Clinical trial NCT02682927
Conditions: Dravet Syndrome Seizure Disorder
Keywords: seizure tonic-atonic clonic epilepsy myoclonic encephalopathy
Sponsor: Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
Start date: 2016-01-15; Completion date: 2020-07-29
Enrollment: 262 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study 1 and Study 3 are the prospective, merged analyses of 2 identical double-blind, placebo-controlled studies, ZX008-1501 and ZX008-1502, to assess the efficacy, safety, and pharmacokinetics of ZX008 when used as adjunctive therapy in pediatric and young adult subjects with Dravet syndrome. Study 1501 and Study 1502 were conducted in parallel; Study 1501 was conducted at approximately 30 study sites in North America; Study 1502 was conducted at approximately 30 study sites in Europe, Asia and Australia. Upon completion of the Baseline Period after initial Screening and Baseline charting of seizure frequency, subjects who qualified for the studies were randomized (1:1:1) in a double-blind manner to receive either 1 of 2 doses of ZX008 (0.2 mg/kg/day or 0.8 mg/kg/day; maximum dose: 30 mg/day) or placebo. Randomization was stratified by age group (\< 6 years, ≥6 to 18 years) to achieve balance across treatment arms, with the target of 25% of subjects in each age group. All subjects were titrated to their randomized dose over a 14-day Titration Period. Following titration, subjects continued treatment at their randomly assigned dose over a 12-week Maintenance Period. Subjects exiting the study underwent a 2-week taper, unless they enrolled in a follow-on study. Subjects were followed for post-study safety monitoring.

Detailed description:

Arms: arm 1: ZX008 (fenfluramine HCl) is supplied as an oral solution in concentrations of 1.25, 2.5, and 5 mg/mL. ZX008 will be administered twice a day (BID) in equally divided doses with food. arm 2: ZX008 (fenfluramine HCl) is supplied as an oral solution in concentrations of 1.25, 2.5, and 5 mg/mL. ZX008 will be administered twice a day (BID) in equally divided doses with food. arm 3: Placebo will be administered twice a day (BID) in equally divided doses with food.
Interventions: intervention 1: ZX008 (Fenfluramine Hydrochloride) intervention 2: Matching Placebo
Intervention descriptions: intervention 1: ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5. The product is sugar free and is intended to be compatible with a ketogenic diet. intervention 2: Placebo solution for ZX008. The product is sugar free and is intended to be compatible with a ketogenic diet.

Protocol documents:
Prot_000.pdf: 
16.1.1
Protocol and Protocol Amendments 
The latest global version of the protocol used during the study is provided in this section. 
Previous DQGcountry-specific versions of the protocol are available on request. 
For Study ZX008-1501: 
Protocol ZX008-1501 Amendment 3.0 dated 31-October-2016
For Study ZX008-1502: 
Protocol ZX008-1502 Amendment 2.0 dated 31-October-2016
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 


Confidential 
Clinical Study Protocol 
Study Title: 
A Multicenter, Randomized, Double-blind, Parallel Group, 
Placebo- controlled Trial of Two Fixed Doses of ZX008 
(Fenfluramine Hydrochloride) Oral Solution as an 
Adjunctive Therapy in Children and Young Adults with 
Dravet Syndrome
Study Number: 
ZX008-1501
Study Product: 
Fenfluramine Hydrochloride Oral Solution; ZX008
IND Number: 
125797
EudraCT Number: 
2015-004167-37 
Sponsor: 
Zogenix International Limited  
A wholly owned subsidiary of Zogenix, Inc.  
5858 Horton Street, Suite 455  
Emeryville, CA 94608 USA
Sponsor's Medical 
Contact: 
  
Date of Study  
Protocol: 
31 October 2016 (Protocol Amendment 3.0) 
18 January 2016 (Protocol Amendment 2) 
18 December 2015 (Protocol Amendment 1) 
02 November 2015 version 1.3 (Original Protocol) 
This protocol includes information and data that contain trade secrets and privileged or confidential information, 
which is the property of the sponsor. This information must not be made public without written permission from the 
sponsor. These restrictions on disclosure will apply equally to all future information supplied to you. This material 
may be disclosed to and used by your personnel and associates as may be necessary to conduct the clinical study. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 2 of 182
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 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 3 of 182
TABLE OF CONTENTS 
Clinical Study Protocol ................................................................................................................ 1
LIST OF PERSONNEL AND ORGANIZATIONS RESPONSIBLE FOR CONDUCT OF 
STUDY ........................................................................................................................... 2
TABLE OF CONTENTS ............................................................................................................. 3
SIGNATURE OF SPONSOR .................................................................................................... 10
SIGNATURE OF COORDINATING INVESTIGATOR ......................................................... 11
SIGNATURE(S) OF THE PRINCIPAL INVESTIGATOR ...................................................... 12
LIST OF ABBREVIATIONS .................................................................................................... 13
STUDY SYNOPSIS ................................................................................................................... 15
1.
INTRODUCTION ........................................................................................................ 25
1.1
BACKGROUND INFORMATION ON INDICATION STUDIED ..... 25
1.1.1
Existing Treatment for Dravet Syndrome .............................................. 25
1.1.2
Other Antiepileptic Medications ............................................................ 26
1.2
BACKGROUND INFORMATION ON STUDY PRODUCT ............. 26
1.3
PRECLINICAL DATA ......................................................................... 27
1.4
BACKGROUND INFORMATION ON REFERENCE PRODUCT .... 28
1.5
RATIONALE FOR CURRENT STUDY .............................................. 28
1.6
RISK-BENEFIT ASSESSMENT .......................................................... 29
2.
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 29
2.1
PRIMARY OBJECTIVE ....................................................................... 29
2.2
KEY SECONDARY OBJECTIVES ..................................................... 29
2.3
ADDITIONAL SECONDARY OBJECTIVES ..................................... 30
2.4
SAFETY OBJECTIVE .......................................................................... 31
2.5
PHARMACOKINETIC OBJECTIVE .................................................. 31
2.6
EXPLORATORY OBJECTIVE ............................................................ 31
2.7
STUDY ENDPOINTS ........................................................................... 31
2.7.1
Efficacy Endpoints ................................................................................. 31
2.7.2
Safety Endpoints .................................................................................... 32
2.7.3
Pharmacokinetic Endpoints ................................................................... 32
3.
INVESTIGATIONAL PLAN ....................................................................................... 32
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 4 of 182
3.1
OVERALL STUDY DESIGN AND PLAN .................................. 32
3.2
NUMBER OF SUBJECTS .................................................................... 33
3.3
STUDY DURATION ............................................................................ 33
3.4
NUMBER OF STUDY CENTERS ....................................................... 33
3.5
RATIONALE FOR STUDY DESIGN AND CHOICE OF 
TREATMENT GROUPS ...................................................................... 33
3.6
PREMATURE TERMINATION OF STUDY ...................................... 34
3.7
STUDY MONITORING PROCEDURES ............................................ 35
3.7.1
Independent Data and Safety Monitoring Committee ........................... 35
3.7.2
International Pediatric Cardiac Advisory Board (IPCAB) .................... 35
4.
SELECTION OF STUDY POPULATION .................................................................. 35
4.1
INCLUSION CRITERIA ...................................................................... 36
4.2
EXCLUSION CRITERIA ..................................................................... 37
4.3
RANDOMIZATION INCLUSION CRITERIA ................................... 38
4.4
SUBJECTS OF REPRODUCTIVE POTENTIAL ................................ 38
4.4.1
Sperm and Egg Donation ....................................................................... 39
4.4.2
Pregnancy............................................................................................... 40
4.5
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT 40
4.6
TERMINATION OF THE CLINICAL STUDY ................................... 42
4.7
REPLACEMENT OF SUBJECTS ........................................................ 42
4.8
ELIGIBILITY FOR EXTENSION STUDY ......................................... 42
5.
INVESTIGATIONAL MEDICINAL PRODUCT INFORMATION .......................... 42
5.1
IDENTITY OF INVESTIGATIONAL MEDICINAL PRODUCT ...... 43
5.1.1 Labeling and Packaging ......................................................................... 43
5.2
DESCRIPTION OF REFERENCE TREATMENT, COMPARATOR, 
AND/OR PLACEBO ............................................................................. 44
5.2.1 Labeling and Packaging ......................................................................... 44
5.3
SHIPMENT AND STORAGE .............................................................. 44
5.4
IMP ACCOUNTABILITY .................................................................... 44
5.5
TREATMENT ADMINISTRATION .................................................... 45
5.5.1 Randomization ....................................................................................... 45
5.5.2 Titration Period ...................................................................................... 45
5.5.3
Maintenance Period ............................................................................... 46
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 5 of 182
5.5.4
Taper Period ........................................................................................... 46
5.5.5
Transition Period.................................................................................... 47
5.6
BLINDING ............................................................................................ 48
5.7
PRIOR AND CONCOMITANT MEDICATION ................................. 48
5.7.1
Vagal Nerve Stimulation ....................................................................... 49
5.7.2
Ketogenic Diet ....................................................................................... 49
5.7.3
Rescue Medication for Seizures ............................................................ 49
5.7.4
Prohibited Concomitant Medication and Food ...................................... 49
5.8
TREATMENT COMPLIANCE ............................................................ 50
6.
VISIT SCHEDULE ...................................................................................................... 50
6.1
BASELINE PERIOD (STUDY DAY -42 TO STUDY DAY -1) ......... 51
6.1.1
Screening, Clinic Visit 1 (Study Day -42) ............................................. 51
6.1.2
Phone Visit 2 (Study Day -21) ............................................................... 53
6.1.3
Clinic Visit 3 (Study Day -1): Randomization ...................................... 53
6.2
TITRATION AND MAINTENANCE PERIODS ................................ 55
6.2.1
Titration Period Study Day 1 ................................................................. 55
6.2.2
Phone Visits 4 and 5 (Titration Period Study Days 4 and 8) ................. 55
6.2.3
Clinic Visit 6 (Titration Period Study Day 15) ...................................... 55
6.2.4
Phone Visit 7 (Maintenance Period Study Day 29) ............................... 56
6.2.5
Clinic Visit 8 (Maintenance Period Study Day 43) ............................... 56
6.2.6
Phone Visit 9 (Maintenance Period Study Day 57) ............................... 58
6.2.7
Clinic Visit 10 (Maintenance Period Study Day 71) ............................. 58
6.2.8
Phone Visit 11 (Maintenance Period Study Day 85) ............................. 59
6.2.9
Clinic Visit 12 (Maintenance Period Study Day 99): End of Study/Early 
Termination ............................................................................................ 59
6.3
POST-DOSE VISIT (CLINIC VISIT 13; STUDY DAY 113) ............. 61
6.4
CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 14; STUDY 
DAY 197-281) ....................................................................................... 62
6.5
ESTIMATED BLOOD VOLUME COLLECTION .............................. 62
7.
EFFICACY, SAFETY, AND PHARMACOKINETIC ASSESSMENTS ................... 64
7.1
EFFICACY ASSESSMENTS ............................................................... 64
7.1.1
Seizure Assessments .............................................................................. 65
7.1.2
Clinical Global Impression - Improvement ........................................... 66
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 6 of 182
7.1.3
Quality of Life in Childhood Epilepsy Scale ......................................... 66
7.1.4
Pediatric Quality of Life Inventory (PedsQL) ....................................... 66
7.1.5
Parent/Caregiver Quality of Life ........................................................... 67
7.2
SAFETY ASSESSMENTS.................................................................... 67
7.2.1
Demographics, Medical/Neurological/Epilepsy History, and Pre-Study 
Medication ............................................................................................. 67
7.2.2
Physical Examinations ........................................................................... 67
7.2.3
Neurological Examinations .................................................................... 68
7.2.4
Vital Signs.............................................................................................. 68
7.2.5
Laboratory Measurements ..................................................................... 68
7.2.6
Plasma Sample for Concomitant Antiepileptic Drug(s) ........................ 69
7.2.7
Electrocardiograms ................................................................................ 69
7.2.8
Doppler Echocardiography .................................................................... 70
7.2.9
Tanner Staging ....................................................................................... 70
7.2.10 Columbia-Suicide Severity Rating Scale ............................................... 70
7.2.11 Adverse Events ...................................................................................... 70
7.2.12 Behavior Rating Inventory of Executive Function (BRIEF) ................. 71
7.3
PHARMACOKINETIC ASSESSMENTS ............................................ 71
7.4
APPROPRIATENESS OF MEASUREMENTS ................................... 71
8.
ADVERSE EVENTS .................................................................................................... 71
8.1
DEFINITIONS ...................................................................................... 71
8.1.1
Adverse Events ...................................................................................... 71
8.1.2
Serious Adverse Events ......................................................................... 73
4.
Results in persistent or significant disability or incapacity. .................. 73
8.1.3
Adverse Events of Special Interest ........................................................ 73
8.1.4
Adverse Events Requiring Hospitalization ............................................ 75
8.2
SEVERITY OF ADVERSE EVENTS .................................................. 75
8.3
CAUSALITY OF ADVERSE EVENTS ............................................... 76
8.4
OBSERVATION PERIOD FOR ADVERSE EVENT REPORTING .. 77
8.5
ADVERSE EVENT REPORTING ....................................................... 77
8.5.1 Adverse Events ...................................................................................... 77
8.6
SERIOUS ADVERSE EVENTS REPORTING .................................... 77
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 7 of 182
8.6.1
Requirements for Immediate Reporting of Serious Adverse Events ..... 78
8.7
REPORTING OF SERIOUS ADVERSE EVENTS BY 
INVESTIGATOR TO IEC/IRB ............................................................ 79
8.8
REPORTING OF EVENTS OTHER THAN SERIOUS ADVERSE 
EVENTS BY INVESTIGATOR TO SPONSOR .................................. 79
8.9
FOLLOW-UP OF ADVERSE EVENTS .............................................. 79
8.9.1
Follow-up of Echocardiogram Findings ................................................ 79
8.10
PREGNANCY ....................................................................................... 82
9.
DATA HANDLING PROCEDURES .......................................................................... 82
9.1
RECORDING OF DATA ...................................................................... 82
9.2
DATA QUALITY ASSURANCE ......................................................... 82
9.3
RECORD RETENTION ........................................................................ 83
10.
STATISTICS ................................................................................................................ 83
10.1
DETERMINATION OF SAMPLE SIZE .............................................. 83
10.2
ANALYSIS POPULATIONS ............................................................... 83
10.2.1 Safety (SAF) Population ........................................................................ 83
10.2.2 Modified Intent-to-Treat (mITT) Population ......................................... 84
10.2.3 Per Protocol (PP) Population ................................................................. 84
10.3
TREATMENT GROUPS ...................................................................... 84
10.4
TREATMENT PERIODS...................................................................... 84
10.5
STATISTICAL ANALYSES AND METHODS .................................. 85
10.5.1 Efficacy Analyses .................................................................................. 85
10.5.2 Safety Analyses...................................................................................... 87
10.5.3 Pharmacokinetic Analyses ..................................................................... 87
10.6
ANALYSES PROVIDED TO AN INDEPENDENT DATA AND 
SAFETY MONITORING COMMITTEE ............................................. 88
11.
ETHICAL & REGULATORY CONSIDERATIONS .................................................. 88
11.1
ETHICAL CONSIDERATIONS ........................................................... 88
11.2
INFORMED CONSENT ....................................................................... 88
11.3
REGULATORY CONSIDERATIONS AND INDEPENDENT ETHICS
COMMITTEE/INSTITUTIONAL REVIEW BOARD......................... 90
11.4
PROTOCOL COMPLIANCE ............................................................... 90
12.
ADMINISTRATIVE ASPECTS .................................................................................. 91
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 8 of 182
12.1
CLINICAL TRIAL AGREEMENT ...................................................... 91
12.2
FINANCIAL DISCLOSURE BY INVESTIGATOR ........................... 91
12.3
CLINICAL STUDY REGISTRATION AND RESULTS DISCLOSURE
 ............................................................................................................... 92
12.4
STUDY FILES AND MATERIALS ..................................................... 92
12.5
INITIATION OF THE STUDY ............................................................ 92
12.6
SUBJECT REIMBURSEMENT ........................................................... 93
12.7
LIABILITY AND INSURANCE .......................................................... 93
12.8
SUBJECT IDENTIFICATION AND CONFIDENTIALITY ............... 93
12.9
MONITORING OF THE STUDY ........................................................ 94
12.10 PROTOCOL AMENDMENTS ............................................................. 95
12.11 AUDITS AND INSPECTIONS............................................................. 95
12.12 CLINICAL STUDY REPORT .............................................................. 95
12.13 USE OF DATA AND PUBLICATIONS .............................................. 96
13.
REFERENCE LIST ...................................................................................................... 97
14.
APPENDICES .............................................................................................................. 99
APPENDIX 1 – LIST OF PROHIBITED CONCOMITANT MEDICATIONS ..................... 100
APPENDIX 2 – COLUMBIA – SUICIDE SEVERITY RATING SCALE ............................ 102
APPENDIX 3 – BEHAVIOR RATING INVENTORY OF EXECUTIVE FUNCTION ....... 108
APPENDIX 4 – QUALITY OF LIFE IN CHILDHOOD EPILEPSY SCALE ....................... 118
APPENDIX 5 – TANNER STAGING ..................................................................................... 131
APPENDIX 6 – PEDSQL (INCLUDING FAMILY IMPACT MODULE) ............................ 133
APPENDIX 7 – EQ-5D-5L QUESTIONNAIRE ..................................................................... 144
APPENDIX 8 – HOSPITAL ANXIETY AND DEPRESSION SCALE ................................. 146
APPENDIX 9 – MAXIMUM ALLOWABLE BLOOD DRAW VOLUMES ........................ 147
APPENDIX 10 – PROTOCOL AMENDMENT 1 SUMMARY OF CHANGES ................... 148
APPENDIX 11 – PROTOCOL AMENDMENT 2 SUMMARY OF CHANGES ................... 161
APPENDIX 12 – PROTOCOL AMENDMENT 3 SUMMARY OF CHANGES ................... 173
Table 1:
Schedule of Assessments........................................................................................................... 22
Table 2:
Investigational Medicinal Product – ZX008 .............................................................................43
Table 3:
Titration Algorithm ................................................................................................................... 46
Table 4:
Taper Algorithm........................................................................................................................ 47
Table 5:
Transition Algorithm................................................................................................................. 47
Table 6:
Time Windows for Assessments ............................................................................................... 50
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 9 of 182
Table 7:
Schedule of Post-Treatment Cardiac Follow-up .......................................................................62
Table 8:
Estimated Blood Volume Collection*.......................................................................................63
Table 9:
Priorities for Blood Sample Collections....................................................................................64
Table 10:
Adverse Events of Special Interest...................................................................74
Table 11:
Severity Definition of Adverse Events.............................................................76
Table 12:
Clinical Measures Enacted Upon Increasing Severity of ECHO Findings ......80
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
80
application and any extensions or variations thereof. 


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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 12 of 182
SIGNATURE(S) OF THE PRINCIPAL INVESTIGATOR
Study Number: 
ZX008-1501 
Study Title: 
A Multicenter, Randomized, Double-blind, 
Parallel Group, Placebo-controlled Trial of Two 
Fixed Doses 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 & Affiliation):
Signature 
Date (Day/Month/Year) 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 13 of 182
LIST OF ABBREVIATIONS
ABBREVATION
DEFINITION
AE
Adverse Event
AED
antiepileptic drug
AESI
Adverse Event of Special Interest
ANCOVA
analysis of covariance
AUC
area under the concentration-time curve
AUC0-t
area under the concentration-time curve from time zero to time=t
BID
bis in die; two times per day
BMI
Body Mass Index
BRIEF
Behavior Rating Inventory for Executive Function
C-SSRS
Columbia-Suicide Severity Rating Scale
CBD
cannabidiol
CFR
Code of Federal Regulations
Cmax
Maximum observed concentration determined directly from the 
concentration-time profile
CYP
cytochrome P450
dL
Deciliter
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
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GH
Growth Hormone
GMP
Good Manufacturing Practices
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
IRB
Institutional Review Board
ABBREVATION
DEFINITION
IU
International Unit
IVR 
Interactive Voice Response 
IWR 
Interactive Web Response (System) 
KD
Ketogenic diet
kg
Kilogram
LH
Luteinizing Hormone
MCSF 
Mean Convulsive Seizure Frequency 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 14 of 182
ABBREVATION
DEFINITION
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 
PedsQL 
Pediatric Quality of Life Inventory 
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 
SD 
Standard Deviation 
SMEI 
Severe Myoclonic Epilepsy Of Infancy 
SUDEP 
Sudden Unexpected Death in Epilepsy 
T+M 
Titration plus Maintenance Periods 
t1/2 
terminal half-life 
THC 
tetrahydrocannabinol 
Tmax 
time to maximum concentration 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
USA 
United States of America 
USP 
United States Pharmacopeia 
VNS 
Vagal Nerve Stimulator/Stimulation 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 15 of 182
STUDY SYNOPSIS 
Study Title: A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled 
Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an 
Adjunctive Therapy in Children and Young Adults with Dravet Syndrome
Study Number: ZX008-1501
Study Product: Fenfluramine Hydrochloride Oral Solution, ZX008
Type of Study:
Efficacy, safety, and pharmacokinetics study
Indication Studied:
Adjunctive therapy in Dravet syndrome
Phase of Development: Phase III
Countries: North America
Sponsor: Zogenix International Limited
Coordinating Investigator: 
Joseph Sullivan, MD
University of California, San 
Francisco San Francisco, CA USA
Estimated Duration of Individual Subject Participation:
The duration of the participation in the study for an individual subject is expected to be up 
to 22 weeks, with a follow-up 3 to 6 months after the last dose of study medication for 
final safety monitoring.
Objectives: 
The primary objective of the study is: 
x
To demonstrate that ZX008 0.8 mg/kg/day is superior to placebo as adjunctive therapy in 
the treatment of Dravet syndrome 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). 
The key secondary objectives of the study are: 
x
To demonstrate that ZX008 0.2 mg/kg/day is superior to placebo as adjunctive therapy in 
the treatment of Dravet syndrome based on change in the frequency of convulsive seizures 
between baseline and T+M. 
x
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints: 
x
The proportion of subjects who achieve a 40% reduction from baseline in convulsive 
seizure frequency. 
x
The proportion of subjects who achieve a 50% reduction from baseline in convulsive 
seizure frequency. 
x
The longest convulsive seizure-free interval.
See Statistical Methods (Section 10.5.1.3) for hierarchical testing 
procedure. Additional secondary efficacy objectives of the study are: 
x To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints:
o
The number of convulsive seizure-free days.
o
The proportion of subjects who achieve 75% reductions from baseline in 
convulsive seizure frequency.
o
The change from baseline in non-convulsive seizure frequency.
o
The change from baseline in convulsive + non-convulsive seizure frequency.
o
The incidence of rescue medication usage.
o
The incidence of hospitalization to treat seizures.
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 16 of 182
o
The incidence of status epilepticus.
x
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are 
(independently) superior to placebo on the following endpoints:
o
Clinical Global Impression – Improvement rating, as assessed by the principal 
investigator.
o
Clinical Global Impression – Improvement rating, as assessed by the 
parent/caregiver.
o
The change from baseline in the Quality of Life in Childhood Epilepsy 
(QOLCE) score to measure quality of life.
o
The change from baseline in the Pediatric Quality of Life Inventory™ (PedsQL) 
score.
o
The change from baseline in PedsQL Family Impact module score.
o
The change from baseline in the quality of life (QoL) of the parent/caregiver 
using the EQ- 5D-5L scale.
o
The change from baseline in affective symptoms of the parent/caregiver 
using the Hospital Anxiety and Depression Scale (HADS).
The safety objective of the study is: 
x
To compare the safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day to placebo with 
regard to adverse events (AEs), laboratory parameters, physical examination, neurological 
examination, vital signs (blood pressure, heart rate, temperature, and respiratory rate), 
electrocardiograms (ECG), echocardiograms (ECHO), and body weight. Cognitive 
Function will be assessed in subjects 5 years and older using the cognition domain score on 
the QOLCE. Cognitive function will be assessed using and age-appropriate versions of the 
BRIEF
The pharmacokinetics (PK) objective of the study is:
x
To characterize the PK of ZX008 0.2 and 0.8 mg/kg/day at steady state in 
subjects ages 2-6 years and 6-18 years with Dravet syndrome.
The exploratory objectives of the study are:
x
To compare the ZX008 0.2 and 0.8 mg/kg/day doses on primary, secondary, safety and PK 
endpoints.
Methodology:
This is a multicenter, double-blind, parallel-group, placebo-controlled, study to assess the 
efficacy, safety, and PK of ZX008 when used as adjunctive therapy in pediatric and young adult 
subjects with Dravet syndrome. Approximately 30 study sites in North America are planned to 
participate. The 6-week Baseline Period will consist of the establishment of initial eligibility 
during a screening visit followed by an observation period where subjects will be assessed for 
baseline seizure activity based on recordings of daily seizure activity entered into a diary. Upon 
completion of the Baseline Period, subjects who qualify for the study will be randomized (1:1:1) 
in a double-blind manner to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; 
maximum dose: 30 mg/day) or placebo.
Randomization will be stratified by age group (< 6 years, 6 years) to ensure balance across 
treatment arms, and at least 40% of subjects will be in each age group. All subjects will be 
titrated to their randomized dose over a 14-day Titration Period. Following titration, subjects will 
continue treatment at their randomly assigned dose over a 12-week Maintenance Period. Total 
treatment time from the beginning of the Titration Period through the end of the Maintenance 
Period is 14 weeks. At the end of the Maintenance Period (or early discontinuation), all subjects 
will undergo a 2-week taper or transition period (Post-Dosing Follow-Up) depending on whether 
they exit the study or are enrolled in the separate long-term open-label extension study. A follow-
up ECG and ECHO will be performed 3-6 months after study drug discontinuation for early 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 17 of 182
termination, or for those subjects who complete the study but do not enter the open-label 
extension study.
Parents/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.
External Individuals and Committees:  
The ZX008 clinical program will employ an Independent Data and Safety Monitoring Committee 
(IDSMC) that will be responsible for safety oversight. A separate International 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.
Number of Subjects:
Approximately 130 subjects will be screened to obtain 115 subjects who enter the Baseline 
Period. Of these 115 subjects, it is estimated that 105 subjects will be randomized into the 
Titration Period. Each clinical site will not randomize more than a maximum of 10 subjects 
without prior consent from the sponsor.
Inclusion Criteria: All subjects must meet all of the following inclusion criteria to be enrolled 
into the study:
1.
Subject is male or non-pregnant, non-lactating female, age 2 to 18 years, inclusive as of 
the day of the Screening Visit. Female subjects of childbearing potential must not be 
pregnant or breast-feeding. Female subjects of childbearing potential must have a 
negative urine pregnancy test. Subjects of childbearing or child-fathering potential must 
be willing to use medically acceptable forms of birth control (see Section 4.4), which 
includes abstinence, while being treated on this study and for 90 days after the last dose 
of study drug.
2.
Subject must have documented medical history to support a clinical diagnosis of 
Dravet syndrome, where convulsive seizures are not completely controlled by current 
antiepileptic drugs.
3.
Subjects must meet all of the following 5 criteria:
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 brain malformation.
e.
Lack of alternative diagnosis.
4.
Subjects must meet at least one of the following 3 criteria:
a.
Emergence of another seizure type, including myoclonic, generalized tonic-
clonic, tonic, atonic, absence and/or focal has developed after the first seizure 
type.
b.
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 
natural and/or fluorescent lighting, as well as certain visual patterns.
c.
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.)
5.
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.
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 18 of 182
6.
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.
7.
Subject has been informed of the nature of the study and informed consent has been 
obtained from the legally responsible parent/guardian.
8.
Subject has provided assent in accordance with Institutional Review Board 
(IRB) requirements, if capable.
9.
Subject’s parent/caregiver is willing and able to be compliant with diary 
completion, visit schedule and study drug accountability.
Exclusion Criteria: 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 pulmonary arterial hypertension.
3.
Subject has current or past history of cardiovascular or cerebrovascular 
disease, such as cardiac valvulopathy, myocardial infarction or stroke. 
4.
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.
5.
Subject is at imminent risk of self-harm or harm to others, in the investigator’s 
opinion, based on clinical interview and responses provided on the Columbia-
Suicide Severity Rating Scale (C-SSRS). Subjects must be excluded if they report 
suicidal behavior in the past 6 months as measured by the C-SSRS at Screening or 
Baseline, which includes suicidal ideation with intent and plan (Item #5). If a 
subject reports suicidal ideation on Item 4 without specific plan, and the 
investigator feels that the subject is appropriate for the study considering the 
potential risks, the investigator must document appropriateness for inclusion, and 
discuss with the parent/caregiver to be alert to mood or behavioral changes, 
especially around times of dose adjustment.
6.
Subject has a current or past history of glaucoma.
7.
Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild 
hepatic impairment (elevated liver enzymes < 3x ULN and/or elevated bilirubin <2x ULN) 
may be entered into the study after review and approval by the Medical Monitor in 
conjunction with the sponsor, in consideration of comorbidities and concomitant 
medications.
8.
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; or 
cyproheptadine (see Appendix 1). (Note: Short- term medication requirements will be 
handled on a per case basis by the Medical Monitor.)
9.
Subject is currently receiving or has received stiripentol in the past 21 days 
prior to Screening.
10.
Subject is currently taking carbamazepine, oxcarbamazepine, eslicarbazepine, 
phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as 
maintenance therapy.
11.
Subject is unwilling to refrain from large or daily servings of grapefruits and/or 
Seville oranges, and their juices beginning with the Baseline Period and 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 19 of 182
throughout the study.
12.
Subject has positive result on urine tetrahydrocannabinol (THC) Panel or whole 
blood cannabidiol (CBD) at the Screening Visit.
13.
Subject has participated in another clinical trial within the past 30 days.
14.
Subject is currently receiving an investigational product.
15.
Subject is unwilling or unable to comply with scheduled visits, drug administration 
plan, laboratory tests, other study procedures, and study restrictions.
16.
Subject has a clinically significant condition, or has had clinically relevant symptoms or a 
clinically significant illness in the 4 weeks prior to the Screening Visit, other than epilepsy, 
that would negatively impact study participation, collection of study data, or pose a risk to 
the subject.
Randomization Inclusion Criteria: Subjects must meet all of the inclusion criteria above 
plus the following criteria, to be randomized:
1.
Subject has been approved for study inclusion by the Epilepsy Study Consortium.
2.
Subject does not have a cardiovascular or cardiopulmonary abnormality based on 
ECHO, ECG or physical examination, including but not limited to trace mitral or 
aortic valve regurgitation or signs of pulmonary hypertension, and is approved for 
entry by the central cardiac reader.
3.
Subject demonstrates a stable baseline with 6 convulsive seizures during the 
6-week Baseline Period, with a minimum of 2 in the first 3 weeks and 2 in the 
second 3 weeks.
4.
Subject’s parent/caregiver has been compliant with diary completion during the 
Baseline Period, in the opinion of the investigator (e.g., at least 90% compliant).
Study Product, Dose, and Mode of Administration:
ZX008 is supplied as an oral solution in concentrations of 1.25, 2.5, and 5 mg/mL. Subjects 
will be randomized to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; 
maximum dose: 30 mg/day) or placebo. Study medication will be administered twice a day 
(BID) in equally divided doses with food.
Reference Product, Dose, and Mode of Administration:
Matching ZX008 placebo is supplied as an oral solution.
Duration of Treatment:
All subjects will receive ZX008 or matching placebo for up to approximately 16 weeks (Titration 
Period=2 weeks; Maintenance Period=12 weeks; Taper/Transition Period=2 weeks). After 
completion of the Maintenance Period, eligible subjects may enroll in the open-label extension 
study, after completion of the transition. Subjects who do not enroll in the open-label extension 
study will undergo a taper off of study medication (doses will be administered in a blinded fashion
similar to the titration, i.e., doses will be decreased in 4-day increments). Follow-up 
cardiovascular safety assessments, including ECG and ECHO, will be performed 3 to 6 months 
following the last dose of study medication.
Criteria for Evaluation:
Efficacy:
x
Number of seizures by type 
x
Convulsive seizure-free interval 
x
Clinical Global Impression – Improvement as assessed by parent/caregiver 
x
Clinical Global Impression – Improvement as assessed by principal investigator 
x
QOLCE to measure changes in quality of life of the subject 
x
PedsQL to measure changes in quality of life of the subject 
x
PedsQL Family Impact module to measure changes in quality of life of the parent/caregiver 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 20 of 182
x
QoL of parent/caregiver using the EQ-5D-5L scale 
x
Affective symptoms of parent/caregiver using the HADS scale 
x
Duration of prolonged seizures (seizure type that, during baseline, had duration >2 minutes) 
x
Number of episodes of status epilepticus 
x
Number of instances of rescue medication use and number of doses 
x
Number of inpatient hospital admissions due to seizures
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 BRIEF will be 
administered to track cognitive function. 
Pharmacokinetics: 
Steady-state plasma fenfluramine PK parameters (maximum observed concentration determined 
directly from the concentration time profile [Cmax], area under the concentration time curve from 
time zero to time=t [AUC0-t], time to maximum concentration [Tmax], and terminal half-life 
[t1/2]) after administration of ZX008 derived using population PK methods.
Sample Size Determination:
The results of the only randomized, placebo-controlled studies in subjects with Dravet syndrome 
can be found in the European Public Assessment Report (EPAR) for stiripentol (EMA, 2007). 
The EPAR summarizes the results from two studies: STICLO France and STICLO Italy. In the 
stiripentol groups, the standard deviation (SD) of the percentage change in seizure frequency 
from baseline to month 2 was 42% in the French trial and 26% in the Italian trial. The analogous 
SDs for placebo groups were 38% and 62%. An SD of 50% was assumed for the primary analysis 
in this trial comparing ZX008 0.8 mg/kg/day to placebo on the change from baseline in seizure 
frequency. Using a two-sided test at the Į=0.05 significance level, a sample size of 35 subjects 
per treatment group affords 90% power to detect a difference in mean change from baseline of 
40 percentage points. Similar assumptions and calculations yield a requirement for an additional 
35 subjects in the 0.2 mg/kg/day ZX008 group. Thus, the total sample size is planned to be 
105 subjects (35 per arm).
Statistical Methods:
Study Populations:
Safety Population: All safety analyses will be performed on the Safety Population defined as all 
randomized subjects who receive at least one dose of study medication. Subjects will be analyzed 
according to the treatment actually received.
Modified Intent-to-Treat (mITT) Population: The mITT Population is defined as all randomized 
subjects who receive at least one dose of study medication and for whom at least 1 week of diary 
data are available. Subjects will be analyzed according to the treatment group to which they were 
randomized. The primary comparison of ZX008 0.8 mg/kg/day to placebo as well as key 
secondary efficacy assessments will be performed on the mITT Population.
Per Protocol (PP) Population: The PP Population is defined as all randomized subjects who 
receive at least one dose of ZX008 or placebo, complete the Maintenance Period, and have no 
major protocol violations that would have a significant impact on clinical outcome.
Efficacy
Primary Efficacy Analysis: The primary efficacy endpoint is the change in the mean convulsive 
seizure frequency (MCSF) per 28 days during the T+M periods compared with Baseline. The 
MCSF will be calculated from all available data collected during the Baseline and treatment 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 21 of 182
periods. The primary endpoint will be analyzed using an analysis of covariance (ANCOVA) 
model with treatment group (three levels) and age group (< 6 years, 6 years) as factors, and with 
Baseline MCSF as a covariate. The primary analysis will compare the ZX008 0.8 mg/kg/day 
group to the placebo group using a two-sided test at the alpha=0.05 level of significance. The 
primary endpoint will also be analyzed using a nonparametric method and if normality 
assumptions are not met, the results of the nonparametric analysis will be used for evaluation of 
the primary endpoint. An additional analysis will be performed to assess the sensitivity of the 
primary analysis to changes in concomitant AED medications that may occur during the course of 
the trial. Specifically, the primary analysis will be repeated with a factor added to indicate 
whether a subject had a change in concomitant AED medication during the T+M period.
Safety
All safety data will be appropriately analyzed by treatment group. The number and percentage of 
subjects with AEs will be displayed by body system and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA). Summaries in terms of severity and relationship 
to study drug will also be provided. Adverse Events of Special Interest (AESI) and Serious AEs 
(SAEs) will be summarized separately in a similar manner. Laboratory tests, vital signs, physical 
examinations, neurological examinations, ECG, Doppler echocardiogram, C-SSRS, Tanner 
Staging results, etc, will be summarized appropriately, by treatment. All safety summaries will be 
based on the Safety Population.
Pharmacokinetics
A population PK model will be fit to the fenfluramine concentration-time data collected during 
the Maintenance Period. This model will be informed by all relevant data available at the time of 
data collection (both adults and pediatrics). The population mean and interindividual variability 
estimates from the fit of the population PK model will be summarized. Derived plasma PK 
parameters (Cmax, AUC0-t, Tmax, and t1/2) will be summarized descriptively by treatment 
group and compared to historical data from adults. Summary statistics for plasma concentrations 
will be provided by PK sampling time.
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 22 of 182
Table 1: 
Schedule of Assessments 
Study Assessments
Baseline Perioda
Titration + Maintenance Period
EOS/
ETb
Post- 
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2
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6
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15
29
43
57
71
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197-281
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X
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X
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X
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X
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X
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X
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X
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X
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X
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

X
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X
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X
X
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X
X
X
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X
X

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X
X
X
X
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12-lead ECG
X
X
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X
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X
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X
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X
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X
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X
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X
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 23 of 182
Table 1: 
Schedule of Assessments continued 
Study Assessments
Baseline Perioda
Titration + Maintenance Period
EOS/
ETb
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15
29
43
57
71
85
99
113
197-281
Clinical Global Impression - 
Improvement (assessed by 
parent/caregiver)
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Clinical Global Impression - 
Improvement (assessed by principal 
investigator)
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BRIEF
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QOLCE
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PedsQL
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EQ-5D-5L (QoL of parent/caregiver)
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X
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HADS (Affect of parent/caregiver)
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Randomize subject
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First Day of Study Drug Administration
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Xj 
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Daily Diary Completion
X
Concomitant Medication
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X
Adverse events
X
Adverse events of special interest
X
Xk 
AED=antiepileptic drug; BMI=body mass index; BRIEF=Behavior Rating Inventory of Executive Function; C=Collect; CBD=cannabidiol;
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 
a: 
The Baseline Period is comprised of the initial screening for the study and the assessment of baseline seizure activity recorded daily in the diary. The 
procedures to be completed at the Screening visit may be completed in a single day or split so that they are completed over the 2-day period (i.e., Days -43 
to -42 or Days -42 to -41). 
b: 
Subjects who are discontinued early and those who complete the study and choose not to enroll in the separate open-label extension will be tapered off study 
medication over an up to 2-week period. 
c: 
Follow-up ECG, ECHO, and physical examination will be performed 3-6 months after early termination, or for those subjects who complete the study but do 
not enter the open-label extension study (see Section 6.4). 
d:  The Visit 8 ECHO must be performed any time between Study Day 40 and Study Day 54. The Visit 12 ECHO must be performed any time between 
Study Day 90 and Study Day 113; if a subject discontinues early from the study, the ECHO should be scheduled as soon as practical. If the Study Day 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 24 of 182
43 ECHO was completed < 30 days prior to early termination, the Visit 12 ECHO will not be performed provided the parent/guardian agrees to bring the 
subject to the clinic for the cardiac follow-up visit. 
e: 
Females of child-bearing  potential 
f: 
Plasma sample for pharmacokinetic assessment will be conducted prior to the dose at Visit 8 and 1, 2, and 4-6 hours after dose administration.  
g: 
Plasma sample for assessment of background AED(s) will be conducted prior to the dose of AED(s) at Visits 3, 6, 8 and 12. 
h: 
Study drug/diary dispensed for the Transition Period for subjects entering the open-label extension study and for the Taper Period for subjects exiting the 
study. 
i: 
Site personnel will review study medication dosing procedure (titration) with parent/caregiver. 
j: 
Study drug administration begins in the morning of Study Day 1. 
k: 
Only adverse events related to cardiac safety will be collected at this visit. 
l: 
Mandatory one time collection any time during or after screening. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 25 of 182
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). 
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). The degree of cognitive impairment appears to 
correlate, at least in part, with the frequency of seizures, and might be a result of repeated 
cerebral hypoxia. Children with DS also encounter a higher incidence of Sudden Unexpected 
Death in Epilepsy (SUDEP; Nashef 2012) than other populations with epilepsy. Indirect 
evidence has linked SUDEP to several possible etiologies, including seizure-induced apnea, 
pulmonary edema, dysregulation of cerebral circulation, and cardiac arrhythmias (Shorvon 
2011), although the actual etiology remains unknown and other mechanisms have not been 
ruled out. The vast majority of patients who survive to adulthood are wholly dependent on 
around-the-clock caregivers and eventually live in institutional care homes. 
1.1.1
Existing Treatment for Dravet Syndrome
DS is a highly treatment-resistant and refractory epilepsy syndrome. Establishment of a seizure-
free condition in affected children, even with anticonvulsant drug polypharmacy, is extremely 
rare, since all seizure types in DS appear to be drug resistant, with minimal improvement on 
currently available anticonvulsant drug therapies (Dravet 2000; Dravet 2005). Moreover, classic 
anticonvulsant medications whose mechanism is via sodium channel blockade, such as 
phenytoin and carbamazepine, increase these children’s seizure frequency and severity. 
To date, only one treatment, Diacomit® (stiripentol) is approved, and only in Europe, Canada, 
Japan, and Australia, as adjunctive therapy in patients with severe myoclonic epilepsy in infancy 
(SMEI, Dravet syndrome), and must be co-administered with clobazam and valproate. 
Stiripentol has not been approved for use in the United States of America, but is available under 
compassionate use protocols at certain clinical sites. 
 fenfluramine has been used as an unlicensed medicine in Belgium at 
2 academic medical centers, currently using an approved protocol under a Belgium Royal 
Decree (government approved prospective observation trial) for the treatment of DS; the 
efficacy and safety of this therapeutic approach have been published in a peer reviewed journal 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 26 of 182
(Ceulemans 2012; Ceulemans 2016) and reported to be very favorable. There are no treatments 
specifically approved for the treatment of DS in the United States of America (USA). 
Accordingly, there remains an unmet need for an approved treatment for children with DS. 
1.1.2
Other Antiepileptic Medications
USA and European Union approved anti-epileptic drug products include valproate, topiramate, 
carbamazepine, oxcarbazepine, lamotrigine, benzodiazepines, phenobarbital, potassium 
bromide, ethosuximide, phenytoin, and vigabatrin. The treatment of DS frequently requires a 
combination of two or three of these compounds, but with continued suboptimal seizure control. 
It cannot be assumed that because a treatment has been shown to be effective in common 
seizure types, that it will be effective in DS. In fact, some commonly used anti- epileptic drugs 
with a sodium channel mechanism of action, such as carbamazepine, oxcarbazepine, phenytoin, 
and lamotrigine, make DS worse. 
A review of the treatment modalities used for DS has been published by Chiron and Dulac 
(Chiron and Dulac 2011). This review indicates that valproate is commonly used as a first-line 
agent to prevent the recurrence of febrile seizures and oral/nasal/rectal benzodiazepine is used 
for any long-lasting seizures. However, the authors comment that these agents are most often 
insufficient. These author experts state that lamotrigine, carbamazepine, and high doses of 
intravenous phenobarbital should be avoided because they may worsen seizures and that 
topiramate, levetiracetam and bromide may provide substantial efficacy as adjunctive therapy 
for some patients. The authors comment that the benefit of these compounds is mild and there 
are no trials to validate the impression of any effect. 
Given the cognitive consequences believed to be caused, at least in part, by frequent childhood 
seizure activity, there is a medical need for a new anticonvulsant treatment that can significantly 
reduce seizure activity in DS. There is the possibility that early, effective seizure control could 
be disease-modifying, leading to an improvement in longer-term outcomes with respect to 
motor impairment, behavioral issues, and cognitive function. 
1.2
BACKGROUND INFORMATION ON STUDY PRODUCT
Zogenix is developing a new formulation of fenfluramine hydrochloride, ZX008, for the 
adjunctive treatment of DS. Fenfluramine is an amphetamine analogue that was first 
synthesized many years ago. It was approved in a large number of countries and widely 
prescribed as an appetite suppressant for the treatment of adult obesity. Brand names for 
fenfluramine formulations included Ponderax, Pondimin and others.  Fenfluramine was also 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 27 of 182
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 2016). There is also a large body of information concerning its clinical safety profile. 
1.3
PRECLINICAL DATA
The pharmacokinetics of fenfluramine, norfenfluramine and their respective isomers has been 
studied in mice, rats, dogs and humans. The pharmacokinetics 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 pharmacokinetics and 
metabolism of fenfluramine after oral administration. In humans, fenfluramine is metabolized 
primarily to norfenfluramine. CYP1A2, CYP2B6, and CYP2D6 appear to be the predominant 
CYP 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 FDA’s mechanistic static model shows that fenfluramine and its major metabolite 
norfenfluramine are unlikely to alter the pharmacokinetics of substrates of these CYP450 enzymes 
in the range of ZX008 doses that will be administered in this study. 
A Good Laboratory Practice dose-range-finding juvenile toxicology and toxicokinetic study, 
which included a 3-week repeat dose main study, and histopathology of heart valves and other 
key organs, found no effect on heart valves or other organs. 
Based on clinical signs and decreased body weight gain, the no-observed-adverse-effect-level for 
this study was 12 mg/kg/day. This is equivalent to a human dose of 1.94 mg/kg/day based on 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 28 of 182
body surface area, and provides a safety factor of 2.4 for the highest dose of 0.8 mg/kg/day that 
will be administered clinically. 
Further details on the preclinical data of ZX008 are available in the Investigator’s Brochure 
(ZX008 IB 2016). The current version is available in the Investigator Study File. 
1.4
BACKGROUND INFORMATION ON REFERENCE PRODUCT
Not applicable. 
1.5
RATIONALE FOR CURRENT STUDY
Based on several published reports of fenfluramine’s successful treatment of refractory 
childhood epilepsy in the 1980s (Aicardi and Gaustaut 1985; Aicardi 1988) and its successful 
treatment of 11 refractory pediatric epilepsy patients in Belgium (Boel 1996), in 2002 Drs. 
Ceulemans and Lagae were granted authorization to prescribe fenfluramine to their patients with 
refractory pediatric epilepsy conditions, including DS, under an approved protocol under a 
Belgium government program (Royal Decree). To date, these pediatric neurologists have DS 
patients (infants, children, young adults, and now also adults), being successfully treated with 
fenfluramine 
 The efficacy and safety of this therapeutic approach has been 
reported to be overwhelmingly favorable. In the most recent assessment of efficacy of these 
patients reported by the investigators in 2016, the average length of treatment was over 12 years, 
with one patient being successfully treated for 26 years (Ceulemans 2016). 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. 
In addition, numerous publications discuss the use of fenfluramine in over 500 children with 
neurobehavioral conditions for the treatment of mostly autism and ADHD, without any reports of 
any cardiovascular adverse events (ZX008 IB 2016). 
Prior to being withdrawn from the market, fenfluramine was marketed at doses of 20 mg and 40 
mg three times daily for the management of obesity in adults. The doses tested thus far in DS 
range from 0.12 to 0.9 mg/kg/day in subjects over 1 year of age to adults. Doses tested in pediatric 
studies evaluating autism and ADHD ranged from 0.65 mg/kg/day to 3.6 mg/kg/day, but a 
commonly used dose was 1.5 mg/kg/day. Occasionally, fixed doses of 30 to 80 mg were used.  
The PK exposure associated with the proposed doses in DS studies of 0.2 mg/kg/day and 
0.8 mg/kg/day administered orally (in equally divided doses BID) is expected to be lower than 
that obtained at the doses used in the past for the treatment of obesity in adults and of 
neurobehavioral conditions in children and adolescents (ZX008 IB 2016). The doses used in this 
study are based on the data from the DS patients being successfully treated in Belgium discussed 
above. 
There are no treatments specifically approved for the treatment of DS in the USA, and in fact, 
commonly used anticonvulsants with a sodium channel mode of action, such as phenytoin and 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 29 of 182
carbamazepine, worsen the condition. Accordingly, there remains a significant unmet need for an 
approved treatment for children and adults with DS. 
1.6 
RISK-BENEFIT ASSESSMENT
As described above, fenfluramine has been used successfully 
 in some DS 
patients to control seizures, without emergence of clinical valvulopathy or pulmonary 
hypertension. Fenfluramine was administered to over 500 children with neurobehavioral 
conditions, including autism and ADHD with good safety and tolerability, most often at a 
1 mg/kg dose. 
The pharmacologic and toxicological profile for the active pharmaceutical ingredient, 
fenfluramine, following oral administration is well established (see ZX008 IB 2016). 
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. 
The approximate volume of blood (108.7 mL) planned for collection from each subject over the 
course of the entire study (Screening to End of Study, but not including repeat or additional tests 
ordered by the investigator) presents no undue risk to the subjects. 
The ZX008 0.2 mg/kg/day and 0.8 mg/kg/day doses are believed to be 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. 
2.
STUDY OBJECTIVES AND ENDPOINTS
2.1
PRIMARY OBJECTIVE
The primary objective of the study is: 
x
To demonstrate that ZX008 0.8 mg/kg/day is superior to placebo as adjunctive therapy in the 
treatment of Dravet syndrome 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). 
2.2
KEY SECONDARY OBJECTIVES
The key secondary objectives of the study are: 
x
To demonstrate that ZX008 0.2 mg/kg/day is superior to placebo as adjunctive therapy in the 
treatment of Dravet syndrome based on change in the frequency of convulsive seizures 
between baseline and T+M. 
x
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints: 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 30 of 182
o
The proportion of subjects who achieve a 40% reduction from baseline in 
convulsive seizure frequency. 
o
The proportion of subjects who achieve a 50% reduction from baseline in 
convulsive seizure frequency. 
o
The longest convulsive seizure-free interval. 
See Statistical Methods (Section 10.5.1.3) for hierarchical testing procedure. 
2.3
ADDITIONAL SECONDARY OBJECTIVES
Other secondary objectives of the study are: 
x
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints: 
o
The number of convulsive seizure-free days. 
o
The proportion of subjects who achieve 75% reductions from baseline in convulsive 
seizure frequency. 
o
The change from baseline in non-convulsive seizure frequency. 
o
The change from baseline in convulsive + non-convulsive seizure frequency 
o
The incidence of rescue medication usage 
o
The incidence of hospitalization to treat seizures 
o
The incidence of status epilepticus. 
x
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints: 
o
Clinical Global Impression – Improvement rating, as assessed by the principal 
investigator. 
o
Clinical Global Impression – Improvement rating, as assessed by the 
parent/caregiver. 
o
The change from baseline in the QOLCE score. 
o
The change from baseline in the PedsQL score. 
o
The change from baseline in the PedsQL Family Impact module score. 
o
The change from baseline in the QoL of the parent/caregiver using the EQ-5D-5L 
scale. 
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The change from baseline in the affective symptoms of the parent/caregiver using the 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 31 of 182
2.4
SAFETY OBJECTIVE
The safety objective of the study is: 
x
To compare the safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day to placebo with 
regard to AEs, laboratory parameters, physical examination, neurological examination, vital 
signs (blood pressure, heart rate [HR], temperature, and respiratory rate), ECGs, ECHOs, 
and body weight. Cognitive Function will be assessed using the cognition domain score on 
the QOLCE and age-appropriate versions of the BRIEF.  
2.5
PHARMACOKINETIC OBJECTIVE
The pharmacokinetic (PK) objective of the study is: 
x
To characterize the PK of ZX008 0.2 and 0.8 mg/kg/day at steady state in subjects ages 2-6 
years and >6-18 years with Dravet syndrome. 
2.6
EXPLORATORY OBJECTIVE
The exploratory objective of the study is: 
x
To compare the ZX008 0.2 and 0.8 mg/kg/day doses on primary, secondary, safety and PK 
endpoints. 
2.7
STUDY ENDPOINTS
2.7.1
Efficacy Endpoints
The efficacy endpoints of the study are: 
x
Number of seizures by type 
x
Convulsive seizure-free interval 
x
Clinical Global Impression – Improvement as assessed by parent/caregiver 
x
Clinical Global Impression – Improvement as assessed by principal investigator 
x
QOLCE to measure changes in quality of life of the subject 
x
PedsQL to measure changes in quality of life of the subject 
x
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x
QoL of the parent/caregiver using the EQ-5D-5L scale 
x
Affective symptoms of the parent/caregiver using the HADS scale 
x
Duration of prolonged seizures (seizure type that, during baseline, had duration 
x
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 32 of 182
x
Number of episodes of status epilepticus 
x
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x
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Safety Endpoints
The safety endpoints of the study are: 
x
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x
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x
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Pharmacokinetic Endpoints
The PK endpoints of the study are: 
x
Steady-state plasma fenfluramine PK parameters (Cmax, AUC0-t, Tmax, and t1/2) after 
administration of ZX008 derived using population PK methods 
3.
INVESTIGATIONAL PLAN
3.1
OVERALL STUDY DESIGN AND PLAN
This is a multicenter, double-blind, parallel-group, placebo-controlled, study to assess the efficacy, 
safety, and PK of ZX008 when used as adjunctive therapy in pediatric and young adult subjects 
with Dravet syndrome. Approximately 30 study sites in North America are planned to participate. 
The 6-week Baseline Period will consist of the establishment of initial eligibility during a 
screening visit followed by an observation period where subjects will be assessed for baseline 
seizure activity based on recordings of daily seizure activity entered into a diary. Upon completion 
of the Baseline Period, subjects who qualify for the study will be randomized (1:1:1) in a double-
blind manner to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; maximum dose: 30 
mg/day) or placebo. Randomization will be stratified by age group (<6 years, 6 years) to ensure 
balance across treatment arms, and at least 40% of subjects will be in each age group. All subjects 
will be titrated to their randomized dose over a 14-day Titration Period. Following titration 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 33 of 182
subjects will continue treatment at their randomly assigned dose over a 12-week Maintenance 
Period. Total treatment time from the beginning of the Titration Period through the end of the 
Maintenance Period is 14 weeks. Parents/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. 
At the end of the Maintenance Period (or early discontinuation), all subjects will undergo a 
2-week taper or transition period (Post-Dosing Follow-Up) depending on whether they exit the 
study or are enrolled in the separate long-term open-label extension study. 
A follow-up ECHO, ECG, and possibly physical examination will be performed 3-6 months 
after study drug discontinuation for early termination, or for those subjects who complete the 
study but do not enter the open-label extension study. 
3.2
NUMBER OF SUBJECTS
Approximately 130 subjects will be screened to obtain 115 subjects who enter the Baseline 
Period. Of these 115 subjects, it is estimated that 105 subjects will be randomized into the 
Titration Period. Each clinical site will not randomize more than a maximum of 10 subjects 
without prior consent from the sponsor. 
3.3
STUDY DURATION
The duration of participation in the study for an individual subject is expected to be up to 22 
weeks, plus follow-up safety visit 3 to 6 months after the last dose: 
x
Baseline Period – 6 weeks 
x
T+M Period - 14 weeks 
x
Post-Dosing Visit – 2 weeks after study completion or early termination 
x
Cardiac Follow-up (ECG and ECHO)– 3-6 months after study drug discontinuation for early 
termination or for subjects who complete the study but do not enroll in the open-label 
extension study. 
3.4
NUMBER OF STUDY CENTERS
The study expects to use up to approximately 30 research centers in North America. Additional 
study centers within or outside of North America may be added if enrollment cannot be 
completed in a timely manner. 
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 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 34 of 182
DS in this study is considered justified. Stratifying the randomization by age group is considered 
appropriate because the frequency and severity of major seizures can be higher in younger 
subjects. The two strata in the study will be subjects aged below 6 years and subjects aged 6 -18 
years. The study design has incorporated a titration period to enable subjects randomized to the 
high dose group adequate time to acclimate to this dose. Following the Titration Period, subjects 
will enter a 12-week Maintenance Period where they will continue on their randomized dose for 
the remainder of the study. The 12-week duration of the Maintenance Period is in keeping with 
the current standard study duration for evaluating the efficacy of chronic medications. Given the 
individual variability in seizure frequency and seizure type in this patient population, the primary 
endpoint, which seeks to compare an appropriate baseline of convulsive seizure frequency to the 
convulsive seizure frequency following treatment, is an appropriate primary endpoint for efficacy 
in this population. 
Subjects will receive investigational medicinal product (IMP; ZX008 or placebo) in addition to 
their existing antiepileptic medications at their stable doses throughout the entire study. Thus, 
subjects receiving placebo will not be denied active therapy; they will continue to receive their 
existing medications at the exact same dosages. As the principal study measurement (convulsive 
seizures) might be considered subjective, a double-blind study design will prevent subjective bias. 
Upon study completion, eligible subjects will be able to receive ZX008 in an open-label extension 
study for up to 1 additional year of treatment. 
3.6
PREMATURE TERMINATION OF STUDY
The sponsor can terminate the study prematurely at any time for medical or ethical reasons at 
individual or at all study sites. The investigator will be notified in writing, outlining the reasons 
for the termination. Instructions will be provided if assessments beyond those described in the 
study protocol need to be conducted. 
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 6.2.9 and Section 6.3. 
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)/IRB. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 35 of 182
3.7
STUDY MONITORING PROCEDURES
3.7.1
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 IDMSC will: 
x
Be responsible for providing recommendations to the sponsor surrounding study conduct 
matters that affect safety. 
x
Review safety data at ad hoc time points and identify if significant safety concerns arise 
during the study. 
x
Review pharmacokinetic data and any other data that may affect subject continuation. 
x
Make recommendations regarding the continuation, suspension, or termination of the study. 
3.7.2
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 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. 
4.
SELECTION OF STUDY POPULATION
The study population will be selected on the basis of the inclusion and exclusion criteria 
described in the sections below. Before evaluating these criteria and deciding on the eligibility of 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 36 of 182
subjects to participate in the study, it is important that the investigator is familiar with the safety 
profile of ZX008 by referring to the Investigator’s Brochure, as supplied by the sponsor. 
4.1
INCLUSION CRITERIA
Subjects meeting all of the following inclusion criteria may be enrolled into the study: 
1. Subject is male or non-pregnant, non-lactating female, age 2 to 18 years, inclusive as of 
the day of the Screening Visit. Female subjects of childbearing potential must not be 
pregnant or breast-feeding. Female subjects of childbearing potential must have a 
negative urine pregnancy test. Subjects of childbearing or child-fathering potential must 
be willing to use medically acceptable forms of birth control (see Section 4.4), which 
includes abstinence, while being treated on this study and for 90 days after the last dose 
of study drug. 
2. Subject must have documented medical history to support a clinical diagnosis of Dravet 
syndrome, where convulsive seizures are not completely controlled by current 
antiepileptic drugs. 
3.
Subjects must meet all of the following 5 criteria: 
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 brain malformation. 
e.
Lack of alternative diagnosis. 
4. Subjects must meet at least one of the following 3 criteria: 
a.
Emergence of another seizure type, including myoclonic, generalized tonic- 
clonic, tonic, atonic, absence and/or focal has developed after the first seizure 
type. 
b. 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 
natural and/or fluorescent lighting, as well as certain visual patterns. 
c.
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.) 
5. 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. 
6. All medications or interventions for epilepsy (including KD and VNS) must be stable 
for at least 4 weeks prior to screening and are expected to remain stable throughout the 
study. 
7. Subject has been informed of the nature of the study and informed consent has been 
obtained from the legally responsible parent/guardian. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 37 of 182
8. Subject has provided assent in accordance with Institutional Review Board (IRB) 
requirements, if capable. 
9. Subject’s parent/caregiver is willing and able to be compliant with diary completion, 
visit schedule and study drug accountability. 
4.2
EXCLUSION CRITERIA
Subjects meeting any of the following exclusion criteria must not be enrolled into the study: 
1.
Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study 
medication. 
2.
Subject has pulmonary arterial hypertension. 
3.
Subject has current or past history of cardiovascular or cerebrovascular disease, such as 
cardiac valvulopathy, myocardial infarction or stroke.  
4.
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. 
5.
Subject is at imminent risk of self-harm or harm to others, in the investigator’s opinion, 
based on clinical interview and/or responses provided on the C-SSRS. Subjects must be 
excluded if they report suicidal behavior in the past 6 months as measured by the C- 
SSRS at Screening or Baseline, which includes suicidal ideation with intent and plan 
(Item #5). If a subject reports suicidal ideation on Item 4 without specific plan, and the 
investigator feels that the subject is appropriate for the study considering the potential 
risks, the investigator must document appropriateness for inclusion, and discuss with the 
parent/caregiver to be alert to mood or behavioral changes, especially around times of 
dose adjustment. 
6.
Subject has a current or past history of glaucoma. 
7.
Subjects with moderate or severe hepatic impairment may not be entered. Asymptomatic 
subjects with mild hepatic impairment (elevated liver enzymes < 3xULN and/or elevated 
bilirubin <2xULN) may be entered into the study after review and approval by the 
Medical Monitor in conjunction with the sponsor, with consideration of potential cause, 
concomitant medications, and other risk factors. 
8.
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; 
or 
cyproheptadine (see Appendix 1). (Note: Short-term medication requirements will be 
handled on a per case basis by the Medical Monitor.) 
9.
Subject is currently receiving or has received stiripentol in the past 21 days prior to 
Screening. 
10. Subject 
is 
currently 
taking 
carbamazepine, 
oxcarbamazepine, 
eslicarbazepine, 
phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as 
maintenance therapy. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 38 of 182
11. Subject is unwilling to refrain from large or daily servings of grapefruits and/or Seville 
oranges, and their juices beginning with the Baseline Period and throughout the study. 
12. Subject has positive result on urine THC Panel or whole blood CBD at the Screening 
Visit. 
13. Subject has participated in another clinical trial within the past 30 days. 
14. Subject is currently receiving an investigational product. 
15. Subject is unwilling or unable to comply with scheduled visits, drug administration 
plan, laboratory tests, other study procedures, and study restrictions. 
16. Subject has a clinically significant condition, or has had clinically relevant symptoms or 
a clinically significant illness in the 4 weeks prior to the Screening Visit, other than 
epilepsy, that would negatively impact study participation, collection of study data, or 
pose a risk to the subject. 
4.3
RANDOMIZATION INCLUSION CRITERIA
Subjects must meet all of the inclusion criteria above plus the following criteria, to be 
randomized: 
1. Subject has been approved for study inclusion by the Epilepsy Study Consortium. 
2. Subject does not have a cardiovascular or cardiopulmonary abnormality based on ECHO, 
ECG or physical examination, including but not limited to trace mitral or aortic valve 
regurgitation or signs of pulmonary hypertension, and is approved for entry by the central 
cardiac reader. 
3. Subject demonstrates a stable baseline with ш6 convulsive seizures during the 6-week 
Baseline Period, with a minimum of 2 in the first 3 weeks and 2 in the second three 
weeks. 
4. Subject’s parent/caregiver has been compliant with diary completion during the 
Baseline Period, in the opinion of the investigator (e.g., at least 90% compliant). 
4.4
SUBJECTS OF REPRODUCTIVE POTENTIAL
Male subjects who are sexually active with a partner of childbearing potential must use, with 
their partner, a condom plus an approved method of highly effective contraception from the time 
of informed consent until 90 days after the last dose of study drug. 
The following methods are acceptable: 
x
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inhibition of ovulation: 
o
oral 
o
intravaginal 
o
transdermal 
x
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 39 of 182
o
oral 
o
injectable 
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x
Surgical sterilization (vasectomy or bilateral tubal occlusion) 
Female subjects who are not of childbearing potential do not need to use any methods of 
contraception. A woman is considered of childbearing potential, unless they are at least 2 years 
post-menopausal or permanently sterile. Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy. 
Female subjects who are sexually active and are of childbearing potential must use, with their 
partner, an approved method of highly effective contraception from the time of informed consent 
until 90 days after the last dose of study drug. 
The following methods are acceptable: 
x
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation and a barrier method (i.e., condom for male partner): 
o
oral 
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o
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x
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barrier method (i.e., condom for male partner):  
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intrauterine hormone-releasing system 
x
Surgical sterilization (vasectomy or bilateral tubal occlusion) 
Alternatively, true abstinence is acceptable when it is in line with the subject’s preferred and 
usual lifestyle. If a subject is usually not sexually active but becomes active, they, with their 
partner, they must comply with the contraceptive requirements detailed above. 
4.4.1
Sperm and Egg Donation
Male subjects should not donate sperm and female subjects should refrain from egg donation 
for the duration of the study and for at least 90 days after the last day of study medication 
administration. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 40 of 182
4.4.2
Pregnancy
Subjects will be instructed that if they/their partner become pregnant during the study this 
should be reported to the investigator. The investigator should also be notified of pregnancy 
occurring during the study but confirmed after completion of the study. In the event that a 
subject/subject’s partner is subsequently found to be pregnant after the volunteer is included 
in the study, then consent will be sought from the partner and, if granted, any pregnancy will 
be followed and the status of mother and/or child will be reported to the sponsor after 
delivery. Any subject reporting a pregnancy during the study will be withdrawn from the 
study and should complete the taper schedule. 
4.5
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT
While subjects are encouraged to complete all study evaluations, subjects may voluntarily 
withdraw from the study for any reason at any time. They may be considered withdrawn if they 
fail to return for visits, or become lost to follow-up for any other reason. 
If premature withdrawal occurs for any reason, the investigator must make a genuine effort to 
determine the primary reason for a subject’s premature withdrawal from the study and record this 
information on the electronic case report form (eCRF). All subjects who withdraw from the study 
with an ongoing AE must be followed until the event is resolved or deemed stable. If a subject 
withdraws prematurely after dosing, all data to be collected prior to discharge from the clinical site 
should be collected at the time of premature discontinuation or at the scheduled discharge. 
For subjects who are lost to follow-up (i.e., 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 (e.g., 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 
form
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 41 of 182
such that treatment outside of the protocol and other than ZX008 is assumed to be in the 
subject’s best interest. Frequent or increased use of rescue medication may be considered 
indicative of worsening. 
8. An “actual suicide attempt” as classified by the Columbia-Suicide Severity Rating Scale 
(C-SSRS). 
9. It is the investigator’s opinion that it is not in the subject’s best interest to continue in the 
study. 
10. Subject is found to be pregnant while on study. 
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 who are discontinued from the clinical investigation for any reason will not be 
replaced. 
Subjects may withdraw their consent to participate in the study at any time without having to 
justify the reason for doing so. The decision to withdraw consent and discontinue participation in 
the study will not prejudice the subject’s future medical treatment in any way. Subjects must be 
discontinued from receiving ZX008 and/or participating in any further study procedures under the 
following circumstances: 
x
The subject or the subject’s legally authorized representative wishes to discontinue 
participation in the study. 
x
The investigator advises that the subject’s safety or well-being could be compromised by 
further participation in the study. 
x
The sponsor requests that a subject discontinues participation in the study (e.g., due to 
suspicion of fraud, multiple enrollments in clinical studies, lack of compliance). 
The IDSMC may request that the study be terminated after review of the safety information at any 
time during the study. The IDMSC will review the data for the development of heart valve disease 
and pulmonary hypertension as they occur on a case-by-case basis and at regular meetings. 
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 eCRF and in the subject’s medical records (e.g., AEs, lack of compliance, lost to 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 42 of 182
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 to that 
time. Specific procedures required are described in Section 6.2.9 and Section 6.3. As far as 
possible, a complete final examination must be performed on all subjects who do not complete the 
study according to the study protocol. 
Data collected until the time a subject discontinues participation in the study will be handled in the 
same manner as data for subjects completing the study. Where possible, further information will 
be collected if any AEs are experienced by a subject after discontinuing participation in the study. 
4.6
TERMINATION OF THE CLINICAL STUDY
If the investigator, the sponsor, the Medical Monitor, or the IDSMC becomes aware of conditions 
or events that suggest a possible hazard to subjects if the clinical study continues, then the clinical 
study may be terminated. The clinical study may be terminated at the sponsor’s discretion at any 
time also in the absence of such a finding. 
Conditions that may warrant termination of the clinical study include, but are not limited to: 
x
The discovery of an unexpected, relevant, or unacceptable risk to the subjects enrolled in the 
clinical study. 
x
Failure to enroll subjects at the required rate. 
x
A decision of the sponsor to suspend or discontinue development of ZX008. 
4.7
REPLACEMENT OF SUBJECTS
Enough subjects will be enrolled in the trial to ensure that approximately 105 subjects are 
randomized into the T+M Period.  Randomized subjects will not be replaced. 
4.8
ELIGIBILITY FOR EXTENSION STUDY
Subjects who complete the 12-week Maintenance Period of this study will be eligible to enroll in 
a planned, separate, open-label extension trial of ZX008 if they meet Inclusion/Exclusion criteria 
for that study regarding their suitability for continued participation in a trial of fenfluramine. 
Subjects must complete the entire 12-week Maintenance Period in order to be offered enrollment 
into the separate, open-label extension trial of ZX008. Those subjects who do not complete the 
12-week Maintenance Period of the study may, on a case-by-case basis, be eligible for entrance 
into the separate open-label extension study 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. 
5.
INVESTIGATIONAL MEDICINAL PRODUCT INFORMATION
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 43 of 182
ZX008/matching placebo will be administered in the current study. A brief description of the 
ZX008 product is provided below (Table 2). 
Table 2: 
Investigational Medicinal Product – ZX008
Study Product
Substance Code 
ZX008
Active Substance (INN) 
Fenfluramine Hydrochloride
Trade Name 
Not applicable
Formulation (including dosage form and strength) 
Solution 1.25, 2.5, and 5 mg/mL
Route/Mode of Administration 
Oral
Manufacturer 
PCI Pharma Services on behalf of Zogenix
International Limited 
 
5.1
IDENTITY OF INVESTIGATIONAL MEDICINAL PRODUCT
ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 
and provided in concentrations of 1.25 mg/mL, 2.5 mg/mL, and 5 mg/mL. The excipients selected 
have been approved for use in the formulations of currently marketed drug products and are 
considered to be safe. The solution formulations will be suitably flavored and colored, and will 
contain preservatives and a thickening agent. The product is sugar free and is intended to be 
compatible with a KD. 
The formulation will be provided in bottles with tamper-evident, child-resistant caps. The 
clinical trials material will be supplied in 1 bottle size with nominal fill volume of 120 mL. 
Matching placebo also will be provided.  Doses to be studied include 0.2 mg/kg/day and 
0.8 mg/kg/day divided into two daily (BID) doses, up to a maximum of 30 mg/day. An 
intermediate dose of 0.4 mg/kg/day will be used for titration. The concentration of ZX008 oral 
solution received by subjects (1.25 mg/mL, 2.5 mg/mL, and/or 5 mg/mL) will be randomized 
across the 3 available concentrations in order to ensure blinding. 
If the parent/caregiver is unable to administer the full dose due to spillage (e.g., dose was spilled 
during measuring, subject spit dose out during administration), he/she should attempt to give the 
full dose noting the extra amount used to fulfill the dose. 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 International Conference on 
Harmonization (ICH), Good Manufacturing Practices (GMP), and Good Clinical Practices (GCP) 
guidelines, and national legal requirements. 
Dosing directions for the product can be found in the IMP handling instructions for the study 
subjects and for the investigator. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 44 of 182
5.2
DESCRIPTION OF REFERENCE TREATMENT, COMPARATOR, 
AND/OR PLACEBO
Placebo solution is identical in aspect and composition to ZX008 and is composed of identical 
ingredients used in the ZX008 formulation, except that it does not contain the active ingredient, 
fenfluramine hydrochloride. 
No comparators or reference treatments will be used. 
5.2.1 
Labeling and Packaging
Placebo solution will be packaged in an identical manner to ZX008. The matching placebo product 
will be packaged and labeled according to current ICH, GMP, and GCP guidelines, and national 
legal requirements. 
Dosing directions for the product can be found in the IMP handling instructions for the study 
subjects and for the investigator. 
5.3
SHIPMENT AND STORAGE
IMP will be supplied to the study sites by the sponsor or its delegate. 
All IMP will be transported, received, stored, and handled strictly in accordance with the 
container or product label, the instructions supplied to the research site and its designated 
pharmacy, the site’s standard operating procedures, and applicable regulations. IMP must be 
stored separately from normal hospital or practice inventories, in a locked facility with access 
limited to the investigator and authorized personnel. The investigator must ensure that the IMP is 
dispensed only to subjects enrolled in this study according to this study protocol. 
Appropriate storage temperature and transportation conditions will be maintained for the study 
drug from the point of manufacture up to delivery of the study drug. Study medication must be 
stored at 15-25°C (59-77°F) with excursions of 5-30°C (41-86°F) permitted; do not freeze. 
Storage and handling instructions of the IMP maintained at the subject’s home are described in 
the subject’s IMP handling instructions. 
All unused IMP will be saved by the site for final disposition according to the sponsor’s 
directive. 
5.4
IMP ACCOUNTABILITY
The investigator or delegate will confirm receipt of all shipments of the IMP in writing using 
the receipt form(s) provided by the sponsor or vendor. 
Assignment of ZX008 or placebo to the subject will be handled through an interactive voice 
randomization (IVR) or Interactive Web Response (IWR) platform. The investigator or delegate 
will be required to register the subject through IVR/IWR and all study medication will be assigned 
to the subject through the IVR/IWR. The IVR/IWR will also maintain a log of all received and 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 45 of 182
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, e.g., pharmacist) original drug accountability form must 
be retained at the study site as verification of final drug accountability. 
Records for the delivery of the IMP to the study site, the inventory at the study site, the use by 
each subject (use by subject will be documented in the subject diary), and the destruction or 
return of the IMP to the sponsor must be maintained by the investigator (or delegate). The records 
will include dates, quantities, batch numbers, and unique code numbers assigned to the IMP and 
to the subjects. The investigator must maintain records documenting that subjects were provided 
with the doses of the IMP specified in this study protocol. Furthermore, the investigator must 
reconcile all IMPs received from the sponsor. The investigator must provide reasons for any 
discrepancies in drug accountability. Forms will be provided by the sponsor to ensure 
standardized and complete drug accountability. 
5.5
TREATMENT ADMINISTRATION
5.5.1 
Randomization
Upon completion of the Baseline Period, subjects who qualify for the study will be randomized 
(1:1:1) in a double-blind manner to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; 
30mg/day maximum) or placebo. The randomization will be stratified by age (<6 years, 6 years) 
to ensure balance across treatment arms, and at least 40% of subjects will be in each age group. 
Subjects will be assigned a randomization number by the IVR/IWR system upon confirmation that 
subject qualifies for enrollment in the Titration Period. Once a randomization number is assigned 
to a subject, the site will record the subject’s initials and identification number on the 
corresponding study drug bottles. Each bottle will contain the assigned treatment (ZX008 0.2 
mg/kg/day, ZX008 0.8 mg/kg/day, or placebo). ZX008 and placebo will be identical, thus 
rendering the study drug and placebo indistinguishable. For each IMP bottle and randomization 
number assigned, the following information will be recorded on the drug accountability form: 
subject initials, unique bottle number, date each bottle is assigned, and drug used and unused 
during the study. 
5.5.2 
Titration 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 IMP will be based on the randomized dose and subject’s weight (kg) at 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 46 of 182
Visit 3 (Study Day -1). At Visit 8 (Study Day 43), if the subject’s weight (kg) has changed 
±25% of the weight at Study Day-1, the IMP dose will be recalculated. Subjects should be 
dosed using the oral dosing syringe provided. 
In order to maintain the blind across all dose groups (Section 5.6) and allow step titration to the 
high dose, the dose for each subject will be titrated starting with a dose of ZX008 
0.2 mg/kg/day (or placebo equivalent) BID. After 4 days at this dose level (Study Day 5), 
subjects randomized to the ZX008 0.8 mg/kg/day group will increase their dose to 
0.4 mg/kg/day (maximum 30 mg/day) while doses in the other two groups will remain 
constant. On Study Day 9, the dose for the 0.8 mg/kg/day group will increase to the target dose 
or a maximum of 30 mg/day. The titration is expected to take a total of 14 days (Table 3). A 
new bottle of IMP will be started by the subject at each level of the titration step. See 
Section 5.6 for more information about the volume of ZX008 or placebo to be administered. 
Table 3: 
Titration Algorithm 
Randomized Group
Titration Step 1
Study Day 1-4
Titration Step 2
Study Days 5-8
Titration Step 3
Study Days 9-14
ZX008 0.2 mg/kg/day
ZX008 0.2 mg/kg/day
ZX008 0.2 mg/kg/day
ZX008 0.2 mg/kg/day
ZX008 0.8 mg/kg/day
ZX008 0.2 mg/kg/day
ZX008 0.4 mg/kg/day
ZX008 0.8 mg/kg/day
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Note: maximum daily dose of ZX008 is 30 mg
5.5.3
Maintenance Period
After completion of the Titration Period, subjects will enter the Maintenance Period and 
continue to receive the randomized dose of ZX008 or placebo and be treated for an additional 
12 weeks. Study medication will continue to be administered BID in the morning and in the 
evening, approximately 12 hours apart, 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. 
5.5.4
Taper Period
Subjects who complete of the Maintenance Period and will not be continuing into the open- 
label extension study, and subjects who discontinue from the study early, will be tapered off of 
study medication.  Study medication will be administered as equal doses BID in the morning 
and in the evening approximately 12 hours apart, 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 should be administered using the oral dosing syringe provided. 
In order to maintain the blind across all dose groups, all subjects who do not continue into the 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 47 of 182
open-extension study will participate in a dose-tapering procedure over the course of 8 days. On 
the first day of the tapering period subjects in the ZX008 0.8 mg/kg/day group will decrease to a 
dose of ZX008 0.4 mg/kg/day BID (maximum 30 mg/day). After 4 days at this dose level 
(Study Day 5), subjects randomized to the ZX008 0.8 mg/kg/day group will decrease their dose 
to 0.2 mg/kg/day. Subjects in the ZX008 0.2 mg/kg/day group will decrease their dose to 
placebo on the first day of tapering while doses in the placebo group will remain constant 
throughout the tapering procedure. On Study Day 9, all subjects will stop taking study 
medication. The taper is expected to take a total of 8 days (Table 4). A new bottle of IMP will 
be started by the subject at each level of the taper step. 
Table 4: 
Taper Algorithm 
Randomized Group
Taper Step 1
Day 1-4 after study completion or 
early termination
Taper Step 2
Days 5-8 after study completion or 
early termination
ZX008 0.2 mg/kg/day
Placebo
Placebo
ZX008 0.8 mg/kg/day
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day
Placebo
Placebo
Placebo
Note:  maximum daily dose of ZX008 is 30 mg.
5.5.5
Transition Period
Subjects who complete the Maintenance Period and will be continuing into the open-label 
extension study will be transitioned from double-blind study medication to open-label ZX008 
(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. 
Study medication should be administered using the oral dosing syringe provided. 
All subjects entering the open-label extension study will be transitioned from their blinded daily 
dose (placebo, 0.2 mg/kg/day, 0.8 mg/kg/day, or 30 mg/day) to the 0.2 mg/kg dose during the 
2-week interval between Visits 12 and 13, without breaking the blind. The IVR/IWR system 
will assign two bottles of IMP to the subject, one for each step in the transition. A new bottle of 
IMP will be started by the subject at each level of the transition step. See Section 5.6 for more 
information about the volume of ZX008 or placebo to be administered. 
Table 5: 
Transition Algorithm 
Dose Group in 
Double-Blind Study
Transition Step 1
Day 1-4 after Visit 12
Transition Step 2
Days 5-14 after Visit 12
ZX008 0.2 mg/kg/day
ZX008 0.2 mg/kg/day
ZX008 0.2 mg/kg/day
ZX008 0.8 mg/kg/day
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 48 of 182
Placebo
ZX008 0.2 mg/kg/day
ZX008 0.2 mg/kg/day
Note: maximum daily dose of ZX008 is 30 mg.
Subjects who had been randomized to placebo increase their dose to 0.2 mg/kg/day beginning 
on Day 1 of the transition (the day following Visit 12). Subjects who had been randomized to 
0.2 mg/kg/day will continue to receive that dose. Subjects who had been randomized to 
0.8 mg/kg/day or were receiving the maximum dose of 30 mg/day decrease to a dose of ZX008 
0.4 mg/kg/day, or a maximum of 30 mg/day. After 4 days at this dose level (Day 5), these 
subjects will decrease their dose to 0.2 mg/kg/day. Subjects will report to the clinic on Day 15 
for enrollment into the open-label extension study. 
5.6
BLINDING
At the end of the Baseline Period, subjects who qualify to enter the study will be randomized to 
receive ZX008 0.2 mg/kg/day, ZX008 0.8 mg/kg/day (maximum dose: 30 mg/day), or placebo 
and assigned a randomization number by the IVR/IWR system. Once a randomization number 
is assigned to a subject, the site will record the subject’s initials on the corresponding study drug 
labels. Each bottle will contain the assigned treatment (ZX008 or placebo) and the ZX008 and 
placebo solutions will be identical. 
The blinding scheme instituted for this study will ensure that the volume of study medication 
taken cannot be associated with the dose group, thus unblinding the study. This is achieved by 
random assignment of different concentrations of the ZX008 oral solution (1.25 mg/mL, 
2.5 mg/mL, and/or 5 mg/mL) by the IVR/IWR system. The IVR/IWR system will instruct site 
personnel to the volume of oral solution to be administered based on that subject’s weight. 
(Dose will be recalculated by the system once at the midpoint of the study.) During the 
Titration, Maintenance, and Taper/Transition Periods, the subjects and study personnel 
(investigators, clinical staff, personnel involved in data collection and analysis, the Medical 
Monitor, and the sponsor) will be blinded to the treatment allocation and to the concentration of 
ZX008 oral solution. If an investigator feels the blind should be broken, he/she can do so when 
necessary for treatment decisions. However, the investigator should endeavor to discuss with 
the Medical Monitor or Sponsor’s Medical Representative, if available. The blind should only 
be broken in the event the knowledge of whether the subject is on active study medication 
versus placebo is needed to determine course of medical treatment for the event. The subject 
will be discontinued from the clinical trial upon breaking of the blind and the decision whether 
the subject can enter the separate open-label extension study will rest with the Sponsor if the 
subject exited Study 1501 prior to completion. 
5.7
PRIOR AND CONCOMITANT MEDICATION
All medications taken by a subject during the Screening and Baseline Seizure Assessment 
Periods are regarded as prior therapy and must be documented in the eCRF. Significant 
medications (e.g., antibiotics) taken within 30 days prior to the Screening visit should also be 
captured. All prior and concomitant AEDs will be collected in the CRF. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 49 of 182
All medications taken by a subject after the first administration of IMP are regarded as 
concomitant medication and must be documented in the eCRF, including over-the-counter 
medication, herbal and vitamin/supplement preparations. Subjects are required to take at least one 
concomitant AED during the study. All subjects will continue to receive their existing AED(s) 
with the same doses throughout the study. Every effort should be made to ensure that the regimen 
of existing medications remains stable during the study; any changes must be discussed with the 
sponsor prior to implementation. If a decrease in a concomitant AED is necessary to manage an 
AE, this must be discussed with the sponsor as soon as possible after implementation if not before 
implementation. 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. 
5.7.1
Vagal Nerve Stimulation
Subjects receiving treatment with a VNS may be included as long as the VNS has been in place 
for at least 6 months prior to entry into the study, the VNS battery is not due for replacement 
during the study, and stimulation parameters have been kept constant for 4 weeks prior to 
screening and must remain so throughout the study. The subject’s use of VNS will be recorded in 
the CRF. 
5.7.2
Ketogenic Diet
Adherence to the KD, or a modified version of KD, is permitted during the study if the dietary 
habits were initiated more than 4 weeks prior to Screening and remain stable throughout the 
study. The subject’s use of KD will be recorded in the CRF. 
5.7.3
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 eCRF. 
Use of rescue medication is permitted during the study and should be recorded on the eCRF (day, 
medication[s], dose[s]) and in the diary (day, timeframe associated with seizure episodes). 
Repeated administrations within the same episode should be recorded separately. 
5.7.4
Prohibited Concomitant Medication and Food
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.  
The following concomitant medications are prohibited during the clinical trial: 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 50 of 182
x
AEDs: Phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, retigabine/ezogabine 
x
Stiripentol (STP): Subjects must be off STP for a minimum of 21 days prior to the Screening 
visit. 
x
Felbamate is prohibited as a concomitant medication unless the subject has been on 
felbamate for at least 18 months prior to screening, has stable liver function and hematology 
laboratory tests, and the dose is expected to remain constant throughout the study. 
x
Drugs that interact with central serotonin, including but not limited to: imipramine, 
monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin-
norepinephrine reuptake inhibitors, vortioxetine 
x
Drugs that increase cardiovascular risk including: atomoxetine and those with noradrenergic 
reuptake properties (NRIs, SNRIs) 
x
Drugs intended to facilitate weight loss 
x
Other:  any form of marijuana, THC and derivatives (including Epidiolex®) 
x
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. 
5.8
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. 
6.
VISIT SCHEDULE
Study procedures will be conducted according to the Schedule of Assessments in Table 1. 
Time windows for all assessments are detailed in Table 6. 
Table 6: 
Time Windows for Assessments 
Visit / Procedure
Time window (relative to scheduled visit / procedure)
Visit 1 (Clinic; Study Day -43 to -42 or -42 to -41): 
Not applicable
Visit 2 (Phone; Study Day -21)
± 3 days
Visit 3 (Clinic; Study Day -1; Randomization)
+ 4 daysa
Visits 4, 5 (Phone: Study Days 4, 8)
± 3 days
Visit 6 (Clinic; Study Day 15)
± 4 days
Visit 7 (Phone: Study Day 29)
± 4 days
Visit 8 (Clinic; Study Day 43)
± 4 days
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 51 of 182
Visit 9 (Phone: Study Day 57)
± 4 days
Visit 10 (Clinic; Study Day 71)
± 4 days
Visit 11 (Phone: Study Day 85)
± 4 days
Visit 12 (Clinic: Study Day 99)
± 4 days
Visit 13 (Clinic; Study Day 113; post dosing)
± 4 days
Visit 14 (ECHO clinic; 3-6 months after last dose)
+ 30 days
Blood collection for ZX008 PK
± 15 minutes
Blood collection for AED concentration
Prior to morning dose of AED medication
AED=antiepileptic drug (s); ECHO=echocardiogram; PK = pharmacokinetics 
a 
In cases where the screening period is extended beyond 42 days, the immediate 42 days before the Randomization visit will 
be used to calculate the baseline seizure frequency
6.1
BASELINE PERIOD (STUDY DAY -42 TO STUDY DAY -1)
The Baseline Period of the study encompasses the screening activities that will occur on Study 
Day -42 as well as the observation period where subjects will be assessed for baseline seizure 
activity based on recordings of daily seizure activity entered into a diary. 
6.1.1
Screening, Clinic Visit 1 (Study Day -42)
Screening is the predetermined series of procedures with which each investigator selects an 
appropriate and representative sample of subjects for enrollment into the study. Select 
screening data will be documented in the IVR/IWR and eCRF. 
Written informed parental or guardian consent and assent of minors (if the subject is capable of 
providing assent) must be obtained before a subject can start any of the screening procedures. The 
procedure(s) for obtaining written informed consent and assent of minor (if the subject is capable 
of providing assent) are described in Section 11.2. 
The Screening visit will occur on Study Day -42; however, the procedures may be split over 
2 consecutive days (e.g., Study Day -43 and Study Day -42 or Study Day -42 and Study Day -41). 
Splitting the visit procedures across 2 nonsequential days requires the approval of the medical 
monitor. The following procedures will be performed for all subjects before the start of seizure 
activity observation: 
x
Obtain written informed consent for the study 
x
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 
x
Review inclusion and exclusion criteria 
x
Record demographic information 
x
Record medical, neurological, and epilepsy history 
x
Record current epilepsy status (number/type/duration seizures per month) 
x
Collect past 6 months (or available duration) of parent/caregiver seizure diary data if 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 52 of 182
available (screen shots of cell phones are acceptable, as are photocopies of paper 
diaries or print outs) and place in source file 
x
Record prior medications 
x
Complete physical examination, including height, weight, and calculation of BMI 
x
Complete neurological examination 
x
12-lead electrocardiogram 
x
Doppler ECHO (this may be obtained any time between Study Day -42 and Study 
Day -21) 
x
Vital signs 
x
Urine pregnancy test for females of child-bearing potential 
x
Laboratory evaluation (serum chemistry, hematology, urinalysis, etc) 
x
Urine THC panel 
x
Whole blood CBD 
x
Obtain blood sample for epilepsy genotype panel 
x
C-SSRS Children’s Baseline/Screening Assessment (Appendix 2) 
x
Instruct parent/caregiver on use of diary 
x
Dispense diary (after above procedures have been concluded) 
x
Record AEs 
x
Record AESIs 
Only eligible subjects as specified by the inclusion and exclusion criteria with an independently 
confirmed diagnosis of DS by the Epilepsy Study Consortium will be enrolled into the study. 
After enrollment into the study, each subject will be issued a “Subject Card” containing 
information about the subject’s participation in the study. The subject or parent/caregiver will be 
advised to retain this card on his person for the entire duration of the study so that the investigator 
or the sponsor can be contacted in case of emergency. 
In certain circumstances the sponsor may allow subjects who did not meet all inclusion/exclusion 
criteria at the time of the Screening Visit to have the screening period extended, or to be re-screened 
for eligibility. In all cases the investigator should consult with the Medical Monitor. Decisions 
whether to permit rescreening resides solely with the sponsor.  
The decision whether to permit extended screening or rescreening can be influenced by many 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 53 of 182
factors individual to that subject case. Some general principles apply: 
1. If baseline seizure screening is extended or the subject is discontinued and then rescreened, the 
screening period for establishing the baseline seizure frequency will be the immediate 6 weeks 
before the randomization visit. 
2. Subjects who are found to be on a prohibited medication at the screening visit may be weaned 
off of that medication provided: 
a.
Decisions to withdraw a disallowed concomitant medication must be made with the 
agreement of the prescribing physician 
b. If the medication has antiepileptic properties, a wash out of at least 5 half-lives 
must be completed before collection of baseline seizure data.  
c.
If a decision has been made to wean off of a medication without antiepileptic 
properties and the 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
Phone Visit 2 (Study Day -21)
Site personnel will contact the subject via telephone on Study Day -21 and record the 
following: 
x
AEs 
x
AESI 
In addition, site personnel with review the diary entries with the parent/caregiver. 
6.1.3
Clinic Visit 3 (Study Day -1): Randomization
This period is intended to ensure that subjects meet the study entry criteria and confirm they have 
experienced 6 convulsive seizures during the 6-week Baseline Period, with at least 2 seizures in 
each 3-week half of the Baseline Period. Subjects must have at least 42 days of prospective diary 
data at Visit 3. Subjects will report to the clinic in the morning on Study Day -1 to allow for 
plasma sample collection for AED pharmacokinetic evaluation prior to the morning dose of these 
medications. Subjects should not take their morning dose(s) of AED medication prior to 
reporting to the clinic. 
The following procedures will be performed on Study Day -1: 
x
Review inclusion and exclusion criteria 
x
Review current seizure activity (number/type/duration) from diary since previous visit 
and calculate the number of convulsive seizures during the first 3 weeks, the second 3 
weeks, and over the full 6-weeks of the observation period. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 54 of 182
x
Record prior medications since previous visit 
x
Complete physical examination, including height and weight, and calculation of BMI 
x
Abbreviated neurological examination 
x
Vital signs 
x
12-lead ECG 
x
Urine pregnancy test for females of child-bearing potential 
x
Laboratory evaluation (serum chemistry, and hematology, and urinalysis) 
x
Collect plasma sample for AED pharmacokinetic evaluation prior to the morning dose 
of study medication(s) 
x
Urine THC panel 
x
Whole blood CBD 
x
Tanner Staging for subjects >7 years of age (Appendix 5) 
x
Collect and review diary with parent/caregiver 
x
Dispense diary 
x
C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
x
BRIEF (Appendix 3) 
x
QOLCE (Appendix 4) 
x
PedsQL (Appendix 6) 
x
PedsQL Family Impact module (Appendix 6) 
x
Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
x
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x
Record AEs 
x
Record AESI 
x
When eligibility for the Titration Period is confirmed, randomize (blinded) subject to 
treatment assignment (ZX008 0.2 mg/kg/day, ZX008 0.8 mg/kg/day, or placebo) 
x
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occurs in the clinic, the next dose should be at least 8 hours later or the following 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 55 of 182
morning. The dose on the following morning will count as Study Day 1.) 
6.2
TITRATION AND MAINTENANCE PERIODS
6.2.1
Titration Period Study Day 1
Subjects will take their first dose of study medication on the morning of Study Day 1. Study 
Day 1 is considered the first day of dosing, even for those subjects that received an in-clinic dose 
on Study Day -1. 
6.2.2
Phone Visits 4 and 5 (Titration Period Study Days 4 and 8)
Site personnel will contact the subject via telephone on Titration Period Study Days 4 and 8 
and record the following: 
x
AEs 
x
AESI 
x
Concomitant medications
In addition, site personnel will review study medication dosing procedure and the diary entries 
with the parent/caregiver. 
6.2.3
Clinic Visit 6 (Titration Period Study Day 15)
Subjects will report to the clinic in the morning on Titration Period Study Day 15. Subjects should 
not take their morning dose(s) of AED medication prior to reporting to the clinic. The following 
procedures will be performed: 
x
Review current seizure activity (number/type/duration) from diary since previous visit 
x
Record concomitant medications 
x
Abbreviated physical examination, including height and weight, and calculation of 
BMI 
x
Abbreviated neurological examination 
x
Obtain vital signs 
x
Urine pregnancy test for females of child-bearing potential 
x
Laboratory evaluation (serum chemistry and hematology, and urinalysis) 
x
Urine THC panel 
x
Whole blood CBD 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 56 of 182
x
Collect plasma sample for AED pharmacokinetic evaluation prior to the morning dose 
of study medication(s) 
x
Collect and review diary with parent/caregiver 
x
Dispense diary 
x
C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
x
Clinical Global Impression – Improvement (assessed by parent/caregiver) 
x
Clinical Global Impression – Improvement (assessed by investigator) 
x
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x
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x
Dispense study medication 
6.2.4
Phone Visit 7 (Maintenance Period Study Day 29)
Site personnel will contact the subject via telephone on Maintenance Period Study Day 29 and 
record the following: 
x
AEs 
x
AESI 
x
Concomitant medications 
In addition, site personnel will review the diary entries with the parent/caregiver. 
6.2.5
Clinic Visit 8 (Maintenance Period Study Day 43)
x
Subjects will report to the clinic in the morning on Maintenance Period Study Day 43. 
Subjects should not take their morning dose(s) of study medication and AED 
medication prior to reporting to the clinic. The following procedures will be 
performed: 
x
Review current seizure activity (number/type/duration) from diary since previous visit 
x
Record concomitant medications 
x
Abbreviated physical examination, including height and weight, and calculation of 
BMI (Note: if the subject’s weight is ±25% of the weight at Study Day-1, the IMP 
dose will be recalculated) 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 57 of 182
x
Obtain vital signs 
x
12-lead electrocardiogram 
x
Doppler ECHO (this must be obtained any time between Study Day 40 and Study 
Day 54) 
x
Urine pregnancy test for females of child-bearing potential 
x
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Urine THC panel 
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Whole blood CBD 
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timepoints: within 1 hour prior to the morning dose of study medication, and 1, 2 and 
4-6 hours after the morning dose of study medication 
x
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of study medication(s) 
x
Collect and review diary with parent/caregiver 
x
Dispense diary 
x
C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
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BRIEF (Appendix 3) 
x
QOLCE (Appendix 4) 
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PedsQL (Appendix 6) 
x
PedsQL Family Impact module (Appendix 6) 
x
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x
Clinical Global Impression – Improvement (assessed by parent/caregiver) 
x
Clinical Global Impression – Improvement (assessed by investigator) 
x
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x
Record AESI 
x
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and review with parent/caregiver 
x
Dispense study medication 
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ZX008 (Fenfluramine Hydrochloride)
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31 October 2016 
Confidential 
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6.2.6
Phone Visit 9 (Maintenance Period Study Day 57)
Site personnel will contact the subject via telephone on Maintenance Period Study Day 57 and 
record the following: 
x
AEs 
x
AESI 
x
Concomitant medications 
In addition, site personnel with review the diary entries with the parent/caregiver. 
6.2.7
Clinic Visit 10 (Maintenance Period Study Day 71)
Subjects will report to the clinic on Maintenance Period Study Day 71. The following 
procedures will be performed: 
x
Review current seizure activity (number/type/duration) from diary since previous visit 
x
Record concomitant medications 
x
Abbreviated physical examination, including height and weight, and calculation of 
BMI 
x
Obtain vital signs 
x
Urine pregnancy test for females of child-bearing potential 
x
Laboratory evaluation (serum chemistry and hematology, and urinalysis) 
x
Urine THC panel 
x
Whole blood CBD 
x
Collect and review diary with parent/caregiver 
x
Dispense diary 
x
C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
x
Clinical Global Impression – Improvement (assessed by parent/caregiver) 
x
Clinical Global Impression – Improvement (assessed by investigator) 
x
Record AEs 
x
Record AESI 
x
Collect used, partially used and unused study medication; perform drug accountability 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 59 of 182
and review with parent/caregiver 
x
Dispense study medication 
At Clinic Visit 10, compliant subjects who have tolerated IMP should be presented with the ICF 
for the open-label extension study. Informed consent for the open-label extension study must be 
signed at Visit 12 or earlier in order to enter the open-label extension study. 
6.2.8
Phone Visit 11 (Maintenance Period Study Day 85)
Site personnel will contact the subject via telephone on Maintenance Period Study Day 85 and 
record the following: 
x
AEs 
x
AESI 
x
Concomitant Medications 
In addition, site personnel with review the diary entries with the parent/caregiver. 
6.2.9
Clinic Visit 12 (Maintenance Period Study Day 99): End of Study/Early 
Termination
The End-of-Study participation for an individual subject occurs after he/she has received IMP for 
12 weeks in the Maintenance Period. At the End-of-Study visit, the subject may enroll into the 
separate extension study if they have completed 12 weeks of treatment in the Maintenance 
Period. Other circumstances for participation in the extension study are described in Section 4.8. 
The End-of-Study visit may also occur if the subject withdraws participation from the study or the 
sponsor terminates the study. If the subject withdraws participation from the study, they may on a 
case-by-case basis, be eligible for entrance into the separate open-label extension study 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. If 
the sponsor terminates the study early, the subject may or may not be offered enrollment into the 
open-label extension, depending on the reason for termination. 
Subjects will visit the clinic for the End-of-Study visit if one the following events occur: 
1. The subject withdraws or is withdrawn from participation in the study. 
2. The sponsor terminates the study. 
3. The subject completes all study related visits and procedures. 
The following procedures will be performed: 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 60 of 182
x
Review current seizure activity (number/type/duration) from diary since previous visit 
x
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x
Complete physical examination, including height and weight, and calculation of BMI 
x
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x
Obtain vital signs 
x
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x
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x
Day 113; if subject terminates early from the study, the ECHO should be scheduled as 
soon as practical). If the Study Day 43 ECHO was completed 30 days prior to early 
termination, the Visit 12 ECHO will not be performed provided the parent/guardian 
agrees to bring the subject to the clinic for the cardiac follow-up visit (see Table 7). 
x
Urine pregnancy test for females of child-bearing potential 
x
Laboratory evaluation (serum chemistry and hematology, and urinalysis) 
x
Urine THC panel 
x
Whole blood CBD 
x
Collect plasma sample for AED pharmacokinetic evaluation prior to the morning dose 
of study medication(s) 
x
Tanner Staging for subjects >7 years of age (Appendix 5) 
x
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x
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x
C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
x
Clinical Global Impression – Improvement (assessed by parent/caregiver) 
x
Clinical Global Impression – Improvement (assessed by investigator) 
x
BRIEF (Appendix 3) 
x
QOLCE (Appendix 4) 
x
PedsQL (Appendix 6) 
x
PedsQL Family Impact module (Appendix 6) 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 61 of 182
x
Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
x
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x
Record AEs 
x
Record AESIs 
x
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and review with parent/caregiver 
x
Dispense study medication 
Informed consent for the open-label extension study must be signed at Visit 12 (if not signed 
earlier) in order to enter the open-label extension study. 
6.3
POST-DOSE VISIT (CLINIC VISIT 13; STUDY DAY 113)
For subjects entering the open-label extension study, the subject will visit the clinic on 
Day 113. The following will be recorded/performed and the subject will immediately be 
enrolled in that separate study: 
x
Review current seizure activity (number/type/duration) from diary since previous visit 
x
AEs 
x
AESIs 
x
Concomitant medications 
x
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
If the subject does not enter the open-label extension study (or discontinues from the study 
early), the subject will visit the clinic on Study Day 113 (or 14 days after the day of 
discontinuation). The following will be recorded/performed: 
x
Review current seizure activity (number/type/duration) from diary since previous visit 
x
AEs 
x
AESIs 
x
Concomitant medications 
x
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 62 of 182
6.4
CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 14; STUDY DAY 197-281)
If the subject completes the study but does not enter the open-label extension 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 7. Subjects on blinded medication who are found to have been on placebo are 
not required to participate in follow-up testing once the blind is broken at the end of the study. 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. 
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, with reports submitted as 
AESI to the ZX008 safety database. 
Table 7: 
Schedule of Post-Treatment Cardiac Follow-up 
Parameter
Duration of Blindeda or Fenfluramine Treatment
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 drugb
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
a If blind is broken at the end of the study and a subject revealed to have taken only placebo, no further testing is 
required.
b    Positive sign or symptom includes any development of valve thickening or regurgitation (“trace” or greater in mitral,
aortic; mild or greater in pulmonary, tricuspid), or sign or symptom indicative of potential pulmonary hypertension 
as adjudicated by the IPCAB.
6.5
ESTIMATED BLOOD VOLUME COLLECTION
The maximum total blood volume collected during the study for clinical laboratory testing, 
genotyping, and PK will be approximately 99.7 mL, as outlined in Table 8. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 63 of 182
Table 8: 
Estimated Blood Volume Collection* 
Assessment 
Baseline Period (study day) 
Titration + Maintenance Period (study day) 
Screening 
(Day -42 to 
-41) 
Randomization 
Day -1 
Day 15 
Day 43 
Day 71 
Day 99 
Total 
Clinical 
Chemistry 
4mL 
4mL 
4mL 
4mL 
4mL 
4mL 
24mL 
LH, FSH, 
Estradiol, 
Testosterone, 
Prolactin 
 
4mL 
 
4mL 
4mL 
4mL 
16mL 
Genotyping 
5 mL 
 
5 mL 
Hematology 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
12mL 
IGF-1, GH 
 
2.5mL 
 
2.5mL 
2.5mL 
2.5mL 
10 mL 
Coagulation 
 
2.7mL 
 
2.7mL 
Cannabidiol 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
12mL 
ZX008 PK 
plasma 
 
4 x 2 mL 
 
8 mL 
AED plasma 
sample 
 
1 x 2 mL 
1 x 2 mL 
1 x 2 mL 
 
1 x 2 mL 
8 mL 
Volume for 
flushing 
indwelling 
catheter 
 
4 x 0.5 mL 
 
2 mL 
Approximate 
total blood 
volume per 
subject 
13mL 
19.2mL 
10mL 
26.5mL 
14.5mL 
16.5mL 
99.7 mL 
FSH=follicle stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; LH-luteinizing hormone; 
PK=pharmacokinetics 
*In concordance with The Seattle Children’s Research Foundation Guidance (Appendix 9), blood 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 64 of 182
collection volumes for children weighing up to 15 kg will be: 
x
the maximum allowable volume of blood in one draw is 22-30 mL (2.5% of total blood 
volume) 
x
the maximum in a 30-day period is 44-60 mL. 
On Day 43/Visit 8 the pharmacokinetic blood draw will be completed as the priority and the blood 
draw for chemistry and hematology will be skipped for those subjects who weigh less than 13.5 kg, 
unless medical concerns (for example, from previous tests or reported side effects) prioritize 
chemistry and/or hematology. 
If blood collection is restricted due to volume or due to inability to draw adequate volume, 
collection should be prioritized as shown in Table 9: 
Table 9: 
Priorities for Blood Sample Collections 
Assessment
Priority
ZX008 PK sample 
Priority 1 
Clinical chemistry 
Priority 2 
Cannabidiol 
Priority 2 
AED plasma sample 
Priority 2 
LH, FSH, estradiol, testosterone, GH, prolactin 
Priority 3 
Hematology 
Priority 3 
IGF-1 
Priority 4 
Genotyping 
One time collection any time during or after 
screening 
Coagulation 
One time collection any time before PK day 
7.
EFFICACY, SAFETY, AND 
PHARMACOKINETIC ASSESSMENTS
For an overview of the study variables and measurement times, see Schedule of Assessments 
(Table 1). 
Variables used to measure treatment compliance with respect to administration of the IMP are 
described in Section 5.8. 
7.1
EFFICACY ASSESSMENTS
Baseline is defined as the seizure frequency during the 6-week Baseline Period. 
Retrospective diary data (up to 6 months) will be collected, if available, for an exploratory 
evaluation of the duration of baseline data capture on interpretation of post-treatment effect. 
For all questionnaires and rating scales, the same evaluator (at the clinical site and 
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Zogenix International Limited
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31 October 2016 
Confidential 
Page 65 of 182
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) 
B: 
Focal With or Without Retained Awareness 
C: 
Secondarily Generalized Tonic Clonic (evolving to bilateral convulsive seizure 
from focal seizure) 
D: 
Generalized Tonic Clonic Convulsion 
E: 
Absence or Atypical Absence 
F: 
Myoclonic 
G: 
Tonic 
H: 
Atonic 
I: 
Clonic 
J: 
Tonic/Atonic (cannot differentiate) 
K: 
Infantile Spasms (if under 3 years of age) 
L: 
Epileptic Spasms (if 3 years of age and older) 
O: 
Other 
Efficacy 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. 
Seizures that evolve into SE will be captured by type and duration (>10 minutes) as are all 
seizures. The diagnosis of SE made by a medical professional should be entered as an SAE if a 
prolonged seizure or series of seizures persists for 30 minutes or longer, regardless of 
administration of rescue medication. SE lasting for less than 30 minutes should be entered as an 
AE, unless one of the other SAE criteria (e.g. hospitalization) are met. If this incident involves 
multiple seizures close in time, the SE definition applies if the seizures are close together such that 
consciousness is not regained between ictal events. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 66 of 182
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. 
The CGI scale measures the change in the subject’s clinical status from a specific point in time, 
i.e., the Baseline Period. The CGI rating scale permits a global evaluation of the subject’s 
improvement over time. The severity of a patient’s condition is rated on a 7-point scale ranging 
from 1 (very much improved) to 7 (very much worse) as follows: 
1=very much improved 
2=much improved 
3=minimally improved  
4= no change 
5=minimally worse 
6=much worse 
7=very much worse 
The parent/caregiver will be asked to indicate the appropriate response that adequately 
describes how their child’s symptoms have improved or worsened relative to baseline before 
the beginning of the study (before any study drug was taken). 
The investigator 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 study (before any study drug was taken). A paragraph describing symptoms 
and function at baseline will be document in the source file prior to rating. 
7.1.3
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. 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). 
The cognitive domain of the QOLCE consists of the following subscales: attention/concentration, 
memory, languages, and "other cognition". Each of these subscales have shown good internal 
reliability and consistency (Cronbach's alpha > 0.80) in the population aged 4 and above. The 
cognitive domain of the QOLCE will be used to assess cognition during study participation in the 
population aged 5 and older as of the subject’s age at baseline. 
7.1.4
Pediatric Quality of Life Inventory (PedsQL)
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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. 
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 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 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.
7.2
SAFETY ASSESSMENTS
7.2.1
Demographics, Medical/Neurological/Epilepsy History, and Pre-Study 
Medication
Subject demographics (sex, age, height, weight, and BMI), all ongoing conditions and relevant 
medical history from the past 5 years (including all major hospitalizations and surgeries) as well 
as the subject’s current medical status will be recorded at the Screening visit. Significant 
medications taken during the 30 days prior to the Screening visit will be documented. 
Medication history will be updated as outlined in Table 1. 
7.2.2
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. 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 
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system, lymph nodes, spine, and extremities. An abbreviated physical examination for each 
subject will cover the following body systems: heart, lungs, and follow up of other systems as 
appropriate based on last exam and reported AEs. 
Any unfavorable findings not present at screening considered by the investigator as clinically 
significant, occurring at any point in the study will be documented in the eCRF as an AE. 
7.2.3
Neurological Examinations
Complete and abbreviated neurological examination will be conducted by the investigator or 
designee during the study as outlined in Table 1. 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. 
Any unfavorable findings not present at screening considered by the investigator as clinically 
significant, occurring at any point in the study will be documented in the eCRF as an AE. 
7.2.4
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. 
7.2.5
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 8: 
x
Hematology: hemoglobin, hematocrit, erythrocytes, erythrocyte mean corpuscular 
volume, leukocytes, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, neutrophils, lymphocytes, monocytes, eosinophils, basophils and 
platelets 
x
Blood Biochemistry: albumin (ALB), alkaline phosphatase (AP), alanine 
aminotransferase (ALT; SGPT), aspartate aminotransferase (AST; SGOT), 
bicarbonate, blood urea nitrogen (BUN), calcium (Ca), carbon dioxide (CO2), chloride 
(Cl), creatinine, creatine kinase, gamma-glutamyl transferase (GGT), 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. 
x
Tests of growth and precocious puberty: Growth hormone (GH), insulin-like growth 
factor-1 (IGF-1, low sensitivity), prolactin, Luteinizing Hormone (LH), Follicle 
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Stimulating Hormone (FSH), testosterone, estradiol 
x
Epilepsy genotype panel 
x
Coagulation: Prothrombin time (PT)/International normalized ratio (INR), activated 
partial thromboplastin time (PTT) 
x
Whole blood cannabidiol 
x
Urinalysis: analysis for pH, glucose, ketones, nitrite, protein, bilirubin, urobilinogen, 
leukocyte esterase, and occult blood. Microscopic analysis will be performed for 
blood, all cell types, and casts. 
x
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childbearing potential. 
x
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x
The investigator will receive the laboratory report from the central laboratory. After 
reviewing the report and evaluating any results that are outside the normal range, 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. 
At Screening, any laboratory values that deviate from the reference ranges and are considered by 
the investigator as clinically relevant must be documented on the medical history form of the 
eCRF. Any deviation outside of the reference range considered by the investigator as clinically 
significant (i.e., classified as an abnormal, clinically significant value) at any visit after screening 
will be documented in the eCRF as an AE (see Section 9). 
7.2.6
Plasma Sample for Concomitant Antiepileptic Drug(s)
Plasma samples to ensure that concomitant antiepileptic drug(s) (AEDs) dosing is within an 
acceptable range will be conducted during the study as outlined in Table 1. Samples collected at 
Visit 6 will be analyzed after collection as a safety measure. Samples collected at other time 
points will be analyzed at study end and do not constitute safety assessments. 
7.2.7
Electrocardiograms
Twelve-lead ECGs will be conducted during study as outlined in Table 1 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. 
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Page 70 of 182
7.2.8
Doppler Echocardiography
Doppler echocardiography will be conducted at a facility with experience for the subject’s age 
during study as outlined in Table 1. Doppler echocardiography uses ultrasound technology to 
examine the heart or blood vessels. An ECHO uses high frequency sound waves to create an 
image of the heart while the use of Doppler technology allows determination of the speed and 
direction of blood flow by utilizing the Doppler effect. Predetermined standard guidelines on the 
proper evaluation of certain measurements, as well as abnormality thresholds, were constructed 
by the sponsor’s 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. 
7.2.9
Tanner Staging
Tanner Staging (Appendix 5) will be assessed for subjects >7 years old during the study as 
outlined in Table 1. Conceptually, pubertal maturation can be described in terms of sequence, 
timing, and tempo. Puberty consists of a series of predictable events, and the sequence of 
changes in secondary sexual characteristics has been categorized by several groups. The staging 
system used most frequently was published by Marshall and Tanner (1969, 1970) and the 
sequence of changes are commonly referred to as ‘Tanner stages’. 
7.2.10
Columbia-Suicide Severity Rating Scale
C-SSRS (Appendix 2) will be assessed during study as outlined in Table 1. 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 Baseline/Screening and 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. 
7.2.11
Adverse Events
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. Details of the definitions and 
categorization of AEs, and procedures for the reporting of AEs, are available in Section 9. 
Severity and causality of AEs will be evaluated according to the criteria specified in Section 8.2 
and Section 8.3, respectively. The observation period for AE reporting is specified in 
Section 8.4. At the beginning of each visit at the study site, the study personnel will specifically 
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inquire about any AEs that might have occurred since the last study site visit. All AEs will be 
recorded on the appropriate eCRF page. 
7.2.12
Behavior Rating Inventory of Executive Function (BRIEF)
The BRIEF is a standardized, validated rating scale to measure executive function in children ages 
2-18within the home and school environments; it will be assessed according to the schedule in 
Table 1. 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), and Plan/Organize/Organization of Materials (anticipate 
future events; set goals; develop steps; grasp main ideas), and Monitor (check work; assess own 
performance). 
7.3
PHARMACOKINETIC ASSESSMENTS
Blood samples for PK assessments of fenfluramine and its metabolite (norfenfluramine) will be 
obtained from all subjects via an indwelling cannula or by venipuncture. 
Blood samples for PK assessment (2 mL) will be obtained at the following time points: 
x
Maintenance Period Study Day 43: within 1 hour prior to the morning dose, and 1, 2, 
and 4-6 hours after the morning dose. 
A total of 4 PK samples will be drawn for each subject for a total of approximately 8 mL of 
blood. 
When blood draws for PK coincide with other assessments, the PK draws take precedence. 
The procedure for the collection and handling of PK samples is outlined in a separate study 
manual. 
7.4
APPROPRIATENESS OF MEASUREMENTS
All of the variables assessed are standard tests or procedures that are commonly used in studies of 
this type. 
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 
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temporally associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product. The period of observation for 
adverse events extends from the time the subject gives informed consent until the end of study. 
Adverse events may include: 
x
Exacerbation (i.e., an increase in the frequency or severity) of a pre-existing condition. 
Illness present before study entry should be recorded in the medical history section of 
the eCRF and only be reported as an AE if there is an increase in the frequency or 
severity of the condition during the study. Exacerbation of seizures is considered an 
AE if there was an increase in frequency beyond the subject's typical pre-study 
fluctuations, or in the event that seizures lengthen in duration in a clinically 
meaningful way compared with baseline, or if a new seizure type emerges. 
x
A clinical event occurring after consent but before IMP administration. 
x
Intercurrent illnesses with an onset after administration of IMP.  
Adverse events do not include: 
x
Medical or surgical procedures (the condition that leads to the procedure is the AE, 
e.g., tonsillitis is the AE if a tonsillectomy is performed) 
x
Situations where an untoward medical occurrence has not taken place. For example: 
o
Planned hospitalizations due to pre-existing conditions, which have not 
worsened. 
o
Hospitalizations that occur for procedures not due to an AE (e.g., cosmetic 
surgery). 
o
Hospitalizations for a diagnostic procedure where the hospital stay is less than 24 
hours in duration or for normal management procedures (e.g., chemotherapy). 
For laboratory safety parameters, any instances of absolute values being outside the reference 
range or changes at any visit after study start that are considered by the investigator as clinically 
significant must be recorded in the eCRF as AEs. In addition, at the investigator’s discretion, 
any changes or trends over time in laboratory parameters can be recorded in the eCRF as AEs if 
such changes or trends are considered to be clinically relevant, even if the absolute values are 
within the reference range. 
Laboratory findings do not need to be reported as AEs in the following cases: 
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 (e.g., hemolysis) and flagged as such by the laboratory in the 
laboratory report. 
3. Abnormal parameters that are obviously biologically implausible (e.g., values that 
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Page 73 of 182
are incompatible with life). 
4. An abnormal laboratory value that cannot be confirmed after a repeated analysis, 
preferably in the same laboratory (e.g., the previous result could be marked as not 
valid and should not necessarily be reported as an AE). 
8.1.2
Serious Adverse Events
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose: 
1.
Results in death – The event must be the cause of death for the SAE to meet this serious 
criterion. 
2.
Is life-threatening – The term “life-threatening” refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it had been more severe. 
3.
Requires in-patient hospitalization or prolongation of existing hospitalization – The 
sponsor considers “hospitalization or prolongation of existing hospitalization” for at least 
24 hours as the defining criterion for an SAE.  Hospital admissions for planned surgery or 
for normal disease management procedures (e.g., 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. 
For the purpose of data collection in this study, a prolonged seizure or series of seizures from 
which the subject does not regain consciousness between ictal events, that is at least 30 
minutes in duration, is termed status epilepticus (SE). 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 nonserious AEs. 
8.1.3
Adverse Events of Special Interest
As per ICH guidance (E2F Development Safety Update Report [2011]), the sponsor has 
identified the following AESIs for the ZX008 program (Table 10). 
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31 October 2016 
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Table 10: 
Adverse Events of Special Interest 
CV/Respiratory
1. Chest pain – any pain in sternal area that is described for example as crushing, burning, sharp, 
stabbing or dull.
2. Dyspnea/shortness of breath – any signs of difficult or labored breathing unrelated to a previous 
medical condition that has not worsened.
3. Persistent cough – longer than 4 weeks without a confirmed identified pathogen (or any other 
persistent cough that the investigator feels is suspicious).
4. Increase in blood pressure >30% from Screening blood pressure or a systolic pressure 140 mmHg 
after repeated measures during one visit. Blood pressure should be repeated at appropriate times 
within the visit.
5. Jugular venous distention- visible bulging of the external jugular veins on either side of the neck
6. New onset heart murmur
7. Pulmonary rales – an abnormal respiratory sound heard during auscultation of the lungs, which is 
also described as a crackle.
8. Tachycardia – a persistent HR >30% above the screening value and unrelated to exercise, 
exertion or anxiety.  Heart rate should be repeated at appropriate times within the visit.
9.
Signs that could indicate right ventricular failure:

Peripheral edema

Ascites

Syncope

Decompensated right ventricular failure – symptoms include shortness of breath, 
frequent coughing especially when lying flat, abdominal swelling and pain, dizziness, 
fainting, and fatigue
10.  Signs on ECHO indicative of potential valvulopathy

valve regurgitation (aortic or mitral)

moderate or severe valve regurgitation (tricuspid or pulmonary)

Mean Mitral valve gradient  4 mmHg

Mean Aortic valve gradient  15 mmHg

Mean Tricuspid valve gradient  4 mmHg

Peak Pulmonary valve gradient  21 mmHg
11. Signs on ECHO indicative of pulmonary hypertension
a. Tricuspid Regurgitation Jet velocity > 2.8 msec with or without the following findings OR
b.
One of the following findings in the absence of being able to measure Tricuspid 
Regurgitation Jet velocity:
i.
Change in right ventricle/left ventricle basal diameter ratio > 1.0
ii.
Right ventricular acceleration time < 100 msec
iii. Dilatation of the inferior caval vein (diameter>21 mm and <50% inspiratory decrease) 
and/or right atrium
iv.  Change in the geometry of the interventricular septum in systole (flattening) with left 
ventricular eccentricity index >1.1 in systole and/or in diastole
v.
Early diastolic pulmonary regurgitation velocity > 2.2 m/sec
vi. Tricuspid Anular Plane Systolic Excursion below 18 mm or below Z-score – 2
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ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
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Table 10: 
Adverse Events of Special Interest (continued)
Metabolic/Endocrine
1. Elevated prolactin level 2x above the upper limit of normal (ULN)
2. Galactorrhea
3. Gynecomastia
4. Increase in fasting serum blood glucose 2x ULN
5. 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. Serotonin syndrome (At least 3 of following symptoms must be present: Agitation, 
restlessness, confusion, both increased HR and blood pressure, dilated pupils, muscle 
twitching, muscle rigidity, hyperhidrosis, diarrhea, headache, shivering, tremors, both nausea 
and vomiting)
2. Hallucinations
3. Psychosis
4. Euphoria
5. Mood disorders: depression and anxiety if they rise to a level of a disorder
6. Suicidal thoughts, ideation or gestures
Genitourinary
1. Priapism
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 Dravet syndrome: 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 nonserious or serious AEs) is to be assessed by the 
investigator as follows (Table 11). 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 76 of 182
Table 11: 
Severity Definition of Adverse Events 
Severity 
Definition 
Mild: 
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living.
Moderate: 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to 
the research participant.
Severe: 
A type of AE that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention.
CDISC SDTM Severity Intensity Scale for Adverse Event Terminology 
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 (e.g., 
natural history of the underlying disease, concomitant medication) will be determined by how 
well the event can be understood in terms of: 
x
Known pharmacology of ZX008 
x
Clinically and/or pathophysiologically plausible context 
x
Reaction of a similar nature previously observed with similar products, or reported in the 
literature for similar products as being product related (e.g., headache, facial flushing, 
pallor) 
x
Plausibility supported by the temporal relationship (e.g., the event being related by time to 
administration or termination of treatment with IMP drug withdrawal or reproduced on 
rechallenge) 
The following classifications should be used in categorization of relatedness: 
Not Related: 
Concomitant illness, accident or event with no reasonable association with 
study drug. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 77 of 182
Related: 
The event follows a reasonable temporal sequence from administration of 
study drug and is definitive pharmacologically; cannot to be attributed to 
concurrent disease or other factors or medications. A clinically reasonable 
response should be observed if the study drug is withdrawn or dose reduced. 
8.4
OBSERVATION PERIOD FOR ADVERSE EVENT REPORTING
The observation period for AE and SAE reporting in an individual subject will start at the time of 
giving written informed consent for participation in the current study and finish 15 days after the 
last dose of study drug or the last visit, whichever is later. For subjects who enroll in the open-
label extension study, ongoing AEs will be followed in that study. 
If the investigator becomes aware of an SAE that has started after the observation period has 
finished, and the event could in some way be associated with IMP (irrespective of whether or 
not it is considered by the investigator to be causally related to IMP), then this must also be 
reported to the sponsor (see Section 8.6). 
8.5
ADVERSE EVENT REPORTING
8.5.1 
Adverse Events
At each clinical evaluation, the investigator (or delegate) will determine whether any AEs have 
occurred. Adverse events will be recorded in the AE page of the eCRF. If known, the medical 
diagnosis of an AE should be recorded in preference to the listing of individual signs and 
symptoms. The investigator must follow up on the course of an AE until resolution or 
stabilization. If an AE is ongoing after the end of study visit, the AE will continue to be followed 
up until resolution or stabilization. 
If, during the study period, a subject presents with a pre-existing condition that was not noted at 
the time of study entry, the condition should be retrospectively recorded in the Medical History 
section of the eCRF. 
8.6 
SERIOUS ADVERSE EVENTS REPORTING
This study will comply with all applicable regulatory requirements and adhere to the full 
requirements of ICH Topic E2A (Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting [1994]). 
In the event of a SAE the investigator or delegate must:  
1. Enter all relevant information in the AE page of the eCRF 
2. Inform the 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 iHC within 24 hours of becoming aware of the SAE.  
All SAEs that occur during the course of the study, beginning the day Informed Consent is 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 78 of 182
signed, 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.
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 (i.e., 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 
eCRF. 
If the minimum requirements for reporting are fulfilled, the investigator should not wait to 
receive additional information to fully document the event before notifying the sponsor. 
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. 
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 
(e.g., 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. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 79 of 182
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 (e.g., 
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 
condition has resolved or stabilized where no further changes are likely, for a minimum of 
6 months from the last dose of study medication, unless it is determined after unblinding that the 
subject did not receive ZX008. 
8.9.1
Follow-up of Echocardiogram Findings
All ECHOs will be evaluated by a central reader 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, triscuspid) will be reported to 
the investigator with grades of normal, trace, mild, moderate or severe. If the ECHO result has 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 80 of 182
progressed in severity since the last reading then new oversight measures will be enacted as 
described below in Levels 1-3. Table 11 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
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Normal
Level 1
Level 1
Level 1
Level 1
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Level 2
Level 2
Level 1
Level 1
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Level 2
Level 1
Level 1
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Level 3
Level 3
Level 3
Level 3
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 (e.g. valproic acid, clobazam, or 
topiramate), alone or in combination, and not maintained the level of seizure 
control achieved with study medication. 
2. If the investigator feels consideration of continued treatment is warranted considering 
benefit and potential risk, and the parent/guardian feels strongly that the child 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 child should provide 
assent if appropriate. 
a.
If both of these conditions are not met, the subject is discontinued from 
treatment. 
3. The investigator prepares a case history and rationale for continuation to be submitted to 
the IDSMC for review, including consideration of effects on seizures and comorbidities. 
4. The 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. IDMSC will review the submission from the Investigator and the IPCAB and unblind the 
subject treatment if warranted. 
6. IDSMC makes a determination of appropriate path, including the possible outcomes: 
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ZX008 (Fenfluramine Hydrochloride)
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31 October 2016 
Confidential 
Page 81 of 182
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 (e.g., valproic acid, clobazam, 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 child be 
maintained on the study medication when understanding the risks, the parent/guardian 
must sign a new consent, which describes the additional risks and the child should 
provide assent if possible. 
a.
If both of these conditions are not met, the subject is discontinued from 
treatment. 
3. The investigator prepares a case history and rationale for continuation to be submitted 
to the IDSMC for review, which includes effects of study medication on seizures and 
comorbidities related to Dravet syndrome. 
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. 
5. IDSMC will review the submission from the Investigator and the IPCAB and unblind 
the subject treatment if warranted. 
6. IDSMC makes a determination of appropriate path, including these possible outcomes: 
a.
Discontinue study medication 
b. Increase frequency of ECHO and ECG monitoring 
c.
Add additional ECG and/or ECHO measures to be monitored 
d. Reduce the dose of study medication 
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ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 82 of 182
8.10 
PREGNANCY
This study is open to female and male subjects. Whenever possible, a pregnancy in a female 
subjects or the female partner of a male subject exposed to IMP should be followed to term so 
as to assess any potential occurrence of congenital anomalies or birth defects. Any follow-up 
information, including premature termination and the status of the mother and child after 
delivery, should be reported by the investigator to the sponsor using a pregnancy 
reporting/outcome form. 
9.
DATA HANDLING PROCEDURES
9.1
RECORDING OF DATA
The investigator (or delegate) will maintain individual records for each subject. These records 
should include dates when a subject visited the study site, study-required information and data, 
and other notes as appropriate. These records constitute source data. 
An eCRF and a subject diary will be provided by the sponsor (or delegate) for each subject 
enrolled into the study. Study site staff will enter data directly into the validated electronic data 
capture (EDC) system by completing the eCRF via a secure internet connection. The investigator 
is responsible for ensuring accurate and proper completion of the eCRF and subject diary for 
recording data according to the instructions given in the eCRF and subject diary. 
All entries in the eCRF must be backed up by the relevant source data at the study site. All 
source data will be kept according to all applicable regulatory requirements (see Section 12.8). 
Source data must be completed legibly for each subject enrolled into the study and signed by the 
investigator (or delegate). 
Data entry in the eCRF and subject diary must be completed in a timely manner so that they 
always reflect the latest observations on the subjects enrolled in the study. 
The subject’s diary will be completed by the parent/caregiver at home. Data entries will be 
reviewed by the investigator for completion and consistency. 
9.2
DATA QUALITY ASSURANCE
An initiation meeting will be held before starting the study, during which the study design, 
procedures to be followed, and measures for ensuring standardized performance will be 
explained by a delegate from the sponsor, and a common understanding of the requirements of 
the study will be reached with the investigator and other relevant personnel at the study site. 
Data generated throughout the study will be monitored and the data entered in the eCRFs will 
be checked against the subject records for completeness and accuracy. The sponsor’s study 
monitor will perform this function. 
The computer system used for study data handling will be fully FDA 21 CFR Part 11 compliant. 
All creation, modification or deletion of electronic study records will be documented through an 
automated Audit Trail. Following completion of eCRF pages and entry of the data into a 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 83 of 182
database, the data will be checked electronically for consistency and plausibility. Data queries 
will be generated for questionable data and response clarification will be sought from the 
investigator. These data queries must be resolved in a timely manner by the investigator (or 
delegate). 
9.3
RECORD RETENTION
A study document binder will be provided by the sponsor for the investigator at each site for all 
requisite study documents (constituting the “Investigator Study File”). 
Following completion of the study, the investigator will retain copies of the approved study 
protocol, ICF, relevant source documents, and all other supporting documentation related to the 
study according to applicable regulatory requirements. 
The investigator is responsible for archiving the Investigator Study File, the subject’s records, 
and the source data according to applicable regulatory requirements. These documents have to 
be archived for at least 15 years or at least 2 years after the last approval of a marketing 
application in an ICH region, but should be retained for longer if required by regulatory 
requirements or by agreement with the sponsor. 
If the investigator can no longer maintain the archive of study records (e.g., 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. 
10.
STATISTICS
10.1
DETERMINATION OF SAMPLE SIZE
The results of the only randomized, placebo-controlled studies in subjects with Dravet syndrome 
can be found in the European Public Assessment Report (EPAR) for stiripentol (EMA, 2007). 
The EPAR summarizes the results from two studies: STICLO France and STICLO Italy. In the 
stiripentol groups, the SD of the percentage change in seizure frequency from baseline to month 
2 was 42% in the French trial and 26% in the Italian trial. The analogous SDs for placebo groups 
were 38% and 62%. An SD of 50% was assumed for the primary analysis in this trial comparing 
ZX008 0.8 mg/kg/day to placebo on the change from baseline in seizure frequency. Using a two-
sided test at the Į=0.05 significance level, a sample size of 35 subjects per treatment group 
affords 90% power to detect a difference in mean change from baseline of 40 percentage points. 
Similar assumptions and calculations yield a requirement for an additional 35 subjects in the 0.2 
mg/kg/day ZX008 group. Thus, the total sample size is planned to be 105 subjects (35 per arm). 
10.2
ANALYSIS POPULATIONS
10.2.1
Safety (SAF) Population
All safety analyses will be performed on the SAF Population defined as all randomized subjects 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 84 of 182
who receive at least one dose of ZX008 or placebo. Subjects will be analyzed according to the 
treatment actually received. 
10.2.2
Modified Intent-to-Treat (mITT) Population
The mITT Population is defined as all randomized subjects who receive at least one dose of 
ZX008 or placebo and for whom at least one week of diary data are available. Subjects will be 
analyzed according to the treatment group to which they were randomized. The primary 
comparison of ZDX008 0.8 mg/kg/day to placebo, as well as key secondary analyses, will be 
performed on the mITT Population. 
10.2.3
Per Protocol (PP) Population
The PP Population is defined as all randomized subjects who receive at least one dose of 
ZX008 or placebo, complete the entire 12 week Maintenance Period, and have no major 
protocol deviations that would have a significant impact on clinical outcome. Subjects will be 
analyzed according to the treatment they received. The primary and key secondary efficacy 
analyses will be repeated on the PP Population if there are substantial differences in the makeup 
of the mITT and PP Populations. 
10.3
TREATMENT GROUPS
Subjects will be randomly assigned to one of three treatment groups: ZX008 0.8 mg/kg/day, 
ZX008 0.2 mg/kg/day, or placebo. 
10.4
TREATMENT PERIODS
Baseline Period 
The Baseline Period covers the approximately 42-day span just prior to randomization and the 
start of treatment. The baseline frequency of convulsive seizures will be calculated from data 
collected during this period. 
Titration Period 
The Titration Period covers the first 14 days of treatment while subjects are titrated to their 
randomized dose. It begins on the first day of treatment (Study Day 1) and extends through 
Study Day 15 regardless of the exact day on which a subject reaches his or her assigned dose. 
The Titration Period applies to all subjects including placebo recipients. 
Maintenance Period 
The Maintenance Period covers the 12 weeks following the end of the titration period. It begins 
on Study Day 16 and extends through Study Day 99. 
Titration +Maintenance (T+M) Period 
The T+M period combines the Titration and Maintenance periods, beginning on Study Day 1 
and extending through Study Day 99. The T+M period is considered the treatment period. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 85 of 182
Follow-up Period 
The Follow-up Period begins immediately at the end of T+M period and extends to a final visit 2 
weeks later; i.e., from Study Day 99 through Study Day 113. Only subjects who do not roll over 
enrollment into the open-label extension will participate in the Follow-up Period. 
10.5
STATISTICAL ANALYSES AND METHODS
All efficacy, safety, and PK 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. 
Efficacy and PK data will be summarized by treatment (ZX008, placebo) age cohort (<6 years 
and 6 years of age), as well as for the total subjects in the population. 
A complete description of the statistical analyses and methods will be available in a SAP, 
which will be finalized before the database is locked. 
10.5.1
Efficacy Analyses
10.5.1.1
Primary Efficacy Analysis
The primary efficacy endpoint is the change in the mean convulsive seizure frequency (MCSF) 
per 28 days between the Baseline and T+M periods. The MCSF will be calculated from all 
available data collected during the Baseline or T+M Periods. 
The primary endpoint will be analyzed using an analysis of covariance (ANCOVA) model with 
treatment group (three levels) and age group (< 6 years, 6 years) as factors, and with baseline 
frequency as a covariate. The primary analysis will compare the ZX008 0.8 mg/kg/day group to 
the placebo group using a two-sided test at the Į=0.05 level of significance. 
Since the ANCOVA used in the primary analysis relies on assumptions of normality, the primary 
endpoint will also be analyzed using a nonparametric method that does not require as stringent 
assumptions. A nonparametric test such as the van Elteren test, which extends the Wilcoxon rank 
sum test to include stratified data, will be used to compare the ZX008 0.8 mg/kg/day group to the 
placebo group while stratifying for age group. If normality assumptions are not met, the results of 
the nonparametric test will be used to assess the primary objective. 
An additional analysis will be performed to assess the sensitivity of the primary analysis to 
changes in dose or type of concomitant AED medications that may occur during the course of 
the trial, which are protocol violations. Specifically, the primary analysis will be repeated with a 
factor added to indicate whether a subject had a change in prescribed dose or type of 
concomitant AED medication during the T+M period. Further exploratory analyses may be 
conducted if changes in concomitant AED medication appear to have a significant impact on the 
primary outcome. 
Additional analyses will compare the percentage changes between the baseline MCSF and the 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 86 of 182
MCSF measured independently during the Titration Period alone and the Maintenance Period 
alone. 
10.5.1.2
Key Secondary Analyses
The first key secondary endpoint – the proportion of subjects who achieve a 40% reduction 
from baseline in convulsive seizure frequency – is derived directly from the primary endpoint. 
That is, the proportion of subjects in the ZX008 0.8 mg/kg/day group who have a change in 
convulsive frequency of at least -40 percentage points will be compared to the analogous 
proportion in the placebo group. The comparison will be made using a logistic regression 
model that incorporates the same factors and covariates as the ANCOVA used in the primary 
analysis. The second secondary endpoint – the proportion achieving a 50% reduction in 
convulsive seizures – will be analyzed similarly. The analyses will be performed using data 
collected over the T+M period. 
The longest interval between convulsive seizures will be calculated for each subject over the 
entire T+M period. The ZX008 0.8 mg/kg/day and placebo groups will be compared using a 
log-rank test. 
The MCSF in the ZX008 0.2 mg/kg/day group will be compared to the placebo group using the 
same methods employed for the primary analysis. Analyses of other key secondary endpoints 
involving the ZX008 0.2 mg/kg/day group will employ similar methods as those used to compare 
ZX008 0.8 mg/kg/day to placebo. Whenever feasible, secondary analyses involving either ZX008 
0.8 mg/kg/day or ZX008 0.2 mg/kg/day will be repeated using post-treatment data collected 
during the Titration Period alone and during the Maintenance Period alone. 
10.5.1.3
Multiplicity Strategy and Testing Hierarchy
The efficacy analyses will employ a serial gatekeeper strategy to maintain the Type 1 error rate at 
Į=0.05 across the family of analyses that support the primary and key secondary objectives. The 
strategy specifies a hierarchy of significance tests where each test acts as a gatekeeper to the tests 
below it. 
The primary and key secondary endpoints will be assessed in the following order beginning 
with comparisons of ZX008 0.8 mg/kg/day to placebo on 
x
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x
The proportion of subjects who achieve a 40% reduction from baseline in convulsive 
seizure frequency. 
x
The proportion of subjects who achieve a 50% reduction from baseline in convulsive 
seizure frequency. 
x
The longest convulsive seizure-free interval. 
The evaluation of key secondary endpoints continues by comparing the ZX008 0.2 mg/kg/day 
group to placebo in the following order: 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 87 of 182
x
The change in MCSF from baseline. 
x
The proportion of subjects who achieve a 40% reduction from baseline in convulsive 
seizure frequency. 
x
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seizure frequency. 
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10.5.2
Safety Analyses
Summaries of safety data will be presented by treatment – ZX008 0.8 mg/kg/day, ZX008 
0.2 mg/kg/day or placebo – separately for the Titration, Maintenance and T+M periods. The 
number and percentage of subjects in each treatment group with AEs will be displayed by body 
system and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA). 
Summaries of AEs by severity and relationship to study drug will also be presented. A separate 
summary will be provided for all serious AEs (SAEs). Selected summaries will be repeated 
broken out by age group, i.e., 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 baseline. Shift tables will be 
presented for each time point where lab results are collected. Mean change from baseline will also 
be calculated for continuous hematology and chemistry results at all time points available. 
Laboratory tests, vital signs, physical examinations, neurological examinations, ECG, Doppler 
echocardiogram, C-SSRS, Tanner Staging results, etc, will be summarized appropriately, by 
treatment. All safety summaries will be based on the SAF Population. 
10.5.3 
Pharmacokinetic Analyses
All data will be evaluated using population PK analysis methods and the methods will be 
described in detail in a separate PK analysis plan. In brief, the plan is to use published data to 
construct a population PK model for fenfluramine in adults. Given the age range of subjects to be 
enrolled in this study, it will be possible to use the known ontogeny of drug disposition in 
children to predict fenfluramine PK in subjects with Dravet syndrome from the population PK 
model. The robustness of the empirical model will then be confirmed by applying the model to 
PK data collected from this study. In this way, the effect of body size, age, and any other 
relevant factors can be quantified to assure that an adequate understanding of fenfluramine PK is 
obtained. 
The full methods and results of the population PK analysis of data from this study will be 
provided in a separate report. The clinical study report will contain a brief summary of the 
analysis including: the population mean and interindividual variability estimates from the fit of  
the population PK model; summary statistics of the plasma concentrations by PK sampling time 
and of the individual, derived plasma PK parameters (Cmax, AUC0-t, Tmax, and t1/2) by 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 88 of 182
treatment group. The clinical study report will also contain a comparison of the PK of 
fenfluramine in the children enrolled in this study to historical data from adults. 
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. 
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 (e.g., during a study initiation visit, via 
e-mail, etc) that all ethical and legal requirements have been met before the first subject is 
enrolled into the study. 
11.2
INFORMED CONSENT
The investigator is responsible for obtaining a subject’s written informed consent to participate 
in the study. 
A Subject Information Sheet and a master ICF will be prepared by the sponsor according to the 
provisions of ICH GCP and local legal requirements. 
All subjects will be informed that the study will be registered in the public database at 
ClinicalTrials.gov in accordance with the FDA Amendments Act of 2007 (Section 12.3). 
Before undergoing screening procedures for possible enrollment into the study, subjects must be 
informed, in an understandable form, about the nature, scope, and possible consequences of the 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 89 of 182
study. This information must be given orally to subjects by a physician or medically qualified 
person (according to applicable regulatory requirements) who is well informed about the nature, 
scope, and possible consequences of the study. Written information about the study will also be 
provided in a Subject Information Sheet. The date on which this oral and written information on 
the study was provided to the subject, and by whom it was provided, must be documented in the 
ICF. 
As specified in ICH GCP Section 4.8 and the US 21CFR Section 50.25, the informed consent 
discussion must emphasize that participation in the study is voluntary and that subjects have the 
right to withdraw their consent at any time without giving a reason and without any disadvantage 
for their subsequent care. 
Subjects must be given ample time and opportunity to inquire about details of the study and to 
consider their participation in the study. If, after reading the Subject Information Sheet and the 
ICF, consent is given to participate in the study, then the ICF must be signed and personally 
dated by the subject and the person conducting the informed consent discussion (and an 
impartial witness, if required). The subject will be provided with a copy of the signed ICF. 
Verification of the signed ICF will be recorded in the subject’s eCRF. The original signed ICF 
will be filed with the subject’s records and/or in the Investigator Study File. 
The Subject Information Sheet and ICF have to be approved by the IEC/IRB before they can be 
used in the study. 
The Subject Information Sheet and ICF must be revised whenever important new information 
becomes available that may be relevant to the subject’s consent. Any revision of these documents 
must be approved by the IEC/IRB before they can be used in the study. Subjects must be 
informed in a timely manner if new information becomes available that may be relevant to their 
willingness to continue participation in the study. The communication of this 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. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 90 of 182
Assent for Subjects Under the Age of Consent (Pediatric Subjects) 
All subjects are under the age of consent (i.e., pediatric subjects under 18 years of age); the 
written informed consent of a legally acceptable representative is required. Pediatric subjects who 
can understand the nature, scope, and possible consequences of the study must also give their 
assent, orally and/or in writing via the assent document, as appropriate. After the ICF and any 
other written information to be provided to subjects has been read and explained to the subject 
and the subject’s legally acceptable representative, and after the subject and the legally acceptable 
representative have orally consented to the subject’s participation in the study and, if capable of 
doing so, the subject has signed and personally dated the assent document, the legally acceptable 
representative should sign and personally date the ICF. By signing the ICF, the legally acceptable 
representative attests that the information in the ICF and any other written information was 
accurately explained to, and apparently understood by, the subject, and that assent was freely 
given by the subject. 
11.3
REGULATORY CONSIDERATIONS AND INDEPENDENT ETHICS 
COMMITTEE/INSTITUTIONAL REVIEW BOARD
The sponsor (or delegate) will submit the appropriate documents to all applicable competent 
regulatory authorities and IEC/IRBs, and will await all relevant approval before enrolling any 
subjects into the study. Written approval should mention the study protocol by study title, study 
number, and version date. 
This study will be conducted under Investigational New Drug (IND) Application and 
documented in accordance with the applicable regulatory guidelines and requirements. 
The sponsor (delegate) will ensure that the investigators conduct the study as stipulated 
in this study protocol and in accordance with all applicable regulatory requirements. The 
sponsor (delegate) is obliged to obtain evidence of the investigator’s qualification to 
perform the clinical study. Therefore, the investigator has to provide a signed and dated 
copy of his or her professional curriculum vitae (prepared no more than 2 years 
beforehand and preferably written in English) before the start of the study, including 
information on his or her experience in conducting 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. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 91 of 182
The investigator should not implement any deviation from, or changes to, the study protocol 
without agreement by the sponsor (delegate) and prior review and documented approval or 
favorable opinion from the IEC/IRB of an amendment to the study protocol. Exceptions include 
only cases of medical emergency to address immediate hazards to study subjects, or when the 
changes involve only logistic or administrative aspects of the study. 
In the event of a medical emergency, the investigator at each site may institute any medical 
procedures deemed appropriate to address an immediate hazard to a subject without prior 
IEC/IRB approval or favorable opinion. As soon as possible, the implemented deviation or 
change, the reason(s) for it, and, if appropriate, the proposed study protocol amendment(s) 
should be submitted to: 
x
The sponsor (delegate) for agreement. 
x
The IEC/IRB for review and approval or favorable opinion (if required). 
x
The applicable competent regulatory authority (if required). 
Details of the procedure for implementing study protocol amendments are available in 
Section 12.10. 
At the earliest opportunity, the investigator (or delegate) must inform the sponsor (delegate) 
about any notable protocol deviations and explain any deviation from the approved study 
protocol in the eCRF and/or in the Protocol Deviation Log, if applicable. 
12.
ADMINISTRATIVE ASPECTS
12.1
CLINICAL TRIAL AGREEMENT
This study will be conducted under a Clinical Trial Agreement between the sponsor (or delegate) 
and the respective institutions representing the study sites. Any financial support given to the 
study sites will be detailed in the Clinical Trial Agreement. The Clinical Trial Agreement, which 
must be signed before the start of any study related procedures, will clearly delineate the 
responsibilities and obligations of the investigator and the sponsor (delegate), and will form the 
contractual basis upon which the study will be conducted. 
12.2
FINANCIAL DISCLOSURE BY INVESTIGATOR
Prior to study initiation, the investigator and any subinvestigator(s) to be directly involved in 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 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 92 of 182
according to the applicable regulatory requirements. 
12.3
CLINICAL STUDY REGISTRATION AND RESULTS DISCLOSURE
The sponsor will provide the relevant study protocol information in a public database 
(ClinicalTrials.gov) before or at commencement of the study, as required by the 2007 FDA 
Amendments Act. The sponsor (delegate) may also provide study information for inclusion in 
national registries according to local regulatory requirements. 
If a potential subject contacts the sponsor regarding participation in the study, the investigator 
agrees that the sponsor (delegate) may forward the relevant study site and contact details to the 
subject. Based on the inclusion and exclusion criteria for the study, the investigator will assess 
the suitability of the subject for enrollment into the study. Results of this study will be disclosed 
according to the relevant regulatory requirements. All publications in peer-reviewed medical 
journals resulting from this study will be listed in the original study protocol registration record 
on ClinicalTrials.gov. 
12.4
STUDY FILES AND MATERIALS
Before the start of any study related procedures, all essential documents specified by ICH GCP 
and other applicable regulations must be available in the relevant files maintained by the sponsor 
(or delegate) and the investigator. An Investigator Study File prepared by the sponsor (or 
delegate), containing all applicable documents for use at the study site, will be made available to 
the investigator before the start of the study. A list of personnel and organizations responsible for 
conduct of the study as well as the list of investigators will be included in the Investigator Study 
File. The respective files will be kept and updated by the sponsor (or delegate) and the 
investigator, as applicable. 
All study documentation and materials maintained in the Investigator Study File at the study site 
must be available for inspection by the sponsor’s study monitor (or delegate) to determine that 
all required documentation is present and correct (see Section 12.9). 
The study may be audited or inspected by qualified delegates from the sponsor or a competent 
regulatory authority (see Section 12.11). 
12.5
INITIATION OF THE STUDY
Before the start of the study at each study site, the sponsor’s study monitor (or delegate) will 
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 eCRF, IMP accountability, and the subject 
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ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 93 of 182
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).
If required by local law, subjects taking part in this study will be insured against any injury 
caused by the study in accordance with the applicable regulatory and legal requirement(s). 
12.8
SUBJECT IDENTIFICATION AND CONFIDENTIALITY
All study documents, including the study protocol and eCRFs, are the confidential property of 
the sponsor and should be treated as such. 
All subjects screened for the study will be documented in a screening log in compliance with the 
requirements of individual study sites. Subjects not enrolled into the study will be documented 
as such in the screening log together with the reason for not having been enrolled. 
The investigator will maintain a personal list of subject names and subject numbers (Subject 
Identification List) for participants in the study to enable records to be identified at a later date. 
These records should be retained in a confidential manner for the duration stipulated by 
applicable regulatory requirements. All subject names will be kept in confidence and will not be 
revealed to the sponsor. Subject names must be made unreadable on any documents made 
available to the sponsor. 
Subjects participating in the study will be identified in the eCRF by the subject number allotted 
to them during the study. 
The ICF will include a statement that all study findings, irrespective of the medium on which they 
are stored, will be handled in strictest confidence in accordance with applicable data protection 
laws (e.g., the European Data Protection Directive [95/46/EC] and the USA Health Insurance 
Portability and Accountability Act [HIPAA]), and will be evaluated by the sponsor and/or a 
competent regulatory authority in an anonymized form. The subjects are also to be informed that 
their medical records may be audited or inspected by qualified delegates from the sponsor or a 
competent regulatory authority. The subject’s written consent authorizing direct access to his 
medical records, and computer processing and publishing of his anonymous personal data, must 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 94 of 182
be obtained prior to participation in the study. 
A subject’s identity will be disclosed by the investigator only in case of emergency (i.e., 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 eCRFs and direct access to related source documents for monitoring purposes as 
frequently as the sponsor deems necessary. These documents include records of tests performed 
as a requirement for participating in the study as well as other medical records required to confirm 
information contained in the eCRF, such as past history and secondary diagnoses. 
Before each monitoring visit, the investigator (or delegate) should record all data generated 
since the last monitoring visit in the eCRF. The investigator and other relevant personnel at 
each study site will be expected to cooperate with the sponsor’s study monitor to assist in 
providing any missing information. 
The study monitor will require access to the Investigator Study File to ensure completeness of 
all documentation required for the study. The study monitor will ensure that the investigator at 
each site has been provided with adequate means for organization and filing of study 
documentation (see Section 12.4). 
The date on which the study monitor (or delegate) visits the study site will be recorded in the 
Site Visit Log. During monitoring visits, the study site’s coordinator (if applicable) and the 
investigator should be available, the source documentation should be accessible, and a suitable 
environment should be provided for the study monitor to review study related documentation. 
The main objectives of monitoring visits conducted by the study monitor include: 
x
Resolution of any problems. 
x
Examination of all study documentation for completion, adherence to the study protocol, 
and possible AEs. 
x
Clarification of inconsistencies or missing data. 
x
Verification of study data against source documents. 
x
Checks that investigator obligations have been fulfilled. 
x
Review of ICFs and dates of consent. 
x
Inspection of IMP with respect to storage, labeling, and documentation. 
x
Drug accountability 
After each subject’s visit to the study site, the investigator (or delegate) will ensure that all data 
have been entered into the eCRF correctly and in a timely manner, after which the investigator 
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ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 95 of 182
will sign the eCRF. 
12.10
PROTOCOL AMENDMENTS
A “substantial” amendment of a study protocol is any written description of change(s) to, or 
formal clarification of, a study protocol that may have a significant impact on the safety or 
physical or mental integrity of subjects, the scientific value of the study, the conduct or 
management of the study, or the quality or safety of any IMP used in the study. The IEC/IRB 
must approve all substantial protocol amendments prior to their implementation. If required by 
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 (e.g., 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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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 96 of 182
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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ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 97 of 182
13.
REFERENCE LIST
Aicardi J and Gastaut H. Treatment of self-induced photosensitive epilepsy with fenfluramine (3 
cases). NEJM 1985; Nov 28;313(22):1419. 
Aicardi J, Gastaut H, and Misès J. Syncopal attacks compulsively self-induced by Valsalva's 
maneuver associated with typical absence seizures. A case report. Arch Neurol 1988 
Aug;45(8):923-5. 
Boel M and Casaer P. Add-On therapy of fenfluramine in intractable self-induced epilepsy. 
Neuropediatrics. 1996; 27: 171-173. 
Center for Disease Control. Cardiac valvulopathy associated with exposure to fenfluramine or 
dexfenfluramine: U.S. Department of Health and Human Services Interim Public Health 
Recommendations, November 1997. Morbidity and Mortality Weekly Report. 1997; 
46(45):1061-1084. 
Ceulemans B, Boel M, Leyssens K, Van Rossem C, Neels P, Jorens PG, Lagae L. Successful 
use of fenfluramine as an add-on treatment for Dravet syndrome. Epilepsia 2012; 53: 1131-
1139.  
Ceulemans, B., Schoonjans, A.-S., Marchau, F., Paelinck, B. P., & Lagae, L.. Five-year 
extended follow-up status of 10 patients with Dravet syndrome treated with fenfluramine. 
Epilepsia 2016 (*):1–6, 2016 http://doi.org/10.1111/epi.13407 
Chiron C and Dulac O. The pharmacologic treatment of Dravet syndrome. Epilepsia 2011; 
52(Suppl. 2):72–75. 
Connolly HM, Crary JL, McGoon MD, Hensrud DD et al.  Valvular heart disease associated with 
fenfluramine-phentermine. New Engl J Med 1997;337(9):581-8. Erratum in: N Engl J Med 1997 
Dec 11;337(24):1783. 
Dravet C, Bureau M, Oguni H, Fukuyama Y, Cokar O. Severe myoclonic epilepsy in infancy: 
Dravet syndrome.  Adv Neurol 2005; 95: 71-102. 
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. 
ICH Topic E2A: Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, 1994. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 98 of 182
Marshall WA, Tanner JM. Variations in the pattern of pubetal changes in boys. Arch Dis Child 
1970; 45:13. 
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Archives of Disease 
in Childhood. 1969;44(235):291-303. 
Nashef L, So EL, Ryvlin P, Tomson T. Unifying the definitions of sudden unexpected death in 
epilepsy. Epilepsia 2012;53, 227–233. 
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. 
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. 
Wong J, Reddy SS, Klein AL. Anorectic drugs and valvular heart disease: a biological and 
clinical perspective.  Cleveland Clinical Journal of Medicine 1998; 65:35-41. 
ZX008 Investigator’s Brochure Version 3, January 5, 2016. 
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31 October 2016 
Confidential 
Page 99 of 182
14.
APPENDICES
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 


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31 October 2016 
Confidential 
Page 100 of 182
APPENDIX 1 – LIST OF PROHIBITED CONCOMITANT MEDICATIONS 
Generic Name 
Generic Name
alfentanil 
naratriptan 
almotriptan 
nefazodone 
alprenolol 
nortriptyline 
amitriptyline 
ondansetron 
amphetamine 
oxcarbazepine 
astemizole 
oxycodone 
atomoxetine 
paroxetine 
bufuralol 
perphenazine 
bupropion 
phenacetin 
buspirone 
phenobarbital 
cafergot 
phenytoin 
cannabidiol 
promethazine 
carbamazepine 
propafenone 
cerivastatin 
retigabine/ezogabine 
citalopram 
risperidone 
clomipramine 
ritonavir 
codeine 
rizatriptan 
cyproheptadine 
selegiline 
desipramine 
sertraline 
dextromethorphan 
stiripentol 
duloxetine 
sumatriptan 
eletriptan 
telaprevir 
encainide 
THC and derivatives 
ergotamine tartrate 
tramadol 
eslicarbazepine 
trazodone 
felbamate 
vortioxetine 
fentanyl 
zolmitriptan 
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31 October 2016 
Confidential 
Page 101 of 182
fluoxetine 
zuclopenthixol 
fluvoxamine 
 
frovatriptan 
 
imipramine 
 
levacetylmethadol (LAAM) 
linezolid 
 
meperidine 
 
methadone 
 
metoclopramide 
 
mexiletine 
 
PUBLIC COPY 
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31 October 2016 
Confidential 
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APPENDIX 2 – COLUMBIA – SUICIDE SEVERITY RATING SCALE
This do
uthorization 
ereof. 


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COPY 
This do
nt cannot be used to support any marketing 
horization 
auth
ation and any extensions or variations 
eof. 
there


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31 October 2016 
Confidential 
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PUBLIC COPY 
This doc
ocument cannot be used to support any marketing 
horization 
auth
application and any extensions or variations 
eof. 
there


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31 October 2016 
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This do
horization 
eof. 


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ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
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PUBLIC COPY 
This document cannot be used to support any marketing 
horization 
autho
on
on and any extensions or variations 
eof. 
thereo


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31 October 2016 
Confidential 
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PUBLIC COPY 
This do
document cannot be used to support any marketing 
thorization 
auth
application and any extensions or variations 
eof. 
thereo


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31 October 2016 
Confidential 
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APPENDIX 3 – BEHAVIOR RATING INVENTORY OF EXECUTIVE 
FUNCTION 
This do
d t
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n
reof. 


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31 October 2016 
Confidential 
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COPY 
This document cannot be used to support any marketing 
zation 
authoriza
ap
application and any extensions or variations thereof. 


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31 October 2016 
Confidential 
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PUBLIC COPY 
This document t cannot be used to support any marketing 
zation 
autho
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APPENDIX 4 – QUALITY OF LIFE IN CHILDHOOD EPILEPSY SCALE
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APPENDIX 5 – TANNER STAGING
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APPENDIX 6 – PEDSQL (INCLUDING FAMILY IMPACT MODULE) 
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APPENDIX 8 – HOSPITAL ANXIETY AND DEPRESSION SCALE 
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APPENDIX 9 – MAXIMUM ALLOWABLE BLOOD DRAW VOLUMES 
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APPENDIX 10 – PROTOCOL AMENDMENT 1
Summary of Changes 
Clarifications and changes were made to the protocol and include the following: 

Sponsor name change 

Added new section of transition for subjects who will enter the open-label extension study 

Removed the following clinical laboratory tests at Visits 1 and 6: LH, FSH, estradiol, 
testosterone, GH, prolactin, and IGF-1 

Clarified the maximum dose of ZX008 is 30 mg/day 

Clarified the collection duration of prior and concomitant AEDs 

Clarified data to be collected with the use of rescue medication 

Moved the BRIEF-P description from the efficacy section to the safety section 

Added new section of collection of data for AEs requiring hospitalization 
Additional clarifications and changes were made based on feedback received from the United 
States Food and Drug Administration, and include the following: 

Clarified randomization inclusion criteria, post-treatment cardiac follow-up, and AESI with 
regard to valve regurgitation seen on ECHO. 

Clarified that the central cardiac reader will provide consultation to the IDSMC when a 
subject may be removed from the study due to development of signs or symptoms 
indicative of valvulopathy, regurgitation, or pulmonary hypertension 

Clarified expedited reporting of cardiac events other than SAEs 

Added section on grading of and follow-up for ECHO findings 
The rationale for each change/clarification also is provided below. 
List of Specific Changes 
Additions are marked in bold and deletions are marked in strikethrough. Minor editorial 
changes, such as the correction of typing or formatting errors, updating headers and footers, 
and tables of contents, etc, are not listed. 
Rationale: There has been a name change for the sponsor’s subsidiary.
Original Text
Amendment Text
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Title page, Signature of Sponsor page, Synopsis, 
Table 2, and document headers
Brabant Pharma Limited
Title page, Signature of Sponsor page, Synopsis, Table 2, 
and document headers
Brabant Pharma Limited Zogenix International Limited
Rationale: A transition period for those subjects entering the open-label extension study has been 
added in order to preserve the study blind and allow all subjects to enter the follow-on study receiving
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open-label study medication.
Original Text
Amendment Text
Synopsis 
Methodology: 
After completion of the Maintenance Period, 
eligible subjects will be offered enrollment in a 
separate open-label extension trial.
Duration of Treatment:
All subjects will receive ZX008 or matching 
placebo for up to approximately 14 weeks 
(Titration Period=2 weeks; Maintenance 
Period=12 weeks). After completion of the 
Maintenance Period, eligible subjects may enroll 
in the open-label extension study.
Table 1. Schedule of Assessments, Footnotes
c: Only for subjects who do not roll over into the 
open-label extension study.
k: Follow-up ECG, ECHO, and physical 
examination will be performed 3-6 months after 
early termination, or for those subjects who 
complete the study but do not enter the open-label 
extension study (see Section 6.4).
l: Only adverse events related to cardiac safety 
will be collected at this visit.
Section 3.1
After completion of the Maintenance Period, 
eligible subjects will be offered enrollment in a 
separate open-label extension trial.
Synopsis 
Methodology: 
At the end of the Maintenance Period (or early 
discontinuation), all subjects will undergo a 2-week 
taper or transition period (Post-Dosing Follow-Up) 
depending on whether they exit the study or are 
enrolled in the separate long-term open-label extension 
study.
Duration of Treatment:
All subjects will receive ZX008 or matching placebo for 
up to approximately 14 16 weeks (Titration Period=2 
weeks; Maintenance Period=12 weeks; 
Taper/Transition=2 weeks). After completion of the 
Maintenance Period, eligible subjects may enroll in the 
open-label extension study, after completion of the 
transition.
Table 1. Schedule of Assessments, Footnotes
(appropriate adjustments were made within the table 
regarding these footnotes)
c: Only for subjects who do not roll over into the open- 
label extension study. Follow-up ECG, ECHO, and 
physical examination will be performed 3-6 months 
after early termination, or for those subjects who 
complete the study but do not enter the open-label 
extension study (see Section 6.4).
k: Follow-up ECG, ECHO, and physical examination will 
be performed 3-6 months after early termination, or for 
those subjects who complete the study but do not enter the 
open-label extension study (see Section 6.4). Only 
adverse events related to cardiac safety will be 
collected at this visit.
l: Only adverse events related to cardiac safety will be 
collected at this visit.
Section 3.1
After completion of the Maintenance Period, eligible 
subjects will be offered enrollment in a separate open-label 
extension trial.   At the end of the Maintenance Period 
(or early discontinuation), all subjects will undergo a 2- 
week taper or transition period (Post-Dosing Follow-
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None 
Up) depending on whether they exit the study or are 
enrolled in the separate long-term open-label extension 
study.
5.5.5 Transition Period
Subjects who complete the Maintenance Period and 
will be continuing into the open-label extension study 
will be transitioned from double-blind study 
medication to open-label ZX008 (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. Study 
medication will be administered using the oral dosing 
syringe provided.
All subjects entering the open-label extension study 
will be transitioned from their blinded daily dose 
(placebo, 0.2 mg/kg/day, 0.8 mg/kg/day, or 30 mg/day) 
to the 0.2 mg/kg dose during the 2-week interval 
between Visits 12 and 13, without breaking the blind. 
The IVR/IWR system will assign two bottles of IMP to 
the subject, one for each step in the transition. A new 
bottle of IMP will be started by the subject at each 
level of the transition step. See Section 5.6 for more 
information about the volume of ZX008 or placebo to 
be administered.
Table 5.  Transition Algorithm
Dose Group 
in Double- 
Blind Study
Transition Step 1 
Day 1-4 after Visit 
12
Transition Step 2
Days 5-14 after
Visit 12
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ZX008 0.2
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ZX008 0.2
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ZX008 0.2
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ZX008 0.2
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Note: maximum daily dose of ZX008 is 30 mg.
Subjects who had been randomized to placebo increase 
their dose to 0.2 mg/kg/day beginning on Day 1 of the 
transition (the day following Visit 12.) Subjects who 
had been randomized to 0.2 mg/kg/day will continue to 
receive that dose. Subjects who had been randomized 
to 0.8 mg/kg/day or were receiving the maximum dose
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Section 6.2.7 
None
Section 6.2.9

Dispense study medication for taper 
subjects not enrolling in the open-label 
extension study
None
Section 6.3 
None
of 30 mg/day decrease to a dose of ZX008 0.4 
mg/kg/day, or a max of 30 mg/day. After 4 days at this 
dose level (Day 5), these subjects will decrease their 
dose to 0.2 mg/kg/day. Subjects will report to the clinic 
on Day 15 for enrollment into the open-label extension 
study.
Section 6.2.7
At Clinic Visit 10, compliant subjects who have 
tolerated IMP should be presented with the ICF for the 
open-label extension study. Informed consent for the 
open-label extension study must be signed at Visit 12 or 
earlier in order to enter the open-label extension study.
Section 6.2.9

Dispense study medication for taper subjects not 
enrolling in the open-label extension study
Informed consent for the open-label extension study 
must be signed at Visit 12 (if not signed earlier) in 
order to enter the open-label extension study.
Section 6.3
For subjects entering the open-label extension study, 
the subject will visit the clinic on Day 113. The 
following will be recorded/performed and the subject 
will immediately be enrolled in that separate study:

Review current seizure activity 
(number/type/duration) from diary since 
previous visit

AEs

AESIs

Concomitant medications

Collect used, partially used and unused study 
medication; perform drug accountability and 
review with parent/caregiver
Rationale: To remove the following clinical laboratory tests at Visits 1 and 6: LH, FSH, estradiol, 
testosterone, GH, prolactin, and IGF-1.
Original Text
Amendment Text
Section 1.6
The approximate volume of blood (108.7 mL) 
planned for collection from each subject over the 
course of the entire study (Screening to End of
Section 1.6
The approximate volume of blood (115.7 108.7 mL) 
planned for collection from each subject over the course of 
the entire study (Screening to End of Study, but not
PUBLIC COPY 
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Original Text
Table 8.   Estimated Blood Volume Collection 
Assessment 
Baseline Period (study day) 
Titration + Maintenance Period (study day) 
Screening 
(Day -42 to -41) 
Randomization 
Day -1
Day 15 
Day 43 
Day 71 
Day 99 
Total 
Clinical chemistry 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
45 mL 
LH, FSH, estradiol, 
testosterone, GH, 
prolactin 
Included in 
Chemistry 
Included in 
Chemistry 
Included in 
Chemistry 
Included in 
Chemistry 
Included in 
Chemistry 
Included in 
Chemistry 
Hematology 
2 mL 
2 mL
2 mL
2 mL
2 mL 
2 mL
12 mL
Genotyping 
5 mL 
-- 
-- 
-- 
-- 
-- 
5 mL 
IGF-1 
3.5 mL 
3.5 mL
3.5 mL
3.5 mL
3.5mL 
3.5 mL
21 mL
Coagulation 
-- 
2.7 mL
--
--
-- 
--
2.7 mL
Cannabidiol 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
12 mL 
ZX008 PK sample 
-- 
--
4 × 2 mL
-- 
--
8 mL
AED plasma sample 
1 x 2 mL 
1 x 2 mL 
1 x 2 mL 
1 x 2 mL 
8 mL 
Volume for flushing 
indwelling catheter 
-- 
-- 
4 × 0.5 mL 
-- 
-- 
2 mL 
Approximate total blood 
volume per subject
20.0 mL 
19.7 mL 
17.0 mL 
27.0 mL 
15.0 mL 
17.0 mL
115.7 mL 
FSH=follicle stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; LH-luteinizing hormone; PK=pharmacokinetics 
 
Amendment Text
Table 8.   Estimated Blood Volume Collection 
Assessment 
Baseline Period (studyday)
Titration + Maintenance Period (study day) 
Screening 
(Day -42 to -41) 
Randomization 
Day -1
Day 15 
Day 43 
Day 71 
Day 99 
Total 
Clinical chemistry 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
45 mL 
LH, FSH, estradiol, 
testosterone, GH, 
prolactin 
Included in 
Chemistry -- 
Included in 
Chemistry 
Included in 
Chemistry --
Included in 
Chemistry 
Included in 
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Included in 
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Hematology 
2 mL 
2 mL
2 mL
2 mL
2 mL 
2 mL
12 mL
Genotyping 
5 mL 
--
--
--
-- 
--
5 mL
IGF-1 
3.5 mL --
3.5 mL 
3.5 mL --
3.5 mL 
3.5mL 
3.5 mL 
21 14 mL 
Coagulation 
-- 
2.7 mL
--
--
-- 
--
2.7 mL
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2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
12 mL 
ZX008 PK sample 
-- 
--
4 × 2 mL
-- 
--
8 mL
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1 x 2 mL
1 x 2 mL
1 x 2 mL
1 x 2 mL
8 mL
Volume for flushing 
indwelling catheter 
-- 
-- 
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-- 
-- 
2 mL 
Approximate total blood 
volume per subject
20.0 16.5 mL 
19.7 mL 
17.0 13.5
mL
27.0 mL 
15.0 mL 
17.0 mL
115.7 
108.7 mL
FSH=follicle stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; LH-luteinizing hormone; PK=pharmacokinetics 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 155 of 182
Rationale: To clarify the maximum dose of ZX008 is 30 mg/day.
Original Text
Amendment Text
Section 5.5.2
After 4 days at this dose level (Study Day 5), 
subjects randomized to the ZX008 0.8 mg/kg/day 
group will increase their dose to 0.4 mg/kg/day 
while doses in the other two groups will remain 
constant.  On Study Day 9, the dose for the
0.8 mg/kg/day group will increase to the target 
dose.
Table 3 
None
Section 5.5.4
On the first day of the tapering period subjects in 
the ZX008 0.8 mg/kg/day group will decrease to a 
dose of ZX008 0.4 mg/kg/day BID.
Table 4 
None
Section 5.5.2
After 4 days at this dose level (Study Day 5), subjects 
randomized to the ZX008 0.8 mg/kg/day group will 
increase their dose to 0.4 mg/kg/day (maximum 30 
mg/day) while doses in the other two groups will remain 
constant. On Study Day 9, the dose for the 0.8 mg/kg/day 
group will increase to the target dose or a maximum of 30 
mg/day.
Table 3
Note: maximum daily dose of ZX008 is 30 mg.
Section 5.5.4
On the first day of the tapering period subjects in the 
ZX008 0.8 mg/kg/day group will decrease to a dose of 
ZX008 0.4 mg/kg/day BID (maximum 30 mg/day).
Table 4
Note: maximum daily dose of ZX008 is 30 mg.
Rationale: To clarify the collection duration of prior and concomitant AEDs.
Original Text
Amendment Text
Section 5.7
All medications taken by a subject during the 
Screening and Baseline Seizure Assessment 
Periods are regarded as prior therapy and must be 
documented in the eCRF. Significant medications 
(e.g., antiepileptic drugs [AEDs], antibiotics) 
taken within 30 days prior to the Screening visit 
should also be captured.
Section 5.7
All medications taken by a subject during the Screening and 
Baseline Seizure Assessment Periods are regarded as prior 
therapy and must be documented in the eCRF. Significant 
medications (e.g., antiepileptic drugs [AEDs], antibiotics) 
taken within 30 days prior to the Screening visit should also 
be captured. All prior and concomitant AEDs will be 
collected in the CRF.
Rationale: To clarify data to be collected with the use of rescue medication.
Original Text
Amendment Text
Section 5.7.3
Use of rescue medication is permitted during the 
study and should be recorded on the eCRF (day, 
time, medication[s], dose[s]) and in the diary (day, 
time). Repeated administrations within the same 
episode should be recorded separately.
Section 5.7.3
Use of rescue medication is permitted during the study and 
should be recorded on the eCRF (day, time, medication[s], 
dose[s]) and in the diary (day, timeframe associated with 
seizure episodes). Repeated administrations within the 
same episode should be recorded separately.
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 156 of 182
Rationale: To move the BRIEF-P description from the efficacy section to the safety section
Original Text
7.1.4 Behavior Rating Inventory of Executive 
Function – Preschool Version (BRIEF-P)
Amendment Text
7.1.4 7.2.12 Behavior Rating Inventory of Executive 
Function – Preschool Version (BRIEF-P)
Rationale: To add new section of collection of data for AEs requiring hospitalization.
Original Text
Amendment Text
None
Section 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 
Dravet syndrome: 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.
Rationale: To clarify randomization inclusion criteria, post-treatment cardiac follow-up, and AESI 
with regard to valve regurgitation seen on ECHO.
Original Text
Amendment Text
Synopsis, Section 4.3, Section 6.4, Section 8.1.3
Synopsis and Section 4.3 
Randomization Inclusion Criteria:
2. Subject does not have a cardiovascular or 
cardiopulmonary abnormality based on ECHO, 
ECG or physical examination, including but not 
limited to any mitral, aortic, tricuspid or 
pulmonary valve regurgitation or signs of 
pulmonary hypertension, and is approved for entry 
by the cardiac central reader.
Section 6.4, Table 6, footnote b
Positive sign or symptom includes any sign of 
valve thickening or regurgitation (mitral, aortic, 
pulmonary, tricuspid), or sign or symptom 
indicative of potential pulmonary hypertension as 
adjudicated by the IPCAB.
Section 8.1.3, Table 8
10.  Signs on ECHO indicative of potential
Synopsis, Section 4.3, Section 6.4, Section 8.1.3
Synopsis and Section 4.3 
Randomization Inclusion Criteria:
2. Subject does not have a cardiovascular or 
cardiopulmonary abnormality based on ECHO, ECG or 
physical examination, including but not limited to any trace 
mitral, or aortic, tricuspid or pulmonary valve regurgitation 
or signs of pulmonary hypertension, and is approved for 
entry by the cardiac central cardiac reader.
Section 6.4, Table 7 footnote b
Positive sign or symptom includes any sign development 
of valve thickening or regurgitation (“trace” or greater in 
mitral, aortic,; mild or greater in pulmonary, tricuspid), or 
sign or symptom indicative of potential pulmonary 
hypertension as adjudicated by the IPCAB.
Section 8.1.3, Table 9
10.  Signs on ECHO indicative of potential valvulopathy
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 157 of 182
valvulopathy
  mild valve regurgitation (aortic, mitral, 
tricuspid, or pulmonary)
 Mean Mitral valve gradient  4 mmHg
 Mean Aortic valve gradient  15 mmHg
 Mean Tricuspid valve gradient > 4 mmHg
 Mean Pulmonary valve gradient > 21 mmHg
 valve regurgitation (aortic or mitral)
  mild valve regurgitation (aortic, mitral, tricuspid, or 
pulmonary)
 Mean Mitral valve gradient  4 mmHg
 Mean Aortic valve gradient  15 mmHg
 Mean Tricuspid valve gradient >  4 mmHg
 Mean Pulmonary valve gradient >  21 mmHg
Rationale: To clarify that the central cardiac reader will provide consultation to the IDSMC when a 
subject may be removed from the study due to development of signs or symptoms indicative of 
valvulopathy, regurgitation, or pulmonary hypertension.
Original Text
Amendment Text
Section 4.5
Subjects may 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 and the investigator believe the 
benefit of continued participation does not 
outweigh the risk.
Section 4.5
Subjects may 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.
Rationale: To clarify expedited reporting of cardiac events other than SAEs.
Original Text
Amendment Text
Section 8.8
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.
4. Hypersensitivity reactions
5. Pulmonary hypertension
6. Cardiac symptoms requiring intervention, or 
valvulopathy
Section 8.8
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
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 158 of 182
Rationale: To add a new section on grading of, and follow-up for, ECHO findings.
Original Text
Amendment Text
None
Section 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, triscuspid) 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 11 describes the severity of ECHO findings 
with the level of increasing oversight if the subject is to 
remain in the study.
Table 11. Clinical Measures Enacted Upon Increasing 
Severity of ECHO Findings
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 (e.g. valproic acid, 
clobazam, or topiramate), alone or in 
combination, and not maintained the 
level of seizure control achieved with 
study medication.
Severity
Valve
Aortic
Mitral
Pulmonary
Tricuspid
Normal
Level 1
Level 1
Level 1
Level 1
Trace
Level 2
Level 2
Level 1
Level 1
Mild
Level 2
Level 2
Level 1
Level 1
Moderate
Level 3
Level 3
Level 3
Level 3
Severe
Level 3
Level 3
Level 3
Level 3
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 159 of 182
2.
If the investigator feels consideration of continued 
treatment is warranted considering benefit and 
potential risks, and the parent/guardian feels 
strongly that the child be maintained on the study 
medication when understanding the risks, the 
parent/guardian must sign a new consent which 
describes the additional risks and the child should 
provide assent if appropriate.
a.
If both of these conditions are not met, 
the subject is discontinued from 
treatment.
3.
The investigator prepares a case history and 
rationale for continuation to be submitted to the 
IDSMC for review, including consideration of 
effects on seizures and comorbidities.
4.
The Co-Chairs of the IPCAB are alerted to the 
request and prepare, after consultation with 
BMS, an evaluation of the cardiopulmonary risks 
and proposed monitoring plan, if applicable for 
submission to the IDMSC.
5.
IDMSC will review the submission from the 
Investigator and the IPCAB and unblind the 
subject treatment if warranted.
6.
IDSMC makes a determination of appropriate 
path, including the possible outcomes:
a.
Discontinue study medication
b.
Increase frequency of ECHO and ECG 
monitoring
c.
Add additional ECG and/or ECHO 
measures to be monitored
d.
Reduce the dose of study medication
Level 3:
1. The investigator will evaluate efficacy to date 
based on study diaries and consult with the 
parent/guardian, and determine whether the 
achieved benefit justifies the consideration of 
continuing study treatment by the IDSMC. 
MINIMAL efficacy criteria for IDSMC 
consideration:
a.
Seizures must be more than 75% 
improved (number of 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 risk of cardiopulmonary
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Page 160 of 182
complications, considering the subject’s 
age and overall health.
c.
Subject has had reasonable trials (dose 
and duration) of other available 
anticonvulsants (e.g., valproic acid, 
clobazam, 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 
the benefit and potential risk, and the 
parent/guardian feels strongly that the child be 
maintained on the study medication when 
understanding the risks, the parent/guardian 
must sign a new consent, which describes the 
additional risk and the child should provide 
assent if possible.
a.
If both of these conditions are not met, 
the subject is discontinued from 
treatment.
3.
The investigator prepares a case history and 
rationale for continuation to be submitted to the 
IDSMC for review, which includes effects of 
study medication on seizures and comorbidities 
related to Dravet syndrome.
4.
The Co-Chairs of the IPCAB are alerted to the 
request, and in consultation with BMS prepare 
an evaluation of the risk and proposed 
monitoring plan if applicable for submission to 
the IDMSC.
5.
IDSMC will review the submission from the 
Investigator and the IPCAB and unblind the 
subject treatment if warranted.
6.
IDSMC makes a determination of appropriate 
path, including these possible outcomes:
a.
Discontinue study medication
b.
Increase frequency of ECHO and ECG 
monitoring
c.
Add additional ECG and/or ECHO 
measures to be monitored
d.
Reduce the dose of study medication
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Page 161 of 182
APPENDIX 11 – PROTOCOL AMENDMENT 2
Summary of Changes 
Clarifications and changes were made to the protocol and include the following: 

Replaced CHU9D with PedsQL 

Updated statistical analysis section to be consistent with the separate statistical analysis 
plan 

Clarified inclusion criterion #7 regarding the requirement for a whole blood sample for a 
broad epilepsy-related gene panel 
A change was made based on feedback received from the United States Food and Drug 
Administration, and include the following: 

Added the assessment of cognition for subjects 5 years of age, so that all study 
participants are now being assessed for cognition using the BRIEF. The description of the 
BRIEF was moved from the efficacy section to the safety section. 
Clarifications and changes were made based on feedback received from the European Voluntary 
Harmonization Procedure Clinical Trials Group, and include the following: 

Updated contraception requirements for the study 

Clarified when subjects must be discontinued from the study 

Clarified that the investigator may discontinue a subject from the study in the case of a 
medical emergency 

Added statistical information regarding sensitivity analyses for concomitant AED 
medication changes during the study 
The rationale for each change/clarification also is provided below. 
List of Specific Changes 
Additions are marked in bold and deletions are marked in strikethrough. Minor editorial 
changes, such as the correction of typing or formatting errors, updating headers and footers, 
tables of contents, and list of references, etc, are not listed. 
Rationale:  To replace the CHU9D with the PedsQL for the assessment of quality of life.
Original Text
Amendment Text
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31 October 2016 
Confidential 
Page 162 of 182
Synopsis, Section 2.3
Additional secondary efficacy objectives of the study 
are:

To demonstrate that the ZX008 0.2 and 0.8 
mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints:
Synopsis, Section 2.3
Additional secondary efficacy objectives of the study 
are:

To demonstrate that the ZX008 0.2 and 0.8 
mg/kg/day dose groups are (independently) superior 
to placebo on the following endpoints:
PUBLIC COPY 
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Page 163 of 182
o
The change from baseline in the Child Health
Utility 9D Scale (CHU9D) score.
Synopsis (Criteria for Evaluation/Efficacy), 
Section 2.7.1

CHU9D to measure changes in quality of life 
of the subject
Table 1 was updated and is not presented here. 
Sections 6.1.3, 6.2.5, and 6.2.9
The following procedures will be performed:

CHU9D (Appendix 6)
Section 7.1.4 Child Health Utility 9D Scale
The CHU9D (Appendix 6) is a pediatric generic 
preference based measure of health-related QoL 
completed by the parent/caregiver on behalf of the 
subject. It consists of a descriptive system and a set of 
preference weights, giving utility values for each 
health state described by the descriptive system, 
allowing the calculation of quality adjusted life years 
for use in cost utility analysis. The CHU9D will be 
conducted according to the schedule in Table 1.
Section 7.1.5
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 using 
2 scales: the EQ-5D-5L and the HADS. 
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.
Appendix 6 was updated and is not presented here.
o The change from baseline in the Child Health 
Utility 9D Scale (CHU9D) Pediatric Quality 
of Life InventoryTM (PedsQL) score.
Synopsis (Criteria for Evaluation/Efficacy), 
Section 2.7.1

CHU9D PedsQL to measure changes in quality 
of life of the subject
Table 1 was updated and is not presented here. 
Sections 6.1.3, 6.2.5, and 6.2.9
The following procedures will be performed:

CHU9D Peds QL (Appendix 6)
Section 7.1.4 Child Health Utility 9D Scale Pediatric 
Quality of Life Inventory
The PedsQL CHU9D (Appendix 6) is a pediatric 
generic preference based modular measure of health- 
related QoL completed by the parent/caregiver on behalf 
of the subject. It consists of a descriptive system and a 
set of preference weights, giving utility values for each 
health state described by the descriptive system, 
allowing the calculation of quality adjusted life years for 
use in cost utility analysis 4 core scales that measure 
physical, emotional, social, and school functioning.
The PedsQL CHU9D will be conducted according to 
the schedule in Table 1.
Section 7.1.5
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 using 2 3 scales: 
the EQ-5D-5L, and 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 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.
Appendix 6 was updated and is not presented here.
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31 October 2016 
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Page 164 of 182
Rationale: To update the statistical sections of the protocol to be consistent with the separate statistical analysis 
plan.
Original Text
Amendment Text
Synopsis, Section 3.1, Section 5.5.1
Synopsis-Methodology
Randomization will be stratified by age group (< 6 
years, 6 to 18 years) to ensure balance across 
treatment arms, and at least 40% of subjects will be in 
each age group.
Synopsis
Synopsis-Statistical Methods/Efficacy
Primary Efficacy Analysis: The primary efficacy 
endpoint is the change in the mean convulsive seizure 
frequency (MCSF) per 28 days during the T+M 
periods compared with Baseline. The MCSF will be 
calculated from all available data collected during the 
Baseline and treatment periods. The primary endpoint 
will be analyzed using an analysis of covariance 
(ANCOVA) model with treatment group (three levels) 
and age group (< 6 years, 6 to 18 years) as factors, 
and with Baseline MCSF as a covariate. The primary 
analysis will compare the ZX008 0.8 mg/kg/day  
group to the placebo group using a two-sided test at 
the alpha=0.05 level of significance.
Since the ANCOVA used in the primary analysis 
relies on assumptions of normality, the primary 
endpoint also will be analyzed using a nonparametric 
method that does not require as stringent assumptions. 
Specifically, the van Elteren test, which extends the 
Wilcoxon rank sum test to include stratified data, will 
be used to compare the ZX008 0.8 mg/kg/day group 
to the placebo group while stratifying for age group. If 
normality assumptions are not met, the results of the 
van Elteren test will be used to assess the primary 
objective.
Section 10.5.1.1
The primary efficacy endpoint is the change in the
Synopsis, Section 3.1, Section 5.5.1
Synopsis-Methodology
Randomization will be stratified by age group (< 6 
years, 6 to 18 years) to ensure balance across treatment 
arms, and at least 40% of subjects will be in each age 
group.
Synopsis
Synopsis-Statistical Methods/Efficacy
Primary Efficacy Analysis: The primary efficacy 
endpoint is the change in the mean convulsive seizure 
frequency (MCSF) per 28 days during the T+M periods 
compared with Baseline. The MCSF will be calculated 
from all available data collected during the Baseline and 
treatment periods. The primary endpoint will be 
analyzed using an analysis of covariance (ANCOVA) 
model with treatment group (three levels) and age group 
(< 6 years, 6 to 18 years) as factors, and with Baseline 
MCSF as a covariate.  The primary analysis will 
compare the ZX008 0.8 mg/kg/day group to the placebo 
group using a two-sided test at the alpha=0.05 level of 
significance. The primary endpoint will also be 
analyzed using a nonparametric method and if 
normality assumptions are not met, the results of the 
nonparametric analysis will be used for evaluation of 
the primary endpoint. An additional analysis will be 
performed to assess the sensitivity of the primary 
analysis to changes in concomitant AED medications 
that may occur during the course of the trial.
Specifically, the primary analysis will be repeated 
with a factor added to indicate whether a subject had 
a change in concomitant AED medication during the 
T+M period.
Since the ANCOVA used in the primary analysis relies 
on assumptions of normality, the primary endpoint also 
will be analyzed using a nonparametric method that 
does not require as stringent assumptions. Specifically, 
the van Elteren test, which extends the Wilcoxon rank 
sum test to include stratified data, will be used to 
compare the ZX008 0.8 mg/kg/day group to the placebo 
group while stratifying for age group. If normality 
assumptions are not met, the results of the van Elteren 
test will be used to assess the primary objective.
Section 10.5.1.1
The primary efficacy endpoint is the change in the mean
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Zogenix International Limited
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31 October 2016 
Confidential 
Page 165 of 182
mean convulsive seizure frequency (MCSF) per 28 
days between the Baseline and T+M periods. The 
MCSF will be calculated from all available data 
collected during the Baseline or T+M Periods.
The primary endpoint will be analyzed using an 
analysis of covariance (ANCOVA) model with 
treatment group (three levels) and age group
(< 6 years, 6 to 18 years) as factors, and with 
baseline frequency as a covariate. The primary 
analysis will compare the ZX008 0.8 mg/kg/day 
group to the placebo group using a two-sided test at 
the Į=0.05 level of significance.
Since the ANCOVA used in the primary analysis 
relies on assumptions of normality, the primary 
endpoint will also be analyzed using a nonparametric 
method that does not require as stringent assumptions. 
Specifically, the van Elteren test, which extends the 
Wilcoxon rank sum test to include stratified data, will 
be used to compare the ZX008 0.8 mg/kg/day group 
to the placebo group while stratifying for age group. If 
normality assumptions are not met, the results of the 
van Elteren test will be used to assess the primary 
objective.
Additional analyses will compare the percentage 
changes between the baseline MCSF and the MCSF 
measured independently during the Titration Period 
alone and the Maintenance Period alone.
Section 10.5.1.2
The longest interval between convulsive seizures will 
be calculated for each subject over the entire T+M 
period. Subjects whose longest interval extends to the 
end of treatment or end of study will be considered 
right-censored. The ZX008 0.8 mg/kg/day and 
placebo groups will be compared using a log-rank
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or variations thereof. 


Zogenix International Limited
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31 October 2016 
Confidential 
Page 166 of 182
convulsive seizure frequency (MCSF) per 28 days 
between the Baseline and T+M periods. The MCSF 
will be calculated from all available data collected 
during the Baseline or T+M Periods.
The primary endpoint will be analyzed using an 
analysis of covariance (ANCOVA) model with 
treatment group (three levels) and age group (< 6 
years, 6 to 18 years) as factors, and with baseline 
frequency as a covariate.
The primary analysis will compare the ZX008
0.8 mg/kg/day group to the placebo group using a 
two- sided test at the Į=0.05 level of significance.
Since the ANCOVA used in the primary analysis 
relies on assumptions of normality, the primary 
endpoint will also be analyzed using a 
nonparametric method that does not require as 
stringent assumptions. Specifically, A 
nonparametric test such as the van Elteren test, 
which extends the Wilcoxon rank sum test to 
include stratified data, will be used to compare the 
ZX008 0.8 mg/kg/day group to the placebo group 
while stratifying for age group. If normality 
assumptions are not met, the results of the van 
Elteren nonparametric test will be used to assess 
the primary objective.
An additional analysis will be performed to 
assess the sensitivity of the primary analysis to 
changes in dose or type of concomitant AED 
medications that may occur during the course of 
the trial, which are protocol violations. 
Specifically, the primary analysis will be 
repeated with a factor added to indicate whether 
a subject had a change in prescribed dose or type 
of concomitant AED medication during the T+M 
period. Further exploratory analyses may be 
conducted if changes in concomitant AED 
medication appear to have a significant impact 
on the primary outcome.
Additional analyses will compare the 
percentage changes between the baseline 
MCSF and the MCSF measured independently 
during the Titration Period alone and the 
Maintenance Period alone.
Section 10.5.1.2
The longest interval between convulsive seizures 
will be calculated for each subject over the entire 
T+M period. Subjects whose longest interval 
extends to the end of treatment or end of study will 
be considered right- censored. The ZX008 0.8 
mg/kg/day and placebo groups will be compared 
using a log-rank test. The median
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extensions or variations thereof. 


Zogenix International Limited
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31 October 2016 
Confidential 
Page 167 of 182
test. The median length of the longest seizure-free 
interval will be presented for each treatment group.
Section 10.5.1.3
The efficacy analyses will employ a serial gatekeeper 
strategy to maintain the Type 1 error rate at Į=0.05 
across the family of analyses that support the primary 
and key secondary objectives. The strategy specifies a 
hierarchy of significance tests where each test acts as 
a gatekeeper to the tests below it. If any test fails to 
achieve significance at the Į=0.05 level, then no test 
lower in the hierarchy can achieve statistical 
significance.
Section 10.5.2
Selected summaries will be repeated broken out by 
age group, i.e., for ages <6 years and 6 to 18 
length of the longest seizure-free interval will be 
presented for each treatment group.
Section 10.5.1.3
The efficacy analyses will employ a serial gatekeeper 
strategy to maintain the Type 1 error rate at Į=0.05 
across the family of analyses that support the primary 
and key secondary objectives. The strategy specifies a 
hierarchy of significance tests where each test acts as a 
gatekeeper to the tests below it. If any test fails to 
achieve significance at the Į=0.05 level, then no test 
lower in the hierarchy can achieve statistical 
significance.
Section 10.5.2
Selected summaries will be repeated broken out by age 
group, i.e., for ages <6 years and 6 to 18 years.
Rationale: To clarify inclusion criterion #7 regarding the requirement for a whole blood sample for a broad 
epilepsy-related gene panel.
Original Text
Amendment Text
Synopsis, Section 4.1
Subject agrees to provide whole blood sample for a 
Dravet syndrome genetic testing panel, if genetic 
screening results from an acceptable commercial 
laboratory or medical center are not available for 
SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, 
GABRD, GABRG2, and PCDH19.
Synopsis, Section 4.1
Subject agrees to provide whole blood sample for a 
broad epilepsy-related gene testing panel Dravet 
syndrome genetic testing panel, if genetic screening 
results from an acceptable commercial laboratory or 
medical center are not available for SCN1A, SCN1B, 
SCN2A, SCN8A, SCN9A, GABRD, GABRG2, and 
PCDH19.
Rationale: To add the assessment of cognition for subjects 5 years of age, so that all study participants are now 
being assessed for cognition using the BRIEF, and to move the description of the BRIEF from the efficacy 
section to the safety section.
Original Text
Amendment Text
Synopsis, Section 2.4
The safety objective of the study is:
o
To compare the safety and tolerability of ZX008
0.2 and 0.8 mg/kg/day to placebo with regard to 
adverse events (AEs), laboratory parameters, 
physical examination, neurological examination, 
vital signs (blood pressure, heart rate, 
temperature, and respiratory rate), 
electrocardiograms (ECG), echocardiograms 
(ECHO), and body weight. Cognitive Function 
will be assessed in subjects 5 years and older 
using the cognition domain score on the QOLCE. 
Cognitive function in subjects <5 years at 
baseline will be assessed using the Brief Rating 
Inventory of Executive Function-Preschool 
version (BRIEF-P).
Synopsis, Section 2.4
The safety objective of the study is:
o
To compare the safety and tolerability of ZX008 0.2
and 0.8 mg/kg/day to placebo with regard to adverse 
events (AEs), laboratory parameters, physical 
examination, neurological examination, vital signs 
(blood pressure, heart rate, temperature, and 
respiratory rate), electrocardiograms (ECG), 
echocardiograms (ECHO), and body weight. 
Cognitive Function will be assessed in subjects 5 
years and older using the cognition domain score on 
the QOLCE.  Cognitive function in subjects <5 
years at baseline will be assessed using age- 
appropriate versions of the Brief Rating Inventory 
of Executive Function-Preschool version (BRIEF- 
P).
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 168 of 182
Synopsis (Criteria for Evaluation/Safety)

The cognition domain of the QOLCE will 
also be used to track cognitive function 
relative to baseline in children 5 years and 
older. The BRIEF-P will be administered to 
children younger than 5 years to track 
cognitive function.
Table 1 was updated and is not presented here. 
Section 2.7.2
The safety endpoints of the study are:

Behavior Rating Inventory of Executive Function, 
Preschool Version ( BRIEF-P) to measure 
cognition in subjects aged 2 to < 5 years at 
baseline

Cognition subscale of QOLCE will be used to 
assess cognitive function for children aged 5 
years and older at baseline
Sections 6.1.3, 6.2.5, and 6.2.9
The following procedures will be performed:

BRIEF-P for subjects < 5 years (Appendix 3)
Section 7.1.12
The BRIEF-P is a standardized, validated rating scale 
to measure executive function in preschool aged 
children within the home and school environments 
that will be assessed according to the schedule in 
Table 1. The BRIEF-P measures multiple aspects of 
executive functioning; scales include Inhibit, Shift, 
Emotional Control, Working Memory, and 
Plan/Organize.
Appendix 3 was updated and is not presented here.
Synopsis (Criteria for Evaluation/Safety), Section 2.7.2

The cognition domain of the QOLCE will also 
be used to track cognitive function relative to 
baseline in children 5 years and older. The 
BRIEF-P will be administered to children 
younger than 5 years to track cognitive 
function.
Table 1 was updated and is not presented here. 
Section 2.7.2
The safety endpoints of the study are:

Behavior Rating Inventory of Executive Function, 
Preschool Version ( BRIEF-P) to measure cognition 
in subjects aged 2 to < 5 years at baseline

Cognition subscale of QOLCE will be used to 
assess cognitive function for children aged 5 years 
and older at baseline
Sections 6.1.3, 6.2.5, and 6.2.9
The following procedures will be performed:

BRIEF-P for subjects < 5 years (Appendix 3)
Section 7.2.12
The BRIEF-P is a standardized, validated rating scale to 
measure executive function in preschool aged children 
ages 2-18 years within the home and school 
environments; that it will be assessed according to the 
schedule in Table 1. The BRIEF-P 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).
Appendix 3 was updated and is not presented here.
Rationale:  To update contraception requirements for the study.
Original Text
Amendment Text
Section 4.4
Subjects who are sexually active must use, with their 
partner, 2 approved methods of highly effective 
contraception from the time of informed consent until
Section 4.4
Subjects who are sexually active must use, with their 
partner, 2 approved methods of highly effective 
contraception from the time of informed consent until
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Zogenix International Limited
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31 October 2016 
Confidential 
Page 169 of 182
90 days after the last dose of study medication.
Two or more of the following methods are acceptable 
and must include at least 1 barrier method:

Surgical sterilization (i.e., bilateral tubal 
ligation/salpingectomy, hysterectomy for female 
subjects or partners; vasectomy for male subjects 
or partners)

Placement of an intrauterine device or 
intrauterine system

Hormonal contraception (implantable, patch, oral, 
injectable)

Barrier methods (for male subjects, this must be a 
condom or their partner’s use of an occlusive cap 
[diaphragm or cervical/vault caps]; for female 
subjects, either their partner’s use of a condom or 
the subject’s use of an occlusive cap [diaphragm 
or cervical/vault caps] with spermicidal 
foam/gel/film/cream/suppository)
Male subjects who have been sterilized or have 
partners of non-childbearing potential (including 
homosexual men) are required to use one barrier 
method of contraception (condom). This is to prevent 
unintended exposure of the partner to the study drug 
via seminal fluid.
Male subjects who have pregnant partners are 
required to use one barrier method of contraception 
(condom).
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, must comply with the 
contraceptive requirements detailed above.
Female subjects of non-childbearing potential, i.e., 
women who are post-menopausal (defined as 
spontaneous amenorrhea for at least 1 year without 
another cause or spontaneous amenorrhea for at least 
6 months confirmed by a follicle stimulating hormone 
[FSH] result of 40 IU/mL), or permanently sterilized 
(e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy, as determined by subject medical 
history), are not required to use any contraception 
during this study.
90 days after the last dose of study medication.
Two or more of the following methods are acceptable 
and must include at least 1 barrier method:

Surgical sterilization (i.e., bilateral tubal 
ligation/salpingectomy, hysterectomy for female 
subjects or partners; vasectomy for male subjects or 
partners)

Placement of an intrauterine device or intrauterine 
system

Hormonal contraception (implantable, patch, oral, 
injectable)

Barrier methods (for male subjects, this must be a 
condom or their partner’s use of an occlusive cap 
[diaphragm or cervical/vault caps]; for female 
subjects, either their partner’s use of a condom or 
the subject’s use of an occlusive cap [diaphragm or 
cervical/vault caps] with spermicidal 
foam/gel/film/cream/suppository)
Male subjects who have been sterilized or have partners 
of non-childbearing potential (including homosexual 
men) are required to use one barrier method of 
contraception (condom). This is to prevent unintended 
exposure of the partner to the study drug via seminal 
fluid.
Male subjects who have pregnant partners are required 
to use one barrier method of contraception (condom).
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, must comply with the 
contraceptive requirements detailed above.
Female subjects of non-childbearing potential, i.e., 
women who are post-menopausal (defined as 
spontaneous amenorrhea for at least 1 year without 
another cause or spontaneous amenorrhea for at least 6 
months confirmed by a follicle stimulating hormone 
[FSH] result of 40 IU/mL), or permanently sterilized 
(e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy, as determined by subject medical 
history), are not required to use any contraception 
during this study.
Male subjects who are sexually active with a partner 
of child-bearing potential must use, with their
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 170 of 182
partner, a condom plus an approved method of 
highly effective contraception from the time of 
informed consent until 90 days after study discharge.
The following methods are acceptable:

Combined (estrogen and progestogen 
containing) hormonal contraception associated 
with inhibition of ovulation:

oral

intravaginal

transdermal

Progestogen-only hormonal contraception 
associated with inhibition of ovulation:

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 30 days following the last follow up visit.
The following methods are acceptable:

Combined (estrogen and progestogen 
containing) hormonal contraception associated 
with inhibition of ovulation:

oral

intravaginal

transdermal

Progestogen-only hormonal contraception 
associated with inhibition of ovulation

oral

injectable

implantable intrauterine device
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 171 of 182

intrauterine hormone-releasing
system

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.
Rationale:  To clarify when subjects must be discontinued from the study.
Original Text
Amendment Text
Section 4.5
Subjects may be discontinued from the study for the 
following reasons, if deemed appropriate by the 
sponsor or investigator: (list of reasons is unchanged).
Section 4.5
Subjects may must be discontinued from the study for 
the following reasons, if deemed appropriate by the 
sponsor or investigator:  (list of reasons is unchanged).
Rationale: To clarify that the investigator may discontinue a subject from the study in the case of a medical 
emergency.
Original Text
Amendment Text
Section 5.6
The blinding scheme instituted for this study will 
ensure that the volume of study medication taken 
cannot be associated with the dose group, thus 
unblinding the study. This is achieved by random 
assignment of different concentrations of the ZX008 
oral solution (1.25 mg/mL, 2.5 mg/mL, and/or
5 mg/mL) by the IVR/IWR system. The IVR/IWR 
system will instruct site personnel to the volume of 
oral solution to be administered based on that 
subject’s weight. (Dose will be recalculated by the 
system once at the midpoint of the study.) During the 
Titration, Maintenance, Taper/Transition Periods, the 
subjects and study personnel (investigators, clinical 
staff, personnel involved in data collection and 
analysis, the Medical Monitor, and the sponsor) will 
be blinded to the treatment allocation and to the 
concentration of ZX008 oral solution. The Medical 
Monitor will have the ability to unblind subjects in the 
case of an emergency.
Section 5.6
The blinding scheme instituted for this study will ensure 
that the volume of study medication taken cannot be 
associated with the dose group, thus unblinding the 
study. This is achieved by random assignment of 
different concentrations of the ZX008 oral solution 
(1.25 mg/mL, 2.5 mg/mL, and/or 5 mg/mL) by the 
IVR/IWR system. The IVR/IWR system will instruct 
site personnel to the volume of oral solution to be 
administered based on that subject’s weight. (Dose will 
be recalculated by the system once at the midpoint of 
the study.) During the Titration, Maintenance, 
Taper/Transition Periods, the subjects and study 
personnel (investigators, clinical staff, personnel 
involved in data collection and analysis, the Medical 
Monitor, and the sponsor) will be blinded to the 
treatment allocation and to the concentration of ZX008 
oral solution. The Medical Monitor will have the ability 
to unblind subjects in the case of an emergency. If an 
investigator feels the blind should be broken, he/she 
can do so when necessary for treatment
decisions. However, the investigator should 
endeavor to discuss with the Medical Monitor or 
Sponsor’s Medical Representative, if available. The 
blind should only be broken in the event the 
knowledge of whether the subject is on active study 
medication versus placebo is needed to determine 
course of medical treatment for the event. The 
subject will be discontinued from the clinical trial
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 172 of 182
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
o
ori
tio
application and any extensions or variations thereof. 


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 173 of 182
APPENDIX 12 – PROTOCOL AMENDMENT 3 
Summary of Changes 
Clarifications and changes were made to the protocol and include the following: 
x
Removed atonic seizures and added tonic-atonic from the types of convulsive seizures in 
Inclusion Criterion #5. 
x
Removal of Inclusion Criterion #7 to clarify that participation in the epilepsy-related genetic 
testing is not required for participation. 
x
Updated the preclinical data information and, based on this information, revised the list of 
prohibited concomitant medications. 
x
Clarified that the number of convulsive seizures during the 6-week baseline period is  6. 
x
Added PedsQL Family Impact module to the efficacy measures. 
x
Clarify study days of Screening during the Baseline Period and the timing of assessments in 
that period. 
x
Collection of blood sample for epilepsy genotype panel is mandatory but not required at 
screening. 
x
Added the list of countries in which Diacomit® (stiripentol) is approved. 
x
Added supporting references to existing citations of data. 
x
Clarified the safety objective. 
x
Specify that the number of study centers is approximate. 
x
Clarified the duration of use of contraception after the last dose of study drug. 
x
Removal of social media policy from the reason or removing a subject from therapy or 
assessment. 
  
The rationale for each change/clarification also is provided below. 
List of Specific Changes 
Additions are marked in bold and deletions are marked in strikethrough. Minor editorial 
changes, such as the correction of typing or formatting errors, updating headers and footers, 
tables of contents, and list of references, etc, are not listed. 
Rationale:  To clarify the types of seizures that satisfy the requirement for the 12 weeks before screening.
Original Text
Amendment Text
Inclusion Criterion, Synopsis and Section 4.1
Subject must have had 4 convulsive seizures 
(tonic-clonic, tonic, atonic, clonic) per 4-week 
period for past 12 weeks prior to screening, by 
parent/guardian report to investigator or 
investigator medical notes. 
Inclusion Criterion, Synopsis and Section 4.1
Subject must have had 4 convulsive seizures 
(tonic-clonic, tonic, tonic-atonic, clonic) per 4-week 
period for past 12 weeks prior to screening, by 
parent/guardian report to investigator or investigator 
medical notes. 
Rationale:  Remove the requirement for participation in epilepsy-related gene testing from the inclusion 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 174 of 182
criteria.
Original Text
Amendment Text
Inclusion Criterion 7, Synopsis and Section 4.1
Subject agrees to provide whole blood sample for a 
broad epilepsy-related gene testing panel.
Inclusion Criterion 7, Synopsis and Section 4.1
Subject agrees to provide whole blood sample for a 
broad epilepsy-related gene testing panel.
Rationale:  Revised the list of prohibited concomitant medications.
Original Text
Amendment Text
Exclusion Criterion 8, Synopsis and Section 4.2
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 (see Appendix 1). (Note: Short-
term medication requirements will be handled on a 
per case basis by the Medical Monitor.)
Exclusion Criterion 8, Synopsis and Section 4.2
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; or cyproheptadine, 
and/or cytochrome P450 (CYP) 2D6/3A4/2B6 
inhibitors/substrates (see Appendix 1). (Note: Short- 
term medication requirements will be handled on a 
per case basis by the Medical Monitor.)
Rationale:  Clarified that the number of convulsive seizures during the 6-week baseline period is ш 6.
Original Text
Amendment Text
Randomization Inclusion Criterion 3, Synopsis and 
Section 4.3
Subject demonstrates a stable baseline with 
>6 convulsive seizures during the 6-week Baseline 
Period, with a minimum of 2 in the first 3 weeks and
2 in the second 3 weeks. 
Section 6.1.3 
This period is intended to ensure that subjects meet the 
study entry criteria and confirm they have experienced 
>6 convulsive seizures during the 6-week Baseline 
Period, with at least 2 seizures in each 3-week half of 
the Baseline Period. 
Randomization Inclusion Criterion 3, Synopsis and 
Section 4.3
Subject demonstrates a stable baseline with > 
ш6 convulsive seizures during the 6-week Baseline 
Period, with a minimum of 2 in the first 3 weeks and 
2 in the second 3 weeks. 
Section 6.1.3 
This period is intended to ensure that subjects meet the 
study entry criteria and confirm they have experienced 
6 >6 convulsive seizures during the 6-week Baseline 
Period, with at least 2 seizures in each 3-week half of 
the Baseline Period. 
Rationale:  Added PedsQL Family Impact module to the efficacy measures.
Original Text
Amendment Text
Synopsis, Criteria for Evaluation: Efficacy
Not applicable 
Section 2.3, Additional Secondary Objectives 
Not applicable 
Section 2.7.1, Efficacy Endpoints 
Not applicable 
Section 6.1.3, 6.2.9 
Not applicable 
Synopsis, Criteria for Evaluation: Efficacy
PedsQL Family Impact module to measure changes 
in quality of life of the parent/caregiver 
Section 2.3, Additional Secondary Objectives 
The change from baseline in the PedsQL Family 
Impact module score. 
Section 2.7.1, Efficacy Endpoints 
PedsQL Family Impact module to measure changes in 
quality of life of the parent/caregiver 
Section 6.1.3, 6.2.9
PedsQL Family Impact module (Appendix 6) 
Rationale:  Clarify study days of Screening during the Baseline Period.
Original Text
Amendment Text
Table 1: Schedule of Assessments 
a: 
The Baseline Period is comprised of the initial screening for the study
Table 1: Schedule of Assessments 
a:
The Baseline Period is comprised of the initial screening for the study and
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31 October 2016 
Confidential 
Page 175 of 182
and the assessment of baseline seizure activity recorded daily in the diary. 
Table 6: Time Windows for Assessments 
Visit 1 (Clinic; Study Day -42 to -41):
the assessment of baseline seizure activity recorded daily in the diary. The 
procedures to be completed at the Screening visit may be completed in a 
single day or split so that they are completed over the 2-day period (i.e., 
Days -43 to -42 or Days -42 to -41). 
Table 6: Time Windows for Assessments 
Visit 1 (Clinic; Study Day -43 to -42 or -42 to -41):
Rationale:  Collection of blood sample for epilepsy genotype panel is mandatory but not required at 
screening.
Original Text 
Amendment Text 
Table 1: Schedule of Assessments 
Table 1: Schedule of Assessments 
     l.  Mandatory one time collection any time during or after screening. 
Rationale:  Added the list of countries in which Diacomit® (stiripentol) is approved.
Original Text
Amendment Text
Section 1.1.1, Existing Treatment for Dravet 
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. 
Stiripentol has not been approved for use in the United 
States of America, but is available under 
compassionate use protocols at certain clinical sites. 
Section 1.1.1, Existing Treatment for Dravet Syndrome 
To date, only one treatment, Diacomit® (stiripentol) is 
approved, and only in Europe, Canada, Japan, and 
Australia, as adjunctive therapy in patients with severe 
myoclonic epilepsy in infancy (SMEI, Dravet syndrome), 
and must be co-administered with clobazam and 
valproate. Stiripentol has not been approved for use in 
the United States of America, but is available under 
compassionate use protocols at certain clinical sites. 
Rationale:  Added a supporting reference to an existing citation of data.
Original Text
Amendment Text
Section 1.5, Existing Treatment for Dravet Syndrome 
For over 27 years, fenfluramine has been used as an 
unlicensed medicine in Belgium at 2 academic medical 
centers, currently using an approved protocol under a 
Belgium Royal Decree (government approved 
prospective observation trial) for the treatment of DS; 
the efficacy and safety of this therapeutic approach 
have been published in a peer reviewed journal and 
reported to be very favorable. There are no treatments 
specifically approved for the treatment of DS in the 
United States of America (USA). Accordingly, there 
remains an unmet need for an approved treatment for 
children with DS. 
Section 1.1.1, Existing Treatment for Dravet Syndrome 
For over 27 years, fenfluramine has been used as an 
unlicensed medicine in Belgium at 2 academic medical 
centers, currently using an approved protocol under a 
Belgium Royal Decree (government approved 
prospective observation trial) for the treatment of DS; the 
efficacy and safety of this therapeutic approach have 
been published in a peer reviewed journal 
(Ceulemans 2012; Ceulemans 2016) and reported to be 
very favorable. There are no treatments specifically 
approved for the treatment of DS in the United States of 
America (USA). Accordingly, there remains an unmet 
need for an approved treatment for children with DS. 
Rationale:  Revised the preclinical data section.
Original Text
Amendment Text
Section 1.3, Preclinical Data 
The pharmacokinetics of fenfluramine, 
norfenfluramine and their respective isomers has been 
studied in mice, rats, dogs and humans. The 
pharmacokinetics 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 
Section 1.3, Preclinical Data 
The pharmacokinetics of fenfluramine, norfenfluramine 
and their respective isomers has been studied in mice, 
rats, dogs and humans. The pharmacokinetics 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 pharmacokinetics and metabolism 
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ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 176 of 182
pharmacokinetics and metabolism of fenfluramine 
after oral administration. In humans, fenfluramine is 
metabolized to norfenfluramine. CYP2C19 and 
CYP2D6 appear to be the predominant CYP enzymes 
that metabolize fenfluramine to norfenfluramine. 
CYP1A2, CYP2B6 and CYP3A4/5 also appear to be 
involved, but to a lesser degree. 
In vitro inhibition and induction studies show that both 
fenfluramine and norfenfluramine cause inhibition of 
CYP2D6, while fenfluramine causes induction of 
CYP3A4 and CYP2B6. Based on the FDA’s 
mechanistic static model, ZX008 is predicted to 
potentially cause clinically significant inhibition of 
CYP2D6 in the range of doses that will be 
administered (ZX008 IB 2016). ZX008 is also 
predicted to cause a clinically significant induction of 
CYP3A4 in most of the doses that will be 
administered. The major metabolite norfenfluramine, 
however, is not expected to cause clinically significant 
inhibition or induction of CYP2B6, 2D6 or 3A4. 
In vitro inhibition and induction studies show that both 
fenfluramine and norfenfluramine cause inhibition of 
CYP2D6, while fenfluramine causes induction of 
CYP3A4 and CYP2B6. Based on the FDA’s 
mechanistic static model, ZX008 is predicted to 
potentially cause clinically significant inhibition of 
CYP2D6 in the range of doses that will be 
administered (ZX008 IB 2016). ZX008 is also 
predicted to cause a clinically significant induction of 
CYP3A4 in most of the doses that will be 
administered. The major metabolite norfenfluramine, 
however, is not expected to cause clinically significant 
inhibition or induction of CYP2B6, 2D6 or 3A4. 
of fenfluramine after oral administration. In humans, 
fenfluramine is metabolized to primarily 
norfenfluramine. CYP2C19CYP1A2, CYP2B6, and 
CYP2D6 appear to be the predominant CYP 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. 
In vitro inhibition and induction studies show that both 
fenfluramine and norfenfluramine cause inhibition of 
CYP2D6, while fenfluramine causes induction of 
CYP3A4 and CYP2B6. Based on the FDA’s mechanistic 
static model, ZX008 is predicted to potentially cause 
clinically significant inhibition of CYP2D6 in the range 
of doses that will be administered (ZX008 IB 2016). 
ZX008 is also predicted to cause a clinically significant 
induction of CYP3A4 in most of the doses that will be 
administered. The major metabolite norfenfluramine, 
however, is not expected to cause clinically significant 
inhibition or induction of CYP2B6, 2D6 or 3A4. 
While in vitro studies showed that both fenfluramine 
and norfenfluramine cause weak inhibition of 
CYP2D6 and fenfluramine causes weak induction of 
CYP3A4 and CYP2B6, further analysis based on the 
FDA’s mechanistic static model shows that 
fenfluramine and its major metabolite 
norfenfluramine are unlikely to alter the 
pharmacokinetics of substrates of these CYP450 
enzymes in the range of ZX008 doses that will be 
administered in this study. 
Rationale:  Added a supporting reference to an existing citation of data.
Original Text
Amendment Text
Section 1.5, Rationale for Current Study
Based on several published reports of fenfluramine’s 
successful treatment of refractory childhood epilepsy 
in the 1980s (Aicardi and Gaustaut 1985; Aicardi 
1988) and its successful treatment of 11 refractory 
pediatric epilepsy patients in Belgium (Boel 1996), in 
2002 Drs. Ceulemans and Lagae were granted 
authorization to prescribe fenfluramine to their patients 
with refractory pediatric epilepsy conditions, including 
DS, under an approved protocol under a Belgium 
Section 1.5, Rationale for Current Study
Based on several published reports of fenfluramine’s 
successful treatment of refractory childhood epilepsy in 
the 1980s (Aicardi and Gaustaut 1985; Aicardi 1988) and 
its successful treatment of 11 refractory pediatric 
epilepsy patients in Belgium (Boel 1996), in 2002 Drs. 
Ceulemans and Lagae were granted authorization to 
prescribe fenfluramine to their patients with refractory 
pediatric epilepsy conditions, including DS, under an 
approved protocol under a Belgium government program 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 177 of 182
government program (Royal Decree). To date, these 
pediatric neurologists have DS patients (infants, 
children, young adults, and now also adults), being 
successfully treated with fenfluramine for over 
27 years. The efficacy and safety of this therapeutic 
approach has been reported to be overwhelmingly 
favorable. In the most recent assessment of efficacy of 
these patients reported by the investigators in, the 
average length of treatment was over 12 years, with 
one patient being successfully treated for 26 years. 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. 
(Royal Decree). To date, these pediatric neurologists 
have DS patients (infants, children, young adults, and 
now also adults), being successfully treated with 
fenfluramine for over 27 years. The efficacy and safety 
of this therapeutic approach has been reported to be 
overwhelmingly favorable. In the most recent assessment 
of efficacy of these patients reported by the investigators 
in, the average length of treatment was over 12 years, 
with one patient being successfully treated for 26 years 
(Ceulemans 2016). 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.
Rationale:  Clarified the safety objective.
Original Text
Amendment Text
Synopsis and Section 2.4, Safety Objective
To compare the safety and tolerability of ZX008 
0.2 and 0.8 mg/kg/day to placebo with regard to 
AEs, laboratory parameters, physical examination, 
neurological examination, vital signs (blood 
pressure, heart rate [HR], temperature, and 
respiratory rate), ECGs, ECHOs, and body weight. 
Cognitive Function will be assessed in subjects 5 
years and older using the cognition domain score 
on the QOLCE. Cognitive function will be 
assessed using age-appropriate versions of the 
BRIEF. 
Synopsis and Section 2.4, Safety Objective
To compare the safety and tolerability of ZX008 0.2 
and 0.8 mg/kg/day to placebo with regard to AEs, 
laboratory parameters, physical examination, 
neurological examination, vital signs (blood pressure, 
heart rate [HR], temperature, and respiratory rate), 
ECGs, ECHOs, and body weight. Cognitive Function 
will be assessed using the cognition domain score on 
the QOLCE and age-appropriate versions of the 
BRIEF. Cognitive Function will be assessed in subjects 
5 years and older using the cognition domain score on 
the QOLCE. Cognitive function will be assessed using 
age-appropriate versions of the BRIEF. 
Rationale:  Clarify that the number of participating study centers is approximately 30.
Original Text
Amendment Text
Section 3.4, Number of Study Centers 
The study expects to use up to 30 research centers 
in North America. Additional study centers within 
or outside of North America may be added if 
enrollment cannot be completed in a timely 
manner. 
Section 3.4, Number of Study Centers 
The study expects to use up to approximately
30 research centers in North America. Additional study 
centers within or outside of North America may be 
added if enrollment cannot be completed in a timely 
manner. 
Rationale:  Clarified the duration of use of contraception after the last dose of study drug and added barrier 
method to the list of acceptable methods of birth control.
Original Text
Amendment Text
Section 4.4 
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 study 
discharge. 
Female subjects who are sexually active and are of 
Section 4.4 
Male subjects who are sexually active with a partner of 
childbearing potential must use, with their partner, a 
condom plus an approved method of highly effective 
contraception from the time of informed consent until 
90 days after the last dose of study drug after study 
discharge. 
Female subjects who are sexually active and are of 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 178 of 182
child-bearing potential must use, with their 
partner, an approved method of highly effective 
contraception from the time of informed consent 
until 30 days following the last follow up visit. 
Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition 
of ovulation: 
Progestogen-only hormonal contraception 
associated with inhibition of ovulation 
childbearing potential must use, with their partner, an 
approved method of highly effective contraception 
from the time of informed consent until 30 days 
following the last follow up visit 90 days after the last 
dose of study drug. 
Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation and a barrier method (i.e., condom for 
male partner): 
Progestogen-only hormonal contraception associated 
with inhibition of ovulation and a barrier method 
(i.e., condom for male partner): 
Rationale:  Removal of social media policy.
Original Text
Amendment Text
Section 4.5 
The subject or members of the subject’s immediate 
family (including grandparents) violate the Social 
Media policy as described in Section 4.9. 
Section 4.9 
Revelations about clinical trial participation and the 
effect(s) of unapproved study medications can 
influence the expectations of potential new study 
subjects and investigators. Throughout their 
participation in this trial, subjects, their 
parent/caregivers and immediate family members, 
including grandparents, can acknowledge participation 
in the study on social media; however, they will be 
required not to divulge suspected or actual IMP 
(ZX008 or placebo), dose, efficacy, or tolerability as it 
can negatively affect the sponsor’s ability to interpret 
study results and possibly to use the study for 
registration. Individuals with serious and/or repeated 
violations of this policy may be required to exit the 
study at the discretion of the sponsor in consultation 
with the principal investigator, without the possibility 
of entering the separate open-label extension study. 
Section 4.5 
The subject or members of the subject’s immediate 
family (including grandparents) violate the Social 
Media policy as described in Section 4.9. 
Section 4.9 
Revelations about clinical trial participation and the 
effect(s) of unapproved study medications can influence 
the expectations of potential new study subjects and 
investigators. Throughout their participation in this trial, 
subjects, their parent/caregivers and immediate family 
members, including grandparents, can acknowledge 
participation in the study on social media; however, they 
will be required not to divulge suspected or actual IMP 
(ZX008 or placebo), dose, efficacy, or tolerability as it 
can negatively affect the sponsor’s ability to interpret 
study results and possibly to use the study for 
registration. Individuals with serious and/or repeated 
violations of this policy may be required to exit the study 
at the discretion of the sponsor in consultation with the 
principal investigator, without the possibility of entering 
the separate open-label extension study. 
Rationale:  Revised the prohibited concomitant medication and foods list, including Appendix 1.
Original Text
Amendment Text
Section 5.7.4 
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. 
Section 5.7.4 
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. 
Appendix 1: replaced, edits not shown herein. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 179 of 182
Appendix 1: replaced, edits not shown herein. 
Rationale:  Clarify the timing of procedures during the baseline period and screening period.
Original Text
Amendment Text
Section 6.1 
The Baseline Period of the study encompasses the 
screening activities that will occur on Study Day -42 
and Study Day -41 as well as the observation period 
where subjects will be assessed for baseline seizure 
activity based on recordings of daily seizure activity 
entered into a diary. With the exception of the Doppler 
ECHO, which may be completed any time during the 
Baseline Period up to Study Day -21, all screening 
assessments will be completed on Study Day -42 and 
Study Day -41. 
The following procedures will be performed during the 
Screening visit, which will occur between Study 
Day -42 and Study Day -41 for all subjects before the 
start of seizure activity observation: 
Section 6.1 
The Baseline Period of the study encompasses the 
screening activities that will occur on Study Day -42 and 
Study Day -41 as well as the observation period where 
subjects will be assessed for baseline seizure activity 
based on recordings of daily seizure activity entered into 
a diary. With the exception of the Doppler ECHO, which 
may be completed any time during the Baseline Period 
up to Study Day -21, all screening assessments will be 
completed on Study Day -42 and Study Day -41. 
The following procedures will be performed during the 
Screening visit, which will occur between Study Day -42 
and Study Day -41 for all subjects before the start of 
seizure activity observation:
The Screening visit will occur on Study Day -42; 
however, the procedures may be split over 
2 consecutive days (e.g., Study Day -43 and Study Day
-42 or Study Day -42 and Study Day -41). Splitting 
the visit procedures across 2 nonsequential days 
requires the approval of the medical monitor. The 
following procedures will be performed for all 
subjects before the start of seizure activity 
observation: 
Rationale:  Added text clarifying procedures for rescreening.
Original Text
Amendment Text
Section 6.1.1 
None. 
Section 6.1.1 
In certain circumstances the sponsor may allow subjects 
who did not meet all inclusion/exclusion criteria at the 
time of the Screening Visit to have the screening period 
extended, or to be re-screened for eligibility. In all cases 
the investigator should consult with the Medical Monitor. 
Decisions whether to permit rescreening resides solely 
with the sponsor.  
The decision whether to permit extended screening or 
rescreening can be influenced by many factors individual 
to that subject case. Some general principles apply: 
1.
If baseline seizure screening is extended or the 
subject is discontinued and then rescreened, the 
screening period for establishing the baseline seizure 
frequency will be the immediate 6 weeks before the 
randomization visit. 
2.
Subjects who are found to be on a prohibited 
medication at the screening visit may be weaned off 
of that medication provided: 
a.
Decisions to withdraw a disallowed concomitant
medication must be made with the agreement of 
the prescribing physician 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 180 of 182
b.
If the medication has antiepileptic properties, a 
wash out of at least 5 half-lives must be 
completed before collection of baseline seizure 
data.  
c.
If a decision has been made to wean off of a 
medication without antiepileptic properties and 
the 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. 
Rationale:  Clarify timing of dosing on Day -1 and Day 1.
Original Text
Amendment Text
Section 6.1.3 
x
Dispense study medication 
Section 6.2.1 
Subjects will begin dosing with IMP in the 
morning of Titration Period Study Day 1. 
Section 6.1.3 
Dispense study medication (If administration of the first 
dose of study medication occurs in the clinic, the next 
dose should be at least 8 hours later or the following 
morning. The dose on the following morning will count 
as Study Day 1.) 
Section 6.2.1 
Subjects will take their first dose of study medication on 
the morning of Study Day 1. Study Day 1 is considered 
the first day of dosing, even for those subjects that 
received an in-clinic dose on Study Day -1. Subjects will 
begin dosing with IMP in the morning of Titration Period 
Study Day 1. 
Rationale:  Revised estimated blood volume collection in Table 8 and text describing volumes for 
collection.
Original Text
Amendment Text
Section 6.5 
The original Table 8 was replaced; edits to this 
table are not shown herein. 
The maximum total blood volume collected during 
the study for clinical laboratory testing, 
genotyping, and PK will be approximately 
108.7 mL, as outlined in Table 8 
Section 6.5 
The original Table 8 was replaced; edits not shown 
herein. A new table, Table 9, showing the priorities for 
blood collection was added.  
The maximum total blood volume collected during the 
study for clinical laboratory testing, genotyping, and PK 
will be approximately 108.7 99.7 mL, as outlined in 
Table 8. 
*In concordance with The Seattle Children’s Research 
Foundation Guidance (Appendix 9), blood collection 
volumes for children weighing up to 15 kg will be: 
x
the maximum allowable volume of blood in 
one draw is 22-30 mL (2.5% of total blood 
volume) 
x
the maximum in a 30-day period is 44-60 mL.
On Day 43/Visit 8 the pharmacokinetic blood draw will 
be completed as the priority and the blood draw for 
chemistry and hematology will be skipped for those 
subjects who weigh less than 13.5 kg, unless medical 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 181 of 182
concerns (for example, from previous tests or reported 
side effects) prioritize chemistry and/or hematology. 
If blood collection is restricted due to volume or due to 
inability to draw adequate volume, collection should be 
prioritized as shown in Table 9:
Rationale:  Clarification of SE as an AE or SAE.
Original Text
Amendment Text
Section 7.1.1 
Seizures that evolve into SE will be captured by 
type and duration (>10 min) 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 
Section 7.1.1 
Seizures that evolve into SE will be captured by type and 
duration (>10 minutes) as are all seizures. The diagnosis 
of SE made by a medical professional should be entered 
as an SAE if a prolonged seizure or series of seizures 
persists for 30 minutes or longer, regardless of 
administration of rescue medication. SE lasting for less 
than 30 minutes should be entered as an AE, unless one 
of the other SAE criteria (e.g. hospitalization) are met. If 
this incident involves multiple seizures close in time, the 
SE definition applies if the seizures are close together 
such that consciousness is not regained between ictal 
events. 
Rationale:  Clarify SAE reporting.
Original Text
Amendment Text
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1501 Clinical Study Protocol Amendment 3 
31 October 2016 
Confidential 
Page 182 of 182
Section 8.6 
For SAEs occurring during the study, the 
investigator or delegate will enter all relevant 
information in the AE page of the eCRF. An 
electronic document containing the AE page and 
other applicable pages of the eCRF must be sent 
(via facsimile or email) to the sponsor together 
with a Notification of Serious Adverse Event at 
Investigator Site cover page, which has been 
signed and dated by the investigator. If an 
electronic document is not able to be generated 
(eg, internet access problem), a handwritten paper 
SAE report must be completed, which must be 
signed and dated by the investigator. 
All SAEs that occur during the course of the study, 
whether or not causally related to IMP must be 
reported immediately via telephone and either 
facsimile or email (within 24 hours of the 
investigator becoming aware of the event) to the 
sponsor and the Medical Monitor. 
Section 8.6 
For SAEs occurring during the study, the 
investigator or delegate will enter all relevant 
information in the AE page of the eCRF. An 
electronic document containing the AE page and 
other applicable pages of the eCRF must be sent (via 
facsimile or email) to the sponsor together with a 
Notification of Serious Adverse Event at 
Investigator Site cover page, which has been signed 
and dated by the investigator. If an electronic 
document is not able to be generated (eg, internet 
access problem), a handwritten paper SAE report 
must be completed, which must be signed and dated 
by the investigator. 
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 iHC within 
24 hours of becoming aware of the SAE.  
All SAEs that occur during the course of the study, 
beginning the day Informed Consent is signed, whether 
or not causally related to IMP must be reported 
immediately via telephone or email (within 24 hours of 
the investigator becoming aware of the event) to the 
sponsor or the Medical Monitor 
Rationale: To evaluate a correlation between study drug and SAE. 
Original Text 
Amendment Text 
Section 8.9 
None. 
Section 8.9  In the event of a SAE a blood sample for 
ZX008 and AED PK should be collected as soon as 
feasible.
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Confidential 
Clinical Study Protocol
Study Title: 
A Multicenter, Randomized, Double-blind, Parallel Group, Placebo- 
controlled Trial of Two Fixed Doses of ZX008 (Fenfluramine 
Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and 
Young Adults with Dravet Syndrome 
Study Number: 
ZX008-1502 
Study Product: 
Fenfluramine Hydrochloride Oral Solution; ZX008 
IND Number: 
125797 
EudraCT Number: 
2015-004167-37 
Sponsor: 
Zogenix International Limited  
A wholly owned subsidiary of Zogenix, Inc. 
5858 Horton Street, Suite 455 
Emeryville, CA 94608 USA 
Sponsor's Medical 
Contact 
Date of Study 
Protocol: 
31 October 2016 (Protocol Amendment 2.0) 
11 January 2016 (Protocol Amendment 1) 
30 October 2015 version 1.0 (Original Protocol) 
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. 
PUBLIC 
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SA 
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be
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any 
016 (Pr
016 (P
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201
extensio
(Protoc
Protoc
ons 
ions or variations 
Inc. 
nc.
thereof. 


Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 2 of 175
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 
This document cannot be used to support any marketing 
spons
ons
authorization 
16
io
supplie
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or
or
application and any extensions or variations thereof. 
d toto
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 3 of 175
TABLE OF CONTENTS 
LIST OF PERSONNEL AND ORGANIZATIONS RESPONSIBLE FOR CONDUCT OF 
STUDY .............................................................................................................................. 2
TABLE OF CONTENTS ......................................................................................................... 3
SIGNATURE OF SPONSOR ................................................................................................ 11
SIGNATURE OF COORDINATING INVESTIGATOR ..................................................... 12
SIGNATURE(S) OF PRINCIPAL INVESTIGATOR(S) ..................................................... 13
Principal Investigator............................................................................................................................... 13
LIST OF ABBREVIATIONS ................................................................................................ 14
Table 1:Schedule of Assessments (continued)........................................................................................ 25
1.
INTRODUCTION ........................................................................................................... 26
1.1
BACKGROUND INFORMATION ON INDICATION STUDIED ......................................... 26
1.1.1
Existing Treatment for Dravet Syndrome .................................................................................. 26
1.1.2
Other Antiepileptic Medications ................................................................................................ 27
1.2
BACKGROUND INFORMATION ON STUDY PRODUCT .................................................. 27
1.3
PRECLINICAL DATA ............................................................................................................. 28
1.4
BACKGROUND INFORMATION ON REFERENCE PRODUCT ........................................ 28
1.5
RATIONALE FOR CURRENT STUDY .................................................................................. 29
1.6
RISK-BENEFIT ASSESSMENT .............................................................................................. 29
2.
STUDY OBJECTIVES AND ENDPOINTS ................................................................... 30
2.1
PRIMARY OBJECTIVE ........................................................................................................... 30
2.2
KEY SECONDARY OBJECTIVES ......................................................................................... 30
2.3
ADDITIONAL SECONDARY OBJECTIVES ......................................................................... 30
2.4
SAFETY OBJECTIVE .............................................................................................................. 31
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 4 of 175
2.5
PHARMACOKINETIC OBJECTIVE ....................................................................................... 31
2.6
EXPLORATORY OBJECTIVE ................................................................................................ 32
2.7
STUDY ENDPOINTS ............................................................................................................... 32
2.7.1
Efficacy Endpoints ..................................................................................................................... 32
2.7.2
Safety Endpoints ........................................................................................................................ 32
2.7.3
Pharmacokinetic Endpoints........................................................................................................ 33
3.
INVESTIGATIONAL PLAN .......................................................................................... 33
3.1
OVERALL STUDY DESIGN AND PLAN .............................................................................. 33
3.2
NUMBER OF SUBJECTS ........................................................................................................ 33
3.3
STUDY DURATION ................................................................................................................ 33
3.4
NUMBER OF STUDY CENTERS ........................................................................................... 34
3.5
RATIONALE FOR STUDY DESIGN AND CHOICE OF TREATMENT GROUPS ............ 34
3.6
PREMATURE TERMINATION OF STUDY .......................................................................... 34
3.7
STUDY MONITORING PROCEDURES ................................................................................. 35
3.7.1
Independent Data and Safety Monitoring Committee ............................................................... 35
3.7.2
International Pediatric Cardiac Advisory Board (IPCAB) ......................................................... 35
4.
SELECTION OF STUDY POPULATION ..................................................................... 36
4.1
INCLUSION CRITERIA ........................................................................................................... 36
4.2
EXCLUSION CRITERIA ......................................................................................................... 37
4.3
RANDOMIZATION INCLUSION CRITERIA ........................................................................ 38
4.4
SUBJECTS OF REPRODUCTIVE POTENTIAL .................................................................... 39
4.4.1
Sperm and Egg Donation ........................................................................................................... 40
4.4.2
Pregnancy................................................................................................................................... 40
4.5
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT ..................................... 40
4.6
TERMINATION OF THE CLINICAL STUDY ....................................................................... 42
4.7
REPLACEMENT OF SUBJECTS ............................................................................................ 42
4.8
ELIGIBILITY FOR EXTENSION STUDY .............................................................................. 42
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 5 of 175
5.
INVESTIGATIONAL MEDICINAL PRODUCT INFORMATION ............................. 43
5.1
IDENTITY OF INVESTIGATIONAL MEDICINAL PRODUCT ........................................... 43
5.1.1
Labeling and Packaging ............................................................................................................. 44
5.2
DESCRIPTION OF REFERENCE TREATMENT, COMPARATOR, AND/OR PLACEBO 44
5.2.1
Labeling and Packaging ............................................................................................................. 44
5.3
SHIPMENT AND STORAGE................................................................................................... 44
5.4
IMP ACCOUNTABILITY ........................................................................................................ 45
5.5
TREATMENT ADMINISTRATION ........................................................................................ 45
5.5.1
Randomization ........................................................................................................................... 45
5.5.2
Titration Period .......................................................................................................................... 46
Table 3 Titration Algorithm .................................................................................................................... 46
5.5.3
Maintenance Period ................................................................................................................... 46
5.5.4
Taper Period ............................................................................................................................... 47
Table 4:Taper Algorithm ........................................................................................................................ 47
5.5.5
Transition Period ........................................................................................................................ 47
Table 5:Transition Algorithm ................................................................................................................. 48
5.6
BLINDING ................................................................................................................................ 48
5.7
PRIOR AND CONCOMITANT MEDICATION ..................................................................... 49
5.7.1
Vagal Nerve Stimulation ............................................................................................................ 49
5.7.2
Ketogenic Diet ........................................................................................................................... 49
5.7.3
Rescue Medication for Seizures ................................................................................................. 49
5.7.4
Prohibited Concomitant Medication and Food .......................................................................... 49
5.8
TREATMENT COMPLIANCE ................................................................................................ 50
6.
VISIT SCHEDULE ......................................................................................................... 50
6.1
BASELINE PERIOD (STUDY DAY -42 TO STUDY DAY -1) ............................................. 51
6.1.1
Screening, Clinic Visit 1 (Study Day -42) ................................................................................. 51
6.1.2
Phone Visit 2 (Study Day -21) ................................................................................................... 53
6.1.3
Clinic Visit 3 (Study Day -1): Randomization ........................................................................... 53
PUBLIC
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 6 of 175
6.2
TITRATION AND MAINTENANCE PERIODS ..................................................................... 54
6.2.1
Titration Period Study Day 1 ..................................................................................................... 54
6.2.2
Phone Visits 4 and 5 (Titration Period Study Days 4 and 8) ..................................................... 54
6.2.3
Clinic Visit 6 (Titration Period Study Day 15) .......................................................................... 54
6.2.4
Phone Visit 7 (Maintenance Period Study Day 29) ................................................................... 55
6.2.5
Clinic Visit 8 (Maintenance Period Study Day 43) ................................................................... 55
6.2.6
Phone Visit 9 (Maintenance Period Study Day 57) ................................................................... 56
6.2.7
Clinic Visit 10 (Maintenance Period Study Day 71) ................................................................. 56
6.2.8
Phone Visit 11 (Maintenance Period Study Day 85) ................................................................. 57
6.2.9
Clinic Visit 12 (Maintenance Period Study Day 99): End of Study/Early Termination ........... 57
6.3
POST-DOSE VISIT (CLINIC VISIT 13; STUDY DAY 113) .................................................. 59
6.4
CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 14; STUDY DAY 197-281) ...................... 59
6.5
ESTIMATED BLOOD VOLUME COLLECTION .................................................................. 60
7.
EFFICACY, SAFETY, AND PHARMACOKINETIC ASSESSMENTS ..................... 62
7.1
EFFICACY ASSESSMENTS ................................................................................................... 62
7.1.1
Seizure Assessments .................................................................................................................. 63
7.1.2
Clinical Global Impression - Improvement ............................................................................... 64
7.1.3
Quality of Life in Childhood Epilepsy Scale ............................................................................. 64
7.1.4
PedsQL Quality of Life Inventory (PedsQL) ............................................................................. 64
7.1.5
Parent/Caregiver Quality of Life ............................................................................................... 64
7.2
SAFETY ASSESSMENTS ........................................................................................................ 65
7.2.1
Demographics, Medical/Neurological/Epilepsy History, and Pre-Study Medication ............... 65
7.2.2
Physical Examinations ............................................................................................................... 65
7.2.3
Neurological Examinations ........................................................................................................ 65
7.2.4
Vital Signs .................................................................................................................................. 66
7.2.5
Laboratory Measurements ......................................................................................................... 66
7.2.6
Plasma Sample for Concomitant Antiepileptic Drug(s) ............................................................. 67
7.2.7
Electrocardiograms .................................................................................................................... 68
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 7 of 175
7.2.8
Doppler Echocardiography ........................................................................................................ 68
7.2.9
Tanner Staging ........................................................................................................................... 68
7.2.10
Columbia-Suicide Severity Rating Scale ................................................................................... 68
7.2.11
Adverse Events .......................................................................................................................... 69
7.2.12
Behavior Rating Inventory of Executive Function (BRIEF) ..................................................... 69
7.3
PHARMACOKINETIC ASSESSMENTS ................................................................................ 69
7.4
APPROPRIATENESS OF MEASUREMENTS ....................................................................... 70
8.
ADVERSE EVENTS ....................................................................................................... 70
8.1
DEFINITIONS .......................................................................................................................... 70
8.1.1
Adverse Events .......................................................................................................................... 70
8.1.2
Serious Adverse Events ............................................................................................................. 71
4.
Results in persistent or significant disability or incapacity. ....................................................... 71
8.1.3
Adverse Events of Special Interest ............................................................................................ 72
8.1.4
Adverse Events Requiring Hospitalization ................................................................................ 74
8.2
SEVERITY OF ADVERSE EVENTS ...................................................................................... 74
8.3
CAUSALITY OF ADVERSE EVENTS ................................................................................... 75
8.4
OBSERVATION PERIOD FOR ADVERSE EVENT REPORTING ...................................... 76
8.5
ADVERSE EVENT REPORTING ............................................................................................ 76
8.5.1
Adverse Events .......................................................................................................................... 76
8.6
SERIOUS ADVERSE EVENTS REPORTING ........................................................................ 76
8.6.1
Requirements for Immediate Reporting of Serious Adverse Events ......................................... 77
8.7
REPORTING OF SERIOUS ADVERSE EVENTS BY INVESTIGATOR TO IEC/IRB ....... 77
8.8
REPORTING OF EVENTS OTHER THAN SERIOUS ADVERSE EVENTS BY 
INVESTIGATOR TO SPONSOR ............................................................................................. 78
8.9
FOLLOW-UP OF ADVERSE EVENTS ................................................................................... 78
8.9.1
Follow-up of Echocardiogram Findings .................................................................................... 78
8.10
PREGNANCY ........................................................................................................................... 80
9.
DATA HANDLING PROCEDURES ............................................................................. 80
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 8 of 175
9.1
RECORDING OF DATA .......................................................................................................... 80
9.2
DATA QUALITY ASSURANCE ............................................................................................. 81
9.3
RECORD RETENTION ............................................................................................................ 81
10. STATISTICS ................................................................................................................... 82
10.1
DETERMINATION OF SAMPLE SIZE .................................................................................. 82
10.2
ANALYSIS POPULATIONS ................................................................................................... 82
10.2.1
Safety (SAF) Population ............................................................................................................ 82
10.2.2
Modified Intent-to-Treat (mITT) Population ............................................................................. 82
10.2.3
Per Protocol (PP) Population ..................................................................................................... 82
10.3
TREATMENT GROUPS ........................................................................................................... 83
10.4
TREATMENT PERIODS .......................................................................................................... 83
10.5
STATISTICAL ANALYSES AND METHODS ...................................................................... 83
10.5.1
Efficacy Analyses ...................................................................................................................... 84
10.5.1.1
Primary Efficacy Analysis .............................................................................. 84
10.5.1.2
Key Secondary Analyses ................................................................................ 84
10.5.1.3
Multiplicity Strategy and Testing Hierarchy .................................................. 85
10.5.2
Safety Analyses .......................................................................................................................... 85
10.5.3
Pharmacokinetic Analyses ......................................................................................................... 86
10.6
ANALYSES PROVIDED TO AN INDEPENDENT DATA AND SAFETY MONITORING 
COMMITTEE ............................................................................................................................ 86
11. ETHICAL & REGULATORY CONSIDERATIONS..................................................... 86
11.1
ETHICAL CONSIDERATIONS ............................................................................................... 86
11.2
INFORMED CONSENT ........................................................................................................... 87
11.3
REGULATORY CONSIDERATIONS AND INDEPENDENT ETHICS 
COMMITTEE/INSTITUTIONAL REVIEW BOARD ............................................................. 88
11.4
PROTOCOL COMPLIANCE.................................................................................................... 89
12. ADMINISTRATIVE ASPECTS ..................................................................................... 89
12.1
CLINICAL TRIAL AGREEMENT .......................................................................................... 89
12.2
FINANCIAL DISCLOSURE BY INVESTIGATOR ................................................................ 90
PUBLIC
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 9 of 175
12.3
CLINICAL STUDY REGISTRATION AND RESULTS DISCLOSURE ............................... 90
12.4
STUDY FILES AND MATERIALS ......................................................................................... 90
12.5
INITIATION OF THE STUDY ................................................................................................. 90
12.6
SUBJECT REIMBURSEMENT ............................................................................................... 91
12.7
LIABILITY AND INSURANCE .............................................................................................. 91
12.8
SUBJECT IDENTIFICATION AND CONFIDENTIALITY ................................................... 91
12.9
MONITORING OF THE STUDY ............................................................................................. 92
12.10
PROTOCOL AMENDMENTS ................................................................................................. 93
12.11
AUDITS AND INSPECTIONS ................................................................................................. 93
12.12
CLINICAL STUDY REPORT .................................................................................................. 93
12.13
USE OF DATA AND PUBLICATIONS .................................................................................. 94
13. REFERENCE LIST ......................................................................................................... 95
14. APPENDICES ................................................................................................................. 97
APPENDIX 1 – LIST OF PROHIBITED CONCOMITANT MEDICATIONS .................. 98
APPENDIX 2 – COLUMBIA – SUICIDE SEVERTY RATING SCALE ......................... 100
APPENDIX 3 – BEHAVIOR RATING INVENTORY OF EXECUTIVE FUNCTION ... 106
APPENDIX 4 – QUALITY OF LIFE IN CHILDHOOD EPILEPSY SCALE .................. 116
APPENDIX 5 – TANNER STAGING ................................................................................ 129
APPENDIX 6 – PEDsQL (INCLUDING FAMILY IMPACT MODULE) ........................ 131
APPENDIX 7 – EQ-5D-5L QUESTIONNAIRE ................................................................ 142
APPENDIX 8 – HOSPITAL ANXIETY AND DEPRESSION SCALE ............................ 144
APPENDIX 9 – MAXIMUM ALLOWABLE BLOOD DRAW VOLUMES .................... 146
APPENDIX 10 – PROTOCOL AMENDMENT 1 SUMMARY OF CHANGES .............. 147
PUBLIC
..........
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...........
..........
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TIONS ..
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This document
DIX 6 –
IX 6 –
PENDI
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 10 of 175
APPENDIX 11 – PROTOCOL AMENDMENT 2 SUMMARY OF CHANGES .............. 166
Table 1:
Schedule of Assessments........................................................................................................................ 24
Table 2:
Investigational Medicinal Product – ZX008 .......................................................................................... 43
Table 3
Titration Algorithm................................................................................................................................. 46
Table 4:
Taper Algorithm...................................................................................................................................... 47
Table 5:
Transition Algorithm............................................................................................................................... 48
Table 6:
Time Windows for Assessments ............................................................................................................ 51
Table 7:
Schedule of Post-Treatment Cardiac Follow-up .................................................................................... 60
Table 8:
Estimated Blood Volume Collection*.................................................................................................... 61
Table 9:
Priorities for Blood Sample Collections................................................................................................. 62
Table 10:
Adverse Events of Special Interest............................................................................................. 73
Table 11:
Severity Definition of Adverse Events....................................................................................... 75
Table 12:
Clinical Measures Enacted Upon Increasing Severity of ECHO Findings................................. 78
PUBLIC COPY 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 13 of 175
SIGNATURE(S) OF PRINCIPAL INVESTIGATOR(S) 
Study Number: ZX008-1502 
Study Title: 
A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled 
Trial of Two Fixed Doses 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 (Day/Month/Year) 
PUB
filled ou
filled ou
BLIC
ent
en
accordin
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 14 of 175
LIST OF ABBREVIATIONS 
ABBREVATION
DEFINITION
AE
Adverse Event
AED
antiepileptic drug
AESI
Adverse Event of Special Interest
ANCOVA
analysis of covariance
AUC
area under the concentration-time curve
AUC0-t
area under the concentration-time curve from time zero to time=t
BID
bis in die; two times per day
BMI
Body Mass Index
BRIEF
Behavior Rating Inventory for Executive Function
C-SSRS
Columbia-Suicide Severity Rating Scale
CBD
cannabidiol
CFR
Code of Federal Regulations
Cmax 
Maximum observed concentration determined directly from the 
concentration-time profile
CYP
cytochrome P450
dL
Deciliter
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
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GH
Growth Hormone
GMP
Good Manufacturing Practices
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
IRB
Institutional Review Board
ABBREVATION 
DEFINITION 
IU 
International Unit 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 15 of 175
ABBREVATION
DEFINITION
IVR 
Interactive Voice Response 
IWR 
Interactive Web Response (System) 
KD 
Ketogenic diet 
kg 
Kilogram 
LH 
Luteinizing Hormone 
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 
PedsQL 
Pediatric Quality of Life Inventory 
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 
SD 
Standard Deviation 
SMEI 
Severe Myoclonic Epilepsy Of Infancy 
SUDEP 
Sudden Unexpected Death in Epilepsy 
T+M 
Titration plus Maintenance Periods 
t1/2 
terminal half-life 
THC 
tetrahydrocannabinol 
Tmax 
time to maximum concentration 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
USA 
United States of America 
USP 
United States Pharmacopeia 
VNS 
Vagal Nerve Stimulator/Stimulation 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 16 of 175
STUDY SYNOPSIS 
Study Title: A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled 
Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an 
Adjunctive Therapy in Children and Young Adults with Dravet Syndrome
Study Number: ZX008-1501
Study Product: Fenfluramine Hydrochloride Oral Solution, ZX008
Type of Study:
Efficacy, safety, and pharmacokinetics study
Indication Studied:
Adjunctive therapy in Dravet syndrome
Phase of Development: Phase III
Countries: Europe, Australia, South Korea
Sponsor: Zogenix International Limited
Coordinating Investigator: 
Lieven Lagae, MD, PhD 
Leuven University, Department of Development and 
Regeneration, Section Pediatric Neurology 
Leuven, Belgium 
Estimated Duration of Individual Subject Participation:
The duration of the participation in the study for an individual subject is expected to be up 
to 22 weeks, with a follow-up 3 to 6 months after the last dose of study medication for 
final safety monitoring.
Objectives: 
The primary objective of the study is: 
x
To demonstrate that ZX008 0.8 mg/kg/day is superior to placebo as adjunctive therapy in 
the treatment of Dravet syndrome 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). 
The key secondary objectives of the study are: 
x
To demonstrate that ZX008 0.2 mg/kg/day is superior to placebo as adjunctive therapy in 
the treatment of Dravet syndrome based on change in the frequency of convulsive seizures 
between baseline and T+M. 
x
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints: 
x
The proportion of subjects who achieve a 40% reduction from baseline in convulsive 
seizure frequency. 
x
The proportion of subjects who achieve a 50% reduction from baseline in convulsive 
seizure frequency. 
x
The longest convulsive seizure-free interval.
See Statistical Methods (Section 10.5.1.3) for hierarchical testing 
procedure. Additional secondary efficacy objectives of the study are: 
x To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints:
o
The number of convulsive seizure-free days.
o
The proportion of subjects who achieve 75% reductions from baseline in 
convulsive seizure frequency.
o
The change from baseline in non-convulsive seizure frequency.
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 17 of 175
o
The change from baseline in convulsive + non-convulsive seizure frequency.
o
The incidence of rescue medication usage.
o
The incidence of hospitalization to treat seizures.
o
The incidence of status epilepticus.
x
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are 
(independently) superior to placebo on the following endpoints:
o
Clinical Global Impression – Improvement rating, as assessed by the principal 
investigator.
o
Clinical Global Impression – Improvement rating, as assessed by the 
parent/caregiver.
o
The change from baseline in the Quality of Life in Childhood Epilepsy 
(QOLCE) score to measure quality of life.
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The change from baseline in the Pediatric Quality of Life Inventory™ (PedsQL) 
score.
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The change from baseline in PedsQL Family Impact module score.
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The change from baseline in the quality of life (QoL) of the parent/caregiver 
using the EQ- 5D-5L scale.
o
The change from baseline in affective symptoms of the parent/caregiver 
using the Hospital Anxiety and Depression Scale (HADS).
The safety objective of the study is: 
x
To compare the safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day to placebo with 
regard to adverse events (AEs), laboratory parameters, physical examination, neurological 
examination, vital signs (blood pressure, heart rate, temperature, and respiratory rate), 
electrocardiograms (ECG), echocardiograms (ECHO), and body weight. Cognitive 
Function will be assessed in subjects 5 years and older using the cognition domain score on 
the QOLCE. Cognitive function will be assessed using and age-appropriate versions of the 
BRIEF
The pharmacokinetics (PK) objective of the study is:
x
To characterize the PK of ZX008 0.2 and 0.8 mg/kg/day at steady state in 
subjects ages 2-6 years and 6-18 years with Dravet syndrome.
The exploratory objectives of the study are:
x
To compare the ZX008 0.2 and 0.8 mg/kg/day doses on primary, secondary, safety and PK 
endpoints.
Methodology:
This is a multicenter, double-blind, parallel-group, placebo-controlled, study to assess the 
efficacy, safety, and PK of ZX008 when used as adjunctive therapy in pediatric and young adult 
subjects with Dravet syndrome. Approximately 30 study sites in Europe, Australia, and South 
Korea are planned to participate. The 6-week Baseline Period will consist of the establishment of 
initial eligibility during a screening visit followed by an observation period where subjects will 
be assessed for baseline seizure activity based on recordings of daily seizure activity entered into 
a diary. Upon completion of the Baseline Period, subjects who qualify for the study will be 
randomized (1:1:1) in a double-blind manner to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 
0.8 mg/kg/day; maximum dose: 30 mg/day) or placebo.
Randomization will be stratified by age group (< 6 years, 6 years) to ensure balance across 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 18 of 175
treatment arms, and at least 40% of subjects will be in each age group. All subjects will be 
titrated to their randomized dose over a 14-day Titration Period. Following titration, subjects will 
continue treatment at their randomly assigned dose over a 12-week Maintenance Period. Total 
treatment time from the beginning of the Titration Period through the end of the Maintenance 
Period is 14 weeks. At the end of the Maintenance Period (or early discontinuation), all subjects 
will undergo a 2-week taper or transition period (Post-Dosing Follow-Up) depending on whether 
they exit the study or are enrolled in the separate long-term open-label extension study. A follow-
up ECG and ECHO will be performed 3-6 months after study drug discontinuation for early 
termination, or for those subjects who complete the study but do not enter the open-label 
extension study.
Parents/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.
External Individuals and Committees:  
The ZX008 clinical program will employ an Independent Data and Safety Monitoring Committee 
(IDSMC) that will be responsible for safety oversight. A separate International 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.
Number of Subjects:
Approximately 130 subjects will be screened to obtain 115 subjects who enter the Baseline 
Period. Of these 115 subjects, it is estimated that 105 subjects will be randomized into the 
Titration Period. Each clinical site will not randomize more than a maximum of 10 subjects 
without prior consent from the sponsor.
Inclusion Criteria: All subjects must meet all of the following inclusion criteria to be enrolled 
into the study:
1.
Subject is male or non-pregnant, non-lactating female, age 2 to 18 years, inclusive as of 
the day of the Screening Visit. Female subjects of childbearing potential must not be 
pregnant or breast-feeding. Female subjects of childbearing potential must have a 
negative urine pregnancy test. Subjects of childbearing or child-fathering potential must 
be willing to use medically acceptable forms of birth control (see Section 4.4), which 
includes abstinence, while being treated on this study and for 90 days after the last dose 
of study drug.
2.
Subject must have documented medical history to support a clinical diagnosis of 
Dravet syndrome, where convulsive seizures are not completely controlled by current 
antiepileptic drugs.
3.
Subjects must meet all of the following 5 criteria:
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 brain malformation.
e.
Lack of alternative diagnosis.
4.
Subjects must meet at least one of the following 3 criteria:
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 19 of 175
a.
Emergence of another seizure type, including myoclonic, generalized tonic-
clonic, tonic, atonic, absence and/or focal has developed after the first seizure 
type.
b.
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 
natural and/or fluorescent lighting, as well as certain visual patterns.
c.
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.)
5.
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.
6.
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.
7.
Subject has been informed of the nature of the study and informed consent has been 
obtained from the legally responsible parent/guardian.
8.
Subject has provided assent in accordance with Institutional Review Board 
(IRB) requirements, if capable.
9.
Subject’s parent/caregiver is willing and able to be compliant with diary 
completion, visit schedule and study drug accountability.
Exclusion Criteria: 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 pulmonary arterial hypertension.
3.
Subject has current or past history of cardiovascular or cerebrovascular 
disease, such as cardiac valvulopathy, myocardial infarction or stroke. 
4.
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.
5.
Subject is at imminent risk of self-harm or harm to others, in the investigator’s 
opinion, based on clinical interview and responses provided on the Columbia-
Suicide Severity Rating Scale (C-SSRS). Subjects must be excluded if they report 
suicidal behavior in the past 6 months as measured by the C-SSRS at Screening or 
Baseline, which includes suicidal ideation with intent and plan (Item #5). If a 
subject reports suicidal ideation on Item 4 without specific plan, and the 
investigator feels that the subject is appropriate for the study considering the 
potential risks, the investigator must document appropriateness for inclusion, and 
discuss with the parent/caregiver to be alert to mood or behavioral changes, 
especially around times of dose adjustment.
6.
Subject has a current or past history of glaucoma.
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 20 of 175
7.
Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild 
hepatic impairment (elevated liver enzymes < 3x ULN and/or elevated bilirubin <2x ULN) 
may be entered into the study after review and approval by the Medical Monitor in 
conjunction with the sponsor, in consideration of comorbidities and concomitant 
medications.
8.
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; or 
cyproheptadine (see Appendix 1). (Note: Short- term medication requirements will be 
handled on a per case basis by the Medical Monitor.)
9.
Subject is currently receiving or has received stiripentol in the past 21 days 
prior to Screening.
10.
Subject is currently taking carbamazepine, oxcarbamazepine, eslicarbazepine, 
phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as 
maintenance therapy.
11.
Subject is unwilling to refrain from large or daily servings of grapefruits and/or 
Seville oranges, and their juices beginning with the Baseline Period and 
throughout the study.
12.
Subject has positive result on urine tetrahydrocannabinol (THC) Panel or whole 
blood cannabidiol (CBD) at the Screening Visit.
13.
Subject has participated in another clinical trial within the past 30 days.
14.
Subject is currently receiving an investigational product.
15.
Subject is unwilling or unable to comply with scheduled visits, drug administration 
plan, laboratory tests, other study procedures, and study restrictions.
16.
Subject has a clinically significant condition, or has had clinically relevant symptoms or a 
clinically significant illness in the 4 weeks prior to the Screening Visit, other than epilepsy, 
that would negatively impact study participation, collection of study data, or pose a risk to 
the subject.
Randomization Inclusion Criteria: Subjects must meet all of the inclusion criteria above 
plus the following criteria, to be randomized:
1.
Subject has been approved for study inclusion by the Epilepsy Study Consortium.
2.
Subject does not have a cardiovascular or cardiopulmonary abnormality based on 
ECHO, ECG or physical examination, including but not limited to trace mitral or 
aortic valve regurgitation or signs of pulmonary hypertension, and is approved for 
entry by the central cardiac reader.
3.
Subject demonstrates a stable baseline with 6 convulsive seizures during the 
6-week Baseline Period, with a minimum of 2 in the first 3 weeks and 2 in the 
second 3 weeks.
4.
Subject’s parent/caregiver has been compliant with diary completion during the 
Baseline Period, in the opinion of the investigator (e.g., at least 90% compliant).
Study Product, Dose, and Mode of Administration:
ZX008 is supplied as an oral solution in concentrations of 1.25, 2.5, and 5 mg/mL. Subjects 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 21 of 175
will be randomized to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; 
maximum dose: 30 mg/day) or placebo. Study medication will be administered twice a day 
(BID) in equally divided doses with food.
Reference Product, Dose, and Mode of Administration:
Matching ZX008 placebo is supplied as an oral solution.
Duration of Treatment:
All subjects will receive ZX008 or matching placebo for up to approximately 16 weeks (Titration 
Period=2 weeks; Maintenance Period=12 weeks; Taper/Transition Period=2 weeks). After 
completion of the Maintenance Period, eligible subjects may enroll in the open-label extension 
study, after completion of the transition. Subjects who do not enroll in the open-label extension 
study will undergo a taper off of study medication (doses will be administered in a blinded fashion
similar to the titration, i.e., doses will be decreased in 4-day increments). Follow-up 
cardiovascular safety assessments, including ECG and ECHO, will be performed 3 to 6 months 
following the last dose of study medication.
Criteria for Evaluation:
Efficacy:
x
Number of seizures by type 
x
Convulsive seizure-free interval 
x
Clinical Global Impression – Improvement as assessed by parent/caregiver 
x
Clinical Global Impression – Improvement as assessed by principal investigator 
x
QOLCE to measure changes in quality of life of the subject 
x
PedsQL to measure changes in quality of life of the subject 
x
PedsQL Family Impact module to measure changes in quality of life of the parent/caregiver 
x
QoL of parent/caregiver using the EQ-5D-5L scale 
x
Affective symptoms of parent/caregiver using the HADS scale 
x
Duration of prolonged seizures (seizure type that, during baseline, had duration >2 minutes) 
x
Number of episodes of status epilepticus 
x
Number of instances of rescue medication use and number of doses 
x
Number of inpatient hospital admissions due to seizures
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 BRIEF will be 
administered to track cognitive function. 
Pharmacokinetics: 
Steady-state plasma fenfluramine PK parameters (maximum observed concentration determined 
directly from the concentration time profile [Cmax], area under the concentration time curve from 
time zero to time=t [AUC0-t], time to maximum concentration [Tmax], and terminal half-life 
[t1/2]) after administration of ZX008 derived using population PK methods.
Sample Size Determination:
The results of the only randomized, placebo-controlled studies in subjects with Dravet syndrome 
can be found in the European Public Assessment Report (EPAR) for stiripentol (EMA, 2007). 
The EPAR summarizes the results from two studies: STICLO France and STICLO Italy. In the 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 22 of 175
stiripentol groups, the standard deviation (SD) of the percentage change in seizure frequency 
from baseline to month 2 was 42% in the French trial and 26% in the Italian trial. The analogous 
SDs for placebo groups were 38% and 62%. An SD of 50% was assumed for the primary analysis 
in this trial comparing ZX008 0.8 mg/kg/day to placebo on the change from baseline in seizure 
frequency. Using a two-sided test at the Į=0.05 significance level, a sample size of 35 subjects 
per treatment group affords 90% power to detect a difference in mean change from baseline of 
40 percentage points. Similar assumptions and calculations yield a requirement for an additional 
35 subjects in the 0.2 mg/kg/day ZX008 group. Thus, the total sample size is planned to be 
105 subjects (35 per arm).
Statistical Methods:
Study Populations:
Safety Population: All safety analyses will be performed on the Safety Population defined as all 
randomized subjects who receive at least one dose of study medication. Subjects will be analyzed 
according to the treatment actually received.
Modified Intent-to-Treat (mITT) Population: The mITT Population is defined as all randomized 
subjects who receive at least one dose of study medication and for whom at least 1 week of diary 
data are available. Subjects will be analyzed according to the treatment group to which they were 
randomized. The primary comparison of ZX008 0.8 mg/kg/day to placebo as well as key 
secondary efficacy assessments will be performed on the mITT Population.
Per Protocol (PP) Population: The PP Population is defined as all randomized subjects who 
receive at least one dose of ZX008 or placebo, complete the Maintenance Period, and have no 
major protocol violations that would have a significant impact on clinical outcome.
Efficacy
Primary Efficacy Analysis: The primary efficacy endpoint is the change in the mean convulsive 
seizure frequency (MCSF) per 28 days during the T+M periods compared with Baseline. The 
MCSF will be calculated from all available data collected during the Baseline and treatment 
periods. The primary endpoint will be analyzed using an analysis of covariance (ANCOVA) 
model with treatment group (three levels) and age group (< 6 years, 6 years) as factors, and with 
Baseline MCSF as a covariate. The primary analysis will compare the ZX008 0.8 mg/kg/day 
group to the placebo group using a two-sided test at the alpha=0.05 level of significance. The 
primary endpoint will also be analyzed using a nonparametric method and if normality 
assumptions are not met, the results of the nonparametric analysis will be used for evaluation of 
the primary endpoint. An additional analysis will be performed to assess the sensitivity of the 
primary analysis to changes in concomitant AED medications that may occur during the course of 
the trial. Specifically, the primary analysis will be repeated with a factor added to indicate 
whether a subject had a change in concomitant AED medication during the T+M period.
Safety
All safety data will be appropriately analyzed by treatment group. The number and percentage of 
subjects with AEs will be displayed by body system and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA). Summaries in terms of severity and relationship 
to study drug will also be provided. Adverse Events of Special Interest (AESI) and Serious AEs 
(SAEs) will be summarized separately in a similar manner. Laboratory tests, vital signs, physical 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 23 of 175
examinations, neurological examinations, ECG, Doppler echocardiogram, C-SSRS, Tanner 
Staging results, etc, will be summarized appropriately, by treatment. All safety summaries will be 
based on the Safety Population.
Pharmacokinetics
A population PK model will be fit to the fenfluramine concentration-time data collected during 
the Maintenance Period. This model will be informed by all relevant data available at the time of 
data collection (both adults and pediatrics). The population mean and interindividual variability 
estimates from the fit of the population PK model will be summarized. Derived plasma PK 
parameters (Cmax, AUC0-t, Tmax, and t1/2) will be summarized descriptively by treatment 
group and compared to historical data from adults. Summary statistics for plasma concentrations 
will be provided by PK sampling time.
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 24 of 175
Table 1: 
Schedule of Assessments 
Study Assessments 
Baseline Perioda
Titration + Maintenance Period
EOS/ 
ETb
Post- 
Dosing 
Cardiac 
Follow- 
up 
Screening 
2 
(Phone) 
Random- 
ization 
Titration Period 
Maintenance Period 
Visit Number 
1 
3 
4, 5 
(Phone) 
6 
7 
(Phone) 
8 
9 
(Phone) 
10 
11 
(Phone) 
12 
13 
14 
Study Day 
-42 
-21 
-1 
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
197-281 
Informed Consent (subject and parent) 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X
X
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Neurological History 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Epilepsy history 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect retrospective seizure diary data 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Medication 
X
X
 
 
 
 
 
 
 
 
 
 
 
Physical Examination, complete 
X
X
 
 
 
 
 
 
 
 
X
Xc 
Physical Examination, abbreviated 
 
 
 
 
 
X
X
X
 
 
 
Xc 
Neurological Examination, complete 
X
 
 
 
 
 
 
 
 
 
 
X
 
 
Neurological Examination, abbreviated 
 
 
X
 
 
X
 
 
 
 
 
 
 
 
Vital signs 
X
X
 
 
X
X
X
X
 
 
Weight, Height, BMI 
X
X
 
 
X
X
X
X
 
 
12-lead ECG 
X
X
 
 
 
 
X
 
 
 
X
Xc 
Doppler ECHO 
X
 
 
 
 
 
Xd 
 
 
 
Xd 
Xc 
Urine pregnancy test 
Xe 
Xe 
 
 
Xe 
Xe 
Xe 
Xe 
 
 
Clinical laboratory evaluation 
(hematology/clinical chemistry/urinalysis, etc) 
X
X
 
 
X
X
X
X
 
 
Plasma sample for ZX008 pharmacokinetics  
 
 
 
 
 
 
4Xf
 
 
 
 
 
 
Plasma sample for background AEDs 
 
 
Xg 
 
 
Xg 
Xg 
 
 
 
Xg 
 
 
Urine THC Panel/Whole blood CBD 
X
X
 
 
X
X
X
X
 
 
Tanner Staging (for subjects >7 years old) 
 
 
X
 
 
 
 
 
 
 
 
X
 
 
Subject Diary 
D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/Dh
C/R 
Epilepsy genotype panel 
Xl
 
 
 
Study Medication 
 
 
D 
Ri 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/Dh
C/R 
C-SSRS 
X
X
 
 
X
X
X
X
 
 
continued
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 25 of 175
Table 1: Schedule of Assessments (continued) 
Study Assessments 
Baseline Perioda
Titration + Maintenance Period 
EOS/ 
ETb
Follow 
-upc
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Follow- 
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Screening 
2 
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Maintenance Period 
Visit Number 
1 
3 
4, 5 
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6 
7 
(Phone) 
8 
9 
(Phone) 
10 
11 
(Phone) 
12 
13 
14 
Study Day 
-42
-21
-1
1
4, 8
15
29 
43
57
71
85
99
113
197-281 
Clinical Global Impression - Improvement 
(assessed by parent/caregiver) 
 
 
 
 
 
X
X
X
X
 
 
Clinical Global Impression - Improvement 
(assessed by principal investigator) 
 
 
 
 
 
X
X
X
X
 
 
BRIEF 
X
X
X
QOLCE 
X
X
X
PedsQL 
X
X
X
EQ-5D-5L (QoL of parent/caregiver) 
X
X
HADS (Affect of parent/caregiver) 
X
X
X
Randomize subject 
X
First Day of Study Drug Administration 
Xj 
Daily Diary Completion 
X
Concomitant Medication 
X
Adverse events 
X
Adverse events of special interest 
X
Xk 
AED=antiepileptic drug; BMI=body mass index; C=Collect; CBD=cannabidiol; D=Dispense; ECG=electrocardiogram; EOS=end of study; ET=early termination; EQ-5D-5L=standardized measure of health status; HADS=Hospital Anxiety 
and Depression Scale; QoL=quality of life; BRIEF-P=Behavior Rating Inventory of Executive Function, Preschool version; QOLCE=Quality of Life in Childhood Epilepsy; R=Review 
a: 
The Baseline Period is comprised of the initial screening for the study and the assessment of baseline seizure activity recorded daily in the diary. The procedures to be completed at the Screening visit may be completed in a single day 
or split so that they are completed over the 2-day period (i.e., Days -43 to -42 or Days -42 to -41). 
b: 
Subjects who are discontinued early and those who complete the study and choose not to enroll in the separate open-label extension will be tapered off study medication over an up to 2-week period. 
c: 
Follow-up ECG, ECHO, and physical examination will be performed 3-6 months after early termination, or for those subjects who complete the study but do not enter the open-label extension study (see Section 6.4). 
d:  
The Visit 8 ECHO must be performed any time between Study Day 40 and Study Day 54. The Visit 12 ECHO must be performed any time between Study Day 90 and Study Day 113; if a subject discontinues early from the study, the 
ECHO should be scheduled as soon as practical. If the Study Day 43 ECHO was completed 30 days prior to early termination, the Visit 12 ECHO will not be performed provided the parent/guardian agrees to bring the subject to the 
clinic for the cardiac follow-up visit. 
e: 
Females of child-bearing potential 
f: 
Plasma sample for pharmacokinetic assessment will be conducted prior to the dose at Visit 8 and 1, 2, and 4-6 hours after dose administration.
g: 
Plasma sample for assessment of background AED(s) will be conducted prior to the dose of AED(s) at Visits 3, 6, 8 and 12. 
h: 
Study drug/diary dispensed for the transition for subjects entering the open-label extension study and for tapering for subjects exiting the study.
i: 
Site personnel will review study medication dosing procedure (titration) with parent/caregiver. 
j: 
Study drug administration begins in the morning of Study Day 1. 
k: 
Only adverse events related to cardiac safety will be collected at this visit. 
l: 
Mandatory one time collection any time during or after screening. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 26 of 175
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). 
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). The degree of cognitive 
impairment appears to correlate, at least in part, with the frequency of seizures, and might be a result 
of repeated cerebral hypoxia. Children with DS also encounter a higher incidence of Sudden 
Unexpected Death in Epilepsy (SUDEP; Nashef 2012) than other populations with epilepsy. Indirect 
evidence has linked SUDEP to several possible etiologies, including seizure-induced apnea, 
pulmonary edema, dysregulation of cerebral circulation, and cardiac arrhythmias (Shorvon 2011), 
although the actual etiology remains unknown and other mechanisms have not been ruled out. The 
vast majority of patients who survive to adulthood are wholly dependent on around-the-clock 
caregivers and eventually live in institutional care homes. 
1.1.1
Existing Treatment for Dravet Syndrome 
DS is a highly treatment-resistant and refractory epilepsy syndrome. Establishment of a seizure-
free condition in affected children, even with anticonvulsant drug polypharmacy, is extremely 
rare, since all seizure types in DS appear to be drug resistant, with minimal improvement on 
currently available anticonvulsant drug therapies (Dravet 2000; Dravet 2005). Moreover, classic 
anticonvulsant medications whose mechanism is via sodium channel blockade, such as phenytoin 
and carbamazepine, increase these children’s seizure frequency and severity. 
To date, only one treatment, Diacomit® (stiripentol) is approved, and only in Europe, Canada, 
Japan, and Australia, as adjunctive therapy in patients with severe myoclonic epilepsy in infancy 
(SMEI, Dravet syndrome), and must be co-administered with clobazam and valproate. Stiripentol 
has not been approved for use in the United States of America, but is available under 
compassionate use protocols at certain clinical sites. 
 fenfluramine has been used as an unlicensed medicine in Belgium at 
2 academic medical centers, currently using an approved protocol under a Belgium Royal Decree 
(government approved prospective observation trial) for the treatment of DS; the efficacy and 
safety of this therapeutic approach have been published in peer reviewed journal 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 27 of 175
(Ceulemans 2012; Ceulemans 2016) and reported to be very favorable. There are no treatments 
specifically approved for the treatment of DS in the United States of America (USA). 
Accordingly, there remains an unmet need for an approved treatment for children with DS. 
1.1.2
Other Antiepileptic Medications 
USA and European Union approved anti-epileptic drug products include valproate, topiramate, 
carbamazepine, oxcarbazepine, lamotrigine, benzodiazepines, phenobarbital, potassium bromide, 
ethosuximide, phenytoin, and vigabatrin. The treatment of DS frequently requires a combination 
of two or three of these compounds, but with continued suboptimal seizure control. It cannot be 
assumed that because a treatment has been shown to be effective in common seizure types, that it 
will be effective in DS. In fact, some commonly used anti- epileptic drugs with a sodium channel 
mechanism of action, such as carbamazepine, oxcarbazepine, phenytoin, and lamotrigine, make 
DS worse. 
A review of the treatment modalities used for DS has been published by Chiron and Dulac 
(Chiron and Dulac 2011). This review indicates that valproate is commonly used as a first-line 
agent to prevent the recurrence of febrile seizures and oral/nasal/rectal benzodiazepine is used for 
any long-lasting seizures. However, the authors comment that these agents are most often 
insufficient. These author experts state that lamotrigine, carbamazepine, and high doses of 
intravenous phenobarbital should be avoided because they may worsen seizures and that 
topiramate, levetiracetam and bromide may provide substantial efficacy as adjunctive therapy for 
some patients. The authors comment that the benefit of these compounds is mild and there are no 
trials to validate the impression of any effect. 
Given the cognitive consequences believed to be caused, at least in part, by frequent childhood 
seizure activity, there is a medical need for a new anticonvulsant treatment that can significantly 
reduce seizure activity in DS. There is the possibility that early, effective seizure control could 
be disease-modifying, leading to an improvement in longer-term outcomes with respect to motor 
impairment, behavioral issues, and cognitive function. 
1.2
BACKGROUND INFORMATION ON STUDY PRODUCT 
Zogenix is developing a new formulation of fenfluramine hydrochloride, ZX008, for the 
adjunctive treatment of DS. Fenfluramine is an amphetamine analogue that was first 
synthesized many years ago. It was approved in a large number of countries and widely 
prescribed as an appetite suppressant for the treatment of adult obesity. Brand names for 
fenfluramine formulations included Ponderax, 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 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 28 of 175
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 2016). There is also a large body of information concerning its clinical 
safety profile. 
1.3
PRECLINICAL DATA 
The pharmacokinetics of fenfluramine, norfenfluramine and their respective isomers has been 
studied in mice, rats, dogs and humans. The pharmacokinetics 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 pharmacokinetics and 
metabolism of fenfluramine after oral administration. In humans, fenfluramine is metabolized 
primarily to norfenfluramine. CYP1A2, CYP2B6 and CYP2D6 appear to be the predominant 
CYP 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 major metabolite norfenfluramine have 
multiple pathways of elimination, interference with a single pathway is unlikely to cause a 
significant change in fenfluramine’s clearance though the probability of an interaction increases 
if multiple elimination mechanisms are affected simultaneously. 
While in vitro studies showed that both fenfluramine and norfenfluramine cause weak inhibition 
of CYP2D6 and fenfluramine causes weak induction of CYP3A4 and CYP2B6, further analysis 
based on the FDA’s mechanistic static model shows that fenfluramine and its major metabolite 
norfenfluramine are unlikely to alter the pharmacokinetics of substrates of these CYP450 
enzymes in the range of ZX008 doses that will be administeredin this study.  
A Good Laboratory Practice dose-range-finding juvenile toxicology and toxicokinetic study, 
which included a 3-week repeat dose main study, and histopathology of heart valves and other 
key organs, found no effect on heart valves or other organs. 
Based on clinical signs and decreased body weight gain, the no-observed-adverse-effect-level 
for this study was 12 mg/kg/day. This is equivalent to a human dose of 1.94 mg/kg/day based 
on body surface area, and provides a safety factor of 2.4 for the highest dose of 0.8 mg/kg/day 
that will be administered clinically.
Further details on the preclinical data of ZX008 are available in the Investigator’s Brochure 
(ZX008 IB 2016). The current version is available in the Investigator Study File. 
1.4
BACKGROUND INFORMATION ON REFERENCE PRODUCT 
Not applicable. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 29 of 175
1.5
RATIONALE FOR CURRENT STUDY 
Based on several published reports of fenfluramine’s successful treatment of refractory childhood 
epilepsy in the 1980s (Aicardi and Gaustaut 1985; Aicardi 1988) and its successful treatment of 
11 refractory pediatric epilepsy patients in Belgium (Boel 1996), in 2002 Drs. 
Ceulemans and Lagae were granted authorization to prescribe fenfluramine to their patients with 
refractory pediatric epilepsy conditions, including DS, under an approved protocol under a 
Belgium government program (Royal Decree). To date, these pediatric neurologists have DS 
patients (infants, children, young adults, and now also adults), being successfully treated with 
fenfluramine 
 The efficacy and safety of this therapeutic approach has been 
reported to be overwhelmingly favorable. In the most recent assessment of efficacy of these 
patients reported by the investigators in 2016, the average length of treatment was over 12 years, 
with one patient being successfully treated for 26 years (Ceulemans 2016). 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. 
In addition, numerous publications discuss the use of fenfluramine in over 500 children with 
neurobehavioral conditions for the treatment of mostly autism and ADHD, without any reports 
of any cardiovascular adverse events (ZX008 IB 2016). 
Prior to being withdrawn from the market, fenfluramine was marketed at doses of 20 mg and 40 
mg three times daily for the management of obesity in adults. The doses tested thus far in DS 
range from 0.12 to 0.9 mg/kg/day in subjects over 1 year of age to adults. Doses tested in 
pediatric studies evaluating autism and ADHD ranged from 0.65 mg/kg/day to 3.6 mg/kg/day, 
but a commonly used dose was 1.5 mg/kg/day. Occasionally, fixed doses of 30 to 80 mg were 
used. The PK exposure associated with the proposed doses in DS studies of 0.2 mg/kg/day and 
0.8 mg/kg/day administered orally (in equally divided doses BID) is expected to be lower than 
that obtained at the doses used in the past for the treatment of obesity in adults and of 
neurobehavioral conditions in children and adolescents (ZX008 IB 2016). The doses used in this 
study are based on the data from the DS patients being successfully treated in Belgium discussed 
above. 
There are no treatments specifically approved for the treatment of DS in the USA, and in fact, 
commonly used anticonvulsants with a sodium channel mode of action, such as phenytoin and 
carbamazepine, worsen the condition. Accordingly, there remains a significant unmet need for an 
approved treatment for children and adults with DS. 
1.6 
RISK-BENEFIT ASSESSMENT 
As described above, fenfluramine has been used successfully for up to 27 years in some DS 
patients to control seizures, without emergence of clinical valvulopathy or pulmonary 
hypertension. Fenfluramine was administered to over 500 children with neurobehavioral 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 30 of 175
conditions, including autism and ADHD with good safety and tolerability, most often at a 
1 mg/kg dose. 
The pharmacologic and toxicological profile for the active pharmaceutical ingredient, 
fenfluramine, following oral administration is well established (see ZX008 IB 2016). 
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. 
The approximate volume of blood (108.7 mL) planned for collection from each subject over the 
course of the entire study (Screening to End of Study, but not including repeat or additional tests 
ordered by the investigator) presents no undue risk to the subjects. 
The ZX008 0.2 mg/kg/day and 0.8 mg/kg/day doses are believed to be 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. 
2.
STUDY OBJECTIVES AND ENDPOINTS 
2.1
PRIMARY OBJECTIVE 
The primary objective of the study is: 
• 
To demonstrate that ZX008 0.8 mg/kg/day is superior to placebo as adjunctive 
therapy in the treatment of Dravet syndrome 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). 
2.2
KEY SECONDARY OBJECTIVES 
The key secondary objectives of the study are: 
• To demonstrate that ZX008 0.2 mg/kg/day is superior to placebo as adjunctive therapy 
in the treatment of Dravet syndrome based on change in the frequency of convulsive 
seizures between baseline and T+M. 
• 
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints: 
o
The proportion of subjects who achieve a 40% reduction from baseline in 
convulsive seizure frequency. 
o
The proportion of subjects who achieve a 50% reduction from baseline in 
convulsive seizure frequency. 
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The longest convulsive seizure-free interval. 
See Statistical Methods (Section 10.5.1.3) for hierarchical testing procedure. 
2.3
ADDITIONAL SECONDARY OBJECTIVES 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 31 of 175
Other secondary objectives of the study are: 
• To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints: 
o
The number of convulsive seizure-free days. 
o
The proportion of subjects who achieve 75% reduction from baseline in 
convulsive seizure frequency. 
o
The change from baseline in non-convulsive seizure frequency.
o
The change from baseline in convulsive + non-convulsive seizure 
frequency 
o
The incidence of rescue medication usage 
o
The incidence of hospitalization to treat seizures 
o
The incidence of status epilepticus. 
• To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints: 
o
Clinical Global Impression – Improvement rating, as assessed by the 
principal investigator. 
o
Clinical Global Impression – Improvement rating, as assessed by the 
parent/caregiver. 
o
The change from baseline in the QOLCE score. 
o
The change from baseline in the PedsQL score. 
o
The change from baseline in the PedsQL Family Impact module score. 
o
The change from baseline in the QoL of the parent/caregiver using the 
EQ-5D-5L scale. 
o
The change from baseline in the affective symptoms of the 
parent/caregiver using the HADS. 
2.4
SAFETY OBJECTIVE 
The safety objective of the study is: 
• To compare the safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day to placebo with 
regard to AEs, laboratory parameters, physical examination, neurological examination, 
vital signs (blood pressure, heart rate [HR], temperature, and respiratory rate), ECGs, 
ECHOs, and body weight Cognitive Function will be assessed using the cognition 
domain score on the QOLCE and age-appropriate versions of the BRIEF. 
2.5
PHARMACOKINETIC OBJECTIVE 
The pharmacokinetic (PK) objective of the study is: 
• To characterize the PK of ZX008 0.2 and 0.8 mg/kg/day at steady state in subjects ages 
2-6 years and >6-18 years with Dravet syndrome. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
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31 October 2016
Confidential 
Page 32 of 175
2.6
EXPLORATORY OBJECTIVE 
The exploratory objective of the study is: 
• To compare the ZX008 0.2 and 0.8 mg/kg/day doses on primary, secondary, safety and 
PK endpoints. 
2.7
STUDY ENDPOINTS 
2.7.1
Efficacy Endpoints 
The efficacy endpoints of the study are: 
• 
Number of seizures by type 
• 
Convulsive seizure-free interval 
• 
Clinical Global Impression – Improvement as assessed by parent/caregiver 
• 
Clinical Global Impression – Improvement 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 the parent/caregiver using the EQ-5D-5L scale 
• 
Affective symptoms of the parent/caregiver using the HADS scale 
• 
Duration of prolonged seizures (seizure type that, during baseline, had duration 
>2 minutes) 
• 
Number of episodes of status epilepticus 
• 
Number of instances of rescue medication use and number of doses 
• 
Number of inpatient hospital admissions due to seizures 
2.7.2
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 
• 
Neurological examination 
• 
12-lead ECGs 
• 
Doppler ECHOs 
• 
Body weight 
• 
BRIEF to measure cognition 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 33 of 175
2.7.3
Pharmacokinetic Endpoints 
The PK endpoints of the study are: 
• 
Steady-state plasma fenfluramine PK parameters (Cmax, AUC0-t, Tmax, and t1/2) 
after administration of ZX008 derived using population PK methods 
3.
INVESTIGATIONAL PLAN 
3.1
OVERALL STUDY DESIGN AND PLAN 
This is a multicenter, double-blind, parallel-group, placebo-controlled, study to assess the 
efficacy, safety, and PK of ZX008 when used as adjunctive therapy in pediatric and young 
adult subjects with Dravet syndrome. Approximately 30 study sites in Europe, Australia, and 
South Korea are planned to participate. The 6-week Baseline Period will consist of the 
establishment of initial eligibility during a screening visit followed by an observation period 
where subjects will be assessed for baseline seizure activity based on recordings of daily 
seizure activity entered into a diary. Upon completion of the Baseline Period, subjects who 
qualify for the study will be randomized (1:1:1) in a double-blind manner to receive 1 of 2 
doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; maximum dose: 30 mg/day) or placebo. 
Randomization will be stratified by age group (<6 years, 6 years) to ensure balance across 
treatment arms, and at least 40% of subjects will be in each age group. All subjects will be 
titrated to their randomized dose over a 14-day Titration Period. Following titration subjects 
will continue treatment at their randomly assigned dose over a 12-week Maintenance Period. 
Total treatment time from the beginning of the Titration Period through the end of the 
Maintenance Period is 14 weeks. Parents/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. 
At the end of the Maintenance Period (or early discontinuation), all subjects will undergo a 
2-week taper or transition period (Post-Dosing Follow-Up) depending on whether they exit the 
study or are enrolled in the separate long-term open-label extension study. 
A follow-up ECHO, ECG, and possibly physical examination will be performed 3-6 months 
after study drug discontinuation for early termination, or for those subjects who complete the 
study but do not enter the open-label extension study. 
3.2
NUMBER OF SUBJECTS 
Approximately 130 subjects will be screened to obtain 115 subjects who enter the Baseline 
Period. Of these 115 subjects, it is estimated that 105 subjects will be randomized into the 
Titration Period. Each clinical site will not randomize more than a maximum of 10 subjects 
without prior consent from the sponsor. 
3.3
STUDY DURATION 
The duration of participation in the study for an individual subject is expected to be up to 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 34 of 175
22 weeks, plus follow-up safety visit 3 to 6 months after the last dose: 
• Baseline Period – 6 weeks 
• T+M Period - 14 weeks 
• Post-Dosing Visit – 2 weeks after study completion or early termination 
• Cardiac Follow-up (ECG and ECHO)– 3-6 months after study drug discontinuation for 
early termination or for subjects who complete the study but do not enroll in the 
open-label extension study. 
3.4
NUMBER OF STUDY CENTERS 
The study expects to use up to approximately 30 research centers in Europe, Australia, and South 
Korea. Additional study centers within or outside of Europe, Australia, and South Korea may be 
added if enrollment cannot be completed in a timely manner. 
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. Stratifying the randomization by age group 
is considered appropriate because the frequency and severity of major seizures can be higher in 
younger subjects. The two strata in the study will be subjects aged below 6 years and subjects 
aged 6 -18 years. The study design has incorporated a titration period to enable subjects 
randomized to the high dose group adequate time to acclimate to this dose. Following the 
Titration Period, subjects will enter a 12-week Maintenance Period where they will continue on 
their randomized dose for the remainder of the study. The 12-week duration of the Maintenance 
Period is in keeping with the current standard study duration for evaluating the efficacy of 
chronic medications. Given the individual variability in seizure frequency and seizure type in this 
patient population, the primary endpoint, which seeks to compare an appropriate baseline of 
convulsive seizure frequency to the convulsive seizure frequency following treatment, is an 
appropriate primary endpoint for efficacy in this population. 
Subjects will receive investigational medicinal product (IMP; ZX008 or placebo) in addition to 
their existing antiepileptic medications at their stable doses throughout the entire study. Thus, 
subjects receiving placebo will not be denied active therapy; they will continue to receive their 
existing medications at the exact same dosages. As the principal study measurement (convulsive 
seizures) might be considered subjective, a double-blind study design will prevent subjective 
bias. Upon study completion, eligible subjects will be able to receive ZX008 in an open-label 
extension study for up to 1 additional year of treatment. 
3.6
PREMATURE TERMINATION OF STUDY 
The sponsor can terminate the study prematurely at any time for medical or ethical reasons at 
individual or at all study sites. The investigator will be notified in writing, outlining the reasons 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 35 of 175
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 6.2.9 and Section 6.3. 
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)/IRB. 
3.7
STUDY MONITORING PROCEDURES 
3.7.1
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 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 pharmacokinetic data and any other data that may affect subject 
continuation. 
• 
Make recommendations regarding the continuation, suspension, or termination 
of the study. 
3.7.2
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 guides its operations, and review of individual subject 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 36 of 175
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. 
4.
SELECTION OF STUDY POPULATION 
The study population will be selected on the basis of the inclusion and exclusion criteria 
described in the sections below. Before evaluating these criteria and deciding on the eligibility 
of subjects to participate in the study, it is important that the investigator is familiar with the 
safety profile of ZX008 by referring to the Investigator’s Brochure, as supplied by the sponsor. 
4.1
INCLUSION CRITERIA 
Subjects meeting all of the following inclusion criteria may be enrolled into the study: 
1. Subject is male or non-pregnant, non-lactating female, age 2 to 18 years, inclusive as of 
the day of the Screening Visit. Female subjects of childbearing potential must not be 
pregnant or breast-feeding. Female subjects of childbearing potential must have a 
negative urine pregnancy test. Subjects of childbearing or child-fathering potential must 
be willing to use medically acceptable forms of birth control (see Section 4.4), which 
includes abstinence, while being treated on this study and for 90 days after the last dose 
of study drug. 
2. Subject must have documented medical history to support a clinical diagnosis of Dravet 
syndrome, where convulsive seizures are not completely controlled by current 
antiepileptic drugs. 
3.
Subjects must meet all of the following 5 criteria: 
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 brain malformation. 
e.
Lack of alternative diagnosis. 
4. Subjects must meet at least one of the following 3 criteria: 
a.
Emergence of another seizure type, including myoclonic, generalized tonic- 
clonic, tonic, atonic, absence and/or focal has developed after the first seizure 
type. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 37 of 175
b. 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 
natural and/or fluorescent lighting, as well as certain visual patterns. 
c.
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.) 
5. 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. 
6. All medications or interventions for epilepsy (including KD and VNS) must be stable for 
at least 4 weeks prior to screening and are expected to remain stable throughout the 
study. 
7. Subject has been informed of the nature of the study and informed consent has been 
obtained from the legally responsible parent/guardian. 
8. Subject has provided assent in accordance with Institutional Review Board (IRB) 
requirements, if capable. 
9. Subject’s parent/caregiver is willing and able to be compliant with diary completion, 
visit schedule and study drug accountability. 
4.2
EXCLUSION CRITERIA 
Subjects meeting any of the following exclusion criteria must not be enrolled into the study: 
1.
Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study 
medication.
2.
Subject has pulmonary arterial hypertension. 
3.
Subject has current or past history of cardiovascular or cerebrovascular disease, such as 
cardiac valvulopathy, myocardial infarction or stroke. 
4.
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. 
5.
Subject is at imminent risk of self-harm or harm to others, in the investigator’s opinion, 
based on clinical interview and/or responses provided on the C-SSRS. Subjects must be 
excluded if they report suicidal behavior in the past 6 months as measured by the C- SSRS 
at Screening or Baseline, which includes suicidal ideation with intent and plan (Item #5). 
If a subject reports suicidal ideation on Item 4 without a 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. 
6.
Subject has a current or past history of glaucoma. 
7.
Subjects with moderate or severe hepatic impairment may not be entered. Asymptomatic 
subjects with mild hepatic impairment (elevated liver enzymes < 3xULN and/or elevated 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 38 of 175
bilirubin <2xULN) may be entered into the study after review and approval by the 
Medical Monitor in conjunction with the sponsor, with consideration of potential cause, 
concomitant medications, and other risk factors. 
8.
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; or cyproheptadine 
(see Appendix 1). (Note: Short-term medication requirements will be handled on a per 
case basis by the Medical Monitor.) 
9.
Subject is currently receiving or has received stiripentol in the past 21 days prior to 
Screening. 
10. Subject 
is 
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carbamazepine, 
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eslicarbazepine, 
phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as 
maintenance therapy. 
11. Subject is unwilling to refrain from large or daily servings of grapefruits and/or Seville 
oranges, and their juices beginning with the Baseline Period and throughout the study. 
12. Subject has positive result on urine THC Panel or whole blood CBD at the Screening 
Visit. 
13. Subject has participated in another clinical trial within the past 30 days. 
14. Subject is currently receiving an investigational product. 
15. Subject is unwilling or unable to comply with scheduled visits, drug administration 
plan, laboratory tests, other study procedures, and study restrictions. 
16. Subject has a clinically significant condition, or has had clinically relevant symptoms or a 
clinically significant illness in the 4 weeks prior to the Screening Visit, other than 
epilepsy, that would negatively impact study participation, collection of study data, or 
pose a risk to the subject. 
4.3
RANDOMIZATION INCLUSION CRITERIA 
Subjects must meet all of the inclusion criteria above plus the following criteria, to be 
randomized: 
1. Subject has been approved for study inclusion by the Epilepsy Study Consortium. 
2. Subject does not have a cardiovascular or cardiopulmonary abnormality based on ECHO, 
ECG or physical examination, including but not limited to trace mitral or aortic, valve 
regurgitation or signs of pulmonary hypertension, and is approved for entry by the central 
cardiac reader. 
3. Subject demonstrates a stable baseline with 6 convulsive seizures during the 6-week 
Baseline Period, with a minimum of 2 in the first 3 weeks and 2 in the second three 
weeks. 
4. Subject’s parent/caregiver has been compliant with diary completion during the 
Baseline Period, in the opinion of the investigator (eg, at least 90% compliant). 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 39 of 175
4.4
SUBJECTS OF REPRODUCTIVE POTENTIAL 
Male subjects who are sexually active with a partner of childbearing potential must use, with their 
partner, a condom plus an approved method of highly effective contraception from the time of 
informed consent until 90 days after the last dose of study drug.
The following methods are acceptable: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation and a barrier method (ie, condom for male partner): 
í
oral 
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transdermal 
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method (ie, condom for male partner): 
í
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injectable 
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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 after the last dose of study drug. 
The following methods are acceptable: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation and a barrier method (i.e., condom for male partner): 
í
oral 
í
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í
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í
oral 
í
injectable 
í
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í
intrauterine hormone-releasing system 
• Surgical sterilization (vasectomy or bilateral tubal occlusion) 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 40 of 175
Alternatively, true abstinence is acceptable when it is in line with the subject’s preferred and 
usual lifestyle. If a subject is usually not sexually active but becomes active, they, with their 
partner, they must comply with the contraceptive requirements detailed above. 
4.4.1
Sperm and Egg Donation 
Male subjects should not donate sperm and female subjects should refrain from egg donation 
for the duration of the study and for at least 90 days after the last day of study medication 
administration. 
4.4.2
Pregnancy 
Subjects will be instructed that if they/their partner become pregnant during the study this should 
be reported to the investigator. The investigator should also be notified of pregnancy occurring 
during the study but confirmed after completion of the study. In the event that a subject/subject’s 
partner is subsequently found to be pregnant after the volunteer is included in the study, then 
consent will be sought from the partner and, if granted, any pregnancy will be followed and the 
status of mother and/or child will be reported to the sponsor after delivery. 
Any subject reporting a pregnancy during the study will be withdrawn from the study and should 
complete the taper schedule. 
4.5
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT 
While subjects are encouraged to complete all study evaluations, subjects may voluntarily 
withdraw from the study for any reason at any time. They may be considered withdrawn if they 
fail to return for visits, or become lost to follow-up for any other reason. 
If premature withdrawal occurs for any reason, the investigator must make a genuine effort to 
determine the primary reason for a subject’s premature withdrawal from the study and record this 
information on the electronic case report form (eCRF). All subjects who withdraw from the study 
with an ongoing AE must be followed until the event is resolved or deemed stable. If a subject 
withdraws prematurely after dosing, all data to be collected prior to discharge from the clinical 
site should be collected at the time of premature discontinuation or at the scheduled discharge. 
For subjects who are lost to follow-up (ie, those subjects whose status is unclear because they 
failed to appear for study visits without stating an intention to withdraw), the investigator 
should show "due diligence" by documenting in the source documents the steps taken to 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. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 41 of 175
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 Columbia-Suicide Severity Rating Scale 
(C-SSRS). 
9. It is the investigator’s opinion that it is not in the subject’s best interest to continue in the 
study. 
10. Subject is found to be pregnant while on study. 
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 who are discontinued from the clinical investigation for any reason will not be 
replaced. 
Subjects may withdraw their consent to participate in the study at any time without having to 
justify the reason for doing so. The decision to withdraw consent and discontinue participation in 
the study will not prejudice the subject’s future medical treatment in any way. Subjects must be 
discontinued from receiving ZX008 and/or participating in any further study procedures under 
the following circumstances: 
• 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). 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 42 of 175
The IDSMC may request that the study be terminated after review of the safety information at 
any time during the study. The IDMSC will review the data for the development of heart valve 
disease and pulmonary hypertension as they occur on a case-by-case basis and at regular 
meetings. 
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 eCRF 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 to 
that time. Specific procedures required are described in Section 6.2.9 and Section 6.3. As far as 
possible, a complete final examination must be performed on all subjects who do not complete 
the study according to the study protocol. 
Data collected until the time a subject discontinues participation in the study will be handled in 
the same manner as data for subjects completing the study. Where possible, further information 
will be collected if any AEs are experienced by a subject after discontinuing participation in the 
study. 
4.6
TERMINATION OF THE CLINICAL STUDY 
If the investigator, the sponsor, the Medical Monitor, or the IDSMC becomes aware of conditions 
or events that suggest a possible hazard to subjects if the clinical study continues, then the clinical 
study may be terminated. The 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. 
4.7
REPLACEMENT OF SUBJECTS 
Enough subjects will be enrolled in the trial to ensure that approximately 105 subjects are 
randomized into the T+M Period.  Randomized subjects will not be replaced. 
4.8
ELIGIBILITY FOR EXTENSION STUDY 
Subjects who complete the 12-week Maintenance Period of this study will be eligible to enroll 
in a planned, separate, open-label extension trial of ZX008 if they meet Inclusion/Exclusion 
criteria for that study regarding their suitability for continued participation in a trial of 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 43 of 175
fenfluramine. 
Subjects must complete the entire 12-week Maintenance Period in order to be offered 
enrollment into the separate, open-label extension trial of ZX008. Those subjects who do not 
complete the 12-week Maintenance Period of the study may, on a case-by-case basis, be eligible 
for entrance into the separate open-label extension study 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. 
5.
INVESTIGATIONAL MEDICINAL PRODUCT INFORMATION 
ZX008/matching placebo will be administered in the current study. A brief description of the 
ZX008 product is provided below (Table 2). 
Table 2: 
Investigational Medicinal Product – ZX008 
Study Product
Substance Code 
ZX008
Active Substance (INN) 
Fenfluramine Hydrochloride
Trade Name 
Not applicable
Formulation (including dosage form and strength)
Solution 1.25, 2.5, and 5 mg/mL 
Route/Mode of Administration 
Oral
Manufacturer
PCI Pharma Services on behalf of Zogenix 
International Limited 
5.1
IDENTITY OF INVESTIGATIONAL MEDICINAL PRODUCT 
ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 
and provided in concentrations of 1.25 mg/mL, 2.5 mg/mL, and 5 mg/mL. The excipients selected 
have been approved for use in the formulations of currently marketed drug products and are 
considered to be safe. The solution formulations will be suitably flavored and colored, and will 
contain preservatives and a thickening agent. The product is sugar free and is intended to be 
compatible with a KD. 
The formulation will be provided in bottles with tamper-evident, child-resistant caps. The clinical 
trials material will be supplied in 1 bottle size with nominal fill volume of 120 mL. Matching 
placebo also will be provided. Doses to be studied include 0.2 mg/kg/day and 
0.8 mg/kg/day divided into two daily (BID) doses, up to a maximum of 30 mg/day. An 
intermediate dose of 0.4 mg/kg/day will be used for titration. The concentration of ZX008 oral 
solution received by subjects (1.25 mg/mL, 2.5 mg/mL, and/or 5 mg/mL) will be randomized 
across the 3 available concentrations in order to ensure blinding. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 44 of 175
If the parent/caregiver is unable to administer the full dose due to spillage (eg, dose was spilled 
during measuring, subject spit dose out during administration), he/she should attempt to give the 
full dose noting the extra amount used to fulfill the dose. 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 International Conference 
on Harmonization (ICH), Good Manufacturing Practices (GMP), and Good Clinical Practices 
(GCP) guidelines, and national legal requirements. 
Dosing directions for the product can be found in the IMP handling instructions for the study 
subjects and for the investigator. 
5.2
DESCRIPTION OF REFERENCE TREATMENT, COMPARATOR, 
AND/OR PLACEBO 
Placebo solution is identical in aspect and composition to ZX008 and is composed of identical 
ingredients used in the ZX008 formulation, except that it does not contain the active ingredient, 
fenfluramine hydrochloride. 
No comparators or reference treatments will be used. 
5.2.1 
Labeling and Packaging 
Placebo solution will be packaged in an identical manner to ZX008. The matching placebo 
product will be packaged and labeled according to current ICH, GMP, and GCP guidelines, and 
national legal requirements. 
Dosing directions for the product can be found in the IMP handling instructions for the study 
subjects and for the investigator. 
5.3
SHIPMENT AND STORAGE 
IMP will be supplied to the study sites by the sponsor or its delegate. 
All IMP will be transported, received, stored, and handled strictly in accordance with the 
container or product label, the instructions supplied to the research site and its designated 
pharmacy, the site’s standard operating procedures, and applicable regulations. IMP must be 
stored separately from normal hospital or practice inventories, in a locked facility with access 
limited to the investigator and authorized personnel. The investigator must ensure that the IMP is 
dispensed only to subjects enrolled in this study according to this study protocol. 
Appropriate storage temperature and transportation conditions will be maintained for the study 
drug from the point of manufacture up to delivery of the study drug. Study medication must be 
stored at 15-25°C (59-77°F) with excursions of 5-30°C (41-86°F) permitted; do not freeze. 
Storage and handling instructions of the IMP maintained at the subject’s home are described in 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 45 of 175
the subject’s IMP handling instructions. 
All unused IMP will be saved by the site for final disposition according to the sponsor’s 
directive. 
5.4
IMP ACCOUNTABILITY 
The investigator or delegate will confirm receipt of all shipments of the IMP in writing using 
the receipt form(s) provided by the sponsor or vendor. 
Assignment of ZX008 or placebo to the subject will be handled through an interactive voice 
randomization (IVR) or Interactive Web Response (IWR) platform. The investigator or delegate 
will be required to register the subject through IVR/IWR and all study medication will be 
assigned to the subject through the IVR/IWR. The IVR/IWR will also maintain a log of all 
received and dispensed medication. 
All supplies must be accounted for throughout the study using the drug accountability form 
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. 
5.5
TREATMENT ADMINISTRATION 
5.5.1
Randomization 
Upon completion of the Baseline Period, subjects who qualify for the study will be randomized 
(1:1:1) in a double-blind manner to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 
0.8 mg/kg/day; 30mg/day maximum) or placebo. The randomization will be stratified by age (<6 
years, 6 years) to ensure balance across treatment arms, and at least 40% of subjects will be in 
each age group. Subjects will be assigned a randomization number by the IVR/IWR system upon 
confirmation that subject qualifies for enrollment in the Titration Period. Once a randomization 
number is assigned to a subject, the site will record the subject’s initials and identification 
number on the corresponding study drug bottles. Each bottle will contain the assigned treatment 
(ZX008 0.2 mg/kg/day, ZX008 0.8 mg/kg/day, or placebo). ZX008 and placebo will be identical, 
thus rendering the study drug and placebo indistinguishable. For each IMP bottle and 
randomization number assigned, the following information will be recorded on the drug 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 46 of 175
accountability form: subject initials, unique bottle number, date each bottle is assigned, and drug 
used and unused during the study. 
5.5.2
Titration 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 IMP will be based on the randomized dose and subject’s weight (kg) at 
Visit 3 (Study Day -1). At Visit 8 (Study Day 43), if the subject’s weight (kg) has changed 
±25% of the weight at Study Day-1, the IMP dose will be recalculated. Subjects should be 
dosed using the oral dosing syringe provided. 
In order to maintain the blind across all dose groups (Section 5.6) and allow step titration to the 
high dose, the dose for each subject will be titrated starting with a dose of ZX008 
0.2 mg/kg/day (or placebo equivalent) BID. After 4 days at this dose level (Study Day 5), 
subjects randomized to the ZX008 0.8 mg/kg/day group will increase their dose to 0.4 
mg/kg/day (maximum 30 mg/day) while doses in the other two groups will remain constant. On 
Study Day 9, the dose for the 0.8 mg/kg/day group will increase to the target dose or a 
maximum of 30 mg/day. The titration is expected to take a total of 14 days (Table 3). A new 
bottle of IMP will be started by the subject at each level of the titration step. See Section 5.6 for 
more information about the volume of ZX008 or placebo to be administered. 
Table 3 
Titration Algorithm 
Randomized Group 
Titration Step 1
Study Day 1-4 
Titration Step 2
Study Days 5-8 
Titration Step 3
Study Days 9-14 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.8 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.4 mg/kg/day 
ZX008 0.8 mg/kg/day 
Placebo 
Placebo 
Placebo 
Placebo 
Note: maximum daily dose of ZX008 is 30 mg 
5.5.3
Maintenance Period 
After completion of the Titration Period, subjects will enter the Maintenance Period and 
continue to receive the randomized dose of ZX008 or placebo and be treated for an additional 
12 weeks. Study medication will continue to be administered BID in the morning and in the 
evening, approximately 12 hours apart, 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. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 47 of 175
5.5.4
Taper Period 
Subjects who complete the Maintenance Period and will not be continuing into the open-label 
extension study, and subjects who discontinue from the study early, will be tapered off of study 
medication. Study medication will be administered as equal doses BID in the morning and in the 
evening approximately 12 hours apart, 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 should be administered using the oral dosing syringe provided. 
In order to maintain the blind across all dose groups, all subjects who do not continue into the 
open-extension study will participate in a dose-tapering procedure over the course of 8 days. On 
the first day of the tapering period subjects in the ZX008 0.8 mg/kg/day group will decrease to a 
dose of ZX008 0.4 mg/kg/day BID (maximum 30 mg/day). After 4 days at this dose level (Study 
Day 5), subjects randomized to the ZX008 0.8 mg/kg/day group will decrease their dose to 0.2 
mg/kg/day. Subjects in the ZX008 0.2 mg/kg/day group will decrease their dose to placebo on 
the first day of tapering while doses in the placebo group will remain constant throughout the 
tapering procedure. On Study Day 9, all subjects will stop taking study medication. The taper is 
expected to take a total of 8 days (Table 4). A new bottle of IMP will be started by the subject at 
each level of the taper step. 
Table 4: 
Taper Algorithm 
Randomized Group 
Taper Step 1
Day 1-4 after study completion or 
early termination 
Taper Step 2 
Days 5-8 after study completion or 
early termination 
ZX008 0.2 mg/kg/day 
Placebo
Placebo 
ZX008 0.8 mg/kg/day 
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day 
Placebo 
Placebo
Placebo 
Note:  maximum daily dose of ZX008 is 30 mg.
5.5.5
Transition Period 
Subjects who complete the Maintenance Period and will be continuing into the open-label 
extension study will be transitioned from double-blind study medication to open-label ZX008 
(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. 
Study medication should be administered using the oral dosing syringe provided. 
All subjects entering the open-label extension study will be transitioned from their blinded daily 
dose (placebo, 0.2 mg/kg/day, 0.8 mg/kg/day, or 30 mg/day) to the 0.2 mg/kg dose during the 2-
week interval between Visits 12 and 13, without breaking the blind. The IVR/IWR system will 
assign two bottles of IMP to the subject, one for each step in the transition. A new bottle of IMP 
will be started by the subject at each level of the transition step. See Section 5.6 for more 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 48 of 175
information about the volume of ZX008 or placebo to be administered. 
Table 5: 
Transition Algorithm 
Dose Group in 
Double-Blind 
Transition Step 1
Day 1-4 after Visit 12 
Transition Step 2 
Days 5-14 after Visit 12 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day
ZX008 0.2 mg/kg/day 
ZX008 0.8 mg/kg/day 
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day 
Placebo 
ZX008 0.2 mg/kg/day
ZX008 0.2 mg/kg/day 
Note:  maximum daily dose of ZX008 is 30 mg.
Subjects who had been randomized to placebo increase their dose to 0.2 mg/kg/day beginning on 
day 1 of the transition (the day following Visit 12; Study Day 100.) Subjects who had been 
randomized to 0.2 mg/kg/day will continue to receive that dose. Subjects who had been 
randomized to 0.8 mg/kg/day or were receiving the maximum dose of 30 mg/day decrease to a 
dose of ZX008 0.4 mg/kg/day. After 4 days at this dose level (day 5; Study Day 104), these 
subjects will decrease their dose to 0.2 mg/kg/day. Subjects will report to the clinic on day 15 
(Study Day 113) for enrollment into the open-label extension study. 
5.6
BLINDING 
At the end of the Baseline Period, subjects who qualify to enter the study will be randomized to 
receive ZX008 0.2 mg/kg/day, ZX008 0.8 mg/kg/day (maximum dose: 30 mg/day), or placebo 
and assigned a randomization number by the IVR/IWR system. Once a randomization number is 
assigned to a subject, the site will record the subject’s initials on the corresponding study drug 
labels. Each bottle will contain the assigned treatment (ZX008 or placebo) and the ZX008 and 
placebo solutions will be identical. 
The blinding scheme instituted for this study will ensure that the volume of study medication 
taken cannot be associated with the dose group, thus unblinding the study. This is achieved by 
random assignment of different concentrations of the ZX008 oral solution (1.25 mg/mL, 
2.5 mg/mL, and/or 5 mg/mL) by the IVR/IWR system. The IVR/IWR system will instruct site 
personnel to the volume of oral solution to be administered based on that subject’s weight. 
(Dose will be recalculated by the system once at the midpoint of the study.) During the 
Titration, Maintenance, Taper/Transition Periods, the subjects and study personnel 
(investigators, clinical staff, personnel involved in data collection and analysis, the Medical 
Monitor, and the sponsor) will be blinded to the treatment allocation and to the concentration of 
ZX008 oral solution. If an investigator feels the blind should be broken, he/she can do so when 
necessary for treatment decisions. However, the investigator should endeavor to discuss with 
the Medical Monitor or Sponsor’s Medical Representative, if available. The blind should only 
be broken in the event the knowledge of whether the subject is on active study medication 
versus placebo is needed to determine course of medical treatment for the event. The subject 
will be discontinued from the clinical trial upon breaking of the blind and the decision whether 
the subject can enter the separate open-label extension study will rest with the Sponsor if the 
subject exited Study 1502 prior to completion. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 49 of 175
5.7
PRIOR AND CONCOMITANT MEDICATION 
All medications taken by a subject during the Screening and Baseline Seizure Assessment 
Periods are regarded as prior therapy and must be documented in the eCRF. Significant 
medications (eg, antibiotics) taken within 30 days prior to the Screening visit should also be 
captured. All prior and concomitant AEDs will be collected in the CRF. 
All medications taken by a subject after the first administration of IMP are regarded as 
concomitant medication and must be documented in the eCRF, including over-the-counter 
medication, herbal and vitamin/supplement preparations. Subjects are required to take at least one 
concomitant AED during the study. All subjects will continue to receive their existing AED(s) 
with the same doses throughout the study. Every effort should be made to ensure that the regimen 
of existing medications remains stable during the study; any changes must be discussed with the 
sponsor prior to implementation. If a decrease in a concomitant AED is necessary to manage an 
AE, this must be discussed with the sponsor as soon as possible after implementation if not 
before implementation. 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. 
5.7.1
Vagal Nerve Stimulation 
Subjects receiving treatment with a VNS may be included as long as the VNS has been in place 
for at least 6 months prior to entry into the study, the VNS battery is not due for replacement 
during the study, and stimulation parameters have been kept constant for 4 weeks prior to 
screening and must remain so throughout the study. The subject’s use of VNS will be recorded in 
the CRF. 
5.7.2
Ketogenic Diet 
Adherence to the KD, or a modified version of KD, is permitted during the study if the dietary 
habits were initiated more than 4 weeks prior to Screening and remain stable throughout the 
study. The subject’s use of KD will be recorded in the CRF. 
5.7.3
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 eCRF. 
Use of rescue medication is permitted during the study and should be recorded on the eCRF (day, 
medication[s], dose[s]) and in the diary (day, timeframe associated with seizure episodes). 
Repeated administrations within the same episode should be recorded separately. 
5.7.4
Prohibited Concomitant Medication and Food 
A list of medications/foods that are to be avoided as ongoing medications or for chronic use if 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 50 of 175
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. 
The following concomitant medications are prohibited during the clinical trial: 
• AEDs: Phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, 
retigabine/ezogabine 
• Stiripentol (STP): Subjects must be off STP for a minimum of 21 days prior to the 
Screening visit. 
• Felbamate is prohibited as a concomitant medication unless the subject has been on 
felbamate for at least 18 months prior to screening, 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, including, but not limited to: imipramine, 
monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin-
norepinephrine reuptake inhibitors, vortioxetine 
• Drugs that increase cardiovascular risk including: atomoxetine and those with noradrenergic 
reuptake properties (NRIs, SNRIs) 
• Drugs intended to facilitate weight loss 
• Other:  any form of marijuana, THC and derivatives (including Epidiolex®) 
5.8
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. 
6.
VISIT SCHEDULE 
Study procedures will be conducted according to the Schedule of Assessments in Table 1. 
Time windows for all assessments are detailed in Table 6. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 51 of 175
Table 6: 
Time Windows for Assessments 
Visit / Procedure
Time window (relative to scheduled visit / procedure)
Visit 1 (Clinic; Study Day -43 to -42 or -42 to -41): 
Not applicable
Visit 2 (Phone; Study Day -21)
± 3 days
Visit 3 (Clinic; Study Day -1; Randomization)
+ 4 daysa
Visits 4, 5 (Phone: Study Days 4, 8)
± 3 days
Visit 6 (Clinic; Study Day 15)
± 4 days
Visit 7 (Phone: Study Day 29)
± 4 days
Visit 8 (Clinic; Study Day 43)
± 4 days
Visit 9 (Phone: Study Day 57)
± 4 days
Visit 10 (Clinic; Study Day 71)
± 4 days
Visit 11 (Phone: Study Day 85)
± 4 days
Visit 12 (Clinic: Study Day 99)
± 4 days
Visit 13 (Clinic; Study Day 113; post dosing)
± 4 days
Visit 14 (ECHO clinic; 3-6 months after last dose)
+ 30 days
Blood collection for ZX008 PK
± 15 minutes
Blood collection for AED concentration
Prior to morning dose of AED medication
AED=antiepileptic drug (s); ECHO=echocardiogram; PK = pharmacokinetics 
a 
In cases where the screening period is extended beyond 42 days, the immediate 42 days before the Randomization visit will 
be used to calculate the baseline seizure frequency
6.1
BASELINE PERIOD (STUDY DAY -42 TO STUDY DAY -1) 
The Baseline Period of the study encompasses the screening activities that will occur on Study 
Day -42 as well as the observation period where subjects will be assessed for baseline seizure 
activity based on recordings of daily seizure activity entered into a diary. 
6.1.1
Screening, Clinic Visit 1 (Study Day -42) 
Screening is the predetermined series of procedures with which each investigator selects an 
appropriate and representative sample of subjects for enrollment into the study. Select 
screening data will be documented in the IVR/IWR and eCRF. 
Written informed parental or guardian consent and assent of minors (if the subject is capable of 
providing assent) must be obtained before a subject can start any of the screening procedures. 
The procedure(s) for obtaining written informed consent and assent of minor (if the subject is 
capable of providing assent) are described in Section 11.2. 
The Screening visit will occur on Study Day -42; however, the procedures may be split over 
2 consecutive days (e.g., Study Day -43 and Study Day -42 or Study Day -42 and Study Day -41). 
Splitting the visit procedures across 2 nonsequential days requires the approval of the medical 
monitor. The following procedures will be performed for all subjects before the start of seizure 
activity observation: 
• 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 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 52 of 175
• 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 6 months (or available duration) of parent/caregiver seizure diary data if 
available (screen shots of cell phones are acceptable, as are photocopies of paper diaries 
or print outs) and place in source file 
• Record prior medications 
• Complete physical examination, including height, weight, and calculation of BMI 
• Complete neurological examination 
• 12-lead electrocardiogram 
• Doppler ECHO (this may be obtained any time between Study Day -42 and Study 
Day -21) 
• 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 Children’s Baseline/Screening Assessment (Appendix 2) 
• Instruct parent/caregiver on use of diary 
• Dispense diary (after above procedures have been concluded)
• Record AEs 
• Record AESIs 
Only eligible subjects as specified by the inclusion and exclusion criteria with an independently 
confirmed diagnosis of DS by the Epilepsy Study Consortium will be enrolled into the study. 
After enrollment into the study, each subject will be issued a “Subject Card” containing 
information about the subject’s participation in the study. The subject or parent/caregiver will be 
advised to retain this card on his person for the entire duration of the study so that the investigator 
or the sponsor can be contacted in case of emergency. 
In certain circumstances the sponsor may allow subjects who did not meet all inclusion/exclusion 
criteria at the time of the Screening Visit to have the screening period extended, or to be re-screened 
for eligibility. In all cases the investigator should consult with the Medical Monitor. Decisions 
whether to permit rescreening resides solely with the sponsor.  
The decision whether to permit extended screening or rescreening can be influenced by many factors 
individual to that subject case. Some general principles apply: 
1. If baseline seizure screening is extended or the subject is discontinued and then rescreened, the 
screening period for establishing the baseline seizure frequency will be the immediate 6 weeks 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 53 of 175
before the randomization visit. 
2. Subjects who are found to be on a prohibited medication at the screening visit may be weaned 
off of that medication provided: 
a.
Decisions to withdraw a disallowed concomitant medication must be made with the 
agreement of the prescribing physician 
b. If the medication has antiepileptic properties, a wash out of at least 5 half-lives must 
be completed before collection of baseline seizure data.  
c.
If a decision has been made to wean off of a medication without antiepileptic 
properties and the 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
Phone Visit 2 (Study Day -21) 
Site personnel will contact the subject via telephone on Study Day -21 and record the 
following: 
• AEs 
• AESI 
In addition, site personnel with review the diary entries with the parent/caregiver. 
6.1.3
Clinic Visit 3 (Study Day -1): Randomization 
This period is intended to ensure that subjects meet the study entry criteria and confirm they 
have experienced 6 convulsive seizures during the 6-week Baseline Period, with at least 2 
seizures in each 3-week half of the Baseline Period. Subjects must have at least 42 days of 
prospective diary data at Visit 3. Subjects will report to the clinic in the morning on Study Day -
1 to allow for plasma sample collection for AED pharmacokinetic evaluation prior to the 
morning dose of these medications. Subjects should not take their morning dose(s) of AED 
medication prior to reporting to the clinic. 
The following procedures will be performed on Study Day -1: 
• Review inclusion and exclusion criteria 
• Review current seizure activity (number/type/duration) from diary since previous visit 
and calculate the number of convulsive seizures during the first 3 weeks, the second 3 
weeks, and over the full 6-weeks of the observation period. 
• Record prior medications since previous visit 
• Complete physical examination, including height and weight, and calculation of BMI 
• Abbreviated neurological examination 
• Vital signs 
• 12-lead ECG 
• Urine pregnancy test for females of child-bearing potential 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 54 of 175
• Laboratory evaluation (serum chemistry, and hematology, and urinalysis) 
• Collect plasma sample for AED pharmacokinetic evaluation prior to the morning dose 
of study medication(s) 
• Urine THC panel 
• Whole blood CBD 
• Tanner Staging for subjects >7 years of age (Appendix 5) 
• Collect and review diary with parent/caregiver 
• Dispense diary 
• C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
• BRIEF (Appendix 3) 
• QOLCE (Appendix 4) 
• PedsQL (Appendix 6) 
• PedsQL Family Impact module (Appendix 6) 
• Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
• Affective symptoms of parent/caregiver using the HADS scale (Appendix 8) 
• Record AEs 
• Record AESI 
• When eligibility for the Titration Period is confirmed, randomize (blinded) subject to 
treatment assignment (ZX008 0.2 mg/kg/day, ZX008 0.8 mg/kg/day, or placebo) 
• Dispense study medication (If administration of the first dose of study medication occurs in 
the clinic, the next dose should be at least 8 hours later or the following morning. The dose 
on the following morning will count as Study Day 1.) 
6.2
TITRATION AND MAINTENANCE PERIODS 
6.2.1
Titration Period Study Day 1 
Subjects will take their first dose of study medication on the morning of Study Day 1. Study Day 1 is 
considered the first day of dosing, even for those subjects that received an in-clinic dose on Study 
Day -1.
6.2.2
Phone Visits 4 and 5 (Titration Period Study Days 4 and 8) 
Site personnel will contact the subject via telephone on Titration Period Study Days 4 and 8 
and record the following: 
• AEs 
• AESI 
• Concomitant medications
In addition, site personnel will review study medication dosing procedure and the diary entries 
with the parent/caregiver. 
6.2.3
Clinic Visit 6 (Titration Period Study Day 15) 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 55 of 175
Subjects will report to the clinic in the morning on Titration Period Study Day 15. 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 
• Abbreviated physical examination, including height and weight, and calculation of BMI 
• Abbreviated neurological examination 
• Obtain vital signs 
• 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 pharmacokinetic evaluation prior to the morning dose 
of study medication(s) 
• Collect and review diary with parent/caregiver 
• Dispense diary 
• C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
• Clinical Global Impression – Improvement (assessed by parent/caregiver) 
• Clinical Global Impression – Improvement (assessed by investigator) 
• Record AEs 
• Record AESI 
• Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
• Dispense study medication 
6.2.4
Phone Visit 7 (Maintenance Period Study Day 29) 
Site personnel will contact the subject via telephone on Maintenance Period Study Day 29 and 
record the following: 
• AEs 
• AESI 
• Concomitant medications 
In addition, site personnel with review the diary entries with the parent/caregiver. 
6.2.5
Clinic Visit 8 (Maintenance Period Study Day 43) 
Subjects will report to the clinic in the morning on Maintenance Period Study Day 43. Subjects 
should not take their morning dose(s) of study medication and 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 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 56 of 175
• Abbreviated physical examination, including height and weight, and calculation of BMI 
(Note: if the subject’s weight is ±25% of the weight at Study Day-1, the IMP dose 
will be recalculated) 
• Obtain vital signs 
• 12-lead electrocardiogram 
• Doppler ECHO (this must be obtained any time between Study Day 40 and Study 
Day 54) 
• 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 ZX008 pharmacokinetic evaluation at the following timepoints: 
within 1 hour prior to the morning dose of study medication, and 1, 2 and 4-6 hours after 
the morning dose of study medication 
• Collect plasma sample for AED pharmacokinetic evaluation prior to the morning dose of 
study medication(s) 
• Collect and review diary with parent/caregiver 
• Dispense diary 
• C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
• BRIEF (Appendix 3) 
• QOLCE (Appendix 4) 
• PedsQL (Appendix 6) 
• Affective symptoms of parent/caregiver using the HADS scale (Appendix 8) 
• Clinical Global Impression – Improvement (assessed by parent/caregiver) 
• Clinical Global Impression – Improvement (assessed by investigator) 
• Record AEs 
• Record AESI 
• Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
• Dispense study medication 
6.2.6
Phone Visit 9 (Maintenance Period Study Day 57) 
Site personnel will contact the subject via telephone on Maintenance Period Study Day 57 and 
record the following: 
• AEs 
• AESI 
• Concomitant medications 
In addition, site personnel with review the diary entries with the parent/caregiver. 
6.2.7
Clinic Visit 10 (Maintenance Period Study Day 71) 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 57 of 175
Subjects will report to the clinic on Maintenance Period Study Day 71. 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 
• Obtain vital signs 
• Urine pregnancy test for females of child-bearing potential 
• Laboratory evaluation (serum chemistry and hematology, and urinalysis) 
• Urine THC panel 
• Whole blood CBD 
• Collect and review diary with parent/caregiver 
• Dispense diary 
• C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
• Clinical Global Impression – Improvement (assessed by parent/caregiver) 
• Clinical Global Impression – Improvement (assessed by investigator) 
• Record AEs 
• Record AESI 
• Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
• Dispense study medication 
At Clinic Visit 10, compliant subjects who have tolerated IMP should be presented with the 
ICF for the open-label extension study. Informed consent for the open-label extension study 
must be signed at Visit 12 or earlier in order to enter the open-label extension study. 
6.2.8
Phone Visit 11 (Maintenance Period Study Day 85) 
Site personnel will contact the subject via telephone on Maintenance Period Study Day 85 and 
record the following: 
• AEs 
• AESI 
• Concomitant Medications 
In addition, site personnel with review the diary entries with the parent/caregiver. 
6.2.9
Clinic Visit 12 (Maintenance Period Study Day 99): End of Study/Early 
Termination 
The End-of-Study participation for an individual subject occurs after he/she has received IMP 
for 12 weeks in the Maintenance Period. At the End-of-Study visit, the subject may enroll into 
the separate extension study if they have completed 12 weeks of treatment in the Maintenance 
Period. Other circumstances for participation in the extension study are described in Section 4.8. 
The End-of-Study visit may also occur if the subject withdraws participation from the study or 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 58 of 175
the sponsor terminates the study.  If the subject withdraws participation from the study, they may 
on a case-by-case basis, be eligible for entrance into the separate open-label extension study 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. If 
the sponsor terminates the study early, the subject may or may not be offered enrollment into the 
open-label extension, depending on the reason for termination. 
Subjects will visit the clinic for the End-of-Study visit if one the following events occur: 
1. The subject withdraws or is withdrawn from participation in the study. 
2. The sponsor terminates the study. 
3. The subject completes all study related visits and procedures. 
The following procedures will be performed: 
• 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 electrocardiogram 
• Doppler ECHO (must be performed any time between Study Day 90 and Study Day 
113; if subject terminates early from the study, the ECHO should be scheduled as soon 
as practical. If the Study Day 43 ECHO was completed 30 days prior to early 
termination, the Visit 12 ECHO will not be performed provided the parent/guardian 
agrees to bring the subject to the clinic for the cardiac follow-up visit (see Table 7). 
• 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 pharmacokinetic evaluation prior to the morning dose 
of study medication(s) 
• Tanner Staging for subjects >7 years of age (Appendix 5) 
• Collect and review diary with parent/caregiver 
• Dispense diary 
• C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
• Clinical Global Impression – Improvement (assessed by parent/caregiver) 
• Clinical Global Impression – Improvement (assessed by investigator) 
• BRIEF (Appendix 3) 
• QOLCE (Appendix 4) 
• PedsQL (Appendix 6) 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 59 of 175
• PedsQL Family Impact module (Appendix 6) 
• Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
• Affective symptoms of parent/caregiver using the HADS scale (Appendix 8) 
• Record AEs 
• Record AESIs 
• Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
• Dispense study medication for taper for subjects not enrolling in the open-label 
extension study 
Informed consent for the open-label extension study must be signed at Visit 12 (if not signed 
earlier) in order to enter the open-label extension study. 
6.3
POST-DOSE VISIT (CLINIC VISIT 13; STUDY DAY 113) 
For subjects entering the open-label extension study, the subject will visit the clinic on Study 
Day 113. The following will be recorded/performed and the subject will immediately be enrolled 
in that separate study: 
• Review current seizure activity (number/type/duration) from diary since previous visit AEs 
• AESIs 
• Concomitant medications 
• Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
If the subject does not enter the open-label extension study (or discontinues from the study 
early), the subject will visit the clinic on Study Day 113 (or 14 days after the day of 
discontinuation). The following will be recorded/performed: 
• Review current seizure activity (number/type/duration) from diary since previous visit 
• AEs 
• AESIs 
• Concomitant medications 
• Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
6.4
CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 14; STUDY DAY 197-281) 
If the subject completes the study but does not enter the open-label extension 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 7. Subjects on blinded medication who are found to have been on placebo are 
not required to participate in follow-up testing once the blind is broken at the end of the study. As 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 60 of 175
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. 
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, with reports submitted 
as AESI to the ZX008 safety database. 
Table 7: 
Schedule of Post-Treatment Cardiac Follow-up 
Parameter
Duration of Blindeda or Fenfluramine Treatment
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 drugb
ECHO
No
Yes,
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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
a If blind is broken at the end of the study and a subject revealed to have taken only placebo, no further testing is 
required.
b    Positive sign or symptom includes any development of valve thickening or regurgitation (“trace” or greater in mitral,
aortic; mild or greater in pulmonary, tricuspid), or sign or symptom indicative of potential pulmonary hypertension 
as adjudicated by the IPCAB.
6.5
ESTIMATED BLOOD VOLUME COLLECTION 
The maximum total blood volume collected during the study for clinical laboratory testing, 
genotyping, and PK will be approximately 99.7 mL, as outlined in Table 8. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 61 of 175
Table 8: 
Estimated Blood Volume Collection* 
Assessment 
Baseline Period (study day) 
Titration + Maintenance Period (study day) 
Screening 
(Day -42 to 
-41) 
Randomization 
Day -1 
Day 15 
Day 43 
Day 71 
Day 99 
Total 
Clinical 
Chemistry 
4mL 
4mL 
4mL 
4mL 
4mL 
4mL 
24mL 
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Testosterone, 
Prolactin 
 
4mL 
 
4mL 
4mL 
4mL 
16mL 
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5 mL 
 
5 mL 
Hematology 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
12mL 
IGF-1, GH 
 
2.5mL 
 
2.5mL 
2.5mL 
2.5mL 
10 mL 
Coagulation 
 
2.7mL 
 
2.7mL 
Cannabidiol 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
12mL 
ZX008 PK 
plasma 
 
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8 mL 
AED plasma 
sample 
 
1 x 2 mL 
1 x 2 mL 
1 x 2 mL 
 
1 x 2 mL 
8 mL 
Volume for 
flushing 
indwelling 
catheter 
 
4 x 0.5 mL 
 
2 mL 
Approximate 
total blood 
volume per 
subject 
13mL 
19.2mL 
10mL 
26.5mL 
14.5mL 
16.5mL 
99.7 mL 
FSH=follicle stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; LH-luteinizing hormone; 
PK=pharmacokinetics 
*In concordance with The Seattle Children’s Research Foundation Guidance (Appendix 9), blood 
collection volumes for children weighing up to 15 kg will be: 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 62 of 175
x
the maximum allowable volume of blood in one draw is 22-30 mL (2.5% of total blood 
volume) 
x
the maximum in a 30-day period is 44-60 mL. 
On Day 43/Visit 8 the pharmacokinetic blood draw will be completed as the priority and the blood 
draw for chemistry and hematology will be skipped for those subjects who weigh less than 13.5 kg, 
unless medical concerns (for example, from previous tests or reported side effects) prioritize 
chemistry and/or hematology. 
If blood collection is restricted due to volume or due to inability to draw adequate volume, collection 
should be prioritized as shown in Table 9: 
Table 9: 
Priorities for Blood Sample Collections 
Assessment
Priority
ZX008 PK sample 
Priority 1 
Clinical chemistry 
Priority 2 
Cannabidiol 
Priority 2 
AED plasma sample 
Priority 2 
LH, FSH, estradiol, testosterone, GH, prolactin 
Priority 3 
Hematology 
Priority 3 
IGF-1 
Priority 4 
Genotyping 
One time collection any time during or after screening 
Coagulation 
One time collection any time before PK day 
7.
EFFICACY, SAFETY, AND PHARMACOKINETIC 
ASSESSMENTS 
For an overview of the study variables and measurement times, see Schedule of Assessments 
(Table 1). 
Variables used to measure treatment compliance with respect to administration of the IMP are 
described in Section 5.8. 
7.1
EFFICACY ASSESSMENTS 
Baseline is defined as the seizure frequency during the 6-week Baseline Period. 
Retrospective diary data (up to 6 months) will be collected, if available, for an exploratory 
evaluation of the duration of baseline data capture on interpretation of post-treatment effect. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 63 of 175
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) 
B: 
Focal With or Without Retained Awareness 
C: 
Secondarily Generalized Tonic Clonic (evolving to bilateral convulsive seizure 
from focal seizure)   ͒
D: 
Generalized Tonic Clonic Convulsion 
E: 
Absence or Atypical Absence 
F: 
Myoclonic 
G: 
Tonic 
H: 
Atonic 
I: 
Clonic 
J: 
Tonic/Atonic (cannot differentiate)  ͒
K: 
Infantile Spasms (if under 3 years of age) 
L: 
Epileptic Spasms (if 3 years of age and older)
O: 
Other 
Efficacy 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. 
Seizures that evolve into SE will be captured by type and duration (>10 minutes) as are all 
seizures. The diagnosis of SE made by a medical professional should be entered as an SAE if a 
prolonged seizure or series of seizures persists for 30 minutes or longer, regardless of 
administration of rescue medication. SE lasting for less than 30 minutes should be entered as an 
AE, unless one of the other SAE criteria (e.g. hospitalization) are met. If this incident involves 
multiple seizures close in time, the SE definition applies if the seizures are close together such 
that consciousness is not regained between ictal events. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 64 of 175
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. 
The CGI scale measures the change in the subject’s clinical status from a specific point in time, 
ie, the Baseline Period. The CGI rating scale permits a global evaluation of the subject’s 
improvement over time. The severity of a patient’s condition is rated on a 7-point scale ranging 
from 1 (very much improved) to 7 (very much worse) as follows: 
1=very much improved 
2=much improved 
3=minimally improved 
4= no change 
5=minimally worse 
6=much worse 
7=very much worse 
The parent/caregiver will be asked to indicate the appropriate response that adequately 
describes how their child’s symptoms have improved or worsened relative to baseline before 
the beginning of the study (before any study drug was taken). 
The investigator 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 study (before any study drug was taken). A paragraph describing symptoms 
and function at baseline will be document in the source file prior to rating. 
7.1.3
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. 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). 
7.1.4
PedsQL 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. 
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 using 3 scales: the EQ-5D-5L, the HADS, and 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 65 of 175
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. This module will not be used in Norway, Sweden, and Denmark. 
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. 
7.2
SAFETY ASSESSMENTS 
7.2.1
Demographics, Medical/Neurological/Epilepsy History, and Pre-Study 
Medication 
Subject demographics (sex, age, height, weight, and BMI), all ongoing conditions and relevant 
medical history from the past 5 years (including all major hospitalizations and surgeries) as 
well as the subject’s current medical status will be recorded at the Screening visit. Significant 
medications taken during the 30 days prior to the Screening visit will be documented. 
Medication history will be updated as outlined in Table 1. 
7.2.2
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. A complete 
standard of care physical examination for each subject will be performed and will cover the 
following body systems: general appearance, skin, eyes, ears, nose, throat, heart, lungs, 
abdomen, neurological system, lymph nodes, spine, and extremities. An abbreviated physical 
examination for each subject will cover the following body systems: heart, lungs, and follow 
up of other systems as appropriate based on last exam and reported AEs. 
Any unfavorable findings not present at screening considered by the investigator as clinically 
significant, occurring at any point in the study will be documented in the eCRF as an AE. 
7.2.3
Neurological Examinations 
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ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 66 of 175
Complete and abbreviated neurological examination will be conducted by the investigator or 
designee during the study as outlined in Table 1. 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. 
Any unfavorable findings not present at screening considered by the investigator as clinically 
significant, occurring at any point in the study will be documented in the eCRF as an AE. 
7.2.4
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. 
7.2.5
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: 
• 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), carbon dioxide (CO2), 
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]), 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 67 of 175
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. 
• 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. 
At Screening any laboratory values that deviate from the reference ranges and are considered  
by the investigator as clinically relevant must be documented on the medical history form of  
the eCRF. Any deviation outside of the reference range considered by the investigator as 
clinically significant (ie, classified as an abnormal, clinically significant value) at any visit after 
screening will be documented in the eCRF as an AE (see Section 9). 
7.2.6
Plasma Sample for Concomitant Antiepileptic Drug(s) 
Plasma samples to ensure that concomitant antiepileptic drug(s) (AEDs) dosing is within an 
acceptable range will be conducted during the study as outlined in Table 1. Samples collected 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 68 of 175
at Visit 6 will be analyzed after collection as a safety measure. Samples collected at other time 
points will be analyzed at study end and do not constitute safety assessments. 
7.2.7
Electrocardiograms 
Twelve-lead ECGs will be conducted during study as outlined in Table 1 after the subject has 
been in the supine position resting for 5 minutes. Heart rate, PR duration, QRS duration, QT 
duration, QTcF (Fridericia's correction formula), and the investigator’s overall interpretation 
will be recorded. 
7.2.8
Doppler Echocardiography 
Doppler echocardiography will be conducted at a facility with experience for the subject’s age 
during study as outlined in Table 1. Doppler echocardiography uses ultrasound technology to 
examine the heart or blood vessels. An ECHO uses high frequency sound waves to create an 
image of the heart while the use of Doppler technology allows determination of the speed and 
direction of blood flow by utilizing the Doppler effect. Predetermined standard guidelines on 
the proper evaluation of certain measurements, as well as abnormality thresholds, were 
constructed by the sponsor’s IPCAB prior to study initiation. These thresholds are provided in 
Table 9 (Adverse Events of Special Interest). A manual of proper ECHO technique for sites is 
provided in a separate document. 
7.2.9
Tanner Staging 
Tanner Staging (Appendix 5) will be assessed for subjects >7 years old during the study as 
outlined in Table 1. Conceptually, pubertal maturation can be described in terms of sequence, 
timing, and tempo. Puberty consists of a series of predictable events, and the sequence of 
changes in secondary sexual characteristics has been categorized by several groups. The 
staging system used most frequently was published by Marshall and Tanner (1969, 1970) and 
the sequence of changes are commonly referred to as ‘Tanner stages’. 
7.2.10
Columbia-Suicide Severity Rating Scale 
C-SSRS (Appendix 2) will be assessed during study as outlined in Table 1. 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 Baseline/Screening and 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 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 69 of 175
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. 
7.2.11
Adverse Events 
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.  Details of the definitions and 
categorization of AEs, and procedures for the reporting of AEs, are available in Section 9. 
Severity and causality of AEs will be evaluated according to the criteria specified in Section 8.2 
and Section 8.3, respectively. The observation period for AE reporting is specified in 
Section 8.4. At the beginning of each visit at the study site, the study personnel will specifically 
inquire about any AEs that might have occurred since the last study site visit. All AEs will be 
recorded on the appropriate eCRF page. 
7.2.12
Behavior Rating Inventory of Executive Function (BRIEF) 
The BRIEF is a standardized, validated rating scale to measure executive function in children 
ages 2-18 years within the home and school environments; it will be assessed according to the 
schedule in Table 1. 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). 
7.3
PHARMACOKINETIC ASSESSMENTS 
Blood samples for PK assessments of fenfluramine and its metabolite (norfenfluramine) will be 
obtained from all subjects via an indwelling cannula or by venipuncture. 
Blood samples for PK assessment (2 mL) will be obtained at the following time points: 
• Maintenance Period Study Day 43: within 1 hour prior to the morning dose, and 1, 2, 
and 4-6 hours after the morning dose. 
A total of 4 PK samples will be drawn for each subject for a total of approximately 8 mL of 
blood. 
When blood draws for PK coincide with other assessments, the PK draws take precedence. 
The procedure for the collection and handling of PK samples is outlined in a separate study 
manual. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 70 of 175
7.4
APPROPRIATENESS OF MEASUREMENTS 
All of the variables assessed are standard tests or procedures that are commonly used in studies 
of this type. 
8.
ADVERSE EVENTS 
8.1
DEFINITIONS 
8.1.1
Adverse Events 
According to ICH guidelines, an AE is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
a causal relationship with this treatment. An AE can, therefore, be any unfavorable and 
unintended sign (including an abnormal, clinically significant laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product. The period of observation for 
adverse events extends from the time the subject gives informed consent until the end of study. 
Adverse events may include: 
• 
Exacerbation (ie, an increase in the frequency or severity) of a pre-existing condition. 
Illness present before study entry should be recorded in the medical history section of 
the eCRF and only be reported as an AE if there is an increase in the frequency or 
severity of the condition during the study. Exacerbation of seizures is considered an 
AE if there was an increase in frequency beyond the subject's typical pre-study 
fluctuations, or in the event that seizures lengthen in duration in a clinically 
meaningful way compared with baseline, or if a new seizure type emerges. 
• 
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: 
o
Planned hospitalizations due to pre-existing conditions, which have not 
worsened. 
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 eCRF as AEs. In addition, at the investigator’s 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 71 of 175
discretion, any changes or trends over time in laboratory parameters can be recorded in the 
eCRF as AEs if such changes or trends are considered to be clinically relevant, even if the 
absolute values are within the reference range. 
Laboratory findings do not need to be reported as AEs in the following cases: 
1. Laboratory parameters are already beyond the reference range, unless a further 
increase/decrease can be considered an exacerbation of a pre-existing condition. 
2. Abnormal laboratory parameters caused by mechanical or physical influences on the 
blood sample (eg, hemolysis) and flagged as such by the laboratory in the laboratory 
report. 
3. Abnormal parameters that are obviously biologically implausible (eg, values that 
are incompatible with life). 
4. An abnormal laboratory value that cannot be confirmed after a repeated analysis, 
preferably in the same laboratory (eg, the previous result could be marked as not 
valid and should not necessarily be reported as an AE). 
8.1.2
Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose: 
1.
Results in death – The event must be the cause of death for the SAE to meet this serious 
criterion. 
2.
Is life-threatening – The term “life-threatening” refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it had been more severe. 
3.
Requires in-patient hospitalization or prolongation of existing hospitalization – The 
sponsor considers “hospitalization or prolongation of existing hospitalization” for at least 
24 hours as the defining criterion for an SAE.  Hospital admissions for planned surgery or 
for normal disease management procedures (eg, chemotherapy) are not considered as 
defining criteria for SAEs. 
4.
Results in persistent or significant disability or incapacity. 
5.
Is a congenital anomaly or birth defect. 
6.
Is medically significant – A medically significant event is defined as an event that does 
not meet any of the other 5 SAE criteria, but which is judged by a physician to potentially 
jeopardize the subject or require medical or surgical intervention to prevent one of the 
above outcomes listed as an SAE criterion. Anaphylaxis that is successfully treated by 
administration of epinephrine prior to other sequelae is an example of a potentially 
medically important event. 
For the purpose of data collection in this study, a prolonged seizure or series of seizures from 
which the subject does not regain consciousness between ictal events, that is at least 30 minutes 
in duration, is termed status epilepticus (SE). A single episode of SE in a 24-hour period, 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 72 of 175
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 nonserious AEs. 
8.1.3
Adverse Events of Special Interest 
As per ICH guidance (E2F Development Safety Update Report [2011]), the sponsor has 
identified the following AESIs for the ZX008 program (Table 10). 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 73 of 175
Table 10: 
Adverse Events of Special Interest 
CV/Respiratory
1. Chest pain – any pain in sternal area that is described for example as crushing, burning, sharp, 
stabbing or dull.
2. Dyspnea/shortness of breath – any signs of difficult or labored breathing unrelated to a previous 
medical condition that has not worsened.
3. Persistent cough – longer than 4 weeks without a confirmed identified pathogen (or any other 
persistent cough that the investigator feels is suspicious).
4. Increase in blood pressure >30% from Screening blood pressure or a systolic pressure 140 mmHg 
after repeated measures during one visit. Blood pressure should be repeated at appropriate times 
within the visit.
5. Jugular venous distention- visible bulging of the external jugular veins on either side of theneck
6. New onset heart murmur
7. Pulmonary rales – an abnormal respiratory sound heard during auscultation of the lungs, which is 
also described as a crackle.
8. Tachycardia – a persistent HR >30% above the screening value and unrelated to exercise, 
exertion or anxiety.  Heart rate should be repeated at appropriate times within the visit.
9.
Signs that could indicate right ventricular failure:

Peripheral edema

Ascites

Syncope

Decompensated right ventricular failure – symptoms include shortness of breath, 
frequent coughing especially when lying flat, abdominal swelling and pain, dizziness, 
fainting, and fatigue
10.  Signs on ECHO indicative of potential valvulopathy

Valve regurgitation (aortic or mitral)

Moderate or severe valve regurgitation (tricuspid or pulmonary)

Mean Mitral valve gradient  4 mmHg

Mean Aortic valve gradient  15 mmHg

Mean Tricuspid valve gradient  4 mmHg

Peak Pulmonary valve gradient  21 mmHg
11. Signs on ECHO indicative of pulmonary hypertension
a.  Tricuspid Regurgitation Jet velocity > 2.8 msec with or without the following findings OR
b.
One of the following findings in the absence of being able to measure Tricuspid 
Regurgitation Jet velocity:
i.
Change in right ventricle/left ventricle basal diameter ratio > 1.0
ii.
 Right ventricular acceleration time < 100 msec
iii.
Dilatation of the inferior caval vein (diameter>21 mm and <50% inspiratory decrease) 
and/or right atrium
iv.  Change in the geometry of the interventricular septum in systole (flattening) with left 
ventricular eccentricity index >1.1 in systole and/or in diastole
v. 
Early diastolic pulmonary regurgitation velocity > 2.2 m/sec
vi.
Tricuspid Anular Plane Systolic Excursion below 18 mm or below Z-score – 2
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 74 of 175
Table 10: 
Adverse Events of Special Interest (continued) 
Metabolic/Endocrine
1. 
Elevated prolactin level 2x above the upper limit of normal (ULN)
2. 
Galactorrhea
3. 
Gynecomastia
4. 
Increase in fasting serum blood glucose 2x ULN
5. 
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. 
Serotonin syndrome (At least 3 of following symptoms must be present: Agitation, restlessness,
confusion, both increased HR and blood pressure, dilated pupils, muscle twitching, muscle rigidity, 
hyperhidrosis, diarrhea, headache, shivering, tremors, both nausea and vomiting)
2. 
Hallucinations
3. 
Psychosis
4. 
Euphoria
5. 
Mood disorders: depression and anxiety if they rise to a level of a disorder
6. 
Suicidal thoughts, ideation or gestures
Genitourinary
1. 
Priapism
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 Dravet syndrome: 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 nonserious or serious AEs) is to be assessed by the investigator as 
follows (Table 11). 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 75 of 175
Table 11: 
Severity Definition of Adverse Events 
Severity 
Definition 
Mild: 
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living.
Moderate: 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to 
the research participant.
Severe: 
A type of AE that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention.
CDISC SDTM Severity Intensity Scale for Adverse Event Terminology 
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. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 76 of 175
8.4
OBSERVATION PERIOD FOR ADVERSE EVENT REPORTING 
The observation period for AE and SAE reporting in an individual subject will start at the time of 
giving written informed consent for participation in the current study and finish 15 days after the 
last dose of study drug or the last visit, whichever is later. For subjects who enroll in the open-label 
extension study, ongoing AEs will be followed in that study. 
If the investigator becomes aware of an SAE that has started after the observation period has 
finished, and the event could in some way be associated with IMP (irrespective of whether or not 
it is considered by the investigator to be causally related to IMP), then this must also be reported 
to the sponsor (see Section 8.6). 
8.5
ADVERSE EVENT REPORTING 
8.5.1 
Adverse Events 
At each clinical evaluation, the investigator (or delegate) will determine whether any AEs have 
occurred. Adverse events will be recorded in the AE page of the eCRF. If known, the medical 
diagnosis of an AE should be recorded in preference to the listing of individual signs and 
symptoms. The investigator must follow up on the course of an AE until resolution or stabilization. 
If an AE is ongoing after the end of study visit, the AE will continue to be followed up until 
resolution or stabilization. 
If, during the study period, a subject presents with a pre-existing condition that was not noted at the 
time of study entry, the condition should be retrospectively recorded in the Medical History section 
of the eCRF. 
8.6
SERIOUS ADVERSE EVENTS REPORTING 
This study will comply with all applicable regulatory requirements and adhere to the full 
requirements of ICH Topic E2A (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting [1994]). 
In the event of a SAE the investigator or delegate must:  
1.
Enter all relevant information in the AE page of the eCRF 
2.
Inform the 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 iHC within 24 hours of becoming aware of the SAE.  
All SAEs that occur during the course of the study, beginning the day Informed Consent is signed, 
whether or not causally related to IMP must be reported immediately via telephone or email (within 
24 hours of the investigator becoming aware of the event) to the sponsor or the Medical Monitor.
Adverse events occurring in the period between the time the subject gave written informed consent 
and the first exposure to IMP that meet one or more of the seriousness criteria for AEs must be 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 77 of 175
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 (i.e., 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 
eCRF. 
If the minimum requirements for reporting are fulfilled, the investigator should not wait to 
receive additional information to fully document the event before notifying the sponsor. 
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. 
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 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 78 of 175
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 
condition has resolved or stabilized where no further changes are likely, for a minimum of 
6 months from the last dose of study medication, unless it is determined after unblinding that the 
subject did not receive ZX008. 
8.9.1
Follow-up of Echocardiogram Findings 
All ECHOs will be evaluated by a central reader 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, triscuspid) 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
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 79 of 175
Normal
Level 1
Level 1
Level 1
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Trace
Level 2
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Mild
Level 2
Level 2
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Moderate
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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 (e.g. valproic acid, clobazam, or 
topiramate), alone or in combination, and not maintained the level of seizure control 
achieved with study medication. 
2. If the investigator feels consideration of continued treatment is warranted considering benefit 
and potential risks, and the parent/guardian feels strongly that the child be maintained on the 
study medication when understanding the risks, the parent/guardian must sign a new consent 
which describes the additional risks and the child should provide assent if appropriate. 
a.
If both of these conditions are not met, the subject is discontinued from 
treatment. 
3. The investigator prepares a case history and rationale for continuation to be submitted to the 
IDSMC for review, including consideration of effects on seizures and comorbidities. 
4. The Co-Chairs of the IPCAB are alerted to the request and prepare, after consultation with 
BMS, an evaluation of the cardiopulmonary risks and proposed monitoring plan if 
applicable, for submission to the IDSMC. 
5. IDMSC will review the submissions from the Investigator and the IPCAB and unblind the 
subject treatment if warranted. 
6. IDSMC makes a determination of appropriate path, including the possible outcomes: 
a.
Discontinue study medication 
b. Increase frequency of ECHO and ECG monitoring 
c.
Add additional ECG and/or ECHO measures to be monitored 
d. Reduce the dose of study medication 
Level 3: 
1. The investigator will evaluate efficacy to date based on study diaries and consult with the 
parent/guardian, and determine whether the achieved benefit justifies the consideration of 
continuing study treatment by the IDSMC. MINIMAL efficacy criteria for IDSMC 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 80 of 175
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, valproic acid, clobazam, 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 child be 
maintained on the study medication when understanding the risks, the parent/guardian must 
sign a new consent which describes the additional risks and the child should provide assent 
if possible. 
a.
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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 Dravet syndrome. 
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. 
5. IDSMC will review the submission from the Investigator and the IPCAB and unblind the 
subject treatment if warranted. 
6. IDSMC makes a determination of appropriate path, including these possible outcomes: 
a.
Discontinue study medication 
b. Increase frequency of ECHO and ECG monitoring 
c.
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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 
subjects or the female partner of a male subject exposed to IMP should be followed to term so as 
to assess any potential occurrence of congenital anomalies or birth defects. Any follow-up 
information, including premature termination and the status of the mother and child after delivery, 
should be reported by the investigator to the sponsor using a pregnancy reporting/outcome form. 
9.
DATA HANDLING PROCEDURES 
9.1
RECORDING OF DATA 
The investigator (or delegate) will maintain individual records for each subject. These records 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 81 of 175
should include dates when a subject visited the study site, study-required information and data, and 
other notes as appropriate. These records constitute source data. 
An eCRF and a subject diary will be provided by the sponsor (or delegate) for each subject enrolled 
into the study. Study site staff will enter data directly into the validated electronic data capture 
(EDC) system by completing the eCRF via a secure internet connection. The investigator is 
responsible for ensuring accurate and proper completion of the eCRF and subject diary for 
recording data according to the instructions given in the eCRF and subject diary. 
All entries in the eCRF must be backed up by the relevant source data at the study site. All source 
data will be kept according to all applicable regulatory requirements (see Section 12.8). Source 
data must be completed legibly for each subject enrolled into the study and signed by the 
investigator (or delegate). 
Data entry in the eCRF and subject diary must be completed in a timely manner so that they 
always reflect the latest observations on the subjects enrolled in the study. 
The subject’s diary will be completed by the parent/caregiver at home. Data entries will be 
reviewed by the investigator for completion and consistency. 
9.2
DATA QUALITY ASSURANCE 
An initiation meeting will be held before starting the study, during which the study design, 
procedures to be followed, and measures for ensuring standardized performance will be explained 
by a delegate from the sponsor, and a common understanding of the requirements of the study will 
be reached with the investigator and other relevant personnel at the study site. 
Data generated throughout the study will be monitored and the data entered in the eCRFs will be 
checked against the subject records for completeness and accuracy. The sponsor’s study monitor 
will perform this function. 
The computer system used for study data handling will be fully FDA 21 CFR Part 11 compliant. 
All creation, modification or deletion of electronic study records will be documented through an 
automated Audit Trail. Following completion of eCRF pages and entry of the data into a database, 
the data will be checked electronically for consistency and plausibility. Data queries will be 
generated for questionable data and response clarification will be sought from the investigator. 
These data queries must be resolved in a timely manner by the investigator (or delegate). 
9.3
RECORD RETENTION 
A study document binder will be provided by the sponsor for the investigator at each site for all 
requisite study documents (constituting the “Investigator Study File”). 
Following completion of the study, the investigator will retain copies of the approved study 
protocol, ICF, relevant source documents, and all other supporting documentation related to the 
study according to applicable regulatory requirements. 
The investigator is responsible for archiving the Investigator Study File, the subject’s records, and 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 82 of 175
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. 
10.
STATISTICS 
10.1
DETERMINATION OF SAMPLE SIZE 
The results of the only randomized, placebo-controlled studies in subjects with Dravet syndrome 
can be found in the European Public Assessment Report (EPAR) for stiripentol (EMA, 2007). The 
EPAR summarizes the results from two studies: STICLO France and STICLO Italy. In the 
stiripentol groups, the SD of the percentage change in seizure frequency from baseline to month 2 
was 42% in the French trial and 26% in the Italian trial. The analogous SDs for placebo groups 
were 38% and 62%. An SD of 50% was assumed for the primary analysis in this trial comparing 
ZX008 0.8 mg/kg/day to placebo on the change from baseline in seizure frequency. Using a two-
sided test at the Į=0.05 significance level, a sample size of 35 subjects per treatment group affords 
90% power to detect a difference in mean change from baseline of 40 percentage points. Similar 
assumptions and calculations yield a requirement for an additional 35 subjects in the 0.2 mg/kg/day 
ZX008 group. Thus, the total sample size is planned to be 105 subjects (35 per arm). 
10.2
ANALYSIS POPULATIONS 
10.2.1
Safety (SAF) Population 
All safety analyses will be performed on the SAF Population defined as all randomized subjects 
who receive at least one dose of ZX008 or placebo. Subjects will be analyzed according to the 
treatment actually received. 
10.2.2
Modified Intent-to-Treat (mITT) Population 
The mITT Population is defined as all randomized subjects who receive at least one dose of 
ZX008 or placebo and for whom at least one week of diary data are available. Subjects will be 
analyzed according to the treatment group to which they were randomized. The primary 
comparison of ZDX008 0.8 mg/kg/day to placebo, as well as key secondary analyses, will be 
performed on the mITT Population. 
10.2.3
Per Protocol (PP) Population 
The PP Population is defined as all randomized subjects who receive at least one dose of ZX008 
or placebo, complete the entire 12 week Maintenance Period, and have no major protocol 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 83 of 175
deviations that would have a significant impact on clinical outcome. Subjects will be analyzed 
according to the treatment they received. The primary and key secondary efficacy analyses will be 
repeated on the PP Population if there are substantial differences in the makeup of the mITT and 
PP Populations. 
10.3
TREATMENT GROUPS 
Subjects will be randomly assigned to one of three treatment groups: ZX008 0.8 mg/kg/day, 
ZX008 0.2 mg/kg/day, or placebo. 
10.4
TREATMENT PERIODS 
Baseline Period 
The Baseline Period covers the approximately 42-day span just prior to randomization and the 
start of treatment. The baseline frequency of convulsive seizures will be calculated from data 
collected during this period. 
Titration Period 
The Titration Period covers the first 14 days of treatment while subjects are titrated to their 
randomized dose. It begins on the first day of treatment (Study Day 1) and extends through Study 
Day 15 regardless of the exact day on which a subject reaches his or her assigned dose. The 
Titration Period applies to all subjects including placebo recipients. 
Maintenance Period 
The Maintenance Period covers the 12 weeks following the end of the titration period. It begins on 
Study Day 16 and extends through Study Day 99. 
Titration +Maintenance (T+M) Period 
The T+M period combines the Titration and Maintenance periods, beginning on Study Day 1 and 
extending through Study Day 99. The T+M period is considered the treatment period. 
Follow-up Period 
The Follow-up Period begins immediately at the end of T+M period and extends to a final visit 2 
weeks later; ie, from Study Day 99 through Study Day 113. Only subjects who do not roll over 
enrollment into the open-label extension will participate in the Follow-up Period. 
10.5
STATISTICAL ANALYSES AND METHODS 
All efficacy, safety, and PK 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. 
Efficacy and PK data will be summarized by treatment (ZX008, placebo) age cohort (<6 years and 
6 years of age), as well as for the total subjects in the population. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 84 of 175
A complete description of the statistical analyses and methods will be available in a SAP, 
which will be finalized before the database is locked. 
10.5.1
Efficacy Analyses 
10.5.1.1
Primary Efficacy Analysis 
The primary efficacy endpoint is the change in the mean convulsive seizure frequency (MCSF) per 
28 days between the Baseline and T+M periods. The MCSF will be calculated from all available 
data collected during the Baseline or T+M Periods. 
The primary endpoint will be analyzed using an analysis of covariance (ANCOVA) model with 
treatment group (three levels) and age group (< 6 years, 6 years) as factors, and with baseline 
frequency as a covariate.  The primary analysis will compare the ZX008 0.8 mg/kg/day group to the 
placebo group using a two-sided test at the Į=0.05 level of significance. 
Since the ANCOVA used in the primary analysis relies on assumptions of normality, the primary 
endpoint will also be analyzed using a nonparametric method that does not require as stringent 
assumptions. A test such as the van Elteren test, which extends the Wilcoxon rank sum test to 
include stratified data, will be used to compare the ZX008 0.8 mg/kg/day group to the placebo 
group while stratifying for age group. If normality assumptions are not met, the results of the van 
Elteren test will be used to assess the primary objective. 
An additional analysis will be performed to assess the sensitivity of the primary analysis to 
changes in dose or type of concomitant AED medications that may occur during the course of the 
trial, which are protocol violations. Specifically, the primary analysis will be repeated with a factor 
added to indicate whether a subject had a change in prescribed dose or type of concomitant AED 
medication during the T+M period. Further exploratory analyses may be conducted if changes in 
concomitant AED medication appear to have a significant impact on the primary outcome. 
Additional analyses will compare the changes between the baseline MCSF and the MCSF measured 
independently during the Titration Period alone and the Maintenance Period alone. 
10.5.1.2
Key Secondary Analyses 
The first key secondary endpoint – the proportion of subjects who achieve a 40% reduction from 
baseline in convulsive seizure frequency – is derived directly from the primary endpoint. That is, 
the proportion of subjects in the ZX008 0.8 mg/kg/day group who have a change in convulsive 
frequency of at least -40 percentage points will be compared to the analogous proportion in the 
placebo group. The comparison will be made using a logistic regression model that incorporates 
the same factors and covariates as the ANCOVA used in the primary analysis. The second 
secondary endpoint – the proportion achieving a 50% reduction in convulsive seizures – will be 
analyzed similarly. The analyses will be performed using data collected over the T+M period. 
The longest interval between convulsive seizures will be calculated for each subject over the 
entire T+M period. The ZX008 0.8 mg/kg/day and placebo groups will be compared using a log-
rank test. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 85 of 175
The MCSF in the ZX008 0.2 mg/kg/day group will be compared to the placebo group using the 
same methods employed for the primary analysis. Analyses of other key secondary endpoints 
involving the ZX008 0.2 mg/kg/day group will employ similar methods as those used to compare 
ZX008 0.8 mg/kg/day to placebo. Whenever feasible, secondary analyses involving either ZX008 
0.8 mg/kg/day or ZX008 0.2 mg/kg/day will be repeated using post-treatment data collected during 
the Titration Period alone and during the Maintenance Period alone. 
10.5.1.3
Multiplicity Strategy and Testing Hierarchy 
The efficacy analyses will employ a serial gatekeeper strategy to maintain the Type 1 error rate at 
Į=0.05 across the family of analyses that support the primary and key secondary objectives. The 
strategy specifies a hierarchy of significance tests where each test acts as a gatekeeper to the tests 
below it. 
The primary and key secondary endpoints will be assessed in the following order beginning 
with comparisons of ZX008 0.8 mg/kg/day to placebo on 
• The change in MCSF from baseline. 
• The proportion of subjects who achieve a 40% reduction from baseline in convulsive 
seizure frequency. 
• The proportion of subjects who achieve a 50% reduction from baseline in convulsive 
seizure frequency. 
• The longest convulsive seizure-free interval. 
The evaluation of key secondary endpoints continues by comparing the ZX008 0.2 mg/kg/day 
group to placebo in the following order: 
• The change in MCSF from baseline. 
• The proportion of subjects who achieve a 40% reduction from baseline in convulsive 
seizure frequency. 
• The proportion of subjects who achieve a 50% reduction from baseline in convulsive 
seizure frequency. 
• The longest convulsive seizure-free interval. 
10.5.2
Safety Analyses 
Summaries of safety data will be presented by treatment – ZX008 0.8 mg/kg/day, ZX008 
0.2 mg/kg/day or placebo – separately for the Titration, Maintenance and T+M periods. The 
number and percentage of subjects in each treatment group with AEs will be displayed by body 
system and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA). 
Summaries of AEs by severity and relationship to study drug will also be presented. A separate 
summary will be provided for all 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 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 86 of 175
proportion of subjects who have lab results that change from baseline. Shift tables will be presented 
for each time point where lab results are collected. Mean change from baseline will also be 
calculated for continuous hematology and chemistry results at all time points available. 
Laboratory tests, vital signs, physical examinations, neurological examinations, ECG, Doppler 
echocardiogram, C-SSRS, Tanner Staging results, etc, will be summarized appropriately, by 
treatment. All safety summaries will be based on the SAF Population. 
10.5.3 
Pharmacokinetic Analyses 
All data will be evaluated using population PK analysis methods and the methods will be 
described in detail in a separate PK analysis plan. In brief, the plan is to use published data to 
construct a population PK model for fenfluramine in adults. Given the age range of subjects to be 
enrolled in this study, it will be possible to use the known ontogeny of drug disposition in children 
to predict fenfluramine PK in subjects with Dravet syndrome from the population PK model. The 
robustness of the empirical model will then be confirmed by applying the model to PK data 
collected from this study. In this way, the effect of body size, age, and any other relevant factors 
can be quantified to assure that an adequate understanding of fenfluramine PK is obtained. 
The full methods and results of the population PK analysis of data from this study will be provided 
in a separate report. The clinical study report will contain a brief summary of the analysis 
including: the population mean and interindividual variability estimates from the fit of the 
population PK model; summary statistics of the plasma concentrations by PK sampling time and of 
the individual, derived plasma PK parameters (Cmax, AUC0-t, Tmax, and t1/2) by treatment group. 
The clinical study report will also contain a comparison of the PK of fenfluramine in the children 
enrolled in this study to historical data from adults.
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 IDMC 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 IDMC 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 IDMC 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. 
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 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 87 of 175
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 the public database at 
ClinicalTrials.gov in accordance with the FDA Amendments Act of 2007 (Section 12.3). 
Before undergoing screening procedures for possible enrollment into the study, subjects must be 
informed, in an understandable form, about the nature, scope, and possible consequences of the 
study. This information must be given orally to subjects by a physician or medically qualified 
person (according to applicable regulatory requirements) who is well informed about the nature, 
scope, and possible consequences of the study. Written information about the study will also be 
provided in a Subject Information Sheet. The date on which this oral and written information on 
the study was provided to the subject, and by whom it was provided, must be documented in the 
ICF. 
As specified in ICH GCP Section 4.8 and the US 21CFR Section 50.25, the informed consent 
discussion must emphasize that participation in the study is voluntary and that subjects have the 
right to withdraw their consent at any time without giving a reason and without any disadvantage 
for their subsequent care. 
Subjects must be given ample time and opportunity to inquire about details of the study and to 
consider their participation in the study. If, after reading the Subject Information Sheet and the 
ICF, consent is given to participate in the study, then the ICF must be signed and personally dated 
by the subject and the person conducting the informed consent discussion (and an impartial 
witness, if required). The subject will be provided with a copy of the signed ICF. 
Verification of the signed ICF will be recorded in the subject’s eCRF. The original signed ICF will 
be filed with the subject’s records and/or in the Investigator Study File. 
The Subject Information Sheet and ICF have to be approved by the IEC/IRB before they can be 
used in the study. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 88 of 175
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 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. 
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 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 89 of 175
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 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 eCRF and/or in the Protocol Deviation Log, if applicable. 
12.
ADMINISTRATIVE ASPECTS 
12.1
CLINICAL TRIAL AGREEMENT 
This study will be conducted under a Clinical Trial Agreement between the sponsor (or delegate) 
and the respective institutions representing the study sites. Any financial support given to the study 
sites will be detailed in the Clinical Trial Agreement. The Clinical Trial Agreement, which must be 
signed before the start of any study related procedures, will clearly delineate the responsibilities 
and obligations of the investigator and the sponsor (delegate), and will form the contractual basis 
upon which the study will be conducted. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 90 of 175
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 
(ClinicalTrials.gov) before or at commencement of the study, as required by the 2007 FDA 
Amendments Act. The sponsor (delegate) may also provide study information for inclusion in 
national registries according to local regulatory requirements. 
If a potential subject contacts the sponsor regarding participation in the study, the investigator 
agrees that the sponsor (delegate) may forward the relevant study site and contact details to the 
subject. Based on the inclusion and exclusion criteria for the study, the investigator will assess the 
suitability of the subject for enrollment into the study. Results of this study will be disclosed 
according to the relevant regulatory requirements. All publications in peer-reviewed medical 
journals resulting from this study will be listed in the original study protocol registration record on 
ClinicalTrials.gov. 
12.4
STUDY FILES AND MATERIALS 
Before the start of any study related procedures, all essential documents specified by ICH GCP and 
other applicable regulations must be available in the relevant files maintained by the sponsor (or 
delegate) and the investigator. An Investigator Study File prepared by the sponsor (or delegate), 
containing all applicable documents for use at the study site, will be made available to the 
investigator before the start of the study. A list of personnel and organizations responsible for 
conduct of the study as well as the list of investigators will be included in the Investigator Study 
File. The respective files will be kept and updated by the sponsor (or delegate) and the investigator, 
as applicable. 
All study documentation and materials maintained in the Investigator Study File at the study site 
must be available for inspection by the sponsor’s study monitor (or delegate) to determine that all 
required documentation is present and correct (see Section 12.9). 
The study may be audited or inspected by qualified delegates from the sponsor or a competent 
regulatory authority (see Section 12.11). 
12.5
INITIATION OF THE STUDY 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 91 of 175
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 eCRF, 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). 
If required by local law, subjects taking part in this study will be insured against any injury 
caused by the study in accordance with the applicable regulatory and legal requirement(s). 
12.8
SUBJECT IDENTIFICATION AND CONFIDENTIALITY 
All study documents, including the study protocol and eCRFs, are the confidential property of the 
sponsor and should be treated as such. 
All subjects screened for the study will be documented in a screening log in compliance with the 
requirements of individual study sites. Subjects not enrolled into the study will be documented as 
such in the screening log together with the reason for not having been enrolled. 
The investigator will maintain a personal list of subject names and subject numbers (Subject 
Identification List) for participants in the study to enable records to be identified at a later date. 
These records should be retained in a confidential manner for the duration stipulated by applicable 
regulatory requirements. All subject names will be kept in confidence and will not be revealed to 
the sponsor. Subject names must be made unreadable on any documents made available to the 
sponsor. 
Subjects participating in the study will be identified in the eCRF by the subject number allotted to 
them during the study. 
The ICF will include a statement that all study findings, irrespective of the medium on which they 
are stored, will be handled in strictest confidence in accordance with applicable data protection laws 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 92 of 175
(eg, the European Data Protection Directive [95/46/EC] and the USA Health Insurance Portability 
and Accountability Act [HIPAA]), and will be evaluated by the sponsor and/or a competent 
regulatory authority in an anonymized form. The subjects are also to be informed that their medical 
records may be audited or inspected by qualified delegates from the sponsor or a competent 
regulatory authority. The subject’s written consent authorizing direct access to his medical records, 
and computer processing and publishing of his anonymous personal data, must be obtained prior to 
participation in the study. 
A subject’s identity will be disclosed by the investigator only in case of emergency (ie, to 
address any immediate health hazard). 
12.9
MONITORING OF THE STUDY 
The investigator at each site will allow the sponsor’s study monitor (or delegate) reasonable access 
to the eCRFs and direct access to related source documents for monitoring purposes as frequently as 
the sponsor deems necessary. These documents include records of tests performed as a requirement 
for participating in the study as well as other medical records required to confirm information 
contained in the eCRF, such as past history and secondary diagnoses. 
Before each monitoring visit, the investigator (or delegate) should record all data generated 
since the last monitoring visit in the eCRF. The investigator and other relevant personnel at 
each study site will be expected to cooperate with the sponsor’s study monitor to assist in 
providing any missing information. 
The study monitor will require access to the Investigator Study File to ensure completeness of all 
documentation required for the study. The study monitor will ensure that the investigator at each 
site has been provided with adequate means for organization and filing of study documentation 
(see Section 12.4). 
The date on which the study monitor (or delegate) visits the study site will be recorded in the Site 
Visit Log. During monitoring visits, the study site’s coordinator (if applicable) and the investigator 
should be available, the source documentation should be accessible, and a suitable environment 
should be provided for the study monitor to review study related documentation. 
The main objectives of monitoring visits conducted by the study monitor include: 
• 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 
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After each subject’s visit to the study site, the investigator (or delegate) will ensure that all data 
have been entered into the eCRF correctly and in a timely manner, after which the investigator will 
sign the eCRF. 
12.10
PROTOCOL AMENDMENTS 
A “substantial” amendment of a study protocol is any written description of change(s) to, or formal 
clarification of, a study protocol that may have a significant impact on the safety or physical or 
mental integrity of subjects, the scientific value of the study, the conduct or management of the 
study, or the quality or safety of any IMP used in the study. The IEC/IRB must approve all 
substantial protocol amendments prior to their implementation. If required by 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.
REFERENCE LIST 
Aicardi J and Gastaut H. Treatment of self-induced photosensitive epilepsy with fenfluramine (3 
cases). NEJM 1985; Nov 28;313(22):1419. 
Aicardi J, Gastaut H, and Misès J. Syncopal attacks compulsively self-induced by Valsalva's 
maneuver associated with typical absence seizures. A case report. Arch Neurol 1988 
Aug;45(8):923-5. 
Boel M and Casaer P. Add-On therapy of fenfluramine in intractable self-induced epilepsy. 
Neuropediatrics. 1996; 27: 171-173. 
Center for Disease Control. Cardiac valvulopathy associated with exposure to fenfluramine or 
dexfenfluramine: U.S. Department of Health and Human Services Interim Public Health 
Recommendations, November 1997. Morbidity and Mortality Weekly Report. 1997; 
46(45):1061-1084. 
Ceulemans B, Boel M, Leyssens K, Van Rossem C, Neels P, Jorens PG, Lagae L. Successful 
use of fenfluramine as an add-on treatment for Dravet syndrome. Epilepsia 2012; 53: 1131-
1139.  
Ceulemans, B., Schoonjans, A.-S., Marchau, F., Paelinck, B. P., & Lagae, L.. Five-year 
extended follow-up status of 10 patients with Dravet syndrome treated with fenfluramine. 
Epilepsia 2016 (*):1–6, 2016 http://doi.org/10.1111/epi.13407 
Chiron C and Dulac O. The pharmacologic treatment of Dravet syndrome. Epilepsia 2011; 
52(Suppl. 2):72–75. 
Connolly HM, Crary JL, McGoon MD, Hensrud DD et al.  Valvular heart disease associated with 
fenfluramine-phentermine. New Engl J Med 1997;337(9):581-8. Erratum in: N Engl J Med 1997 
Dec 11;337(24):1783. 
Dravet C, Bureau M, Oguni H, Fukuyama Y, Cokar O. Severe myoclonic epilepsy in infancy: 
Dravet syndrome.  Adv Neurol 2005; 95: 71-102. 
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. 
ICH Topic E2A: Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, 1994. 
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Marshall WA, Tanner JM. Variations in the pattern of pubetal changes in boys. Arch Dis Child 
1970; 45:13. 
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Archives of Disease 
in Childhood. 1969;44(235):291-303. 
Nashef L, So EL, Ryvlin P, Tomson T. Unifying the definitions of sudden unexpected death in 
epilepsy. Epilepsia 2012;53, 227–233. 
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. 
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. 
Wong J, Reddy SS, Klein AL. Anorectic drugs and valvular heart disease: a biological and 
clinical perspective.  Cleveland Clinical Journal of Medicine 1998; 65:35-41. 
ZX008 Investigator’s Brochure Version 3, January 5, 2016. 
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14.
APPENDICES 
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APPENDIX 1 – LIST OF PROHIBITED CONCOMITANT MEDICATIONS 
Generic Name 
Generic Name
alfentanil 
naratriptan 
almotriptan 
nefazodone 
alprenolol 
nortriptyline 
amitriptyline 
ondansetron 
amphetamine 
oxcarbazepine 
astemizole 
oxycodone 
atomoxetine 
paroxetine 
bufuralol 
perphenazine 
bupropion 
phenacetin 
buspirone 
phenobarbital 
cafergot 
phenytoin 
cannabidiol 
promethazine 
carbamazepine 
propafenone 
cerivastatin 
retigabine/ezogabine 
citalopram 
risperidone 
clomipramine 
ritonavir 
codeine 
rizatriptan 
cyproheptadine 
selegiline 
desipramine 
sertraline 
dextromethorphan 
stiripentol 
duloxetine 
sumatriptan 
eletriptan 
telaprevir 
encainide 
THC and derivatives 
ergotamine tartrate 
tramadol 
eslicarbazepine 
trazodone 
felbamate 
vortioxetine 
fentanyl 
zolmitriptan 
fluoxetine 
zuclopenthixol 
PUBLIC 
IC
BL
U
P
COPY 
parox
a
PY
per
PY
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This document
methorp
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loxetine 
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fluvoxamine 
 
frovatriptan 
 
imipramine 
 
levacetylmethadol (LAAM) 
linezolid 
 
meperidine 
 
methadone 
 
metoclopramide 
 
mexiletine 
 
COPY 
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g
tin
ke
a
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authorization 
titi
ati
za
ori
th
au
application and any extensions or variations 
ns
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thereof. 
f
eo
er
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APPENDIX 2 – COLUMBIA – SUICIDE SEVERTY RATING SCALE 
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APPENDIX 5 – TANNER STAGING 
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APPENDIX 7 – EQ-5D-5L QUESTIONNAIRE 
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APPENDIX 8 – HOSPITAL ANXIETY AND DEPRESSION SCALE 
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APPENDIX 9 – MAXIMUM ALLOWABLE BLOOD DRAW VOLUMES 
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APPENDIX 10 – PROTOCOL AMENDMENT 1 
Summary of Changes 
Clarifications and changes were made to the protocol and include the following: 
• Sponsor name change 
• Removed the following clinical laboratory tests at Visits 1 and 6: LH, FSH, estradiol, 
testosterone, GH, prolactin, and IGF-1 
• Clarified the maximum dose of ZX008 is 30 mg/day 
• Clarified the collection duration of prior and concomitant AEDs 
• Clarified data to be collected with the use of rescue medication 
• Added new section of collection of data for AEs requiring hospitalization 
• Replaced CHU9D with PedsQL 
• Updated statistical analysis section to be consistent with the separate statistical analysis 
plan 
• Clarified study duration for participants 
• Clarified inclusion criterion #7 regarding the requirement for a whole blood sample for a 
broad epilepsy-related gene panel 
• Added requirement that subjects who may qualify for and plan to enroll into the separate 
open-label extension study at the end of this study should be consented prior to Visit 12 
• Clarified for all questionnaires and rating scales when rater substitution is acceptable for the 
clinic staff and the parent/caregiver 
Clarifications and changes were made based on feedback received from the United States Food 
and Drug Administration, and include the following: 
• Clarified randomization inclusion criteria, post-treatment cardiac follow-up, and AESI with 
regard to valve regurgitation seen on ECHO. 
• Clarified that the central cardiac reader will provide consultation to the IDSMC when a 
subject may be removed from the study due to development of signs or symptoms 
indicative of valvulopathy, regurgitation, or pulmonary hypertension 
• Clarified expedited reporting of cardiac events other than SAEs 
• Added section on grading of and follow-up for ECHO findings 
• Added the assessment of cognition for subjects 5 years of age, so that all study 
participants are now being assessed for cognition using the BRIEF. The description of the 
BRIEF was moved from the efficacy section to the safety section. 
Clarifications and changes were made based on feedback received from the European Voluntary 
Harmonization Procedure Clinical Trials Group, and include the following: 
• Updated contraception requirements for the study 
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• Clarified when subjects must be discontinued from the study 
Clarified that the investigator may discontinue a subject from the study in the case of a medical 
emergency 
• Added statistical information regarding sensitivity analyses for concomitant AED 
medication changes during the study 
The rationale for each change/clarification also is provided below. 
List of Specific Changes 
Additions are marked in bold and deletions are marked in strikethrough. Minor editorial 
changes, such as the correction of typing or formatting errors, updating headers and footers, 
tables of contents, and list of references, etc, are not listed. 
Rationale: There has been a name change for the sponsor’s subsidiary.
Original Text 
Amendment Text
Title page, Signature of Sponsor page, Synopsis, 
Table 2, and document headers 
Brabant Pharma Limited 
Title page, Signature of Sponsor page, Synopsis, Table 
2, and document headers 
Brabant Pharma Limited Zogenix International 
Limited
Rationale: To replace the CHU9D with the PedsQL for the assessment of quality of life. 
Original Text 
Amendment Text
Synopsis, Section 2.3 
Additional secondary efficacy objectives of the study 
are: 
• 
To demonstrate that the ZX008 0.2 and 0.8 
mg/kg/day dose groups are (independently) 
superior to placebo on the following endpoints: 
o
The change from baseline in the Child Health
Utility 9D Scale (CHU9D) score. 
Synopsis (Criteria for Evaluation/Efficacy), Section 
2.7.1 
• 
CHU9D to measure changes in quality of life 
of the subject 
Table 1 was updated and is not presented here. 
Sections 6.1.3, 6.2.5, 6.2.9, and 7.1.4 
The following procedures will be performed: 
• 
CHU9D (Appendix 6) 
Appendix 6 was updated and is not presented here. 
Section 7.1.5 
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 using 
Synopsis, Section 2.3
Additional secondary efficacy objectives of the study 
are: 
• 
To demonstrate that the ZX008 0.2 and 0.8 
mg/kg/day dose groups are (independently) superior 
to placebo on the following endpoints: 
o
The change from baseline in the Child Health
Utility 9D Scale (CHU9D) PedsQL score. 
Synopsis (Criteria for Evaluation/Efficacy), Section 
2.7.1 
• 
CHU9D PedsQL to measure changes in quality 
of life of the subject 
Table 1 was updated and is not presented here. 
Sections 6.1.3, 6.2.5, 6.2.9, and 7.1.4 
The following procedures will be performed: 
• 
CHU9D Peds QL (Appendix 6) 
Appendix 6 was updated and is not presented here. 
Section 7.1.5 
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 using 2 3 scales: 
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2 scales: the EQ-5D-5L and the HADS. 
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, and 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 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. This 
module will not be used in Norway, Sweden, and 
Denmark.
Rationale: To update the statistical sections of the protocol to be consistent with the separate statistical analysis 
plan. 
Original Text 
Amendment Text 
Synopsis, Section 3.1, Section 5.5.1 
Synopsis-Methodology 
Randomization will be stratified by age group (< 6 
years, 6 to 18 years) to ensure balance across 
treatment arms, and at least 40% of subjects will be in 
each age group. 
Synopsis 
Synopsis-Statistical Methods/Efficacy 
Primary Efficacy Analysis: The primary efficacy 
endpoint is the change in the mean convulsive seizure 
frequency (MCSF) per 28 days during the T+M 
periods compared with Baseline. The MCSF will be 
calculated from all available data collected during the 
Baseline and treatment periods. The primary endpoint 
will be analyzed using an analysis of covariance 
(ANCOVA) model with treatment group (three levels) 
and age group (< 6 years, 6 to 18 years) as factors, 
and with Baseline MCSF as a covariate. The primary 
analysis will compare the ZX008 0.8 mg/kg/day 
group to the placebo group using a two-sided test at 
the alpha=0.05 level of significance. 
Since the ANCOVA used in the primary analysis 
relies on assumptions of normality, the primary 
endpoint also will be analyzed using a nonparametric 
method that does not require as stringent assumptions. 
Specifically, the van Elteren test, which extends the 
Wilcoxon rank sum test to include stratified data, will 
be used to compare the ZX008 0.8 mg/kg/day group 
to the placebo group while stratifying for age group. If 
normality assumptions are not met, the results of the 
Synopsis, Section 3.1, Section 5.5.1 
Synopsis-Methodology 
Randomization will be stratified by age group (< 6 
years, 6 to 18 years) to ensure balance across treatment 
arms, and at least 40% of subjects will be in each age 
group. 
Synopsis 
Synopsis-Statistical Methods/Efficacy 
Primary Efficacy Analysis: The primary efficacy 
endpoint is the change in the mean convulsive seizure 
frequency (MCSF) per 28 days during the T+M periods 
compared with Baseline. The MCSF will be calculated 
from all available data collected during the Baseline and 
treatment periods. The primary endpoint will be 
analyzed using an analysis of covariance (ANCOVA) 
model with treatment group (three levels) and age group 
(< 6 years, 6 to 18 years) as factors, and with Baseline 
MCSF as a covariate.  The primary analysis will 
compare the ZX008 0.8 mg/kg/day group to the placebo 
group using a two-sided test at the alpha=0.05 level of 
significance. The primary endpoint will also be 
analyzed using a nonparametric method and if 
normality assumptions are not met, the results of the 
nonparametric analysis will be used for evaluation of 
the primary endpoint. An additional analysis will be 
performed to assess the sensitivity of the primary 
analysis to changes in concomitant AED medications 
that may occur during the course of the trial. 
Specifically, the primary analysis will be repeated 
with a factor added to indicate whether a subject had 
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van Elteren test will be used to assess the primary 
objective. 
Section 10.5.1.1 
The primary efficacy endpoint is the change in the 
mean convulsive seizure frequency (MCSF) per 28 
days between the Baseline and T+M periods. The 
MCSF will be calculated from all available data 
collected during the Baseline or T+M Periods. 
The primary endpoint will be analyzed using an 
analysis of covariance (ANCOVA) model with 
treatment group (three levels) and age group (< 6 
years, 6 to 18 years) as factors, and with baseline 
frequency as a covariate. The primary analysis will 
compare the ZX008 0.8 mg/kg/day group to the 
placebo group using a two-sided test at the Į=0.05 
level of significance. 
Since the ANCOVA used in the primary analysis 
relies on assumptions of normality, the primary 
endpoint will also be analyzed using a nonparametric 
method that does not require as stringent assumptions. 
Specifically, the van Elteren test, which extends the 
Wilcoxon rank sum test to include stratified data, will 
be used to compare the ZX008 0.8 mg/kg/day group 
to the placebo group while stratifying for age group. If 
normality assumptions are not met, the results of the 
van Elteren test will be used to assess the primary 
objective. 
Additional analyses will compare the percentage 
changes between the baseline MCSF and the MCSF 
measured independently during the Titration Period 
alone and the Maintenance Period alone. 
a change in concomitant AED medication during the 
T+M period. 
Since the ANCOVA used in the primary analysis relies 
on assumptions of normality, the primary endpoint also 
will be analyzed using a nonparametric method that 
does not require as stringent assumptions. Specifically, 
the van Elteren test, which extends the Wilcoxon rank 
sum test to include stratified data, will be used to 
compare the ZX008 0.8 mg/kg/day group to the placebo 
group while stratifying for age group. If normality 
assumptions are not met, the results of the van Elteren 
test will be used to assess the primary objective. 
Section 10.5.1.1 
The primary efficacy endpoint is the change in the mean 
convulsive seizure frequency (MCSF) per 28 days 
between the Baseline and T+M periods. The MCSF will 
be calculated from all available data collected during the 
Baseline or T+M Periods. 
The primary endpoint will be analyzed using an analysis 
of covariance (ANCOVA) model with treatment group 
(three levels) and age group (< 6 years, 6 to 18 years) 
as factors, and with baseline frequency as a covariate. 
The primary analysis will compare the ZX008 
0.8 mg/kg/day group to the placebo group using a two- 
sided test at the Į=0.05 level of significance. 
Since the ANCOVA used in the primary analysis relies 
on assumptions of normality, the primary endpoint will 
also be analyzed using a nonparametric method that 
does not require as stringent assumptions. Specifically, 
A test such as the van Elteren test, which extends the 
Wilcoxon rank sum test to include stratified data, will be 
used to compare the ZX008 0.8 mg/kg/day group to the 
placebo group while stratifying for age group. If 
normality assumptions are not met, the results of the van 
Elteren test will be used to assess the primary objective. 
An additional analysis will be performed to assess 
the sensitivity of the primary analysis to changes in 
dose or type of concomitant AED medications that 
may occur during the course of the trial, which are 
protocol violations. Specifically, the primary analysis 
will be repeated with a factor added to indicate 
whether a subject had a change in prescribed dose or 
type of concomitant AED medication during the 
T+M period. Further exploratory analyses may be 
conducted if changes in concomitant AED 
medication appear to have a significant impact on 
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Section 10.5.1.2 
The longest interval between convulsive seizures will 
be calculated for each subject over the entire T+M 
period. Subjects whose longest interval extends to the 
end of treatment or end of study will be considered 
right-censored. The ZX008 0.8 mg/kg/day and 
placebo groups will be compared using a log-rank 
test. The median length of the longest seizure-free 
interval will be presented for each treatment group. 
Section 10.5.1.3 
The efficacy analyses will employ a serial gatekeeper 
strategy to maintain the Type 1 error rate at Į=0.05 
across the family of analyses that support the primary 
and key secondary objectives. The strategy specifies a 
hierarchy of significance tests where each test acts as 
a gatekeeper to the tests below it. If any test fails to 
achieve significance at the Į=0.05 level, then no test 
lower in the hierarchy can achieve statistical 
significance. 
Section 10.5.2 
Selected summaries will be repeated broken out by 
age group, ie, for ages <6 years and 6 to 18 years. 
the primary outcome.
Additional analyses will compare the percentage 
changes between the baseline MCSF and the MCSF 
measured independently during the Titration Period 
alone and the Maintenance Period alone. 
Section 10.5.1.2 
The longest interval between convulsive seizures will be 
calculated for each subject over the entire T+M period. 
Subjects whose longest interval extends to the end of 
treatment or end of study will be considered right- 
censored. The ZX008 0.8 mg/kg/day and placebo groups 
will be compared using a log-rank test. The median 
length of the longest seizure-free interval will be 
presented for each treatment group. 
Section 10.5.1.3 
The efficacy analyses will employ a serial gatekeeper 
strategy to maintain the Type 1 error rate at Į=0.05 
across the family of analyses that support the primary 
and key secondary objectives. The strategy specifies a 
hierarchy of significance tests where each test acts as a 
gatekeeper to the tests below it. If any test fails to 
achieve significance at the Į=0.05 level, then no test 
lower in the hierarchy can achieve statistical 
significance. 
Section 10.5.2 
Selected summaries will be repeated broken out by age 
group, ie, for ages <6 years and 6 to 18 years. 
Rationale: To clarify inclusion criterion #7 regarding the requirement for a whole blood sample for a broad 
epilepsy-related gene panel. 
Original Text 
Amendment Text
Synopsis, Section 4.1 
Subject agrees to provide whole blood sample for a 
Dravet syndrome genetic testing panel, if genetic 
screening results from an acceptable commercial 
laboratory or medical center are not available for 
SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, 
GABRD, GABRG2, and PCDH19. 
Synopsis, Section 4.1
Subject agrees to provide whole blood sample for a 
broad epilepsy-related gene testing panel Dravet 
syndrome genetic testing panel, if genetic screening 
results from an acceptable commercial laboratory or 
medical center are not available for SCN1A, SCN1B, 
SCN2A, SCN8A, SCN9A, GABRD, GABRG2, and 
PCDH19. 
Rationale:  To clarify the study duration for participants.
Original Text 
Amendment Text
Synopsis 
Duration of Treatment: All subjects will receive 
ZX008 or matching placebo for up to approximately 
14 weeks (Titration Period=2 weeks; Maintenance 
Period=12 weeks). After completion of the 
Synopsis
Duration of Treatment: All subjects will receive ZX008 
or matching placebo for up to approximately 14 16 
weeks (Titration Period=2 weeks; Maintenance 
Period=12 weeks; Taper/Transition=2 weeks). After 
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31 October 2016
Confidential 
Page 153 of 175
Maintenance Period, eligible subjects may enroll in 
the open-label extension study. 
completion of the Maintenance Period, eligible subjects 
may enroll in the open-label extension study, after 
completion of the transition. 
Rationale: To add the requirement that subjects who may qualify for and plan to enroll into the separate open- 
label extension study at the end of this study be consented prior to Visit 12.
Original Text 
Amendment Text 
Section 6.2.7 
None 
Section 6.2.9 
None 
Section 6.2.7 
At Clinic Visit 10, compliant subjects who have 
tolerated IMP should be presented with the ICF for 
the open-label extension study. Informed consent for 
the open-label extension study must be signed at 
Visit 12 or earlier in order to enter the open-label 
extension study. 
Section 6.2.9 
Informed consent for the open-label extension study 
must be signed at Visit 12 (if not signed earlier) in 
order to enter the open-label extension study. 
Rationale: To clarify for all questionnaires and rating scales when rater substitution is acceptable for the clinic 
staff and the parent/caregiver. 
Original Text 
Amendment Text
Section 7.1 
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. If that evaluator 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. 
Section 7.1
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. If that evaluator 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. 
Rationale: To add the assessment of cognition for subjects 5 years of age, so that all study participants are now 
being assessed for cognition using the BRIEF, and to move the description of the BRIEF from the efficacy 
section to the safety section. 
Original Text 
Amendment Text
Synopsis, Section 2.4 
The safety objective of the study is: 
o
To compare the safety and tolerability of ZX008 
0.2 and 0.8 mg/kg/day to placebo with regard to 
adverse events (AEs), laboratory parameters, 
physical examination, neurological examination,
vital signs (blood pressure, heart rate,
Synopsis, Section 2.4
The safety objective of the study is: 
o
To compare the safety and tolerability of ZX008 0.2
and 0.8 mg/kg/day to placebo with regard to adverse 
events (AEs), laboratory parameters, physical 
examination, neurological examination, vital signs 
(blood pressure, heart rate, temperature, and 
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Zogenix International Limited
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31 October 2016
Confidential 
Page 154 of 175
temperature, and respiratory rate), 
electrocardiograms (ECG), echocardiograms 
(ECHO), and body weight. Cognitive Function 
will be assessed in subjects 5 years and older 
using the cognition domain score on the QOLCE. 
Cognitive function in subjects <5 years at 
baseline will be assessed using the Brief Rating 
Inventory of Executive Function-Preschool 
version (BRIEF-P). 
Synopsis (Criteria for Evaluation/Safety) 
• 
The cognition domain of the QOLCE will 
also be used to track cognitive function 
relative to baseline in children 5 years and 
older. The BRIEF-P will be administered to 
children younger than 5 years to track 
cognitive function. 
Table 1 was updated and is not presented here. 
Section 2.7.2 
The safety endpoints of the study are: 
• 
Behavior Rating Inventory of Executive Function, 
Preschool Version (BRIEF-P) to measure 
cognition in subjects aged 2 to < 5 years at 
baseline 
Sections 6.1.3, 6.2.5, and 6.2.9, 
The following procedures will be performed: 
• 
BRIEF-P for subjects < 5 years (Appendix 3) 
Section 7.1.4 
The BRIEF-P is a standardized, validated rating scale 
to measure executive function in preschool aged 
children within the home and school environments 
that will be assessed according to the schedule in 
Table 1. The BRIEF-P measures multiple aspects of 
executive functioning; scales include Inhibit, Shift, 
Emotional Control, Working Memory, and 
Plan/Organize. 
Appendix 3 was updated and is not presented here. 
respiratory rate), electrocardiograms (ECG), 
echocardiograms (ECHO), and body weight. 
Cognitive Function will be assessed in subjects 5 
years and older using the cognition domain score on 
the QOLCE.  Cognitive function in subjects <5 
years at baseline will be assessed using age- 
appropriate versions of the Brief Rating Inventory 
of Executive Function-Preschool version (BRIEF- 
P). 
Synopsis (Criteria for Evaluation/Safety), Section 2.7.2 
• 
The cognition domain of the QOLCE will also 
be used to track cognitive function relative to 
baseline in children 5 years and older. The 
BRIEF will be administered to children 
younger than 5 years to track cognitive 
function. 
Table 1 was updated and is not presented here. 
Section 2.7.2 
The safety endpoints of the study are: 
• 
Behavior Rating Inventory of Executive Function, 
Preschool Version (BRIEF-P) to measure cognition 
in subjects aged 2 to < 5 years at baseline 
Sections 6.1.3, 6.2.5, and 6.2.9 
The following procedures will be performed: 
• 
BRIEF-P for subjects < 5 years (Appendix 3) 
Section 7.2.12 
The BRIEF-P is a standardized, validated rating scale to 
measure executive function in preschool aged children 
ages 2-18 years within the home and school 
environments; that it will be assessed according to the 
schedule in Table 1. The BRIEF-P 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). 
Appendix 3 was updated and is not presented here. 
Rationale:  To update contraception requirements for the study.
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 155 of 175
Original Text 
Amendment Text
Section 4.4 
Subjects who are sexually active must use, with their 
partner, 2 approved methods of highly effective 
contraception from the time of informed consent until 
90 days after the last dose of study medication. 
Two or more of the following methods are acceptable 
and must include at least 1 barrier method: 
• 
Surgical sterilization (ie, bilateral tubal 
ligation/salpingectomy, hysterectomy for female 
subjects or partners; vasectomy for male subjects 
or partners) 
• 
Placement of an intrauterine device or 
intrauterine system 
• 
Hormonal contraception (implantable, patch, oral, 
injectable) 
• 
Barrier methods (for male subjects, this must be a 
condom or their partner’s use of an occlusive cap 
[diaphragm or cervical/vault caps]; for female 
subjects, either their partner’s use of a condom or 
the subject’s use of an occlusive cap [diaphragm 
or cervical/vault caps] with spermicidal 
foam/gel/film/cream/suppository) 
Male subjects who have been sterilized or have 
partners of non-childbearing potential (including 
homosexual men) are required to use one barrier 
method of contraception (condom). This is to prevent 
unintended exposure of the partner to the study drug 
via seminal fluid. 
Male subjects who have pregnant partners are 
required to use one barrier method of contraception 
(condom). 
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, must comply 
with the contraceptive requirements detailed above. 
Female subjects of non-childbearing potential, ie, 
women who are post-menopausal (defined as 
spontaneous amenorrhea for at least 1 year without 
another cause or spontaneous amenorrhea for at least 
6 months confirmed by a follicle stimulating hormone 
[FSH] result of 40 IU/mL), or permanently sterilized 
Section 4.4
Subjects who are sexually active must use, with their 
partner, 2 approved methods of highly effective 
contraception from the time of informed consent until 
90 days after the last dose of study medication. 
Two or more of the following methods are acceptable 
and must include at least 1 barrier method: 
•
Surgical sterilization (ie, bilateral tubal 
ligation/salpingectomy, hysterectomy for female 
subjects or partners; vasectomy for male subjects or 
partners) 
•
Placement of an intrauterine device or intrauterine 
system 
•
Hormonal contraception (implantable, patch, oral, 
injectable) 
•
Barrier methods (for male subjects, this must be a 
condom or their partner’s use of an occlusive cap 
[diaphragm or cervical/vault caps]; for female 
subjects, either their partner’s use of a condom or 
the subject’s use of an occlusive cap [diaphragm or 
cervical/vault caps] with spermicidal 
foam/gel/film/cream/suppository) 
Male subjects who have been sterilized or have partners 
of non-childbearing potential (including homosexual 
men) are required to use one barrier method of 
contraception (condom). This is to prevent unintended 
exposure of the partner to the study drug via seminal 
fluid. 
Male subjects who have pregnant partners are required 
to use one barrier method of contraception (condom). 
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, must comply with the 
contraceptive requirements detailed above. 
Female subjects of non-childbearing potential, ie, 
women who are post-menopausal (defined as 
spontaneous amenorrhea for at least 1 year without 
another cause or spontaneous amenorrhea for at least 6 
months confirmed by a follicle stimulating hormone 
[FSH] result of 40 IU/mL), or permanently sterilized 
(eg, tubal occlusion, hysterectomy, bilateral 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 156 of 175
(eg, tubal occlusion, hysterectomy, bilateral 
salpingectomy, as determined by subject medical 
history), are not required to use any contraception 
during this study. 
salpingectomy, as determined by subject medical 
history), are not required to use any contraception 
during this study. 
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 study discharge. 
The following methods are acceptable: 
• 
Combined (estrogen and progestogen 
containing) hormonal contraception associated 
with inhibition of ovulation: 
í
oral 
í
intravaginal 
í
transdermal 
• 
Progestogen-only hormonal contraception 
associated with inhibition of ovulation: 
í
oral 
í
injectable 
í
implantable intrauterine device 
í
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 30 days following the last follow up visit. 
The following methods are acceptable: 
• 
Combined (estrogen and progestogen 
containing) hormonal contraception associated 
with inhibition of ovulation: 
í
oral 
í
intravaginal 
í
transdermal 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 157 of 175
• 
Progestogen-only hormonal contraception 
associated with inhibition of ovulation 
í
oral 
í
injectable 
í
implantable intrauterine device 
í
intrauterine hormone-releasing 
system 
• 
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. 
Rationale:  To clarify when subjects must be discontinued from the study.
Original Text 
Amendment Text
Section 4.5 
Subjects may be discontinued from the study for the 
following reasons, if deemed appropriate by the 
sponsor or investigator: (list of reasons is unchanged). 
Section 4.5
Subjects may must be discontinued from the study for 
the following reasons, if deemed appropriate by the 
sponsor or investigator:  (list of reasons is unchanged). 
Rationale: To clarify that the investigator may discontinue a subject from the study in the case of a medical 
emergency. 
Original Text 
Amendment Text
Section 5.6 
The blinding scheme instituted for this study will 
ensure that the volume of study medication taken 
cannot be associated with the dose group, thus 
unblinding the study. This is achieved by random 
assignment of different concentrations of the ZX008 
oral solution (1.25 mg/mL, 2.5 mg/mL, and/or 
5 mg/mL) by the IVR/IWR system. The IVR/IWR 
system will instruct site personnel to the volume of 
oral solution to be administered based on that 
subject’s weight. (Dose will be recalculated by the 
system once at the midpoint of the study.) During the 
Titration, Maintenance, Taper/Transition Periods, the 
subjects and study personnel (investigators, clinical 
staff, personnel involved in data collection and 
analysis, the Medical Monitor, and the sponsor) will 
be blinded to the treatment allocation and to the 
concentration of ZX008 oral solution. The Medical 
Monitor will have the ability to unblind subjects in the 
case of an emergency. 
Section 5.6 
The blinding scheme instituted for this study will ensure 
that the volume of study medication taken cannot be 
associated with the dose group, thus unblinding the 
study. This is achieved by random assignment of 
different concentrations of the ZX008 oral solution 
(1.25 mg/mL, 2.5 mg/mL, and/or 5 mg/mL) by the 
IVR/IWR system. The IVR/IWR system will instruct 
site personnel to the volume of oral solution to be 
administered based on that subject’s weight. (Dose will 
be recalculated by the system once at the midpoint of 
the study.) During the Titration, Maintenance, 
Taper/Transition Periods, the subjects and study 
personnel (investigators, clinical staff, personnel 
involved in data collection and analysis, the Medical 
Monitor, and the sponsor) will be blinded to the 
treatment allocation and to the concentration of ZX008 
oral solution. The Medical Monitor will have the ability 
to unblind subjects in the case of an emergency. If an 
investigator feels the blind should be broken, he/she 
can do so when necessary for treatment decisions. 
However, the investigator should endeavor to discuss 
with the Medical Monitor or Sponsor’s Medical 
Representative, if available. The blind should only be 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 158 of 175
broken in the event the knowledge of whether the 
subject is on active study medication versus placebo 
is needed to determine course of medical treatment 
for the event. The subject will be discontinued from 
the clinical trial upon breaking of the blind and the 
decision whether the subject can enter the separate 
open-label extension study will rest with the Sponsor 
if the subject exited Study 1502 prior to completion. 
Rationale: To remove the following clinical laboratory tests at Visits 1 and 6: LH, FSH, estradiol, testosterone, 
GH, prolactin, and IGF-1. 
Original Text 
Amendment Text
Section 1.6 
The approximate volume of blood (108.7 mL) 
planned for collection from each subject over the 
course of the entire study (Screening to End of Study, 
but not including repeat or additional tests ordered by 
the investigator) presents no undue risk to the 
subjects. 
Section 6.5 
The maximum total blood volume collected during the 
study for clinical laboratory testing, genotyping, and 
PK will be approximately 115.7 mL. 
Section 1.6
The approximate volume of blood (115.7 108.7 mL) 
planned for collection from each subject over the course 
of the entire study (Screening to End of Study, but not 
including repeat or additional tests ordered by the 
investigator) presents no undue risk to the subjects. 
Section 6.5 
The maximum total blood volume collected during the 
study for clinical laboratory testing, genotyping, and PK 
will be approximately 115.7 108.7 mL. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 159 of 175
Original Text 
Table 8.   Estimated Blood Volume Collection 
Assessment 
Baseline Period (study day) 
Titration + Maintenance Period (study day) 
Screening 
(Day -42 to -41) 
Randomization 
Day -1 
Day 15 
Day 43 
Day 71 
Day 99 
Total 
Clinical chemistry 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
45 mL 
LH, FSH, estradiol, 
testosterone, GH, 
prolactin 
Included in 
Chemistry 
Included in 
Chemistry 
Included in 
Chemistry 
Included in 
Chemistry 
Included in 
Chemistry 
Included in 
Chemistry 
Hematology 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
12 mL 
Genotyping 
5 mL 
-- 
-- 
-- 
-- 
-- 
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IGF-1 
3.5 mL 
3.5 mL 
3.5 mL 
3.5 mL 
3.5mL 
3.5 mL 
21 mL 
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-- 
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-- 
-- 
-- 
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2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
12 mL 
ZX008 PK sample 
-- 
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-- 
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8 mL 
AED plasma sample 
1 x 2 mL 
1 x 2 mL 
1 x 2 mL 
1 x 2 mL 
8 mL 
Volume for flushing 
indwelling catheter 
-- 
-- 
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-- 
-- 
2 mL 
Approximate total blood 
volume per subject
20.0 mL 
19.7 mL 
17.0 mL 
27.0 mL 
15.0 mL 
17.0 mL
115.7 mL 
 FSH=follicle stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; LH-luteinizing hormone; PK=pharmacokinetics 
 
Amendment Text 
Table 8.   Estimated Blood Volume Collection 
Assessment 
Baseline Period (study day) 
Titration + Maintenance Period (study day) 
Screening 
(Day -42 to -41) 
Randomization 
Day -1 
Day 15 
Day 43 
Day 71 
Day 99 
Total 
Clinical chemistry 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
7.5 mL 
45 mL 
LH, FSH, estradiol, 
testosterone, GH, 
prolactin 
Included in 
Chemistry -- 
Included in 
Chemistry 
Included in 
Chemistry --
Included in 
Chemistry 
Included in 
Chemistry 
Included in 
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Hematology 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
12 mL 
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5 mL 
-- 
-- 
-- 
-- 
-- 
5 mL 
IGF-1 
3.5 mL -- 
3.5 mL
3.5 mL --
3.5 mL
3.5mL 
3.5 mL
21 14 mL
Coagulation 
-- 
2.7 mL 
-- 
-- 
-- 
-- 
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2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
12 mL 
ZX008 PK sample 
-- 
-- 
4 × 2 mL 
-- 
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8 mL 
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1 x 2 mL 
1 x 2 mL 
1 x 2 mL 
1 x 2 mL 
8 mL 
Volume for flushing 
indwelling catheter 
-- 
-- 
4 × 0.5 mL 
-- 
-- 
2 mL 
Approximate total blood 
volume per subject
20.0 16.5 mL 
19.7 mL 
17.0 13.5
mL
27.0 mL 
15.0 mL 
17.0 mL
115.7 
108.7 mL
FSH=follicle stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; LH-luteinizing hormone; PK=pharmacokinetics 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 160 of 175
Rationale: To clarify the maximum dose of ZX008 is 30 mg/day.
Original Text 
Amendment Text
Section 5.5.2 
After 4 days at this dose level (Study Day 5), subjects 
randomized to the ZX008 0.8 mg/kg/day group will 
increase their dose to 0.4 mg/kg/day while doses in 
the other two groups will remain constant. On Study 
Day 9, the dose for the 0.8 mg/kg/day group will 
increase to the target dose. 
Table 3 
None 
Section 5.5.4 
On the first day of the tapering period subjects in the 
ZX008 0.8 mg/kg/day group will decrease to a dose of 
ZX008 0.4 mg/kg/day BID. 
Table 4 and Table 5 
None 
Section 5.5.2
After 4 days at this dose level (Study Day 5), subjects 
randomized to the ZX008 0.8 mg/kg/day group will 
increase their dose to 0.4 mg/kg/day (maximum 30 
mg/day) while doses in the other two groups will 
remain constant. On Study Day 9, the dose for the 0.8 
mg/kg/day group will increase to the target dose or a 
maximum of 30 mg/day. 
Table 3 
Note: maximum daily dose of ZX008 is 30 mg. 
Section 5.5.4 
On the first day of the tapering period subjects in the 
ZX008 0.8 mg/kg/day group will decrease to a dose of 
ZX008 0.4 mg/kg/day BID (maximum 30 mg/day). 
Table 4 and Table 5 
Note: maximum daily dose of ZX008 is 30 mg. 
Rationale: To clarify the collection duration of prior and concomitant AEDs.
Original Text 
Amendment Text
Section 5.7 
All medications taken by a subject during the 
Screening and Baseline Seizure Assessment Periods 
are regarded as prior therapy and must be documented 
in the eCRF. Significant medications (eg, antiepileptic 
drugs [AEDs], antibiotics) taken within 30 days prior 
to the Screening visit should also be captured. 
Section 5.7
All medications taken by a subject during the Screening 
and Baseline Seizure Assessment Periods are regarded 
as prior therapy and must be documented in the eCRF. 
Significant medications (eg, antiepileptic drugs [AEDs], 
antibiotics) taken within 30 days prior to the Screening 
visit should also be captured. All prior and 
concomitant AEDs will be collected in the CRF. 
Rationale: To clarify data to be collected with the use of rescue medication.
Original Text 
Amendment Text
Section 5.7.3 
Use of rescue medication is permitted during the 
study and should be recorded on the eCRF (day, time, 
medication[s], dose[s]) and in the diary (day, time). 
Repeated administrations within the same episode 
should be recorded separately. 
Section 5.7.3
Use of rescue medication is permitted during the study 
and should be recorded on the eCRF (day, time, 
medication[s], dose[s]) and in the diary (day, timeframe 
associated with seizure episodes). Repeated 
administrations within the same episode should be 
recorded separately. 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 161 of 175
Rationale: To add new section of collection of data for AEs requiring hospitalization.
Original Text 
Amendment Text
None 
Section 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 Dravet syndrome: 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.
Rationale: To clarify randomization inclusion criteria, post-treatment cardiac follow-up, and AESI with regard to 
valve regurgitation seen on ECHO. 
Original Text 
Amendment Text
Synopsis, Section 4.3, Section 6.4, Section 8.1.3
Synopsis and Section 4.3 
Randomization Inclusion Criteria: 
2. Subject does not have a cardiovascular or 
cardiopulmonary abnormality based on ECHO, ECG 
or physical examination, including but not limited to 
any mitral, aortic, tricuspid or pulmonary valve 
regurgitation or signs of pulmonary hypertension, and 
is approved for entry by the cardiac central reader. 
Section 6.4, Table 6, footnote b 
Positive sign or symptom includes any sign of valve 
thickening or regurgitation (mitral, aortic, pulmonary, 
tricuspid), or sign or symptom indicative of potential 
pulmonary hypertension as adjudicated by the IPCAB. 
Section 8.1.3, Table 8 
10. Signs on ECHO indicative of potential 
valvulopathy 
•  mild valve regurgitation (aortic, mitral, tricuspid, 
or pulmonary) 
• Mean Mitral valve gradient  4 mmHg 
• Mean Aortic valve gradient  15 mmHg 
• Mean Tricuspid valve gradient > 4 mmHg 
• Mean Pulmonary valve gradient > 21 mmHg 
Synopsis, Section 4.3, Section 6.4, Section 8.1.3
Synopsis and Section 4.3 
Randomization Inclusion Criteria: 
2. Subject does not have a cardiovascular or 
cardiopulmonary abnormality based on ECHO, ECG or 
physical examination, including but not limited to any 
trace mitral, or aortic, tricuspid or pulmonary valve 
regurgitation or signs of pulmonary hypertension, and is 
approved for entry by the cardiac central cardiac reader. 
Section 6.4, Table 7 footnote b 
Positive sign or symptom includes any sign 
development of valve thickening or regurgitation 
(“trace” or greater in mitral, aortic,; mild or greater 
in pulmonary, tricuspid), or sign or symptom indicative 
of potential pulmonary hypertension as adjudicated by 
the IPCAB. 
Section 8.1.3, Table 9 
10.  Signs on ECHO indicative of potential valvulopathy 
• valve regurgitation (aortic or mitral) 
•  mild valve regurgitation (aortic, mitral, tricuspid, or 
pulmonary) 
• Mean Mitral valve gradient  4 mmHg 
• Mean Aortic valve gradient  15 mmHg 
• Mean Tricuspid valve gradient >  4 mmHg 
• Mean Pulmonary valve gradient >  21 mmHg 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 162 of 175
Normal Values for Children 2-18 years 
• 
No regurgitation 
• 
Mean Mitral valve gradient  < 4 mmHg 
• 
Mean Aortic valve gradient < 15 mmHg 
• 
Mean Tricuspid valve gradient < 4mmHg 
• 
Mean Pulmonary valve gradient < 21mmHg 
Normal Values for Children 2-18 years 
•
No regurgitation 
•
Mean Mitral valve gradient  < 4 mmHg 
•
Mean Aortic valve gradient < 15 mmHg 
•
Mean Tricuspid valve gradient < 4mmHg 
•
Mean Pulmonary valve gradient < 21mmHg 
Rationale: To clarify that the central cardiac reader will provide consultation to the IDSMC when a subject may 
be removed from the study due to development of signs or symptoms indicative of valvulopathy, regurgitation, or 
pulmonary hypertension.
Original Text 
Amendment Text
Section 4.5 
Subjects may 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 and the investigator believe the benefit of 
continued participation does not outweigh the risk. 
Section 4.5
Subjects may 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. 
Rationale: To clarify expedited reporting of cardiac events other than SAEs.
Original Text 
Amendment Text
Section 8.8 
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 
Section 8.8
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 
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Rationale: To add a new section on grading of, and follow-up for, ECHO findings.
Original Text 
Amendment Text
None 
Section 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, 
triscuspid) 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 11 
describes the severity of ECHO findings with the 
level of increasing oversight if the subject is to 
remain in the study. 
Table 11. Clinical Measures Enacted Upon 
Increasing Severity of ECHO Findings 
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 
(e.g. valproic acid, clobazam, or 
topiramate), alone or in combination, 
and not maintained the level of 
seizure control achieved with study 
medication. 
2.
If the investigator feels consideration of 
Severity 
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Mitral
Pulmonary 
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Level 1
Level 1 
Level 1
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Level 2
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Level 1
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Level 2
Level 2
Level 1 
Level 1
Moderate 
Level 3 
Level 3 
Level 3 
Level 3 
Severe
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Level 3
Level 3 
Level 3
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ZX008 (Fenfluramine Hydrochloride)
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31 October 2016
Confidential 
Page 164 of 175
continued treatment is warranted considering 
benefit and potential risks, and the 
parent/guardian feels strongly that the child be 
maintained on the study medication when 
understanding the risks, the parent/guardian 
must sign a new consent which describes the 
additional risks and the child should provide 
assent if appropriate. 
a. If both of these conditions are not
met, the subject is discontinued from 
treatment. 
3.
The investigator prepares a case history and 
rationale for continuation to be submitted to 
the IDSMC for review, including consideration 
of effects on seizures and comorbidities. 
4.
The Co-Chairs of the IPCAB are alerted to the 
request and prepare, after consultation with 
BMS, an evaluation of the cardiopulmonary 
risks and proposed monitoring plan, if 
applicable for submission to the IDMSC. 
5.
IDMSC will review the submission from the 
Investigator and the IPCAB and unblind the 
subject treatment if warranted. 
6.
IDSMC makes a determination of appropriate 
path, including the possible outcomes: 
a.
Discontinue study medication 
b.
Increase frequency of ECHO and 
ECG monitoring 
c.
Add additional ECG and/or ECHO 
measures to be monitored 
d.
Reduce the dose of study medication 
Level 3: 
1. The investigator will evaluate efficacy to date 
based on study diaries and consult with the 
parent/guardian, and determine whether the 
achieved benefit justifies the consideration of 
continuing study treatment by the IDSMC. 
MINIMAL efficacy criteria for IDSMC 
consideration: 
a.
Seizures must be more than 75% 
improved (number of 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 risk of cardiopulmonary 
complications, considering the 
subject’s age and overall health. 
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31 October 2016
Confidential 
Page 165 of 175
c.
Subject has had reasonable trials 
(dose and duration) of other 
available anticonvulsants (eg, 
valproic acid, clobazam, 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 
the benefit and potential risk, and the 
parent/guardian feels strongly that the child 
be maintained on the study medication when 
understanding the risks, the parent/guardian 
must sign a new consent, which describes the 
additional risk and the child should provide 
assent if possible. 
a.
If both of these conditions are not 
met, the subject is discontinued from 
treatment. 
3.
The investigator prepares a case history and 
rationale for continuation to be submitted to 
the IDSMC for review, which includes effects 
of study medication on seizures and 
comorbidities related to Dravet syndrome. 
4.
The Co-Chairs of the IPCAB are alerted to 
the request, and in consultation with BMS 
prepare an evaluation of the risk and 
proposed monitoring plan if applicable for 
submission to the IDMSC. 
5.
IDSMC will review the submission from the 
Investigator and the IPCAB and unblind the 
subject treatment if warranted. 
6.
IDSMC makes a determination of 
appropriate path, including these possible 
outcomes: 
a.
Discontinue study medication 
b.
Increase frequency of ECHO and 
ECG monitoring 
c.
Add additional ECG and/or ECHO 
measures to be monitored 
d.
Reduce the dose of study medication 
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ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 166 of 175
APPENDIX 11 – PROTOCOL AMENDMENT 2 
Summary of Changes 
Clarifications and changes were made to the protocol and include the following: 
x
Removed atonic seizures and added tonic-atonic from the types of convulsive seizures in 
Inclusion Criterion #5. 
x
Removal of Inclusion Criterion #7 to clarify that participation in the epilepsy-related genetic 
testing is not required for participation. 
x
Updated the preclinical data information and, based on this information, revised the list of 
prohibited concomitant medications. 
x
Clarified that the number of convulsive seizures during the 6-week baseline period is  6. 
x
Added PedsQL Family Impact module to the efficacy measures. 
x
Clarify study days of Screening during the Baseline Period and the timing of assessments in 
that period. 
x
Collection of blood sample for epilepsy genotype panel is mandatory but not required at 
screening. 
x
Added the list of countries in which Diacomit® (stiripentol) is approved. 
x
Added supporting references to existing citations of data. 
x
Clarified the safety objective. 
x
Specify that the number of study centers is approximate. 
x
Clarified the duration of use of contraception after the last dose of study drug. 
x
Removal of social media policy from the reason or removing a subject from therapy or 
assessment. 
  
The rationale for each change/clarification also is provided below. 
List of Specific Changes 
Additions are marked in bold and deletions are marked in strikethrough. Minor editorial 
changes, such as the correction of typing or formatting errors, updating headers and footers, 
tables of contents, and list of references, etc, are not listed. 
Rationale:  To clarify the types of seizures that satisfy the requirement for the 12 weeks before screening.
Original Text
Amendment Text
Inclusion Criterion, Synopsis and Section 4.1
Subject must have had 4 convulsive seizures (tonic-
clonic, tonic, atonic, clonic) per 4-week period for past 
12 weeks prior to screening, by parent/guardian report 
to investigator or investigator medical notes. 
Inclusion Criterion, Synopsis and Section 4.1
Subject must have had 4 convulsive seizures 
(tonic-clonic, tonic, tonic-atonic, atonic, clonic) per 
4-week period for past 12 weeks prior to screening, 
by parent/guardian report to investigator or 
investigator medical notes. 
Rationale:  Remove the requirement for participation in epilepsy-related gene testing from the inclusion 
criteria.
Original Text
Amendment Text
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ZX008 (Fenfluramine Hydrochloride)
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31 October 2016
Confidential 
Page 167 of 175
Inclusion Criterion 7, Synopsis and Section 4.1
Subject agrees to provide whole blood sample for a 
broad epilepsy-related gene testing panel.
Inclusion Criterion 7, Synopsis and Section 4.1
Subject agrees to provide whole blood sample for a 
broad epilepsy-related gene testing panel.
Rationale:  Revised the list of prohibited concomitant medications.
Original Text
Amendment Text
Exclusion Criterion 8, Synopsis and Section 4.2
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 (see Appendix 1). (Note: Short- 
term medication requirements will be handled on a per 
case basis by the Medical Monitor.)
Exclusion Criterion 8, Synopsis and Section 4.2
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; or
cyproheptadine, and/or cytochrome P450 (CYP) 
2D6/3A4/2B6 inhibitors/substrates (see Appendix 
1). (Note: Short- term medication requirements 
will be handled on a per case basis by the Medical 
Monitor.)
Rationale:  Clarified that the number of convulsive seizures during the 6-week baseline period is  6.
Original Text
Amendment Text
Randomization Inclusion Criterion 3, Synopsis and 
Section 4.3
Subject demonstrates a stable baseline with 
>6 convulsive seizures during the 6-week Baseline 
Period, with a minimum of 2 in the first 3 weeks and 2 
in the second 3 weeks. 
Section 6.1.3 
This period is intended to ensure that subjects meet the 
study entry criteria and confirm they have experienced >6 
convulsive seizures during the 6-week Baseline Period, 
with at least 2 seizures in each 3-week half of the Baseline 
Period. 
Randomization Inclusion Criterion 3, Synopsis and 
Section 4.3
Subject demonstrates a stable baseline with > 
ш6 convulsive seizures during the 6-week Baseline 
Period, with a minimum of 2 in the first 3 weeks 
and 2 in the second 3 weeks. 
Section 6.1.3 
This period is intended to ensure that subjects meet 
the study entry criteria and confirm they have 
experienced 6 >6 convulsive seizures during the 6-
week Baseline Period, with at least 2 seizures in each 
3-week half of the Baseline Period. 
Rationale:  Added PedsQL Family Impact module to the efficacy measures.
Original Text
Amendment Text
Synopsis, Criteria for Evaluation: Efficacy
Not applicable 
Section 2.3, Additional Secondary Objectives 
Not applicable 
Section 2.7.1, Efficacy Endpoints 
Not applicable 
Section 6.1.3, 6.2.9 
Not applicable 
Synopsis, Criteria for Evaluation: Efficacy
PedsQL Family Impact module to measure 
changes in quality of life of the parent/caregiver 
Section 2.3, Additional Secondary Objectives 
The change from baseline in the PedsQL Family 
Impact module score. 
Section 2.7.1, Efficacy Endpoints 
PedsQL Family Impact module to measure changes 
in quality of life of the parent/caregiver 
Section 6.1.3, 6.2.9
PedsQL Family Impact module (Appendix 6) 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
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31 October 2016
Confidential 
Page 168 of 175
Rationale:  Clarify study days of Screening during the Baseline Period.
Original Text
Amendment Text
Table 1: Schedule of Assessments 
a: 
The Baseline Period is comprised of the initial screening for the study and 
the assessment of baseline seizure activity recorded daily in the diary. 
Table 6: Time Windows for Assessments 
Visit 1 (Clinic; Study Day -42 to -41):
Table 1: Schedule of Assessments 
a: 
The Baseline Period is comprised of the initial screening for the study 
and the assessment of baseline seizure activity recorded daily in the diary. 
The procedures to be completed at the Screening visit may be 
completed in a single day or split so that they are completed over the 2-
day period (i.e., Days -43 to -42 or Days -42 to -41). 
Table 6: Time Windows for Assessments 
Visit 1 (Clinic; Study Day -43 to -42 or -42 to -41):
Rationale:  Collection of blood sample for epilepsy genotype panel is mandatory but not required at 
screening.
Original Text 
Amendment Text 
Table 1: Schedule of Assessments 
Table 1: Schedule of Assessments 
     
     l.   Mandatory one time collection any time during or after      
screening. 
Rationale:  Added the list of countries in which Diacomit® (stiripentol) is approved.
Original Text
Amendment Text
Section 1.1.1, Existing Treatment for Dravet 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. Stiripentol has not been approved 
for use in the United States of America, but is available 
under compassionate use protocols at certain clinical sites.
Section 1.1.1, Existing Treatment for Dravet 
Syndrome 
To date, only one treatment, Diacomit® (stiripentol) is 
approved, and only in Europe, Canada, Japan, and 
Australia, as adjunctive therapy in patients with 
severe myoclonic epilepsy in infancy (SMEI, Dravet 
syndrome), and must be co-administered with 
clobazam and valproate. Stiripentol has not been 
approved for use in the United States of America, but 
is available under compassionate use protocols at 
certain clinical sites. 
Rationale:  Added a supporting reference to an existing citation of data.
Original Text
Amendment Text
Section 1.5, Existing Treatment for Dravet Syndrome 
For over 27 years, fenfluramine has been used as an 
unlicensed medicine in Belgium at 2 academic medical 
centers, currently using an approved protocol under a 
Belgium Royal Decree (government approved prospective 
observation trial) for the treatment of DS; the efficacy and 
safety of this therapeutic approach have been published in 
a peer reviewed journal and reported to be very favorable. 
There are no treatments specifically approved for the 
treatment of DS in the United States of America (USA). 
Accordingly, there remains an unmet need for an approved 
treatment for children with DS. 
Section 1.1.1, Existing Treatment for Dravet 
Syndrome 
For over 27 years, fenfluramine has been used as an 
unlicensed medicine in Belgium at 2 academic medical 
centers, currently using an approved protocol under a 
Belgium Royal Decree (government approved 
prospective observation trial) for the treatment of DS; 
the efficacy and safety of this therapeutic approach 
have been published in a peer reviewed journal 
(Ceulemans 2012; Ceulemans 2016) and reported to 
be very favorable. There are no treatments specifically 
approved for the treatment of DS in the United States 
of America (USA). Accordingly, there remains an 
unmet need for an approved treatment for children 
with DS. 
Rationale:  Revised the preclinical data section.
Original Text
Amendment Text
Section 1.3, Preclinical Data 
The pharmacokinetics of fenfluramine, norfenfluramine 
Section 1.3, Preclinical Data 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 169 of 175
and their respective isomers has been studied in mice, rats, 
dogs and humans. The pharmacokinetics 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 pharmacokinetics and metabolism of 
fenfluramine after oral administration. In humans, 
fenfluramine is metabolized to norfenfluramine. CYP2C19 
and CYP2D6 appear to be the predominant CYP enzymes 
that metabolize fenfluramine to norfenfluramine. CYP1A2, 
CYP2B6 and CYP3A4/5 also appear to be involved, but to 
a lesser degree. 
In vitro inhibition and induction studies show that both 
fenfluramine and norfenfluramine cause inhibition of 
CYP2D6, while fenfluramine causes induction of CYP3A4 
and CYP2B6. Based on the FDA’s mechanistic static 
model, ZX008 is predicted to potentially cause clinically 
significant inhibition of CYP2D6 in the range of doses that 
will be administered (ZX008 IB 2016). ZX008 is also 
predicted to cause a clinically significant induction of 
CYP3A4 in most of the doses that will be administered. 
The major metabolite norfenfluramine, however, is not 
expected to cause clinically significant inhibition or 
induction of CYP2B6, 2D6 or 3A4. 
In vitro inhibition and induction studies show that both 
fenfluramine and norfenfluramine cause inhibition of 
CYP2D6, while fenfluramine causes induction of CYP3A4 
and CYP2B6. Based on the FDA’s mechanistic static 
model, ZX008 is predicted to potentially cause clinically 
significant inhibition of CYP2D6 in the range of doses that 
will be administered (ZX008 IB 2016). ZX008 is also 
predicted to cause a clinically significant induction of 
CYP3A4 in most of the doses that will be administered. 
The major metabolite norfenfluramine, however, is not 
expected to cause clinically significant inhibition or 
induction of CYP2B6, 2D6 or 3A4. 
norfenfluramine and their respective isomers has been 
studied in mice, rats, dogs and humans. The 
pharmacokinetics 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 
pharmacokinetics and metabolism of fenfluramine 
after oral administration. In humans, fenfluramine is 
metabolized to primarily norfenfluramine. CYP2C19 
CYP1A2, CYP2B6 and CYP2D6 appear to be the 
predominant CYP enzymes that metabolize 
fenfluramine to norfenfluramine. CYP1A2, CYP2B6 
and CYP3A4/5  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. 
In vitro inhibition and induction studies show that both 
fenfluramine and norfenfluramine cause inhibition of 
CYP2D6, while fenfluramine causes induction of 
CYP3A4 and CYP2B6. Based on the FDA’s 
mechanistic static model, ZX008 is predicted to 
potentially cause clinically significant inhibition of 
CYP2D6 in the range of doses that will be 
administered (ZX008 IB 2016). ZX008 is also 
predicted to cause a clinically significant induction of 
CYP3A4 in most of the doses that will be 
administered. The major metabolite norfenfluramine, 
however, is not expected to cause clinically significant 
inhibition or induction of CYP2B6, 2D6 or 3A4. 
While in vitro studies showed that both 
fenfluramine and norfenfluramine cause weak 
inhibition of CYP2D6 and fenfluramine causes 
weak induction of CYP3A4 and CYP2B6, further 
analysis based on the FDA’s mechanistic static 
model shows that fenfluramine and its major 
metabolite norfenfluramine are unlikely to alter the 
pharmacokinetics of substrates of these CYP450 
enzymes in the range of ZX008 doses that will be 
administered in this study. 
Rationale:  Added a supporting reference to an existing citation of data.
Original Text
Amendment Text
Section 1.5, Rationale for Current Study
Based on several published reports of fenfluramine’s 
successful treatment of refractory childhood epilepsy in the 
Section 1.5, Rationale for Current Study
Based on several published reports of fenfluramine’s 
successful treatment of refractory childhood epilepsy 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 170 of 175
1980s (Aicardi and Gaustaut 1985; Aicardi 1988) and its 
successful treatment of 11 refractory pediatric epilepsy 
patients in Belgium (Boel 1996), in 2002 Drs. Ceulemans 
and Lagae were granted authorization to prescribe 
fenfluramine to their patients with refractory pediatric 
epilepsy conditions, including DS, under an approved 
protocol under a Belgium government program (Royal 
Decree). To date, these pediatric neurologists have DS 
patients (infants, children, young adults, and now also 
adults), being successfully treated with fenfluramine for 
over 27 years. The efficacy and safety of this therapeutic 
approach has been reported to be overwhelmingly 
favorable. In the most recent assessment of efficacy of 
these patients reported by the investigators in, the average 
length of treatment was over 12 years, with one patient 
being successfully treated for 26 years. 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. 
in the 1980s (Aicardi and Gaustaut 1985; Aicardi 
1988) and its successful treatment of 11 refractory 
pediatric epilepsy patients in Belgium (Boel 1996), in 
2002 Drs. Ceulemans and Lagae were granted 
authorization to prescribe fenfluramine to their patients 
with refractory pediatric epilepsy conditions, including 
DS, under an approved protocol under a Belgium 
government program (Royal Decree). To date, these 
pediatric neurologists have DS patients (infants, 
children, young adults, and now also adults), being 
successfully treated with fenfluramine for over 
27 years. The efficacy and safety of this therapeutic 
approach has been reported to be overwhelmingly 
favorable. In the most recent assessment of efficacy of 
these patients reported by the investigators in, the 
average length of treatment was over 12 years, with 
one patient being successfully treated for 26 years 
(Ceulemans 2016). 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.
Rationale:  Clarified the safety objective.
Original Text
Amendment Text
Synopsis and Section 2.4, Safety Objective
To compare the safety and tolerability of ZX008 0.2 
and 0.8 mg/kg/day to placebo with regard to AEs, 
laboratory parameters, physical examination, 
neurological examination, vital signs (blood pressure, 
heart rate [HR], temperature, and respiratory rate), 
ECGs, ECHOs, and body weight. Cognitive Function 
will be assessed in subjects 5 years and older using the 
cognition domain score on the QOLCE. Cognitive 
function will be assessed using age-appropriate 
versions of the BRIEF. 
Synopsis and Section 2.4, Safety Objective
To compare the safety and tolerability of ZX008 0.2 
and 0.8 mg/kg/day to placebo with regard to AEs, 
laboratory parameters, physical examination, 
neurological examination, vital signs (blood pressure, 
heart rate [HR], temperature, and respiratory rate), 
ECGs, ECHOs, and body weight. Cognitive 
Function will be assessed using the cognition 
domain score on the QOLCE and age-appropriate 
versions of the BRIEF. Cognitive Function will be 
assessed in subjects 5 years and older using the 
cognition domain score on the QOLCE. Cognitive 
function will be assessed using age-appropriate 
versions of the BRIEF. 
Rationale:  Clarify that the number of participating study centers is approximately 30.
Original Text
Amendment Text
Section 3.4, Number of Study Centers 
The study expects to use up to 30 research centers in 
Europe, Australia, and South Korea. Additional study 
centers within or outside of Europe, Australia, and 
South Korea may be added if enrollment cannot be 
completed in a timely manner. 
Section 3.4, Number of Study Centers 
The study expects to use up to approximately
30 research centers in Europe, Australia, and South 
Korea. Additional study centers within or outside of 
Europe, Australia, and South Korea may be added if 
enrollment cannot be completed in a timely manner. 
Rationale:  Clarified the duration of use of contraception after the last dose of study drug and added barrier 
method to the list of acceptable methods of birth control.
Original Text
Amendment Text
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 171 of 175
Section 4.4 
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 study discharge. 
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 30 days 
following the last follow up visit. 
Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation: 
Progestogen-only hormonal contraception associated 
with inhibition of ovulation 
Section 4.4 
Male subjects who are sexually active with a partner 
of childbearing potential must use, with their partner, 
a condom plus an approved method of highly 
effective contraception from the time of informed 
consent until 90 days after the last dose of study 
drug after study discharge. 
Female subjects who are sexually active and are of 
childbearing potential must use, with their partner, an 
approved method of highly effective contraception 
from the time of informed consent until 30 days 
following the last follow up visit 90 days after the 
last dose of study drug. 
Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation and a barrier method (i.e., condom for 
male partner): 
Progestogen-only hormonal contraception associated 
with inhibition of ovulation and a barrier method 
(i.e., condom for male partner): 
Rationale:  Removal of social media policy.
Original Text
Amendment Text
Section 4.5 
The subject or members of the subject’s immediate 
family (including grandparents) violate the Social 
Media policy as described in Section 4.9. 
Section 4.9 
Revelations about clinical trial participation and the 
effect(s) of unapproved study medications can influence 
the expectations of potential new study subjects and 
investigators. Throughout their participation in this trial, 
subjects, their parent/caregivers and immediate family 
members, including grandparents, can acknowledge 
participation in the study on social media; however, they 
will be required not to divulge suspected or actual IMP 
(ZX008 or placebo), dose, efficacy, or tolerability as it can 
negatively affect the sponsor’s ability to interpret study 
results and possibly to use the study for registration. 
Individuals with serious and/or repeated violations of this 
policy may be required to exit the study at the discretion of 
the sponsor in consultation with the principal investigator, 
without the possibility of entering the separate open-label 
extension study. 
Section 4.5 
The subject or members of the subject’s immediate 
family (including grandparents) violate the Social 
Media policy as described in Section 4.9. 
Section 4.9 
Revelations about clinical trial participation and the 
effect(s) of unapproved study medications can 
influence the expectations of potential new study 
subjects and investigators. Throughout their 
participation in this trial, subjects, their 
parent/caregivers and immediate family members, 
including grandparents, can acknowledge participation 
in the study on social media; however, they will be 
required not to divulge suspected or actual IMP 
(ZX008 or placebo), dose, efficacy, or tolerability as it 
can negatively affect the sponsor’s ability to interpret 
study results and possibly to use the study for 
registration. Individuals with serious and/or repeated 
violations of this policy may be required to exit the 
study at the discretion of the sponsor in consultation 
with the principal investigator, without the possibility 
of entering the separate open-label extension study. 
Rationale:  Revised the prohibited concomitant medication and foods list, including Appendix 1.
Original Text
Amendment Text
Section 5.7.4 
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 
Section 5.7.4 
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 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 172 of 175
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. 
Appendix 1: replaced, edits not shown herein. 
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. 
Appendix 1: replaced, edits not shown herein. 
Rationale:  Clarify the window for assessments (Table 6).
Original Text
Amendment Text
Section 6, Table 6 
Visit 3 (Clinic; Study Day ± 4 daysa
Section 6, Table 6 
Visit 3 (Clinic; Study Day -
± + 4 daysa
Rationale:  Clarify the timing of procedures during the baseline period and screening period.
Original Text
Amendment Text
Section 6.1 
The Baseline Period of the study encompasses the 
screening activities that will occur on Study Day -42 and 
Study Day -41 as well as the observation period where 
subjects will be assessed for baseline seizure activity based 
on recordings of daily seizure activity entered into a diary. 
With the exception of the Doppler ECHO, which may be 
completed any time during the Baseline Period up to Study 
Day -21, all screening assessments will be completed on 
Study Day -42 and Study Day -41. 
The following procedures will be performed during the 
Screening visit, which will occur between Study Day -42 
and Study Day -41 for all subjects before the start of 
seizure activity observation: 
Section 6.1 
The Baseline Period of the study encompasses the 
screening activities that will occur on Study Day -42 
and Study Day -41 as well as the observation period 
where subjects will be assessed for baseline seizure 
activity based on recordings of daily seizure activity 
entered into a diary. With the exception of the Doppler 
ECHO, which may be completed any time during the 
Baseline Period up to Study Day -21, all screening 
assessments will be completed on Study Day -42 and 
Study Day -41. 
The following procedures will be performed during the 
Screening visit, which will occur between Study 
Day -42 and Study Day -41 for all subjects before the 
start of seizure activity observation:
The Screening visit will occur on Study Day -42; 
however, the procedures may be split over 
2 consecutive days (e.g., Study Day -43 and Study 
Day -42 or Study Day -42 and Study Day -41). 
Splitting the visit procedures across 2 
nonsequential days requires the approval of the 
medical monitor. The following procedures will be 
performed for all subjects before the start of 
seizure activity observation: 
Rationale:  Added text clarifying procedures for rescreening.
Original Text
Amendment Text
Section 6.1.1 
None. 
Section 6.1.1 
In certain circumstances the sponsor may allow 
subjects who did not meet all inclusion/exclusion 
criteria at the time of the Screening Visit to have the 
screening period extended, or to be re-screened for 
eligibility. In all cases the investigator should consult 
with the Medical Monitor. Decisions whether to permit 
rescreening resides solely with the sponsor.  
The decision whether to permit extended screening or 
rescreening can be influenced by many factors 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 173 of 175
individual to that subject case. Some general principles 
apply: 
1.
If baseline seizure screening is extended or the 
subject is discontinued and then rescreened, the 
screening period for establishing the baseline 
seizure frequency will be the immediate 6 weeks 
before the randomization visit. 
2.
Subjects who are found to be on a prohibited 
medication at the screening visit may be weaned 
off of that medication provided: 
a.
Decisions to withdraw a disallowed 
concomitant medication must be made with 
the agreement of the prescribing physician 
b.
If the medication has antiepileptic properties, 
a wash out of at least 5 half-lives must be 
completed before collection of baseline 
seizure data.  
c.
If a decision has been made to wean off of a 
medication without antiepileptic properties 
and the 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. 
Rationale:  Clarify timing of dosing on Day -1 and Day 1.
Original Text
Amendment Text
Section 6.1.3 
x
Dispense study medication 
Section 6.2.1 
Subjects will begin dosing with IMP in the morning of 
Titration Period Study Day 1. 
Section 6.1.3 
Dispense study medication (If administration of the 
first dose of study medication occurs in the clinic, the 
next dose should be at least 8 hours later or the 
following morning. The dose on the following 
morning will count as Study Day 1.) 
Section 6.2.1 
Subjects will take their first dose of study medication 
on the morning of Study Day 1. Study Day 1 is 
considered the first day of dosing, even for those 
subjects that received an in-clinic dose on Study Day -
1. Subjects will begin dosing with IMP in the morning 
of Titration Period Study Day 1. 
Rationale:  Revised estimated blood volume collection in Table 8 and text describing volumes for collection.
Original Text
Amendment Text
Section 6.5 
The original Table 8 was replaced; edits to this table 
are not shown herein. 
The maximum total blood volume collected during the 
study for clinical laboratory testing, genotyping, and 
PK will be approximately 108.7 mL, as outlined in 
Table 8. 
Section 6.5 
The original Table 8 was replaced; edits not shown 
herein. A new table, Table 9, showing the priorities for 
blood collection was added.  
The maximum total blood volume collected during the 
study for clinical laboratory testing, genotyping, and 
PK will be approximately 108.7 99.7 mL, as outlined 
in Table 8. 
*In concordance with The Seattle Children’s 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 174 of 175
Research Foundation Guidance (Appendix 9), blood 
collection volumes for children weighing up to 15 kg 
will be: 
x
the maximum allowable volume of blood in 
one draw is 22-30 mL (2.5% of total blood 
volume) 
x
the maximum in a 30-day period is 44-60 
mL. 
On Day 43/Visit 8 the pharmacokinetic blood draw 
will be completed as the priority and the blood draw 
for chemistry and hematology will be skipped for 
those subjects who weigh less than 13.5 kg, unless 
medical concerns (for example, from previous tests 
or reported side effects) prioritize chemistry and/or 
hematology. 
If blood collection is restricted due to volume or due 
to inability to draw adequate volume, collection 
should be prioritized as shown in Table 9:
Rationale:  Clarification of SE as an AE or SAE.
Original Text
Amendment Text
Section 7.1.1 
Seizures that evolve into SE will be captured by type 
and duration (>10 min) 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 
Section 7.1.1 
Seizures that evolve into SE will be captured by type 
and duration (>10 minutes) as are all seizures. The 
diagnosis of SE made by a medical professional should 
be entered as an SAE if a prolonged seizure or series 
of seizures persists for 30 minutes or longer, regardless 
of administration of rescue medication. SE lasting for 
less than 30 minutes should be entered as an AE, 
unless one of the other SAE criteria (e.g. 
hospitalization) are met. If this incident involves 
multiple seizures close in time, the SE definition 
applies if the seizures are close together such that 
consciousness is not regained between ictal events. 
Rationale:  Clarify SAE reporting.
Original Text
Amendment Text
Section 8.6 
For SAEs occurring during the study, the investigator 
or delegate will enter all relevant information in the 
AE page of the eCRF. An electronic document 
containing the AE page and other applicable pages of 
the eCRF must be sent (via facsimile or email) to the 
sponsor together with a Notification of Serious 
Adverse Event at Investigator Site cover page, 
which has been signed and dated by the investigator. If 
an electronic document is not able to be generated (eg, 
internet access problem), a handwritten paper SAE 
report must be completed, which must be signed and 
dated by the investigator. 
Section 8.6 
For SAEs occurring during the study, the 
investigator or delegate will enter all relevant 
information in the AE page of the eCRF. An 
electronic document containing the AE page and 
other applicable pages of the eCRF must be sent 
(via facsimile or email) to the sponsor together 
with a Notification of Serious Adverse Event at 
Investigator Site cover page, which has been 
signed and dated by the investigator. If an 
electronic document is not able to be generated 
(eg, internet access problem), a handwritten paper 
SAE report must be completed, which must be 
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Zogenix International Limited
ZX008 (Fenfluramine Hydrochloride)
ZX008-1502 Clinical Study Protocol Amendment 2 
31 October 2016
Confidential 
Page 175 of 175
All SAEs that occur during the course of the study, 
whether or not causally related to IMP must be 
reported immediately via telephone and either 
facsimile or email (within 24 hours of the investigator 
becoming aware of the event) to the sponsor and the 
Medical Monitor. 
signed and dated by the investigator. 
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 iHC within 
24 hours of becoming aware of the SAE.  
All SAEs that occur during the course of the study, 
beginning the day Informed Consent is signed, 
whether or not causally related to IMP must be 
reported immediately via telephone or email (within 
24 hours of the investigator becoming aware of the 
event) to the sponsor or the Medical Monitor. 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 (i.e., within 24 hours of the 
investigator becoming aware of the event) to the 
sponsor and the Medical Monitor. 
Rationale:  To evaluate a correlation between study drug and SAE. 
Original Text 
Amendment Text 
Section 8.9 
None. 
Section 8.9  In the event of a SAE a blood sample 
for ZX008 and AED PK should be collected as soon 
as feasible.
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SAP_001.pdf: 
16.1.9 
Documentation of Statistical Methods 
This section contains: 
Statistical Analysis Plan (Studies ZX008-1501 & ZX008-1502) dated 19 September 2017 
Zogenix International Limited 
ZX008
ZX008 Study 1 
Final Clinical Study Report
Confidential
ZX008-1501 Study 1
Page 1 of 59
______________________________________________________________________________________________
______________________________________________________________________________________________


STATISTICAL ANALYSIS PLAN 
Zogenix International Limited 
ZX008 Study 1 
STATISTICAL ANALYSIS PLAN 
Zogenix International Limited 
A subsidiary of Zogenix, Inc. 
5858 Horton Street, Suite 455 
Emeryville, CA 94608 USA 
A Multicenter, Randomized, Double-blind, Parallel Group, 
Placebo-controlled Trial of Two Fixed Doses of ZX008 
(Fenfluramine Hydrochloride) Oral Solution as an Adjunctive 
Therapy in Children and Young Adults with Dravet Syndrome 
A Statistical Analysis Plan Prepared Prospectively to Report Results 
from Study 1: 120 Subjects Entered into Zogenix Protocols ZX008-1501 
and ZX008-1502 
Version 2.1 Final 
September 19, 2017 
Prepared by:
Michael Lock, Ph.D. and Gail Farfel, Ph.D. 
Zogenix International, Limited 
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. 
Zogenix International Limited 
ZX008
ZX008 Study 1 
Final Clinical Study Report
Confidential
ZX008-1501 Study 1
Page 2 of 59
______________________________________________________________________________________________
______________________________________________________________________________________________


Zogenix International Limited 
ZX008
ZX008 Study 1 
Final Clinical Study Report
Confidential
ZX008-1501 Study 1
Page 3 of 59
______________________________________________________________________________________________
______________________________________________________________________________________________


STATISTICAL ANALYSIS PLAN 
Zogenix International Limited 
ZX008 Study 1 
CONFIDENTIAL
  Version 2.1:  19 September 2017  
 Page 2 of 58  
 
REVISION HISTORY 
•
Statistical Analysis Plan Study 1 and 2, DRAFT 1.0 13 Sept 2016
•
Statistical Analysis Plan Study 1, version 2.0  10 August 2017
•
Statistical Analysis Plan Study 1, version 2.1  19 September 2017
Zogenix International Limited 
ZX008
ZX008 Study 1 
Final Clinical Study Report
Confidential
ZX008-1501 Study 1
Page 4 of 59
______________________________________________________________________________________________
______________________________________________________________________________________________


CONFIDENTIAL
  Version 2.0:  10 August 2017       
      Page 3 of 58
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................................... 6 
SCOPE ............................................................................................................................................................ 8 
1.
INTRODUCTION ............................................................................................................................ 9 
2.
STUDY OBJECTIVES .................................................................................................................... 9 
2.1 
Primary Objective ........................................................................................................................... 9 
2.2 
Key Secondary Objectives .............................................................................................................10 
2.3 
Additional Secondary Objectives ..................................................................................................10 
2.4 
Safety Objective .............................................................................................................................11 
2.5 
Pharmacokinetic Objective ............................................................................................................11 
2.6 
Exploratory Objective ....................................................................................................................11 
3.
STUDY DESIGN ............................................................................................................................11 
3.1 
Overall Study Design and Plan ......................................................................................................11 
3.2 
Treatment Arms .............................................................................................................................12 
3.3 
Treatment Periods ..........................................................................................................................12 
3.4 
Randomization ...............................................................................................................................15 
4.
SCHEDULE OF ASSESSMENTS .................................................................................................16 
5.
ANALYSIS POPULATIONS .........................................................................................................18 
5.1 
Enrolled Population .......................................................................................................................18 
5.2 
Randomized Population .................................................................................................................18 
5.3 
Safety (SAF) Population ................................................................................................................18 
5.4 
Modified Intent-to-treat (mITT) Population ..................................................................................18 
5.5 
Per Protocol (PP) Population .........................................................................................................18 
6.
STATISTICAL METHODOLOGY ................................................................................................18 
6.1 
Statistical and Analytical Issues .....................................................................................................18 
6.1.1 
Statistical Methods .............................................................................................................18 
6.1.2 
Multiplicity Strategy and Testing Hierarchy ......................................................................19 
6.1.3 
Subgroups ..........................................................................................................................20 
6.1.4 
Baseline Definition ............................................................................................................20 
6.1.5 
Other Definitions ...............................................................................................................20 
6.1.6 
Visit Windows and Period Start/Stop Dates ......................................................................20 
6.1.7 
Handling of Dropouts and Missing Data ...........................................................................21 
Zogenix International Limited 
ZX008
ZX008 Study 1 
Final Clinical Study Report
Confidential
ZX008-1501 Study 1
Page 5 of 59
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STATISTICAL ANALYSIS PLAN 
Zogenix International Limited 
ZX008 Study 1 
CONFIDENTIAL
  Version 2.1:  19 September 2017  
 Page 4 of 58  
6.1.8 
Conversion of time interval ...............................................................................................22 
6.1.9 
Pooling of Investigative Sites ............................................................................................23 
6.1.10 
Determination of Sample Size .......................................................................................23 
6.2 
Subject Characteristics ...................................................................................................................24 
6.2.1 
Subject Disposition ............................................................................................................24 
6.2.2 
Protocol Deviations ............................................................................................................24 
6.2.3 
Demographic and Baseline Characteristics ........................................................................25 
6.2.4 
Treatment Exposure and Compliance ................................................................................25 
6.2.5 
Prior and Concomitant Medications and Therapies ...........................................................26 
6.2.6 
Prior and Concomitant Antiepileptic Treatment ................................................................27 
6.2.7 
Medical History .................................................................................................................27 
6.3 
Efficacy Analysis ...........................................................................................................................27 
6.3.1 
Primary Efficacy Analysis .................................................................................................27 
6.3.2 
Key Secondary Analysis ....................................................................................................30 
6.3.3 
Additional Secondary Endpoint Analysis ..........................................................................32 
6.3.4 
Exploratory Analyses .........................................................................................................39 
6.4 
Safety Analysis ..............................................................................................................................40 
6.4.1 
Adverse Events ..................................................................................................................40 
6.4.2 
Adverse Events of Special Interest (AESI) ........................................................................42 
6.4.3 
Physical Examination.........................................................................................................43 
6.4.4 
Neurological Examination .................................................................................................43 
6.4.5 
Vital Signs, Weight, and BMI ............................................................................................44 
6.4.6 
Electrocardiogram ..............................................................................................................44 
6.4.7 
Doppler Echocardiography ................................................................................................44 
6.4.8 
Tanner Staging ...................................................................................................................45 
6.4.9 
Laboratory Parameters .......................................................................................................45 
6.4.10 
Columbia-Suicide Severity Rating Scale .......................................................................46 
6.4.11 
Brief Rating Inventory of Executive Function (BRIEF and BRIEF-P) .........................48 
6.5 
PK/PD Analysis .............................................................................................................................48 
6.6 
Analysis of Other Assessments ......................................................................................................48 
6.7 
Interim Analysis .............................................................................................................................48 
6.8 
Independent Data Safety Monitoring Committee ..........................................................................48 
Zogenix International Limited 
ZX008
ZX008 Study 1 
Final Clinical Study Report
Confidential
ZX008-1501 Study 1
Page 6 of 59
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____________________________________________________________________________________________________________


STATISTICAL ANALYSIS PLAN 
Zogenix International Limited 
ZX008 Study 1 
CONFIDENTIAL
  Version 2.1:  19 September 2017  
 Page 5 of 58  
6.9 
Changes to Methods Planned in the Protocol ................................................................................49 
7.
REFERENCES ................................................................................................................................50 
8.
APPENDICES .................................................................................................................................51 
Zogenix International Limited 
ZX008
ZX008 Study 1 
Final Clinical Study Report
Confidential
ZX008-1501 Study 1
Page 7 of 59
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STATISTICAL ANALYSIS PLAN 
Zogenix International Limited 
ZX008 Study 1 
CONFIDENTIAL
  Version 2.1:  19 September 2017  
 Page 6 of 58  
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-related quality of life 
ET 
Early Termination 
FDA 
U.S. Food and Drug Administration 
HADS 
Hospital Anxiety and Depression Scale 
HR 
heart rate 
IDSMC 
Independent Data Safety Monitoring Committee 
IMP 
Investigational Medicinal Product 
IPCAB 
International Pediatric Cardiology Advisory Board 
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 
minute(s) 
mITT 
modified Intent-to-Treat 
mL 
milliliter 
MMRM 
Mixed Effects Model for Repeated Measures 
Zogenix International Limited 
ZX008
ZX008 Study 1 
Final Clinical Study Report
Confidential
ZX008-1501 Study 1
Page 8 of 59
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STATISTICAL ANALYSIS PLAN 
Zogenix International Limited 
ZX008 Study 1 
CONFIDENTIAL
  Version 2.1:  19 September 2017  
 Page 7 of 58  
ABBREVATION 
DEFINITION 
msec 
millisecond 
PedsQL 
Pediatric Quality of Life Inventory 
PD 
pharmacodynamic 
PDCO 
Pediatric Committee of the European Medicines Agency 
PK 
pharmacokinetic 
PP 
Per Protocol 
QoL 
Quality of Life 
QOLCE 
Quality of Life in Childhood EpilepsyQuality of Life 
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 (14 wks, randomized treatment 
period)  
TEAE 
Treatment Emergent Adverse Event 
THC 
Tetrahydrocannabinol 
TSH 
Thyroid Stimulating Hormone 
WHO 
World Health Organization Drug Dictionary 
ZX008 
Proprietary name for Fenfluramine Hydrochloride 
Zogenix International Limited 
ZX008
ZX008 Study 1 
Final Clinical Study Report
Confidential
ZX008-1501 Study 1
Page 9 of 59
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STATISTICAL ANALYSIS PLAN 
Zogenix International Limited 
ZX008 Study 1 
CONFIDENTIAL
  Version 2.1:  19 September 2017  
 Page 8 of 58  
SCOPE 
Zogenix is conducting two identical Phase 3 studies of ZX008, Study ZX008-1501 (Study 1501) 
and Study ZX008-1502 (Study 1502). Study 1501 is being conducted in the United States and 
Canada; Study 1502 is being conducted in Europe and Australia. Approximately 120 subjects 
with Dravet syndrome, a rare form of pediatric epilepsy, are planned for randomization into each 
study in three treatment groups: 0.2 mg/kg/day ZX008, 0.8 mg/kg/day ZX008 and placebo 
(n=40/group). Due to slow enrollment into both trials, the databases for the two trials will be combined 
and the first 120 subjects to be randomized will be analyzed and reported as Study 1, covered by this 
Statistical Analysis Plan (SAP).  Additional randomized subjects (over N=120) are intended to be 
reported as Study 2, and a separate SAP will cover those analyses.  Primary and key secondary 
analyses in the Study 1 SAP remain as stated in the protocols and as described in the Study 1 
draft SAP with some changes delineated in this SAP based on FDA feedback.  
Zogenix International Limited 
ZX008
ZX008 Study 1 
Final Clinical Study Report
Confidential
ZX008-1501 Study 1
Page 10 of 59
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____________________________________________________________________________________________________________


STATISTICAL ANALYSIS PLAN 
Zogenix International Limited 
ZX008 Study 1 
CONFIDENTIAL
  Version 2.1:  19 September 2017  
 Page 9 of 58  
1. INTRODUCTION
ZX008 (low dose 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. The clinical development plan includes two identical Phase 3 studies 
for ZX008, Study 1501 and Study 1502. Study 1501 is being conducted in the US and Canada and 
Study 1502 is being conducted in Europe and Australia. Both studies are multicenter, double- 
blind, parallel-group, and placebo-controlled, designed to assess the efficacy, safety, and 
pharmacokinetics (PK) of ZX008 when used as adjunctive therapy in pediatric and young adult 
subjects with DS. Within each study subjects who qualify for entry will be randomized (1:1:1) in a 
double-blind manner to receive either a low dose of ZX008 (0.2 mg/kg/day), a high dose of ZX008 
(0.8 mg/kg/day), or placebo. The pre-specified efficacy, safety, and PK objectives and endpoints 
for both studies are identical. 
This Statistical Analysis Plan (SAP) is based on the protocols for Study ZX008-1501 version 3.0 
dated Oct 31, 2016, and Study ZX008-1502 version 2.0 dated Oct 31, 2016, which are identical in 
design, conduct, and randomization scheme. Due to slow enrollment into both trials, the databases for 
the two trials will be combined and the first 119 subjects to be randomized will be analyzed and reported 
as Study 1, covered by this Statistical Analysis Plan (SAP).  Additional randomized subjects (over 
N=120) are intended to be reported as Study 2, and a separate SAP will cover those analyses.  Primary 
and key secondary analyses in the Study 1 SAP remain as stated in the two protocols and as 
described in the draft Study 1 SAP with some changes based on FDA feedback.  
2. STUDY OBJECTIVES
2.1 PRIMARY OBJECTIVE
The primary objective of Study 1 is:
•
To demonstrate that ZX008 0.8 mg/kg/day is superior to placebo as adjunctive therapy in the
treatment of Dravet syndrome 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).
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2.2 KEY SECONDARY OBJECTIVES 
The key secondary objectives of Study 1 are: 
•
To demonstrate that ZX008 0.2 mg/kg/day is superior to placebo as adjunctive therapy in the
treatment of Dravet syndrome based on change in the frequency of convulsive seizures
between baseline and T+M.
•
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently)
superior to placebo on the following endpoints:
o
The proportion of subjects who achieve a ≥50% reduction from baseline in
convulsive seizure frequency.
o
The longest convulsive seizure-free interval.
2.3 ADDITIONAL SECONDARY OBJECTIVES 
•
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently)
superior to placebo on the following endpoints:
o
The number of convulsive seizure-free days.
o
The proportion of subjects who achieve ≥25%, or ≥75% reductions from
baseline in convulsive seizure frequency.
o
The change from baseline in non-convulsive seizure frequency.
o
The change from baseline in convulsive + non-convulsive seizure frequency
o
The incidence of rescue medication usage
o
The incidence of hospitalization to treat seizures
o
The incidence of status epilepticus.
•
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently)
superior to placebo on the following endpoints:
o
Clinical Global Impression – Improvement rating, as assessed by the
principal investigator.
o
Clinical Global Impression – Improvement rating, as assessed by the
parent/caregiver.
o
The change from baseline in the Quality of Life in Childhood Epilepsy
(QOLCE) score.
o
The change from baseline in the Pediatric Quality of Life Inventory™
(PedsQL) score.
o
The change from baseline in the PedsQL Family Impact module score.
o
The change from baseline in the QoL of the parent/caregiver using the EQ-
5D-5L scale.
o
The change from baseline in the affective symptoms of the parent/caregiver
using the Hospital Anxiety and Depression Scale (HADS).
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2.4 SAFETY OBJECTIVE 
The safety objective of the Study 1 is: 
•
To compare the safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day to placebo with
regard to AEs, laboratory parameters, physical examination, neurological examination, vital
signs (blood pressure, heart rate [HR], temperature, and respiratory rate), ECGs, ECHOs, and
bodyweight. Cognitive function will be assessed using age-appropriate versions of the Brief
Rating Inventory of Executive Function (BRIEF).
2.5 PHARMACOKINETIC OBJECTIVE 
The pharmacokinetic (PK) objective of Study 1 is: 
•
To characterize the PK of ZX008 0.2 and 0.8 mg/kg/day at steady state in subjects ages 2-6
years and >6-18 years with Dravet syndrome.
2.6 EXPLORATORY OBJECTIVE 
The exploratory objective of the Study 1 is: 
•
To compare the ZX008 0.2 and 0.8 mg/kg/day doses on primary, secondary, safety and PK
endpoints.
3. STUDY DESIGN
3.1 OVERALL STUDY DESIGN AND PLAN
Both Study 1501 and Study 1502 are multicenter, double-blind, parallel-group, placebo-controlled 
studies designed to assess the efficacy, safety, and PK of ZX008 when used as adjunctive therapy 
in pediatric and young adult subjects with Dravet syndrome. Study 1501 will be conducted at 
approximately 30 study sites in North America; Study1502 will be conducted at approximately 30 
study sites in Europe and Australia. Study 1501 and Study 1502 are being conducted in parallel; 
thus, combining subjects from the two identically designed studies enables an earlier evaluation of 
the safety and efficacy of ZX008 than analysis at the time of full enrollment of each study 
independently. This earlier analysis enables an earlier determination of the benefit-risk profile of 
ZX008, to minimize the total subject exposures should the risk-benefit profile not be positive. 
The expected study period of 22 weeks comprises a Baseline period (6weeks), a Treatment period 
(14weeks) (2 weeks titration + 12 weeks maintenance), and a Post Dosing visit 2 weeks after study 
completion or early termination.   
Upon study completion, eligible subjects will be able to receive ZX008 in an open-label extension 
study for up to 1 additional year of treatment.  There will be cardiac safety follow-up of 3 to 6 
months after study drug discontinuation for early termination or for subjects who complete the study 
but do not enroll in the open-label extension study. Subjects from France, Germany and the 
Netherlands will have a CV follow-up visit approximately 24 months after the last dose of active 
study medication. Follow safety visit results will be reported separately.  
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Upon completion of the Baseline Period, subjects who qualify for the study will be randomized 
(1:1:1) in a double-blind manner to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; 
30mg/day maximum) or placebo. The randomization will be stratified by age (<6 years, ≥6 years) to 
ensure balance across treatment arms, with the target of 25% of subjects in each age group. Subjects 
will be assigned a randomization number by the IVR/IWR system upon confirmation that subject 
qualifies for enrollment in the Titration Period. Once a randomization number is assigned to a 
subject, the site will record the subject’s initials and identification number on the corresponding 
study drug bottles. Each bottle will contain the assigned treatment (ZX008 0.2 mg/kg/day, ZX008 0.8 
mg/kg/day, or placebo). ZX008 and placebo will be identical, thus rendering the study drug and 
placebo indistinguishable. The randomization scheme and block size for Studies 1501 and 1502 are 
the same, so combination of the data from the two studies will not skew the intended randomization 
into the three treatment groups.  
Study 1 will include the first 120 randomized subjects from Study 1501 and Study 1502. Once 
enrollment in Study 1 is complete (i.e., when subjects 1 to 120 are randomized), the subjects will be 
treated and followed through their last study visit. After the last of the subjects in Study 1 has either 
discontinued or completed treatment, the database will be locked for those subjects and Study 1 be 
reported as per this SAP.  
3.2 TREATMENT ARMS 
Treatment ARM A:  ZX008 0.2 mg/kg/day 
ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 and 
provided in concentrations of 1.25 mg/mL, 2.5 mg/mL, and 5 mg/mL. 
ZX008 0.2 mg/kg/day will be divided into two daily doses up to a maximum of 30 mg/day. 
Treatment ARM B:  ZX008 0.8 mg/kg/day 
ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 and 
provided in concentrations of 1.25 mg/mL, 2.5 mg/mL, and 5 mg/mL. 
ZX008 0.8 mg/kg/day will be divided into two daily doses up to a maximum of 30 mg/day. 
Treatment ARM C:  Placebo 
Placebo is identical in aspect and composition to ZX008 and is composed of identical ingredients 
used in the ZX008 formulation, except that it does not contain the active ingredient, fenfluramine 
hydrochloride 
Placebo will be given twice daily. 
3.3 TREATMENT PERIODS 
Titration 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 
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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 Investigational Medicinal Product (IMP) will be based on the randomized dose 
and subject’s weight at Visit 3 (Day -1). At Visit 8 (Day 43), if the subject’s weight has changed 
±25% of the weight at Day-1, the IMP dose will be recalculated. Subjects will be dosed using the oral 
dosing syringe provided. 
In order to maintain the blind across all dose groups and allow step titration to the high dose, the dose 
for each subject will be titrated starting with a dose of ZX008 0.2 mg/kg/day (or placebo equivalent) 
BID. After 4 days at this dose level (Day 5), subjects randomized to the ZX008 0.8 mg/kg/day group 
will increase their dose to 0.4 mg/kg/day while doses in the other two groups will remain constant. 
On Day 9, the dose for the 0.8 mg/kg/day group will increase to the target dose. The titration is 
expected to take a total of 14 days (Table 2). A new bottle of IMP will be started by the subject at 
each level of the titration step. 
Table 2: 
Titration Algorithm 
Randomized Group 
Titration Step 1 
Study Day 1-4 
Titration Step 2 
Study Days 5-8 
Titration Step 3 
Study Days 9-14 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.8 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.4 mg/kg/day 
ZX008 0.8 mg/kg/day 
Placebo 
Placebo 
Placebo 
Placebo 
Note: maximum daily dose of ZX008 is 30 mg. 
Maintenance Period: 
After completion of the Titration Period, subjects will enter the Maintenance Period and continue to 
receive the randomized dose of ZX008 or placebo and be treated for an additional 12 weeks.  Study 
medication will continue to be administered BID in the morning and in the evening, approximately 
12 hours apart, 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. 
Taper Period: 
Subjects who complete the Maintenance Period and will not be continuing into the open-label 
extension study and subjects who discontinue from the study early will be tapered off from study 
medication. 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. 
In order to maintain the blind across all dose groups, all subjects who do not continue into the open-
extension study will participate in a dose-tapering procedure over the course of 8 days. On the first 
day of the tapering period subjects in the ZX008 0.8 mg/kg/day group will decrease to a dose of 
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ZX008 0.4 mg/kg/day BID (maximum 30mg/day).  After 4 days at this dose level (Day 5), subjects 
randomized to the ZX008 0.8 mg/kg/day group will decrease their dose to 0.2 mg/kg/day. Subjects in 
the ZX008 0.2 mg/kg/day group will decrease their dose to placebo on the first day of tapering while 
doses in the placebo group will remain constant throughout the tapering procedure.  On Day 9, all 
subjects will stop taking study medication. The taper is expected to take a total of 8 days (Table 3). A 
new bottle of IMP will be started by the subject at each level of the taper step. 
Table 3.  
Taper Algorithm 
Randomized Group 
Taper Step 1  
Day 1-4 after study completion 
or early termination 
Taper Step 2 
Days 5-8 after study completion 
or early termination 
ZX008 0.2 mg/kg/day 
Placebo 
Placebo 
ZX008 0.8 mg/kg/day 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
Placebo 
Placebo 
Placebo 
Note: maximum daily dose of ZX008 is 30 mg. 
Transition Period: 
Subjects who complete the Maintenance Period and will be continuing into the open-label extension 
study will be transitioned from double-blind study medication to open-label ZX008 (Table 4).  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. Study medication will be 
administered using the oral dosing syringe provided. 
All subjects entering the open-label extension study will be transitioned from their blinded daily dose 
(placebo, 0.2 mg/kg/day, 0.8 mg/kg/day, or 30 mg/day) to the 0.2 mg/kg dose during the 2-week 
interval between Visits 12 and 13, without breaking the blind. The IVR/IWR system will assign two 
bottles of IMP to the subject, one for each step in the transition. A new bottle of IMP will be started 
by the subject at each level of the transition step.  
Table 4.  
Transition Algorithm 
Dose Group in Double-
Blind Study 
Transition Step 1  
Day 1-4 after Visit 12 
Transition Step 2 
Days 5-14 after Visit 12 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.8 mg/kg/day 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
Placebo 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
Note: maximum daily dose of ZX008 is 30 mg. 
Subjects who had been randomized to placebo increase their dose to 0.2 mg/kg/day beginning on Day 
1 of the transition (the day following Visit 12.) Subjects who had been randomized to 0.2 mg/kg/day 
will continue to receive that dose. Subjects who had been randomized to 0.8 mg/kg/day or were 
receiving the maximum dose of 30 mg/day decrease to a dose of ZX008 0.4 mg/kg/day, or a 
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maximum of 30 mg/day.  After 4 days at this dose level (Day 5), these subjects will decrease their 
dose to 0.2 mg/kg/day. Subjects will report to the clinic on Day 15 for enrollment into the open-label 
extension study.
Data from the Taper or Transition period will not be included towards the planned efficacy endpoints 
except where specified, but will be included in the safety analyses. 
3.4 RANDOMIZATION 
Treatment assignments are assigned independently within Study 1501 and Study 1502. 
Specifically, each trial assigns treatments using randomized permuted blocks; i.e., treatments are 
assigned in blocks to ensure exact balance among treatments within each block. The blocking is 
applied across the entire trial such that newly enrolled subjects are randomized to the next 
available treatment regardless of the site or country where they enroll. This approach assures 
balance among treatment groups within each trial at any point during enrollment. Combining data 
from two trials means that two sets of randomized blocks will be used, which would have 
approximately the same effect as doubling the block size in a single trial. Increasing the block size 
is expected to have little impact on a trial of 120 subjects. Moreover, combining the first 120 
randomized subjects from Study 1501 and Study 1502 to create Study 1 preserves balance among 
the three treatment groups in each of Study 1 and Study 2, yielding approximately 40 subjects per 
arm, the number required to maintain full statistical power. 
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4. SCHEDULE OF ASSESSMENTS
Table 1: Schedule of Assessments
Baseline Perioda 
Titration + Maintenance Period 
EOS/ 
ETb 
Post-
Dosing 
Cardiac 
Follow-up 
Study Assessments 
Screening 
Random-
ization 
Titration Period 
Maintenance Period 
Visit Number 
1 
2 
(Phone
) 
3 
4, 5 
(Phone) 
6 
7  
(Phone
) 
8 
9  
(Phone
) 
10 
11 
(Phone
) 
12 
13  
14 
Study Day 
-42 to -41 
-21
-1
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
3-24 mo
post dose 
Informed Consent (subject and parent) 
X 
Inclusion/Exclusion Criteria 
X 
X 
Demographics 
X 
Medical/Neurological History 
X 
Epilepsy history 
X 
Collect retrospective seizure diary data 
X 
Prior Medication 
X 
X 
Physical Examination, complete 
X 
X 
X 
Xc 
Physical Examination, abbreviated  
X 
X 
X 
Xc 
Neurological Examination, complete 
X 
X 
Neurological Examination, abbreviated 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Weight, Height, BMI 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
Xc 
Doppler ECHO 
X 
Xd 
Xd 
Xc 
Urine pregnancy test 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Clinical laboratory evaluation (hematology/clinical 
chemistry/urinalysis, etc) 
X 
X 
X 
X 
X 
X 
Plasma sample for ZX008 pharmacokinetics 
4Xf 
Plasma sample for background AEDs 
Xg 
Xg 
Xg 
Xg 
Urine THC Panel/Whole blood CBD 
X 
X 
X 
X 
X 
X 
Tanner Staging (for subjects >7 years old) 
X 
X 
Subject Diary 
D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/Dh 
C/R 
Epilepsy genotype panel 
X 
Study Medication 
D 
Ri 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/Dh 
C/R 
C-SSRS 
X 
X 
X 
X 
X 
X 
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Table 1: Schedule of Assessment (Continued) 
Baseline Perioda 
Titration + Maintenance Period 
EOS/ 
ETb 
Post-
Dosing 
Cardiac 
Follow-
up 
Study Assessments 
Screening 
Random-
ization 
Titration Period 
Maintenance Period 
Visit Number 
1 
2 
(Phone)
3 
4, 5 
(Phone)
6 
7  
(Phone)
8 
9  
(Phone)
10 
11 
(Phone) 
12 
13  
14 
Study Day 
-42 to -41 
-21
-1 
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
3-24 mo
post dose 
Clinical Global Impression - Improvement 
(assessed by parent/caregiver) 
X 
X 
X 
X 
Clinical Global Impression - Improvement 
(assessed by principal investigator) 
X 
X 
X 
X 
BRIEF 
X 
X 
X 
QOLCE 
X 
X 
X 
PedsQL 
X 
X 
X 
EQ-5D-5L (QoL of parent/caregiver) 
X 
X 
HADS (Affect of parent/caregiver) 
X 
X 
X 
Randomize subject 
X 
First Day of Study Drug Administration 
Xj 
Daily Diary Completion  
X 
Concomitant Medication 
X 
Adverse events 
X 
Adverse events of special interest 
X 
Xk 
AED=antiepileptic drug; BMI=body mass index; BRIEF=Behavior Rating Inventory of Executive Function; C=Collect; CBD=cannabidiol; 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 
a: 
The Baseline Period is comprised of the initial screening for the study and the assessment of baseline seizure activity recorded daily in the diary. 
b: 
Subjects who are discontinued early and those who complete the study and choose not to enroll in the separate open-label extension will be tapered off study medication over an up to 2-week period. 
c: 
Follow-up ECG, ECHO, and physical examination if warranted will be performed 3-6 months after early termination, or for those subjects who complete the study but do not enter the open-label extension study  
d: 
The Visit 8 ECHO must be performed any time between Study Day 40 and Study Day 54.  The Visit 12 ECHO must be performed any time between Study Day 90 and Study Day 113; if a subject discontinues early from the study, the 
ECHO should be scheduled as soon as practical.  If the Study Day 43 ECHO was completed < 30 days prior to early termination, the Visit 12 ECHO will not be performed provided the parent/guardian agrees to bring the subject to the 
clinic for the cardiac follow-up visit. 
e: 
Females of child-bearing potential 
f: 
Plasma sample for pharmacokinetic assessment will be conducted prior to the dose at Visit 8 and 1, 2, and 4-6 hours after dose administration. 
g: 
Plasma sample for assessment of background AED(s) will be conducted prior to the dose of AED(s) at Visits 3, 6, 8 and 12. 
h: 
Study drug/diary dispensed for the Transition Period for subjects entering the open-label extension study and for the Taper Period for subjects exiting the study. 
i: 
Site personnel will review study medication dosing procedure (titration) with parent/caregiver. 
j: 
Study drug administration begins in the morning of Study Day 1. 
k: 
Only adverse events related to cardiac safety will be collected at this visit. 
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5. ANALYSIS POPULATIONS
5.1 ENROLLED POPULATION
The Enrolled Set includes all subjects who signed the informed consent form.  This population 
will be used to present overall study disposition data and the number of subjects in each study 
population. 
5.2 RANDOMIZED POPULATION 
The Randomized Set includes all subjects randomized to receive study treatment. This is the 
Intention-to-treat (ITT) population.  
5.3 SAFETY (SAF) POPULATION 
All safety analyses will be performed on the SAF Population defined as all randomized subjects 
who receive at least one dose of ZX008 or placebo. Subjects will be analyzed according to the 
treatment group to which they were randomized. 
5.4 MODIFIED INTENT-TO-TREAT (MITT) POPULATION 
The mITT Population is defined as all randomized subjects who receive at least one dose of 
ZX008 or placebo and for whom at least one week of diary data are available. Subjects will be 
analyzed according to the treatment group to which they were randomized. The primary 
comparison of ZDX008 0.8 mg/kg/day to placebo, as well as key secondary analyses, will be 
performed on the mITT Population. 
5.5 PER PROTOCOL (PP) POPULATION 
The PP Population includes all randomized subjects who receive at least one dose of ZX008 or 
placebo, complete at least 4 weeks of the Maintenance Period, and have no important protocol 
deviations that would have a significant impact on clinical outcome. Subjects will be analyzed 
according to the treatment group to which they were randomized.  Protocol deviations will be 
reviewed and the list of deviations warranting exclusion from the PP Population will be finalized 
prior to study unblinding. 
The primary and key secondary efficacy analyses will be repeated on the PP Population if there 
are substantial differences in the makeup of the mITT and PP Populations. 
6. STATISTICAL METHODOLOGY
6.1 STATISTICAL AND ANALYTICAL ISSUES
6.1.1 Statistical Methods
Tabulations for Study 1 will be produced for appropriate demographic, baseline, efficacy and 
safety parameters.  Continuous data will be summarized using descriptive statistics including the 
number of observations, 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 described in the 
sections below. 
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All efficacy parameters will be summarized by descriptive statistics. Two-sided statistical 
significance testing (alpha level = 0.05) comparing each active treatment to placebo will be 
performed for the primary and secondary endpoints as described below, unless otherwise noted. 
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. 
6.1.2 Multiplicity Strategy and Testing Hierarchy 
Multiplicity issues in the statistical inference in this study arise from two sources: (a) multiple 
treatment comparisons, and (b) multiple endpoints.  
The efficacy analyses will employ a serial gatekeeper strategy to maintain the Type 1 error rate at 
α=0.05 across the family of analyses that support the primary and key secondary objectives. 
All statistical analyses will be performed and results tabulated with test statistics, p-values, and/or 
95% confidence intervals. 
Formal statistical testing will be performed for 1 primary endpoint and 2 secondary endpoints, for 
the comparison of ZX008 0.8 mg/kg with Placebo, and between ZX008 0.2 mg/kg with Placebo. 
Hence there are 6 formal hypothesis tests: 1 primary hypothesis test and 5 secondary hypothesis 
tests. To preserve the overall Type 1 error rate at α=0.05, these tests will proceed as follows: 
Step 1: The primary efficacy endpoint (mean convulsive seizure frequency per 28 days) will be 
formally tested first between the 0.8 mg/kg and Placebo group. If the comparison is statistically 
significant at the α=0.05 (2-sided) level, hypothesis testing will proceed to Step 2. Otherwise 
formal testing of the other hypotheses stops. 
Step 2: The secondary efficacy endpoint, the proportion of subjects who achieve a ≥50% 
reduction from baseline in convulsive seizure frequency, will be compared between the 0.8 mg/kg 
and Placebo group. If the comparison is statistically significant at the α=0.05 (2-sided) level, 
hypothesis testing will proceed to Step 3. Otherwise formal testing of the other hypotheses stops. 
Step 3: The endpoint, the longest convulsive seizure-free interval will be compared between 0.8 
mg/kg and Placebo. If the comparison is statistically significant at the α=0.05 (2-sided) level, 
hypothesis testing will proceed to Step 4. Otherwise formal testing stops. 
Step 4: The mean convulsive seizure frequency per 28 days will be formally tested first between 
the 0.2 mg/kg and Placebo group. If the comparison is statistically significant at the α=0.05 (2-
sided) level, hypothesis testing will proceed to Step 5. Otherwise formal testing of the other 
hypotheses stops. 
Step 5: The secondary efficacy endpoint, the proportion of subjects who achieve a ≥50% 
reduction from baseline in convulsive seizure frequency, will be compared between the 0.2 mg/kg 
and Placebo group. If the comparison is statistically significant at the α=0.05 (2-sided) level, 
hypothesis testing will proceed to Step 6. Otherwise formal testing of the other hypotheses stops. 
Step 6: The endpoint, the longest convulsive seizure-free interval will be compared between 0.2 
mg/kg and Placebo using a significance level of α=0.05 (2-sided). 
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6.1.3 Subgroups 
Select efficacy and safety outputs may be further broken down by the following subgroups: 
•
Age strata: <6 years, ≥6 years.
6.1.4 Baseline Definition 
Baseline 
Baseline period consists of 42 days immediately preceding first 
administration of study treatment. 
Any assessment performed during these 42 days before first 
administration of study treatment will be considered for baseline 
assessment. 
Study day 1 will be the first day of study drug administration, which 
is either the date of randomization, or the day after the randomization 
date. 
For the change in the frequency of convulsive seizures endpoint, 
baseline will include all data from the baseline period of 42 days 
immediately preceding Day 1(Visit 3).  For all other endpoints, 
baseline is the last non-missing result from the Baseline period prior 
to receipt of the first administration of study treatment. 
6.1.5 Other Definitions 
Treatment completers are those subjects that are compliant with IMP at least 85% of dosing days 
and fulfill at least one of the following criteria: 
•
Subjects that did not discontinue from the trial prior to end of study visit at Day 99 ± 4
days (Visit 12).
•
Subjects that complete the Treatment Period T+M starting from study Day 1 (Visit 3)
through the protocol defined end of study visit at Day 99 ± 4 days (Visit 12).
•
Subjects that enroll in the open label extension study.
6.1.6 Visit Windows and Period Start/Stop Dates 
The following rules will be used to window data into treatment periods for by treatment period 
tabulations.  For all by-visit tabulations, the nominal visit as recorded on the CRF will be used. 
Double 
Blind 
Treatment 
Period 
The Double-Blind Treatment Period start date is the date of first dose. The 
Double-Blind Treatment Period end date is the last date the patient was on 
study treatment. 
The Double-Blind Treatment Period consists of 16 weeks from first 
treatment start date, which includes 2 weeks of Titration period, 12 weeks of 
Maintenance period and 2 weeks of Taper/Transition period, therefore the 
end date would be considered the date at Visit 13. 
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For subjects who discontinue early from the study, the double-blind 
treatment period end date will be the date at the early termination visit (Visit 
12). 
Titration 
Period 
The Titration Period covers the first 14 ± 4 days of treatment while subjects 
are titrated to their randomized dose. It begins on the first day of treatment 
(Study Day 1) and extends through Visit 6 (when the patient has reached 
their randomization dose). The Titration Period applies to all subjects 
including placebo recipients.  If a subject withdraws from the study prior to 
treatment in the maintenance period, all safety assessments and events up to 
and including the date of study withdrawal will be tabulated in the titration 
period. 
Maintenance 
Period 
The Maintenance Period covers the 12 weeks following the end of the 
titration period. It begins on the date of Visit 6 + 1 day and extends through 
the end of study/early termination visit (Visit 12). 
Titration + 
Maintenance 
Period 
(T+M) 
The T+M period combines the Titration and Maintenance periods, beginning 
on the date of first treatment (Study Day 1) and extending the end of 
study/end of treatment visit. The T+M period is considered the treatment 
period. 
Taper/Transi
tion Period 
The Taper/Transition period consists of 2 weeks starting from end of 
study/early termination visit (Visit 12) + 1 day. 
For patients who are not entering into the open-label extension study, 
patients will gradually be tapered off of study medication. 
For patients who are entering the open-label extension study, patients will 
enter the transition phase where all patients will be on a dose of 
0.2mg/kg/day at the end of this phase. The end date of this period is 
considered to be the date recorded at Visit 13. 
6.1.7 Handling of Dropouts and Missing Data  
There will be no imputation of missing data for efficacy endpoints. 
Seizure Diaries: 
Seizures are recorded in the Daily Seizure Diary (DSD), while the End of Day Diary (EDD) 
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 seizure 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.
Handling of missing date information for AEs: 
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•
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.
Adverse event 
Partial 
/Missing 
Start 
date 
Missing day – If Adverse event day is missing but month and year is present then 
Impute the 1st of the month unless month is same as month of first dose of study drug 
then impute first dose date.  
Missing day and month – If adverse event day and month 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. 
Adverse event 
Partial 
/Missing 
End date 
Missing day – If AE end day is missing but month and year are present then Impute 
the last day of the month unless month is same as month of last dose of study drug 
then impute last dose date.  
Missing day and month – If AE has missing day and month but year is present then 
impute 31st December unless year is the same as first dose date then impute last dose 
date.  
Completely Missing – need to look at whether the AE is still ongoing before 
imputing a date and also when it started in relation to study drug. If the ongoing flag 
is missing then assume that AE is still present (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 
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1 month = 30.4 days 
1 year       = 365.25 days 
6.1.9 Pooling of Investigative Sites 
There are approximately 60 sites participating in Studies 1501 and 1502 from US, Canada, 
Belgium, Denmark, France, Germany, Italy, Norway, Spain, Sweden, United Kingdom and 
Australia. Approximately 35 sites will contribute randomized subjects to Study 1. It is likely that 
the number of patients recruited by some sites will be small. The primary analysis will use data 
pooled across sites.  Differences among regions may be explored if warranted.  
6.1.10 Determination of Sample Size 
The sample sizes for Zogenix Studies 1501 and 1502 were calculated based on the results of two 
trials with stiripentol reported in the European Public Assessment Report (EPAR) for stiripentol 
(EMA, 2007). The stiripentol EPAR summarizes the results from two studies: STICLO France 
and STICLO Italy. In the stiripentol groups, the standard deviation (SD) of the percentage change 
in seizure frequency from baseline to month 2 was 42% in the French trial and 26% in the Italian 
trial. The analogous SDs for placebo groups were 38% and 62%. An SD of 50% was assumed for 
the primary analysis in Protocols 1501 and 1502 that compares ZX008 0.8 mg/kg/day to placebo 
on the change from baseline in seizure frequency. Using a two-sided test at the α=0.05 
significance level, a sample size of 35 subjects per treatment group affords 90% power to detect a 
difference in mean change from baseline of 40 percentage points. Similar assumptions and 
calculations yielded a requirement for an additional 35 subjects in the 0.2 mg/kg/day ZX008 
group. The total sample size for each study was therefore set at 105 subjects. 
In December 2016 results from a double-blind, placebo-controlled Phase 3 study with Epidiolex 
to treat seizures in Dravet syndrome were presented at the American Epilepsy Society Meeting 
(http://ir.gwpharm.com/events.cfm). In the Epidiolex study, active drug reduced seizures by 39% 
compared to a reduction of 13% in the placebo.  Review of the data suggested that the standard 
deviation was relatively large, likely above 50% in both treatment groups.  In consideration of 
this new data, the sample size was re-estimated for the ZX008 studies to assume a SD of 55%, 
higher than the previous estimate of 50%.  Other assumptions in the sample size calculation 
remained unchanged. A sample size of approximately 120 subjects (40 per arm) affords 90% 
power to detect a difference in mean change from baseline of 40 percentage points with 55% SD. 
Considering the variability seen in the STILCO and Epidiolex trials, the sample size for Study 1 
and Study 2 is set at 120 subjects, 40 per treatment arm. Note that the change in assumed SD was 
based entirely on data from external trials. Efficacy data from both Study 1501 and 1502 are still 
blinded and were not used in re-estimating the required sample size.  
The enrollment for Study 1 will consist of the first 120 subjects to be randomized into either 
Study 1501 or Study 1502.  Study 1 will be analyzed per this prospectively prepared Statistical 
Analysis Plan for Study 1; Version 2.0.  Subjects who withdraw early will not be replaced. 
Subjects who are randomized into Study 1501 or Study 1502 after the first 120 randomized 
subjects will be analyzed in Study 2, per a separate statistical analysis plan. 
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6.2 SUBJECT CHARACTERISTICS 
6.2.1 Subject Disposition 
Subject disposition will be presented per treatment group and overall. 
For describing the subject disposition, the following will be summarized by number and 
percentage: 
•
Subjects enrolled (only overall)
•
Subjects enrolled but not randomized and reason for not-randomized (only overall)
•
Subjects randomized
•
SAF
•
mITT
•
PP
•
Subjects assigned to SAF, mITT, PP and discontinued the study and reason.
•
Number of subjects in the trial per trial period/phase (Titration Phase, Maintenance
Phase, Follow-up Period) will be presented for SAF and mITT sets.
•
Trial completers.
-
Trial completers continuing in the open-label extension study
-
Trial completers not continuing in the open-label extension study
For subjects enrolled but not randomized to treatment and for the reasons for not being 
randomized the denominator used to calculate the percentage will be the number of enrolled 
subjects. For all other calculations the denominator will be the number of subjects randomized. 
All subject data will be listed using the enrolled population and sorted by treatment and site. 
6.2.2 Protocol Deviations 
Major protocol deviations will be summarized overall and by site based on the SAF. Major 
protocol deviations are those that have the potential to impact patient safety or affect data 
integrity. Major protocol deviations will be grouped into categories and may include categories 
such as 
•
Violation of inclusion/exclusion criteria
•
Violation of randomization inclusion criteria
•
Time schedule deviations of IMP
•
Non-compliance regarding intake of IMP
•
Inappropriate intake of concomitant medication
•
Missing essential data
•
Subject not discontinued as per protocol
•
Other non-compliance
Multiple deviations can occur in the same subject and thus a subject can be counted in more than 
1 deviation category. 
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Major and minor protocol deviations will be presented in a subject data listing for the all enrolled 
population, sorted by treatment and site. 
6.2.3 Demographic and Baseline Characteristics 
Subject demographics and baseline characteristics will be summarized descriptively per treatment 
group and overall, for the SAF and mITT populations.  
6.2.3.1 Subject Demographics 
The following demographic characteristics will be summarized: 
•
Age[Years]
•
Categorical age as <6 years and ≥6 years.
•
Sex
•
Race
•
Ethnicity
•
Height [m]
•
Weight [kg]
•
BMI [kg/m2]
All subject demographics data will be listed for the enrolled population. 
6.2.3.2 Other Baseline Characteristics 
Epilepsy/seizure history and epilepsy genotype panel data will be descriptively summarized as 
per data type (categorical).  Genetic data will be summarized as the proportion who have or do 
not have mutations of the SCN1A gene.  Additional analyses of genetic data will be prepared in a 
separate report. 
All subject baseline characteristics will be listed for the enrolled population. 
6.2.4 Treatment Exposure and Compliance 
6.2.4.1 Treatment Exposure 
Treatment exposure data will be summarized 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, and will be 
summarized using n, mean, standard error, median, minimum, Q1, Q3 and maximum.  
This will be calculated as: 
Date of last IMP intake – Date of first IMP intake + 1 
Time on treatment will be summarized by treatment group. 
6.2.4.2 Compliance 
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, 
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compliance will be calculated by assuming that a missed dose=0% of dose consumed, 
partial=50% of dose consumed, and full=100% of dose consumed. For each subject, a daily 
compliance score will be thus obtained.  
Compliance will be summarized for the SAF and mITT populations over the course of T+M and 
Maintenance only, reported by treatment group.   
6.2.5 Prior and Concomitant Medications and Therapies 
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 and concomitant: 
Concomitant medications will be defined as those medications that were initiated after study drug 
administration or those that were ongoing at the time of study drug administration. 
The medication will be assumed to be prior medication if it cannot be definitively shown that the 
medication did not start or continue during the treatment period. 
If the start date or stop date of a medication is partially missing, the date will be compared as far 
as possible with the date of the start of administration of study drug.    The following approach 
will be taken: 
•
If the start date of medication is complete and occurs on or after the day of the first dose,
the medication will be assumed concomitant.  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 will
only be excluded as being concomitant if the start month/year is before the month/year of
study drug administration and if the stop date (either full date, month and year if missing
day, or year if missing month and day) is before study drug administration.
•
If the start day and month are missing but the start year is complete, a medication will
only be excluded as concomitant if the start year is before the year of study drug
administration and if the stop date (either full date, month and year if missing day, or year
if missing month and day) is before study drug administration.
•
If the start date is completely missing and the stop date is prior to first dose or completely
missing, the medication will be assumed to be a prior medication.
Medication will be summarized and sorted alphabetically separately for prior and concomitant 
medication by Anatomical Therapeutic Chemical (ATC) categories (Level 2: pharmacological or 
therapeutic subgroup and Level 3: chemical or therapeutic or pharmacological subgroup) and 
WHO-DD drug code. For each medication the number and percentage of subjects will be 
displayed.  
Summary tables will be presented on SAF population. 
All prior and concomitant medications/treatments will be listed for the enrolled population. 
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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 will be defined and analyzed for the SAF similar to 
concomitant medications as described in section 6.2.5. 
All prior and concomitant antiepileptic treatments will be listed for the enrolled population. 
6.2.7 Medical History 
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. 
All prior and concomitant medical history data of subjects will be listed for the enrolled 
population. 
6.3 EFFICACY ANALYSIS 
The analysis of the primary and secondary efficacy parameters will be performed on the mITT 
population, except where noted.  
The primary and key secondary efficacy analyses will be repeated on the PP Population if there 
are substantial differences between the makeup of the mITT and PP population, in order to assess 
the impact of major protocol deviations on the key inference.  
All primary and key secondary variables will be analyzed for data obtained for the T+M period, 
and will be repeated for data obtained during the M period only. 
6.3.1 Primary Efficacy Analysis 
The primary efficacy endpoint is the change in the mean convulsive seizure frequency (MCSF) 
per 28 days between the Baseline and T+M periods. For each subject, the CSF will be calculated 
from all available data collected during the Baseline and T+M Periods, and the treatment group 
mean convulsive seizure frequency per 28 days (MCSF) will be calculated for the baseline and 
T+M period. 
The baseline period is the 42 days immediately preceding the Randomization visit and the T+M 
period is planned for 14 weeks. However, actual durations will be computed for each subject 
based on the individual subject’s start and stop dates for each period, except that if the baseline 
period is longer than 42 days, the average for the baseline period will be taken over the 42 days 
immediately preceding the Randomization visit.  
The convulsive seizure frequency will be counted from the daily diary records provided by the 
Subject or Parent/Caregiver. 
For any individual subject, the convulsive seizure frequency per 28 days during the baseline 
period (CSFB) will be derived as follows: 
CSFB =
28 × Total number of convulsive seizures during the Baseline Period
Total number of days in the Baseline Period with nonmissing diary data
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For each treatment group, the mean is obtained by averaging over the subjects in the treatment 
group. 
Similarly, for each subject, the convulsive seizure frequency per 28 days for the T+M period 
(MCSFT+M) is derived as below: 
data
diary 
 
nonmissing
 with 
period
 
M
+
T
 
in the
 
days
 
of
number 
 
Total
period
 
M
+
T
 
in the
 
seizures
 
convulsive
 
of
number 
 
Total
28
CSF
M
T+
×
=
The percentage change from baseline for any individual subject will be estimated by 
 (CSFT+M - CSFB)*100/CSFB
The difference from baseline will be estimated by CSF𝑇𝑇+𝑀𝑀−CSF𝐵𝐵. 
Corresponding treatment group means are designated with “M” preceding the quantity. For each 
treatment group, descriptive statistics for MCSF during baseline, T+M and M only, as well as the 
differences and % changes from baseline, will include the number of observations, mean, 
standard deviation, median, minimum and maximum, overall and by age group (<6 years, ≥6 
years). 
6.3.1.1 Primary Analysis 
T+M Period: 
The primary analysis will compare the ZX008 0.8 mg/kg/day group to the placebo group using a 
two-sided test at the α=0.05 level of significance. 
The primary endpoint (CSFT+M) will be analyzed using an analysis of covariance (ANCOVA) 
model with treatment group (three levels) and age group (< 6 years, ≥6 years) as factors, log 
baseline CSFB as a covariate and log CSFT+M as response.  Treatment group mean differences 
from placebo will be estimated via least squares means from the analysis model along with 95% 
confidence intervals and associated 2-sided p-values. Estimated treatment differences and CI 
endpoints will be exponentiated for presentation. 
The nullhypothesis 
H0: 𝜇𝜇Z0.8 −𝜇𝜇P = 0, 
will be tested against the alternative 
HA: 𝜇𝜇Z0.8 −𝜇𝜇P ≠0, 
where µZ0.8 and µP represent the ZX008 0.8 mg/kg and Placebo group means (on the log scale), 
respectively.  
Rejection of the null hypothesis in favor of the alternative, in the presence of a statistically 
significantly smaller mean convulsive seizure frequency for the treatment group compared to the 
placebo group, (two-sided p-value < 0.05) will be regarded as evidence of a treatment benefit in 
favor of the 0.8 mg/kg group. 
Sample SAS code for the ANCOVA described above is as follows: 
proc glm data=temp; 
class agegrp trtp; 
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model csftm = bcsf agegrp trtp  / SS3; 
lsmeans  trtp / pdiff stderr; 
where  trtp = randomized treatment group (with codes 1, 2, 3 indicating placebo, 0.2 mg, and 0.8 
mg groups). 
bcsf = log( CSF𝐵𝐵),  
csftm = log(CSFT+M + 1) 
agegrp = age group. 
Additional statements may be used to obtain estimates and associated 95% confidence 
intervals. Endpoints of the CIs may be exponentiated to obtain CI on the original scale. 
Fitted values and residuals may be plotted to check model assumptions.  
Since the ANCOVA used in the primary analysis relies on assumptions of normality, the 
primary endpoint will also be analyzed 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 baseline CSFB as a covariate and ranks of CSFT+M as response, and 
the results will be used to assess the primary objective. If normality assumptions are not 
met, the results of the nonparametric test will be used to assess the primary objective.  
M Period only: 
The primary analysis described above will be repeated using data from the Maintenance period 
only as response.  For subjects who did not reach the Maintenance period, their Transition period 
data will be used to represent their M period data. 
A similar ANCOVA model will be used, and if distributional assumptions are not met, a 
nonparametric analysis will be performed.   
Treatment by baseline seizure category interaction:  The primary analysis described above will be 
repeated with baseline seizure frequency as a categorical variable, rather than a covariate.  
Baseline seizure frequency per 28 days will be categorized as either < 10; 10-50; or >50. 
6.3.1.2 Supplementary and Sensitivity Analyses 
Impact of AED Medications 
Subjects in the study are required to be on stable background therapy. An additional analysis will 
be performed to assess the impact on the primary analysis of changes in dose or type of 
concomitant AED medications, which are protocol violations, that may occur during the course of 
the study. Specifically, the percentage of subjects who had a change in dose or type of 
concomitant AED medication will be compared between treatments. For this analysis, each 
subject will be classified according to whether the subject had a change in the prescribed dose or 
type of concomitant AED medication during the T+M period. Fisher’s exact tests will be used to 
compare the active dose group with the placebo group.  
Per protocol Analysis 
Additionally, the primary efficacy analysis will be repeated on the per protocol population (which 
excludes subjects with important protocol deviations that may affect the inference on efficacy 
such as a change in dose or type of concomitant AED medication). 
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Percentage Reduction from Baseline 
The ANCOVA employed in the primary analysis uses log CSFT+M as the response adjusts for 
baseline seizure frequency by incorporating CSFB as a factor in the model. The alternative 
approach described here calculates the percentage change in CSF from baseline directly and uses 
that quantity as the response variable in an ANCOVA model. Specifically, the ANCOVA will use 
the percentage change from the T+M period to baseline as the response variable, baseline CSF as 
a covariate, and treatment and age stratum as classification factors. The analyses will be repeated 
for the M period only using the baseline as covariate. 
If the distributional assumptions for the parametric analysis are not met, a nonparametric 
ANCOVA will be used for the ranks of the dependent variable as response, using the ranks of the 
baseline as covariate. 
Criteria for Establishing Efficacy 
While several supportive and/or supplementary analyses are specified above, the main criterion 
for demonstrating efficacy will be the primary analysis using the log transform for the mITT 
population. It is conceivable that some or all of these supplemental analyses may not reach 
statistical significance. However, it is expected that the direction of effect will be in favor of the 
test treatment. As an example, a statistically significantly smaller least squares adjusted MCSF 
for the treatment group compared to placebo, in the presence of a smaller proportion of subjects 
on 0.8 mg/kg than Placebo subjects increasing their dose of concomitant AEDs will be strong 
evidence for efficacy of the experimental treatment. 
6.3.2 Key Secondary Analysis 
6.3.2.1 MCSF for ZX008 0.2 mg/kg/day versus Placebo 
The MCSF during the T+M period will be analyzed and compared between the ZX008 0.2 
mg/kg/day group and the placebo group using the same methods employed for the primary 
analysis. Following the same strategy as the ZX008 0.8 mg/kg/day comparison, a nonparametric 
analysis using ranks will be used for the ZX008 0.2 mg/kg/day comparison if the assumptions of 
the parametric ANCOVA model are not met. 
The analysis will be repeated for the M period. 
Similar supplementary analyses will be performed as for the comparison of the 0.8 mg/kg group 
with placebo. 
6.3.2.2 Proportion with ≥50% Reduction from Baseline in Convulsive Seizure Frequency 
Subjects with a percent reduction in convulsive seizures of at least 50 percentage points from 
baseline will be identified and the overall proportion within each treatment tabulated.  That is, the 
proportion of subjects in the ZX008 0.8 mg/kg/day group who have a decrease in convulsive 
frequency of at least -50 percentage points will be compared to the analogous proportion in the 
placebo group.   
Similarly, the proportion of subjects in the ZX008 0.2 mg/kg/day group who have a change in 
convulsive frequency of at least -50 percentage points will be compared to the analogous 
proportion in the placebo group. 
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The comparison between treatment groups will be made using a logistic regression model that 
incorporates the same factors as the ANCOVA used in the primary analysis.  This will model a 
categorical response variable (achieved 50 percentage point reduction, yes or no) as a function of 
treatment group (ZX008 and placebo) and age group (< 6 years, ≥6 years).   
Raw descriptive statistics will be presented by treatment group, and will include the number and 
proportion of subjects < 6 years, ≥6 years, and overall achieving the reduction along with the 
model estimated odds ratio (including a 95% confidence interval) and p-value for comparison of 
ZX008 0.8mg/kg/day to placebo and ZX008 0.2mg/kg/day to placebo separately.   
6.3.2.3 Longest Interval between Convulsive Seizures 
The longest interval between convulsive seizures will be analyzed. 
For each subject, the longest interval between convulsive seizures will be calculated over the 
entire T+M period. This will be derived as the maximum of the number of days between 
consecutive convulsive seizures. The intervals between consecutive convulsive seizures 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 seizure occurs on five days having 
dates as Date1, Date2, Date3, Date4 and Date5, where 
Date5>Date4>Date3>Date2>Date1≥Date0, and let LDT = Last date of treatment in the 
maintenance period, where LDT ≥ Date5, then the time interval between convulsive seizures will 
be calculated as follows: 
I1=Date2 - Date1  
I2=Date3 - Date2  
I3=Date4 – Date3, 
I4=Date5 – Date4. 
For completeness, we calculate the time to the first seizure as 
I0=Date1 – Date0,  
and the time from the last seizure to end of treatment as 
I5 = LDT – Date5. 
Here the duration of the longest interval =Maximum (I0, I1, I2, I3, I4, I5). 
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If the subject does not experience a seizure during treatment, then the last available diary date 
will be used to compute the duration of the longest interval as follows: 
The longest interval=last available diary date – Date0 
The median time of the longest convulsive seizure-free interval will be presented. Additional 
summary statistics will be presented, including mean, minimum, maximum, the 25th and 75th 
percentiles, 95% confidence intervals on the difference in medians between groups (Hodges-
Lehman estimator).   
The Wilcoxon rank sum test will be used to test for differences between each treatment arm and 
placebo, and the p-value from this test will be presented.  A histogram presenting the percentage 
of subjects whose longest seizure free interval is <10, 11-20, 21-40, 41-60, 61-84, and ≥84 days 
will accompany all descriptive statistics and all data will be provided in a data listing. 
6.3.3 Additional Secondary Endpoint Analysis 
6.3.3.1 Number of Convulsive Seizure Free Days 
Convulsive seizure free days will be taken from the parent/caregiver diary data. 
A convulsive seizure free day will be defined as a day for which diary data are available and no 
convulsive seizures have been reported.  The total number of convulsive seizure free days will be 
summed for the entire T+M period and similarly for the baseline period. 
Seizure free days per 28 days at baseline = (number of seizure free days during 
baseline)*28/(number of days during baseline with non-missing diary data) 
Seizure free days per 28 days during T+M Period = (number of seizure free days during T+M 
Period)*28/(number of days during T+M Period with non-missing diary data) 
Statistical comparison of treatment groups and placebo on the number of seizure free days per 28 
days during T + M using the baseline as covariate will be done with a similar approach as the 
primary analysis. 
6.3.3.2 Responder Analyses: Proportion with ≥25, or 75% Reduction from Baseline in 
Convulsive Seizure Frequency 
A response curve will be generated for the mITT population. This graph will plot the % of 
subjects (y-axis) against percentage reduction in seizure frequency per 28 days in the T+M period 
(x-axis). The horizontal axis will be the % reduction, and the vertical axis will be the % of 
subjects achieving ≥ that % reduction.  In the graph, subjects experiencing an increase or no 
decrease in seizure frequency (i.e., ≤0 % reduction) will be regarded as having a 0% reduction in 
seizure frequency. Hence the ordinate for the 0 time point may not necessarily be at 100%.  For 
example, if 15% of subjects have no reduction in seizure frequency during T+M period compared 
to the baseline period, the graph will start on the y-axis at 85%. The graph will be generated for 
all subjects, by treatment group. 
•
The proportion achieving a ≥25% reduction from baseline in convulsive seizures will be
analyzed for both treatment groups (ZX008 0.2 mg/kg/day and ZX008 0.8 mg/kg/day)
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comparing independently with placebo, using the same method employed for the ≥50% 
reduction from baseline endpoint. 
•
The proportion achieving a ≥75% reduction from baseline in convulsive seizures will be
analyzed for both treatment groups (ZX008 0.2 mg/kg/day and ZX008 0.8 mg/kg/day)
comparing independently with placebo, using the same method employed for the ≥50%
reduction from baseline endpoint.
A second response curve will be generated in which subjects who experience an increase in 
seizure frequency will be represented on the curve at horizontal axis at the position representing 
their increase in seizure frequency. Increases in seizure frequency will be represented to the left 
of the vertical axis on the figure. 
6.3.3.3 Change from Baseline in Non-Convulsive Seizure Frequency 
Algorithms for calculating mean non-convulsive seizure frequency and percent change from 
baseline will follow the methods as described for the primary endpoint using a nonparametric 
ANCOVA to analyze the data, with ranks of the baseline non-CSFB as a covariate and ranks of 
non-CSFT+M as response,. 
Change from baseline in non-convulsive seizures will be presented by seizure types (e.g., focal, 
generalized). 
6.3.3.4 Change from Baseline in Convulsive + Non-Convulsive Seizure Frequency 
The change from baseline in convulsive + non-convulsive seizure frequency will be calculated as 
described for the primary endpoint, but considering both convulsive and non-convulsive seizures. 
Algorithms for calculating mean convulsive and non-convulsive seizure frequency and percent 
change from baseline will follow the methods as described for the primary endpoint using a 
nonparametric ANCOVA to analyze the data, with ranks of the baseline convulsive + non-CSFB 
as a covariate and ranks of convulsive + non-CSFT+M as response, 
6.3.3.5 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.  They second and third round 
might use different medications or different doses than the first round of rescue meds. 
Rescue medication will be summarized by treatment group and by active treatment vs. Placebo 
for the following: 
•
The number of days rescue medication was taken (normalized to 28 days) will be
summarized separately for the Baseline and T+M periods by the mean (SD) as well as the
median and range. Multiple medications taken on the same day will be counted once for
that day. The ZX008 group will be compared to the placebo group using a rank
ANCOVA analogous to that described in Section 6.3.1.1. Specifically, the rank
ANCOVA will use the ranks of rescue medication frequency during T+M as the
response, and will incorporate treatment group as a factor and the ranks of rescue
medication frequency during Baseline as a covariate.
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•
The number of medications used per episode will be summarized using similar
descriptive statistics as above. Rescue medications related to an episode of SE are
considered to be all rescue administered on the day of the SE (or seizure lasting >10
min). If more than one episode of SE or a seizure lasting >10 min occurred in a single
day, the rescue medication for that episode is all rescue administered after the seizure
until the start time of the next prolonged seizure.
6.3.3.6 Incidence of Hospitalization to Treat Seizures 
Hospitalization data will be captured in the CRF and will be used to calculate incidence. 
The number and percentage of subjects who utilized medical center care to treat a seizure will be 
presented by treatment group for the T+M period.  Statistical comparisons of the differences 
between treatment and placebo groups will be based on Cochran-Mantel-Haenszel test stratified 
by age group. 
6.3.3.7 Incidence of Status Epilepticus 
The incidence of status epilepticus 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 for the baseline and the T+M period per 28 days.  Statistical 
comparisons of the differences between treatment and placebo groups will be based on Fisher’s 
exact test. 
In addition, from the diary data, change from baseline in the number and percentage of 
convulsive seizures with duration >10 min for the baseline and T+M period will be reported. The 
number and percentage of subjects will be presented by treatment group for the baseline and the 
T+M period per 28 days.  Statistical comparisons of the differences between treatment and 
placebo groups will be based on Fisher’s exact test. 
All seizures recorded in the AE database as status epilepticus should also be included in the 
seizure diary. An edit check will be performed to identify the overlap between seizures identified 
as AE of SE and seizures entered into the diary as seizures > 10 min. The “calculated” number 
and percentage of subjects experiencing SE will be presented by treatment group, defined as 
individuals who experience either an AE of SE, medical treatment for SE, or a seizure lasting 
longer than 10 min. Each subject will be represented once regardless of incidence. Statistical 
comparisons of the differences between treatment and placebo groups will be based on Fisher’s 
exact test. 
A second calculation will present the number of incidences of SE, according to the above 
definition, by treatment group normalized to per 28 days. In this analysis, a single subject may 
have more than one episode of SE, but an episode of  SE recorded as both an AE and as a seizure 
longer than 10 min will be counted as a single episode.  Statistical comparisons of the differences 
between treatment and placebo groups will be based on Fisher’s exact test. 
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6.3.3.8 Duration of Prolonged Seizures 
Duration of convulsive seizures at baseline and on treatment will be presented by treatment group 
using categories as <2 min, 2-10 min and >10 min.  
To obtain a baseline probability distribution for the 3 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 % of subjects’ seizures that were <2 min in duration, 
the % between 2-10 min in duration, and the % >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 T+M period, we will proceed similarly, to obtain 
a distribution for the T+M period.  
It is expected that treatment with ZX008 will result in shorter duration of seizures (as well as 
fewer seizures) during T+M compared to placebo, i.e., the probability of longer seizures (>10 
min) will be higher for the placebo group than for the ZX008 arms. This may be assessed by 
comparing the probability of a >10 min seizure during T+M to the same during baseline, for a 
treatment group, to the same for the Placebo group. It is expected that the ZX008 group will have 
greater odds of a reduction in proportion of seizures >10 min than the Placebo group. However, 
treatment with ZX008 may result in fewer seizures overall yet the duration of residual seizures 
may not be shorter.  Should the primary or key secondary endpoints be positive for a given 
dose(s), but the duration of seizures not be shortened per above, exploratory evaluations may be 
undertaken to better understand the effect. 
6.3.3.9 Clinical Global Impression – Improvement Rating, as assessed by the 
Parent/Caregiver 
The parent/caregiver and the investigator will rate their global impression of the subject’s 
condition at each clinic visit after randomization: end of Titration period (Visit 6), Maintenance 
period (Visit 8 and 10), and at End of study (Visit 12). 
The CGI-I scale measures the change in the subject’s clinical status from a specific point in time, 
i.e., the Baseline Period. The CGI-I rating scale permits a global evaluation of the subject’s
improvement over time. The severity of a 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 mean (SD) CGI-I score, and the number and percentage of subjects who showed 
improvement (i.e., had a score of 3 or lower), and the number and percentage who did not 
improve (i.e., had a score of 4 or higher) will be presented for each for each treatment group at 
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each assessment timepoint. Each assessment time point will also include a comparison between 
each active treatment and the placebo group using the Cochran-Mantel-Haenszel test stratified by 
age group, and a frequency distribution of the number and percentage of subjects in each category 
in the scale. A histogram of the frequency distribution will be presented. 
The number and percentage of subjects who showed good or very good improvement (i.e., had a 
score of 2 or lower), and the number and percentage who did not improve (i.e., had a score of 3 or 
higher) will also be presented for each for each treatment group at each assessment timepoint as 
an exploratory analysis.   
Individual subject CGI data will be listed. 
6.3.3.10 Clinical Global Impression – Improvement Rating, as assessed by the Principal 
Investigator 
CGI-I score data assessed by the principal investigator will be summarized and analyzed using 
the same methods used for CGI-I score data recorded by parent/caregiver as above. 
6.3.3.11 Quality of Life in Childhood Epilepsy (QOLCE) Scale 
The parent/caregiver will complete this questionnaire for the QOLCE. This assessment looks at 
how epilepsy affects day-to-day functioning of their child in various life areas, including physical 
activities, well-being, cognition, social activities, behavior and general health, at baseline period 
(Visit 3), at Maintenance period (Visit 8) and at End of study/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.  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.  After transformation, the 
subscales are computed by averaging across subscale items.  Subscale scores are then averaged to 
obtain an overall quality of life score.  The higher the subscale and overall quality of life scores, 
the better the response. 
Table 2: Subscale of QOLCE: 
Domain 
Subscale 
Item 
Section 3: Physical 
Physical Restrictions 
3.1 a-j 
Section 3: Physical 
Energy/Fatigue 
3.2 a,b 
Section 4: Well-being 
Depression 
4.1 a,d,e,l 
Section 4: Well-being 
Anxiety 
4.1 b,g,j,n,o,p 
Section 4: Well-being 
Control/helplessness 
4.1 c,f,h,i 
Section 4: Well-being 
Self-esteem 
4.1 k,m,q,r,s 
Section 5: Cognition 
Attention/Concentration 
5.1 a,d,e,f,g 
Section 5: Cognition 
Memory 
5.1 j,k,l,m,n,o 
Section 5: Cognition 
Language 
5.1 p,q,r,s,t,u,v,w 
Section 5: Cognition 
Other Cognitive 
5.1 b,c,h 
Section 6: Social Activities 
Social Interactions 
6.1 c,f,h 
Section 6: Social Activities 
Social Activities 
6.2, 6.3, 6.4 
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Section 6: Social Activities 
Stigma Item 
6.1 i 
Section 7: Behavior 
Behavior 
7.1 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) 
Overall quality of life 
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 End of Study/ET. The 
change from baseline for each treatment group will be summarized by the mean (SD) and 
treatment groups will be compared using pairwise Wilcoxon tests.  
Individual subject data for the domains will be listed. 
6.3.3.12 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 (Visit 3) and at End of study (Visit 12) using the EQ-5D-5L. The responsible 
parent/caregiver was permitted to opt out of completing the EQ-5D-5L. 
The EQ-5D-5L health questionnaire is a health-related quality of life instrument with 5 
dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each 
dimension has 5 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 proportion (%) of 
subjects in each Item score (No Problems, Slight Problems, Moderate Problem, Severe Problem, 
Extreme Problems) by treatment at baseline and at the end of study. In addition, the item scores 
will be classified into two categories as “No Problems” and “Problems,” the latter comprised of 
slight, moderate, severe and extreme problems. Summary results will show number of patients 
and proportion (%) with “No Problems” and with “Problems” by treatment at baseline and at end 
of study.   
For the VAS measure of overall self-rated health status, descriptive statistics summary results will 
be presented for the VAS score showing number of subjects, mean, standard deviation, median, 
and range by each treatment at baseline and end of study time points.  
The change from baseline in VAS will be calculated by subtracting the VAS score at baseline 
from the VAS score obtained at End of Study/ET. The change in VAS will be summarized using 
descriptive statistics, and treatment groups will be compared using pairwise Wilcoxon tests. 
The quality of life of parent/caregiver individual data will be listed using EQ-5D-5L scale. 
6.3.3.13 Parent/Caregiver Assessment using HADS Scale 
The HADS is a tool commonly used to determine the levels of anxiety and depression that a 
person is experiencing and is administered to the primary parent/caregiver to assess these 
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symptoms longitudinally during the study.  The responsible parent/caregiver was permitted to opt 
out of the HADS. The HADS 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 7 relate to depression. 
Each item has 4 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.   
Summary descriptive statistics including the mean and SD will be generated separately for the 
Anxiety and Depression dimensions at both Baseline and at End or Study/ET. In addition, each 
subject will be categorized at each time point based on the score cut-offs below which were 
validated on adult patients in a treatment setting.   
Score 
Category 
0-7 
Normal 
8-10 
Borderline abnormal 
11-21 
Abnormal 
Summary statistics will include number and proportion (%) of subjects in each of the categories 
above at each study visit.   
In additional, the total score for Anxiety and Depression will be generated. Descriptive statistics 
summaries including mean, median, standard deviation, median and range will be summarized for 
each treatment at Baseline and End of Study/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 and the difference between 
treatment groups will be assessed using pairwise Wilcoxon tests. 
The individual item outcomes will be presented in the subject data listing. 
6.3.3.14 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 8 items for Physical Functioning, and 5 questions each for Emotional, Social, and 
School Functioning. 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. A mean score is calculated as the sum of the items 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 completed items in a scale. The scaled results will be 
combined across age categories to produce a single score for each functional area. 
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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 at both Baseline and 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 treatment groups will be 
compared on the Total Score using pairwise Wilcoxon tests. 
6.3.3.15 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 6 items for Physical Functioning, 5 items each for Emotional Functioning, Cognitive 
Functioning and Worry, 4 for Social Functioning, and 3 for Communication. There are 
additionally 3 questions for Daily Activities and 5 for Family Relationships.  
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. A mean score 
is calculated as the sum of the items 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 completed 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. 
6.3.4 Exploratory Analyses 
Exploratory analysis may be performed by comparing of ZX008 0.2 and 0.8 mg/kg/day doses on 
primary, secondary, safety and PK endpoints. 
Thus, all comparisons planned for ZX008 to placebo may be repeated to compare the ZX008 0.2 
and 0.8 mg/kg/day doses. 
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Additional exploratory analyses may include descriptive summaries of the primary endpoint by: 
•
genetic mutation data
•
seizure type
•
baseline seizure frequency
•
Age (greater than or equal to 13 years at baseline)
6.4 SAFETY ANALYSIS 
All safety analyses will be performed for the Safety population as defined in Section 5.3 (SAF) 
and will be reported by treatment group as well as ZX008 combined for the 16-week treatment 
period unless noted otherwise. 
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 the end of the titration/transition period (Visit 13). For 
patients who continue into the open-label extension study, AEs of special interest will continue to 
be monitored for up to 6 months after the last dose of study medication. 
A TEAE is defined as any AE that based on start date information occurs after the first intake of 
study treatment. Safety tables will present TEAE data by assigned treatment group through Visit 
13. 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 unrelated.  If the AE is thought to be definitely, probably or 
possibly related to study drug then it is to be categorized as related.  Possibly or definitely 
unrelated is categorized as unrelated. Any missing relationship will be considered as “related.” 
The severity of AEs (whether nonserious or serious AEs) will be assessed by the investigator as 
follows: 
Severity Definition of Adverse Events: 
Mild - A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living. 
Moderate - A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the research participant. 
Severe - A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
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. 
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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
•
Death
The percentage denominator for the calculation of percentage will be the number of subjects in 
the SAF.  
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
•
Serious TEAEs
•
TEAEs by Maximum Severity
•
Study Drug Related TEAEs
•
All AEs that lead to premature discontinuation from the study
One additional summary table will tally the number and percent of subjects in each treatment 
group who experience an AE that occurs in at least 5% of subjects. The summary will be 
presented by preferred term in decreasing order of incidence. 
No inferential statistical methods (i.e., methods that yield p-values) will be used to compare 
treatment groups on the frequency or severity of AEs. 
These summaries will be provided for the T+M 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
•
Deaths
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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 in below table- 
Table 5 – Adverse Events of Special Interest: 
CV/Respiratory 
1. Chest pain – any pain in sternal area that is described for example as crushing, burning, sharp,
stabbing or dull.
2. Dyspnea/shortness of breath – any signs of difficult or labored breathing unrelated to a previous
medical condition that has not worsened.
3. Persistent cough – longer than 4 weeks without a confirmed identified pathogen (or any other
persistent cough that the investigator feels is suspicious).
4. Increase in blood pressure >30% from Screening blood pressure or a systolic pressure ≥140
mmHg after repeated measures during one visit.  Blood pressure should be repeated at
appropriate times within the visit. 
5. Jugular venous distention- visible bulging of the external jugular veins on either side of the neck
6. New onset heart murmur
7. Pulmonary rales – an abnormal respiratory sound heard during auscultation of the lungs, which is
also described as a crackle.
8. Tachycardia – a persistent HR >30% above the screening value and unrelated to exercise, exertion
or anxiety.  Heart rate should be repeated at appropriate times within the visit.
9. Signs that could indicate right ventricular failure:
•
Peripheral edema
•
Ascites
•
Syncope
•
Decompensated right ventricular failure – symptoms include shortness of breath, frequent
coughing especially when lying flat, abdominal swelling and pain, dizziness, fainting, and
fatigue
10.
Signs on ECHO indicative of potential valvulopathy
•
valve regurgitation (aortic or mitral)
•
≥ mild valve regurgitation (tricuspid or pulmonary)
•
Mean Mitral valve gradient ≥ 4 mmHg
•
Mean Aortic valve gradient ≥ 15 mmHg
•
Mean Tricuspid valve gradient ≥ 4 mmHg
•
Mean Pulmonary valve gradient ≥ 21 mmHg
11. Signs on ECHO indicative of pulmonary hypertension
a.
Tricuspid Regurgitation Jet velocity > 2.8 msec with or without the following findings OR
b.
One of the following findings in the absence of being able to measure Tricuspid
Regurgitation Jet velocity:
i.
Change in right ventricle/left ventricle basal diameter ratio > 1.0
ii.
Right ventricular acceleration time < 100 msec
iii. Dilatation of the inferior caval vein (diameter>21 mm and <50% inspiratory decrease)
and/or right atrium
iv.
Change in the geometry of the interventricular septum in systole (flattening) with left
ventricular eccentricity index >1.1 in systole and/or in diastole
v.
Early diastolic pulmonary regurgitation velocity > 2.2 m/sec
vi. Tricuspid Anular Plane Systolic Excursion below 18 mm or below Z-score – 2
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Metabolic/Endocrine 
1. Elevated prolactin level ≥2x above the upper limit of normal (ULN)
2. Galactorrhea
3. Gynecomastia
4. Increase in fasting serum blood glucose ≥2x ULN
5. Hypoglycemia – serum blood glucose more than 20% below the glucose level on Day -1 value or
more than 10% below LLN (reference range 60 – 140 mg/dL)
Neuropsychiatric 
1. Serotonin syndrome (At least 3 of following symptoms must be present: Agitation, restlessness,
confusion, both increased HR and blood pressure, dilated pupils, muscle twitching, muscle
rigidity, hyperhidrosis, diarrhea, headache, shivering, tremors, both nausea and vomiting) 
2. Hallucinations
3. Psychosis
4. Euphoria
5. Mood disorders: depression and anxiety if they rise to a level of a disorder
6. Suicidal thoughts, ideation or gestures
Genitourinary 
1. Priapism
MedDRA SMQs will be employed as applicable to identify each AESI category or manually 
assigned through review. This will be completed and documented prior to study unblinding. 
Adverse events of special interests will be summarized by treatment group and by system organ 
class and preferred term for the T+M Period. 
All adverse events of special interest will listed separately. 
6.4.3 Physical Examination 
A complete physical examination will be performed at Screening Visit (Visit 1), day of 
randomization (visit 3) prior to first dose of study medication, and at the EOS visit. An 
abbreviated physical exam is performed at Day 15 (Visit 6), 43 (Visit 8), and 71 (Visit 10). A 
complete or abbreviated physical exam may be performed at the Cardiac follow-up visit for 
patients who do not enter the open-label extension study if clinically warranted.   
All physical examination results will be presented in a subject data listing, including the 
description of abnormalities. New, clinically meaningful abnormalities will be reported as 
adverse events. 
6.4.4 Neurological Examination 
A complete neurological examination will be performed at Screening Visit (Visit 1) and EOS 
(Visit 13). An abbreviated neurological examination will be performed at randomization (visit 3) 
and at Visit 6. 
Shift tables representing neurological exam results from randomization to EOS will be presented 
by body system. 
All neurological examination results will be presented in a subject data listing, including the 
description of abnormalities. 
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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 at screening visit (visit 1), randomization (visit 
3) prior to first dose of study medication, titration period (visit 6), and maintenance period (visit 8
and visit 10) and at EOS visit (visit 12).
The mean value and change from baseline to each on-study evaluation will be summarized for 
vital signs and weight by treatment group.  Vital signs, Weight and BMI data will be presented 
for each patient in a data listing. 
For each subject with a clinically meaningful abnormality in vital signs, weight, or BMI (to be 
supplied by Sponsor), a table will be produced organized by parameter that lists each subject, age, 
sex, day of most abnormal value, the most abnormal value, and the reference range. 
A listing of each subject’s values will be created. 
6.4.6 Electrocardiogram 
12-Lead ECGs data (PR, QRS, QT, QTcF, and HR) will be documented for subjects during study 
at baseline (Visit 1 and Visit 3), Day 43 (Visit 8), at End of Study (Visit 12) and at Cardiac 
Follow-up (Visit 14). 
Analysis of Echocardiograms will be included in a separate report from Biomedical Systems. 
All ECG values will be presented in the subject data listing. In addition to the subject data listing 
with all ECG values, a listing of all abnormal, clinically relevant findings will be presented 
organized by subject, by parameter, then by visit. 
6.4.7 Doppler Echocardiography 
Color Doppler echocardiography (ECHO) will be conducted at a facility with experience for the 
subject’s age at Screening, Maintenance period (Visit 8), End of study (Visit 12), and Cardiac 
Follow-up (Visit 14). ECHO uses ultrasound technology to examine the heart or blood vessels. 
An ECHO uses high frequency sound waves to create an image of the heart while the use of 
Doppler technology allows determination of the speed and direction of blood flow by utilizing the 
Doppler effect. Predetermined standard guidelines on the proper evaluation of certain 
measurements, as well as abnormality thresholds, were constructed by the sponsor’s IPCAB prior 
to study initiation. These thresholds are provided in the below table: 
Signs on ECHO indicative of potential 
Valvulopathy 
•
valve regurgitation (aortic or mitral)
•
≥ mild valve regurgitation (tricuspid,
or pulmonary)
•
Mean Mitral valve gradient ≥ 4 mmHg
•
Mean Aortic valve gradient ≥ 15
mmHg
•
Mean Tricuspid valve gradient >
4mmHg
•
Peak Pulmonary valve gradient >
21mmHg
Normal Values for Children 2-18 years 
•
No regurgitation
•
Mean Mitral valve gradient < 4 mmHg
•
Mean Aortic valve gradient < 15
mmHg
•
Mean Tricuspid valve gradient <
4mmHg
•
Peak Pulmonary valve gradient <
21mmHg
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Signs on ECHO indicative of pulmonary hypertension 
a. Tricuspid Regurgitation Jet velocity > 2.8 msec with or without the following findings OR
b. One of the following findings in the absence of being able to measure Tricuspid Regurgitation
Jet
velocity:
i. Change in right ventricle/left ventricle basal diameter ratio > 1.0
ii. Right ventricular acceleration time < 100 msec
iii. Dilatation of the inferior caval vein (diameter>21 mm and <50% inspiratory decrease) and/or
right atrium
iv. Change in the geometry of the interventricular septum in systole (flattening) with left
ventricular
eccentricity index >1.1 in systole and/or in diastole
v. Early diastolic pulmonary regurgitation velocity > 2.2 m/sec
vi. Tricuspid Anular Plane Systolic Excursion below 18 mm or below Z-score – 2
Results of ECHOs will be presented in a separate report from Biomedical Systems. 
6.4.8 Tanner Staging 
Tanner Staging will be assessed for subjects >7 years old during the study at baseline period 
(Visit 3) and End of study (Visit 12). Conceptually, pubertal maturation can be described in terms 
of sequence, timing, and tempo.  Puberty consists of a series of predictable events, and the 
sequence of changes in secondary sexual characteristics has been categorized by several groups.  
The onset and progress of pubertal changes will be recorded on a 5 point scale for boys and girls 
separately. Boys are rated for genital development and pubic hair growth through stage I to stage 
V. Girls are rated for breast development and pubic hair growth through stage I to stage V.
The number and percentage of subjects in each Tanner Stage will be presented for all visits by 
treatment group separately for boys and girls overall and also broken out for the following age 
groups: 
>7years to <=11,
>11years to <=15,
>15years to <=18.
All Tanner staging data will be presented in the subject data listing.
6.4.9 Laboratory Parameters
Laboratory safety parameters will be analyzed by a central laboratory using standard validated 
methods. 
All laboratory safety data will be collected as per the schedule of assessments given in Table 1. 
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
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kinase, gamma-glutamyl transferase (GGT), globulin, glucose, lactate dehydrogenase 
(LDH), phosphorus, potassium (K), sodium (Na), thyroid function, thyroid stimulating 
hormone (TSH), total bilirubin, direct bilirubin, total cholesterol, total protein, 
triglycerides, uric acid. 
•
Tests of growth and precocious puberty: Growth hormone (GH), insulin-like growth
factor-1 (IGF-1, low sensitivity), prolactin, Luteinizing Hormone (LH), Follicle
Stimulating Hormone (FSH), testosterone, estradiol
•
Coagulation: Prothrombin time (PT)/International normalized ratio (INR), activated
partial thromboplastin time (PTT)
•
Whole blood cannabidiol
•
Urinalysis: analysis for pH, glucose, ketones, nitrite, protein, bilirubin, urobilinogen,
leukocyte esterase, and occult blood. Microscopic analysis will be performed for blood,
all cell types, and casts.
•
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 by treatment group. Changes from baseline will also be presented for all 
continuous laboratory parameters by treatment group over time. 
Categorical laboratory parameters will be summarized by presenting the number and % of 
subjects by visit and by treatment arm. 
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 Potentially Clinically Significant (Extreme) laboratory results will be 
provided.  
6.4.10 Columbia-Suicide Severity Rating Scale 
Columbia-Suicide Severity Rating Scale data will be collected as per at screening visit (Visit 1), 
at randomization (visit 3), Titration period (at visit 6), maintenance period (at Visit 8 and 10) and 
at End of study visit (Visit 12). 
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. 
All individual subject C-SSRS data will be listed. 
Suicidal Ideation: 
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 The following outcomes are C-SSRS categories for suicidal ideation and have binary responses 
(yes/no): 
Category 
Outcome Description 
1 
Wish to be dead 
2 
Non-specific active suicidal thoughts 
3 
Active suicidal ideation with any methods (not plan) without intent to act 
4 
Active suicidal ideation with some intent to act, without specific plan 
5 
Active suicidal ideation with specific plan and intent 
Suicidal ideation is assessed as a “yes” answer at any time during the T + M 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 T + M period. The denominator will be the number of subjects
completing the C-SSRS at least once during the T + M Treatment period.
Suicidal Behavior: 
The following outcomes are C-SSRS categories for suicidal behavior and have binary responses 
(yes/no): 
Category 
Outcome Description 
6 
Preparatory acts or behavior 
7 
Aborted attempt 
8 
Interrupted attempt 
9 
Actual attempt (non-fatal) 
10 
Completed suicide 
Suicidal behavior is assessed as a “yes” answer at any time during the T + M 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 T + M period. The denominator will be the number of subjects 
completing the C-SSRS at least once during the T + M period. 
Suicidal Ideation or Behavior: 
An overall composite will be provided similar to the suicidal ideation and behavior endpoints, but 
will instead count a subject if any of the C-SSRS questions 1 through 10 are marked as ‘yes’ 
anything during the T+M period. 
Self-injurious behavior without suicidal intent: 
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The number and percentage of subjects having reported anytime during the T+M 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 and BRIEF-P) 
The Behavior Rating Inventory of Executive Function (BRIEF™)  and its preschool version, 
BRIEF-P, 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 (i.e. at Randomization (Visit 3), at Maintenance period (Visit 8) and at End of 
study visit (Visit 12)).  
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.  
For the BRIEF and the BRIEF-P, 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 
for the Safety population (SAF). 
6.5 PK/PD ANALYSIS 
The bioanalytical methods for the determination of individual plasma concentrations of 
fenfluramine and its metabolite (norfenfluramine) will be reported together with the plasma 
concentration results in separate bioanalytical reports. These bioanalytical reports will be issued 
as a separate report. 
6.6 ANALYSIS OF OTHER ASSESSMENTS 
Not applicable 
6.7 INTERIM ANALYSIS 
No formal interim analysis is planned for Study 1 However, the cohort of subjects that comprise 
Study 1 are subsets of subjects from Study 1501 and Study 1502.   
Unblinding for Study 1 will not occur until data cleaning is completed and all decisions regarding 
protocol deviations warranting exclusion from the per protocol population have been made. 
Personnel from the sponsor or any designee who become unblinded for the purposes of data 
cleaning and database lock for Study 1 will not participate in decision-making regarding subjects’ 
data for Study 2 (the remainder of subjects entering Study 1501 or Study 1502) to avoid any real 
or apparent bias in such decisions. 
6.8 INDEPENDENT DATA SAFETY MONITORING COMMITTEE 
The IDSMC is an independent advisory body that monitors participant safety, data quality and 
progress of all clinical trials. The IDSMC charter will outline the roles and responsibilities of the 
committee and guide its operations and frequency of meetings. The IDSMC will consist of 
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individuals external to the sponsor who have relevant clinical trial expertise and experience in 
safety assessment. 
At regularly defined intervals, the IDSMC will convene to review and monitor study progress, 
AEs and SAEs, other measures of safety such as ECGs or ECHOs, and efficacy data as dictated 
by the charter. 
The 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.
The list of tables, listings, and figures will be provided to the IDSMC as per IDSMC charter. 
6.9 CHANGES TO METHODS PLANNED IN THE PROTOCOL  
•
The 1501 and 1502 protocols set a target that 40% of enrolled subjects to be less than 6
years old, but candidate subjects have been older than expected. Consequently, the
enrollment target has been revised to ensure that at least 25% of subjects are less than 6
years old.
•
Protocols 1501 and 1502 state that efficacy and safety endpoints will be repeated
separately for the titration and maintenance periods, however this is not planned to be
conducted –Data from the T+M Period will be summarized and analyzed for all
endpoints, and separate analyses of titration or maintenance periods will be generated
only for selected endpoints.
•
Protocols 1501 and 1502 state that analyses of safety data will be presented by treatment
actually received. However, safety data will be presented by randomized treatment group
except where noted otherwise.
•
Protocols 1501 and 1502 provide sample size calculations to support a total study sample
of 105 subjects, 35 per treatment group.  A revised sample size calculation has increased
the sample size to 40 subjects per treatment group, for a total of approximately120
subjects.
•
Protocols 1501 and 1502 state that a sensitivity analysis for the primary efficacy endpoint
will be conducted by adding a factor indicating whether a subject had a change in
prescribed dose or type of concomitant AED medication during the T+M Period,
however this is not planned to be conducted. Instead it is planned to compare the
treatment groups with respect to the proportion of subjects who changed dose and/or type
of AED concomitant medication during the T+M Period.
•
Protocols 1501 and 1502 state that the longest interval between convulsive seizures will
be analyzed using a log-rank test. However, further considerations of this endpoint
suggest that while the first seizure-free interval may be subject to independent censoring,
the second and later seizure-free intervals are subject to dependent censoring. Moreover,
the last seizure-free interval is subject to intercept sampling, hence a longer seizure-free
interval is more likely to be censored. Finally, the number of seizures or seizure-free
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intervals is informative about the underlying distribution, as subjects at a higher risk of 
experiencing recurrent events are likely to have shorter and hence more seizure-free 
intervals during the 84 day treatment period. Thus, a simple analysis comparing medians 
of the largest seizure free intervals was proposed.  
•
Responder analyses – Protocols 1501 and 1502 include a ≥40% response analysis as one
of the key secondary endpoints. It was decided to not include this endpoint.
•
An analysis of the percentage of subjects who achieve a 25% reduction in seizures was
added. The number of subjects whose seizures worsen during the study will be included,
along with the percentage of worsening.
•
The Protocol states that the BRIEF rating scale will be used to evaluate cognition in
children aged 2-18.  The BRIEF-P will be used for children aged 2-4, and the BRIEF will
evaluate children aged 5-18.
•
Interim analysis – Protocols 1501 and 1502 do not delineate an interim analysis.
However, this Study 1 Analysis Plan is a pooled analysis of data from the first 120
subjects to be randomized into studies 1501 and 1502, in order to assess the benefit and
risk at an earlier timepoint than fully recruiting each trial independently.  Both studies
will continue to enroll, and the remaining approximately 120 subjects will be analyzed as
Study 2, under a separate analysis plan.
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. 
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. 
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. 
ICH Topic E2F: Development Safety Update Report, 2011. 
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. 
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8. APPENDICES
APPENDIX 1:  LIST OF PLANNED TABLES, FIGURES AND LISTINGS 
Table/ 
Figure/ 
Listing 
Number 
Table Header 
14.1 
Demographic data and other baseline characteristics 
14.1.1 
Subject disposition 
Table 
14.1.1.1 
Overall subject disposition – all enrolled subjects 
Table 
14.1.1.2 
Major protocol deviations – Safety Population 
Table 
14.1.1.3 
Study Populations 
14.1.2 
 Demographic and other baseline characteristics 
Table 
14.1.2.1 
Demographic and Baseline Characteristics – Safety Population 
Table 
14.1.2.2 
Demographic and Baseline Characteristics – mITT Population 
14.1.3 
Medical history 
Table 
14.1.3.1 
Medical history– Safety Population 
14.1.4 
Prior and concomitant medication/treatment 
Table 
14.1.4.1 
Prior medications – Safety Population 
Table 
14.1.4.2 
Concomitant medications – Safety Population 
Table 
14.1.4.3 
Prior Antiepileptic Treatment – Safety Population 
Table 
14.1.4.4.1 
Concomitant Antiepileptic Treatment  – Safety Population 
Table 
14.1.4.4.2 
Number of Subjects by Number of Concomitant Antiepileptic 
Treatments 
14.1.5 
Treatment Exposure and compliance 
Table 
14.1.5.1 
Duration of Treatment Exposure – Safety Population 
Table 
14.1.5.2 
Compliance to IMP intake  – Safety Population  
14.2 
Efficacy, pharmacokinetics, and pharmacodynamics 
14.2.1 
Efficacy – ZX008 0.8 and 0.2 mg/kg/day vs Placebo 
Table 
14.2.1.1.1 
Convulsive seizure frequency per 28 days : Summary Statistics – 
mITT Population 
Table 
14.2.1.1.2 
Convulsive seizure frequency per 28 days, by Age Group : 
Summary Statistics – mITT Population 
Table 
14.2.1.2 
Convulsive seizure frequency per 28 days : Parametric Analysis 
– mITT Population
Table 
14.2.1.3 
Convulsive seizure frequency per 28 days : Nonparametric 
Analysis – mITT Population 
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Table 
14.2.1.4 
% Change in convulsive seizure frequency per 28 days: 
Parametric Analysis – mITT Population 
Table 
14.2.1.5 
% Change in convulsive seizure frequency per 28 days : 
Nonparametric Analysis – mITT Population 
Table 
14.2.1.6 
Mean change in convulsive seizure frequency – exploratory 
efficacy analysis of subjects who are SCN1A mutation positive, 
vs all else – mITT Population (if sufficient number of  subjects 
are not SCN1A positive) 
Table 
14.2.1.7 
Convulsive seizure frequency per 28 days : Parametric Analysis 
– PP Population
Table 
14.2.1.8 
Convulsive seizure frequency per 28 days : Nonparametric 
Analysis – PP Population 
Table 
14.2.1.9 
% Change in convulsive seizure frequency per 28 days: 
Parametric Analysis – PP Population 
Table 
14.2.1.10 
% Change in convulsive seizure frequency per 28 days : 
Nonparametric Analysis – PP Population 
Table 
14.2.1.11 
Convulsive seizure frequency per 28 days by baseline convulsive 
seizure frequency category: Parametric Analysis -  mITT 
Population 
14.2.2 
Efficacy – Proportion of subjects who achieve various % 
reductions in convulsive seizure frequency 
Table 
14.2.2.1 
Percent reduction in convulsive seizure frequency – mITT 
population 
Figure 
14.2.2.2.1 
Cumulative Response Curve for - % subjects experiencing 
various % reductions in convulsive seizure frequency 
Figure 
14.2.2.2.2 
Cumulative Response Curve for - % subjects experiencing 
various % reductions in convulsive seizure frequency – All 
subjects increased and decreased 
Table 
14.2.2.3 
Percent reduction in convulsive seizure frequency  – PP 
Population <Only create if PP and mITT different> 
Figure 
14.2.2.4 
 Cumulative Response Curve for - % subjects experiencing 
various % reductions in convulsive seizure frequency - PP 
Population <Only create if PP and mITT different> 
14.2.3 
Efficacy – Longest  interval between convulsive seizures 
Table 
14.2.3.1 
Longest interval between convulsive seizures – mITT Population 
Figure 
14.2.3.2 
Histogram of  longest interval between convulsive seizures – 
mITT Population 
Table 
14.2.3.3 
Longest interval between convulsive seizures – PP Population 
<Only create if PP and mITT different> 
Figure 
14.2.3.4 
Histogram of  longest interval between convulsive seizures – PP 
Population <Only create if PP and mITT different> 
14.2.4 
Efficacy – Number of convulsive seizure free days 
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Table 
14.2.4.1 
Number of convulsive seizure free days –Parametric Analysis - 
mITT Population 
Table 
14.2.4.2 
Number of convulsive seizure free days - Nonparametric 
Analysis – mITT Population 
14.2.6 
Efficacy – Change from baseline in non-convulsive and 
convulsive + non-convulsive seizure frequency 
Table 
14.2.6.1 
Change from baseline in non-convulsive seizure 
frequency:Nonparametric Analysis –mITT Population, 
Table 
14.2.6.2 
Change from baseline in convulsive + non-convulsive  seizure 
frequency, , Nonparametric Analysis –mITT Population –  
14.2.7 
Efficacy – Incidence of rescue medication 
Table 
14.2.7.1 
Days with Rescue Medication Usage,  – mITT Population 
Table 
14.2.7.2 
Days with Rescue Medication Usage,  – PP Population <Only 
create if PP and mITT different> 
Table 
14.2.7.3 
Number of Rescue Medications per Episode – mITT Population 
14.2.8 
Efficacy – Hospitalization and Resource Utilization for 
Treatment of Seizures  
Table 
14.2.8.1 
Hospitalization and Other Healthcare Resource Utilization to 
Treat Seizure -  – mITT Population 
14.2.9 
Efficacy – Incidence of Status Epilepticus, and duration of 
prolonged seizures 
Table 
14.2.9. 1 
Number of episodes of status epilepticus,   - mITT Population 
Table 
14.2.9. 2 
Duration of Seizures -  - mITT Population 
14.2.10 
Efficacy – Clinical Global Impression – Improvement rating 
by Parent/Caregiver and Investigator 
Table 
14.2.10.1 
Clinical Global Impression, Parent/Caregiver Rating – mITT 
Population 
Figure 
14.2.10.2 
Clinical Global Impression, Parent/Caregiver Rating – mITT 
Population 
Table 
14.2.10.3 
Clinical Global Impression, Investigator Rating – mITT 
Population 
Figure 
14.2.10.4 
Clinical Global Impression, Investigator Rating – mITT 
Population 
14.2.11 
Efficacy – Quality of Life in Childhood Epilepsy Scale 
Table 
14.2.11.1 
Quality of Life in Childhood Epilepsy (QOLCE)  – mITT 
population 
14.2.12 
Efficacy – Peds QL 
Table 
14.2.12.1 
PedsQL Pediatric Quality of Life Inventory (Version 4.0) - 
Parent Report – mITT Population 
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Table 
14.2.12.2 
PedsQL Family Impact Module (Version 2.0) – Parent Report – 
mITT Population 
14.2.13 
Efficacy –Quality of Life of the Parent /Caregiver using EQ-
5D-5L Scale 
Table 
14.2.13.1 
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 
Efficacy –Parent /Caregiver Ratings 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): Summary Descriptive Statistics – 
mITT population 
14.3 
Safety 
14.3.1 
Summary of adverse events 
Table 
14.3.1.1 
Overview of number of subjects with TEAE, DB Treatment 
Period  – Safety Population 
Table 
14.3.1.2 
Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term – Safety Population  
Table 
14.3.1.3 
TEAEs leading to study discontinuation by primary SOC and PT 
– Safety Population
Table 
14.3.1.4 
Serious TEAEs by primary SOC and PT – Safety Population
Table 
14.3.1.5 
Related TEAEs by primary SOC and PT – Safety Population
Table 
14.3.1.6 
TEAEs by Maximum Severity by SOC and PT– Safety 
Population  
Table 
14.3.1.7 
Treatment-Emergent Adverse Events occurring in ≥5% of 
subjects by MedDRA System Organ Class and Preferred Term - 
Safety Population  
Table 
14.3.1.8 
Overview of  number of subjects with Treatment-Emergent 
Adverse Events of Special Interest – Safety Population 
Table 
14.3.1.9 
Treatment-Emergent Adverse Events of Special Interest (AESI) 
by SOC and PT – Safety Population 
14.3.2 
Listings of Deaths, Other Serious and Significant Adverse 
Events 
Table 
14.3.2.1 
Listing of Deaths 
Table 
14.3.2.2 
Listing of SAEs 
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Table 
14.3.2.3 
Listing of Discontinuations Due to AE 
14.3.4 
Summary of Laboratory Data 
Table 
14.3.4.1 
Laboratory parameters – Hematology– Safety Population 
Table 
14.3.4.2 
Laboratory parameters – Biochemistry– Safety Population 
Table 
14.3.4.4 
Laboratory parameters – Urinalysis – Safety Population 
Table 
14.3.4.4.1 
Laboratory parameters – Urinalysis (Quantitative parameters) – 
Safety Population 
Table 
14.3.4.4.2 
Laboratory parameters – Urinalysis (Categorical parameters) – 
Safety Population 
Table 
14.3.4.5 
Laboratory parameters – Tests of growth and precocious puberty 
–Safety Population
Table 
14.3.4.6 
Laboratory parameters – Epilepsy genotype panel – descriptive 
statistics – Safety Population 
14.4.1 
Vital Signs 
Table 
14.4.1.1 
Vital signs parameters – Safety Population 
14.4.4 
Tanner Staging 
Table 
14.4.4.1 
Tanner staging by age group for Boys– Safety Population 
Table 
14.4.4.2 
Tanner staging by age group for Girls– Safety Population 
14.4.5 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Table 
14.4.5.1 
Number of Patients with Suicidal Ideation, Suicidal Behavior, 
and Self-Injurious Behavior without Suicidal Intent Based on the 
C-SSRS  – Safety Population
Table 
14.4.5.2 
Columbia Suicide Severity-Rating Scale (C-SSRS)- Shift Table 
of Changes in C-SSRS Categories During Treatment - Safety 
Population 
14.4.6 
Brief Rating Inventory of Executive Function- (BRIEF) 
Table 
14.4.6.1 
 BRIEF-P – Scoring summary table by treatment group – Safety 
Population  
Table 
14.4.6.2 
BRIEF – Scoring summary table by treatment group – Safety 
Population 
16.1.9.2 
Statistical Output 
Output 
16.1.9.2.1 
Output from Primary Efficacy Analysis 
Output 
16.1.9.2.2 
Output from Secondary Efficacy Analyses 
16.2 
Subject data listing 
16.2.1 
Subject disposition and discontinuation 
Listing 
16.2.1.1 
Subject completion/discontinuation 
16.2.2 
Protocol deviations 
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Listing 
16.2.2.1 
Protocol deviations 
16.2.3 
Subjects excluded from analysis 
Listing 
16.2.3.1 
Violation of inclusion/exclusion and/or randomization inclusion 
criteria  
Listing 
16.2.3.2 
Subject allocation to trial populations 
16.2.4 
Demographic data and other baseline characteristics 
Listing 
16.2.4.1 
Demographic data  
Listing 
16.2.4.2 
Medical history  
Listing 
16.2.4.3 
Prior and concomitant medications and therapies/treatments 
Listing 
16.2.4.4 
Prior and concomitant antiepileptic Drugs (AEDs) 
Listing 
16.2.4.5 
Rescue Medications 
16.2.5 
Treatment exposure and compliance 
Listing 
16.2.5.1 
IMP Intake per day during Treatment  
Listing 
16.2.5.2 
IMP Intake – self reported compliance with dosing 
Listing 
16.2.5.3 
Drug Accountability  
16.2.6 
Efficacy data 
Listing 
16.2.6.1 
Convulsive seizure – duration and number of occurrences per 
subject (Diary data)  
Listing 
16.2.6.2 
Non-Convulsive seizure – by type, duration and number of 
occurrences per subject (Diary data)  
Listing 
16.2.6.3 
Longest interval between convulsive seizures and convulsive 
seizure free days per subject 
Listing 
16.2.6.4 
Percent reduction in convulsive seizure frequency from baseline 
Listing 
16.2.6.5 
Clinical Global Impression – Improvement rating as assessed by 
the Parent/Caregiver and Investigator 
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 
Parent/Caregiver Ratings 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)
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Listing 
16.2.6.9.5 
Pediatric Quality of Life Inventory (Peds QL) – Family Impact 
Module 
16.2.7 
Adverse events 
Listing 
16.2.7.1 
Adverse events 
Listing 
16.2.7.2 
Adverse events of special interests (AESI) 
16.2.8 
Laboratory data 
Listing 
16.2.8.1.1 
Laboratory Data Hematology parameters 
Listing 
16.2.8.1.2 
Extreme Value Laboratory Parameters - Hematology 
Listing 
16.2.8.2.1 
Laboratory Data Biochemistry parameters 
Listing 
16.2.8.2.2 
Extreme Value Laboratory Parameters - Biochemistry 
Listing 
16.2.8.3.1 
Laboratory Data Coagulation parameters 
Listing 
16.2.8.3.2 
Extreme Value Laboratory Parameters – Coagulation  
Listing 
16.2.8.4.1 
Laboratory Data Urinalysis parameters 
Listing 
16.2.8.4.2 
Extreme Value Urinalysis Data 
Listing 
16.2.8.5 
Tests of growth and precocious puberty 
Listing 
16.2.8.6 
Urine Pregnancy test  
Listing 
16.2.8.7 
Urine THC panel 
Listing 
16.2.8.8 
Whole blood cannabidiol 
16.2.9 
Other Safety Data 
Listing 
16.2.9.1.1 
Vital signs  
Listing 
16.2.9.1.2 
Abnormal Vital Signs Data 
Listing 
16.2.9.2 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Listing 
16.2.9.3.1 
Behavior Rating Inventory of Executive Function – Preschool 
Version (BRIEF-P) 
Listing 
16.2.9.3.2 
Behavior Rating Inventory of Executive Function (BRIEF) 
Listing 
16.2.9.4 
Tanner Staging 
Listing 
16.2.9.5 
Physical Examination  
Listing 
16.2.9.6 
Neurological Examination 
Listing 
16.2.9.7 
Epilepsy genotype panel 
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16.1.9 
Documentation of Statistical Methods 
The document listed below is provided in this section. 
Statistical Analysis Plan (Study ZX008-1501 & Study ZX008-1502) dated 21-May-2020
Statistical Analysis Plan (Study ZX008-1501 & Study ZX008-1502) for Cardiovascular Endpoints 
dated 09-June-2020 
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Statistical Analysis Plan 
Sponsor: Zogenix International Limited; Protocol No.: ZX008 Study 2 (ZX008-1501 and ZX008-1502) 
 
This document is confidential. 
SAP Version: Final 1.0 21-May-2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 1 of 78 
Statistical Analysis Plan for Interventional Studies 
 
Sponsor Name: Zogenix International Limited 
 
Protocol Number: ZX008 Study 2 (ZX008-1501 and ZX008-1502) 
 
Protocol Title: A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Trial of Two 
Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children 
and Young Adults with Dravet Syndrome 
 
Protocol Version and Date: ZX008-1501: 02-Nov-2015 Version 1.3 
18-Dec-2015 (Amendment 1.0)  
18-Jan-2016 (Amendment 2.0) 
              31-Oct-2016 (Amendment 3.0 ) 
             
            ZX008-1502: 30-Oct-2015 Version 1.0  
 
        11-Jan-2016 (Amendment 1.0)  
                                                            31-Oct-2016 (Amendment 2.0)  
                                                            07-Feb-2019 (Amendment 2.4.3) 
 
 
Syneos Health Project Code: 7012988 
 
 
  
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Zogenix International Limited. 
Acceptance of this document constitutes agreement by the recipient that no information contained herein 
will be published or disclosed without prior written authorization from an official of Zogenix International 
Limited. However, this document may be disclosed to appropriate Institutional Review Board and Ethics 
Committees or duly authorized representatives of a national regulatory authority under the condition that 
they are requested to keep it confidential. In the event of an actual or suspected breach of this obligation, 
Syneos Health should be notified promptly. 
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application and any extensions or variations thereof. 


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Statistical Analysis Plan 
Sponsor: Zogenix International Limited; Protocol No.: ZX008 Study 2 (ZX008-1501 and ZX008-1502) 
 
 
 
This document is confidential. 
SAP Version: Final 1.0 21-May-2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 4 of 78 
Table of Contents 
Revision History ...................................................................................................................... 2 
Approvals .............................................................................................................................. 3 
SCOPE ................................................................................................................................. 10 
1. 
Purpose ........................................................................................................................ 11 
1.1. 
Responsibilities ................................................................................................. 11 
1.2. 
Timings of Analyses........................................................................................... 11 
2. 
Study Objectives ........................................................................................................... 12 
2.1. 
Primary Objective .............................................................................................. 12 
2.2. 
Secondary Objective(s)...................................................................................... 12 
2.3. 
Brief Description ................................................................................................ 13 
2.4. 
Subject Selection ............................................................................................... 14 
2.5. 
Determination of Sample Size ............................................................................ 14 
2.6. 
Treatment Assignment & Blinding ...................................................................... 14 
2.7. 
Administration of Study Medication .................................................................... 15 
2.8. 
Study Procedures and Flowchart........................................................................ 17 
3. 
Endpoints ..................................................................................................................... 21 
3.1. 
Primary Efficacy Endpoint .................................................................................. 21 
4.1. 
Pharmacokinetic Endpoints................................................................................ 22 
4.2. 
Safety Endpoints ............................................................................................... 22 
4.3. 
Exploratory Endpoints........................................................................................ 22 
5. 
Analysis Populations ..................................................................................................... 23 
5.1. 
Randomized / Enrolled Population ..................................................................... 23 
5.2. 
Safety (SAF) Population .................................................................................... 23 
5.3. 
Modified Intent-to-Treat (mITT) Population ......................................................... 23 
5.4. 
Per Protocol (PP) Population ............................................................................. 23 
5.5. 
Protocol Deviations ............................................................................................ 23 
6. 
General Aspects for Statistical Analysis ......................................................................... 24 
6.1. 
General Methods ............................................................................................... 24 
6.2. 
Key Definitions .................................................................................................. 24 
6.3. 
Multiplicity Strategy and Testing Hierarchy ......................................................... 24 
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Statistical Analysis Plan 
Sponsor: Zogenix International Limited; Protocol No.: ZX008 Study 2 (ZX008-1501 and ZX008-1502) 
 
 
 
This document is confidential. 
SAP Version: Final 1.0 21-May-2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 5 of 78 
6.4. 
Missing Data...................................................................................................... 25 
6.5. 
Visit Windows .................................................................................................... 28 
6.6. 
Pooling of Centers ............................................................................................. 29 
6.7. 
Subgroups......................................................................................................... 29 
7. 
Demographic, Other Baseline Characteristics and Medication........................................ 30 
7.1. 
Subject Disposition and Withdrawals .................................................................. 30 
7.2. 
Demographic and Other Baseline Characteristics ............................................... 30 
7.3. 
Medical History and Concomitant Diseases ........................................................ 31 
7.4. 
Other Baseline Characteristics ........................................................................... 31 
7.5. 
Medication ......................................................................................................... 31 
7.5.1. 
Prior Medication and Concomitant Medication .............................................31 
7.5.2. 
Prior and Concomitant Antiepileptic Treatments ...........................................32 
8. 
Efficacy......................................................................................................................... 33 
8.1. 
Primary Efficacy Endpoint and Analysis.............................................................. 33 
8.2. 
Secondary Efficacy Endpoint(s) and Analyses .................................................... 35 
8.2.1. 
Key Secondary Analysis...........................................................................35 
8.2.2. 
Additional Secondary Endpoint Analysis .....................................................37 
8.2.3. 
Exploratory Analyses ...............................................................................45 
9. 
Analysis Of Pharmacokinetics ....................................................................................... 46 
10. Safety ........................................................................................................................... 47 
10.1. Extent of Exposure ............................................................................................ 47 
10.2. Treatment Compliance....................................................................................... 47 
10.3. Adverse Events ................................................................................................. 47 
10.4. Laboratory Evaluations ...................................................................................... 51 
10.5. Vital Signs ......................................................................................................... 52 
10.6. ECG .................................................................................................................. 52 
10.7. Doppler Echocardiography................................................................................. 53 
10.8. Physical Examination......................................................................................... 53 
10.9. Neurological Examination .................................................................................. 53 
10.10. Tanner Staging .................................................................................................. 53 
10.11. Columbia-Suicide Severity Rating Scale............................................................. 54 
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Statistical Analysis Plan 
Sponsor: Zogenix International Limited; Protocol No.: ZX008 Study 2 (ZX008-1501 and ZX008-1502) 
 
 
 
This document is confidential. 
SAP Version: Final 1.0 21-May-2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 6 of 78 
10.12. Brief Rating Inventory of Executive Function (BRIEF and BRIEF-P) .................... 55 
11. Interim Analyses ........................................................................................................... 56 
12. Changes from Analysis Planned in Protocol................................................................... 57 
13. Programming Considerations ........................................................................................ 59 
13.1. General Considerations ..................................................................................... 59 
13.2. Table, Listing, and Figure Format....................................................................... 59 
13.2.1. 
General .................................................................................................59 
13.2.2. 
Headers.................................................................................................59 
13.2.3. 
Display Titles ..........................................................................................60 
13.2.4. 
Column Headers .....................................................................................60 
13.2.5. 
Body of the Data Display ..........................................................................60 
13.2.6. 
Footnotes ..............................................................................................63 
14. Quality Control .............................................................................................................. 64 
15. Index of Tables, Figures and Listings ............................................................................ 65 
16. Reference List .............................................................................................................. 78 
 
 
 
 
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Statistical Analysis Plan 
Sponsor: Zogenix International Limited; Protocol No.: ZX008 Study 2 (ZX008-1501 and ZX008-1502) 
 
 
 
This document is confidential. 
SAP Version: Final 1.0 21-May-2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 10 of 78 
SCOPE 
Zogenix is conducting two identical Phase 3 studies of ZX008, Study ZX008-1501 (Study 1501) and 
Study ZX008-1502 (Study 1502). Study 1501 is being conducted in the United States and Canada; 
Study 1502 is being conducted in Europe, Australia and Japan. Approximately 120 subjects with 
Dravet syndrome, a rare form of pediatric epilepsy, are planned for randomization into each study in 
three treatment groups: 0.2 mg/kg/day ZX008, 0.8 mg/kg/day ZX008 and placebo (n=40/group). Due 
to slow enrollment into both trials, the databases for the two trials were combined and the first 120 
subjects randomized were analyzed and reported as Study 1.  Additional randomized subjects (over 
N=120) are intended to be reported as Study 2, and are  covered in this Statistical Analysis Plan 
(SAP).  Primary and key secondary analyses in the Study 2 SAP remain as stated in the protocols 
and as described in the Study 2 draft SAP with some changes delineated in this SAP based on FDA 
feedback.  
 
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Statistical Analysis Plan 
Sponsor: Zogenix International Limited; Protocol No.: ZX008 Study 2 (ZX008-1501 and ZX008-1502) 
 
 
 
This document is confidential. 
SAP Version: Final 1.0 21-May-2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 11 of 78 
1. 
Purpose 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables and 
figures which will be produced, and the statistical methodologies that will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives, and allow for review by regulatory 
authorities according to stated guidelines. 
This Statistical Analysis Plan (SAP) is based on the protocols for Study ZX008-1501 version 3.0 dated 
Oct 31, 2016, and Study ZX008-1502 version 2.4.3 dated Feb 7, 2019.  The two protocols are identical in 
design, conduct, and randomization scheme; the latest amendment for Study 1502 added Japan. 
1.1. 
Responsibilities 
Syneos Health will perform the statistical analyses and are responsible for the production and quality 
control of all tables, figures and listings with the exception of pharmacokinetics (PK), electrocardiogram 
(ECG), and echocardiogram (ECHO).  
There are separate analysis plans for PK and for electrocardiogram (ECG) and echocardiogram (ECHO) 
data .  
ERT (formerly BioMedical Systems), will provide analyses of ECG and ECHO data. 
1.2. 
Timings of Analyses 
The primary analysis of safety and efficacy is planned after all subjects complete the final study visit or 
terminate early from the study, and after all databases are locked. 
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Statistical Analysis Plan 
Sponsor: Zogenix International Limited; Protocol No.: ZX008 Study 2 (ZX008-1501 and ZX008-1502) 
 
 
 
This document is confidential. 
SAP Version: Final 1.0 21-May-2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 12 of 78 
2. 
Study Objectives 
2.1. 
Primary Objective 
The primary objective of Study 2 is: 
• 
To demonstrate that ZX008 0.8 mg/kg/day is superior to placebo as adjunctive therapy in the 
treatment of Dravet syndrome 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). 
2.2. 
Secondary Objective(s) 
The key secondary objectives of Study 2 are: 
 
• 
To demonstrate that ZX008 0.2 mg/kg/day is superior to placebo as adjunctive therapy in the 
treatment of Dravet syndrome based on change in the frequency of convulsive seizures between 
baseline and T+M. 
• 
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) superior 
to placebo on the following endpoints: 
o The proportion of subjects who achieve a ≥50% reduction from baseline in convulsive 
seizure frequency. 
o The longest convulsive seizure-free interval. 
 
Additional Secondary Objectives: 
 
• 
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) superior 
to placebo on the following endpoints: 
o The number of convulsive seizure-free days. 
o The proportion of subjects who achieve ≥25%, or ≥75%, or 100%, or near seizure-free (ie, 
at most 1 convulsive seizure)  reductions from baseline in convulsive seizure frequency. 
o The change from baseline in non-convulsive seizure frequency. 
o The change from baseline in convulsive + non-convulsive seizure frequency 
o The incidence of rescue medication usage 
o The incidence of hospitalization to treat seizures 
o The incidence of status epilepticus. 
• 
To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) superior 
to placebo on the following endpoints: 
o Clinical Global Impression – Improvement rating, as assessed by the principal 
investigator. 
o Clinical Global Impression – Improvement rating, as assessed by the parent/caregiver. 
o The change from baseline in the Quality of Life in Childhood Epilepsy (QOLCE) score. 
o The change from baseline in the Pediatric Quality of Life Inventory™ (PedsQL) score. 
o The change from baseline in the PedsQL Family Impact module score. 
o The change from baseline in the QoL of the parent/caregiver using the EQ-5D-5L scale. 
o The change from baseline in the affective symptoms of the parent/caregiver using the 
Hospital Anxiety and Depression Scale (HADS). 
 
The safety objective of the Study 2 is: 
 
• 
To compare the safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day to placebo with regard to 
AEs, laboratory parameters, physical examination, neurological examination, vital signs (blood 
pressure, heart rate [HR], temperature, and respiratory rate), ECGs, ECHOs, and bodyweight. 
Cognitive function will be assessed using age-appropriate versions of the Brief Rating Inventory of 
Executive Function (BRIEF). 
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Statistical Analysis Plan 
Sponsor: Zogenix International Limited; Protocol No.: ZX008 Study 2 (ZX008-1501 and ZX008-1502) 
 
 
 
This document is confidential. 
SAP Version: Final 1.0 21-May-2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 13 of 78 
Pharmacokinetic Objective: 
 
• 
The pharmacokinetic (PK) objective of Study 2 is: 
• 
To characterize the PK of ZX008 0.2 and 0.8 mg/kg/day at steady state in subjects ages 2-6 years 
and >6-18 years with Dravet syndrome. 
 
Exploratory Objective 
 
The exploratory objective of the Study 2 is: 
• 
To compare the ZX008 0.2 and 0.8 mg/kg/day doses on primary, secondary, safety and PK 
endpoints. 
 
2.3. 
Brief Description 
Both Study 1501 and Study 1502 are multicenter, double-blind, parallel-group, placebo-controlled 
studies designed to assess the efficacy, safety, and PK of ZX008 when used as adjunctive therapy in 
pediatric and young adult subjects with Dravet syndrome. Study 1501 was conducted at approximately 
30 study sites in North America; Study 1502 was conducted at approximately 30 study sites in Europe, 
Australia, and Japan. For Study 1502 Japan was added in 2019 whereas Europe and Australia started 
in 2015. Approximately 36 sites will contribute randomized subjects to Study 1502. 
The expected study period of 22 weeks comprises a Baseline period (6 weeks), a Treatment period (14 
weeks) (2 weeks titration + 12 weeks maintenance), and a Post Dosing visit 2 weeks after study 
completion or early termination.   
Upon study completion, eligible subjects will be able to receive ZX008 in an open-label extension study 
for up to 1 additional year of treatment.  There will be cardiac safety follow-up of 3 to 6 months after study 
drug discontinuation for early termination or for subjects who complete the study but do not enroll in the 
open-label extension study. Subjects from France, Germany and the Netherlands will have a cardiac 
safety follow-up visit approximately 24 months after the last dose of active study medication. Follow-up 
safety visit results will be reported separately.  
Upon completion of the Baseline Period, subjects who qualify for the study will be randomized (1:1:1) in a 
double-blind manner to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; 30mg/day 
maximum) or placebo. The randomization will be stratified by age (<6 years, ≥6 years) to ensure balance 
across treatment arms, with the target of 25% of subjects in each age group. Subjects will be assigned a 
randomization number by the IWR system upon confirmation that subject qualifies for enrollment in the 
Titration Period. Once a randomization number is assigned to a subject, the site will record the subject’s 
initials and identification number on the corresponding study drug bottles. Each bottle will contain the 
assigned treatment (ZX008 0.2 mg/kg/day, ZX008 0.8 mg/kg/day, or placebo). ZX008 and placebo will be 
identical, thus rendering the study drug and placebo indistinguishable. The randomization scheme and 
block size for Studies 1501 and 1502 are the same, so combination of the data from the two studies will 
not skew the intended randomization into the three treatment groups.  
Due to slow enrollment, Studies 1501 and 1502 were merged into a single dataset for analysis and 
reporting. The first 119 subjects randomized comprised Study 1, which was reported in September 2017. 
This analysis enabled an earlier determination of the benefit-risk profile of ZX008, to minimize the total 
subject exposures should the risk-benefit profile not be positive.  The subsequent approximately 120 
subjects to be randomized, comprise Study 2. Study 2 represents the cohort of subjects in Studies 1501 
and 1502 whose data were not included in Study 1. 
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Statistical Analysis Plan 
Sponsor: Zogenix International Limited; Protocol No.: ZX008 Study 2 (ZX008-1501 and ZX008-1502) 
 
 
 
This document is confidential. 
SAP Version: Final 1.0 21-May-2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 14 of 78 
Study 1501 and Study 1502 are being conducted in parallel with each study independently assigning 
treatments using randomized permuted blocks; thus, combining subjects from the two identically 
designed studies meant that 2 sets of randomized blocks were used, which had approximately the same 
effect as doubling the block size in a single study.  Combining the first 120 randomized subjects from 
Study 1501 and Study 1502 to create Study 1 and Study 2 preserves the balance among the 3 treatment 
groups in each of Study 1 and Study 2, yielding approximately 40 subjects per arm, the number required 
to maintain full statistical power. 
After the last of the subjects in Study 2 has either discontinued or completed treatment, the database 
will be locked for those subjects and Study 2 will be reported as per this SAP. 
2.4. 
Subject Selection 
The study population will be selected on the basis of the inclusion and exclusion criteria described in the 
protocol. 
 
2.5. 
Determination of Sample Size 
The sample sizes for Zogenix Studies 1501 and 1502 were calculated based on the results of two trials 
with stiripentol reported in the European Public Assessment Report (EPAR) for stiripentol (EMA, 2007). 
The stiripentol EPAR summarizes the results from two studies: STICLO France and STICLO Italy. In the 
stiripentol groups, the standard deviation (SD) of the percentage change in seizure frequency from 
baseline to month 2 was 42% in the French trial and 26% in the Italian trial. The analogous SDs for 
placebo groups were 38% and 62%. An SD of 50% was assumed for the primary analysis in Protocols 
1501 and 1502 that compares ZX008 0.8 mg/kg/day to placebo on the change from baseline in seizure 
frequency. Using a two-sided test at the α=0.05 significance level, a sample size of 35 subjects per 
treatment group affords 90% power to detect a difference in mean change from baseline of 40 percentage 
points. Similar assumptions and calculations yielded a requirement for an additional 35 subjects in the 0.2 
mg/kg/day ZX008 group. The total sample size for each study was therefore set at 105 subjects. 
 
In December 2016 results from a double-blind, placebo-controlled Phase 3 study with Epidiolex® 
(cannabidiol) to treat seizures in Dravet syndrome were presented at the American Epilepsy Society 
Meeting (http://ir.gwpharm.com/events.cfm). In the Epidiolex study, active drug reduced seizures by 39% 
compared to a reduction of 13% in the placebo.  Review of the data suggested that the standard deviation 
was relatively large, likely above 50% in both treatment groups.  In consideration of this new data, the 
sample size was re-estimated for the ZX008 studies to assume a SD of 55%, higher than the previous 
estimate of 50%.  Other assumptions in the sample size calculation remained unchanged. A sample size 
of approximately 120 subjects (40 per arm) affords 90% power to detect a difference in mean change 
from baseline of 40 percentage points with 55% SD.  Considering the variability seen in the STILCO and 
Epidiolex trials, the sample size for Study 1 and Study 2 is set at 120 subjects, 40 per treatment arm. 
Note that the change in assumed SD was based entirely on data from external trials. Efficacy data from 
both Study 1501 and 1502 are still blinded and were not used in re-estimating the required sample size.  
 
2.6. 
Treatment Assignment & Blinding 
Subjects in Study 2 were originally in either Study 1501 or Study 1502. Upon completion of the 
Baseline Period, subjects who qualify for the study will be randomized (1:1:1) in a double-blind manner 
to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; 30mg/day maximum) or placebo. The 
randomization was stratified by age (<6 years, ≥6 years) to ensure balance across treatment arms, with 
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Statistical Analysis Plan 
Sponsor: Zogenix International Limited; Protocol No.: ZX008 Study 2 (ZX008-1501 and ZX008-1502) 
 
 
 
This document is confidential. 
SAP Version: Final 1.0 21-May-2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 15 of 78 
a target of ≥25% of subjects in each age group. Subjects were assigned a randomization number by 
IWR system upon confirmation that the subject qualified for enrollment in the Titration Period. Once a 
randomization number was assigned to a subject, the site recorded the subject’s initials and 
identification number on the corresponding study drug bottles.  
Each bottle contained the assigned treatment (ZX008 0.2 mg/kg/day, ZX008 0.8 mg/kg/day, or 
placebo). ZX008 and placebo were identical, thus rendering the study drug and placebo 
indistinguishable. The blinding scheme instituted for this study ensured that the volume of study 
medication taken could not be associated with the dose group, thus unblinding the study. This was 
achieved by random assignment of different concentrations of the ZX008 oral solution (1.25 mg/mL, 2.5 
mg/mL, and/or 5 mg/mL) by the IVR/IWR system. The IWR system instructed site personnel to the 
volume of oral solution to be administered based on that subject’s weight. (Dose was to be recalculated 
by the system once at the midpoint of the study.) During the Titration, Maintenance, and 
Taper/Transition Periods, the subjects and study personnel (investigators, clinical staff, personnel 
involved in data collection and analysis, the Medical Monitor, and the sponsor) were blinded to the 
treatment allocation and to the concentration of ZX008 oral solution. 
Prior to database lock for Study 1 an unblinding plan was implemented. The purpose of unblinding plan 
was to provide specific information and guidance to the Clinical Development Team, Clinical 
Operations Team, Biostatistics, Project Management, and other functions regarding plans for 
unblinding key team members for analysis of Study 1 top-line data and final Tables, Listings, and 
Figures (TLFs).  ‘Unblinding’ is defined as having access to subject-level data (i.e., subject data listings 
or the randomization codes) that provides information regarding randomized dose group, treatment 
effect, and safety.  Access to aggregated data (ie, group-level tables and figures) does not constitute 
‘unblinding’ and for the purposes of data cleaning and database lock, these individuals were still 
considered ‘blinded’.   
Personnel from the sponsor or any designee who became unblinded for the purposes of data cleaning 
and database lock for Study 1 did not participate in any decision-making regarding subjects’ data for 
Study 2 to avoid any real or apparent bias in such decisions. Study 2 was to be completed by a blinded 
study team with personnel distinct from the unblinded team that worked on Study 1. 
2.7. 
Administration of Study Medication 
ZX008 is supplied as an oral solution in concentrations of 1.25, 2.5, and 5 mg/mL. Subjects were 
randomized to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; maximum dose: 30 mg/day) 
or placebo. Placebo is identical in aspect and composition to ZX008 and is composed of identical 
ingredients used in the ZX008 formulation, except that it does not contain the active ingredient, 
fenfluramine hydrochloride. 
 
Study medication was administered twice a day (BID) in equally divided doses with food. 
 
• 
Treatment ARM A:  ZX008 0.2 mg/kg/day 
• 
Treatment ARM B:  ZX008 0.8 mg/kg/day 
• 
Treatment ARM C:  Placebo 
 
Treatment Periods: 
 
Titration Period: 
Study medication was administered as equal doses BID in the morning and in the evening approximately 
12 hours apart, with food. Each dose should have been separated by a minimum of 8 hours and a 
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Statistical Analysis Plan 
Sponsor: Zogenix International Limited; Protocol No.: ZX008 Study 2 (ZX008-1501 and ZX008-1502) 
 
 
 
This document is confidential. 
SAP Version: Final 1.0 21-May-2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 16 of 78 
maximum of 12 hours. A missed dose of study medication was to be taken later up to 8 hours before the 
next scheduled dose; otherwise, the missed dose should not be given. 
Administration of the Investigational Medicinal Product (IMP) was based on the randomized dose and 
subject’s weight at Visit 3 (Day -1). At Visit 8 (Day 43), if the subject’s weight changed ±25% of the weight 
at Day-1, the IMP dose was recalculated. Subjects were dosed using the oral dosing syringe provided. 
In order to maintain the blind across all dose groups and allow step titration to the high dose, the dose for 
each subject was titrated starting with a dose of ZX008 0.2 mg/kg/day (or placebo equivalent) BID. After 4 
days at this dose level (Day 5), subjects randomized to the ZX008 0.8 mg/kg/day group increased their 
dose to 0.4 mg/kg/day while doses in the other two groups remained constant. On Day 9, the dose for the 
0.8 mg/kg/day group increased to the target dose. The titration was expected to take a total of 14 days 
(Table 1). A new bottle of IMP was started by the subject at each level of the titration step. 
Table 1: Titration Algorithm 
 
Randomized Group 
Titration Step 1  
Study Day 1-4 
Titration Step 2 
Study Days 5-8 
Titration Step 3 
Study Days 9-14 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day  ZX008 0.2 mg/kg/day ZX008 0.2 mg/kg/day  
ZX008 0.8 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.4 mg/kg/day ZX008 0.8 mg/kg/day 
Placebo 
Placebo 
Placebo 
Placebo 
Note: maximum daily dose of ZX008 is 30 mg. 
 
 
Maintenance Period: 
After completion of the Titration Period, subjects entered the Maintenance Period and continued to 
receive the randomized dose of ZX008 or placebo and be treated for an additional 12 weeks.  Study 
medication continued to be administered BID in the morning and in the evening, approximately 12 hours 
apart, with food. Each dose was to be separated by a minimum of 8 hours and a maximum of 12 hours.  
A missed dose of study medication may have been taken later up to 8 hours before the next scheduled 
dose; otherwise, the missed dose was not to be given. 
 
Taper Period: 
 
Subjects who complete the Maintenance Period and were not continuing into the open-label extension 
study and subjects who discontinued from the study early were to be tapered off from study medication. 
Study medication was administered as equal doses BID in the morning and in the evening approximately 
12 hours apart, with food.  Each dose should have been separated by a minimum of 8 hours and a 
maximum of 12 hours.  A missed dose of study medication may have been taken later up to 8 hours 
before the next scheduled dose; otherwise, the missed dose should not be given. IMP was administered 
using the oral dosing syringe provided. 
In order to maintain the blind across all dose groups, all subjects who did not continue into the open-
extension study participated in a dose-tapering procedure over the course of 8 days. On the first day of 
the tapering period subjects in the ZX008 0.8 mg/kg/day group decreased to a dose of ZX008 0.4 
mg/kg/day BID (maximum 30mg/day).  After 4 days at this dose level (Day 5), subjects randomized to the 
ZX008 0.8 mg/kg/day group decreased their dose to 0.2 mg/kg/day. Subjects in the ZX008 0.2 mg/kg/day 
group decreased their dose to placebo on the first day of tapering while doses in the placebo group 
remained constant throughout the tapering procedure.  On Day 9, all subjects stopped taking study 
medication. The taper was expected to take a total of 8 days (Table 2). A new bottle of IMP was started 
by the subject at each level of the taper step. 
Table 2. Taper Algorithm 
 
 
Randomized Group 
Taper Step 1  
Day 1-4 after study completion 
or early termination 
Taper Step 2 
Days 5-8 after study completion 
or early termination 
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Statistical Analysis Plan 
Sponsor: Zogenix International Limited; Protocol No.: ZX008 Study 2 (ZX008-1501 and ZX008-1502) 
 
 
 
This document is confidential. 
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Filing requirements: TMF 
Page 17 of 78 
ZX008 0.2 mg/kg/day 
Placebo  
Placebo 
ZX008 0.8 mg/kg/day 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
Placebo 
Placebo 
Placebo 
Note: maximum daily dose of ZX008 is 30 mg. 
 
Transition Period: 
Subjects who completed the Maintenance Period and were continuing into the open-label extension study 
were to be transitioned from double-blind study medication to open-label ZX008 (Table 3).  Study 
medication was administered as equal doses BID in the morning and in the evening approximately 12 
hours apart, with food.  Each dose should have been separated by a minimum of 8 hours and a maximum 
of 12 hours.  A missed dose of study medication may have been taken later up to 8 hours before the next 
scheduled dose; otherwise, the missed dose should not be given. Study medication was administered 
using the oral dosing syringe provided. 
All subjects entering the open-label extension study were transitioned from their blinded daily dose 
(placebo, 0.2 mg/kg/day, 0.8 mg/kg/day, or 30 mg/day) to the 0.2 mg/kg dose during the 2-week interval 
between Visits 12 and 13, without breaking the blind. The IWR system assigned two bottles of IMP to the 
subject, one for each step in the transition. A new bottle of IMP was started by the subject at each level of 
the transition step.  
Table 3. Transition Algorithm 
Dose Group in Double-
Blind Study 
Transition Step 1  
Day 1-4 after Visit 12 
Transition Step 2 
Days 5-14 after Visit 12 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.8 mg/kg/day 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
Placebo 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
Note: maximum daily dose of ZX008 is 30 mg. 
 
Subjects who had been randomized to placebo increased their dose to 0.2 mg/kg/day beginning on Day 1 
of the transition (the day following Visit 12.) Subjects who had been randomized to 0.2 mg/kg/day 
continued to receive that dose. Subjects who had been randomized to 0.8 mg/kg/day or were receiving 
the maximum dose of 30 mg/day decreased to a dose of ZX008 0.4 mg/kg/day, or a maximum of 30 
mg/day.  After 4 days at this dose level (Day 5), these subjects decreased their dose to 0.2 mg/kg/day. 
Subjects were to report to the clinic on Day 15 for enrollment into the open-label extension study. 
Data from the Taper or Transition period will not be included towards the planned efficacy endpoints 
except where specified, but will be included in the safety analyses. 
2.8. 
Study Procedures and Flowchart 
The full list and timing of study procedures is provided in Table 4. 
 
 
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Statistical Analysis Plan 
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Table 4: Schedule of Assessments 
 
Baseline Perioda 
Titration + Maintenance Period 
 
EOS/ 
ETb 
 
Post-
Dosing 
Cardiac 
Follow-up 
 
Study Assessments 
 
Screening 
 
Random-
ization 
 
Titration Period 
 
Maintenance Period 
Visit Number 
1 
2 
(Phone) 
3 
 
4, 5 
(Phone) 
6 
7  
(Phone) 
8 
9  
(Phone) 
10 
11 
Phone) 
12 
13  
 
14 
Study Day 
-42 to -41 
-21  
-1 
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
3-24 mo 
post 
dose 
Inf ormed Consent (subject and parent) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Neurological History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epilepsy  history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect retrospective seizure diary data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Medication 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Phy sical Examination, complete 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
Xc 
Phy sical Examination, abbreviated  
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
Xc 
Neurological Examinat on, complete 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Neurological Examinat on, abbreviated 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Vital signs 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Weight, Height, BMI 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
12-lead ECG 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Xc 
Doppler ECHO 
X 
 
 
 
 
 
Xd 
 
 
 
Xd 
 
Xc 
Urine pregnancy test 
Xe 
 
Xe 
 
 
Xe 
 
Xe 
 
Xe 
 
Xe 
 
 
Clinical laboratory evaluation (hematology/clinical 
chemistry/urinalysis, etc) 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Plasma sample for ZX008 pharmacokinetics 
 
 
 
 
 
 
 
4Xf 
 
 
 
 
 
 
Plasma sample for background AEDs 
 
 
Xg 
 
 
Xg 
 
Xg 
 
 
 
Xg 
 
 
Urine THC Panel/Whole blood CBD 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Tanner Staging (f or subjects >7 years old) 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Subject Diary 
D 
R 
C/R/D 
 
R 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/Dh 
C/R 
 
Epilepsy  genotype panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study  Medication 
 
 
D 
 
Ri 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/Dh 
C/R 
 
C-SSRS 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
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Statistical Analysis Plan 
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Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
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Page 19 of 78 
 
Table 4: Schedule of Assessment (Continued) 
 
Baseline Perioda 
Titration + Maintenance Period 
 
EOS/ 
ETb 
 
Post-
Dosing 
Cardiac 
Follow-up 
 
Study Assessments 
 
Screening 
 
Random-
ization 
 
Titration Period 
 
Maintenance Period 
Visit Number 
1 
2 
(Phone) 
3 
 
4, 5 
(Phone) 
6 
7  
(Phone) 
8 
9  
(Phone) 
10 
11 
Phone) 
12 
13  
 
14 
Study Day 
-42 to -41 
-21  
-1 
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
3-24 mo 
post 
dose 
Clinical Global Impression - Improvement 
(assessed by parent/caregiver) 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
Clinical Global Impression - Improvement 
(assessed by principal investigator) 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
BRIEF 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
QOLCE 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
PedsQL 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
EQ-5D-5L (QoL of  parent/caregiver) 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
HADS (Affect of parent/caregiver) 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Randomize subject 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
First Day of Study Drug Administration 
 
 
 
Xj 
 
 
 
Daily  Diary Completion  
X 
 
Concomitant Medication 
 
 
 
X 
 
Adv erse events 
X 
 
Adv erse events of special interest 
X 
Xk 
AED=antiepileptic drug; BMI=body mass index; BRIEF=Behavior Rating Inventory of Executive Function; C=Collect; CBD=cannabidiol; 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=Rev iew 
a: 
The Baseline Period is comprised of the initial screening for the study and the assessment of baseline seizure activ ty recorded daily in the diary. 
b: 
Subjects who are discontinued early and those who complete the study and choose not to enroll in the separate open-label extension will be tapered off study medication over an up to 2-week period. 
c: 
Follow-up ECG, ECHO, and physical examination if warranted will be performed 3-6 months after early termination, or f or those subjects who complete the study but do not enter the open-label extension study  
d: 
The Visit 8 ECHO must be performed any time between Study Day 40 and Study Day 54.  The Visit 12 ECHO must be performed any time between Study Day 90 and Study Day 113; if a subject discontinues early 
f rom the study, the ECHO should be scheduled as soon as pract cal.  If the Study Day 43 ECHO was completed < 30 days prior to early termination, the Visit 12 ECHO will not be performed provided the 
parent/guardian agrees to bring the subject to the clinic for the cardiac follow-up visit. 
e: 
Females of child-bearing potential 
f : 
Plasma sample for pharmacokinetic assessment will be conducted prior to the dose at Visit 8 and 1, 2, and 4-6 hours after dose administration. 
g: 
Plasma sample for assessment of background AED(s) will be conducted prior to the dose of AED(s) at Visits 3, 6, 8 and 12. 
h: 
Study  drug/diary dispensed for the Transition Period for subjects entering the open-label extension study and for the Taper Period for subjects exiting the study. 
i: 
Site personnel will rev iew study medication dosing procedure (titration) with parent/caregiver. 
j: 
Study  drug administration begins in the morning of Study Day 1. 
k: 
Only  adv erse events related to cardiac safety will be collected at this visit. 
l: 
Mandatory  one time collection any time during or after screening. 
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The targeted study day and allowable windows for visits in are reproduced from the protocol below. Early 
termination visits will be mapped to a visit based on these windows. 
Table 5. Time Windows for Assessments 
Visit / Procedure 
Time window (relative to scheduled visit / 
procedure) 
Visit 1 (Clinic; Study Day -43 to -42 or -42 to -41): 
Not applicable 
Visit 2 (Phone; Study Day -21) 
± 3 days 
Visit 3 (Clinic; Study Day -1; Randomization) 
+ 4 daysa 
Visits 4, 5 (Phone: Study Days 4, 8) 
± 3 days 
Visit 6 (Clinic; Study Day 15) 
± 4 days 
Visit 7 (Phone: Study Day 29) 
± 4 days 
Visit 8 (Clinic; Study Day 43) 
± 4 days 
Visit 9 (Phone: Study Day 57) 
± 4 days 
Visit 10 (Clinic; Study Day 71) 
± 4 days 
Visit 11 (Phone: Study Day 85) 
± 4 days 
Visit 12 (Clinic: Study Day 99) 
± 4 days 
Visit 13 (Clinic; Study Day 113; post dosing) 
± 4 days 
Visit 14 (ECHO clinic; 3-6 months after last dose) 
+ 30 days 
Blood collection for ZX008 PK 
± 15 minutes 
Blood collection for AED concentration 
Prior to morning dose of AED medication 
AED=antiepileptic drug (s); ECHO=echocardiogram; PK = pharmacokinetics 
a In cases w here the screening period is extended beyond 42 days, the immediate 42 days before the Randomization 
visit w ill be used to calculate the baseline seizure frequency 
 
 
 
 
 
 
 
 
 
 
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3. 
Endpoints 
3.1. 
Primary Efficacy Endpoint 
The change from baseline in the mean convulsive seizure frequency (MCSF) in combined Titration and 
Maintenance Periods (T+M) in the ZX008 0.8 mg/kg/day group compared to the placebo group. 
The primary endpoint will be assessed using a parametric analysis of covariance (ANCOVA). MCSF will 
be log-trnasformed prior to analysis. If the assumptions of the parametric ANCOVA model are not met, 
the primary endpoint will be assessed using a nonparametric ANCOVA where MCSF is rank-transformed 
prior to analysis. 
4. 
Key Secondary Efficacy Endpoints 
The key secondary endpoints of Study 2 are: 
• 
Change from baseline in in the mean convulsive seizure frequency (MCSF) in T+M in the ZX008 
0.2 mg/kg/day group compared to the placebo group. 
The change from baseline in MCSF for the ZX008 0.2 mg/kg/day group will be analyzed using the 
same methods as the primary analysis. 
• 
ZX008 0.2 and 0.8 mg/kg/day dose groups compared independently versus placebo on the 
• 
The proportion of subjects who achieve a ≥50% reduction from baseline in convulsive 
seizure frequency. 
The proportion in each ZX008 treatment group will be compared independently to placebo 
using logistic regression analysis. 
• 
The longest convulsive seizure-free interval during T+M. 
Each ZX008 treatment groups will be compared to placebo on the longest interval using an 
independent Wilcoxon rank-sum test. 
 
The additional secondary endpoints are: 
 
ZX008 0.2 and 0.8 mg/kg/day dose groups compared independently versus placebo on the 
• 
The number of convulsive seizure-free days. 
• 
The proportion of subjects who achieve ≥25%, ≥75%, or 100% reductions from baseline in 
convulsive seizure frequency. 
• 
The proportion of subjects with at most 1 (ie, ≤1 convulsive seizure) during T+M. 
• 
The change from baseline in non-convulsive seizure frequency. 
• 
The change from baseline in convulsive + non-convulsive seizure frequency 
• 
The incidence of rescue medication usage 
• 
The incidence of hospitalization to treat seizures 
• 
The incidence of status epilepticus. 
• 
Clinical Global Impression – Improvement rating, as assessed by the principal investigator. 
• 
Clinical Global Impression – Improvement rating, as assessed by the parent/caregiver. 
• 
The change from baseline in the Quality of Life in Childhood Epilepsy (QOLCE) score. 
• 
The change from baseline in the Pediatric Quality of Life Inventory™  (PedsQL) score. 
• 
The change from baseline in the PedsQL Family Impact module score. 
• 
The change from baseline in the QoL of the parent/caregiver using the EQ-5D-5L scale. 
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• 
The change from baseline in the affective symptoms of the parent/caregiver using the Hospital 
Anxiety and Depression Scale (HADS). 
 
4.1. 
Pharmacokinetic Endpoints 
The PK endpoints of the study are: 
• 
Steady-state plasma fenfluramine PK parameters (Cmax, AUC0-t, Tmax, and t1/2) after 
administration of ZX008 derived using population PK methods 
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 
• 
Neurological examination 
• 
12-lead ECGs 
• 
Doppler ECHOs 
• 
Body weight 
• 
BRIEF to measure cognition 
 
4.3. 
Exploratory Endpoints 
ZX008 0.2 mg/kg/day compared versus ZX008 0.8 mg/kg/day on primary, secondary, safety and PK 
endpoints mentioned above. 
 
Exploratory Analyses due to Covid-19 
Additional exploratory analyses may be conducted to determine the impact of Covid-19, including but not 
limited to, protocol deviations, missed visits and missing data, alternative data collection.  Any exploratory 
analyses related to Covid-19 will be described in the Clinical Study Report. 
 
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5. 
Analysis Populations 
5.1. 
Randomized / Enrolled Population 
The Enrolled Population includes all subjects who signed the informed consent form.  This population will 
be used to present overall study disposition data and the number of subjects in each study population. 
The Randomized Population includes all subjects randomized to receive study treatment.  
5.2. 
Safety (SAF) Population  
All safety analyses will be performed on the SAF Population defined as all randomized subjects who 
receive at least one dose of ZX008 or placebo. Subjects will be analyzed according to the treatment 
group to which they were randomized. 
5.3. 
Modified Intent-to-Treat (mITT) Population 
The mITT Population is defined as all randomized subjects who receive at least one dose of ZX008 or 
placebo and for whom at least one week of diary data are available. Subjects will be analyzed according 
to the treatment group to which they were randomized. The primary comparison of ZX008 0.8 mg/kg/day 
to placebo, as well as key secondary analyses, will be performed on the mITT Population. 
5.4. 
Per Protocol (PP) Population  
The PP Population includes all randomized subjects who receive at least one dose of ZX008 or placebo, 
complete at least 4 weeks of the Maintenance Period, and have no important protocol deviations that would 
have a significant impact on clinical outcome. Subjects will be analyzed according to the treatment group 
to which they were randomized.  Protocol deviations will be reviewed and the list of deviations warranting 
exclusion from the PP Population will be finalized prior to study unblinding. 
The primary and key secondary efficacy analyses will be repeated on the PP Population. 
5.5. 
Protocol Deviations 
Major protocol deviations will be summarized overall and by site based on the SAF population. Major 
protocol deviations are those that have the potential to impact subject safety and/or affect data integrity 
and/or the efficacy conclusions. Major protocol deviations will be grouped into categories and may include 
categories, including but not limited to: 
− 
Violation of inclusion/exclusion criteria 
− 
Violation of randomization inclusion criteria 
− 
Non-compliance regarding intake of IMP 
− 
Inappropriate intake of concomitant medication 
− 
Subject not discontinued as per protocol 
− 
Other non-compliance 
 
Multiple deviations can occur in the same subject and thus a subject can be counted in more than 1 
deviation category. 
Major and minor protocol deviations will be presented in a subject data listing for the enrolled population, 
sorted by treatment, site, and subject.  
Deviations will be reviewed prior to the database lock of Study 2 data to determine which deviations will 
be classified as leading to exclusion from the PP population. 
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6. 
General Aspects for Statistical Analysis 
6.1. 
General Methods 
All statistical analyses will be performed using SAS statistical software (Version 9.4 or later). 
Study 2 summaries will be presented by treatment group (Placebo, ZX008 0.2 mg/kg/day, ZX008 0.8 
mg/kg/day).  
Continuous data will be summarized using descriptive statistics including means, standard deviations, 
medians, lower and upper quartiles, minimum and maximum values. Categorical variables will be 
summarized with frequencies and percentages. Confidence intervals will be calculated for key parameters 
or estimates as warranted. 
Two-sided statistical significance testing (α= 0.05) comparing each active treatment to placebo will be 
performed for the primary and secondary endpoints as described below, unless otherwise noted. 
All relevant collected subject data will be included in listings. All subjects entered into the database will be 
included in data listings. 
Unless otherwise specified in the subsequent sections, in the event of multiple assessments at a given 
planned time point, the latest collected value will be used for the summarization. 
6.2. 
Key Definitions 
Study Day: Study Day 1 is considered the day after Randomization Visit 3. Study day will be calculated 
relative to the Study Day 1. For any date on or after the Study 1, study day will be calculated as 
assessment date – Study Day 1 + 1. For any date prior to the Study 1, study day will be calculated as 
assessment date – Study Day 1. There will be no Study Day 0. 
Baseline Value: Baseline period consists of 42 days immediately preceding Study Day 1. Any 
assessment performed during these 42 days preceding Study Day 1 will be considered for baseline 
assessment.  
For the change in the frequency of convulsive seizures endpoint, baseline will include all data from the 
baseline period of 42 days immediately preceding Study Day 1.  For all other endpoints, baseline is the 
last non-missing result from the Baseline period prior to Study Day 1. 
Other Definitions: 
Treatment completers are those subjects that are compliant with IMP at least 85% of dosing days and 
fulfill at least one of the following criteria: 
• Subjects that did not discontinue from the trial prior to end of study visit at Day 99 ± 4 days (Visit 12). 
• Subjects that complete the Treatment Period (T+M) starting from Study Day 1 through the protocol 
defined end of study visit at Day 99 ± 4 days (Visit 12). 
• Subjects that enroll in the open label extension study. 
 
6.3. 
Multiplicity Strategy and Testing Hierarchy 
Multiplicity issues in the statistical inference in this study arise from two sources: (a) multiple treatment 
comparisons, and (b) multiple endpoints.  
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The efficacy analyses will employ a serial gatekeeper strategy to maintain the Type 1 error rate at α=0.05 
across the family of analyses that support the primary and key secondary objectives. 
All statistical analyses will be performed and results tabulated with test statistics, p-values, and/or 95% 
confidence intervals. 
Formal statistical testing will be performed for 1 primary endpoint and 2 secondary endpoints, for the 
comparison of ZX008 0.8 mg/kg with Placebo, and between ZX008 0.2 mg/kg with Placebo. Hence there 
are 6 formal hypothesis tests: 1 primary hypothesis test and 5 secondary hypothesis tests. To preserve 
the overall Type 1 error rate at α=0.05, these tests will proceed as follows: 
 
Step 1: The primary efficacy endpoint (mean convulsive seizure frequency per 28 days) will be formally 
tested first between the 0.8 mg/kg and Placebo group. If the comparison is statistically significant at the 
α=0.05 (2-sided) level, hypothesis testing will proceed to Step 2. Otherwise formal testing of the other 
hypotheses stops. 
 
Step 2: The secondary efficacy endpoint, the proportion of subjects who achieve a ≥50% reduction from 
baseline in convulsive seizure frequency, will be compared between the 0.8 mg/kg and Placebo group. If 
the comparison is statistically significant at the α=0.05 (2-sided) level, hypothesis testing will proceed to 
Step 3. Otherwise formal testing of the other hypotheses stops. 
 
Step 3: The endpoint, the longest convulsive seizure-free interval will be compared between 0.8 mg/kg 
and Placebo. If the comparison is statistically significant at the α=0.05 (2-sided) level, hypothesis testing 
will proceed to Step 4. Otherwise formal testing stops. 
 
Step 4: The mean convulsive seizure frequency per 28 days will be formally tested first between the 0.2 
mg/kg and Placebo group. If the comparison is statistically significant at the α=0.05 (2-sided) level, 
hypothesis testing will proceed to Step 5. Otherwise formal testing of the other hypotheses stops. 
 
Step 5: The secondary efficacy endpoint, the proportion of subjects who achieve a ≥50% reduction from 
baseline in convulsive seizure frequency, will be compared between the 0.2 mg/kg and Placebo group. If 
the comparison is statistically significant at the α=0.05 (2-sided) level, hypothesis testing will proceed to 
Step 6. Otherwise formal testing of the other hypotheses stops. 
 
Step 6: The endpoint, the longest convulsive seizure-free interval will be compared between 0.2 mg/kg 
and Placebo using a significance level of α=0.05 (2-sided). 
 
6.4. 
Missing Data 
Imputation for missing data is used in the sensitivity efficacy analyses. 
Seizure Diaries: 
Seizures are recorded in the Daily Seizure Diary (DSD). The  End of Day Diary (EDD) provides Yes/No 
confirmation that seizures were experienced for a specific date or that the date was seizure free.  The 
DSD was programmed to allow for up to 7 days of retrospective entry for daily seizures and to allow entry 
for EDD by 11:59 pm each day to confirm (Y/N) each day whether the day was seizure-free. Changes 
outside these parameters would therefore need to be made via the Data Clarification Request (DCR) 
process. Additionally, through a pre-specified process DCRs were used to categorize new seizures that 
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emerged during the treatment period. Specifically, new seizures were entered into the DSD as “Other” 
and after review of the seizure description by the Epilepsy Study Consortium, “Other” was updated to the 
appropriate clinical term via DCR.  
DCR data were processed prior to applying the missing data rules described below: 
• 
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 seizure 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.   
 
Based on analyses of the blinded, pre-lock database for Study 1, seizures clusters that were entered into 
the DSD without a number of seizures in the cluster had a value of 3 was imputed for the seizure count.  
Missing Data Due to Dropouts: 
The issue of missing data has gained much attention subsequent to the National Academy of Science 
Report on the Treatment and Handling of Missing Data (NAS Report, 2010). Within the context of the 
studies, missing data arise from two sources: intermittent missing assessments (such as missing diary 
data), and as a result of dropouts prior to the end of the titration + maintenance periods.  
In Study 1, only 2 (out of the 119) subjects had more than 7 days of missing diary data while on treatment 
(before dropout). The rates of dropout in the pivotal trials was 7.56% (9/119) in Study 1. Dropouts that are 
related to treatment response leave the possibility that the analysis of efficacy endpoints, which relies on 
assumptions of data being missing at random (MAR), may be violated. It is possible, though, that data 
may be missing not at random (MNAR).  Differential dropouts leading to missing assessments may thus 
affect the inference on the primary endpoint. 
The primary analysis method, in so far as it uses the convulsive seizure frequency averaged over the 
entire treatment period, in effect, assumes that a dropout would have followed the mean profile 
experienced up to that point in time when the subject dropped out from the study. Alternative, explicit, 
ways of addressing the issue of missing seizure data due to dropouts may be considered. (Kenward 
2015)Two methods were chosen for minimal impact on variability of estimates as well as their simplicity. 
It is assumed that the planned duration of T+M  for Study 1 and Study 2 subjects is 14 weeks (98 days). 
S1: Worst value substituted: In this analysis, for a subject who drops out of treatment, if the convulsive 
seizure frequency during T+M is lower than the baseline value, the baseline value will be substituted for 
the subject from the point of withdrawal to the end of the planned duration of T+M. However, if it is higher 
than the baseline, there will be no substitution. The CSF for the planned duration of T+M will then be 
computed as a weighted mean of the value before dropout, and the imputed value after dropout. The 
weights will be the proportion of planned duration of T+M before and after dropout. The statistical analysis 
(parametric ANCOVA with log CSFT+M as response and log CSFB as covariate, along with age group, 
treatment (2 factors: placebo, ZX008)) will then be performed on the resulting dataset. Treatment 
comparisons will be based on the least squares means and standard errors obtained from the ANCOVA. 
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S2: Intermediate Missing Day and Post-Discontinuation Imputation: Intermediate missing days should be 
imputed as the worse observed outcome for that patient if the patient was assigned to an active arm or 
zero seizures if the patient was assigned to placebo.  
For patients who discontinued the study, the day of discontinuation should be imputed as the worse 
observed outcome if assigned to ZX008 and as zero counts if the patient was assigned to placebo. The 
remaining days should be imputed using the baseline seizure counts for all arms. 
For cluster seizures that were reported as uncountable, the assigned number of seizures in the cluster is 
assigned as the worst cluster value for each individual subject in the active arm, and assigned as the 
mean baseline seizure count if the subject was assigned to placebo. 
 
Handling of missing date information for AEs: 
1. 
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.  
2. 
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. 
3. 
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. 
 
Adverse event 
Partial  
/Missing  
Start 
date 
Missing day – If Adverse event start day is missing but month and year is present then 
Impute the 1st of the month unless month is same as month of first dose of study drug 
then impute first dose date.  
 
Missing day and month – If adverse event start 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. 
 
 
Adverse event 
Partial 
/Missing 
End date 
Missing day – If AE end day is missing but month and year are present then Impute 
the last day of the month unless month is same as month of last dose of study drug 
then impute last dose date.  
 
Missing day and month – If AE has missing day and month but year is present then 
impute 31st December unless year is the same as first dose date then impute last 
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dose date.  
  
Completely Missing – need to look at whether the AE is still ongoing before imputing 
a date and also when it started in relation to study drug. If the ongoing flag is missing 
then assume that AE is still present (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. 
 
6.5. 
Visit Windows 
The following rules will be used to window data into treatment periods for by treatment period tabulations.  
For all by-visit tabulations, the nominal visit as recorded on the CRF will be used. 
Double Blind 
Treatment 
Period 
The Double-Blind Treatment Period start date is the date of first treatment, Study 
Day 1 (ie, the day after V3). The Double-Blind Treatment Period end date is the last 
date the patient was on study treatment. 
The Double-Blind Treatment Period consists of 16 weeks from first treatment start 
date, which includes 2 weeks of Titration period, 12 weeks of Maintenance period 
and 2 weeks of Taper/Transition period; therefore the end date would be 
considered the date at Visit 13. 
For subjects who discontinue early from the study, the double-blind treatment 
period end date will be the date at the early termination visit (Visit 12). 
Titration 
Period 
The Titration Period covers the first 14 ± 4 days of treatment while subjects are 
titrated to their randomized dose. It begins on the first day of treatment (Study Day 
1) and extends through Visit 6 (when the patient has reached their randomization 
dose). The Titration Period applies to all subjects including placebo recipients.  If a 
subject withdraws from the study prior to treatment in the maintenance period, all 
safety assessments and events up to and including the date of study withdrawal will 
be tabulated in the titration period. 
Maintenance 
Period 
The Maintenance Period covers the 12 weeks following the end of the titration 
period. It begins on the date of Visit 6 + 1 day and extends through the end of 
study/early termination visit (Visit 12). 
Titration + 
Maintenance 
Period (T+M) 
The T+M period combines the Titration and Maintenance periods, beginning on the 
date of first treatment (Study Day 1) and extending to the end of study/end of 
treatment visit. The T+M period is considered the treatment period. 
Taper/Transiti
on Period 
The Taper/Transition period consists of 2 weeks starting from end of study/early 
termination visit (Visit 12) + 4 day. 
For patients who are not entering into the open-label extension study, patients will 
gradually be tapered off of study medication. 
For patients who are entering the open-label extension study, patients will enter the 
transition phase where all patients will be on a dose of 0.2 mg/kg/day at the end of 
this phase. The end date of this period is considered to be the date recorded at Visit 
13. 
 
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6.6. 
Pooling of Centers 
There are approximately 60 sites participating in Studies 1501 and 1502 from US, Canada, Belgium, 
Denmark, France, Germany, Italy, Japan, Norway, Spain, Sweden, United Kingdom, and Australia.  For 
Study 1502 Japan was added in 2019 whereas Europe and Australia started in 2016. Approximately 36 
sites will contribute randomized subjects to Study 2. It is likely that the number of patients recruited by 
some sites will be small. The primary analysis will use data pooled across sites.  Differences among 
regions may be explored if warranted.  
6.7. 
Subgroups 
Select efficacy and safety outputs may be further broken down by the following subgroups: 
• 
Age strata: <6 years, ≥6 years. 
• 
Japanese subjects, Non-Japanese subjects 
• 
Sex 
• 
Race 
SCN1A Mutation Yes/No 
 
 
 
 
 
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7. 
Demographic, Other Baseline Characteristics and Medication 
7.1. 
Subject Disposition and Withdrawals 
Subject disposition will be presented per treatment group and overall. 
For describing the subject disposition, the following will be summarized by number and percentage: 
• 
Subjects enrolled (only overall) 
• 
Subjects enrolled but not randomized and reason for not-randomized (only overall) 
• 
Subjects randomized 
• 
SAF 
• 
mITT 
• 
PP 
• 
Subjects assigned to SAF, mITT, PP and discontinued the study and reason. 
• 
Number of subjects in the trial per trial period/phase (Titration Phase, Maintenance Phase, 
Follow-up Period) will be presented for SAF and mITT sets. 
• 
Trial completers. 
o Trial completers continuing in the open-label extension study 
o Trial completers not continuing in the open-label extension study 
For subjects enrolled but not randomized to treatment and for the reasons for not being randomized the 
denominator used to calculate the percentage will be the number of enrolled subjects. For all other 
calculations the denominator will be the number of subjects randomized.  
All subject data will be listed using the enrolled population and sorted by treatment and site. 
7.2. 
Demographic and Other Baseline Characteristics 
Subject demographics and baseline characteristics will be summarized descriptively per treatment group 
and overall, for the SAF and mITT populations as well as for Japan and Non-Japan sub-groups.  
The following demographic characteristics will be summarized: 
• 
Age[Years] 
• 
Categorical age as <6 years and ≥6 years. 
• 
Sex 
• 
Race 
• 
Ethnicity 
• 
Height [m] 
• 
Weight [kg] 
• 
BMI [kg/m2] 
All subject demographics data will be listed for the enrolled population. 
Below are conversions that may be applied: 
Age at Study day 1 = (Study day 1) visit date - date of birth + 1) / 365.25 and truncated to complete years. 
Height (in cm) = height (in inches) * 2.54 
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Weight (in kg) = weight (in lbs) * 0.4536 
BMI (kg/m2) = Weight(kg)/[Height(m)2] 
7.3. 
Medical History and Concomitant Diseases 
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. 
All prior and concomitant medical history data of subjects will be listed for the enrolled population. 
7.4. 
Other Baseline Characteristics 
Other baseline characteristics such as epilepsy/seizure history and epilepsy genotype panel data will be 
descriptively summarized as per data type (categorical).  Genetic data will be summarized as the 
proportion who have or do not have mutations of the SCN1A gene.  Additional analyses of genetic data 
may be prepared in a separate report. 
All subject baseline characteristics will be listed for the enrolled population. 
7.5. 
Medication 
7.5.1. 
Prior Medication and Concomitant Medication  
Medication (collected on prior medications, and concomitant medications eCRF page) will be coded using 
the World Health Organization Drug Dictionary (WHO-DD) Format B3 Version Sep2017 or later.  
The following algorithm will be used to define prior and concomitant. 
Prior medications will be those with a stop date prior to first dose administration. 
Concomitant medications will be defined as those medications that were initiated after study drug 
administration or those medications that were ongoing at the date of first study drug administration. 
The medication will be assumed to be prior medication if it cannot be definitively shown that the 
medication did not start or continue during the treatment period. 
If the start date or stop date of a medication is partially missing, the date will be compared as far as 
possible with the date of the start of administration of study drug. The following approach will be taken: 
• 
If the start date of medication is complete and occurs on or after the day of the first full dose, the 
medication will be assumed concomitant. If the start date occurs prior to the first full dose date but 
the end date is on or after the first dose date or the medication is recorded as ongoing, the 
medication will be considered concomitant. 
• 
If the start day is missing but the start month and year are complete, a medication will only be 
excluded as being concomitant if the start month/year is before the month/year of study drug 
administration and if the stop date (either full date, month and year if missing day, or year if 
missing month and day) is before study drug administration. 
• 
If the start day and month are missing but the start year is complete, a medication will only be 
excluded as concomitant if the start year is before the year of study drug administration and if the 
stop date (either full date, month and year if missing day, or year if missing month and day) is 
before study drug administration. 
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• 
If the start date is completely missing and the stop date is prior to first dose or completely 
missing, the medication will be assumed to be a prior medication. 
Medication will be summarized and sorted alphabetically separately for prior and concomitant medication 
by Anatomical Therapeutic Chemical (ATC) categories (Level 2: pharmacological or therapeutic subgroup 
and Level 3: chemical or therapeutic or pharmacological subgroup) and WHO-DD drug code. For each 
medication the number and percentage of subjects will be displayed.  
Medication summary tables will be presented for the SAF population. 
All prior and concomitant medications/treatments will be listed for the enrolled population. 
7.5.2. 
Prior and Concomitant Antiepileptic Treatments  
Antiepileptic treatments (collected on the prior antiepileptic medications, and concomitant medications 
eCRF page) will be coded using the World Health Organization Drug Dictionary (WHO-DD) Format B3 
Version Sep2017 or later. Anti-epileptic medications will be identified using any drug entered on the prior-
antiepileptic medication.  
Prior and concomitant antiepileptic medications will be defined and analyzed for the safety population 
similar to concomitant medications as described in Section 7.5.1. 
All prior and concomitant antiepileptic treatments will be listed for the enrolled population. 
 
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8. 
Efficacy 
The analysis of the primary and secondary efficacy parameters will be performed on the mITT population, 
except where noted.  
The primary and key secondary efficacy analyses will be repeated on the PP Population.  
All primary and key secondary variables will be analyzed for data obtained for the T+M period, and will be 
repeated for data obtained during the M period only. 
 
8.1. 
Primary Efficacy Endpoint and Analysis 
The primary efficacy endpoint is the change in the mean convulsive seizure frequency (MCSF) per 28 
days between the Baseline and T+M periods. For each subject, the CSF will be calculated from all 
available data collected during the Baseline and T+M Periods, and the treatment group mean convulsive 
seizure frequency per 28 days (MCSF) will be calculated for the baseline and T+M period.  
The baseline period is the 42 days immediately preceding the Randomization visit and the T+M period is 
planned for 14 weeks. However, actual durations will be computed for each subject based on the 
individual subject’s start and stop dates for each period, except that if the baseline period is longer than 
42 days, the average for the baseline period will be taken over the 42 days immediately preceding the 
Randomization visit.  
The convulsive seizure frequency will be counted from the daily diary records provided by the Subject or 
Parent/Caregiver. 
For any individual subject, the convulsive seizure frequency per 28 days during the baseline period 
(CSFB) will be derived as follows: 
CSFB = 28 ×  Total number of convulsive seizures during the Baseline Period
Total number of days in the Baseline Period with nonmissing diary data  
For each treatment group, the mean is obtained by averaging over the subjects in the treatment group. 
Similarly, for each subject, the convulsive seizure frequency per 28 days for the T+M period (MCSFT+M) is 
derived as below: 
 
The percentage change from baseline for any individual subject will be estimated by 
 (CSFT+M - CSFB)*100/CSFB 
The difference from baseline will be estimated by CSFT+M −CSFB. 
Corresponding treatment group means are designated with “M” preceding the quantity. For each 
treatment group, descriptive statistics for MCSF during baseline, T+M and M only, as well as the 
differences and % changes from baseline, will include the number of observations, mean, standard 
deviation, median, minimum and maximum, overall and by age group (<6 years, ≥6 years). 
data
diary 
 
nonmissing
 with 
period
 
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in the
 
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of
number 
 
Total
period
 
M
+
T
 
in the
 
seizures
 
convulsive
 
of
number 
 
Total
28
CSF
M
T+
×
=
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Statistical Analysis Plan 
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Primary Analysis 
T+M Period: 
The primary analysis will compare the ZX008 0.8 mg/kg/day group to the placebo group using a two-
sided test at the α=0.05 level of significance. 
The primary endpoint (CSFT+M) will be analyzed using an analysis of covariance (ANCOVA) model with 
treatment group (three levels) and age group (< 6 years, ≥6 years) as factors, log baseline CSFB as a 
covariate and log CSFT+M as response.  Treatment group mean differences from placebo will be 
estimated via least squares means from the analysis model along with 95% confidence intervals and 
associated 2-sided p-values. Estimated treatment differences and CI endpoints will be exponentiated for 
presentation. 
The null hypothesis 
 
H0: 𝜇𝜇Z0.8 −𝜇𝜇P = 0, 
will be tested against the alternative 
HA: 𝜇𝜇Z0.8 −𝜇𝜇P ≠0, 
where µZ0.8 and µP represent the ZX008 0.8 mg/kg and Placebo group means (on the log scale), 
respectively.  
Rejection of the null hypothesis in favor of the alternative, in the presence of a statistically significantly 
smaller mean convulsive seizure frequency for the treatment group compared to the placebo group, (two-
sided p-value < 0.05) will be regarded as evidence of a treatment benefit in favor of the 0.8 mg/kg group. 
Sample SAS code for the ANCOVA described above is as follows: 
   
proc glm data=temp; 
 
class agegrp trtp; 
model csftm = bcsf agegrp trtp  / SS3; 
lsmeans  trtp / pdiff stderr; 
where  trtp = randomized treatment group (with codes 1, 2, 3 indicating placebo, 0.2 mg, and 0.8 mg 
groups). 
    
bcsf = log( CSF𝐵𝐵),  
      
csftm = log(CSFT+M + 1) 
agegrp = age group. 
Additional statements may be used to obtain estimates and associated 95% confidence intervals. 
Endpoints of the CIs may be exponentiated to obtain CI on the original scale. Fitted values and residuals 
will be plotted to check model assumptions.  
Since the ANCOVA used in the primary analysis relies on assumptions of normality, the primary endpoint 
will also be analyzed 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 baseline CSFB as a covariate 
and ranks of CSFT+M as response, and the results will be used to assess the primary objective. If 
normality assumptions are not met, the results of the nonparametric test will be used to assess the 
primary objective.  
The primary analysis described above will be repeated using data from the Maintenance period only as 
response.  For subjects who did not reach the Maintenance period, their Transition period data will be 
used to represent their M period data. 
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A similar ANCOVA model will be used, and if distributional assumptions are not met, a nonparametric 
analysis will be performed.   
Treatment by baseline seizure category interaction:  The primary analysis described above will be 
repeated with baseline seizure frequency as a categorical variable, rather than a covariate.  Baseline 
seizure frequency per 28 days will be categorized as either < 10; 10-50; or >50. 
Supplementary and Sensitivity Analyses 
Per protocol Analysis 
Additionally, the primary efficacy analysis will be repeated on the per protocol population (which excludes 
subjects with important protocol deviations that may affect the inference on efficacy such as a change in 
dose or type of concomitant AED medication). 
Percentage Reduction from Baseline 
The ANCOVA employed in the primary analysis uses log CSFT+M as the response adjusts for baseline 
seizure frequency by incorporating CSFB as a factor in the model. The alternative approach described 
here calculates the percentage change in CSF from baseline directly and uses that quantity as the 
response variable in an ANCOVA model. Specifically, the ANCOVA will use the percentage change from 
the T+M period to baseline as the response variable, baseline CSF as a covariate, and treatment and age 
stratum as classification factors. The analyses will be repeated for the M period only using the baseline as 
covariate.  
If the distributional assumptions for the parametric analysis are not met, a nonparametric ANCOVA will be 
used for the ranks of the dependent variable as response, using the ranks of the baseline as covariate. 
Criteria for Establishing Efficacy 
While several supportive and/or supplementary analyses are specified above, the main criterion for 
demonstrating efficacy will be the primary analysis using the log transform for the mITT population. It is 
conceivable that some or all of these supplemental analyses may not reach statistical significance. 
However, it is expected that the direction of effect will be in favor of the test treatment. As an example, a 
statistically significantly smaller least squares adjusted MCSF for the treatment group compared to 
placebo, in the presence of a smaller proportion of subjects on 0.8 mg/kg than Placebo subjects 
increasing their dose of concomitant AEDs will be strong evidence for efficacy of the experimental 
treatment. 
8.2. 
Secondary Efficacy Endpoint(s) and Analyses 
8.2.1. 
Key Secondary Analysis 
MCSF for ZX008 0.2 mg/kg/day versus Placebo 
The MCSF during the T+M period will be analyzed and compared between the ZX008 0.2 mg/kg/day 
group and the placebo group using the same methods employed for the primary analysis. Following the 
same strategy as the ZX008 0.8 mg/kg/day comparison, a nonparametric analysis using ranks will be 
used for the ZX008 0.2 mg/kg/day comparison if the assumptions of the parametric ANCOVA model are 
not met. 
The analysis will be repeated for the M period. 
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Proportion with ≥50% Reduction from Baseline in Convulsive Seizure Frequency 
Subjects with a percent reduction in convulsive seizures of at least 50 percentage points from baseline 
will be identified and the overall proportion within each treatment tabulated.  That is, the proportion of 
subjects in the ZX008 0.8 mg/kg/day group who have a decrease in convulsive frequency of at least -50 
percentage points will be compared to the analogous proportion in the placebo group.   
Similarly, the proportion of subjects in the ZX008 0.2 mg/kg/day group who have a change in convulsive 
frequency of at least -50 percentage points will be compared to the analogous proportion in the placebo 
group. 
The comparison between treatment groups will be made using a logistic regression model that 
incorporates the same factors as the ANCOVA used in the primary analysis.  This will model a categorical 
response variable (achieved 50 percentage point reduction, yes or no) as a function of treatment group 
(ZX008 and placebo) and age group (< 6 years, ≥6 years).  Comparisons between treatment groups will 
also be made using pairwise Fisher’s exact tests since the logistic regression models may not converge in 
all circumstances. 
Raw descriptive statistics will be presented by treatment group, and will include the number and 
proportion of subjects < 6 years, ≥6 years, and overall achieving the reduction along with the model 
estimated odds ratio (including a 95% confidence interval) and p-values from both logistic regression and 
Fisher’s test for comparison of ZX008 0.8mg/kg/day to placebo and ZX008 0.2mg/kg/day to placebo 
separately.   
Longest Interval between Convulsive Seizures 
The longest interval between convulsive seizures will be analyzed. 
For each subject, the longest interval between convulsive seizures will be calculated over the entire T+M 
period. This will be derived as the maximum of the number of days between consecutive convulsive 
seizures. The intervals between consecutive convulsive seizures 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 seizure occurs on five days having dates as 
Date1, Date2, Date3, Date4 and Date5, where Date5>Date4>Date3>Date2>Date1≥Date0, and let LDT = 
Last date of treatment in the maintenance period, where LDT ≥ Date5, then the time interval between 
convulsive seizures will be calculated as follows: 
I1=Date2 - Date1  
I2=Date3 - Date2  
I3=Date4 – Date3, 
I4=Date5 – Date4. 
For completeness, we calculate the time to the first seizure as 
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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 
The median time of the longest convulsive seizure-free interval will be presented. Additional summary 
statistics will be presented, including mean, minimum, maximum, the 25th and 75th percentiles, 95% 
confidence intervals on the difference in medians between groups (Hodges-Lehman estimator).   
The Wilcoxon rank sum test will be used to test for differences between each treatment arm and placebo, 
and the p-value from this test will be presented.  A histogram presenting the percentage of subjects 
whose longest seizure free interval is <10, 11-20, 21-40, 41-60, 61-84, and ≥84 days will accompany all 
descriptive statistics and all data will be provided in a data listing. 
8.2.2. 
Additional Secondary Endpoint Analysis 
Number of Convulsive Seizure Free Days 
Convulsive seizure free days will be taken from the parent/caregiver diary data. 
A convulsive seizure free day will be defined as a day for which diary data are available and no 
convulsive seizures have been reported.  The total number of convulsive seizure free days will be 
summed for the entire T+M period and similarly for the baseline period. 
Seizure free days per 28 days at baseline = (number of seizure free days during baseline)*28/(number of 
days during baseline with non-missing diary data) 
Seizure free days per 28 days during T+M Period = (number of seizure free days during T+M 
Period)*28/(number of days during T+M Period with non-missing diary data) 
Statistical comparison of treatment groups and placebo on the number of seizure free days per 28 days 
during T + M using the baseline as covariate will be done with a similar approach as the primary analysis. 
Responder Analyses: Proportion with ≥25 , 75% or 100% Reduction from Baseline in Convulsive 
Seizure Frequency 
A response curve will be generated for the mITT population. This graph will plot the % of subjects (y-axis) 
against percentage reduction in seizure frequency per 28 days in the T+M and M periods (x-axis). The 
horizontal axis will be the % reduction, and the vertical axis will be the % of subjects achieving ≥ that % 
reduction.  In the graph, subjects experiencing an increase or no decrease in seizure frequency (i.e., 
≤0 % reduction) will be regarded as having a 0% reduction in seizure frequency. Hence the ordinate for 
the 0 time point may not necessarily be at 100%.  For example, if 15% of subjects have no reduction in 
seizure frequency during T+M period compared to the baseline period, the graph will start on the y-axis at 
85%. The graph will be generated for all subjects, by treatment group. 
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• 
The proportion achieving a ≥25% reduction from baseline in convulsive seizures will be analyzed 
for both treatment groups (ZX008 0.2 mg/kg/day and ZX008 0.8 mg/kg/day) comparing 
independently with placebo, using the same methods employed for the ≥50% reduction from 
baseline endpoint. 
• 
The proportion achieving a ≥75% reduction from baseline in convulsive seizures will be analyzed 
for both treatment groups (ZX008 0.2 mg/kg/day and ZX008 0.8 mg/kg/day) comparing 
independently with placebo, using the same methods employed for the ≥50% reduction from 
baseline endpoint. 
• 
The proportion achieving a 100% reduction from baseline in convulsive seizures, i.e., seizure-
freedom, will be analyzed for both treatment groups (ZX008 0.2 mg/kg/day and ZX008 0.8 
mg/kg/day) comparing independently with placebo, using the same methods employed for the 
≥50% reduction from baseline endpoint.  
• 
The proportion of subjects with near seizure freedom during the T+M period. Near seizure-
freedom will be defined as having 0 or 1 seizures leading to a drop in the T+M period. These are 
additional secondary endpoints. Groups will be compared using the same methods employed for 
the ≥50% reduction from baseline endpoint. 
A second response curve will be generated in which subjects who experience an increase in seizure 
frequency will be represented on the curve at horizontal axis at the position representing their increase in 
seizure frequency. Increases in seizure frequency will be represented to the left of the vertical axis on the 
figure. 
Change from Baseline in Non-Convulsive Seizure Frequency 
Algorithms for calculating mean non-convulsive seizure frequency and percent change from baseline will 
follow the methods as described for the primary endpoint using a nonparametric ANCOVA to analyze the 
data, with ranks of the baseline non-CSFB as a covariate and ranks of non-CSFT+M as response,. 
Change from baseline in non-convulsive seizures will be presented by seizure types (e.g., focal, 
generalized). 
Change from Baseline in Convulsive + Non-Convulsive Seizure Frequency 
The change from baseline in convulsive + non-convulsive seizure frequency will be calculated as 
described for the primary endpoint, but considering both convulsive and non-convulsive seizures. 
Algorithms for calculating mean convulsive and non-convulsive seizure frequency and percent change 
from baseline will follow the methods as described for the primary endpoint using a nonparametric 
ANCOVA to analyze the data, with ranks of the baseline convulsive + non-CSFB as a covariate and ranks 
of convulsive + non- CSFT+M as response, 
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.  They second and third round might use different 
medications or different doses than the first round of rescue meds. 
Rescue medication will be summarized by treatment group and by active treatment vs. Placebo for the 
following: 
• 
The number of days rescue medication was taken (normalized to 28 days) will be summarized 
separately for the Baseline ,T+M periods and change from baseline by the mean (SD) as well as 
the median and range. Multiple medications taken on the same day will be counted once for that 
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day. The ZX008 group will be compared to the placebo group using a rank ANCOVA analogous 
to that described in Section 8.1 Primary analysis. Specifically, the rank ANCOVA will use the 
ranks of rescue medication frequency during T+M as the response, and will incorporate treatment 
group as a factor and the ranks of rescue medication frequency during Baseline as a covariate. 
• 
The number of medications used per episode will be summarized using similar descriptive 
statistics as above. Rescue medications related to an episode of SE are considered to be all 
rescue administered on the day of the SE (or seizure lasting >10 min). If more than one episode 
of SE or a seizure lasting >10 min occurred in a single day, the rescue medication for that 
episode is all rescue administered after the seizure until the start time of the next prolonged 
seizure.   
 
Incidence of Hospitalization to Treat Seizures 
Hospitalization data will be captured in the CRF and will be used to calculate incidence.  
 
The number and percentage of subjects who utilized medical center care to treat a seizure will be 
presented by treatment group for the T+M period.  Statistical comparisons of the differences between 
treatment and placebo groups will be based on Cochran-Mantel-Haenszel test stratified by age group. 
 
Incidence of Status Epilepticus 
The incidence of status epilepticus 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 for the baseline and the T+M period per 28 days.  
In addition, the number and percentage of subjects who experience at least one convulsive seizure with 
duration >10 min will be reported for the baseline and T+M period.  
All seizures recorded in the AE database as status epilepticus should also be included in the seizure 
diary. An edit check will be performed to identify the overlap between seizures identified as AE of SE and 
seizures entered into the diary as seizures > 10 min. The “calculated” number and percentage of subjects 
experiencing SE will be presented by treatment group, defined as individuals who experience either an 
AE of SE, medical treatment for SE, or a seizure lasting longer than 10 min. Each subject will be 
represented once regardless of incidence.  
A statistical comparison of the differences between the ZX008 0.8 mg/kg/day and placebo groups will be 
based on a logistic regression model with a categorical response (experienced at least one SE as an AE 
or a seizure >10 minutes during T+M, yes or no) as a function of treatment group (active or placebo), age 
group (< 6 years, ≥ 6 years), and a categorical baseline variable (experienced at least one SE as an AE 
or a seizure >10 minutes during Baseline, yes or no). An anolgous model will be used to compare the 
ZX008 0.2 mg/kg/day group to placebo. 
The number of incidences of status epilepticus will be cross-tabulated against the incidences of rescue 
medication uses (Yes/No). Cochran–Mantel–Haenszel test (CMH) test will be used to test the general 
association between incidences of SE and rescue medication uses.  
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Duration of Prolonged Seizures 
Duration of convulsive seizures at baseline and on treatment will be presented by treatment group using 
categories as <2 min, 2-10 min and >10 min.  
To obtain a baseline probability distribution for the 3 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 % of subjects’ seizures that were <2 min in duration, the % between 2-10 min in 
duration, and the % >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 T+M period, we will proceed similarly, to obtain a 
distribution for the T+M period.  
It is expected that treatment with ZX008 will result in shorter duration of seizures (as well as fewer 
seizures) during T+M compared to placebo, i.e., the probability of longer seizures (>10 min) will be higher 
for the placebo group than for the ZX008 arms. This may be assessed by comparing the probability of a 
>10 min seizure during T+M to the same during baseline, for a treatment group, to the same for the 
Placebo group. It is expected that the ZX008 group will have greater odds of a reduction in proportion of 
seizures >10 min than the Placebo group. However, treatment with ZX008 may result in fewer seizures 
overall yet the duration of residual seizures may not be shorter.  Should the primary or key secondary 
endpoints be positive for a given dose(s), but the duration of seizures not be shortened per above, 
exploratory evaluations may be undertaken to better understand the effect. 
Clinical Global Impression – Improvement Rating, as assessed by the Parent/Caregiver 
The parent/caregiver and the investigator will rate their global impression of the subject’s condition at 
each clinic visit after randomization: end of Titration period (Visit 6), Maintenance period (Visit 8 and 10), 
and at End of study (Visit 12). 
The CGI-I scale measures the change in the subject’s clinical status from a specific point in time, i.e., the 
Baseline Period. The CGI-I rating scale permits a global evaluation of the subject’s improvement over 
time. The severity of a 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 mean (SD) CGI-I score, and the number and percentage of subjects who showed improvement (i.e., 
had a score of 3 or lower), and the number and percentage who did not improve (i.e., had a score of 4 or 
higher) will be presented for each for each treatment group at each assessment timepoint. Each 
assessment time point will also include a comparison between each active treatment and the placebo 
group using the Cochran-Mantel-Haenszel test stratified by age group, and a frequency distribution of the 
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number and percentage of subjects in each category in the scale. A histogram of the frequency 
distribution will be presented. 
The number and percentage of subjects who were much or very much improvement (i.e., had a score of 2 
or lower), and the number and percentage who were minimally improved or did not improve (i.e., had a 
score of 3 or higher) will also be presented for each for each treatment group at each assessment 
timepoint as an exploratory analysis.   
 
Individual subject CGI data will be listed. 
 
Clinical Global Impression – Improvement Rating, as assessed by the Principal Investigator 
CGI-I score data assessed by the principal investigator will be summarized and analyzed using the same 
methods used for CGI-I score data recorded by parent/caregiver as above. 
 
Quality of Life in Childhood Epilepsy (QOLCE) Scale 
The parent/caregiver will complete this questionnaire for the QOLCE. This assessment looks at how 
epilepsy affects day-to-day functioning of their child in various life areas, including physical activities, well-
being, cognition, social activities, behavior and general health, at baseline period (Visit 3), at Maintenance 
period (Visit 8) and at End of study/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: 1-0, 2-25, 3-50, 4-75, 5-100.  After transformation, a 
score for each subject for each subscale is calculated  by averaging that subject’s responses to each item 
in the  subscale. [A value of 0 represents the lowest or poorest score and 100 reflects the highest level of 
functioning.]  The 16 subscale scores per subject are then averaged to obtain an overall quality of life 
score for each subject. The mean and SD 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 2: Subscale of QOLCE: 
Domain 
Subscale 
Item 
Section 3: Physical 
Physical Restrictions 
3.1 a-j 
Section 3: Physical 
Energy/Fatigue 
3.2 a,b 
Section 4: Well-being 
Depression 
4.1 a,d,e,l 
Section 4: Well-being 
Anxiety 
4.1 b,g,j,n,o,p 
Section 4: Well-being 
Control/helplessness 
4.1 c,f,h,i 
Section 4: Well-being 
Self-esteem 
4.1 k,m,q,r,s 
Section 5: Cognition 
Attention/Concentration 
5.1 a,d,e,f,g 
Section 5: Cognition 
Memory 
5.1 j,k,l,m,n,o 
Section 5: Cognition 
Language 
5.1 p,q,r,s,t,u,v,w 
Section 5: Cognition 
Other Cognitive 
5.1 b,c,h 
Section 6: Social Activities 
Social Interactions 
6.1 c,f,h 
Section 6: Social Activities 
Social Activities 
6.1 a, e, 6.2  
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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* 
*An Overall Quality of Life Score can be computed by adding each subscale score for each individual and 
then dividing by 16.  
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 End of Study/ET. The change 
from baseline for each treatment group will be summarized by the mean (SD) and treatment groups will 
be compared using pairwise Wilcoxon tests.  
Individual subject data for the domains will be listed. 
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 (Visit 3) and at End of study (Visit 12) using the EQ-5D-5L. The responsible parent/caregiver 
was permitted to opt out of completing the EQ-5D-5L. 
The EQ-5D-5L health questionnaire is a health-related quality of life instrument with 5 dimensions: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 
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 proportion (%) of subjects in each Item 
score (No Problems, Slight Problems, Moderate Problem, Severe Problem, Extreme Problems) by 
treatment at baseline and at the end of study. In addition, the item scores will be classified into two 
categories as “No Problems” and “Problems,” the latter comprised of slight, moderate, severe and 
extreme problems. Summary results will show number of patients and proportion (%) with “No Problems” 
and with “Problems” by treatment at baseline and at end of study.   
For the VAS measure of overall self-rated health status, descriptive statistics summary results will be 
presented for the VAS score showing number of subjects, mean, standard deviation, median, and range 
by each treatment at baseline and end of study time points.  
 
The change from baseline in VAS will be calculated by subtracting the VAS score at baseline from the 
VAS score obtained at End of Study/ET. The change in VAS will be summarized using descriptive 
statistics, and treatment groups will be compared using pairwise Wilcoxon tests. 
 
The quality of life of parent/caregiver individual data will be listed using EQ-5D-5L scale. 
 
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Parent/Caregiver Assessment using HADS Scale 
The HADS is a tool commonly used to determine the levels of anxiety and depression that a person is 
experiencing and is administered to the primary parent/caregiver to assess these symptoms longitudinally 
during the study.  The responsible parent/caregiver was permitted to opt out of the HADS. The HADS 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 7 relate to depression. 
Each item has 4 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.   
 
Summary descriptive statistics including the mean and SD will be generated separately for the Anxiety 
and Depression dimensions at both Baseline and at End or Study/ET. In addition, each subject will be 
categorized at each time point based on the score cut-offs below which were validated on adult patients 
in a treatment setting.   
 
Score 
Category  
0-7 
Normal 
8-10 
Borderline abnormal 
11-21 
Abnormal 
 
Summary statistics will include number and proportion (%) of subjects in each of the categories above at 
each study visit.   
In additional, the total score for Anxiety and Depression will be generated. Descriptive statistics 
summaries including mean, median, standard deviation, median and range will be summarized for each 
treatment at Baseline and End of Study/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 and the difference between treatment 
groups will be assessed using pairwise Wilcoxon tests. 
The individual item outcomes will be presented in the subject data listing. 
 
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 8 items for Physical Functioning, and 5 questions each for Emotional, Social, and School 
Functioning. 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. A mean score is 
calculated as the sum of the items 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 
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completed 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 at both Baseline and 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 treatment groups will be compared on the 
Total Score using pairwise Wilcoxon tests. 
 
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 6 items for Physical Functioning, 5 items each for Emotional Functioning, Cognitive Functioning 
and Worry, 4 for Social Functioning, and 3 for Communication. There are additionally 3 questions for 
Daily Activities and 5 for Family Relationships.  
 
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. A mean score is calculated as the 
sum of the items 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 completed 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. 
 
 
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8.2.3. 
Exploratory Analyses 
Exploratory analysis may be performed by comparing of ZX008 0.2 and 0.8 mg/kg/day doses on primary, 
secondary, safety and PK endpoints. 
Thus, all comparisons planned for ZX008 to placebo may be repeated to compare the ZX008 0.2 and 0.8 
mg/kg/day doses. 
Additional exploratory analyses may include descriptive summaries of the primary endpoint by: 
• 
SCN1a Mutation Status  
• 
seizure type 
• 
baseline seizure frequency 
• 
Age (greater than or equal to 13 years at baseline)  
• 
Concomitant AED: VPA, CLB, VPA+CLB 
• 
Number of concomitant AEDs 
 
 
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9. 
Analysis Of Pharmacokinetics 
The bioanalytical methods for the determination of individual plasma concentrations of fenfluramine and 
its metabolite (norfenfluramine) will be reported together with the plasma concentration results in separate 
bioanalytical reports. These bioanalytical reports will be issued as a separate report. 
 
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10. Safety 
All safety analyses will be performed for the Safety population (SAF) and will be reported by treatment 
group as well as ZX008 combined for the 16-week treatment period unless noted otherwise. 
10.1. 
Extent of Exposure 
Treatment exposure data will be summarized and analyzed for the SAF population. 
Duration of total exposure to ZX008 (i.e., time on treatment (in days)) will be calculated per subject as the 
number of days with IMP intake during the trial, and will be summarized using n, mean, standard error, 
median, minimum, Q1, Q3 and maximum.  
This will be calculated as: 
Date of last IMP intake – Date of first IMP intake + 1 
Time on treatment will be summarized by treatment group. 
10.2. 
Treatment Compliance  
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 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 over the course of T+M and 
Maintenance only, reported by treatment group.   
 
10.3. 
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 
the end of the titration/transition period (Visit 13). For patients who continue into the open-label extension 
study, AEs of special interest will continue to be monitored for up to 6 months after the last dose of study 
medication. 
A TEAE is defined as any AE that based on start date information occurs after the first intake of study 
treatment. Safety tables will present TEAE data by assigned treatment group through Visit 13.  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 unrelated.  If the AE is thought to be definitely, probably or possibly 
related to study drug then it is to be categorized as related.  Possibly or definitely unrelated is categorized 
as unrelated. Any missing relationship will be considered as “related.” 
The severity of AEs (whether nonserious or serious AEs) will be assessed by the investigator as follows: 
Severity Definition of Adverse Events: 
Mild - A type of AE that is usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily living. 
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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. 
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. 
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 
• 
TEAEs that lead to death 
• 
TEAE leading to discontinuation of study treatment 
 
The percentage denominator for the calculation of percentage will be the number of subjects in the SAF.  
Incidence of Treatment Emergent Adverse Events 
The following summaries will display the number and percentage of subjects with an adverse event as 
well as the corresponding number of events by system organ class (SOC) and preferred term (sorted 
alphabetically): 
• 
All TEAEs  
• 
Serious TEAEs   
• 
TEAEs by Maximum Severity 
• 
Study Drug Related TEAEs 
• 
All AEs that lead to premature discontinuation from the study 
Additional summary tables will tally the number and percent of subjects in each treatment group who 
experience an AE that occurs in at least 2%, and at least 5%, of subjects. The summary will be presented 
by preferred term in decreasing order of incidence. 
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A table  will be provided  for TEAEs (preferred term) where  the percentage of subjects in a ZX008 arm 
who experience the event  exceeds the percentage of subjects in the Placebo group with the event and 
occurs with a frequency of at least 2%. 
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 T+M 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 
• 
Deaths 
Adverse Events by Age and Gender 
The following summary tabulations will be provided to explore the incidence of AEs within age and sex 
subgroups:  
• 
All TEAEs by Age (<6 years, ≥6 years) 
• 
All TEAEs by Sex (Females, Males) 
Adverse Events by Concomitant Medication Usage 
The following summary tabulations will be provided to explore the incidence of AEs by concomitant 
medication usage:  
• 
Valproate 
• 
Clobazam 
• 
Topiramate 
Adverse Events by Contry 
The following summary tabulations will be provided to explore the incidence of AEs by contry:  
• 
Japan 
• 
Non-Japan 
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 in below Table 6. 
Table 6 – Adverse Events of Special Interest: 
CV/Respiratory 
• Chest pain – any pain in sternal area that is described for example as crushing, burning, 
sharp, stabbing or dull.  
• Dyspnea/shortness of breath – any signs of difficult or labored breathing unrelated to a 
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previous medical condition that has not worsened.   
• Persistent cough – longer than 4 weeks without a confirmed identified pathogen (or any 
other persistent cough that the investigator feels is suspicious). 
• Increase in blood pressure >30% from Screening blood pressure or a systolic pressure 
≥140 mmHg after repeated measures during one visit.  Blood pressure should be 
repeated at appropriate times within the visit.   
• Jugular venous distention- visible bulging of the external jugular veins on either side of 
the neck 
• New onset heart murmur  
• Pulmonary rales – an abnormal respiratory sound heard during auscultation of the lungs, 
which is also described as a crackle.    
• Tachycardia – a persistent HR >30% above the screening value and unrelated to 
exercise, exertion or anxiety.  Heart rate should be repeated at appropriate times 
within the visit.  
• Signs that could indicate right ventricular failure: 
• Peripheral edema  
• Ascites  
• Syncope  
• Decompensated right ventricular failure – symptoms include shortness of breath, 
frequent coughing especially when lying flat, abdominal swelling and pain, dizziness, 
fainting, and fatigue  
• 
Signs on ECHO indicative of potential valvulopathy 
1. valve regurgitation (aortic or mitral) 
2. ≥ mild valve regurgitation (tricuspid or pulmonary) 
3. Mean Mitral valve gradient ≥ 4 mmHg 
4. Mean Aortic valve gradient ≥ 15 mmHg 
5. Mean Tricuspid valve gradient ≥ 4 mmHg 
6. Mean Pulmonary valve gradient ≥ 21 mmHg 
• 
Signs on ECHO indicative of pulmonary hypertension 
a.  Tricuspid Regurgitation Jet velocity > 2.8 msec with or without the following findings 
OR  
b. One of the following findings in the absence of being able to measure Tricuspid 
Regurgitation Jet velocity: 
i. 
Change in right ventricle/left ventricle basal diameter ratio > 1.0 
ii. Right ventricular acceleration time < 100 msec 
 iii. Dilatation of the inferior caval vein (diameter>21 mm and <50% inspiratory 
decrease) and/or right atrium 
iv.  Change in the geometry of the interventricular septum in systole (flattening) with 
left ventricular eccentricity index >1.1 in systole and/or in diastole 
v. Early diastolic pulmonary regurgitation velocity > 2.2 m/sec 
vi. Tricuspid Anular Plane Systolic Excursion below 18 mm or below Z-score – 2 
 
Metabolic/Endocrine 
• Elevated prolactin level ≥2x above the upper limit of normal (ULN) 
• Galactorrhea 
• Gynecomastia 
• Increase in fasting serum blood glucose ≥2x ULN 
• Hypoglycemia – serum blood glucose more than 20% below the glucose level on Day -1 
value or more than 10% below LLN (reference range 60 – 140 mg/dL) 
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Neuropsychiatric 
1. Serotonin syndrome (At least 3 of following symptoms must be present: Agitation, 
restlessness, confusion, both increased HR and blood pressure, dilated pupils, muscle 
twitching, muscle rigidity, hyperhidrosis, diarrhea, headache, shivering, tremors, both 
nausea and vomiting) 
2. Hallucinations 
3. Psychosis 
4. Euphoria 
5. Mood disorders: depression and anxiety if they rise to a level of a disorder  
6. Suicidal thoughts, ideation or gestures 
Genitourinary 
1. Priapism 
 
MedDRA SMQs will be employed as applicable to identify each AESI category or manually assigned 
through review. This will be completed and documented prior to study unblinding. 
Adverse events of special interests will be summarized by treatment group and by system organ class 
and preferred term for the T+M Period. 
All adverse events of special interest will listed separately. 
10.4. 
Laboratory Evaluations 
Laboratory safety parameters will be analyzed by a central laboratory using standard validated methods. 
All laboratory safety data will be collected as per the schedule of assessments. 
The following continuous laboratory parameters will be analyzed: 
1. Hematology: hemoglobin, hematocrit, erythrocytes, erythrocyte mean corpuscular volume, 
leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils and platelets 
2. 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. 
3. 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 
4. Coagulation: Prothrombin time (PT)/International normalized ratio (INR), activated partial 
thromboplastin time (PTT) 
5. Whole blood cannabidiol 
6. 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. 
7. Urine pregnancy test: Urine pregnancy testing will be performed in female subjects of 
childbearing potential. 
8. Urine THC panel 
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Observed continuous laboratory data will be descriptively summarized by type of laboratory 
test/parameter by treatment group. Changes from baseline will also be presented for all continuous 
laboratory parameters by treatment group over time. 
Categorical laboratory parameters will be summarized by presenting the number and % of subjects by 
visit and by treatment arm. 
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 Potentially Clinically Significant (Extreme) laboratory results will be provided. 
A listing of subjects with markedly extreme abnormal laboratory results will be provided, and additional 
explorations of the data may be conducted as warranted. Additionally, summaries of abnormal lab results 
by parameter will be provided to investigate changes in platelet count and prolactin in greater detail. The 
summaries include: 
• 
Subjects with decrease (≥25% from baseline) in Platelets count with  normal platelet count at 
baseline 
• 
Subjects with decrease (≥25% from baseline) in Platelets count relative to baseline (whether 
normal or abnormal) platelet count 
• 
Subjects with increase (≥25% from baseline) in prolactin with normal baseline 
• 
Subjects with increase (≥25% from baseline) in prolactin with normal baseline, and had seizure 
event within 48 hours prior to prolactin 
10.5. 
Vital Signs  
Vital signs data including blood pressure, heart rate, temperature, respiratory rate, weight, and BMI will be 
documented for subjects during study at screening visit (visit 1), randomization (visit 3) prior to first dose of 
study medication, titration period (visit 6), and maintenance period (visit 8 and visit 10) and at EOS visit 
(visit 12). 
The mean value and change from baseline to each on-study evaluation will be summarized for vital signs 
and weight by treatment group.  Vital signs, Weight and BMI data will be presented for each patient in a 
data listing. 
For each subject with a clinically meaningful abnormality in vital signs, weight, or BMI (to be supplied by 
Sponsor), a table will be produced organized by parameter that lists each subject, age, sex, day of most 
abnormal value, the most abnormal value, and the reference range. 
A listing of each subject’s values will be created. 
10.6. 
ECG 
12-Lead ECGs data (PR, QRS, QT, QTcF, and HR) will be documented for subjects during study at 
baseline (Visit 1 and Visit 3), Day 43 (Visit 8), at End of Study (Visit 12) and at Cardiac Follow-up (Visit 
14). 
Analysis of Echocardiograms will be included in a separate report from ERT. 
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All ECG values will be presented in the subject data listing. In addition to the subject data listing with all 
ECG values, a listing of all abnormal, clinically relevant findings will be presented organized by subject, 
by parameter, then by visit. 
10.7. 
Doppler Echocardiography 
Color Doppler echocardiography (ECHO) will be conducted at a facility with experience for the subject’s 
age at Screening, Maintenance period (Visit 8), End of study (Visit 12), and Cardiac Follow-up (Visit 14). 
ECHO uses ultrasound technology to examine the heart or blood vessels. An ECHO uses high frequency 
sound waves to create an image of the heart while the use of Doppler technology allows determination of 
the speed and direction of blood flow by utilizing the Doppler effect. Predetermined standard guidelines 
on the proper evaluation of certain measurements, as well as abnormality thresholds, were constructed 
by the sponsor’s IPCAB prior to study initiation. These thresholds are provided in Cardiovascular SAP. 
 
Results of ECHOs will be presented in a separate report from ERT.  
10.8. 
Physical Examination 
A complete physical examination will be performed at Screening Visit (Visit 1), day of randomization (visit 
3) prior to first dose of study medication, and at the EOS visit. An abbreviated physical exam is performed 
at Day 15 (Visit 6), 43 (Visit 8), and 71 (Visit 10). A complete or abbreviated physical exam may be 
performed at the Cardiac follow-up visit for patients who do not enter the open-label extension study if 
clinically warranted.   
All physical examination results will be presented in a subject data listing, including the description of 
abnormalities. New, clinically meaningful abnormalities will be reported as adverse events. 
10.9. 
Neurological Examination 
A complete neurological examination will be performed at Screening Visit (Visit 1) and EOS (Visit 13). An 
abbreviated neurological examination will be performed at randomization (visit 3) and at Visit 6. 
Shift tables representing neurological exam results from randomization to EOS will be presented by body 
system. 
All neurological examination results will be presented in a subject data listing, including the description of 
abnormalities. 
10.10. 
Tanner Staging 
Tanner Staging will be assessed for subjects >7 years old during the study at baseline period (Visit 3) and 
End of study (Visit 12). Conceptually, pubertal maturation can be described in terms of sequence, timing, 
and tempo.  Puberty consists of a series of predictable events, and the sequence of changes in 
secondary sexual characteristics has been categorized by several groups.  The onset and progress of 
pubertal changes will be recorded on a 5 point scale for boys and girls separately. Boys are rated for 
genital development and pubic hair growth through stage I to stage V. Girls are rated for breast 
development and pubic hair growth through stage I to stage V. 
The number and percentage of subjects in each Tanner Stage will be presented for all visits by treatment 
group separately for boys and girls overall and also broken out for the following age groups: 
>7 years to <=11,  
>11 years to <=15, 
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Suicidal behavior is assessed as a “yes” answer at any time during the T + M 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 T + 
M period. The denominator will be the number of subjects completing the C-SSRS at least once during 
the T + M period. 
Suicidal Ideation or Behavior: 
An overall composite will be provided similar to the suicidal ideation and behavior endpoints, but will 
instead count a subject if any of the C-SSRS questions 1 through 10 are marked as ‘yes’ anytime during 
the T+M period. 
Self-injurious behavior without suicidal intent: 
The number and percentage of subjects having reported anytime during the T+M period experiencing a 
‘Self-injurious behavior without suicidal intent’ event (Question 11) will be provided. 
10.12. 
Brief Rating Inventory of Executive Function (BRIEF and BRIEF-P)  
The Behavior Rating Inventory of Executive Function (BRIEF™)  and its preschool version, BRIEF-P, 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 (i.e. at 
Randomization (Visit 3), at Maintenance period (Visit 8) and at End of study visit (Visit 12)).  
 
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.  
For the BRIEF and the BRIEF-P, 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 for the Safety 
population (SAF). 
 
 
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11. Interim Analyses 
No formal interim analysis is planned for Study 2.   
Unblinding for Study 2 will not occur until data cleaning is completed and all decisions regarding protocol 
deviations warranting exclusion from the per protocol population have been made.  
 
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12. Changes from Analysis Planned in Protocol 
• 
The 1501 and 1502 protocols set a target that 40% of enrolled subjects to be less than 6 years 
old, but candidate subjects have been older than expected. Consequently, the enrollment target 
has been revised to ensure that at least 25% of subjects are less than 6 years old. 
• 
Protocols 1501 and 1502 state that efficacy and safety endpoints will be repeated separately for 
the titration and maintenance periods, however this is not planned to be conducted –Data from 
the T+M Period will be summarized and analyzed for all endpoints, and separate analyses of 
titration or maintenance periods will be generated only for selected endpoints. 
• 
Protocols 1501 and 1502 state that analyses of safety data will be presented by treatment 
actually received. However, safety data will be presented by randomized treatment group except 
where noted otherwise. 
• 
Protocols 1501 and 1502 provide sample size calculations to support a total study sample of 105 
subjects, 35 per treatment group.  A revised sample size calculation has increased the sample 
size to 40 subjects per treatment group, for a total of approximately120 subjects. 
• 
Protocols 1501 and 1502 state that a sensitivity analysis for the primary efficacy endpoint will be 
conducted by adding a factor indicating whether a subject had a change in prescribed dose or 
type of concomitant AED medication during the T+M Period, however this is not planned to be 
conducted. Instead it is planned to compare the treatment groups with respect to the proportion of 
subjects who changed dose and/or type of AED concomitant medication during the T+M Period.  
• 
Protocols 1501 and 1502 state that the longest interval between convulsive seizures will be 
analyzed using a log-rank test. However, further considerations of this endpoint suggest that 
while the first seizure-free interval may be subject to independent censoring, the second and later 
seizure-free intervals are subject to dependent censoring. Moreover, the last seizure-free interval 
is subject to intercept sampling, hence a longer seizure-free interval is more likely to be censored. 
Finally, the number of seizures or seizure-free intervals is informative about the underlying 
distribution, as subjects at a higher risk of experiencing recurrent events are likely to have shorter 
and hence more seizure-free intervals during the 84 day treatment period. Thus, a simple 
analysis comparing medians of the largest seizure free intervals was proposed.  
• 
Responder analyses – Protocols 1501 and 1502 include a ≥40% response analysis as one of the 
key secondary endpoints. It was decided to not include this endpoint as the ≥50% response 
analysis is considered clinically meaningful.  
• 
An analysis of the percentage of subjects who achieve a 25% reduction in seizures was added. 
The number of subjects whose seizures worsen during the study will be included, along with the 
percentage of worsening. 
• 
The Protocol states that the BRIEF rating scale will be used to evaluate cognition in children aged 
2-18.  The BRIEF-P will be used for children aged 2-4, and the BRIEF will evaluate children aged 
5-18. 
• 
The protocol included the exploratory objective to compare the ZX008 0.2 mg/kg/day and ZX008 
0.8 mg/kg/day doses on primary , secondary, safety, and PK endpoints. Comparisons between 
doses were not made using inferential statistics. 
• 
The protocol states that subjects will enter information daily into the diary; in some cases, data 
could not be entered directly into the diary and had to be entered via the DCR process. These 
data were analyzed in the same manner as data entered directly. 
• 
An analysis of the percentage of subjects who achieve a 100% reduction (near seizure-free) in 
seizures was added. The number of subjects whose seizures worsen during the study will be 
included, along with the percentage of worsening. 
• 
Intermediate missing day and post-discontinuation imputation was added: Intermediate missing 
days should be imputed as the worse observed outcome for that patient if the patient was 
assigned to an active arm or zero seizures if the patient was assigned to placebo.  
For patients who discontinued the study, the day of discontinuation should be imputed as the 
worse observed outcome if assigned to ZX008 and as zero counts if the patient was assigned to 
placebo. The remaining days should be imputed using the baseline seizure counts for all arms. 
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• 
Impute the number of siezures in an uncountable cluster was added. Such an impuatation is 
necessary to make it possible to calculate seizure frequency. For cluster seizures that were 
reported as uncountable, the assigned number of seizures in the cluster is assigned as 3. 
 
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13. Programming Considerations 
All tables, data listings, figures (TLFs), and statistical analyses will be generated using SAS® for 
Windows, Release 9.4 (SAS® Institute Inc., Cary, NC, USA). Computer-generated table, listing and figure 
output will adhere to the following specifications. 
13.1. 
General Considerations 
• One SAS program can create several outputs. / A separate SAS program will be created for each 
output. 
• One output file can contain several outputs. / Each output will be stored in a separate file. 
• Output files will be delivered in Word format / pdf format. 
• Numbering of TLFs will follow ICH E3 guidance. 
13.2. 
Table, Listing, and Figure Format 
13.2.1. 
General 
• All TFLs will be produced in landscape format, unless otherwise specified. 
• All TFLs will be produced using the Courier New font, size 8  which is the smallest acceptable point 
size for the Regulatory Authorities. 
• The data displays for all TFLs will have a minimum blank 1-inch margin on all 4 sides. 
• Headers and footers for figures will be in Courier New font, size 8 which is the smallest acceptable 
point size for the Regulatory Authorities. 
• Legends will be used for all figures with more than 1 variable, group, or item displayed. 
• TFLs will be in black and white (no color), unless otherwise specified 
• Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TFLs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used (see below). 
• Only standard keyboard characters will be used in the TFLs. Special characters, such as non-
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
display math symbols (e.g., μ). Certain subscripts and superscripts (e.g., cm2, Cmax) will be 
employed on a case-by-case basis. 
• Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, 
as appropriate. 
13.2.2. 
Headers 
• All output should have the following header at the top left of each page: 
• <Sponsor Name> Protocol <XXX> (Syneos Health study number <xxx>) 
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• Draft/Final Run <date> 
• All output should have Page n of N at the top or bottom right corner of each page. TFLs are 
internally paginated in relation to the total length (i.e., the page number should appear sequentially 
as page n of N, where N is the total number of pages in the table). 
• The date output was generated should appear along with the program name as a footer on each 
page. 
13.2.3. 
Display Titles 
• Each FL are identified by the designation and a numeral. (i.e., Table 14.1.1). ICH E3 numbering is 
strongly recommended, but sponsor preferences are obtained before final determination A decimal 
system (x.y and x.y.z) are used to identify TFLs with related contents. The title is centered. The 
analysis set are identified on the line immediately following the title. The title and table designation 
are single spaced. A solid line spanning the margins will separate the display titles from the 
•  Column headers. There will be 1 blank line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
(ITT Analysis Set) 
 
13.2.4. 
Column Headers 
• Column headings are displayed immediately below the solid line described above in initial upper-
case characters. 
• In the case of efficacy tables, the variable (or characteristic) column will be on the far left followed 
by the treatment group columns and total column (if applicable). P-values may be presented under 
the total column or in separate p-value column (if applicable). Within-treatment comparisons may 
have p-values presented in a row beneath the summary statistics for that treatment. 
• For numeric variables, include “unit” in column or row heading when appropriate. 
• Analysis set sizes will be presented for each treatment group in the column heading as (N=xx) (or 
in the row headings, if applicable). This is distinct from the ‘n’ used for the descriptive statistics 
representing the number of subjects in the analysis set. 
• The order of treatments in the tables and listings will be Placebo first in the case of placebo 
controlled studies and Active comparators first in the case of active comparator trials, followed by a 
total column (if applicable). 
13.2.5. 
Body of the Data Display 
13.2.5.1. 
General Conventions 
Data in columns of a table or listing are formatted as follows: 
• Alphanumeric values are left-justified; 
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• Whole numbers (e.g., counts) are right-justified; and 
• Numbers containing fractional portions are decimal aligned. 
13.2.5.2. 
Table Conventions 
• Units will be included where available 
• If the categories of a parameter are ordered, then all categories between the maximum and 
minimum category are presented in the table, even if n=0 for all treatment groups in a given 
category that is between the minimum and maximum level for that parameter. For example, the 
frequency distribution for symptom severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
 
Where percentages are presented in these tables, zero percentages will not be presented and so counts 
of 0 will be presented as 0 and not as 0 (0%). 
• If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the 
Study, etc.), then only those categories for which there is at least 1 subject represented in 1 or 
more groups are included. 
• An Unknown or Missing category are added to each parameter for which information is not 
available for 1 or more subjects.  
• Unless otherwise specified, the estimated mean and median for a set of values are printed out to 1 
more significant digit than the original values, and standard deviations are printed out to 2 more 
significant digits than the original values. The minimum and maximum should report the same 
significant digits as the original values. For example, for systolic blood pressure: 
N 
  XX 
Mean 
XXX.X 
Std Dev 
 X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
 
• P-values are output in the format: “0.xxxx”, where xxxx is the value rounded to 4 decimal places. 
Every p-value less than 0.0001 will be presented as <0.0010. If the p-value are less than 0.0001, 
then present as <0.0001. If the p-value is returned as >0.9999, then present as >0.9999. 
• Percentage values are printed to one decimal place, in parentheses with no spaces, one space 
after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to display values that round down 
to 0.0.  A common convention is to display as '<0.1', or as appropriate with additional decimal 
places. Unless otherwise noted, for all percentages, the number of subjects in the analysis set for 
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the treatment group who have an observation will be the denominator. Percentages after zero 
counts should not be displayed and percentages equating to 100% are presented as 100%, without 
decimal places.  
• Tabular display of data for medical history, prior/concomitant medications, and all tabular displays 
of adverse event data are presented by the body system, treatment class, or SOC with the highest 
occurrence in the active treatment group in decreasing order, assuming all terms are coded. Within 
the body system, drug class and SOC, medical history (by preferred term), drugs (by ATC1 code), 
and adverse events (by preferred term) are displayed in decreasing order. If incidence for more 
than 1 term is identical, they should then be sorted alphabetically. Missing descriptive statistics or 
p-values which cannot be estimated are reported as “-”. 
• The percentage of subjects is normally calculated as a proportion of the number of subjects 
assessed in the relevant treatment group (or overall) for the analysis set presented. However, 
careful consideration is required in many instances due to the complicated nature of selecting the 
denominator, usually the appropriate number of subjects exposed. Describe details of this in 
footnotes or programming notes. 
• For categorical summaries (number and percentage of subjects) where a subject can be included 
in more than one category, describe in a footnote or programming note if the subject are included 
in the summary statistics for all relevant categories or just 1 category and the criteria for selecting 
the criteria. 
• Where a category with a subheading (such as system organ class) has to be split over more than 
one page, output the subheading followed by “(cont)” at the top of each subsequent page.  The 
overall summary statistics for the subheading should only be output on the first relevant page. 
13.2.5.3. 
Listing Conventions 
• Listings will be sorted for presentation in order of treatment groups as above, subject number, 
visit/collection day, and visit/collection time. 
• Missing data are represented on subject listings as either a hyphen (“-”) with a corresponding 
footnote (“- = unknown or not evaluated”), or as “N/A”, with the footnote “N/A = not applicable”, 
whichever is appropriate. 
• Dates are printed in SAS DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing portions of dates are 
represented on subject listings as dashes (--JUL2000). Dates that are missing because they are 
not applicable for the subject are output as “N/A”, unless otherwise specified. 
• All observed time values are to be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study. 
• Units will be included where available 
13.2.5.4. 
Figure Conventions 
• Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint 
(e.g., treatment mean change from Baseline) values will be displayed on the Y-axis. 
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13.2.6. 
Footnotes 
• A solid line spanning the margins will separate the body of the data display from the footnotes.  
• All footnotes will be left justified with single-line spacing immediately below the solid line 
underneath the data display. 
• Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, etc. if a 
reference footnote. Each new footnote should start on a new line, where possible. 
• Subject specific footnotes are avoided, where possible. 
• Footnotes will be used sparingly and add value to the table, figure, or listing. If more than six lines 
of footnotes are planned, then a cover page is strongly recommended to be used to display 
footnotes, and only those essential to comprehension of the data will be repeated on each page.  
• The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, date the program was run, and the listing source (i.e., 
‘Program : myprogram.sas    Listing source: 16.x.y.z’). 
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14. Quality Control 
SAS programs are developed to produce output such as analysis data sets, summary tables, data listings, 
figures or statistical analyses. An overview of the development of programs is detailed in Syneos Health 
SOP Developing Statistical Programs (3907)  . 
Syneos Health SOPs Developing Statistical Programs (3907) and  Conducting the Transfer of Biostatistical 
Deliverables (3908) describes the quality control procedures that are performed for all SAS programs and 
output. Quality control is defined here as the operational techniques and activities undertaken to verify that 
the SAS programs produce the output by checking for their logic, efficiency and commenting and by review 
of the produced output.”   
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15. Index of Tables, Figures and Listings 
Table/ 
Figure/ 
Listing 
Number 
Table Header 
14.1 
Demographic data and other baseline characteristics 
  
14.1.1 
Subject disposition 
Table 
14.1.1.1 
Overall Subject Disposition – All Enrolled Subjects 
Table 
14.1.1.1a 
Overall Subject Disposition (Japan) – All Enrolled Subjects 
Table 
14.1.1.1b 
Overall Subject Disposition (Non-Japan) – All Enrolled Subjects 
Table 
14.1.1.2 
Major Protocol Deviations – Safety Population 
Table 
14.1.1.2a 
Major Protocol Deviations (Japan) – Safety Population 
Table  
14.1.1.3 
Study Populations 
  
14.1.2 
 Demographic and other baseline characteristics 
Table 
14.1.2.1 
Demographic and Baseline Characteristics – Safety Population 
Table 
14.1.2.1a 
Demographic and Baseline Characteristics (Japan) – Safety Population 
Table 
14.1.2.1b 
Demographic and Baseline Characteristics (Non-Japan) – Safety 
Population 
Table 
14.1.2.2 
Demographic and Baseline Characteristics – mITT Population 
Table 
14.1.2.2a 
Demographic and Baseline Characteristics (Japan) – mITT Population 
Table 
14.1.2.2b 
Demographic and Baseline Characteristics (Non-Japan) – mITT Population 
Table 
 
14.1.2.3 
 
Demographic and Baseline Characteristics for Study 2 Subjects, by Original 
Randomized Study (1501/1502) – Study 2-mITT Population 
Table 
 
14.1.2.3a 
 
Demographic and Baseline Characteristics for Study 2 Subjects, by Original 
Randomized Study (1501/1502) (Non-Japan) – Study 2-mITT Population 
  
14.1.3 
Medical history 
Table 
14.1.3.1 
Medical History – Safety Population 
  
14.1.4 
Prior and concomitant medication/treatment 
Table 
14.1.4.1 
Prior Medications – Safety Population 
Table 
14.1.4.2 
Concomitant Medications – Safety Population 
Table 
14.1.4.3 
Prior Antiepileptic Treatment – Safety Population 
Table 
14.1.4.3a 
Prior Antiepileptic Treatment (Japan) – Safety Population 
Table 
14.1.4.3b 
Prior Antiepileptic Treatment (Non-Japan) – Safety Population 
Table 
14.1.4.4.1 
Concomitant Antiepileptic Treatment  – Safety Population 
Table 
14.1.4.4.1a 
Concomitant Antiepileptic Treatment (Japan) – Safety Population 
Table 
14.1.4.4.1b 
Concomitant Antiepileptic Treatment  (Non-Japan) – Safety Population 
Table 
14.1.4.4.2 
Number of Concomitant Antiepileptic Treatments 
Table 
14.1.4.4.2a 
Number of Concomitant Antiepileptic Treatments (Japan) 
Table 
14.1.4.4.2b 
Number of Concomitant Antiepileptic Treatments (Non-Japan) 
  
14.1.5 
Treatment Exposure and compliance 
Table 
14.1.5.1 
Duration of Treatment Exposure – Safety Population 
Table 
14.1.5.1a 
Duration of Treatment Exposure (Japan) – Safety Population 
Table 
14.1.5.1b 
Duration of Treatment Exposure (Non-Japan) – Safety Population 
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Table 
14.1.5.2 
Compliance to IMP Intake – Safety Population  
Table 
14.1.5.2a 
Compliance to IMP Intake (Japan) – Safety Population  
Table 
14.1.5.2b 
Compliance to IMP Intake (Non-Japan) – Safety Population  
  
14.2 
Efficacy, pharmacokinetics, and pharmacodynamics 
  
14.2.1 
Efficacy – ZX008 0.8 and 0.2 mg/kg/day vs Placebo 
Table 
14.2.1.1.1 
Convulsive Seizure Frequency per 28 Days : Summary Statistics – mITT 
Population 
Table 
14.2.1.1.1a 
Convulsive Seizure Frequency per 28 Days : Summary Statistics (Japan) – 
mITT Population 
Table 
14.2.1.1.1b 
Convulsive Seizure Frequency per 28 Days : Summary Statistics (Non-
Japan) – mITT Population 
Table 
14.2.1.1.2 
Convulsive Seizure Frequency per 28 Days, by Age Group : Summary 
Statistics – mITT Population 
Table 
14.2.1.1.2a 
Convulsive Seizure Frequency per 28 Days, by Age Group : Summary 
Statistics (Japan) – mITT Population 
Table 
14.2.1.1.2b 
Convulsive Seizure Frequency per 28 Days, by Age Group : Summary 
Statistics (Non-Japan) – mITT Population 
Table 
14.2.1.1.3 
Convulsive Seizure Frequency per 28 Days, by Sex : Summary Statistics – 
mITT Population 
Table 
14.2.1.1.3a 
Convulsive Seizure Frequency per 28 Days, by Sex : Summary Statistics 
(Japan) – mITT Population 
Table 
14.2.1.1.3b 
Convulsive Seizure Frequency per 28 Days, by Sex : Summary Statistics 
(Non-Japan) – mITT Population 
Table 
14.2.1.1.4 
Convulsive Seizure Frequency per 28 Days, by Race : Summary Statistics 
– mITT Population 
Table 
14.2.1.1.4a 
Convulsive Seizure Frequency per 28 Days, by Race : Summary Statistics 
(Japan) – mITT Population 
Table 
14.2.1.1.4b 
Convulsive Seizure Frequency per 28 Days, by Race : Summary Statistics 
(Non-Japan) – mITT Population 
Table  
14.2.1.2 
Convulsive Seizure Frequency per 28 Days : Parametric Analysis – mITT 
Population 
Table  
14.2.1.2a 
Convulsive Seizure Frequency per 28 Days : Parametric Analysis (Japan) – 
mITT Population 
Table  
14.2.1.2b 
Convulsive Seizure Frequency per 28 Days : Parametric Analysis (Non-
Japan) – mITT Population 
Table 
 
14.2.1.2c  
 
Convulsive seizure frequency per 28 days During Double-blind Treatment 
for Study 2 by Original Randomized Study (1501/1502): Parametric 
Analysis – Study 2 - mITT Population 
Table  
14.2.1.2.1 
Convulsive Seizure Frequency per 28 Days, by Age Group : Parametric 
Analysis – mITT Population 
Table  
14.2.1.2.1a 
Convulsive Seizure Frequency per 28 Days, by Age Group : Parametric 
Analysis (Japan) – mITT Population 
Table  
14.2.1.2.2 
Convulsive Seizure Frequency per 28 Days, by Sex: Parametric Analysis – 
mITT Population 
Table  
14.2.1.2.2a 
Convulsive Seizure Frequency per 28 Days, by Sex: Parametric Analysis 
(Japan) – mITT Population 
Table  
14.2.1.2.3 
Convulsive Seizure Frequency per 28 Days, by Race : Parametric Analysis 
– mITT Population 
Table 
14.2.1.3 
Convulsive Seizure Frequency per 28 Days : Nonparametric Analysis – 
mITT Population 
Table 
14.2.1.3a 
Convulsive Seizure Frequency per 28 Days : Nonparametric Analysis 
(Japan) – mITT Population 
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Table 
14.2.1.3b 
Convulsive Seizure Frequency per 28 Days : Nonparametric Analysis (Non-
Japan) – mITT Population 
Table 
14.2.1.5 
% Change in Convulsive Seizure Frequency per 28 Days : Nonparametric 
Analysis – mITT Population 
Table 
14.2.1.5a 
% Change in Convulsive Seizure Frequency per 28 Days : Nonparametric 
Analysis (Japan) – mITT Population 
Table 
14.2.1.5b 
% Change in Convulsive Seizure Frequency per 28 Days : Nonparametric 
Analysis (Non-Japan) – mITT Population 
Table 
14.2.1.7 
Convulsive Seizure Frequency per 28 Days : Parametric Analysis – PP 
Population 
Table 
14.2.1.7b 
Convulsive Seizure Frequency per 28 Days : Parametric Analysis (Non-
Japan)  – PP Population 
Table 
14.2.1.8 
Convulsive Seizure Frequency per 28 Days : Nonparametric Analysis – PP 
Population 
Table 
14.2.1.8b 
Convulsive Seizure Frequency per 28 Days : Nonparametric Analysis (Non-
Japan)  – PP Population 
Table 
14.2.1.10 
% Change in Convulsive Seizure Frequency per 28 Days : Nonparametric 
Analysis – PP Population 
Table 
14.2.1.10b 
% Change in Convulsive Seizure Frequency per 28 Days : Nonparametric 
Analysis (Non-Japan) – PP Population 
Table 
14.2.1.11 
Convulsive Seizure Frequency per 28 Days by Baseline  Convulsive 
Seizure Frequency Category: Nonparametric Analysis -  mITT Population 
Table 
14.2.1.11a 
Convulsive Seizure Frequency per 28 Days by Baseline  Convulsive 
Seizure Frequency Category: Nonparametric Analysis (Japan) -  mITT 
Population 
Table 
14.2.1.11b 
Convulsive Seizure Frequency per 28 Days by Baseline  Convulsive 
Seizure Frequency Category: Nonparametric Analysis (Non-Japan) -  mITT 
Population 
  
14.2.2 
Efficacy – Proportion of subjects who achieve various % reductions in 
Convulsive Seizure Frequency 
Table 
14.2.2.1 
Percent Reduction in Convulsive Seizure Frequency – mITT Population 
Table 
14.2.2.1a 
Percent Reduction in Convulsive Seizure Frequency (Japan) – mITT 
Population 
Table 
14.2.2.1b 
Percent Reduction in Convulsive Seizure Frequency (Non-Japan) – mITT 
Population 
Figure  
14.2.2.2.1 
Cumulative Response Curve for % Reductions in Convulsive Seizure 
Frequency 
Figure  
14.2.2.2.1a 
Cumulative Response Curve for % Reductions in Convulsive Seizure 
Frequency (Japan) 
Figure  
14.2.2.2.1b 
Cumulative Response Curve for Various % Reductions in Convulsive 
Seizure Frequency (Non-Japan) 
Figure  
14.2.2.2.2 
Cumulative Response Curve for % Reductions in Convulsive Seizure 
Frequency – All Subjects Increased And Decreased 
Figure  
14.2.2.2.2a 
Cumulative Response Curve for % Reductions in Convulsive Seizure 
Frequency – All Subjects Increased And Decreased (Japan) 
Figure  
14.2.2.2.2b 
Cumulative Response Curve for % Reductions in Convulsive Seizure 
Frequency – All Subjects Increased And Decreased (Non-Japan) 
Table 
14.2.2.3 
Percent Reduction in Convulsive Seizure Frequency  – PP Population  
Table 
14.2.2.3b 
Percent Reduction in Convulsive Seizure Frequency  (Non-Japan) – PP 
Population  
Figure  
14.2.2.4 
Cumulative Response Curve for % Reductions in Convulsive Seizure 
Frequency - PP Population  
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Figure  
14.2.2.4b 
 Cumulative Response Curve for % Reductions in Convulsive Seizure 
Frequency (Non-Japan) - PP Population  
  
14.2.3 
Efficacy – Longest  interval between convulsive seizures 
Table 
14.2.3.1 
Longest Interval Between Convulsive Seizures – mITT Population 
Table 
14.2.3.1a 
Longest Interval Between Convulsive Seizures (Japan) – mITT Population 
Table 
14.2.3.1b 
Longest Interval Between Convulsive Seizures (Non-Japan) – mITT 
Population 
Figure 
14.2.3.2 
Boxplot of Distribution of Longest Interval Between Convulsive Seizures – 
mITT Population 
Figure 
14.2.3.2a 
Boxplot of Distribution of Longest Interval Between Convulsive Seizures 
(Japan) – mITT Population 
Figure 
14.2.3.2b 
Boxplot of Distribution of Longest Interval Between Convulsive Seizures 
(Non-Japan) – mITT Population 
Table 
14.2.3.3 
Longest Interval Between Convulsive Seizures – PP Population  
Table 
14.2.3.3a 
Longest Interval Between Convulsive Seizures (Japan) – PP Population  
Table 
14.2.3.3b 
Longest Interval Between Convulsive Seizures (Non-Japan) – PP 
Population  
Figure 
14.2.3.4 
Boxplot of Distribution of Longest Interval Between Convulsive Seizures – 
PP Population  
Figure 
14.2.3.4a 
Boxplot of Distribution of Longest Interval Between Convulsive Seizures 
(Japan) – PP Population  
Figure 
14.2.3.4b 
Boxplot of Distribution of Longest Interval Between Convulsive Seizures 
(Non-Japan) – PP Population  
  
14.2.4 
Efficacy – Number of convulsive seizure free days 
Table 
14.2.4.2 
Number of Convulsive Seizure Free Days - Nonparametric Analysis – mITT 
Population 
Table 
14.2.4.2a 
Number of Convulsive Seizure Free Days - Nonparametric Analysis (Japan) 
– mITT Population 
Table 
14.2.4.2b 
Number of Convulsive Seizure Free Days - Nonparametric Analysis (Non-
Japan) – mITT Population 
  
14.2.6 
Efficacy – Change from baseline in non-convulsive and convulsive + 
non-convulsive seizure frequency 
Table 
14.2.6.1 
Change from Baseline  in Non-convulsive Seizure 
Frequency:Nonparametric Analysis – mITT Population 
Table 
14.2.6.1a 
Change from Baseline  in Non-convulsive Seizure 
Frequency:Nonparametric Analysis (Japan) – mITT Population 
Table 
14.2.6.1b 
Change from Baseline  in Non-convulsive Seizure 
Frequency:Nonparametric Analysis (Non-Japan) – mITT Population 
Table 
14.2.6.2 
Change from Baseline  in Convulsive + Non-convulsive  Seizure 
Frequency, , Nonparametric Analysis – mITT Population 
Table 
14.2.6.2a 
Change from Baseline  in Convulsive + Non-convulsive  Seizure 
Frequency, , Nonparametric Analysis (Japan) – mITT Population 
Table 
14.2.6.2b 
Change from Baseline  in Convulsive + Non-convulsive  Seizure 
Frequency, , Nonparametric Analysis (Non-Japan) – mITT Population 
  
14.2.7 
Efficacy – Incidence of rescue medication 
Table 
14.2.7.1 
Days with Rescue Medication Usage – mITT Population 
Table 
14.2.7.1a 
Days with Rescue Medication Usage (Japan) – mITT Population 
Table 
14.2.7.3 
Number of Rescue Medications per Episode – mITT Population 
Table 
14.2.7.3a 
Number of Rescue Medications per Episode (Japan) – mITT Population 
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14.2.8 
Efficacy – Hospitalization and Resource Utilization for Treatment of 
Seizures  
Table 
14.2.8.1 
Hospitalization and Other Healthcare Resource Utilization to Treat Seizure 
– mITT Population 
Table 
14.2.8.1a 
Hospitalization and Other Healthcare Resource Utilization to Treat Seizure 
(Japan) – mITT Population 
  
14.2.9 
Efficacy – Incidence of Status Epilepticus, and duration of prolonged 
seizures 
Table 
14.2.9. 1 
Number of Episodes of Status Epilepticus - mITT Population   
Table 
14.2.9. 1a 
Number of Episodes of Status Epilepticus (Japan) - mITT Population   
Table 
14.2.9. 2 
Duration of Seizures - mITT Population 
Table 
14.2.9. 2a 
Duration of Seizures (Japan) - mITT Population 
Table 
14.2.9.3 
Episodes of Status Epilepticus by Rescue Medication Use - mITT 
Population 
Table 
14.2.9.3a 
Episodes of Status Epilepticus by Rescue Medication Uses (Japan) - mITT 
Population 
  
14.2.10 
Efficacy – Clinical Global Impression – Improvement rating by 
Parent/Caregiver and Investigator 
Table 
14.2.10.1 
Clinical Global Impression – Improvement Rating by Parent/Caregiver – 
mITT Population 
Table 
14.2.10.1a 
Clinical Global Impression – Improvement Rating by Parent/Caregiver 
(Japan) – mITT Population 
Table 
14.2.10.1b 
Clinical Global Impression – Improvement Rating by Parent/Caregiver 
(Non-Japan) – mITT Population 
Figure 
14.2.10.2 
Distribution of Clinical Global Impression – Improvement Rating by 
Parent/Caregiver – mITT Population 
Figure 
14.2.10.2a 
Distribution of Clinical Global Impression – Improvement Rating by 
Parent/Caregiver (Japan) – mITT Population 
Figure 
14.2.10.2b 
Distribution of Clinical Global Impression – Improvement Rating by 
Parent/Caregiver (Non-Japan) – mITT Population 
Table 
14.2.10.3 
Clinical Global Impression – Improvement Rating by Investigator  – mITT 
Population 
Table 
14.2.10.3a 
Clinical Global Impression – Improvement Rating by Investigator (Japan) – 
mITT Population 
Table 
14.2.10.3b 
Clinical Global Impression – Improvement Rating by Investigator (Non-
Japan) – mITT Population 
Figure 
14.2.10.4 
Distribution of Clinical Global Impression-Improvement Rating by 
Investigator  – mITT Population 
Figure 
14.2.10.4a 
Distribution of Clinical Global Impression-Improvement Rating by 
Investigator (Japan) – mITT Population 
Figure 
14.2.10.4b 
Distribution of Clinical Global Impression-Improvement Rating by 
Investigator (Non-Japan) – mITT Population 
  
14.2.11 
Efficacy – Quality of Life in Childhood Epilepsy Scale 
Table 
14.2.11.1 
Quality of Life in Childhood Epilepsy (QOLCE)  – mITT population 
Table 
14.2.11.1a 
Quality of Life in Childhood Epilepsy (QOLCE) (Japan) – mITT population 
  
14.2.12 
Efficacy – Peds QL 
Table 
14.2.12.1 
PedsQL Pediatric Quality of Life Inventory (Version 4.0) - Parent Report – 
mITT Population 
Table 
14.2.12.1a 
PedsQL Pediatric Quality of Life Inventory (Version 4.0) - Parent Report 
(Japan) – mITT Population 
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Table 
14.2.12.2 
PedsQL Family Impact Module (Version 2.0) – Parent Report – mITT 
Population 
Table 
14.2.12.2a 
PedsQL Family Impact Module (Version 2.0) (Japan) – Parent Report – 
mITT Population 
  
14.2.13 
Efficacy –Quality of Life of the Parent /Caregiver using EQ-5D-5L Scale 
Table 
14.2.13.1 
QOL of Parent/Caregiver Based on EQ-5D-5L: Health Profile Summary 
Original Response Categories  – mITT Population 
Table 
14.2.13.1a 
QOL of Parent/Caregiver Based on EQ-5D-5L: Health Profile Summary 
Original Response Categories (Japan) – 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 
14.2.13.2a 
QOL of Parent/Caregiver Based on EQ-5D-5L:  Health Profile Summary 
Using Dichotomized Response Categories (Japan) – 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 
Table 
14.2.13.3a 
QOL of Parent/Caregiver Based on EQ-5D-5L: Overall Health Status Using 
VAS (0-100) Scale (Japan) - mITT Population 
  
14.2.14 
Efficacy –Parent /Caregiver Ratings 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 
14.2.14.1a 
Parent/Caregiver Ratings Based on Hospital Anxiety and Depression Scale 
(HADS): Normal; Borderline Abnormal; and  Abnormal Categories (Japan) – 
mITT population 
Table 
14.2.14.2 
Parent/Caregiver Ratings Based on Hospital Anxiety and Depression Scale 
(HADS): Summary Descriptive Statistics – mITT population 
Table 
14.2.14.2a 
Parent/Caregiver Ratings Based on Hospital Anxiety and Depression Scale 
(HADS): Summary Descriptive Statistics (Japan) – mITT population 
 
14.2.15 
Other Efficacy 
Table 
 
14.2.15.1 
Percentage reduction in convulsive seizure frequency per 28 days for Study 
2 Subjects, by Original Randomized Study - mITT Population 
Table 
 
14.2.15.3 
 
Duration of the Longest Interval (days) Between Convulsive Seizures for 
Study 2 Subjects, by Original Randomized Study (1501/1502) - mITT 
Population 
Table 
 
14.2.15.3b 
 
Duration of the Longest Interval (days) Between Convulsive Seizures for 
Study 2 Subjects, by Original Randomized Study (1501/1502) (Non-Japan) 
- mITT Population 
Table 
 
14.2.15.4 
 
Convulsive seizure frequency per 28 days During Double-blind Treatment 
by baseline convulsive seizure frequency category: Parametric Analysis, by 
BCSF Category (<10, 10-50, >50) - mITT Population 
Table 
 
14.2.15.4a 
 
Convulsive seizure frequency per 28 days During Double-blind Treatment 
by baseline convulsive seizure frequency category: Parametric Analysis, by 
BCSF Category (<10, 10-50, >50) (Japan) - mITT Population 
Table 
 
14.2.15.5 
 
Convulsive seizure frequency per 28 days During Double-blind Treatment : 
Parametric Analysis, by Sex - mITT Population 
Table 
 
14.2.15.5a 
 
Convulsive seizure frequency per 28 days During Double-blind Treatment : 
Parametric Analysis, by Sex (Japan) - mITT Population 
Table 
 
14.2.15.6 
 
Convulsive seizure frequency per 28 days During Double-blind Treatment: 
Parametric Analysis, by Concomitant Valproate Use - mITT Population 
Table 
 
14.2.15.6a 
 
Convulsive seizure frequency per 28 days During Double-blind Treatment: 
Parametric Analysis, by Concomitant Valproate Use (Japan) - mITT 
Population 
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Table 
 
14.2.15.7 
 
Convulsive seizure frequency per 28 days During Double-blind Treatment: 
Parametric Analysis, by Concomitant Clobazam Use - mITT Population 
Table 
 
14.2.15.7a 
 
Convulsive seizure frequency per 28 days During Double-blind Treatment: 
Parametric Analysis, by Concomitant Clobazam Use (Japan) - mITT 
Population 
Table 
 
14.2.15.9 
 
Convulsive seizure frequency per 28 days During Double-blind Treatment: 
Parametric Analysis, by SCN1A Mutation Positive/Negative - mITT 
Population 
Table 
 
14.2.15.9a 
 
Convulsive seizure frequency per 28 days During Double-blind Treatment: 
Parametric Analysis, by SCN1A Mutation Positive/Negative (Japan) - mITT 
Population 
Figure 
14.2.15.10 
 
Scatterplot of Percentage Change  in CSF per 28 days vs. Actual Dose 
Administered During Double-blind Treatment (mg/kg/day) - mITT Population 
Figure 
14.2.15.10a 
 
Scatterplot of Percentage Change  in CSF per 28 days vs. Actual Dose 
Administered During Double-blind Treatment (mg/kg/day) (Japan) - mITT 
Population 
Figure 
14.2.15.10b 
 
Scatterplot of Percentage Change  in CSF per 28 days vs. Actual Dose 
Administered During Double-blind Treatment (mg/kg)/day (Non-Japan)  - 
mITT Population 
Figure 
14.2.15.11 
Scatterplot of Percent Change in CSF per 28 days vs. Actual  dose 
(mg/day) - mITT Population 
Figure 
14.2.15.11a 
Scatterplot of Percent Change in CSF per 28 days vs. Actual  dose 
(mg/day) (Japan) - mITT Population 
Figure 
14.2.15.11b 
Scatterplot of Percent Change in CSF per 28 days vs. Actual  dose 
(mg/day) (Non-Japan) - mITT Population 
Table 
 
14.2.15.12 
 
Convulsive seizure frequency per 28 days – Sensitivity Analysis S1 Worst 
value substituted for dropouts - mITT Population 
Table 
 
14.2.15.12a 
 
Convulsive seizure frequency per 28 days – Sensitivity Analysis S1 Worst 
value substituted for dropouts (Non-Japan) - mITT Population 
Table 
14.2.15.13 
 
Convulsive seizure frequency per 28 days – Sensitivity Analysis S2 
Differential imputation method for dropouts - mITT Population 
Table 
14.2.15.13a 
 
Convulsive seizure frequency per 28 days – Sensitivity Analysis S2 
Differential imputation method for dropouts (Non-Japan) - mITT Population 
Table 
14.2.15.14 
 
Convulsive Seizure Frequency per 28 Days (Intermediate Missing Day and 
Post-Discontinuation Imputation): Parametric Analysis - mITT Population 
Table 
14.2.15.15 
 
Convulsive Seizure Frequency per 28 Days (Intermediate Missing Day, 
Post-Discontinuation, and Cluster Imputation): Parametric Analysis - mITT 
Population 
 
 
 
  
14.3 
Safety 
  
14.3.1 
Summary of adverse events 
Table 
14.3.1.1 
Overview of Number of Subjects with TEAE, DB Treatment Period  – Safety 
Population 
Table 
14.3.1.1a 
Overview of Number of Subjects with TEAE, DB Treatment Period  (Japan) 
– Safety Population 
Table 
14.3.1.1b 
Overview of Number of Subjects with TEAE, DB Treatment Period  (Non-
Japan) – Safety Population 
Table 
14.3.1.2 
Treatment-Emergent Adverse Events by MedDRA System Organ Class and 
Preferred Term – Safety Population  
Table 
14.3.1.2a 
Treatment-Emergent Adverse Events by MedDRA System Organ Class and 
Preferred Term (Japan) – Safety Population  
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Table 
14.3.1.2b 
Treatment-Emergent Adverse Events by MedDRA System Organ Class and 
Preferred Term (Non-Japan) – Safety Population  
Table 
14.3.1.3 
TEAEs Leading to Study Discontinuation by Primary SOC and PT – Safety 
Population  
Table 
14.3.1.3a 
TEAEs Leading to Study Discontinuation by Primary SOC and PT (Japan) – 
Safety Population  
Table 
14.3.1.3b 
TEAEs Leading to Study Discontinuation by Primary SOC and PT (Non-
Japan) – Safety Population  
Table 
14.3.1.4 
Serious TEAEs by Primary SOC and PT – Safety Population 
Table 
14.3.1.4a 
Serious TEAEs by Primary SOC and PT (Japan) – Safety Population 
Table 
14.3.1.4b 
Serious TEAEs by Primary SOC and PT (Non-Japan) – Safety Population 
Table 
14.3.1.5 
Related TEAEs by Primary SOC and PT – Safety Population 
Table 
14.3.1.5a 
Related TEAEs by Primary SOC and PT (Japan) – Safety Population 
Table 
14.3.1.5b 
Related TEAEs by Primary SOC and PT (Non-Japan) – Safety Population 
Table 
14.3.1.6 
TEAEs by Maximum Severity by SOC and PT– Safety Population  
Table 
14.3.1.6a 
TEAEs by Maximum Severity by SOC and PT (Japan) – Safety Population  
Table 
14.3.1.6b 
TEAEs by Maximum Severity by SOC and PT (Non-Japan) – Safety 
Population  
Table 
14.3.1.7 
Treatment-Emergent Adverse Events Occurring in >=5% of Subjects by 
MedDRA System Organ Class and Preferred Term - Safety Population  
Table 
14.3.1.7a 
Treatment-Emergent Adverse Events Occurring in >=5% of Subjects by 
MedDRA System Organ Class and Preferred Term (Japan) - Safety 
Population  
Table 
14.3.1.7b 
Treatment-Emergent Adverse Events Occurring in >=5% of Subjects by 
MedDRA System Organ Class and Preferred Term (Non-Japan) - Safety 
Population  
Table 
14.3.1.8 
Overview of  Number of Subjects with Treatment-Emergent Adverse Events 
of Special Interest – Safety Population 
Table 
14.3.1.8a 
Overview of  Number of Subjects with Treatment-Emergent Adverse Events 
of Special Interest (Japan) – Safety Population 
Table 
14.3.1.8b 
Overview of  Number of Subjects with Treatment-Emergent Adverse Events 
of Special Interest (Non-Japan) – Safety Population 
Table 
14.3.1.9 
Treatment-Emergent Adverse Events of Special Interest (AESI) by SOC 
and PT – Safety Population 
Table 
14.3.1.9a 
Treatment-Emergent Adverse Events of Special Interest (AESI) by SOC 
and PT (Japan) – Safety Population 
Table 
14.3.1.9b 
Treatment-Emergent Adverse Events of Special Interest (AESI) by SOC 
and PT (Non-Japan) – Safety Population 
Table 
 
14.3.1.10  
 
 
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 
 
14.3.1.10a 
 
 
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) (Japan) - Safety Population 
Table 
 
14.3.1.11 
 
 
Treatment-related TEAEs that Occurred in at least 5% of Subjects During 
Double-blind Period by Preferred Term, Mean Time to Onset (days) and 
Mean Duration (days) - Safety Population 
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Table 
 
14.3.1.11a 
 
 
Treatment-related TEAEs that Occurred in at least 5% of Subjects During 
Double-blind Period by Preferred Term, Mean Time to Onset (days) and 
Mean Duration (days) (Japan) - Safety Population 
Table 
 
14.3.1.12 
 
 
Treatment-related TEAEs that Occurred in at least 5% of Subjects During 
Double-blind Period by Preferred Term With Number of Events and Number 
of Resolved Events With Number of Events and Number of Resolved 
Events - Safety Population 
Table 
 
14.3.1.12a 
 
 
Treatment-related TEAEs that Occurred in at least 5% of Subjects During 
Double-blind Period by Preferred Term With Number of Events and Number 
of Resolved Events With Number of Events and Number of Resolved 
Events (Japan) - Safety Population 
Table 
 
14.3.1.13 
 
Treatment-Emergent Adverse Events During Double-blind Treatment 
Period by Concomitant Usage of Valproate, MedDRA System Organ Class, 
and Preferred Term - Safety Population 
Table 
 
14.3.1.13a  
 
Treatment-Emergent Adverse Events During Double-blind Treatment 
Period by Concomitant Usage of Valproate, MedDRA System Organ Class, 
and Preferred Term (Japan) - Safety Population 
Table 
 
14.3.1.14 
 
Treatment-Emergent Adverse Events During Double-blind Treatment 
Period by Concomitant Usage of Clobazam, MedDRA System Organ Class, 
and Preferred Term - Safety Population 
Table 
 
14.3.1.14a  
 
Treatment-Emergent Adverse Events During Double-blind Treatment 
Period by Concomitant Usage of Clobazam, MedDRA System Organ Class, 
and Preferred Term (Japan) - Safety Population 
Table 
 
14.3.1.15 
 
Treatment-Emergent Adverse Events During Double-blind Treatment 
Period by Concomitant Usage of Topiramate, MedDRA System Organ 
Class, and Preferred Term - Safety Population 
Table 
 
14.3.1.15a  
 
Treatment-Emergent Adverse Events During Double-blind Treatment 
Period by Concomitant Usage of Topiramate, MedDRA System Organ 
Class, and Preferred Term (Japan) - Safety Population 
Table 
 
14.3.1.16  
 
Treatment-Emergent Adverse Events During Double-blind Treatment 
Period by Age Group, MedDRA System Organ Class, and Preferred Term - 
Safety Population 
Table 
 
14.3.1.16a  
 
Treatment-Emergent Adverse Events During Double-blind Treatment 
Period by Age Group, MedDRA System Organ Class, and Preferred Term 
(Japan) - Safety Population 
Table 
 
14.3.1.17 
 
 
Treatment-Emergent Adverse Events of Anaphylactic Reactions, 
Angioedema, Asthma/Bronchospasm, Hypersensitivity, and Drug Reaction 
with eosinophilia and systemic symptoms syndrome During Double-blind 
Treatment Period by MedDRA System Organ Class and Preferred Term - 
Safety Population 
Table 
 
14.3.1.17a  
 
 
Treatment-Emergent Adverse Events of Anaphylactic Reactions, 
Angioedema, Asthma/Bronchospasm, Hypersensitivity, and Drug Reaction 
with eosinophilia and systemic symptoms syndrome During Double-blind 
Treatment Period by MedDRA System Organ Class and Preferred Term 
(Japan) - Safety Population 
Table 
 
14.3.1.18  
 
 
Serious Treatment-Emergent Adverse Events 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 
 
14.3.1.18a  
 
 
Serious Treatment-Emergent Adverse Events During Double-blind 
Treatment Period by MedDRA System Organ Class and Preferred Term 
with Mean Time to Onset (days) and Mean Duration (days) (Japan) - Safety 
Population 
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Table 
 
14.3.1.19 
 
 
Serious Treatment-Emergent Adverse Events During Double-blind 
Treatment Period by MedDRA System Organ Class and Preferred Term 
with Number of Events and Number of Resolved Events - Safety Population 
Table 
 
14.3.1.19a  
 
 
Serious Treatment-Emergent Adverse Events During Double-blind 
Treatment Period by MedDRA System Organ Class and Preferred Term 
with Number of Events and Number of Resolved Events (Japan) - Safety 
Population 
Table 
14.3.1.20 
 
Treatment-Emergent Adverse Events Occurred More Frequent in ZX008 
than Placebo (>=2%) During Double-blind Treatment Period by Preferred 
Term - Safety Population 
Table 
14.3.1.20a  
 
Treatment-Emergent Adverse Events Occurred More Frequent in ZX008 
than Placebo (>=2%) During Double-blind Treatment Period by Preferred 
Term (Japan) - Safety Population 
Table 
14.3.1.20b  
 
Treatment-Emergent Adverse Events Occurred More Frequent in ZX008 
than Placebo (>=2%) During Double-blind Treatment Period by Preferred 
Term (Non-Japan) - Safety Population 
Table 
14.3.1.21  
Treatment-emergent Adverse Events with Onset During the Titration Period 
- Safety Population 
Table 
14.3.1.21a  
Treatment-emergent Adverse Events with Onset During the Titration Period 
(Japan) - Safety Population 
14.3.2 
Listings of Deaths, Other Serious and Significant Adverse Events 
Table 
14.3.2.1 
Listing of Deaths 
Table 
14.3.2.2 
Listing of SAEs 
Table 
14.3.2.3 
Listing of Discontinuations Due to AE 
  
14.3.4 
Summary of Laboratory Data 
Table 
14.3.4.1 
Laboratory Parameters – Hematology– Safety Population 
Table 
14.3.4.1a 
Laboratory Parameters – Hematology (Japan) – Safety Population 
Table 
14.3.4.1b 
Laboratory Parameters – Hematology (Non-Japan) – Safety Population 
Table 
14.3.4.2 
Laboratory Parameters – Biochemistry– Safety Population 
Table 
14.3.4.2a 
Laboratory Parameters – Biochemistry (Japan) – Safety Population 
Table 
14.3.4.2b 
Laboratory Parameters – Biochemistry (Non-Japan) – Safety Population 
Table 
14.3.4.4 
Laboratory Parameters – Urinalysis – Safety Population 
Table 
14.3.4.4a 
Laboratory Parameters – Urinalysis (Japan) – Safety Population 
Table 
14.3.4.4b 
Laboratory Parameters – Urinalysis (Non-Japan) – Safety Population 
Table 
14.3.4.4.1 
Laboratory Parameters – Urinalysis (Quantitative Parameters) – Safety 
Population 
Table 
14.3.4.4.1a 
Laboratory Parameters – Urinalysis (Quantitative Parameters) (Japan) – 
Safety Population 
Table 
14.3.4.4.1b 
Laboratory Parameters – Urinalysis (Quantitative Parameters) (Non-Japan) 
– Safety Population 
Table 
14.3.4.4.2 
Laboratory Parameters – Urinalysis (Categorical Parameters) – Safety 
Population 
Table 
14.3.4.4.2a 
Laboratory Parameters – Urinalysis (Categorical Parameters) (Japan) – 
Safety Population 
Table 
14.3.4.4.2b 
Laboratory Parameters – Urinalysis (Categorical Parameters) (Non-Japan) 
– Safety Population 
Table 
14.3.4.5 
Laboratory Parameters – Tests Of Growth And Precocious Puberty –Safety 
Population 
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Table 
14.3.4.5a 
Laboratory Parameters – Tests Of Growth And Precocious Puberty (Japan) 
–Safety Population 
Table 
14.3.4.5b 
Laboratory Parameters – Tests Of Growth And Precocious Puberty (Non-
Japan) –Safety Population 
Table 
14.3.4.6 
Laboratory Parameters – Epilepsy Genotype Panel – Descriptive Statistics 
– Safety Population 
Table 
14.3.4.6a 
Laboratory Parameters – Epilepsy Genotype Panel – Descriptive Statistics 
(Japan) – Safety Population 
Table 
14.3.4.6b 
Laboratory Parameters – Epilepsy Genotype Panel – Descriptive Statistics 
(Non-Japan) – Safety Population 
Table 
14.3.4.7 
Listing of Most Abnormal Laboratory Parameters – Hematology - Safety 
Population 
Table 
14.3.4.7a 
Listing of Most Abnormal Laboratory Parameters – Hematology (Japan) - 
Safety Population 
Table 
14.3.4.8 
Listing of Most Abnormal Laboratory Parameters – Biochemistry - Safety 
Population 
Table 
14.3.4.8a 
Listing of Most Abnormal Laboratory Parameters – Biochemistry (Japan) - 
Safety Population 
Table 
14.3.4.9 
Listing of Most Abnormal Laboratory Parameters – Urinalysis - Safety 
Population 
Table 
14.3.4.9a 
Listing of Most Abnormal Laboratory Parameters – Urinalysis (Japan) - 
Safety Population 
Table 
 
14.3.4.10 
 
Number of Subjects with Decrease in Platelets Count During Double-blind 
Study Period with Normal Platelet Count at Baseline - Safety Population 
Table 
 
14.3.4.10a 
 
Number of Subjects with Decrease in Platelets Count During Double-blind 
Study Period with Normal Platelet Count at Baseline (Japan) - Safety 
Population 
Table 
 
14.3.4.11 
 
Number of Subjects with Decrease in Platelets Count During Therapy 
Relative to any Baseline Platelet Count - Safety Population 
Table 
 
14.3.4.11a 
 
Number of Subjects with Decrease in Platelets Count During Therapy 
Relative to any Baseline Platelet Count (Japan) - Safety Population 
Table 
14.3.4.12 
Number of subjects who had prolactin Increase at each visit week - Safety 
Population 
Table 
14.3.4.12a 
Number of subjects who had prolactin Increase at each visit week (Japan) - 
Safety Population 
Table 
 
14.3.4.13 
Number of subjects who had prolactin Increase with seizure event within 48 
hours prior to prolactin increase at each visit week - Safety Population 
Table 
 
14.3.4.13a 
 
Number of subjects who had prolactin Increase with seizure event within 48 
hours prior to prolactin increase at each visit week (Japan) - Safety 
Population 
14.4.1 
Vital Signs 
Table 
14.4.1.1 
Vital Signs Parameters – Safety Population 
Table 
14.4.1.1a 
Vital Signs Parameters (Japan) – Safety Population 
Table 
14.4.1.1b 
Vital Signs Parameters (Non-Japan) – Safety Population 
  
14.4.4 
Tanner Staging 
Table 
14.4.4.1 
Tanner Staging by Age Group for Boys – Safety Population 
Table 
14.4.4.1a 
Tanner Staging by Age Group for Boys (Japan) – Safety Population 
Table 
14.4.4.2 
Tanner Staging by Age Group for Girls – Safety Population 
Table 
14.4.4.2a 
Tanner Staging by Age Group for Girls (Japan) – Safety Population 
  
14.4.5 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
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Table 
14.4.5.1 
Number of Patients with Suicidal Ideation, Suicidal Behavior, and Self-
Injurious Behavior without Suicidal Intent Based on the C-SSRS  – Safety 
Population 
Table 
14.4.5.2 
Columbia Suicide Severity-Rating Scale (C-SSRS)- Shift Table of Changes 
in C-SSRS Categories During Treatment - Safety Population 
  
14.4.6 
Brief Rating Inventory of Executive Function- (BRIEF) 
Table 
14.4.6.1 
BRIEF-P – Scoring Summary Table by Treatment Group – Safety 
Population  
Table 
14.4.6.2 
BRIEF – Scoring Summary Table by Treatment Group – Safety Population 
 
16.1.9.2 
Statistical Output 
Output 
16.1.9.2.1 
Output from Primary Efficacy Analysis 
Output 
16.1.9.2.2 
Output from Secondary Efficacy Analyses 
 
 
 
  
16.2 
Subject data listing 
  
16.2.1  
Subject disposition and discontinuation 
Listing 
16.2.1.1 
Subject Completion/Discontinuation 
  
16.2.2 
Protocol deviations 
Listing 
16.2.2.1 
Protocol Deviations 
  
16.2.3 
Subjects excluded from analysis 
Listing 
16.2.3.1 
Violation of Inclusion/Exclusion and/or Randomization Inclusion Criteria  
Listing 
16.2.3.2 
Subject Allocation to Trial Populations  
  
16.2.4  
Demographic data and other baseline characteristics 
Listing 
16.2.4.1 
Demographic Data  
Listing 
16.2.4.2 
Medical History  
Listing 
16.2.4.3.1 
Prior Medications and Therapies/Treatments  
Listing 
16.2.4.3.2 
Concomitant Medications and Therapies/Treatments  
Listing 
16.2.4.4.1 
Prior Antiepileptic Drugs (AEDs) 
Listing 
16.2.4.4.2 
Concomitant Antiepileptic Drugs (AEDs) 
  
16.2.5 
Treatment exposure and compliance 
Listing 
16.2.5.1 
IMP Intake per day during Treatment  
Listing 
16.2.5.2 
IMP Intake – Self Reported Compliance with Dosing 
Listing 
16.2.5.3 
Drug Accountability  
  
16.2.6 
Efficacy data 
Listing 
16.2.6.1 
Convulsive Seizure – Duration and Number of Occurrences per Subject 
(Diary Data)  
Listing 
16.2.6.2 
Non-Convulsive Seizure – by Type, Duration and Number of Occurrences 
per Subject (Diary Data)  
Listing 
16.2.6.3 
Longest Interval between Convulsive Seizures and Convulsive Seizure 
Free Days per Subject 
Listing 
16.2.6.4 
Percent Reduction in Convulsive Seizure Frequency from Baseline   
Listing 
16.2.6.5 
Clinical Global Impression – Improvement Rating as Assessed by the 
Parent/Caregiver and Investigator 
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 
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Listing 
16.2.6.8 
Parent/Caregiver Ratings 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 
  
16.2.7  
Adverse events 
Listing 
16.2.7.1 
Adverse Events 
Listing 
16.2.7.2 
Adverse Events Of Special Interests (AESI) 
  
16.2.8 
Laboratory data 
Listing 
16.2.8.1.1 
Laboratory Data Hematology Parameters 
Listing 
16.2.8.1.2 
Extreme Value Laboratory Parameters - Hematology 
Listing 
16.2.8.2.1 
Laboratory Data Biochemistry Parameters 
Listing 
16.2.8.2.2 
Extreme Value Laboratory Parameters - Biochemistry 
Listing 
16.2.8.3.1 
Laboratory Data Coagulation Parameters 
Listing 
16.2.8.3.2 
Extreme Value Laboratory Parameters – Coagulation  
Listing 
16.2.8.4.1 
Laboratory Data Urinalysis Parameters 
Listing 
16.2.8.4.2 
Extreme Value Urinalysis Data 
Listing 
16.2.8.5 
Tests of Growth and Precocious Puberty 
Listing 
16.2.8.6 
Urine Pregnancy Test  
Listing 
16.2.8.7 
Urine THC Panel 
Listing 
16.2.8.8 
Whole Blood Cannabidiol 
  
16.2.9 
Other Safety Data 
Listing 
16.2.9.1.1 
Vital Signs  
Listing 
16.2.9.1.2 
Abnormal Vital Signs Data 
Listing 
16.2.9.2 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Listing 
16.2.9.3.1 
Behavior Rating Inventory of Executive Function – Preschool Version 
(BRIEF-P) 
Listing 
16.2.9.3.2 
Behavior Rating Inventory of Executive Function (BRIEF) 
Listing 
16.2.9.4 
Tanner Staging 
Listing 
16.2.9.5 
Physical Examination  
Listing 
16.2.9.6 
Neurological Examination 
Listing 
16.2.9.7 
Epilepsy Genotype Panel 
 
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16. Reference List 
Dravet C, Bureau M, Oguni H, Fukuyama Y, Cokar O.  Severe myoclonic epilepsy in infancy: 
Dravet syndrome.  Adv Neurol 2005; 95: 71-102. 
 
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/hum
an_med_000742.jsp&mid=WC0b01ac058001d124.  Accessed 31 July 2015. 
Hurst, DL.  Epidemiology of severe myoclonic epilepsy of infancy.  Epilepsia 1990;31:397-400. 
  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. 
  ICH Topic E2F: Development Safety Update Report, 2011. 
  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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan 
Status: Final Version 1.0 
Revised: 09Jun2020 
Protocol #: ZX008-1501, ZX008-1502; “Study 2” 
Page 1 of 23 
 
 
STATISTICAL ANALYSIS PLAN FOR CARDIOVASCULAR 
ENDPOINTS  
 
Study Title: 
A Multicenter, Randomized, Double-blind, Parallel Group, Placebo 
controlled Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) 
Oral Solution as an Adjunctive Therapy in Children and Young Adults with 
Dravet Syndrome 
 
Investigational 
Product: 
ZX008 
 
Sponsor Study No.: 
ZX008-1501 and ZX008-1502; “Study 2” 
 
SAP Status: 
V1.0 
 
Date of SAP: 
09Jun2020 
 
SAP Prepared by: 
ERT 
 
Sponsor: 
Zogenix International Limited 
A subsidiary of Zogenix, Inc. 
5858 Horton Street, Suite 455 
Emeryville, CA 94608 USA 
 
 
 
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Statistical Analysis Plan 
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Revised: 09Jun2020 
Protocol #: ZX008-1501, ZX008-1502; “Study 2” 
Page 4 of 23 
 
 
Table of Contents 
ABBREVIATIONS AND DEFINITIONS OF TERMS .................................................................................... 6 
1. INTRODUCTION ....................................................................................................................................... 8 
2. STUDY DESIGN AND CARDIOVASCULAR ANALYSIS OBJECTIVES ................................................ 9 
2.1 
General Design and Plan ............................................................................................................ 9 
2.2 
Objectives .................................................................................................................................. 10 
2.2.1. 
Cardiovascular Safety Objectives ..................................................................................... 10 
2.3 
Endpoints ................................................................................................................................... 10 
2.3.1 
ECG ....................................................................................................................................... 10 
2.3.1.1 
Main Focus of ECG Analysis ........................................................................................ 10 
2.3.1.2 
Other ECG Analyses ..................................................................................................... 10 
2.3.1.3 
Listing for Abnormalities ................................................................................................ 12 
2.3.2 
Echocardiograms ................................................................................................................... 12 
2.3.2.1 
Main Focus for Echocardiograms ................................................................................. 12 
2.3.2.2 
Other Echocardiographic Analysis ................................................................................ 12 
2.3.2.3 
Heat Maps ..................................................................................................................... 13 
2.4 
Study Population ....................................................................................................................... 13 
2.4.1 
Inclusion Criteria Related to Cardiac Safety .......................................................................... 13 
2.4.2 
Exclusion Criteria Related to Cardiac Safety ......................................................................... 13 
2.4.3 
Sample Size ........................................................................................................................... 14 
2.5 
Randomization and Blinding ...................................................................................................... 14 
3. 
CARDIAC SAFETY DATA COLLECTION AND ANALYSIS ............................................................ 14 
3.1 
ECG Assessment ...................................................................................................................... 14 
3.1.1 
Equipment .............................................................................................................................. 14 
3.1.2 
Transfer of ECGs ................................................................................................................... 14 
3.1.3 
Collection of ECGs ................................................................................................................ 14 
3.1.4 
Definition of Baseline ............................................................................................................. 14 
3.1.5 
Variables Measured ............................................................................................................... 14 
3.1.6 
Clinical Analysis of ECGs ...................................................................................................... 15 
3.1.7 
Non-Digital ECG Evaluation .................................................................................................. 15 
3.2 
Echocardiographic Analysis ...................................................................................................... 15 
3.2.1 
Equipment .............................................................................................................................. 15 
3.2.2 
Transfer of Echocardiograms ................................................................................................ 15 
3.2.3 
Collection of Echocardiograms .............................................................................................. 15 
3.2.4 
Definition of Baseline ............................................................................................................. 15 
3.2.5 
Variables Measured ............................................................................................................... 15 
3.2.6 
Clinical Analysis of ECHOs .................................................................................................... 15 
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Page 5 of 23 
 
3.2.7 
Alert Criteria ........................................................................................................................... 16 
4. 
STATISTICAL ANALYSIS ................................................................................................................. 16 
4.1 
General Principles and Considerations ..................................................................................... 16 
4.2 
Analysis Population ................................................................................................................... 16 
4.2.1 
Handling of Missing Data ....................................................................................................... 17 
4.3 
Interim Analysis ......................................................................................................................... 17 
4.4 
Multiplicity Adjustments ............................................................................................................. 17 
4.5 
Primary Analyses ....................................................................................................................... 17 
4.5.1 
Electrocardiogram .................................................................................................................. 17 
4.5.2 
Echocardiogram ..................................................................................................................... 17 
4.6 
Secondary Analyses .................................................................................................................. 17 
4.7 
Additional Analysis .................................................................................................................... 17 
4.8 
Categorical Analysis .................................................................................................................. 17 
5. 
TABLES, FIGURES, AND LISTINGS ................................................................................................ 18 
6. 
REFERENCES ................................................................................................................................... 22 
REVISION HISTORY .................................................................................................................................. 23 
 
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Statistical Analysis Plan 
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Revised: 09Jun2020 
Protocol #: ZX008-1501, ZX008-1502; “Study 2” 
Page 6 of 23 
 
Abbreviations and Definitions of Terms 
ΔΔQTcF Change from baseline and placebo (Double-Delta) in QTcF 
ACI 
Abnormal Clinically Insignificant 
ANOVA 
Analysis of Variance 
APCS 
Abnormal Potentially Clinically Significant 
bpm 
Beats per minute 
Cmax 
Maximum Plasma Concentration 
CI 
Confidence Interval 
CL/F 
Oral dose apparent clearance 
DS 
Dravet’s Syndrome 
ECG  
Electrocardiogram 
Emax 
Maximum Effect 
GSMB 
Global Superimposed Median Beat 
kg 
Kilogram 
h, hr 
Hour 
HR 
Heart Rate 
m 
Minutes 
mg 
Milligram 
mL 
Milliliter 
mm 
Millimeter(s) 
mmHg 
Millimeters of Mercury 
ms 
Millisecond(s) 
N 
Sample Size 
ng 
Nanogram 
PAH 
Pulmonary Arterial Hypertension 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PR 
Interval between the start of the P wave and start of the Q wave 
QRS 
QRS waves complex on the electrocardiogram tracing  
QT 
Interval between the start of the Q wave and the end of the T wave  
QTc 
Corrected QT duration  
QTcF 
QT interval corrected using Fridericia’s formula 
RR 
The time interval between consecutive heart beats. 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
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Statistical Analysis Plan 
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s 
Second(s) 
SMEI 
Severe Monoclonal Epilepsy of Infancy 
SUPED 
Sudden Infant Death in Epilepsy 
tmax 
Time to maximum concentration (Cmax) 
t1/2 
Half-life associated with terminal phase of the concentration-time profile 
TdP 
Torsade de Pointes 
ZX008 
Fenfluramine Hydrochloride 
 
 
 
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Statistical Analysis Plan 
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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. Cognitive 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). The degree of cognitive impairment appears to correlate, at least in part, with the frequency of seizures, 
and might be a result of repeated cerebral hypoxia. Children with DS also encounter a higher incidence of 
Sudden Unexpected Death in Epilepsy (SUDEP; Nashef 2012) than other populations with epilepsy. Indirect 
evidence has linked SUDEP to several possible etiologies, including seizure-induced apnea, pulmonary edema, 
dysregulation of cerebral circulation, and cardiac arrhythmias (Shorvon2011), although the actual etiology 
remains unknown and other mechanisms have not been ruled out. The vast majority of patients who survive to 
adulthood are wholly dependent on around-the-clock caregivers and usually live in institutional care homes. 
 
The primary known pharmacologic action of fenfluramine is serotonin release in the CNS (Baumann, 2014); 
preliminary evidence suggests a role for other mechanisms of action as well. Fenfluramine is readily absorbed 
after oral administration with an oral bioavailability of 60-70% (Bever and Perry, 1997) and a Tmax of 4 hours 
(Beckett & Brookes, 1967). Terminal half-life (t1/2) is approximately 20 hours for the parent and 30 hours for the 
active metabolite, norfenfluramine. Metabolism occurs primarily by Cytochrome P450 (CYP)1A2, CYP2B6 and 
CYP2D6. CYP2C9, CYP2C19 and CYP3A4 also appear to be involved, but to a lesser degree. Elimination of the 
drug and its metabolites is largely renal. The drug readily crosses the blood brain barrier and is widely distributed 
in all tissues. 
 
When fenfluramine was marketed for treatment of obesity at doses of 60-120 mg/day, reports of cardiac valvular 
disease emerged (Connolly, 1997). The FDA issued an advisory request for information from similar cases and 
eventually requested voluntary withdrawal of fenfluramine and dexfenfluramine from the market in 1997.  
There were 144 individuals reported to have valvulopathy involving fenfluramine or dexfenfluramine in the initial 
1997 communication (CDC, 1997). Of 113 confirmed cases, 111 occurred among women; the median age was 
44 years (range: 22-68 years). Of these 113 cases, 2 (2%) used fenfluramine alone; 16 (14%) dexfenfluramine 
alone; 89 (79%) a combination of fenfluramine and phentermine; and 6 (5%) a combination of all 3 drugs. The 
median duration of drug use was 9 months (range: 1-39 months). Overall, 87 (77%) of the 113 cases were 
symptomatic and 24 (27%) required valve replacements.  
 
The prevalence of valve lesions was assessed for patients who were exposed to these drugs but who had no 
obvious history of cardiac disease or cardiac symptoms in 5 independent unpublished echocardiographic 
surveys submitted to FDA in 1997. These surveys demonstrated a prevalence of valvular disease meeting the 
case definition ranging from 30.0% to 38.3% (overall: 32.8%; 95% confidence interval=27.7%-38.9%). However, 
subsequent studies sought to estimate the risk of valvulopathy in fenfluramine-treated adult obese patients and 
found fenfluramine-associated valvular disease was less common than the original observational reports 
suggested, approximately 9.6% for aortic valve dysfunction (range 5.0% to 26.3%) and 3.1% for mitral 
regurgitation of mild severity or greater (Loke, 2002; Sachdev, 2002).  
 
In 1981, a report was published describing 2 patients who developed pulmonary hypertension while taking 
fenfluramine (Douglas, 1981). Additional rare cases, some of which were severe or even fatal, were reported 
subsequently (McMurray, 1986; Pouwels, 1990). 
 
Zogenix has evaluated the effect of multiple oral administrations of therapeutic (30 mg/day, ie, 15 mg BID) and 
supratherapeutic (120 mg/day, ie, 60 mg BID) doses of ZX008 on the heart rate corrected QT interval using 
Fridericia’s formula (QTcF) in healthy adult volunteers (Study 1603). The supratherapeutic ZX008 dose of 120 
mg/day provided a 4-fold higher dose than the maximum dose planned for clinical use, while maintaining a 
reasonable safety margin. This study demonstrated that there is no significant effect of ZX008 on QTc intervals 
at either the therapeutic or supratherapeutic dose; multiple therapeutic and supratherapeutic doses of ZX008 do 
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Statistical Analysis Plan 
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not prolong QTcF intervals. Following multiple doses of 15 mg and 60 mg ZX008, trough levels of fenfluramine 
and norfenfluramine indicated that steady state was effectively reached prior to the end of the 7-day interval 
Zogenix has reported safety and efficacy data from 2 adequate and well controlled studies, Study 1 and Study 
1504 Cohort 2, and 1 interim analysis from the open-label extension study (Study 1503). Study 1 represents the 
first 119 subjects randomized in two identical and parallel studies, 1501 and 1502, and compared 2 doses of 
ZX008, 0.2 mg/kg/day and 0.8 mg/kg/day (up to a maximum of 30 mg/day), to placebo in subjects receiving 
standard of care anti-epileptic treatments excluding stiripentol (STP). Study 1504 Cohort 2 compared a dose of 
ZX008 0.5 mg/kg/day (up to a maximum of 20 mg/day) to placebo in subjects receiving standard of care anti-
epileptic treatments where administration of STP (in combination with clobazam [CLB] and/or valproate [VPA]; 
i.e., the STP regimen) was mandatory. A prospectively-defined cardiovascular monitoring program that 
employed color Doppler echocardiography (ECHO) and electrocardiograms was implemented in the ZX008 
clinical program (all Dravet syndrome trials) to monitor for valvular heart disease (VHD) or pulmonary artery 
hypertension (PAH); this ECHO program was designed with input from FDA and from cardiology experts. As of 
the writing of this Statistical Analysis Plan, no study subject in the entire ZX008 program, has developed VHD or 
PAH.  
 
This Statistical Analysis Plan (SAP) for Cardiovascular Endpoints outlines the planned analyses to support the 
assessment of electrocardiographic (ECG) and echocardiographic data in the Study 2 clinical study report. Study 
2 represents all subjects enrolled in Study 1501 and 1502 who were not included in Study 1. The planned 
analyses identified in this SAP may be included in regulatory submissions, and exploratory analyses not defined 
in this SAP may be performed to support a more thorough understanding of the safety data. All post-hoc or 
unplanned analyses performed not identified in this SAP will be documented. 
 
Documents used to develop this SAP are: 
 
Study Protocol ZX008-1501 (Amendment 3.0, 31-October-2016). 
 
Study Protocol ZX008-1502 (Amendment 2.4.3, 07-February-2019). 
 
Study 1 Statistical Analysis Plan (Version 2.1, 17-September-2017). 
 
CAMI 7 12-Lead Analysis Plan for use with Eli 150c (Inventive Health/Zogenix) (Version 1.0, 11-
January-2016). 
 
ZX008 Investigational Brochure (Version 7, 31-July-2019). 
 
2. Study Design and Cardiovascular Analysis Objectives 
2.1 General Design and Plan 
 
Study 2 contains pooled data from two studies, 1501 and 1502. Both studies are multicenter, randomized, 
double-blind, parallel group, placebo-controlled trials of two fixed doses of ZX008 (Fenfluramine Hydrochloride) 
oral solution as adjunctive therapy in children and young adults with Dravet syndrome. The first 119 subjects 
randomized were reported as Study 1; Study 2 represents all subjects enrolled in Study 1501 and 1502 who 
were not included in Study 1.  
 
Each subject is assigned to one of 2 treatments (0.2 mg/kg or 0.8 mg/kg) or placebo.Treatments were assigned 
on a 1:1:1 basis.  
 
Electrocardiograms (ECGs) and echocardiograms (ECHOs) are being analyzed by ERT (formerly Biomedical 
Systems (St. Louis, MO)). 
 
All ECGs were reviewed and interpreted by a board-certified cardiologist. Echocardiograms were reviewed by 
two, board-certified cardiologists. In the case of a discrepancy between the readers, the echocardiogram was 
sent to adjudicators for final reading. At the initiation of the ZX008 Program, the International (Pediatric) 
Cardiology Advisory Board (ICAB) was set-up to oversee the vendor’s ECHO readings. ICAB members were 
chosen solely based on their academic credentials and experience, with the Chair being chosen based upon 
his/her seniority and respect in the field of echocardiography. When there was a differing interpretation of 
findings in an ECHO of any subject between the vendor and ICAB (either in the alert level of valvular 
regurgitation or presence or absence of pulmonary hypertension), the following process occurred: a telephone 
conference call was to be held with the vendor ERT cardiology readers and ICAB reader and ICAB Chair (if the 
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Statistical Analysis Plan 
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Chair was reader,then only he/she will be on call) to discuss the ECHO findings and try to come to an agreement 
on interpretation; if agreement could not be reached then ICAB Chair read the ECHO and his/her reading 
become the official reading. This one ECHO report was then be sent to the IDSMC. 
2.2 Objectives 
 
The primary objective of Study 2 is to demonstrate that ZX008 0.8 mg/kg/day is superior to placebo as 
adjunctive therapy in the treatment of Dravet syndrome 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). 
Safety endpoints of the study include the assessment for cardiac toxicity as demonstrated by ECG and ECHO. 
 
2.2.1. 
Cardiovascular Safety Objectives 
The primary cardiovascular safety objective of this analysis is to evaluate the effect of ZX008 on the heart as 
demonstrated by both the 12-lead ECG and ECHO. 
 
Variables included in the analysis are listed below. These will be compared between Placebo and the 0.2 mg/kg 
and 0.8 mg/kg groups independently. 
2.3 Endpoints 
2.3.1 
ECG 
The change from baseline will be calculated and compared between placebo and the two dosing groups (0.2 
mg/kg and 0.8 mg/kg) for the main and secondary ECG endpoints for each of the variables and subgroups 
listed. 
2.3.1.1 
Main Focus of ECG Analysis 
The main focus for ECG will be the mean change between measurements of QT interval corrected using 
Fridericia’s formula (QTcF) for ZX008 and placebo after baseline adjustment, (ΔΔQTcF), calculating the upper 
bound of the one-sided 95% confidence interval.  
2.3.1.2 
Other ECG Analyses 
Other secondary endpoints that will be presented by dose and subgroups are: 
 
Mean QTcF duration including changes from baseline (∆QTcF) 
 
Mean QRS duration (including changes from baseline (∆QRS) and from placebo and baseline (∆∆QRS) 
 
Mean PR interval measurements (including changes from baseline (∆PR) and from placebo and 
baseline (∆∆PR) 
 
Mean Heart rate (including changes from baseline (∆HR) and from placebo and baseline (∆∆HR) 
 
Categorical analyses for each variable and subgroup listed below: 
o 
QTcF (number and percentage of subjects, by dose) 
Age 
Gender 
Values 
0 to < 12 years 
Males and Females 
< 320 ms 
≥ 320ms to ≤ 450 ms 
> 450 ms to ≤480 ms 
> 480 ms 
12 to 18 years 
Males  
< 320 ms 
≥ 320 ms to ≤ 450 ms 
> 450 ms to 500 ms 
> 500 ms 
12 to 18 years 
Females 
< 320 ms 
≥ 320 ms to ≤ 470 ms 
> 470 ms to≤ 500 ms 
> 500 ms 
 
 
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o 
For all ages QTcF changes from baseline (number and percentage of subjects, by dose) 
 
≤ 30 ms 
 
> 30 ms to ≤ 60 ms 
 
> 60 ms 
o 
QRS (number and percentage of subjects, by dose) 
Age 
Gender 
Values 
2 to <6 years 
 
Males and Females 
 
≤ 90 ms 
>90ms to ≤100ms 
> 100 ms 
≤ 100 ms 
6 to < 12 years 
Males and Females 
> 100 ms to ≤ 110 ms 
> 110 ms 
≤110ms 
>110 ms to ≤ 120ms 
 
12 to 18 years 
 
Males and Females 
>120ms 
≤ 90 ms 
 
 
o 
PR (number and percentage of subjects, by dose) 
Age 
Gender 
Values 
2 to <6 years 
 
Males and Females 
≤ 90 ms 
> 90ms to ≤ 150 ms 
>150 ms 
6 to < 12 years 
 
Males and Females 
≤ 100 ms 
> 100 ms to ≤ 170 ms 
>170 ms 
 
12 to 17 years 
 
Males and Females 
≤110ms 
>110 ms to ≤ 180ms 
>180ms 
18 years 
Males and Females 
≤120 ms 
>120 ms to ≤ 220ms 
>220 ms 
 
o 
Heart rate (number and percentage of subjects, by dose) 
Age 
Gender 
Values 
2 to <6 years 
Males and Females 
<80 bpm 
≥80 bpm to ≤140bpm 
> 140 bpm to ≤ 180 bpm 
> 180 bpm 
Increase or decrease from 
baseline > 20 bpm 
6 to < 12 years 
Males and Females 
<60 bpm 
≥60 bpm to ≤120bpm 
> 120 bpm to ≤ 150 bpm 
> 150 bpm 
Increase or decrease from 
baseline > 20 bpm 
12 to 18 years 
Males and Females 
< 50 bpm 
≥50 bpm to ≤100bpm 
> 100 bpm to ≤ 150 bpm 
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> 150 bpm 
Increase or decrease from 
baseline > 20 bpm 
o 
Overall characterization of normal and abnormal ECGs and the number and percentage of 
subjects with normal and abnormal ECGs. ECGs will be characterized as Normal, Abnormal 
Clinically Insignificant (ACI), or Abnormal Potentially Clinically Significant (APCS). The number 
and percentage of ECGs within each category will be calculated by dose. 
o 
Number and percentage of subjects that develop abnormalities of repolarization on treatment, as 
manifest by new ST and T wave abnormalities. The number and percentage of ECGs within 
each category will be calculated by dose. 
Analysis for specific arrhythmias: Torsade de Pointes (TdP), ventricular tachycardia/fibrillation, atrial 
fibrillation/flutter, supraventricular tachycardia, etc., including associations between specific ECG findings and 
selected clinical adverse events of interest will be explored as appropriate (events that may signal pro-
arrhythmia: syncope, palpitations, dizziness, tachycardia, etc.). Shift tables will be constructed for arrhythmias.  
2.3.1.3 
Listing for Abnormalities 
Listings for ECG abnormalities by dosing, subject, and time-point will be provided for the following: 
 
Heart Rates 
 
PR-Interval 
 
QRS Duration 
 
QT-Interval 
 
First degree AV-Block 
 
Second degree AV-Block (Type 1) 
 
Second degree AV-Block (Type 2) 
 
Third-degree (complete) AV-Block 
 
2.3.2 
Echocardiograms 
2.3.2.1 
Main Focus for Echocardiograms 
The main focus for the echocardiographic analysis is the regurgitation score for the mitral and aortic valves at 
each time-point with the main focus being the development of clinically meaningful (pathologic) changes in valve 
regurgitation (definitions and thresholds defined below). 
 
Number of subjects who meet the FDA case definition of drug associated valvulopathy-aortic 
regurgitation ≥ mild and/or mitral regurgitation ≥ moderate 
 
Number of subjects with ≥ trace mitral or aortic regurgitation at least one time post-baseline 
 
Number of subjects with ≥ trace mitral or aortic regurgitation at end of study 
 
Number of subjects within each mitral or aortic regurgitation score by visit  
 
Number of subjects with clinically confirmed Valvular heart disease (VHD) 
2.3.2.2 
Other Echocardiographic Analysis 
Other, secondary endpoints include: 
 
Number of subjects within each tricuspid or pulmonic regurgitation score by visit 
 
Number of subjects with normal or trace tricuspid or pulmonic regurgitation at baseline and ≥ mild 
tricuspid or pulmonic regurgitation at end of study 
 
Pulmonary Artery Systolic Pressure (PASP) 
o 
Mean change from baseline at end of study 
o 
Mean maximum change from baseline at anytime during therapy 
o 
Number of subjects with change from baseline at anytime during therapy: 
 
> 10 mmHg 
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 
>15 mmHg 
 
>20 mmHg 
o 
Number of subjects with PASP>35 mmHg at anytime during therapy  
 
Right ventricular outflow tract (RVOT) acceleration time (will be used only as confirmatory variables for 
pulmonary hypertension) 
o 
Mean Change from Baseline in RVOT (msec) by visit 
o 
Number of subjects with Baseline ≥100 msec and at EOS/ET RVOT <100 msec 
o 
Number of subjects with any RVOT measurement < 100 msec post-baseline 
Summary of the number of ECHOs per subject will also be presented. 
 
2.3.2.3 
Heat Maps 
Heat maps will be constructed for all valve scores to visualize longitudinal changes, if any, in regurgitation 
measures in individual subjects over time. An example of a heat map is shown below. 
 
Dosing 
Subjects 
Visit 1 
Visit 8 
Visit 12 
Placebo 
2 subjects 
Absent 
Absent 
ECHO 
Placebo 
5 subjects 
Absent 
Trace 
Trace 
Placebo 
1 subject 
Absent 
Mild 
Trace 
ZX008 0.2 mg/kg/day 
4 subjects 
Absent 
Absent 
Absent 
…. 
 
 
 
 
Note: different colors represent the valve scores such as No ECHO, Absent, Absent, Mild, Moderate, and 
Severe.  
2.4 Study Population 
Male and female subjects, aged 2 to 18 years of age with a medical history and clinical diagnosis of Dravet 
syndrome who meet other eligibility criteria could be enrolled in the study. This section includes the inclusion and 
exclusion criteria related to cardiac safety.  
 
2.4.1 
Inclusion Criteria Related to Cardiac Safety 
No inclusion criteria were related to cardiac safety. 
 
2.4.2 
Exclusion Criteria Related to Cardiac Safety 
Subjects must not meet any of the following criteria to be eligible for study participation: 
 
Subject has Pulmonary Arterial Hypertension (PAH) 
 
Subject has current or past history of cardiovascular or cerebrovascular disease, such as cardiac 
valvulopathy, myocardial infarction or stroke. 
 
Subject is receiving concomitant therapy with: centrally-acting anorectic agents; monoaminoxidase 
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. (Note: Short-term medication requirements will be handled on a per case basis by 
the Medical Monitor.) 
 
Subject does not have a cardiovascular or cardiopulmonary abnormality based on ECHO, ECG or 
physical examination, including but not limited to trace mitral or aortic valve regurgitation or signs of 
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pulmonary hypertension, and is approved for entry by the central cardiac reader. 
 
 
2.4.3 
Sample Size 
No formal sample size calculations were conducted related to cardiac safety for Study 2. Study 2 includes all 
subjects enrolled in ZX008-1501 and ZX008-1502 except the first 119 subjects which comprise Study 1. 
2.5 Randomization and Blinding 
Each subject was randomized in a 1:1:1 fashion and receive one of the following treatments: 
A. 0.2 mg/kg/day ZX008 
B. 0.8 mg/kg/day (up to 30 mg/day) ZX008 
C. Placebo 
Neither the subjects nor the investigator knew which treatment is being administered. 
 
3. Cardiac Safety Data Collection and Analysis 
3.1 ECG Assessment 
3.1.1 
Equipment 
Twelve-Lead Electrocardiograms were collected on a Mortara ELI-150c ECG machine (Milwaukee, WI) located 
at each clinical site. 
 
3.1.2 
Transfer of ECGs 
Electrocardiograms were digitally transferred to ERT for analysis. 
 
3.1.3 
Collection of ECGs 
The clinical ECG database will be derived from 12-lead ECGs collected from the ELI-150c ECG machines. 
 
Single, 12-lead ECGs were collected at Screening, Baseline (Visit 3), Week 6 (Visit 8), and Week 14 (Visit 12). 
ECGs were collected after the subjects had been in supine position resting for ≥5 minutes.  
 
The time of the ECG was not controlled. 
 
3.1.4 
Definition of Baseline 
The baseline for this study will be the data collected from the ECG taken at Baseline (Visit 3). 
 
3.1.5 
Variables Measured 
At the central laboratory, using CAMI software (or equivalent), the cardiac technician will annotate the Global 
Superimposed Median Beat (GSMB).  
 
The following variables will be measured or calculated on each ECG: 
 
QRS duration 
 
PR interval 
 
Heart rate (10 second average) 
 
QT  
o 
The QT interval will be measured from the earliest detection of depolarization in any lead 
(beginning of the Q or R wave) to the latest detection of repolarization in any lead (end of the T-
wave).  
 
QTcF 
 
The RR interval will be reported, from which the corrected QT interval (QTc) using Fridericia’s formula (QTcF) 
will be calculated. 
Fridericia’s correction:
3
/
1
RR
QT
QTcF 
 where QT, RR, and QTcF are expressed in seconds. 
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For convenience, QT, RR, PR, QRS, andQTcFwill be shown in milliseconds (ms) in the tables, figures and 
listings. 
 
3.1.6 
Clinical Analysis of ECGs 
The over-reading cardiologist will give a clinical interpretation for each ECG at each time point. These will be 
presented in the data listing provided at the end of the study. Each ECG will be classified as Normal (N), 
Abnormal Clinically Insignificant (ACI), or Abnormal Potentially Clinically Significant (APCS). 
 
3.1.7 
Non-Digital ECG Evaluation 
Data not acquired using the ECG equipment provided by ERT will not be eligible for centralized reading, nor will 
it be included in the database.  
3.2 Echocardiographic Analysis 
3.2.1 
Equipment 
Site-owned equipment was used for the collection of echocardiograms. 
 
Prior to being qualified for subject enrollment, all echocardiographers were required to participate in a WebEx 
PowerPoint training presentation and transferred test data to BMS. The WebEx session consisted of reviewing 
protocol specific views, study related forms and the process of uploading the images through web portal. 
 
Each echocardiographer was required to submit a certification ECHO. The certification ECHO was performed on 
a non-study participant. The participating ECHO facility was informed during the training session that they would 
not be able to perform ECHOs on true study subjects until they received a “passed” Certification ECHO 
Evaluation Form.  
 
3.2.2 
Transfer of Echocardiograms 
Electrocardiograms were either digitally transferred or copied to CD and sent via courier to ERT for analysis. 
 
3.2.3 
Collection of Echocardiograms 
ECHOs were taken at Screening, Week 6 (Visit 8), and Week 14 (Visit 12). For each ECHO, cardiac technicians 
check to make sure the Nyquist Limit (color scale) was set between 60 cm/s and 80 cm/s.  All sonographers at 
the study sites submitted a certification ECHO before study ECHOs were obtained. 
 
The time of the ECHO was not controlled. 
 
3.2.4 
Definition of Baseline 
The baseline for this study will be the data collected from the ECHO taken at Screening. 
 
3.2.5 
Variables Measured 
Echocardiograms were evaluated by two cardiologists using DigiView software. Details of the assessment and 
adjudication process are available in the ECHO operations manual for these studies. 
 
In addition to assessing each valve (Mitral, Aortic, Tricuspid, and Pulmonary) for regurgitation, the following 
variables were measured or calculated on each ECHO: 
 
Right Ventricular Outflow Tract Acceleration Tim (RVOT) 
 
Pulmonary Artery Systolic Pressure (PASP) 
 
Pulmonic Valve Peak Regurgitation Jet Velocity (PVPR) 
 
3.2.6 
Clinical Analysis of ECHOs 
Each ECHO was read, independently by two physicians.  A third physician was assigned as an adjudicator.  The 
adjudicator read the ECHO if the any of the following discrepancies occurred between the first and second 
reader: 
 
Aortic valve findings were not identical 
 
Mitral valve findings were not identical 
 
LVFS difference between the two physicians was >5% 
 
LVEF difference between the two physicians was >10% 
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 
PASP difference between the two physicians was >10 mmHg 
 
Clinical significance between the two readers was not identical 
 
The adjudicator chose which of the two readings was the final reading. 
 
3.2.7 
Alert Criteria 
Echocardiographic alert criteria included: 
 
Valve regurgitation (aortic or mitral) 
 
≥ moderate valve regurgitation (tricuspid or pulmonic) 
 
Mean mitral valve gradient ≥ 4 mmHg 
 
Mean aortic valve gradient ≥ 15 mmHg 
 
Mean tricuspid valve gradient ≥ 4 mmHg 
 
Peak pulmonic valve gradient ≥ 21 mmHg 
 
Tricuspid regurgitation jet velocity > 2.8 meters/sec with orwithout the findings OR  
 
One of the following findings in the absence of being able to measure tricuspid regurgitation jet velocity: 
o 
Change in right ventricle/left ventricle basal diameter ratio > 1.0 
o 
Right ventricular outflow tract flow acceleration time < 100 msec 
o 
Dilation of the inferior cava vein (diameter > 21mm and <50% inspiratory collapse) and/or right 
atrial dilatation 
o 
Change in the geometry of the interventricular septum in systole (flattening) with left ventricular 
eccentricity index >1.1 in systole and/or in diastole 
o 
Early diastolic pulmonary regurgitation velocity > 2.2 m/sec 
o 
Tricuspid Annular Plane Systolic Excursion below 18 mm or below Z-score – 2 
4. Statistical Analysis 
The statistical analyses of the cardiac safety data are designed to assess the potential toxicity of ZX008 when 
administered for up to 14 weeks as adjunctive treatment for children and young adults with Dravet syndrome.  
4.1 General Principles and Considerations 
This section describes the algorithms and conventions that will generally apply to program analyses and to the 
formatting of the data, as required to perform the proposed summary tabulations and to create the individual 
subject data listings. Unless otherwise indicated, these specifications will apply to all analyses. For details on the 
tables and figures that will be created, please refer to Section 5, Tables, Figures, and Listings. 
 
The statistical analysis will be reported using summary tables, figures, and data listings. 
 
ECG and ECHO variables at each time point will be obtained. Changes from baseline will be calculated and 
compared for each of 0.2 and 0.8 mg/kg/day treatment groups to placebo. The primary outcome is the 
assessment for the development of valvular heart disease and pulmonary arterial hypertension. 
 
Continuous variables will be summarized using descriptive statistics (i.e., total number [n], mean, standard 
deviation [SD], minimum, maximum, and 95% CI). Results will be presented to one or two decimal places for 
means and SD, as appropriate. 
 
Qualitative variables will be presented as category counts and percentages. Percentages will be presented to 
one decimal place. 
 
All dates will be displayed in DDMMMYYYY format (e.g.,15DEC2012).  
 
All analyses will be carried out using SAS Version 9.4 or higher.  
4.2 Analysis Population 
ECG and ECHO data will be analyzed using a Safety Population, including all randomized subjects who 
received at least one dose of study medication in Study 2, excluding the 119 subjects in Study 1.  
 
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As there are few subjects per site, no comparisons between sites will be conducted. 
 
4.2.1 
Handling of Missing Data 
All data available will be used for the analysis. Missing data points will not exclude the rest of the subject’s data 
from analysis, and missing data will not be imputed. 
4.3 Interim Analysis 
No interim analysis is scheduled for this trial. 
4.4 Multiplicity Adjustments 
No adjustments for multiplicity will be made for the primary cardiovascular endpoint. 
4.5 Primary Analyses 
4.5.1 
Electrocardiogram 
The primary ECG objective is to evaluate the effect of ZX008 0.8 mg/kg/day (max 30 mg/day) on QTcF.  
 
The primary analysis of the QTcF is the mean baseline-adjusted difference between treatment and placebo and 
will be performed using an analysis of variance (ANOVA) for each post-dose time point. The ANOVA model will 
include a fixed effect for treatment. The upper bound of the one-sided 95% CI (or, equivalently, two-sided 90% 
CI) of the mean baseline-adjusted difference between treatment and placebo QTcF (ΔΔQTcF) will be calculated 
from the ANOVA for each time point.  
 
The general formula to calculate the ΔΔQTcF at the ith timepoint is: 
Mean ΔΔQTcFi = Mean ΔQTcFi for the active group - Mean ΔQTcFi for the placebo group, based on the 
ANOVA model, where i = at ith timepoint and ΔQTcFti =QTcFtion Day 1 –QtcFti at Baseline (i.e., Day -
1), where ti = at ith time point for subject t 
 
4.5.2 
Echocardiogram 
The primary ECHO objective is to evaluate the effect of ZX008 0.8 mg/kg/day (max 30 mg/day)on the mitral and 
aortic valves, and in particular evaluating for the development of VHD and PAH.  
 
The number and percentage of subjects with each category of valvular regurgitation will be calculated by 
regimen and visit for each valve (Mitral, Aortic, Tricuspid, and Pulmonary), based on age (where appropriate. 
 
PASP will be analyzed for mean, mean maximum change from baseline at each time point, as well as changes 
in PASP compared to baseline using 5, 10 and 15 mmHg differences. Abnormal values will be categorized by 
regimen and visit. 
 
The primary analysis of the mitral and aortic valves is the change from baseline in regurgitation category 
between treatment and placebo and will be performed using an ANOVA model with effect for treatment. 
4.6 Secondary Analyses 
Analyses conducted with 0.8 mg/kg/day (max 30 mg/day) ZX008 will be conducted with 0.2 mg/kg/day ZX008. 
Central tendency analyses will be conducted to include per-visit data and changes from baseline and placebo for 
the ECG and ECHO values for all subjects. The variables for analysis are listed in sections 2.3.1.2 and 2.3.2.2. 
4.7 Additional Analysis 
Additional analysis may be used, as appropriate. 
4.8 Categorical Analysis 
Categorical data will be reported as both numbers and percentages and will include changes from baseline in 
both ECG and ECHO variables.  
 
 
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5. Tables, Figures, and Listings 
Number 
Title 
Table 1.1.1 
Means, Mean Differences from Baseline and Upper Bound of One-Sided 95% CI from 
ANOVA for ECG Data - QTcF, Safety Population - Males and Females, 0 to <12 Years 
Table 1.1.2 
Means, Mean Differences from Baseline and Upper Bound of One-Sided 95% CI from 
ANOVA for ECG Data - QTcF, Safety Population - Males, 12 to 18 Years 
Table 1.1.3 
Means, Mean Differences from Baseline and Upper Bound of One-Sided 95% CI from 
ANOVA for ECG Data - QTcF, Safety Population - Females, 12 to 18 Years 
Table 1.1.4 
Means, Mean Differences from Baseline and Upper Bound of One-Sided 95% CI from 
ANOVA for ECG Data - QTcF, Safety Population - Males, 0 to <12 Years 
Table 1.1.5 
Means, Mean Differences from Baseline and Upper Bound of One-Sided 95% CI from 
ANOVA for ECG Data - QTcF, Safety Population - Females, 0 to <12 Years 
Table 1.2.1 
Means, Mean Differences from Baseline and Upper Bound of One-Sided 95% CI from 
ANOVA for ECG Data - Heart Rate, Safety Population - Males and Females, 2 to < 6 Years 
Table 1.2.2 
Means, Mean Differences from Baseline and Upper Bound of One-Sided 95% CI from 
ANOVA for ECG Data - Heart Rate, Safety Population - Males and Females, 6 to < 12 
Years 
Table 1.2.3 
Means, Mean Differences from Baseline and Upper Bound of One-Sided 95% CI from 
ANOVA for ECG Data - Heart Rate, Safety Population - Males and Females, 12 to 18 
Years 
Table 1.3.1 
Means, Mean Differences from Baseline and Upper Bound of One-Sided 95% CI from 
ANOVA for ECG Data - QRS Duration, Safety Population - Males and Females, 2 to < 6 
Years 
Table 1.3.2 
Means, Mean Differences from Baseline and Upper Bound of One-Sided 95% CI from 
ANOVA for ECG Data - QRS Duration, Safety Population - Males and Females, 6 to < 12 
Years 
Table 1.3.3 
Means, Mean Differences from Baseline and Upper Bound of One-Sided 95% CI from 
ANOVA for ECG Data - QRS Duration, Safety Population - Males and Females, 12 to 17 
Years 
Table 1.3.4 
Means, Mean Differences from Baseline and Upper Bound of One-Sided 95% CI from 
ANOVA for ECG Data - QRS Duration, Safety Population - Males and Females, 18 Years 
Table 1.4.1 
Means, Mean Differences from Baseline and Upper Bound of One-Sided 95% CI from 
ANOVA for ECG Data - PR-Interval, Safety Population - Males and Females, 2 to < 6 
Years 
Table 1.4.2 
Means, Mean Differences from Baseline and Upper Bound of One-Sided 95% CI from 
ANOVA for ECG Data - PR-Interval, Safety Population - Males and Females, 6 to < 12 
Years 
Table 1.4.3 
Means, Mean Differences from Baseline and Upper Bound of One-Sided 95% CI from 
ANOVA for ECG Data - PR-Interval, Safety Population - Males and Females, 12 to 17 
Years 
Table 1.4.4 
Means, Mean Differences from Baseline and Upper Bound of One-Sided 95% CI from 
ANOVA for ECG Data - PR-Interval, Safety Population - Males and Females, 18 Years 
Table 1.5 
Means, Mean Differences from Baseline, and Mean Differences from Placebo and Baseline 
for ECG Data - QT-Interval, Safety Population 
Table 2.1.1 
Categorical Summary of ECG Data - QTcF, Safety Population - Males and Females, 0 to 
<12 Years 
Table 2.1.2 
Categorical Summary of ECG Data - QTcF, Safety Population - Males, 12 to 18 Years 
Table 2.1.3 
Categorical Summary of ECG Data - QTcF, Safety Population - Females, 12 to 18 Years 
Table 2.1.4 
Categorical Summary for ECG Data - QTcF Change from Baseline, Safety Population - 
Males and Females, 0 to <12 Years 
Table 2.1.5 
Categorical Summary for ECG Data - QTcF Change from Baseline, Safety Population - 
Males, 12 to 18 Years 
Table 2.1.6 
Categorical Summary for ECG Data - QTcF Change from Baseline, Safety Population - 
Females, 12 to 18 Years 
Table 2.2.1 
Categorical Summary of ECG Data - Heart Rate and Change from Baseline, Safety 
Population - Males and Females, 2 to <6 Years 
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Number 
Title 
Table 2.2.2 
Categorical Summary of ECG Data - Heart Rate and Change from Baseline, Safety 
Population - Males and Females, 6 to < 12 Years 
Table 2.2.3 
Categorical Summary of ECG Data - Heart Rate and Change from Baseline, Safety 
Population - Males and Females, 12 to 18 Years 
Table 2.3.1 
Categorical Summary of ECG Data - QRS Duration, Safety Population - Males and 
Females, 2 to < 6 Years 
Table 2.3.2 
Categorical Summary of ECG Data - QRS Duration, Safety Population - Males and 
Females, 6 to < 12 Years 
Table 2.3.3 
Categorical Summary of ECG Data - QRS Duration, Safety Population - Males and 
Females, 12 to 17 Years 
Table 2.3.4 
Categorical Summary of ECG Data - QRS Duration, Safety Population - Males and 
Females, 18 Years 
Table 2.4.1 
Categorical Summary of ECG Data - PR-Interval, Safety Population - Males and Females, 
2 to < 6 Years 
Table 2.4.2 
Categorical Summary of ECG Data - PR-Interval, Safety Population - Males and Females, 
6 to < 12 Years 
Table 2.4.3 
Categorical Summary of ECG Data - PR-Interval, Safety Population - Males and Females, 
12 to 17 Years 
Table 2.4.4 
Categorical Summary of ECG Data - PR-Interval, Safety Population - Males and Females, 
18 Years 
Table 2.5.1 
Results to Support Heat Maps of Mitral Valve Results, Safety Population 
Table 2.5.2 
Results to Support Heat Maps of Aortic Valve Results, Safety Population 
Table 2.5.3 
Results to Support Heat Maps of Tricuspid Valve Results, Safety Population 
Table 2.5.4 
Results to Support Heat Maps of Pulmonic Valve Results, Safety Population 
Table 3 
ECG Classification by Dosing and Visit, Safety Population 
Table 4.1.1 
Number of Subjects within Each Regurgitation Score by Visit - Mitral Valve, Safety 
Population 
Table 4.1.2 
Number of Subjects within Each Regurgitation Score by Visit - Aortic Valve, Safety 
Population 
Table 4.1.3 
Number of Subjects within Each Regurgitation Score by Visit - Tricuspid Valve, Safety 
Population 
Table 4.1.4 
Number of Subjects within Each Regurgitation Score by Visit - Pulmonic Valve, Safety 
Population 
Table 4.2 
Summary of Number of ECHOs per Subject, Safety Population 
 
 
Table 5.1.1 
Means, Mean Differences from Baseline at End of Study and Maximum and Upper Bound 
of One-Sided 95% CI from ANOVA for ECHO Data - PASP, Safety Population 
Table 5.1.2 
Means, Mean Differences from Baseline by Visit and Upper Bound of One-Sided 95% CI 
from ANOVA for ECHO Data - RVOT, Safety Population 
Table 5.1.3 
Means, Mean Differences from Baseline by Visit and Upper Bound of One-Sided 95% CI 
from ANOVA for ECHO Data - PVPR, Safety Population 
Table 6.1.1 
Number of Subjects with Mitral Valvular Heart Disease Per FDA Definitions, Safety 
Population 
Table 6.1.2 
Number of Subjects with Aortic Valvular Heart Disease Per FDA Definitions, Safety 
Population 
Table 6.2.1 
Number of Subjects with Any ≥ Trace Regurgitation Post-Baseline - Mitral Valve, Safety 
Population 
Table 6.2.2 
Number of Subjects with Any ≥ Trace Regurgitation Post-Baseline - Aortic Valve, Safety 
Population 
 
 
Table 6.3.1 
Number of Subjects with ≥ Trace Regurgitation at End of Study - Mitral Valve, Safety 
Population 
Table 6.3.2 
Number of Subjects with ≥ Trace Regurgitation at End of Study - Aortic Valve, Safety 
Population 
Table 6.4 
Number of Subjects with Clinically Confirmed Valvular Heart Disease (VHD), Safety 
Population 
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Number 
Title 
Table 6.5.1 
Number of Subjects with Normal or Trace at Baseline and Any ≥Mild at End of Study - 
Tricuspid Valve, Safety Population 
Table 6.5.2 
Number of Subjects with Normal or Trace at Baseline and Any ≥Mild at End of Study - 
Pulmonic Valve, Safety Population 
Table 6.6 
Number of Subjects with Any PASP Change from Baseline >10, >15, >20 mmHg, Safety 
Population 
Table 6.7 
Number of Subjects with Any PASP >35 mmHg, Safety Population 
Table 6.8 
Number of Subjects with RVOT ≥100 msec at Baseline and <100 msec at EOS/ET, Safety 
Population 
Table 6.9 
Number of Subjects with Any RVOT <100 msec Post-Baseline, Safety Population 
Table 7 
Categorical Summary of ECHO Data, Difference from Baseline, Safety Population 
Table 8 
ECG Overall Findings by Dosing, Visit, and Abnormal Comment, Safety Population 
 
 
Figure 1.1 
Plot of Mean (SE) QTcF by Visit, Safety Population - Males and Females, 0 to <12 Years 
Figure 1.2 
Plot of Mean (SE) QTcF by Visit, Safety Population - Males, 12 to 18 Years 
Figure 1.3 
Plot of Mean (SE) QTcF by Visit, Safety Population - Females, 12 to 18 Years 
Figure 2.1 
Plot of Mean (SE) Heart Rate by Visit, Safety Population - Males and Females, 2 to < 6 
Years 
Figure 2.2 
Plot of Mean (SE) Heart Rate by Visit, Safety Population - Males and Females, 6 to < 12 
Years 
Figure 2.3 
Plot of Mean (SE) Heart Rate by Visit, Safety Population - Males and Females, 12 to 18 
Years 
Figure 3.1 
Plot of Mean (SE) QRS Duration by Visit, Safety Population - Males and Females, 2 to < 6 
Years 
Figure 3.2 
Plot of Mean (SE) QRS Duration by Visit, Safety Population - Males and Females, 6 to < 
12 Years 
Figure 3.3 
Plot of Mean (SE) QRS Duration by Visit, Safety Population - Males and Females, 12 to 
17 Years 
Figure 3.4 
Plot of Mean (SE) QRS Duration by Visit, Safety Population - Males and Females, 18 
Years 
Figure 4.1 
Plot of Mean (SE) PR Interval by Visit, Safety Population - Males and Females, 2 to < 6 
Years 
Figure 4.2 
Plot of Mean (SE) PR Interval by Visit, Safety Population - Males and Females, 6 to < 12 
Years 
Figure 4.3 
Plot of Mean (SE) PR Interval by Visit, Safety Population - Males and Females, 12 to 17 
Years 
Figure 4.4 
Plot of Mean (SE) PR Interval by Visit, Safety Population - Males and Females, 18 Years 
Figure 5.1 
Plot of Mean (SE) QTcF Change from Baseline by Visit, Safety Population - Males and 
Females, 0 to <12 Years 
Figure 5.2 
Plot of Mean (SE) QTcF Change from Baseline by Visit, Safety Population - Males, 12 to 
18 Years 
Figure 5.3 
Plot of Mean (SE) QTcF Change from Baseline by Visit, Safety Population - Females, 12 
to 18 Years 
Figure 6.1 
Plot of Mean (SE) Heart Rate Change from Baseline by Visit, Safety Population - Males 
and Females, 2 to < 6 Years 
Figure 6.2 
Plot of Mean (SE) Heart Rate Change from Baseline by Visit, Safety Population - Males 
and Females, 6 to < 12 Years 
Figure 6.3 
Plot of Mean (SE) Heart Rate Change from Baseline by Visit, Safety Population - Males 
and Females, 12 to 18 Years 
Figure 7.1 
Plot of Mean (SE) QRS Change from Baseline by Visit, Safety Population - Males and 
Females, 2 to < 6 Years 
Figure 7.2 
Plot of Mean (SE) QRS Change from Baseline by Visit, Safety Population - Males and 
Females, 6 to < 12 Years 
Figure 7.3 
Plot of Mean (SE) QRS Change from Baseline by Visit, Safety Population - Males and 
Females, 12 to 17 Years 
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Number 
Title 
Figure 7.4 
Plot of Mean (SE) QRS Change from Baseline by Visit, Safety Population - Males and 
Females, 18 Years 
Figure 8.1 
Plot of Mean (SE) PR-Interval Change from Baseline by Visit, Safety Population - Males 
and Females, 2 to < 6 Years 
Figure 8.2 
Plot of Mean (SE) PR-Interval Change from Baseline by Visit, Safety Population - Males 
and Females, 6 to < 12 Years 
Figure 8.3 
Plot of Mean (SE) PR-Interval Change from Baseline by Visit, Safety Population - Males 
and Females, 12 to 17 Years 
Figure 8.4 
Plot of Mean (SE) PR-Interval Change from Baseline by Visit, Safety Population - Males 
and Females, 18 Years 
Figure 9.1 
Change in Category Between Baseline (Visit 1) and Visit 8 - Mitral Valve, Safety 
Population 
Figure 9.2 
Change in Category Between Baseline (Visit 1) and Visit 8 - Aortic Valve, Safety 
Population 
Figure 9.3 
Change in Category Between Baseline (Visit 1) and Visit 8 - Tricuspid Valve, Safety 
Population 
Figure 9.4 
Change in Category Between Baseline (Visit 1) and Visit 8 - Pulmonic Valve, Safety 
Population 
Figure 9.5 
Change in Category Between Baseline (Visit 1) and Visit 12 - Mitral Valve, Safety 
Population 
Figure 9.6 
Change in Category Between Baseline (Visit 1) and Visit 12 - Aortic Valve, Safety 
Population 
Figure 9.7 
Change in Category Between Baseline (Visit 1) and Visit 12 - Tricuspid Valve, Safety 
Population 
Figure 9.8 
Change in Category Between Baseline (Visit 1) and Visit 12 - Pulmonic Valve, Safety 
Population 
Figure 9.9 
Change in Category Between Visit 8 and Visit 12 - Mitral Valve, Safety Population 
Figure 9.10 
Change in Category Between Visit 8 and Visit 12 - Aortic Valve, Safety Population 
Figure 9.11 
Change in Category Between Visit 8 and Visit 12 - Tricuspid Valve, Safety Population 
Figure 9.12 
Change in Category Between Visit 8 and Visit 12 - Pulmonic Valve, Safety Population 
Figure 10 
Mean Pulmonary Artery Systolic Pressure by Visit, Safety Population 
Figure 11 
Mean Right Ventricular Outflow Tract Acceleration Time by Visit, Safety Population 
Figure 12 
Mean Pulmonic Valve Peak Regurgitation Jet Velocity by Visit, Safety Population 
Figure 13 
Scatter Plot of Pulmonary Artery Systolic Pressure by Visit, Safety Population 
 
 
Listing 1.1 
Raw ECG Data by Subject and Visit, Safety Population 
Listing 1.2 
ECG Comments, Safety Population 
Listing 2.1 
Raw Echo Data by Subject and Visit, Safety Population 
 
 
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6. References 
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Sandtner W, Sitte HH. Evidence for a role of transporter-mediated currents in the depletion of brain serotonin 
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Beckett AH, Brookes LG. The absorption and urinary excretion in man of fenfluramine and its main metabolites. 
Journal of Pharmacy and Pharmacology 1967; 19: 49S-52S. 
 
Bever KA, Perry PJ. Dexfenfluramine hydrochloride: An anorexic agent. Am J Health-Syst Pharm 1997; 
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Center for Disease Control. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: 
U.S. Department of Health and Human Services Interim Public Health Recommendations, November 1997. 
Morbidity and Mortality Weekly Report. 1997; 46(45):1061-1084. 
 
Connolly HM, Crary JL, McGoon MD, Hensrud DD et al. Valvular heart disease associated with fenfluramine-
phentermine. New Engl J Med 1997;337(9):581-8. Erratum in: N Engl J Med 1997 Dec 11;337(24):1783. 
 
Douglas JC, Munro JF, Kitchin AH, Muir AL, Proudfoot AT. Pulmonary hypertension and fenfluramine. British 
Medical Journal 1981; 283: 881-883. 
 
Dravet C. Les epilepsies graves de l’enfant. Vie Med. 1978; 8:543–548. 
 
Fridericia LS (1920), Die SystolendauerimElektrocardiogrammbeinormalenMenchen und beiHerzkranken. Acta 
Med Scan 53; 469-486. 
 
 
Garnett CE, Beasley N, Bhattaram VA, Jadhau PR, Madabushi R, Stockbridge N, Tornoe CW, Zhu H, Gobburu 
J. Concentration – QT relationships play a key role in the evaluation of proarrhythmic risk during regulatory 
review. J Clin Pharm 2009, 48:13-18. 
 
Hurst, DL. Epidemiology of severe myoclonic epilepsy of infancy. Epilepsia1990;31:397-400. 
 
Iribarren C, AD Round, JA Peng, M Lu, JG Zaroff, TJ Holve, A Prasad, P Stang. Validation of a population based 
method to assess drug-induced alterations in the QT interval: a self-controlled crossover study. 
Pharmacoepidemiology and Drug Safety 2013; 22:1222-1232. 
 
McMurray J, Bloomfield P, Miller H. Irreversible pulmonary hypertension after treatment with fenfluramine. British 
Medical Journal 1986; 292: 239-240. 
Nashef L, So EL, Ryvlin P, Tomson T. Unifying the definitions of sudden unexpected death inepilepsy. Epilepsia 
2012;53, 227–233. 
 
Pouwels HMN, Smeets JLRM, Cheriex EC, Wouters EFM. Pulmonary hypertension and fenfluramine. European 
Respiratory Journal 1990; 3: 606-607. 
 
Shorvon S, Tomson T. Sudden unexpected death in epilepsy. Lancet 2011;378: 2028–38. 
 
ZX008 Investigator’s Brochure. Edition 5.0. 28 April 2017. Zogenix International Limited. 
 
ZX008-1501: A Multicenter, Randomized, Double-blind, Parallel Group, 
Placebo- controlled Trial of Two Fixed Doses of ZX008(Fenfluramine Hydrochloride) Oral Solution as 
anAdjunctive Therapy in Children and Young Adults withDravet Syndrome. 31 October 2016 (Protocol 
Amendment 3.0). 
 
ZX008-1502: A Multicenter, Randomized, Double-blind, Parallel Group, Placebo ControlledTrial of Two Fixed 
Doses of ZX008 (FenfluramineHydrochloride) Oral Solution as an Adjunctive Therapy in Children andYoung 
Adults with Dravet Syndrome. 31 October 2016 (Protocol Amendment 2.0). 
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