Conditions: CDD
Keywords: CKDL5 Deficiency Disorder
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 7
Healthy volunteers: no

Brief summary:
This study will be enrolling 10 patients, ages 2-18 years old, with a confirmed genetic/clinical diagnosis of CDKL5 Deficiency Disorder (CDD) in an open label trial of fenfluramine for seizure control. Patients will be titrated over 14 days to a dose of ZX008 0.8 mg/kg/day (maximum dose 30 mg/d).

Detailed description:

Arms:
arm 1: Study medication will be administered as equal doses twice a day in the morning and in the evening approximately 12 hours apart.

Patients will first be titrated over 14 days to a dose of ZX008 0.8 mg/kg/day (maximum dose 30 mg/d).

After completion of the Titration Period, patients will continue to receive the ZX008 0.8 mg/kg/day dose and be treated for an additional 12 weeks (Maintenance Period). Study medication will continue to be administered twice a day in the morning and in the evening, approximately 12 hours apart.

After completion of the Maintenance Period, patients will enter the Taper Period, where they will decrease from 0.8 mg/kg twice a day to a dose of 0.4 mg/kg twice a day (maximum 30 mg/day). After 4 days at this dose level, patients will decrease their dose to 0.2 mg/kg/day. On day 9 of the Taper Period, all participants will stop taking study medication.

Interventions: intervention 1: Fenfluramine Hydrochloride
Intervention descriptions: intervention 1: Oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 and provided in concentrations of 2.5 mg/mL. Manufactured by Andersonbrecon, Inc. on behalf of Zogenix International Limited.

Protocol document:
Prot_SAP_000.pdf: 
 
 
Official Title: 
Fenfluramine in CKDL5 Deficiency Disorder (CDD)   
NCT Number: 
NCT03861871 
Study Number: 
18-01530 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
January 25, 2021 
 
 


 
 
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FENFLURMAINE IN CKDL5 DEFICIENCY DISORDER (CDD) 
 
Principal Investigator: 
 
 
Principal Investigator: Orrin Devinsky, MD 
New York University Comprehensive Epilepsy Center 
223 East 34th Street 
New York, NY 10016 US 
Phone number: 646-558-0801 
Email: Orrin.Devinsky@nyumc.org 
 
NYULMC Study Number: 
s18-01530 
 
Funding Sponsor: 
Zogenix International Limited  
Siena Court, Broadway 
Maidenhead, Berkshire SL6 1NJ, United Kingdom 
IND Number:  
143731 
Study Product: 
ZX008 
Study Product Provider:  
Zogenix 
 
Initial version: [06 June 2019] 
Version 2.0: 
[25 June 2019] 
Version 3.0: 
[24 Oct 2019] 
Version 3.0: 
[09 Sep 2020] 
Version 4.0: 
[11 Jan 2021] 
Amended: 
[date] 
Amended: 
[date] 
Amended: 
[date] 
Amended: 
[date] 
Amended: 
[date] 
 
 


Study number: s18-01530 
 
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Statement of Compliance 
 
This study will be conducted in accordance with the Code of Federal Regulations on the 
Protection of Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as 
applicable, any other applicable US government research regulations, and institutional research 
policies and procedures. The International Conference on Harmonisation (“ICH”) Guideline for 
Good Clinical Practice (“GCP”) (sometimes referred to as “ICH-GCP” or “E6”) will be applied 
only to the extent that it is compatible with FDA and DHHS regulations. The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place without 
prior agreement from the sponsor and documented approval from the Institutional Review Board 
(IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. All 
personnel involved in the conduct of this study have completed Human Subjects Protection 
Training. 
 
 


Study number: s18-01530 
 
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Table of Contents 
STATEMENT OF COMPLIANCE ................................................................................................................ II 
LIST OF ABBREVIATIONS ........................................................................................................................ VI 
PROTOCOL SUMMARY ............................................................................................................................. 1 
1. 
KEY ROLES ......................................................................................................................................... 4 
2. 
INTRODUCTION, BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ................... 4 
2.1BACKGROUND INFORMATION 
AND RELEVANT LITERATURE: NAME 
AND DESCRIPTION 
OF 
THE 
INVESTIGATIONAL AGENT ............................................................................................................................. 4 
2.1.1 
Preclinical Data ........................................................................................................................ 4 
2.1.2 
Clinical Data in Epilepsy ............................................................................................................ 5 
2.1.3 
Dose Rationale (if applicable) ..................................................................................................... 6 
2.2 
RATIONALE .................................................................................................................................... 6 
2.3 
POTENTIAL RISKS & BENEFITS ........................................................................................................ 6 
2.3.1 
Side effects ................................................................................................................................ 6 
2.3.2 
Echocardiogram findings ............................................................................................................ 7 
3. 
OBJECTIVES AND PURPOSE ............................................................................................................ 8 
3.1 
PRIMARY OBJECTIVE ...................................................................................................................... 8 
3.2 
SECONDARY OBJECTIVES ............................................................................................................... 8 
4. 
STUDY DESIGN AND ENDPOINTS .................................................................................................... 9 
4.1 
DESCRIPTION OF STUDY DESIGN .................................................................................................... 9 
4.2 
STUDY ENDPOINTS......................................................................................................................... 9 
4.2.1 
Primary Study Endpoints ............................................................................................................ 9 
4.2.2 
Secondary Study Endpoints ......................................................................................................... 9 
4.2.3 Safety Endpoints ............................................................................................................................. 9 
5. 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................................. 9 
5.1 
INCLUSION CRITERIA ...................................................................................................................... 9 
5.2 
EXCLUSION CRITERIA ................................................................................................................... 10 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION .......................................................................... 11 
5.4 
DURATION OF STUDY PARTICIPATION ............................................................................................ 12 
5.5 
TOTAL NUMBER OF PARTICIPANTS AND SITES ................................................................................ 12 
5.6 
PARTICIPANT WITHDRAWAL OR TERMINATION ................................................................................ 12 
5.6.1 
Reasons for Withdrawal or Termination..................................................................................... 12 
5.6.2 
Handling of Participant Withdrawals or Termination ................................................................. 13 
5.7 
PREMATURE TERMINATION OR SUSPENSION OF STUDY .................................................................. 13 
6 
STUDY AGENT .................................................................................................................................. 14 
6.1 
STUDY AGENT DESCRIPTION ........................................................................................................ 14 
6.1.1 
Acquisition .............................................................................................................................. 14 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ................................................................... 14 
6.1.3 
Product Storage and Stability.................................................................................................... 14 
6.1.4 
Dosing and Administration ....................................................................................................... 15 
6.1.5 
Route of Administration ............................................................................................................ 15 
6.1.6 
Starting Dose and Dose Escalation Schedule .............................................................................. 15 
6.1.7 
Taper Period ........................................................................................................................... 15 
6.1.8 
Dose Adjustments/Modifications/Delays .................................................................................... 15 
6.1.9 
Duration of Therapy ................................................................................................................. 16 
6.1.10 
Tracking of Dose...................................................................................................................... 16 
7 
STUDY PROCEDURES AND SCHEDULE ........................................................................................ 16 
7.1 
STUDY SPECIFIC PROCEDURES .................................................................................................... 16 


Study number: s18-01530 
 
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7.2 
CLINICAL LABORATORY EVALUATIONS ........................................................................................... 16 
7.3 
PROCEDURES .............................................................................................................................. 17 
7.4 
QUESTIONNAIRES ......................................................................................................................... 17 
7.5 
STUDY SCHEDULE ........................................................................................................................ 18 
7.5.1 
Core study ............................................................................................................................... 18 
7.5.2 
Extension ................................................................................................................................ 22 
7.5.3 
End of treatment ...................................................................................................................... 22 
7.5.4 
Unscheduled Visit .................................................................................................................... 23 
7.6 
CONCOMITANT MEDICATIONS ....................................................................................................... 23 
7.7 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ........................................................ 23 
7.8 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE ........................................................ 23 
8 
ASSESSMENT OF SAFETY ............................................................................................................... 23 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ...................................................................................... 23 
8.1.1 
Definition of Adverse Events (AE) ............................................................................................. 24 
8.1.2 
Definition of Serious Adverse Events (SAE) ................................................................................ 24 
8.1.3 
Definition of Unanticipated Problems (UP) ................................................................................ 24 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT ....................................................................................... 25 
8.2.1 
Severity of Event ...................................................................................................................... 25 
8.2.2 
Relationship to Study Agent ...................................................................................................... 25 
8.2.3 
Expectedness ........................................................................................................................... 26 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP .................................... 26 
8.4 
REPORTING PROCEDURES – NOTIFYING THE IRB .......................................................................... 27 
8.4.1 
Adverse Event Reporting and Serious Adverse Event Reporting ................................................... 28 
8.4.2 
Unanticipated Problem Reporting ............................................................................................. 28 
8.4.3 
Reporting of Pregnancy ............................................................................................................ 28 
8.5 
REPORTING PROCEDURES – NOTIFYING THE STUDY SPONSOR ...................................................... 29 
8.6 
REPORTING PROCEDURES – NOTIFYING THE FDA ......................................................................... 29 
8.7 
STUDY HALTING RULES ................................................................................................................ 30 
8.8 
SAFETY OVERSIGHT ..................................................................................................................... 30 
9 
STATISTICAL CONSIDERATIONS ................................................................................................. 30 
9.1 
STATISTICAL AND ANALYTICAL PLANS (SAP) ................................................................................. 30 
9.2 
SAMPLE SIZE ............................................................................................................................... 30 
10 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .................................. 31 
11 
ETHICS/PROTECTION OF HUMAN SUBJECTS............................................................................. 31 
11.1 
ETHICAL STANDARD ..................................................................................................................... 31 
11.2 
INSTITUTIONAL REVIEW BOARD ..................................................................................................... 31 
11.3 
INFORMED CONSENT PROCESS .................................................................................................... 32 
11.3.1 
Consent/Assent and Other Informational Documents Provided to Participants .............................. 32 
11.3.2 
Consent Procedures and Documentation .................................................................................... 32 
11.4 
PARTICIPANT AND DATA CONFIDENTIALITY .................................................................................... 33 
12 
DATA HANDLING AND RECORD KEEPING .................................................................................. 33 
12.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES .............................................................. 33 
12.2 
STUDY RECORDS RETENTION ....................................................................................................... 34 
12.3 
PROTOCOL DEVIATIONS ............................................................................................................... 34 
13 
STUDY FINANCES ............................................................................................................................ 34 
13.1 
FUNDING SOURCE ........................................................................................................................ 34 
13.2 
COSTS TO THE PARTICIPANT ......................................................................................................... 34 
14 
CONFLICT OF INTEREST POLICY ................................................................................................ 35 
15  REFERENCES ....................................................................................................................................... 35 
16. APPENDIX ............................................................................................................................................ 36 


Study number: s18-01530 
 
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Study number: s18-01530 
 
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List of Abbreviations 
 
 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CSOC 
Clinical Study Oversight Committee 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data and Safety Monitoring Board 
FFR 
Federal Financial Report 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
OHSR 
Office of Human Subjects Research 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
US 
United States 


Study number: 
 
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Protocol Summary 
Title 
Fenfluramine in CKDL5 Deficiency Disorder (CDD) 
Brief Summary 
We will enroll 10 patients, ages 2-35 years old, with a confirmed 
genetic/clinical diagnosis of CDKL5 Deficiency Disorder (CDD) in an open 
label trial of fenfluramine for seizure control.   
 
Protocol – patients will be titrated over 14 days to a dose of ZX008 0.8 
mg/kg/day (maximum dose 30 mg/d) 
Phase 
NA 
Objectives 
Decrease in seizure frequency and change in impression and quality of life 
Methodology 
Open label  
Endpoint 
Primary outcome: 
Median monthly convulsive seizure frequency 
 
Secondary outcomes: 
1. Caregiver/Investigator Global Impression of Change (C/IGIC). The 
parent/caregiver and investigator rated change on a 7-point scale: 1-very 
much improved; 2-much improved; 3-minimally improved; 4-no change; 
5-minimally worse; 6-much worse; and 7-very much worse 
2. Quality of Life in Childhood Epilepsy Scale (13).  A low-burden 
parent/caregiver completed assessment that looks at how epilepsy affects 
day-to-day functioning of their child in various life areas, including 
physical activities, well-being, cognition, social activities, behavior and 
general health. 
3. Pediatric Quality Of Life Inventory (PEDS-QL). 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 during a specific time frame 
Study Duration 
14 weeks with extension available  
Duration of IP 
administration 
14  weeks with extension available  
Population 
confirmed genetic/clinical diagnosis of CDKL5 Deficiency Disorder (CDD)  
Study Sites 
1: NYU Comprehensive Epilepsy Center. 
Number of 
participants 
10 patients: 7: ages 2-18 years old 
                    Max of 3: ages 18-35 years old 
Description of Study 
Agent 
Liquid 
Key Procedures 
Blood draws, questionnaires, Doppler echocardiogram, electrocardiogram 
 
 


Study number: s18-01530 
 
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Protocol Activity: 
Week (±7 days) 
Baseline 
Week 0 
 
Safety 
call   
Week 2 
Week 6 
Safety call   
Week 10 
Safety 
call   
Week 14 
Post 
Taper 
Follow 
up  
Visit 
1 
Safety 
call   
2 
3 
Safety call   
4 
Safety 
call  
5/End of 
study/ End of 
treatment/ 
Withdrawal 
visit 
 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medical history  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 
X 
 
Physical and 
neurological exam and 
Vital signs 
X 
 
X 
X 
 
X 
 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EKG 
X 
 
 
X 
 
 
 
X 
 
Echo 
X 
 
 
X 
 
 
 
X 
 
C/IGIC 
X 
 
X 
X 
 
X 
 
X 
 
QOLCE 
X 
 
X 
X 
 
X 
 
X 
 
PEDS-QOL 
X 
 
X 
X 
 
X 
 
X 
 
Hematology & 
Chemistry 
(draw/handling) (CBC, 
CMP, LFTs, BUN, 
Creatinine), Coagulation 
 
X 
 
X 
X 
 
X 
 
X 
 
HCG (urine and serum) 
X 
 
X 
X 
 
X 
 
X 
 
THC  (urine and serum) 
X 
 
X 
X 
 
X 
 
X 
 
Urinalysis 
X 
 
X 
X 
 
X 
 
X 
 
AED levels /Clobazam 
X 
 
 
X 
 
X 
 
X 
 
Study diary provided  
X 
 
X 
X 
 
X 
 
X 
 
Study diary collected 
 
 
X 
X 
 
X 
 
X 
 
Study drug dispensed 
X 
 
X 
X 
 
X 
 
X* 
 
Study Drug 
administration  
X 
 
 
 
 
 
 
 
 
Study drug compliance 
dosing schedule and 
return dosing schedule  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant/other 
medications/supplements  
X 
X 
X 
X 
X 
X 
X 
X 
X 


Study number: s18-01530 
 
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*If subject continues to extension visit 
 
 
 
Extension  
Protocol 
Activity: 
Week (±7 
days) 
Exten
sion 
Visit  
 
Safety call  
Extension 
Visit  
 
Safety call  
Extension Visit  
 
Safety call  
End of 
Treatment/
Withdrawal  
Post Taper Follow 
up  
Inclusion/excl
usion criteria 
X 
X 
X 
X 
X 
X 
X 
 
Medical 
history  
X 
X 
X 
X 
X 
X 
X 
X 
Physical and 
neurological 
exam and 
Vital signs 
X 
 
X 
 
X 
 
X 
 
Adverse 
events 
X 
X 
X 
X 
X 
X 
X 
X 
EKG 
X 
 
X 
 
X 
 
X 
 
Echo 
X 
 
X 
 
X 
 
X 
 
C/IGIC 
X 
 
X 
 
X 
 
X 
 
QOLCE 
X 
 
X 
 
X 
 
X 
 
PEDS-QOL 
X 
 
X 
 
X 
 
X 
 
Hematology 
& Chemistry 
(draw/handlin
g) (CBC, 
CMP, LFTs, 
BUN, 
Creatinine), 
Coagulation 
X 
 
X 
 
X 
 
X 
 
HCG (urine 
and serum) 
X 
 
X 
 
X 
 
X 
 
THC (urine 
and serum) 
X 
 
X 
 
X 
 
X 
 
Urinalysis 
X 
 
X 
 
X 
 
X 
 
AED levels 
/Clobazam 
X 
 
X 
 
X 
 
X 
 
Study diary 
provided  
X 
 
X 
 
X 
 
X 
 
Study diary 
collected  
X 
 
X 
 
X 
 
X 
 
Study 
dispensed  
X 
 
X 
 
X 
 
X 
 
Study drug 
compliance 
dosing 
schedule  and 
return dosing 
schedule 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant/
other 
medications/s
upplements  
X 
X 
X 
X 
X 
X 
X 
X 


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1. Key Roles 
Principal Investigator: Orrin Devinsky, MD 
New York University Comprehensive Epilepsy Center 
223 East 34th Street 
New York, NY 10016 US 
Phone number: 646-558-0801 
Email: Orrin.Devinsky@nyumc.org 
2. Introduction, Background Information and Scientific Rationale 
 
2.1Background Information and Relevant Literature: Name and Description of the 
Investigational Agent  
Fenfluramine is an amphetamine analogue that was 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”) to treat adult obesity. 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 was considered unfavorable to treat obesity in adults, 
establishing seizure control in Dravet syndrome, Lennox-Gastaut syndrome (LGS) or other 
refractory catastrophic childhood epilepsies might lead to a more acceptable risk/benefit profile 
for fenfluramine.  The high rate of mortality and severe intellectual and quality of life 
impairments in severe childhood epilepsies1, 2 makes any effective drug or therapy a potentially 
life-saving option. 
As a result of the earlier extensive use of fenfluramine in adult obesity, 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 (2017).4 
There is also a large body of information concerning its clinical safety profile. 
2.1.1 
Preclinical Data 
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 


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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. 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 (Days 7 to 76 pp). 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 lowest-observed-adverse-effect level (LOAEL) of 3.5 mg/kg/day is a human 
equivalent dose (HED) of 0.833 mg/kg/day when converted on the basis of body surface in 
mg/m2, based on a reference body weight for a 20-kg child. No new target organs were 
identified in juvenile animals, and there were no permanent effects on sexual maturation or 
reproductive function when juvenile animals were administered fenfluramine from the neonatal 
period through adulthood.4 
2.1.2 
Clinical Data in Epilepsy 
There have been several published reports of fenfluramine’s successful treatment of 
refractory childhood epilepsy in the 1980s.(Aicardi and Gaustaut, 1985; Aicardi et al., 1988). 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 and Casaer, 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 an update of their fenfluramine study. The study 
population was expanded to 22 patients with intractable or self-induced seizures, including the 
previous 11 patients (Casaer and Boel, 2002). The duration of treatment was 1 to 12 years.  
Among the 22 patients treated, 6 (27%) became seizure-free, 10 (45%) had a 90% reduction in 
seizure frequency and 6 (27%) were non-responders. Fenfluramine was effective in multiple 
seizures types in Dravet syndrome (DS), a drug resistant pediatric epileptic encephalopathy 
syndrome (Ceulemans et al., 2012; Schoonjans 2015 et al,; Ceulemans et al,, 2016). 4 
Zogenix is currently evaluating ZX008 in DS in three Phase 3 double-blind, randomized, 
placebo-controlled studies (clinicaltrials.gov identifiers: NCT02826863, NCT02682927, and 
NCT02926898).  Currently, a cohort of refractory Lennox-Gastaut syndrome (LGS) patients in 
Belgium are being treated in a Phase 2 open-label, pilot, dose-finding trial of fenfluramine as an 
add-on therapy to conventional therapy (Study S58545; clinicaltrials.gov identifier: 
NCT02655198). Subjects aged 3 to 18 years, fulfilling the diagnostic criteria for LGS as 
described by the International League Against Epilepsy (ILAE) in 1989, who have failed at least 
two AEDs (including vagal nerve stimulation (VNS), and have had at least 4 documented 
convulsive seizures (generalized tonic-clonic, tonic, atonic, and focal seizures with a motor 


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component and on at least 2 AEDs at stable doses in the prior 4 weeks are eligible for this study 
(Lagae et al., 2016).  A similar study has been initiated in the United States.4 
For the Belgium LGS study, subjects establish baseline convulsive seizure frequency 
over 4 weeks and are then treated with fenfluramine at a starting dose of 0.2 mg/kg/day. In non-
responders (<50% convulsive seizure frequency decrease), the dose is up titrated every 4 weeks 
from 0.2 mg/kg/day to 0.4 mg/kg/day, and up to a maximum dose of 0.8 mg/kg/day for up to 20 
weeks if the patient remains a non-responder per protocol definition.4 
Interim results are available on the anticonvulsant effects of adjunctive treatment with 
ZX008 in the first 13 patients with LGS from Study S58545 (9 males, 4 female).  Fenfluramine 
treatment was started at a mean age of 11.4 years (range 3 to 17 years), administered at a 
maximum of 0.8 mg/kg/day and added to each patient’s current AED regimen. Prior to enrolling 
in the trial, all patients had failed on at least 3 other AEDs. By November 2016, 8 patients had 
completed all 20 weeks of the treatment period, 4 patients withdrew before study end, and 1 
patient remained on treatment, having completed 16 weeks of treatment. Of the 4 patients who 
withdrew before study end, 1 withdrew due to worsening of seizures following elective surgery, 
and 3 withdrew due to adverse events (2 decreased alertness, 1 insomnia). Seven of the 13 
patients (54%) achieved at least a 50% reduction in the number of convulsive seizures during the 
study at doses of 0.2mg/kg (3 patients), 0.4mg/kg (3 patients) and 0.6mg/kg (1 patient). Despite 
not attempting to dose to maximal efficacy a dose response appears to be emerging with a 2-fold 
increase in the number of responders at the 0.4 mg/kg/day vs. 0.2 mg/kg/day dose. The most 
common treatment emergent adverse events to date include decreased appetite in 3 patients, 
decreased alertness/fatigue in 3 patients, and insomnia in 2 patients. ZX008 has been well 
tolerated in this small, open-label study, and no patients have exhibited any clinical signs of 
cardiovascular or cardiopulmonary adverse events as of the November 2016 data cut. 
(ZX008 IB 2017).4 
2.1.3 Dose Rationale  
Based on clinical data to date. Patient will be dosed up to 0.8 mg/kg/d or 30 mg/d 
maximum. It will be twice daily dosing. Fenfluramine was administered to over 500 children 
with neurobehavioral conditions, including autism and ADHD with good safety and tolerability, 
at doses in the range of 0.65 to 3.6 mg/kg/day (most common dose of 1.5 mg/kg/day) for up to 
12 months.4 
2.2 Rationale 
The lack of consistent efficacy and individual tolerability and safety concerns with 
current treatments available have resulted in the continued significant unmet need for a new 
treatment with a novel mechanism of action for children and adults with CDD. 
2.3 Potential Risks & Benefits 
Fenfluramine is effective in multiple seizures types in Dravet syndrome (DS), another 
very drug resistant pediatric epileptic encephalopathy syndrome.  In a recent Phase III study of 
119 DS patients, the median reduction of convulsive seizures was 64% greater than placebo3 in 
the group that received 0.8 mg/kg/day and 34% for the group that received 0.2 mg/kg/day of 
fenfluramine. 
2.3.1 Side effects 
The most common AEs observed in children and young adults the ongoing studies of 


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ZX008 include decreased appetite, pyrexia, diarrhea, lethargy, and somnolence.  However, there 
is limited data in the pediatric population, largely based on the Belgium and the more recent 
Phase 3 trial cited above.4 
2.3.2 
Echocardiogram findings  
Findings from echocardiograms will be discussed between the investigator, local cardiologist and 
parent/caregiver/legal or authorized representative to determine risk versus benefit of the study to 
the subject.  
ECHOs will be done at NYU. If caregivers/patients are not able to travel to NYU 
facility, doppler echocardiography can be done at a local facility.  Readings will be sent back 
to site for evaluation.  Findings related to pulmonary hypertension or valvulopathy on any of 
the four valves (aortic, mitral, pulmonary, tricuspid) will be reported to the investigator with 
grades of normal, trace, mild, moderate or severe. If the ECHO result has progressed in 
severity since the last reading, then new oversight measures will be enacted as described 
below in Levels 1-3. Table 12 describes the severity of ECHO findings with the level of 
increasing oversight if the subject is to remain in the study. 
 
Table 1: Clinical Measures Enacted Upon Increasing Severity of ECHO Findings 
 
Severity 
Valve 
Aortic 
Mitral 
Pulmonary 
Tricuspid 
Normal 
Level 1 
Level 1 
Level 1 
Level 1 
Trace 
Level 2 
Level 2 
Level 1 
Level 1 
Mild 
Level 2 
Level 2 
Level 1 
Level 1 
Moderate 
Level 3 
Level 3 
Level 3 
Level 3 
Severe 
Level 3 
Level 3 
Level 3 
Level 3 
 
Level 1: Continue per protocol 
Level 2: 
1. If there is a desire to continue study medication: 
a. The investigator will evaluate the efficacy to date based on study diaries 
and consult with the parent/guardian, and determine whether study 
treatment was associated with significant, meaningful benefit in 
number, severity and/or duration of seizures and/or on the impact on 
daily functioning. 
b. The investigator will consider whether the subject has had reasonable trials 
(dose and duration) of other available anticonvulsants (e.g. valproic acid, 
clobazam, or topiramate), alone or in combination, and not maintained the 
level of seizure control achieved with study medication. 
2. If the investigator feels consideration of continued treatment is warranted 
considering benefit and potential risk, and the parent/guardian feels strongly that the 
child be maintained on the study medication when understanding the risks, the 
parent/guardian must sign a new consent which describes the additional risk and the 
child should provide assent if appropriate. 
a. If both of these conditions are not met, the subject is discontinued 
from treatment. 


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3. Investigator and Institutional Cardiologist make 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. MINIMAL efficacy criteria: 
a. Seizures must be more than 75% improved (number of convulsive 
seizures per 28 days) on treatment over baseline, and improvement must 
be consistent. 
b. The number, type, duration, and distribution of seizures at baseline should be 
of a severity, which justifies the risks of cardiopulmonary complications, 
considering the subject’s age and overall health. 
c. Subject has had reasonable trials (dose and duration) of other available 
anticonvulsants (e.g., valproic acid, clobazam, topiramate), alone or in 
combination, and not maintained the level of seizure control achieved with 
study medication. 
2. If the investigator feels consideration of continued treatment is warranted 
considering benefit and potential risks, and the parent/guardian feels strongly that 
the child be maintained on the study medication when understanding the risks, 
the parent/guardian must sign a new consent, which describes the additional risks 
and the child should provide assent if possible. 
a. If both of these conditions are not met, the subject is discontinued 
from treatment. 
3. Investigator and Institutional Cardiologist make a determination of appropriate path, 
including these possible outcomes: 
a. Discontinue study medication 
b. Increase frequency of ECHO and ECG monitoring 
c. Add additional ECG and/or ECHO measures to be monitored 
d. Reduce the dose of study medication 
3. Objectives and Purpose 
3.1 Primary Objective 
Median reduction in monthly convulsive seizure frequency 
3.2 Secondary Objectives  
o Caregiver/Investigator Global Impression of Change (C/IGIC). The parent/caregiver and 
investigator rated change on a 7-point scale: 1-very much improved; 2-much improved; 
3-minimally improved; 4-no change; 5-minimally worse; 6-much worse; and 7-very 
much worse 
o Quality of Life in Childhood Epilepsy Scale .  A low-burden parent/caregiver completed 
assessment that looks at how epilepsy affects day-to-day functioning of their child in 


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various life areas, including physical activities, well-being, cognition, social activities, 
behavior and general health in comparison to other children their age,  
o PEDS-QL. 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 during a specific time 
frame. 
4. Study Design and Endpoints 
4.1 Description of Study Design 
The study to be conducted is  an expanded access program for intermediate size 
population use. 
 
4.2  Study Endpoints 
4.2.1 
Primary Study Endpoints 
Median reduction in monthly convulsive seizure frequency. For continuation after initial 
study period, patients must have a ≥ 40% reduction in convulsive seizure frequency over 
baseline. 
4.2.2 
Secondary Study Endpoints 
Evaluate changes from Baseline in cognitive, motor, and behavioral function as well as 
QOL following fenfluramine treatment. 
4.2.3 Safety Endpoints 
The safety endpoints the study are: 
• 
Adverse events 
• 
Laboratory safety (hematology, chemistry, coagulation, urinalysis) 
• 
Vital signs (blood pressure, heart rate, temperature, and respiratory rate) 
• 
Physical examination 
• 
Neurological examination 
• 
Questionnaires to measure changes in cognition of the subject 
• 
12-lead ECGs 
• 
Doppler ECHOs 
• 
Body weight  
5. Study Enrollment and Withdrawal 
All subjects and/or their parent/legal guardian must sign the appropriate informed consent 
prior to beginning any study-related activities, including Screening procedures. Additionally, an 
assent form should be signed by subjects age 7 to 17 years old, unless lacking capacity. 
5.1 Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the 
following criteria: 
1. 
Confirmed clinical/genetic diagnosis of CDKL5 Deficiency Disorder CDD 


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2. 
Ages 2-35 years old. Subject is male or non-pregnant, non-lactating female.  
Female subjects of childbearing potential must not be pregnant or breast-feeding. Female 
subjects of childbearing potential must have a negative urine pregnancy test. Subjects of 
childbearing or child-fathering potential must be willing to use medically acceptable 
forms of birth control, which includes abstinence, while being treated on this study and 
for 30 days after the last dose of study drug. 
 
 
3. 
Subject has been informed of the nature of the study and informed consent has 
been obtained from the legally responsible parent/guardian. 
 
4. 
Subject has provided assent in accordance with Investigational Review 
Board/Independent Ethics Committee (IRB/IEC) requirements 
 
 
5. 
Subject’s caregiver is willing and able to be compliant with diary completion, 
visit schedule and study drug accountability. 
 
6. 
Subjects must be receiving a therapeutically relevant and stable dose of anti-
seizure medications, dietary therapies for epilepsy or vagus nerve stimulation settings for 
at least 4 weeks prior to screening and are expected to remain stable throughout the initial 
14 weeks of the study. Medication changes are allowed during the extension portion. 
 
 
7. 
≥4 convulsive seizures (tonic-clonic, tonic, atonic, clonic, focal motor) per 4-
week period; each convulsive seizure must last ≥3 seconds. 
 
8. 
Subject is 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 Receiving at least 1 concomitant AED and up to 4 concomitant AEDs, 
inclusive. Rescue medications for seizures are not counted towards the total number of 
AEDs. 
 
5.2 Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation 
in this study: 
1. Subject has a known hypersensitivity to fenfluramine or any of the excipients in 
the study medication. 
 
2. Subject has current or past history of cardiovascular or cerebrovascular disease, 
myocardial infarction or stroke. 
 
3. 
 Subject 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, and patent foramen ovale 


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with reversal of shunt. (note: Patent foramen ovale or a bicuspid valve are is not 
considered exclusionary, but may be associated with the following diseases, which 
are exclusionary: coarctation of the aorta, Turner syndrome, supravalvular aortic 
stenosis, subvalvular aortic stenosis, patent ductus arteriosus, Sinus of Valsalva 
aneurysm, ventricular septal defect, Shone’s complex, ascending aortic aneurysm, 
Loeys-Dietz syndrome, ACTA2 mutation familial thoracic aortic aneurysm 
syndrome, and MAT2A mutation familial thoracic aortic aneurysm syndrome). 
 
4. Subject has current or recent history of Anorexia Nervosa, bulimia, or depression 
within the prior year that required medical treatment or psychological treatment for a 
duration greater than 1 month. 
 
5.  Subjects who are currently on formulations of CBD (other than Epidiolex) , 
CBD/THC or any MMJ. 
 
6. Subject who have  positive urine tetrahydrocannabinol (THC) Panel or whole blood 
cannabidiol (CBD) who have not been prescribed Epidiolex. 
 
7. Subject has participated in another clinical trial within the past 30 days (calculated 
from that study’s last scheduled visit). 
 
8. Subject is at imminent risk of self-harm or harm to others, in the investigator’s 
opinion, based on clinical interview.    
 
9. Subject has a current or past history of glaucoma. 
 
10.  Subject is receiving concomitant therapy with: centrally-acting anorectic 
agents; monoamine-oxidase inhibitors; any centrally-acting compound with 
clinically appreciable amount of serotonin agonist or antagonist properties, 
including serotonin reuptake inhibition; atomoxetine, or other centrally-
acting noradrenergic agonist; or cyproheptadine. (see appendix 1) 
 
11. Subject has moderate or severe hepatic impairment. Asymptomatic subjects with 
mild hepatic impairment (elevated liver enzymes <3x upper limited of normal [ULN] 
and/or elevated bilirubin <2x ULN) may be entered into the study after review and 
approval by the Medical Monitor in conjunction with the sponsor, in consideration of 
comorbidities and concomitant medications. 
5.3 Strategies for Recruitment and Retention 
During a routine visit at the NYU Comprehensive Epilepsy Center, subjects who meet 
criteria for the study (or their parents/legal guardians) will be asked if they would like to 
participate in the study. Note: some subjects may hear of this study from other parents with CDD 
or from the International Foundation for CDKL5 Research (https://www.cdkl5.com), which lists 
studies for patients with CDD.  Such subjects who contact the Principal Investigator or research 
staff will be screened for their potential to participate based on inclusion and exclusion criteria.   
Male and female subjects of any ethnicity between ages of 2 and 35 (inclusive) will be 


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assessed for inclusion, with no more than 3 patients between the ages of 18-35.  
During the routine visit, the investigator will inform each prospective 
subject/parent/legal guardian of the nature of the study, and explain the potential risks and 
study-related procedures. If the subject/parent/legal guardian agrees, they will be given the 
informed consent documents to read and sign prior to starting any study procedures. Only the 
Principal Investigator, sub-investigators, and other research personnel listed on the study will 
have access to subject information. Once the study subject/parent/legal guardian has signed the 
informed consent, the investigator will explain the study during the routine visit. If necessary, the 
investigator will inform the subject and surrogate that a capacity assessment will be performed to 
determine whether the subject is capable of providing an informed decision to participate in the 
study. At this time, a capacity assessment will be conducted if the subject does not refuse the 
assessment. Capacity will be assessed through neurological examinations and neuropsychology 
reports conducted by the physician as well as learning and/or development delays that have been 
documented. If there is already documentation of lack of capacity, no assessment will be needed. 
If it has been determined by the investigator that the subject has capacity, they will be given the 
assent form to review. The investigator will go over the study as described in the assent form 
including study visits and procedures. The subject will be allowed time to ask questions. If the 
subject is comfortable, then they can sign the assent. All documentation will be placed in the 
study binder and documented in the study visit note. A copy of the informed assent and consent 
documents will be given to the subject and the subject’s parent/legal guardian. Screening 
procedures may begin. The Screening Period is 4 weeks, during which study candidates must 
complete a diary documenting the frequency and duration of seizures. 
 
Refer to Section 7 for the Schedule of Events and specific requirements for each study 
visit. 
5.4 Duration of Study Participation 
Subject participation will be a total of 14 weeks with extension available.  
5.5 Total Number of Participants and Sites  
Approximately 10 patients with a confirmed genetic/clinical diagnosis of CDKL5 
Deficiency Disorder (CDD) will be recruited for the study from the Principal Investigator’s and 
co-investigator’s clinical practice at New York University Comprehensive Epilepsy Center 
(NYUCEC) or from families that contact the Principal Investigator. Male and female subjects of 
any ethnicity between ages of 2 and 35 (inclusive) will be assessed for inclusion, with no more 
than 3 patients between the ages of 18-35.  
5.6 Participant Withdrawal or Termination 
5.6.1 
Reasons for Withdrawal or Termination 
 
A subject may be discontinued from study drug at any time if the subject, subject’s legal 
guardian, or the investigator feels that it is not in the subject’s best interest to continue. 
The following is a list of possible reasons for study drug discontinuation: 
1. Parental/legal guardian withdrawal of consent. 
 
2. Subject is not compliant with study procedures. 
 


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3. Protocol violation requiring discontinuation of study drug. 
 
4. Severe adverse events, including significant toxicity such as severe cognitive or 
behavioral toxicity, impaired liver and renal function, or impaired hematopoiesis 
 
5. Seizure exacerbation not attributable to other known provocative factors. 
 
6. Interaction with concomitant AED regimen that leads to unacceptable toxicity. 
Medication adjustments will be avoided, if possible, and may require the subject 
to exit the study, at the discretion of the Investigator. 
 
Specific drug-related toxicities will be assessed and managed by the Principal Investigator. 
 
Depending on the nature of the signs (eg, changes in serum chemistries, liver function 
tests) or symptoms (eg, rash), the subject will be assessed to determine the severity and 
likelihood of relation to study medication. Based on this assessment, the medication may be 
discontinued, the dose may be reduced, or the drug may be continued with ongoing assessment. 
If the study drug is discontinued due to a suspected toxicity, it will only be restarted if there is 
strong evidence that the toxicity was likely not related to the study medication (eg, liver tests 
were elevated due to a cytomegalovirus infection). 
 
If a subject must discontinue study drug, the method for discontinuation from study drug 
will be determined based on the type of reaction and/or reason for withdrawal. For example, if 
the subject experiences a rapidly progressive rash, it would lead to abrupt cessation of study 
drug, but if subject experiences excess tiredness, study drug may be tapered off. A discussion of 
the method of cessation will occur between the subject and/or subject’s parent/legal guardian and 
the physician. 
5.6.2 
Handling of Participant Withdrawals or Termination 
For all subjects who withdraw from the study, there will be 1 final telephone/email 
follow-up 4 weeks after the last dose of study drug (Post taper Follow-up Visit). If the 
subject/parent/legal guardian cannot be contacted after 4 phone calls to subject/parent/legal 
guardian, a certified letter will be sent to the subject/parent/legal guardian. 
 
Refer to Section 7 for the Schedule of Events and specific requirements for each study visit.  
5.7 Premature Termination or Suspension of Study 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or termination, will 
be provided by the suspending or terminating party to Principal investigator. If the study is prematurely 
terminated or suspended, the PI will promptly inform the IRB and will provide the reason(s) for the 
termination or suspension. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 


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• 
Determination of futility 
Study may resume once concerns about safety, protocol compliance, data quality is addressed and 
satisfy the sponsor, IRB and/or FDA. 
 
6 Study Agent   
Investigational Medicinal Product – ZX008 
Substance Code 
ZX008 
Active Substance (INN) 
Fenfluramine Hydrochloride 
Trade Name 
Not applicable 
Formulation (including dosage form and strength) 
Solution  2.5mg/mL 
Route/Mode of Administration 
Oral 
Manufacturer 
Andersonbrecon, Inc. on behalf of Zogenix 
International Limited 
6.1 Study Agent Description 
ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered 
to pH 5 and provided in concentrations of 2.5 mg/mL. The excipients selected have been 
approved for use in the formulations of currently marketed drug products and are considered to 
be safe. The solution 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 ketogenic 
diet.  The doses to be studied will be 0.8 mg/kg/day divided into two daily doses, up to a 
maximum of 30 mg/day.  
6.1.1 
Acquisition 
The investigational medicinal product (IMP) will be supplied to the study site 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. 
6.1.2 
Formulation, Appearance, Packaging, and Labeling 
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. The ZX008 product will be packaged and labeled according 
to current International Conference on Harmonization (ICH), Good Manufacturing Practices 
(GMP), and Good Clinical Practices (GCP) guidelines, and national legal requirements. 
Dosing directions for the product can be found in the IMP handling instructions for the 
study subjects and for the investigator.  
6.1.3 
Product Storage and Stability 
Appropriate storage temperature and transportation conditions will be maintained for the 
study drug from the point of manufacture up to delivery of the study drug. Study medication 
must be stored at 15-25°C (59-77°F) with excursions of 5-30°C (41-86°F) permitted; do not 


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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. 
6.1.4 
Dosing and Administration 
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. 
6.1.5 
Route of Administration 
Medication is given orally.  
6.1.6 
Starting Dose and Dose Escalation Schedule 
Patients will be titrated over 14 days to a dose of ZX008 0.8 mg/kg/day (maximum dose 
30 mg/d). 
Titration schedule 
 
 Day 1-4 
Day 5-8 
Day 9-14 
ZX008 0.2 
mg/kg/day  
ZX008 0.4 
mg/kg/day  
ZX008 0.8 
mg/kg/day 
 
After completion of the Titration Period, subjects will enter the Maintenance Period and 
continue to receive this dose of ZX008 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. 
6.1.7 
Taper Period 
Subjects will decrease from 0.8 mg/kg BID to a dose of 0.4 mg/kg BID (maximum 30 
mg/day or). After 4 days at this dose level, subjects will decrease their dose to 0.2 mg/kg/day.  
On Study Day 9, all subjects will stop taking study medication. The taper is expected to take a 
total of 8 days. 
Taper schedule 
 
Day 5-8 after end of 
study/ study 
withdrawal 
Day 9-14 after end of 
study/ study 
withdrawal 
ZX008 0.4 mg/kg/day  
ZX008 0.2 mg/kg/day 
 
6.1.8 
Dose Adjustments/Modifications/Delays 
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 re-administered. Care must be taken not to 
overdose. If the amount spilled is not known, the parent/caregiver should not give additional 


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medication to avoid potential overdose. 
6.1.9 
Duration of Therapy 
Duration of therapy will be14 weeks with extension available.  
6.1.10 Tracking of Dose 
The study team will assess and track subject compliance with the study drug regimen via 
clinical evaluations and follow-up email or phone calls.  
7 Study Procedures and Schedule 
7.1 Study Specific Procedures 
-Medical history: Any medical problems/conditions throughout subject’s body system, 
relevant medical events and/or procedures/surgery  
  
-Medication history: complete medication history of any anti-epileptic medications; 
current history other prescription and over-the-counter medications. 
 
-Physical examination: vital signs including temperature, height and weight and organ 
systems to be assessed 
 
-Neurological examination: examination of sensory neurons, motor responses and 
reflexes 
 
-Biological specimen collection and laboratory evaluations.  
 
-Procedures: Doppler Echocardiography and Electrocardiograms  
 
-Questionnaires and seizure diary 
7.2 Clinical Laboratory Evaluations 
-Hematology: hemoglobin, hematocrit, white blood cells (WBC) with differential count, 
platelet count. 
 
-Coagulation: Prothrombin time (PT)/International normalized ratio (INR), activated 
partial thromboplastin time (PTT) 
 
-Biochemistry: comprehensive metabolic panel, creatinine, total bilirubin, alanine 
aminotransferase (ALT), aspartate and aminotransferase (AST) albumin (ALB), alkaline 
phosphatase (AP), alanine aminotransferase (ALT; SGPT), aspartate aminotransferase 
(AST; SGOT), bicarbonate, blood urea nitrogen (BUN), calcium (Ca), carbon dioxide 
(CO2),chloride (Cl), creatinine, creatine kinase, gamma-glutamyl transferase (GGT), 
globulin, glucose, lactate dehydrogenase (LDH), phosphorus, potassium (K), sodium 
(Na), thyroid function (T3, T4, and thyroid stimulating hormone [TSH]), total 
bilirubin, direct bilirubin, total cholesterol, total protein, triglycerides, uric acid. 
 


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-Urinalysis: dipstick urinalysis, including protein, hemoglobin and glucose; if dipstick is 
abnormal, complete urinalysis with microscopic evaluation is required. 
 
-Urine or serum pregnancy test: usually to be done within 24 hours prior to study 
intervention and results must be available prior to administration of study product. 
 
- Urine or serum THC test: usually to be done within 24 hours prior to study 
intervention and results must be available prior to administration of study product. 
 
-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. 
 
Blood work will be about 8.0 – 20.0mL (about 2-4 teaspoons) of blood depending on the 
amount of concomitant medications.  
 
If caregivers/patients are not able to travel to the NYU facility due to COVID-19 travel 
restrictions, clinical laboratory evaluations can be completed at a local facility. 
7.3 Procedures 
Electrocardiograms: Twelve-lead ECGs will be conducted during study as outlined 
after the subject has been in the supine position resting for ≥5 minutes. Heart rate, PR 
duration, QRS duration, QT duration, and the investigator’s overall interpretation will be 
recorded. 
 
Doppler Echocardiography: Doppler echocardiography will be conducted at the 
hospital facility with experience for the subject’s age. If caregivers/patients are not able 
to travel to NYU facility, doppler echocardiography can be done at a local facility. 
Doppler echocardiography can be done +/- 7 days from study visit. 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 prior to study initiation. Readings will be sent back to site to determine the 
appropriate benefit is and any findings consistent with cardiac valvopathy or pulmonary 
hypertension.   
7.4 Questionnaires 
*Given the profound intellectual disability of this population (ie, adults have intelligence 
of <age 5), the pediatric versions will be used for both children and adults. * 
 
-Caregiver Global Impression of Change (CGIC). The parent/caregiver rated change 
on a 7-point scale: 1-very much improved; 2-much improved; 3-minimally improved; 4-
no change; 5-minimally worse; 6-much worse; and 7-very much worse 
-Investigator Global Impression of Change (IGIC). The investigator rated change on a 


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7-point scale: 1-very much improved; 2-much improved; 3-minimally improved; 4-no 
change; 5-minimally worse; 6-much worse; and 7-very much worse 
-Quality of Life in Childhood Epilepsy Scale (13).  A low-burden parent/caregiver 
completed assessment that looks at how epilepsy affects day-to-day functioning of their 
child in various life areas, including physical activities, well-being, cognition, social 
activities, behavior and general health in comparison to other children their age,  
-Pediatric Quality of Life Inventory (PEDS-QL). 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 during a specific time frame 
7.5 Study Schedule 
7.5.1 Core study 
7.5.1.1 Baseline 
Visit 1 Baseline (Week 0) 
Baseline (Visit 1) will occur at NYU CEC.  Procedures will proceed as follows: 
• Obtain written informed consent/assent. 
• Determine if the subject meets the preliminary eligibility criteria: 
o Collect demographic information 
o Collect current and relevant medical history 
o Identify concomitant medications used 
o Identify and confirm stable use AED medications  
o ≥4 convulsive seizures (tonic-clonic, tonic, atonic, clonic, focal motor) per 4-
week period; each convulsive seizure must last ≥3 seconds. 
If the subject meets the preliminary eligibility criteria, the following assessments will be 
performed: 
• Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and body 
temperature): perform in sitting position 
• Physical and neurological examination including Height and weight 
• EKG and echocardiogram  
• Complete the following assessments: 
o Caregiver and Investigator Global Impression of Change 
o QOLCE 
o PEDS-QOL 
• Blood draw for clinical laboratory evaluations: 
o Complete blood count (CBC), comprehensive metabolic panel (CMP) 
Serum/Urine human chorionic gonadotropin (HCG), as applicable (sample taken 
only for female subjects of childbearing potential), and antiepileptic medication 
levels  


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• Urinalysis 
• Urine or serum THC  
• Record any AEs occurring since signing the ICF and any that occur during this visit 
• Instruct subject or subject’s caregiver to keep a seizure diary for the next 2 weeks, including 
the following information: 
o Seizure type and duration 
o Use of rescue medications 
• Dispense study drug and review administration instructions and titration schedule 
• First dose given in office 
• Instruct subject to return in 2 weeks for Visit 2 
Safety call telephone  
The safety call will occur between visit 1 and visit 2. It will proceed as follows: 
• Record any AEs occurring since last visit and any that occur during this visit 
• Issues with titration schedule 
• Record any changes in concomitant medications 
Visit 2 (Week 2) 
Visit (Week 2) as follows: 
• Physical and neurological examination and height and weight 
• Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and body 
temperature): performed after the subject has been in a sitting position for 3–5 minutes 
• Collect seizure diary and review entries 
• Record any AEs occurring since last visit and any that occur during this visit 
• Record any changes in concomitant medications 
• Complete the following assessments: 
o Caregiver and Investigator Global Impression of Change 
o QOLCE 
o PEDS-QOL 
• Blood draw for Complete blood count (CBC), comprehensive metabolic panel (CMP) 
Serum/Urine human chorionic gonadotropin (HCG), as applicable (sample taken only for 
female subjects of childbearing potential)  
• Urinalysis 
• Urine or serum THC  
• Dispense new seizure diary and review instructions for completion 
• Dispense study drug and review administration instructions 
• Instruct subject to return in 4 weeks for Visit 3 
 


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Visit 3 (Week 6) 
The subject will return to the site for Visit 3.  Procedures at Visit 3 will proceed as follows: 
• Physical and neurological examination and height and weight 
• Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and body 
temperature): performed after the subject has been in a sitting position for 3–5 minutes 
•  EKG and echocardiogram  
• Collect seizure diary and review entries 
• Record any AEs occurring since last visit and any that occur during this visit 
• Blood draw for Complete blood count (CBC), comprehensive metabolic panel (CMP) 
Serum/Urine human chorionic gonadotropin (HCG), as applicable (sample taken only for 
female subjects of childbearing potential) , and antiepileptic medication levels 
• Urinalysis 
• Urine or serum THC  
• Complete the following assessments: 
o Caregiver and Investigator Global Impression of Change 
o QOLCE 
o PEDS-QOL 
• Record any changes in concomitant medications 
• Dispense new seizure diary and review instructions for completion 
• Review returned study drug and compliance 
• Dispense study drug and review administration instructions 
• Instruct subject to return in 4 weeks for Visit 4 
Safety call telephone  
The safety call will occur between visit 3 and visit 4. It will proceed as follows: 
• Record any AEs occurring since last visit and any that occur during this visit 
• Record any changes in concomitant medications 
Visit 4 (Week 10) 
The subject will return to the site for Visit 4.  Visit 4 will proceed as follows: 
• Physical and neurological examination and height and weight 
• Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and body 
temperature): performed after the subject has been in a sitting position for 3–5 minutes 
• Collect seizure diary and review entries 
• Record any AEs occurring since last visit and any that occur during this visit 
• Record any changes in concomitant medications 
• Complete the following assessments: 
o Caregiver and Investigator Global Impression of Change 
o QOLCE 
o PEDS-QOL 


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• Blood draw for Complete blood count (CBC), comprehensive metabolic panel (CMP) 
Serum/Urine human chorionic gonadotropin (HCG), as applicable (sample taken only for 
female subjects of childbearing potential), and antiepileptic medication levels  
• Urinalysis 
• Urine or serum THC  
• Dispense new seizure diary and review instructions for completion 
• Dispense study drug and review administration instructions 
• Instruct subject to return in 4 weeks for Visit 5 
Safety call telephone  
The safety call will occur between visit 4 and visit 5. It will proceed as follows: 
• Record any AEs occurring since last visit and any that occur during this visit 
• Record any changes in concomitant medications 
Visit 5/End of study/ End of treatment/ Withdrawal visit (Week 14) 
Visit 5 will proceed as follows: 
• Physical and neurological examination and height and weight 
• Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and body 
temperature): performed after the subject has been in a sitting position for 3–5 minutes 
• EKG and echocardiogram  
• Collect seizure diary and review entries 
• Record any AEs occurring since last visit and any that occur during this visit 
• Record any changes in concomitant medications 
• Complete the following assessments: 
o Caregiver and Investigator Global Impression of Change 
o QOLCE 
o PEDS-QOL 
• Blood draw for Complete blood count (CBC), comprehensive metabolic panel (CMP) 
Serum/Urine human chorionic gonadotropin (HCG), as applicable (sample taken only for 
female subjects of childbearing potential), and antiepileptic medication levels  
• Urinalysis 
• Urine or serum THC  
• For those subjects who have responded (response level ≥ 40%) and will like to continue in to 
the extension study: 
o Dispense new seizure diary and review instructions for completion 
o Dispense study drug and review administration instructions 
o Instruct subject to return in 12 weeks for Extension visit 1  
• For those subjects who have not responded and will not continue in to the extension study: 
o Taper schedule will be given 
o Subject have final post taper follow up in 4 weeks after the last dose  


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7.5.2 Extension  
Extension visits 
If study medication provide benefit to the subject (response level ≥ 40%), study medication will 
be provided until FDA approval or program discontinuation by Zogenix. The subject will return 
to the site every 12 weeks for extension visits. This includes: 
•  Physical and neurological examination and height and weight 
• Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and body 
temperature): performed after the subject has been in a sitting position for 3–5 minutes 
• EKG and echocardiogram  
• Collect seizure diary and review entries 
• Record any AEs occurring since last visit and any that occur during this visit 
• Record any changes in concomitant medications 
• Complete the following assessments: 
o Clinical Caregiver/Investigator Global Impression of Change 
o QOLCE 
o PEDS-QOL 
• Blood draw for Complete blood count (CBC), comprehensive metabolic panel (CMP) 
Serum/Urine human chorionic gonadotropin (HCG), as applicable (sample taken only for 
female subjects of childbearing potential), and antiepileptic medication levels  
• Urinalysis 
• Urine or serum THC  
• Dispense new seizure diary and review instructions for completion 
• Dispense masked study drug and review administration instructions 
• Instruct subject to return in 12 weeks for next visit  
Safety call telephone 
The safety call will occur between extension visit. It will proceed as follows: 
• Record any AEs occurring since last visit and any that occur during this visit 
• Record any changes in concomitant medications 
7.5.3 End of treatment 
End of treatment/ Withdrawal visit  
End of treatment/withdrawal will proceed as follows: 
• Physical and neurological examination and height and weight 
• Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and body 
temperature): performed after the subject has been in a sitting position for 3–5 minutes 
• EKG and echocardiogram  
• Collect seizure diary and review entries 
• Record any AEs occurring since last visit and any that occur during this visit 


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• Record any changes in concomitant medications 
• Complete the following assessments: 
o Clinical  Caregiver/Investigator Global Impression of Change 
o QOLCE 
o PEDS-QOL 
• Blood draw for Complete blood count (CBC), comprehensive metabolic panel (CMP) 
Serum/Urine human chorionic gonadotropin (HCG), as applicable (sample taken only for 
female subjects of childbearing potential), and antiepileptic medication levels  
• Urinalysis 
• Urine or serum THC  
• Subject have final post taper follow up in 4 weeks after the last dose  
Post Taper Follow-up  
The Follow-up visit is to occur 4 weeks after the last dose of study drug,  
It will proceed as follows: 
• Record any AEs occurring since last visit and any that occur during this visit 
• Record any changes in concomitant medications 
• Return any study medications  
 
7.5.4 Unscheduled Visit 
• Record any AEs occurring since last visit and any that occur during this visit 
• Record any changes in concomitant medications 
7.6 Concomitant Medications 
All concomitant prescription medications taken during study participation will be recorded on 
the case report forms (CRFs). For this protocol, a prescription medication is defined as a 
medication that can be prescribed only by a properly authorized/licensed clinician. Medications 
to be reported in the CRF are concomitant prescription medications, over-the-counter 
medications and non-prescription medications. Epidiolex is only acceptable CBD preparation 
that may be included. All other formulations are excluded. 
 
7.7 Prohibited Medications, Treatments, and Procedures 
Treatment with other investigational medications will not be permitted. 
7.8 Participant Access to Study Agent at Study Closure 
Zogenix will continue to supply study medication to those subjects that received benefit from the 
study after participant are no longer enrolled in the study.  
8 Assessment of Safety 
8.1 Specification of Safety Parameters  
• Treatment-emergent adverse events will be continuously reported throughout the study 


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• Each patient will undergo a Doppler echocardiographic (ECHO) and ECG examinations 
during the baseline period and again at weeks 6, 14, and every 3 months thereafter during 
the extension study and End of treatment/withdrawal visits. 
• All ECHOs readings will be sent to the site for evaluation and will be graded as to 
presence and severity of cardiac valve regurgitation 
8.1.1 
Definition of Adverse Events (AE) 
An adverse event (AE) is any symptom, sign, illness or experience that develops or 
worsens in severity during the course of the study.  Intercurrent illnesses or injuries should 
be regarded as adverse events.  Abnormal results of diagnostic procedures are considered to 
be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
8.1.2 
Definition of Serious Adverse Events (SAE) 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE 
that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance. They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  
8.1.3 
Definition of Unanticipated Problems (UP) 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency  (i.e. not described in study-related 
documents such as the IRB-approved protocol or consent form, the investigators brochure, 
etc) 
• Related or possibly related to participation in the research (i.e. possibly related means 
there is a reasonable possibility that the incident experience, or outcome may have been 


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caused by the procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
 
8.2 Classification of an Adverse Event 
8.2.1 
Severity of Event 
The following grading system will be used to describe severity. 
• Grade 1: Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities. 
• Grade 2: Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning. 
• Grade 3: Severe – Events interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually potentially life-
threatening or incapacitating. 
8.2.2 
Relationship to Study Agent 
The clinician’s assessment of an AE's relationship to study agent (drug, biologic, 
device) is part of the documentation process, but it is not a factor in determining what is or 
is not reported in the study. If there is any doubt as to whether a clinical observation is an 
AE, the event should be reported. All AEs must have their relationship to study agent 
assessed. In a clinical trial, the study product must always be suspect. To help assess, the 
following guidelines are used: 
 
• Related – The AE is known to occur with the study agent, there is a reasonable possibility 
that the study agent caused the AE, or there is a temporal relationship between the study 
agent and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study agent and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the study 
agent caused the event, there is no temporal relationship between the study agent and 
event onset, or an alternate etiology has been established. 
 
For all collected AEs, the clinician who examines and evaluates the participant will 
determine the AE’s causality based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below: 
 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to drug administration and 
cannot be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory 
rechallenge procedure if necessary. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after administration of the drug, is unlikely to be 


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attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (dechallenge). Rechallenge information is not required 
to fulfill this definition. 
• Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, 
other factors may have contributed to the event (e.g., the participant’s clinical condition, 
other concomitant events). Although an AE may rate only as “possibly related” soon after 
discovery, it can be flagged as requiring more information and later be upgraded to 
“probably related” or “definitely related,” as appropriate. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to drug administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of 
the trial medication) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant 
treatments). 
• Not Related – The AE is completely independent of study drug administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
8.2.3 
Expectedness 
Principal Investigator will be responsible for determining whether an AE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of 
the event is not consistent with the risk information previously described for the study 
agent. 
8.3 Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an AE or SAE may come to the attention of study personnel during 
study visits and interviews of a study participant presenting for medical care, or upon review by 
a study monitor. All AEs including local and systemic reactions not meeting the criteria for 
SAEs will be captured on the appropriate CRF. Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE. UPs will be recorded in 
the data collection system throughout the study. 
Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of severity to be performed. AEs characterized as intermittent 
require documentation of onset and duration of each episode. 
The PI will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation. At each study visit, the investigator will inquire about the occurrence of AE/SAEs 
since the last visit. Events will be followed for outcome information until resolution or 
stabilization.  
All unresolved adverse events should be followed by the investigator until the events are 


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resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the investigator should instruct each subject to report any subsequent event(s) 
that the subject, or the subject’s personal physician, believes might reasonably be related to 
participation in this study.  The investigator should notify the study sponsor of any death or 
adverse event occurring at any time after a subject has discontinued or terminated study 
participation that may reasonably be related to this study.  The sponsor should also be notified if 
the investigator should become aware of the development of cancer or of a congenital anomaly 
in a subsequently conceived offspring of a subject that has participated in this study.  
8.4 Reporting Procedures – Notifying the IRB  
Federal regulations require timely reporting by investigators to their local IRB of 
unanticipated problems posing risks to subjects or others. The following describes the NYULMC 
IRB reporting requirements, though Investigators at participating sites are responsible for 
meeting the specific requirements of their IRB of record. 
 
Report Promptly, but no later than 5 working days: 
Researchers are required to submit reports of the following problems promptly but no 
later than 5 working days from the time the investigator becomes aware of the event: 
• Unanticipated problems including adverse events that are unexpected and related 
– Unexpected: An event is “unexpected” when its specificity and severity are not 
accurately reflected in the protocol-related documents, such as the IRB-approved 
research protocol, any applicable investigator brochure, and the current IRB-
approved informed consent document and other relevant sources of information, 
such as product labeling and package inserts. 
– Related to the research procedures: An event is related to the research 
procedures if in the opinion of the principal investigator or sponsor, the event was 
more likely than not to be caused by the research procedures. 
– Harmful: either caused harm to subjects or others, or placed them at increased 
risk 
 
 Other Reportable events: 
The following events also require prompt reporting to the IRB, though no later than 5 
working days: 
• Complaint of a research subject when the complaint indicates unexpected risks 
or the complaint cannot be resolved by the research team. 
• Protocol deviations or violations (includes intentional and 
accidental/unintentional deviations from the IRB approved protocol) for any of 
the following situations: 
– one or more participants were placed at increased risk of harm 
– the event has the potential to occur again 
– the deviation was necessary to protect a subject from immediate harm 
• Breach of confidentiality 
•  Incarceration of a participant when the research was not previously approved 
under Subpart C and the investigator believes it is in the best interest of the 
subject to remain on the study. 
•  New Information indicating a change to the risks or potential benefits of the 
research, in terms of severity or frequency. (e.g. analysis indicates lower-than-


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expected response rate or a more severe or frequent side effect; Other research 
finds arm of study has no therapeutic value; FDA labeling change or withdrawal 
from market). 
 
Reporting Process 
The reportable events noted above will be reported to the IRB using the form: 
“Reportable Event Form” or as a written report of the event (including a description of 
the event with information regarding its fulfillment of the above criteria, follow-
up/resolution and need for revision to consent form and/or other study documentation). 
8.4.1 
Adverse Event Reporting and Serious Adverse Event Reporting 
Adverse events and serious adverse events will be reported to the IRB on a spreadsheet 
including timeframe, severity, relatedness and action during annual reporting. 
 
8.4.2 Unanticipated Problem Reporting 
 
Incidents or events that meet the OHRP criteria for UPs require the creation and 
completion of an UP report form. It is the site investigator’s responsibility to report UPs 
to their IRB and to the study sponsor. The UP report will include the following 
information: 
 
• Protocol identifying information: protocol title and number, PI’s name, and the 
IRB project number; 
• A detailed description of the event, incident, experience, or outcome; 
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP; 
• A description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline: 
 
• UPs that are SAEs will be reported to the IRB and to the study sponsor within 7 
days of the investigator becoming aware of the event. 
• Any other UP will be reported to the IRB and to the study sponsor within 7 days 
of the investigator becoming aware of the problem. 
• All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or 
designee), and OHRP within7 days of the IR’s receipt of the report of the problem 
from the investigator. 
 
8.4.3 
Reporting of Pregnancy 
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 


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and the status of mother and/or child will be reported to the sponsor after delivery.  
 
Any subject reporting a pregnancy during the study will be withdrawn from the study and 
should complete the taper schedule. 
8.5 Reporting Procedures – Notifying the Study Sponsor 
The study clinician will complete a SAE Form within the following timelines: 
 
• All deaths and immediately life-threatening events, whether related or unrelated, 
will be recorded on the SAE Form and submitted to the DCC/study sponsor 
within 24 hours of site awareness. See Section 1, Key Roles for contact 
information. 
• Other SAEs regardless of relationship will be submitted to the DCC/study sponsor 
within 72 hours of site awareness. 
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems 
the event to be chronic or the adherence to be stable. Other supporting documentation of the 
event may be requested by the DCC/study sponsor and should be provided as soon as possible.  
As a follow-up to the initial report, within the following 48 hours of awareness of the event, 
the investigator shall provide further information, as applicable, on the unanticipated event or the 
unanticipated problem in the form of a written narrative.  This should include a copy of the 
completed Unanticipated Problem form, and any other diagnostic information that will assist the 
understanding of the event.  Significant new information on ongoing unanticipated adverse 
effects shall be provided promptly to the study sponsor. 
8.6 Reporting Procedures – Notifying the FDA  
The drug sponsor is required to report certain study events in an expedited fashion to the FDA.  
These written notifications of adverse events are referred to as IND safety reports. The following 
describes the IND safety reporting requirements by timeline for reporting and associated type of 
event: 
 
• Within 7 calendar days (via telephone or facsimile report) 
Any study event that is: 
– associated with the use of the study drug 
– unexpected,  
– fatal or life-threatening 
 
• Within 15 calendar days (via written report) 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later 
found to fit the criteria for reporting (reporting within 15 calendar days from 
when event was deemed reportable). 
Any finding from tests in laboratory animals that:  


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– suggest a significant risk for human subjects including reports of mutagenicity, 
teratogenicity, or carcinogenicity. 
 
Additional reporting requirements 
Sponsors are also required to identify in IND safety reports all previous reports concerning 
similar adverse events and to analyze the significance of the current event in light of the previous 
reports. 
 
Reporting Process 
Adverse events may be submitted on FDA Form 3500A or in a narrative format. If supplied as in 
a narrative format, the minimum information to be supplied is noted above at the beginning of 
section 8.3. The contact information for submitting IND safety reports is noted below: 
 
[Include the FDA Division, contact person, telephone number and fax number here] 
 
8.7 Study Halting Rules 
If the investigator becomes aware of conditions such as adverse events that if additional 
similar events occurred may warrant halting or termination of the clinical study, the 
investigator will notify Zogenix within 24 hours.  They will convene an ad hoc meeting 
by teleconference or in writing as soon as possible so that both parties can discuss and 
agree on the best path forward which may include: 
– 
Modification to the study protocol 
– 
Modification to safety monitoring 
– 
Steps to be taken if additional similar adverse events are observed 
 
8.8 Safety Oversight 
It is the responsibility of the Principal Investigator to oversee the safety of the study at 
his/her site.  This safety monitoring will include careful assessment and appropriate reporting of 
adverse events as noted above, as well as the construction and implementation of a site data and 
safety-monitoring plan. Medical monitoring will include an assessment of the number and type 
of serious adverse events.  
9 Statistical Considerations 
9.1 Statistical and Analytical Plans (SAP) 
There will be no formal statistical methodology but rather descriptive statistics to 
quantify the primary and secondary outcome measures as well as the frequency and severity of 
adverse effects. All subjects participating in this study will have their data analyzed with 
descriptive statistics for both the primary and secondary analyses. 
9.2 Sample Size 
No statistical methods were used to determine the sample size for this study. The 
principal investigator has requested for expanded access use, 21 CFR 312.315 in an intermediate 
size patient population of 10. The total number of subjects expected to participate at NYU 
Comprehensive Epilepsy Center is 10. 


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10 Source Documents and Access to Source Data/Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. It is acceptable to use CRFs as source documents. If this is the case, it should 
be stated in this section what data will be collected on CRFs and what data will be collected from 
other sources. 
The study case report form (CRF) is the primary data collection instrument for the study.  
All data requested on the CRF must be recorded.  All missing data must be explained.  If a space 
on the CRF is left blank because the procedure was not done or the question was not asked, write 
“N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries should be 
printed legibly in black ink.  If any entry error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and enter the correct data above it.  All such 
changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and 
date it. 
Access to study records will be limited to IRB-approved members of the study team. The 
investigator will permit study-related monitoring, audits, and inspections by the IRB/EC, the 
sponsor, government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
11 Ethics/Protection of Human Subjects 
11.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with 
Regulations for the Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 
CFR Part 50, 21 CFR Part 56, and/or the ICH E6. 
11.2 Institutional Review Board 
The protocol, informed consent/assent forms, recruitment materials, and all participant 
materials will be submitted to the IRB for review and approval. Approval of both the protocol 
and the consent/assent form must be obtained before any participant is enrolled. Any amendment 
to the protocol will require review and approval by the IRB before the changes are implemented 
to the study. All changes to the consent form will be IRB approved; a determination will be made 
regarding whether previously consented participants need to be re-consented. 


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11.3 Informed Consent Process 
11.3.1 Consent/Assent and Other Informational Documents Provided to Participants 
Consent forms describing in detail the study agent, study procedures, and risks are 
given to the participants. Capacity assessment will be conducted by Dr. Orrin Devinsky. 
He is board certified Neurologist and Epileptologist and Director of both the NYU 
Comprehensive Epilepsy Center and St. Barnabas Institute for Neurology & 
Neurosurgery. He is experienced in dealing with various neurological diseases and 
multiple clinical trials.   
Capacity will be assessed through neurological examinations conducted by the 
physician as well as documented learning and/or development delays. Previous 
neurological records and neuropsychological assessments will be used to determine 
whether the subject has t the capacity to assent. Consent forms describing in detail the 
study agent, study procedures, and risks will be given to the parent/guardian and written 
documentation of informed consent is required prior to starting 
intervention/administering study product. Dr. Orrin Devinsky will obtain consent and 
explain and/or answer any questions that should arise. This will be done in a private 
patient examination room at the NYU Comprehensive Epilepsy Center. The consent 
materials are submitted with this protocol. Study participant and written documentation 
of informed consent is required prior to starting intervention/administering study product.  
11.3.2 Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
Extensive discussion of risks and possible benefits of participation will be provided to the 
participants and their families. Consent forms will be IRB-approved and the participant 
will be asked to read and review the document. The investigator will explain the research 
study to the participant and answer any questions that may arise. All participants will 
receive a verbal explanation in terms suited to their comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research participants. 
Participants will have the opportunity to carefully review the written consent form and 
ask questions prior to signing. The participants should have the opportunity to discuss the 
study with their surrogates or think about it prior to agreeing to participate. The 
participant will sign the informed consent document prior to any procedures being done 
specifically for the study. The participants may withdraw consent at any time throughout 
the course of the trial. A copy of the signed informed consent document will be given to 
the participants for their records. The rights and welfare of the participants will be 
protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study. For individuals under 18 
years of age, assent will be obtained using an IRB approved age-appropriate assent form. 
If a subject turns 18 during study participation, he or she will be re-consented as an adult. 
For subjects 18 or older, consent will be obtained with the IRB approved consent form.  
A copy of the signed informed consent document will be stored in the subject’s 
research record. The consent process, including the name of the individual obtaining 
consent, will be thoroughly documented in the subject’s research record. Any alteration 
to the standard consent process (e.g. use of a translator, consent from a legally authorized 
representative, consent document presented orally, etc.) and the justification for such 


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alteration will likewise be documented.  
11.4 Participant and Data Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information  
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at 
the end of their scheduled study period. 
Participant confidentiality is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their agents. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the sponsor. 
The study monitor, other authorized representatives of the sponsor, representatives of the 
IRB or pharmaceutical company supplying study product may inspect all documents and records 
required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by local IRB and Institutional regulations. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at NYU Langone Medical Center. This will not 
include the participant’s contact or identifying information. Rather, individual participants and 
their research data will be identified by a unique study identification number. The study data 
entry and study management systems used by clinical sites and by NYU Langone Medical 
Center research staff will be secured and password protected. At the end of the study, all study 
databases will be de-identified and archived at the NYU Langone Medical Center. 
12 Data Handling and Record Keeping 
12.1 Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site PI. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black ink is required to ensure clarity of reproduced copies. When making 
changes or corrections, cross out the original entry with a single line, and initial and date the 


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change. We will not: ERASE, OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON 
THE ORIGINAL. 
Copies of the electronic CRF (eCRF), if used, will be provided for use as source 
documents and maintained for recording data for each participant enrolled in the study. Data 
reported in the eCRF derived from source documents should be consistent with the source 
documents or the discrepancies should be explained and captured in a progress note and 
maintained in the participant’s official electronic study record. 
Clinical data (including AEs, concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into study site database. Clinical data will be 
entered directly from the source documents. 
12.2 Study Records Retention 
Study documents will be retained for the longer of 3 years after close-out, 5 years after 
final reporting/publication, or 2 years after the last approval of a marketing application is 
approved for the drug for the indication for which it is being investigated or 2 years after the 
investigation is discontinued and FDA is notified if no application is to be filed or if the 
application has not been approved for such indication. No records will be destroyed without the 
written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform the 
investigator when these documents no longer need to be retained. 
12.3  Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual 
of Procedures (MOP) requirements. The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions 
are to be developed by the site and implemented promptly. 
These practices are consistent with ICH E6: 
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 5.1 Quality Assurance and Quality Control, section 5.1.1 
• 5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
It is the responsibility of the site PI/study staff to use continuous vigilance to identify and 
report deviations. Protocol deviations must be reported to the local IRB at the annual 
continuation.  
13 Study Finances 
13.1 Funding Source 
Zogenix will provide study medication and funding to support this study. 
13.2 Costs to the Participant 
Zogenix will provide the study medicine free of charge to participating research subjects for 
the duration of this study.  
The subjects will be receiving medical care as a part of this research study. Subjects or their 
insurance company will not be charged or held responsible or the costs of that care. All costs 
related to procedures and assessments associated with participating in this study will be free of 
charge. 
Procedures that are part of routine care or to assess the subject’s health but are not mandatory 
for the study will not be covered. The subject’s individual insurance or government health 


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insurance program may not cover certain services, items, or procedures. This may be discussed 
with the subject’s insurance carrier in advance. The subject/parent/legal guardian will be 
responsible for any co-payments and/or deductibles for services rendered. 
The subject and/or the subject’s health insurance may be billed for the costs of medical care 
during this study if these expenses would have happened even if the subject was not in the study, 
or if the subject’s insurance agrees in advance to pay. If the subject has health insurance, the cost 
of these services will be billed to the subject’s insurance company. If the subject’s 
insurance does not cover these costs or the subject does not have insurance, these costs will be 
the subject’s responsibility. 
14 Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the trial. All 
study group members will disclose all conflicts of interest and will establish a mechanism for the 
management of all reported dualities of interest.   
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by the NYU Langone Conflict of Interest Management Unit (CIMU) with a 
Committee-sanctioned conflict management plan that has been reviewed and approved by the 
study sponsor prior to participation in this study. All NYULMC investigators will follow the 
applicable conflict of interest policies. 
15  References 
1. Devinsky, O, Hesdorffer DC, Thurman DJ, Lhatoo S, Richerson G. 
Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. 
Lancet Neurol. 2016 Sep;15(10):1075-88. 
 
2. Guerrini R, Parrini E.Epilepsy in Rett syndrome, and CDKL5- and FOXG1-gene-related 
encephalopathies. Epilepsia. 2012 Dec ;53(12):2067-78. 
 
3. Lagae ,Lieven; Sullivan, Joseph E.; Cross ,J. Helen; Devinsky,Orri,; Guerrini,Renzo, 
Meyer ,Anna; Knupp,Kelly G.; Laux, Linda C.,; Miller, Ian; Nikanorova,Marina; 
Polster,Tilman; Talwar ,Dinesh; Farfel,Gail M.; Galer,Bradley S.; Gammaitoni,Arnold; 
Morrison,Glenn; Mistry,Arun; and Ceulemans, Berten. ZX008 (Fenfluramine) in Dravet 
Syndrome: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial. 
Abstract. Abst. 2.434), 2017. 
4. ZX008. Fenfluramine Hydrochloride. Investigator’s Brochure, Edition 5. Zogenix 
International Limited: A Wholly Owned Subsidiary of Zogenix, Inc. 28 Apr 2017. 
 
 


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16. APPENDIX 
APPENDIX 1 – LIST OF PROHIBITED CONCOMITANT 
MEDICATIONS 
 
Generic Name 
Generic Name 
alfentanil 
naratriptan 
almotriptan 
nefazodone 
alprenolol 
nortriptyline 
amitriptyline 
ondansetron 
amphetamine 
oxcarbazepine 
astemizole 
oxycodone 
atomoxetine 
paroxetine 
bufuralol 
pergolide 
bupropion 
perphenazine 
buspirone 
phenacetin 
cafergot 
phenobarbital 
Cannabidiol: that is not Epidiolex 
phenytoin 
carbamazepine 
promethazine 
cerivastatin 
propafenone 
cabergoline 
retigabine/ezogabine 
citalopram 
risperidone 
clomipramine 
ritonavir 
codeine 
rizatriptan 
cyproheptadine 
selegiline 
dasatinib 
sertraline 
desipramine 
sumatriptansertraline 
dextromethorphan 
telaprevir 
duloxetine 
THC and derivatives 
eletriptan 
tramadol 
encainide 
trazodone 
ergotamine tartrate 
vortioxetine 
eslicarbazepine 
zolmitriptan 
felbamate 
zuclopenthixol 
fentanyl 
fluoxetine 
fluvoxamine 
frovatriptan 
imipramine 
interferon 
levacetylmethadol (LAAM) 


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linezolid 
meperidine 
methadone 
metoclopramide 
mexiletine