An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy for Seizures in Patients With Rare Seizure Disorders Such as Epileptic Encephalopathies Including Dravet Syndrome and Lennox-Gastaut Syndrome
Phase: PHASE3
Conditions: Dravet Syndrome, Lennox Gastaut Syndrome, Epileptic Encephalopathy
Sponsor: Zogenix, Inc.

 
ZX008, Fenfluramine Hydrochloride
ZX008-1900/EP0215 Clinical Study Protocol Amendment 4.0
22 September2022
Confidential 
Page 1 of 105  
 
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 for Seizures in Patients with Rare Seizure 
Disorders Such as Epileptic Encephalopathies Including Dravet 
Syndrome and Lennox-Gastaut Syndrome 
Study Number: 
ZX008-1900/EP0215 
Study Product: 
Fenfluramine Hydrochloride Oral Solution; ZX008 
IND Number: 
125797, 132604 
EudraCT: 
2019-001331-31 
Sponsor: 
Zogenix International Limited 
an indirectly wholly owned subsidiary of Zogenix Inc. which is a 
directly wholly owned subsidiary of UCB Biosciences,  
4000 Paramount Pkwy, Suite 200, Morrisville, NC 27560, USA 
Sponsor's Medical 
Contact 
 
Study Physician 
UCB Biosciences Inc 
 
Date/Version of 
Study Protocol: 
22 September 2022 (Amendment 4.0) 
27 July 2020 (Amendment 3.1)  
13 July 2020 (Amendment 3.0) 
04 Sep 2019 (Amendment 2.2) 
11 July 2019 (Amendment 2.0) 
22 April 2019 (Amendment 1.0) 
1 March 2019 (Original) 
A list of personnel and organizations responsible for the conduct of the study will be supplied to 
study sites as part of the Investigator Study File. This list will be updated by the Sponsor or the 
Sponsor's agent and provided to study sites as needed. 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF TABLES ...........................................................................................................................5 
SIGNATURE OF SPONSOR ..........................................................................................................6 
SIGNATURES OF COORDINATING INVESTIGATOR .............................................................7 
SIGNATURE(S) OF PRINCIPAL INVESTIGATOR(S) ...............................................................8 
LIST OF ABBREVIATIONS ..........................................................................................................9 
STUDY SYNOPSIS ......................................................................................................................11 
1. 
INTRODUCTION ......................................................................................................18 
1.1. 
Background Information on Indication Studied .........................................................18 
1.2. 
Background Information on Study Product ................................................................20 
1.3. 
Preclinical Data ...........................................................................................................20 
1.4. 
Clinical Pharmacology ................................................................................................21 
1.5. 
Clinical Data ...............................................................................................................22 
1.6. 
Rationale for Current Study ........................................................................................25 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................27 
2.1. 
Primary Objective .......................................................................................................27 
2.2. 
Secondary Objectives .................................................................................................27 
2.3. 
Study Endpoints ..........................................................................................................27 
3. 
INVESTIGATIONAL PLAN .....................................................................................29 
3.1. 
Overall Study Design and Plan ...................................................................................29 
3.2. 
Number of Subjects ....................................................................................................30 
3.3. 
Study Duration ............................................................................................................30 
3.4. 
Number of Study Centers ...........................................................................................30 
3.5. 
Rationale for Study Design .........................................................................................30 
3.6. 
Premature Termination of Study ................................................................................31 
3.7. 
Study Monitoring Procedures .....................................................................................31 
4. 
SELECTION OF STUDY POPULATION ................................................................33 
4.1. 
Inclusion Criteria ........................................................................................................33 
4.2. 
Exclusion Criteria .......................................................................................................33 
4.3. 
Subjects of Reproductive Potential .............................................................................34 
4.4. 
Removal of Subjects from Therapy or Assessment ....................................................36 
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ZX008, Fenfluramine Hydrochloride
ZX008-1900/EP0215 Clinical Study Protocol Amendment 4.0
22 September2022
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4.5. 
Termination of the Clinical Study ..............................................................................38 
4.6. 
Replacement of Subjects .............................................................................................38 
5. 
INVESTIGATIONAL MEDICINAL PRODUCT INFORMATION ........................39 
5.1. 
Identity of Investigational Medicinal Product ............................................................39 
5.2. 
Shipment and Storage .................................................................................................39 
5.3. 
Investigational Medicinal Product Accountability .....................................................40 
5.4. 
Treatment Administration ...........................................................................................40 
5.5. 
Blinding ......................................................................................................................42 
5.6. 
Prior and Concomitant Medication .............................................................................42 
5.7. 
Treatment Compliance ................................................................................................44 
6. 
VISIT SCHEDULE ....................................................................................................45 
6.1. 
Open-label Extension Treatment Period .....................................................................45 
6.2. 
EOS/ET Follow Up Visit (Clinic Visit 8; EOS/ET +14 days) ...................................49 
6.3. 
Cardiac Follow Up Visit (Clinic Visit 9; last dose + 6 Months) ................................49 
6.4. 
Estimated Blood Volume Collection ..........................................................................50 
6.5. 
Specific guidance related to COVID-19 pandemic ....................................................51 
7. 
EFFECTIVENESS, SAFETY, AND PHARMACOKINETIC 
ASSESSMENTS.........................................................................................................52 
7.1. 
Effectiveness Assessments .........................................................................................52 
7.2. 
Safety Assessments .....................................................................................................53 
7.3. 
Appropriateness of Measurements .............................................................................56 
8. 
ADVERSE EVENTS..................................................................................................57 
8.1. 
Definitions ..................................................................................................................57 
8.2. 
Severity of Adverse Events ........................................................................................59 
8.3. 
Causality of Adverse Events .......................................................................................59 
8.4. 
Observation Period for Adverse Event Reporting ......................................................60 
8.5. 
Adverse Event Reporting ............................................................................................60 
8.6. 
Serious Adverse Events Reporting .............................................................................61 
8.7. 
Reporting of Serious Adverse Events by Investigator to IEC/IRB ............................62 
8.8. 
Reporting of Events Other Than Serious Adverse Events by Investigator to 
Sponsor .......................................................................................................................62 
8.9. 
Follow-up of Adverse Events .....................................................................................62 
8.10. 
Pregnancy ...................................................................................................................65 
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22 September2022
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9. 
DATA HANDLING PROCEDURES ........................................................................66 
9.1. 
Recording of Data .......................................................................................................66 
9.2. 
Data Quality Assurance ..............................................................................................66 
9.3. 
Record Retention ........................................................................................................66 
10. 
STATISTICS ..............................................................................................................68 
10.1. 
Determination of Sample Size ....................................................................................68 
10.2. 
Analysis Populations ..................................................................................................68 
10.3. 
Treatment Groups .......................................................................................................68 
10.4. 
Treatment Periods .......................................................................................................68 
10.5. 
Statistical Analyses and Methods ...............................................................................69 
10.6. 
Analyses Provided to an Independent Data and Safety Monitoring 
Committee ...................................................................................................................70 
11. 
ETHICAL & REGULATORY CONSIDERATIONS ...............................................71 
11.1. 
Ethical Considerations ................................................................................................71 
11.2. 
Informed Consent .......................................................................................................71 
11.3. 
Regulatory Considerations and Independent Ethics Committee/Institutional 
Review Board .............................................................................................................72 
11.4. 
Protocol Compliance ..................................................................................................73 
12. 
ADMINISTRATIVE ASPECTS ................................................................................74 
12.1. 
Clinical Trial Agreement ............................................................................................74 
12.2. 
Financial Disclosure by Investigator ..........................................................................74 
12.3. 
Clinical Study Registration and Results Disclosure ...................................................74 
12.4. 
Study Files and Materials ...........................................................................................74 
12.5. 
Initiation of the Study .................................................................................................75 
12.6. 
Subject Reimbursement ..............................................................................................75 
12.7. 
Liability and Insurance ...............................................................................................75 
12.8. 
Subject Identification and Confidentiality ..................................................................75 
12.9. 
Monitoring of the Study..............................................................................................76 
12.10. 
Protocol Amendments ................................................................................................77 
12.11. 
Audits and Inspections ................................................................................................77 
12.12. 
Clinical Study Report .................................................................................................77 
12.13. 
Use of Data and Publications ......................................................................................78 
13. 
REFERENCE LIST ....................................................................................................79 
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14. 
APPENDICES ............................................................................................................82 
14.1. 
Appendix 1  List of Restricted Concomitant Medications .......................................82 
14.2. 
Appendix 2  Columbia  Suicide Severity Rating Scale ..........................................83 
14.3. 
Appendix 3  Clinical Global Impression  Severity (CGI-S) ...................................86 
14.4. 
Appendix 4  Clinical Global Impression  Improvement (CGI-I) ...........................88 
14.5. 
Appendix 5  Maximum Allowable Blood Draw Volumes .......................................90 
14.6. 
Appendix 6 - Study Conduct During COVID-19 .......................................................91 
14.7. 
Appendix 7- Summary of Protocol Amendment 3.0 ..................................................94 
 
LIST OF TABLES 
Table 1. 
Schedule of Assessments for Subjects ........................................................................15 
Table 2.  
Investigational Medicinal Product  ZX008 ...............................................................39 
Table 3.  
Taper Algorithm .........................................................................................................42 
Table 4.  
Time Windows for Assessments ................................................................................45 
Table 5.  
Schedule of Post-Treatment Cardiac Follow-up .........................................................50 
Table 6. 
Estimated Blood Volume Collectiona .........................................................................50 
Table 7.  
Severity Definition of Adverse Eventsa ......................................................................59 
Table 8. 
Clinical Measures Enacted Upon Increasing Severity of ECHO Findings ................63 
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ZX008-1900/EP0215 Clinical Study Protocol Amendment 4.0
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SIGNATURE OF SPONSOR 
 
Study Number:  ZX008-1900 
Study Title: 
An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 
(Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy for 
Seizures in Patients with Rare Seizure Disorders Such as Epileptic 
Encephalopathies Including Dravet Syndrome and Lennox-Gastaut Syndrome 
___________________________________________________________________________ 
 
: 
 
 
Development Lead, Epilepsy  
UCB Biosciences Inc.  
4000 Paramount Pkwy, Suite 
, Morrisville, NC 27560, 
USA  
 
________________________ 
___________________________ 
 (Signature)  
(Date [DD/MMM/YYYY])  
 
On behalf of 
: 
 
UCB Biosciences Inc. 
 
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ZX008-1900/EP0215 Clinical Study Protocol Amendment 4.0
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SIGNATURES OF COORDINATING INVESTIGATOR 
Study Number:  ZX008-1900/EP0215 
Study Title: 
An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 
(Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy for 
Seizures in Patients with Rare Seizure Disorders Such as Epileptic 
Encephalopathies Including Dravet Syndrome and Lennox-Gastaut Syndrome 
___________________________________________________________________________ 
 
Co-Coordinating Investigator: 
 
 
 University of California, San Francisco 
 
 San Francisco, CA USA 
 
 
 
 
 
__________________________________________ 
___________________________ 
 (Signature)  
(Date [DD/MMM/YYYY])  
 
 
 
 
 
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ZX008-1900/EP0215 Clinical Study Protocol Amendment 4.0
22 September2022
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SIGNATURE(S) OF PRINCIPAL INVESTIGATOR(S) 
Study Number: ZX008-1900/EP0215 
Study Title: 
An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 
(Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy for 
Seizures in Patients with Rare Seizure Disorders Such as Epileptic 
Encephalopathies Including Dravet Syndrome and Lennox-Gastaut 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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ZX008, Fenfluramine Hydrochloride
ZX008-1900/EP0215 Clinical Study Protocol Amendment 4.0
22 September2022
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LIST OF ABBREVIATIONS 
ABBREVATION 
DEFINITION 
AE 
adverse event 
AED 
antiepileptic drug 
ANCOVA 
analysis of covariance 
AS 
atonic seizure 
BID 
bis in die; 2 times per day 
BMI 
body mass index 
CBD 
cannabidiol 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression - Improvement 
CRO 
Contract Research Organization 
CRF 
case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450 
dL 
deciliter 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
EOS 
end of study 
ET 
early termination 
FS 
focal seizure 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GH 
growth hormone 
GTC 
Generalized Tonic Clonic (seizure) 
GMP 
Good Manufacturing Practices 
GP 
general practitioner 
HADS 
Hospital Anxiety and Depression Scale 
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 
ICAB 
International Cardiology Advisory Board 
IRB 
Institutional Review Board 
IWR 
interactive web response (system) 
KD 
ketogenic diet 
kg 
kilogram 
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ZX008-1900/EP0215 Clinical Study Protocol Amendment 4.0
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ABBREVATION 
DEFINITION 
LGS 
Lennox-Gastaut syndrome 
LH 
luteinizing hormone 
LLN 
lower limit of normal 
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 
SAE 
serious adverse event 
SAF 
safety population 
SD 
standard deviation 
SE 
status epilepticus 
SMEI 
severe myoclonic epilepsy of infancy 
SoA 
schedule of assessments 
STP 
stiripentol 
SUDEP 
sudden unexpected death in epilepsy 
TEAE 
Treatment Emergent Adverse Event 
THC 
tetrahydrocannabinol 
TS 
tonic seizure 
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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ZX008-1900/EP0215 Clinical Study Protocol Amendment 4.0
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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 for Seizures in Patients with Rare Seizure Disorders 
Such as Epileptic Encephalopathies Including Dravet Syndrome and Lennox-Gastaut Syndrome 
Study Number: ZX008-1900 
Study Product: Fenfluramine Hydrochloride Oral Solution, ZX008 
Type of Study: 
Long-term safety 
Indication(s) Studied:  
Rare Seizure Disorders Such as Epileptic Encephalopathies, 
including Dravet syndrome and Lennox-Gastaut syndrome 
Phase of Development: Phase III  
Countries: North America, Europe, Australia, and Japan 
Sponsor: Zogenix International Limited  
Co-Coordinating Investigator: 
 
Estimated Duration of Individual Subject Participation: 
Participation for subjects will be voluntary until approval of ZX008 has been obtained from regulatory 
-
specific requirements in addition to legal and regulatory guidelines in the subjects  country of residence, or 
until the investigational product development for 
, whichever 
comes first. 
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 on the following effectiveness measures: 
- Investigator assessment of convulsive 
 or 100% [ie, 
seizure-free] improvement) 
- Clinical Global Impression  Improvement (CGI-I) rating, global and symptomatic, as assessed by 
the investigator 
- CGI-I rating, global and symptomatic, as assessed by the parent/caregiver 
 
Methodology: This is an international, multicenter, open-label, long-term safety study of ZX008 in patients 
with rare seizure disorders, epileptic encephalopathy, including Dravet syndrome or Lennox-Gastaut syndrome. 
Subjects eligible for participation are those with Dravet syndrome who are currently enrolled in 
Study ZX008-1503, or those with LGS who have successfully completed Study ZX008-1601-Part 2, and are 
candidates for continued treatment with ZX008 for an extended period of time, or those with Dravet syndrome, 
Lennox-Gastaut syndrome, or another epileptic encephalopathy who have completed participation in a 
Zogenix-sponsored study and have been invited to participate in this study. Participation in this OLE study is 
entirely voluntary  
Subject will be eligible to participate in this trial until approval of ZX008 has been obtained from regulatory 
-
specific requirements in addition to legal and regulatory guidelines in the subjects country of residence, or until 
the investigational product development for 
, whichever 
comes first. Subjects entering this OLE study who have participated in 1503 or 1601 will receive ZX008 
initially at the dose prescribed at the last visit in Study 1503 or Study 1601 Part 2, but will have the volume  
adjusted according to weight of the patient. Dose increases, to a maximum of 0.8 mg/kg/day (maximum 30 
mg/day) for subjects not receiving concomitant stiripentol (STP) or 0.5 mg/kg/day (maximum 20 mg/day) for 
subjects receiving concomitant stiripentol (STP), during this OLE study should not occur more frequently than 
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every 7 days in dose increments of not more than 0.2 mg/kg/day. Dose increases may only occur after a review 
indicates a change in medication regimen is warranted. Dose decreases for tolerability or safety concerns can 
occur 
clinical situation. 
ZX008 dose adjustments outside of these parameters should be discussed with the Contract Research 
Organization (CRO) Medical Monitor prior to initiation.  
Changes in dosage of concomitant AEDs may be implemented as clinically necessary, and concomitant AEDs 
may be withdrawn completely, but all subjects must remain on a minimum of 1 concomitant AED plus ZX008 
unless it is deemed clinically appropriate by the investigator (after discussion with the CRO Medical Monitor) 
to dose as monotherapy. New concomitant AEDs or anti-epileptic treatments may be introduced at the 
as would be typically indicated in clinical practice. Clinical worsening leading to a 
change in medication must be documented in the source notes and case report form (CRF) and all medication 
dose changes must be documented with a clinical explanation and justification. Any addition of a new AED 
must be discussed with the CRO Medical Monitor prior to implementation.  
Echocardiograms (ECHO) and other safety assessments detailed in the schedule of assessments (SoA) will be 
conducted every 6 months unless more frequent follow-up is clinically indicated or required by the Sponsor or 
IDSMC. A Follow-up visit and a cardiac safety assessment will be performed after study drug discontinuation 
for subjects who do not transition to commercially available ZX008. Subjects who transition to commercially 
available ZX008 will not return for a follow-up after EOS/ET or a cardiac follow up after last dose but must 
have had an ECHO within 3 to 6 months before the transition date and will have follow-up ECHOs within 
required timeframe while on commercial drug supply.  
Caregivers will be asked to use a diary to record the number/type of seizures to support investigator 
determination of treatment benefit; however, diary data collection is not mandatory, nor will it be collected in 
the database. A schedule of assessments is provided in Table 1. 
External Committees:  The ZX008 clinical program will employ an Independent Data and Safety Monitoring 
Committee (IDSMC) that will be responsible for safety oversight until the safety oversight is transferred back 
to the Sponsor or the drug is approved in a major market for the studied indications. A separate International 
Cardiology Advisory Board (ICAB) will monitor the cardiac safety of the ZX008 clinical trials. ECHOs will be 
centrally read (ERT, Inc.) and interpreted using pre-specified criteria, and if necessary, with review by the 
ICAB.  
Number of Subjects: Up to approximately 650 subjects from 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 currently enrolled in core Study ZX008-1503  
OR 
Subject has successfully completed core Study ZX008-1601-Part 2  
OR 
Subject with a rare seizure disorder, such as epileptic encephalopathy, that has successfully completed 
another Zogenix-sponsored clinical trial with ZX008, and has been invited to participate in this study 
by the Sponsor. 
2. Subjects must, in the medical opinion of the Investigator, be candidates for continued treatment for an 
extended period of time with ZX008 (ie, subject has demonstrated a clinically meaningful benefit with 
ZX008 in the prior trial, and benefits of continued treatment outweigh potential risks).  
3. Subject is male or a nonpregnant, nonlactating female. Female subjects of childbearing potential must 
not be pregnant or breast-feeding. Female subjects of childbearing potential must have a negative 
pregnancy test prior to study entry. 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 been informed of the nature of the study and informed consent has been obtained from the 
legally responsible parent/guardian. 
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5. Subject has provided assent in accordance with Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) requirements, if capable. 
6. 
study procedures, 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 cardiac valvulopathy or pulmonary hypertension that the investigator, ICAB, 
IDSMC, or Sponsor deems reason for exclusion.  
3. Subject is at imminent risk of self-
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. 
4. 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 CRO Medical Monitor in 
conjunction with the Sponsor, in consideration of comorbidities and concomitant medications. 
5. Administration of a prohibited medication (see section 5.6.2) within 14 days of receiving ZX008. 
6. Subject is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory 
tests, other study procedures, and study restrictions. 
7. 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. 
8. Subject has participated in another clinical treatment trial within the past 30 days (ie, the last visit of 
the previous study was in the past 30 days), with the exception of a ZX008 clinical study. 
Reference Product, Dose, and Mode of Administration: 
Not applicable.  
Duration of Treatment: 
All subjects will receive ZX008 until approval of ZX008 has been obtained from regulatory authorities for the 
-specific 
requirements in addition to legal and regulatory guidelines in the subjects country of residence, or until the 
investigational product development for 
, whichever comes 
first.  All subjects who discontinue from the study treatment and do not transition directly to commercial 
product will undergo up to 2-weeks taper of study medication.  
Criteria for Evaluation: 
Safety:  
AEs, vital signs (blood pressure, heart rate, temperature, and respiratory rate), physical examination, 
neurological examination, Doppler ECHOs, and body height/weight will be assessed at each visit. Laboratory 
safety parameters (hematology, chemistry), 12 -lead ECGs, EEGs (in Italy only), and chest-x-ray (in France 
and Netherlands only), will be assessed as clinically indicated. 
Effectiveness (assessed at each visit): 
 
CGI-I global and for cognition, behavior, motor abilities, as assessed by parent/caregiver 
 
CGI-I global and for cognition, behavior, motor abilities, as assessed by investigator (or designee) 
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Percent improvement in seizure burden as assessed by the investigator (or designee) 
Assessments by the investigator (or designee) should be performed by the same rater for each subject 
whenever possible. If the rater changes permanently, a new baseline CGI-S (Appendix 3) should be 
established (see Section 7.1). 
The same parent/caregiver should perform each assessment. If the same parent/caregiver is not available, 
the assessment should be skipped.  
Sample Size Determination: 
The sample size will be determined by the number of subjects who participate in Study ZX008-1503 or 
ZX008-1601 Part 2 and who volunteer for the extension study and meet the necessary criteria for enrollment.  
Statistical Methods: 
Study Populations 
Safety Population: Safety analyses will be performed on the Safety Population defined as all subjects who 
receive at least 1 dose of ZX008 during this study. 
Safety  
The number and percentage of subjects who experience treatment emergent AEs will be displayed by System 
Organ Class (SOC) 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 (SAEs) will 
be summarized separately in a similar manner. Vital signs, physical examinations, neurological examinations, 
ECHO, and body height/weight will be summarized using appropriate methods. Abnormal findings on clinical 
laboratories, ECGs, EEGs, and chest x-rays that are recorded as adverse events will be summarized. 
Effectiveness 
The treating physician (or designee) will rate their global impression of the 
condition 
at Visit 1 to establish a reference baseline CGI-S (appendix 3), and then at each visit with the CGI-I throughout 
treatment with ZX008 according to the Schedule of Assessments. The severity of a 
condition will be 
rated on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse) by indicating the 
appropriate response that adequately describes how the 
symptoms have improved or worsened 
relative to the reference baseline. The CGI-I will also be completed by the parent/caregiver. The mean (SD) 
CGI-I score, and the number and percentage of subjects who showed improvement (ie, had a score of 3 or 
lower), or clinically meaningful improvement (i.e., had a score of 2 or lower) will be presented for each 
assessment timepoint. Global CGI-I score and CGI-I score for cognition, behavior and motor abilities will be 
summarized and analyzed using the same methods, as described above. Investigators will also rate overall 
change in convulsive 
or 100% (ie, seizure-free) improvement 
compared to last visit. 
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Table 1. 
Schedule of Assessments for Subjects  
Study Assessments 
 
OLE Treatment Period* 
Follow-up 
Cardiac Follow-up 
Visit Number 
Visit 1a 
Visits 2, 3, 4, 
5, 6 
(Months 6, 
12, 18, 24, 
30) 
Visit 7 (EOS/ET) 
Month 36 
Visit 8  
EOS/ET+ 14 days  
Visit 9h 
last dose + 6 months 
Study Day 
1a 
180, 360, 
540, 720, 900 
(window: ±7 
days) 
1080 
(window: ±7 days) 
14 days after 
EOS/ET  
6 months post 
last dose 
Informed Consent 
Xa 
 
 
 
 
Entry Criteria Review 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Epilepsy History 
X 
 
 
 
 
Abbreviated 
Physical/Neurological 
Examination 
Xb 
X f 
X 
X m 
X 
Vital signs 
X 
X 
X 
 
 
Weight, Height, BMI 
X 
X 
X 
X 
 
ECGb,c 
X 
X 
X 
 
X 
Doppler ECHOd 
X 
X 
X 
 
X 
Chest X-ray (France and 
Netherlands only)b, e 
X 
X 
X 
 
X 
EEG (Italy only)b, c,i 
X 
X 
X 
 
 
Pregnancy Testg 
X 
X 
X 
 
 
Clinical laboratory 
evaluation  
(hematology/clinical 
chemistry)  
Xb 
X f 
X f 
 
 
Plasma sample for 
background AEDs  
 
X f 
X f 
 
  
C-SSRS 
X 
X 
X 
 
 
Investigator CGI-Severity 
Rating (reference baseline) 
X 
 
 
 
 
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Parent/Caregiver CGI-
Severity Rating (reference 
baseline) 
X 
 
 
 
 
CGI-I (assessed by 
parent/caregiver) 
 
X 
X 
 
 
CGI-I (assessed by 
investigator) 
 
X 
X 
 
 
Overall change in seizure 
frequency (assessed by 
investigator) 
X 
X 
X 
 
 
Study Medication 
D 
C/R/Dk 
C/R/D 
C/R 
 
Seizure Diary 
 R (if applicable  
R (if 
applicable) 
R (if applicable) 
 
 
Concomitant Medications 
Xj 
X 
----------------------------------------X------------------------------------------- 
Adverse Events 
Xj 
X 
----------------------------------------X------------------------------------------- 
 
BMI=body mass index; C=Collect; CGI-I=Clinical Global Impression-Improvement; D=Dispense; ECG=electrocardiogram; EOS=end of study; ET=early 
termination; R=Review 
*: Subjects will receive ZX008 treatment in this study 
until a managed access program is established as allowed per country-specific requirements in addition to legal and regulatory guidelines in the subject s 
, whichever comes first. In that 
regard, participation could be extended beyond 36 months if none of the conditions above mentioned are met.  
a: 
 
Assessments conducted at the End of Study Visit of 1503, 1601 Part 2, or other Zogenix protocol as applicable will be used for Visit 1 of this Protocol. 
Continuation of treatment in this study should be discussed at the start of the visit, at latest. For subjects who wish to continue, informed consent/assent 
must be obtained before conducting any assessments or distributing study drug under this protocol.  
b: 
 
As clinically indicated based on medical history, and/or signs/symptoms. Abnormal clinically significant findings must be reported as adverse events. 
c: 
 
Conducted and read locally. Abnormal clinically significant observations must be reported as adverse events. 
d: 
 
ECHO will be performed every 6 months, starting with Visit 1, unless more frequent ECHO is clinically indicated. 
e: 
 
In France and Netherlands only. Subjects in France and Netherlands will have an additional Chest X-ray 24 months after study completion. 
f: 
 
As clinically indicated. A full physical and/or neurological examination may be performed, if warranted. Abnormal clinically significant observations must 
be reported as adverse events. 
g: 
 
Females of child-bearing potential 
h: 
 
For subjects who do not continue with commercially available ZX008, a follow up will be performed 14 days after study completion or early termination 
and a follow-up ECHO, and physical examination will be performed 6 months after last dose. Subjects in the United Kingdom will have an additional 
follow-up 12 months after study completion; subjects in France, Germany, and Netherlands will have an additional follow-up 24 months after study 
completion. 
i: 
 
In Italy only.  
j: 
 
Ongoing medications and ongoing adverse events should be captured in the CRF. 
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k: 
l: 
m:   
 
At the Principal Investigators discretion Study Drug can be collected/reviewed/dispensed at 3 month intervals.  
Seizure Diary from core study to be reviewed, if applicable. 
As appropriate based on last exam and reported AEs 
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1. 
INTRODUCTION 
1.1. 
Background Information on Indication Studied 
 
ZX008 (fenfluramine hydrochloride) is under development for the adjunctive treatment of 
patients with Dravet syndrome 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. 
A
 directly 
contribute additional cognitive and behavioral impairments over those expected from the 
underlying etiology alone and that suppression of epileptic activity might minimize this 
Scheffer 2017). 
Future development plans for ZX008 may include other rare epilepsy disorders and other 
epileptic encephalopathies. 
About Dravet Syndrome 
Dravet syndrome is a rare and severe form of epilepsy first described by Charlotte Dravet in 
1978 (Dravet 1978). The condition most commonly appears during the first year of life as 
frequent febrile seizures. As the condition progresses, other types of seizures typically occur, 
including myoclonic seizures and status epilepticus (SE) (Dravet 1978). Following the 
appearance of these seizures, affected children develop several co-morbid conditions including 
psychomotor regression, ataxia, sleep disturbance, and cognitive impairment. Intellectual 
impairment begins to become apparent around age 2 years due to lack of intellectual/behavioral 
progression. Children with Dravet syndrome often have a lack of coordination, poor development 
of language, hyperactivity, and difficulty relating to others (Dravet 1978; Hurst 1990). The degree 
of cognitive impairment appears to correlate, at least in part, with the frequency of seizures, and 
might be a result of repeated cerebral hypoxia. Children with Dravet syndrome also encounter a 
higher incidence of sudden unexpected death in epilepsy (SUDEP; Nashef 2012) than other 
populations with epilepsy. Indirect evidence has linked SUDEP to several possible etiologies, 
including seizure-induced apnea, pulmonary edema, dysregulation of cerebral circulation, and 
cardiac arrhythmias (Shorvon 2011), although the actual etiology remains unknown and other 
mechanisms have not been ruled out. The vast majority of patients who survive to adulthood are 
wholly dependent on around-the-clock caregivers and eventually live in institutional care homes. 
About Lennox-Gastaut Syndrome 
LGS is a rare epileptic encephalopathy. Onset of LGS usually occurs most commonly before age 
11, with a peak between 3 and 5 years of age (Arzimanoglou 2009; Hancock 2013). Patients with 
LGS account for 5 to 10% of children with seizures (Panayiotopoulos 2005). The diagnosis of 
LGS includes clinical signs combined with typical electroencephalograph (EEG) features. The 
clinical presentation of LGS is heterogeneous, however LGS is always characterized by a triad of 
symptoms: multiple seizure types, slow spike-and-wave EEG, and abnormal cognitive 
development. The most common seizure types are generalized tonic-clonic seizures, tonic 
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ther seizure types that occur in some LGS patients include atypical absences, 
nonconvulsive seizures, focal seizures, and myoclonic seizures. Nearly all LGS patients have 
treatment-resistant, lifelong epilepsy. Prognosis for LGS is very poor: 5% of children die, 80
90% continue having seizures into adulthood, and nearly all have cognitive and behavioral 
problems (Panayiotopoulos 2005). Children and adults with LGS have an enormous impact on 
their families, and efforts to improve the quality of life for these patients are complex. 
1.1.1. 
Existing Treatment for Dravet Syndrome 
Diacomit® (stiripentol) was recently approved in the United States, and has been approved for 
many years in Canada, Europe, and Japan to treat seizures associated with Dravet syndrome. 
Stiripentol (STP) must be co-administered with clobazam (US label) or clobazam and valproate 
(ex-US label). STP can significantly impact plasma concentrations of other AEDs, most notably 
clobazam. The complex drug-drug interactions of STP with other medications requires close 
monitoring and close management of side effects.  
Fintepla® and Epidiolex® (cannabidiol) has recently been approved by the FDA and EMA 
(Fintepla®, Epidyolex®) for the treatment of seizures associated with Dravet syndrome.  
Other therapies, topiramate, levetiracetam, and bromide may provide efficacy as adjunctive 
therapy for some patients (Chiron 2011). Published uncontrolled studies with levetiracetam 
(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 phenobarbital 
should be avoided because they often exacerbate seizures (Sazgar 2005; Wirrell 2016; 
de Lange 2018). Rescue medications (clonazepam, diazepam, lorazepam, and midazolam, etc) 
are often used to stop prolonged seizures that may evolve to SE and require emergency 
intervention.  
1.1.2. 
Existing Treatment for Lennox-Gastaut Syndrome 
Currently, there are 8 approved anti-epileptic drug (AED) products for LGS in the US: 
felbamate, topiramate, lamotrigine, rufinamide, clonazepam, clobazam, cannabidiol 
(Epidiolex®) and fenfluramine (Fintepla®). Two AEDs are approved in Japan for the treatment 
of LGS: lamotrigine (2008) and rufinamide (2013). Nine AEDs are approved for the treatment of 
LGS in Europe: felbamate, topiramate, lamotrigine, rufinamide, clonazepam, clobazam, 
valproate,  nitrazepam, and cannabidiol (Epidyolex®). Other pharmacologic (valproate, 
benzodiazepines, zonisamide) and nonpharmacologic (KD, VNS, surgery) treatments also are 
prescribed based on clinical experience.  
Because patients with LGS experience a range of different seizure types, the condition is 
notoriously difficult to treat (Arzimanoglou 2009) and seizures in LGS are usually not fully 
controlled (Hancock 2013). Initial treatment for LGS is usually monotherapy with 1 of the 
currently approved AEDs. If this is not successful, which is the most common case, a second 
agent is usually added; although some physicians move on to the second drug as monotherapy 
(Wheless 2007; Arzimanoglou 2009). The treatment of LGS frequently requires a combination 
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of 2 or more of these compounds, but with continued suboptimal seizure control. The 
recommendation is to attempt to use drugs that have different mechanisms of action and the least 
amount of interaction with each other. After lack of response to 2 or more AEDs, 
nonpharmacological treatments such as KD, VNS, or surgery may be considered. A treatment 
that has been shown to be effective in common certain seizure types cannot be assumed to be 
effective in patients with LGS to treat that seizure type. 
1.2. 
Background Information on Study Product 
Zogenix is developing ZX008, an oral solution of fenfluramine hydrochloride, for the treatment 
of seizures associated with Dravet syndrome and for the treatment of seizures associated 
Lennox-Gastaut syndrome. Fenfluramine is a racemic compound containing dexfenfluramine 
and levofenfluramine. The stereochemical configuration of the d or (+) isomer (also known as 
dexfenfluramine or dextrofenfluramine) corresponds to the S enantiomer, and the configuration 
of the l or (-) isomer (levofenfluramine) corresponds to the R enantiomer. The active 
pharmaceutical ingredient (API) in the ZX008 drug product is fenfluramine hydrochloride. 
Fenfluramine was approved in Europe in the 1960s, and in the United States (Pondimin 
NDA 16618) in the 1970s as an appetite suppressant at a dose of 60 to 120 mg/day for the 
treatment of adult obesity. Fenfluramine was also used extensively in an off-label combination 
-
mine) was 
also approved and marketed as Adifax, Redux® (NDA 20-344), and others as an anorectic 
medication. Fenfluramine (racemate) was sold in 118 countries and was in clinical use for 20 to 
30 years in France (1962), the Netherlands (1963), the United Kingdom (1966), Australia (1966), 
Spain (1966), Belgium (1966), South Africa (1968), Canada (1971, Germany (1972), Italy 
(1973), and the US (1973). Approximately 50 million Europeans were treated with fenfluramine 
for appetite suppression between 1963 and 1996 (Barceloux 2012) and the US Department of 
Health and Human Services estimated an exposure of over 61 million patient months prior to its 
global withdrawal in 1997 (CDC 1997). 
Fenfluramine was withdrawn from world-wide markets in the late 1990s due to its association 
with cardiac valve abnormalities (CDC 1997; Connolly 1997; Wong 1998). Published case 
reports have also reported cases of primary pulmonary hypertension claiming to be associated 
with fenfluramine (Douglas 1981; McMurray 1986; Pouwels 1990; EMA 1999). The drug was 
not controlled where it was marketed, other than the United States, where it was classified as a 
Schedule IV drug under the Drug Enforcement Agency. A process was underway in the United 
States to propose the descheduling fenfluramine and its d(+) enantiomer, dexfenfluramine, 
immediately prior to their removal from the market (Federal Register 1997). 
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 Investigator Brochure 2020). There is also a large body of information concerning its 
clinical safety profile. 
1.3. 
Preclinical Data 
The pharmacokinetics of fenfluramine, norfenfluramine and their respective isomers have been 
studied in mice, rats, dogs and humans. The PK in humans differs from that of other species, 
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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.  
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 
gh 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 
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. 
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 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 details on the preclinical d
(ZX008 IB 2022 v10.0). 
1.4. 
Clinical Pharmacology 
Please see the ZX008 IB for details on clinical pharmacology (ZX008 IB 2022 v10.0). 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. 
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 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 safe dosing used in Study 1504 
Cohort 2; thus, no dose adjustment is recommended when fenfluramine is coadministered 
with CBD.  
 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 
1.5. 
Clinical Data 
1.5.1. 
Dravet Syndrome 
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 
interval between convulsive seizures.  
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 
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interval between convulsive seizures.  
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 
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 
 
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 
ported 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 
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 hospitalization in a 9-year old female who was 
discontinued from the study; SAEs of seizure leading to hospitalization, drowsiness, reduced 
appetite, and weight loss in a 3-year old male who was discontinued from the study (The 
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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 2-year old male in the placebo group; lethargy in a 7-
year old female 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 
-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 80/3
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 2022 v.10.0 for more detailed information on the safety and 
efficacy of ZX008. 
1.5.2. 
Lennox-Gastaut Syndrome 
Currently, a small cohort of refractory patients with Lennox-Gastaut syndrome in Belgium are 
being treated in an ongoing Phase 2 open-label, pilot, dose-finding trial of fenfluramine as an 
add-on therapy to conventional therapy (Lagae 2017; Study S58545; clinicaltrials.gov identifier: 
NCT02655198).  
The study includes a 20-
then held at that dose until the end of the 20-week period, and an Extension period, in which 
subjects are titrated to maximum efficacy and tolerability. Subjects aged 3 to 18 years, fulfilling 
the diagnostic criteria for LGS as described by the ILAE in 1989, who have failed at least 
2 AEDs (including VNS), and have had at least 4 documented convulsive seizures and on at least 
two AEDs at stable doses in the prior 4 weeks are eligible for this study. After the initial 4-week 
baseline period to record seizure type and frequency, treatment with fenfluramine, 
0.2 mg/kg/day, is 
major motor seizure frequency (GTC+TS+AS+FS). At the 8-week visit (following 4 weeks of 
ZX008 treatment), subjects who were nonresponders and have no intolerable side effects receive 
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an increased dose of 0.4 mg/kg/day. At the 12-week visit, subjects who were nonresponders and 
have no intolerable side effects receive an increased dose of 0.8 mg/kg/day. At any visit, subjects 
quency remain at their currently 
administered dose. As this is a pilot dose-finding study, it is important to note that per protocol, 
baseline. It is possible that a higher dose could result in even greater seizure reduction. The 
maximum allowed dose is 30 mg/day.  
Results have been presented for the 13 LGS subjects who completed the Core study: (Lagae 2017). 
Overall, subjects had received a median of 8 years of antiepileptic treatment and were failing a 
median of 5 AEDs prior to entry. Upon study entry, patients were taking a median of 
4 concurrent anti-epileptic therapies. All subjects received ZX008 treatment for at least 20 weeks 
with the exception of 3 subjects who discontinued due to lack of efficacy; of which 2 also 
discontinued due to side effects. For subjects who completed the 20-week Core period, the 
median seizure frequency was reduced from a mean of 60 major motor seizures per month in the 
pre-ZX008 baseline period to a mean of 22 major motor seizures per month at the end of the 
Core ZX008 treatment period. At week 20, 8 of the 13 enrolled patients (62%) had at least a 50% 
reduction in major motor seizures with ZX008 treatment. Nine of the 13 patients completed the 
6 of 9 patients (67%) had at least a 50% reduction in major motor seizures and 2 of 9 (22%) had 
a 75% or greater seizure reduction. In the Extension period, there was a 58% median reduction in 
seizure frequency as compared to baseline. The most common treatment emergent adverse 
events to date include decreased appetite (n=4) and decreased alertness/fatigue (n=3). Sleep 
problems, tiredness, and sleepiness were each reported in 1 subject. 
No clinical signs of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) 
have been observed in any patients in the Belgian cohort (ZX008 IB 2022v.10.0). 
1.6. 
Rationale for Current Study 
As described above, Zogenix has conducted 2 positive double-blind, randomized, placebo-
controlled studies in Dravet syndrome. Additionally, long-term safety and efficacy data for up to 
3 years in some subjects has been collected. Based on the results from Study 1 and Study 1504 in 
Dravet syndrome, Zogenix has submitted a New Drug Application (NDA) to the United States 
Food and Drug Administration, and a Marketing Authorization Application (MAA) to the 
European Medicines Agency. Zogenix also has one double-blind placebo-controlled study 
ongoing in Lennox-Gastaut syndrome (Study 1601; NCT number: 
NCT03355209). This is a 2-part study. Part 1 is a double-blind, parallel-group, placebo-
controlled study to assess the efficacy and safety of 2 doses of ZX008 when used as adjunctive 
therapy for seizures in children and adult subjects with LGS. The primary study endpoint is 
assessed from Part 1 data. Part 2 is a 1-year open-label, flexible-dose extension for subjects 
completing Part 1 of the study. 
Study 1503 is soon to be completed, and Study 1601 Part 2 provided treatment for up to 1 year. 
The main purpose of this open-label study is to continue to provide treatment to patients with 
Dravet syndrome or Lennox-Gastaut syndrome who may still derive clinically meaningful 
benefit from ZX008 after completing Study 1503 or Study 1601 Part 2, until the product is 
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approved, or a managed access program is established as allowed per country-specific 
requirements in addition to legal and regulatory guidelines in the subjects country of residence, 
Sponsor, whichever comes first.  
This study (1) additionally provides an opportunity to continue to evaluate the long-term safety 
of ZX008 in Dravet syndrome and Lennox-Gastaut syndrome until the product is approved and 
available via prescription; and, (2) may serve as an open-label extension study for patients with 
rare seizure disorders and epileptic encephalopathies who have participated in other Zogenix-
sponsored clinical trials of ZX008.  
 
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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 
 To assess the effect of ZX008 on the following effectiveness measures: 
 
or 100% [ie, seizure-free] improvement) 
 Clinical Global Impression  Improvement (CGI-I) rating, global and symptomatic, 
as assessed by the investigator 
 CGI-I rating, global and symptomatic, as assessed by the parent/caregiver 
2.3. 
Study Endpoints 
2.3.1. 
Safety Endpoints 
The safety endpoints of the study are: 
 AEs 
 Laboratory safety (hematology, chemistry) 
 Vital signs (blood pressure, heart rate, temperature, and respiratory rate) 
 Physical examination 
 Neurological examination 
 Electrocardiogram (ECGs) 
 Doppler echocardiogram (ECHOs) 
 Body weight/height 
 Chest x-ray (subjects in France and Netherlands only) 
 Electroencephalogram (EEG) (in Italy only) 
Laboratory safety parameters (hematology, chemistry), ECGs, EEGs (in Italy only), and chest-x-
ray (in France and Netherlands only), will only be assessed as clinically indicated.  
For results disclosure on public registries (e.g ClinicalTrials.gov and EudraCT), only incidence 
of TEAEs will be publicly disclosed as a Primary Endpoint. The remaining Safety Endpoints are 
considered as other for the purpose of public data disclosure. 
 
2.3.2. 
Effectiveness Endpoints 
The effectiveness endpoints of the study are: 
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 CGI-I, global and symptomatic, as assessed by parent/caregiver 
 CGI-I, global and symptomatic, as assessed by investigator (or designee) 
 Percent improvement in seizure burden as assessed by the investigator (or designee) 
Assessments by the investigator (or designee) should be performed by the same rater for each 
subject whenever possible. If the rater changes permanently, a new baseline CGI-S (Appendix 3) 
should be established (see Section 7.1). 
The same parent/caregiver should perform each assessment. If the same parent/caregiver is not 
available, the assessment should be skipped.  
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This is an international, multicenter, open-label, long-term safety study of ZX008 in patients 
with epileptic encephalopathy, including Dravet syndrome or Lennox-Gastaut syndrome. 
Subjects eligible for participation are those with Dravet syndrome who are currently enrolled in 
Study ZX008-1503, or those with Lennox-Gastaut syndrome who have successfully completed 
Study ZX008-1601-Part 2, and are candidates for continued treatment with ZX008 for an 
extended period of time, or those with Dravet syndrome, Lennox-Gastaut syndrome, or another 
epileptic encephalopathy who have completed participation in another Zogenix-sponsored study 
and have been invited to participate in this study.  
Subjects having transitioned from ZX008-1503, ZX008-1601 or who have participated in 
another Zogenix-sponsored study will be eligible to participate in this trial until approval of 
managed access program is established as allowed per country-specific requirements in addition 
to legal and regulatory guidelines in the subjects country of residence, or until the investigational 
first. 
All subjects who discontinue from the study treatment and do not transition directly to 
commercial product will undergo up to 2-weeks taper of study medication. (Note subjects 
enrolled in the United Kingdom will have an additional follow-up safety visit 12 months after the 
last dose; subjects enrolled in Germany, France, and Netherlands will have an additional follow-
up safety visit at 24 months after the last dose).  
Subjects entering this OLE study who have participated in 1503 or 1601 will receive ZX008 
initially at the dose prescribed at the last visit in Study 1503 or Study 1601 Part 2, but will have 
the volume adjusted according to weight of the patient. Dose increases, to a maximum of 0.8 
mg/kg/day (maximum 30 mg/day) for subjects not receiving concomitant STP or 0.5 mg/kg/day 
(maximum 20 mg/day) for subjects receiving concomitant STP, during this OLE study should 
not occur more frequently than every 7 days in dose increments of not more than 0.2 
mg/kg/day. Dose increases (as per mg/kg) may only occur after a review of reported adverse 
indicates a change in medication regimen is warranted. Dose decreases for tolerability or safety 
tion, in dose amounts and frequency appropriate 
for the clinical situation. ZX008 dose adjustments outside of these parameters should be 
discussed with the CRO Medical Monitor prior to initiation.  
Changes in dosage of concomitant AEDs may be implemented as clinically necessary, and 
concomitant AEDs may be withdrawn completely, but all subjects must remain on a minimum of 
1 concomitant AED plus ZX008 unless it is deemed clinically appropriate by the investigator 
(after discussion with the CRO Medical Monitor) to dose as monotherapy. New concomitant 
AEDs or anti-
typically indicated in clinical practice. Clinical worsening leading to a change in medication 
must be documented in the source notes and case report form (CRF) and all medication dose 
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changes must be documented with a clinical explanation and justification. Any addition of a new 
AED must be discussed with the CRO Medical Monitor prior to implementation.  
Echocardiograms (ECHO) and other safety assessments detailed in the schedule of assessments 
(SoA) will be conducted every 6 monthsunless more frequent follow-up is clinically indicated or 
required by the Sponsor or IDSMC. A follow-up visit and a cardiac safety assessment will be 
performed after study drug discontinuation for subjects who do not transition to commercially 
available ZX008. Subjects who transition to commercially available ZX008 will not return for a 
follow-up after EOS/ET or a cardiac follow up after last dose but must have had an ECHO 
within 3 to 6 months before the transition date and will have follow-up ECHOs within required 
timeframe while on commercial drug supply. 
Caregivers will be asked to use a diary to record the number/type of seizures to support 
investigator determination of treatment benefit; however, diary data collection is not mandatory, 
nor will it be collected in the database. A schedule of assessments is provided in Table 1. 
3.2. 
Number of Subjects 
Up to approximately 650 subjects from the core studies may be enrolled. The number of subjects 
is dependent on the number who participate in Study ZX008-1503 or ZX008-1601 Part 2 and 
who volunteer for the extension study and meet the necessary criteria for enrollment. 
3.3. 
Study Duration 
Subjects having transitioned from ZX008-1503, ZX008-1601 or who have participated in 
another Zogenix-sponsored study, will be eligible to participate in this trial until approval of 
managed access program is established as allowed per country-specific requirements in addition 
to legal and regulatory guidelines in the subjects country of residence, or until the investigational 
first.. 
All subjects who discontinue from the study treatment and do not transition directly to 
commercial product will undergo up to 2-weeks taper of study medication. (Note subjects 
enrolled in the United Kingdom will have an additional follow-up safety visit 12 months after the 
last dose; subjects enrolled in Germany, France, and Netherlands will have an additional follow-
up safety visit at 24 months after the last dose). 
3.4. 
Number of Study Centers 
The study expects approximately 150 participating research centers in North America, Europe, 
Australia, and Japan.  
3.5. 
Rationale for Study Design  
All subjects enrolled will receive ZX008. Dose administration is intended to be consistent with 
that of intended clinical practice. The duration of the studywill allow for collection of 
appropriate data to further characterize the safety profile of ZX008. 
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3.6. 
Premature Termination of Study 
The Sponsor can terminate the study prematurely at any time for medical, ethical, or business 
reasons at individual study sites or at all study sites. The investigator will be notified in writing 
and instructions will be provided for termination procedures.  
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 6.1.3 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 
The responsibilities of the IDSMC on the safety oversight can be transferred back to the Sponsor 
at any time during the course of the study. 
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3.7.2. 
International Cardiac Advisory Board (ICAB) 
The ICAB is an advisory body to the Sponsor that assists in monitoring cardiac safety of the 
ZX008 clinical trials and provides advice to the IDMSC. The ICAB consists of individuals 
external to the Sponsor who have relevant experience in cardiology, pediatric cardiology, and 
echocardiography. The ICAB will advise the Sponsor and the IDSMC on the cardiac safety 
monitoring plan, including alert criteria and decision pathway for subject management relative to 
cardiac safety in the clinical studies of ZX008 when requested. ICAB members also provide 
secondary review or adjudication of ECHOs, as well as risk assessment, as needed. 
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4. 
SELECTION OF STUDY POPULATION 
The study population will be selected on the basis of the inclusion and exclusion criteria 
described in the sections below.  
4.1. 
Inclusion Criteria 
Subjects meeting all of the following inclusion criteria may be enrolled into the study: 
1. Subject is currently enrolled in core Study ZX008-1503 and remains a candidate for 
continuous treatment for an extended period of time. 
OR 
Subject has successfully completed core Study ZX008-1601-Part 2 and remains a 
candidate for continuous treatment for an extended period of time. 
OR 
Subject with epileptic encephalopathy has successfully completed another Zogenix-
sponsored clinical trial with ZX008, remains a candidate for continuous treatment for an 
extended period of time, and has been invited to participate in this study by the Sponsor. 
2. Subjects must, in the medical opinion of the Investigator, be candidates for continued 
treatment for an extended period of time with ZX008 (ie, subject has demonstrated a 
clinically meaningful benefit with ZX008 in the prior trial, and benefits of continued 
treatment outweigh potential risks).  
3. Subject is male, or nonpregnant, nonlactating female. Female subjects of childbearing 
potential must not be pregnant or breast-feeding. Female subjects of childbearing 
potential must have a negative pregnancy test prior to study entry. 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 been informed of the nature of the study and informed consent has been 
obtained from the legally responsible parent/guardian. 
5. Subject has provided assent in accordance with Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) requirements, if capable. 
6. 
willing and able to be compliant with study procedures, visit 
schedule and study drug accountability. 
4.2. 
Exclusion Criteria 
Subjects meeting any of the following exclusion criteria must not be enrolled into the study: 
1. Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study 
medication. 
2. Subject has current cardiac valvulopathy or pulmonary hypertension that the investigator, 
ICAB, IDSMC, or Sponsor deems reason for exclusion  
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3. Subject is at imminent risk of self-harm or harm to 
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 CSSRS 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. 
4. 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 CRO Medical Monitor in conjunction with the Sponsor, in consideration of 
comorbidities and concomitant medications. 
5. Administration of a prohibited medication (see section 5.6.2), within 14 days of receiving 
ZX008. 
6. Subject is unwilling or unable to comply with scheduled visits, drug administration plan, 
laboratory tests, other study procedures, and study restrictions.  
7. 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. 
8. Subject has participated in another clinical treatment trial within the past 30 days (ie, the 
last visit of the previous study was in the past 30 days), with the exception of a ZX008 
clinical study. 
4.3. 
Subjects of Reproductive Potential 
Male subjects who are sexually active with a partner of childbearing potential must use, with 
their partner, a condom plus an approved method of highly effective contraception from the time 
of informed consent until 90 days after the last dose of study drug. 
The following methods are acceptable: 
 Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
 Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o oral 
o injectable 
o implantable intrauterine device 
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o intrauterine hormone-releasing system 
 Surgical sterilization (vasectomy or bilateral tubal occlusion) 
Female subjects who are not of childbearing potential do not need to use any methods of 
contraception. A woman is considered of childbearing potential, unless they are at least 2 years 
post-menopausal or permanently sterile, or if she has not yet reached menarche. Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
Female subjects who are sexually active and are of childbearing potential must use, with their 
partner, an approved method of highly effective contraception from the time of informed consent 
until 90 days after the last dose of study drug. 
The following methods are acceptable: 
 Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation and a barrier method (ie, condom for male partner): 
o oral 
o intravaginal 
o transdermal 
 Progestogen-only hormonal contraception associated with inhibition of ovulation and a 
barrier method (ie, condom for male partner):  
o oral 
o injectable 
o implantable intrauterine device 
o intrauterine hormone-releasing system 
 Surgical sterilization (vasectomy or bilateral tubal occlusion) 
usual lifestyle. If a subject is usually not sexually active but becomes active, they, with their 
partner, must comply with the contraceptive requirements detailed above. 
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 stud
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 
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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.  
If premature withdrawal occurs for any reason, the investigator must make a genuine effort to 
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:  
1. Development of signs or symptoms indicative of cardiac valvulopathy or regurgitation 
(mitral, aortic, tricuspid, pulmonary valves), or pulmonary hypertension for which 
IDSMC or the Sponsor, in consultation with the ICAB, 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 and 
continued participation puts the subject and/or outcomes of the study at risk. 
3. Subject requires or starts using an unacceptable or prohibited concomitant medication. 
4. 
longer meets the inclusion criteria or develops any of the exclusion criteria. 
5. In the opinion of the investigator or Sponsor, 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. Subject experiences clinically significant worsening of seizures or other symptoms for 
which the investigator determines treatment with ZX008 is no longer beneficial. A 
clinically meaningful worsening is an increase in frequency, severity or duration of 
existing seizures, or (in some cases) emergence of a new seizure type. Frequent or 
increased use of rescue medication may be considered indicative of worsening. 
8. Subject experiences significant weight loss as determined by the investigator, that has not 
stabilized or recovered. 
9. 
-SSRS. 
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10. It is the investigator
or S
continue in the study. 
11. Subject is found to be pregnant while on study. Subject will be withdrawn following the 
taper schedule; all safety follow-up activities must be completed. 
Discontinuation decisions will be made at each participating site by the site investigator. 
Discontinuation decisions due to development of cardiovascular or cardiopulmonary 
complications may be made by the IDMSC or the Sponsor, with input from the ICAB and the 
investigator.  
If feasible, the process of discontinuation should be discussed with the CRO 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 CRO 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 
Subjects must be 
discontinued from receiving ZX008 and/or participating in any further study procedures under 
the following circumstances: 
 The subject or the 
tative wishes to discontinue 
participation in the study 
 
-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.  
In the event that the study is terminated prematurely then the procedure for termination should be 
followed as described in Section 3.6.  
The reason for, and date of discontinuation from participation in the study must be recorded in 
s, lack of compliance, lost to 
follow-up, etc). If possible, the subject
ly authorized representative should confirm 
his decision in writing. 
The investigator will attempt to complete all procedures usually required at the end of the study 
n in the study is discontinued or as close as possible to 
that time. Specific procedures required are described in Section 6.1.3 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.  
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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 CRO Medical Monitor, or the IDSMC becomes aware of 
conditions or events that suggest a possible hazard to subjects if the clinical study continues, then 
the clinical study may be terminated. The decision to terminate the study is solely with the 
Sponsor. The clinical study may be terminated at the Sponsor
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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5. 
INVESTIGATIONAL MEDICINAL PRODUCT INFORMATION 
ZX008 will be administered in the current study. A brief description of the ZX008 product is 
provided below (Table 2). 
Table 2.  
Investigational Medicinal Product  ZX008 
 
Study Product 
Substance Code 
ZX008  
Active Substance (INN) 
Fenfluramine Hydrochloride 
Trade Name 
Not applicable 
Formulation (including dosage form and strength) 
Solution 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 
 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.  
Flexible dosing will be studied, up to 0.8 mg/kg/day divided into 2 daily doses, up to a maximum 
of 30 mg/day (subjects taking concomitant STP will receive up to 0.5 mg/kg/day, up to a 
maximum of 20 mg/day). 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. 
5.2. 
Shipment and Storage 
IMP will be supplied to the study sites by the Sponsor or its delegate. 
All IMP will be transported, received, stored, and handled strictly in accordance with the 
container or product label, the instructions supplied to the research site and its designated 
The IMP must be 
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stored separately from normal hospital or practice inventories, in a locked facility with access 
limited to the investigator and authorized personnel. The investigator must ensure that the IMP is 
dispensed only to subjects enrolled in this study according to this study protocol. 
Appropriate storage temperature and transportation conditions will be maintained for the study 
drug from the point of manufacture up to delivery of the study drug. Study medication must be 
stored at 15 to 25°C (59 to 77°F) with excursions of 5 to 40°C (41 to 104°F) permitted; do not 
refrigerate or freeze. 
scribed in 
 
directive. 
5.3. 
Investigational Medicinal Product 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 IWR platform. The 
investigator or delegate will be required to register the subject through IWR and all study 
medication will be assigned to the subject through the IWR. The 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. Drug accountability is the process of 
documenting all aspects of drug receipt, storage, use, and disposition so that a full accounting of 
each unit can be made. This includes administration and return and/or destruction of study drug. 
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, 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. 
Open-label Extension 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 or without food. Each dose should be separated by a 
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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.  
During the OLE Treatment Period, all subjects will continue receiving ZX008 at the dose 
prescribed at the last visit in Study 1503 or Study 1601 Part 2 but will have the volume adjusted 
according to weight of the patient. The starting dose for subjects entering this study from another 
Zogenix-sponsored clinical study of ZX008 (not to exceed 0.8 mg/kg/day or 30 mg/day) will be 
determined through consultation between the investigator and CRO Medical Monitor. Dose 
increases, to a maximum of 0.8 mg/kg/day (maximum 30 mg/day) for subjects not receiving 
concomitant STP or 0.5 mg/kg/day (maximum 20 mg/day) for subjects receiving concomitant 
STP, during this OLE should not occur more frequently than every 7 days in dose increments of 
0.2 mg/kg/day.  
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 (as per mg/kg) may only occur after a review of seizures and reported AEs, and 
and/or duration indicates a change in 
medication regimen is warranted. Dose decreases for tolerability can occur 
discretion, in dose amounts and frequency appropriate for the clinical situation. ZX008 dose 
adjustments outside of these parameters should be discussed with the CRO Medical Monitor 
prior to initiation.  
Changes in dosage of concomitant AEDs may be implemented as clinically necessary, and 
concomitant AEDs may be withdrawn completely, but all subjects must remain on a minimum of 
1 concomitant AED plus ZX008 unless it is deemed clinically appropriate by the investigator 
(after discussion with the CRO Medical Monitor) to dose as monotherapy. New concomitant 
AEDs or anti-
as would be 
typically indicated in clinical practice. The description of clinical worsening must be 
documented in the source notes and case report form (CRF) and all medication dose changes 
must be documented with a clinical explanation and justification. Any addition of a new AED 
must be discussed with the CRO Medical Monitor prior to implementation.  
5.4.2. 
Taper Period 
All subjects (those who complete the OLE Treatment Period and those who discontinue from the 
study early) will be tapered off of study medication.  
The tapering scheme is a 2-step process as described in Table 3.  
Study medication will be administered as equal doses BID in the morning and in the evening, 
approximately 12 hours apart. Each dose should be separated by a minimum of 8 hours and a 
maximum of 12 hours. A missed dose of study medication may be taken later up to 8 hours 
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before the next scheduled dose; otherwise, the missed dose should not be given. IMP will be 
administered using the oral dosing syringe provided.  
Table 3.  
Taper Algorithm  
Current Dose 
Taper Step 1  
Days 1-4 after study completion or 
early termination 
Taper Step 2 
Days 5-8 after study completion or 
early termination 
ZX008 0.2 mg/kg/day 
Not applicable 
Not applicable 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
Not applicable 
ZX008 0.5 mg/kg/day 
(for subjects taking 
concomitant STP) 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.6 mg/kg/day 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.8 mg/kg/day  
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
Note:  maximum daily dose of ZX008 is 30 mg (or 20 mg for subjects taking concomitant STP). 
 
5.5. 
Blinding 
This is an open-label study.  
5.6. 
Prior and Concomitant Medication 
All medications taken by a subject after the first administration of IMP in this study, and those 
that started before the first administration of IMP and are continuing, are regarded as 
concomitant medication and must be documented in the eCRF, including over-the-counter 
medication, herbal and vitamin/supplement preparations.  
Subjects are required to take at least 1 concomitant AED during study participation. Changes in 
dosage of concomitant AEDs may be implemented as clinically necessary, and concomitant 
AEDs may be withdrawn completely, but all subjects must remain on a minimum of 
1 concomitant AED plus ZX008. New concomitant AEDs or anti-epileptic treatments may be 
l worsening in seizure 
type, frequency, and/or duration. A clinically meaningful worsening would be an increase in 
frequency, severity or duration of existing seizures, or emergence of a new seizure type that is 
not associated with a transient illness. The description of clinical worsening must be documented 
in the source notes and case report form (CRF) and all medication dose changes must be 
documented with a clinical explanation and justification. Any addition of a new AED must be 
discussed with the CRO Medical Monitor.  
It should be noted for any subject receiving hypoglycemic agents, the investigator should 
consider diabetic medication changes in the setting of weight loss and hypoglycemia. 
5.6.1. 
Rescue Medication for Seizures 
The subject's usual or prescribed regimen and frequency of rescue therapy for seizures should be 
entered into the concomitant medication sections of the eCRF and identified as a rescue 
medication by selecting the appropriate box.  
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Use of rescue medication is permitted during the study. 
5.6.2. 
Prohibited and Restricted Concomitant Medications  
 
The following concomitant medications/foods are prohibited during the clinical trial: 
 Alcohol in all forms (wine, beer, liquors) and amounts is prohibited during the study.  
 Felbamate is prohibited as a concomitant medication unless the subject has been on 
felbamate for at least 18 months prior to the core study Screening visit, has stable liver 
function and hematology laboratory tests, and the dose is expected to remain constant 
throughout the study. 
 Drugs that increase cardiovascular risk: e.g., atomoxetine 
 Drugs intended to facilitate weight loss and centrally-acting anorectic agents: e.g. 
Lorcaserin, Phentermine, Naltrexone-bupropion, Phentermine-topiramate, 
Diethylpropion, Benzphetamine-Phendimetrazine            
 Monoamine oxidase inhibitors (MAOIs): e.g. Isocarboxazid, Selegiline, 
Tranylcypromine, Phenelzine    
  
 
Chronic/long term use of a prohibited medication is considered a major protocol deviation 
 
Restricted Concomitant Medication 
A representative list of medications that should be avoided, if possible, during study participation 
is provided in Appendix 1. If medical necessity requires the use of 1 or more medications listed 
in Appendix 1 during the course of the study, the CRO Medical Monitor must first be contacted 
for approval.   
 
The list includes, but is not limited to: 
 
 Drugs that interact with central serotonin should be avoided: e.g., selective serotonin-
norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors 
(SSRIs), tricyclic antidepressants (TCAs), bupropion, triptans, dietary supplements such 
dextromethorphan, lithium, tramadol, and antipsychotics with serotonergic agonist 
activity. Subjects receiving these medications should be monitored closely for the 
emergence of signs and symptoms of Serotonin syndrome, which include mental status 
changes (e.g. agitation, hallucinations and coma) autonomic instability (e.g. tachycardia, 
labile blood pressure and hyperthermia), neuromuscular aberrations (e.g. hyperreflexia 
and incoordination) and/or gastrointestinal symptoms (e.g. nausea, vomiting and 
diarrhea). If serotonin syndrome is suspected, treatment with ZX008 should be stopped 
immediately and symptomatic treatment should be started.Cyproheptadine is a potent 
serotonin receptor antagonist and may therefore decrease the efficacy of ZX008. If 
cyproheptadine is used in conjunction with ZX008, patients should be monitored 
appropriately. 
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 Chloroquine or Hydroxychloroquine is prohibited during the study unless prescribed in 
urgent cases for short term use with approval from the CRO Medical Monitor. 
 
 
5.7. 
Treatment Compliance 
Subjects will bring their used, partially used, and unused IMP to every study visit. Treatment 
compliance will be monitored by measuring the volume by weight of IMP in these bottles and 
comparing to the dispensation log. 
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6. 
VISIT SCHEDULE 
Study procedures will be conducted according to the Schedule of Assessments in Table 1. Time 
windows for all assessments are detailed in Table 4. 
Table 4.  
Time Windows for Assessments 
Visit / Procedure 
Time window (relative to scheduled visit / procedure) 
Visit 1 (Clinic; Study Day 1)  
Not applicable: same as the last visit in Study 1503 or 
Study 1601 Part 2, or other ZX008 study as applicable 
Visits 2, 3, 4, 5, 6 (Months 6, 12, 18, 24, 30; 
Days 180, 360, 540, 720, 900) 
± 7 days 
Visit 7 (EOS; Study Day 1080) a   
Visit 8 (EOS/ET + 14 days) 
 
Visit 9 (Last Dose + 6 months)b    
± 7 days 
 
a Subjects will receive ZX008 treatment in this study until approval of ZX008 has been obtained from 
country-specific requirements in addition to legal and regulatory guidelines in the subject s country of 
Sponsor, whichever comes first.  In that regard, participation could be extended beyond 36 months if none of 
the conditions above mentioned are met. 
b Depending on country requirements. See Table 7 for details. 
6.1. 
Open-label Extension 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 must be obtained 
before a subject can start any of the Visit 1 procedures. For subjects entering this OLE study 
from Study 1503 or Study 1601 Part 2, Visit 1 will be the same as the last visit in Study 1503 or 
Study 1601 Part 2. Assessments conducted at the End of Study Visit of 1503 or 1601 Part 2 that 
are identical to assessments required at Visit 1 will not be repeated. Continuation of treatment in 
this study should be discussed at the start of the visit. For subjects who wish to continue, 
informed consent/assent must be obtained before conducting any assessments or distributing 
study drug under this protocol. Visit 1 will be identical to the last visit of another ZX008 study, 
as applicable, and the same rules will apply for assessments and continuation. 
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.  
Only eligible subjects as specified by the inclusion and exclusion criteria who have successfully 
completed the core study and who meet all other eligibility criteria will be enrolled into study 
ZX008-1900. 
6.1.1. 
Clinic Visit 1 (Study Day 1; Transition Visit) 
Assessments conducted at the End of Study Visit that are identical to the assessments listed 
below will not be repeated. However, data associated with these assessments will be entered in 
the eCRFs.  
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 Obtain written informed consent for the study 
 Review inclusion and exclusion criteria 
 Record demographic information 
 Record medical epilepsy history 
 Record concomitant medications 
 Complete abbreviated physical examination, as clinically indicated based on medical 
history, and/or signs/symptoms. Abnormal clinically significant findings must be 
reported as adverse events. 
 Record height, weight, and calculation of BMI 
 Complete abbreviated neurological examination, as clinically indicated based on medical 
history, and/or signs/symptoms. Abnormal clinically significant findings must be 
reported as adverse events. 
 ECG, as clinically indicated (conducted and read locally). Abnormal clinically significant 
findings must be reported as adverse events. 
 Doppler ECHO  
 Chest X-ray (in France and Netherlands only), as clinically indicated. Abnormal 
clinically significant findings must be reported as adverse events. 
 EEG (in Italy only), as clinically indicated. Abnormal clinically significant findings must 
be reported as adverse events. 
 Vital signs 
 Pregnancy test for females of child-bearing potential 
 Laboratory evaluation (serum chemistry, hematology) 
 C-SSRS Since Last Visit Assessment (Appendix 2) 
 CGI-Severity (assessed by parent/caregiver) 
 CGI-Severity (assessed by investigator)  
 Seizure assessment (assessed by investigator) 
 Record AEs 
 Dispense study medication 
 
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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6.1.2. 
Clinic Visits 2, 3, 4, 5, 6 (Months 6, 12, 18, 24, 30)  
Subjects will report to the clinic in the morning of Clinic Visits 2 through up to Visit 6. The 
following procedures will be performed: 
 Record concomitant medications 
 Abbreviated physical examination, as clinically indicated. A full physical and/or 
neurological examination may be performed, if warranted. Abnormal clinically 
significant findings must be reported as adverse events. 
 Abbreviated neurological examination, as clinically indicated. A full physical and/or 
neurological examination may be performed, if warranted. Abnormal clinically 
significant findings must be reported as adverse events. 
 Height and weight, and calculation of BMI 
 Obtain vital signs 
 ECG, as clinically indicated (conducted and read locally). Abnormal clinically significant 
findings must be reported as adverse events. 
 Doppler ECHO  
 Chest X-ray (in France and Netherlands only), if clinically indicated, Abnormal clinically 
significant findings must be reported as adverse events. 
 EEG (in Italy only), if clinically indicated, Abnormal clinically significant findings must 
be reported as adverse events. 
 Pregnancy test for females of child-bearing potential 
 Laboratory evaluation (serum chemistry and hematology), as clinically indicated. 
Abnormal clinically significant findings must be reported as adverse events. 
 Collect plasma sample for AED PK evaluation (as clinically indicated) 
 C-SSRS Since Last Visit Assessment (Appendix 2) 
 CGI-I, global and symptomatic (assessed by parent/caregiver) 
 CGI-I, global and symptomatic (assessed by investigator) 
 Seizure assessment (assessed by investigator) 
 Record AEs 
 Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
 Dispense study medication 
6.1.3. 
Clinic Visit 7 (Month 36): End of Study/Early Termination 
The End-of-Study participation for an individual subject occurs when approval of ZX008 has 
when a managed access 
program is established as allowed per country-specific requirements in addition to legal and 
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regulatory guidelines in the subjects country of residence, or when the investigational product 
 In 
that regard, participation could be extended beyond 36 months if none of the conditions above 
mentioned are met at Visit 7.  
. The End-of-Study visit may also occur if the subject withdraws participation from the study.  
Subjects will visit the clinic for the End-of-Study Visit if 1 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. ZX008 is approved by 
access program is established as allowed per country-specific requirements in addition to 
legal and regulatory guidelines in the subjects country of residence, or the investigational 
product d
comes first. 
The following procedures will be performed: 
 Record concomitant medications 
 Abbreviated physical examination, as clinically indicated. A full physical and/or 
neurological examination may be performed, if warranted. Abnormal clinically 
significant findings must be reported as adverse events. 
 Abbreviated neurological examination, as clinically indicated. A full physical and/or 
neurological examination may be performed, if warranted. Abnormal clinically 
significant findings must be reported as adverse events. 
 Height and weight, and calculation of BMI 
 Obtain vital signs 
 ECG, as clinically indicated (conducted and read locally). Abnormal clinically significant 
findings must be reported as adverse events. 
 Doppler ECHO  
 Chest X-ray (in France and Netherlands only), as clinically indicated, Abnormal 
clinically significant findings must be reported as adverse events. 
 EEG (in Italy only), as clinically indicated, Abnormal clinically significant findings must 
be reported as adverse events.  
 Pregnancy test for females of child-bearing potential 
 Laboratory evaluation (serum chemistry and hematology), as clinically indicated. 
Abnormal clinically significant findings must be reported as adverse events. 
 Collect plasma sample for AED PK evaluation (as clinically indicated) 
 C-SSRS Since Last Visit Assessment (Appendix 2) 
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 CGI-I, global and symptomatic (assessed by parent/caregiver) 
 CGI-I, global and symptomatic (assessed by investigator) 
 Seizure assessment (assessed by investigator) 
 Record AEs 
 Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
 
6.2. 
EOS/ET Follow Up Visit (Clinic Visit 8; EOS/ET +14 days) 
If the subject completes the study (or discontinues from the study early), and is not switching to 
commercially available drug, the subject will visit the clinic 14 days after the EOS/ET).  The 
following procedures will be performed at the 14 day follow up visit: 
  
 
Abbreviated physical examination (as appropriate based on last exam and reported AEs) 
 
Abbreviated neurological examination (as appropriate based on last exam and reported 
AEs). 
 
Record AEs 
 
Record Concomitant Medications 
 
Weight 
 
Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
 
6.3. 
Cardiac Follow Up Visit (Clinic Visit 9; last dose + 6 Months)  
If the subject completes the study (or discontinues from the study early), and is not switching to 
commercially available drug, the subject will visit the clinic 6 months after the last dose. At the 6 
month follow up visit, the following procedures will be performed, with additional follow-ups 
based on country of residence (see table 5).  
       Abbreviated physical/neurological examination. A full physical and/or neurological 
examination may be performed, if warranted. Abnormal clinically significant findings 
must be reported as adverse events. 
       12-lead ECG (conducted and read locally) 
       Doppler ECHO  
       Record AEs 
       Record concomitant medications 
 
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 5. As the ECHO and ECG will be administered 
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in a separate clinic than the pediatric neurology clinic, an asymptomatic subject receiving a 
second follow-up ECHO and ECG does not require a physical examination.  
Subjects with positive findings on ECHO, ECG and/or physical examination should continue to 
be followed until the finding is resolved or stable and unlikely to change, with reports submitted 
as AEs to the ZX008 safety database.  
If the subject completes the study (or discontinues from the study early) and is switching to 
commercially available drug, the subject will complete the EOS visit and follow the drug 
 physician. 
The EOS/ET and cardiac follow-up visits are not required. 
 
Table 5.  
Schedule of Post-Treatment Cardiac Follow-up 
Parameter 
 
Have had any clinically significant cardiac 
sign or symptom regardless of the time on 
study druga 
ECHO and ECG 
Follow-up 
6 months post-treatmentb in UK: 
additional 12-month follow-up in 
Germany, France, Netherlands: 
additional 24-month follow-up 
Follow-up 
6-24 months post-treatmentb, and every 
6 months until resolved, or stable and 
unlikely to change 
Physical examination 
Follow-up 
14 days after EOS.ET and 
6 months post- treatment only 
 
Follow-up 
6 months post- treatment, and every 6 
months until resolved, or stable and unlikely 
to change 
Chest x-ray (subjects 
enrolled in France or 
Netherlands only) 
Follow-up 
6, and 24 months post-treatment 
Follow-up 
6, and 24 months post- treatment and every 6 
months until resolved, or stable and unlikely 
to change 
a Sign or symptom includes any development of valve thickening or regurgitation (mild or greater in aortic; 
moderate or greater in mitral, pulmonary, tricuspid), or sign or symptom indicative of potential pulmonary 
hypertension as adjudicated by the ICAB. 
b Subjects who discontinue and do not continue with commercially available drug are required to have follow-
ups at 6 months post-treatment. Subjects enrolled in the UK will also have an additional 12-month follow-up. 
Subjects enrolled in Germany, France, and Netherlands will have an additional 24-month follow-up. 
6.4. 
Estimated Blood Volume Collection 
The maximum total blood volume collected during the study for clinical laboratory testing and 
PK will be approximately 80.5 mL, as outlined in Table 6. 
Table 6. 
Estimated Blood Volume Collectiona 
Assessment/ 
(Study Day) 
 
OLE Treatment Period (Study Day) 
1 
180, 360, 540, 720, 900 
1080b 
Total 
Clinical chemistry  
7.5 
7.5 mL at each visit 
7.5 mL 
52.5 mL 
Hematology  
2 
2 mL at each visit 
2 mL 
14 mL 
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Assessment/ 
(Study Day) 
 
OLE Treatment Period (Study Day) 
1 
180, 360, 540, 720, 900 
1080b 
Total 
AED plasma sample 
1 x 2 mL 
1 x 2 mL at each visit 
1 x 2 mL 
14 mL 
Approximate total blood volume per 
subject  
11.5 mL 
11.5 mL at each visit 
11.5 mL 
80.5 mL 
a In 
Appendix 3), blood collection 
volumes for children weighing up to 15 kg will be: 
 
the maximum allowable volume of blood in 1 draw is 22-30 mL (2.5% of total blood volume) 
 
the maximum in a 30-day period is 44-60 mL 
b If the participation of the subject is extended beyond day 1080, 11.5 mL of blood will be collected per extra visit. 
 
6.5. 
Specific guidance related to COVID-19 pandemic 
In alignment with health authority regulations, such as the US Food and Drug Administration 
and European Medicine Agency, protocol exceptions may be made where necessary to eliminate 
apparent immediate hazards to study patients. 
Subjects may not be able to attend their next visit because they cannot/will not travel or they are 
not allowed to visit the hospital except for emergency cases. Principal Investigators and study 
site personnel are asked to work closely with their patients to determine a course of action that 
supports the rights, safety and welfare of participants and ensure as little impact on the integrity 
of the research as possible.  
Should any study visit be impacted by the COVID-19 pandemic (e.g. shelter in place, travel 
restrictions, etc...) please refer to appendix 6 for further guidance on visit scheduling, occurrence, 
and assessment completion.   
 
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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). 
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 ratings, 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 ratings 
completed by the parent/caregiver, if the same parent/caregiver cannot complete the rating at a 
visit, the rating will not be completed. 
7.1.1. 
Seizure Assessments 
Based on discussions with the parent/caregiver, clinical evaluation, and review of an optional 
seizure diary, the percent improvement in seizure burden will be assessed by the investigator on 
a 5-
-fee] improvement. 
7.1.2. 
Clinical Global Impression - Severity 
At Visit 1 of this OLE study, both the parent/caregiver and the investigator will rate their global 
reference baseline for ongoing CGI-I 
ratings.  
The investigator and the parent/caregiver (independently) will perform 4 ratings (Appendix 3). 
 overall, and for each of the 3 symptoms of interest 
(cognition, behavior, and motor abilities) will be rated on a 7-point scale ranging from 1 (very 
much improved) to 7 (very much worse) as follows:  
1=normal, not at all ill 
2=borderline ill 
3=mildly ill 
4=moderately ill 
5=markedly ill 
6=severely ill 
7=among the most extremely ill 
 
The parent/caregiver will be asked to indicate the appropriate response that adequately describes 
the subject
condition overall and symptoms relative to expectations for age and development.  
The investigator will be asked to indicate the appropriate response that adequately describes how 
condition overall and symptoms relative to their total clinical experience with this 
patient population.  
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7.1.3. 
Clinical Global Impression - Improvement 
Both the parent/caregiver and the investigator will rate their global impression of the subject  
condition throughout the study according to the schedule in Table 1.  
The Clinical Global Impression (CGI) scale measures the change in the 
clinical status 
from a specific point in time. The CGI rating scale permits a global evaluation of the 
improvement over time.  
The investigator and the parent/caregiver (independently) will perform 4 ratings (Appendix 4). 
The improvement of a pat
(cognition, behavior, and motor abilities). The improvement 
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 the 
s improved or worsened relative to the rating provided at 
Visit 1.  
The investigator will be asked to indicate the appropriate response that adequately describes how 
the 
 improved or worsened relative the rating provided at Visit 1.  
7.2. 
Safety Assessments 
7.2.1. 
Demographics, Epilepsy History, and Concomitant Medication 
Subject demographics, diagnosis (ie, Dravet syndrome or Lennox-Gastaut syndrome), and 
current medications will be carried over from the core study. 
7.2.2. 
Physical Examinations 
Abbreviated physical examinations will be conducted by the investigator or designee during the 
study as outlined in Table 1. An abbreviated physical examination will be based on medical 
history and/or signs/symptoms and cover the following body systems:  heart, lungs, and follow 
up of other systems as appropriate based on last exam and reported AEs. A full physical 
examination (ie, general appearance, skin, eyes, ears, nose, throat, heart, lungs, abdomen, 
neurological system, lymph nodes, spine, and extremities) may be performed, if warranted. 
Abnormal clinically significant observations must be reported as adverse events.  
7.2.3. 
Neurological Examinations 
Abbreviated neurological examinations will be conducted by the investigator or designee during 
the study as outlined in Table 1. An abbreviated neurological follow-up examination for each 
subject will evaluate any symptoms or systems found to be abnormal and unstable or potentially 
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unstable that might evolve during study treatment, or to investigate any reported or observed 
AEs. A full neurological examination (ie, cranial nerves, muscle strength and tone, reflexes, 
coordination, sensory function, and gait) may be performed, if warranted. Abnormal clinically 
significant observations must be reported as adverse events.  
7.2.4. 
Vital Signs 
Vital signs including blood pressure, heart rate, temperature, and respiratory rate will be 
documented for subjects during study as outlined in Table 1. 
7.2.5. 
Laboratory Measurements 
Laboratory safety parameters will be analyzed as clinically indicated, using standard validated 
methods. Parameters to be assessed will be at the discretion of the investigator. 
The following parameters may be assessed by the laboratory as described in Table 1: 
 Hematology: hemoglobin, hematocrit, erythrocytes, erythrocyte mean corpuscular 
volume, leukocytes, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, neutrophils, lymphocytes, monocytes, eosinophils, basophils and platelets 
 Blood Biochemistry: albumin (ALB), alkaline phosphatase (AP), alanine 
aminotransferase (ALT; SGPT), aspartate aminotransferase (AST; SGOT), bicarbonate, 
blood urea nitrogen (BUN), calcium (Ca), chloride (Cl), creatinine, creatine kinase, 
gamma-glutamyl transferase (GGT), globulin, glucose, lactate dehydrogenase (LDH), 
phosphorus, potassium (K), sodium (Na), total bilirubin, direct bilirubin, total cholesterol, 
total protein, triglycerides, uric acid.  
 Urine or serum pregnancy test: Pregnancy testing will be performed in female subjects of 
childbearing potential. 
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). 
7.2.6. 
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 when clinically indicated, as outlined in Table 1.  
7.2.7. 
Electrocardiograms 
Twelve-lead ECGs will be conducted as clinically indicated after the subject has been in the 
supine position resting for  5 minutes. Heart rate, PR duration, QRS duration, QT duration, 
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QTcF (Fridericia's correction formula)
recorded. 
7.2.8. 
Doppler Echocardiography 
Doppler echocardiography will be conducted 
during study as outlined in Table 1. Doppler echocardiography uses ultrasound technology to 
examine the heart or blood vessels. An ECHO uses high frequency sound waves to create an 
image of the heart while the use of Doppler technology allows determination of the speed and 
direction of blood flow by utilizing the Doppler effect. A manual of proper ECHO technique for 
sites is provided in a separate document. 
7.2.9. 
Chest X-ray (France and Netherlands only) 
For subjects enrolled in France and Netherlands only, an anterior/posterior chest x-ray will be 
obtained as clinically indicated. 
7.2.10. 
Electroencephalogram (EEG) (Italy only) 
Routine electroencephalogram (r-EEG) will be obtained as clinically indicated at centers in Italy 
only. The potential for EEG to induce seizures should be considered and if a patient is 
determined to be at high risk for EEG-induced seizure, then EEG should not be conducted. 
Standard clinical measures should be in place to mitigate against EEG-induced seizure. As these 
EEGs are considered exploratory, they should be locally read and stored in the site files. EEG 
recordings will not be captured in the CRF. 
7.2.11. 
Columbia-Suicide Severity Rating Scale 
The Columbia-Suicide Severity Rating Scale (Appendix 2) will be assessed during study as 
outlined in Table 1. The C-SSRS is a validated rating scale that assesses suicidal behavior and 
ideation. The scale is used to assess and track suicide events and provides a summary measure of 
suicidal tendency. The C-SSRS version 1/14/19 (Since Last Visit) will be used in this study as 
appropriate for the age and level of intellectual development. 
Subjects who are younger than 7 years chronologically, or who are judged by the investigator not 
to have the mental capacity to understand the questions as specified on the C-SSRS, will not 
complete the rating. The investigator should use his/her judgment to substitute intellectually-
appropriate questions to probe the tendency for self-harm. 
If a subject with the intellectual capacity to complete the C-SSRS has their 7th birthday during 
the study, use of the C-SSRS should be initiated at subsequent visits. 
7.2.12. 
Adverse Events 
Adverse events will be collected from the time of signing the informed consent form/assent form 
until the end of the study, including the follow-up clinic visit. For subjects who participated in 1 
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-
1900. 
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Details of the definitions and categorization of AEs, and procedures for the reporting of AEs, are 
available in Section 8. 
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. 
Appropriateness of Measurements 
All of the variables assessed are standard tests or procedures that are commonly used in studies 
of this type. 
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8. 
ADVERSE EVENTS 
8.1. 
Definitions 
8.1.1. 
Adverse Events 
According to ICH guidelines, an AE is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
a causal relationship with this treatment. An AE can, therefore, be any unfavorable and 
unintended sign (including an abnormal, clinically significant laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product. The period of observation for 
adverse events extends from Visit 1 of ZX008-1900 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 ZX008-1900. 
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 the last visit 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: 
o Planned hospitalizations due to pre-existing conditions, which have not worsened 
o Hospitalizations that occur for procedures not due to an AE (eg, cosmetic surgery) 
o Hospitalizations for a diagnostic procedure where the hospital stay is less than 
24 hours in duration or for normal management procedures (eg, chemotherapy) 
For laboratory safety parameters, any instances of absolute values being outside the reference 
range or changes at any visit after study start that are considered by the investigator as clinically 
significant must be recorded in the CRF as AEs. 
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. 
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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  
-
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 
24 hours as the defining criterion for an SAE. Hospital admissions for planned surgery or 
for normal disease management procedures (eg, chemotherapy) are not considered as 
defining criteria for SAEs.  
4. Results in persistent or significant disability or incapacity. 
5. Is a congenital anomaly or birth defect? 
6. Is medically significant  A medically significant event is defined as an event that does 
not meet any of the other 5 SAE criteria, but which is judged by a physician to potentially 
jeopardize the subject or require medical or surgical intervention to prevent 1 of the 
above outcomes listed as an SAE criterion. Anaphylaxis that is successfully treated by 
administration of epinephrine prior to other sequelae is an example of a potentially 
medically important event. 
The most important term should be selected as the criteria for the SAE. Medically significant 
should be used when none of the other terms apply. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are defined as SAEs that do not 
meet determination of expectedness as determined in accordance with applicable product 
information (Investigator's Brochure or other reference documentation). Upon receipt of a SAE 
report from an investigator site, all suspected adverse reactions related to the IMP which occur 
within the clinical trial will be assessed for expectedness. Any SAE not listed in the reference 
documentation is considered a Suspected Unexpected Serious Adverse Reaction (SUSAR). 
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SUSARs will be reported by the Sponsor, or its designee, in compliance with local legal 
requirements. During the course of the study, the Sponsor will report within required timelines 
all SAEs that are both unexpected and at least reasonably related to the IMP (SUSARs) to the 
Health Authorities, IECs / IRBs as appropriate and to the Investigators. This study will comply 
with all applicable regulatory requirements and adhere to the full requirements of ICH Topic 
E2A (Clinical Safety Data Management: Definitions and Standards for Expedited Reporting 
[1994]).  
For the purpose of data collection in this study, a prolonged seizure or series of seizures from 
which the subject does not regain consciousness between ictal events, that is at least 30 minutes 
in duration, is termed status epilepticus (SE). A single episode of SE in a 24-hour period, 
regardless of whether rescue medication was administered, should be entered in the AE log. If 2 
or more episodes occur within 24 hours, each lasting 30 minutes or more, an SAE of SE should 
be recorded. Hospitalization to manage SE, regardless of the number of episodes, should be 
reported as an SAE. 
Adverse events that do not fall into the above categories are defined as nonserious AEs. 
8.2. 
Severity of Adverse Events 
The severity of AEs (whether nonserious or serious AEs) is to be assessed by the investigator as 
follows (Table 7). 
Table 7.  
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 
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 
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 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 will start at Visit 1 of ZX008-1900 and finish 
15 days after the last dose of study drug or the last visit, whichever is later. For subjects who 
enroll in the open-label extension study from 1 of the core studies, 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. 
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. 
For results disclosure on public registries (e.g ClinicalTrials.gov), treatment-emergent adverse 
events will be included. 
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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:  
All SAEs that occur during the course of the study, beginning at Visit 1, whether or 
not causally related to IMP must be reported immediately via telephone or email or 
EDC (within 24 hours of the investigator becoming aware of the event) to the 
Sponsor or the CRO Medical Monitor. 
1. Enter all relevant information into SAE eCRF, via the EDC. 
2. In the event that EDC is down or not accessable the site can send a paper SAE form 
to the Safety team within 24 hours of becoming aware of the SAE and then enter 
the SAE into the eCRF page once the EDC is back up and accessible. 
 
Adverse events occurring in the period between the time the subject gave written informed 
consent and the first exposure to IMP that meet 1 or more of the seriousness criteria for AEs 
must be reported to the Sponsor and the CRO 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 CRO 
Medical Monitor.  
Contact details and guidance for reporting SAEs are provided below:  
Serious adverse event reporting (24h) 
Fax 
Europe and Rest of the World: +32 2 386 24 21 
US and Canada: +1 800 880 6949 or +1 866 890 3175 
Email 
Global: DS_ICT@ucb.com 
 
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 
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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 CRO 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 i
 
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  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. For results disclosure on public registries (e.g 
ClinicalTrials.gov), treatment-emergent serious adverse events will be included. 
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 CRO 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 
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follow-
. Details of the 
the Sponsor  Global Clinical Safety and 
Pharmacovigilance and the CRO Medical Monitor.  
Subjects who are discontinued from the study or complete the study and have been found to have 
any signs of valvulopathy or pulmonary hypertension on ECHO will be followed until the 
condition has resolved or stabilized where no further changes are likely, for a minimum of 
6 months from the last dose of study medication. 
8.9.1. 
 Follow-up of Echocardiogram Findings  
All ECHOs will be evaluated by a central reader from ERT, Inc. (ERT), in consultation with the 
ICAB, if warranted. Findings related to pulmonary hypertension or valvulopathy on any of the 
4 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 8 describes the severity of ECHO findings with the level of increasing oversight if the 
subject is to remain in the study. 
Table 8. 
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 
 
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 if available 
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 
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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. 
3. The investigator prepares a case history and rationale for continuation to be submitted to 
the IDSMC or Sponsor safety representative/physician for review, including 
consideration of effects on seizures and comorbidities. 
4. The Co-Chairs of the ICAB are alerted to the request and prepare, after consultation with 
an evaluation of the cardiopulmonary risk and proposed monitoring plan if applicable, for 
submission to the IDSMC or Sponsor safety representative/physician. 
5. IDSMC/Sponsor safety representative/physician will review the submission from the 
Investigator and the ICAB. 
6. IDSMC/Sponsor safety representative/physician 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 if available and 
consult with the parent/guardian, and determine whether the achieved benefit justifies the 
consideration of continuing study treatment by the IDSMC/Sponsor safety 
representative/physician. Minimal efficacy criteria for IDSMC/Sponsor safety 
representative/physician 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 
 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 or Sponsor safety representative/physician for review, which includes effects 
of study medication on seizures and comorbidities related to Dravet syndrome. 
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4. The Co-Chairs of the ICAB are alerted to the request, and in consultation with ERT 
prepare an evaluation of the risks and proposed monitoring plan if applicable for 
submission to the IDSMC/Sponsor safety representative/physician. 
5. IDSMC/Sponsor safety representative/physician will review the submission from the 
Investigator and the ICAB. 
6. IDSMC/Sponsor safety representative/physician 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 
 
When there is disagreement of findings in an ECHO of any subject between the ERT and ICAB 
(either in the alert level of valvular regurgitation or presence or absence of pulmonary 
hypertension), the following process will occur:  
A telephone conference call will be held with the vendor ERT cardiology readers and ICAB 
reader and ICAB Chair (if the Chair was reader, then only s/he will be on call) to discuss and try 
to come to an agreement on interpretation; if agreement cannot be reached then the ICAB Chair 
will read the ECHO and his/her reading will become the official reading. 
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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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 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 for recording data according to the instructions given 
in the CRF.  
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 must be completed in a timely manner so that they always reflect the latest 
observations on the subjects enrolled in the study.  
An optional subject  diary can be completed by the parent/caregiver at home. Data entries can 
be reviewed by the investigator for completion and consistency when performing the Seizure 
Assessment.  
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 Sponsor or designee, 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
 
or designee 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). 
9.3. 
Record Retention 
A study document binder will be provided by the Sponsor for the investigator at each site for all 
 
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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 i
and the source data according to applicable regulatory requirements. These documents have to be 
archived for at least 15 years or at least 2 years after the last approval of a marketing application 
in an ICH region, but should be retained for longer if required by regulatory requirements or by 
agreement with the Sponsor.  
If the investigator can no longer maintain the archive of study records (eg, due to retirement or 
relocation), the Sponsor must be informed in writing about any change in responsibility for 
record retention, including the name of the new responsible party, contact information, and 
location of the study records. Records may not be destroyed without prior written consent from 
the Sponsor. 
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10. 
STATISTICS 
10.1. 
Determination of Sample Size 
The sample size will be determined by the number of subjects who participate in core studies 
Study ZX008-1503 or Study ZX008-1601 Part 2 and who volunteer for the extension study and 
meet the necessary criteria for enrollment. Up to 650 subjects may be eligible to participate in 
this extension study.  
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 1 dose of ZX008 during this 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 
1 dose of ZX008 and have at least 1 valid efficacy assessment during the open label extension. 
Effectiveness analyses, such as evaluating the improvement in seizure burden, 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 1 dose of ZX008, 
complete the entire OLE Treatment Period of this open label extension, and have no major 
protocol deviations that would have a significant impact on clinical outcome. 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 
The pre-ZX008 baseline period is equivalent to the core study pre-randomization baseline 
period, ie, the approximately 42-day (Dravet syndrome) or 28-day (Lennox-Gastaut syndrome) 
span just prior to randomization and start of treatment in the double-blind studies.  
Open-label Extension Treatment Period 
The OLE Treatment Period covers the periodduring which subjects will receive open label 
treatment with ZX008 until approval of ZX008 has been obtained from regulatory authorities for 
-
specific requirements in addition to legal and regulatory guidelines in the subjects country of 
r
by the Sponsor, whichever comes first .  
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Post-dosing Period 
The Post-dosing Period begins immediately at the end of OLE Treatment Period and extends for 
2 weeks. 
10.5. 
Statistical Analyses and Methods 
All safety and effectiveness 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 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; 
 years 
 years; 
. 
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. Main Effectiveness Analysis 
The main effectiveness endpoint is the CGI-I. The treating physician will rate their global 
-I throughout treatment with ZX008 according 
to the Schedule of Assessments. 
-point 
scale ranging from 1 (very much improved) to 7 (very much worse) by indicating the appropriate 
ve improved or worsened 
relative to reference baseline CGI-S (Appendix 3) established at Visit 1. The CGI-I will be 
repeated by the parent/caregiver. The mean (SD) CGI-I score, and the number and percentage of 
subjects who showed improvement (ie, had a score of 3 or lower), or clinically meaningful 
improvement (ie, had a score of 2 or lower) will be presented for each assessment timepoint. 
Global CGI-I score and CGI-I score for cognition, behavior and motor abilities assessed by the 
principal investigator and parent/caregiver will be summarized and analyzed using the same 
methods, as described above. Investigators will also rate overall change in seizure frequency as 
100% (seizure-free) improvement compared to last visit. 
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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 IDS
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. The 
oversight of safety and IDSMC responsibilities can be transferred back to the S
s 
representative/study physician at any time.  
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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 
nsent 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. 
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.  
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Verification of the signed ICF will be record
 
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 
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. 
 
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 
fter the subject or 
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 
informed cons
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 
acceptable representative have orally conse
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. 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. 
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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 i
inical 
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. 
11.3. 
Protocol Compliance  
The investigator must conduct the study in compliance with this study protocol as agreed to by 
the Sponsor and, if required, by any competent regulatory authority, and which has been 
approved by, or given a favorable opinion by, the IEC/IRB. 
The investigator should not implement any deviation from, or changes to, the study protocol 
without agreement by the Sponsor (delegate) and prior review and documented approval or 
favorable opinion from the IEC/IRB of an amendment to the study protocol. Exceptions include 
only cases of medical emergency to address immediate hazards to study subjects, or when the 
changes involve only logistic or administrative aspects of the study. 
In the event of a medical emergency, the investigator at each site may institute any medical 
procedures deemed appropriate to address an immediate hazard to a subject without prior 
IEC/IRB approval or favorable opinion. As soon as possible, the implemented deviation or 
change, the reason(s) for it, and, if appropriate, the proposed study protocol amendment(s) 
should be submitted to: 
 The Sponsor (delegate) for agreement 
 The IEC/IRB for review and approval or favorable opinion (if required) 
 The applicable competent regulatory authority (if required) 
Details of the procedure for implementing study protocol amendments are available in 
Section 12.10. 
At the earliest opportunity, the investigator (or delegate) must inform the Sponsor (delegate) 
about any notable protocol deviations and explain any deviation from the approved study 
protocol in the CRF and/or in the Protocol Deviation Log, if applicable. 
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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 1 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 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. 
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All study documentation and materials maintained in the Investigator Study File at the study site 
must be available for inspection by the Sponsor
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
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
(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 
if available. 
12.6. 
Subject Reimbursement 
Where relevant, subjects will be reimbursed for reasonable travel costs associated with 
participation in this study, after presentation of receipts for the travel in question, at a rate to be 
approved by the IEC/IRB. Subjects will not be paid for participating in the study.  
12.7. 
Liability and Insurance 
The civil liability of the involved parties with respect to financial loss due to personal injury and 
other damage that may arise as a result of this study being conducted are governed by the 
applicable legal requirement(s). 
The Sponsor will provide insurance to the investigator if required by the applicable regulatory 
and legal requirement(s). 
If required by local law, subjects taking part in this study will be insured against any injury 
caused by the study in accordance with the applicable regulatory and legal requirement(s).  
12.8. 
Subject Identification and Confidentiality 
All study documents, including the study protocol and 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 
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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 
medical records, and computer processing and publishing of his anonymous personal data, must 
be obtained prior to participation in the study. 
tity 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
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. 
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
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 
inator (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 and relevant medical records for completion, 
adherence to the study protocol, and possible AEs 
 Clarification of inconsistencies or missing data 
 Verification of study data against source documents 
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 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 
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 
n of change(s) to, or 
formal clarification of, a study protocol that may have a significant impact on the safety or 
physical or mental integrity of subjects, the scientific value of the study, the conduct or 
management of the study, or the quality or safety of any IMP used in the study. The IEC/IRB 
must approve all substantial protocol amendments prior to their implementation. If required by 
applicable local regulatory requirements, the local regulatory authority must also approve all 
substantial protocol amendments prior to their implementation. 
non
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 nonsubstantial protocol amendments. The substantial and nonsubstantial 
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 
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be signed by the Sponsor
e coordinating investigator (if 
applicable). 
Progress reports and/or a summary of the clinical study report will be provided to the IEC/IRB 
and competent regulatory authorities in accordance with applicable requirements. 
12.13. 
Use of Data and Publications 
The rights and obligations of investigators and the Sponsor concerning any formal presentation 
or publication of data collected as a direct or indirect result of this study will be addressed 
specifically in the Clinical Trial Agreement for the study (see Section 12.1). 
For multicenter studies, the first publication must be based upon all data obtained from all 
analyses, as stipulated in the study protocol by the biostatistician and not by the investigators. 
Investigators participating in multicenter studies must agree not to present data gathered 
individually or by a subgroup of study sites before the full, initial publication is available or 
5 years after the last clinical study visit, whichever is later, unless this has been agreed to by all 
other investigators and by the Sponsor. 
The Sponsor must receive a copy of any intended communications in advance of the proposed 
submission date. This is to allow the Sponsor time to review the communication for accuracy 
(thus avoiding potential discrepancies with submissions to regulatory authorities), to verify that 
confidential and/or proprietary information is not inadvertently divulged, to provide any relevant 
supplementary information, and to allow establishment of co-authorship (as appropriate). The 
authorship of communications arising from pooled data will include investigators from study 
sites that contributed data as well as relevant personnel from the Sponsor. Ownership of all data 
will remain with the Sponsor. 
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13. 
REFERENCE LIST 
Amemiya K, Sheevers H. Wheeler J. Developmental and Reproductive Toxicity Safety 
Assessment of Fenfluramine. Unpublished report. Final 19 March 2020.  
Andrade DM, Hamani C, Lozano AM, Wennberg RA. Dravet syndrome and deep brain 
stimulation: seizure control after 10 years of treatment. Epilepsia. 2010;51:1314 1316. 
Arzimanoglou A, French J, Blume WT, et al. Lennox-Gastaut syndrome: a consensus approach 
on diagnosis, assessment, management, and trial methodology. Lancet Neurol. 
2009;8(1):82-93. 
Barceloux DG. Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive 
Plants. Hoboken, New Jersey, USA, John Wiley & Sons. (3 February 2012). pp. 255-262.  
Caraballo RH. Nonpharmacologic treatments of Dravet syndrome: focus on the ketogenic diet. 
Epilepsia. 2011a;52(Suppl 2):79 82.  
Caraballo R, Vaccarezza M, Cersosimo R, et al. Long-term follow-up of the ketogenic diet for 
refractory epilepsy: multicenter Argentineal experience in 216 pediatric patients. Seizure. 
2011b;20:640-645.  
Center for Disease Control. Cardiac valvulopathy associated with exposure to fenfluramine or 
dexfenfluramine: U.S. Department of Health and Human Services Interim Public Health 
Recommendations, November 1997. Morbid Mortal Week Rep. 1997;46(45):1061-1084. 
Chiron C and Dulac O. The pharmacologic treatment of Dravet syndrome. Epilepsia. 
2011;52(Suppl. 2):72 75. 
Connolly HM, Crary JL, McGoon MD, Hensrud DD, et al. Valvular heart disease associated 
with fenfluramine-phentermine. New Engl J Med 1997;337(9):581-8. Erratum in: N Engl 
J Med. 1997;337(24):1783. 
de Lange IM, Gunning B, Sonsma ACM, et al. Influence of contraindicated medication use on 
cognitive outcome in Dravet syndrome and age at first afebrile seizure as a clinical 
predictor in SCN1A-related seizure phenotypes. Epilepsia. 2018;59:1154-1165. 
Douglas JC, Munro JF, Kitchin AH, et al. Pulmonary hypertension and fenfluramine. Br Med J. 
1981;283:881-883. 
Vie Med. 1978;8:543 548. 
European Medicines Evaluatio1`n Agency (EMA). Committee for Proprietary Medicinal 
Products, 1999. 
http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2009/12/WC500 
017629.pdf  
Hancock EC, Cross JH. Treatment of Lennox-Gastaut syndrome. Cochrane Database of 
Systematic Reviews 2013, Issue 2. Art. No.: CD003277. DOI: 
10.1002/14651858.CD003277.pub3. 
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Hurst DL. Epidemiology of severe myoclonic epilepsy of infancy. Epilepsia. 1990;31:397 400. 
Iannetti P, Parisi P, Spalice A, et al. Addition of verapamil in the treatment of severe myoclonic 
epilepsy in infancy. Epilepsy Res. 2009;85(1):89-95. 
ICH Topic E2F: Development Safety Update Report, 2011. 
ICH Topic E2A: Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, 1994. 
Lagae B, Schoonjans A, Gammaitoni A, Galer B, Ceulemans B. A pilot, open-label study of the 
effectiveness and tolerability of low dose fenfluramine (ZX008) in Lennox-Gastaut 
syndrome: Findings from a long-term extension. American Epilepsy Society Annual 
Meeting 2017: Abstract 2.284. 
McMurray J, Bloomfield P, Miller H. Irreversible pulmonary hypertension after treatment with 
fenfluramine. Br Med J. 1986;292:239-240. 
Morford LL, Inman-Wood SL, Gudelsky GA, et al. (Impaired spatial and sequential learning in 
rats treated neonatally with d-fenfluramine. Euro J Neurosci. 2002;16:491 500. 
doi:10.1046/j.1460-9568.2002.02100.x 
Nashef L, So EL, Ryvlin P, Tomson T. Unifying the definitions of sudden unexpected death in 
epilepsy. Epilepsia. 2012;53:227 233. 
Panayiotopoulos C. Epileptic encephalopathies in infancy and early childhood in which the 
epileptiform abnormalities may contribute to progressive dysfunction. In 
Panayiotopoulos C (Ed) The epilepsies: seizures, syndromes and management. 
Oxfordshire, UK: Bladon Medical Publishing, 2005:137 206. 
Pouwels HMN, Smeets JLRM, Cheriex EC, Wouters EFM. Pulmonary hypertension and 
fenfluramine. Euro Respir J. 1990;3:606-607. 
Sazgar M, Bourgeois BF. Aggravation of epilepsy by antiepileptic drugs. Pediatr Neurol. 
2005;33(4):227-234.  
Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper 
of the ILAE commission for classification and terminology. Epilepsia. 2017;58:512-521.  
Striano P, Coppola A, Pezzella M, et al. An open-label trial of levetiracetam in severe myoclonic 
epilepsy of infancy. Neurology. 2007;69:250 254. 
Webb RH, Gentles TL, Stirling JW, et al. Valvular regurgitation using portable echocardiography in a 
healthy student population: Implications for rheumatic heart disease screening. J Am Soc 
Echocardiogr. 2015;28(8):981-988. 
Wheless JW, Clarke DF, Arzimanoglou A, et al. Treatment of pediatric epilepsy: European 
expert opinion, 2007. Epileptic Disord. 2007;9:353 412. 
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Williams MT, Morford LL, McCrea AE, et al. Administration of d,l-fenfluramine to rats 
produces learning deficits in the Cincinnati water maze but not the Morris water maze: 
relationship to adrenal cortical output. Neurotoxicol Teratol. 2002;24(6):783 796. 
Wirrell EC. Treatment of Dravet syndrome. Canadian J Neurolig Sci. (Le Journal Canadien Des 
Sciences Neurologiques). 2016;43(Suppl3):S13 S18. 
http://doi.org/10.1017/cjn.2016.249.  
Wong J, Reddy SS, Klein AL. Anorectic drugs and valvular heart disease: a biological and 
clinical perspective. Cleveland Clin J Med. 1998;65:35-41. 
Zamponi N, Passamonti C, Cappanera S, Petrelli C. Clinical course of young patients with 
Dravet syndrome after vagal nerve stimulation. Eur J Paediatr Neurol. 2011;15:8-14.  
 
ZX008 Investigator
 
 
 
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13.1. 
APPENDICES                                                                                       
Appendix 1  List of Restricted Concomitant Medications 
The below table lists examples of medications that should be avoided if possible 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). If medical necessity 
requires the use of 1 or more of these medications during the course of the study, please contact 
the CRO Medical Monitor for approval. 
ADHD Medications 
Amphetamine and derivates 
Methamphetamine 
Guanfacine  
Methylphenidate  
Dextroamphetamine 
Lisdexamfetamine 
Bupropion  
Dexmethylphenidate  
Clonidine  
 
Anti-arrhythmics 
Antibiotics 
Anti-nausea 
Anti-pyretic 
Mexiletine 
Linezolid 
Metoclopramide 
Phenacetin 
Propafenone 
 
Ondansetron 
 
Anticonvulsants 
Retigabine/ezogabine 
 
Antidepressants (SSRIs, SNRIs, NRIs) 
Amitriptyline 
Clomipramine 
Fluvoxamine 
Paroxetine 
Bupropion 
Desipramine 
Imipramine 
Sertraline 
Buspirone 
Duloxetine 
Nefazodone 
Trazodone 
Citalopram 
Fluoxetine 
Nortriptyline 
Vortioxetine 
Antihistamines 
Astemizole 
Hydroxyzine  
Chlorphenamine  
 
Cyproheptadine 
Cetirizine 
Diphenhydramine  
 
Anti-migraine 
Almotriptan 
Eletriptan 
Naratriptan 
Sumatriptan 
Cafergot 
Ergotamine tartrate 
Rizatriptan 
Zolmitriptan 
Antipsychotics/Neuroleptics (serotonin agonists/ antagonists, noradrenergic agonists/antagonists) 
Amisulpride 
Clonidine 
Paliperidone 
Risperidone 
Amphetamine 
Guanfacine 
Perospirone 
Sulpiride 
Aripiprazole 
Levomepromazine 
Perphenazine 
Ziprasidone 
Asenapine 
Methylphenidate 
Promethazine 
Zuclopenthixol 
Clozapine 
Olanzapine 
Quetiapine 
 
Anti-viral 
Beta Blocker 
Chemotherapy 
Cough Suppressant 
Interferon 
Alprenolol 
Dasatinib 
Dextromorphan 
Ritonavir 
Bufuralol 
 
 
Telaprevir 
 
 
 
Decongestants (allowed for short-term use only) 
Statins 
Phenylpropanolamine 
 
Cerivastatin 
 
Ergot Alkaloids, their derivatives, and Antiparkinson agents 
Pergolide  
Cabergoline  
Ergotamine Tartrate 
 
Opioids 
Alfentanil 
Levacetylmethadol (LAAM) 
Meperidine 
Oxycodone 
Codeine 
Fentanyl 
Methadone 
Tramadol 
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13.2. 
Appendix 2  Columbia  Suicide Severity Rating Scale 
 
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13.3. 
Appendix 3  Clinical Global Impression  Severity (CGI-S)  
 
 
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13.4. 
Appendix 4  Clinical Global Impression  Improvement (CGI-I) 
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13.5. 
Appendix 5  Maximum Allowable Blood Draw Volumes 
 
 
 
 
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13.6. Appendix 6 - 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-
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 6, 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, ho
the overall visit page to capture the basis for missing or alternatively collected (i.e. 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 
 
Seizure assessment (by Investigator) when possible 
 
Scales and Questionnaires, when applicable and if feasible 
o 
C-SSRS 
o 
CGI-I (Global and Symptomatic, by Investigator and Parent/Caregiver)  
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3. End-of-Study/Early Termination (EOS/ET) and Follow-up Visits:  
Cardiac follow-up visits must be conducted in-person. 
For the EOS/ET visit and Post-Dosing Follow-up visits (ie, 2 weeks after the last dose), 
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.  
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 
 
Seizure assessment (by Investigator) when possible 
EOS/ET for subjects transitioning to Commercial drug:  
For the EOS/ET visit (Visit 7) and Post-Dosing Follow-up visit (Visit 8), 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 had 
an ECHO within 3 to 6 months before the transition date. Subjects who transition to 
commercially available drug will have follow-up ECHOs within the required timeframe 
while on commercial drug.  
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 CRO medical monitor is required to determine a course of 
action, which may include approval to delay further for a pre-specified duration, subject 
withdrawal, or other actions. The risk/benefit analysis will take into account AEs, previous 
assessment findings, duration of delay, clinical improvement while on study drug (seizure 
and non-seizure outcomes), and region-specific risk of attending in-person visits to 
complete the assessments.  
Doppler ECHO:   
If subjects are unable to travel to the study site due to COVID-19 circumstances, ECHOs 
may be delayed up to an additional 3 months from the protocol-designated ECHO due date 
(for a total of 9 months from the time of the last ECHO) for subjects that exhibited the 
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following on their previous, most recent ECHO: absent aortic regurgitation, absent or trace 
mitral regurgitation, and PASP <30 mmHg. 
 
-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 
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 
and there were no findings meeting Level 2 criteria (see Protocol Table8) the Cardiac 
Follow-up Visit may be skipped.  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 
ECG, Chest X-ray and EEG:   
If clinically indicated and where applicable, delays in these assessments may be 
hing the risk/benefit of 
the clinical necessity of the assessment versus the risk of an in-person visit. All decisions 
should be documented appropriately in the source documentation. If not conducted at the 
study site, ECG, chest X-ray and EEG can be performed at any qualified local facility with 
results to be sent to the Principal Investigator for safety overread and documentation.  
If the ECG (or in the case of certain country-specific regulations: Chest X-ray or EEG) 
was conducted within 30 days of a scheduled Cardiac Follow-up Visit, these assessments 
do not need to be repeated at the Cardiac Follow-up Visit provided there were no 
significant findings that require additional follow-up.  
Clinical Laboratory Assessments: 
Laboratory assessments may be delayed up to 6 weeks. If further delay is required, and 
they are clinically indicated by the investigator, laboratory assessments may be conducted 
at local laboratory facilities. Local lab results are to be sent to the Principal Investigator for 
safety overread.  
If results from the most recent assessments are within normal range or documented as 
clinically insignificant, further delays to obtaining laboratory assessments may be 
implemented based on clinical judgmental.   
5. Alternative Dispensation for Study Drug 
Shipments of investigational product may be sent by courier from site pharmacy to the 
-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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13.7. 
Appendix 7- Summary of Protocol Amendment 4.0 
Changes were made to protocol Amendment 3.1 to include updating the version number and date 
to Protocol Amendment 4.0 22 September 2022, as well as study number, sponsor signatories 
and affiliation, reflective its acquisition by UCB Pharma Inc. Language was modified to clarify 
how the end of study participation will occur. These changes required edits to the Synopsis, 
Schedule of Assessments, Sections 1.6, 3.1, 3.3, 6.1.3 and 10.4.  
Further changes were made to the Synopsis, sections 3.7.1 and 4.4, 8.9.1 and 10.6 to reflect the 
opportunity to transfer of safety oversight back to the sponsor at any time during the study 
conduct.  
Further updates were made to Section 1 to be updated with the newest information version of the 
ZX008 Investigator Brochure 2022 v10.0. Clarification was made on the affiliation of the study 
medical monitors throughout the document as well as on the result disclosure on public registries 
(Sections 2.3 and 8.5.1). Further changes included updating Section 8.6 to reflect the contact 
details for SAE reporting, 
 
List of Specific Changes 
 
Additions are marked in blue and red underline and deletions are marked in blue and red 
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 first appear in the protocol, but several items are 
grouped by rationale. 
 
1.  Updates were made to the Synopsis, Section 1.6, 3.1, 3.3, 6.1.3 and Section 10.4 concerning 
subjects end of study participation 
 
Synopsis:  
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Section 1.6 
 
 
 
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Section 3.1 
 
Section 3.3 
 
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Section 6.1.3:  
 
Section 10.4:  
 
 
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2. Updates were made to the Synopsis, sections XX and XX to reflect the opportunity to transfer 
of safety oversight back to the sponsor at any time during the study conduct 
Synopsis:  
 
Section 3.7.1:  
 
 
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Section 4.4:  
 
 
Section 8.9.1:  
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Section 10.6:  
 
 
3. Section 1 was updated with the newest information and version of ZX008 Investigator 
Brochure 2022. The Reference List was also updated to include Investigator Brochure version 
10.0.  
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4. Updates were made to Sections 2.3 and 8.5.1 to clarify the result disclosure on public 
registries. 
Section 2.3:  
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Section 8.5.1:  
 
 
 
 
 
 
 
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5. Section 8.6 was updated to reflect the current contact details for SAE Reporting.  
 
 
 
 
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