An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride HCl) Oral Solution as an Adjunctive Therapy in Children and Young Adults With Dravet Syndrome
Phase: PHASE3
Conditions: Dravet Syndrome
Sponsor: Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.

This protocol includes information and data that contain trade secrets and privileged or confidential information, which is the property of the 
Sponsor. This information must not be made public without written permission from the Sponsor. These restrictions on disclosure will apply 
equally to all future information supplied to you. This material may be disclosed to and used by your personnel and associates as may be 
necessary to conduct the clinical study. 
Confidential
Clinical Study Protocol
Study Title:
An Open-Label Extension Trial to Assess the Long-Term Safety of 
ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive 
Therapy in Children and Young Adults with Dravet Syndrome 
Study Number:
ZX008-1503 
Study Product:
Fenfluramine Hydrochloride Oral Solution; ZX008 
IND Number:
125797 
EudraCT:
2016-002804-14 
Sponsor:
Zogenix International Limited
A wholly owned subsidiary of Zogenix, Inc.  
5959 Horton Street, 
 
Emeryville, CA 94608 USA 
Sponsor's Medical 
Contact 
Zogenix, Inc.
Date/Version of 
Study Protocol: 
03 August 2020 (amendment 5.0: ROW)
02 February 2018 (amendment 4.0: ROW) 
05 May 2017 (amendment 3.0: ROW) 
01 November 2016 (amendment 2.0: ROW) 
13 September 2016 (amendment 1.2.1: ROW) 
31 May 2016 (amendment 1.2: ROW) 
07 March 2016 (original)
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 2 of 194  
LIST OF PERSONNEL AND ORGANIZATIONS RESPONSIBLE FOR 
CONDUCT OF STUDY
A list of personnel and organizations responsible for the conduct of the study will be supplied to 
study sites as part of the Investigator Study File. This list will be updated by the Sponsor or the 
Sponsor's agent and provided to study sites as needed.
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
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application and any extensions or variations thereof. 

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

Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
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Confidential
Page 28 of 194  
Table 2. 
Schedule of Assessments for Subjects from Core Study ZX008-1504 
Study Assessments
OLE Treatment Period
Post-Dosing
Cardiac Follow-up
Visit Number
Visit 1a
Visit 2b
Visits 3-15
(Months 1, 2, 3, 6, 9, 12, 15, 18, 
21, 24, 27, 30, and 33)
Visit 16c
(EOS/ET) 
Month 36
Visit 17m
Visit 18, 19m
Study Day
1a
15
30, 60, 90, 180, 270, 365, 455, 
545, 635, 725. 815, 905, 995
1085
1099
3 and 6 months post last dose
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Phone
Informed Consent
X
Entry Criteria
X
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X
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Xa
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Physical Examination, abbreviated
X
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X
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X
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(hematology/clinical chemistry/urinalysis, etc)
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Xi
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X
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Xj
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Xa
X
X
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Xa
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X
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 29 of 194  
Table 2. 
Schedule of Assessments for Subjects from Core Study ZX008-1504 (continued)
Study Assessments
OLE Treatment Period
Post-Dosing
Cardiac Follow-up
Visit Number
Visit 1a
Visit 2b
Visits 3-15
(Months 1, 2, 3, 6, 9, 12, 15, 
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(EOS/ET) 
Month 36
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1a
15
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1085
1099
3 and 6 months post last dose
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Phone
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X
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X
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Adverse Events
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EOS=end of study; ET=early termination; EQ-5D-5L=standardized measure of health status; HADS=Hospital Anxiety and Depression Scale; PedsQL=Pediatric Quality of Life Inventory; QoL=quality of life; QOLCE=Quality of 
Life in Childhood Epilepsy; R=Review
NOTE:  If a subject has a birthday during the study that makes a previously unrequired assessment now required (eg, Tanner staging in a male subject who turns 8 years old during the study), this assessment(s) should be initiated 
at visits subsequent to the birthday.
a:
For subjects from the core Study ZX008-1504 Cohort 1, use data collected at the last visit of the transition period; for subjects from core Study ZX008-1504 Cohort 2 use data collected at the Visit 12 and Visit 13.
For de novo subjects, a screening period up to 28 days is required. During this period, informed consent is required prior to any study-related procedures.  All results to determine eligibility must be reviewed prior to 
receiving the first dose of study drug at Visit 1.  
For subjects from ZX008-1504 Cohort 2 and de novo subjects, clinical laboratory, ECHO, and ECG results must be available and meet eligibility criteria prior to receiving the first dose of study drug at Visit 1.
b:
At the discretion of the investigator, Visit 2 may be conducted as a phone visit.
c:
Or early termination.
d:
Follow-up ECG, ECHO, and physical examination will be performed 3 and 6 months after study completion or early termination (see Section 6.3).
e;
Unless complete neurological examination is warranted based on significant changes in subject status, use data collected at the last visit of the transition period of Study ZX008-1504 Cohort 1 and for subjects from Study 
ZX008-1504 Cohort 2, use data collected at the Visit 12.
f:
ECHOs will be performed at Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, and 33.
g:
The Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, and 33 ECHO may be performed any time within 3 weeks prior to the study visit. If a subject discontinues early from the study, the ECHO should be scheduled as soon as 
practical (see Table 7).
h:
Females of child-bearing potential
i:
Unless clinical laboratory evaluation is warranted based on significant changes in subject status, use data collected at the last visit of the transition period of Study ZX008-1504 Cohort 1; for subjects from Study ZX008-
1504 Cohort 2, use data collected at the Visit 12. For Visit 2, clinical laboratory evaluation is optional based on subject status.
j:
Visits 6, 15, and 27.
k:
Visits 3 and 4 (Months 1 and 2) only.
l:
m:
Only adverse events related to cardiac safety will be collected at this visit (see Table 7).
For subjects who are entering the separate extension trial or who transition to commercially available drug, post-dosing and cardiac safety follow-up visits are not required in this trial. 
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ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
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Page 30 of 194  
1.
INTRODUCTION
1.1
BACKGROUND INFORMATION ON INDICATION STUDIED
ZX008 (fenfluramine hydrochloride) is under clinical development for the adjunctive treatment 
of patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome. Fenfluramine 
(Fintepla®) is authorized for sale in the United States for the treatment of seizures associated 
with Dravet syndrome in patients 2 years of age and older 
Dravet syndrome, previously known as severe myoclonic epilepsy of infancy (SMEI), is a rare 
and severe form of epilepsy first described by Charlotte Dravet in 1978 (Dravet 1978). The 
International League Against Epilepsy (ILAE) considers Dravet syndrome a developmental and 
epileptic encephalopathy, “a condition in which the epileptic activity itself may directly 
contribute additional cognitive and behavioral impairments over those expected from the 
underlying etiology alone and that suppression of epileptic activity might minimize this 
additional impairment” (Scheffer 2017). 
Dravet syndrome is estimated to affect 1 out of every 15,700 live births in the US and less than 
1 in 20,000 persons in the European Union (Wu 2015; EMA 2014). Dravet syndrome is 
responsible for 7% of the severe epilepsies starting before the age of 3 years (Ceulemans 2004). 
The diagnosis of Dravet syndrome is based on clinical signs and symptoms, though the 
presence of a mutation in the SCN1A gene is considered a likely, though not definitive, marker 
for the disorder (Dravet 2011; Fujiwara 2006). Dravet syndrome is usually not diagnosed until 
at least 1 year of age (Cooper 2016) and is characterized by medically intractable seizures along 
with motor and neurodevelopmental comorbidities. Onset of the first seizure typically occurs in 
the first year of life (usually at 5 to 8 months of age) in otherwise healthy infants and most 
often consists of prolonged, unilateral or generalized, clonic seizures provoked by fever 
(Orphanet 2014; Ceulemans 2004; Dravet 2011). These patients will have poor response or 
worsening seizures to standard antiepileptic drugs, in particular, sodium channel antagonist 
medications (Dravet 2011).  
After the first year, other types of seizures often begin to occur with high frequency and include 
(1) convulsive seizures consisting of generalized clonic seizures, generalized tonic-clonic 
(GTC) seizures or alternating unilateral clonic seizures (in the youngest patients, they often 
evolve into status epilepticus [SE]); (2) myoclonic seizures (appearing between the ages of 1 
and 5 years); (3) atypical absences (appearing at different ages between 4 months and 6 years 
or later); (4) focal seizures with or without secondary generalization (appearing between the 
ages 4 months and 4 years); or (5) rarely, tonic seizures (TS) (Dravet 2011). Individuals with 
Dravet syndrome are at higher risk for SE that often results in injury and hospitalization 
(Ceulemans 2004). A high incidence for SUDEP (sudden expected death in epilepsy) exists in 
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Zogenix International Limited
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Confidential
Page 31 of 194  
Dravet syndrome with the major risk factor being the frequency of generalized tonic-clonic 
seizures (Harden 2017).  
Dravet syndrome is highly treatment-resistant and affects infants, children, adolescents, and 
adults. In general, convulsive seizure semiology is similar in patients across ages, although 
seizures tend to become less frequent and less severe in patients with Dravet syndrome as they 
enter adulthood (Lagae 2018). Generalized convulsive seizures, mostly reported as generalized 
tonic-clonic seizures persist into adulthood, often with a focal onset. These seizures are less 
frequent than in childhood and are mostly nocturnal. Some of these major convulsive seizures 
may have less typical aspects, for example, bilateral or asymmetric tonic posturing, followed in 
some cases by a tonic vibratory state or clonic movements (Oguni, 2001; Akiyama 2009). 
Throughout the lives of patients with Dravet syndrome, frequent and disabling seizures are 
associated with significant neurobehavioral, cognitive, developmental, and motor 
comorbidities,
1.1.1
Existing Treatment for Dravet Syndrome 
Currently no treatment algorithm exists for Dravet syndrome as recommended by the ILAE 
(International League Against Epilepsy) or any other similar medical entity. The main 
treatment goal in Dravet syndrome aims to reduce the frequency, duration, and severity of 
seizures with the ultimate goal of complete or near-complete seizure-freedom (Wirrell 2017). 
Attaining seizure-freedom or near seizure-freedom may be particularly important during the 
early developmental years. However, even with currently available AED polypharmacy, 
seizure-freedom or near seizure-freedom is rarely achieved (Dravet 2000; Dravet 2005, 
Dravet 2011, Chiron 2011). Commonly prescribed anticonvulsant medications, the sodium 
channel antagonists such as phenytoin and carbamazepine, exacerbate seizures in Dravet 
syndrome and are thus not useful (Wirrell 2016). Treatment for Dravet syndrome involves 
finding the best combination of medicines to treat seizures with tolerable side effects, 
preventing SE, and reducing comorbidity and mortality risk. Elimination or significant 
reduction of prolonged convulsive seizures and SE should represent the highest priority in 
treatment (Wirrell 2017).
Stiripentol and cannabidiol are the only 2 treatments approved for seizures associated with 
Dravet syndrome. 
Other therapies, topiramate (TPM), levetiracetam (LEV), and bromide may provide efficacy as 
adjunctive therapy for some patients (Chiron 2011). Published uncontrolled studies with LEV 
(Striano 2007), verapamil (Iannetti 2009), ketogenic diet (KD) (Caraballo 2011a; Caraballo 
2011b), deep brain stimulation (Andrade 2010), and vagal nerve stimulation (VNS) (Zamponi 
2011) show infrequent clinically meaningful improvement. Carbamazepine, oxcarbazepine, 
lamotrigine, phenytoin, vigabatrin, and high doses of intravenous (IV) phenobarbital should be 
avoided because they often exacerbate seizures (Sazgar 2005; Wirrell 2016; de Lange 2018). 
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Zogenix International Limited
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Page 32 of 194  
Rescue medications (clonazepam, diazepam, lorazepam, and midazolam, etc) are often used to 
stop prolonged seizures that may evolve to SE and require emergency intervention.  
Due to the severe and refractory nature of seizures associated with Dravet syndrome and given 
the risks of premature death from SUDEP, cognitive deficits, and other neurological 
consequences, there remains an urgent unmet medical need for the treatment of convulsive 
seizures associated with Dravet syndrome. The frequent and disabling seizures of different 
types, and the associated significant neurobehavioral, cognitive, developmental, and motor 
comorbidities that characterize Dravet syndrome, have a major negative impact on the patient's 
quality of life, as well as on their families. The neurobehavioral, cognitive, developmental, and 
motor comorbidities are at least partly caused by the poor control of seizures resulting in 
ongoing damage to the brain (Wolff 2006; Ragona 2011; Nabbout 2013; Wirrell 2016). A high 
incidence for SUDEP exists in Dravet syndrome with the major risk factor being the frequency 
of generalized tonic-clonic GTC seizures. 
Dravet syndrome drains a family emotionally, physically, and financially. Parents/caregivers 
suffer emotional exhaustion and anxiety related to the “fear of the next seizure” and “will this 
be the seizure that kills my child” (Campbell 2018). Patients with the highest seizure frequency 
tend to have more comorbidities and a lower quality of life (Lagae 2017). A 2006 study 
identified the challenges faced by parents caring for children with Dravet syndrome, reporting 
that the combination of persistent, severe seizures, together with developmental, behavioral, 
and sleep issues result in a high caregiver stress load with little ability to find respite and relief 
(Nolan 2006). The comorbid conditions, high mortality, disorder management requirements, 
and difficulties with family adaptation result in constant distress (Skluzacek 2011). In addition, 
Dravet syndrome is associated with extensive healthcare costs due to increased medical care 
use and intensive caregiver supervision as well as indirect burdens such as losses of 
productivity, family time, and leisure (Whittington 2018). The unremitting seizure episodes 
account for a high degree of healthcare resource utilization including hospitalizations, 
emergency room visits, and emergency transport services (Strzelczyk 2014). Aras and 
coworkers report 4 or more emergency room admissions in > 10% of children and up to 30 
admissions per year for some (Aras 2015). The impacts of Dravet syndrome typically not 
considered by healthcare professionals when making treatment decisions include the child’s 
expressive and receptive communications with family members, disruption of daily activities, 
and caregivers’ social interactions (Villas 2017; Nabbout 2013). 
A more effective treatment for Dravet syndrome that will abolish or significantly reduce 
seizure activity in a higher proportion of patients and provide periods of seizure freedom is 
urgently needed. Moreover, such outcomes could also lessen chronic brain injury and 
neuroinflammation due to unremitting seizures and thus potentially also improve Dravet 
syndromes’ associated comorbidities. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 33 of 194  
1.2
BACKGROUND INFORMATION ON STUDY PRODUCT
Zogenix is developing a new formulation of fenfluramine hydrochloride, ZX008, for the 
adjunctive treatment of DS. Fenfluramine was approved in a large number of countries and 
widely prescribed as an appetite suppressant for the treatment of adult obesity. Brand names for 
fenfluramine formulations included Ponderax, Pondimin and others. Fenfluramine was also 
used extensively in an off-label combination with phentermine (“Fen-Phen”). Fenfluramine is a 
racemic compound and the single enantiomer D-fenfluramine (dexfenfluramine) was also 
approved and marketed as Adifax, Redux, and others.  
Fenfluramine was introduced in the USA in 1973. Products containing fenfluramine and 
D-fenfluramine were withdrawn from the USA market in 1997 after reports of heart valve 
disease and pulmonary hypertension (Connolly 1997; CDC 1997; Wong 1998). While the 
risk/benefit relationship for fenfluramine is thus considered unfavorable for the treatment of 
obesity in adults, establishing seizure control in DS or any of the catastrophic childhood 
epilepsies might lead to a more acceptable risk/benefit profile for fenfluramine, especially if 
lower doses can be used successfully. 
As a result of this previous extensive use of fenfluramine, there is a large body of information 
in the public domain concerning its pharmacology, toxicology and use in the treatment of 
obesity (ZX008 IB). There is also a large body of information concerning its clinical safety 
profile.
1.3
CLINICAL DATA
Zogenix has conducted 2 positive, adequate and well-controlled, multi-national, randomized, 
double-blind, placebo-controlled trials of ZX008 in subjects with Dravet syndrome aged 2 to 18 
years, Study 1 and Study 1504 Cohort 2. Study 1 compared 2 doses of ZX008, 0.8 mg/kg/day
and 0.2 mg/kg/day, to placebo in subjects receiving standard of care anti-epileptic treatments
excluding stiripentol (STP). Study 1504 Cohort 2 compared a dose of ZX008 0.5 mg/kg/day to
placebo in subjects who were receiving stable standard of care anti-epileptic treatments where
administration of STP (in combination with clobazam [CLB] and/or valproate [VPA]; ie, the
STP regimen) was mandatory. These subjects were randomized to receive ZX008 or placebo in 
addition to their current standard of care treatments. The dose of 0.5 mg/kg/day was selected to 
account for the anticipated drug interaction when ZX008 was administered in combination with 
STP.  
The primary efficacy measure in both studies was the change from baseline in the frequency of 
convulsive seizures (per 28 days) during the combined 14-week (Study 1) or 15-week 
(Study 1504 Cohort 2) Treatment period. Key secondary objectives in both studies included a 
comparison of subjects who experienced at least a 50% reduction in monthly convulsive 
seizure frequency (also known as the ≥ 50% Responder Rate), and the median longest seizure 
free interval between convulsive seizures.  
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ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 34 of 194  
Both Study 1 and Study 1504 Cohort 2 met the primary efficacy endpoint and all key secondary 
efficacy endpoints. In Study 1, subjects randomized to ZX008 0.8 mg/kg/day achieved a 
reduction in mean monthly (28 days) baseline-adjusted CSF of 62.3% compared to placebo 
(P < 0.001) and subjects randomized to ZX008 0.2 mg/kg/day achieved a 32.4% reduction 
compared to placebo (P = 0.021). In Study 1504 Cohort 2, in which all subjects were taking 
STP, subjects randomized to ZX008 0.5 mg/kg/day achieved a 54.0% reduction compared to 
placebo (P < 0.001).  
Controlling for multiplicity with a hierarchical testing procedure, all key secondary endpoints 
were met in both studies, for ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups (Study 1) and 
ZX008 0.5 mg/kg/day (Study 1504 Cohort 2). In Study 1, the proportion of subjects achieving a 
≥ 50% reduction from Baseline in CSF was 67.5% for the ZX008 0.8 mg/kg/day group, and 
38.5% for the 0.2 mg/kg/day group, with both groups being statistically significantly different 
from placebo (12.5%; P < 0.001 and P = 0.009, respectively). In Study 1504 Cohort 2, 53.5% 
of subjects randomized to ZX008 0.5 mg/kg/day compared to 4.5% of subjects randomized to 
placebo achieved a ≥ 50% reduction from Baseline in CSF (P <0.001).  
ZX008 was generally well tolerated in both Study 1 and Study 1504 Cohort 2. Though more 
subjects randomized to ZX008 than to placebo reported TEAEs during the double-blind 
studies, the percent of subjects with serious TEAEs was similar. Additionally, the adverse 
events observed in the program were either already known to be associated with fenfluramine, 
are common to many other antiepileptic drugs being prescribed to these patients, and/or are 
common to the age group and population studied. Specifically, the most common adverse 
events seen were diarrhea, fatigue, pyrexia, upper respiratory tract infection, blood glucose 
decreased, weight decreased, decreased appetite, lethargy and tremor. No valvular heart 
disease, pulmonary arterial hypertension or abnormal valve structure was observed in any 
subject at any time during the entire program.  
In an integrated analysis of safety of the double-blind studies, 117 (95.9%) subjects in any 
ZX008 treatment group and 68 (81.0%) subjects in the combined placebo group reported at 
least 1 TEAE. The most common (≥ 10%) TEAEs reported in subjects receiving any dose of 
ZX008 were: blood glucose decreased, constipation, decreased appetite, diarrhea, 
echocardiogram abnormal, fall, fatigue, lethargy, nasopharyngitis, pyrexia, seizure, 
somnolence, status epilepticus, tremor, upper respiratory tract infection, vomiting, and weight 
decreased. All of the echocardiogram abnormal TEAEs were trace mitral or trace aortic valve 
regurgitation, which are normal physiological findings seen in healthy children (Webb 2015).  
Fifteen (12.3%) subjects in any ZX008 treatment group and 11 (13.1%) subjects in the 
combined placebo group reported at least 1 serious TEAE. The most frequently reported (≥5%) 
serious AEs (SAEs) were status epilepticus and seizure. A total of 3 (2.5%) subjects in any
ZX008 treatment group and 1 (1.2%) subject in the combined placebo group reported a serious 
TEAE determined by Investigators to be related to the study drug. In Study 1, two subjects, 
both of whom were in the ZX008 0.8 mg/kg/day group, reported SAEs that were considered by 
the Investigator to be related to study drug: SAEs of lethargy, and diarrhea leading to 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 35 of 194  
hospitalization in a 
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leading to hospitalization, drowsiness, reduced appetite, and weight loss in a 
who was discontinued from the study (The recorded weight loss was less than 1 kg.) In Study 
1504 Cohort 2, two subjects reported SAEs that were considered by the Investigator to be 
related to study drug: 2 episodes of seizure cluster, and seizure leading to hospitalization in a 
 in the placebo group; lethargy in a 
 in the ZX008 0.5 mg/kg/day 
group who was discontinued from the study. During the double-blind treatment periods, 7 
(5.7%) subjects in any ZX008 treatment group and 1 (1.2%) subject in the combined placebo 
group reported a TEAE that lead to discontinuation from study participation. There were no 
deaths during the double-blind treatment periods.
Subjects in Study 1 and Study 1504 if eligible could participate in this study, Study 1503, an 
open-label long-term, safety extension study. In a safety update of Study 1503 (cut-off date 14-
Oct 2019, n=330 enrolled), the median percent change in CSF compared to baseline (core 
study) for the overall open-label Treatment period (Day 1 to End of Study [EOS]) was -66.8% 
(P <0.001). The reduction from baseline in monthly CSF observed at Month 1 of the open-label 
Treatment period was maintained through Month 24, the longest treatment duration included in 
the analysis. A total of 317/330 subjects reported at least 1 TEAE during the open-label 
Treatment period. The most common (≥ 10%) TEAEs reported during the open-label Study 
1503 at the time of the cut-off date were blood glucose decreased, decreased appetite, diarrhea, 
ear infection, echocardiogram abnormal, influenza, nasopharyngitis, pyrexia, seizure, and upper 
respiratory tract infection. As in the double-blind studies, all of the echocardiogram abnormal 
TEAEs in Study 1503 were trace mitral or trace aortic valve regurgitation, which are not 
considered pathologic as stated in current guidelines on the use of ECHO for the assessment of 
valve function (Zoghbi 2017, Lancellotti 2010a, Lancellotti 2010b) . At least 1 treatment-
emergent SAE was reported by 80/330 (24.2%) subjects. The most frequently reported (≥ 5%) 
SAE was seizure, occurring in 24/330 (7.3%) of subjects. A total of 176/330 subjects (53.3%) 
experienced at least 1 TEAE that was considered to be related to study treatment and 8/330 
subjects (2.4%) reported at least 1 SAE that was considered to be related to study treatment. 
A total of 11/330 (3.3%) subjects discontinued due to a TEAE. 
Please reference the ZX008 IB for more detailed information on the safety and efficacy of 
ZX008. 
1.4
PRECLINICAL DATA
The pharmacokinetics (PK) of fenfluramine, norfenfluramine and their respective isomers has 
been studied in mice, rats, dogs and humans. The PK in humans differs from that of other 
species, with a longer duration of exposure to both the parent and the metabolite. In vitro 
metabolism studies have shown that there are large species differences in PK and metabolism 
of fenfluramine after oral administration. A 10-week GLP juvenile toxicology and toxicokinetic 
study in rats, which included fenfluramine hydrochloride doses of 3.5, 9 and 20 mg/kg/day by 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 36 of 194  
oral gavage for 10 weeks (Days 7 to 76 postpartum).  The data from the juvenile toxicology 
studies suggest that the effects of fenfluramine in juvenile animals (CNS-related clinical signs, 
effects on body weight and food consumption, and neurobehavioral deficits) are similar to 
effects previously reported in neonatal and adult rats (ZX008 IB). There was no evidence of 
CNS-related histopathology findings.; Importantly, there were also no histopathologic findings 
in aortic or mitral cardiac valves, and no adverse effects on any other tissues at necropsy.  
The NOAEL for the juvenile rats was determined to be 9 mg/kg/day. A NOAEL of 9 
mg/kg/day corresponds to PND 76 AUC0-t of 3480 hr*ng/mL for males and 4680 hr*ng/mL 
for females for fenfluramine, and 4470 hr*ng/mL for males and 6210 hr*ng/mL for females for 
norfenfluramine. The AUC(0-t) at the NOAEL in this study, 9 mg/kg/day, provided a safety 
factor (both sexes combined) of approximately 3-fold or higher for fenfluramine and 
approximately 6-fold or higher for norfenfluramine. 
Further preclinical data on ZX008 are available in the Investigator’s Brochure (ZX008 IB). 
1.5
PHARMACOKINETICS 
Fenfluramine is metabolized to norfenfluramine. CYP1A2, CYP2B6 and CYP2D6 appear to be 
the predominant CYP (cytochrome P450) enzymes that metabolize fenfluramine to 
norfenfluramine. CYP2C9, CYP2C19 and CYP3A4 also appear to be involved, but to a lesser 
degree. There is also some contribution of renal clearance to the elimination of dexfenfluramine 
(8% - 16%) and nordexfenflurmaine (7% - 8%) from the body. Because fenfluramine and its 
active metabolite norfenfluramine have multiple pathways of elimination, interference with a 
single pathway is unlikely to cause a significant change in fenfluramine’s clearance though the 
probability of an interaction increases if multiple elimination mechanisms are affected 
simultaneously. 
While in vitro studies showed that both fenfluramine and norfenfluramine cause weak 
inhibition of CYP2D6 and fenfluramine causes weak induction of CYP3A4 and CYP2B6, 
further analysis based on the Food and Drug Administration’s (FDA’s) mechanistic static 
model shows that fenfluramine and its major metabolite norfenfluramine are unlikely to alter 
the PK of substrates of these CYP450 enzymes in the range of ZX008 doses that will be 
administered in this study. 
Study 1 and Study 1504 Cohort 2 
Pharmacokinetic parameters of fenfluramine and norfenfluramine for patients with Dravet 
syndrome were determined using a population pharmacokinetic (PopPK) model developed 
using PK data from both healthy volunteers and patients with Dravet syndrome and are 
provided in the Table 3 below. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 37 of 194  
Table 3 
Post Hoc Estimates of Fenfluramine and Norfenfluramine Steady-State 
Pharmacokinetic Parameters in Subjects with Dravet Syndrome in Study 1 
(Geometric Mean [CV%])
Analyte:
Fenfluramine
Norfenfluramine
ZX008 Dose
0.2 mg/kg/day
0.8 mg/kg/day
0.2 mg/kg/day
0.8 mg/kg/day
Cmax (ng/mL)
18.5 (29.1)
68.0 (40.7)
9.60 (52.8)
37.8 (49.9)
AUC0-24 (ng.hr/mL)
375 (32.9)
1390 (43.5)
220 (55.5)
872 (52.1)
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(Min, Max)
3.00 (3.00 to 3.50)
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4.00 (3.50 to 5.00)
4.50 (3.50 to 5.00)
Source: ICPD Report 00445-3, Table 5.
Abbreviations: AUC0-24 = area under the plasma concentration-time curve from time 0 to 24 hours; BID = twice daily; 
Cmax = peak plasma drug concentration; CV= coefficient of variation; Max = maximum; Min = minimum; Tmax = time of peak 
plasma drug concentration. 
Study 1504 Cohort 2 required STP as a concomitant medication. Although the dose of ZX008 
in Study 1504 Cohort 2 was lower than the high dose in Study 1, fenfluramine AUC0-24 values 
were approximately 130% higher in Study 1504 Cohort 2, than the high dose in Study 1, and 
norfenfluramine AUC0-24 values were approximately 60% lower than in Study 1. However, the 
clinical results indicated that the efficacy and AE profile were similar between Study 1 and 
Study 1504, indicating that the dose adjustment studied for the concomitant use of the STP 
regimen met the intended clinical outcome.
1.6
CLINICAL PHARMACOLOGY 
Please see the ZX008 IB for details on clinical pharmacology. Below are the clinical 
pharmacology conclusions.  
•
Coadministration of ZX008 with the STP regimen (STP with CLB and/or VPA) resulted in 
an increased fenfluramine and decreased norfenfluramine concentrations, and therefore a 
dose adjustment is used in the clinical trials.
•
STP is the predominant perpetrator of the interaction; while VPA and CLB do not have a 
significant independent impact on the PK of fenfluramine or norfenfluramine, whether 
administered with or without STP.
•
Coadministration of ZX008 with CBD at steady state resulted in increased fenfluramine 
concentrations but this increase was within the range of 
 dosing used in Study 1504 
Cohort 2; thus, no dose adjustment is recommended when fenfluramine is coadministered 
with CBD. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 38 of 194  
•
In the population PK analysis, intrinsic patient factors (age, gender, race/ethnicity, and 
BMI) demonstrated no substantial impact on the clearance or exposure to fenfluramine or 
norfenfluramine when dosed on a mg/kg basis to a maximum of 30 mg/day. 
•
ZX008 had no effect on QTc intervals at either the therapeutic or supratherapeutic dose, 
and no relationship was observed between fenfluramine or norfenfluramine exposure and 
QTcF.
•
ZX008 exhibited approximately dose proportional PK over a 4-fold range of doses (15 to 
120 mg/day). 
•
CYP450 metabolizer genotype for CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP3A4 
had no impact on the PK of fenfluramine or norfenfluramine. 
1.7
BACKGROUND INFORMATION ON REFERENCE PRODUCT
Not applicable.
1.8
RATIONALE FOR CURRENT STUDY
The rationale for conducting this open-label extension study is primarily to evaluate the long-
term safety of ZX008 in DS. This protocol also provides the opportunity for continued 
treatment for subjects responding to treatment from the Phase 3 double-blind studies, and an 
opportunity for initial treatment with ZX008 for subjects randomized to placebo in those 
studies. 
1.9
RATIONALE FOR INCLUDING DE NOVO SUBJECTS
Subjects who are >18 to ≤35 years of age at the time of screening, and who meet all other 
eligibility criteria may be eligible for participation after discussion with the Medical Monitor 
and sponsor about the potential risks and benefits for receiving ZX008.  Participation for these 
subjects will be at the discretion of the sponsor.   
Epileptic seizures tend to become less frequent and less severe after childhood; however, the 
mortality rate remains high.  One study on the long-term outcome of 24 adult patients with DS 
reported 5 (20.8%) deaths, at a mean age of 24.8 years, one by status epilepticus, three by 
sudden unexpected death in epilepsy (SUDEP), and one of unknown cause (Genton 2011). 
Fever sensitivity (temperature variations) persists throughout the clinical course of DS, but its 
impact on seizure frequency and severity is milder than in infancy. Generalized convulsive 
seizures, mostly reported as generalized tonic-clonic seizures persist, often with a focal onset 
but are less frequent than in childhood and mostly nocturnal. Some of these major convulsive 
seizures have less typical aspects, for example, bilateral or asymmetric tonic posturing, 
followed in some cases by a tonic vibratory state or clonic movements (Oguni 2001; 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 39 of 194  
Akiyama 2010). Other seizures like myoclonic seizures, atypical absences, and complex partial 
seizures are less common in adulthood.  Motor abnormalities are also common in adulthood, as 
is intellectual disability. Dependency in adulthood is nearly constant. 
Including subjects >18 to ≤35 years of age provides the opportunity to investigate the impact of 
ZX008 on DS outcomes as subjects transition to adulthood.
1.10
RISK-BENEFIT ASSESSMENT
Fenfluramine has been used successfully for up to 30 years in Belgium in refractory pediatric 
epilepsy patients, including those with DS (Boel 1996, Ceulemans 2012, Ceulemans 2016, 
Schoonjans 2016, Schoonjans 2017). The efficacy and safety of this therapeutic approach has 
been reported to be overwhelmingly favorable. Of the 15 DS treated patients, 10 (67%) were 
reported as seizure-free, with the average time of seizure-freedom being 6 years (range 1-19 
years). Twelve patients (87%) had a greater than 90% reduction in seizure frequency and 14 
patients (93%) with greater than 70% reduction in seizure frequency. No patients experienced 
emergence of clinical valvulopathy or pulmonary hypertension. The doses tested thus far in DS 
range from 0.12 to 0.9 mg/kg/day in subjects over 1 year of age to adults. Fenfluramine has 
also been administered to over 500 children with neurobehavioral conditions, including autism 
and ADHD with good safety and tolerability. Doses tested in these pediatric studies ranged 
from 0.65 mg/kg/day to 3.6 mg/kg/day, but a commonly used dose was 1.5 mg/kg/day. 
Occasionally, fixed doses of 30 to 80 mg were used. 
In addition, ZX008 demonstrated a statistically significant and clinically meaningful reduction 
in monthly convulsive seizure frequency in Study 1 and Study 1504 Cohort 2 and was 
generally well tolerated.  There was no clinical or echocardiographic evidence of cardiac 
valvulopathy or pulmonary hypertension and no patient discontinued participation or required a 
change in monitoring in the study due to cardiac factors. The PK exposure associated with the 
doses of ZX008 in the DS studies of 0.2 mg/kg/day to 0.8 mg/kg/day administered orally [in 
equally divided doses twice per day (BID)] is expected to be lower than that obtained at the 
doses used in the past for the treatment of obesity in adults and of neurobehavioral conditions 
in children and adolescents (ZX008 IB). The doses used in this study are based on the data 
from the DS patients being successfully treated in Belgium discussed above and supported by 
results from Study 1 and Study 1504 Cohort 2. 
Interim results from this open-label study show that the effects observed during the double-
blind studies were durable and long-lasting; the reduction in convulsive seizures for subjects in 
Study 1503 was maintained throughout study participation of up to 3 years at the time of the 
interim analysis, with no evidence for developing tolerance. The pharmacologic and 
toxicological profile for the active pharmaceutical ingredient, fenfluramine, following oral 
administration is well established (ZX008 IB).
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 40 of 194  
The safety monitoring practices employed by this protocol are adequate to protect the subjects’
safety and should detect expected and unexpected treatment-emergent adverse events. Subjects 
will be enrolled into this study from the core studies where they had been transitioned to the 
lowest dose of ZX008 (0.2 mg/kg/day; maximum 30 mg/day or 20 mg/day for subjects from 
ZX008-1504 Cohort 1 dose regimen 3 or Cohort 2) and will remain on this dose for the first 
month of this study. After this time, the dose of ZX008 may be adjusted based on effectiveness 
and tolerability. For subjects that participated in core studies ZX008-1501, ZX008-1502, and 
dose regimen 1 or 2 from Cohort 1 of ZX008-1504 dose increases may be made in increments 
of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day (maximum dose 30 mg/day), and these 
increases should not occur earlier than every 14 days at each dose level. For subjects that 
participated in core study ZX008-1504 Cohort 1 dose regimen 3 and Cohort 2 and are receiving 
concomitant STP the first dose change will be to 0.4 mg/kg/day and the final dose change will 
be to 0.5 mg/kg/day, but not to exceed 20 mg/day. Dose increases may only occur after a 
review of the diary and reported adverse events (AEs), and if, in the investigator’s opinion, 
seizure frequency, severity, and/or duration indicates a change in medication regimen is 
warranted. Dose decreases for tolerability can occur at the investigator’s discretion, in dose 
amounts and frequency appropriate for the situation. Dose adjustments outside of these 
parameters must be discussed with the Medical Monitor prior to initiation.  
It is acknowledged that the initial dose of ZX008 in this study, 0.2 mg/kg/day, may or may not 
be effective or may be less effective than 0.8 mg/kg/day (or 0.5 mg/kg/day for subjects taking 
concomitant STP) for some subjects and some subjects may experience a worsening of their 
seizure condition after transitioning to the lower dose. However, there is benefit in identifying a 
minimally effective dose for all subjects in the study since the cardiotoxicity of fenfluramine 
appears to be dose-related in adults. The dosing instructions of this protocol permit dose 
adjustment during the first month of fixed dosing at 0.2 mg/kg/day if a clinically meaningful 
worsening occurs, such as an increase in frequency, severity or duration of existing seizures, or 
emergence of a new seizure type. 
The approximate volume of blood (240 mL) planned for collection from each subject over the 
course of the entire study (approximately 3 years, but not including repeat or additional tests 
ordered by the investigator) presents no undue risk to the subjects. 
The ZX008 0.2 mg/kg/day, 0.4 mg/kg/day, 0.6 mg/kg/day, 0.8 mg/kg/day, and 0.5 mg/kg/day 
(in subjects taking concomitant STP) doses are believed to be therapeutic doses, which could 
provide sufficient anti-epileptic support for a sustained period of time during the study.  
The available information suggests that the present clinical study has an acceptable risk-benefit 
ratio.
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 41 of 194  
2.
STUDY OBJECTIVES AND ENDPOINTS
2.1
PRIMARY OBJECTIVE
The primary objective of the study is: 
•
To assess the long-term safety and tolerability of ZX008. 
2.2
SECONDARY OBJECTIVES 
The secondary objectives of the study are: 
• To assess the effect of ZX008 relative to the pre-ZX008 baseline on the following 
effectiveness measures:
- The change in the frequency of convulsive seizures from Visit 3 to Visit 8 (ie, Day 31 
to Day 365) and for the entire Year 1 treatment period (ie, Visit 1/Day 1 to Visit 8/ 
Day 365) 
- The proportion of subjects who achieve a ≥ 40%, ≥ 50%, and ≥ 75% reduction in 
convulsive seizure frequency 
- The longest convulsive seizure-free interval
- The percentage of convulsive seizure-free days
- The non-convulsive seizure frequency 
- The convulsive + non-convulsive seizure frequency
• To estimate the incidence of the following on subjects receiving ZX008: 
- Use of rescue medication
- Hospitalization to treat seizures
- Status epilepticus (SE)
• To assess the effect of ZX008 relative to the pre-ZX008 baseline on the following QoL 
measures:
- Quality of Life in Childhood Epilepsy (QOLCE) score 
- Pediatric Quality of Life Inventory™ (PedsQL score) 
- PedsQL Family Impact module score 
- QoL of the parent/caregiver using the standardized measure of health status 
(EQ-5D-5L scale
- Affective symptoms of the parent/caregiver using the Hospital Anxiety and Depression 
Scale (HADS)
• To assess the effect of ZX008 on the following QoL measures: 
- Clinical Global Impression – Improvement (CGI-I) rating, as assessed by the principal 
investigator 
- CGI-I rating, as assessed by the parent/caregiver 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 42 of 194  
2.3
EXPLORATORY OBJECTIVES
The exploratory objectives for subjects who participated in core study ZX008-1504 are: 
• To assess the effect of ZX008 on the following QoL measures: 
- Sleep quality and mealtime behavior, as assessed by the parent/caregiver 
- Karolinska Sleep Scale
- Health and social care resource use (These measures include planned and unplanned 
hospital visits, use of ambulances, General Practitioner (GP) visits, speech and 
language therapy utilization, occupational and physical therapy utilization) 
2.4
STUDY ENDPOINTS
2.4.1
Effectiveness Endpoints
The effectiveness endpoints of the study are: 
•
Number of seizures by type 
•
Convulsive seizure-free interval
•
CGI-I as assessed by parent/caregiver
•
CGI-I as assessed by principal investigator 
•
QOLCE to measure changes in quality of life of the subject
•
PedsQL to measure changes in quality of life of the subject 
•
PedsQL Family Impact module to measure changes in quality of life of the 
parent/caregiver
•
QoL of parent/caregiver using the EQ-5D-5L scale
•
Affective symptoms of parent/caregiver using the HADS (in parents/caregivers from 
core studies ZX008-1501 and ZX008-1502 only) 
•
Duration of prolonged seizures (seizure type that, during pre-Z008 baseline, had 
duration > 2 minutes) 
•
Number of episodes of SE
•
Number of instances of rescue medication use and number of doses 
•
Number of inpatient hospital admissions due to seizures 
2.4.2
Safety Endpoints
The safety endpoints of the study are: 
•
AEs
•
Laboratory safety (hematology, chemistry, urinalysis) 
•
Vital signs (blood pressure, heart rate, temperature, and respiratory rate)
•
Physical examination
•
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 43 of 194  
•
12-lead electrocardiogram (ECGs) 
•
Doppler echocardiogram (ECHOs) 
•
Body weight 
•
Behavior Rating Inventory for Executive Function (BRIEF) to measure 
cognition 
2.4.3
Exploratory Endpoints 
For subjects who participated in core study ZX008-1504 only, the exploratory endpoints of this 
study are: 
•
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occupational and physical therapy, in addition to acute hospital and institutional length 
of stay, loss of work, etc. 
•
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•
Mealtime behavior
•
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 44 of 194  
3.
INVESTIGATIONAL PLAN
3.1
OVERALL STUDY DESIGN AND PLAN
This is an international, multicenter, open-label, long-term safety study of ZX008 in pediatric 
and young adult subjects with DS. Subjects eligible for participation are those who have 
successfully completed 14 weeks of treatment in core studies ZX008-1501 or ZX008-1502, and 
15 weeks of treatment in core study ZX008-1504 Cohort 2, or successfully completed core 
study ZX008-1504 Cohort 1, and are candidates for continuous treatment for an extended 
period of time. In addition, subjects who are >18 to ≤35 years of age at the time of screening, 
and who meet all other eligibility criteria may be eligible for participation after discussion with 
the Medical Monitor and sponsor about the potential risks and benefits for receiving ZX008.  
Participation for these subjects will be at the discretion of the sponsor.  
This trial will consist of an up to 36-month open-label extension (OLE) Treatment Period and a 
2-week Post-Dosing Period. Thus, subjects who complete this trial will have been treated with 
ZX008 for a minimum of up to 3 years (including their participation in both the core study and 
this study). Subjects who did not participate in one of the core studies will undergo a screening 
period up to 28 days to confirm eligibility prior to receiving their first dose in the OLE 
Treatment Period
During the OLE Treatment Period, all subjects will be treated initially with 0.2 mg/kg/day for 
1 month to assess effectiveness of this dose in all study subjects. After 1 month at a dose of 
0.2 mg/kg/day, the investigator may adjust the dose of each subject based on effectiveness and 
tolerability. For subjects who are not receiving concomitant STP, including de novo subjects 
and those who participated in core studies ZX008-1501, ZX008-1502, and dose regimen 1 or 2 
from Cohort 1 of ZX008-1504, dose changes should be made in increments of 0.2 mg/kg/day, 
to a maximum of 0.8 mg/kg/day but not to exceed total dose of 30 mg/day. For subjects who
are receiving concomitant STP, including de novo subjects and those who participated in core 
study ZX008-1504 Cohort 1 dose regimen 3 and Cohort 2, and the first dose change will be to 
0.4 mg/kg/day and the final dose change will be to 0.5 mg/kg/day, but not to exceed 20 mg/day.  
Dose increases should not occur earlier than every 14 days at each dose level. Dose increases 
may only occur after a review of the diary and reported AEs, and if, in the investigator’s 
opinion, seizure frequency, severity, and/or duration indicates a change in medication regimen 
is warranted. Dose decreases for tolerability can occur at the investigator’s discretion, in dose 
amounts and frequency appropriate for the situation. ZX008 dose adjustments outside of these 
parameters should be discussed with the Medical Monitor prior to initiation.  
In addition, if a subject has been stable on the same dose of ZX008 for 6 months or longer, 
investigators may adjust the doses of one or more of the other concomitant AEDs as per typical 
clinical practice. Concomitant AEDs may be withdrawn completely but all subjects must 
remain on a minimum of 1 concomitant AED plus ZX008. No new concomitant AEDs or 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 45 of 194  
antiepileptic treatments may be introduced while in this study. All medication dose changes 
must be documented with a clinical explanation and justification. Concomitant AED dose 
adjustments outside of these parameters should be discussed with the Medical Monitor prior to 
initiation.  
If after approximately the midway point of the first 30 days on ZX008 0.2 mg/kg/day there is a 
clinically meaningful worsening in seizure type, frequency, and/or duration compared with the 
recent treatment in the core study, the investigator, in consultation with the Medical Monitor, 
may increase the dose to 0.4 mg/kg/day (maximum 30 mg/day for subjects who are not 
receiving concomitant STP; 20 mg/day for subjects who are receiving concomitant STP). A 
clinically meaningful worsening would be an increase in frequency, severity or duration of 
existing seizures, or emergence of a new seizure type. The description of the clinical worsening 
must be documented in the source notes and case report form (CRF). Further increase to 0.8 
mg/kg/day (maximum 30 mg/day for subjects who are not receiving concomitant STP and to 
0.5 m/kg/day (maximum 20 mg/day) for subjects who are receiving concomitant STP) could 
also be undertaken for the same conditions after a minimum of 4 days on 0.4 mg/kg/day, if the 
condition has not stabilized on the 0.4 mg/kg/day dose. Dosing outside of the specified range 
(ie, 0.2 to 0.8 mg/kg/day or 0.5 mg/kg/day for subjects who are receiving concomitant STP) 
may be considered after consultation between the investigator and Medical Monitor. 
A follow-up ECG and ECHO will be performed 3 and 6 months after study drug 
discontinuation for early termination and for those subjects who complete the study. 
Caregivers will use a diary daily to record the number/type of seizures, dosing, and use of 
rescue medication. A schedule of assessments is provided in Table 1 and Table 2. 
After at least 1 year of treatment in Study 1503 subjects who participated in one of the core 
studies will transition to a separate extension study (Study 1900) once that study is approved 
and the study site is initiated. Continuation in a separate extension protocol will be based on 
benefit/risk and continued eligibility criteria being met. De novo subjects must have 
participated in this trial for at least 3 months with at least 1 ECHO completed and continue to 
meet eligibility requirements to be eligible to transition to a separate extension protocol. 
Alternatively, subjects will transition to commercial product once it is available. For subjects 
who are entering the separate extension trial or who transition to commercially available drug, 
post-dosing and cardiac safety follow-up visits are not required in this trial. Subjects who 
transition to commercially available drug must have an ECHO within 3-6 months before
starting commercial drug and will have follow-up ECHOs within the required timeframe while 
on commercial drug.  
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3.2
NUMBER OF SUBJECTS
Up to approximately 340 subjects from the core studies and up to 50 subjects who did not 
participate in the core studies may be enrolled. 
3.3
STUDY DURATION
The duration of participation in the study for an individual subject is expected to be up to 158 
weeks, plus follow-up safety visit 3 and 6 months after the last dose: 
•
OLE Treatment Period - 36 months (156 weeks)
•
Post-Dosing Visit - 2 weeks after study completion or early termination
•
Cardiac Follow-up (ECG and ECHO) - 3 and 6 months after study drug discontinuation 
for early termination and for those subjects who complete the study; not applicable to 
subjects who transition to commercial product. 
3.4
NUMBER OF STUDY CENTERS
The study expects to use up to approximately 75 research centers in North America, Europe, 
Australia and Japan.  
3.5
RATIONALE FOR STUDY DESIGN AND CHOICE OF TREATMENT 
GROUPS
It is recognized that performing clinical studies in young children or in subjects with reduced 
cognitive capacity presents particular practical and ethical issues. However, given the 
seriousness of DS, and the possible consequences of current inadequate treatments, the use of 
children with DS in this study is considered justified. The study design has incorporated an 
initial 1-month of treatment at the lowest dose (ZX008 0.2 mg/kg/day) after which time the 
investigator may adjust the dose based on effectiveness and tolerability. After the first month, 
dose increases will be made incrementally every 14 days to ensure adequate time to acclimate
to the new dose. Dose decreases for tolerability can occur at the investigator’s discretion, in 
dose amounts and frequency appropriate for the situation. The duration of the study, up to 36 
months, will allow for collection of appropriate data to characterize the safety profile of 
ZX008. 
3.6
PREMATURE TERMINATION OF STUDY
The Sponsor can terminate the study prematurely at any time for medical or ethical reasons at 
individual study sites or at all study sites. The investigator will be notified in writing, outlining 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 47 of 194  
the reasons for the termination. Instructions will be provided if assessments beyond those 
described in the study protocol need to be conducted.  
If the study is terminated prematurely for any reason, the investigator should promptly inform 
the subjects participating at his or her study site and should ensure that appropriate alternative 
therapy is available and that End-of-Study procedures are conducted, as described in 
Section 6.1.5 and Section 6.2. 
All study materials including investigational medicinal product (IMP) and completed, partially 
completed, and blank documentation, except documents needed for archiving requirements, 
will be returned to the Sponsor. The study monitor will ensure that any outstanding data 
clarification issues and queries are resolved, and that all study records at the study site are 
complete.
In accordance with applicable regulatory requirements, the Sponsor will promptly inform the 
competent regulatory authorities of the termination and its reason(s), and the investigator or 
Sponsor will promptly inform the Independent Ethics Committee (IEC)/Institutional Review 
Board (IRB). 
3.7
STUDY MONITORING PROCEDURES
3.7.1
Independent Data and Safety Monitoring Committee (IDSMC)
The Independent Data and Safety Monitoring Committee (IDSMC) is an independent advisory 
body that monitors participant safety, data quality and progress of the clinical trial. The IDSMC 
charter will outline the roles and responsibilities of the committee and guide its operations and 
frequency of meetings. The IDSMC will consist of individuals external to the Sponsor who 
have relevant clinical trial expertise and experience in safety assessment.
At regularly defined intervals, the IDSMC will convene to review and monitor study progress, 
AEs and SAEs, other measures of safety such as ECGs or ECHOs, and efficacy data as dictated 
by the charter.  
The IDMSC will:
•
Be responsible for providing recommendations to the Sponsor surrounding study 
conduct matters that affect safety
•
Review safety data at ad hoc time points and identify if significant safety concerns arise 
during the study 
•
Review PK data and any other data that may affect subject continuation
•
Make recommendations regarding the continuation, suspension, or termination of the 
study 
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3.7.2
International Pediatric Cardiac Advisory Board (IPCAB) 
The International Pediatric Cardiac Advisory Board (IPCAB) is an advisory body to the 
Sponsor that monitors cardiac safety of the ZX008 clinical trials and provides advice to the 
IDSMC. The IPCAB charter outlines the roles and responsibilities of the committee and guide 
its operations, and review of individual subject cases. The IPCAB consists of individuals 
external to the Sponsor who have relevant experience in cardiology, pediatric cardiology, and 
echocardiography. The IPCAB will advise the Sponsor and the IDSMC on the cardiac safety 
monitoring plan, including alert criteria and decision pathway for subject management relative 
to cardiac safety in the clinical studies of ZX008.  
All ECHO examinations performed throughout the trial will be sent to an experienced pediatric 
cardiologist central reader (Biomedical Systems, Inc.). If the central reader classifies a subject 
as having met a pre-defined threshold value indicative of potential cardiac valvulopathy or 
pulmonary hypertension, or any other unexpected cardiac adverse event, the case will then be 
sent for secondary adjudication by one or more members of the IPCAB according to the 
procedures outlined in the IPCAB manual. In addition, member of the IPCAB will perform 
audits of ECHOs deemed normal by the central cardiac reader. 
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Confidential
Page 49 of 194  
4.
SELECTION OF STUDY POPULATION 
The study population will be selected on the basis of the inclusion and exclusion criteria 
described in the sections below.  
4.1
INCLUSION CRITERIA
Subjects meeting all of the following inclusion criteria may be enrolled into the study: 
1. Subject is aged 2 to 18 years inclusive, as of the day of the core study Screening Visit.  
2. Subject has satisfactorily completed the core study in the opinion of the investigator and 
the Sponsor. 
NOTE: Those subjects who do not complete the 12-week Maintenance Period of the 
core study may, on a case-by-case basis, be eligible for entrance after consideration of 
the circumstances of the early termination and the potential benefit-risk of continued 
participation in a ZX008 trial. The decision whether to permit open-label extension 
study participation resides solely with the Sponsor, who may consult with the site 
investigator, the IPCAB and/or the IDSMC. 
3. Subject is male or non-pregnant, non-lactating female. Female subjects of childbearing 
potential must not be pregnant or breast-feeding. Female subjects of childbearing 
potential must have a negative urine pregnancy test. Subjects of childbearing or child-
fathering potential must be willing to use medically acceptable forms of birth control, 
which includes abstinence, while being treated on this study and for 90 days after the 
last dose of study drug. 
4. Subject has documented medical history to support a clinical diagnosis of DS, where 
convulsive seizures are not completely controlled by current antiepileptic drugs. 
5. Subject has been informed of the nature of the study and informed consent has been 
obtained from the legally responsible parent/guardian. 
6. Subject has provided assent in accordance with IRB/IEC requirements, if capable.
7. Subject’s caregiver is willing and able to be compliant with diary completion, visit 
schedule and study drug accountability. 
8. Subject’s parent/caregiver has been compliant with diary completion during the core 
study, in the opinion of the investigator (eg, at least 90% compliant). 
9. Subjects entering from study ZX008-1504 must be receiving a therapeutically relevant 
and stable dose of CLB and/or VPA, and STP (Cohort 1 dose regimen 3 and Cohort 2 
only) for at least 4 weeks prior to screening and are expected to remain stable 
throughout the study. 
10. Subjects who are >18 to ≤35 years of age at the time of screening and did not 
participate in one of the core studies must meet criteria 3 to 7 above and the following 
criteria below in order to be considered for participation. Participation is at the 
discretion of the Sponsor: 
a. Onset of seizures in the first year of life in an otherwise healthy infant.
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b. A history of seizures that are either generalized tonic-clonic or unilateral
clonic or bilateral clonic, and are prolonged.
c. Initial development is normal.
d. History of normal brain MRI without cortical brainmalformation.
e. Lack of alternative diagnosis.
f.
Meets one of the following 3 confirmatory diagnostic criteria:
i. Emergence of another seizure type, including myoclonic,
generalized tonic-clonic, tonic, atonic, absence and/or focal has
developed after the first seizure type.
ii. Prolonged exposure to warm temperatures induces seizures and/or 
seizures are associated with fevers due to illness or vaccines, hot
baths, high levels of activity and sudden temperature changes 
and/or seizures are induced by strong naturaland/or fluorescent 
lighting, as well as certain visualpatterns.
iii. Genetic test results consistent with a diagnosis of Dravet syndrome
(pathogenic, likely pathogenic, variant of unknown significance, or
inconclusive but unlikely to support an alternative diagnosis.)
g. Subject has been approved for study inclusion by the Epilepsy Study 
Consortium.
h. Subject does not have an exclusionary cardiovascular or cardiopulmonary 
abnormality based on ECHO, ECG or physical examination and is approved for 
entry by the central cardiac reader.  Exclusionary abnormalities include, but are 
not limited to:
i. Mild or greater mitral or aortic valve regurgitation in subjects >18 yrs of 
age
ii. Possible signs of pulmonary hypertension with abnormal or greater than 
upper limit of normal values 
iii. Evidence of diastolic dysfunction
i.
Subject must have had ≥4 convulsive seizures (tonic, tonic-atonic, tonic-
clonic, clonic) per 4-week period for past 12 weeks prior to screening, by 
parent/guardian report to investigator or investigator medical notes.
j.
All medications or interventions for epilepsy (including ketogenic diet [KD] 
and vagal nerve stimulation [VNS]) must be stable for at least 4 weeks prior 
to screening and are expected to remain stable throughout the study.
11. Subject’s parent/caregiver is willing and able to be compliant with diary 
completion, visit schedule and study drug accountability.
4.2
EXCLUSION CRITERIA
Subjects meeting any of the following exclusion criteria must not be enrolled into the study:
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ZX008, Fenfluramine Hydrochloride
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Confidential
Page 51 of 194  
1. Subject has a known hypersensitivity to fenfluramine or any of the excipients in the 
study medication. 
2. Subject has current or past history of cardiovascular or cerebrovascular disease, 
myocardial infarction or stroke.
3. Subject from one of the core studies with current cardiac valvulopathy or pulmonary 
hypertension that the investigator, parent, IPCAB, IDSMC, or Sponsor deems clinically 
significant and warrants discontinuation of study medication. 
4. For de novo subjects: possible signs of pulmonary hypertension with abnormal or 
greater than upper limit of normal values 
5. Subject has current or recent history of anorexia nervosa, bulimia, or depression within 
the prior year that required medical treatment or psychological treatment for a duration 
greater than 1 month. 
6. Subject is at imminent risk of self-harm or harm to others, in the investigator’s opinion, 
based on clinical interview and responses provided on the Columbia-Suicide Severity 
Rating Scale (C-SSRS). Subjects must be excluded if they report suicidal behavior as 
measured by the C-SSRS Since Last Visit, which includes suicidal ideation with intent 
and plan (Item #5). If a subject reports suicidal ideation on Item 4 without specific plan, 
and the investigator feels that the subject is appropriate for the study considering the 
potential risks, the investigator must document appropriateness for inclusion, and 
discuss with the parent/caregiver to be alert to mood or behavioral changes, especially 
around times of dose adjustment. 
7. Subject has a current or past history of glaucoma. 
8. Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild 
hepatic impairment (elevated liver enzymes < 3x upper limited of normal [ULN] and/or 
elevated bilirubin < 2x ULN) may be entered into the study after review and approval 
by the Medical Monitor in conjunction with the Sponsor, in consideration of 
comorbidities and concomitant medications.
9. Subject is receiving concomitant therapy with: centrally-acting anorectic agents; 
monoamine-oxidase inhibitors; any centrally-acting compound with clinically 
appreciable amount of serotonin agonist or antagonist properties, including serotonin 
reuptake inhibition; atomoxetine, or other centrally-acting noradrenergic agonist; 
cyproheptadine, and/or cytochrome P450 (CYP) 2D6/3A4/2B6 inhibitors/substrates 
(Appendix 1). (Note: Short-term medication requirements will be handled on a per case 
basis by the Medical Monitor.) 
10. Subject is currently taking carbamazepine, oxcarbazepine, eslicarbazepine, 
phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as 
maintenance therapy.
11. For subjects entering from core studies ZX008-1501, ZX008-1502, or ZX008-1504 
(Cohort 1/dose regimens 1 &2):  Subject is currently receiving or has received STP in 
the past 21 days prior to core study Visit 1. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
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Confidential
Page 52 of 194  
12. Subject is unwilling to refrain from large or daily servings of grapefruits and/or Seville 
oranges, and their juices beginning with Visit 1 and throughout the study. 
13. Subject has positive result on urine tetrahydrocannabinol (THC) Panel or whole blood 
cannabidiol (CBD) at Visit 1.
14. Subject is unwilling or unable to comply with scheduled visits, drug administration 
plan, laboratory tests, other study procedures, and study restrictions. 
15.  Subject has a clinically significant condition, or has had clinically relevant symptoms 
or a clinically significant illness in the 4 weeks prior to Visit 1, other than epilepsy, that 
would negatively impact study participation, collection of study data, or pose a risk to 
the subject, including chronic obstructive pulmonary disease, interstitial lung disease, or portal 
hypertension. 
16. Subject has participated in another clinical trial within the past 30 days (ie, the last visit 
of the previous study was in the past 30 days), with the exception of the core studies. 
4.3
SUBJECTS OF REPRODUCTIVE POTENTIAL
Male subjects who are sexually active with a partner of child-bearing potential must use, with 
their partner, a condom plus an approved method of highly effective contraception from the 
time of informed consent until 90 days after the last dose of study drug. 
The following methods are acceptable: 
•
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inhibition of ovulation:  
−
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−
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−
transdermal 
•
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−
oral 
−
injectable 
−
implantable intrauterine device
−
intrauterine hormone-releasing system
•
Surgical sterilization (vasectomy or bilateral tubal occlusion)
Female subjects who are not of child-bearing potential do not need to use any methods of 
contraception. A woman is considered of childbearing potential, unless they are at least 2 years 
post-menopausal or permanently sterile. Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy. 
Female subjects who are sexually active and are of child-bearing potential must use, with their 
partner, an approved method of highly effective contraception from the time of informed 
consent until 90 days following the last dose of study drug. 
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Zogenix International Limited
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ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 53 of 194  
The following methods are acceptable: 
•
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation and a barrier method (ie, condom for male partner): 
−
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−
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−
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Surgical sterilization (vasectomy or bilateral tubal occlusion)
Alternatively, true abstinence is acceptable when it is in line with the subject’s preferred and 
usual lifestyle. If a subject is usually not sexually active but becomes active, they, with their 
partner, they must comply with the contraceptive requirements detailed above.
4.3.1
Sperm and Egg Donation 
Male subjects should not donate sperm and female subjects should refrain from egg donation 
for the duration of the study and for at least 90 days after the last day of study medication 
administration.
4.3.2
Pregnancy
Subjects will be instructed that if they/their partner become pregnant during the study this 
should be reported to the investigator. The investigator should also be notified of pregnancy 
occurring during the study but confirmed after completion of the study. In the event that a 
subject/subject’s partner is subsequently found to be pregnant after the subject is included in 
the study, then consent will be sought from the partner and, if granted, any pregnancy will be 
followed and the status of mother and/or child will be reported to the Sponsor after delivery. 
Any subject reporting a pregnancy during the study will be withdrawn from the study and 
should complete the taper schedule. 
4.4
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT
While subjects are encouraged to complete all study evaluations, subjects may voluntarily 
withdraw from the study for any reason at any time. They may be considered withdrawn if they 
fail to return for visits, or become lost to follow-up for any other reason.  
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 54 of 194  
If premature withdrawal occurs for any reason, the investigator must make a genuine effort to 
determine the primary reason for a subject’s premature withdrawal from the study and record 
this information on the CRF. All subjects who withdraw from the study with an ongoing AE 
must be followed until the event is resolved or deemed stable. If a subject withdraws 
prematurely after dosing, all data to be collected prior to discharge from the clinical site should 
be collected at the time of premature discontinuation or at the scheduled discharge.  
For subjects who are lost to follow-up (ie, those subjects whose status is unclear because they 
failed to appear for study visits without stating an intention to withdraw), the investigator 
should show "due diligence" by documenting in the source documents the steps taken to 
contact the subject (eg, dates of telephone calls, registered letters). 
Subjects must be discontinued from the study for the following reasons, if deemed appropriate 
by the Sponsor or investigator:  
1. Development of signs or symptoms indicative of cardiac valvulopathy or regurgitation 
(mitral, aortic, tricuspid, pulmonary valves), or pulmonary hypertension for which 
IDSMC, in consultation with the IPCAB, the central cardiac reader, and the investigator 
believe the benefit of continued participation does not outweigh the risk. 
2. Subject is found to have entered the clinical investigation in violation of the protocol. 
3. Subject requires or starts using the use of an unacceptable or contraindicated 
concomitant medication. 
4. Subject’s condition changes after entering the clinical investigation so that the subject no 
longer meets the inclusion criteria or develops any of the exclusion criteria. 
5. Subject is noncompliant with procedures set forth in the protocol in an ongoing or 
repeated manner. 
6. Subject experiences an AE that warrants withdrawal from the clinical investigation. 
7. Clinically significant worsening of seizures, judged by investigator or subject/caregiver
such that treatment outside of the protocol and other than ZX008 is assumed to be in the 
subject’s best interest. Frequent or increased use of rescue medication may be considered 
indicative of worsening. 
8. An “actual suicide attempt” as classified by the C-SSRS. 
9. It is the investigator’s opinion that it is not in the subject’s best interest to continue in the 
study. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 55 of 194  
10. Subject is found to be pregnant while on study.  
Discontinuation decisions will be made at each participating site by the site investigator, except 
that discontinuations due to development of cardiovascular or cardiopulmonary complications 
are to be made by the IDMSC with input from the IPCAB and the investigator.  
If feasible, the process of discontinuation should be discussed with the Medical Monitor. The 
decisions regarding the discontinuation of the investigational therapy, whether the study 
medication should be stopped immediately or tapered should be discussed with the Medical 
Monitor, but final decisions about the process will remain at the discretion of the site principal 
investigator.  
Subjects may withdraw their consent to participate in the study at any time without having to 
justify the reason for doing so. The decision to withdraw consent and discontinue participation 
in the study will not prejudice the subject’s future medical treatment in any way. Subjects must 
be discontinued from receiving ZX008 and/or participating in any further study procedures 
under the following circumstances: 
•
The subject or the subject’s legally authorized representative wishes to discontinue 
participation in the study 
•
The investigator advises that the subject’s safety or well-being could be compromised 
by further participation in the study 
•
The Sponsor requests that a subject discontinues participation in the study (eg, due to 
suspicion of fraud, multiple enrollments in clinical studies, lack of compliance, etc)
The IDSMC may request that the study be terminated after review of the safety information at
any time during the study. The IDSMC will review the data for the development of heart valve 
disease and pulmonary hypertension as they occur on a case-by-case basis and at regular 
meetings.  
In the event that the study is terminated prematurely then the procedure for termination should 
be followed as described in Section 3.6. Concern for the interests of the subject will always
prevail over the interests of the study. 
The reason for, and date of discontinuation from participation in the study must be recorded in 
detail in the CRF and in the subject’s medical records (eg, AEs, lack of compliance, lost to 
follow-up, etc). If possible, the subject/subject’s legal representative should confirm his 
decision in writing. 
The investigator will attempt to complete all procedures usually required at the end of the study 
at the time when the subject’s participation in the study is discontinued or as close as possible 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 56 of 194  
to that time. Specific procedures required are described in Section 6.1.5 and Section 6.2. As far 
as possible, a complete final examination must be performed on all subjects who do not 
complete the study according to the study protocol.  
Data collected until the time a subject discontinues participation in the study will be handled in 
the same manner as data for subjects completing the study. Where possible, further information 
will be collected if any AEs are experienced by a subject after discontinuing participation in the 
study. 
4.5
TERMINATION OF THE CLINICAL STUDY
If the investigator, the Sponsor, the Medical Monitor, or the IDSMC becomes aware of 
conditions or events that suggest a possible hazard to subjects if the clinical study continues, 
then the clinical study may be terminated. The clinical study may be terminated at the 
Sponsor’s discretion at any time also in the absence of such a finding. 
Conditions that may warrant termination of the clinical study include, but are not limited to: 
•
The discovery of an unexpected, relevant, or unacceptable risk to the subjects enrolled 
in the clinical study
•
Failure to enroll subjects at the required rate
•
A decision of the Sponsor to suspend or discontinue development of ZX008  
4.6
REPLACEMENT OF SUBJECTS
Enrolled subjects will not be replaced. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 57 of 194  
5.
INVESTIGATIONAL MEDICINAL PRODUCT INFORMATION
ZX008 will be administered in the current study. A brief description of the ZX008 product is 
provided below (Table 4).
Table 4. 
Investigational Medicinal Product – ZX008
Study Product
Substance Code
ZX008
Active Substance (INN)
Fenfluramine Hydrochloride
Trade Name
Not applicable
Formulation (including dosage form and strength)
Solution 2.5 mg/mL
Route/Mode of Administration 
Oral
Manufacturer
PCI Pharma Services on behalf of Zogenix 
International Limited
5.1
IDENTITY OF INVESTIGATIONAL MEDICINAL PRODUCT
ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 
and provided in a concentration of 2.5 mg/mL. The excipients selected have been approved for 
use in the formulations of currently marketed drug products and are considered to be safe. The 
solution formulation will be suitably flavored, and will contain preservatives and a thickening 
agent. The product is sugar free and is intended to be compatible with a ketogenic diet (KD). 
The formulation will be provided in bottles with tamper-evident, child-resistant caps. 
Doses to be studied include 0.2 mg/kg/day, 0.4 mg/kg/day, 0.6 mg/kg/day, and 0.8 mg/kg/day 
divided into two daily doses, up to a maximum of 30 mg/day. If the parent/caregiver is unable 
to administer the full dose due to spillage (eg, dose was spilled during measuring, subject spit 
dose out during administration), he/she should attempt to give the full dose noting the extra 
amount used to fulfil the dose. Care must be taken not to overdose. If the amount spilled is 
not known, the parent/caregiver should not give additional medication to avoid potential 
overdose. 
5.1.1
Labeling and Packaging 
The ZX008 product will be packaged and labeled according to current ICH, Good 
Manufacturing Practices (GMP), and GCP guidelines, and national legal requirements. 
Dosing directions for the product can be found in the IMP handling instructions for the study 
subjects and for the investigator. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 58 of 194  
5.2
DESCRIPTION OF REFERENCE TREATMENT, COMPARATOR, 
AND/OR PLACEBO
No comparators, reference treatments, or placebo will be used in this study. 
5.3
IMP ACCOUNTABILITY
The investigator or delegate will confirm receipt of all shipments of the IMP in writing using 
the receipt form(s) provided by the Sponsor or vendor. 
Assignment of ZX008 bottles to the subject will be handled through an interactive voice 
response (IVR) or Interactive Web Response (IWR) platform. The investigator or delegate will 
be required to register the subject through IVR/IWR and all study medication will be assigned 
to the subject through the IVR/IWR. The IVR/IWR will also maintain a log of all received and 
dispensed medication. 
All supplies must be accounted for throughout the study using the drug accountability form 
provided by the Sponsor before the start of the study. At the end of the study, the dated and 
signed (by the investigator or delegate, eg, pharmacist) original drug accountability form must 
be retained at the study site as verification of final drug accountability. 
Records for the delivery of the IMP to the study site, the inventory at the study site, the use by 
each subject (use by subject will be documented in the subject diary), and the destruction or 
return of the IMP to the Sponsor must be maintained by the investigator (or delegate). The 
records will include dates, quantities, batch numbers, and unique code numbers assigned to the 
IMP and to the subjects. The investigator must maintain records documenting that subjects 
were provided with the doses of the IMP specified in this study protocol. Furthermore, the 
investigator must reconcile all IMPs received from the Sponsor. The investigator must provide 
reasons for any discrepancies in drug accountability. Forms will be provided by the Sponsor to
ensure standardized and complete drug accountability.
5.4
TREATMENT ADMINISTRATION
5.4.1
OLE Treatment Period
The investigator (or delegate) will dispense IMP only to subjects included in this study 
following the procedures set out in this study protocol. 
Study medication will be administered as equal doses BID in the morning and in the evening, 
approximately 12 hours apart, with food. Each dose should be separated by a minimum of 
8 hours and a maximum of 12 hours. A missed dose of study medication may be taken later up 
to 8 hours before the next scheduled dose; otherwise, the missed dose should not be given. 
Administration of the initial IMP will be based on the 0.2 mg/kg/day (maximum 30 mg/day or 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 59 of 194  
20 mg/day for subjects taking concomitant STP) dose and subject’s weight at Visit 1 (Study 
Day 1). At Visits 5 to 15 (Months 3 to 33), if the subject’s weight has changed ± 25% of the 
weight from the previous dose calculation, the IMP dose will be recalculated. Subjects will be 
dosed using the oral dosing syringe provided. 
During the OLE Treatment Period, all subjects will be treated initially with 0.2 mg/kg/day for 
1 month to assess effectiveness of this dose in all study subjects. After 1 month at a dose of 
ZX008 0.2 mg/kg/day, the investigator may adjust the dose of each subject based on 
effectiveness and tolerability.  
Dose changes should be made in increments of 0.2 mg/kg/day, as follows: 
•
Subjects who are not receiving concomitant STP: may increase to a maximum of 
0.8 mg/kg/day but not to exceed total dose of 30 mg/day 
•
Subjects who are receiving concomitant STP: the first dose change will be to 
0.4 mg/kg/day and the final dose change will be to 0.5 mg/kg/day, but not to exceed 
20 mg/day  
Dose increases should not occur earlier than every 14 days at each dose level. Dose increases 
may only occur after a review of the diary and reported AEs, and if, in the investigator’s 
opinion, seizure frequency, severity, and/or duration indicates a change in medication regimen 
is warranted. Dose decreases for tolerability can occur at the investigator’s discretion, in dose 
amounts and frequency appropriate for the situation. ZX008 dose adjustments outside of these 
parameters should be discussed with the Medical Monitor prior to initiation.  
If after approximately the midway point of the first 30 days on ZX008 0.2 mg/kg/day there is a 
clinically meaningful worsening in seizure type, frequency, and/or duration compared with the 
recent treatment in the core study, the investigator, in consultation with the Medical Monitor, 
may increase the dose to 0.4 mg/kg/day (maximum 30 mg/day for subjects who are not 
receiving concomitant STP; 20 mg/day for subjects who are receiving concomitant STP). A 
clinically meaningful worsening would be an increase in frequency, severity or duration of 
existing seizures, or emergence of a new seizure type. The description of clinical worsening 
must be documented in the source notes and case report form (CRF). Further increase to 
0.8 mg/kg/day (maximum 30 mg/day) for subjects who are not receiving concomitant STP, and 
to 0.5 mg/kg/day (maximum: 20 mg/day) for subjects who are receiving concomitant STP 
could also be undertaken for the same conditions after a minimum of 4 days on 0.4 mg/kg/day, 
if the condition has not stabilized on the 0.4 mg/kg/day dose; however, the maximal dose 
determined for subjects on concomitant STP must not be exceeded. Dosing outside of the 
specified range (ie, 0.2 to 0.8 mg/kg/day or 0.5 mg/kg/day for subjects taking concomitant 
STP) may be considered after consultation between the investigator and Medical Monitor. 
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5.4.2
Taper Period
All subjects (those who complete the OLE Treatment Period or those who discontinue from the 
study early and are not transitioning to another ZX008 extension study or treatment with
commercial drug) will be tapered off of study medication.  
5.4.2.1
Taper Period for Subjects not Receiving Concomitant STP
The tapering scheme is a 2-step process for subjects who are not receiving concomitant STP, 
including subjects from core studies ZX008-1501 and ZX008-1502, and from study ZX008-
1504 Cohort 1/Regimens 1&2. This is described in Table 5.  
Study medication will be administered as equal doses BID in the morning and in the evening, 
approximately 12 hours apart, with food. Each dose should be separated by a minimum of 
8 hours and a maximum of 12 hours. A missed dose of study medication may be taken later up 
to 8 hours before the next scheduled dose; otherwise, the missed dose should not be given. IMP 
will be administered using the oral dosing syringe provided.  
Table 5.  
Taper Algorithm for Subjects from Core Studies ZX008-1501, ZX008-1502, 
and ZX008-1504 Cohort 1/Regimens 1&2Not Receiving Concomitant STP 
Current Dose
Taper Step 1 
Days 1-4 after study completion or 
early termination
Taper Step 2
Days 5-8 after study completion or 
early termination
ZX008 0.2 mg/kg/day
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ZX008 0.4 mg/kg/day
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ZX008 0.2 mg/kg/day
ZX008 0.8 mg/kg/day
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day
Note:  maximum daily dose of ZX008 is 30 mg.
5.4.2.2
Taper Period for Subjects from Core Study ZX008-1504 Cohort 1 Regimen 3 and 
Cohort 2 Receiving Concomitant STP
The tapering scheme is a 3-step process for subjects receiving concomitant STP, including 
subjects from core study ZX008-1504 Cohort 1 Regimen 3 and Cohort 2, and is described in 
Table 6.  
Study medication will be administered as equal doses BID in the morning and in the evening, 
approximately 12 hours apart, with food. Each dose should be separated by a minimum of 
8 hours and a maximum of 12 hours. A missed dose of study medication may be taken later up 
to 8 hours before the next scheduled dose; otherwise, the missed dose should not be given. IMP 
will be administered using the oral dosing syringe provided. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 61 of 194  
Table 6.  
Taper Algorithm for Subjects Receiving Concomitant STP
Current Dose
Taper Step 1 
Days 1-4 after study 
completion or early 
termination
Taper Step 2
Days 5-8 after study 
completion or early 
termination
Taper Step 3
Days 9-14 after study 
completion or early 
termination
ZX008 0.2 mg/kg/day
Not applicable
Not applicable
Not applicable
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day
Not applicable
Not applicable
ZX008 0.5 mg/kg/day
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day
Not applicable
Note:  maximum daily dose of ZX008 is 20 mg.
5.5
BLINDING
This is an open-label study.  
5.6
PRIOR AND CONCOMITANT MEDICATION
All prior and concomitant medication will be collected in the CRF.
All medications taken by a subject after the first administration of IMP are regarded as 
concomitant medication and must be documented in the CRF, including over-the-counter 
medication, herbal and vitamin/supplement preparations.  
Subjects are required to take at least one concomitant AED throughout the study. During at 
least the first 6 months of the study, subjects will continue to receive their existing AEDs at the 
same dose as prior to initiating this study. However, once the subject has been stable on a 
ZX008 dose for at least 6 months with good seizure control, investigators will be allowed as 
per typical clinical practice to alter one or more other concomitant AED doses as deemed 
clinically appropriate. Concomitant AEDs may be withdrawn completely but all subjects must 
remain on a minimum of 1 concomitant AED plus ZX008. No new concomitant AEDs may be 
introduced while in this study. All medication dose changes must be documented with a clinical 
explanation and justification. Concomitant AED dose adjustments outside of these parameters 
should be discussed with the Medical Monitor prior to initiation.  
Non-study medications and therapies that are considered necessary for the subject’s welfare 
and will not interfere with the response to the study medication may be given at the discretion 
of the investigator, informing the Medical Monitor as soon as possible. 
It should be noted for any subject receiving hypoglycemic agents, the investigator should 
consider diabetic medication changes in the setting of weight loss and hypoglycemia.  
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 62 of 194  
5.6.1
Vagal Nerve Stimulation
Subjects receiving treatment with vagal nerve stimulation (VNS) may be included as long as 
the VNS has been in place for at least 6 months prior to entry into the core study, or for de novo 
subjects prior to first dose in the OLE, and stimulation parameters have been kept constant for 
4 weeks prior to core study Visit 1. During at least the first 6 months of the study, VNS 
stimulation parameters will be kept constant. However, once the subject has been stable on a 
ZX008 dose for at least 6 months with good seizure control, investigators will be allowed as 
per typical clinical practice to alter VNS stimulation parameters as deemed clinically 
appropriate. All VNS stimulation parameter changes must be documented with a clinical 
explanation and justification. VNS stimulation parameter adjustments outside of these 
boundaries should be discussed with the Medical Monitor prior to initiation. The subject’s use 
of VNS will be recorded in the CRF. 
5.6.2
Ketogenic Diet
Adherence to the KD, or a modified version of KD, is permitted during the study if the dietary 
habits were initiated more than 4 weeks prior to entry into the core study, or for de novo 
subjects 4 weeks prior to first dose in the OLE. During at least the first 6 months of the study, 
the KD will be adhered to. However, once the subject has been stable on a ZX008 dose for at 
least 6 months with good seizure control, investigators will be allowed as per typical clinical 
practice to alter the KD as deemed clinically appropriate. All KD changes must be documented 
with a clinical explanation and justification. KD adjustments outside of these parameters should 
be discussed with the Medical Monitor prior to initiation. The subject’s use of KD will be 
recorded in the CRF.
5.6.3
Rescue Medication for Seizures
The subject's usual or prescribed regimen and frequency of rescue therapy for seizures should 
be entered into the prior and/or concomitant medication sections of the CRF.   
Use of rescue medication is permitted during the study and should be recorded on the CRF
(day, medication[s], dose[s]) and in the diary (day, timeframe associated with seizure episodes). 
Repeated administrations within the same episode should be recorded separately.
5.6.4
Prohibited Concomitant Medication and Food 
Alcohol in all forms (wine, beer, liquors) and amounts is prohibited during the study. The 
following concomitant medications/foods are prohibited during the clinical trial:
•
AEDs: Phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, retigabine/ezogabine 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
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• STP: Subjects who are not receiving concomitant STP, including de novo subjects and 
those from core studies ZX008-1501, ZX008-1502, and ZX008-1504 Cohort 1/Dose 
Regimens 1&2 only, must be off STP for a minimum of 21 days prior to the core study 
or OLE Screening visit. 
•
Felbamate is prohibited as a concomitant medication unless the subject has been on 
felbamate for at least 18 months prior to the core study or OLE Screening visit, has 
stable liver function and hematology laboratory tests, and the dose is expected to remain 
constant throughout the study. 
•
Drugs that interact with central serotonin: imipramine, monoamine oxidase inhibitors, 
selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, 
vortioxetine 
•
Drugs that increase cardiovascular risk: atomoxetine
•
Drugs intended to facilitate weight loss
•
Other: any form of marijuana, THC and derivatives (including Epidiolex®) 
•
Drugs/foods that potentially interact with ZX008 via the CYP2D6, CYP3A4, and/or 
CYP2B6 pathways: A list of medications/foods that are to be avoided as ongoing 
medications or for chronic use if initiated during the study from the time of signing the 
informed consent form (ICF) until the end-of-study visit (or early termination) is 
provided in Appendix 1. If medical necessity requires short-term use of one or more of 
these medications during the course of the study, please contact the Medical Monitor for 
approval. 
5.7
TREATMENT COMPLIANCE
Each subject or parent/caregiver will record the dose, dosing frequency and IMP consumption 
in the subject’s diary. Subjects will bring their used, partially used, and unused IMP to every 
study visit. Treatment compliance will be monitored by measuring the volume of IMP in these 
bottles and comparing to the dispensation log and diary records.  
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 64 of 194  
6.
VISIT SCHEDULE
Study procedures will be conducted according to the Schedule of Assessments in Table 1 and 
Table 2. Time windows for all assessments are detailed in Table 7. For details on alternative 
procedures and allowances regarding study conduct during COVD-19 refer to Appendix 11. 
Table 7. 
Time Windows for Assessments
Visit / Procedure
Time window (relative to scheduled visit / procedure)
Visit 1 (Clinic; Study Day 1) 
Not applicable (this is the same visit as Visit 13 from the 
core study)
Visits 2 (Clinic/Phone; Study Day 15)
± 3 days
Visits 3-15 (Clinic: Study Days 30, 60, 90, 180, 
270, 365, 455, 545, 635, 725, 815, 905, 995)
± 4 days
Visit 16 (Clinic; Study Day 1085)
± 4 days
Visit 17 (Clinic; Study Day 1099; post dosing)
± 4 days
Visit 18, 19 (ECHO clinic; 3 and 6 months after 
last dose)
+ 30 days
Blood collection for AED concentration
Prior to morning dose of AED medication
AED=antiepileptic drug (s); ECHO=echocardiogram
6.1
OLE TREATMENT PERIOD
Review of inclusion and exclusion criteria and written informed parental or guardian consent 
and assent of minors (if the subject is capable of providing assent) for this study, including 
collection of HADs, EQ-5D-5L, and PedQL Family Impact Module ratings of parent/caregiver 
symptoms and quality of life, must be obtained before a subject can start any of the Visit 1
procedures.  
The procedure(s) for obtaining written informed consent and assent of minor (if the subject is 
capable of providing assent) are described in Section 11.2. For subjects from the core studies it 
is assumed that consent for this study will have been obtained prior to completion of 
procedures at
•
ZX008-1501 and ZX008-1502 Visit 12/End of Study 
•
The last visit of the transition period of ZX008-1504 Cohort 1 
•
ZX008-1504 Cohort 2 Visit 12/End of Study 
For de novo subjects, consent for this study must be obtained prior to any study-related 
procedures. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 65 of 194  
Only eligible subjects as specified by the inclusion and exclusion criteria who have 
successfully completed the core study, or who are >18 to ≤35 years of age at the time of 
screening and who meet all other eligibility criteria, will be enrolled into study ZX008-1503. 
6.1.1
Screening Visit for de novo Subjects
For de novo subjects a screening period up to 28 days is required to determine eligibility prior 
to dosing. Clinical laboratory results and all ECHO/ECG results must be available and meet 
eligibility criteria prior to receiving the first dose of study medication at Visit 1. The following 
procedures will be performed during this screening period for all de novo subjects before the 
first dose of study medication: 
•
Obtain written informed consent for the study 
•
Obtain written informed consent from parent/caregiver to collect PedsQL Family 
Impact, HADS, and EQ-5D-5L ratings of parent/caregiver symptoms and quality of life 
•
Review inclusion and exclusion criteria 
•
Record demographic information 
•
Record medical, neurological, and epilepsy history 
•
Record current epilepsy status (number/type/duration seizures per month) 
•
Collect past 3 months (or available duration) of parent/caregiver seizure diary data if 
available (screen shots of cell phones are acceptable, as are photocopies of paper diaries 
or print outs) and place in source file 
•
Record prior medications 
•
Complete physical examination, including height, weight, and calculation of BMI 
•
Complete neurological examination 
•
12-lead electrocardiogram
•
Doppler ECHO (this must be obtained and results provided prior to starting ZX008) 
•
Vital signs
•
Urine pregnancy test for females of child-bearing potential 
•
Laboratory evaluation (serum chemistry, hematology, urinalysis, etc) 
•
Urine THC panel
•
Whole blood CBD 
•
Obtain blood sample for epilepsy genotype panel 
•
C-SSRS Baseline/Screening Assessment (Appendix 2) 
•
CGI-I (assessed by parent/caregiver)
•
CGI-I (assessed by investigator)  
•
BRIEF (Appendix 3) 
•
QOLCE (Appendix 4) 
•
Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
•
Affective symptoms of parent/caregiver using the HADS scale (Appendix 8) 
•
Instruct parent/caregiver on use of diary 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 66 of 194  
•
Dispense diary (after above procedures have been concluded) 
•
Record AEs
Review inclusion/exclusion criteria, including echocardiogram, ECG, clinical laboratory 
results, and approval from the Epilepsy Study Consortium.  Only eligible subjects as specified 
by the inclusion and exclusion criteria with an independently confirmed diagnosis of DS by the 
Epilepsy Study Consortium, and approved by the sponsor, will be enrolled into the study and 
receive study medication. 
After enrollment into the study, each subject will be issued a “Subject Card” containing 
information about the subject’s participation in the study. The subject or parent/caregiver will 
be advised to retain this card on his person for the entire duration of the study so that the 
investigator or the sponsor can be contacted in case of emergency. 
In certain circumstances the sponsor may allow subjects who did not meet all 
inclusion/exclusion criteria during the Screening period to have the screening period extended, 
or to be re-screened for eligibility. In all cases the investigator should consult with the Medical 
Monitor. Decisions whether to permit rescreening resides solely with the sponsor.  
The decision whether to permit extended screening or rescreening can be influenced by many 
factors individual to that subject case. Some general principles apply: 
1. Subjects who are found to be on a prohibited medication at the screening visit may be 
weaned off of that medication provided: 
a.
Decisions to withdraw a disallowed concomitant medication must be made with the 
agreement of the prescribing physician 
b. If the medication has antiepileptic properties, a wash out of at least 5 half-lives must 
be completed before collection of baseline seizure data. 
If a decision has been made to wean off of a medication without antiepileptic properties and the 
wash-out period (at least 5 half-lives) is expected to be shorter than 5 weeks, then the subject 
may remain in screening and chart seizures using the seizure diary.
6.1.2
Clinic Visit 1 (Study Day 1; Transition from Core Study) 
6.1.2.1
Clinic Visit 1 for Subjects from Core Studies ZX008-1501 or ZX008-1502 
The following procedures will be performed during Visit 1 (Visit 13 of ZX008-1501 and 
ZX008-1502): 
•
Record demographic information
•
Vital signs
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 67 of 194  
•
Record prior and concomitant medications (use core study Visit 13 information)  
•
Urine pregnancy test for females of child-bearing potential 
•
Tanner Staging for subjects >7 to ≤18 years of age (Appendix 5) 
•
Instruct parent/caregiver on use of diary 
•
Record ongoing AEs as medical history (use core study Visit 13 information) 
•
Record ongoing adverse events of special interest (AESIs) as medical history (use core 
study Visit 13 information) 
•
Dispense diary (after above procedures have been concluded) 
•
Dispense study medication
Data collected from Visit 12/End of Study for the core study may be used for the following 
procedures unless otherwise indicated: 
•
Record medical, neurological, and epilepsy history 
•
Complete physical examination, including height, weight, and calculation of body mass 
index (BMI) 
•
Complete neurological examination (use data collected at core study Visit 12, unless 
there was a significant change in subject status warranting a new complete examination)
•
12-lead ECG 
•
Doppler ECHO  
•
Laboratory evaluation (serum chemistry, hematology, urinalysis, etc) (use core study 
Visit 12 information, unless investigator determines new laboratory evaluation is 
warranted due to change in subject status) 
•
Urine THC panel  
•
Whole blood CBD  
•
Tanner Staging for subjects > 7 to ≤18 years of age (Appendix 5) 
•
C-SSRS Children’s Since Last Visit Assessment (Appendix 2)  
•
CGI-I (assessed by parent/caregiver)
•
CGI-I (assessed by investigator)  
•
BRIEF (Appendix 3) 
•
QOLCE (Appendix 4) 
•
PedsQL (Appendix 6) (only for subjects from the core studies) 
•
Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
Affective symptoms of parent/caregiver using the HADS scale (Appendix 8). After enrollment 
into the study, each subject will be issued a new “Subject Card” containing information about 
the subject’s participation in the study. The subject or parent/caregiver will be advised to retain 
this card on his person for the entire duration of the study so that the investigator or the Sponsor 
can be contacted in case of emergency.
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 68 of 194  
6.1.2.2
Clinic Visit 1 for Subjects from Core Study ZX008-1504 
The following procedures will be performed during Visit 1(the last transition period of 
ZX008 1504 Cohort 1 and Visit 12 of ZX008-1504 Cohort 2): 
•
Record demographic information 
•
Vital signs
•
Urine pregnancy test for females of child-bearing potential 
Data collected from the last transition period of Cohort 1 and Visit 12/End of Study for 
Cohort 2 procedures may be used unless otherwise indicated: 
•
Record medical, neurological, and epilepsy history 
•
Record prior and concomitant medications  
•
Complete physical examination, including height, weight, and calculation of BMI  
•
Complete neurological examination (use core study Visit 12 information for subjects 
who participated in Cohort 2, and use core study information from the last transition 
period visit for subjects who participated in Cohort 1, unless there was a significant 
change in subject status warranting a new complete examination) 
•
12-lead ECG 
•
Doppler ECHO 
•
Laboratory evaluation (serum chemistry, hematology, urinalysis, etc) (use data collected 
at core study Visit 12 for subjects who participated in Cohort 2, and use core study 
information from the last transition period visit for subjects who participated in 
Cohort 1, unless investigator determines new laboratory evaluation is warranted due to 
change in subject status)
•
Urine THC panel 
•
Whole blood CBD  
•
Tanner Staging for subjects > 7 to ≤18 years of age (Appendix 5) 
•
C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
•
CGI-I (assessed by parent/caregiver) 
•
CGI-I (assessed by investigator)  
•
BRIEF (Appendix 3) 
•
QOLCE (Appendix 4) 
•
PedsQL (Appendix 6) (only for subjects from the core studies) 
•
Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
•
Healthcare utilization questions 
•
Karolinska Sleepiness Scale (Appendix 10) 
•
Sleep quality and meal time behavior questions  
•
Instruct parent/caregiver on use of diary 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 69 of 194  
•
Record ongoing AEs as medical history 
•
Record ongoing AESIs as medical history 
•
Dispense diary (after above procedures have been concluded) 
•
Dispense study medication 
After enrollment into the study, each subject will be issued a new “Subject Card” containing 
information about the subject’s participation in the study. The subject or parent/caregiver will 
be advised to retain this card on his person for the entire duration of the study so that the 
investigator or the Sponsor can be contacted in case of emergency.
6.1.3
Clinic/Phone Visit 2 (Study Day 15) 
Visit 2 is to be performed in the clinic. At the discretion of the investigator, this visit may be
performed via phone. 
If Visit 2 is performed in the clinic, subjects will report to the clinic in the morning of that day. 
Subjects should not take their morning dose(s) of AED medication prior to reporting to the 
clinic. The following procedures will be performed:
•
Review current seizure activity (number/type/duration) from diary since previous visit  
•
Record concomitant medications since previous visit 
•
Abbreviated physical examination, including height and weight, and calculation of BMI 
•
Abbreviated neurological examination
•
Vital signs
•
Laboratory evaluation (serum chemistry, hematology, urinalysis, etc) (only if 
investigator determines new laboratory evaluation is warranted due to change in subject 
status since Visit 1)
•
Collect plasma sample for AED PK evaluation prior to the morning dose of study 
medication(s)
•
Collect and review diary with parent/caregiver
•
Dispense diary
•
Record AEs
•
Record AESI
•
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver
•
Dispense study medication 
If the visit is performed as a phone visit, site personnel will contact the subject on Study 
Day 15 and record/review the following: 
•
Concomitant medications
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 70 of 194  
•
AEs
•
AESI
•
Study medication use 
•
Diary entries
6.1.4
Clinic Visits 3-15 (Months, 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33)  
Subjects will report to the clinic in the morning of Clinic Visits 3 through 15. Subjects should 
not take their morning dose(s) of AED prior to reporting to the clinic. The following procedures 
will be performed: 
•
Review current seizure activity (number/type/duration) from diary since previous visit  
•
Record concomitant medications
•
Abbreviated physical examination, including height and weight, and calculation of BMI 
•
Abbreviated neurological examination 
•
Obtain vital signs
•
12-lead ECG
•
Doppler ECHO (at Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33) 
•
Urine pregnancy test for females of child-bearing potential 
•
Laboratory evaluation (serum chemistry and hematology, and urinalysis)
•
Urine THC panel
•
Whole blood CBD 
•
Collect plasma sample for AED PK evaluation prior to the morning dose of study 
medication(s)
•
Tanner Staging for subjects > 7 to ≤18 years of age (Visits 6, 15, and 27 only) 
(Appendix 5) 
•
Collect and review diary with parent/caregiver
•
Dispense diary
•
C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
•
CGI-I (assessed by parent/caregiver)
•
CGI-I (assessed by investigator) 
•
BRIEF (Appendix 3) 
•
QOLCE (Appendix 4) 
•
PedsQL (Appendix 6) (only for subjects from the core studies) 
•
Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
•
Affective symptoms of parent/caregiver using the HADS scale (Appendix 8) (for 
subjects from core studies ZX008-1501 and ZX008-1502 only) 
•
Healthcare utilization questions (for subjects from core study ZX008-1504 only)
•
Karolinska Sleepiness Scale (Appendix 10) (for subjects from core study ZX008-1504 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 71 of 194  
•
Sleep quality and mealtime behavior questions (for subjects from core study ZX008-
1504 only) 
•
Study medication palatability assessment (Visits 3 and 4 only) 
•
Record AEs
•
Record AESI
•
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver
•
Dispense study medication 
6.1.5
Clinic Visit 16 (Month 36): End of Study/Early Termination 
The End-of-Study participation for an individual subject occurs after he/she has received IMP
for 3 years in the OLE Treatment Period or if the subject is transitioning to receive ZX008 in a 
separate extension protocol when available or until ZX008 is approved in a subject’s country of 
residence and listed on a patient’s health plan formulary, whichever occurs first.. The End-of-
Study visit may also occur if the subject withdraws participation from the study or the Sponsor 
terminates the study.  
Subjects will visit the clinic for the End-of-Study visit if one the following events occur: 
1. The subject withdraws or is withdrawn from participation in the study. 
2. The Sponsor terminates the study. 
3. The subject completes all study related visits and procedures. 
4. The subject is being transitioned to another extension study or transitioning to 
commercially available drug. 
The following procedures will be performed:
•
Review current seizure activity (number/type/duration) from diary since previous visit  
•
Record concomitant medications
•
Complete physical examination, including height and weight, and calculation of BMI 
•
Complete neurological examination 
•
Obtain vital signs
•
12-lead ECG
•
Doppler ECHO (must be performed any time between Study Day 1064 and Study 
Day 1085; if subject terminates early from the study, the ECHO should be scheduled as 
soon as practical). If the Month 3, 6, 9, 12,1 5, 18, 21, 24, 27, 30, or 33 ECHO was 
completed ≤ 30 days prior to early termination, the Visit 12 ECHO will not be 
performed provided the parent/guardian agrees to bring the subject to the clinic for the 
cardiac follow-up visit (Table 8).
•
Urine pregnancy test for females of child-bearing potential 
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•
Laboratory evaluation (serum chemistry and hematology, and urinalysis) 
•
Urine THC panel
•
Whole blood CBD 
•
Collect plasma sample for AED PK evaluation prior to the morning dose of study 
medication(s)
•
Tanner Staging for subjects > 7 to ≤18 years of age (Appendix 5) 
•
Collect and review diary with parent/caregiver
•
C-SSRS Children’s Since Last Visit Assessment (Appendix 2) 
•
CGI-I (assessed by parent/caregiver)
•
CGI-I (assessed by investigator) 
•
BRIEF (Appendix 3) 
•
QOLCE (Appendix 4) 
•
PedsQL (Appendix 6) (only for subjects from the core studies) 
•
Parent/Caregiver QoL using the EQ-5D-5L scale (Appendix 7) 
•
Affective symptoms of parent/caregiver using the HADS scale (Appendix 8) (for 
subjects from core studies ZX008-1501 and ZX008-1502 only) 
•
Healthcare utilization questions (for subjects from core study ZX008-1504 only)
•
Karolinska Sleepiness Scale (Appendix 10) (for subjects from core study ZX008-1504 
only) 
•
Sleep quality and mealtime behavior questions (for subjects from core study ZX008-
1504 only) 
•
Record AEs
•
Record AESI
•
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver
•
Dispense study medication (not applicable for subjects transitioning to another 
extension protocol or to commercial drug) 
6.2
POST-DOSE VISIT (CLINIC VISIT 17; STUDY DAY 1099) 
If the subject completes the study (or discontinues from the study early), and is not 
transitioning to another extension protocol or switching to commercially available drug, the 
subject will visit the clinic on Study Day 1099 (or 14 days after the day of discontinuation) 
The following procedures will be performed: 
•
Record AEs
•
Record AESI
•
Record concomitant medications
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Zogenix International Limited
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•
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver
6.3
CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 18, 19; 3 AND 6 MONTHS) 
AFTER LAST DOSE OF IMP
If the subject completes the study or discontinues from the study early, the subject will return to 
the clinic for follow-up cardiac testing (ECHO, ECG, and in some cases, physical 
examination). The timing and frequency of exams are in Table 8. As the ECHO and ECG will 
be administered in a separate clinic than the pediatric neurology clinic, an asymptomatic 
subject receiving a second follow-up ECHO and ECG does not require a physical examination. 
Cardiac follow-up visits are not required for subjects who have entered another ZX008 
extension study or have transitioned to commercial drug. 
Subjects with positive findings on ECHO, ECG and/or physical examination should continue to 
be followed until the finding is resolved or stable and unlikely to change.  
If the subject is switching to commercially available drug, (subjects must have an ECHO within 
3-6 months before starting commercial drug) the subject will complete the EOS visit and follow 
the drug administration process outlined for commercial product as advised by the subject’s 
physician. The post dosing and cardiac follow-up visits are not required. 
Table 8. 
Schedule of Post-Treatment Cardiac Follow-up
Duration of Fenfluramine Treatment
Parameter
Less than 
2 weeks 
Cumulative
2 to 4 weeks
> 4 and 
< 13 weeks
> 13 weeks
Have had any cardiac 
sign or symptom 
regardless of the time 
on study druga
ECHO
No
Yes, 
3 months post- 
treatment
Yes, 
3 months post- 
treatment
Yes, 
3 and 6 months post-
treatment
Yes, 
3 and 6 months post-
treatment, and until 
resolved, or stable and 
unlikely to change
ECG
No
Yes, 
3 months post- 
treatment
Yes, 
3 months post- 
treatment
Yes, 
3 and 6 months post-
treatment
Yes,
3 and 6 months post-
treatment and until 
resolved, or stable and 
unlikely to change
Physical 
examination
No
Yes, 
3 months post- 
treatment
Yes, 
3 months post- 
treatment
Yes, 
3 months post- 
treatment only
Yes,
3 and 6 months post-
treatment, and until 
resolved, or stable and 
unlikely to change
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aortic; mild or greater in pulmonary, tricuspid), or sign or symptom indicative of potential pulmonary hypertension as 
adjudicated by the IPCAB.
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6.4
ESTIMATED BLOOD VOLUME COLLECTION
The maximum total blood volume collected during the study for clinical laboratory testing, 
genotyping, and PK will be approximately 240.0 mL, as outlined in Table 9. 
Table 9. 
Estimated Blood Volume Collectiona
OLE Treatment Period (study day)
Assessment/ 
(Study Day)
15
30, 60, 90. 180, 270. 365, 455, 545, 635, 725, 815, 905, 995, 1085
Total 
Clinical chemistry 
--
7.5 mL at each visit
105 mL
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testosterone, GH, prolactin
--
Included
in Chemistry
Hematology 
--
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28 mL
IGF-1 
-- 
3.5 mL at each visit
49 mL
Cannabidiol
--
2 mL at each visit
28 mL
AED plasma sample
1 x 2 mL
1 x 2 mL at each visit
30 mL
Approximate total blood 
volume per subject 
2.0 mL
17.0 mL at each visit
240.0 mL
FSH=follicle stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; LH-luteinizing hormone
aIn concordance with The Seattle Children’s Research Foundation Guidance (Appendix 9), 
blood collection volumes for children weighing up to 15 kg will be:
•
The maximum allowable volume of blood in one draw is 22-30 mL (2.5% of total blood 
volume) 
•
The maximum in a 30-day period is 44-60 mL 
6.5
STUDY CONDUCT DURING COVD-19 
In March 2020, the World Health Organization declared a global pandemic related to an illness 
caused by a novel coronavirus known as COVID-19. Alternative procedures and allowances 
are permitted due to restrictions related to COVID-19, including delays to in-person visits and 
specific assessments, performing remote phone or video visits if in-person visits cannot be 
conducted, and arranging shipments of investigational product directly to subjects. These 
allowances are detailed in Appendix 11. Though every attempt should be made to conduct 
study visits as described in this protocol, any implementation of alternative processes should be 
properly documented, including what was done differently, which assessments or visits were 
missed or performed via phone or video. 
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7.
EFFECTIVENESS, SAFETY, AND PHARMACOKINETIC
ASSESSMENTS 
For an overview of the study variables and measurement times, see Schedule of Assessments 
(Table 1 and Table 2).
Variables used to measure treatment compliance with respect to administration of the IMP are 
described in Section 5.7. 
7.1
EFFECTIVENESS ASSESSMENTS
For all questionnaires and rating scales, the same evaluator (at the clinical site and 
parent/caregiver) will complete the assessments for the duration of the study. Substitutions at 
the clinic with another rater that has established inter-rater reliability is acceptable on an 
infrequent basis. For the in-clinic questionnaires and rating scales completed by the 
parent/caregiver, if the same parent/caregiver cannot complete the questionnaire/rating scale at 
a visit, the questionnaire/rating scale will not be completed. For the diary, the same 
parent/caregiver will complete all entries throughout the study.
7.1.1
Seizure Assessments 
Seizure frequency by type and duration (< 2 minutes, 2-10 minutes, > 10 minutes) will be 
recorded daily by the parent/caregiver in a diary. Seizure types include:
A: 
Hemiclonic (note lateralization – right body, left body, or independent right and left) 
B1: Focal With or Without Clear, Observable Motor Signs 
B2: Focal Without Clear, Observable Motor Signs 
C:  
Secondarily Generalized Tonic Clonic (evolving to bilateral convulsive seizure from 
focal seizure)
D:  Generalized Tonic Clonic Convulsion 
E:
Absence or Atypical Absence
F:  
Myoclonic 
G:  Tonic 
H:  Atonic 
I:  
Clonic 
J: 
Tonic/Atonic (cannot differentiate; also known as ‘drop attack’) 
K:  Infantile Spasms (if under 3 years of age) 
L:  
Epileptic Spasms (if 3 years of age and older) 
O: 
Other
Effectiveness endpoints that will be derived from the diary data include frequency of 
convulsive seizures and of all seizures, and the number/duration of seizure free intervals. 
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Page 76 of 194  
Seizures that evolve into SE will be captured by type and duration (> 10 minutes) as are all
seizures. The diagnosis of SE should be entered as an AE or SAE if a prolonged seizure or 
series of seizures persists for 30 minutes or longer, regardless of administration of rescue 
medication. If this incident involves multiple seizures close in time, the SE definition applies if 
the seizures are close together such that consciousness is not regained between ictal events. 
7.1.2
Clinical Global Impression - Improvement
Both the parent/caregiver and the investigator will rate their global impression of the subject’s
condition throughout the study according to the schedule in Table 1 and Table 2.   
The Clinical Global Impression (CGI) scale measures the change in the subject’s clinical status 
from a specific point in time. The CGI rating scale permits a global evaluation of the subject’s 
improvement over time. The severity of a patient’s condition is rated on a 7-point scale ranging 
from 1 (very much improved) to 7 (very much worse) as follows:  
1=very much improved 
2=much improved 
3=minimally improved
4= no change 
5=minimally worse
6=much worse 
7=very much worse 
The parent/caregiver will be asked to indicate the appropriate response that adequately 
describes how their child’s symptoms have improved or worsened relative to baseline before 
the beginning of the core study (before any study drug was taken). 
The investigator will be asked to indicate the appropriate response that adequately describes 
how the subject’s symptoms have improved or worsened relative to baseline before the 
beginning of the core study (before any study drug was taken). 
7.1.3
Quality of Life in Childhood Epilepsy Scale
The QOLCE (Appendix 4), a low-burden parent/caregiver completed assessment that looks at 
how epilepsy affects day-to-day functioning of their child in various life areas, including 
physical activities, well-being, cognition, social activities, behavior and general health, will be 
conducted according to the schedule in Table 1 and Table 2. The QOLCE has been validated in 
children aged 4 and older, and there are published data on the use of the QOLCE in children 
with epilepsy as young as 2 years of age (Sabaz 2000; Talarska 2007).  
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Confidential
Page 77 of 194  
7.1.4
Pediatric Quality of Life Inventory (PedsQL)
The PedsQL (Appendix 6) is a pediatric modular measure of health-related QoL completed by 
the parent/caregiver on behalf of the subject. It consists of 4 core scales that measure physical, 
emotional, social, and school functioning. The PedsQL will be conducted according to the 
schedule in Table 1 and Table 2. The PedsQL will only be conducted in subjects who enter 
from the core studies (ie, PedQL will not be performed on de novo subjects >18 years of age). 
7.1.5
Parent/Caregiver Quality of Life  
The impact on the quality of life of the parent/caregiver responsible for a patient with DS will 
be assessed according to the schedule in Table 1 and Table 2 using 3 scales: the EQ-5D-5L, the 
HADS, and the PedsQL Family Impact Module. Parents/caregivers who do not give consent to 
collect these ratings scales will not complete them. The same parent/caregiver should complete 
these ratings throughout the study. If that person is not available at the visit, the scales should 
not be completed.  
The EQ-5D-5L (Appendix 7) is a standardized measure of health status used to provide a 
simple, generic assessment for clinical and economic appraisal. It consists of 6 questions and 
can be completed in less than 10 minutes.
The HADS (Appendix 8) is a tool commonly used to determine the levels of anxiety and 
depression that a person is experiencing. It is a 14-item scale that generates ordinal data. Seven 
of the items relate to anxiety and 7 relate to depression.  
The PedsQL Family Impact module (Appendix 6) is designed to measure the impact of 
pediatric chronic health conditions on parents and the family by measuring parent self-reported 
physical, emotional, social, and cognitive functioning, communication, worry, and family daily 
activities relationships. The PedsQL Family Impact module will not be assessed in the 
Netherlands.
The parent/caregiver will be asked to indicate the appropriate response that adequately 
describes how the care of their child with DS has impacted their quality of life using the scales 
described above.
7.1.6
Study Medication Palatability Assessment 
The palatability and overall acceptability of the IMP will be assessed indirectly by the 
parent/caregiver responsible for the patient according to the schedule in Table 1 and Table 2
using 3 questions: 
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QUESTION 1: Over the past month, on the basis of the reaction ⁄ facial expression of your 
child, do you think that the medicine’s taste and texture are: 
•
Acceptable to your child 
•
Not acceptable to your child 
QUESTION 2: Over the past month, please rate how much your child likes/dislikes the 
medicine’s taste using the following grading scale: 
•
5 (likes it very much) 
•
4 (likes it) 
•
3 (neither likes it or dislikes)
•
2 (dislikes it) 
•
1 (dislikes it very much)
QUESTION 3: Over the past month, do you sometimes have problems giving the medicine to 
your child due to its taste or texture? 
•
No
•
Yes 
o
How often?  

Every day in the past month 

Once to several times every week in the past month

Once or several times in the past month
7.2
EXPLORATORY ASSESSMENTS
The following exploratory assessments will be conducted for subjects who participated in core 
study ZX008-1504 only. 
7.2.1
Sleep Quality and Meal Time Behavior Questions
The parent/caregiver will be asked to indicate the appropriate response that adequately 
describes their child’s sleep quality and eating behavior since starting IMP based on the 
following questions: 
1. Since your child has started taking the study medication in this study, have you noticed that 
s/he has been waking in the middle of the night or very early in the morning more than usual? 
o
My child’s sleep is more disturbed than it was before s/he started the study medication 
o
My child’s sleep patterns are the same as they were before starting the study medication
o
My child sleeps better than s/he did before starting the study medication
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2. Since your child has started taking the study medication in this study, have you noticed that 
s/he has had a change in their mealtime behavior? 
o
My child has worse meal time behavior since starting the study medication
o
My child’s meal time behavior has not changed since starting the study medication 
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7.2.2
Karolinska Sleepiness Scale
The Karolinska Sleepiness Scale (Appendix 10) will be administered according to the schedule 
in Table 2. The Karolinska Sleepiness scale is a self-report scale that measures the subject’s 
drowsiness. It is a 9-point verbally anchored scale, which ranges from ‘extremely alert’ at one 
end of the scale to ‘extremely sleepy – fighting sleep’ at the other end of the scale. Within this 
study, the scale will be completed by the observer in an exploratory manner.
7.2.3
Healthcare Utilization Questions
In order to better understand the healthcare resource burden associated with the management of 
DS, caregivers will be asked which of the following hospital and community-based healthcare 
services they had interactions with over the preceding month: emergency room services, 
ambulance, planned and unplanned hospitalization, family physician services, speech and 
language therapy, occupational therapy, and physical therapy. This information will be 
captured in the CRF. 
7.3
SAFETY ASSESSMENTS
7.3.1
Demographics, Medical/Neurological/Epilepsy History, and Pre-Study 
Medication
Subject demographics (sex, age, height, weight, and BMI), all ongoing conditions and relevant 
medical history from the past 5 years (including all major hospitalizations and surgeries) as 
well as the subject’s current medical status and current medications will be carried over from 
the core study. 
7.3.2
Physical Examinations 
Complete and abbreviated physical examinations, including height and weight, will be 
conducted by the investigator or designee during the study as outlined in Table 1 and Table 2. 
A complete standard of care physical examination for each subject will be performed and will 
cover the following body systems: general appearance, skin, eyes, ears, nose, throat, heart, 
lungs, abdomen, neurological system, lymph nodes, spine, and extremities. An abbreviated 
physical examination for each subject will cover the following body systems:  heart, lungs, and 
follow up of other systems as appropriate based on last exam and reported AEs.  
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Any unfavorable findings not present at Visit 12 of the core study considered by the 
investigator as clinically significant, occurring at any point in the study will be documented in 
the CRF as an AE. 
7.3.3
Neurological Examinations 
Complete and abbreviated neurological examination will be conducted by the investigator or 
designee during the study as outlined in Table 1 and Table 2. A complete standard of care 
neurological examination for each subject will be performed and will cover the following: 
cranial nerves, muscle strength and tone, reflexes, coordination, sensory function, and gait. An 
abbreviated neurological follow-up examination for each subject will evaluate any symptoms 
or systems found to be abnormal and unstable or potentially unstable that might evolve during 
study treatment, or to investigate any reported or observed AEs.  
7.3.4
Vital Signs
Vital signs including blood pressure, heart rate, temperature, and respiratory rate will be 
documented for subjects during study as outlined in Table 1 and Table 2. 
7.3.5
Laboratory Measurements
Laboratory safety parameters will be analyzed using standard validated methods.  
The following parameters will be assessed by the laboratory as described in Table 1 and 
Table 2, and Table 9: 
•
Hematology: hemoglobin, hematocrit, erythrocytes, erythrocyte mean 
corpuscular volume, leukocytes, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, neutrophils, lymphocytes, monocytes, 
eosinophils, basophils and platelets 
•
Blood Biochemistry: albumin (ALB), alkaline phosphatase (AP), alanine 
aminotransferase (ALT; SGPT), aspartate aminotransferase (AST; SGOT), 
bicarbonate, blood urea nitrogen (BUN), calcium (Ca), chloride (Cl), creatinine, 
creatine kinase, gamma-glutamyl transferase (GGT), globulin, glucose, lactate 
dehydrogenase (LDH), phosphorus, potassium (K), sodium (Na), thyroid 
function (T3, T4, and thyroid stimulating hormone [TSH]), total bilirubin, direct 
bilirubin, total cholesterol, total protein, triglycerides, uric acid.  
•
Tests of growth and precocious puberty: growth hormone (GH), insulin-like 
growth factor-1 (IGF-1, low sensitivity), prolactin, luteinizing hormone (LH), 
follicle stimulating hormone (FSH), testosterone, estradiol 
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Page 81 of 194  
•
Whole blood cannabidiol 
•
Urinalysis: analysis for pH, glucose, ketones, nitrite, protein, bilirubin, 
urobilinogen, leukocyte esterase, and occult blood. Microscopic analysis will be 
performed for blood, all cell types, and casts. 
•
Urine pregnancy test: Urine pregnancy testing will be performed in female 
subjects of childbearing potential. 
•
Urine THC panel
The investigator will receive the laboratory report from the central laboratory. After reviewing 
the report and evaluating any results that are outside the normal range, the investigator must 
sign and date the laboratory report.  
Tests resulting in abnormal laboratory values that have been classified by the investigator as 
abnormal, clinically significant should be repeated as soon as possible after receiving the 
laboratory report to rule out laboratory errors.
Any deviation outside of the reference range considered by the investigator as clinically 
significant (ie, classified as an abnormal, clinically significant value) at any visit will be 
documented in the CRF as an AE (Section 9).
7.3.6
Plasma Sample for Concomitant Antiepileptic Drug(s)
Plasma samples to ensure that concomitant AEDs dosing is within an acceptable range will be 
conducted during the study as outlined in Table 1 and Table 2. All samples will be analyzed at 
study end and do not constitute safety assessments. 
7.3.7
Electrocardiograms
Twelve-lead ECGs will be conducted during study as outlined in Table 1 and Table 2 after the 
subject has been in the supine position resting for ≥ 5 minutes. Heart rate, PR duration, QRS 
duration, QT duration, QTcF (Fridericia's correction formula), and the investigator’s overall 
interpretation will be recorded. 
7.3.8
Doppler Echocardiography 
Doppler echocardiography will be conducted at a facility with experience for the subject’s age 
during study as outlined in Table 1 and Table 2. Doppler echocardiography uses ultrasound
technology to examine the heart or blood vessels.  An ECHO uses high frequency sound waves 
to create an image of the heart while the use of Doppler technology allows determination of the 
speed and direction of blood flow by utilizing the Doppler effect. Predetermined standard 
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guidelines on the proper evaluation of certain measurements, as well as abnormality thresholds, 
were constructed by the Sponsor’s IPCAB prior to study initiation. These thresholds are 
provided in Table 10 (Adverse Events of Special Interest). A manual of proper ECHO 
technique for sites is provided in a separate document. 
7.3.9
Tanner Staging
Tanner Staging (Appendix 5) will be assessed for subjects >7 years old during the study as 
outlined in Table 1 and Table 2. Conceptually, pubertal maturation can be described in terms of 
sequence, timing, and tempo. Puberty consists of a series of predictable events, and the 
sequence of changes in secondary sexual characteristics has been categorized by several 
groups. The staging system used most frequently was published by Marshall and Tanner (1969, 
1970) and the sequence of changes are commonly referred to as ‘Tanner stages’.  
7.3.10
Columbia-Suicide Severity Rating Scale
C-SSRS (Appendix 2) will be assessed during study as outlined in Table 1 and Table 2. The 
C-SSRS is a validated rating scale that assesses suicidal behavior and ideation. The scale is 
used to assess and track suicide events and provides a summary measure of suicidal tendency. 
The C-SSRS version 6/23/10 (Children’s Since Last Visit) will be used in this study as 
appropriate for the age and level of intellectual development.
Subjects who are younger than 7 years chronologically, or who are judged by the investigator 
not to have the mental capacity to understand the questions as specified on the C-SSRS, will 
not complete the rating. The investigator should use his/her judgment to substitute 
intellectually-appropriate questions to probe the tendency for self-harm.
If a subject with the intellectual capacity to complete the C-SSRS has their 7th birthday during 
the study, use of the C-SSRS should be initiated at subsequent visits. 
7.3.11
Adverse Events
For de novo subjects, adverse events will be collected from the time of signing the informed 
consent form/assent form until the end of the study, including the follow-up clinic visit. For 
subjects who participated in one of the core studies, adverse events that occur after signing 
informed consent for this study, but before Visit 1 will be recorded as adverse events in the 
core study and medical history in ZX008-1503. 
Details of the definitions and categorization of AEs, and procedures for the reporting of AEs, 
are available in Section 8. 
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Page 83 of 194  
Severity and causality of AEs will be evaluated according to the criteria specified in Section 8.2
and Section 8.3, respectively. The observation period for AE reporting is specified in
Section 8.4. At the beginning of each visit at the study site, the study personnel will specifically 
inquire about any AEs that might have occurred since the last study site visit. All AEs will be 
recorded on the appropriate CRF page.  
7.3.12
Behavior Rating Inventory of Executive Function (BRIEF) 
The BRIEF is a standardized, validated rating scale to measure executive function. Age-
appropriate versions of the BRIEF (BRIEF-P: 2 to 5 year olds; BRIEF: 6 to 18 year olds; 
BRIEF-A: 19 to 35 year olds) will be assessed according to the schedule in Table 1 and 
Table 2. The BRIEF measures multiple aspects of executive functioning; scales include Inhibit 
(control impulses; stop behavior), Shift (move freely from one activity/situation to another; 
transition; problem-solving flexibility), Emotional Control (modulate emotional responses 
appropriately), Initiate (begin activity; generate ideas), Working Memory (hold information in 
mind for purpose of completing task), Plan/Organize/Organization of Materials (anticipate 
future events; set goals; develop steps; grasp main ideas), and Monitor (check work; assess own 
performance). 
7.4
APPROPRIATENESS OF MEASUREMENTS
All of the variables assessed are standard tests or procedures that are commonly used in studies 
of this type. 
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8.
ADVERSE EVENTS 
8.1
DEFINITIONS
8.1.1
Adverse Events 
According to ICH guidelines, an AE is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment. An AE can, therefore, be any unfavorable and 
unintended sign (including an abnormal, clinically significant laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product. For de novo subjects, the 
period of observation for adverse events extends from the time the subject gives informed 
consent until the end of study. For subjects who participated in one of the core studies, the 
period of observation for adverse events extends from Visit 1 of ZX008-1503 until the end of 
study. Adverse events that occur after signing informed consent for this study, but before 
Visit 1 will be recorded as adverse events in the core study and medical history in ZX008-1503. 
Adverse events may include: 
•
Illness present before core study entry should be recorded in the medical history 
section of the CRF along with any ongoing AEs that were present at Visit 13 of the 
core study. These events should only be reported as an AE if there is an increase in 
the frequency or severity of the condition from the core study  
•
Exacerbation of seizures is considered an AE if there was an increase in frequency 
beyond the subject's typical pre-core study fluctuations, or in the event that seizures 
lengthen in duration in a clinically meaningful way compared with core study 
baseline, or if a new seizure type emerges  
•
A clinical event occurring after consent but before IMP administration
•
Intercurrent illnesses with an onset after administration of IMP
Adverse events do not include: 
•
Medical or surgical procedures (the condition that leads to the procedure is the AE, 
eg, tonsillitis is the AE if a tonsillectomy is performed) 
•
Situations where an untoward medical occurrence has not taken place. For example:
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 85 of 194  
o
Hospitalizations that occur for procedures not due to an AE (eg, cosmetic 
surgery) 
o
Hospitalizations for a diagnostic procedure where the hospital stay is less than 
24 hours in duration or for normal management procedures (eg, chemotherapy) 
For laboratory safety parameters, any instances of absolute values being outside the reference 
range or changes at any visit after study start that are considered by the investigator as 
clinically significant must be recorded in the CRF as AEs. In addition, at the investigator’s 
discretion, any changes or trends over time in laboratory parameters can be recorded in the 
CRF as AEs if such changes or trends are considered to be clinically relevant, even if the 
absolute values are within the reference range.
Laboratory findings do not need to be reported as AEs in the following cases: 
1. Laboratory parameters are already beyond the reference range, unless a further 
increase/decrease can be considered an exacerbation of a pre-existing condition. 
2. Abnormal laboratory parameters caused by mechanical or physical influences on the 
blood sample (eg, hemolysis) and flagged as such by the laboratory in the 
laboratory report. 
3. Abnormal parameters that are obviously biologically implausible (eg, values that 
are incompatible with life).
4. An abnormal laboratory value that cannot be confirmed after a repeated analysis, 
preferably in the same laboratory (eg, the previous result could be marked as not 
valid and should not necessarily be reported as an AE).  
8.1.2
Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose:
1.
Results in death – The event must be the cause of death for the SAE to meet this serious 
criterion.
2.
Is life-threatening – The term “life-threatening” refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it had been more severe. 
3.
Requires in-patient hospitalization or prolongation of existing hospitalization – The 
Sponsor considers “hospitalization or prolongation of existing hospitalization” for at 
least 24 hours as the defining criterion for an SAE. Hospital admissions for planned 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 86 of 194  
surgery or for normal disease management procedures (eg, chemotherapy) are not 
considered as defining criteria for SAEs.  
4.
Results in persistent or significant disability or incapacity.
5.
Is a congenital anomaly or birth defect. 
6.
Is medically significant – A medically significant event is defined as an event that does 
not meet any of the other 5 SAE criteria, but which is judged by a physician to 
potentially jeopardize the subject or require medical or surgical intervention to prevent 
one of the above outcomes listed as an SAE criterion. Anaphylaxis that is successfully 
treated by administration of epinephrine prior to other sequelae is an example of a 
potentially medically important event.
•
The most important term should be selected as the criteria for the SAE.  Medically 
significant should be used when none of the other terms apply, for cases in which, had 
there not been intervention, one of the other SAE outcomes would have likely 
occurred. For example, anaphylaxis successfully treated with an epinephrine injection 
would be a medically important event.
•
For the purpose of data collection in this study, a prolonged seizure or series of 
seizures from which the subject does not regain consciousness between ictal events, 
that is at least 30 minutes in duration, is termed SE. A single episode of SE in a 24-
hour period, regardless of whether rescue medication was administered, should be 
entered in the AE log as well as in the seizure diary. If two or more episodes occur 
within 24 hours, each lasting 30 minutes or more, an SAE of SE should be recorded. 
Hospitalization to manage SE, regardless of the number of episodes, should be 
reported as an SAE.
Adverse events that do not fall into the above categories are defined as non-serious AEs.
8.1.3
Adverse Events of Special Interest
As per ICH guidance (E2F Development Safety Update Report [2011]), the Sponsor has 
identified the following AESIs for the ZX008 program (Table 10). 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 87 of 194  
Table 10. 
Adverse Events of Special Interest
Metabolic/Endocrine
1.
Elevated prolactin level ≥2x above the upper limit of normal (ULN)
2.
Hypoglycemia – serum blood glucose more than 20% below the glucose level on Study Day -1 value or
more than 10% below LLN (reference range 60 – 140 mg/dL)
Neuropsychiatric
1.
Suicidal thoughts, ideation or gestures
LLN = lower limit of normal; ULN = upper limit of normal
8.1.4
Adverse Events Requiring Hospitalization
If a subject is treated in a medical facility (hospital, emergency room, free-standing clinic) 
related to the occurrence of any AE, the following data will be collected to model health care 
utilization in patients with DS: AE/reason for hospitalization/clinic visit; duration of the visit in 
hours/days; admission to intensive care unit; and name/number of procedures performed, 
including but not limited to, electroencephalogram, ECG, ECHO, positive emission 
tomography (PET) scan, magnetic resonance imaging (MRI), x-ray, computed tomography 
(CT) scan, surgery, and lumbar puncture/spinal tap. 
8.2
SEVERITY OF ADVERSE EVENTS
The severity of AEs (whether non-serious or serious AEs) is to be assessed by the investigator 
as follows (Table 11 ).
Table 11.  
Severity Definition of Adverse Eventsa
Severity
Definition
Mild
A type of AE that is usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily living.
Moderate
A type of AE that is usually alleviated with additional specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the research participant.
Severe
A type of AE that interrupts usual activities of daily living, or significantly affects clinical 
status, or may require intensive therapeutic intervention.
a
Clinical Data Interchange Standards Consortium Study Data Tabulation Model Severity Intensity Scale for 
Adverse Event Terminology
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 88 of 194  
8.3
CAUSALITY OF ADVERSE EVENTS
The causal relationship of an AE to IMP must always be assessed by the investigator. All AEs 
will be classified as either related or not related to IMP. If a causality assessment is not 
provided for an AE (including an SAE), that AE will be considered as related to IMP.  
The degree of certainty with which an AE is attributed to IMP or an alternative cause (eg, 
natural history of the underlying disease, concomitant medication) will be determined by how 
well the event can be understood in terms of: 
•
Known pharmacology of ZX008 
•
Clinically and/or pathophysiologically plausible context 
•
Reaction of a similar nature previously observed with similar products, or reported in 
the literature for similar products as being product related (eg, headache, facial flushing, 
pallor) 
•
Plausibility supported by the temporal relationship (eg, the event being related by time 
to administration or termination of treatment with IMP drug withdrawal or reproduced 
on rechallenge)
•
The following classifications should be used in categorization of relatedness:
1. Not Related: 
Concomitant illness, accident or event with no reasonable association with 
study drug. 
2. Related: 
The event follows a reasonable temporal sequence from administration of 
study drug and is definitive pharmacologically; cannot to be attributed 
to concurrent disease or other factors or medications. A clinically reasonable 
response should be observed if the study drug is withdrawn or dose reduced. 
8.4
OBSERVATION PERIOD FOR ADVERSE EVENT REPORTING
The observation period for AE and SAE reporting for de novo subjects will start at the time of 
giving written informed consent for participation in the current study and finish 15 days after 
the last dose of study drug or the last visit, whichever is later. For subjects who participated in 
one of the core studies, the observation period for adverse events will start at Visit 1 of 1503 
and finish 15 days after the last dose of study drug or the last visit, whichever is later. Ongoing 
AEs from the core studies will be considered medical history unless there is an increase in the 
frequency or severity of the condition from the core study. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 89 of 194  
If the investigator becomes aware of an SAE that has started after the observation period has 
finished, and the event could in some way be associated with IMP (irrespective of whether or 
not it is considered by the investigator to be causally related to IMP), then this must also be 
reported to the Sponsor (see Section 8.6).
8.5
ADVERSE EVENT REPORTING
8.5.1
Adverse Events
At each clinical evaluation, the investigator (or delegate) will determine whether any AEs have 
occurred. Adverse events will be recorded in the AE page of the CRF. If known, the medical 
diagnosis of an AE should be recorded in preference to the listing of individual signs and 
symptoms. The investigator must follow up on the course of an AE until resolution or 
stabilization. If an AE is ongoing after the end of study visit, the AE will continue to be 
followed up until resolution or stabilization. 
If, during the study period, a subject presents with a pre-existing condition that was not noted at 
the time of study entry, the condition should be retrospectively recorded in the Medical History 
section of the CRF. 
8.6
SERIOUS ADVERSE EVENTS REPORTING
This study will comply with all applicable regulatory requirements and adhere to the full 
requirements of ICH Topic E2A (Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting [1994]).
In the event of a SAE the investigator or delegate must:  
1. Enter all relevant information in the AE page of the eCRF. 
2. Inform the Medical Monitor or the Sponsor of the SAE via email or telephone within 
24 hours of becoming aware of the SAE. 
3. Follow the initial notification with a completed SAE report form. The SAE form 
must be emailed or faxed to Inventive Health Care within 24 hours of becoming 
aware of the SAE. 
All SAEs that occur during the course of the study, beginning the day Informed Consent 
is signed for de novo subjects and at Visit 1 for subjects from the core studies, whether or 
not causally related to IMP must be reported immediately via telephone or email (within
24 hours of the investigator becoming aware of the event) to the Sponsor or the Medical 
Monitor.  
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 90 of 194  
Adverse events occurring in the period between the time the subject gave written informed 
consent and the first exposure to IMP that meet one or more of the seriousness criteria for AEs 
must be reported to the sponsor and the Medical Monitor in the same manner as other SAEs 
and will be included in the clinical study database.  
Any SAE that occurs 15 days after the last dose of study drug or the last visit, whichever is 
later that is considered to be causally related to IMP must be reported immediately (ie, within 
24 hours of the investigator becoming aware of the event) to the Sponsor and the Medical 
Monitor.  
Contact details and guidance for reporting SAEs will be provided to study site before the study 
starts.
8.6.1
Requirements for Immediate Reporting of Serious Adverse Events
The minimum reporting requirements for immediate reporting of SAEs include: 
1. Identifiable subject
2. Suspected drug product 
3. Event description 
4. Identifiable reporting source 
In addition, the investigator must: 
1. Report all SAEs to the relevant IRB/IEC within the timeframe specified by the 
IRB/IEC.
2. Submit follow-up reports to the Sponsor Global Clinical Safety and 
Pharmacovigilance and the Medical Monitor until the SAE has resolved, or, in the 
case of permanent impairment, until stabilized.
3. Ensure that the AE term(s) and causality assessment for all SAEs is entered in the 
CRF.
If the minimum requirements for reporting are fulfilled, the investigator should not wait to 
receive additional information to fully document the event before notifying the Sponsor.  
When submitting SAE reports to the Sponsor, subjects should be identified only by their
subject number and study number. The investigator should not include the subject’s name and 
address.
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 91 of 194  
SAE Update reports can be submitted to the Sponsor any time that additional relevant 
information becomes available. In cases of death, the investigator should supply the Sponsor 
and the IEC/IRB (as applicable, see Section 8.7) with any additional requested information as it 
becomes available (eg, autopsy reports and detailed medical reports). Once an SAE is reported 
to the Sponsor’s Safety Group, a Safety Specialist may contact the investigator with follow-up 
questions. 
The procedure to be followed if an ongoing AE becomes an SAE after the end of the 
observation period for AEs is described in Section 8.9. 
8.7
REPORTING OF SERIOUS ADVERSE EVENTS BY INVESTIGATOR TO 
IEC/IRB
The timeframe within an IEC/IRB must be notified of a death or an unexpected SAE 
considered at least possibly related to the IMP is stipulated by each individual IEC/IRB. The 
investigator is responsible for complying with the requirements for IEC/IRB notification. The 
investigator will notify the relevant IEC/IRB within the applicable timeframe by forwarding the 
safety report (eg, MedWatch/CIOMS form) completed by the Sponsor for the notifiable event.  
8.8
REPORTING OF EVENTS OTHER THAN SERIOUS ADVERSE EVENTS 
BY INVESTIGATOR TO SPONSOR
Even if none of the criteria for an SAE are fulfilled, any of the following events must be 
reported by the investigator to the Medical Monitor within 72 hours from the time the 
investigator is notified.
1. Hypersensitivity reactions 
2. Pulmonary hypertension 
3. Cardiac symptoms requiring intervention, or valvulopathy, if identified 
outside of study-related monitoring
8.9
FOLLOW-UP OF ADVERSE EVENTS 
Every effort should be made to follow-up subjects who continue to experience an AE or an 
SAE on completion of the study or until the AE resolves. All follow-up information (and 
attempted follow-up contacts) should be documented in the subject’s medical records. Details 
of the subject’s progress should also be submitted to the Sponsor’s Global Clinical Safety and 
Pharmacovigilance and the Medical Monitor. In the event of a SAE, a blood sample for ZX008 
and AED PK should be collected as soon as feasible. 
Subjects who are discontinued from the study or complete the study and have been found to 
have any signs of valvulopathy or pulmonary hypertension on ECHO will be followed until the 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 92 of 194  
condition has resolved or stabilized where no further changes are likely, for a minimum of 
6 months from the last dose of study medication. 
8.9.1
 Follow-up of Echocardiogram Findings  
All ECHOs will be evaluated by a central reader from BioMedical Systems, Inc. (BMS), in 
consultation with the IPCAB, if warranted. Findings related to pulmonary hypertension or 
valvulopathy on any of the four valves (aortic, mitral, pulmonary, tricuspid) will be reported to 
the investigator with grades of normal, trace, mild, moderate, or severe. If the ECHO result has 
progressed in severity since the last reading, then new oversight measures will be enacted as 
described below in Levels 1-3. Table 12 describes the severity of ECHO findings with the level 
of increasing oversight if the subject is to remain in the study. 
Table 12. 
Clinical Measures Enacted Upon Increasing Severity of ECHO Findings
Severity
Valve
Aortic
Mitral
Pulmonary
Tricuspid
Trace 
Level 1
Level 1
Level 1
Level 1
Mild (≤18 years)
Level 2
Level 1
Level 1
Level 1
Mild (>18 years)
Level 2
Level 1
Level 1
Level 1
Moderate
Level 3
Level 2
Level 2
Level 2
Severe
Level 3
Level 3
Level 3
Level 3
Level 1: Continue per protocol 
Level 2:
1. If there is a desire to continue study medication: 
a. The investigator will evaluate the efficacy to date based on study diaries and 
consult with the parent/guardian, and determine whether study treatment was 
associated with significant, meaningful benefit in number, severity and/or 
duration of seizures and/or on the impact on daily functioning. 
b. The investigator will consider whether the subject has had reasonable trials (dose 
and duration) of other available anticonvulsants (eg, VPA, CLB, or topiramate), 
alone or in combination, and not maintained the level of seizure control achieved 
with study medication. 
2. If the investigator feels consideration of continued treatment is warranted considering 
benefit and potential risk, and the parent/guardian feels strongly that the subject be 
maintained on the study medication when understanding the risks, the parent/guardian 
must sign a new consent which describes the additional risk and the subject should 
provide assent if appropriate. 
a.
If both of these conditions are not met, the subject is discontinued from 
treatment.
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 93 of 194  
3. The investigator prepares a case history and rationale for continuation to be submitted to 
the IDSMC for review, including consideration of effects on seizures and comorbidities.
4. The Co-Chairs of the IPCAB are alerted to the request and prepare, after consultation 
with BMS, an evaluation of the cardiopulmonary risk and proposed monitoring plan if 
applicable, for submission to the IDSMC.
5. IDSMC will review the submission from the Investigator and the IPCAB and unblind the 
subject’s core study treatment, if warranted.
6. IDSMC makes a determination of appropriate path, including the possible outcomes:
a. Discontinue study medication 
b. Increase frequency of ECHO and ECG monitoring 
c. Add additional ECG and/or ECHO measures to be monitored 
d. Reduce the dose of study medication 
Level 3:
1. The investigator will evaluate efficacy to date based on study diaries and consult with 
the parent/guardian, and determine whether the achieved benefit justifies the 
consideration of continuing study treatment by the IDSMC. MINIMAL efficacy 
criteria for IDSMC consideration:
a. Seizures must be more than 75% improved (number of convulsive seizures per 
28 days) on treatment over baseline, and improvement must be consistent.  
b. The number, type, duration, and distribution of seizures at baseline should be of a 
severity, which justifies the risks of cardiopulmonary complications, considering 
the subject’s age and overall health. 
c. Subject has had reasonable trials (dose and duration) of other available 
anticonvulsants (eg, VPA, CLB, topiramate), alone or in combination, and not 
maintained the level of seizure control achieved with study medication. 
2. If the investigator feels consideration of continued treatment is warranted considering 
benefit and potential risks, and the parent/guardian feels strongly that the subject be 
maintained on the study medication when understanding the risks, the parent/guardian 
must sign a new consent, which describes the additional risks and the subject should 
provide assent if possible. 
a. If both of these conditions are not met, the subject is discontinued from 
treatment.
3. The investigator prepares a case history and rationale for continuation to be submitted 
to the IDSMC for review, which includes effects of study medication on seizures and 
comorbidities related to DS. 
4. The Co-Chairs of the IPCAB are alerted to the request, and in consultation with BMS 
prepare an evaluation of the risks and proposed monitoring plan if applicable for 
submission to the IDSMC.
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 94 of 194  
5. IDSMC will review the submission from the Investigator and the IPCAB and unblind 
the subject’s core study treatment, if warranted.
6. IDSMC makes a determination of appropriate path, including these possible outcomes: 
a. Discontinue study medication 
b. Increase frequency of ECHO and ECG monitoring 
c. Add additional ECG and/or ECHO measures to be monitored 
d. Reduce the dose of study medication 
8.10
PREGNANCY
This study is open to female and male subjects. Whenever possible, a pregnancy in a female 
subject or the female partner of a male subject exposed to IMP should be followed to term so as 
to assess any potential occurrence of congenital anomalies or birth defects. Any follow-up 
information, including premature termination and the status of the mother and child after 
delivery, should be reported by the investigator to the Sponsor using a pregnancy 
reporting/outcome form.  
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 95 of 194  
9.
DATA HANDLING PROCEDURES
9.1
RECORDING OF DATA
The investigator (or delegate) will maintain individual records for each subject. These records 
should include dates when a subject visited the study site, study-required information and data, 
and other notes as appropriate. These records constitute source data.  
A CRF and a subject diary will be provided by the Sponsor (or delegate) for each subject 
enrolled into the study. Study site staff will enter data directly into the validated electronic data 
capture (EDC) system by completing the CRF via a secure internet connection. The 
investigator is responsible for ensuring accurate and proper completion of the CRF and subject 
diary for recording data according to the instructions given in the CRF and subject diary.  
All entries in the CRF must be backed up by the relevant source data at the study site. All 
source data will be kept according to all applicable regulatory requirements (Section 12.8). 
Source data must be completed legibly for each subject enrolled into the study and signed by 
the investigator (or delegate).  
Data entry in the CRF and subject diary must be completed in a timely manner so that they
always reflect the latest observations on the subjects enrolled in the study.  
The subject’s diary will be completed by the parent/caregiver at home. Data entries will be 
reviewed by the investigator for completion and consistency.  
9.2
DATA QUALITY ASSURANCE
An initiation meeting will be held before starting the study, during which the study design, 
procedures to be followed, and measures for ensuring standardized performance will be 
explained by a delegate from the Sponsor, and a common understanding of the requirements of 
the study will be reached with the investigator and other relevant personnel at the study site. 
Data generated throughout the study will be monitored and the data entered in the CRFs will be 
checked against the subject records for completeness and accuracy. The Sponsor’s study 
monitor will perform this function.
The computer system used for study data handling will be fully 21 Code of Federal Regulations 
(CFR) Part 11 compliant. All creation, modification or deletion of electronic study records will 
be documented through an automated Audit Trail. Following completion of CRF pages and 
entry of the data into a database, the data will be checked electronically for consistency and 
plausibility. Data queries will be generated for questionable data and response clarification will 
be sought from the investigator. These data queries must be resolved in a timely manner by the 
investigator (or delegate).
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
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Confidential
Page 96 of 194  
9.3
RECORD RETENTION
A study document binder will be provided by the Sponsor for the investigator at each site for 
all requisite study documents (constituting the “Investigator Study File”).  
Following completion of the study, the investigator will retain copies of the approved study 
protocol, ICF, relevant source documents, and all other supporting documentation related to the 
study according to applicable regulatory requirements.  
The investigator is responsible for archiving the Investigator Study File, the subject’s records, 
and the source data according to applicable regulatory requirements. These documents have to 
be archived for at least 15 years or at least 2 years after the last approval of a marketing 
application in an ICH region, but should be retained for longer if required by regulatory 
requirements or by agreement with the Sponsor.  
If the investigator can no longer maintain the archive of study records (eg, due to retirement or 
relocation), the Sponsor must be informed in writing about any change in responsibility for 
record retention, including the name of the new responsible party, contact information, and 
location of the study records. Records may not be destroyed without prior written consent from 
the Sponsor. 
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ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 97 of 194  
10.
STATISTICS
10.1
DETERMINATION OF SAMPLE SIZE
The sample size will be determined by the number of subjects who participate in 1 of 3 core 
studies (Study ZX008-1501, Study ZX008-1502, or Study ZX008-1504) and who volunteer for 
the extension study and meet the necessary criteria for enrollment. Approximately 100-120 
subjects are expected to participate in each of the core studies; thus, if all participants also 
enroll in the extension, the total sample size of the extension study would be approximately 340. 
10.2
ANALYSIS POPULATIONS
10.2.1
Safety (SAF) Population 
Safety analyses will be performed on the Safety (SAF) Population defined as all subjects who 
receive at least one dose of ZX008 during the open label extension. 
10.2.2
Modified Intent-to-Treat (mITT) Population 
The modified Intent-to-Treat (mITT) Population is defined as all subjects who receive at least 
one dose of ZX008 and have valid seizure data during the open label extension. Effectiveness 
analyses, such as evaluating the change in the frequency of convulsive seizures, will be 
performed on the mITT Population. 
10.2.3
Per Protocol (PP) Population  
The Per Protocol (PP) Population is defined as all subjects who receive at least one dose of 
ZX008, complete the entire OLE Treatment Period of the open label extension, and have no 
major protocol deviations that would have a significant impact on clinical outcome. Key 
effectiveness analyses will be repeated on the PP Population in addition to the mITT 
Population. 
10.3
TREATMENT GROUPS
All subjects will receive ZX008 and will be considered a single treatment group.
10.4
TREATMENT PERIODS
Pre-ZX008 Baseline Period 
For subjects who receive ZX008 in Study ZX008-1501, Study ZX008-1502, or Study 
ZX008-1504 Cohort 2, the pre-ZX008 baseline period is equivalent to the core study pre-
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34

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ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 98 of 194  
randomization baseline period, ie, the approximately 42-day span just prior to randomization 
and start of treatment in the core study.  
For subjects who receive placebo in Study ZX008-1501, Study ZX008-1502, or Study 
ZX008-1504 Cohort 2, the pre-ZX008 baseline period begins with the core study pre-
randomization baseline period and extends through the entire span of the core study up to the 
transition period. The pre-ZX008 baseline period for a subject ends when that subject receives 
their first treatment with ZX008.
Study ZX008-1504 Cohort 1 have a shortened (exploratory) baseline period of approximately 
12 days (after the single-dose PK assessment) and this will be used in an exploratory manner. 
For de novo subjects, the pre-ZX008 baseline period is the screening period of up to 28 days 
prior to receiving the first dose. 
The baseline frequency of convulsive seizures will be calculated from data collected during the 
entire length of the pre-ZX008 baseline period. 
Open-Label Extension Treatment Period 
The OLE Treatment Period covers the 36 months during which subjects will receive open label 
treatment with ZX008.
Post-dosing Period 
The Post-dosing Period begins immediately at the end of OLE Treatment Period and extends 
for 2 weeks.
After at least 1 year of treatment in Study 1503 subjects who participated in one of the core 
studies will transition to a separate extension study (Study 1900) once that study is approved 
and the study site is initiated. Continuation in a separate extension protocol will be based on 
benefit/risk and continued eligibility criteria being met. De novo subjects must have 
participated in this trial for at least 3 months with at least 1 ECHO completed and continue to 
meet eligibility requirements to be eligible to transition to a separate extension protocol. 
Alternatively, subjects will transition to commercial product once it is available if they have 
had an ECHO within 3-6 months before starting commercial drug. For subjects who are 
entering the separate extension trial or who transition to commercially available drug, post-
dosing and cardiac safety follow-up visits are not required in this trial. Subjects who transition 
to commercially available drug will have follow-up ECHOs within the required timeframe 
while on commercial drug.  
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 99 of 194  
10.5
STATISTICAL ANALYSES AND METHODS
All safety, effectiveness and exploratory data will be summarized. Continuous data will be 
summarized using descriptive statistics including means, standard deviations, medians, lower 
and upper quartiles, and ranges. Categorical variables will be summarized with frequencies and 
percentages. Confidence intervals will be calculated for key parameters or estimates as 
warranted.
A complete description of the statistical analyses and methods will be available in a statistical 
analysis plan (SAP), which will be finalized before the database is locked.
10.5.1
Safety Analyses 
Adverse events will be monitored throughout each core study and the open label extension. 
Adverse events will be considered to be treatment emergent (TEAE) if they begin between the 
first day of treatment with ZX008 and the last day of the Post-dosing period or occur prior to 
first ZX008 treatment but increase in severity after ZX008 treatment begins.
The number and percentage of subjects in each treatment group with TEAEs will be displayed 
by body system and preferred term using the Medical Dictionary for Regulatory Activities 
(MedDRA). A table will enumerate the TEAEs that occur in at least 5% of subjects. A separate 
summary will be provided for all serious AEs (SAEs). Selected summaries will be repeated 
broken out by age group, ie, for ages < 6 years and ≥ 6 years.
Hematology and chemistry laboratory results will be summarized using shift tables that tabulate 
the proportion of subjects who have lab results that change from pre-ZX008 baseline, where 
pre-ZX008 baseline values will be determined from lab results obtained prior to first treatment 
with ZX008. The shift tables will be presented for each time point where lab results are 
collected. Mean change from pre-ZX008 baseline will also be calculated for continuous 
hematology and chemistry results at all time points available.
Physical examinations, vital signs, ECG, ECHO and body weight will be summarized 
appropriately. All safety summaries will be based on the SAF Population.  
10.5.2
Effectiveness Analyses 
10.5.2.1
Key Effectiveness Analysis
The key effectiveness endpoint is the change in the convulsive seizure frequency per 28 days 
between the pre-ZX008 Baseline and OLE Treatment Period. The frequency of convulsive 
seizures during a given period will be derived from the number and type of events recorded in 
subject diaries. The seizure frequency per 28 days will be calculated as the number of seizures 
recorded divided by the number of days in the period and multiplied by 28. The convulsive 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 100 of 194  
seizure frequency will be calculated from all available data collected during either the 
pre-ZX008 Baseline or OLE Treatment Periods.  
Both the mean and median frequency of convulsive seizures will be presented for the 
pre-ZX008 Baseline Period and the OLE Treatment Period. The significance of the change 
between periods will be assessed using an analysis of covariance (ANCOVA) model with age 
group (< 6 years, ≥ 6 years) as a factor and with pre-ZX008 baseline frequency as a covariate. 
Other factors may be included in the model if they are found to be informative during analyses 
of the core studies. 
Since the ANCOVA relies on assumptions of normality, the key effectiveness endpoint will 
also be analyzed using a nonparametric method that does not require as stringent assumptions. 
A test such as the stratified Wilcoxon signed rank test will be used to assess the change from 
baseline while stratifying by age group. 
An additional analysis will be performed to assess the sensitivity of the key effectiveness 
analysis to changes in dose or type of concomitant AED medications that may occur during the 
course of the trial. Specifically, the analysis will be repeated with a factor added to the model to 
indicate whether a subject had a change in prescribed dose or type of concomitant AED 
medication during the OLE Treatment Period. Further exploratory analyses may be conducted 
if changes in concomitant AED medication appear to have a significant impact on the 
effectiveness of ZX008. 
Only subjects from Studies ZX008-1501, ZX008-1502, and Cohort 2 of ZX008-1504 will be 
included in change from baseline analyses of effectiveness. Subjects from Study ZX008-1504 
Cohort 1 will be excluded from such analyses since they will enter the OLE Treatment Period 
without first participating in a baseline period that includes a formal assessment of pre-ZX008 
seizure frequency.
10.5.2.2
Other Secondary Analyses
Methods similar to those used for the key effectiveness analysis will also be used to assess the 
change in frequency of non-convulsive seizures and the composite endpoint of non-convulsive 
plus convulsive seizures. The proportion of subjects who achieve a ≥40% reduction from 
baseline in convulsive seizure frequency, along with its 95% CI, will be reported. A similar 
summary will be reported for the proportion of subjects who achieve a ≥50% reduction from 
baseline. The analyses will be performed using data collected over the open label OLE 
Treatment Period. 
The longest interval between convulsive seizures will be calculated for each subject over the 
entire OLE Treatment Period. The median interval will be presented. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 101 of 194  
Palatability will be assessed through descriptive statistical methods. For example, the 
percentage of parents or caregivers who consider the medicine’s taste and texture to be 
acceptable to the subject will be presented along with a 95% CI at each time point data are 
available.
QoL measures will be summarized by descriptive statistic for each time point where they are 
obtained. Where appropriate, the significance of the change from baseline will be assessed 
using mixed effects models for repeated measures.
10.6
ANALYSES PROVIDED TO AN INDEPENDENT DATA AND SAFETY 
MONITORING COMMITTEE
A safety oversight monitoring plan will be in place with an IDSMC evaluating data from the 
subjects. Details will be provided in the IDSMC charter. The IDSMC’s primary responsibility 
is to ensure that study subjects are not exposed to unanticipated harm that could have been 
prevented by timely review and intervention. The IDSMC is established to review safety data at 
predefined time points, and to recommend to the Sponsor whether to continue, modify, or 
terminate the study as necessary. The IDSMC is composed of expert permanent members who 
cover relevant specialties (neurology, cardiology, pediatrics, and statistics). The IDSMC 
members may request assistance from a number of additional and hoc members if needed.
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 102 of 194  
11.
ETHICAL & REGULATORY CONSIDERATIONS
11.1
ETHICAL CONSIDERATIONS
The procedures set out in this study protocol are designed to ensure that the Sponsor and the 
investigator abide by the principles of the current ICH GCP guideline on the conduct, 
evaluation and documentation of this study, as described in ICH Topic E6 Guideline. ICH GCP 
is an international ethical and scientific quality standard for designing, conducting, recording, 
and reporting studies that involve the participation of human subjects. Compliance with this 
standard provides public assurance that the rights, safety, and well-being of study subjects are 
protected, and that the clinical study data are credible.
The study will also be carried out according to all applicable international and national 
regulatory requirements. 
The Sponsor and the investigator must inform each other (eg, during a study initiation visit, via 
e-mail, etc) that all ethical and legal requirements have been met before the first subject is 
enrolled into the study. 
11.2
INFORMED CONSENT
The investigator is responsible for obtaining a subject’s written informed consent to participate 
in the study. 
A Subject Information Sheet and a master ICF will be prepared by the Sponsor according to the 
provisions of ICH GCP and local legal requirements. 
All subjects will be informed that the study will be registered in a public database at (eg, 
ClinicalTrials.gov) in accordance with the local country requirements. 
Before undergoing screening for possible enrollment into the study, subjects must be informed, 
in an understandable form, about the nature, scope, and possible consequences of the study. 
This information must be given orally to subjects by a physician or medically qualified person 
(according to applicable regulatory requirements) who is well informed about the nature, scope, 
and possible consequences of the study. Written information about the study will also be 
provided in a Subject Information Sheet. The date on which this oral and written information 
on the study was provided to the subject, and by whom it was provided, must be documented in 
the ICF.
As specified in ICH GCP Section 4.8 and the US 21CFR Section 50.25, the informed consent 
discussion must emphasize that participation in the study is voluntary and that subjects have the 
right to withdraw their consent at any time without giving a reason and without any 
disadvantage for their subsequent care. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 103 of 194  
Subjects must be given ample time and opportunity to inquire about details of the study and to 
consider their participation in the study. If, after reading the Subject Information Sheet and the 
ICF, consent is given to participate in the study, then the ICF must be signed and personally 
dated by the subject and the person conducting the informed consent discussion (and an 
impartial witness, if required). The subject will be provided with a copy of the signed ICF.  
Verification of the signed ICF will be recorded in the subject’s CRF. The original signed ICF 
will be filed with the subject’s records and/or in the Investigator Study File. 
The Subject Information Sheet and ICF have to be approved by the IEC/IRB before they can be 
used in the study. 
The Subject Information Sheet and ICF must be revised whenever important new information 
becomes available that may be relevant to the subject’s consent. Any revision of these 
documents must be approved by the IEC/IRB before they can be used in the study. Subjects 
must be informed in a timely manner if new information becomes available that may be 
relevant to their willingness to continue participation in the study. The communication of this 
information should be documented by having all parties concerned sign and personally date the 
revised ICF.
Subject or Subject’s Legally Acceptable Representative Unable to Read
If a subject is unable to read, or if a legally acceptable representative is unable to read, an 
impartial witness should be present during the entire informed consent discussion. After the 
ICF and any other written information provided to the subject, parent or guardian has been read 
and explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the ICF, 
the witness should also sign and personally date the ICF. By signing the ICF, the witness attests 
that the information in the ICF and any other written information was accurately explained to, 
and apparently understood by, the subject or the subject’s legally acceptable representative, and 
that informed consent was freely given by the subject or the subject’s legally acceptable 
representative.
Assent for Subjects Under the Age of Consent (Pediatric Subjects)
All subjects are under the age of consent (ie, pediatric subjects under 18 years of age); the 
written informed consent of a legally acceptable representative is required. Pediatric subjects 
who can understand the nature, scope, and possible consequences of the study must also give 
their assent, orally and/or in writing via the assent document, as appropriate. After the ICF and 
any other written information to be provided to subjects has been read and explained to the 
subject and the subject’s legally acceptable representative, and after the subject and the legally 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 104 of 194  
acceptable representative have orally consented to the subject’s participation in the study and, if 
capable of doing so, the subject has signed and personally dated the assent document, the 
legally acceptable representative should sign and personally date the ICF. By signing the ICF, 
the legally acceptable representative attests that the information in the ICF and any other 
written information was accurately explained to, and apparently understood by, the subject, and 
that assent was freely given by the subject. 
11.3
REGULATORY CONSIDERATIONS AND INDEPENDENT ETHICS 
COMMITTEE/INSTITUTIONAL REVIEW BOARD
The Sponsor (or delegate) will submit the appropriate documents to all applicable competent 
regulatory authorities and IEC/IRBs, and will await all relevant approval before enrolling any 
subjects into the study. Written approval should mention the study protocol by study title, study 
number, and version date. 
This study will be conducted under Investigational New Drug (IND) Application and
documented in accordance with the applicable regulatory guidelines and requirements. 
The Sponsor (delegate) will ensure that the investigators conduct the study as stipulated in this 
study protocol and in accordance with all applicable regulatory requirements. The Sponsor 
(delegate) is obliged to obtain evidence of the investigator’s qualification to perform the 
clinical study. Therefore, the investigator has to provide a signed and dated copy of his or her 
professional curriculum vitae (prepared no more than 2 years beforehand and preferably written 
in English) before the start of the study, including information on his or her experience in 
conducting clinical studies according to ICH GCP and other applicable regulatory 
requirements.
Written notification of the identity and occupation of the members of the IEC/IRB is also 
required by the Sponsor (delegate). Should the IEC/IRB be unwilling to provide this 
information, a letter stating that the committee was constituted in accordance with applicable 
regulatory requirements should be provided. 
11.4
PROTOCOL COMPLIANCE 
The investigator must conduct the study in compliance with this study protocol as agreed to by 
the Sponsor and, if required, by any competent regulatory authority, and which has been 
approved by, or given a favorable opinion by, the IEC/IRB. 
The investigator should not implement any deviation from, or changes to, the study protocol 
without agreement by the Sponsor (delegate) and prior review and documented approval or 
favorable opinion from the IEC/IRB of an amendment to the study protocol. Exceptions include 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 105 of 194  
only cases of medical emergency to address immediate hazards to study subjects, or when the 
changes involve only logistic or administrative aspects of the study. 
In the event of a medical emergency, the investigator at each site may institute any medical 
procedures deemed appropriate to address an immediate hazard to a subject without prior 
IEC/IRB approval or favorable opinion. As soon as possible, the implemented deviation or 
change, the reason(s) for it, and, if appropriate, the proposed study protocol amendment(s) 
should be submitted to: 
•
The Sponsor (delegate) for agreement
•
The IEC/IRB for review and approval or favorable opinion (if required) 
•
The applicable competent regulatory authority (if required) 
Details of the procedure for implementing study protocol amendments are available in 
Section 12.10. 
At the earliest opportunity, the investigator (or delegate) must inform the Sponsor (delegate)
about any notable protocol deviations and explain any deviation from the approved study 
protocol in the CRF and/or in the Protocol Deviation Log, if applicable. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 106 of 194  
12.
ADMINISTRATIVE ASPECTS
12.1
CLINICAL TRIAL AGREEMENT
This study will be conducted under a Clinical Trial Agreement between the Sponsor (or 
delegate) and the respective institutions representing the study sites. Any financial support 
given to the study sites will be detailed in the Clinical Trial Agreement. The Clinical Trial 
Agreement, which must be signed before the start of any study related procedures, will clearly 
delineate the responsibilities and obligations of the investigator and the Sponsor (delegate), and 
will form the contractual basis upon which the study will be conducted.  
12.2
FINANCIAL DISCLOSURE BY INVESTIGATOR
Prior to study initiation, the investigator and any subinvestigator(s) to be directly involved in 
the treatment or evaluation of study subjects at each study site will disclose to the Sponsor 
(delegate) any relevant financial or proprietary interests in either the study product or the 
Sponsor company. The appropriate disclosure form(s) will be provided by the Sponsor 
(delegate) for this purpose. Any relevant updates to the financial disclosure information that 
occur during the conduct of the study, or during one year after completion of the study, will be 
provided by the investigator and subinvestigator(s) to the Sponsor (delegate). All financial 
disclosure information provided by the investigator and subinvestigator(s) will be submitted to 
appropriate competent authorities according to the applicable regulatory requirements. 
12.3
CLINICAL STUDY REGISTRATION AND RESULTS DISCLOSURE
The Sponsor will provide the relevant study protocol information in a public database (eg, 
ClinicalTrials.gov) before or at commencement of the study, as required by local country 
requirements. The Sponsor (delegate) may also provide study information for inclusion in 
national registries according to local regulatory requirements. 
If a potential subject contacts the Sponsor regarding participation in the study, the investigator 
agrees that the Sponsor (delegate) may forward the relevant study site and contact details to the 
subject. Based on the inclusion and exclusion criteria for the study, the investigator will assess 
the suitability of the subject for enrollment into the study. Results of this study will be 
disclosed according to the relevant regulatory requirements. All publications in peer-reviewed 
medical journals resulting from this study will be listed in the original study protocol 
registration record on public databases (eg, ClinicalTrials.gov).  
12.4
STUDY FILES AND MATERIALS
Before the start of any study related procedures, all essential documents specified by ICH GCP 
and other applicable regulations must be available in the relevant files maintained by the 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 107 of 194  
Sponsor (or delegate) and the investigator. An Investigator Study File prepared by the Sponsor 
(or delegate), containing all applicable documents for use at the study site, will be made 
available to the investigator before the start of the study. A list of personnel and organizations 
responsible for conduct of the study as well as the list of investigators will be included in the 
Investigator Study File. The respective files will be kept and updated by the Sponsor (or 
delegate) and the investigator, as applicable. 
All study documentation and materials maintained in the Investigator Study File at the study 
site must be available for inspection by the Sponsor’s study monitor (or delegate) to determine 
that all required documentation is present and correct (see Section 12.9). 
The study may be audited or inspected by qualified delegates from the Sponsor or a competent 
regulatory authority (see Section 12.11).
12.5
INITIATION OF THE STUDY
Before the start of the study at each study site, the Sponsor’s study monitor (or delegate) will 
visit the study site to ensure adequacy of the facilities and to discuss responsibilities regarding 
study protocol adherence with the investigator and other personnel involved in the study. 
The investigator may not enroll any subjects into the study before the Sponsor has received 
written approval or a favorable opinion from the IEC/IRB for conducting the study and a 
formal meeting has been conducted by the Sponsor’s study monitor (or delegate) to initiate the 
study (study initiation visit). This meeting will include an inventory of study supplies and a 
detailed review of the study protocol and procedures, the CRF, IMP accountability, and the 
subject diary. 
12.6
SUBJECT REIMBURSEMENT
Where relevant, subjects will be reimbursed for reasonable travel costs associated with 
participation in this study, after presentation of receipts for the travel in question, at a rate to be 
approved by the IEC/IRB. Subjects will not be paid for participating in the study.  
12.7
LIABILITY AND INSURANCE
The civil liability of the involved parties with respect to financial loss due to personal injury 
and other damage that may arise as a result of this study being conducted are governed by the 
applicable legal requirement(s).
The Sponsor will provide insurance to the investigator if required by the applicable regulatory 
and legal requirement(s).
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 108 of 194  
If required by local law, subjects taking part in this study will be insured against any injury 
caused by the study in accordance with the applicable regulatory and legal requirement(s).  
12.8
SUBJECT IDENTIFICATION AND CONFIDENTIALITY
All study documents, including the study protocol and CRFs, are the confidential property of 
the Sponsor and should be treated as such. 
All subjects screened for the study will be documented in a screening log in compliance with 
the requirements of individual study sites. Subjects not enrolled into the study will be 
documented as such in the screening log together with the reason for not having been enrolled.  
The investigator will maintain a personal list of subject names and subject numbers (Subject 
Identification List) for participants in the study to enable records to be identified at a later date. 
These records should be retained in a confidential manner for the duration stipulated by 
applicable regulatory requirements. All subject names will be kept in confidence and will not 
be revealed to the Sponsor. Subject names must be made unreadable on any documents made 
available to the Sponsor. 
Subjects participating in the study will be identified in the CRF by the subject number allotted 
to them during the study.  
The ICF will include a statement that all study findings, irrespective of the medium on which 
they are stored, will be handled in strictest confidence in accordance with applicable data 
protection laws (eg, the European Data Protection Directive [95/46/EC] and the USA Health 
Insurance Portability and Accountability Act), and will be evaluated by the Sponsor and/or a 
competent regulatory authority in an anonymized form. The subjects are also to be informed 
that their medical records may be audited or inspected by qualified delegates from the Sponsor 
or a competent regulatory authority. The subject’s written consent authorizing direct access to 
his medical records, and computer processing and publishing of his anonymous personal data, 
must be obtained prior to participation in the study. 
A subject’s identity will be disclosed by the investigator only in case of emergency (ie, to 
address any immediate health hazard).
12.9
MONITORING OF THE STUDY
The investigator at each site will allow the Sponsor’s study monitor (or delegate) reasonable 
access to the CRFs and direct access to related source documents for monitoring purposes as 
frequently as the Sponsor deems necessary. These documents include records of tests 
performed as a requirement for participating in the study as well as other medical records 
required to confirm information contained in the CRF, such as past history and secondary 
diagnoses. 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 109 of 194  
Before each monitoring visit, the investigator (or delegate) should record all data generated 
since the last monitoring visit in the CRF. The investigator and other relevant personnel at each 
study site will be expected to cooperate with the Sponsor’s study monitor to assist in providing 
any missing information. 
The study monitor will require access to the Investigator Study File to ensure completeness of 
all documentation required for the study. The study monitor will ensure that the investigator at 
each site has been provided with adequate means for organization and filing of study 
documentation (see Section 12.4).
The date on which the study monitor (or delegate) visits the study site will be recorded in the 
Site Visit Log. During monitoring visits, the study site’s coordinator (if applicable) and the 
investigator should be available, the source documentation should be accessible, and a suitable 
environment should be provided for the study monitor to review study related documentation. 
The main objectives of monitoring visits conducted by the study monitor include: 
•
Resolution of any problems 
•
Examination of all study documentation for completion, adherence to the study 
protocol, and possible AEs
•
Clarification of inconsistencies or missing data
•
Verification of study data against source documents 
•
Checks that investigator obligations have been fulfilled 
•
Review of ICFs and dates of consent 
•
Inspection of IMP with respect to storage, labeling, and documentation 
•
Drug accountability 
After each subject’s visit to the study site, the investigator (or delegate) will ensure that all data 
have been entered into the CRF correctly and in a timely manner, after which the investigator 
will sign the CRF.
12.10
PROTOCOL AMENDMENTS
A “substantial” amendment of a study protocol is any written description of change(s) to, or 
formal clarification of, a study protocol that may have a significant impact on the safety or 
physical or mental integrity of subjects, the scientific value of the study, the conduct or 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 110 of 194  
management of the study, or the quality or safety of any IMP used in the study. The IEC/IRB 
must approve all substantial protocol amendments prior to their implementation. If required by 
applicable local regulatory requirements, the local regulatory authority must also approve all 
substantial protocol amendments prior to their implementation.
A “non-substantial” amendment of a study protocol includes minor corrections or clarifications 
that have no significant impact on the way the study is to be conducted and has no effect on the 
safety of participating subjects (eg, change in study monitor, contact details, etc.). If required 
by applicable local regulatory requirements, the IEC/IRB, and/or the local regulatory authority 
should be notified of all non-substantial protocol amendments. The substantial and non-
substantial protocol amendments will be integrated into an updated study protocol at the 
discretion of the Sponsor if the changes to the original study protocol are numerous, or if 
required by applicable regulatory requirements. 
12.11
AUDITS AND INSPECTIONS
The study may be audited or inspected by qualified delegates from the Sponsor or a competent 
regulatory authority.  
In the event of an audit by the Sponsor, the investigator must make all study related 
documentation available to the auditor(s). Regulatory authorities may request access to all 
study related documentation, including source documents, for inspection and copying in 
keeping with applicable regulations. The Sponsor will immediately notify the investigator (or 
vice versa) of an upcoming audit or inspection. 
If an audit or inspection occurs, the investigator and relevant personnel at the study site must 
allocate sufficient time to discuss the findings and any relevant issues. 
12.12
CLINICAL STUDY REPORT
After completion of the study, a clinical study report covering clinical and statistical aspects of 
the study will be prepared by the Sponsor (or delegate) in consultation with the coordinating 
investigator. As required by the applicable regulatory requirements, the clinical study report 
will be signed by the Sponsor’s responsible medical officer as well as the coordinating 
investigator (if applicable). 
Progress reports and/or a summary of the clinical study report will be provided to the IEC/IRB 
and competent regulatory authorities in accordance with applicable requirements. 
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12.13
USE OF DATA AND PUBLICATIONS
The rights and obligations of investigators and the Sponsor concerning any formal presentation 
or publication of data collected as a direct or indirect result of this study will be addressed 
specifically in the Clinical Trial Agreement for the study (see Section 12.1).
For multicenter studies, the first publication must be based upon all data obtained from all 
analyses, as stipulated in the study protocol by the biostatistician and not by the investigators. 
Investigators participating in multicenter studies must agree not to present data gathered 
individually or by a subgroup of study sites before the full, initial publication is available or 
5 years after the last clinical study visit, whichever is later, unless this has been agreed to by all 
other investigators and by the Sponsor. 
The Sponsor must receive a copy of any intended communications in advance of the proposed 
submission date. This is to allow the Sponsor time to review the communication for accuracy 
(thus avoiding potential discrepancies with submissions to regulatory authorities), to verify that 
confidential and/or proprietary information is not inadvertently divulged, to provide any 
relevant supplementary information, and to allow establishment of co-authorship (as 
appropriate). The authorship of communications arising from pooled data will include 
investigators from study sites that contributed data as well as relevant personnel from the 
Sponsor. Ownership of all data will remain with the Sponsor. 
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13.
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14.
APPENDICES
14.1
APPENDIX 1 – LIST OF PROHIBITED CONCOMITANT MEDICATIONS 
alfentanil
mexiletine
almotriptan
naratriptan
alprenolol
nefazodone
amitriptyline
nortriptyline
amphetamine
ondansetron
astemizole
oxcarbazepine
atomoxetine
oxycodone
bufuralol
paroxetine
bupropion
perphenazine
buspirone
phenacetin
cafergot
phenobarbital
cannabidiol
phenytoin
carbamazepine
promethazine
cerivastatin
propafenone
citalopram
retigabine/ezogabine
clomipramine
risperidone
codeine
ritonavir
cyproheptadine
rizatriptan
desipramine
selegiline
dextromethorphan
sertraline
duloxetine
sumatriptan
eletriptan
telaprevir
encainide
thc and derivatives
ergotamine tartrate
tramadol
eslicarbazepine
trazodone
felbamate
vortioxetine
fentanyl
zolmitriptan
fluoxetine
zuclopenthixol
fluvoxamine
frovatriptan
imipramine
levacetylmethadol (laam)
linezolid
meperidine
methadone
metoclopramide
PUBLIC 
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va
v
thereof. 

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

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

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PUB
UB
UBLIC COPY 
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14.5
APPENDIX 5 – TANNER STAGING
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14.6
APPENDIX 6 – PEDSQL
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14.7
APPENDIX 7 – EQ-5D-5L QUESTIONNAIRE
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14.8
APPENDIX 8 – HOSPITAL ANXIETY AND DEPRESSION SCALE
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14.9
APPENDIX 9 – MAXIMUM ALLOWABLE BLOOD DRAW VOLUMES
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14.10
APPENDIX 10 – KAROLINSKA SLEEPINESS SCALE
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14.11
APPENDIX 11 - STUDY CONDUCT DURING COVID-19 
In March 2020, the World Health Organization declared a global pandemic related to an illness caused 
by a novel coronavirus known as COVID-19.  As a result, public health initiatives, such as laws, 
regulations and policies were enacted at country and institutional levels to protect the health of the 
general public. These initiatives and policies have affected the ability of study sites to conduct the trial 
per protocol and the ability of the sponsor and/or delegate to conduct trial oversight and monitoring 
visits. 
In an effort to support the rights, safety and welfare of subjects and ensure as little impact on the 
integrity of the research as possible the following alternative processes have been implemented due to 
restrictions related to COVID-19. Though every attempt should be made to conduct study visits per 
protocol, any implementation of alternative processes should be properly documented.  
1. Allowance of Delays to In-person Study Visits
If sites are unable to conduct study visits, or subjects are unable to travel to the study site due to 
COVID-19 circumstances, an in-person visit may be delayed up to 6 weeks from the protocol-
defined visit due date. Data will need to be entered per normal procedures in the EDC, with a 
description indicating COVID-19 as the cause for delay in response to queries. If a subject is unable 
to travel to the study site within this expanded 6-week window, a telephone or video telemedicine 
visit should be attempted, as described below. If a telephone or video telemedicine visit cannot be 
conducted in the 6-week window, the visit should be considered missed and the next scheduled visit 
conducted.   
2. Allowance of Remote Telemedicine/Telephone/Video Visits:
Visit 1 should be conducted in person. For Visits 2 through 15, remote visits via telephone or video 
are acceptable when subjects are unable to travel to the site for in-person visits due to COVID-19 
circumstances. The following information should be collected and recorded in the source 
documentation and in the EDC where applicable. Log pages (e.g. AEs, concomitant medication 
changes) will be entered normally as they are not associated with specific visits; assessment forms 
located within a particular visit page will also be entered normally, however, queries will be fired to 
capture specific information explaining the basis for missing or alternatively collected (ie. remote) 
data. Detailed instruction for EDC entry may be found in the CRF Completion Guidelines (CCGs). 
•
Date and time of the telephone/video visit
•
Any changes in health status 
•
AEs/SAE assessment
•
Concomitant medication query
•
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abnormalities in seizure activity
•
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o
Tanner Staging 
3. End-of-Study/Early Termination (EOS/ET) and Follow-up Visits:  
Cardiac follow-up visits must be conducted in-person. 
EOS/ET for subjects tapering off ZX008: 
For the EOS/ET visit (Visit 16) and Post-Dosing Follow-up visit (Visits 17-19), every attempt 
should be made to conduct these visits in-person. For subjects tapering off study-drug that are 
unable to come to the study site, the EOS/ET and Post-Dosing Follow-up visits may be conducted 
via telephone or video. However, subjects should return to the study site in person, as soon as 
feasible to conduct any safety assessments that were unable to be evaluated remotely.  If an in-
person visit cannot be scheduled within 6 months of the EOS/ET and/or Post-Dosing Follow-up 
visit windows, these visits will be considered as missed.
EOS/ET for subjects transitioning to Commercial drug: 
For the EOS/ET visit (Visit 16) and Post-Dosing Follow-up visit (Visit 17), every attempt should be 
made to conduct these visits in-person. For subjects tapering off study-drug that are unable to come 
to the study site, the EOS/ET and Post-Dosing Follow-up visits may be conducted via telephone or 
video. However, subjects should return to the study site in person, as soon as feasible to conduct any 
safety assessments that were unable to be evaluated remotely. Subjects who transition to 
commercially available drug must have an ECHO within 3-6 months before starting commercial 
drug and will have follow-up ECHOs within the required timeframe while on commercial drug.
EOS/ET for subjects transitioning to another extension study: 
For subjects transitioning into another ZX008 extension study that are unable to attend the EOS/ET 
visit due to restrictions to traveling to the study site, delays in the start-up of the extension study, or 
other COVID-related delays, the EOS/ET visit may be delayed until an in-person visit is conducted. 
Therefore, subjects may remain on study for longer than the planned duration of participation. If the 
delay is over 6 weeks, medical monitor review and approval is required. If approval to extend 
beyond 6 weeks ins granted, telephone or video visits should be conducted at least every 12 weeks 
until the in-person EOS/ET transitional visit to the other extension study is performed. The 
telephone or video visits will collect the following data, at minimum:
•
Date and time of the telephone/video visit
•
Any changes in health status  
•
AEs/SAE assessment
•
Concomitant medication query
•
Review seizure and medication diary with parent/caregiver for compliance and any 
abnormalities in seizure activity
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ZX008, Fenfluramine Hydrochloride
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Confidential
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4. Allowance of delays to ECHO, ECG, Chest X-Ray, EEG and clinical lab assessments 
when in-person study visits are missed or delayed
If it is not possible to obtain the assessments as described below, a documented risk/benefit 
discussion with the medical monitor is required to determine a course of action, which may 
include approval to delay further for a pre-specified duration, subject withdrawal, or other 
actions. The risk/benefit analysis will take into account report of drug effectiveness, AEs, 
previous assessment findings, duration of delay, clinical improvement while on study drug 
(seizure and non-seizure outcomes), and region-specific risk of attending in-person visits to 
complete the assessments. 
Doppler ECHO:   
If subjects are unable to travel to the study site due to COVID-19 circumstances, ECHOs may be 
delayed up to an additional 3 months from the protocol-designated ECHO due date (for a total of 6 
months from the time of the last ECHO) for subjects that exhibited the following on their previous, 
most recent ECHO: absent aortic regurgitation, absent or trace mitral regurgitation, and PASP <30 
mmHg.
All subjects with regurgitation ≥ trace aortic regurgitation, ≥mild mitral regurgitation, or PASP ≥30 
mmHg may have ECHO delayed from the protocol-designated ECHO due date by up to 6 weeks 
only In those cases where an ECHO cannot be performed in the specified time period at the study-
authorized facility by a certified sonographer, the Sponsor may approve administration of the 
ECHO at an alternative facility to minimize subject’s need for travel. If the ECHO cannot be 
performed, a risk/benefit analysis must be conducted as described above.
If a delayed ECHO was conducted within 30 days of a scheduled Cardiac Follow-up Visit, this 
assessment does not need to be repeated at the Cardiac Follow-up Visit provided there were no 
findings meeting Level 2 criteria (see Protocol Table 12) that require additional follow-up. 
ECG, Chest X-ray and EEG:  
If clinically indicated and where applicable, delays in these assessments may be implemented based 
on the investigators’ clinical discretion, weighing the risk/benefit of the clinical necessity of the 
assessment versus the risk of an in-person visit. All decisions should be documented appropriately 
in the source documentation. If not conducted at the study site, ECG, chest X-ray and EEG can be 
performed at any qualified local facility. If not conducted at the study site, results should be sent to 
the Principal Investigator for safety overread and documentation. If Level 2 or greater findings were 
observed, then the Cardiac Follow-up Visit should be re-scheduled from the date of the delayed 
ECHO.
If the ECG (or in the case of certain country-specific regulations: Chest X-ray or EEG) was 
conducted within 30 days of a scheduled Cardiac Follow-up Visit, these assessments do not need to 
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Zogenix International Limited
ZX008, Fenfluramine Hydrochloride
ZX008-1503 Clinical Study Protocol Amendment 5.0 (ROW) 03 August 2020
Confidential
Page 169 of 194  
be repeated at the Cardiac Follow-up Visit provided there were no significant findings that require 
additional follow-up. 
Clinical Laboratory Assessments:
If clinically indicated and where applicable, delays in these assessments may be implemented based 
on the investigators’ clinical discretion, weighing the risk/benefit of the clinical necessity of the 
assessment versus the risk of an in-person visit. All decisions should be documented appropriately 
in the source documentation. If not conducted at the study site, clinical laboratory assessments can 
be performed at any qualified local facility with results sent to the Principal Investigator for safety 
overread and documentation.  
5. Alternative Dispensation for Study Drug 
Shipments of investigational product may be sent by courier from site pharmacy to the subject’s 
home via Sponsor-approved processes if the subject cannot or will not attend the dispensation 
visit(s). This shipment of drug should be arranged for patients who are due in the clinic for a drug 
dispensation visit. Other alternative dispensation, such as curbside pickup, may be implemented 
provided they are approved by the Sponsor and appropriate safeguards are taken to ensure 
compliance with existing regulatory requirements for maintaining investigational product 
accountability. Detailed instructions for drug handling, storage, accountability, etc. are described in 
the Pharmacy Manual.  
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ZX008, Fenfluramine Hydrochloride
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Confidential
Page 170 of 194  
SUMMARY OF PROTOCOL AMENDMENT 5.0 
Clarifications and changes were made to the protocol amendment 5.0 to include study conduct 
information for the COVID-19 pandemic, updated background information related to existing 
treatments for Dravet and additional clinical and pre-clinical study data made available in the 
updated ZX008 IB. 
List of Specific Changes
Additions are marked by underlined font and deletions are marked in strikethrough. Minor 
editorial and non-substantive changes, such as the correction of typing or formatting errors, 
updated use of abbreviations, updating headers and footers, tables of contents, list of 
abbreviations, signature pages, etc, are not listed. Note that the list of specific changes below is 
presented in the order in which they appear in the protocol. 
1. Zogenix Address Change: 
Title Page and Signature Page: 
2.  Addition of the following text regarding transition of subjects to a separate ZX008 
extension protocol or to commercial drug.  
Study Synopsis: 
Table 1: Schedule of Assessments for Subjects from Core Studies ZX008-1501 and 
ZX008-1502, and de Novo Subjects and Table 2: Schedule of Assessments for Subjects in 
Core Study ZX008-1504 
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LIC 
C
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COPY 
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ns 
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C
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Section 3.1: Overall Study Design and Plan 
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Section 10.4: Treatment Periods 
3. Update to include Japan in list of participating centers
LIC 
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4.  Updated background information related to existing treatments for Dravet and additional 
clinical and pre-clinical study data made available in the updated ZX008 IB. 
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5.
Updates to the data available for Risk-Benefit Section 1.8 
6.  Reference to ZX008 IB 2016 updated to ZX008 IB. 
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7.  Provides study conduct information during the COVID-19 Pandemic 
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Confidential
Page 194 of 194  
8. Table 11 updated to Table 12. Table was amended to reflect the latest safety database, 
contained in the NDA and MAA and updated in the 120-day Safety update, the lack of 
appearance of valvular heart disease or PAH in any subject supports the removal of 
IDSMC oversight of mild mitral regurgitation in children. It further supports utilization of 
the Level 2 review for moderate mitral, pulmonic and tricuspid regurgitation in the 
absence of any indicators of PAH. 
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