A Two-Part Study of ZX008 in Children and Adults With Lennox-Gastaut Syndrome (LGS); Part 1: A Randomized, Double-blind, Placebo-controlled Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as Adjunctive Therapy for Seizures in Children and Adults With LGS, Followed by Part 2: An Open-label Extension to Assess Long-Term Safety of ZX008 in Children and Adults With LGS
Phase: PHASE3
Conditions: Lennox Gastaut Syndrome
Sponsor: Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.

Confidential 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Two-Part Study of ZX008 in Children and Adults with 
Lennox-Gastaut Syndrome (LGS); Part 1: A Randomized, 
Double-blind, Placebo-controlled Trial of Two Fixed Doses 
of ZX008 (Fenfluramine Hydrochloride) Oral Solution as 
Adjunctive Therapy for Seizures in Children and Adults with 
LGS, Followed by Part 2: An Open-label Extension to 
Assess Long-Term Safety of ZX008 in Children and Adults 
with LGS 
Study Number: 
ZX008-1601 
Study Product: 
Fenfluramine Hydrochloride Oral Solution; ZX008 
IND Number: 
132604 
EudraCT Number: 
2017-002628-26 
Sponsor: 
Zogenix International Limited  
A wholly owned subsidiary of UCB Biosciences, Inc. 
4000 Paramount Pkwy, 
Morrisville, NC 27560, USA 
Sponsor's Medical 
Contact: 
Program Physician 
UCB Biosciences Inc 
Date and Version of 
Study Protocol: 
25 July 2022 (PA 4.0 Japan) 
29 July 2020 (PA 3.2 Japan) 
29 October 2018 (PA 1.6.1 Japan) 
Based on 10 January 2018 (Amendment 1.0 ROW)  
This protocol includes information and data that contain trade secrets and privileged or confidential information, 
which is the property of the sponsor. This information must not be made public without written permission from the 
sponsor. These restrictions on disclosure will apply equally to all future information supplied to you. This material 
may be disclosed to and used by your personnel and associates as may be necessary to conduct the clinical study. 
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ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
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LIST OF PERSONNEL AND ORGANIZATIONS RESPONSIBLE FOR 
CONDUCT OF STUDY 
A list of personnel and organizations responsible for the conduct of the study will be 
supplied to study sites as part of the Investigator Study File. This list will be updated by 
the sponsor or the sponsor's agent and provided to study sites as needed. 
 
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ZX008 (Fenfluramine Hydrochloride) 
ZX008-1601 Clinical Study PA 4.0 (Japan) 25 July 2022 
 
Confidential 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ............................................................................................... 1 
LIST OF PERSONNEL AND ORGANIZATIONS RESPONSIBLE FOR CONDUCT OF 
STUDY ........................................................................................................................... 2 
TABLE OF CONTENTS ............................................................................................................. 3 
SIGNATURE OF SPONSOR .................................................................................................... 11 
SIGNATURE OF COORDINATING INVESTIGATOR ......................................................... 12 
SIGNATURE(S) OF THE PRINCIPAL INVESTIGATOR ...................................................... 13 
LIST OF ABBREVIATIONS .................................................................................................... 14 
STUDY SYNOPSIS ................................................................................................................... 16 
1. 
INTRODUCTION ........................................................................................................ 34 
1.1 BACKGROUND INFORMATION ON INDICATION STUDIED ........ 34 
1.1.1 Existing Treatment for LGS ................................................................... 34 
1.2 BACKGROUND INFORMATION ON STUDY PRODUCT ................. 35 
1.3 CLINICAL DATA .................................................................................... 35 
1.4 PHARMACOKINETICS, PRECLINICAL DATA, AND CLINICAL 
PHARMACOLOGY .......................................................................................... 38 
1.4.1 Pharmacokinetics ................................................................................... 38 
1.4.2 Preclinical Data ...................................................................................... 39 
1.4.3 Clinical Pharmacology ........................................................................... 39 
1.5 BACKGROUND INFORMATION ON REFERENCE PRODUCT ....... 40 
1.6 RATIONALE FOR CURRENT STUDY ................................................. 40 
1.7 RISK-BENEFIT ASSESSMENT ............................................................. 42 
2. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 43 
2.1 PART 1 ...................................................................................................... 43 
2.1.1 PRIMARY OBJECTIVE ....................................................................... 43 
2.1.2 KEY SECONDARY OBJECTIVES ...................................................... 43 
2.1.3 ADDITIONAL SECONDARY OBJECTIVES ..................................... 43 
2.1.4 SAFETY OBJECTIVE .......................................................................... 44 
2.1.5 PHARMACOKINETIC OBJECTIVE ................................................... 44 
2.1.6 EXPLORATORY OBJECTIVES .......................................................... 45 
2.2 PART 2 ...................................................................................................... 45 
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2.2.1 PRIMARY OBJECTIVE ....................................................................... 45 
2.2.2 SECONDARY OBJECTIVES ............................................................... 45 
2.2.3 EXPLORATORY OBJECTIVES .......................................................... 46 
2.3 STUDY ENDPOINTS .............................................................................. 46 
2.3.1 Efficacy Endpoints ................................................................................. 46 
2.3.2 Safety Endpoints .................................................................................... 47 
2.3.3 Exploratory Endpoints ........................................................................... 47 
3. 
INVESTIGATIONAL PLAN ....................................................................................... 48 
3.1 OVERALL STUDY DESIGN AND PLAN ..................................... 48 
3.2 NUMBER OF SUBJECTS ....................................................................... 49 
3.3 STUDY DURATION ............................................................................... 49 
3.4 NUMBER OF STUDY CENTERS .......................................................... 50 
3.5 RATIONALE FOR STUDY DESIGN AND CHOICE OF TREATMENT 
GROUPS ............................................................................................................ 51 
3.6 RATIONALE FOR STUDY DESIGN AND CHOICE OF TREATMENT 
GROUPS ............................................................................................................ 51 
3.7 PREMATURE TERMINATION OF STUDY ......................................... 52 
3.8 STUDY MONITORING PROCEDURES ................................................ 52 
3.8.1 Independent Data Safety Monitoring Committee .................................. 52 
3.8.2 International Cardiac Advisory Board (ICAB) ...................................... 53 
4. 
SELECTION OF STUDY POPULATION .................................................................. 54 
4.1 PART 1 ...................................................................................................... 54 
4.1.1 INCLUSION CRITERIA ....................................................................... 54 
4.1.2 EXCLUSION CRITERIA ...................................................................... 55 
4.2 RANDOMIZATION INCLUSION CRITERIA ....................................... 56 
4.3 PART 2 ...................................................................................................... 57 
4.4 SUBJECTS OF REPRODUCTIVE POTENTIAL ................................... 58 
4.4.1 Sperm and Egg Donation ....................................................................... 59 
4.4.2 Pregnancy ............................................................................................... 59 
4.5 REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT .... 59 
4.6 TERMINATION OF THE CLINICAL STUDY ...................................... 61 
4.7 REPLACEMENT OF SUBJECTS ........................................................... 61 
5. 
INVESTIGATIONAL MEDICINAL PRODUCT INFORMATION .......................... 62 
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5.1 IDENTITY OF INVESTIGATIONAL MEDICINAL PRODUCT .......... 62 
5.1.1 Labeling and Packaging ........................................................................ 62 
5.2 DESCRIPTION OF REFERENCE TREATMENT, COMPARATOR, 
AND/OR PLACEBO ......................................................................................... 63 
5.2.1 Labeling and Packaging ........................................................................ 63 
5.3 SHIPMENT AND STORAGE .................................................................. 63 
5.4 IMP ACCOUNTABILITY ....................................................................... 63 
5.5 TREATMENT ADMINISTRATION ....................................................... 64 
5.5.1 Part 1: Randomization ........................................................................ 64 
5.5.1.1 Blinding ........................................................................................... 64 
5.5.2 Part 1: Titration Period ....................................................................... 65 
5.5.3 Part 1: Maintenance Period .................................................................... 66 
5.5.4 Part 1: Taper Period (for subjects not entering Part 2)........................... 66 
5.5.5 Part 1: Transition Period ........................................................................ 67 
5.5.6 Part 2: OLE Treatment Period................................................................ 68 
5.5.7 Taper Period ........................................................................................... 69 
5.6 PRIOR AND CONCOMITANT MEDICATION .................................... 70 
5.6.1 Vagal Nerve Stimulation ........................................................................ 71 
5.6.2 Ketogenic Diet ....................................................................................... 71 
5.6.3 Rescue Medication for Seizures ............................................................. 71 
5.6.4 Prohibited Concomitant Medications ..................................................... 71 
5.7 TREATMENT COMPLIANCE................................................................ 72 
6. 
VISIT SCHEDULE ...................................................................................................... 73 
6.1 
Part 1 ............................................................................................................................. 73 
6.1.1 BASELINE PERIOD (STUDY DAY -28 TO STUDY DAY -1) ......... 73 
6.1.1.1. Screening, Clinic Visit 1 (Study Day -28) ......................................... 73 
6.1.1.2. Phone Visit 2 (Study Day -15) ........................................................... 75 
6.1.1.3. Clinic Visit 3 (Study Day -1): Randomization ................................... 75 
6.1.2 TITRATION AND MAINTENANCE PERIODS ................................. 77 
6.1.2.1 Titration Period Study Day 1 .............................................................. 77 
6.1.2.2 Phone Visits 4 and 5 (Titration Period Study Days 4 and 8) .............. 77 
6.1.2.3 Clinic Visit 6 (Titration Period Study Day 15) ................................... 77 
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6.1.2.4 Phone Visit 7 (Maintenance Period Study Day 29) ............................ 77 
6.1.2.5 Clinic Visit 8 (Maintenance Period Study Day 43) ............................ 78 
6.1.2.6 Phone Visit 9 (Maintenance Period Study Day 57) ............................ 78 
6.1.2.7 Clinic Visit 10 (Maintenance Period Study Day 71) .......................... 79 
6.1.2.8 Phone Visit 11 (Maintenance Period Study Day 85) .......................... 79 
6.1.2.9 Clinic Visit 12 (Maintenance Period Study Day 99): End of 
Study/Early Termination.................................................................................... 79 
6.1.3 POST-DOSE VISIT (CLINIC VISIT 13; STUDY DAY 113) .............. 81 
6.1.4 CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 14; 3 and 6 months 
after last dose) .................................................................................................... 81 
6.2 
Part 2 ............................................................................................................................. 82 
6.2.1 
Clinic Visit 15 (OLE Study Day 1) .............................................................................. 83 
6.2.2 
Clinic/Phone Visit 16 (OLE Study Day 15) ................................................................. 84 
6.2.3 
Clinic Visits 17-21 (OLE Months, 1, 2, 3, 6, and 9) .................................................... 85 
6.2.4 
Clinic Visit 22 (OLE Month 12) ................................................................................... 86 
6.2.5 
Clinic Visits 23-41 (OLE Months 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 
57, 60, 63, 66, 69) ......................................................................................................... 87 
6.2.6 
Clinic Visit 42:  End of Study/Early Termination ........................................................ 88 
6.2.7 
POST-DOSE VISIT (CLINIC Visit 43; 14 DAYS AFTER LAST DOSE OF IMP) .. 90 
6.2.8 
CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 44, 45; 3 AND 6 MONTHS AFTER 
LAST DOSE OF IMP) ................................................................................................. 90 
6.3 
STUDY CONDUCT DURING COVID-19 ................................................................. 91 
6.4 
ESTIMATED BLOOD VOLUME COLLECTION ..................................................... 91 
7. 
EFFICACY, SAFETY, AND PHARMACOKINETIC ASSESSMENTS ................... 94 
7.1 EFFICACY/EFFECTIVENESS ASSESSMENTS ................................... 94 
7.1.1 Seizure Assessments .............................................................................. 94 
7.1.2 Clinical Global Impression - Improvement ............................................ 95 
7.1.3 Vineland Adaptive Behavior Scale (VABS) .......................................... 96 
7.1.4 QOLCE .................................................................................................. 96 
7.1.5 Parent/Caregiver Affective Symptoms .................................................. 96 
7.2 SAFETY ASSESSMENTS ....................................................................... 97 
7.2.1 Demographics, Medical/Neurological/Epilepsy History, and Pre-Study 
Medication ......................................................................................................... 97 
7.2.2 Adverse Events ....................................................................................... 97 
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7.2.3 Physical Examinations ........................................................................... 97 
7.2.4 Neurological Examinations .................................................................... 97 
7.2.5 Vital Signs (Including Height and Weight) ........................................... 98 
7.2.6 Laboratory Measurements ...................................................................... 98 
7.2.7 Plasma Sample for Concomitant Antiepileptic Drug(s) ......................... 99 
7.2.8 Electrocardiograms ................................................................................ 99 
7.2.9 Doppler Echocardiography .................................................................... 99 
7.2.10 Behavior Rating Inventory of Executive Function (BRIEF) ............... 99 
7.2.11 Tanner Staging ................................................................................... 100 
7.2.12 Columbia-Suicide Severity Rating Scale ........................................... 100 
7.3 PHARMACOKINETIC ASSESSMENTS ............................................. 100 
7.4 EPILEPSY GENOTYPE PANEL ........................................................... 100 
7.5 APPROPRIATENESS OF MEASUREMENTS .................................... 101 
8. 
ADVERSE EVENTS.................................................................................................. 102 
8.1 DEFINITIONS ........................................................................................ 102 
8.1.1 Adverse Events ..................................................................................... 102 
8.1.2 Serious Adverse Events ........................................................................ 103 
8.1.3 Adverse Events of Special Interest ...................................................... 104 
8.2 SEVERITY OF ADVERSE EVENTS .................................................... 104 
8.3 CAUSALITY OF ADVERSE EVENTS ................................................ 105 
8.4 OBSERVATION PERIOD FOR ADVERSE EVENT REPORTING ... 105 
8.5 ADVERSE EVENT REPORTING ......................................................... 106 
8.5.1 Adverse Events ................................................................................... 106 
8.6 SERIOUS ADVERSE EVENTS REPORTING .................................... 106 
8.6.1 Requirements for Immediate Reporting of Serious Adverse Events ... 107 
8.7 REPORTING OF SERIOUS ADVERSE EVENTS BY INVESTIGATOR 
TO IEC/IRB ..................................................................................................... 107 
8.8 REPORTING OF EVENTS OTHER THAN SERIOUS ADVERSE 
EVENTS BY INVESTIGATOR TO SPONSOR ............................................ 108 
8.9 FOLLOW-UP OF ADVERSE EVENTS ................................................ 108 
8.9.1 Follow-up of Echocardiogram Findings .............................................. 108 
8.10 PREGNANCY ..................................................................................... 110 
9. 
DATA HANDLING PROCEDURES ........................................................................ 110 
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9.1 RECORDING OF DATA ....................................................................... 110 
9.2 DATA QUALITY ASSURANCE .......................................................... 111 
9.3 RECORD RETENTION ......................................................................... 111 
10. 
STATISTICS .............................................................................................................. 112 
10.1 STATISTICAL ANALYSIS: PART 1 ................................................. 112 
10.1.1 DETERMINATION OF SAMPLE SIZE .......................................... 112 
10.1.2 ANALYSIS POPULATIONS ............................................................ 112 
10.1.2.1 Safety (SAF) Population ................................................................. 112 
10.1.2.2 Modified Intent-to-Treat (mITT) Population .................................. 113 
10.1.2.3 Per Protocol (PP) Population .......................................................... 113 
10.1.3 SUBJECT COHORTS ....................................................................... 113 
10.1.3.1 Cohort A .......................................................................................... 113 
10.1.3.2 Cohort B .......................................................................................... 113 
10.1.4 TREATMENT GROUPS ................................................................... 113 
10.1.5 TREATMENT PERIODS .................................................................. 113 
10.1.6 STATISTICAL ANALYSES AND METHODS............................... 114 
10.1.6.1 Efficacy Analyses............................................................................ 114 
10.1.6.2 Safety Analyses ............................................................................... 115 
10.1.6.3 Pharmacokinetic Analyses .............................................................. 116 
10.2 STATISTICAL ANALYSIS: PART 2 ................................................. 116 
10.2.1 ANALYSIS POPULATIONS ............................................................ 116 
10.2.1.1 OLE Population ............................................................................... 116 
10.2.1.2 OLE mITT Population .................................................................... 116 
10.2.2 TREATMENT GROUPS ................................................................... 116 
10.2.3 TREATMENT PERIODS .................................................................. 116 
10.2.4 STATISTICAL ANALYSES AND METHODS............................... 117 
10.2.4.1 Safety Analyses ............................................................................... 117 
10.2.4.2 Effectiveness Analyses.................................................................... 117 
10.2.5 ANALYSES PROVIDED TO AN INDEPENDENT DATA AND 
SAFETY MONITORING COMMITTEE ....................................................... 117 
11. 
ETHICAL & REGULATORY CONSIDERATIONS................................................ 117 
11.1 ETHICAL CONSIDERATIONS .......................................................... 117 
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11.2 INFORMED CONSENT ...................................................................... 118 
11.3 REGULATORY CONSIDERATIONS AND INDEPENDENT ETHICS 
COMMITTEE/INSTITUTIONAL REVIEW BOARD................................... 119 
11.4 PROTOCOL COMPLIANCE ............................................................... 120 
12. 
ADMINISTRATIVE ASPECTS ................................................................................ 120 
12.1 CLINICAL TRIAL AGREEMENT ...................................................... 120 
12.2 FINANCIAL DISCLOSURE BY INVESTIGATOR ........................... 120 
12.3 CLINICAL STUDY REGISTRATION AND RESULTS DISCLOSURE
 
121 
12.4 STUDY FILES AND MATERIALS .................................................... 121 
12.5 INITIATION OF THE STUDY ............................................................ 121 
12.6 SUBJECT REIMBURSEMENT ........................................................... 122 
12.7 LIABILITY AND INSURANCE ......................................................... 122 
12.8 SUBJECT IDENTIFICATION AND CONFIDENTIALITY .............. 122 
12.9 MONITORING OF THE STUDY ........................................................ 123 
12.10 PROTOCOL AMENDMENTS .......................................................... 123 
12.11 AUDITS AND INSPECTIONS .......................................................... 124 
12.12 CLINICAL STUDY REPORT ........................................................... 124 
12.13 USE OF DATA AND PUBLICATIONS ........................................... 124 
13. 
REFERENCE LIST .................................................................................................... 126 
14. 
APPENDICES ............................................................................................................ 129 
APPENDIX 1 – LIST OF PROHIBITED CONCOMITANT MEDICATIONS ..................... 129 
APPENDIX 2 – COLUMBIA – SUICIDE SEVERITY RATING SCALE ............................ 131 
APPENDIX 3 – BEHAVIOR RATING INVENTORY OF EXECUTIVE FUNCTION ....... 136 
APPENDIX 4 – VINELAND ADAPTIVE BEHAVIOR SCALE .......................................... 146 
APPENDIX 5 – TANNER STAGING ..................................................................................... 164 
APPENDIX 6 – QOLCE QUALITY OF LIFE ........................................................................ 167 
APPENDIX 7 – HOSPITAL ANXIETY AND DEPRESSION SCALE ................................. 179 
APPENDIX 8 – ZARIT CAREGIVER BURDEN INVENTORY .......................................... 182 
APPENDIX 9 – MAXIMUM ALLOWABLE BLOOD DRAW VOLUMES ........................ 184 
APPENDIX 10 – STUDY CONDUCT DURING COVID-19 ................................................ 185 
APPENDIX 11 - SUMMARY OF PROTOCOL AMENDMENT 4.0 .................................... 188 
 
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Confidential 
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LIST OF TABLES 
Table 1. 
Schedule of Assessments: Part 1 ....................................................................... 29 
Table 2. 
Schedule of Assessments: Part 2 Cohort B only................................................ 31 
Table 3               Post Hoc Estimates of Fenfluramine and Norfenfluramine Steady-State 
Pharmacokinetic Parameters in Subjects with Dravet Syndrome in Study 1 (Geometric Mean 
[CV%]) .......................................................................................................................................... 38 
Table 4: 
Investigational Medicinal Product – ZX008 ...................................................... 62 
Table 5: 
Titration Algorithm for Part 1 ............................................................................ 66 
Table 6: 
Taper Algorithm for Part 1 ................................................................................ 67 
Table 7: 
Transition Algorithm for Part 1 ......................................................................... 67 
Table 8.  
Taper Algorithm for Part 2 ................................................................................ 69 
Table 9: 
Time Windows for Assessments in Part 1 ......................................................... 73 
Table 10: 
Schedule of Post-Treatment Cardiac Follow-up for Part 1 ................................ 82 
Table 11: 
Time Windows for Assessments in Part 2 ......................................................... 83 
Table 12. 
Schedule of Post-Treatment Cardiac Follow-up for Part 2 ................................ 91 
Table 13: 
Maximum Estimated Blood Volume Collection for Part 1* ............................. 92 
Table 14. 
Maximum Estimated Blood Volume Collection for Part 2* ............................. 92 
Table 15: 
Priorities for Blood Sample Collections ............................................................ 93 
Table 16: 
Adverse Events of Special Interest .................................................................. 104 
Table 17: 
Severity Definition of Adverse Events ............................................................ 105 
Table 18: 
Clinical Measures Enacted Upon Increasing Severity of ECHO Findings ..... 108 
 
 
 TABLE OF FIGURES 
 
Figure 1; Study Schema ................................................................................................................ 50 
 
 
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SIGNATURE OF SPONSOR 
Study Number: 
ZX008-1601 
PA 4.0(Japan) 
25 July 2022 
Study Title: 
A Two-Part Study of ZX008 in Children and 
Adults with Lennox-Gastaut Syndrome 
(LGS); Part 1: A Randomized, Double-blind, 
Placebo-controlled Trial of Two Fixed Doses 
of ZX008 (Fenfluramine Hydrochloride) Oral 
Solution as Adjunctive Therapy for Seizures 
in Children and Adults with LGS, Followed 
by Part 2: An Open-label extension to Assess 
Long-Term Safety of ZX008 in Children and 
Adults with LGS 
Sponsor’s Responsible Officer: 
 
  
Zogenix International Limited  
A wholly owned subsidiary of UCB 
Biosciences, Inc. 
4000 Paramount Pkwy, 
, 
Morrisville, NC 27560, USA 
 
 
Signature 
 
On behalf of 
:  
UCB Biosciences Inc. 
 
Date (Day/Month/Year) 
 
 
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SIGNATURE OF COORDINATING INVESTIGATOR 
Study Number: 
ZX008-1601  
PA 4.0 (Japan) 
25 July 2022 
 
Study Title: 
A Two-Part Study of ZX008 in Children and 
Adults with Lennox-Gastaut Syndrome 
(LGS); Part 1: A Randomized, Double-blind, 
Placebo-controlled Trial of Two Fixed Doses 
of ZX008 (Fenfluramine Hydrochloride) Oral 
Solution as Adjunctive Therapy for Seizures 
in Children and Adults with LGS, Followed 
by Part 2: An Open-label extension to Assess 
Long-Term Safety of ZX008 in Children and 
Adults with LGS 
Coordinating Investigator: 
 
Children’s Hospital Colorado 
Anschutz Medical Campus 
Aurora, CO   80045 
 
 
 
Signature 
Date (Day/Month/Year) 
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SIGNATURE(S) OF THE PRINCIPAL INVESTIGATOR 
Study Number: 
ZX008-1601  
PA 4.0 (Japan) 
25July 2022 
Study Title: 
A Two-Part Study of ZX008 in Children and 
Adults with Lennox-Gastaut Syndrome (LGS); 
Part 1: A Randomized, Double-blind, Placebo-
controlled Trial of Two Fixed Doses of ZX008 
(Fenfluramine Hydrochloride) Oral Solution as 
Adjunctive Therapy for Seizures in Children and 
Adults with LGS, Followed by Part 2: An Open-
label Extension to Assess Long-Term Safety of 
ZX008 in Children and Adults with LGS 
I have read this study protocol, including all appendices. By signing this study 
protocol, I agree to conduct the clinical study, following approval by an Independent 
Ethics Committee (IEC)/Institutional Review Board (IRB), in accordance with the 
study protocol, the current International Conference on Harmonization (ICH) 
Guideline for Good Clinical Practice (GCP), and applicable regulatory requirements. I 
will ensure that all personnel involved in the study under my direction will be informed 
about the contents of this study protocol and will receive all necessary instructions for 
performing the study according to the study protocol. 
Name and affiliation to be filled out by the investigator 
Principal Investigator  
(Name & Affiliation): 
 
 
 
 
 
 
Signature 
Date (Day/Month/Year) 
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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AE 
Adverse Event 
AED 
Antiepileptic drug 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of covariance 
AS 
Atonic seizure 
AUC 
Area under the concentration-time curve 
AUC0-t 
Area under the concentration-time curve from time zero to time=t 
BID 
bis in die; two times per day 
BMI 
Body Mass Index 
BRIEF 
Behavior Rating Inventory of Executive Function 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
Cavg•ss 
Average plasma concentration 
CBD 
Cannabidiol 
CFR 
Code of Federal Regulations 
CGI 
Clinical Global Impression 
Cmax 
Maximum observed concentration determined directly from the 
concentration-time profile 
CRF 
Case report form 
CS 
Clonic seizures 
Cyp 
Cytochrome p450 
dL 
Deciliter 
DS 
Dravet syndrome 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
electronic Case Report Form 
EEG 
electroencephalogram 
EOS 
End Of Study 
EPAR 
European Public Assessment Report 
ET 
Early Termination 
FS 
Focal seizure 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GH 
Growth Hormone 
GMP 
Good Manufacturing Practices 
GTC 
Generalized tonic-clonic seizure 
HADS 
Hospital Anxiety and Depression Scale 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
IDSMC 
Independent Data and Safety Monitoring Committee 
IEC 
Independent Ethics Committee 
IGF-1 
Insulin-like Growth Factor-1 
ILAE 
International League Against Epilepsy 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
ICAB 
International Cardiology Advisory Board 
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ABBREVIATION 
DEFINITION 
IRB 
Institutional Review Board 
IU 
International Unit 
IWR 
Interactive Web Response (System) 
KD 
Ketogenic diet 
kg 
Kilogram 
Leiter-3 
Leiter International Performance Scale-Revised 
LGS 
Lennox-Gastaut syndrome 
LH 
Luteinizing Hormone 
M 
Maintenance period 
MCDS 
Mean change in number of seizures that results in drops 
MCSF 
Mean Convulsive Seizure Frequency 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mg/kg/day 
Milligram per kilogram per day 
Min 
Minutes 
mITT 
Modified Intent-to-Treat 
mL 
Milliliter 
MS 
Myoclonic seizure 
OLE 
Open-label extension 
PopPK model 
Population Pharmacokinetic model 
PK 
Pharmacokinetics 
PP 
Per Protocol 
QoL 
Quality of Life 
QOLCE 
Quality of Life in Childhood Epilepsy 
QTcF 
corrected QT interval using Fredericia method 
SAE 
Serious Adverse Event 
SAF 
safety population 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Status epilepticus 
SMEI 
Severe Myoclonic Epilepsy Of Infancy 
STP 
Stiripentol 
SUDEP 
Sudden Unexpected Death in Epilepsy 
T+M 
Titration plus Maintenance Periods 
t1/2 
Terminal half-life 
TA 
Tonic/atonic seizure 
THC 
Tetrahydrocannabinol 
Tmax 
Time to maximum concentration 
TS 
Tonic seizure 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
USA 
United States of America 
USP 
United States Pharmacopeia 
VABS 
Vineland Adaptive Behavior Scale 
VNS 
Vagal Nerve Stimulator/Stimulation 
ZX008 
Fenfluramine Hydrochloride Oral Solution 
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STUDY SYNOPSIS 
Study Title: A Two-Part Study of ZX008 in Children and Adults with Lennox-Gastaut 
Syndrome (LGS); Part 1: A Randomized, Double-blind, Placebo-controlled Trial of Two 
Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as Adjunctive Therapy 
for Seizures in Children and Adults with LGS, Followed by Part 2: An Open-label Extension 
to Assess Long-Term Safety of ZX008 in Children and Adults with LGS 
Study Number: ZX008-1601 
Study Product: Fenfluramine Hydrochloride Oral Solution, ZX008 
Type of Study: 
Part 1: Efficacy and safety study 
Part 2: Long-term safety study 
Indication Studied:  
Adjunctive therapy for seizures in Lennox-
Gastaut syndrome (LGS) 
Phase of Development: Phase III  
Countries: North America, Europe, Japan, and 
Australia 
Sponsor: Zogenix International Limited  
Coordinating Investigator:  
Estimated Duration of Individual Subject Participation: 
The duration of participation in the study for an individual subject in the double-blind study (Part 1) is 
expected to be up to 20 weeks. The duration of participation in the open-label extension (Part 2) is up 
to 72 months or until ZX008 is approved in a subject’s country of residence and listed on a patient’s 
health plan formulary, whichever occurs first. The total participation time is up to approximately 77 
months.  Regardless of whether subjects end participation early, do not continue with the open-label 
extension, or roll over to the open-label extension, all subjects who do not transition to commercial 
drug will have a follow-up visit 3 to 6 months after the last dose of study medication for final safety 
monitoring.  
Objectives: 
The primary objective of Part 1 is the primary objective of the entire study. 
Part 1 
The primary objective of Part 1 is: 
x To evaluate the effect of ZX008 0.8 mg/kg/day versus placebo as adjunctive therapy for the 
treatment of uncontrolled seizures in children and adults with Lennox-Gastaut syndrome (LGS) 
based on the change in frequency of seizures that result in drops between baseline and the 
combined Titration and Maintenance Periods (T+M) 
The key secondary objectives of Part 1 are: 
x To evaluate the effect of ZX008 0.2 mg/kg/day versus placebo as adjunctive therapy for the 
treatment of uncontrolled seizures in children and adults with LGS based on the change in 
frequency of seizures that result in drops between baseline and T+M 
x To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo on the 
proportion of subjects who achieve a ≥50% reduction from baseline in the frequency of seizures 
that result in drops 
x To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo on the 
Clinical Global Impression – Improvement rating, as assessed by the Principal Investigator 
 
See Statistical Methods (Section 10.1.5.1) for hierarchical testing procedure. 
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Additional secondary efficacy objectives of Part 1 are: 
x To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo on the 
following endpoints: 
- Change in the frequency of all countable motor seizures between baseline and T+M 
(countable seizures include: generalized tonic-clonic seizures [GTC], tonic seizures [TS], 
clonic seizures [CS], atonic seizures [AS], tonic/atonic seizures [TA], clearly recognizable 
focal seizures [FS], and myoclonic seizures [MS] that result in a drop)  
- Change in the frequency of all countable seizures (ie, motor and non-motor) between baseline 
and T+M 
- Change in frequency of seizures that result in drops between baseline and the Maintenance 
Period (M) 
- Change in the frequency of countable motor seizures that do not result in drops between 
baseline and M 
- The proportion of subjects who achieve a worsening or no change (i.e ≤ 0% reduction), >0%,  
≥25%, ≥50%, ≥75%, 100% reduction, and “near seizure freedom” (ie, 0 or 1 seizures) 
between baseline and T+M, and baseline and M, in all countable motor seizures (GTC, TS, 
AS, TA, FS, MS with a drop); in countable motor seizures that do not result in drops; and in 
all seizures that result in drops  
- Number of seizure-free days, defined as 1) days with no countable seizures and 2) days with 
no seizures that result in drops 
- Longest interval between seizures that result in drops 
x To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo on the 
following endpoints: 
- Clinical Global Impression – Improvement rating, as assessed by the parent/caregiver 
The safety objectives of Part 1 are: 
x To evaluate the safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day versus placebo with 
regard to adverse events (AEs), laboratory parameters, physical examination, neurological 
examination, vital signs (blood pressure, heart rate, temperature, and respiratory rate), 
electrocardiograms (ECG), echocardiograms (ECHO), body weight, and BMI  
x To evaluate the change from baseline in cognition using age-appropriate Behavior Rating 
Inventory of Executive Function (BRIEF) 
The pharmacokinetic (PK) objective of Part 1 is: 
x To evaluate the PK of ZX008 0.2 and 0.8 mg/kg/day at steady state in subjects <18 years and 
≥18 years with LGS using a non-compartmental analysis; and obtain exposure data that will be 
used in population pharmacokinetic (PopPK) analysis, the results of which will be reported 
separately.. 
The exploratory objectives of Part 1 are: 
x To compare the ZX008 0.2 and 0.8 mg/kg/day doses on primary, secondary and safety endpoints 
x To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo on the 
following endpoints: 
- The frequency of rescue medication usage 
- The incidence of medical services used to treat seizures 
- The incidence of status epilepticus 
- The change from baseline in behavior using the Vineland Adaptive Behavior Scale (VABS) 
(Cohort A) 
- The change from baseline in QoL using the Quality of Life in Childhood Epilepsy (QOLCE) 
Assessment 
- The change from baseline in caregiver burden using the Zarit Caregiver Burden Inventory 
- The change from baseline in affective symptoms of the parent/caregiver using the Hospital 
Anxiety and Depression Scale (HADS) 
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Part 2 
The primary objective of Part 2 is:  
x 
To assess the long-term safety and tolerability of ZX008 in children and adults with LGS with 
regard to adverse events (AEs), laboratory parameters, physical examination, neurological 
examination, suicidality, cognition (BRIEF), vital signs (blood pressure, heart rate, 
temperature, and respiratory rate), electrocardiograms (ECG), echocardiograms (ECHO), body 
weight, and BMI. 
The secondary objectives of Part 2 are: 
x To assess the effect of ZX008 relative to the baseline on the following effectiveness measures: 
- The change in the frequency of seizures that result in drops 
- The change in the frequency of all countable motor seizures (GTC, TS, CS, AS, TA, FS, MS 
with a drop) 
- The change in the frequency of all countable seizures 
- The proportion of subjects who achieve a worsening or no change (ie, ≤0% reduction),>0%, 
≥25%, ≥50%, ≥75%, 100% reduction, and “near seizure freedom” (ie 0 or 1 seizures) in 
frequency of all countable seizures that result in drops, countable motor seizures that do not 
result in drops, all countable motor seizures, all countable seizures, and all countable seizures 
that do not result in drops 
- Number of seizure-free days, defined as 1) days with no countable seizures and 2) days with 
no seizures that result in drops 
- Longest interval between seizures that result in drops 
 
x To evaluate the effect of ZX008 on the following endpoints: 
- Clinical Global Impression – Improvement rating, as assessed by the Principal Investigator 
- Clinical Global Impression – Improvement rating, as assessed by the parent/caregiver 
The exploratory objectives of Part 2 are: 
x To determine the incidence of the following on subjects receiving ZX008: 
- The incidence of medical services used to treat seizures 
- The incidence of status epilepticus 
- The use of rescue medication 
x To assess the effect of ZX008 on the following measures: 
- The change from baseline in QoL using the QOLCE 
- The change from baseline in caregiver burden using the Zarit Caregiver Burden Inventory 
- The change from baseline in affective symptoms of the parent/caregiver using the Hospital 
Anxiety and Depression Scale (HADS) 
 
Methodology: 
This is an international multicenter study being conducted in two parts.  Up to approximately 80 study 
sites in North America, Europe, Japan, and Australia are initially planned to participate.  Part 1 is a 
double-blind, parallel-group, placebo-controlled, study to assess the efficacy and safety of two doses 
of ZX008 when used as adjunctive therapy for seizures in children and adult subjects with LGS. The 
study will include 2 cohorts: Cohort A will include randomized subjects from North America, Europe, 
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and Australia; Cohort B will include randomized subjects from Japan only. The primary study 
endpoint is assessed from Part 1 Cohort A data. The primary analysis will be conducted when the last 
subject in Cohort A has completed Part 1. Cohort B will be analyzed independently with  an interim 
analysis occurring after the last subject in Cohort B completes 12 months in Part 2 and a final analysis 
when the last subject in Cohort B completes Part 2. Part 2 will be an open-label, flexible-dose 
extension for subjects completing Part 1 of the study. 
 
Part 1 will consist of a 4-week baseline, 2-week titration, 12-week maintenance, and 2-week taper or 
transition period.  The 4-week Baseline Period will consist of the establishment of initial eligibility 
during a screening visit to include an assessment of cardiac parameters (ECG and ECHO), followed by 
an observation period where subjects will be assessed for baseline seizure frequency based on 
recordings of daily seizure activity entered into a diary.  Upon completion of the Baseline Period, 
subjects who qualify for the study will be randomized (1:1:1) in a double-blind manner to receive 1 of 
2 doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; maximum dose: 30 mg/day [or 0.5 mg/kg/day, 
maximum 20 mg/day, for subjects taking concomitant stiripentol (STP)]) or placebo.  Randomization 
will be stratified by weight (<37.5 kilograms [kg], ≥37.5 kg) to ensure balance across treatment arms, 
and at least 25% of subjects will be in each weight group. All subjects will be titrated to their blinded 
randomized dose over a 2-week Titration Period. Following titration, subjects will continue treatment 
at their randomly assigned dose over a 12-week Maintenance Period. Total treatment time from the 
beginning of the Titration Period through the end of the Maintenance Period is 14 weeks.  Subjects 
will have ECG and ECHO assessments at weeks 6 and 14 during the Maintenance Period.  At the end 
of the Maintenance Period (or early discontinuation), all subjects will undergo a blinded 2-week taper 
or transition period (Post-Dosing Follow-Up) depending on whether they exit the study or are enrolled 
in Part 2, the long-term open-label extension, respectively. A follow-up ECG and ECHO will be 
performed 3-6 months after study drug discontinuation for early termination, or for those subjects who 
complete the study but do not enter the open-label extension part.  If there are any findings at the 3-
month post-dose follow-up, a second follow-up will be repeated at 6 months and then every 3 months 
until resolved or stabilized. 
 
Part 2 is an open-label, long-term safety study of ZX008 for subjects who have successfully completed 
14 weeks of treatment (titration + maintenance) in Part 1 and are candidates for continuous treatment 
for an extended period of time; subjects who have not completed the entire 14 weeks of treatment in 
Part 1 may be eligible to participate in Part 2 on a case-by-case basis and only following sponsor 
approval. Part 2 will consist of a 12-month Open-Label Extension (OLE) Treatment Period and a 2-
week Post-Dosing Period. Thus, subjects who complete 12 months of OLE in Part 2 will have been 
treated with ZX008 for at least 70 weeks (including their participation in both Part 1 and Part 2). If 
marketing approval is not yet received after the end of the OLE Treatment Period, treatment may be 
extended on an annual basis in order to provide continuity of treatment for subjects who are enrolled 
in Part 2 of the study until ZX008 is approved in the subject’s country of residence and listed on a 
patient’s health plan formulary. Up to -5 annual extensions can be applied, for a total treatment time of 
up to  72 months in the OLE. Continuation will be based on review of safety/tolerability and 
effectiveness, and be offered for subjects who continue to meet eligibility requirements, comply with 
investigator’s instructions, and for whom the investigator judges benefit outweighs risk. 
 
During Part 2 all subjects will be treated initially with 0.2 mg/kg/day for 1 month to assess 
effectiveness of this dose in all study subjects and determine the minimally effective dose. After 1 
month at a dose of 0.2 mg/kg/day, the investigator may adjust the dose for each subject based on 
effectiveness and tolerability. Dose changes should be made in maximum increments of 0.2 
mg/kg/day, to a maximum of 0.8 mg/kg/day (or 0.5 mg/kg/day for subjects taking concomitant STP) 
but not to exceed total dose of 30 mg/day (or 20 mg/day for sujects taking concomitant STP).  During 
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the 12-month OLE subjects will have ECG and ECHO assessments at months 1, 3, 6, and 9, and at the 
end of study visit. In the event the OLE is extended, subjects will continue to have ECG (if clinically 
indicated) and ECHO assessments every 6 months until the end of their participation in the study. 
 
A follow-up ECG and ECHO will be performed at 3 and 6 months after study drug discontinuation for 
early termination and for those subjects who complete Part 2. If there are any findings at a post-dose 
follow-up, another follow-up will scheduled every 3 months until resolved or stabilized. Subjects who 
transition to commercially available ZX008 will not return for these follow-ups, but must have an 
ECHO within 3 to 6 months of the transition date and will have follow-up ECHOs within required 
timeframs while on commercial drug supply. 
 
In both Part 1 and the first 12 months of Part 2, parents/caregivers will use a diary every day to record 
the number of seizures, type of seizures, time and duration of seizures, whether the seizure resulted in 
a drop, dosing of study drug, and use of rescue medication. Seizures that result in a drop are defined as 
seizures involving the entire body, trunk, or head that led to a fall, injury, slumping in a chair, or the 
subject’s head hitting a surface or that could have led to a fall or injury, depending on the patient’s 
position at the time of the seizure.  
 
A schedule of assessments for Part 1 is provided in Table 1 and for Part 2 in Table 2. 
 
External Individuals and Committees:  The ZX008 clinical program will employ an Independent 
Data and Safety Monitoring Committee (IDSMC) that will be responsible for safety oversight. A 
separate International Cardiology Advisory Board (ICAB) advises the Sponsor on matters of cardiac 
safety of the ZX008 clinical trials.  ECGs and Doppler ECHOs will be centrally read and interpreted 
under blinded conditions using pre-specified criteria, and if necessary, with review by the ICAB. 
Number of Subjects: 
Approximately 340 subjects will be screened and approximately 250 subjects will be randomized into 
Part 1 Cohort A, and at least 30 and up to 50 subjects will be randomized into Part 1 Cohort B. The 
number of screened subjects may exceed 340 depending on the screen fail rate.  Only subjects that 
participated in Part 1 are eligible for participation in Part 2. Each clinical site will not randomize more 
than a maximum of 15 subjects into Part 1 without prior consent from the sponsor. 
Selection Criteria for Part 1 
Inclusion Criteria: All subjects must meet all of the following inclusion criteria to be enrolled into 
the study: 
1. Subject is male or non-pregnant, non-lactating female, age 2 to 35 years, inclusive as of the 
day of the Screening Visit.  Female subjects of childbearing potential must not be pregnant or 
breast-feeding. Female subjects of childbearing potential must have a negative urine or serum 
pregnancy test at screening. Subjects of childbearing or child-fathering potential must be 
willing to use medically acceptable forms of birth control (see Section 4.4), which includes 
abstinence, while being treated on this study and for 90 days after the last dose of study drug. 
2. Subject must have a diagnosis of Lennox-Gastaut syndrome, where seizures that result in 
drops are not completely controlled by current antiepileptic treatments. (Subjects without a 
formal diagnosis may still be enrolled after review and consultation between the Investigator 
and Sponsor, and in some cases, the Epilepsy Study Consortium.  Final decisions on 
enrollment are at the discretion of the sponsor if all other criteria are met.) 
3. Subjects must meet all of the following 4 criteria for Lennox-Gastaut syndrome, as defined in 
this protocol: 
a. Onset of seizures at 11 years of age or younger. 
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b. Multiple seizure types (must include TS or TA), including countable motor seizures 
that result in drops. Countable motor seizure types eligible for inclusion are: GTC, TS, 
CS, AS, FS with observable motor symptoms, and MS with a drop.  
c. Abnormal cognitive development. 
d. Evidence of EEG in the medical history that shows abnormal background activity 
accompanied by slow spike and wave pattern <2.5 Hz. (Acceptable evidence includes 
a copy of the EEG trace, EEG report, or physician note that appropriately describes 
the EEG findings.) 
4. Subject must have had at least 8 drop seizures in the last 4 weeks prior to Screening (minimum 
of 4 drop seizures in the first two weeks and 4 in the last two weeks before Screening), by 
parent/guardian report to investigator or investigator medical notes 
5. Receiving at least 1 concomitant AED and up to 4 concomitant AEDs, inclusive. KD and 
VNS are permitted but do not count towards the total number of AEDs.  Rescue medications 
for seizures are not counted towards the total number of AEDs. 
6. All medications or interventions for epilepsy (including KD and VNS) must be stable for at 
least 4 weeks prior to screening and are expected to remain stable throughout the study. 
7. Subject has been informed of the nature of the study and informed consent has been obtained 
from the legally responsible parent/guardian. 
8. Subject has provided assent in accordance with Institutional Review Board (IRB)/Ethics 
Committee requirements, if capable. 
9. Subject’s parent/caregiver is willing and able to be compliant with diary completion, visit 
schedule and study drug accountability. 
 
Exclusion Criteria: Subjects who meet any of the following exclusion criteria will not be enrolled 
into the study: 
1. Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study 
medication. 
2. Subject’s etiology of seizures is a degenerative neurological disease.  
3. Subject has a history of hemiclonic seizures in the first year of life. 
4. Subject only has drop seizures in clusters, where individual seizures cannot be counted 
reliably. 
5. Subject has pulmonary arterial hypertension. 
6. Subject has current or past history of cardiovascular or cerebrovascular disease, such as 
cardiac valvulopathy, myocardial infarction or stroke, or clinically significant structural 
cardiac abnormality, including but not limited to mitral valve prolapse, atrial or ventricular 
septal defects, patent ductus arteriosis (note: Patent Foramen Ovale or a bicuspid valve are not 
considered exclusionary). 
7. Subject has current or recent history of Anorexia Nervosa, bulimia, or depression within the 
prior year that required medical treatment or psychological treatment for a duration greater 
than 1 month. 
8. Subject has a current or past history of glaucoma. 
9. Subject has had an anoxic episode requiring resuscitation within 6 months of the Screening 
Visit. 
10. Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild hepatic 
impairment (elevated liver enzymes < 3x ULN and/or elevated bilirubin <2x ULN) may be 
entered into the study after review and approval by the Medical Monitor in conjunction with 
the sponsor, in consideration of comorbidities and concomitant medications. 
11. Subject has severe renal impairment (estimated glomerlular filtration rate <30mL/min/1.73m2) 
12. Subject is receiving concomitant therapy with any of the following: centrally-acting anorectic 
agents; monoamine-oxidase inhibitors; any centrally-acting compound with clinically 
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appreciable amount of serotonin agonist or antagonist properties, including serotonin reuptake 
inhibition; other centrally-acting noradrenergic agonists, including atomoxetine; or 
cyproheptadine (see Appendix 1 for a list of prohibited medications). (Note: Short-term 
medication requirements for prohibted medications will be handled on a per case basis by the 
Medical Monitor.) 
13. Subject has positive result on urine or serum tetrahydrocannabinol (THC) Panel or whole 
blood cannabidiol (CBD) at the Screening Visit. 
14. Subject is taking felbamate for less than 1 year prior to screening and/or does not have stable 
liver function and hematology laboratory tests, and/or the dose has not been stable for at least 
60 days prior to the Screening Visit. 
15. Subject is known to be human immunodeficiency virus (HIV) positive. 
16. Subject is known to have active viral hepatitis (B or C)  
17. Subject is currently receiving an investigational product. 
18. Subject has participated in another clinical trial within the past 30 days (calculated from that 
study’s last scheduled visit). Participation in non-treatment trials will be reviewed by the 
medical monitor.  
19. Subject is at imminent risk of self-harm or harm to others, in the investigator’s opinion, based 
on clinical interview and responses provided on the Columbia-Suicide Severity Rating Scale 
(C-SSRS).  Subjects must be excluded if they report suicidal behavior in the past 6 months as 
measured by the C-SSRS at Screening or Baseline, which includes suicidal ideation with 
intent and plan (Item #5). If a subject reports suicidal ideation on Item 4 without specific plan, 
and the investigator feels that the subject is appropriate for the study considering the potential 
risks, the investigator must document appropriateness for inclusion, and discuss with the 
parent/caregiver to be alert to mood or behavioral changes, especially around times of dose 
adjustment. 
20. Subject is unwilling or unable to comply with scheduled visits, drug administration plan, 
laboratory tests, other study procedures, and study restrictions.  
21. Subject is institutionalized in a general nursing home (ie, in a facility that does not provide 
skilled epilepsy care). 
22. Subject does not have a reliable caregiver who can provide seizure diary information 
throughout the study. 
23. Subject has a clinically significant condition, including chronic obstructive pulmonary disease, 
interstitial lung disease, or portal hypertension, or has had clinically relevant symptoms or a 
clinically significant illness in the 4 weeks prior to the Screening Visit, other than epilepsy, 
that would negatively impact study participation, collection of study data, or pose a risk to the 
subject. 
Randomization Inclusion Criteria: Subjects must meet all of the inclusion criteria and none of the 
exclusion criteria above and meet the following criteria in order to be randomized: 
1. Subject has been approved for study inclusion by the Epilepsy Study Consortium. 
2. Subject does not have an exclusionary cardiovascular or cardiopulmonary abnormality based 
on ECHO, ECG or physical examination and is approved for entry by the central cardiac 
reader.  Exclusionary abnormalities include, but are not limited to: 
a. Trace or greater mitral or aortic valve regurgitation in subjects ≤18 years of age 
b. Mild or greater mitral or aortic valve regurgitation in subjects >18 years of age 
c. Possible signs of pulmonary hypertension with abnormal or greater than upper range 
of normal values 
d. Evidence of left ventricular dysfunction (systolic or diastolic) 
3. Subject demonstrates a stable baseline with ≥ 2 seizures per week resulting in drops during the 
4-week Baseline Period. 
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4. Subject’s parent/caregiver has been compliant with diary completion during the Baseline 
Period, in the opinion of the Investigator and Sponsor. 
 
Selection Criteria for Part 2 
To be included in Part 2: 
1. Subjects must continue to meet the Selection Criteria for Part 1 (except for criteria related to 
seizure frequency).  If a subject entering Part 2 does not meet Randomization Criteria 2 
regarding cardiovascular abnormalities, Section 8.9.1 Follow-up of Cardiovascular Findings 
will be applied to determine eligibility to continue into Part 2. 
2. All subjects must have satisfactorily completed Part 1 of the study in the opinion of the 
investigator and the sponsor. 
3. Review of inclusion and exclusion criteria and written informed parental or guardian consent 
and assent of minors (if the subject is capable of providing assent) for Part 2 must be obtained 
before a subject can start any of the Part 2 Visit 15 procedures. 
4. Subjects must, in the medical opinion of the Investigator, be candidates for continued 
treatment for an extended period of time with ZX008. Candidates for continuous treatment 
should not meet Discontinuation criteria listed in Section 4.5 and should not meet the 
following criteria: 
a. Clinically meaningful worsening of seizures, judged by Investigator or 
subject/caregiver such that treatment outside of the protocol and other than ZX008 is 
assumed to be in the subject’s best interest. A clinically meaningful worsening is an 
increase in frequency, severity or duration of existing seizures, or (in some cases) 
emergence of a new seizure type. Frequent or increased use of rescue medication may 
be considered indicative of worsening. 
b. Clinically significant clinical laboratory findings (e.g. elevated ALT levels, decrease 
in platelet count, etc. that are CTCAE Grade 3 or higher) in subjects with no prior 
relevant history, that were not present during Baseline, are confirmed by a repeat test 
within a week, and not attributable to other concomitant medications. 
c. Weight loss >15% during the T+M period that has not stabilized and is considered, in 
the opinion of the Investigator, detrimental to continuing treatment with ZX008.  
5. Those subjects who do not complete the 12-week Maintenance Period of Part 1 may, on a 
case-by-case basis, be eligible for entrance after consideration of the circumstances of the 
early termination and the potential benefit-risk of continued participation in a ZX008 trial. The 
decision whether to permit participation in Part 2 for subjects who do not complete Part 1 
resides solely with the sponsor, who will require a formal request for early Part 2 continuation 
to be made by the site investigator as well as an evaluation of risk/benefit. The sponsor may 
also consult with the ICAB and/or the IDSMC, and take into consideration evidence of the 
following for approval: 
a. The subject is experiencing a worsening in condition that is not likely to be related to 
Part 1 treatment, in the opinion of the Investigator 
b. The subject has progressed at least half-way through Part 1 (i.e. Visit 8) 
c. The subject has been compliant with assessments and requirements of Part 1 
d. The subject does not exhibit other contraindications to initiating open-label treatment 
 
 Study Product, Dose, and Mode of Administration: 
ZX008 is supplied as an oral solution in concentrations of 1.25, 2.5, and 5 mg/mL. Subjects will be 
randomized to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; maximum dose: 
30 mg/day) or placebo.  Study medication will be administered twice a day (BID) in equally divided 
doses. (Note that subjects taking concomitant STP will be randomized to 0.5 mg/kg/day, maximum 
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Page 24 of 198 
dose 20 mg/day, or equivalent volume of placebo.  Subjects randomized to 0.5 mg/kg/day will be 
included in analyses with the subjects randomized to 0.8 mg/kg/day not taking STP.) 
Reference Product, Dose, and Mode of Administration: 
Matching ZX008 placebo is supplied as an oral solution.  
Duration of Treatment: 
In Part 1 all subjects will receive ZX008 or matching placebo for up to approximately 16 weeks 
(Titration Period=2 weeks; Maintenance Period=12 weeks; Taper/Transition Period=2 weeks). At the 
end of the 12-week Maintenance Period, eligible subjects may enroll into Part 2, the open-label 
extension, after completing a 2-week transition period with blinded study medication.  Subjects who 
enroll in Part 2 will have the option to receive ZX008 for up to 72 months (plus a 2-week taper at the 
end of the open-label extension), or until ZX008 is approved in the subject’s country of residence and 
listed on a patient’s health plan formulary, whichever comes first.  Subjects who do not enroll in the 
open-label extension will undergo a taper off of study medication (doses will be administered in a 
blinded fashion similar to the titration, ie, doses will be decreased in 4-day increments). Follow-up 
cardiovascular safety assessments, including ECG and ECHO, will be performed following the last 
dose of study medication for all subjects that do not transition to commercial drug, regardless of 
whether they complete the entire study or terminate early, unless the subject was known to be taking 
placebo (ie, blind was broken). These follow-ups will occur 3 months following the last dose of study 
medication for any subject taking the medication for 2-13 weeks, and 3 and 6 months following the 
last dose for any subject taking the medication for >13 weeks. If there are any findings at a post-dose 
follow-up, another follow-up will scheduled every 3 months until resolved or stabilized. Subjects who 
transition to commercially available ZX008 will not return for a follow-up after EOS/ET or a cardiac 
follow up after last dose but must have had an ECHO within 3 to 6 months before the transition date 
and will have follow-up ECHOs within required timeframe while on commercial drug supply. 
Criteria for Evaluation: 
Efficacy: 
The efficacy endpoints for Part 1 of the study are: 
Primary Endpoint: 
Percent change from baseline in the frequency of seizures that result in drops in the combined 
Titration and Maintenance Periods (T+M) in the ZX008 0.8 mg/kg/day group compared to the placebo 
group.  
Key Secondary Endpoints: 
x 
Change from baseline in the frequency of seizures that result in drops in T+M in the ZX008 
0.2 mg/kg/day group compared to the placebo group.  
x 
Proportion of subjects who achieve a ≥50% reduction from baseline in the frequency of 
seizures that result in drops comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups 
independently versus placebo 
x 
Proportion of subjects who achieve clinically-meaningful improvement (much or very much 
improved) in the Clinical Global Impression – Improvement as assessed by Principal 
Investigator comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently 
versus placebo. 
Additional Secondary Endpoints: 
x 
Change from baseline in the frequency of all countable motor seizures in T+M in the ZX008 
0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo 
o Countable motor seizures include: generalized tonic-clonic seizures [GTC], tonic 
seizures [TS], clonic seizures [CS], atonic seizures [AS], tonic/atonic seizures [TA], 
clearly recognizable focal seizures [FS], and myoclonic seizures [MS] that result in a 
drop 
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x 
Change from baseline in the frequency of countable seizures that result in drops 
x 
Change from baseline in the frequency of seizures that result in drops between baseline and 
the Maintenance Period (M) 
x 
Change from baseline in frequency of countable seizures that do not result in drops 
x 
Proportion of subjects who achieve a worsening from baseline (ie <= 0% reduction), or >0%,  
≥25%, ≥50%, ≥75%, 100% reduction, and “near seizure freedom” (ie 0 or 1 seizures) between 
baseline and T+M, and baseline and M, in all countable motor seizures; in countable motor 
seizures that do not result in drops; in all countable seizures; in all countable seizures that do 
not result in drops; and in all seizures that result in drops 
x 
Number of seizure-free days in the baseline, M and T+M period defined as 1) days with no 
countable seizures and 2) days with no seizures that result in drops 
x 
The longest interval (days) between seizures that result in drops comparing the ZX008 
0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo 
x 
Clinical Global Impression – Improvement as assessed by the parent/caregiver 
The efficacy endpoints for Part 2 of the study are: 
x 
The change from baseline in the frequency of seizures that result in drops.  
x 
The change from baseline in the frequency of all countable motor seizures (GTC, TS, CS, AS, 
TA, FS, MS with a drop) 
x 
The change from baseline in the frequency of all countable seizures 
x 
The proportion of subjects who achieve a worsening from baseline (ie <= 0% reduction), or 
>0%,   ≥ 25%, ≥ 50%, ≥ 75%, 100% reduction, and “near seizure freedom” (ie 0 or 1 seizures) 
from baseline in frequency of all countable seizures that result in drops, countable motor 
seizures that do not result in drops, all countable motor seizures, all countable seizures, and all 
countable seizures that do not result in drops 
x 
Number of seizure-free days, defined as 1) days with no countable seizures and 2) days with 
no seizures that result in drops 
x 
Clinical Global Impression – Improvement rating, as assessed by the Investigator. 
x 
Clinical Global Impression – Improvement rating, as assessed by the parent/caregiver. 
 
Safety: 
The safety endpoints for Part1 and Part 2 of the study are: 
x 
AEs 
x 
Laboratory safety (hematology, chemistry, urinalysis) 
x 
Vital signs (blood pressure, heart rate, temperature, and respiratory rate) 
x 
Physical examination 
x 
Neurological examination 
x 
BRIEF to measure changes in cognition of the subject 
x 
Columbia Suicidality Severity Rating Scale (C-SSRS) 
x 
12-lead ECGs 
x 
Doppler ECHOs 
x 
Body weight and BMI 
 
Exploratory: 
The exploratory endpoints for Part 1 and Part 2 of the study are: 
x 
Incidence of status epilepticus 
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x 
Incidence of rescue medication usage 
x 
Number of days rescue medication used 
x 
Incidence in use of medical services to treat seizures 
x 
The change from baseline in behavior using the Vineland Adaptive Behavior Scale (VABS) 
(Part 1 Cohort A only) 
x 
The change from baseline in quality of life using the QOLCE 
x 
The change from baseline in caregiver burden using the Zarit Caregiver Burden Inventory 
x 
The change from baseline in affective symptoms of parent/caregiver using the HADS scale 
 
Pharmacokinetics: 
Steady-state plasma fenfluramine and norfenfluramine PK parameters (maximum and minimum 
plasma concentration (Cmin ss, Cmax ss) and area under the concentration time curve from time zero 
to time=t and time=24 hours (AUC0-t, AUC0-24) after administration of ZX008 derived using a 
population pharmacokinetic model. 
Sample Size Determination: 
The sample size for Part 1 Cohort A was estimated under the assumption that adding ZX008 at 0.8 
mg/kg/day to current therapy will lead to a mean decrease in the frequency of drop seizures that is 30 
percentage points lower than adding placebo to current therapy. The variability expected in the trial 
was estimated from the confidence intervals reported in a Phase 3 trial of clobazam for patients with 
Lennox-Gastaut syndrome (Ng, 2011) leading to an assumption that the SD is 50%. Under these 
assumptions, and using a Wilcoxon rank-sum test to approximate the primary analysis, a sample size 
of 63 subjects per treatment group affords 90% power to detect a difference between groups that is 
significant at the α=0.05 level. Assuming a 20% drop-out rate prior to the start of the maintenance 
period yields a requirement for an additional 16 subjects per group for a total of 79 subjects per 
treatment group.  Similar calculations for the 0.2 mg/kg/day ZX008 group lead to a total required 
sample size of 237. The number of subjects randomized into Part 1 Cohort A is estimated to be 
approximately 250 due to the long baseline period. The sample size of 10 to 15 subjects per treatment 
group in Cohort B is expected to provide a descriptive assessment of whether the treatment effect in 
Japanese subjects is similar to that observed in Cohort A subjects from the rest of the world. 
Statistical Methods: 
Part 1 
The primary analyses of the study will be performed on data from Part 1 Cohort A after the last 
subject enrolled in Cohort A has completed the last study visit of Part 1. Data from Part 1, Cohort B 
will be analyzed independently after the last subject in Cohort B completes Part 1. An interim analysis 
of Part 2 will be performed after all Cohort B subjects complete 12 months in Part 2.  A secondary 
analysis will be conducted after the last Cohort B subject has enrolled and completed the last study 
visit of Part 2. Analysis results for Part 1 from Cohort A and Cohort B may be compared through 
descriptive statistics, and if reasonable, some analyses may be performed using data from Cohort A 
and Cohort B combined. Subjects randomized to 0.5 mg/kg/day (ie, those taking concomitant STP) 
will be grouped with subjects randomized to 0.8 mg/kg/day for all efficacy analyses.  
Efficacy 
Primary Efficacy Analysis:  The primary efficacy endpoint for Part 1 is the percent change in 
frequency of seizures that result in drops (DSF: drop seizure frequency) per 28 days between the T+M 
and Baseline periods in Cohort A. The DCF will be calculated from all available data collected during 
the Baseline and treatment periods without imputation. The percent change in DSF will be calculated 
as the change in DSF between T+M and Baseline / DSF during Baselineu 100. Both the mean and 
median percent change in DCF frequency will be presented. The primary endpoint will be assessed 
using an non-parametric rank analysis of covariance (ANCOVA) with treatment and weight groups 
(<37.5 kg, ≥37.5 kg) as factors, and with Baseline MCDS as a covariate rank baseline DSF as a 
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covariate, and rank percent change in DSF from baseline as the response variable.  The primary 
analysis will compare the ZX008 0.8 mg/kg/day group to the placebo group at the alpha=0.05 level of 
significance. The difference between the ZX008 0.8 mg/kg/day and placebo groups in percent change 
in DSF, and its 95% confidence interval, will be estimated using the Hodges-Lehmann method. As a 
sensitivity analysis, the primary endpoint will also be analyzed using a parametric ANCOVA that 
incorporates treatment group and weight group as factors, log baseline DSF as a covariate; and log 
DSF during T+M as the response variable. Another sensitivity analysis will use a Wilcoxon rank-sum 
test to compare the ZX008 0.8 mg/kg/day group to the placebo group. Part 1 Cohort B will be 
analyzed using analogous methods.  
A key secondary analysis will compare the ZX008 0.2 mg/kg/day group to the placebo group on 
percent change in DSF using the same method as the primary analysis. Other key secondary analyses 
will compare the ZX008 0.8 and 0.2 mg/kg/day groups to the placebo group on the proportion of 
subjects who achieve a ≥50% reduction from baseline in DSF. The analyses will utilize independent 
logistic regression models that incorporate the same factors and covariate as the primary analysis. Two 
other key secondary analyses will compare both ZX008 dose groups (independently) to placebo on the 
proportion of subjects assessed by the Principal Investigator as minimally, much, or very much 
improved on the Clinical Global Impression – Improvement (CGI-I). The comparisons will employ 
separate Cochran-Mantel-Haenszel tests (CMH) stratified by weight strata. A serial gatekeeper 
strategy will be used to maintain the Type 1 error rate at α=0.05 across the family of analyses that 
support the primary and key secondary objectives. 
Safety  
All safety data will be appropriately analyzed by treatment group. The number and percentage of 
subjects with AEs will be displayed by body system and preferred term using the Medical Dictionary 
for Regulatory Activities (MedDRA). Summaries in terms of severity and relationship to study drug 
will also be provided. Adverse Events of Special Interest (AESI) and Serious AEs (SAEs) will be 
summarized separately in a similar manner. Laboratory tests, vital signs, physical examinations, 
neurological examinations, ECG, Doppler echocardiogram, C-SSRS, Tanner Staging results, etc, will 
be summarized appropriately, by treatment. All safety summaries will be based on the Safety 
Population. 
Pharmacokinetics 
Model derived plasma PK parameters (Cmax_ss, Cmin_ss, AUC0-t, AUC0-24) will be summarized 
descriptively by treatment group, when sufficient data are available. A PopPK model of 
fenfluramine, previously developed using data from healthy adults and pediatric patients with 
Dravet syndrome, will be updated to include the fenfluramine and norfenfluramine concentration-
time data collected during the Maintenance Period of Part 1. This model will be informed by all 
relevant data available at the time of data collection (both adults and pediatrics). The results from 
the PopPK modeling will be reported separately and conducted according to a separate SAP. 
Part 2 
The primary objective of Part 2 is to assess the long-term safety and tolerability of ZX008 in 
children and adults with LGS with regard to AEs, laboratory parameters, physical examination, 
neurological examination, vital signs, ECG, ECHO, body weight, and BMI. 
The number and percentage of subjects who experience treatment emergent AEs will be displayed by 
body system and preferred term using MedDRA. Summaries in terms of severity and relationship to 
study drug will also be provided. SAEs will be summarized separately in a similar manner. Laboratory 
tests, vital signs, physical examinations, neurological examinations, ECG, ECHO, cognition and body 
weight will be summarized using appropriate methods. 
Effectiveness will be assessed by the change from baseline (prior to randomization into Part 1) in DSF. 
The DSF per 28 days will be calculated as the number of seizures that result in drops divided by the 
number of days in the period and multiplied by 28. The change in DSF during the first 12 months of 
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Part 2 OLE Treatment Period will be calculated as the difference between DSF during the OLE and the 
baseline DSF measured prior to randomization in Part 1. Both the mean and median percent change in 
DCF will be presented and the statistical significance of the percent change will be assessed using a 
Wilcoxon signed-rank test. Other secondary assessments will be compared to baseline from prior to Part
1, or by visit throughout Part 1 and the first 12 months of Part 2, as appropriate. 
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Table 1. 
Schedule of Assessments: Part 1 
Study Assessments – PART 1 
Baseline Perioda 
Titration + Maintenance Period 
 
EOS/ 
ETb 
 
Post-
Dosingl 
Cardiac 
Follow-
upc 
 
Visit Number 
 
Screening 
 
Random-
ization 
 
Titration Period 
 
Maintenance Period 
1 
2 
(Phone) 
3 
 
4, 5 
(Phone) 
6 
7  
(Phone) 
8 
9  
(Phone) 
10 
11 
(Phone) 
12 
13  
 
14 
Study Day 
-28  
-15  
-1 
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
197 
Informed Consent (subject and 
parent/caregiver) 
X 
 
 
 
 
 
 
 
 
 
 
X  
(Part 2) 
 
 
Inclusion/Exclusion Criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Neurological History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epilepsy history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review retrospective seizure 
diary data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Medication, including AEDs 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination, complete 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
Optional 
Physical Examination, 
abbreviated  
 
 
 
 
 
Xm 
 
Xm 
 
Xm 
 
 
 
Xc 
Neurological Examination, 
complete 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Neurological Examination, 
abbreviated 
 
 
X 
 
 
Xm 
 
Xm 
 
Xm 
 
 
 
 
Vital signs 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Weight 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
12-lead ECG 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Xc 
Doppler ECHO 
X 
 
 
 
 
 
Xd 
 
 
 
Xd 
 
Xc 
Urine or Serum Pregnancy Test 
Xe 
 
Xe 
 
 
 
 
Xe 
 
 
 
Xe 
 
 
Clinical laboratory evaluation 
(hematology/ chemistry/urinalysiso, etc) 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Plasma sample for ZX008 PK 
 
 
 
 
 
 
 
Xf 
 
 
 
 
 
 
Plasma sample for background 
AEDs 
 
 
Xg 
 
 
Xg 
 
X 
 
Xg 
 
Xg 
 
 
Urine or serum THC Panel 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Whole blood CBD 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Tanner Staging (for subjects >7 to 
18 years old) 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Subject Diary 
D 
R 
C/R/D 
 
R 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/Dh 
C/R 
 
Epilepsy genotype panel 
(optional) 
 
X 
 
 
Study Medication 
 
 
D 
 
Ri 
C/R/D 
R 
C/R/D 
R 
C/R/D 
R 
C/R/Dh 
C/R 
 
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Study Assessments – PART 1 
Baseline Perioda 
Titration + Maintenance Period 
 
EOS/ 
ETb 
 
Post-
Dosingl 
Cardiac 
Follow-
upc 
 
Visit Number 
 
Screening 
 
Random-
ization 
 
Titration Period 
 
Maintenance Period 
1 
2 
(Phone) 
3 
 
4, 5 
(Phone) 
6 
7  
(Phone) 
8 
9  
(Phone) 
10 
11 
(Phone) 
12 
13  
 
14 
Study Day 
-28  
-15  
-1 
1 
4, 8 
15 
29 
43 
57 
71 
85 
99 
113 
197 
C-SSRS 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Clinical Global Impression - 
Improvement (assessed by 
parent/caregiver) 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
Clinical Global Impression - 
Improvement (assessed by 
investigator) 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
HADS (Effect of 
parent/caregiver) 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
BRIEF 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
QOLCE 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Zarit Burden 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Randomize subject 
 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
First Day of Study Drug 
Administration 
 
 
Xj 
Xj 
 
 
 
Daily Diary Completion  
X 
 
Concomitant Medication 
 
 
 
X 
 
Adverse events 
X 
 
Adverse events of special interest 
X 
Xk 
AED=antiepileptic drug; BMI=body mass index; C=Collect; CBD=cannabidiol; D=Dispense; ECG=electrocardiogram; EOS=end of study; ET=early termination; HADS=Hospital Anxiety and Depression Scale; BRIEF=Behavior Rating Inventory of Executive 
Function; QoL=quality of life; R=Review 
a: 
The Baseline Period is comprised of the initial screening for the study and the assessment of baseline seizure activity recorded daily in the diary. The procedures to be completed at the Screening visit may be completed in a single day or split so that they are 
completed over the 2-day period. 
b: 
Subjects who are discontinued early and those who complete the study and choose not to enroll in the separate open-label extension will be tapered off study medication over an up to 2-week period. 
c: 
The safety follow-up visit will be conducted for subjects who either terminate early from Part 1, or who complete Part 1 but do not enter Part 2. Standard follow-up visits should occur 3 and 6 months after the last dose. If there are any findings at the last post-
dose follow-up, a follow-up visit will be repeated every 3 months until resolved or stabilized. 
d: 
The Visit 8 ECHO must be performed any time between Study Day 40 and Study Day 54.  The Visit 12 ECHO must be performed any time between Study Day 90 and Study Day 113; if a subject discontinues early from the study, the ECHO should be 
scheduled as soon as practical.  If the Study Day 43 ECHO was completed < 30 days prior to early termination, the Visit 12 ECHO will not be performed provided the parent/guardian agrees to bring the subject to the clinic for the cardiac follow-up visit. 
e: 
Females of child-bearing potential 
f: 
Plasma sample for pharmacokinetic assessment will be conducted prior to the dose at Visit 8 and 1, 2, and 4-6 hours after dose administration. 
g: 
Plasma sample for assessment of background AED(s) will be conducted prior to the dose of AED(s) at Visits 3, 8 and 12 (Visits 6 and 10 only if clinically indicated). Plasma sample may be collected after the morning dose of AED(s) are taken, if preferable, as 
long as the time of last dose is accurately recorded. 
h: 
Study drug/diary dispensed for the Transition Period for subjects entering the open-label extension and for the Taper Period for subjects exiting the study. 
i: 
Site personnel will review study medication dosing procedure (titration) with parent/caregiver. 
j: 
Study drug administration begins in the clinic on Study Day -1. Study Day 1 is considered the first day of dosing, even though subjects received an in-clinic dose on Study Day -1. The first dose taken in the clinic will be recorded in the eCRF, but not the 
subject diary; the next dose on the morning of Study Day 1 will be the first entry in the subject’s diary. 
k: 
Only adverse events related to cardiac safety will be collected at this visit. 
l: 
Visit 13 may be conducted as a phone call, provided diaries and study medication are returned by this time. 
m: 
An abbreviated physical and/or neurological examination to be conducted as appropriate based on last exam and reported AEs. 
n: 
Randomization should not occur prior to receiving approval from the Epilepsy Study Consortium and ERT ECHO results. 
o: 
Urine for urinalysis may be collected at home, the night before the clinic visit, as long as collection procedures are followed to maintain sample stability. 
 
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Table 2. 
Schedule of Assessments: Part 2 Cohort B only 
 
After Visit 26/ Month 24 (or a later visit if V26/ Month 24 visit has already been performed at the time of Protocol Amendment 4.0 
approval), in clinic study visits will occur every 6 months until ZX008 is approved by the subject country of residence and listed on 
the patient health plan formulary. A phone visit will be performed between in clinic visits (with a 3-month interval).During the phone 
visits, only a review of concomitant medications, adverse events and adverse events of special interest will be performed.  
 
Last Visit Number/Study Month pre approval 
of Amendment 4.0 
Next In Clinic Visits to be Scheduled (until ZX008 approval by health authority) 
-Every 6 months- 
Visit 26 / Month 24 
Visit 28/M30 
Visit 30/M36 
Visit 32/M42 
Visit 34/M48 
Visit 36/M54 
Visit 27 / Month 27 
Visit 29/M33 
Visit 31/M39 
Visit 33/M45 
Visit 35/M51 
 
Visit 28 / Month 30 
Visit 30/M36 
Visit 32/M42 
Visit 34/M48 
Visit 36/M54 
 
Visit 29 / Month 33 
Visit 31/M39 
Visit 33/M45 
Visit 35/M51 
 
 
Visit 30 / Month 36 
Visit 32/M42 
Visit 34/M48 
Visit 36/M54 
 
 
 
 
Study Assessments – PART 2 
OLE Treatment Period** 
Post-
Dosing 
Cardiac Follow-up 
Visit Number 
Visit 15a 
 
Visit 16b 
Visits 17-21 
(Months 1, 2, 
3, 6 and 9**) 
Visit 22 
(Month 12) 
Visits 23-41 (Months 
15, 18, 21, 24, 27, 30, 
33, 36, 39, 42, 45, 48, 
51, 54, 57, 60, 63, 66, 
69) 
Visit 42c 
(EOS/ET) 
 
Visit 43 
 
Visit  44 and 45 
 
OLE Study Day 
1a 
15 
 30, 60, 90, 
180, and 270 
360 
450, 540, 630, 720, 
810, 900, 990, 1080, 
1170, 1260, 1350, 
1440, 1530, 1620, 
1710, 1800, 1890, 
1980, 2070 
2160 
2174k,q 
(3 and 6 months post 
last dose)d,k 
Clinic 
Phone 
Clinic 
Phone 
Informed Consent 
X 
 
 
 
X** 
X** 
 
 
 
 
Entry Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics 
Xa 
 
 
 
 
 
 
 
 
 
Medical/Neurological History 
Xa 
 
 
 
 
 
 
 
 
 
Epilepsy History 
Xa 
 
 
 
 
 
 
 
 
 
Physical Examination, complete 
Xa 
 
 
 
X 
 
 
X 
 
X 
Physical Examination, abbreviated 
 
Xm 
 
Xm 
 
Xm 
 
 
Xm 
X 
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Confidential 
Page 32 of 198 
Study Assessments – PART 2 
OLE Treatment Period** 
Post-
Dosing 
Cardiac Follow-up 
Visit Number 
Visit 15a 
 
Visit 16b 
Visits 17-21 
(Months 1, 2, 
3, 6 and 9**) 
Visit 22 
(Month 12) 
Visits 23-41 (Months 
15, 18, 21, 24, 27, 30, 
33, 36, 39, 42, 45, 48, 
51, 54, 57, 60, 63, 66, 
69) 
Visit 42c 
(EOS/ET) 
 
Visit 43 
 
Visit  44 and 45 
 
Neurological Examination, complete 
Xe 
 
 
 
X 
 
 
X 
 
 
Neurological Examination, abbreviated 
 
Xm 
 
Xm 
 
Xm 
 
 
Xm 
 
Vital signs 
X 
X 
 
X 
X 
X 
 
X 
 
 
Weight 
Xa 
X 
 
X 
X 
X 
 
X 
X 
 
Height 
Xa 
 
 
 
X 
 
 
X 
 
 
12-lead ECG 
Xa 
 
 
X 
X 
Xq 
 
Xq 
 
X 
Doppler ECHO 
Xa 
 
 
Xf,g 
X 
Xg 
 
X 
 
X 
Urine or Serum Pregnancy Testh 
Xa 
 
 
Xn 
X 
X 
 
X 
 
 
Clinical laboratory evaluation  
(hematology/chemistry/urinalysisp, etc) 
Xi 
Xi 
 
Xn 
X 
Xq 
 
Xq 
 
 
Urine or serum THC Panel 
Xa 
 
 
Xn 
X 
 
 
Xs 
 
 
Whole blood CBD 
Xa 
 
 
Xn 
X 
 
 
Xs 
 
 
Plasma sample for background AEDs 
 
Xm 
 
Xn 
X 
Xq 
 
Xq 
 
 
Tanner Staging (for subjects >7 to 18 years old) 
Xa 
 
 
Xj 
X 
 
 
Xs 
 
 
C-SSRS 
Xa 
 
 
X 
X 
X 
 
X 
 
 
CGI-I (assessed by parent/caregiver) 
Xa 
 
 
X 
X 
X 
 
X 
 
 
CGI-I (assessed by investigator) 
Xa 
 
 
X 
X 
X 
 
X 
 
 
Overall change in seizure frequency 
(assessed by investigator) 
 
 
 
 
 
Xr 
 
Xr 
 
 
HADS (Effect of parent/caregiver) 
Xa 
 
 
Xo 
X 
 
 
Xs 
 
 
BRIEF 
Xa 
 
 
Xo 
X 
 
 
Xs 
 
 
QOLCE 
Xa 
 
 
Xo 
X 
 
 
Xs 
 
 
Zarit Burden 
Xa 
 
 
 
X 
 
 
Xs 
 
 
Subject Diary 
C/R/D 
C/R/D 
R 
C/R/D 
Xr 
Xr 
 
C/Rr 
C/R 
 
Study Medication 
C/R/D 
C/R 
R 
C/R/D 
C/R/D 
C/R/D 
 
C/R/D 
C/R 
 
Daily Diary Completion 
---------------------- X -------------------------------- 
 
 
Concomitant Medication 
Xa 
----------------------------------------------X-------------------------------------------------- 
 
Adverse Events 
Xa 
----------------------------------------------X-------------------------------------------------- 
 
Adverse events of special interest 
Xa 
----------------------------------------------X-------------------------------------------------- 
Xl 
 
 
 
 
AED=antiepileptic drug; BMI=body mass index; C=Collect; CBD=cannabidiol; D=Dispense; ECG=electrocardiogram; EOS=end of study; ET=early termination; HADS=Hospital Anxiety and Depression Scale; BRIEF=Behavior Rating Inventory of Executive Function; 
QoL=quality of life; R=Review; 
a: 
Use data collected at Visit 12 of Part 1. 
b: 
At the discretion of the investigator, Visit 16 may be conducted as a phone visit. 
c: 
Or early termination. 
d: 
Safety Follow-up visits will be conducted for subjects who terminate early from Part 2 and for those who complete Part 2. Standard follow-up visits should occur 3 and 6 months after the last dose. If there are any findings at a post-dose 
follow-up, a follow-up visit will be scheduled every 3 months until resolved or stabilized. 
e: 
Use Part 1 Visit 12 information unless complete neurological examination is warranted based on significant changes in subject status. 
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Confidential 
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Study Assessments – PART 2 
OLE Treatment Period** 
Post-
Dosing 
Cardiac Follow-up 
Visit Number 
Visit 15a 
 
Visit 16b 
Visits 17-21 
(Months 1, 2, 
3, 6 and 9**) 
Visit 22 
(Month 12) 
Visits 23-41 (Months 
15, 18, 21, 24, 27, 30, 
33, 36, 39, 42, 45, 48, 
51, 54, 57, 60, 63, 66, 
69) 
Visit 42c 
(EOS/ET) 
 
Visit 43 
 
Visit  44 and 45 
 
f: 
ECHOs will be performed at Months 1, 3, 6, and 9. 
g: 
The Months 3, 6, 9, 12, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 & 72 ECHO may be performed any time within 3 weeks prior to the study visit. If a subject discontinues early from the study, the ECHO should be 
scheduled as soon as practical. 
h: 
Females of child-bearing potential 
i: 
For Visit 15, use data collected at Part 1 Visit 12 unless clinical laboratory evaluation is warranted based on significant changes in subject status. For Visit 16, clinical laboratory evaluation is optional based on subject status. 
j: 
Visit 20 only. 
k: 
For subjects who are transitioning to commercial drug, do not initiate drug taper or conduct post-dosing and cardiac follow-up visits. 
l: 
Only adverse events related to cardiac safety will be collected at this visit. 
m: 
An abbreviated physical and/or neurological examination to be conducted as appropriate based on last exam and reported AEs. 
n: 
Visits 19, 20, and 21 (Months 3, 6, and 9) only. 
o: 
Visit 20 (Month 6) only 
p: 
Urine for urinalysis may be collected at home, the night before the clinic visit, as long as collection procedures are followed to maintain sample stability. 
q 
r: 
 
 
s: 
As clinically indicated for subjects extending Part 2 participation past 12 months. Abnormal clinically significant findings must be reported as adverse events. 
Electronic diary is to be used the first 12 months of Part 2, and should be reviewed and collected on Visit 22 (for subjects continuing in Part 2 of the study) or Visit 42 (for subjects who do not continue in Part 2 of the study past 12 months). 
After 12 months in Part 2, seizure diaries are not required. Rather, based on discussions with the parent/caregiver, clinical evaluation, and review of any documentation provided by the caregivers, investigators will assess the percent 
improvement in seizure burden on a 5-point scale: <25%, ≥25%, ≥50%, ≥75%, 100% [ie, seizure-fee] improvement. 
Only applicable for subjects ending Part 2 participation within the first 12 months. Not applicable for subjects who completed Visit 22 and extended participation in Part 2. 
 
** If marketing approval is not yet received after the end of the OLE Treatment Period, treatment may be extended on an annual basis in order to provide continuity of treatment for subjects who are enrolled in Part 2 of the study. Up to 5 
annual extensions can be applied, for a total treatment time of 72 months in the OLE. Continuation will be based on review of safety/tolerability and effectiveness, and be offered for subjects who continue to meet eligibility requirements, 
comply with investigator’s instructions, and for whom the investigator judges benefit outweighs risk. The decision to extend and informed consent should be completed before the start of the first visit of each annual extension ( i.e. Month 
12, 24, 36, 48 and  60). After approval from Investigator and Sponsor for extension and starting after Visit26/Month24 (or a later visit if Visit26/Month24 visit has already occurred at the time of Protocol Amendment 4.0 approval) , subject 
will return to the clinic every 6 months and have a phone visit 3 months after the in clinic visit for each 1-year extension, until up to Month 72. The End of Study will be Visit 42. Further extensions can then be applied as required if 
marketing approval is not yet received 
 
 
 
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Confidential 
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1. 
INTRODUCTION 
1.1 
BACKGROUND INFORMATION ON INDICATION STUDIED 
ZX008 (fenfluramine hydrochloride) is under clinical development for the adjunctive treatment 
of patients with Dravet syndrome and Lennox-Gastaut syndrome (LGS). Fenfluramine 
(Fintepla®) is authorized for sale in the United States for the treatment of seizures associated 
with Dravet syndrome in patients 2 years of age and older. 
LGS is a rare epileptic encephalopathy.  Onset of LGS usually occurs most commonly before 
age 11, with a peak between 3 and 5 years of age (Arzimanoglou 2009; Hancock and Cross, 
2013). Patients with LGS account for 5–10% of children with seizures (Panayiotopoulos 2005). 
The diagnosis of LGS includes clinical signs combined with typical EEG features. The clinical 
presentation of LGS is heterogeneous, however LGS is always characterized by a triad of 
symptoms: multiple seizure types, slow spike-and-wave EEG, and abnormal cognitive 
development. The most common seizure types are generalized tonic-clonic seizures, tonic 
seizures, atonic seizures, and tonic/atonic seizures, all of which most often can result in “drop 
attacks.” Other seizure types that occur in some LGS patients include atypical absences, non-
convulsive seizures, focal seizures, and myoclonic seizures. Nearly all LGS patients have 
treatment-resistant, lifelong epilepsy. Prognosis for LGS is very poor: 5% of children die, 80–
90% continue having seizures into adulthood, and nearly all have cognitive and behavioral 
problems (Panayiotopoulos 2005).  Children and adults with LGS have an enormous impact on 
their families, and efforts to improve the quality of life for these patients are complex. 
1.1.1 
Existing Treatment for LGS 
Currently, two drugs are approved in Japan for the treatment of Lennox-Gastaut syndrome: 
lamotrigine (2008) and rufinamide (2013). Nine AEDs are approved for treating Lennox-
Gastaut syndrome EU-wide and in selected EU Member States: felbamate, topiramate, 
lamotrigine, rufinamide, clonazepam, clobazam, valproate, nitrazepam, and cannabidiol 
(Epidyolex®). The same AEDs are approved in the US except valproate and nitrazepam. Other 
pharmacologic (valproate, benzodiazepines, zonisamide) and non-pharmacologic (KD, VNS, 
surgery) treatments also are prescribed based on clinical experience.  
Because patients with LGS experience a range of different seizure types, the condition is 
notoriously difficult to treat (Arzimanoglou 2009, Cross 2017) and seizures in LGS are usually 
not fully controlled (Hancock, 2013). Initial treatment for LGS is usually monotherapy with 
one of the currently approved AEDs.  If this is not successful, which is the most common case, 
a second agent is usually added; although some physicians move on to the second drug as 
monotherapy (Wheless 2007; Arzimanoglou 2009). The treatment of LGS frequently requires 
a combination of 2 or more of these compounds, but with continued suboptimal seizure 
control. The recommendation is to attempt to use drugs that have different mechanisms of 
action and the least amount of interaction with one other. After lack of response to 2 or more 
AEDs, non-pharmacological treatments such as KD, VNS, or surgery may be considered. A 
treatment that has been shown to be effective in common certain seizure types cannot be 
assumed to be effective in patients with LGS to treat that seizure type. 
Given the suboptimal treatment of seizures in the majority of LGS patients, even with 
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Confidential 
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polytherapy, and the developmental and cognitive consequences believed to be caused, at least 
in part, by frequent childhood seizure activity, there is a medical need for a new anticonvulsant 
treatment with a novel mechanism of action that can significantly reduce seizure activity in 
LGS.  
1.2 
BACKGROUND INFORMATION ON STUDY PRODUCT 
Zogenix is developing a new formulation of fenfluramine hydrochloride, ZX008, for the 
adjunctive treatment of seizures associated with LGS. Fenfluramine is an amphetamine 
analogue that was first synthesized many years ago. It was approved in a large number of 
countries and widely prescribed as an appetite suppressant for the treatment of adult 
obesity. Brand names for fenfluramine formulations included Ponderax and Pondimin.  
Fenfluramine was also used extensively in an off-label combination with phentermine 
(“Fen-Phen”). Fenfluramine is a racemic compound and the single enantiomer D-
fenfluramine (dexfenfluramine) was also approved and marketed for the treatment of 
obesity as Adifax, Redux, and others. 
Fenfluramine was introduced in the USA in 1973. Products containing fenfluramine and D- 
fenfluramine were withdrawn from all markets between 1997 and 2000 after reports of heart 
valve disease and pulmonary hypertension (Connolly 1997; CDC 1997; Wong 1998). While 
the risk/benefit relationship for fenfluramine is thus considered unfavorable for the treatment 
of obesity in adults, establishing seizure control in LGS or any of the refractory catastrophic 
childhood epilepsies might lead to a more acceptable risk/benefit profile for fenfluramine. 
As a result of this previous extensive use of fenfluramine, there is a large body of information 
in the public domain concerning its pharmacology, toxicology and use in the treatment of 
obesity.  These data are summarized in the ZX008 Investigator Brochure (ZX008 IB). There 
is also a large body of information concerning its clinical safety profile. 
1.3 
CLINICAL DATA 
Two double-blind, placebo-controlled, randomized Phase 3 studies (Study 1 and Study 1504 
Cohort 2) of ZX008 in children and young adults with Dravet syndrome have been completed. 
Study 1 investigated two doses of ZX008 (0.2 and 0.8 mg/kg/day) or placebo and included 119 
subjects with Dravet syndrome from North America, Europe and Australia. Study 1504 Cohort 2 
included 87 subjects from North America and Europe, and compared addition of ZX008 
(0.5 mg/kg/day) or placebo in subjects who were receiving standard of care anti-epileptic 
treatments where administration of STP was mandatory.  
The primary efficacy measure in both studies was the change from baseline in the frequency of 
convulsive seizures (per 28 days) during the combined 14-week (Study 1) or 15-week (Study 
1504 Cohort 2) Titration and Maintenance periods (T+M). The primary analysis in Study 1 
compared ZX008 0.8 mg/kg/day to placebo and in Study 1504 Cohort 2 compared ZX008 0.5 
mg/kg/day to placebo. A key secondary measure in Study 1 compared the 0.2 mg/kg/day group 
to the placebo group on the same measure. Other key secondary measures in both studies 
included a comparison of the ≥ 50% Responder Rate (ie, the number of subjects with a ≥ 50% 
reduction in the frequency of convulsive seizures), and the longest seizure free interval. 
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Both Study 1 and Study 1504 Cohort 2 met the primary endpoint with a highly statistically 
significant reduction in convulsive seizures in all active treatment groups.  
In Study 1, subjects randomized to ZX008 0.8 mg/kg/day and 0.2 mg/kg/day had a median 
baseline convulsive seizure frequency of 20.7 and 17.5, respectively, compared to 27.3 for 
subjects randomized to placebo. Subjects randomized to ZX008 0.8 mg/kg/day (n= 40) achieved 
a 62.3% greater reduction in mean monthly convulsive seizure frequency (P<0.001) compared to 
those in the placebo group (n=40). In addition, subjects randomized to ZX008 0.2 mg/kg/day 
(n=39) had a 32.4% reduction compared to placebo (P = 0.021). Comparing the seizure reduction 
results for the 2 doses of ZX008 in Study 1 suggests a dose-response effect on seizures. The 
pattern of individual responses in the ZX008 0.2 mg/kg/day group supports the selection of 0.2 
mg/kg/day as the minimally effective dose. 
In Study 1504 Cohort 2, subjects randomized to ZX008 0.5 mg/kg/day had a median baseline 
convulsive seizure frequency 14.0 compared to 10.7 for subjects randomized to placebo. 
Subjects randomized to ZX008 0.5 mg/kg/day achieved a 54.0% reduction compared to placebo 
(P < 0.001).  
Controlling for multiplicity with a hierarchical testing procedure, all key secondary endpoints 
were met in both studies, for ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups (Study 1) and 
ZX008 0.5 mg/kg/day (Study 1504 Cohort 2). In Study 1, the proportion of subjects achieving a 
≥ 50% reduction from Baseline in CSF was 67.5% for the ZX008 0.8 mg/kg/day group, and 
38.5% for the 0.2 mg/kg/day group, with both groups being statistically significantly different 
from placebo (12.5%; P < 0.001 and P = 0.009, respectively). In Study 1504 Cohort 2, 53.5% of 
subjects randomized to ZX008 0.5 mg/kg/day compared to 4.5% of subjects randomized to 
placebo achieved a ≥ 50% reduction from Baseline in CSF (P <0.001).  
The proportion of subjects with a ≥ 50% reduction in monthly convulsive seizure frequency 
was also highly statistically significant for all ZX008 dose groups compared to placebo, 
with 38.5%, 53.5%, and 67.5% of subjects in the 0.2 mg/kg/day, 0.5 mg/kg/day, and 0.8 
mg/kg/day cohorts achieving ≥ 50% reduction as compared to 8.3% in placebo. 
Additionally, in Study 1, subjects randomized to ZX008 0.2 and 0.8 mg/kg/day had a 
median 15- and 25-day convulsive seizure-free interval, respectively, compared to 9.5 days 
for placebo (P = 0.035 and P < 0.001). In Study 1504 Cohort 2, subjects randomized to 
ZX008 0.5 mg/kg/day had a median 22-day convulsive seizure-free interval compared to 
13 days for placebo (P < 0.004). 
ZX008 was generally well tolerated in both Study 1 and Study 1504 Cohort 2. Though more 
subjects randomized to ZX008 than to placebo reported TEAEs during the double-blind studies, 
the percent of subjects with serious TEAEs was similar. Additionally, the adverse events 
observed in the program were either already known to be associated with fenfluramine, are 
common to many other antiepileptic drugs being prescribed to these patients, and/or are common 
to the age group and population studied. Specifically, the most common adverse events seen 
were diarrhea, fatigue, pyrexia, upper respiratory tract infection, blood glucose decreased, weight 
decreased, decreased appetite, lethargy and tremor. No valvular heart disease, pulmonary arterial 
hypertension or abnormal valve structure was observed in any subject at any time during the 
entire program.  
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Confidential 
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In an integrated analysis of safety of the double-blind studies, 117 (95.9%) subjects in any 
ZX008 treatment group and 68 (81.0%) subjects in the combined placebo group reported at least 
1 TEAE. The most common (≥ 10%) TEAEs reported in subjects receiving any dose of ZX008 
were: blood glucose decreased, constipation, decreased appetite, diarrhea, echocardiogram 
abnormal, fall, fatigue, lethargy, nasopharyngitis, pyrexia, seizure, somnolence, status 
epilepticus, tremor, upper respiratory tract infection, vomiting, and weight decreased. All of the 
echocardiogram abnormal TEAEs were trace mitral or trace aortic valve regurgitation, which are 
normal physiological findings seen in healthy children (Webb 2015). A total of 15 (12.3%) 
subjects in any ZX008 treatment group and 11 (13.1%) subjects in the combined placebo group 
reported at least 1 serious TEAE. The most frequently reported (≥ 5%) serious AEs (SAEs) were 
status epilepticus and seizure. A total of 76 (62.3%) subjects in any ZX008 treatment group and 
22 (26.2%) subjects in the combined placebo group reported a TEAE determined by the 
Investigators to be related to the study drug, and 3 (2.5%) subjects in any ZX008 treatment group 
and 1 (1.2%) subject in the combined placebo group reported a serious TEAE determined to be 
related to the study drug. During the double-blind treatment periods, 7 (5.7%) subjects in any 
ZX008 treatment group and 1 (1.2%) subject in the combined placebo group reported a TEAE 
that lead to discontinuation from study participation. There were no deaths during the double-
blind treatment periods. 
Subjects in Study 1 and Study 1504 if eligible could participate in Study 1503, an open-label 
long-term, safety extension study that is currently ongoing. All subjects in Study 1503 started 
ZX008 at 0.2 mg/kg/day and could flexibly titrate to a maximum dose of 0.8 mg/kg/day, 
maximum 30 mg/day (if not receiving a concomitant STP regimen) or 0.5 mg/kg/day, maximum 
20 mg/day (if receiving concomitant STP regimen), based on effectiveness, safety and 
tolerability. Though primarily a safety study, subjects in Study 1503 maintained a daily seizure 
diary and continued to complete rating scales on overall effectiveness and quality of life 
measures. 
In a safety update of Study 1503 (cut-off date 14-Oct-2019, n=330 enrolled), the median percent 
change in CSF compared to baseline (core study) for the overall open-label Treatment period 
(Day 1 to End of Study [EOS]) was -66.8% (P <0.001). The reduction from baseline in monthly 
CSF observed at Month 1 of the open-label Treatment period was maintained through Month 24, 
the longest treatment duration included in the analysis. A total of 317/330 subjects reported at 
least 1 TEAE during the open-label Treatment period. The most common (≥ 10%) TEAEs 
reported during the open-label Study 1503 at the time of the cut-off date were blood glucose 
decreased, decreased appetite, diarrhea, ear infection, echocardiogram abnormal, influenza, 
nasopharyngitis, pyrexia, seizure, and upper respiratory tract infection. As in the double-blind 
studies, all of the echocardiogram abnormal TEAEs in Study 1503 were trace mitral or trace 
aortic valve regurgitation, which are not considered pathologic as stated in current guidelines on 
the use of ECHO for the assessment of valve function (Zoghbi 2017, Lancellotti 2010a, 
Lancellotti 2010b). At least 1 treatment-emergent SAE was reported by 80/330 (24.2%) subjects. 
The most frequently reported (≥ 5%) SAE was seizure, occurring in 24/330 (7.3%) of subjects. A 
total of 176/330 subjects (53.3%) experienced at least 1 TEAE that was considered to be related 
to study treatment and 8/330 subjects (2.4%) reported at least 1 SAE that was considered to be 
related to study treatment. A total of 11/330 (3.3%) subjects discontinued due to a TEAE. 
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Confidential 
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Please reference the ZX008 IB for more detailed information on the safety and efficacy of 
ZX008. 
 
1.4 
PHARMACOKINETICS, PRECLINICAL DATA, AND CLINICAL 
PHARMACOLOGY 
1.4.1 
Pharmacokinetics 
The pharmacokinetics of fenfluramine, norfenfluramine and their respective isomers have been 
studied in mice, rats, dogs and humans. Fenfluramine and norfenfluramine were more slowly 
eliminated in humans than in other species. In vitro metabolism studies have shown 
considerable species differences in the metabolism of fenfluramine, with no single species 
having a profile similar to humans. No human-specific metabolites were detected and both rat 
and dog showed good coverage of the human fenfluramine metabolites. In humans, 
fenfluramine is metabolized primarily to norfenfluramine. Fenfluramine is partially 
metabolized by CYP1A2, CYP2B6, and CYP2D6, with additional metabolism by CYP2C9, 
CYP2C19, and CYP3A4. Norfenfluramine does not appear to be strong substrate of any 
CYP450 enzyme, but is metabolized by CYP1A2, CYP2B6, CYP2C19, and CYP2D6 in vitro. 
There is also some contribution of renal clearance to the elimination of dexfenfluramine 
(8%-16%) and nordexfenflurmaine (7%-8%) from the body. Because fenfluramine and its 
active metabolite norfenfluramine have multiple pathways of elimination, interference with a 
single pathway is unlikely to cause a significant change in fenfluramine’s clearance though the 
probability of an interaction increases if multiple elimination mechanisms are affected 
simultaneously. 
While in vitro studies showed that both fenfluramine and norfenfluramine cause weak 
inhibition of CYP2D6 and fenfluramine causes weak induction of CYP3A4 and CYP2B6, 
further analysis based on the FDA’s mechanistic static model shows that fenfluramine and its 
major metabolite norfenfluramine are unlikely to alter the pharmacokinetics of substrates of 
CYP450 enzymes in the range of ZX008 doses that will be administered in this study. 
In Study 1 and Study 1504 Cohort 2, pharmacokinetic parameters of fenfluramine and 
norfenfluramine for patients with Dravet syndrome were determined using a population 
pharmacokinetic (PopPK) model developed using PK data from both healthy volunteers and 
patients with Dravet syndrome. The Study 1 data are provided in Table 3. 
Table 3               Post Hoc Estimates of Fenfluramine and Norfenfluramine Steady-State 
Pharmacokinetic Parameters in Subjects with Dravet Syndrome in Study 1 (Geometric Mean 
[CV%]) 
Analyte: 
Fenfluramine 
Norfenfluramine 
ZX008 Dose 
0.2 mg/kg/day 
0.8 mg/kg/day 
0.2 mg/kg/day 
0.8 mg/kg/day 
Cmax (ng/mL) 
18.5 (29.1) 
68.0 (40.7) 
9.60 (52.8) 
37.8 (49.9) 
AUC0-24 (ng.hr/mL) 
375 (32.9) 
1390 (43.5) 
220 (55.5) 
872 (52.1) 
Tmax (hr) Median 
(Min, Max) 
3.00 (3.00 to 3.50) 
3.00 (3.00 to 3.50) 
4.00 (3.50 to 5.00) 
4.50 (3.50 to 5.00) 
Source: ICPD Report 00445-3, Table 5. 
Abbreviations: AUC0-24 = area under the plasma concentration-time curve from time 0 to 24 hours; BID = twice daily; 
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Cmax = peak plasma drug concentration; CV= coefficient of variation; Max = maximum; Min = minimum; Tmax = time of peak 
plasma drug concentration.  
Study 1504 Cohort 2 required STP as a concomitant medication. Although the dose of ZX008 in 
Study 1504 Cohort 2 was lower than the high dose in Study 1, fenfluramine AUC0-24 values 
were approximately 130% higher in Study 1504 Cohort 2, than the high dose in Study 1, and 
norfenfluramine AUC0-24 values were approximately 60% lower than in Study 1. However, the 
clinical results indicated that the efficacy and AE profile were similar between Study 1 and 
Study 1504, indicating that the dose adjustment studied for the concomitant use of the STP 
regimen met the intended clinical outcome. 
1.4.2 
Preclinical Data 
A 10-week GLP juvenile toxicology and toxicokinetic study in rats, which included 
fenfluramine doses of 3.5, 9 and 20 mg/kg/day by oral gavage for 10 weeks (post natal day 
(PND) 7 to 76). The data from the juvenile toxicology studies suggest that the effects of 
fenfluramine in juvenile animals (CNS-related clinical signs, effects on body weight and food 
consumption, and neurobehavioral deficits) are similar to effects previously reported in 
neonatal and adult rats (Morford, 2002; Williams, 2002). There was no evidence of CNS 
histopathology; importantly, there were also no histopathologic findings in aortic or mitral 
cardiac valves, and no adverse effects on any other tissues at necropsy.  
The NOAEL for the juvenile rats was determined to be 9 mg/kg/day. A NOAEL of 9 mg/kg/day 
corresponds to PND 76 AUC0-t of 3480 hr*ng/mL for males and 4680 hr*ng/mL for females for 
fenfluramine, and 4470 hr*ng/mL for males and 6210 hr*ng/mL for females for norfenfluramine. 
The AUC(0-t) at the NOAEL provided a safety factor (both sexes combined) of approximately 3-
fold or higher for fenfluramine and approximately 6-fold or higher for norfenfluramine. 
1.4.3 
Clinical Pharmacology 
Please see the ZX008 IB for details on clinical pharmacology. Below are the clinical 
pharmacology conclusions.  
x 
Coadministration of ZX008 with the STP regimen (STP with CLB and/or VPA) resulted 
in an increased fenfluramine and decreased norfenfluramine concentrations, and 
therefore a dose adjustment is used in the clinical trials. 
x 
STP is the predominant perpetrator of the interaction; while VPA and CLB do not have 
a significant independent impact on the PK of fenfluramine or norfenfluramine, whether 
administered with or without STP. 
x 
Coadministration of ZX008 with CBD at steady state resulted in increased fenfluramine 
concentrations but this increase was within the range of safe dosing used in Study 1504 
Cohort 2; thus, no dose adjustment is recommended when fenfluramine is 
coadministered with CBD.  
x 
In the population PK analysis, intrinsic patient factors (age, gender, race/ethnicity, and 
BMI) demonstrated no substantial impact on the clearance or exposure to fenfluramine 
or norfenfluramine when dosed on a mg/kg basis to a maximum of 30 mg/day.  
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x 
ZX008 had no effect on QTc intervals at either the therapeutic or supratherapeutic dose, 
and no relationship was observed between fenfluramine or norfenfluramine exposure 
and QTcF. 
x 
ZX008 exhibited approximately dose proportional PK over a 4-fold range of doses (15 
to 120 mg/day). 
x 
CYP450 metabolizer genotype for CYP1A2, CYP2B6, CYP2C19, CYP2D6, or 
CYP3A4 had no impact on the PK of fenfluramine or norfenfluramine. 
Further details on the preclinical data of ZX008 are available in the Investigator’s Brochure 
(ZX008 IB). The current version is available in the Investigator Study File. 
1.5 
BACKGROUND INFORMATION ON REFERENCE PRODUCT 
Not applicable. 
1.6 
RATIONALE FOR CURRENT STUDY 
There have been several published reports of fenfluramine’s successful treatment of 
refractory childhood epilepsy in the 1980s (Aicardi 1985; Aicardi 1988) and its successful 
treatment of 11 refractory pediatric epilepsy patients in Belgium (Boel 1996).   
A number of small studies and case series have been published describing the use of 
fenfluramine in epilepsy.  In 1996, a Belgian group reported on the use of fenfluramine in 11 
children (ages 18 months to 15.5 years old) with refractory or self-induced epilepsy (Boel 1996).  
Patients were treated with fenfluramine at 0.5 – 1 mg/kg/day for 3 to 8.5 years (average duration 
5 years 7 months). Seven children (64%) became seizure-free and the remaining 4 patients 
experienced ≥75% reduction in seizure frequency. 
In 2002, Casaer and Boel published a brief update of their study with fenfluramine. The study 
population was expanded to 22 patients with intractable or self-induced seizures, including the 
previously reported 11 patients (Casaer 2002). The duration of treatment was between 1 and 12 
years. In this study, of the 22 patients treated, 6 (27%) became seizure-free, 10 (45%) patients 
had a 90% reduction in seizure frequency and 6 (27%) patients were non-responders. 
Fenfluramine was also shown to be effective in multiple seizures types in Dravet syndrome (DS), 
another very drug resistant pediatric epileptic encephalopathy syndrome (Ceulemans 2012; 
Schoonjans 2015; Ceulemans 2016; Schoonjans 2017). Zogenix is currently evaluating ZX008 in 
Dravet Syndrome in two Phase 3 double-blind, randomized, placebo-controlled studies and one 
open-label extension (clinicaltrials.gov identifiers: NCT02826863, NCT02682927, and 
NCT02823145). 
Currently, a small cohort of refractory patients with Lennox-Gastaut syndrome in Belgium are 
being treated in an ongoing Phase 2 open-label, pilot, dose-finding trial of fenfluramine as an 
add-on therapy to conventional therapy (Lagae, 2017; Study S58545; clinicaltrials.gov identifier: 
NCT02655198).  
The study includes a 20-week Core period, in which subjects are titrated to ≥50% response and 
then held at that dose until the end of the 20-week period, and an Extension period, in which 
subjects are titrated to maximum efficacy and tolerability.  Subjects aged 3 to 18 years, fulfilling 
the diagnostic criteria for LGS as described by the ILAE in 1989, who have failed at least two 
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AEDs (including VNS), and have had at least 4 documented convulsive seizures (General Tonic 
Clonic, Tonic Seizures, Atonic Seizure, and Focal Seizure with a motor component) and on at 
least two AEDs at stable doses in the prior 4 weeks are eligible for this study.  After the initial 4-
week baseline period to record seizure type and frequency, treatment with fenfluramine, 0.2 
mg/kg/day, is initiated. An efficacy response (“responder”) is defined as a ≥50% reduction in 
major motor seizure frequency (GTC+TS+AS+FS).  At the 8-week visit (following 4 weeks of 
ZX008 treatment), subjects who were non-responders and have no intolerable side effects 
receive an increased dose of 0.4 mg/kg/day.  At the 12-week visit, subjects who were non-
responders and have no intolerable side effects receive an increased dose of 0.8 mg/kg/day.  At 
any visit, subjects who achieve a ≥50% reduction in major motor seizure frequency remain at 
their currently administered dose.  As this is a pilot dose-finding study, it is important to note 
that per protocol, dose escalation stops when a subject’s convulsive seizure frequency is reduced 
by ≥50% of baseline.  It is possible that a higher dose could result in even greater seizure 
reduction.  The maximum allowed dose is 30 mg/day.  
Results have been presented for the 13 LGS subjects who completed the Core study: (Lagae, 
2017). Overall, subjects had received a median of 8 years of antiepileptic treatment and were 
failing a median of 5 AEDs prior to entry. Upon study entry, patients were taking a median of 4 
concurrent anti-epileptic therapies. All subjects received ZX008 treatment for at least 20 weeks 
with the exception of 3 subjects who discontinued due to lack of efficacy; of which 2 also 
discontinued due to side effects. For subjects who completed the 20-week Core period, the 
median seizure frequency was reduced from a mean of 60 major motor seizures per month in the 
pre-ZX008 baseline period to a mean of 22 major motor seizures per month at the end of the 
Core ZX008 treatment period. At week 20, 8 of the 13 enrolled patients (62%) had at least a 50% 
reduction in major motor seizures with ZX008 treatment. Nine of the 13 patients completed the 
Core period and entered the Extension period. At the time of each of subjects’ most recent visit, 
6 of 9 patients (67%) had at least a 50% reduction in major motor seizures and 2 of 9 (22%) had 
a 75% or greater seizure reduction. In the Extension period, there was a 58% median reduction in 
seizure frequency as compared to baseline. The most common treatment emergent adverse 
events to date include decreased appetite (n=4) and decreased alertness/fatigue (n=3). Sleep 
problems, tiredness, and sleepiness were each reported in one subject. 
No clinical signs of valvulopathy or pulmonary hypertension have been observed in any patients 
in the Belgian cohort  (ZX008 IB ). 
In addition, numerous publications discuss the use of fenfluramine in over 500 children with 
neurobehavioral conditions for the treatment of mostly autism and ADHD, without any reports 
of any cardiovascular adverse events (summarized in ZX008 IB ). 
Prior to being withdrawn from the market, fenfluramine was marketed at doses of 20 mg and 
40 mg three times daily for the management of obesity in adults. The doses tested thus far in DS 
range from 0.12 to 0.9 mg/kg/day in subjects over 1 year of age to adults in the Belgian cohort, 
and 0.2 and 0.8 mg/kg/day in the Zogenix Phase 3 trials. Doses tested in pediatric studies 
evaluating autism and ADHD ranged from 0.65 mg/kg/day to 3.6 mg/kg/day, but a commonly 
used dose was 1.5 mg/kg/day. Occasionally, fixed doses of 30 to 80 mg were used.  The PK 
exposure associated with the doses in the LGS study of 0.2 mg/kg/day and 0.8 mg/kg/day, 
administered orally (in equally divided doses BID) is expected to be lower than that obtained at 
the doses used in the past for the treatment of obesity in adults and of neurobehavioral conditions 
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in children and adolescents (ZX008 IB ). The doses used in this study are based on the data from 
the DS and LGS patients being successfully treated in Belgium discussed above. 
In summary, fenfluramine has been shown to be effective in reducing the frequency of seizures 
in patients with Dravet syndrome and LGS, and its activity persists over a long duration of time 
(Ceulemans 2012, Ceulemans 2016, Schoonjans 2017, Lagae 2018). Though the mechanism 
remains to be fully elucidated, data from in vitro receptor binding, functional assays, and 
zebrafish models suggest that fenfluramine reduces seizures by acting as an agonist at the 5-
HT1D and the 5-HT2C receptors and by acting on the sigma-1 receptor. Fenfluramine may 
also exert anti-seizure activity through the 5-HT1A and the 5-HT2A receptors (ZX008 IB 
2018).  
The lack of consistent efficacy and individual tolerability and safety concerns with current 
treatments available for LGS have resulted in the continued significant unmet need for a new 
treatment with a novel mechanism of action for children and adults with LGS. 
The rationale for conducting the Part 2 open-label extension period is primarily to evaluate the 
long-term safety of ZX008 in subjects with LGS. This protocol also provides the opportunity 
for continued treatment for subjects responding to treatment from Part 1 and an opportunity for 
initial treatment with ZX008 for subjects randomized to placebo in Part 1. The study will also 
allow access to ZX008 for the treatment of LGS for eligible Japanese subjects until 
commercial product is available, as it is not approved in Japan. The period from the approval 
of this drug to its launch is positioned as a post-marketing study.  
1.7 
RISK-BENEFIT ASSESSMENT 
As described above, fenfluramine has been used successfully for up to 30 years in Belgium 
in refractory pediatric epilepsy patients, including those with LGS and DS (Boel 1996, 
Ceulemans 2012, Schoonjans 2015, Schoonjans 2017). The doses tested thus far in DS 
range from 0.12 to 0.9 mg/kg/day in subjects over 1 year of age to adults. No patients have 
developed valvulopathy or pulmonary hypertension.  
The clinical benefit of ZX008 in the Lennox-Gastaut syndrome has been evaluated in 
an open label study (Lagae 2017, 2018) as mentioned in Section 1.6.  In addition, 2 
positive, adequate and well-controlled, multi-national, randomized, double-blind, 
placebo-controlled trials of ZX008 in subjects with Dravet syndrome, Study 1 and 
Study 1504 Cohort 2, demonstrated a statistically significant and clinically 
meaningful reduction in monthly convulsive seizure frequency and was generally 
well tolerated.  There was no clinical or echocardiographic evidence of cardiac 
valvulopathy or pulmonary hypertension in any study and no patient discontinued 
participation or required a change in monitoring in the study due to cardiac factors. 
The PK exposure associated with the doses of ZX008 in the Dravet syndrome studies 
of 0.2 mg/kg/day to 0.8 mg/kg/day administered orally [in equally divided doses 
twice per day (BID)] is lower than that obtained at the doses used in the past for the 
treatment of obesity in adults and of neurobehavioral conditions in children and 
adolescents (ZX008 IB). The doses used in this study are based on the data from the 
patients being successfully treated in Belgium discussed above, Study 1, and Study 
1504 Cohort 2 data. 
The pharmacologic and toxicological profile for the active pharmaceutical ingredient, 
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fenfluramine, following oral administration is well established (see ZX008 IB ). 
The safety monitoring practices employed by this protocol are adequate to protect the subjects’ 
safety and should detect expected and unexpected treatment-emergent adverse events, and are 
the same as those currently being utilized for the global Phase 3 DS program. 
The approximate volume of blood (194.0 mL) planned for collection from each subject over the 
course of the entire study (Screening to End of Study Part 2, but not including repeat or 
additional tests ordered by the investigator) presents no undue risk to the subjects. 
The ZX008 0.2 mg/kg/day and 0.8 mg/kg/day doses are believed to be likely therapeutic doses, 
which could provide sufficient anti-epileptic effect for a sustained period of time during the 
study. 
The available information suggests that the present clinical study has an acceptable risk-benefit 
ratio. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
PART 1 
2.1.1 
PRIMARY OBJECTIVE 
The primary objective of Part 1 is the primary objective of the entire study. 
The primary objective of Part 1 is: 
x To evaluate the effect of ZX008 0.8 mg/kg/day versus placebo as adjunctive therapy for 
the treatment of uncontrolled seizures in children and adults with Lennox-Gastaut 
syndrome (LGS) based on the change in frequency of seizures that result in drops 
between baseline and the combined Titration and Maintenance Periods (T+M). 
2.1.2 
KEY SECONDARY OBJECTIVES 
The key secondary objectives of Part 1 are: 
x To evaluate the effect of ZX008 0.2 mg/kg/day versus placebo as adjunctive therapy for 
the treatment of uncontrolled seizures in children and adults with LGS based on the 
change in frequency of seizures that result in drops between baseline and T+M. 
– To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus 
placebo on the proportion of subjects who achieve a ≥50% reduction from 
baseline in the frequency of seizures that result in drops. 
– To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus 
placebo on the Clinical Global Impression – Improvement rating, as assessed by 
the principal investigator. 
See Statistical Methods (Section 10.1.5.1) for hierarchical testing procedure. 
2.1.3 
ADDITIONAL SECONDARY OBJECTIVES 
Additional secondary objectives of the study are: 
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x To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo 
on the following endpoints: 
– Change in the frequency of all countable motor seizures between baseline and T+M 
(countable seizures include: generalized tonic-clonic seizures [GTC], tonic seizures 
[TS], clonic seizures [CS], atonic seizures [AS], tonic/atonic seizures [TA], 
clearly recognizable focal seizures [FS], and myoclonic seizures [MS] that result 
in a drop). 
– Change in the frequency of all countable seizures (ie, motor and non-motor) 
between baseline and T+M 
– Change in frequency of seizures that result in drops between baseline and the 
Maintenance Period (M) 
– Change in the frequency of countable motor seizures that do not result in drops 
between baseline and M 
– The proportion of subjects who have a worsening or no change (i.e. ≤ 0% 
reduction), >0%,  ≥25%, ≥50%, ≥75%, 100% reduction, and “near seizures 
freedom” (ie 0 or 1 seizures) between baseline and T+M, and baseline and M, in 
all countable motor seizures (GTC, TS, AS, TA, FS, MS with a drop); in 
countable motor seizures that do not result in drops; in all countable seizures; in 
all countable seizures that do not result in drops; and in all seizures that result in 
drops  
–  
– Longest interval between seizures that result in drops 
– Number of seizure-free days, defined as 1) days with no countable seizures and 2) 
days with no seizures that result in drops 
x To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo 
on the Clinical Global Impression – Improvement rating, as assessed by the 
parent/caregiver. 
2.1.4 
SAFETY OBJECTIVE 
The safety objectives of Part 1 are: 
x To evaluate the safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day versus placebo 
with regard to adverse events (AEs), laboratory parameters, physical examination, 
neurological examination, vital signs (blood pressure, heart rate, temperature, and 
respiratory rate), electrocardiograms (ECG), echocardiograms (ECHO), body weight, and 
BMI 
x To evaluate the change from baseline in cognition using age-appropriate versions of the 
BRIEF 
2.1.5 
PHARMACOKINETIC OBJECTIVE 
The pharmacokinetic (PK) objective of the study is: 
x To evaluate the PK of ZX008 0.2 and 0.8 mg/kg/day at steady state in subjects < 18 
years and ≥18 years with LGS using a non-compartmental analysis; and obtain 
exposure data that will be used in population pharmacokinetic (PopPK) analysis, the 
results of which will be reported separately. 
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2.1.6 
EXPLORATORY OBJECTIVES 
The exploratory objectives of the study are: 
x To compare the ZX008 0.2 and 0.8 mg/kg/day doses on primary, secondary, and safety 
endpoints. 
x To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo 
on the following endpoints: 
– The frequency of rescue medication usage 
– The incidence of medical services to treat seizures 
– The incidence of status epilepticus 
– The change from baseline in behavior using the Vineland Adaptive Behavior 
Scale (VABS)(Cohort A) 
– The change from baseline in QoL using the QOLCE 
– The change from baseline in caregiver burden using the Zarit Caregiver Burden 
Inventory  
– The change from baseline in affective symptoms of the parent/caregiver using the 
Hospital Anxiety and Depression Scale (HADS) 
2.2 
PART 2 
2.2.1 
PRIMARY OBJECTIVE 
The primary objective of Part 2 is to assess the long-term safety and tolerability of ZX008 in 
children and adults with LGS with regard to adverse events (AEs), laboratory parameters, 
physical examination, neurological examination,  cognition (BRIEF), vital signs (blood pressure, 
heart rate, temperature, and respiratory rate), ECG, ECHO, body weight, and BMI. 
2.2.2 
SECONDARY OBJECTIVES 
The secondary objectives of Part 2 are: 
x To assess the effect of ZX008 relative to the baseline on the following effectiveness 
measures: 
- The change in the frequency of seizures that result in drops 
- The change in the frequency of all countable motor seizures (GTC, TS, CS, AS, TA, FS, 
MS with a drop) 
- The change in the frequency of all countable seizures 
- The proportion of subjects who have a worsening or no change (i.e. ≤ 0% reduction), >0 
%,  ≥25%, ≥50%, ≥75%, 100% reduction, and “near seizure freedom (ie, 0 or 1 seizures) 
in frequency of all countable seizures that result in drops, countable motor seizures that 
do not result in drops, all countable motor seizures, all countable seizures, and all 
countable seizures that do not result in drops 
- Number of seizure-free days, defined as 1) days with no countable seizures and 2) days 
with no seizures that result in drops 
- Longest interval between seizures that result in drops 
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x  To evaluate the effect of ZX008 on the following endpoints: 
- Clinical Global Impression – Improvement rating, as assessed by the principal 
investigator 
- Clinical Global Impression – Improvement rating, as assessed by the parent/caregiver 
2.2.3 
EXPLORATORY OBJECTIVES 
The exploratory objectives of Part 2 are: 
x To estimate the incidence of the following on subjects receiving ZX008: 
- The incidence medical services use to treat seizures 
- The incidence of status epilepticus 
- The use of rescue medication 
x To assess the effect of ZX008 on the following measures: 
- The change from baseline in affective symptoms of the parent/caregiver using the HADS 
- The change from baseline in QoL using the QOLCE 
- The change from baseline in caregiver burden using the Zarit Caregiver Burden 
Inventory 
2.3 
STUDY ENDPOINTS 
2.3.1 
Efficacy Endpoints 
The efficacy endpoints for Part 1 of the study are: 
Primary Endpoint: 
x Percent change from baseline in the frequency of seizures that result in drops in the 
combined Titration and Maintenance Periods (T+M) in the ZX008 0.8 mg/kg/day group 
compared to the placebo group. 
 
Key Secondary Endpoints: 
x Change from baseline in the frequency of seizures that result in drops in T+M in the 
ZX008 0.2 mg/kg/day group compared to the placebo group 
x Proportion of subjects who achieve a ≥50% reduction from baseline in the frequency of 
seizures that result in drops comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day 
groups independently versus placebo 
x 
Proportion of subjects who achieve improvement (minimally, much, or very much 
improved) in the Clinical Global Impression – Improvement as assessed by Principal 
Investigator comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups 
independently versus placebo. 
x Number, frequency, and duration of countable seizures that result in drops 
x Number, frequency, and duration of countable seizures that do not result in drops 
x Number, frequency, and duration of all countable seizures by type  
x Proportion of subjects who achieve a ≥25%, ≥50%, ≥75%, or 100% reduction from 
baseline in seizure frequency 
x Number of seizure-free days 
x Clinical Global Impression – Improvement as assessed by parent/caregiver 
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The efficacy endpoints for Part 2 of the study are: 
x The change from baseline in the frequency of seizures that result in drops.  
x The change from baseline in the frequency of all countable motor seizures (GTC, TS, CS, 
AS, TA, FS, MS with a drop) 
x The change from baseline in the frequency of all countable seizures 
x The proportion of subjects who achieve a worsening from baseline (i.e. <= 0% 
reduction), or >0%,   ≥ 25%, ≥ 50%, ≥ 75%, and 100% reduction from baseline in 
frequency of all countable seizures that result in drops, countable motor seizures that do 
not result in drops, all countable motor seizures, all countable seizures, and all countable 
seizures that do not result in drops 
x Number of seizure-free days, defined as 1) days with no countable seizures and 2) days 
with no seizures that result in drops 
x Number of instances of rescue medication use and number of doses of rescue medication 
x Longest interval between seizures that result in drops 
x Clinical Global Impression – Improvement rating, as assessed by the Principal 
Investigator. 
x Clinical Global Impression – Improvement rating, as assessed by the parent/caregiver. 
2.3.2 
Safety Endpoints 
The safety endpoints for Part1 and Part 2 of the study are: 
x AEs 
x Laboratory safety (hematology, chemistry, urinalysis) 
x Vital signs (blood pressure, heart rate, temperature, and respiratory rate) 
x Body weight and BMI 
x Physical examination 
x Neurological examination 
x BRIEF to measure changes in cognition of the subject 
x Columbia Suicidality Severity Rating Scale (C-SSRS) 
x 12-lead ECGs 
x Doppler ECHOs 
2.3.3 
Exploratory Endpoints 
The exploratory endpoints for Part 1 and Part 2 of the study are: 
x The incidence of medical services used to treat seizures 
x The incidence of status epilepticus 
x Incidence of rescue medication usage 
x Number of days rescue medication used 
x The change from baseline in behavior using the Vineland Adaptive Behavior Scale 
(VABS) (Part 1 Cohort A only) 
x The change from baseline in quality of life using the QOLCE 
x The change from baseline in caregiver burden using the Zarit Caregiver Burden Inventory 
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x The change from baseline in affective symptoms of parent/caregiver using the HADS 
scale 
3. 
INVESTIGATIONAL PLAN 
3.1 
OVERALL STUDY DESIGN AND PLAN 
This is an international multicenter study being conducted in two parts.  Up to approximately 
80 study sites in North America, Europe, Japan, and Australia are initially planned to 
participate.  Part 1 is a double-blind, parallel-group, placebo-controlled, study to assess the 
efficacy and safety of two doses of ZX008 when used as adjunctive therapy for seizures in 
children and adult subjects with LGS. Part 1 will include 2 cohorts: Cohort A will include 
randomized subjects from North America, Europe, and Australia; Cohort B will include 
randomized subjects from Japan only. The primary study endpoint is assessed from Part 1 
Cohort A data. The primary analysis will be conducted when the last subject in Cohort A has 
completed Part 1.  Part 2 will be an open-label, flexible-dose extension for subjects completing 
Part 1 of the study. 
Part 1 will consist of a 4-week baseline, 2-week titration, 12-week maintenance, and 2-week 
taper or transition period.  The 4-week Baseline Period will consist of the establishment of 
initial eligibility during a screening visit to include an assessment of cardiac parameters (ECG 
and ECHO), followed by an observation period where subjects will be assessed for baseline 
seizure frequency based on recordings of daily seizure activity entered into a diary.  Upon 
completion of the Baseline Period, subjects who qualify for the study will be randomized 
(1:1:1) in a double-blind manner to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 0.8 
mg/kg/day; maximum dose: 30 mg/day) or placebo.  Randomization will be stratified by 
weight (<37.5 kilograms [kg], ≥37.5 kg) to ensure balance across treatment arms, and at least 
25% of subjects will be in each weight group. All subjects will be titrated to their blinded 
randomized dose over a 2-week Titration Period. Following titration, subjects will continue 
treatment at their randomly assigned dose over a 12-week Maintenance Period. Total treatment 
time from the beginning of the Titration Period through the end of the Maintenance Period is 
14 weeks.  Subjects will have ECG and ECHO assessments at weeks 6 and 14 during the 
Maintenance Period.  At the end of the Maintenance Period (or early discontinuation), all 
subjects will undergo a 2-week taper or transition period (Post-Dosing Follow-Up) depending 
on whether they exit the study or are enrolled in Part 2, the long-term open-label extension, 
respectively. A follow-up ECG and ECHO will be performed after study drug discontinuation 
for early termination, or for those subjects who complete the study but do not enter the open-
label extension (Part 2), as outlined in Table 9. 
Part 2 is an open-label, long-term safety study of ZX008 for subjects who have successfully 
completed 14 weeks of treatment (titration + maintenance) in Part 1, are candidates for 
continuous treatment for an extended period of time, have met the Selection Criteria for Part 1 
(except for criteria related to seizure frequency), and signed informed consent/assent forms 
prior to the start of Part 2. Subjects who have not completed the entire 14 weeks of treatment in 
Part 1 may be eligible to participate in Part 2 on a case-by-case basis and only following 
sponsor approval. Other requirements for participation in Part 2 are described in Section 4.3. 
Part 2 will consist of a 12-month Open-Label Extension (OLE) Treatment Period and a 2-week 
Post-Dosing Period. Thus, subjects who complete 12 months of OLE in Part 2 will have been 
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treated with ZX008 for at least 70 weeks (including their participation in both Part 1 and Part 
2). If marketing approval is not yet received after the end of the OLE Treatment Period, 
treatment may be extended on an annual basis in order to provide continuity of treatment for 
subjects who are enrolled in Part 2 of the study until ZX008 is approved in the subject’s 
country of residence and listed on a patient’s health plan formulary. Up to 5 annual extensions 
can be applied, for a total treatment time of 72 months in the OLE. Continuation will be based 
on review of safety/tolerability and effectiveness, and be offered for subjects who continue to 
meet eligibility requirements, comply with investigator’s instructions, and for whom the 
investigator judges benefit outweighs risk. 
During Part 2 all subjects will be treated initially with 0.2 mg/kg/day for 1 month to assess 
effectiveness of this dose in all study subjects and determine the minimally effective dose. 
After 1 month at a dose of 0.2 mg/kg/day, the investigator may adjust the dose for each subject 
based on effectiveness and tolerability. Dose changes should be made in maximum increments 
of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day but not to exceed total dose of 30 
mg/day.  During the 12-month OLE subjects will have ECG and ECHO assessments at months 
1, 3, 6, and 9, and at the end of study visit. In the event the OLE is extended, subjects will 
continue to have ECG (if clinically indicated) and ECHO assessments every 6 months until the 
end of their participation in the study. See Section 5.5 for instructions on dosing and dose 
adjustments. 
A follow-up ECG and ECHO will be performed after study drug discontinuation for early 
termination and for those subjects who complete Part 2, as outlined in Table 11. Subjects who 
transition to commercially available ZX008 will not return for these follow-ups, but must have 
an ECHO within 3 to 6 months of the transition date and will have follow-up ECHOs within 
required timeframes while on commercial drug supply. 
In both Part 1 and the first 12 months of Part 2, parents/caregivers will use a diary every day to 
record the number of seizures, type of seizures, time and duration of seizures, whether the 
seizure resulted in a drop, dosing of study drug, and use of rescue medication.     
A schedule of assessments for Part 1 is provided in Table 1 and for Part 2 in Table 2. 
3.2 
NUMBER OF SUBJECTS 
Approximately 340 subjects will be screened to obtain 250 subjects randomized into Part 1 
Cohort A (75 subjects per treatment arm) , and at least 30 (and up to 50) subjects will be 
randomized into Part 1 Cohort B.  The number of screened subjects may exceed 340 
depending on the screen fail rate. Each clinical site will not randomize more than a maximum 
of 15 subjects without prior consent from the sponsor. 
3.3 
STUDY DURATION 
The duration of participation in the study for an individual subject is expected to be up to 
20 weeks in Part 1 to include: 
x  Baseline Period – 4 weeks 
x T+M Period - 14 weeks 
x Taper/Transition Period – 2 weeks after  
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Subjects who do not enroll in the open-label extension (Part 2) will undergo a taper off of study 
medication;  eligible subjects who enroll in the open-label extension will undergo a 2-week 
transition period  
Subjects who enroll in Part 2 will have the option to receive ZX008 for up to 72months 
(plus a 2-week taper at the end of the open-label extension), or until ZX008 is approved 
in the subject’s country of residence and listed on a patient’s health plan formulary, 
whichever occurs first 
Follow-up cardiovascular safety assessments, including ECG and ECHO, will be 
performed following the last dose of study medication for all subjects that do not 
transition to commercial drug, regardless of whether they complete the entire study or 
terminate early. These follow-ups will occur 3 months following the last dose of study 
medication for any subject taking the medication for 2-13 weeks, and 3 and 6 months 
following the last dose for any subject taking the medication for >13 weeks. If there are 
any findings at a post-dose follow-up, another follow-up will be repeated every 3 months 
until resolved or stabilized. Subjects who transition to commercially available ZX008 
will not return for a follow-up after EOS/ET or a cardiac follow up after last dose but 
must have had an ECHO within 3 to 6 months before the transition date and will have 
follow-up ECHOs within required timeframe while on commercial drug supply. 
The study schema is shown in Figure 1. 
 
Figure 1; Study Schema 
 
3.4 
NUMBER OF STUDY CENTERS 
The study expects to use up to approximately 80 research centers from North America, 
Europe, Japan, or Australia. Additional study centers within or outside of these geographic 
areas may be added if enrollment cannot be completed in a timely manner.  Sites also may be 
closed if they fail to enroll. 
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3.5 
RATIONALE FOR STUDY DESIGN AND CHOICE OF 
TREATMENT GROUPS 
It is recognized that performing clinical studies in young children or in subjects with reduced 
cognitive capacity presents particular practical and ethical issues. However, given the 
seriousness of LGS, and the possible consequences of current inadequate treatments, the 
inclusion of children with LGS and adults with LGS who may have intellectual disability in 
this study is considered justified. Eligible subjects include males and females between 2 and 
35 years of age inclusive. Because an accurate diagnosis of LGS is difficult in children 
younger than 2 years, and seizures that result in drops may not be accurately counted in this 
age group, children younger than 2 years are not included.  Although seizures persist into 
adulthood, the primary seizure types and the treatment setting may differ, thus adults older 
than 35 years have not been included in this protocol.  
Stratifying the randomization by weight is considered appropriate since the daily dosage of 
ZX008 increases with weight up to a maximum of 30 mg/day. The two strata in the study will 
be subjects who weigh less than 37.5 kg and subjects who weigh 37.5 kg or more.  The study 
design has incorporated a titration period to enable subjects randomized to the high dose group 
adequate time to acclimate to this dose. Following the Titration Period, subjects will enter a 
12-week Maintenance Period where they will continue on their randomized dose for the 
remainder of the study. The 12-week duration of the Maintenance Period is in keeping with the 
current standard study duration for evaluating the efficacy of chronic medications. Given the 
individual variability in seizure frequency and seizure type in this patient population, the 
primary endpoint, which seeks to compare an appropriate baseline of motor seizure that can 
result in a drop frequency to the motor seizure that can result in a drop frequency following 
treatment, is an appropriate primary endpoint for efficacy in this population. 
Subjects will receive investigational medicinal product (IMP; ZX008 or placebo) in addition to 
their existing antiepileptic medications at their stable doses throughout the entire Part 1. Thus, 
subjects receiving placebo will not be denied active therapy; they will continue to receive their 
existing medications at the exact same dosages. As the principal study measurement (seizures 
that result in drops) might be considered subjective, a double-blind study design will prevent 
subjective bias. Upon completion of Part 1, eligible subjects will be able to receive ZX008 in 
Part 2, the open-label extension, for up to 5 additional years of treatment. 
 
3.6 
RATIONALE FOR STUDY DESIGN AND CHOICE OF 
TREATMENT GROUPS 
Initial enrollment in Study 1601 was planned at up to 115 study sites in North America, 
Europe, Australia, and Japan. During the first 14 months of enrollment (ie, between November 
2017 and January 2019), 50% of patients were randomized. During the next 5 months of 
enrollment (ie, between February 2019 and June 2019), enrollment proceeded faster than 
projected, with the remaining 50% of patients being randomized across a total of 70 active 
sites.   
The speed of enrollment signifies the strong need for new medications for patients with LGS. 
Amending the Study 1601 protocol to split enrollment into 2 cohorts -- Cohort A (randomized 
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subjects from North America, Europe, and Australia) and Cohort B (randomized subjects from 
Japan only) -- and pre-specifying the primary analysis endpoint in the protocol and statistical 
analysis plan to include only subjects from Cohort A allows analyses to be conducted on a 
suitable number of subjects that are in accordance with the sample size estimations.  Moreover, 
this approach allows evaluation of ZX008 in a Japanese population as part of a global clinical 
study while adhering to the requirements of the sample size estimation.  The number of 
subjects in Japan will be increased from 15 to at least 30 (with the possibility to include up to 
50) in order to provide a suitable sample for comparison, acknowledging that the speed of 
enrollment in Japan could mimic that of the other countries. 
Japan has a large patient population with a high unmet medical need. Cultural differences 
between Japanese patients and Western patients are well documented in the literature.  
Moreover, due to operational challenges in clinical trial conduct, patients in Japan are typically 
not included in global studies, and when they are, it is often in very small numbers 
proportionally. Analyzing Cohorts A and B independently enables a properly powered primary 
analysis on Cohort A while providing the opportunity to increase enrollment in Japan in Cohort 
B, thus allowing for a more substantial comparison of safety and efficacy between Japanese 
patients and non-Japanese patients. 
3.7 
PREMATURE TERMINATION OF STUDY 
The sponsor can terminate the study prematurely at any time for medical, ethical, or 
administrative reasons at individual or at all study sites. The investigator will be notified in 
writing, outlining the reasons for the termination. Instructions will be provided if assessments 
beyond those described in the study protocol need to be conducted. 
The Independent Data Safety Monitoring Committee (IDSMC) may request that the study be 
terminated after review of the safety information at any time during the study.  
If the study is terminated prematurely for any reason, the investigator should promptly inform 
the subjects participating at his or her study site and should ensure that appropriate follow-up 
care is available and that End-of-Study procedures are conducted, as described in 
Section 6.1.2.9 and Section 6.2.4. 
All study materials including IMP (unless prior approval for onsite destruction is granted by 
sponsor) and completed, partially completed, and blank documentation, except documents 
needed for archiving requirements, will be returned to the sponsor. The study monitor will 
ensure that any outstanding data clarification issues and queries are resolved, and that all study 
records at the study site are complete. 
In accordance with applicable regulatory requirements, the sponsor will promptly inform the 
competent regulatory authorities of the termination and its reason(s), and the investigator or 
sponsor will promptly inform the Independent Ethics Committee (IEC)/IRB. 
3.8 
STUDY MONITORING PROCEDURES 
3.8.1 
Independent Data Safety Monitoring Committee 
The IDSMC is an independent advisory body that monitors participant safety, data quality and 
progress of the clinical trial. The IDSMC charter will outline the roles and responsibilities of 
the committee and guide its operations and frequency of meetings. The IDSMC will consist of 
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individuals external to the sponsor who have relevant clinical trial expertise and experience in 
safety assessment. 
At regularly defined intervals, the IDSMC will convene to review and monitor study progress, 
AEs and SAEs, other measures of safety such as ECGs or ECHOs, and efficacy data as dictated 
by the charter. 
The IDMSC will: 
x Be responsible for providing recommendations to the sponsor surrounding study conduct 
matters that affect safety. The IDMSC will review the data for the development of heart 
valve disease and pulmonary hypertension as they occur on a case-by-case basis and at 
regular meetings. 
x Review safety data at ad hoc time points and identify if significant safety concerns arise 
during the study. 
x Review data that may affect subject continuation. 
x Make recommendations regarding the continuation, suspension, or termination of the 
study. 
 
3.8.2 
International Cardiac Advisory Board (ICAB) 
The ICAB is an advisory body to the sponsor that assists in monitoring cardiac safety of the 
ZX008 clinical trials and provides advice to the IDMSC. The ICAB consists of individuals 
external to the sponsor who have relevant experience in cardiology, pediatric cardiology, and 
echocardiography. The ICAB will advise the sponsor and the IDSMC on the cardiac safety 
monitoring plan, including alert criteria and decision pathway for subject management relative 
to cardiac safety in the clinical studies of ZX008 when requested.  ICAB members also 
provide secondary review or adjudication of ECHOs and ECGs, as well as risk assessment, as 
needed. 
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4. 
SELECTION OF STUDY POPULATION 
The study population will be selected on the basis of the inclusion and exclusion criteria 
described in the sections below. Before evaluating these criteria and deciding on the eligibility 
of subjects to participate in the study, it is important that the investigator is familiar with the 
safety profile of ZX008 by referring to the Investigator’s Brochure, as supplied by the 
sponsor.  Subjects receiving concomitant STP are not prohibited from study participation. For 
these subjects the maximum dose will be 0.5 mg/kg/day, with a maximum 20 mg/day, or 
equivalent placebo volume. For analyses purposes these subjects will be grouped with 
subjects randomized to 0.8 mg/kg/day.  The dose of 0.5 mg/kg/day (maximum 20 mg/day) 
was selected for concomitant administration with STP based on the predicted effects of 
concomitant STP on ZX008 and the dose that best matches the exposure for the reference 
dose (ie, 0.8 mg/kg/day with a maximum of 30 mg/day, in the absence of STP). Both the 
mg/kg and maximum dose were modified to ensure the best match of exposure in young 
children (0.5 mg/kg/day) as well as to ensure that individual older patients did not have 
excursions in exposure (20 mg/day). 
4.1 
PART 1 
4.1.1 
INCLUSION CRITERIA 
Subjects meeting all of the following inclusion criteria may be enrolled into the study: 
1. Subject is male or non-pregnant, non-lactating female, age 2 to 35 years, inclusive as of 
the day of the Screening Visit.  Female subjects of childbearing potential must not be 
pregnant or breast-feeding. Female subjects of childbearing potential must have a 
negative urine or serum pregnancy test at screening. Subjects of childbearing or child-
fathering potential must be willing to use medically acceptable forms of birth control 
(see Section 4.4), which includes abstinence, while being treated on this study and for 
90 days after the last dose of study drug. 
2. Subject must have a diagnosis of Lennox-Gastaut syndrome, where seizures that result 
in drops are not completely controlled by current antiepileptic treatments. (Subjects 
without a formal diagnosis may still be enrolled at sponsor discretion if all other criteria 
are met.) 
3. Subjects must meet all of the following 4 criteria for Lennox-Gastaut syndrome, as 
defined in this protocol: 
a. Onset of seizures at 11 years of age or younger. 
b. Multiple seizure types (must include TS or TA), including countable motor 
seizures that result in drops. Countable motor seizure types eligible for inclusion 
are: GTC, TS, CS, AS, FS with observable motor symptoms, and MS that result 
in a drop.  
c. Abnormal cognitive development. 
d. Evidence of EEG in the medical history that shows abnormal background 
activity accompanied by slow spike and wave pattern <2.5 Hz. (Acceptable 
evidence includes a copy of the EEG trace, EEG report, or physician note that 
appropriately describes the EEG findings.) 
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4. Subject must have had at least 8 drop seizures in the last 4 weeks prior to Screening 
(minimum of 4 drop seizures in the first two weeks and 4 in the last two weeks before 
baseline), by parent/guardian report to investigator or investigator medical notes 
5. Receiving at least 1 concomitant AED and up to 4 concomitant AEDs, inclusive. KD 
and VNS are permitted but do not count towards the total number of AEDs.  Rescue 
medications for seizures are not counted towards the total number of AEDs. 
6. All medications or interventions for epilepsy (including KD and VNS) must be stable 
for at least 4 weeks prior to screening and are expected to remain stable throughout the 
study. 
7. Subject has been informed of the nature of the study and informed consent has been 
obtained from the legally responsible parent/guardian. 
8. Subject has provided assent in accordance with Institutional Review Board (IRB)/Ethics 
Committee requirements, if capable. 
9. Subject’s parent/caregiver is willing and able to be compliant with diary completion, 
visit schedule and study drug accountability. 
4.1.2 
EXCLUSION CRITERIA 
Subjects who meet any of the following exclusion criteria must not be enrolled into the study: 
1. Subject has a known hypersensitivity to fenfluramine or any of the excipients in the 
study medication. 
2. Subject’s etiology of seizures is a degenerative neurological disease.  
3. Subject has a history of hemiclonic seizures in the first year of life. 
4. Subject only has drop seizure clusters, where individual seizures cannot be counted 
reliably. 
5. Subject has pulmonary arterial hypertension. 
6. Subject has current or past history of cardiovascular or cerebrovascular disease, such as 
cardiac valvulopathy, myocardial infarction or stroke, or clinically significant structural 
cardiac abnormality, including but not limited to mitral valve prolapse, atrial or 
ventricular septal defects, patent ductus arteriusis (note: Patent Foramen Ovale or a 
bicuspid valve are not considered exclusionary). 
7. Subject has current or recent history of Anorexia Nervosa, bulimia, or depression within 
the prior year that required medical treatment or psychological treatment for a duration 
greater than 1 month. 
8. Subject has a current or past history of glaucoma. 
9. Subject has had an anoxic episode requiring resuscitation within 6 months of the 
Screening Visit. 
10. Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild 
hepatic impairment (elevated liver enzymes < 3x ULN and/or elevated bilirubin <2x 
ULN) may be entered into the study after review and approval by the Medical Monitor 
in conjunction with the sponsor, in consideration of comorbidities and concomitant 
medications. 
11. Subject has severe renal impairment (estimated glomerular filtration rate 
<30mL/min/1.73m2) 
12. Subject is receiving concomitant therapy with: centrally-acting anorectic agents; 
monoamine-oxidase inhibitors; any centrally-acting compound with clinically 
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appreciable amount of serotonin agonist or antagonist properties, including serotonin 
reuptake inhibition; other centrally-acting noradrenergic agonists, including 
atomoxetine; or cyproheptadine (see Appendix 1 for a list of prohibited medications). 
(Note: Short-term medication requirements for prohibted medications will be handled 
on a per case basis by the Medical Monitor.) 
13. Subject has positive result (as defined in the laboratory manual) on urine or serum 
tetrahydrocannabinol (THC) Panel or whole blood cannabidiol (CBD) at the Screening 
Visit. 
14. Subject is taking felbamate for less than 1 year prior to screening and/or does not have 
stable liver function and hematology laboratory tests, and/or the dose has not been 
stable for at least 60 days prior to the Screening Visit. 
15. Subject is known to be human immunodeficiency virus (HIV) positive. 
16. Subject is known to have active viral hepatitis (B or C).. 
17. Subject is currently receiving an investigational product. 
18. Subject has participated in another clinical trial within the past 30 days (calculated from 
that study’s last scheduled visit). Participation in non-treatment trials will be reviewed 
by the Medical Monitor. 
19. Subject is at imminent risk of self-harm or harm to others, in the investigator’s opinion, 
based on clinical interview and responses provided on the Columbia-Suicide Severity 
Rating Scale (C-SSRS).  Subjects must be excluded if they report suicidal behavior in 
the past 6 months as measured by the C-SSRS at Screening or Baseline, which includes 
suicidal ideation with intent and plan (Item #5). If a subject reports suicidal ideation on 
Item 4 without specific plan, and the investigator feels that the subject is appropriate for 
the study considering the potential risks, the investigator must document 
appropriateness for inclusion, and discuss with the parent/caregiver to be alert to mood 
or behavioral changes, especially around times of dose adjustment. 
20. Subject is unwilling or unable to comply with scheduled visits, drug administration 
plan, laboratory tests, other study procedures, and study restrictions.  
21. Subject is institutionalized in a general nursing home (ie, in a facility that does not 
provide skilled epilepsy care). 
22. Subject does not have a reliable caregiver who can provide seizure diary information 
throughout the study. 
23. Subject has a clinically significant condition, including chronic obstructive pulmonary 
disease, interstitial lung disease, or portal hypertension, or has had clinically relevant 
symptoms or a clinically significant illness in the 4 weeks prior to the Screening Visit, 
other than epilepsy, that would negatively impact study participation, collection of 
study data, or pose a risk to the subject. 
4.2 
RANDOMIZATION INCLUSION CRITERIA 
Subjects must meet all of the inclusion criteria and none of the exclusion criteria 
above and meet the following criteria in order to be randomized: 
1. Subject has been approved for study inclusion by the Epilepsy Study Consortium. 
2. Subject does not have an exclusionary cardiovascular or cardiopulmonary abnormality 
based on ECHO, ECG or physical examination and is approved for entry by the central 
cardiac reader.  Exclusionary abnormalities include, but are not limited to: 
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a. Trace or greater mitral or aortic valve regurgitation in subjects <18 years of age 
b. Mild or greater mitral or aortic valve regurgitation in subjects >18 yrs of age 
c. Possible signs of pulmonary hypertension with abnormal or greater than upper 
range of normal values 
d. Evidence of left ventricular dysfunction (systolic or diastolic) 
3. Subject demonstrates a stable baseline with ≥ 2 seizures per week resulting in 
drops during the 4-week Baseline Period. 
4. Subject’s parent/caregiver has been compliant with diary completion during 
the Baseline Period, in the opinion of the investigator and sponsor. 
4.3 
PART 2 
To be included in Part 2: 
1. Subjects must continue to meet the Selection Criteria for Part 1 (except for criteria 
related to seizure frequency). If a subject entering Part 2 does not meet Randomization 
Criteria 2 regarding cardiovascular abnormalities, Section 8.9.1 Follow-up of 
Cardiovascular Findings will be applied to determine eligibility to continue into Part 2. 
2. All subjects must have satisfactorily completed Part 1 of the study in the opinion of the 
investigator and the sponsor. 
3. Review of inclusion and exclusion criteria and written informed parental or guardian 
consent and assent of minors (if the subject is capable of providing assent) for Part 2 
must be obtained before a subject can start any of the Part 2 Visit 15 procedures. 
4. Subjects must, in the medical opinion of the Investigator, be candidates for continued 
treatment for an extended period of time with ZX008. Candidates for continuous 
treatment should not meet Discontinuation criteria listed in Section 4.5 and should not 
meet the following criteria: 
• 
Clinically meaningful worsening of seizures, judged by Investigator or 
subject/caregiver such that treatment outside of the protocol and other than 
ZX008 is assumed to be in the subject’s best interest. A clinically meaningful 
worsening is an increase in frequency, severity or duration of existing seizures, 
or (in some cases) emergence of a new seizure type. Frequent or increased use 
of rescue medication may be considered indicative of worsening. 
• 
Clinically significant clinical laboratory findings (e.g. elevated ALT levels, 
decrease in platelet count, etc. that are CTCAE Grade 3 or higher) in subjects 
with no prior relevant history, that were not present during Baseline, are 
confirmed by a repeat test within a week, and not attributable to other 
concomitant medications. 
• 
Weight loss >15% during the T+M period that has not stabilized and is 
considered, in the opinion of the Investigator, detrimental to continuing 
treatment with ZX008.  
5. Those subjects who do not complete the 12-week Maintenance Period of Part 1 may, on 
a case-by-case basis, be eligible for entrance after consideration of the circumstances of 
the early termination and the potential benefit-risk of continued participation in a 
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ZX008 trial. The decision whether to permit participation in Part 2 for subjects who do 
not complete Part 1 resides solely with the sponsor, will require a formal request for 
early Part 2 continuation to be made by the Investigator as well as an evaluation of 
risk/benefit. The Sponsor who may consult with the site investigator, the ICAB and/or 
the IDSMC, and take into consideration evidence of the following for approval: 
a. The subject is experiencing a worsening in condition that is not likely to be 
related to Part 1 treatment, in the opinion of the Investigator 
b. The subject has progressed at least half-way through Part 1 (i.e. Visit 8) 
c. The subject has been compliant with assessments and requirements of Part 1 
d. The subject does not exhibit other contraindications to initiating open-label 
treatment 
4.4 
SUBJECTS OF REPRODUCTIVE POTENTIAL 
Male subjects who are sexually active with a partner of childbearing potential must use, with 
their partner, a condom plus an approved method of highly effective contraception from the 
time of informed consent until 90 days after the last dose of study drug. 
The following methods are acceptable: 
x Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
x Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o oral 
o injectable 
o implantable intrauterine device 
o intrauterine hormone-releasing system 
x Surgical sterilization (vasectomy or bilateral tubal occlusion) 
Female subjects who are not of childbearing potential do not need to use any methods of 
contraception. A woman is considered of childbearing potential, unless they are at least 2 years 
post-menopausal or permanently sterile, or if she has not yet reached menarche. Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. 
Female subjects who are sexually active and are of childbearing potential must use, with their 
partner, an approved method of highly effective contraception from the time of informed 
consent until 90 days after the last dose of study drug. 
The following methods are acceptable: 
x Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation and a barrier method (ie, condom for male partner): 
o oral 
o intravaginal 
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o transdermal 
x Progestogen-only hormonal contraception associated with inhibition of ovulation and a 
barrier method (ie, condom for male partner):  
o oral 
o injectable 
o implantable intrauterine device 
o intrauterine hormone-releasing system 
x Surgical sterilization (vasectomy or bilateral tubal occlusion) 
Alternatively, true abstinence is acceptable when it is in line with the subject’s preferred and 
usual lifestyle. If a subject is usually not sexually active but becomes active, they, with their 
partner, they must comply with the contraceptive requirements detailed above. 
4.4.1 Sperm and Egg Donation 
Male subjects should not donate sperm and female subjects should refrain from egg donation 
for the duration of the study and for at least 90 days after the last day of study medication 
administration. 
4.4.2 Pregnancy 
Subjects will be instructed that if they/their partner become pregnant during the study this 
should be reported to the investigator. The investigator should also be notified of 
pregnancy occurring during the study but confirmed after completion of the study. In the 
event that a subject/subject’s partner is subsequently found to be pregnant after the 
volunteer is included in the study, then consent will be sought from the partner and, if 
granted, any pregnancy will be followed and the status of mother and/or child will be 
reported to the sponsor after delivery. Any subject reporting a pregnancy during the study 
will be withdrawn from the study drug by completing the taper schedule. All safety 
follow-up activities must be completed. 
4.5 
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT 
While subjects are encouraged to complete all study evaluations, subjects may voluntarily 
withdraw from the study for any reason at any time. They may be considered withdrawn if they 
fail to return for visits, or become lost to follow-up for any other reason. 
If premature withdrawal occurs for any reason, the investigator must make a genuine effort to 
determine the primary reason for a subject’s premature withdrawal from the study and record 
this information on the electronic case report form (eCRF). All subjects who withdraw from the 
study with an ongoing AE must be followed until the event is resolved or deemed stable. If a 
subject withdraws prematurely after dosing, all data to be collected prior to discharge from the 
clinical site should be collected at the time of premature discontinuation or at the scheduled 
discharge. 
For subjects who are lost to follow-up (ie, those subjects whose status is unclear because they 
failed to appear for study visits without stating an intention to withdraw), the investigator 
should show "due diligence" by documenting in the source documents the steps taken to 
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contact the subject (eg, dates of telephone calls, registered letters). 
Subjects must be discontinued from the study for the following reasons, if deemed appropriate 
by the sponsor or investigator: 
1. Development of signs or symptoms indicative of cardiac valvulopathy or regurgitation 
(mitral, aortic, tricuspid, pulmonary valves), or pulmonary hypertension for which 
IDSMC, in consultation with cardiac readers and the investigator believe the benefit 
of continued participation does not outweigh the risk. 
2. Subject is found to have entered the clinical investigation in violation of the protocol. 
3. Subject requires or starts using unacceptable or contraindicated 
concomitant medications, or currently utilized chronic daily seizure 
therapy is changed. 
4. Subject’s condition changes after entering the clinical investigation so that the subject 
no longer meets the inclusion criteria or develops any of the exclusion criteria. 
5. Subject is noncompliant with procedures set forth in the protocol in an ongoing 
or repeated manner. 
6. Subject experiences an AE that warrants withdrawal from the clinical investigation. 
7. Clinically significant worsening of seizures, judged by investigator or subject/caregiver 
such that treatment outside of the protocol and other than ZX008 is assumed to be in 
the subject’s best interest. Frequent or increased use of rescue medication may be 
considered indicative of worsening. 
8. An “actual suicide attempt” as classified by the Columbia-Suicide Severity Rating 
Scale (C-SSRS). 
9. It is the investigator’s opinion that it is not in the subject’s best interest to continue in 
the study. 
10. Subject is found to be pregnant while on study. Subject will be withdrawn following the 
taper schedule; all safety follow-up activities must be completed. 
Discontinuation decisions will be made at each participating site by the site investigator. 
Discontinuations due to development of cardiovascular or cardiopulmonary complications are 
to be made by the IDMSC. 
If feasible, the process of discontinuation should be discussed with the Medical Monitor. The 
decisions regarding the discontinuation of the investigational therapy, whether the study 
medication should be stopped immediately or tapered should be discussed with the Medical 
Monitor, but final decisions about the process will remain at the discretion of the site principal 
investigator. 
Subjects who are discontinued from the clinical investigation for any reason will not be 
replaced. 
Subjects may withdraw their consent to participate in the study at any time without having to 
justify the reason for doing so. The decision to withdraw consent and discontinue participation 
in the study will not prejudice the subject’s future medical treatment in any way.  
Subjects must be discontinued from receiving ZX008 and/or participating in any further study 
procedures under the following circumstances: 
x The subject or the subject’s legally authorized representative wishes to discontinue 
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participation in the study. 
x The investigator advises that the subject’s safety or well-being could be compromised by 
further participation in the study. 
x The sponsor requests that a subject discontinues participation in the study (eg, due to 
suspicion of fraud, multiple enrollments in clinical studies, lack of compliance). 
In the event that the study is terminated prematurely then the procedure for termination should 
be followed as described in Section 3.7. Concern for the interests of the subject will always 
prevail over the interests of the study. 
The reason for, and date of discontinuation from participation in the study must be recorded in 
detail in the eCRF and in the subject’s medical records (eg, AEs, lack of compliance, lost to 
follow-up, etc). If possible, the subject/subject’s legally authorized representative should 
confirm his decision in writing. 
The investigator will attempt to complete all procedures usually required at the end of the study 
at the time when the subject’s participation in the study is discontinued or as close as possible 
to that time. Specific procedures required for each Part of the study are described in Section 
6.1.2.9 and Section 6.2.4. As far as possible, a complete final examination must be performed 
on all subjects who do not complete the study according to the study protocol. 
Data collected until the time a subject discontinues participation in the study will be handled in 
the same manner as data for subjects completing the study. Where possible, further information 
will be collected if any AEs are experienced by a subject after discontinuing participation in the 
study. 
4.6 
TERMINATION OF THE CLINICAL STUDY 
If the investigator, the sponsor, the Medical Monitor, or the IDSMC becomes aware of 
conditions or events that suggest a possible hazard to subjects if the clinical study continues, 
then the clinical study may be terminated. The decision to terminate the study lies  solely with 
the sponsor. The clinical study may be terminated at the sponsor’s discretion at any time also in 
the absence of such a finding. 
Conditions that may warrant termination of the clinical study include, but are not limited to: 
x The discovery of an unexpected, relevant, or unacceptable risk to the subjects enrolled in 
the clinical study. 
x Failure to enroll subjects at the required rate. 
x A decision of the sponsor to suspend or discontinue development of ZX008. 
4.7 
REPLACEMENT OF SUBJECTS 
Enough subjects will be enrolled in Part 1 of the trial to ensure that approximately 250 
subjects are randomized into the T+M Period of Part 1 Cohort A, and at least 30 subjects 
are randomized into Part 1 Cohort B.  Randomized subjects will not be replaced. 
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5. 
INVESTIGATIONAL MEDICINAL PRODUCT INFORMATION 
ZX008/matching placebo will be administered in the current study. A brief description of the 
ZX008 product is provided below (Table 4). 
Table 4: 
Investigational Medicinal Product – ZX008 
 
Study Product 
 
Substance Code 
ZX008 
 
Active Substance (INN) 
Fenfluramine Hydrochloride 
 
Trade Name 
Not applicable 
 
Formulation (including dosage form and strength) 
Solution 1.25, 2.5, and 5 
mg/mL Route/Mode of Administration 
Oral 
 
Manufacturer 
PCI Pharma Services on behalf of Zogenix 
  
International Limited 
 
 
5.1 
IDENTITY OF INVESTIGATIONAL MEDICINAL PRODUCT 
ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 
and provided in concentrations of 1.25 mg/mL, 2.5 mg/mL, and 5 mg/mL. The excipients 
selected have been approved for use in the formulations of currently marketed drug products 
and are considered to be safe. The solution formulations will be suitably flavored, and will 
contain preservatives and a thickening agent. The product is sugar free and is intended to be 
compatible with a KD. 
The formulation for Part 1 will be provided in bottles with tamper-evident, child-resistant 
caps. The clinical trials material will be supplied in 1 bottle size with nominal fill volume 
of 120 mL. Matching placebo also will be provided.  Doses to be studied include ZX008 
0.2 mg/kg/day and ZX008 0.8 mg/kg/day divided into two daily (BID) doses, up to a 
maximum of 30 mg/day (subjects taking concomitant STP will receive 0.5 mg/kg/day, up 
to a maximum of 20 mg/day, or equivalent volume of placebo). An intermediate dose of 
0.4 mg/kg/day will be used for titration. The concentration of ZX008 oral solution received 
by subjects (1.25 mg/mL, 2.5 mg/mL, and/or 5 mg/mL) will be randomized across the 3 
available concentrations in order to ensure blinding. 
For Part 2 flexible dosing will be studied, up to 0.8 mg/kg/day divided into two daily 
doses, up to a maximum of 30 mg/day (subjects taking concomitant STP will receive up to 
0.5 mg/kg/day, up to a maximum of 20 mg/day).  ZX008 drug product will be provided in 
a concentration of 2.5 mg/mL in 1 bottle size with nominal fill volume of 120 mL. 
5.1.1 
Labeling and Packaging 
The ZX008 product will be packaged and labeled according to current International Conference 
on Harmonization (ICH), Good Manufacturing Practices (GMP), and Good Clinical Practices 
(GCP) guidelines, and national legal requirements. 
Dosing directions for the product can be found in the Pharmacy Manual for the study 
subjects and for the investigator. 
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5.2 
DESCRIPTION OF REFERENCE TREATMENT, 
COMPARATOR, AND/OR PLACEBO 
Placebo solution is identical in aspect and composition to ZX008 and is composed of identical 
ingredients used in the ZX008 formulation, except that it does not contain the active ingredient, 
fenfluramine hydrochloride.  Subjects randomized to placebo will receive concentration 
equivalent volumes of investigational product that does not include the active ingredient. 
No comparators or reference treatments will be used. 
5.2.1 
Labeling and Packaging 
Placebo solution will be packaged in an identical manner to ZX008. The matching placebo 
product will be packaged and labeled according to current ICH, GMP, and GCP guidelines, and 
national legal requirements. 
Dosing directions for the product can be found in the IMP handling instructions for the study 
subjects and for the investigator. 
5.3 
SHIPMENT AND STORAGE 
IMP will be supplied to the study sites by the sponsor or its delegate. 
All IMP will be transported, received, stored, and handled strictly in accordance with the 
container or product label, the instructions supplied to the research site and its designated 
pharmacy, the site’s standard operating procedures, and applicable regulations. IMP must be 
stored separately from normal hospital or practice inventories, in a locked facility with access 
limited to the investigator and authorized personnel. The investigator must ensure that the IMP 
is dispensed only to subjects enrolled in this study according to this study protocol. 
Appropriate storage temperature and transportation conditions will be maintained for the study 
drug from the point of manufacture up to delivery of the study drug. Study medication must be 
stored at 15-25°C (59-77°F) with excursions of 5-40°C (41-104°F) permitted; do not refrigerate 
or freeze. 
Storage and handling instructions of the IMP maintained at the subject’s home are described in 
the subject’s IMP handling instructions. 
All unused IMP will be saved by the site for final disposition according to the sponsor’s 
directive. 
5.4 
IMP ACCOUNTABILITY 
The investigator or delegate will confirm receipt of all shipments of the IMP in writing using 
the receipt form(s) provided by the sponsor or vendor. 
Assignment of ZX008 or placebo to the subject will be handled through an interactive voice 
randomization (IVR) or Interactive Web Response (IWR) platform. The investigator or 
delegate will be required to register the subject through IVR/IWR and all study medication will 
be assigned to the subject through the IVR/IWR. The IVR/IWR will also maintain a log of all 
received and dispensed medication. 
All supplies must be accounted for throughout the study using the drug accountability form 
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provided by the sponsor before the start of the study. Drug accountability is the process of 
documenting all aspects of IMP receipt, storage, use, and disposition so that a full accounting 
of each unit can be made.  This includes administration, and return and/or destruction of IMP. 
At the end of the study, the dated and signed (by the investigator or delegate, eg, pharmacist) 
original drug accountability form must be retained at the study site as verification of final 
drug accountability. 
Records for the delivery of the IMP to the study site, the inventory at the study site, the use by 
each subject (use by subject will be documented in the subject diary), and the destruction or 
return of the IMP to the sponsor must be maintained by the investigator (or delegate). The 
records will include dates, quantities, batch numbers, and unique code numbers assigned to the 
IMP and to the subjects. The investigator must maintain records documenting that subjects 
were provided with the doses of the IMP specified in this study protocol. Furthermore, the 
investigator must reconcile all IMPs received from the sponsor. The investigator must provide 
reasons for any discrepancies in drug accountability. Forms will be provided by the sponsor to 
ensure standardized and complete drug accountability. 
5.5 
TREATMENT ADMINISTRATION 
5.5.1 
Part 1: Randomization 
Upon completion of the Baseline Period in Part 1, subjects who qualify for the study will be 
randomized (1:1:1) in a double-blind manner to receive 1 of 2 doses of ZX008 (0.2 mg/kg/day, 
0.8 mg/kg/day; 30mg/day maximum [0.5 mg/kg/day; 20 mg/day maximum for subjects taking 
concomitant STP]) or placebo. The randomization will be stratified by weight (<37.5 kg, ≥37.5 
kg) to ensure balance across treatment arms, with a target of at least 25% in each weight group. 
Subjects will be assigned a randomization number by the IWR system upon confirmation that 
subject qualifies for enrollment in the Titration Period. Once a randomization number is 
assigned to a subject, the site will record the subject’s initials and identification number on the 
corresponding study drug bottles. Each bottle will contain the appropriate concentration and 
volume of liquid to administer the assigned treatment (ZX008 0.2 mg/kg/day, ZX008 0.8 
mg/kg/day [or 0.5 mg/kg/day for subjects taking concomitant STP], or placebo). ZX008 and 
placebo will be identical, thus rendering the study drug and placebo indistinguishable. For each 
IMP bottle and randomization number assigned, the following information will be recorded on 
the drug accountability form: subject initials, unique bottle number, date each bottle is 
assigned, and drug used and unused during the study. 
5.5.1.1 
Blinding 
The blinding scheme instituted for this study will ensure that the volume of study medication 
taken cannot be associated with the dose group, thus unblinding the study. This is achieved by 
random assignment of different concentrations of the ZX008 oral solution (1.25 mg/mL, 
2.5 mg/mL, and/or 5 mg/mL) by the IWR system. The IWR system will instruct site personnel 
to the volume of oral solution to be administered based on that subject’s weight. (Dose will be 
recalculated by the system based on weight once at the midpoint of the study.) During the 
Titration, Maintenance, and Taper/Transition Periods, the subjects and study personnel 
(investigators, clinical staff, personnel involved in data collection and analysis, the Medical 
Monitor, and the sponsor) will be blinded to the treatment allocation and to the concentration of 
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ZX008 oral solution. If an investigator feels the blind should be broken, he/she can do so when 
necessary for treatment decisions. However, the investigator should endeavor to discuss with 
the Medical Monitor or Sponsor’s Medical Representative, if available. The blind should only 
be broken in the event the knowledge of whether the subject is on active study medication 
versus placebo is needed to determine course of medical treatment for the event. The subject 
will be discontinued from the clinical trial upon breaking of the blind and the decision whether 
the subject can enter Part 2 will rest with the Sponsor if the subject exited Part 1 prior to 
completion. 
5.5.2 
Part 1: Titration Period 
The investigator (or delegate) will dispense IMP only to subjects included in Part 1 of 
this study following the procedures set out in this study protocol. Subjects will be 
required to stay in the clinic for monitoring of adverse reactions until the investigator 
determines it is safe to leave. Those considered by the investigator to need further 
monitoring will be hospitalized until the investigator determines they can be safely 
discharged. 
Study medication will be administered as equal doses BID in the morning and in the evening 
approximately 12 hours apart. Each dose should be separated by a minimum of 8 hours and a 
maximum of 12 hours. A missed dose of study medication may be taken later up to 8 hours 
before the next scheduled dose; otherwise, the missed dose should not be given. 
If the parent/caregiver is unable to administer the full dose due to spillage (eg, dose was spilled 
during measuring, subject spit dose out during administration), he/she should attempt to give 
the full dose noting the extra amount used to fulfill the dose. If the subject vomits within the 
first 15 minutes of administration the dose may be readministered. Care must be taken not to 
overdose. If the amount spilled is not known, the parent/caregiver should not give additional 
medication to avoid potential overdose. 
Administration of the IMP will be based on the randomized dose and subject’s weight (kg) at 
Visit 3 (Part 1; Study Day -1). At Visit 8 (Part 1; Study Day 43), if the subject’s weight (kg) 
has changed ±25% of the weight at Part 1; Study Day-1, the IMP dose will be recalculated. 
Subjects should be dosed using the oral dosing syringe provided. 
In order to maintain the blind across all dose groups in Part 1 (Section 5.5.1.1) and allow step 
titration to the high dose, the dose for each subject will be titrated starting with a dose of 
ZX008 0.2 mg/kg/day (or placebo equivalent) BID. After 4 days at this dose level (Study Day 
5), subjects randomized to the ZX008 0.8 mg/kg/day (or 0.5 mg/kg/day for subjects taking 
concomitant STP) group will increase their dose to 0.4 mg/kg/day (maximum 30 mg/day or 20 
mg/day for subjects taking concomitant STP) while doses in the other two groups will remain 
constant. On Study Day 9, the dose for the 0.8 mg/kg/day group (or 0.5 mg/kg/day for 
subjects taking concomitant STP) will increase to the target dose or a maximum of 30 mg/day 
(or 20 mg/day for subjects taking concomitant STP). The titration is expected to take a total of 
14 days (Table 5). A new bottle of IMP will be started by the subject at each level of the 
titration step. See Section 5.1 for more information about the volume of ZX008 or placebo to 
be administered.  If a subject does not tolerate IMP during titration, slower titration may be 
considered after consultation with the Medical Monitor. 
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Table 5: 
Titration Algorithm for Part 1 
 
Randomized Group 
Titration Step 1 
Study Day 1-4 
Titration Step 2 
Study Days 5-8 
Titration Step 3 
Study Days 9-14 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.8 mg/kg/day 
(0.5 mg/kg/day for subjects 
taking concomitant STP) 
ZX008 0.2 mg/kg/day 
ZX008 0.4 mg/kg/day 
ZX008 0.8 mg/kg/day  
(0.5 mg/kg/day for subjects 
taking concomitant STP) 
Placebo 
Placebo 
Placebo 
Placebo 
Note: maximum daily dose of ZX008 is 30 mg (20mg for subjects taking concomitant STP) 
 
5.5.3 
Part 1: Maintenance Period 
After completion of the Titration Period, subjects will enter the Maintenance Period and 
continue to receive the randomized dose of ZX008 or placebo and be treated for an additional 
12 weeks. Study medication will continue to be administered BID in the morning and in the 
evening, approximately 12 hours apart. Each dose should be separated by a minimum of 8 
hours and a maximum of 12 hours. A missed dose of study medication may be taken later up 
to 8 hours before the next scheduled dose; otherwise, the missed dose should not be given. 
5.5.4 
Part 1: Taper Period (for subjects not entering Part 2) 
Subjects who complete the Maintenance Period and will not be continuing into Part 2, the 
open-label extension, and subjects who discontinue from Part 1 early, will be tapered off of 
study medication.  Study medication will be administered as equal doses BID in the morning 
and in the evening approximately 12 hours apart. Each dose should be separated by a minimum 
of 8 hours and a maximum of 12 hours. A missed dose of study medication may be taken later 
up to 8 hours before the next scheduled dose; otherwise, the missed dose should not be given. 
IMP should be administered using the oral dosing syringe provided. 
If the parent/caregiver is unable to administer the full dose due to spillage (eg, dose was spilled 
during measuring, subject spit dose out during administration), he/she should attempt to give 
the full dose noting the extra amount used to fulfill the dose. If the subject vomits within the 
first 15 minutes of administration the dose may be readministered. Care must be taken not to 
overdose. If the amount spilled is not known, the parent/caregiver should not give additional 
medication to avoid potential overdose. 
In order to maintain the blind across all dose groups, all subjects who do not continue into Part 
2 will participate in a blinded dose-tapering procedure over the course of 8 days. On the first 
day of the tapering period subjects in the ZX008 0.8 mg/kg/day group (or 0.5 mg/kg/day for 
subjects taking concomitant STP) will decrease to a dose of ZX008 0.4 mg/kg/day BID 
(maximum 30 mg/day or 20 mg/day for subjects taking concomitant STP). After 4 days at this 
dose level (Study Day 5), subjects in this group will decrease their dose to 0.2 mg/kg/day. 
Subjects in the ZX008 0.2 mg/kg/day group will decrease their dose to placebo on the first day 
of tapering while doses in the placebo group will remain constant throughout the tapering 
procedure. On Study Day 9, all subjects will stop taking study medication. The taper is 
expected to take a total of 8 days (Table 6). A new bottle of IMP will be started by the subject 
at each level of the taper step. 
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Table 6: 
Taper Algorithm for Part 1 
 
 
Randomized Group 
Taper Step 1 
Day 1-4 after study completion or 
early termination 
Taper Step 2 
Days 5-8 after study completion or 
early termination 
ZX008 0.2 mg/kg/day 
Placebo 
Placebo 
ZX008 0.8 mg/kg/day 
(0.5 mg/kg/day for subjects 
taking concomitant STP) 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
Placebo 
Placebo 
Placebo 
Note:  maximum daily dose of ZX008 is 30 mg. (20mg for subjects taking concomitant STP) 
 
5.5.5 
Part 1: Transition Period 
Subjects who complete the Maintenance Period and will be continuing into the open-label 
extension (Part 2) will be transitioned from double-blind study medication to open-label ZX008 
(Table 7).  
All subjects entering the open-label extension (Part 2) will be transitioned from their blinded 
daily dose to the 0.2 mg/kg dose during the 2-week interval between Visits 12 and 15, without 
breaking the blind. The IWR system will assign two bottles of IMP to the subject, one for each 
step in the transition. A new bottle of IMP will be started by the subject at each level of the 
transition step. See Section 5.1 for more information about the volume of ZX008 or placebo to 
be administered. 
Table 7: 
Transition Algorithm for Part 1 
Dose Group in Double-
Blind Study 
Transition Step 1 
Day 1-4 after Visit 12 
Transition Step 2 
Days 5-14 after Visit 12 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.8 mg/kg/day 
(0.5 mg/kg/day for subjects taking 
concomitant STP) 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
Placebo 
ZX008 0.2 mg/kg/day 
ZX008 0.2 mg/kg/day 
Note: maximum daily dose of ZX008 is 30 mg (or 20 mg for subjects taking concomitant STP). 
 
Subjects who had been randomized to placebo increase their dose to 0.2 mg/kg/day beginning 
on Day 1 of the transition. The first dose should be taken in the clinic during Visit 12. Subjects 
will be required to stay in the clinic for monitoring of adverse reactions until the investigator 
determines it is safe to leave. Those considered by the investigator to need further monitoring 
will be hospitalized until the investigator determines they can be safely discharged. Subjects 
who had been randomized to 0.2 mg/kg/day will continue to receive that dose. Subjects who 
had been randomized to 0.8 mg/kg/day or were receiving the maximum dose of 30 mg/day (or 
subjects taking concomitant STP and randomized to 0.5 mg/kg/day; 20 mg/day maximum) 
decrease to a dose of ZX008 0.4 mg/kg/day, or a maximum of 30 mg/day (20 mg/day for 
subjects taking concomitant STP). After 4 days at this dose level (Day 5), these subjects will 
decrease their dose to 0.2 mg/kg/day. Subjects will report to the clinic on Day 14 for enrollment 
into the open-label extension. 
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Study medication will be administered as equal doses BID in the morning and in the evening 
approximately 12 hours apart. Each dose should be separated by a minimum of 8 hours and a 
maximum of 12 hours. A missed dose of study medication may be taken later up to 8 hours 
before the next scheduled dose; otherwise, the missed dose should not be given. Study 
medication should be administered using the oral dosing syringe provided. 
If the parent/caregiver is unable to administer the full dose due to spillage (eg, dose was spilled 
during measuring, subject spit dose out during administration), he/she should attempt to give the 
full dose noting the extra amount used to fulfill the dose. If the subject vomits within the first 15 
minutes of administration the dose may be readministered. Care must be taken not to overdose. If 
the amount spilled is not known, the parent/caregiver should not give additional medication to 
avoid potential overdose. 
5.5.6 
Part 2: OLE Treatment Period 
During the Part 2 OLE Treatment Period, all subjects will be treated initially with 0.2 mg/kg/day 
for 1 month to assess effectiveness of this dose in all study subjects. After 1 month at a dose of 
ZX008 0.2 mg/kg/day, the investigator may adjust the dose of each subject based on 
effectiveness and tolerability.  
Administration of the initial IMP will be based on the 0.5 mg/kg/day (maximum 30 mg/day or 20 
mg/day for subjects taking concomitant STP) dose and subject’s weight recorded for Visit 15 
(Part 2; Study Day 1). At Visits 19, 20, and 21 of Part 2 (Months 3, 6, and 9), if the subject’s 
weight has changed ± 25% of the weight  recorded for Visit 15, the IMP dose will be 
recalculated. Subjects will be dosed using the oral dosing syringe provided. 
Dose increases should not occur earlier than every 14 days at each dose level. Dose increases 
may only occur after a review of the diary and reported AEs, and if, in the investigator’s opinion, 
seizure frequency, severity, and/or duration indicates a change in medication regimen is 
warranted. Temporary dose decreases for tolerability can occur at the investigator’s discretion, in 
dose amounts and frequency appropriate for the situation. Subsequent dose rechallenge should 
occur at the investigator’s discretion in consultation with the Medical Monitor.  ZX008 dose 
adjustments outside of these parameters should be discussed with the Medical Monitor and must 
be approved by the Sponsor prior to initiation.  
If after approximately the midway point of the first 30 days on ZX008 0.2 mg/kg/day there is a 
clinically meaningful worsening in seizure type, frequency, and/or duration compared with the 
recent treatment in the core study, the investigator, in consultation with the Medical Monitor and 
approval of the sponsor, may increase the dose to 0.4 mg/kg/day (maximum 30 mg/day or 20 
mg/day for subjects taking concomitant STP). A clinically meaningful worsening would be an 
increase in frequency, severity or duration of existing seizures, or (in some cases) emergence of a 
new seizure type. The description of clinical worsening must be documented in the source notes 
and case report form (CRF). Further increase to 0.8 mg/kg/day (maximum 30 mg/day or 0.5 
mg/kg/day; maximum 20 mg/day for subjects taking concomitant STP) could also be undertaken 
for the same conditions after a minimum of 4 days on 0.4 mg/kg/day, if the condition has not 
stabilized on the 0.4 mg/kg/day dose. Dosing outside of the specified range (ie, up to 0.8 
mg/kg/day [or 0.5 mg/kg/day for subjects taking concomitant STP]) may be considered after 
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consultation between the investigator and Medical Monitor and approval of the Sponsor; 
however, excursions over 30 mg/day (or 20 mg/day for subjects taking concomitant STP) are 
prohibited. 
Study medication will be administered as equal doses BID in the morning and in the evening, 
approximately 12 hours apart. Each dose should be separated by a minimum of 8 hours and a 
maximum of 12 hours. A missed dose of study medication may be taken later up to 8 hours 
before the next scheduled dose; otherwise, the missed dose should not be given. 
If the parent/caregiver is unable to administer the full dose due to spillage (eg, dose was spilled 
during measuring, subject spit dose out during administration), he/she should attempt to give the 
full dose noting the extra amount used to fulfill the dose. If the subject vomits within the first 15 
minutes of administration the dose may be readministered. Care must be taken not to overdose. If 
the amount spilled is not known, the parent/caregiver should not give additional medication to 
avoid potential overdose. 
5.5.7 
Taper Period 
All subjects (those who complete the Part 2 OLE Treatment Period and those who discontinue 
from the study early) will be tapered off of study medication, unless they are transitioning to 
commercial drug.  
The tapering scheme is a 2-step process as described in Table 8.  
Study medication will be administered as equal doses BID in the morning and in the evening, 
approximately 12 hours apart. Each dose should be separated by a minimum of 8 hours and a 
maximum of 12 hours. A missed dose of study medication may be taken later up to 8 hours 
before the next scheduled dose; otherwise, the missed dose should not be given. IMP will be 
administered using the oral dosing syringe provided.  
Table 8.  
Taper Algorithm for Part 2 
 
 
Current Dose 
Taper Step 1  
Days 1-4 after study 
completion or early 
termination 
Taper Step 2 
Days 5-8 after study completion 
or early termination 
ZX008 0.2 mg/kg/day 
Not applicable 
Not applicable 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
Not applicable 
ZX008 0.5 mg/kg/day 
(for subjects taking 
concomitant STP) 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.6 mg/kg/day 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.8 mg/kg/day  
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
Note:  maximum daily dose of ZX008 is 30 mg (or 20 mg for subjects taking concomitant STP). 
 
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5.6 
PRIOR AND CONCOMITANT MEDICATION 
All medications taken by a subject before receiving study medication (ie, during the Screening 
and Baseline Seizure Assessment Periods in Part 1) and stopped before the first administration of 
IMP are regarded as prior therapy and must be documented in the eCRF. Significant medications 
(eg, antibiotics) taken within 30 days prior to the Screening visit should also be captured. All 
prior and concomitant AEDs will be collected in the eCRF. 
All medications taken by a subject after the first administration of IMP, including those that 
started before the first administration of IMP and are continuing, are regarded as concomitant 
medication and must be documented in the eCRF, including over-the-counter medication, herbal 
and vitamin/supplement preparations.  
Subjects are required to take at least one concomitant AED during study participation. No new 
concomitant AEDs may be introduced while in this study without discussion with the Medical 
Monitor prior to initiation. Non-study medications and therapies (this does not include KD, VNS, 
and RNS) that are considered necessary for the subject’s welfare and will not interfere with the 
response to the study medication may be given at the discretion of the investigator, informing the 
Medical Monitor as soon as possible.  
It should be noted for any subject receiving hypoglycemic agents, the investigator should 
consider diabetic medication changes in the setting of weight loss and hypoglycemia. 
Part 1 
All subjects will continue to receive their existing AED(s) with the same doses throughout the 
Part 1 Double-blind Treatment Period. Every effort should be made to ensure that the regimen of 
existing medications remains stable during Part 1; any changes must be discussed with the 
sponsor prior to implementation. If a decrease in a concomitant AED is necessary to manage an 
AE, this must be discussed with the sponsor as soon as possible after implementation if not 
before implementation. Increases in dose or number of concomitant AEDs are not permitted 
during Part 1 of the study.   
Part 2 
During at least the first 6 months of the Part 2 OLE Treatment Period, subjects will continue to 
receive their existing AEDs at the same dose and frequency as prior to starting Part 2. However, 
once the subject has been stable on a ZX008 dose for at least 6 months with good seizure control, 
investigators will be allowed as per typical clinical practice to alter one or more other 
concomitant AED doses as deemed clinically appropriate. Subjects who achieve robust seizure 
control may be considered to decrease concomitant AEDs earlier than 6 months after 
review/discussion with the Medical Monitor and approval from the Sponsor. Concomitant AEDs 
may be withdrawn completely but all subjects must remain on a minimum of 1 concomitant 
AED plus ZX008. Addition of new concomitant AEDs must be discussed with and approved by 
the Medical Monitor prior to initiation. AED doses may be lowered for safety considerations at 
any time.  All medication dose changes must be documented with a clinical explanation and 
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justification. Concomitant AED dose adjustments outside of these parameters should be 
discussed with the Medical Monitor prior to initiation.   
5.6.1 
Vagal Nerve Stimulation 
Subjects receiving treatment with a VNS may be included as long as the VNS has been in place 
for at least 6 months prior to entry into the study, the VNS battery is not due for replacement 
during the study, and stimulation parameters have been kept constant for 4 weeks prior to 
screening and must remain so throughout the study. VNS may not be the only anti-epileptic 
treatment (ie, it does not count as an AED but it does count as a treatment for LGS).  The 
subject’s use of VNS will be recorded in the eCRF. 
During at least the first 6 months of the Part 2 OLE Treatment Period, VNS stimulation 
parameters will be kept constant. However, once the subject has been stable on a ZX008 dose for 
at least 6 months with good seizure control, investigators will be allowed as per typical clinical 
practice to alter VNS stimulation parameters as deemed clinically appropriate. All VNS 
stimulation parameter changes must be documented with a clinical explanation and justification. 
VNS stimulation parameter adjustments outside of these boundaries should be discussed with the 
Medical Monitor prior to initiation.  
5.6.2 
Ketogenic Diet 
Adherence to the KD, or a modified version of KD, is permitted during the study if the dietary 
habits were initiated more than 4 weeks prior to Screening and remain stable throughout the 
study. KD may not be the only anti-epileptic treatment (ie, it does not count as an AED but 
does count as a treatment for LGS). The subject’s use of KD will be recorded in the eCRF. 
During at least the first 6 months of the Part 2 OLE Treatment Period, the KD will be adhered to. 
However, once the subject has been stable on a ZX008 dose for at least 6 months with good 
seizure control, investigators will be allowed as per typical clinical practice to alter the KD as 
deemed clinically appropriate. All KD changes must be documented with a clinical explanation 
and justification. KD adjustments outside of these parameters should be discussed with the 
Medical Monitor prior to initiation. 
5.6.3 
Rescue Medication for Seizures 
The subject's usual or prescribed regimen and frequency of rescue therapy for seizures should 
be entered into the concomitant medication sections of the eCRF and identified as a rescue 
medication by selecting the appropriate box. 
Use of rescue medication is permitted during the study and should be recorded on the eCRF 
(day, medication[s], dose[s]) and in the diary (day, timeframe associated with seizure episodes). 
Repeated administrations within the same episode should be recorded separately. 
5.6.4 
Prohibited Concomitant Medications 
Examples of concomitant medications in the classes prohibited are listed in Appendix 1 and 
summarized below.  If medical necessity requires short-term use of one or more of these 
medications during the course of the study, please contact the Medical Monitor for approval. 
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x Felbamate is prohibited as a concomitant medication unless the subject has been on 
felbamate for at least 12 months prior to screening, has stable liver function and 
hematology laboratory tests, and the dose has been stable for at least 60 days prior to 
screening and is expected to remain constant throughout the study. 
x Products that contain cannabis and/or cannabinoids are prohibited for the duration of 
pariticpation in the study. 
x Drugs that interact with central serotonin: imipramine, monoamine oxidase inhibitors, 
selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, 
vortioxetine. 
x Drugs that increase cardiovascular risk: e.g. atomoxetine. 
x Drugs intended to facilitate weight loss. 
x Ergot alkaloids and their derivatives, including pergolide and cabergoline 
x Phenylpropanolamine and other decongestants may be used for short-term use only. 
5.7 
TREATMENT COMPLIANCE 
Each subject or parent/caregiver will record the dose, dosing frequency and IMP consumption 
in the subject’s diary. Subjects will bring their used, partially used, and unused IMP to every 
study visit. Treatment compliance will be monitored by measuring the volume of IMP in 
these bottles and comparing to the dispensation log and diary records. 
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6. 
VISIT SCHEDULE 
6.1 
Part 1 
Study procedures for the Part 1 Double-blind Treatment Period will be conducted 
according to the Schedule of Assessments in Table 1. Time windows for all assessments 
in Part 1 are detailed in Table 9 
 
Table 9: 
Time Windows for Assessments in Part 1 
Visit / Procedure 
Time window (relative to scheduled visit / procedure) 
Visit 1 (Clinic; Study Day -29 to -28 or -28 to -27): 
Not applicable 
Visit 2 (Phone; Study Day -15) 
± 3 days 
Visit 3 (Clinic; Study Day -1; Randomization) 
+ 4 daysa 
Visits 4, 5 (Phone: Study Days 4, 8) 
± 3 days 
Visit 6 (Clinic; Study Day 15) 
± 4 days 
Visit 7 (Phone: Study Day 29) 
± 4 days 
Visit 8 (Clinic; Study Day 43) 
± 4 days 
Visit 9 (Phone: Study Day 57) 
± 4 days 
Visit 10 (Clinic; Study Day 71) 
± 4 days 
Visit 11 (Phone: Study Day 85) 
± 4 days 
Visit 12 (Clinic: Study Day 99) 
± 4 days 
Visit 13 (Clinic; Study Day 113; post dosing) 
± 4 days 
Visit 14 (ECHO clinic; 3-6 months after last dose) 
+ 30 days 
Blood collection for ZX008 PK 
± 15 minutes 
AED=antiepileptic drug (s); ECHO=echocardiogram; PK = pharmacokinetics 
a 
In cases where the screening period is extended beyond 28 days, the immediate 28 days before the Randomization visit 
will be used to calculate the baseline seizure frequency 
 
6.1.1 
BASELINE PERIOD (STUDY DAY -28 TO STUDY DAY -1) 
The Baseline Period of the study encompasses the screening activities that will occur on 
Study Day -28 as well as the observation period where subjects will be assessed for baseline 
seizure activity based on recordings of daily seizure activity entered into a diary. 
6.1.1.1. 
Screening, Clinic Visit 1 (Study Day -28) 
Screening is the predetermined series of procedures with which each investigator selects an 
appropriate and representative sample of subjects for enrollment into the study. Select 
screening data will be documented in the IWR and eCRF. 
Written informed parental or guardian consent and assent of minors (if the subject is capable of 
providing assent) must be obtained before a subject can start any of the screening procedures. 
The procedure(s) for obtaining written informed consent and assent of minor (if the subject is 
capable of providing assent) are described in Section 11.2. 
The Screening visit will occur on Study Day -28; however, the procedures may be split over 
2 consecutive days (eg, Study Day -29 and Study Day -28 or Study Day -28 and Study Day -27). 
Splitting the visit procedures across 2 nonsequential days requires the approval of the medical 
monitor. The following procedures will be performed for all subjects before the start of seizure 
activity observation: 
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x 
Obtain written informed consent for the study 
x 
Obtain written informed consent from parent/caregiver to collect information about 
parent/caregiver symptoms and burden via the Zarit Caregiver Burden, and HADS 
rating 
x 
Review inclusion and exclusion criteria 
x 
Review retrospective seizure diary data 
x 
Record demographic information 
x 
Record medical, neurological, and epilepsy history 
x 
Record current epilepsy status (number/type/duration seizures per month); submit 
form to Epilepsy Study Consortium 
x 
Collect past 6 months (or available duration) of parent/caregiver seizure diary data 
if available (screen shots of cell phones are acceptable, as are photocopies of paper 
diaries or print outs) and place in source file 
x 
Record prior medications 
x 
Complete physical examination, including height and weight 
x 
Complete neurological examination 
x 
12-lead electrocardiogram 
x 
Doppler ECHO (this may be obtained any time between Study Day -28 and 
Study Day -15) 
x 
Vital signs 
x 
Urine or serum pregnancy test for females of child-bearing potential 
x 
Laboratory evaluation (serum chemistry, hematology, immunoglobulin, and 
urinalysis) 
x 
Urine or serum THC panel 
x 
Whole blood CBD 
x 
C-SSRS Baseline/Screening Assessment (Appendix 2) 
x 
Instruct parent/caregiver on use of diary 
x 
Dispense diary (after above procedures have been concluded; the 28-day period for 
determining baseline seizure frequency begins when screening assessments are 
completed and the seizure diary is dispensed) 
x 
Record AEs 
x 
Record AESIs 
Only eligible subjects as specified by the inclusion and exclusion criteria who are 
independently confirmed to be eligible by the Epilepsy Study Consortium will be enrolled into 
the study. 
After enrollment into the study, each subject will be issued a “Subject Card” containing 
information about the subject’s participation in the study. The subject or parent/caregiver will be 
advised to retain this card on his person for the entire duration of the study so that the investigator 
or the sponsor can be contacted in case of emergency. 
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In certain circumstances the sponsor may allow subjects who did not meet all inclusion/exclusion 
criteria at the time of the Screening Visit to have the screening period extended, or to be re-
screened for eligibility. In all cases the investigator should consult with the Medical Monitor. 
Decisions whether to permit rescreening resides solely with the sponsor.  
The decision whether to permit extended screening or rescreening can be influenced by many 
factors individual to that subject case. Some general principles apply: 
1. If baseline seizure screening is extended or the subject is discontinued and then rescreened, 
the screening period for establishing the baseline seizure frequency will be the immediate 
4 weeks before the randomization visit. 
2. Subjects who are found to be on a prohibited medication at the screening visit may be 
weaned off of that medication provided: 
a. Decisions to withdraw a disallowed concomitant medication must be made with 
the agreement of the prescribing physician 
b. If the medication has antiepileptic properties, a wash out of at least 5 half-lives 
must be completed before collection of baseline seizure data.  
c. If a decision has been made to wean off of a medication without antiepileptic 
properties and the washout period (at least 5 half-lives) is expected to be shorter 
than 3 weeks, then the subject may remain in screening and chart seizures using 
the seizure diary. 
3. 
If screening is extended, laboratory and ECHO assessments must be at least 6 weeks 
current at the time of Randomization. Assessments older than 6 weeks will need to be 
repeated prior to Randomization. If laboratory assessments are repeated within 2 weeks of 
Randomization, samples do not need to be collected during Visit 3, provided valid results 
are obtained. 
6.1.1.2. 
Phone Visit 2 (Study Day -15) 
Site personnel will contact the subject via telephone on Study Day -15 and record the 
following: 
x AEs 
x AESI 
In addition, site personnel with review the diary entries with the parent/caregiver. Ensure diary is 
being completed daily; if diary compliance is low (i.e. <90%), re-train parent/caregiver. 
6.1.1.3. 
Clinic Visit 3 (Study Day -1): Randomization 
This period is intended to ensure that subjects meet the study entry criteria and confirm they 
have experienced ≥ 2 seizures resulting in drops per week during the 4-week Baseline Period. 
Subjects must have at least 28 days of prospective diary data at Visit 3.  
The following procedures will be performed on Study Day -1: 
x 
Review inclusion and exclusion criteria 
x 
Review current seizure activity (number/type/duration) from diary since previous 
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visit and calculate the number of seizures resulting in drops per week and over the 
4-week observation period. 
x 
Ensure approval for enrollment has granted by the Epilepsy Study Consortium and 
after ECHO review (ERT). 
x 
Record prior medications since previous visit 
x 
Complete physical examination, including weight 
x 
Abbreviated neurological examination 
x 
Vital signs 
x 
12-lead ECG 
x 
Urine or serum pregnancy test for females of child-bearing potential 
x 
Laboratory evaluation (serum chemistry, hematology, immunoglobulin, hormones, 
coagulation,, and urinalysis (urine for urinalysis may be collected at home, the 
night before the clinic visit, as long as collection procedures are followed to 
maintain sample stability)) 
x 
Collect plasma sample for AED pharmacokinetic evaluation (must document time 
of last dose) 
x 
Urine or serum THC panel 
x 
Whole blood CBD 
x 
Obtain (optional) blood sample for epilepsy genotype panel (if not obtained at this 
visit, it should be obtained by Visit 12) 
x 
Tanner Staging for subjects >7 to 18 years of age (Appendix 5) 
x 
Collect, review, and dispense diary. Ensure diary is being completed daily; if diary 
compliance is low (i.e. <90%), re-train parent/caregiver. 
x 
C-SSRS Since Last Visit Assessment (Appendix 2) 
x 
BRIEF (Appendix 3) 
x 
QOLCE (Appendix 6) 
x 
HADS (Appendix 7) 
x 
Zarit Caregiver Burden Inventory (Appendix 8) 
x 
Record AEs 
x 
Record AESI 
x 
When eligibility for the Titration Period is confirmed, obtain treatment assignment 
from the IWR 
x 
Dispense and administer study medication. Subjects will be required to stay in the 
clinic for monitoring of adverse reactions until the investigator determines it is safe 
to leave. Those considered by the investigator to need further monitoring will be 
hospitalized until the investigator determines they can be safely discharged. The 
first dose taken in the clinic will be recorded in the eCRF, but not the subject diary, 
and the next dose should be at least 8 hours later or the following morning. The 
dose on the following morning will count as Study Day 1 and be recorded in the 
subject diary. 
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6.1.2 
TITRATION AND MAINTENANCE PERIODS 
6.1.2.1 
Titration Period Study Day 1 
Subjects will take their second dose of study medication on the morning of Study Day 1. Study 
Day 1 is considered the first day of dosing, even though subjects received an in-clinic dose on 
Study Day -1. 
6.1.2.2 
Phone Visits 4 and 5 (Titration Period Study Days 4 and 8) 
Site personnel will contact the subject via telephone on Titration Period Study Days 4 and 8 
and record the following: 
x AEs 
x AESI 
x Concomitant medications 
In addition, site personnel will review study medication dosing procedure and the diary entries 
with the parent/caregiver. 
6.1.2.3 
Clinic Visit 6 (Titration Period Study Day 15) 
Subjects will report to the clinic in the morning on Titration Period Study Day 15. The 
following procedures will be performed: 
x Review current seizure activity (number/type/duration) from diary since previous visit 
x Record concomitant medications 
x Obtiain weight 
x Obtain vital signs 
x Collect, review, and dispense diary. Ensure diary is being completed daily; if diary 
compliance is low (i.e. <90%), re-train parent/caregiver. 
x C-SSRS Since Last Visit Assessment (Appendix 2) 
x Clinical Global Impression – Improvement (assessed by parent/caregiver) 
x Clinical Global Impression – Improvement (assessed by investigator) 
x Record AEs 
o Perform an abbreviated physical and/or neurological examination as appropriate 
based on last exam and reported AEs 
o Collect plasma sample for AED pharmacokinetic evaluation if clinically 
indicated (must document time of last dose) 
x Record AESI 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x Dispense study medication 
6.1.2.4 
Phone Visit 7 (Maintenance Period Study Day 29) 
Site personnel will contact the subject via telephone on Maintenance Period Study Day 29 and 
record the following: 
x AEs 
x AESI 
x Concomitant medications 
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In addition, site personnel will review the diary entries with the parent/caregiver. Ensure diary 
is being completed daily; if diary compliance is low (i.e. <90%), re-train parent/caregiver. 
6.1.2.5 
Clinic Visit 8 (Maintenance Period Study Day 43) 
x Subjects will report to the clinic in the morning on Maintenance Period Study Day 43. 
Subjects should not take their morning dose(s) of study medication. The following 
procedures will be performed: 
x Review current seizure activity (number/type/duration) from diary since previous visit 
x Record concomitant medications 
x Obtain weight (Note: if the subject’s weight is ±25% of the weight at Study Day-1, 
the IMP dose will be recalculated) 
x Obtain vital signs 
x 12-lead electrocardiogram 
x Doppler ECHO (this must be obtained any time between Study Day 40 and Study 
Day 54) 
x Urine or serum pregnancy test for females of child-bearing potential 
x Laboratory evaluation (serum chemistry, hematology, immunoglobulin hormones, and 
urinalysis (urine for urinalysis may be collected at home, the night before the clinic visit, 
as long as collection procedures are followed to maintain sample stability)) 
x Urine or serum THC panel 
x Whole blood CBD 
x Collect plasma sample for ZX008 pharmacokinetic evaluation at the following 
timepoints: within 1 hour prior to the morning dose of study medication, and 1, 2 and 4-6 
hours after the morning dose of study medication 
x Collect plasma sample for AED pharmacokinetic evaluation (must document time of last 
dose) 
x Collect, review, and dispense diary. Ensure diary is being completed daily; if diary 
compliance is low (i.e. <90%), re-train parent/caregiver. 
x C-SSRS Since Last Visit Assessment (Appendix 2) 
x Zarit Caregiver Burden Inventory (Appendix 8) 
x Clinical Global Impression – Improvement (assessed by parent/caregiver) 
x Clinical Global Impression – Improvement (assessed by investigator) 
x Perform an abbreviated physical and/or neurological examination as appropriate based on 
last exam and reported AEs 
x Record AESI 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x Dispense study medication 
6.1.2.6 
Phone Visit 9 (Maintenance Period Study Day 57) 
Site personnel will contact the subject via telephone on Maintenance Period Study Day 57 and 
record the following: 
x AEs 
x AESI 
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x Concomitant medications 
In addition, site personnel with review the diary entries with the parent/caregiver. Ensure diary 
is being completed daily; if diary compliance is low (i.e. <90%), re-train parent/caregiver. 
6.1.2.7 
Clinic Visit 10 (Maintenance Period Study Day 71) 
Subjects will report to the clinic on Maintenance Period Study Day 71. The following 
procedures will be performed: 
x Review current seizure activity (number/type/duration) from diary since previous visit 
x Record concomitant medications 
x Obtain weight 
x Obtain vital signs 
x Collect, review, and dispense diary. Ensure diary is being completed daily; if diary 
compliance is low (i.e. <90%), re-train parent/caregiver. 
x C-SSRS Since Last Visit Assessment (Appendix 2) 
x Clinical Global Impression – Improvement (assessed by parent/caregiver) 
x Clinical Global Impression – Improvement (assessed by investigator) 
x Record AEs 
x Perform an abbreviated physical and/or neurological examination as appropriate based on 
last exam and reported AEs 
x Collect plasma sample for AED pharmacokinetic evaluation if clinically indicated 
x Record AESI 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x Dispense study medication 
At Clinic Visit 10, compliant subjects who have tolerated IMP should be presented with the 
ICF for the open-label extension (Part 2). Informed consent for the open-label extension 
should be signed at Visit 12 or earlier in order to enter the open-label extension. 
6.1.2.8 
Phone Visit 11 (Maintenance Period Study Day 85) 
Site personnel will contact the subject via telephone on Maintenance Period Study Day 85 and 
record the following: 
x AEs 
x AESI 
x Concomitant Medications 
In addition, site personnel with review the diary entries with the parent/caregiver. Ensure diary 
is being completed daily; if diary compliance is low (i.e. <90%), re-train parent/caregiver. 
6.1.2.9 
Clinic Visit 12 (Maintenance Period Study Day 99): End of Study/Early 
Termination 
The End-of-Study participation in Part 1 for an individual subject occurs after he/she has 
received IMP for 12 weeks in the Maintenance Period. At the Part 1 End-of-Study visit, the 
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subject may enroll into the Part 2 OLE Treatment Period if they have completed 12 weeks of 
treatment in the Maintenance Period. Other circumstances for participation in Part 2 are 
described in Section 4.3. Informed consent for the Part 2 OLE Treatment Period should be 
signed before data collection begins on Visit 12 (if not signed earlier) in order to participate in 
Part 2. 
The End-of-Study visit may also occur if the subject withdraws participation from the study or 
the sponsor terminates the study. If the subject withdraws participation from the study, they 
may on a case-by-case basis, be eligible for entrance into the Part 2 OLE Treatment Period 
after consideration of the circumstances of the early termination and the potential benefit- risk 
of continued participation in a ZX008 trial. The decision whether to permit Part 2 participation 
resides solely with the sponsor, who may consult with the site investigator. If the sponsor 
terminates the study early, the subject may or may not be offered enrollment into Part 2, 
depending on the reason for termination. 
Subjects will visit the clinic for the End-of-Study visit if one the following events occur: 
1. The subject withdraws or is withdrawn from participation in the study. 
2. The sponsor terminates the study. 
3. The subject completes all study related visits and 
procedures. The following procedures will be performed: 
x Review current seizure activity (number/type/duration) from diary since previous visit 
x Record concomitant medications 
x Complete physical examination, including height and weight 
x Complete neurological examination 
x Obtain vital signs 
x 12-lead electrocardiogram 
x Doppler ECHO (must be performed any time between Study Day 90 and Study Day 113; 
if subject terminates early from the study, the ECHO should be scheduled as soon as 
practical). If the Study Day 43 ECHO was completed ≤30 days prior to early termination, 
the Visit 12 ECHO will not be performed provided the parent/guardian agrees to bring 
the subject to the clinic for the cardiac follow-up visit (see Table 9). 
x Urine or serum pregnancy test for females of child-bearing potential 
x Laboratory evaluation (serum chemistry, hematology, immunoglobulin, hormones, and 
urinalysis (urine for urinalysis may be collected at home, the night before the clinic visit, 
as long as collection procedures are followed to maintain sample stability)) 
x Urine or serum THC panel 
x Whole blood CBD 
x Collect plasma sample for AED pharmacokinetic evaluation (must document time of last 
dose) 
x Tanner Staging for subjects >7 to 18 years of age (Appendix 5) 
x Collect, review, and dispense diary. Ensure diary is being completed daily; if diary 
compliance is low (i.e. <90%), re-train parent/caregiver 
x C-SSRS Since Last Visit Assessment (Appendix 2) 
x Clinical Global Impression – Improvement (assessed by parent/caregiver) 
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x Clinical Global Impression – Improvement (assessed by investigator) 
x BRIEF (Appendix 3) 
x QOLCE (Appendix 6) 
x HADS (Appendix 7) 
x Zarit Caregiver Burden Inventory (Appendix 8) 
x Record AEs 
x Record AESIs 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x Dispense study medication for taper for subjects not continuing into Part 2.  
x Dispense and administer study medication for transition for subjects continuing into Part 
2. Subjects will be required to stay in the clinic for monitoring of adverse reactions until 
the investigator determines it is safe to leave. Those considered by the investigator to 
need further monitoring will be hospitalized until the investigator determines they can be 
safely discharged.   
6.1.3 POST-DOSE VISIT (CLINIC VISIT 13; STUDY DAY 113) 
For subjects entering the Part 2 OLE Treatment Period, the subject will visit the 
clinic on Day 113, which will also be Part 2 Day 1.  The procedures described in 
Section 6.2 will be followed.   
 
If the subject does not enter the Part 2 OLE Treatment Period (or discontinues from the 
study early), the subject will visit the clinic on Study Day 113 (or 14 days after the day of 
discontinuation). If necessary, Visit 13 may be conducted as a phone call, provided diaries 
and study medication are returned by this time. The following will be recorded/performed: 
x Review current seizure activity (number/type/duration) from diary since previous visit 
x AEs 
x AESIs 
x Concomitant medications 
x Collect and review diary with parent/caregiver 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
6.1.4 CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 14; 3 and 6 months after 
last dose) 
If the subject completes the study but does not enter the Part 2 OLE Treatment Period or 
discontinues from the study early, the subject will return to the clinic after study drug 
discontinuation for follow-up cardiac testing. The timing and frequency of exams are in Table 
10. Subjects on blinded medication who are found to have been on placebo are not required to 
participate in follow-up testing once the blind is broken. As the ECHO and ECG will be 
administered in a separate clinic than the pediatric neurology clinic, an asymptomatic subject 
receiving a follow-up ECHO and ECG does not require a physical examination. 
Subjects with positive findings on safety evaluations at post-dose follow-ups should have 
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repeat examinations every 3 months until the finding is resolved or stable and unlikely to 
change, with reports submitted as AEs to the ZX008 safety database. 
Table 10: 
Schedule of Post-Treatment Cardiac Follow-up for Part 1 
 
 
 
 
Parameter 
Duration of Blindeda or Fenfluramine Treatment 
 
Less than 
2 weeks 
Cumulative 
 
 
2 and 
<13 weeks 
>13 weeks 
Have had any cardiac sign or symptom 
regardless of the time on study drugb 
ECHO 
No 
Yes, 
3 months post- 
treatment 
Yes, 
3 and 6 months 
post-treatment 
Yes, 
3 and 6 months post- treatment, and every 
3 months until resolved, or stable and 
unlikely to change 
ECG 
No 
Yes, 
3 months post- 
treatment 
Yes, 
3 and 6 months 
post-treatment 
Yes, 
3 and 6 months post- treatment and every 3 
months until resolved, or stable and 
unlikely to change 
Physical 
examination 
No 
Yes, 
3 months post- 
treatment 
Yes, 
3 months post- 
treatment only 
Yes, 
3 and 6 months post- treatment, and every 
3 months until resolved, or stable and 
unlikely to change 
a If blind is broken at the end of the study and a subject revealed to have taken only placebo, no further testing is 
required. 
b    Positive sign or symptom includes any development of valve thickening or regurgitation (“trace” or greater in mitral, 
aortic; mild or greater in pulmonary, tricuspid), or sign or symptom indicative of potential pulmonary hypertension 
as adjudicated by the ICAB. 
 
6.2 
Part 2 
Review of inclusion and exclusion criteria and written informed parental or guardian consent 
and assent of minors (if the subject is capable of providing assent) for Part 2 must be obtained 
before a subject can start any of the Part 2 Visit 15 procedures.  This includes review and 
approval (or adjudication if required) of the ECG and/or ECHO findings by the central reader, 
and approval for continuation in the open-label extension (if applicable) by the IDSMC. 
Only eligible subjects as specified by the inclusion and exclusion criteria who have 
successfully completed Part 1, or have permission from the Sponsor, will be enrolled into 
Part 2. Other circumstances for participation in Part 2 are described in Section 4.3. 
Study procedures for the Part 2 OLE Treatment Period will be conducted according to 
the Schedule of Assessments in Table 2. Time windows for all assessments are detailed 
in Table 11. 
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Table 11: 
Time Windows for Assessments in Part 2 
Visit / Procedure 
Time window (relative to scheduled 
visit / procedure) 
Visit 15 (Clinic; OLE Study Day 1)  
± 4 daysa 
Visits 16 (Clinic/Phone; OLE Study Day 15) 
± 3 days 
Visits 17-41 (Clinic: OLE Study Days 30, 60, 90, 180, 270, 360, 
450, 540*, 630, 720*, 810, 900*, 990, 1080*, 1170,1260*, 1350, 
1440*,1530, 1620*, 1710, 1800*, 1890, 1980*, 2070) 
± 4 days 
Visit 42 (Clinic; OLE Study Day2160; EOS) 
± 4 days 
Visit 43 (Clinic; OLE Study Day 2174; post dosing) 
± 4 days 
Visit 44, 45 (ECHO clinic; 3 and 6 months after last dose) 
+ 30 days 
AED=antiepileptic drug (s); ECHO=echocardiogram 
a In the case of a required safety review of a Visit 12 ECHO alert, the transition period between Visit 12 and Vist 15 may be 
extended up to 14 days to allow time for adjudication. 
*If marketing approval is not yet received after the end of the OLE Treatment Period, treatment may be extended on an annual basis in order to provide continuity 
of treatment for subjects who are enrolled in Part 2 of the study. Up to 5 annual extensions can be applied, for a total treatment time of 72 months in the OLE. 
Continuation will be based on review of safety/tolerability and effectiveness, and be offered for subjects who continue to meet eligibility requirements, comply 
with investigator’s instructions, and for whom the investigator judges benefit outweighs risk. The decision to extend and informed consent should be completed 
before the start of the first visit of the extension (e.g. Month 12,  24, 36, 48 or 60). After approval from Investigator and Sponsor for extension and starting after 
Visit 26/ Month24 (or at a later visit if Visit 26/ Month 24 visit has already occured at the time of Protocol Amendment 4.0 approval), subject will return to the 
clinic every 6 months for the 1 year extension (i.e. Month 30, 36). The End of Study will be Visit 42, unless another extension is granted, in which case the subject 
will continue to return for clinic visits every 6 months and will have a phone visit 3 months after the in-clinic visit.. Further extensions can then be applied as 
required if marketing approval is not yet received. 
 
6.2.1 
Clinic Visit 15 (OLE Study Day 1) 
Part 2 Visit 15 will occur 14 days (± 4 days) after Part 1 Visit 12. The 14-day transition period 
preceding Visit 15 may be extended up to 14 days in the case of a required safety adjudication of 
a Visit 12 ECHO alert.  
The following procedures will be performed during Visit 15: 
x Ensure entry criteria for Part 2 are met 
x Vital signs 
x Record prior and concomitant medications (use core study Visit 12 information)  
x Instruct parent/caregiver on use of diary 
x Record ongoing AEs as medical history  
x Record ongoing AESI as medical history  
x Collect, review, and dispense diary (after above procedures have been concluded) 
x Dispense study medication 
Data collected from Part 1 Visit 12 may be used for the following procedures unless otherwise 
indicated: 
x Record medical, neurological, and epilepsy history 
x Complete physical examination, including height and weight (use data collected at Part 1 
Visit 12, unless there was a significant change in subject status warranting a new 
complete examination) 
x Complete neurological examination (use data collected at Part 1 Visit 12, unless there 
was a significant change in subject status warranting a new complete examination) 
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x 12-lead ECG  
x Doppler ECHO  
x Laboratory evaluation (serum chemistry, hematology, immunoglobulin, hormones, and 
urinalysis) (use Part 1 Visit 12 information, unless investigator determines new 
laboratory evaluation is warranted due to change in subject status) (if collecting urine for 
urinalysis, urine may be collected at home, the night before the clinic visit, as long as 
collection procedures are followed to maintain sample stability) 
x Pregnancy test 
x Urine or serum THC panel  
x Whole blood CBD  
x C-SSRS Since Last Visit Assessment (Appendix 2)  
x CGI-I (assessed by parent/caregiver) 
x CGI-I (assessed by investigator)  
x BRIEF (Appendix 3) 
x QOLCE (Appendix 6) 
x HADS (Appendix 7) 
x Zarit Caregiver Burden Inventory (Appendix 8) 
 
6.2.2 
Clinic/Phone Visit 16 (OLE Study Day 15) 
Part 2 Visit 16 may be performed in the clinic, or, at the discretion of the investigator, performed 
via phone. 
If Visit 16 is performed in the clinic, subjects will report to the clinic in the morning of that day. 
The following procedures will be performed: 
x Review current seizure activity (number/type/duration) from diary since previous visit  
x Record concomitant medications since previous visit 
x Obtain weight 
x Vital signs 
x Laboratory evaluation (serum chemistry, hematology, immunoglobulin, hormones, and 
urinalysis) (only if investigator determines new laboratory evaluation is warranted due to 
change in subject status since Visit 15) (if collecting urine for urinalysis, urine may be 
collected at home, the night before the clinic visit, as long as collection procedures are 
followed to maintain sample stability) 
x Collect, review, and dispense diary. Ensure diary is being completed daily; if diary 
compliance is low (i.e. <90%), re-train parent/caregiver. 
x Record AEs 
o Perform an abbreviated physical and/or neurological examination as appropriate 
based on last exam and reported AEs 
o Collect plasma sample for AED pharmacokinetic evaluation if clinically indicated 
(must document time of last dose) 
x Record AESI 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
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x Collect and review study medication 
If the visit is performed as a phone visit, site personnel will contact the subject on Study Day 15 
and record/review the following: 
x Concomitant medications 
x AEs 
x AESI 
x Study medication use 
x Diary entries 
6.2.3 
Clinic Visits 17-21 (OLE Months, 1, 2, 3, 6, and 9)  
Subjects will report to the clinic for Part 2 Clinic Visits 17 through 21. The following procedures 
will be performed: 
x Review current seizure activity (number/type/duration) from diary since previous visit  
x Record concomitant medications 
x Obtain weight (Note: if the subject’s weight is ±25% of the weight at Part 2 Day 15, 
the IMP dose will be recalculated) 
x Obtain vital signs 
x 12-lead ECG 
x Doppler ECHO (at Months 1, 3, 6, and 9) 
x Urine or serum pregnancy test for females of child-bearing potential (at Months 3, 6, and 
9) 
x Laboratory evaluation (serum chemistry, hematology, immunoglobulin, hormones, and 
urinalysis; at Months 3, 6 and 9 unless otherwise clinically indicated) (urine for urinalysis 
may be collected at home, the night before the clinic visit, as long as collection 
procedures are followed to maintain sample stability) 
x Urine or serum THC panel (at Months 3, 6 and 9) 
x Whole blood CBD (at Months 3, 6, and 9) 
x Collect plasma sample for AED PK and document time of last dose (at Months 3, 6, and 
9 unless otherwise clinically indicated) 
x Tanner Staging for subjects > 7 to 18 years of age (Month 6 only) (Appendix 5) 
x Collect, review, and dispense diary. Ensure diary is being completed daily; if diary 
compliance is low (i.e. <90%), re-train parent/caregiver. 
x C-SSRS Since Last Visit Assessment (Appendix 2) 
x CGI-I (assessed by parent/caregiver) 
x CGI-I (assessed by investigator) 
x BRIEF (Month 6 only) (Appendix 3) 
x QOLCE (Month 6 only) (Appendix 6) 
x HADS (Month 6 only) (Appendix 7) 
x Record AEs 
o Perform an abbreviated physical and/or neurological examination as appropriate 
based on last exam and reported AEs 
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o Collect plasma sample for AED pharmacokinetic evaluation if clinically 
indicated 
x Record AESI 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x Dispense study medication 
 
The next study visit should be Visit 30 (EOS), unless a 1-year extension is granted. If 
extending study participation, the decision should be made during Visit 21 (or at least prior to 
conducting Visit 22 procedures) by the Investigator and the consent from the subject or 
parent/caregiver obtained. After approval from Investigator and Sponsor for extension, 
Subject will return every 3 months for the 1 year extension (i.e. Month 12, 15, 18, 21). The 
End of Study will be Visit 30, on the 24th month of OLE, unless another 1 year extension is 
granted, in which case the subject will continue to return for clinic visits every 3 months (i.e. 
Month 24, 27, 30, 33) until the EOS Visit 30 on the 36th month of OLE. 
6.2.4 
Clinic Visit 22 (OLE Month 12) 
Subjects will report to the clinic and the following procedures will be performed: 
x Review current seizure activity (number/type/duration) from diary since previous visit  
x Record concomitant medications 
x Obtain weight (Note: if the subject’s weight is ±25% of the weight at Part 2 Day 15, 
the IMP dose will be recalculated) 
x Complete physical examination, including height and weight, and calculation of BMI 
x Complete neurological examination 
x Obtain vital signs 
x 12-lead ECG 
x Doppler ECHO (must be performed any time between Study Day 344 and Study 
Day 365). 
x Urine or serum pregnancy test for females of child-bearing potential 
x Laboratory evaluation (serum chemistry and hematology, and urinalysis) 
x Urine or serum THC panel 
x Whole blood CBD 
x Collect plasma sample for AED PK evaluation (must document time of last dose) 
x Tanner Staging for subjects > 7 to 18 years of age (Appendix 5) 
x Collect and review diary 
x C-SSRS Since Last Visit Assessment (Appendix 2) 
x CGI-I (assessed by parent/caregiver) 
x CGI-I (assessed by investigator) 
x BRIEF (Appendix 3) 
x QOLCE (Appendix 6) 
x HADS (Appendix 7) 
x Zarit Caregiver Burden Inventory (Appendix 8) 
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x Record AEs 
x Record AESI 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x Dispense study medication 
6.2.5 
Clinic Visits 23-41 (OLE Months 15, 18, 21, 24, 27, 30, 33, 36, 39, 
42, 45, 48, 51, 54, 57, 60, 63, 66, 69) 
If marketing approval is not yet received after the the end of the OLE Treatment Period, 
treatment may be extended on an annual basis in order to provide continuity of treatment for 
subjects who are enrolled in Part 2 of the study. Continuation will be based on review of 
safety/tolerability and effectiveness, and be offered for subjects who continue to meet eligibility 
requirements, comply with investigator’s instructions, and for whom the investigator judges 
benefit outweighs risk. 
From Visit 26/Month 24 (or a later visit if Visit 26/Month 24 has already occurred at the time of 
Protocol Amendment 4.0 approval), if approved for the extensions, subjects will report to the 
clinic every 6 months and will have a phone visit 3 months after each in-clinic visit for Part 2 
Clinic Visits 26 through 41.  
The following procedures will be performed during in-clinic visits: 
x Record concomitant medications 
x Obtain weight (Note: if the subject’s weight is ±25% of the weight at Part 2 Day 15, 
the IMP dose will be recalculated) 
x Obtain vital signs 
x Abbreviated physical examination, as appropriate based on last exam and reported AEs 
x Abbreviated neurological examination, as appropriate based on last exam and reported 
AEs 
x 12-lead ECG, if clinically indicated  
x Doppler ECHO 
x Urine or serum pregnancy test for females of child-bearing potential 
x Only if clinically indicated: 
o Laboratory evaluation (serum chemistry, hematology, immunoglobulin, 
hormones, and urinalysis) (urine for urinalysis may be collected at home, the 
night before the clinic visit, as long as collection procedures are followed to 
maintain sample stability) 
o Collect plasma sample for AED PK and document time of last dose 
x Seizure Assessment by Investigator 
x C-SSRS Since Last Visit Assessment (Appendix 2) 
x CGI-I (assessed by parent/caregiver) 
x CGI-I (assessed by investigator) 
x Record AEs 
x Record AESI 
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x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x Dispense study medication 
 
The following procedures will be performed during phone visits: 
x Record concomitant medications 
x Record AEs 
x Record AESI 
 
The next study visit after Visit 25/Month 21, Visit 29/Month 33, Visit 33/Month 45, Visit 
37/Month 57 or Visit 41/Month 69  should be Visit 42 (EOS), unless another 1-year extension is 
granted. If extending study participation, the decision should be made during the in-clinic visit 
preceeding the annual reconduction by the Investigator and the consent from the subject or 
parent/caregiver obtained. After approval from Investigator and Sponsor for extension and 
starting after Visit26/Month 24 (or a later visit if Visit 26/Month 24 has already occurred at the 
time of Protocol Amendment 4.0 approval), subject will return to the clinic every 6 months and 
will have a phone visit 3 months after each in-clinic visit for the 1 year extension. The End of 
Study will be Visit 42, the 72nd month of the OLE, or until ZX008 is approved in the subject’s 
country of residence and listed on a patient’s health plan formulary, whichever occurs first. 
 
6.2.6 
Clinic Visit 42:  End of Study/Early Termination 
The End-of-Study participation in Part 2 for an individual subject occurs after he/she has 
received IMP for up to 5 years in the Part 2 OLE Treatment Period, or until ZX008 is approved 
in a subject’s country of residence and listed on a patient’s health plan formulary, whichever 
occurs first. The End-of-Study visit may also occur if the subject withdraws participation from in 
Part 2 or the Sponsor terminates the study.  
Subjects will visit the clinic for the End-of-Study visit if one the following events occur: 
1. The subject withdraws or is withdrawn from participation in the study. 
2. The Sponsor terminates the study. 
3. The subject completes all study related visits and procedures (at least up to Month 12, 
but extensions may be granted for up to 72 months). 
4. ZX008 is approved in a subject’s country of residence and is listed on a patient’s 
health plan formulary 
The following procedures will be performed for subjects who did not extend Part 2 participation 
past 12 months: 
x Review current seizure activity (number/type/duration) from diary since previous visit  
x Record concomitant medications 
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x Complete physical examination, including height and weight, and calculation of BMI 
x Complete neurological examination 
x Obtain vital signs 
x 12-lead ECG 
x Doppler ECHO (must be performed within 3 weeks of the visit; if subject terminates 
early from the study, the ECHO should be scheduled as soon as practical). If the previous 
ECHO was completed ≤ 30 days prior to early termination, the Visit 30 ECHO will not 
be performed provided the parent/guardian agrees to bring the subject to the clinic for the 
cardiac follow-up visit (see Table 12). 
x Urine or serum pregnancy test for females of child-bearing potential 
x Laboratory evaluation (serum chemistry, hematology, immunoglobulin, hormones, and 
urinalysis) (urine for urinalysis may be collected at home, the night before the clinic visit, 
as long as collection procedures are followed to maintain sample stability) 
x Urine or serum THC panel 
x Whole blood CBD 
x Collect plasma sample for AED PK evaluation (must document time of last dose) 
x Tanner Staging for subjects > 7 to 18 years of age (Appendix 5) 
x Collect and review diary C-SSRS Since Last Visit Assessment (Appendix 2) 
x CGI-I (assessed by parent/caregiver) 
x CGI-I (assessed by investigator) 
x BRIEF (Appendix 3) 
x QOLCE (Appendix 6) 
x HADS (Appendix 7) 
x Zarit Caregiver Burden Inventory (Appendix 8) 
x Record AEs 
x Record AESI 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x Dispense study medication (not applicable for subjects transitioning to commercial drug) 
The following procedures will be performed for subjects who are extended Part 2 participation 
past 12 months: 
x Record concomitant medications 
x Complete physical examination, including height and weight, and calculation of BMI 
x Complete neurological examination 
x Obtain vital signs 
x Doppler ECHO (must be performed within 3 weeks of the visit; if subject terminates 
early from the study, the ECHO should be scheduled as soon as practical). If the previous 
ECHO was completed ≤ 30 days prior to early termination, the Visit 30 ECHO will not 
be performed provided the parent/guardian agrees to bring the subject to the clinic for the 
cardiac follow-up visit (see Table 12). 
x Urine or serum pregnancy test for females of child-bearing potential 
x Only if clinically indicated: 
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o Collect plasma sample for AED PK evaluation (must document time of last 
dose) 
o Laboratory evaluation (serum chemistry, hematology, immunoglobulin, 
hormones, and urinalysis) (urine for urinalysis may be collected at home, the 
night before the clinic visit, as long as collection procedures are followed to 
maintain sample stability) 
o 12-lead ECG 
x Collect and review diary C-SSRS Since Last Visit Assessment (Appendix 2) 
x CGI-I (assessed by parent/caregiver) 
x CGI-I (assessed by investigator) 
x Seizure assessment by investigator 
x Record AEs 
x Record AESI 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
x Dispense study medication (not applicable for subjects transitioning to commercial drug) 
 
6.2.7 
POST-DOSE VISIT (CLINIC Visit 43; 14 DAYS AFTER LAST 
DOSE OF IMP) 
If the subject completes the study (or discontinues from the study early), and is not switching to 
commercially available drug, the subject will visit the clinic for Visit 43 (14 days after the EOS 
or day of discontinuation). Visit 43 may be conducted as a phone call if physical and 
neurological examinations are not clinically indicated, provided diaries (if applicable) and study 
medication are returned by this time. The following procedures will be performed: 
x Review current seizure activity (number/type/duration) from diary since previous visit 
x Record AEs 
x Perform an abbreviated physical and/or neurological examination as appropriate based on 
last exam and reported AEs 
x Obtain weight 
x Record AESI 
x Record concomitant medications 
x Collect and review diary with parent/caregiver 
x Collect used, partially used and unused study medication; perform drug accountability 
and review with parent/caregiver 
 
6.2.8 
CARDIAC FOLLOW-UP VISIT (CLINIC VISIT 44, 45; 3 AND 6 
MONTHS AFTER LAST DOSE OF IMP) 
If the subject completes Part 2 or discontinues from the Part 2 early, and is not switching to 
commercially available drug, the subject will return to the clinic for follow-up cardiac testing. 
The timing and frequency of exams are in Table 12. As the ECHO and ECG will be administered 
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in a separate clinic than the pediatric neurology clinic, an asymptomatic subject receiving a 
second follow-up ECHO and ECG does not require a physical examination.  
Subjects with positive findings on safety follow-up examinations should continue to be followed 
until the finding is resolved or stable and unlikely to change.  
If the subject completes the study (or discontinues from the study early) and is switching to 
commercially available drug, the subject will complete the EOS visit and follow the drug 
administration process outlined for commercial product as advised by the subject’s physician. 
The EOS/ET and cardiac follow-up visits are not required. 
 
Table 12. 
Schedule of Post-Treatment Cardiac Follow-up for Part 2 
 
Duration of Fenfluramine Treatment 
 
 
 
Parameter 
 
Less than  
2 weeks 
Cumulative 
 
 
2 and  
≤ 13 weeks 
 
 
 
> 13 weeks 
Have had any cardiac sign or symptom 
regardless of the time on study druga 
ECHO 
No 
Yes,  
3 months post- 
treatment 
Yes,  
3 and 6 months 
post-treatment 
Yes,  
3 and 6 months post-treatment, and until 
resolved, or stable and unlikely to change 
ECG 
No 
Yes,  
3 months post- 
treatment 
Yes,  
3 and 6 months 
post-treatment 
Yes, 
3 and 6 months post-treatment and until 
resolved, or stable and unlikely to change 
Physical 
examination 
No 
Yes,  
3 months post- 
treatment 
Yes,  
3 months post- 
treatment only 
Yes, 
3 and 6 months post-treatment, and until 
resolved, or stable and unlikely to change 
a Positive sign or symptom includes any development of valve thickening or regurgitation (“trace” or greater in mitral, 
aortic; mild or greater in pulmonary, tricuspid), or sign or symptom indicative of potential pulmonary hypertension as 
adjudicated by the ICAB. 
 
6.3 
STUDY CONDUCT DURING COVID-19 
In March 2020, the World Health Organization declared a global pandemic related to an illness 
caused by a novel coronavirus known as COVID-19. Alternative procedures and allowances are 
permitted due to restrictions related to COVID-19, including delays to in-person visits and 
specific assessments, performing remote phone or video visits if in-person visits cannot be 
conducted, and arranging shipments of investigational product directly to subjects. These 
allowances are detailed in Appendix 10. Though every attempt should be made to conduct study 
visits as described in this protocol, any implementation of alternative processes should be 
properly documented, including what was done differently, and which assessments or visits were 
missed or performed via phone or video. 
6.4 
ESTIMATED BLOOD VOLUME COLLECTION 
The maximum total blood volume collected during Part 1 of the study for clinical laboratory 
testing, genotyping, and PK will be approximately 84.0 mL, as outlined in Table 13 The 
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maximum total blood volume collected during Part 2 of the study for clinical laboratory testing 
and PK will be variable as the clinical laboratory testing will be performed as clinically indicated 
for the majority of in clinic visits after Visit26/Month 24, and will be approximately 104.0 mL at 
the minimum and will equal up to 351.5 mL , as outlined in Table 14. 
Table 13: 
Maximum Estimated Blood Volume Collection for Part 1* 
PART 1 
Visit 1 
(Day -28) 
Visit 3 
(Day -1) 
Visit 8 
(Day 43) 
Visit 12 
(Day 99) 
TOTAL 
Coagulation 
  
3.0 mL 
  
  
3.0 mL 
Chemistry 
5.0 mL 
5.0 mL 
5.0 mL 
5.0 mL 
20.0 mL 
Pregnancy test (serum) 
included in 
Chemistry 
included in 
Chemistry 
included in 
Chemistry 
included in 
Chemistry 
0.0 mL 
Hormones 
  
5.0 mL 
5.0 mL 
5.0 mL 
15.0 mL 
Immunoglobulin 
2.5 mL 
2.5 mL 
2.5 mL 
2.5 mL 
10.0 mL 
Hematology 
2.0 mL 
2.0 mL 
2.0 mL 
2.0 mL 
8.0 mL 
Genotype Panel 
  
4.0 mL 
  
  
4.0 mL 
AED PK plasma sample* 
  
2.0 mL 
2.0 mL 
2.0 mL 
6.0 mL 
ZX008 PK plasma sample 
  
  
8.0 mL 
  
8.0 mL 
Volume for flushing indwelling 
catheter 
  
  
2.0 
  
2.0 mL 
Cannabidiol/THC 
2.0 mL 
2.0 mL 
2.0 mL 
2.0 mL 
8.0 mL 
TOTAL 
11.5 mL 
25.5 mL 
28.5 mL 
18.5 mL 
84.0 mL 
AED=Anti-epileptic drugs; PK=pharmacokinetics 
*Blood collection for AED pharmacokinetic evaluation may be collected on Visits 6 and 10 if clinically indicated. If 
collected during these visits, the total blood volume per subject would equal up to 88.0 mL. 
 
Table 14. 
Maximum Estimated Blood Volume Collection for Part 2* 
PART 2 
Visit 19 
(Day 90) 
Visit 20 (Day 
180) 
Visit 21 (Day 
270) 
Visit 22 (Day 
360) 
Visits 23-
42 (in 
clinic 
only) 
TOTAL 
Chemistry 
5.0 mL 
5.0 mL 
5.0 mL 
5.0 mL 
 
20.0 mL 
Pregnancy test 
(serum) 
included in 
Chemistry 
included in 
Chemistry 
included in 
Chemistry 
included in 
Chemistry 
2.5 mL 
2.5 mL 
Hormones 
5.0 mL 
5.0 mL 
5.0 mL 
5.0 mL 
 
20.0 mL 
Immunoglobulin 
2.5 mL 
2.5 mL 
2.5 mL 
2.5 mL 
 
10.0 mL 
Hematology 
2.0 mL 
2.0 mL 
2.0 mL 
2.0 mL 
 
8.0  mL 
AED PK plasma 
sample 
2.0 mL 
2.0 mL 
2.0 mL 
2.0 mL 
 
8.0 mL 
Cannabidiol/THC 
2.0 mL 
2.0 mL 
2.0 mL 
2.0 mL 
 
8.0 mL 
TOTAL 
18.5 mL 
18.5 mL 
18.5 mL 
18.5 mL 
 30 mL 
104.0 mL 
AED=Anti-epileptic drugs; PK=pharmacokinetics 
*Laboratory testing may be conducted on Visits 16-18 and 23-42 if clinically indicated. After Visit 26, in-clinic visits will 
occur every 6 months. If collected during these visits, the total blood volume per subject would equal up to 351.5mL. 
*In concordance with The Seattle Children’s Research Foundation Guidance (Appendix 9), 
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blood collection volumes for children weighing up to 15 kg will be: 
x The maximum allowable volume of blood in one draw is 22-30 mL (2.5% of total blood 
volume) 
x The maximum in a 30-day period is 44-60 mL. 
On Part 1 Day 43/Visit 8 the pharmacokinetic blood draw will be completed as the priority and 
the blood draw for chemistry and hematology will be skipped for those subjects who weigh less 
than 13.5 kg, unless medical concerns (for example, from previous tests or reported side effects) 
prioritize chemistry and/or hematology. 
If blood collection is restricted due to volume or due to inability to draw adequate volume, 
collection should be prioritized as shown in Table 15 
Table 15: 
Priorities for Blood Sample Collections 
Assessment 
Priority 
ZX008 PK sample 
Priority 1 
Clinical chemistry 
Priority 2 
Cannabidiol 
Priority 2 
AED plasma sample 
Priority 2 
LH, FSH, estradiol, testosterone, GH, 
prolactin 
Priority 3 
Hematology 
Priority 3 
IGF-1 
Priority 4 
Genotyping 
One time optional collection any time during or after Visit 3 
(Randomization) in Part 1 
Coagulation 
One time collection any time before Part 1 PK day 
 
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7. 
EFFICACY, SAFETY, AND PHARMACOKINETIC 
ASSESSMENTS 
For an overview of the study variables and measurement times, see Schedule of 
Assessments (Table 1 and Table 2). 
Variables used to measure treatment compliance with respect to administration of the IMP are 
described in Section 5.7. 
7.1 
EFFICACY/EFFECTIVENESS ASSESSMENTS 
Baseline is defined as the frequency of motor seizures resulting in drops during the 4-week 
Baseline Period prior to administration of IMP. 
Retrospective diary data (up to 6 months) will be collected, if available, for an 
exploratory evaluation of the duration of baseline data capture on interpretation of post-
treatment effect. 
For all questionnaires and rating scales, the same evaluator (at the clinical site and 
parent/caregiver) should complete the assessments for the duration of the study. Substitutions 
at the clinic with another rater that has established inter-rater reliability is acceptable on an 
infrequent basis. For the in-clinic questionnaires and rating scales completed by the 
parent/caregiver, if the same parent/caregiver cannot complete the questionnaire/rating scale at 
a visit, the questionnaire/rating scale will not be completed. For the diary, the same 
parent/caregiver will complete all entries throughout the study. 
7.1.1 
Seizure Assessments 
Seizure frequency by type and duration will be recorded daily by the parent/caregiver in 
a diary during Part 1 and up to 12 months in Part 2 (i.e., up to Visit 22). Seizure types 
include: 
A: 
Hemiclonic (note lateralization – right body, left body, or independent right 
and left) 
B: 
Focal With or Without Retained Awareness 
C: 
Secondarily Generalized Tonic Clonic (evolving to bilateral convulsive 
seizure from focal seizure) 
D: 
Generalized Tonic Clonic 
Convulsion E: 
Absence or Atypical 
Absence 
F: 
Myoclonic 
G: 
Tonic 
H: 
Atonic 
I: 
Clonic 
J: 
Tonic/Atonic (cannot differentiate) 
K: 
Infantile Spasms (if under 3 years of age) 
L: 
Epileptic Spasms (if 3 years of age and older)  
O: 
Other* 
* “Other” indicates a seizure type that cannot be classified in any of the above seizure 
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types A-L. All other seizures must be classified appropriately based on the 
Investigator’s medical opinion and Epilepsy Study Consortium approval. 
Parents/caregivers will also indicate in the diary entry whether the seizure resulted in a drop, or 
would have resulted in a drop were it not for the position (ie, in a chair).  This includes seizures 
involving the entire body, trunk, or head that led to a fall, injury, slumping in a chair, or the 
subject’s head hitting a surface or that could have led to a fall or injury, depending on the 
patient’s position at the time of the seizure. 
Efficacy/effectiveness endpoints that will be derived from the diary data include frequency of 
seizures that result in drops and seizures that do not result in drops, motor seizures, and all 
seizures, and the number/duration of seizure-free intervals. 
Seizures that evolve into status epilepticus (SE) will be captured by type and duration (>10 
minutes) as are all seizures. SE should be entered as an SAE if a prolonged seizure or series of 
seizures persists for 30 minutes or longer, regardless of administration of rescue medication, 
and is either diagnosed by a medical professional or occurs more than once in a day. SE lasting 
for less than 30 minutes should be entered as an AE, unless one of the other SAE criteria (eg, 
hospitalization) are met. If this incident involves multiple seizures close in time, the SE 
definition applies if the seizures are close together such that consciousness is not regained 
between ictal events. 
After 12 months in Part 2, seizure diaries are not required. Rather, based on discussions with 
the parent/caregiver, clinical evaluation, and review of any documentation provided by the 
caregivers, investigators will assess the percent improvement in seizure burden on a 5-point 
scale: <25%, ≥25%, ≥50%, ≥75%, 100% [ie, seizure-fee] improvement. 
7.1.2 
Clinical Global Impression - Improvement 
Both the parent/caregiver and the investigator will rate their global impression of the subject’s 
condition throughout the study according to the schedule in Table 1 and Table 2. 
The CGI scale measures the change in the subject’s clinical status from a specific point in time, 
ie, the Baseline Period. The CGI rating scale permits a global evaluation of the subject’s 
improvement over time. The severity of a patient’s condition is rated on a 7-point scale ranging 
from 1 (very much improved) to 7 (very much worse) as follows: 
1=very much improved 
2=much improved 
3=minimally improved  
4= no change 
5=minimally worse 
6=much worse 
7=very much worse 
The parent/caregiver will be asked to indicate the appropriate response that adequately 
describes how their child’s symptoms have improved or worsened relative to baseline before 
the beginning of the study (before any study drug was taken). 
The investigator (or appropriately trained designee) will be asked to indicate the appropriate 
response that adequately describes how the subject’s symptoms have improved or worsened 
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relative to baseline before the beginning of the study (before any study drug was taken). A 
paragraph describing symptoms and function at baseline will be document in the source file 
prior to rating. 
7.1.3 
Vineland Adaptive Behavior Scale (VABS) 
The VABS (Appendix 4) is a parent/caregiver completed assessment that looks at the personal 
and social skills of individuals from birth through adulthood.  Because adaptive behavior 
refers to an individual's typical performance of the day-to-day activities required for personal 
and social sufficiency, these scales assess what a person actually does, rather than what he or 
she is able to do.  The VABS assesses adaptive behavior in 4 domains: communication, daily 
living skills, socialization, motor skills, and will be conducted according to the schedule in 
Table 1.  
7.1.4 
QOLCE 
The QOLCE (Appendix 6) is a parent/caregiver completed assessment that looks at how epilepsy 
affects day-to-day functioning of their child in various life areas, including physical activities, 
well-being, cognition, social activities, behavior and general health, will be conducted according 
to the schedule in Table 1 and Table 2. The QOLCE has been validated in children aged 4 and 
older, and there are published data on the use of the QOLCE in children with epilepsy as young 
as 2 years of age (Sabaz et al., 2000; Talarska 2007).  
7.1.5 
Parent/Caregiver Affective Symptoms 
7.1.5.1 The impact on anxiety and depressive symptoms of the parent/caregiver 
responsible for a patient with LGS will be assessed according to the schedule in Table 
1 and Table 2 using 2 scales: the HADS and the Zarit Caregiver Burden Inventory. 
Parents/caregivers who do not give consent to collect this rating scale will not 
complete them. The same parent/caregiver should complete this rating throughout the 
study. If that person is not available at the visit, the scale should not be 
completed.Hospital Anxiety and Depression Scale (HADS) 
The HADS (Appendix 7) is a tool commonly used to determine the levels of anxiety and 
depression that a person is experiencing. It is a 14-item scale that generates ordinal data. Seven 
of the items relate to anxiety and 7 relate to depression. 
The HADS (Appendix 7) is a tool commonly used to determine the levels of anxiety and 
depression that a person is experiencing. It is a 14-item scale that generates ordinal data. Seven 
of the items relate to anxiety and 7 relate to depression. 
7.1.5.2 Zarit Caregiver Burden Inventory 
The impact on caregiver burden will be assessed according to the schedule in Table 1 and Table 
2 using the Zarit Caregiver Burden Inventory. Parents/caregivers who do not give consent to 
collect this rating scale will not complete them. The same parent/caregiver should complete this 
rating throughout the study. If that person is not available at the visit, the scale should not be 
completed. 
The Zarit Caregiver Burden Inventory (Appendix 8) is a 22-item inventory derived from the 
original 29-item Zarit inventory. It is the most widely used standardized, validated scale to 
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assess caregiver burden, administered previously in various neurological disorders, including 
epilepsy (Kim, 2010; Westphal-Guitti, 2007). The 22 items evaluate the effect of disease on the 
caregiver’s QOL, psychological suffering, financial difficulty, shame, guilt, and difficulty in 
social and family relationships. Scores range from 0 to 88 with higher scores indicating higher 
burden (<20: little or no burden, 21–40: mild-to-moderate burden, 41–60: moderate-to severe 
burden, 61–88: severe burden). 
7.2 
SAFETY ASSESSMENTS 
7.2.1 
Demographics, Medical/Neurological/Epilepsy History, and Pre-Study 
Medication 
Subject demographics (sex, age, height, weight, and BMI), all ongoing conditions and relevant 
medical history from the past 5 years (including all major hospitalizations and surgeries) as 
well as the subject’s current medical status will be recorded at the Screening visit. Significant 
medications taken during the 30 days prior to the Screening visit will be documented. 
Medication history will be updated as outlined in Table 1 and Table 2. 
7.2.2 
Adverse Events 
Adverse events (AEs) will be collected from the time of signing the informed consent 
form/assent form until the end of the study, including the follow-up clinic visit. Details of the 
definitions and categorization of AEs, and procedures for the reporting of AEs, are available in 
Section 9. 
Severity and causality of AEs will be evaluated according to the criteria specified in Section 8.2 
and Section 8.3, respectively. The observation period for AE reporting is specified in Section 
8.4. At the beginning of each visit at the study site, the study personnel will specifically inquire 
about any AEs that might have occurred since the last study site visit.  As described below, an 
abbreviated physical and/or neurological examination for each subject will be conducted based 
on reported AEs.All AEs will be recorded on the appropriate eCRF page. 
7.2.3 
Physical Examinations 
Complete and abbreviated physical examinations, including height and weight, will be 
conducted by the investigator or designee during the study as outlined in Table 1 and Table 2. 
A complete standard of care physical examination for each subject will be performed and will 
cover the following body systems: general appearance, skin, eyes, ears, nose, throat, heart, 
lungs, abdomen, neurological system, lymph nodes, spine, and extremities. An abbreviated 
physical examination for each subject will cover the following body systems: heart, lungs, and 
follow up of other systems as appropriate based on last exam and reported AEs. 
Any unfavorable findings not present at screening, or worsened from the baseline assessment 
and considered by the investigator as clinically significant, occurring at any point in the 
study will be documented in the eCRF as an AE. 
7.2.4 
Neurological Examinations 
Complete and abbreviated neurological examination will be conducted by the investigator or 
designee during the study as outlined in Table 1 and Table 2. A complete standard of care 
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neurological examination for each subject will be performed and will cover the following: 
cranial nerves, muscle strength and tone, reflexes, coordination, sensory function, and gait. 
An abbreviated neurological follow-up examination for each subject will evaluate any 
symptoms or systems found to be abnormal and unstable or potentially unstable that might 
evolve during study treatment, or to investigate any reported or observed AEs. 
Any unfavorable findings not present at screening, or worsened from the baseline assessment 
and considered by the investigator as clinically significant, occurring at any point in the 
study will be documented in the eCRF as an AE. 
7.2.5 
Vital Signs (Including Height and Weight) 
Height, weight, and vital signs (blood pressure, heart rate, temperature, and respiratory 
rate) will be documented for subjects during study as outlined in Table 1 and Table 2. 
7.2.6 
Laboratory Measurements 
Laboratory safety parameters will be analyzed using standard validated methods. 
The following parameters will be assessed by the laboratory as described in Table 1, 
Table 2 and Table 10: 
x Hematology: hemoglobin, hematocrit, erythrocyte mean corpuscular volume, 
leukocytes, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, neutrophils, lymphocytes, monocytes, eosinophils, basophils and 
platelets 
x Blood Biochemistry: albumin (ALB), alkaline phosphatase (ALP), alanine 
aminotransferase (ALT; SGPT), aspartate aminotransferase (AST; SGOT), bicarbonate, 
blood urea nitrogen (BUN), calcium (Ca), carbon dioxide (CO2), chloride (Cl), 
creatinine, creatine kinase, gamma-glutamyl transferase (GGT), glucose, lactate 
dehydrogenase (LDH), phosphorus, potassium (K), sodium (Na), total bilirubin, direct 
bilirubin, total cholesterol, total protein, triglycerides, uric acid, eGFR. 
x Tests of growth and precocious puberty: Growth hormone (GH), insulin-like growth 
factor-1 (IGF-1), prolactin, Luteinizing Hormone (LH), Follicle Stimulating Hormone 
(FSH), testosterone, estradiol, thyroid function (T3, T4, and thyroid stimulating 
hormone [TSH]), 
x Immunoglobulin (IgG, IgA, IgM) 
x Epilepsy genotype panel 
x Coagulation: Prothrombin time (PT)/International normalized ratio (INR), activated 
partial thromboplastin time (PTT) 
x Whole blood cannabidiol 
x Urinalysis: analysis for pH, glucose, ketones, nitrite, protein, bilirubin, urobilinogen, 
leukocyte esterase, and occult blood. Microscopic analysis will be performed for blood, 
all cell types, and casts. 
x Urine or serum pregnancy test: Urine or serum pregnancy testing will be performed in 
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female subjects of childbearing potential. 
x Urine or serum THC panel 
x The investigator will receive the laboratory report from the central laboratory. After 
reviewing the report and evaluating any results that are outside the normal range for 
clinical significance, the investigator must sign and date the laboratory report in a 
timely fashion. 
Tests resulting in abnormal laboratory values that have been classified by the investigator as 
abnormal, clinically significant should be repeated as soon as possible after receiving the 
laboratory report to rule out laboratory errors. 
At Screening, any laboratory values that deviate from the reference ranges that are not 
exclusionary and are considered by the investigator as clinically relevant must be documented 
on the medical history form of the eCRF. Any deviation outside of the reference range 
considered by the investigator as clinically significant (ie, classified as an abnormal, clinically 
significant value) at any visit after screening will be documented in the eCRF as an AE (see 
Section 9). 
7.2.7 
Plasma Sample for Concomitant Antiepileptic Drug(s) 
Plasma samples to ensure that concomitant AEDs dosing is within an acceptable range will be 
conducted during the study as outlined in Table 1 and Table 2. All samples will be analyzed at 
study end and do not constitute safety assessments. (Importantly, plasma samples for 
concomitant AEDs can be performed at any time if considered clinically indicated. In these 
instances results will be provided to the unblinded Medical Monitor and discussed with the 
Principal Investigator.) 
7.2.8 
Electrocardiograms 
Twelve-lead ECGs will be conducted during study as outlined in Table 1 and Table 2 after 
the subject has been in the supine position resting for ≥5 minutes. Heart rate, PR duration, 
QRS duration, QT duration, QTcF (Fridericia's correction formula), and the investigator’s 
overall interpretation will be recorded. 
7.2.9 
Doppler Echocardiography 
Doppler echocardiography will be conducted at a facility with experience for the subject’s age 
during study as outlined in Table 1 and Table 2. Doppler echocardiography uses ultrasound 
technology to examine the heart or blood vessels. An ECHO uses high frequency sound 
waves to create an image of the heart while the use of Doppler technology allows 
determination of the speed and direction of blood flow by utilizing the Doppler effect. 
Predetermined standard guidelines on the proper evaluation of certain measurements, as well 
as abnormality thresholds, were constructed by the sponsor’s ICAB prior to study initiation. 
These thresholds are provided in Table 9 and Table 11. A manual of proper ECHO technique 
for sites is provided in a separate document. 
7.2.10 
Behavior Rating Inventory of Executive Function (BRIEF) 
The Behavior Rating Inventory of Executive Function (BRIEF) is a parent or teacher report 
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measure designed to address the multidimensional nature of the executive function construct and 
will be used to assess the effects of ZX008 on cognition. The BRIEF assesses eight theoretically 
and statistically derived subdomains of executive function. It was designed to be used for a wide 
range of childhood disorders in order to augment traditional clinic-based assessments, and to 
provide an increased level of ecological validity for clinical assessments (Rabbit, 1997).  Age-
appropriate versions of the BRIEF .(BRIEF-P: 2 to 5 year olds; BRIEF: 6 to 18 year olds; 
BRIEF-A: 19 to 35 year olds), will be conducted according to the schedule in Table 1.  
7.2.11 
Tanner Staging 
Tanner Staging (Appendix 5) will be assessed for subjects >7 to 18 years old during the study 
as outlined in Table 1 and Table 2. Conceptually, pubertal maturation can be described in 
terms of sequence, timing, and tempo. Puberty consists of a series of predictable events, and 
the sequence of changes in secondary sexual characteristics has been categorized by several 
groups. The staging system used most frequently was published by Marshall and Tanner 
(1969, 1970) and the sequence of changes are commonly referred to as ‘Tanner stages’. 
7.2.12 
Columbia-Suicide Severity Rating Scale 
C-SSRS (Appendix 2) will be assessed during study as outlined in Table 1 and Table 2. The C-
SSRS is a validated rating scale that assesses suicidal behavior and ideation. The scale is used 
to assess and track suicide events and provides a summary measure of suicidal tendency. Age 
and intellectual development appropriate versions of the C-SSRS ( Baseline/Screening and 
Since Last Visit) will be used in this study. 
Subjects who are younger than 7 years chronologically, or who are judged by the investigator 
not to have the mental capacity to understand the questions as specified on the C-SSRS, will 
not complete the rating. The investigator should use his/her judgment to substitute 
intellectually-appropriate questions to probe the tendency for self-harm. 
7.3 
PHARMACOKINETIC ASSESSMENTS 
Blood samples for PK assessments of fenfluramine and its metabolite (norfenfluramine) will be 
obtained from all subjects via an indwelling cannula or by venipuncture. 
Blood samples for PK assessment (2 mL) will be obtained at the following time points: 
x 
Part 1 Study Day 43: within 1 hour prior to the morning dose, and 1 (± 15 min), 2 (± 15 
min), and 4-6 hours after the morning dose. 
A total of 4 PK samples will be drawn for each subject for a total of approximately 8 mL of 
blood. 
When blood draws for PK coincide with other assessments, the PK draws take precedence. 
The procedure for the collection and handling of PK samples is outlined in a separate study 
manual. 
7.4 
EPILEPSY GENOTYPE PANEL 
Optional blood samples for genetic analysis are being collected for a comprehensive analysis 
for a broad epilepsy gene panel that will be analyzed at the end of the study to investigate 
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genetic characteristics of study responders and non-responders.  Whole genome sequencing is 
not being performed. Testing is restricted to a 377 childhood epilepsy gene panel; thus, the risk 
of revealing clinically relevant or medically actionable incidental findings is low. Samples may 
be retained for up to 24 months after the end of the study.  
The field of genetics related to epileptic encephalopathies are developing rapidly, thus, in the 
event that new theories emerge on the genetics associated with LGS, the retained samples 
might be used to investigate this genotype in the study population. Results of genetic testing 
will only be provided upon written request; therefore, unless required by law individual results 
of genotyping will not be disseminated outside of the Sponsor, including to the study site.  
Genotyping samples will be double-coded (pseudonymized) so that it is impossible to trace 
back the personal identifying information from the sample number. 
7.5 
APPROPRIATENESS OF MEASUREMENTS 
All of the variables assessed are standard tests or procedures that are commonly used in studies 
of this type. 
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8. 
ADVERSE EVENTS 
8.1 
DEFINITIONS 
8.1.1 
Adverse Events 
According to ICH guidelines, an AE is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment. An AE can, therefore, be any unfavorable and 
unintended sign (including an abnormal, clinically significant laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product. The period of observation for 
adverse events extends from the time the subject gives informed consent until the end of study. 
Adverse events may include: 
x 
Exacerbation (ie, an increase in the frequency or severity) of a pre-existing condition. 
Illness present before study entry should be recorded in the medical history section of 
the eCRF and only be reported as an AE if there is an increase in the frequency or 
severity of the condition during the study. Exacerbation of seizures is considered an AE 
if there was an increase in frequency beyond the subject's typical pre-study fluctuations, 
or in the event that seizures lengthen in duration in a clinically meaningful way 
compared with baseline, or if a new seizure type emerges. 
x 
A clinical event occurring after consent but before IMP administration. 
x 
Intercurrent illnesses with an onset after administration of IMP.  
Adverse events do not include: 
x 
Medical or surgical procedures (the condition that leads to the procedure is the AE, 
eg, tonsillitis is the AE if a tonsillectomy is performed) 
x 
Situations where an untoward medical occurrence has not taken place. For example: 
x 
Planned hospitalizations due to pre-existing conditions, which have not worsened. 
x 
Hospitalizations that occur for procedures not due to an AE (eg, cosmetic surgery). 
x 
Hospitalizations for a diagnostic procedure where the hospital stay is less than 24 
hours in duration or for normal management procedures (eg, chemotherapy). 
For laboratory safety parameters, any instances of absolute values being outside the reference 
range or changes at any visit after study start that are considered by the investigator as 
clinically significant must be recorded in the eCRF as AEs. In addition, at the investigator’s 
discretion, any changes or trends over time in laboratory parameters can be recorded in the 
eCRF as AEs if such changes or trends are considered to be clinically relevant, even if the 
absolute values are within the reference range. 
Laboratory findings do not need to be reported as AEs in the following cases: 
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1. Laboratory parameters are already beyond the reference range, unless a further 
increase/decrease can be considered an exacerbation of a pre-existing 
condition. 
2. Abnormal laboratory parameters caused by mechanical or physical influences on 
the blood sample (eg, hemolysis) and flagged as such by the laboratory in the 
laboratory report. 
3. Abnormal parameters that are obviously biologically implausible (eg, values 
that are incompatible with life). 
4. An abnormal laboratory value that cannot be confirmed after a repeated analysis, 
preferably in the same laboratory (eg, the previous result could be marked as 
not valid and should not necessarily be reported as an AE). 
8.1.2 
Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose: 
1. 
Results in death – The event must be the cause of death for the SAE to meet this 
serious criterion. 
2. 
Is life-threatening – The term “life-threatening” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it had been more severe. 
3. 
Requires in-patient hospitalization or prolongation of existing hospitalization – 
The sponsor considers “hospitalization or prolongation of existing hospitalization” for 
at least 24 hours as the defining criterion for an SAE.  Hospital admissions for planned 
surgery or for normal disease management procedures (eg, chemotherapy) are not 
considered as defining criteria for SAEs. 
4. 
Results in persistent or significant disability or incapacity. 
5. 
Is a congenital anomaly or birth defect. 
6. 
Is medically significant – A medically significant event is defined as an event that 
does not meet any of the other 5 SAE criteria, but which is judged by a physician to 
potentially jeopardize the subject or require medical or surgical intervention to prevent 
one of the above outcomes listed as an SAE criterion. Anaphylaxis that is successfully 
treated by administration of epinephrine prior to other sequelae is an example of a 
potentially medically important event. 
The most important term should be selected as the criteria for the SAE.  Medically 
significant should be used when none of the other terms apply. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are defined as SAEs that do 
not meet determination of expectedness as determined in accordance with applicable 
product information (Investigator's Brochure or other reference documentation). Upon 
receipt of a SAE report from an Investigator site, all suspected adverse reactions related to 
the IMP which occur within the clinical trial will be assessed for expectedness. Any SAE 
not listed in the reference documentation is considered a Suspected Unexpected Serious 
Adverse Reaction (SUSAR). SUSARs will be reported by the Sponsor, or its designee, in 
compliance with local legal requirements. During the course of the study, the Sponsor will 
report within required timelines all SAEs that are both unexpected and at least reasonably 
related to the IMP (SUSARs) to the Health Authorities, IECs / IRBs as appropriate and to 
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the Investigators. This study will comply with all applicable regulatory requirements and 
adhere to the full requirements of ICH Topic E2A (Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting [1994]).  
For the purpose of data collection in this study, a prolonged seizure or series of seizures 
from which the subject does not regain consciousness between ictal events, that is at least 
30 minutes in duration, is termed status epilepticus (SE). SE should be entered as an SAE if a 
prolonged seizure or series of seizures persists for 30 minutes or longer, regardless of 
administration of rescue medication, and is either diagnosed by a medical professional or 
occurs more than once in a day. SE lasting for less than 30 minutes should be entered as an 
AE, unless one of the other SAE criteria (eg, hospitalization) are met. If this incident 
involves multiple seizures close in time, the SE definition applies if the seizures are close 
together such that consciousness is not regained between ictal events. 
Adverse events that do not fall into the above categories are defined as nonserious AEs. 
8.1.3 
Adverse Events of Special Interest 
As per ICH guidance (E2F Development Safety Update Report [2011]), the sponsor has 
identified the following AESIs for the ZX008 program (Table 16). 
Table 16: 
Adverse Events of Special Interest 
 
Metabolic/Endocrine 
1. Elevated prolactin level ≥2x above the upper limit of normal (ULN) 
2. Hypoglycemia – <3.0 mmol/l or 54 mg/dl, whether that level is associated with symptoms 
or not  
Neuropsychiatric 
1. Suicidal thoughts, ideation or gestures 
8.2 
SEVERITY OF ADVERSE EVENTS 
The severity of AEs (whether nonserious or serious AEs) is to be assessed by the 
investigator as follows (Table 17). 
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Table 17: 
Severity Definition of Adverse Events 
Severity 
Definition 
Mild: 
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living. 
Moderate: 
A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of 
daily living, causing discomfort but poses no significant or permanent 
risk of harm to the research participant. 
Severe: 
A type of AE that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention. 
  
8.3 
CAUSALITY OF ADVERSE EVENTS 
The causal relationship of an AE to IMP must always be assessed by the investigator. All 
AEs will be classified as either related or not related to IMP. If a causality assessment is 
not provided for an AE (including an SAE), that AE will be considered as related to IMP. 
The degree of certainty with which an AE is attributed to IMP or an alternative cause (eg, 
natural history of the underlying disease, concomitant medication) will be determined by 
how well the event can be understood in terms of: 
x Known pharmacology of ZX008 
x Clinically and/or pathophysiologically plausible context 
x Reaction of a similar nature previously observed with similar products, or reported in the 
literature for similar products as being product related (eg, headache, facial flushing, 
pallor) 
x Plausibility supported by the temporal relationship (eg, the event being related by time to 
administration or termination of treatment with IMP drug withdrawal or reproduced on 
rechallenge) 
The following classifications should be used in categorization of relatedness: 
Not Related: 
Concomitant illness, accident or event with no reasonable association with 
study drug. 
Related: 
The event follows a reasonable temporal sequence from administration of 
study drug and is definitive pharmacologically; cannot to be attributed to 
concurrent disease or other factors or medications. A clinically reasonable 
response should be observed if the study drug is withdrawn or dose 
reduced. 
8.4 
OBSERVATION PERIOD FOR ADVERSE EVENT REPORTING 
The observation period for AE and SAE reporting in an individual subject will start at the time 
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of giving written informed consent for participation in the current study and finish 15 days after 
the last dose of study drug or the last visit, whichever is later. For subjects who enroll in the 
open-label extension (Part 2), ongoing AEs will be followed in that study. 
If the investigator becomes aware of an SAE that has started after the observation period has 
finished, and the event could in some way be associated with IMP (irrespective of whether or 
not it is considered by the investigator to be causally related to IMP), then this must also be 
reported to the sponsor (see Section 8.6). 
8.5 
ADVERSE EVENT REPORTING 
8.5.1 
Adverse Events 
At each clinical evaluation, the investigator (or delegate) will determine whether any AEs have 
occurred. Adverse events will be recorded in the AE page of the eCRF. If known, the medical 
diagnosis of an AE should be recorded in preference to the listing of individual signs and 
symptoms. The investigator must follow up on the course of an AE until resolution or 
stabilization. If an AE is ongoing after the end of study visit, the AE will continue to be 
followed up until resolution or stabilization. 
If, during the study period, a subject presents with a pre-existing condition that was not noted at 
the time of study entry, the condition should be retrospectively recorded in the Medical History 
section of the eCRF. 
8.6 
SERIOUS ADVERSE EVENTS REPORTING 
This study will comply with all applicable regulatory requirements and adhere to the full 
requirements of ICH Topic E2A (Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting [1994]). 
In the event of a SAE the investigator or delegate must:  
1. Enter all relevant information in the AE page of the eCRF 
2. Inform the safety group and/or the Medical Monitor of the SAE via email or fax 
within 24 hours of becoming aware of the SAE. 
3. Follow the initial notification with a completed SAE report form. The SAE form must 
be emailed or faxed to iHC within 24 hours of becoming aware of the SAE.  
All SAEs that occur during the course of the study, beginning the day Informed Consent 
is signed, whether or not causally related to IMP must be reported immediately via fax or 
email (within 24 hours of the investigator becoming aware of the event) to the 
sponsor/designee or the Medical Monitor.  
Adverse events occurring in the period between the time the subject gave written informed 
consent and the first exposure to IMP that meet one or more of the seriousness criteria for AEs 
must be reported to the sponsor/designee and the Medical Monitor in the same manner as 
other SAEs and will be included in the clinical study database. 
Any SAE that occurs 15 days after the last dose of study drug or the last visit, whichever is later 
that is considered to be causally related to IMP must be reported immediately (ie, within 24 
hours of the investigator becoming aware of the event) to the sponsor/designee and the 
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Medical Monitor. 
Contact details and guidance for reporting SAEs will be provided to study site before the study 
starts. 
8.6.1 
Requirements for Immediate Reporting of Serious Adverse Events 
The minimum reporting requirements for immediate reporting of SAEs include: 
1. Identifiable subject 
2. Suspected drug product 
3. Event description 
4. Identifiable reporting 
source In addition, the investigator 
must: 
1. Report all SAEs to the relevant IRB/IEC within the timeframe specified by 
the IRB/IEC. 
2. Submit follow-up reports to the sponsor Global Clinical Safety and 
Pharmacovigilance/designee and the Medical Monitor until the SAE has 
resolved, or, in the case of permanent impairment, until stabilized. 
3. Ensure that the AE term(s) and causality assessment for all SAEs is entered in 
the eCRF. 
If the minimum requirements for reporting are fulfilled, the investigator should not wait to 
receive additional information to fully document the event before notifying the 
sponsor/designee. 
When submitting SAE reports to the sponsor/designee, subjects should be identified only by 
their subject number and study number. The investigator should not include the subject’s name 
and address. 
SAE update reports can be submitted to the sponsor/designee any time that additional relevant 
information becomes available. In cases of death, the investigator should supply the 
sponsor/designee and the IEC/IRB (as applicable, see Section 8.7) with any additional 
requested information as it becomes available (eg, autopsy reports and detailed medical 
reports). Once an SAE is reported to the sponsor/designee’s Safety Group, a Safety Specialist 
may contact the investigator with follow-up questions. 
The procedure to be followed if an ongoing AE becomes an SAE after the end of the 
observation period for AEs is described in Section 8.9. 
8.7 
REPORTING OF SERIOUS ADVERSE EVENTS BY INVESTIGATOR 
TO IEC/IRB 
The timeframe within an IEC/IRB must be notified of a death or an unexpected SAE 
considered at least possibly related to the IMP is stipulated by each individual IEC/IRB. The 
investigator is responsible for complying with the requirements for IEC/IRB notification. The 
investigator will notify the relevant IEC/IRB within the applicable timeframe by forwarding the 
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safety report (eg, MedWatch/CIOMS form) completed by the sponsor/designee for the 
notifiable event. 
8.8 
REPORTING OF EVENTS OTHER THAN SERIOUS ADVERSE 
EVENTS BY INVESTIGATOR TO SPONSOR 
Even if none of the criteria for an SAE are fulfilled, any of the following events must be 
reported by the investigator to the Medical Monitor within 72 hours from the time the 
investigator is notified. 
1. Hypersensitivity reactions 
2. Pulmonary hypertension 
3. Cardiac symptoms requiring intervention, or valvulopathy, if 
identified outside of study-related monitoring 
8.9 
FOLLOW-UP OF ADVERSE EVENTS 
Every effort should be made to follow-up subjects who continue to experience an AE or an 
SAE on completion of the study or until the AE resolves. All follow-up information (and 
attempted follow-up contacts) should be documented in the subject’s medical records. Details 
of the subject’s progress should also be submitted to the sponsor/designee’s Global Clinical 
Safety and Pharmacovigilance and the Medical Monitor. 
Subjects who are discontinued from the study or complete the study and have been found to have 
any signs of valvulopathy or pulmonary hypertension on ECHO will be followed until the 
condition has resolved or stabilized where no further changes are likely, for a minimum of 
6 months from the last dose of study medication, unless it is determined after unblinding that the 
subject did not receive ZX008. 
8.9.1 
Follow-up of Echocardiogram Findings 
All ECHOs will be evaluated by a central reader, in consultation with the ICAB, if 
warranted. Findings related to pulmonary hypertension or valvulopathy on any of the four 
valves (aortic, mitral, pulmonary, tricuspid) will be reported to the investigator with grades of 
normal, trace, mild, moderate or severe. If the ECHO result has progressed in severity since 
the last reading then new oversight measures will be enacted as described below in Table 18 
which describes the severity of ECHO findings with the level of increasing oversight if the 
subject is to remain in the study. 
Table 18: 
Clinical Measures Enacted Upon Increasing Severity of ECHO Findings 
 
Severity 
Valve 
Aortic 
Mitral 
Pulmonary 
Tricuspid 
Trace (≤18 years) 
Level 2 
Level 2 
Level 1 
Level 1 
Trace (>18 years) 
Level 1 
Level 1 
Level 1 
Level 1 
Mild (≤18 years) 
Level 2 
Level 2 
Level 1 
Level 1 
Mild (>18 years) 
Level 2 
Level 1 
Level 1 
Level 1 
Moderate 
Level 3 
Level 3 
Level 3 
Level 3 
Severe 
Level 3 
Level 3 
Level 3 
Level 3 
 
Level 1:   Continue per protocol 
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Level 2: 
1. If there is a desire to continue study medication: 
a. The investigator will evaluate the efficacy to date based on study diaries 
and consult with the parent/guardian, and determine whether study 
treatment was associated with significant, meaningful benefit in number, 
severity and/or duration of seizures and/or on the impact on daily 
functioning. 
b. The investigator will consider whether the subject has had reasonable trials 
(dose and duration) of other available anticonvulsants (eg, valproic acid, 
clobazam, or topiramate), alone or in combination, and not maintained the 
level of seizure control achieved with study medication. 
2. If the investigator feels consideration of continued treatment is warranted considering 
benefit and potential risk, and the parent/guardian feels strongly that the subject be 
maintained on the study medication when understanding the risks, the parent/guardian 
must sign a new consent which describes the additional risks and the subject should 
provide assent if appropriate. 
a. If both of these conditions are not met, the subject is discontinued 
from treatment. 
3. The investigator prepares a case history and rationale for continuation to be submitted 
to the IDSMC for review, including consideration of effects on seizures and 
comorbidities. 
4. The cardiac reviewers (from the central reader, and potentially ICAB) prepare an 
evaluation of the cardiopulmonary risks and proposed monitoring plan if applicable, 
for submission to the IDSMC. 
5. IDMSC will review the submissions from the Investigator and cardiac central reader 
and unblind the subject treatment if warranted. 
6. IDSMC makes a determination of appropriate path, including the possible outcomes: 
a. Discontinue study medication 
b. Increase frequency of ECHO and ECG monitoring 
c. Add additional ECG and/or ECHO measures to be monitored 
d. Reduce the dose of study medication 
Level 3: 
1. The investigator will evaluate efficacy to date based on study diaries and consult 
with the parent/guardian, and determine whether the achieved benefit justifies the 
consideration of continuing study treatment by the IDSMC. MINIMAL efficacy 
criteria for IDSMC consideration: 
a. Seizures must be more than 75% improved (number of motor seizures per 28 
days) on treatment over baseline, and improvement must be consistent. 
b. The number, type, duration, and distribution of seizures at baseline should be of 
a severity, which justifies the risks of cardiopulmonary complications, 
considering the subject’s age and overall health. 
c. Subject has had reasonable trials (dose and duration) of other available 
anticonvulsants (eg, valproic acid, clobazam, topiramate), alone or in 
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combination, and not maintained the level of seizure control achieved with 
study medication. 
2. If the investigator feels consideration of continued treatment is warranted 
considering benefit and potential risks, and the parent/guardian feels strongly that 
the child be maintained on the study medication when understanding the risks, the 
parent/guardian must sign a new consent, which describes the additional risks and 
the child should provide assent if possible. 
a. If both of these conditions are not met, the subject is discontinued 
from treatment. 
3. The investigator prepares a case history and rationale for continuation to be submitted 
to the IDSMC for review, which includes effects of study medication on seizures and 
comorbidities related to LGS. 
4. The cardiac reviewers (from the central reader, and potentially ICAB) prepare an 
evaluation of the cardiopulmonary risks and proposed monitoring plan if applicable, 
for submission to the IDSMC. 
5. IDMSC will review the submissions from the Investigator and cardiac central reader 
and unblind the subject treatment if warranted. 
6. IDSMC makes a determination of appropriate path, including these possible 
outcomes: 
a. Discontinue study medication 
b. Increase frequency of ECHO and ECG monitoring 
c. Add additional ECG and/or ECHO measures to be monitored 
8.10 
PREGNANCY 
This study is open to female and male subjects. Whenever possible, a pregnancy in a female 
subjects or the female partner of a male subject exposed to IMP should be followed to term so 
as to assess any potential occurrence of congenital anomalies or birth defects. Any follow-up 
information, including premature termination and the status of the mother and child after 
delivery, should be reported by the investigator to the sponsor/designee using a pregnancy 
reporting/outcome form. 
9. 
DATA HANDLING PROCEDURES 
9.1 
RECORDING OF DATA 
The investigator (or delegate) will maintain individual records for each subject. These records 
should include dates when a subject visited the study site, study-required information and data, 
and other notes as appropriate. These records constitute source data. 
An eCRF and a subject diary will be provided by the sponsor (or delegate) for each subject 
enrolled into the study. Study site staff will enter data directly into the validated electronic data 
capture (EDC) system by completing the eCRF via a secure internet connection. The 
investigator is responsible for ensuring accurate and proper completion of the eCRF and subject 
diary for recording data according to the instructions given in the eCRF and subject diary. 
All entries in the eCRF must be backed up by the relevant source data at the study site. All 
source data will be kept according to all applicable regulatory requirements (see Section 12.8). 
Source data must follow good documentation practices, be completed legibly for each subject 
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enrolled into the study and signed by the investigator (or delegate). 
Data entry in the eCRF and subject diary must be completed in a timely manner so that they 
always reflect the latest observations on the subjects enrolled in the study. 
The subject’s diary will be completed by the parent/caregiver at home. Data entries will be 
reviewed by the investigator for completion and consistency. 
9.2 
DATA QUALITY ASSURANCE 
An initiation meeting will be held before starting the study, during which the study design, 
procedures to be followed, and measures for ensuring standardized performance will be 
explained by a delegate from the sponsor, and a common understanding of the requirements of 
the study will be reached with the investigator and other relevant personnel at the study site. 
Data generated throughout the study will be monitored and the data entered in the eCRFs will 
be checked against the subject records for completeness and accuracy. The sponsor’s study 
monitor will perform this function. 
The computer system used for study data handling will be fully FDA 21 CFR Part 11 
compliant. All creation, modification or deletion of electronic study records will be 
documented through an automated Audit Trail. Following completion of eCRF pages and entry 
of the data into a database, the data will be checked electronically for consistency and 
plausibility. Data queries will be generated for questionable data and response clarification will 
be sought from the investigator. These data queries must be resolved in a timely manner by the 
investigator (or delegate). 
9.3 
RECORD RETENTION 
A study document binder will be provided by the sponsor for the investigator at each site for all 
requisite study documents (constituting the “Investigator Study File”). 
Following completion of the study, the investigator will retain copies of the approved study 
protocol, ICF, relevant source documents, and all other supporting documentation related to the 
study according to applicable regulatory requirements. 
The investigator is responsible for archiving the Investigator Study File, the subject’s records, 
and the source data according to applicable regulatory requirements. These documents have to 
be archived for at least 15 years or at least 2 years after the last approval of a marketing 
application in an ICH region, but should be retained for longer if required by regulatory 
requirements or by agreement with the sponsor. 
If the investigator can no longer maintain the archive of study records (eg, due to retirement or 
relocation), the sponsor must be informed in writing about any change in responsibility for 
record retention, including the name of the new responsible party, contact information, and 
location of the study records. Records may not be destroyed without prior written consent from 
the sponsor. 
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10. 
STATISTICS 
10.1 
STATISTICAL ANALYSIS: PART 1 
The primary analyses of the study will be performed on data from Part 1 Cohort A after the last  
subject enrolled in Cohort A has completed the last study visit of Part 1. Data from Part 1, 
Cohort B will be analyzed independently after the last subject in Cohort B completes Part 1. 
An interim analysis of Part 2 will be performed after all Cohort B subjects complete 12 months 
in Part 2.  A secondary analysis will be conducted after the last Cohort B subject has enrolled 
and completed the last study visit of Part 2.  Analysis results for Part 1 from Cohort A and 
Cohort B will be compared through descriptive statistics, and if reasonable, some analysis may 
be performed using data from Cohort A and Cohort B combined. Subjects randomized to 0.5 
mg/kg/day (ie, those taking concomitant STP) will be grouped with subjects randomized to 
0.8 mg/kg/day for all efficacy analyses. 
10.1.1 
DETERMINATION OF SAMPLE SIZE 
The sample size for Part 1 Cohort A was estimated under the assumption that adding ZX008 at 
0.8 mg/kg/day to current therapy will lead to a mean decrease in drop seizures that is 30 
percentage points greater than adding placebo to current therapy. For example, if adding placebo 
leads to a 10% decrease in seizures, then adding the high dose of ZX008 would be expected to 
decrease seizures by at least 40%. 
The variability expected in the trial was estimated from a Phase 3 trial of clobazam for patients 
with Lennox-Gastaut syndrome (Ng 2011) leading to an assumption that the SD is 50%. Other 
assumptions include an allowance for 20% dropouts between randomization and the start of the 
maintenance period.  
Under these assumptions, and using a Wilcoxon rank-sum test to approximate the primary 
comparison between the ZX008 0.8 mg/kg/day and placebo groups, a sample size of 63 subjects 
per treatment group affords 90% power to detect a difference between groups that is significant 
at the α=0.05 level. Assuming a 20% drop-out rate prior to the start of the maintenance period 
yields a requirement for an additional 16 subjects per group for a total of 79 subjects per 
treatment group.  Similar calculations for the 0.2 mg/kg/day ZX008 group lead to a total required 
sample size of 237. The number of subjects randomized into Part 1 Cohort A is estimated to be 
approximately 250 due to the long baseline period. 
The sample size of 10 to 15 subjects per treatment group in Cohort B is expected to provide a 
descriptive assessment of whether the treatment effect in Japanese subjects is similar that 
observed in Cohort A subjects from the rest of the world. 
10.1.2 
ANALYSIS POPULATIONS 
10.1.2.1 
Safety (SAF) Population 
All Part 1 safety analyses will be performed on the SAF Population defined as all randomized 
subjects who receive at least one dose of ZX008 or placebo.  
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10.1.2.2 
Modified Intent-to-Treat (mITT) Population 
The mITT Population is defined as all randomized subjects who receive at least one dose of 
ZX008 or placebo and for whom at least one week of diary data are available. Subjects will be 
analyzed according to the treatment group to which they were randomized. The primary 
comparison of ZDX008 0.8 mg/kg/day to placebo, who complete at least 4 weeks of diary 
data in the maintenance period, as well as key secondary analyses, will be performed on the 
mITT Population. 
10.1.2.3 
Per Protocol (PP) Population 
The PP Population is defined as all randomized subjects who receive at least one dose of 
ZX008 or placebo, and have no major protocol deviations that would have a significant 
impact on clinical outcome.  
10.1.3 
SUBJECT COHORTS 
10.1.3.1 
Cohort A 
Cohort A comprises all randomized subjects from North America, Europe, and Australia 
10.1.3.2 
Cohort B 
Cohort B comprises all randomized subjects from Japan only. 
10.1.4 
TREATMENT GROUPS 
Subjects will be randomly assigned to one of three treatment groups: ZX008 0.8 mg/kg/day, 
ZX008 0.2 mg/kg/day, or placebo. 
10.1.5 
TREATMENT PERIODS 
Baseline Period 
The Baseline Period covers the 28 days immediately prior to randomization. The baseline 
frequency of seizures that lead to drops will be calculated from data collected during this period. 
Titration Period 
The Titration Period covers the first 14 days of treatment while subjects are titrated to their 
randomized dose. It begins on the first full day of treatment (Study Day 1) and extends 
through Study Day 15 regardless of the exact day on which a subject reaches his or her 
assigned dose. The Titration Period applies to all subjects including placebo recipients. 
Maintenance Period 
The Maintenance Period covers the 12 weeks following the end of the titration period. It begins 
on Study Day 16 and extends through Study Day 99. 
Titration +Maintenance (T+M) Period 
The T+M period combines the Titration and Maintenance periods, beginning on Study Day 1 
and extending through Study Day 99. The T+M period is considered the treatment period. 
Taper/Transition Period 
The Taper/Transition Period begins immediately at the end of T+M period and extends to Visit 
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13, 2 weeks later; ie, from Study Day 99 through Study Day 113.  
10.1.6 
STATISTICAL ANALYSES AND METHODS 
All efficacy, safety, and PK data will be summarized by cohort. Continuous data will be 
summarized using descriptive statistics including means, standard deviations, medians, lower 
and upper quartiles, and ranges. Categorical variables will be summarized with frequencies and 
percentages. Confidence intervals will be calculated for key parameters or estimates as 
warranted. 
A complete description of the statistical analyses and methods will be available in a SAP, 
which will be finalized before the database is locked. 
10.1.6.1 
Efficacy Analyses 
Primary Efficacy Analysis 
The primary efficacy endpoint for Part 1 is the percent change in frequency of seizures that 
result in drops (DSF: drop seizure frequency) per 28 days between the combined Titration and 
Maintenance (T+M) and Baseline periods in Cohort A. The DSF will be calculated from all 
available data collected during the Baseline and T+M Periods without imputation. The percent 
change from baseline DSF will be calculated as the the change in DSF between T+M and 
Baseline / DSF during Baselineu 100. Both the mean and median percent change in DSF Both 
the mean and median percent change in DSF will be presented. 
The primary endpoint will be assessed using a nonparametric, rank analysis of covariance 
(ANCOVA) with treatment group (ZX008 0.8 mg/kg/day, ZX008 0.2 mg/kg/day or placebo) 
and weight group (<37.5 kg, ≥37.5 kg) as factors;rank baseline DSF as a covariate; and rank 
percent change in DSF from baseline as the response variable. The primary analysis will 
compare the ZX008 0.8 mg/kg/day group to the placebo group at the α=0.05 level of 
significance. The difference between the ZX008 0.8 mg/kg/day group and the placebo group in 
percent change in DSF, and its 95% confidence interval, will be estimated using the Hodges-
Lehmann method. 
As a sensitivity analysis, the primary endpoint will also be analyzed using a parametric 
ANCOVA that incorporates treatment group and weight group as factors; log baseline DSF as a 
covariate; and log DSF during T+M as the response variable. Significance will be assessed by a 
model contrast that compares the ZX008 0.8 mg/kg/day group to the placebo group. The size of 
the treatment effect will be estimated by exponentiating the difference between the ZX008 0.8 
mg/kg/day group and the placebo group derived from the model. Another sensitivity analysis 
will compare the ZX008 0.8 mg/kg/day group to the placebo group using a Wilcoxon rank-sum 
test. 
Key Secondary Analyses 
The first key secondary endpoint for the ZX008 0.8 mg/kg/day group – the proportion of 
subjects who achieve a ≥50% reduction from baseline in the frequency of seizures that result in 
drops – is derived directly from the primary endpoint, but is widely considered a benchmark for 
clinical meaningfulness of a medical intervention for seizures. The comparison will be made 
using a logistic regression model that incorporates the same factors and covariate as the 
ANCOVA used in the primary analysis. The second key secondary endpoint – the proportion of 
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subjects assessed by the Investigator as minimally, much, or very much improved on the CGI-I 
will be analyzed using a Cochran-Mantel-Haenszel test (CMH) stratified by weight strata. 
The percent change from baseline DSF in the ZX008 0.2 mg/kg/day group will be compared to 
the placebo group using the same methods employed for the primary analysis. In particular, the 
same ANCOVA model will be used. Nonparametric methods will be used if normality 
assumptions do not hold. Analyses of other key secondary endpoints involving the ZX008 0.2 
mg/kg/day group will employ similar methods as those used to compare ZX008 0.8 mg/kg/day 
to placebo. 
Multiplicity Strategy and Testing Hierarchy 
The efficacy analyses will employ a serial gatekeeper strategy to maintain the Type 1 error rate 
at α=0.05 across the family of analyses that support the primary and key secondary objectives. 
The strategy specifies a hierarchy of significance tests where each test acts as a gatekeeper to 
the tests below it. 
The hierarchy starts with the primary analysis comparing ZX008 0.8 mg/kg/day to placebo 
on the percent change from baseline in DSF. The next two steps in the hierarchy also entail 
comparisons of ZX008 0.8 mg/kg/day to placebo on two key secondary endpoints. The last 
three steps in the hierarchy all involve comparisons of ZX008 0.2 mg/kg/day to placebo. 
Below is a complete list of steps in the testing hierarchy in order: 
1. 
Compare ZX008 0.8 mg/kg/day to placebo on the percent change in DSF from 
baseline in DSF. 
2. 
Compare ZX008 0.8 mg/kg/day to placebo on the proportion of subjects who 
achieve a ≥50% reduction from baseline in DSF. 
3. 
Compare ZX008 0.8 mg/kg/day to placebo on the change from baseline in the 
number of all countable motor seizures. 
4. 
Compare ZX008 0.2 mg/kg/day to placebo on the percent change from baseline in 
DSF. 
5. 
Compare ZX008 0.2 mg/kg/day to placebo on the proportion of subjects who 
achieve a ≥50% reduction from baseline in the DSF. 
6. 
Compare ZX008 0.2 mg/kg/day to placebo on the CGI-I at Visit 12. 
Part 1 Cohort B 
Efficacy analyses for Part 1 Cohort B will use the same methods as described for Part 1 Cohort 
A. Some subsets analyses may not be feasible in Cohort B due to its smaller sample size. 
10.1.6.2 
Safety Analyses 
Summaries of safety data will be presented by treatment – ZX008 0.8 mg/kg/day, ZX008 
0.2 mg/kg/day or placebo – for the T+M period. The number and percentage of subjects in 
each treatment group with AEs will be displayed by body system and preferred term using the 
Medical Dictionary for Regulatory Activities (MedDRA). Summaries of AEs by severity and 
relationship to study drug will also be presented. A separate summary will be provided for all 
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serious AEs (SAEs). If warranted, selected summaries will be repeated broken out by weight 
group, ie, for subjects who weigh <37.5 kg and those who weigh ≥37.5 kg. 
Laboratory tests, vital signs, physical examinations, neurological examinations, ECG, Doppler 
echocardiogram, C-SSRS, Tanner Staging results, etc, will be summarized appropriately, by 
treatment. All safety summaries will be based on the SAF Population. 
10.1.6.3 
Pharmacokinetic Analyses 
Model-derived plasma PK parameters of fenfluramine and norfenfluramine (Cmax_ss, 
Cmin_ss, , AUC0-t, AUC0-24) will be summarized descriptively by treatment group when 
sufficient data are available. A population PK model, previously developed using data 
from healthy adults and pediatric patients with Dravet syndrome, will updated to include 
the fenfluramine and norfenflurmaine concentration-time data collected during the 
Maintenance Period. This model will be informed by all relevant data available at the time 
of data collection (both adults and pediatrics). The results from the PopPK modeling will 
be reported separately and conducted according to a separate SAP. 
10.2 
STATISTICAL ANALYSIS: PART 2 
Safety and effectiveness will be assessed  in the subjects who continue into Part 2 of the study in 
which all subjects receive open-label ZX008. 
10.2.1 
ANALYSIS POPULATIONS 
10.2.1.1 
OLE Population 
Safety analyses for Part 2 will be performed on the OLE Safety Population defined as all 
subjects who receive at least one dose of ZX008 during the open label extension. 
10.2.1.2 
OLE mITT Population 
The OLE mITT Population is defined as all randomized subjects who receive at least one dose 
of ZX008 and have valid seizure data during the open label extension. 
10.2.2 
TREATMENT GROUPS 
All subjects in Part 2 will receive ZX008 and will be considered a single treatment group. 
Selected data summaries may be broken out by the treatment received during Part 1 and/or 
average dose received during Part 2. 
10.2.3 
TREATMENT PERIODS 
Open-Label Extension (OLE) Treatment Period 
The OLE Treatment Period covers the duration during which subjects receive open label 
treatment with ZX008. 
OLE Taper Period 
The OLE Taper Period begins immediately after the OLE Treatment period and extends for 2 
weeks. 
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10.2.4 
STATISTICAL ANALYSES AND METHODS 
10.2.4.1 
Safety Analyses 
The number and percentage of subjects who experience treatment emergent AEs will be 
displayed by body system and preferred term using MedDRA. Summaries in terms of severity 
and relationship to study drug will also be provided. SAEs will be summarized separately in a 
similar manner. Laboratory tests, vital signs, physical examinations, neurological 
examinations, ECG, ECHO, cognition and body weight will be summarized using appropriate 
methods. 
10.2.4.2 
Effectiveness Analyses 
Effectiveness will be assessed by the change from baseline (prior to randomization into Part 1) 
in DSF. The DSF per 28 days will be calculated as the number of seizures recorded divided by 
the number of days in the period and multiplied by 28. The change in DSF during the OLE 
Treatment Period will be calculated as the difference between DSF during the OLE and the 
baseline DSF measuredprior to randomization in Part 1. The percent change in DSF is the 
change in DSF between OLE and Baseline / DSF during Baseline x 100. Both the mean and 
median percent change in DSF will be presented and the statistical significance of the percent 
change will be assessed using a Wilcoxon signed-rank test.  Other secondary assessments will 
be compared to baseline from prior to Part 1, or by visit throughout Part 1 and Part 2, as 
appropriate. 
For subjects continuing in Part 2 past Visit 22, effectiveness will be assessed by investigator 
rating of overall change in seizure frequency (<25%, ≥25%, ≥50%, or ≥75%, 100% (seizure-
free) improvement compared to last visit). 
10.2.5 
ANALYSES PROVIDED TO AN INDEPENDENT DATA AND SAFETY 
MONITORING COMMITTEE 
A safety oversight monitoring plan will be in place with an IDSMC evaluating data from the 
subjects. Details will be provided in the IDSMC charter. The IDSMC’s primary responsibility 
is to ensure that study subjects are not exposed to unanticipated harm that could have been 
prevented by timely review and intervention. The IDSMC is established to review safety data 
at predefined time points, and to recommend to the sponsor whether to continue, modify, or 
terminate the study as necessary. The IDSMC is composed of expert permanent members who 
cover relevant specialties. The IDSMC members may request assistance from a number of 
additional and ad hoc members if needed. 
11. 
ETHICAL & REGULATORY CONSIDERATIONS 
11.1 
ETHICAL CONSIDERATIONS 
The procedures set out in this study protocol are designed to ensure that the sponsor and the 
investigator abide by the principles of the current ICH GCP guideline on the conduct, 
evaluation and documentation of this study, as described in ICH Topic E6 Guideline. ICH GCP 
is an international ethical and scientific quality standard for designing, conducting, recording, 
and reporting studies that involve the participation of human subjects. Compliance with this 
standard provides public assurance that the rights, safety, and well-being of study subjects are 
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protected and consistent with the principles of the Declaration of Helsinki, and that the clinical 
study data are credible. 
The study will also be carried out according to all applicable international and national 
regulatory requirements. 
The sponsor and the investigator must inform each other (eg, during a study initiation visit, via 
e-mail, etc) that all ethical and legal requirements have been met before the first subject is 
enrolled into the study. 
11.2 
INFORMED CONSENT 
The investigator is responsible for obtaining a subject’s written informed consent to participate 
in the study. 
A Subject Information Sheet and a master ICF will be prepared by the sponsor according to the 
provisions of ICH GCP and local legal requirements. 
All subjects will be informed that the study will be registered in the public database at 
ClinicalTrials.gov in accordance with the FDA Amendments Act of 2007 (Section 12.3). 
Before undergoing screening procedures for possible enrollment into the study, subjects must 
be informed, in an understandable form, about the nature, scope, and possible consequences of 
the study. This information must be given orally to subjects by a physician or medically 
qualified person (according to applicable regulatory requirements) who is well informed about 
the nature, scope, and possible consequences of the study. Written information about the study 
will also be provided in a Subject Information Sheet. The date on which this oral and written 
information on the study was provided to the subject, and by whom it was provided, must be 
documented in the ICF. 
As specified in ICH GCP Section 4.8 and the US 21CFR Section 50.25, the informed consent 
discussion must emphasize that participation in the study is voluntary and that subjects have the 
right to withdraw their consent at any time without giving a reason and without any 
disadvantage for their subsequent care. 
Subjects must be given ample time and opportunity to inquire about details of the study and to 
consider their participation in the study. If, after reading the Subject Information Sheet and the 
ICF, consent is given to participate in the study, then the ICF must be signed and personally 
dated by the subject and the person conducting the informed consent discussion (and an 
impartial witness, if required). The subject will be provided with a copy of the signed ICF. 
Verification of the signed ICF will be recorded in the subject’s eCRF. The original signed ICF 
will be filed with the subject’s records and/or in the Investigator Study File. 
The Subject Information Sheet and ICF have to be approved by the IEC/IRB before they can be 
used in the study. 
The Subject Information Sheet and ICF must be revised whenever important new information 
becomes available that may be relevant to the subject’s consent. Any revision of these 
documents must be approved by the IEC/IRB before they can be used in the study. Subjects 
must be informed in a timely manner if new information becomes available that may be 
relevant to their willingness to continue participation in the study. The communication of this 
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information should be documented by having all parties concerned sign and personally date the 
revised ICF. 
Subject or Subject’s Legally Acceptable Representative Unable to Read 
If a subject is unable to read, or if a legally acceptable representative is unable to read, an 
impartial witness should be present during the entire informed consent discussion. After the 
ICF and any other written information provided to the subject, parent or guardian has been read 
and explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the ICF, 
the witness should also sign and personally date the ICF. By signing the ICF, the witness attests 
that the information in the ICF and any other written information was accurately explained to, 
and apparently understood by, the subject or the subject’s legally acceptable representative, and 
that informed consent was freely given by the subject or the subject’s legally acceptable 
representative. 
Assent for Subjects Under the Age of Consent (Pediatric Subjects) 
All subjects are under the age of consent (ie, pediatric subjects under 18 years of age); the 
written informed consent of a legally acceptable representative is required. Pediatric subjects 
who can understand the nature, scope, and possible consequences of the study must also give 
their assent, orally and/or in writing via the assent document, as appropriate. After the ICF and 
any other written information to be provided to subjects has been read and explained to the 
subject and the subject’s legally acceptable representative, and after the subject and the legally 
acceptable representative have orally consented to the subject’s participation in the study and, if 
capable of doing so, the subject has signed and personally dated the assent document, the 
legally acceptable representative should sign and personally date the ICF. By signing the ICF, 
the legally acceptable representative attests that the information in the ICF and any other 
written information was accurately explained to, and apparently understood by, the subject, and 
that assent was freely given by the subject. 
11.3 
REGULATORY CONSIDERATIONS AND INDEPENDENT 
ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD 
The sponsor (or delegate) will submit the appropriate documents to all applicable competent 
regulatory authorities and IEC/IRBs, and will await all relevant approval before enrolling any 
subjects into the study. Written approval should mention the study protocol by study title, study 
number, and version date. 
This study will be conducted under Investigational New Drug (IND) Application and 
documented in accordance with the applicable regulatory guidelines and requirements. 
The sponsor (delegate) will ensure that the investigators conduct the study as 
stipulated in this study protocol and in accordance with all applicable regulatory 
requirements. The sponsor (delegate) is obliged to obtain evidence of the 
investigator’s qualification to perform the clinical study. Therefore, the investigator 
has to provide a signed and dated copy of his or her professional curriculum vitae 
(prepared no more than 2 years beforehand and preferably written in English) before 
the start of the study, including information on his or her experience in conducting 
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clinical studies according to ICH GCP and other applicable regulatory requirements. 
Written notification of the identity and occupation of the members of the IEC/IRB is also 
required by the sponsor (delegate). Should the IEC/IRB be unwilling to provide this 
information, a letter stating that the committee was constituted in accordance with applicable 
regulatory requirements should be provided. 
11.4 
PROTOCOL COMPLIANCE 
The investigator must conduct the study in compliance with this study protocol as agreed to by 
the sponsor and, if required, by any competent regulatory authority, and which has been 
approved by, or given a favorable opinion by, the IEC/IRB. 
The investigator should not implement any deviation from, or changes to, the study protocol 
without agreement by the sponsor (delegate) and prior review and documented approval or 
favorable opinion from the IEC/IRB of an amendment to the study protocol. Exceptions include 
only cases of medical emergency to address immediate hazards to study subjects, or when the 
changes involve only logistic or administrative aspects of the study. 
In the event of a medical emergency, the investigator at each site may institute any medical 
procedures deemed appropriate to address an immediate hazard to a subject without prior 
IEC/IRB approval or favorable opinion. As soon as possible, the implemented deviation or 
change, the reason(s) for it, and, if appropriate, the proposed study protocol amendment(s) 
should be submitted to: 
x The sponsor (delegate) for agreement. 
x The IEC/IRB for review and approval or favorable opinion (if required). 
x The applicable competent regulatory authority (if required). 
Details of the procedure for implementing study protocol amendments are available in 
Section 12.10. 
At the earliest opportunity, the investigator (or delegate) must inform the sponsor (delegate) 
about any notable protocol deviations and explain any deviation from the approved study 
protocol in the eCRF and/or in the Protocol Deviation Log, if applicable. 
12. 
ADMINISTRATIVE ASPECTS 
12.1 
CLINICAL TRIAL AGREEMENT 
This study will be conducted under a Clinical Trial Agreement between the sponsor (or 
delegate) and the respective institutions representing the study sites. Any financial support 
given to the study sites will be detailed in the Clinical Trial Agreement. The Clinical Trial 
Agreement, which must be signed before the start of any study related procedures, will clearly 
delineate the responsibilities and obligations of the investigator and the sponsor (delegate), and 
will form the contractual basis upon which the study will be conducted. 
12.2 
FINANCIAL DISCLOSURE BY INVESTIGATOR 
Prior to study initiation, the investigator and any subinvestigator(s) to be directly involved in 
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the treatment or evaluation of study subjects at each study site will disclose to the sponsor 
(delegate) any relevant financial or proprietary interests in either the study product or the 
sponsor company. The appropriate disclosure form(s) will be provided by the sponsor 
(delegate) for this purpose. Any relevant updates to the financial disclosure information that 
occur during the conduct of the study, or during one year after completion of the study, will be 
provided by the investigator and subinvestigator(s) to the sponsor (delegate). All financial 
disclosure information provided by the investigator and subinvestigator(s) will be submitted to 
appropriate competent authorities according to the applicable regulatory requirements. 
12.3 
CLINICAL STUDY REGISTRATION AND RESULTS DISCLOSURE 
The sponsor will provide the relevant study protocol information in a public database 
(ClinicalTrials.gov) before or at commencement of the study, as required by the 2007 FDA 
Amendments Act. The sponsor (delegate) may also provide study information for inclusion in 
national registries according to local regulatory requirements. 
If a potential subject contacts the sponsor regarding participation in the study, the investigator 
agrees that the sponsor (delegate) may forward the relevant study site and contact details to the 
subject. Based on the inclusion and exclusion criteria for the study, the investigator will assess 
the suitability of the subject for enrollment into the study. Results of this study will be 
disclosed according to the relevant regulatory requirements. All publications in peer-reviewed 
medical journals resulting from this study will be listed in the original study protocol 
registration record on ClinicalTrials.gov. 
12.4 
STUDY FILES AND MATERIALS 
Before the start of any study related procedures, all essential documents specified by ICH GCP 
and other applicable regulations must be available in the relevant files maintained by the 
sponsor (or delegate) and the investigator. An Investigator Study File prepared by the sponsor 
(or delegate), containing all applicable documents for use at the study site, will be made 
available to the investigator before the start of the study. A list of personnel and organizations 
responsible for conduct of the study as well as the list of investigators will be included in the 
Investigator Study File. The respective files will be kept and updated by the sponsor (or 
delegate) and the investigator, as applicable. 
All study documentation and materials maintained in the Investigator Study File at the study 
site must be available for inspection by the sponsor’s study monitor (or delegate) to determine 
that all required documentation is present and correct (see Section 12.9). 
The study may be audited or inspected by qualified delegates from the sponsor or a competent 
regulatory authority (see Section 12.11). 
12.5 
INITIATION OF THE STUDY 
Before the start of the study at each study site, the sponsor’s study monitor (or delegate) will 
ensure adequacy of the facilities and discuss responsibilities regarding study protocol 
adherence with the investigator and other personnel involved in the study. 
The investigator may not enroll any subjects into the study before the sponsor has received 
written approval or a favorable opinion from the IEC/IRB for conducting the study and a 
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formal meeting has been conducted by the sponsor’s study monitor (or delegate) to initiate the 
study (study initiation visit).  
12.6 
SUBJECT REIMBURSEMENT 
Where relevant, subjects will be reimbursed for reasonable travel costs associated with 
participation in this study, after presentation of receipts for the travel in question, at a rate to be 
approved by the IEC/IRB. Subjects will not be paid for participating in the study. 
12.7 
LIABILITY AND INSURANCE 
The civil liability of the involved parties with respect to financial loss due to personal injury 
and other damage that may arise as a result of this study being conducted are governed by the 
applicable legal requirement(s). 
The sponsor will provide insurance to the investigator if required by the applicable regulatory 
and legal requirement(s). 
If required by local law, subjects taking part in this study will be insured against any injury 
caused by the study in accordance with the applicable regulatory and legal requirement(s). 
12.8 
SUBJECT IDENTIFICATION AND CONFIDENTIALITY 
All study documents, including the study protocol and eCRFs, are the confidential property of 
the sponsor and should be treated as such. 
All subjects screened for the study will be documented in a screening log in compliance with 
the requirements of individual study sites. Subjects not enrolled into the study will be 
documented as such in the screening log together with the reason for not having been enrolled. 
The investigator will maintain a personal list of subject names and subject numbers (Subject 
Identification List) for participants in the study to enable records to be identified at a later date. 
These records should be retained in a confidential manner for the duration stipulated by 
applicable regulatory requirements. All subject names will be kept in confidence and will not 
be revealed to the sponsor. Subject names must be made unreadable on any documents made 
available to the sponsor. 
Subjects participating in the study will be identified in the eCRF by the subject number allotted 
to them during the study. 
The ICF will include a statement that all study findings, irrespective of the medium on which 
they are stored, will be handled in strictest confidence in accordance with applicable data 
protection laws (eg, the European Data Protection Directive [95/46/EC] and the USA Health 
Insurance Portability and Accountability Act [HIPAA]), and will be evaluated by the sponsor 
and/or a competent regulatory authority in an anonymized form. The subjects are also to be 
informed that their medical records may be audited or inspected by qualified delegates from the 
sponsor or a competent regulatory authority. The subject’s written consent authorizing direct 
access to his medical records, and computer processing and publishing of his anonymous 
personal data, must be obtained prior to participation in the study. 
A subject’s identity will be disclosed by the investigator only in case of emergency (ie, to 
address any immediate health hazard). 
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12.9 
MONITORING OF THE STUDY 
The investigator at each site will allow the sponsor’s study monitor (or delegate) reasonable 
access to the eCRFs and direct access to related source documents for monitoring purposes as 
frequently as the sponsor deems necessary. These documents include records of tests performed 
as a requirement for participating in the study as well as other medical records required to 
confirm information contained in the eCRF, such as past history and secondary diagnoses. 
 
Before each monitoring visit, the investigator (or delegate) should record all data generated 
since the last monitoring visit in the eCRF. The investigator and other relevant personnel at 
each study site will be expected to cooperate with the sponsor’s study monitor to assist in 
providing any missing information. 
The study monitor will require access to the Investigator Study File to ensure completeness of 
all documentation required for the study. The study monitor will ensure that the investigator at 
each site has been provided with adequate means for organization and filing of study 
documentation (see Section 12.4). 
The date on which the study monitor (or delegate) visits the study site will be recorded in the 
Site Visit Log. During monitoring visits, the study site’s coordinator (if applicable) and the 
investigator should be available, the source documentation should be accessible, and a suitable 
environment should be provided for the study monitor to review study related documentation. 
The main objectives of monitoring visits conducted by the study monitor include: 
x Resolution of any problems. 
x Examination of all study documentation for completion, adherence to the study protocol, 
and possible AEs. 
x Clarification of inconsistencies or missing data. 
x Verification of study data against source documents. 
x Checks that investigator obligations have been fulfilled. 
x Review of ICFs and dates of consent. 
x Inspection of IMP with respect to storage, labeling, and documentation. 
x Drug accountability 
After each subject’s visit to the study site, the investigator (or delegate) will ensure that all data 
have been entered into the eCRF correctly and in a timely manner, after which the investigator 
will sign the eCRF. 
12.10 
PROTOCOL AMENDMENTS 
A “substantial” amendment of a study protocol is any written description of change(s) to, or 
formal clarification of, a study protocol that may have a significant impact on the safety or 
physical or mental integrity of subjects, the scientific value of the study, the conduct or 
management of the study, or the quality or safety of any IMP used in the study. The IEC/IRB 
must approve all substantial protocol amendments prior to their implementation. If required by 
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applicable local regulatory requirements, the local regulatory authority must also approve all 
substantial protocol amendments prior to their implementation. 
A “non-substantial” amendment of a study protocol includes minor corrections or clarifications 
that have no significant impact on the way the study is to be conducted and has no effect on the 
safety of participating subjects (eg, change in study monitor, contact details, etc). If required by 
applicable local regulatory requirements, the IEC/IRB, and/or the local regulatory authority 
should be notified of all non-substantial protocol amendments. The substantial and non- 
substantial protocol amendments will be integrated into an updated study protocol at the 
discretion of the sponsor if the changes to the original study protocol are numerous, or if 
required by applicable regulatory requirements. 
12.11 
AUDITS AND INSPECTIONS 
The study may be audited or inspected by qualified delegates from the sponsor or a competent 
regulatory authority. 
In the event of an audit by the sponsor, the investigator must make all study related 
documentation available to the auditor(s). Regulatory authorities may request access to all 
study related documentation, including source documents, for inspection and copying in 
keeping with applicable regulations. The sponsor will immediately notify the investigator (or 
vice versa) of an upcoming audit or inspection. 
If an audit or inspection occurs, the investigator and relevant personnel at the study site must 
allocate sufficient time to discuss the findings and any relevant issues. 
12.12 
CLINICAL STUDY REPORT 
After completion of the study, a clinical study report covering clinical and statistical aspects of 
the study will be prepared by the sponsor (or delegate) in consultation with the coordinating 
investigator. As required by the applicable regulatory requirements, the clinical study report 
will be signed by the sponsor’s responsible medical officer as well as the coordinating 
investigator (if applicable). 
Progress reports and/or a summary of the clinical study report will be provided to the IEC/IRB 
and competent regulatory authorities in accordance with applicable requirements. 
12.13 
USE OF DATA AND PUBLICATIONS 
The rights and obligations of investigators and the sponsor concerning any formal presentation 
or publication of data collected as a direct or indirect result of this study will be addressed 
specifically in the Clinical Trial Agreement for the study (see Section 12.1). 
For multicenter studies, the first publication must be based upon all data obtained from all 
analyses, as stipulated in the study protocol by the biostatistician and not by the investigators. 
Investigators participating in multicenter studies must agree not to present data gathered 
individually or by a subgroup of study sites before the full, initial publication is available or 
5 years after the last clinical study visit, whichever is later, unless this has been agreed to by all 
other investigators and by the sponsor. 
The sponsor must receive a copy of any intended communications in advance of the proposed 
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submission date. This is to allow the sponsor time to review the communication for accuracy 
(thus avoiding potential discrepancies with submissions to regulatory authorities), to verify that 
confidential and/or proprietary information is not inadvertently divulged, to provide any 
relevant supplementary information, and to allow establishment of co-authorship (as 
appropriate). The authorship of communications arising from pooled data will include 
investigators from study sites that contributed data as well as relevant personnel from the 
sponsor. Ownership of all data will remain with the sponsor. 
 
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13. 
REFERENCE LIST 
Aicardi J and Gastaut H. Treatment of self-induced photosensitive epilepsy with fenfluramine 
(3 cases). NEJM 1985; Nov 28;313(22):1419. 
Aicardi J, Gastaut H, and Misès J. Syncopal attacks compulsively self-induced by 
Valsalva's maneuver associated with typical absence seizures. A case report. Arch Neurol 
1988 Aug;45(8):923-5. 
Arzimanoglou A, French J, Blume WT, Cross JH, et al. Lennox-Gastaut syndrome: a consensus 
approach on diagnosis, assessment, management, and trial methodology. Lancet Neurol 
2009;8(1):82-93. 
Boel M and Casaer P. Add-On therapy of fenfluramine in intractable self-induced 
epilepsy. Neuropediatrics. 1996; 27: 171-173. 
Casaer P and Boel M. Fenfluramine as a potential antiepileptic drug. Epilepsia. 2002; 43(2): 205-
206. 
Center for Disease Control. Cardiac valvulopathy associated with exposure to fenfluramine 
or dexfenfluramine: U.S. Department of Health and Human Services Interim Public Health 
Recommendations, November 1997. Morbidity and Mortality Weekly Report. 1997; 
46(45):1061-1084. 
Ceulemans B, Boel M, Leyssens K, Van Rossem C, Neels P, Jorens PG, Lagae L. Successful 
use of fenfluramine as an add-on treatment for Dravet syndrome. Epilepsia 2012; 53: 1131-
1139.  
Ceulemans B, Schoonjans A, Marchau F, Paelinck B, Lagae, L. Five-year extended follow-up 
status of 10 patients with Dravet syndrome treated with fenfluramine. Epilepsia 2016; 1-6.   
Connolly HM, Crary JL, McGoon MD, Hensrud DD et al.  Valvular heart disease associated 
with fenfluramine-phentermine. New Engl J Med 1997;337(9):581-8. Erratum in: N Engl J 
Med 1997 Dec 11;337(24):1783. 
Cross JH. Auvin S, Falip M, Striano P, Arzimanoglou A. Expert opinion on the management of 
Lennox-Gastaut syndrome: treatment algorithms and practical considerations. Front Neurol. 
2007;8:505. 
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. 
ICH Topic E2F: Development Safety Update Report, 2011. 
ICH Topic E2A: Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting, 1994. 
Kim KR, Lee E, Namkoong K, Lee YM, Lee JS, and Kim HD, “Caregiver's burden and 
quality of life in mitochondrial disease,” Pediatric Neurology, vol. 42, no. 4, pp. 271–276, 
2010. 
Lagae L, Schoonjans A, Gammaitoni AR, Galer BS, Ceulemans B. A pilot, open-label study of 
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the effectiveness and tolerability of low-dose ZX008 (fenfluramine HCl) in Lennox-Gastaut 
syndrome. Epilepsia, 2018; doi: 10.1111/epi.14540 
Lagae B, Schoonjans A, Gammaitoni A, Galer B, and 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. 
Lancellotti P, Tribouilloy C, Hagendorff A, Moura L, Popescu BA, Agricola E, et al. European 
Association of Echocardiography recommendations for the assessment of valvular 
regurgitation. Part 1: aortic and pulmonary regurgitation (native valve disease). Eur J 
Echocardiogr. 2010;11(3):223-244. 
Lancellotti P, Moura L, Pierard LA, Agricola E, Popescu BA, Tribouilloy C, et al. European 
Association of Echocardiography recommendations for the assessment of valvular 
regurgitation. Part 2: mitral and tricuspid regurgitation (native valve disease). Eur J 
Echocardiogr. 2010;11(4):307-332. 
Marshall WA, Tanner JM. Variations in the pattern of pubetal changes in boys. Arch Dis Child 
1970; 45:13. 
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 
1969;44(235):291-303. 
Morford, L. L., Inman-Wood, S. L., Gudelsky, G. A., Williams, M. T. and Vorhees, C. V. 
(2002), Impaired spatial and sequential learning in rats treated neonatally with d-fenfluramine. 
European Journal of Neuroscience, 16: 491–500. doi:10.1046/j.1460-9568.2002.02100.x 
Ng Y, Conry J, Drummond R, Stolle J, Weinberg M for the OV-1012 Study 
Investigators. Randomized, phase III study results of clobazam in Lennox–Gastaut 
syndrome. Neurology 2011; 77:1473–1481. 
Panayiotopoulos C. Epileptic encephalopathies in infancy and early childhood in which the 
epileptiform abnormalities may contribute to progressive dysfunction. In Panayiotopoulos C (Ed) 
The epilepsies: seizures, syndromes and management. Oxfordshire, UK: Bladon Medical 
Publishing, 2005:137–206. 
Rabbit, P. (Ed.). (1997). /react-text Methodology of frontal and executive function react-text: 
2931 . East Sussex, UK: Psychology Press. 
Sabaz, M., Cairns, D. R., Lawson, J. A., Nheu, N., Bleasel, A. F., & Bye, A. M. (2000). 
Validation of a new quality of life measure for children with epilepsy. Epilepsia, 41(6), 765–774. 
Schoonjans A, Marchau F, Paelinck B, Gunning B, Verhoeven JS, Gammaitoni AR, Galer BS, 
Lagae L, Ceulemans B. Low-Dose Fenfluramine Provides Significant and Long-Term Seizure 
Reduction in Dravet Syndrome: Update and Follow-Up of the Prospective Study. American 
Epilepsy Society Annual Meeting 2017: Abstract 3.264. 
Schoonjans A-S, Lagae L, Ceulemans B. Low-dose fenfluramine in the treatment of neurologic 
disorders: experience in Dravet syndrome. Therapeutic Advances in Neurological Disorders. 
2015;8(6):328-338. doi:10.1177/1756285615607726. 
Talarska, D. (2007). The usefulness of Quality of Life Childhood Epilepsy (QOLCE) 
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questionnaire in evaluating the quality of life of children with epilepsy. Advances in Medical 
Sciences, 52 Suppl 1, 191–193. 
Webb RH, Gentles TL, Stirling JW, et al. Valvular regurgitation using portable 
echocardiography in a healthy student population: implications for rheumatic heart disease 
screening. J Am Soc Echocardiogr. 2015;28:981 988. 
Westphal-Guitti C, Alonso NB, Migliorini RCVP et al., “Quality of life and burden in caregivers 
of patients with epilepsy,” The Journal of Neuroscience Nursing, vol. 39, no. 6, pp. 354–360, 
2007. 
Wheless JW, Clarke DF, Arzimanoglou A, et al. Treatment of pediatric epilepsy: European 
expert opinion, 2007. Epileptic Disord 2007;9:353–412. 
Williams, M. T., Morford, L. L., McCrea, A. E., Wood, S. L., & Vorhees, C. V. (2002). 
Administration of d,l-fenfluramine to rats produces learning deficits in the Cincinnati water maze 
but not the Morris water maze: relationship to adrenal cortical output. Neurotoxicology and 
Teratology, 24(6), 783–796. 
Wong J, Reddy SS, Klein AL. Anorectic drugs and valvular heart disease: a biological and 
clinical perspective.  Cleveland Clinical Journal of Medicine 1998; 65:35-41. 
ZX008 Investigator’s Brochure Version 8, 2020. 
 
 
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14. 
APPENDICES 
APPENDIX 1 – LIST OF PROHIBITED CONCOMITANT 
MEDICATIONS 
The below table lists examples of medications in the classes prohibited under the exclusion 
criteria defined in the protocol, but it is not an exhaustive list. Please consult the medical monitor 
in your region if a participant is on a medication that falls into any prohibited classifications but 
is not listed in the below table. 
ADHD Medications 
Atomoxetine  
Amphetamine and derivates 
Methamphetamine 
Guanfacine  
Methylphenidate  
Lisdexamfetamine 
Bupropion  
Dexmethylphenidate  
Dextroamphetamine  
Clonidine  
 
Anti-arrhythmics 
Antibiotics 
Anti-nausea 
Anti-pyretic 
Mexiletine 
Linezolid 
Metoclopramide 
Phenacetin 
Propafenone 
 
Ondansetron 
 
Anticonvulsants 
Felbamate** 
Retigabine/ezogabine 
THC and derivatives 
 
Epidiolex 
Cannabidiol products 
 
 
Antidepressants (SSRIs, SNRIs, NRIs) 
Amitriptyline 
Clomipramine 
Fluvoxamine 
Paroxetine 
Bupropion 
Desipramine 
Imipramine 
Sertraline 
Buspirone 
Duloxetine 
Nefazodone 
Trazodone 
Citalopram 
Fluoxetine 
Nortriptyline 
Vortioxetine 
Antihistamines 
Astemizole 
Hydroxyzine  
Chlorphenamine  
 
Cyproheptadine 
 
Diphenhydramine  
 
Anti-migraine 
Almotriptan 
Eletriptan 
Naratriptan 
Sumatriptan 
Cafergot 
Ergotamine tartrate 
Rizatriptan 
Zolmitriptan 
Antipsychotics/Neuroleptics (serotonin agonists/ antagonists, noradrenergic agonists/antagonists) 
Amisulpride 
Guanfacine 
Paliperidone 
Risperidone 
Amphetamine 
Haloperidol 
Perospirone 
Sulpiride 
Aripiprazole 
Levomepromazine 
Perphenazine 
Ziprasidone 
Asenapine 
Lurasidone 
Promethazine 
Zuclopenthixol 
Clozapine 
Methylphenidate 
Propanolol 
 
Clonidine 
Olanzapine 
Quetiapine 
 
Anti-viral 
Beta Blocker 
Chemotherapy 
Cough 
Suppressant 
Interferon 
Alprenolol 
Dasatinib 
Dextromethorphan 
Ritonavir 
Bufuralol 
 
 
Telaprevir 
 
 
 
Centrally-acting anorectic agents 
Lorcaserin 
Phentermine 
Naltrexone-
bupropion  
Phentermine-
topiramate 
Diethylpropion 
Benzphetamine 
Phendimetrazine 
Decongestants (allowed for short-term use only) 
Statins 
Phenylpropanolamine 
 
Cerivastatin 
 
Ergot Alkaloids, their derivatives, and Antiparkinson agents 
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Pergolide  
Cabergoline  
Ergotamine Tartrate 
 
Monoamine-oxidase inhibitors 
Isocarboxazid  
Selegiline 
Tranylcypromine 
Phenelzine  
Opioids 
Alfentanil 
Levacetylmethadol (LAAM) 
Meperidine 
Oxycodone 
Codeine 
Fentanyl 
Methadone 
Tramadol 
 
*Felbamate is prohibited as a concomitant medication unless the subject has been on felbamate for at 
least 12 months prior to screening, has stable liver function and hematology laboratory tests, the dose 
has been stable for at least 60 days prior to screening and is expected to remain constant throughout the 
study. 
 
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APPENDIX 5 – TANNER STAGING 
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APPENDIX 6 – QOLCE QUALITY OF LIFE 
 
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APPENDIX 7 – HOSPITAL ANXIETY AND DEPRESSION SCALE 
Hospital Anxiety and Depression Scale (HADS) 
 
Tick the box beside the reply that is closest to how you have been feeling in the past   week. 
Don’t take too long over you replies: your immediate is  best. 
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D 
A 
 
D 
A 
 
 
I feel tense or 'wound up': 
I feel as if I am slowed down: 
 
3 
Most of the time 
3 
Nearly all the time 
 
2 
A lot of the time 
2 
Very often 
 
1 
From time to time, occasionally 
1 
Sometimes 
 
0 
Not at all 
0 
Not at all 
 
 
 
 
 
I still enjoy the things I used to 
enjoy: 
I get a sort of frightened feeling like 
'butterflies' in the stomach: 
0 
 
Definitely as much 
0 
Not at all 
1 
 
Not quite so much 
1 
Occasionally 
2 
 
Only a little 
2 
Quite Often 
3 
 
Hardly at all 
3 
Very Often 
 
 
 
 
 
I get a sort of frightened feeling as if 
something awful is about to  
happen: 
I have lost interest in my  appearance: 
 
3 
Very definitely and quite badly 
3 
Definitely 
 
2 
Yes, but not too badly 
2 
I don't take as much care as I should 
 
1 
A little, but it doesn't worry me 
1 
I may not take quite as much care 
 
0 
Not at all 
0 
I take just as much care as ever 
 
 
 
 
 
I can laugh and see the funny side 
of things: 
I feel restless as I have to be on the 
move: 
0 
 
As much as I always could 
3 
Very much indeed 
1 
 
Not quite so much now 
2 
Quite a lot 
2 
 
Definitely not so much now 
1 
Not very much 
3 
 
Not at all 
0 
Not at all 
 
 
Worrying thoughts go through my 
mind: 
I look forward with enjoyment to 
things: 
 
3 
A great deal of the time 
0 
As much as I ever did 
 
2 
A lot of the time 
1 
Rather less than I used to 
 
1 
From time to time, but not too often 
2 
Definitely less than I used to 
 
0 
Only occasionally 
3 
Hardly at all 
 
 
 
 
 
I feel cheerful: 
I get sudden feelings of panic: 
3 
 
Not at all 
3 
Very often indeed 
2 
 
Not often 
2 
Quite often 
1 
 
Sometimes 
1 
Not very often 
0 
 
Most of the time 
0 
Not at all 
 
 
 
 
 
I can sit at ease and feel relaxed: 
I can enjoy a good book or radio or TV 
program: 
 
0 
Definitely 
0 
Often 
 
1 
Usually 
1 
Sometimes 
 
2 
Not Often 
2 
Not often 
 
3 
Not at all 
3 
Very seldom 
Please check you have answered all the questions 
 
Scoring: 
Total score: Depression (D)   
 
0-7 
= Normal 
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8-10 = Borderline abnormal (borderline case) 11-21 = Abnormal (case) 
 
 
 
 
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APPENDIX 8 – ZARIT CAREGIVER BURDEN INVENTORY 
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APPENDIX 9 – MAXIMUM ALLOWABLE BLOOD DRAW VOLUMES 
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APPENDIX 10 – STUDY CONDUCT DURING COVID-19 
In March 2020, the World Health Organization declared a global pandemic related to an illness caused by 
a novel coronavirus known as COVID-19.  As a result, public health initiatives, such as laws, regulations 
and policies were enacted at country and institutional levels to protect the health of the general public. 
These initiatives and policies have affected the ability of study sites to conduct the trial per protocol and 
the ability of the sponsor and/or delegate to conduct trial oversight and monitoring visits.  
In an effort to support the rights, safety and welfare of subjects and ensure as little impact on the integrity 
of the research as possible the following alternative processes have been implemented due to restrictions 
related to COVID-19. Though every attempt should be made to conduct study visits per protocol, any 
implementation of alternative processes should be properly documented. If there are no impacts or 
accomodations for COVID-19 at a study site, these allowances must not be followed. 
1. Allowance of Delays to In-person Study Visits 
If sites are unable to conduct study visits, or subjects are unable to travel to the study site due to 
COVID-19 circumstances, an in-person visit may be delayed up to 6 weeks from the protocol-defined 
visit due date. Data will need to be entered per normal procedures in the EDC, with a description 
indicating COVID-19 as the cause for delay in response to queries. If a subject is unable to travel to 
the study site within this expanded 6-week window, a telephone or video telemedicine visit should be 
attempted, as described below. If a telephone or video telemedicine visit cannot be conducted in the 
6-week window, the visit should be considered missed and the next scheduled visit conducted.  
2. Allowance of Remote Telemedicine/Telephone/Video Visits:  
Visits 1-5 should be conducted in person. For Visits 6, 8, 10, 15-21, remote visits via telephone or 
video are acceptable when subjects are unable to travel to the site for in-person visits due to COVID-
19 circumstances. The following information should be collected and recorded in the source 
documentation and in the EDC where applicable. Log pages (e.g. AEs, concomitant medication 
changes) will be entered normally as they are not associated with specific visits; assessment forms 
located within a particular visit page will also be entered normally, however, queries will be fired to 
capture specific information explaining the basis for missing or alternatively collected (ie. remote) 
data. Detailed instruction for EDC entry may be found in the CRF Completion Guidelines (CCGs). 
x Date and time of the telephone/video visit 
x Any changes in health status  
x AEs/SAE assessment 
x Concomitant medication query 
x Review seizure and medication diary with parent/caregiver for compliance and any 
abnormalities in seizure activity 
x Scales and Questionnaires, when applicable and if feasible 
o C-SSRS 
o CGI-I (by Investigator and Parent/Caregiver) 
o BRIEF 
o Tanner Staging 
o QOLCE 
o Zarit Caregiver Burden 
o HADS  
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3. End-of-Study/Early Termination (EOS/ET) and Follow-up Visits:  
Cardiac follow-up visits (Visits 14, 24, or 25) must be conducted in-person. 
 
EOS/ET for subjects tapering off ZX008: 
For the EOS/ET visit (Visit 12 or 22) and Post-Dosing Follow-up visit (Visit 13 or 23), every attempt 
should be made to conduct these visits in-person. For subjects tapering off study-drug that are unable 
to come to the study site, the EOS/ET and Post-Dosing Follow-up visits may be conducted via 
telephone or video. However, subjects should return to the study site in person, as soon as feasible to 
conduct any safety assessments that were unable to be evaluated remotely. If an in-person visit cannot 
be scheduled within 6 months of the EOS/ET and/or Post-Dosing Follow-up visit windows to conduct 
the required safety assessments, these assessments will be considered as missed. 
 
EOS/ET for subjects transitioning to another Extension Study: 
For subjects transitioning into another ZX008 extension study that are unable to attend the EOS/ET 
visit due to restrictions to traveling to the study site, delays in the start-up of the extension study, or 
other COVID-related delays, the EOS/ET visit may be delayed until an in-person visit is conducted. 
Therefore, subjects may remain on study for longer than the planned duration of participation. If the 
delay is over 6 weeks, medical monitor review and approval is required. If approval to extend beyond 
6 weeks is granted,  telephone or video visits should be conducted at least every 12 weeks until the in-
person EOS/ET transitional visit to the other extension study is performed. The telephone or video 
visits will collect the following data, at minimum: 
x Date and time of the telephone/video visit 
x Any changes in health status  
x AEs/SAE assessment 
x Concomitant medication query 
x Review seizure and medication diary with parent/caregiver for compliance and any 
abnormalities in seizure activity 
4. Allowance of delays to ECHO, ECG, Chest X-Ray, EEG and clinical lab assessments when in-
person study visits are missed or delayed 
If it is not possible to obtain the above assessments as described below, a documented 
risk/benefit discussion with the medical monitor is required to determine a course of action, 
which may include approval to delay further for a pre-specified duration, subject withdrawal, 
or other actions. The risk/benefit analysis will take into account AEs, previous assessment 
findings, duration of delay, clinical improvement while on study drug (seizure and non-seizure 
outcomes), and region-specific risk of attending in-person visits to complete the assessments. 
 
Doppler ECHO:   
If subjects are unable to travel to the study site due to COVID-19 circumstances, ECHOs may be 
delayed up to an additional 3 months from the protocol-designated ECHO due date (for a total of 6 
months from the time of the last ECHO) for subjects that exhibited the following on their previous, 
most recent ECHO: absent aortic regurgitation, absent or trace mitral regurgitation, and PASP <30 
mmHg. 
All subjects with regurgitation ≥ trace aortic regurgitation, ≥mild mitral regurgitation, or PASP ≥30 
mmHg may have ECHO delayed from the protocol-designated ECHO due date by up to 6 weeks 
only.  
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In those cases where an ECHO cannot be performed in the specified time period at the study-
authorized facility by a certified sonographer, the Sponsor may approve administration of the ECHO 
at an alternative facility to minimize need for travel. If the ECHO cannot be performed, a benefit 
risk/benefit analysis must be conducted as described above. 
If a delayed ECHO was conducted within 30 days of a scheduled Cardiac Follow-up Visit and there 
were no findings meeting Level 2 criteria (see Protocol Table 17), the Cardiac Follow-up Visit may 
be cancelled. If Level 2 or greater findings were observed, then the Cardiac Follow-up Visit should be 
rescheduled 3 months from the date of the delayed ECHO.  
ECG, Chest X-ray and EEG:   
If clinically indicated and where applicable, delays in these assessments may be implemented based 
on the investigators’ clinical discretion, weighing the risk/benefit of the clinical necessity of the 
assessment versus the risk of an in-person visit. All decisions should be documented appropriately in 
the source documentation. If not conducted at the study site, ECG, chest X-ray and EEG can be 
performed at any qualified local facility with results sent to the Principal Investigator for safety 
overread and documentation.  
If the ECG (or in the case of certain country-specific regulations: Chest X-ray or EEG) was 
conducted within 30 days of a scheduled Cardiac Follow-up Visit, these assessments do not need to 
be repeated at the Cardiac Follow-up Visit provided there were no significant findings that require 
additional follow-up.  
Clinical Laboratory Assessments: 
If clinically indicated and where applicable, delays in these assessments may be implemented based 
on the investigators’ clinical discretion, weighing the risk/benefit of the clinical necessity of the 
assessment versus the risk of an in-person visit. All decisions should be documented appropriately in 
the source documentation. If not conducted at the study site, clinical laboratory assessments can be 
performed at any qualified local facility with results sent to the Principal Investigator for safety 
overread and documentation.  
5. Alternative Dispensation for Study Drug 
Shipments of investigational product may be sent by courier from site pharmacy to the subject’s home 
via Sponsor-approved processes if the subject cannot or will not attend the dispensation visit(s). This 
shipment of drug should be arranged for patients who are due in the clinic for a drug dispensation 
visit. Other alternative dispensation, such as curbside pickup, may be implemented provided they are 
approved by the Sponsor and appropriate safeguards are taken to ensure compliance with existing 
regulatory requirements for maintaining investigational product accountability. Detailed instructions 
for drug handling, storage, accountability, etc. are described in the Pharmacy Manual.  
 
 
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APPENDIX 11 - SUMMARY OF PROTOCOL AMENDMENT 4.0 
Rationale for Protocol Amendment 4.0 
The protocol is being amended to simplify the visit schedule and reduce burden on the remaining 
participating subjects and their caregivers in Japan. The reduced in-clinic visit schedule (in-clinic 
visits every six months) will provide longitudinal safety data in an open-label setting which will 
inform the ongoing monitoring of Safety and Efficacy for Lennox-Gastaut syndrome subjects 
receiving fenfluramine as an Investigational Product. The reduction in in-clinic visit frequency is 
also considered to reduce risk for subjects in terms of exposure to COVID19 during a period 
when the global pandemic still poses considerable uncertainty. The assessment of cardiac 
function by ECHO performed every six months is aligned with the Sponsor’s Global Safety 
Surveillance for fenfluramine which has now achieved approval in the US and Europe for the 
indication of Dravet’s Syndrome. Information on seizure data and study drug administration will 
continue to be reported by the parents/caregivers which will enable the Investigator to monitor 
the subject appropriately and assess benefit-risk despite the decrease in visit schedule. A phone 
visit will be performed in between in-clinic visits to collect adverse events, concomitant 
medications and any change in the health status of the subject. Further detail is presented in the 
Summary of Change section.  
This amendment also extends the subject’s study participation for up to 5 years in Part 2, to 
allow subjects to remain on treatment until ZX008 becomes commercially available in the 
subject’s country of residence. 
 
List of Specific Changes 
Additions are marked in red and deletions are marked in strikethrough. Minor editorial and 
nonsubstantive changes, such as the correction of typing or formatting errors, updated use of 
abbreviations, updating headers and footers, tables of contents, list of abbreviations, signature 
pages, etc., are not listed. The list of specific changes below is grouped by rationale and not 
necessarily presented in the order in which they appear in the protocol. 
 
1. Update of Sponsor Information (address, sponsor’s representative and medical contact) 
to reflect the acquisition of Zogenix International Limited by UCB Biosciences Inc.  
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2. Update to extend the subject’s study participation in Part 2 to up to 5 years (5 annual 
extensions, 72 months) 
Updates were made to the protocol language in study synopsis, sections  3.1, 3.3, 3.5, 6.2. Table 
2: Schedule of Assessments: Part 2 Cohort B only- and Table 11 have also been updated to add 
study visits to accommodate protocol extension to up to 5 years, Month 72 (see. next section for 
detailed modifications) 
Study Synopsis/ Study duration 
 
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Study synopsis/Methodology  
 
Section 3.1:  
 
Section 3.3:  
 
Section 3.5:  
 
Section 6.2.5:  
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Section 6.2.6:  
 
 
3. Update to reduce the in-clinic study visit schedule to every 6 months.  
From Visit 26/Month 24 (or a later visit if Visit 26/Month 24 has already occurred at the time of 
Protocol Amendment 4.0 approval), subjects will perform in-clinic visits every 6 months. Study 
visits have been added to accommodate the addition of the annual extensions for up to 5 years. 
Phone visits will be performed between in-clinic visits (3 months after the last in-clinic visit).   
Updates were made to Table 2 and Table 11, as well as Sections 6.2 in order to increase the 
number of visits (phone or in-clinic visits) up to 72 months. Visit numbers have been updated 
accordingly.  
 
Study Synopsis/ Methodology 
 
 
Table 2: Schedule of Assessments: Part 2 Cohort B only 
 
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Table 11: Time Windows for Assessments in Part 2:  
 
Section 6.2.5:  
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4. Updates to the blood volume collected during the study.  
The range of blood volume collected during Part 2 has been updated to reflect the reduced visit 
schedule from V26/Month24 (or a later visit if V26/Month24 has already occurred at the time of 
PA4.0 approval).   
 
Section 6.4:  
 
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5. Update to clarify the timing of analysis of 1601 Cohort A and Cohort B 
Clarification has been made to reflect the timing of data analysis performed for Cohort A and 
Cohort B.   
Updates have been made to study synopsis and sections 10.1 
Study Synopsis/ Methodology:  
 
Study Synopsis/ Statistical Methods:  
 
 
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Section 10.1:  
 
 
6. Addition of language to define the study status between drug approval and launch in 
Japan 
Language has  been added in section 1.6. 
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7. Clarification on the dispensation of study drug to subjects transitioning to commercial 
drug 
Updates has been made to section 6.2.6:  
 
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