx
25JUL2017/64
21.82
-0.95
-4.17
Xxxx
18AUG2017/88
22.72
-0.05
-0.22
ZX008-1504-1001-46
16
F
No
Xxxx
25JAN2017/-124
113.76
Y
Xxxx
29MAY2017/1
106
-7.76
-6.82
xxxx
27JUN2017/30
105.01
-8.75
-7.69
Programming note: use shell as used for the IDMC. Use the shell for 16.2.9.1.9 for
Listing 16.2.9.1.9.1
Subjects with Weight Decrease >5% during Treatment (Japan)
PUBLIC COPY 
xxx
IC
xxx
Xxxx
BLIC
Xxxx
Xxxx
BL
Xxxx
X
B
X
This document cannot be used to support any marketing authorization 
uth
national
zat
national L
03
03
do
TIAL
s d
TIAL
be
ke
t Date/Day
ma
Date/Day
16JAN20
ny
16JAN20
m
29MA
an
29MA
27
a
27
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t
x
Xxxx
ed
Xxxx
Xxxx
sed
Xxxx
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s
xxx
se
se the
no
the shell
no
shell f
application and any extensions or variations thereof. 
a
ny
the
Weigh
ns
Weigh
(kg
n
(kg
17/
ri
17/-
ia
-109
iat
109
tio
AY2017/25
aria
AY2017/25
7JUN2017/54
va
7JUN2017/54
24JUL2017/
r v
24JUL2017/
27JA
o
27JA
2
x
or
or 16.2.9.1.9
nd
16.2.9.1.9


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Listing 16.2.9.2
Listing of Items on Columbia-Suicide Severity Rating Scale (C-SSRS)for Individual Subjects
Safety Population
Subject
Visit/Time-
reatment
number
point
Response
Comment
XXXX
XXXXX
Visit 1,
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
PUBLIC COPY 
eting authorization 
uth
national
zat
national L
03
03
alal Subjects
g a
Subjects
et
et
This document c
do
TIAL
s d
TIAL
um
t cannot be used to support any market
ns thereof. 
he
s
applica
a pli
plication and any extensions or variations


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XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
Xxxx
xxxxxxxxxx
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXX
Visit 3
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
PUBLIC COPY 
ting authorization 
uth
national
zat
national L
03
03
ut
This docum
do
TIAL
s d
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um
ument c
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ns thereof. 
XX
o
XX
app
a plica
plication and any extensions or variation


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XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXXX
…….
XXXX
XXXXX
Visit 4, Visit 5,
Visit 6, Visit 7,
Visit 8…Visit 16
XXXX
XXXXXXXXXX
XXXX
XXXXXXXXX
Programming notes:
-
List only for subjects who answered “yes” to at least one question. For those subject, list all their C-SSRS data for all time points.
-
Use the 16.2.9.2 shell for
Listing 16.2.9.2.1
Listing of Items on Columbia-Suicide Severity Rating Scale (C-SSRS)for Individual Subjects (Japan)
Safety Population
PUBLIC COPY 
marketing authorization 
uth
national
zat
national L
03
03
ut
This document cannot be used
do
TIAL
s d
TIAL
e question.
e u
question.
Listing
ot
Listing of
ot
of Item
t 
Item
ed
ed to suppo
port any m
variations thereof. 
XXXX
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application and any exte
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ms
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tensions or 
or va


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Listing 16.2.9.3.1
Behavior Rating Inventory of Executive Function (BRIEF-P) Individual Responses
Randomized Treatment: XXX
Subject
Identifier
Visit
Question Category
Question
Response
SUBJID
AVISITN/AVISI
T
AVALC
XXXX
Baseline
XXXXX
Visit 8
XXXXX
Visit 12/EOS
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
.
Programming Note: Organize by items within scale scores, for all five scales.
Programming Note: provide the raw responses, not imputed responses
Programming Note: Use the shell for 16.2.9.3.1 for
Listing 16.2.9.3.1.1
Behavior Rating Inventory of Executive Function (BRIEF-P) Individual Responses (Japan)
PUBLIC COPY 
arketing authorization 
uth
national
zat
national L
03
03
ses
ses
ket
ar
t ca
in
t
in scale
t ca
scale sco
c
sco
This document
do
TIAL
s d
TIAL
ponses, not 
nt 
ponses, not 
16.2.9.3.1 f
en
16.2.9.3.1 f
cannot be used to support any mar
ns thereof. 
he
ns
tion
es,
o
es, for
on
for all
on
all five
n
five
applicati
a
imputed resp
atio
imputed resp
or
c
or
n and any extensions or variations


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Listing 16.2.9.3.2
Behavior Rating Inventory of Executive Function (BRIEF-P) Summary Scales
Subject
Identifier
Visit
Summary Scale
Score
SUBJID
AVISITN/AVISIT
PARCATx?
AVAL
XXXX
Baseline(Core)
Inhibit
XXXXX
Visit 12/EOS
Shift
Emotional Control
Working Memory
Plan/Organize
Inhibitory Self-Control Index (ISCI) (Inhibit + EC)[1]
Flexibility Index (FI) (Shift + EC)[2]
…
Emergent Metacognition Index (EMI) (WM + PO)[3]
Global Executive Composite (GEC) (Inhibit + Shift + EC + WM + PO) [4]
Inconsistency Score
Inconsistency Classification
…
Negativity Score
Negativity Classification
.
PUBLIC COPY 
Y
OPY
O
CO
C C
ze
L
ze
LIC
BL
bitory
UB
bitory Self
UB
Self
UB
PU
xibili
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xibili
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annot be used to support any marketing authorization 
uth
national
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national L
03
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y
t
y Scales
ting
Scales
tin
rke
ar
ma
y m
ny
an
t
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su
ntrol
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o s
Index (
s
(
o s
to
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(FI) (Sh
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us
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be
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ment can
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and any extensions or variations thereof. 
ere
th
s 
on
tio
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SCI)
si
SCI) (Inhibit
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(Inhibit
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app
app


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.
Programming note: the scores take into account the algorithm for handling missing responses.
Programming Note: Organize by scales, then index, and list inconsistency and negativity last.
Programming note: Use the shell for 16.2.9.3.2 for
Listing 16.2.9.3.2.1
Behavior Rating Inventory of Executive Function (BRIEF-P) Summary Scales (Japan)
PUBLIC COPY 
sting
PY
sting 16.2.9
PY
16.2.9
xecutive
OP
xecutive Fu
P
Fu
g authorization 
uth
national
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This document cannot be used to support any marketing 
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2.1
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2.1
tion
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tion (BRIEF
an
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of. 
f
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a
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P)
P) Summary
ari
Summary


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Programming Note: Use Listing shell 16.2.9.3.1 for the following listigns. Organize by items within scale scores, for all eight scales.
Listing 16.2.9.3.3
Behavior Rating Inventory of Executive Function (BRIEF) Individual Responses
Listing 16.2.9.3.3 1
Behavior Rating Inventory of Executive Function (BRIEF) Individual Responses (Japan)
Listing 16.2.9.3.5
Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) Individual Responses
Listing 16.2.9.3.5.1
Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) Individual Responses (Japan)
Footnote: OLE Last Visit = Last available measurement during the OLE study
Programming Note: Use Listing shell 16.2.9.3.2 to produce the following listings. Organize by scales, then index, and list inconsistency and negativity last.
Listing 16.2.9.3.4
Behavior Rating Inventory of Executive Function (BRIEF) Summary Scales
Listing 16.2.9.3.4.1
Behavior Rating Inventory of Executive Function (BRIEF) Summary Scales (Japan)
Listing 16.2.9.3.6
Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) Summary Scales
Listing 16.2.9.3.6.1
Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) Summary Scales (Japan)
Footnote: OLE Last Visit = Last available measurement during the OLE study
PUBLIC COPY 
ction
Y
ction –
Y
–
Listing
OP
Listing 1
P
1
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C
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CO
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esponses
ting
esponses
dual
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dual Respon
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Version (BRI
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.9.3.5.1
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Adult Versio
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by scales,
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at


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 232 of 234
Draft 3.0: 04Aug2020
Listing 16.2.9.4
Tanner Staging
Sex:  Boys
Tanner Stage for
Subject Identifier
Age Group
Sex [1]
Visit
Was the Exam performed
Visit Date/Day#
Genital/Breast
Development [2]
Pubic Hair Growth [3]
XXXX
>7years to <=11/>11years to
<=15/>15years to <=18
Male
Visit 1
Visit 3
---
Visit 8
Yes/No
DDMMMYYYY/XX
X
x
XXXX
---
XXXX
---
.
.
# Relative to first dose of study treatment. [1] Table for girls registers Female in this column.
[2] Boys are rated for genital development and pubic hair growth
[3] Girls are rated for breast development and pubic hair growth
Programming Note: Use the 16.2.9.4 shell for
Listing 16.2.9.4.1
Tanner Staging (Japan)
PUBLIC COPY 
Y
sit
C
sit 8
C C
8
Yes/No
OPY
Yes/No
PY
O
C
LIC
BL
BL
BL
BL
BL
UB
PU
P
thorization 
national
zat
national L
03
03
ed to support any marketing auth
rk
a
rformed
y m
rformed
a
y
ny
p
up
su
su
su
su
o s
to
d
This document cannot be use
do
TIAL
s d
TIAL
ed
e
use
Female
us
Female in
s
in t
s
t
h
b
h
wth
t b
wth
uth
xtensions or variations thereof. 
s t
Visit
tio
Visit Date/D
tio
Date/D
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DDM
ia
DDM
ia
ri
o
s
on
io
ns
en
en
application and any exten
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en
en
en
xte
ex e
isis column.
ex
column.


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 233 of 234
Draft 3.0: 04Aug2020
Listing 16.2.9.5
Physical Examination
Subject
Identifier
Visit [1]
Was the physical
Exam performed
Visit Date/
Day #
Category
Result
Details of Abnormality
XXXX
Complete(Visit 1,Visit 8)
Abbreviated(Visit 2 -7)
Yes
No
DDMMMYYYY/
XX
General Appearance
Skin
HEENT
Respiratory
Abdomen
Cardiovascular
Abdomen
Lymph Node
Spine
Extremities
Other: TEXT
Not done
Normal
Abnormal
TEXT
XXXX
XXXX
.
.
.
# Relative to first dose of study treatment.
[1]Complete physical examination done at Visit 1 and Visit 16/ET/EOS, and at the 3 and 6 month cardiac follow-up visits; an abbreviated physical examination is done at clinic Visit 2 through Visit 16.
Programming note: Use the Listing 16.2.9.5 shell for
Listing 16.2.9.5.1
Physical Examination (Japan)
PUBLIC COPY 
HEEN
Y
HEEN
Resp
PY
Resp
A
P
A
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
no
nce
m
nce
atory
an
atory
omen
t a
omen
Cardiovascu
ort 
Cardiovascu
Abdome
po
Abdome
Lymp
pp
Lymp
S
p
S
and
an
and Visit
ann
Visit 16
n
16
5 shell
t c
shell for
c
for
rk tin
uth
application and any extensions or variations thereof. 
a
nd
Resu
h
Resu
ar
ar
n
h
s
h Node
s o
Node
pine
n
pine
Extremities
on
Extremities
Other:
sio
Other:
/ET/EOS,
an
/ET/EOS, and
n
and
s t er


TLF Shells
Zogenix International Limited 
ZX008-1503
CONFIDENTIAL
Page 234 of 234
Draft 3.0: 04Aug2020
Listing 16.2.9.6
Neurological Examination
Subject
Identifier
Visit [1]
Visit Date/
Day #
Was the
neurological exam
performed
Category
Result
Details of Abnormality
XXXX
Complete(Visit 1,
Visit 8)
Abbreviated(Visit 2 -7)
DDMMMYYYY/
XX
Yes
No
Cranial nerves
Muscle strength and tone
Sensory function
Coordination
Gait
Reflexes
Normal
Abnormal
TEXT
XXXX
XXXX
#: Relative to first dose of study treatment.
[1]Complete neurological examination done at Visit 1 and Visit 16/ET/EOS; an abbreviated neurological examination is done at clinic Visit 2 through Visit 16.
Programming note: Use the Listing 16.2.9.6 shell for
Listing 16.2.9.6.1
Neurological Examination (Japan)
PUBLIC COPY 
anial
Y
anial ne
Y
ne
Muscle
PY
Muscle
Y
Sens
OP
Sens
C
O
C
thorization 
national
zat
national L
03
03
This document cannot be used to support any marketing auth
do
TIAL
s d
TIAL
be
ength
an
ength and
any
and to
y
to
y function
t a
function
rdination
ort
rdination
Gait
p
Gait
Reflexes
pp
Reflexes
isit
t
isit 16/ET/EO
t b
16/ET/EO
m
tin
uth
ons thereof. 
Resu
ns
Resu
application and any extensions or variation
a
ny
ne
ne
OS;
OS; an
a
an abbrev
an
abbrev
on
er