Clinical trial NCT03790137
Conditions: Photosensitive Epilepsy
Keywords: Sunflower Syndrome Epilepsy
Sponsor: Elizabeth Anne Thiele
Start date: 2019-05-31; Completion date: 2024-07-19
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Sunflower Syndrome (also referred to as Self-induced Photosensitive Epilepsy) is a rare epileptic disorder characterized by a distinctive seizure that manifests itself in a highly stereotyped physical behavior. Seizure types associated with Sunflower Syndrome include absence seizures and generalized tonic-clonic seizures. Individuals with Sunflower Syndrome obsessively seek out a light source, stare at the light source, and wave one hand in front of their eye(s). Electroencephalogram (EEG) features include generalized spike and wave discharges interictally, and typically strong photoparoxysmal response during photic stimulation.

Currently, Sunflower syndrome is poorly characterized in medical literature and is often misunderstood at the clinical level. The name self-induced photosensitive epilepsy may be a misnomer as research concerning the neurochemical and neuropsychological pathways cannot conclusively determine that it is self-induced (conscious behavior) as the name implies. Although some reports have concluded that the hand waiving induces the seizure, these findings are not consistent throughout scientific literature. In fact, an EEG report found that the seizures can begin simultaneously with the hand waving. This suggests that the hand waving may in fact be part of the seizure, not the cause.

There are no treatments specifically approved for the treatment of Sunflower Syndrome in the United States. Broad spectrum anticonvulsant medications, including sodium valproate, lamotrigine, levetiracetam, and clobazam, have not shown full efficacy in seizure prevention in patients with Sunflower Syndrome. Accordingly, there remains a significant unmet need for an approved treatment for children and adults with Sunflower Syndrome.

Because this epilepsy typically does not respond to anticonvulsant medications, and because Aicardi described the successful treatment with fenfluramine of at least one child with this syndrome, the investigators of this study will investigate if fenfluramine is an effective, safe and well tolerated treatment for Sunflower Syndrome.

The primary objective of this study is to determine the efficacy of ZX008 on seizure frequency in children and young adults with Sunflower Syndrome. The goal of treatment is to provide a 30 percent or greater reduction of generalized tonic-clonic seizures and/or hand waving associated with absence seizures.

Secondary objectives of the study include evaluation of the effect of ZX008 (fenfluramine hydrochloride) on EEG patterns and quality of life. Patients with Sunflower Syndrome often experience low self-esteem, bullying due to the unusual motor movements associated with their seizures, school performance issues, anxiety, and depression.

The study population will include pediatric and young adult patients seen by Elizabeth A. Thiele, M.D., Ph.D. at MGH's Pediatric Epilepsy Clinic who were identified as candidates. The Principal Investigator (PI) will follow up to 20 patients with Sunflower Syndrome who will be taking ZX008.

Detailed description:

Arms: arm 1: The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) seen by Elizabeth A. Thiele, M.D., Ph.D. at MGH's Pediatric Epilepsy Clinic. Subjects will be treated on an outpatient basis and will not require hospital admission. The treatment group will receive the investigational new drug, Fenfluramine Hydrochloride for approximately 4 months. Patients that benefit from this treatment will remain on medication through an extension phase of the study.
Interventions: intervention 1: Fenfluramine Hydrochloride
Intervention descriptions: intervention 1: Fenfluramine Hydrochloride will be supplied to the treatment group as an oral solution in a concentration of 2.5 mg/mL. Subjects will receive their daily dose of Fenfluramine Hydrochloride in two doses (one in the morning and one in the evening). After a four week baseline, subjects that meet enrollment criteria will enter a titration period. The starting dose will be 0.2 mg/kg/day for the first 14 days. The dose will be increased every 2 weeks as tolerated by 0.2 mg/kg/day, to a maximum dose of 0.7 mg/kg/day, or a total maximum dose of 26 mg/day. The subject will remain on a dose of 0.7 mg/kg/day, 26 mg/day, or maximum tolerated daily dose through the end of the core study period.

Protocol documents:
Prot_001.pdf: 
Detailed Protocol Version Date 02/21/2020 
 
1
DETAILED PROTOCOL: Treatment with Open-Label ZX008 
(Fenfluramine Hydrochloride) in Epilepsy Patients with 
Sunflower Syndrome  
 
Version: November 9th, 2020  
 
Version 8 
 
I. BACKGROUND AND SIGNIFICANCE 
 
Drug resistant epilepsy is a serious and potentially life-threatening 
condition that impacts the day to day functioning of those affected. 
Patients with drug resistant epilepsy are at a higher risk for Sudden 
Unexpected Death in Epilepsy (SUDEP), as frequency of generalized 
tonic-clonic seizures, poly therapy, number of anti-epileptic drugs 
(AED) used, and propensity for nocturnal seizures are the leading risk 
factors for SUDEP. Annual SUDEP risk for patients with epilepsy is 
1/1000; whereas SUDEP risk for patients with drug resistant epilepsy 
is 1/150. 
 
Patients with drug resistant epilepsy do not respond or respond 
incompletely to FDA approved AEDs. Children living with drug resistant 
epilepsy are particularly vulnerable, and urgently need more effective 
medications because those suffering from early-onset and high seizure 
burden epilepsies suffer the greatest neurodevelopmental problems, 
including intellectual disability and autism. In some syndromes such as 
Dravet Syndrome, recent evidence suggests that more effective early 
control of epilepsy is associated with better developmental outcomes 
than in children who were treated 20-30 years ago (Chieffo et al., 
2011).  
 
Sunflower Syndrome (also referred to as Self-induced Photosensitive 
Epilepsy) is a rare epileptic disorder characterized by a distinctive seizure 
that manifests itself in a highly stereotyped physical behavior. Seizure 
types associated with Sunflower Syndrome include absence seizures and 
generalized tonic-clonic seizures. Associated with these seizures, 
individuals with Sunflower Syndrome obsessively seek out a light source, 
stare at the light source, and wave one hand in front of their eye (Belcastro 
& Striano, 2014; Ames, 1971; Aicardi & Gastaut, 1985). 
Electroencephalogram (EEG) features include generalized spike and wave 
discharges interictally, and typically a strong photoparoxysmal response 
during photic stimulation (Belcastro & Striano, 2014; Ames & Saffer, 
1983). 
 


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Currently, Sunflower Syndrome is poorly characterized in scientific 
literature and often misunderstood at the clinical level. The name self-
induced photosensitive epilepsy may be a misnomer as research 
concerning the neurochemical and neuropsychological pathways have not 
been enough to truly characterize it as a self-induced (conscious behavior) 
as the name implies.  Although some reports have concluded that the hand 
waiving induces the seizure, these findings are not consistent throughout 
scientific literature (Belcastro & Striano, 2014; Livingston & Torres, 1964). 
In fact, an EEG report found that the seizures can begin prior to the hand 
waving. This suggests that the hand waving may in fact be part of the 
seizure, not the cause (Livingston & Torres, 1964). 
 
Preclinical Data:  
 
Fenfluramine has been studied in young rats. In those neurochemical 
experiments, fenfluramine was shown to reduce activity and to induce 
learning and memory deficits. Fenfluramine was also shown to reduce 
certain chemicals in the brain, including serotonin, but the long-term 
effects of this are not known (Fuller, Snoddy, & Robertson, 1988). 
 
The relevance of the animal data to humans is not known. Not many 
learning and memory studies have been conducted with fenfluramine 
in humans. 
 
Clinical Data: Fenfluramine in Epilepsy  
 
Aicardi and Gastaut wrote a letter to the NEJM in 1985 describing the 
successful use of fenfluramine in 3 children with self-induced photic 
sensitive epilepsy.  The description of the first of the three patients 
matches that of Sunflower Syndrome (Aicardi & Gastaut, 1985). 
Additionally, there have been several published reports of 
fenfluramine’s successful treatment of refractory childhood epilepsy in 
the 1980’s, as well as, its successful treatment of 11 pediatric patients 
with refractory or self-induced epilepsy, not specifically Sunflower 
Syndrome, in Belgium.  
 
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 & Casaer, 1996). Subjects were treated with 
fenfluramine at 0.5 to 1.0 mg/kg/day for 3 to 8.5 years. Sixty four 
percent of the subjects became seizure free and the remaining 36% of 
subjects experienced greater than or equal to 75% reduction in seizure 
frequency. By 2002, this study’s population had been expanded to 22 
patients with intractable or self-induced seizures who underwent 


Detailed Protocol Version Date 02/21/2020 
 
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treatment between 1 to 12 years. Of the 22 patients treated, 27% (6) 
became seizure-free, 45% (10) patients had a 90% reduction in 
seizure frequency and 27% (6) patients were non-responders. 
 
Zogenix, Inc. is currently evaluating fenfluramine hydrochloride 
(ZX008) in Dravet Syndrome (DS) in three Phase 3 double-blind, 
randomized, placebo-controlled studies, in which our site participated. 
Dravet Syndrome is a rare form of refractory epilepsy, which exhibits 
similar seizure types, as those seen in Sunflower Syndrome. This study 
enrolled 119 subjects across sites in the United States, Canada, 
Europe, and Australia. “The median age of subjects was 8 years 
(range, 2-18 years). Following a six-week baseline observation period, 
subjects were randomized to one of three treatment groups: ZX008 
0.8 mg/kg/day (30 mg maximum daily dose; n=40), ZX008 0.2 
mg/kg/day (n=39) and placebo (n=40) in which ZX008 or placebo was 
added to current regimens of antiepileptic drugs. Subjects were 
titrated to their target dose over two weeks and then remained at that 
fixed dose for 12 weeks. The mean baseline convulsive seizure 
frequency across the study groups was approximately 40 seizures per 
month. 
 
The primary efficacy measure was a comparison of the change in 
mean monthly convulsive seizure frequency between ZX008 0.8 
mg/kg/day and placebo during the 14-week treatment period 
compared with the 6-week baseline observation period. Subjects 
taking ZX008 0.8 mg/kg/day achieved a 63.9% reduction in mean 
monthly convulsive seizures compared to placebo (p<0.001). The 
median percent reduction in monthly convulsive seizure frequency was 
72.4% among ZX008 0.8 mg/kg/day subjects compared to 17.4% in 
placebo subjects. 
 
A key secondary endpoint was the same analysis for a comparison of 
ZX008 0.2 mg/kg/day and placebo. Subjects taking ZX008 0.2 
mg/kg/day achieved a reduction in mean monthly convulsive seizures 
of 33.7% compared to placebo (p=0.019). Collectively, these top-line 
data suggest a dose-response relationship for ZX008 in the adjunctive 
treatment of convulsive seizures in Dravet syndrome” (“Zogenix 
Announces Positive Top-line Results from Pivotal Phase 3 Clinical Trial 
of ZX008 in Dravet Syndrome”, September 2017). 
 
There are no treatments specifically approved for the treatment of 
Sunflower Syndrome in the United States. Broad spectrum 
anticonvulsant medications, including sodium valproate, lamotrigine, 
levetiracetam, and clobazam, have not shown full efficacy in seizure 


Detailed Protocol Version Date 02/21/2020 
 
4
prevention in patients with Sunflower Syndrome. Accordingly, there 
remains a significant unmet need for an approved treatment for 
children and adults with Sunflower Syndrome. 
 
As this epilepsy typically does not respond to anticonvulsant 
medications, and since Aicardi described the successful treatment with 
fenfluramine of at least one child with this syndrome, we would like to 
investigate if fenfluramine is an effective, safe and well tolerated 
treatment for Sunflower Syndrome.   
 
II. SPECIFIC AIMS 
 
The primary objective of this study is the determine the efficacy of 
ZX008 on seizure frequency in children and young adults with 
Sunflower Syndrome. The goal of treatment is to provide a 30 percent 
or greater reduction of generalized tonic-clonic seizures and/or hand 
waving associated with absence seizures.  
 
Secondary objectives of the study include evaluation of the effect of 
ZX008 (fenfluramine hydrochloride) on EEG patterns and quality of 
life. Patients with Sunflower Syndrome often experience low self-
esteem, bullying due to the unusual motor movements associated with 
their seizures, school performance issues, anxiety, and depression.  
 
III. SUBJECT SELECTION 
 
The study population will include pediatric and young adult patients 
seen by Elizabeth A. Thiele, M.D., Ph.D. at MGH’s Pediatric Epilepsy 
Clinic who were identified as candidates. The Principal Investigator (PI) 
will follow up to 20 patients with Sunflower Syndrome who will be 
taking ZX008. 
 
The inclusion criteria for enrollment in this study include:   
 
• Subject is male or non-pregnant, non-lactating female, age 4 to 
25 years, inclusive as of the day of the screening visit. Female 
subjects of childbearing potential must have a negative serum 
pregnancy test at screening. Subjects of childbearing or child-
fathering potential must be willing to use medically acceptable 
forms of birth control, which includes abstinence, while in this 
study and for 90 days after the last dose of study drug. 
• Subjects must have a diagnosis of Sunflower Syndrome, where 
seizures are not completely controlled by their current treatment 
plan.  


Detailed Protocol Version Date 02/21/2020 
 
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• Subjects must experience seizures including absence seizures 
and/or generalized tonic-clonic seizures which involve seeking 
out a light source, staring at the light source, and waving one 
hand in front of their eye(s). Subject’s must experience an 
average of 6 handwaving associated with absence seizures 
and/or generalized tonic-clonic seizures per week. 
• Evidence of EEG in the medical history that shows generalized 
spike and wave discharges between seizures and a strong 
photoparoxysmal response during photic stimulation. Acceptable 
evidence includes a copy of the EEG trace, EEG report, or 
physician note that appropriately describes the EEG findings.  
• All medications or interventions for epilepsy must be stable for at 
least 4 weeks prior to screening and are expected to remain 
stable until Month 3.  
• Subject and/or parent/guardian has been informed of the nature 
of the study and informed consent has been obtained from the 
subject and/or legally responsible parent/guardian. 
• Subject has provided assent in accordance with Institutional 
Review Board (IRB)/Ethics Committee requirements, if capable. 
• Subjects parent/caregiver is willing and able to be compliant 
with diary completion, visit schedule, and study drug 
accountability. 
 
The exclusion criteria for enrollment in this study include:  
 
• Subject has a known hypersensitivity to fenfluramine 
hydrochloride or any other ingredients in the investigational 
drug. 
• Subject’s etiology of seizures is a degenerative neurological 
disease. 
• Subject is pregnant. 
• Subject is not willing to comply with a method of birth control 
acceptable to the LPI (Licensed Physician Investigator) during 
the study and for 90 days following completion of the study. 
• Subject is breastfeeding.  
• Subject has a history of drug or alcohol abuse.  
• Subject has pulmonary arterial hypertension. 
• 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 with reversal of shunt. 
(note: bicuspid valve is not considered exclusionary, but may be 


Detailed Protocol Version Date 02/21/2020 
 
6
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). 
• 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. 
• Subject has a current or past history of glaucoma. 
• Subject has had an anoxic episode requiring resuscitation within 
6 months of the screening visit. 
• Subject has moderate or severe hepatic impairment. 
Asymptomatic subjects with mild hepatic impairment (elevated 
liver enzymes < 3x upper limit of normal (ULN) and/or elevated 
bilirubin <2x ULN) may be entered into the study after review 
and approval by the Medical Monitor in conjunction with the 
sponsor, in consideration of comorbidities and concomitant 
medications. 
• Subject has severe renal impairment (estimated glomerular 
filtration rate <30mL/min/1.73m2) 
• 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; other centrally-acting noradrenergic agonists, 
including atomoxetine; or cyproheptadine. (Note: Short-term 
medication requirements for prohibited medications will be 
handled on a per case basis by the medical monitor.) 
• Subject is receiving a dose of Epidiolex that is above the labeled 
dosing recommendations for that product. (20 
milligrams/kilogram/day)  
• Subjects is using an artisanal formulation of CBD 
• Subject has been taking felbamate for less than 1 year prior to 
screening and/or does not have stable liver function and 
hematology laboratory tests, and/or the dose has not been 
stable for at least 60 days prior to the screening visit. 
• Subject is known to be human immunodeficiency virus (HIV) 
positive. 
• Subject is known to have active viral hepatitis (B or C). 
• Subject is currently receiving an investigational medicinal 
product. 


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• Subject has participated in another clinical trial within the past 
30 days (calculated from that study’s last scheduled visit). 
Participation in non-treatment trials will be reviewed by the 
medical monitor. 
• Subject is at imminent risk of self-harm or harm to others, in the 
investigator’s opinion. 
• Subject is unwilling or unable to comply with scheduled visits, 
drug administration plan, laboratory tests, other study 
procedures, and study restrictions. 
• Subject is institutionalized in a general nursing home (i.e., in a 
facility that does not provide skilled epilepsy care). 
• Subject does not have a reliable caregiver who can provide 
seizure diary information throughout the study. 
• Subject has a clinically significant condition, or has had clinically 
relevant symptoms or a clinically significant illness in the 4 
weeks prior to the Screening Visit, other than epilepsy, that 
would negatively impact study participation, collection of study 
data, or pose a risk to the subject. 
 
IV. SUBJECT ENROLLMENT 
 
This site will independently be studying the efficacy of ZX008 on 
seizure frequency in children and young adults with Sunflower 
Syndrome and the effects of ZX008 on EEG patterns and quality of life. 
 
Informed consent will be obtained for each subject who participates in 
the study by the LPI and be documented in writing with the PHRC 
approved consent form.  The LPI and/or the research nurse will initially 
explain the study, provide the informed consent form, and answer any 
questions from the subjects and their family members.  Subjects will 
be given adequate time to make their decision. Subjects will have the 
opportunity to take the consent form home, and call back if they wish 
to participate. Subjects will also be encouraged to discuss any 
concerns they have with other health care providers. Informed consent 
for all subjects will be obtained by Elizabeth A. Thiele, M.D., Ph.D.. The 
potential for coercion will be avoided through ensuring the subject that 
participation in the study is completely voluntary, and that deciding 
not to take part in the study will not affect the care or benefits to 
which the subject is otherwise entitled. Subjects will be enrolled in the 
study once informed consent has been obtained. Only the LPI will be 
obtain consent from the subject, the subject’s parent/guardian or the 
subject’s surrogate 
 


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8
For subjects who are older than 18 years of age with impaired decision 
making, and subjects under 18 years of age, legal consent to 
participate in research will be provided by a parent or an individual 
authorized under applicable state or local law to provide consent on 
the subject’s behalf to general medical care. When enrolling a subject 
who is younger than 18 it is sufficient for consent to be obtained from 
just one parent. Before the LPI allows an individual other than a parent 
to consent on behalf of a child, she will document the basis for the 
individual’s authority to consent on behalf of the child to general 
medical care and place any relevant documentation in the research 
file.  
 
In addition to permission of the parent(s) or guardian, assent to 
participate in the study must be obtained from each child age 7 to 17 
years old who, in the opinion of the LPI, is able to provide assent 
based on their age, maturity or psychological state. When obtained, 
assent for subjects 14 through 17 years of age will be documented 
using the PHRC approved Consent Form and assent for subjects 7 
through 13 years of age will be documented in writing using the PHRC 
approved Assent Form. When assent is not obtained, the LPI will 
document the rationale in the research records. 
 
The following categories of surrogates (listed in general order of 
preference) may provide consent in writing on behalf of potential 
subjects incapable of providing informed consent: 
1. Court appointed guardian with specific authority to consent to 
participation in research or authority to make health care 
decisions for a class of diagnostic and therapeutic decisions 
inclusive of the proposed research; 
2. Health care proxy/person with durable power of attorney with 
specific authority for making health care decisions inclusive of 
the proposed research; or 
3. Spouse, adult child, or other close family member who knows 
the subject well and has been involved in their care. 
 
 
Assent of subjects will be a requirement for participation in the 
research unless the subject is incapable of giving assent due to his/her 
medical condition. If the individual objects to participation, s/he will 
not be enrolled. When surrogate consent is relied upon, the LPI will 
ensure that the surrogate understands that his or her decisions should 
be based on “substituted judgment.” This means that the decision 
reflects a potential subject's own views when s/he had the capacity to 
express them. The PHRC preferred order of surrogates will be followed, 


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and the Investigator will document the relationship of the surrogate to 
the subject in the research record. 
  
V. STUDY PROCEDURES 
 
The investigational drug to be used in this study is fenfluramine 
hydrochloride (ZX008) manufactured by Zogenix, Inc.. 
 
ZX008 will be supplied as an oral solution in a concentration of 2.5 
mg/mL. The subjects will be treated on an outpatient basis and will not 
require hospital admission. ZX008 will be administered on a twice daily 
basis.  
 
The study will initially consist of a 4 week baseline period, during 
which handwaving associated with absence seizures and/or 
generalized tonic-clonic seizures will be recorded in a seizure diary on 
a daily basis. Subjects will meet enrollment criteria if they have an 
average of 6 generalized tonic-clonic and/or handwaving associated 
absence seizure per week.  
 
If enrollment criteria is met, the subject will enter a titration period. 
The starting dose will be 0.2 mg/kg/day for the first 14 days. The dose 
will be increased every 2 weeks as tolerated by 0.2 mg/kg/day, to a 
maximum dose of 0.8 mg/kg/day, or a total maximum dose of 30 
mg/day. The subject will remain on 0.8 mg/kg/day, 30 mg/day, or 
maximum tolerated dose for a 6 week maintenance period.  
 
Site personnel will call the subject and/or their parent/caregiver every 
11-14 days during the titration period before their next scheduled dose 
increase.  
 
There will be 5 study visits within a 6 month period. After Visit 5, visits 
will occur every 6 months for an assessment in the clinic for subjects 
who respond to treatment with at least a 30% reduction in seizure 
frequency.  
 
Seizure frequency will be tracked with the use of a daily seizure log. In 
the event that seizure frequency is markedly reduced compared to 
baseline after starting the study drug the LPI will discuss with the 
subject and/or their caregiver about adjusting the dose of concomitant 
seizure medications. If seizure frequency is markedly increased 
compared to baseline after discontinuing other medications which were 
taken as standard of care the LPI may decide to adjust dose of other 
seizure medications or reintroduce the medications that were taken as 


Detailed Protocol Version Date 02/21/2020 
 
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part of standard of care. The use of these strategies will be decided on 
a case to case basis.  
 
IND Visit Schedule 
Visit Number 
Visit Type 
Time Point 
1 
Baseline  
Day -28  
2 
Titration 
Day 1 (+14 days) 
3 
Titration and/or 
Maintenance  
28 days from Visit 2 
(±7 days) 
4 
Maintenance 
56 days from Visit 2 
(±14 days) 
5 
Maintenance 
84 days from Visit 2 
(±14 days) 
Continuous 
Maintenance 
Each 6 Months 
following Visit 5 
(±14 days) 
 
  
When applicable, at each study visit, subjects will be given an 
information sheet detailing the potential risk for adverse events seen 
up to that point, along with any other relevant study updates, how 
they will be monitored and what measures will be taken if a subject 
does experience an adverse event. 
 
For each blood draw, approximately 5 mL of blood will be drawn from 
the subject.   
 
At Visit 1, 2, 3, 4, 5, (Day -28, Day 1, Day 28, Day 56, Day 84)  
 and All Sequential Visits  
 
For the period during which COVID-19 contingency plans are in place 
at Partners/MGH, all study visits, including the Screening Visit, will be 
conducted as telemedicine appointments through a PHS IS-approved 
Zoom software. A weblink will be provided to subjects ahead of each 
appointment.  
 
For study visits conducted as telemedicine appointments, required 
study procedures will be performed at sites local to the subject. We 
will provide each subject with location and scheduling information for 
their respective local site. The required study procedures that will be 
performed locally are:   
• Echocardiograms (Visits 1, 5 and Extension Visits 1 and 2)  
• Labs (CBC, CMP, AED) (as required by Principal Investigator)  
 


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Echocardiograms, and labs (CBC, CMP, AED) conducted locally will be 
sent to the Principal Investigator to ensure patient safety, and, in the 
case of ECHOs returning positive results, will be sent to a central 
reader, BioMedical Systems, Inc. (BMS). 
 
These visits will take about 2 hours. During these visits, the following 
will be conducted: 
 
• All the study eligibility criteria will be reviewed to confirm that 
the subject is still eligible. 
• The subjects past and current medical, neurological, and epilepsy 
history will be reviewed at Visit 1 only.   
• The study doctor will review the subject’s current epilepsy status 
from the previous visit including: the amount of seizures they had, 
the types of seizures they experienced, and the duration of each 
of their seizure types. 
• The subject will be asked about their health and the medicines 
that they have taken or are currently taking.  
• Perform a physical and neurological exam.  These exams are a 
series of simple questions and tests that provide very important 
information about the subject’s systems. During the neurological 
exam, the treatment doctor will ask the subject to stand straight 
and walk, see how well the subject can move during the visit, 
and talk to the subject to see how they are doing.  The 
treatment doctor will also look at the subject’s eyes and see how 
their face, arms, and legs feel when touched. 
• Vital signs including: blood pressure, heart rate, respiratory rate, 
along with height, and weight will be measured.  
• If the subject is a female and able to become pregnant, a urine 
or blood pregnancy test will be done at every visit.  The subject 
will not be allowed to enter or continue in the study if they are 
pregnant. If given permission, we will tell their parents the 
results of the test. If no permission is given, the study doctor 
may decide, based on the subject’s age, maturity, or medical 
condition, to tell the subjects parents this information.   
• Laboratory tests will be done.  Approximately 5 mL 
(approximately 1 teaspoons) of blood will be taken from the 
subject’s arm using a needle. The blood sample will be tested 
for: complete blood count with differential (CBC with diff) and a 
complete metabolic panel on Visits 1, 2, 3, 4, 5, and all 
subsequent visits. Current  anticonvulsant medication levels will 
be tested on Visits 1, 3, 5, and on other Visits as clinically 
indicated. Laboratory tests will be completed locally and results 
sent to the Principal Investigator to ensure patient safety. 


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• The subject’s seizure diary will be reviewed with the subject 
and/or 
their 
parent/caregiver. 
The 
subject 
and/or 
their 
parent/caregiver will record in their paper seizure diary daily. All 
of the subject’s seizure types, along with the frequency and 
duration of each seizure, will be recorded in the subject’s seizure 
diary. The subject and/or their parent/caregiver will record in the 
seizure diary if rescue medication was administered.  
• Review of any current adverse events and/or adverse events of 
special interest experienced by the subject after the previous visit. 
• The subject will be provided with new study drug bottles.  
• During Visit 1, 5, and 7, a 4 to 6 hour electroencephalogram 
(EEG) will be performed (only for patients 1-10). This procedure 
will be done in order to analyze electrical activity in the brain. 
Changes in the brain wave patterns as well as photo paroxysmal 
response will be monitored. 
• At Visit 1, 5 and all subsequent visits a Doppler echocardiogram 
(ECHO) will be done using ultrasound waves for examination of 
the heart.  This will be performed at a cardiology clinic/office which 
may be separate from the study doctor’s office, and may be done 
on a different day. The subject might receive a sedative 
medication for this procedure if they cannot be still for the test.  
In this test, the subject will be lying on a bed and a person will 
move a wand on their chest. This transmits information to a 
monitor to tell how well the subject’s heart beats and moves inside 
their chest. It may also indicate if the subject has an increase in 
blood pressure in the arteries in their lungs. ECHOs will be 
completed locally and, if positive results are returned, it will be 
sent to a central reader, BioMedical Systems, Inc. (BMS) to ensure 
patient safety. 
• At Visit 2, 5, and all subsequent visits, the subject and/or the 
subject’s parent/caregiver will be asked to complete the 
following: 
o The Columbia-Suicide Severity Rating Scale (C-SSRS) 
questionnaire to see if they have ever thought about 
harming or killing themselves or behaved like they wanted 
to harm or kill themselves, if applicable.  
o Premonitory Urge Scale  
o If the subject is between 7-18 years he/she will be asked 
to complete: 
▪ the Beck Self Report Inventory – to assess self-
concept, depression, anxiety, anger and disruptive 
behaviors 
▪ Children’s Florida Obsessive-Compulsive Inventory 


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▪ Children’s Yale-Brown Obsessive-Compulsive 
symptoms 
o If the subject’s age is 18 years or older he/she will be 
asked to complete: 
▪ Beck depression inventory. 
▪ Beck Anxiety inventory 
▪ Yale-Brown Obsessive-Compulsive symptoms 
o The subject’s caregiver/parent will be asked to complete 
questionnaires to measure the subject’s health as it relates 
to quality of life, and how their condition affects their day-
to-day activities and health. The questionnaires that will be 
given include:  
▪ Behavioral Rating Inventory of Executive Function 
(BRIEF) – to assess executive function 
▪ Quality of Life in Childhood Epilepsy Questionnaire 
(QOLCE) – to assess mood, social relationships, 
behaviors) 
▪ Attention Deficit Hyperactivity Disorder (ADHD) 
checklist – to assess for hyperactivity and inattention 
• At Visit 2, Visit 5, and Visit 7, Neuropsychological testing will be 
done to assess cognitive function using the following tests (only 
for patients 1-10):  
▪ Weschler Abbreviated Scale of Intelligence (WASI-II 
subtests) 
o If the subject is between 7-16 years he/she will be asked 
to complete: 
▪ Weschler Intelligence Scale for Children (WISC-IV) -
Working Memory subtests 
▪ Weschler Intelligence Scale for Children (WISC-IV) -
Processing Speed subtests 
o If the subject’s age is 16 years or older he/she will be 
asked to complete: 
▪ Weschler Adult Intelligence Scales IV (WAIS-IV) 
▪ WAIS IV Coding and symbol search 
o If a study visit is conducted via virtual visit, we will send 
subjects and their parent/caregiver the questionnaires via 
mail and the subjects will return them back to us after 
completion at the study visit.  
 
Safety Telephone Calls (Day 14, Day 42, Day 70) 
At times during the study, the site personnel will call the subject and/or 
their parent/caregiver to see if they are adjusting well and whether they 
are having any difficulties on the medication. The subject will be 


Detailed Protocol Version Date 02/21/2020 
 
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contacted by the study team by telephone at day 14, day 42, and day 
70after the start of study drug and the following will be discussed: 
 
1. Review of any current adverse events and/or adverse events of 
special interest that the subject has experienced. 
2. Review of all medicines the subject is currently taking. 
 
Virtual Visits 
 
Virtual visits will be conducted in between scheduled clinic visits in the 
extension portion of the study to assess patient wellbeing. After a year 
of follow up in the extension period, virtual visits will be conducted as 
deemed necessary by the LPI. Partners enterprise platforms (Patient 
Gateway) will be used to conduct these visits.  
 
Post-Dosing Telephone Follow-Up Visit (14 Days After Last 
Dose of ZX008) 
 
After the subject has completed the study, or discontinues from the 
study early, the site personnel will call the subject and/or their 
parent/caregiver at the Post-Dosing Telephone Follow-Up Visit (14 
days after the day of discontinuation): 
 
• Review the subject’s current epilepsy status since the previous 
visit including: the amount of seizures they had, the types of 
seizures they experience, and the duration of each of their seizure 
types. 
• Review about how the subject is feeling and what medicines they 
have taken.  
• Review of any current adverse events and/or adverse events of 
special interest experienced by them, after the previous visit. 
• The subject’s seizure diary will be reviewed with them or their 
parent/caregiver.  
 
Cardiac Follow-up (3 Months After Last Dose of ZX008): to 
examine the heart 
 
If the subject has taken study medication for longer than 14 days and 
then leaves the study, or if the subject completes the study, the study 
doctor will perform the following tests and procedures after 3 months 
of study treatment discontinuation. If a problem with the subject’s 


Detailed Protocol Version Date 02/21/2020 
 
15
heart is detected, these procedures might be repeated after another 3 
months: 
• The study doctor will examine the subject (physical 
examination).  
• A Doppler ECHO will be done using sound waves for examination 
of the heart. The subject may receive a sedative medication for 
this procedure if they cannot be still for the test. 
• Review of any side effects related to heart safety experienced by 
the subject after the previous visit.  
 
If the subject is found to have positive findings on ECHO and/or 
physical examination at the 3-month post dose follow-up the subject 
will have repeat examinations at 6 months post-dose and then every 3 
months until the finding is resolved or stable and unlikely to change, 
with reports submitted to the ZX008 safety database. 
 
Shipment of ZX008 study drug 
 
If Study Visit 2 is conducted as a telemedicine appointment, we will 
ship a supply of ZX008 to the subject’s home via FedEx to arrive on 
the day of the scheduled Study Visit 2. If it arrives prior to this visit, or 
if the visit is re-scheduled for any reason, the subject will be advised 
not to administer any study drug prior to the study visit and to store it 
in a cool, dry place at room temperature.  
 
Shipments of ZX008 will be sent to subject’s homes via FedEx as they 
require new supply. Study staff will review the schedule of these 
shipments with the subject as they may vary for each subject.  
 
VI. BIOSTATISTICAL ANALYSIS 
 
The data variables to be collected from each subject will include: 
• The number and type of seizures occurring per day 
• The duration of the seizures 
• Complete blood count with differential (CBC with diff), a complete 
metabolic panel, and current levels of anticonvulsant medication 
levels 
• EEG patterns 
• Quality of life assessments 
 
 
VII. RISKS AND DISCOMFORTS 
 


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Risks of Taking ZX008 
 
Any research study has risks, which may include things that could 
make the subject sick, make the subject feel uncomfortable, or harm 
them. The subject might experience side effects related to the 
treatment drug while participating in the treatment.  The subject will 
be watched carefully for any side effects; however, the study team 
does not know all the effects that ZX008 may have on the subject.  
The study team may give the subject medicines to help reduce side 
effects.  These side effects may be mild or serious.  In some cases, 
these side effects might be long lasting, or permanent, and may even 
be life threatening.   
 
Allergic Reaction:  
 
Any drug has a possible risk for an allergic reaction.  If the subject has 
any symptoms that could be an allergic reaction such as feeling faint, 
having skin swelling, or having difficulty breathing, or experience any 
worrying health issue, they should seek immediate local medical 
assistance and then contact the study site. 
 
Thickening of Heart Valves; Pulmonary Hypertension: 
 
When the active ingredient in ZX008, fenfluramine, was on the market 
for the treatment of obesity in adults who were overweight from the 
1970s through the 1990s, some adults developed thickening of heart 
valves and pulmonary hypertension (high pressure in blood vessels in 
the lung that makes it difficult to breathe normally).  After stopping 
the medication, some patients’ heart valves returned to normal, some 
remained stable but abnormal, and some had surgery to correct the 
condition.  Generally, if these problems do occur, they develop slowly 
over time.  The subject will be administered ECHOs during the study to 
very carefully watch for early signs that the subject’s heart valves are 
thickening and to look for early signs of pulmonary hypertension.  If 
there are heart valve changes, the subject will re-review the risk and 
potential benefit of the study medication with the study doctor and 
discuss further options. The subject may withdraw at this or any other 
time. If the subject experiences any chest pain, persistent cough, 
shortness of breath, wheezing, extreme fatigue, or dizziness, they 
should contact the study staff immediately to discuss whether they 
should have a clinic visit or other tests. 
 
If a Subject Has a Positive Finding on Their Echocardiogram: 
 


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A positive finding on one of the echocardiograms may indicate that one 
or more of the subject’s heart’s valves are not functioning normally. 
This detected abnormality may not be associated with any physical 
symptoms. There are four valves in the heart: the aortic, mitral, 
tricuspid, and pulmonary. If one or more of these valves are not 
working properly and the subject continues in this study, they may be 
at an increased risk. We cannot know for certain whether a positive 
finding is the result of ZX008 and we do not know for certain whether 
the condition will worsen with continued use of ZX008. Some adults 
who have taken the same medication components in ZX008 and 
developed heart abnormalities have remained stable for years, while 
some adults who have taken the medication for obesity (excess 
overweight) developed heart problems that interfered with daily 
activities, and a small number have needed surgery or a procedure to 
improve heart function. 
 
All ECHOs will be evaluated by a central reader from BioMedical 
Systems, Inc. (BMS). The primary investigator and local cardiologist 
will receive notification in the event of any ECHO findings consistent 
with pulmonary hypertension or valvulopathy on any of the four valves 
(aortic, mitral, pulmonary, tricuspid) 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 1 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 
 
 
 
 
Level 1: Continue per protocol 
 


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18
Level 2: 
 
1.  If there is a desire to continue study medication: 
a. The principal 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 principal investigator will consider whether the subject 
has had reasonable trials (dose and duration) of other 
available anticonvulsants, alone or in combination, and not 
maintained the level of seizure control currently achieved 
with study medication. 
2. If the principal 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 statement acknowledging 
their understanding of the positive findings and possible risks 
associated with continuing in the study. The child should provide 
assent if appropriate. If both of these conditions are not met, the 
subject is discontinued from treatment. 
3. The principal investigator prepares a case history and rationale 
for continuation to review with the local cardiologist, including 
consideration of effects on seizures and comorbidities. 
4. The principal investigator and local cardiologist will 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 principal 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 for consideration: 


Detailed Protocol Version Date 02/21/2020 
 
19
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, alone or in combination, 
and not maintained the level of seizure control achieved 
with study medication. 
2. If the principal 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 statement acknowledging 
their understanding of the positive findings and possible risks 
associated with continuing in the study. The child should provide 
assent if appropriate. If both of these conditions are not met, the 
subject is discontinued from treatment. 
3.  The principal investigator prepares a case history and rationale 
for continuation to review with the local cardiologist, including 
consideration of effects on seizures and comorbidities. 
4. The principal investigator and local cardiologist will evaluate the 
risks and proposed monitoring plan, if applicable.  
5. The principal investigator and local cardiologist will 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 
 
Weight Decrease or Appetite Decrease  
 
The study staff will take precautions against the possibility of weight 
loss and/or decreased appetite by monitoring weight at each study 
visit. If there is a notable decrease in weight or appetite, the study 
staff will refer the subject to a licensed dietician or gastrointestinal 
specialist. If it is determined that the weight loss is related to the 
study drug the LPI may decide to decrease the dose of study drug. 
This will be determined on a case to case basis.     
 


Detailed Protocol Version Date 02/21/2020 
 
20
Additional Risk 
 
The subject taking part in this treatment involves some risks and 
possible discomfort as noted below: 
 
• If the treatment does not work for the subject, the subject may see 
no change or an increase in their seizures. If there is an increase in 
seizure frequency the LPI may decide to lower the dose of the study 
drug or other seizure medications.   
• The treatment drug may cause unpleasant side effects or reactions, 
as described below.   
• Since ZX008 is investigational, there may be risks and side effects 
that are unknown.  Any drug has a possible risk of an allergic 
reaction.   
 
 
ZX008 (Fenfluramine Hydrochloride) 
 
Animal Models: 
 
Fenfluramine has been studied in young rats. In those studies, 
fenfluramine was given in doses similar to those the subject may 
receive and was shown to reduce activity and to induce learning and 
memory deficits. Fenfluramine was also shown to reduce certain 
chemicals in the brain, including serotonin, but the long-term effects of 
this are not known. 
 
The relevance of the animal data to humans is not known. Not many 
learning and memory studies have been conducted with fenfluramine 
in humans. Of those that are published, the results are variable with 
some studies reporting no effect while other studies report some 
decrements or some improvements. Two studies have been conducted 
in children. Children were dosed daily for four weeks in one study and 
for four months in the other study. At the highest dose, which was 1.5 
mg/kg/day in both studies, no adverse effects of fenfluramine were 
found on learning and memory tasks in either study. 
 
In Human Trials: 
 
The possible side effects of fenfluramine (as observed in 3 open-label 
studies involving pediatric and young adult populations with Dravet 
Syndrome at doses of up to 30 mg/ day) were: 
 
• Somnolence (sleepiness/ drowsiness) 


Detailed Protocol Version Date 02/21/2020 
 
21
• Anorexia 
• Status Epilepticus (a seizure lasting more than five minutes or when 
seizures occur close together and the person is not able to recover 
in between seizures for more than five minutes) 
• Decreased appetite 
• Abnormal behavior  
• Mild heart valve thickening without clinical significance 
• Seizures/Seizure cluster (seizure clusters are when seizures occur 
in groups over several hours or days) 
• Vomiting 
 
In addition, fenfluramine has been studied in 13 clinical trials in an 
obese adult population at doses of 60-120 mg/day. The commonly 
reported adverse events from these trials were: 
 
Most Common Adverse Events (15-16% of study subjects had these 
symptoms): 
• Diarrhea 
• Drowsiness 
 
Less Frequent Adverse Events (2-7% of study subjects): 
• Dizziness 
• Elevated mood 
• Frequent urination 
• Headache 
• Insomnia 
• Tiredness 
 
Fenfluramine has also been studied in small trials in children and 
adolescents with autism and/or ADHD (attention deficit hyperactivity 
disorder). The commonly reported adverse events from these trials 
were: 
 
• Drowsiness 
• Increased withdrawal symptoms 
• Irritability 
• Lack of energy 
• Sleeplessness (insomnia) 
• Weight Loss 
 


Detailed Protocol Version Date 02/21/2020 
 
22
Risks from the study procedures: 
 
• Blood Sample Collection:  Taking blood from the subject’s arm 
may sometimes cause pain/discomfort at the site where the blood is 
drawn, bruising, bleeding, occasional lightheadedness, redness, 
and/or swelling, and, rarely, feeling faint or infection.  
• EEG (electroencephalogram): Skin irritation is rare but could 
occur during or after an EEG from the sensors, gel, or glue that is 
used.  
• ECHO (echocardiogram):  An ECHO is a test that uses sound 
waves to examine the subject’s heart.  A technician will place sensors 
on the subject’s chest that are connected by wires to a machine and 
the technician will then move a wand over their chest.  The wand 
may have a small amount of cool gel on the end to make it move 
more easily.  The subject may feel some pressure on the chest during 
this procedure.  If they need to receive a sedative because they are 
unable to stay still for this procedure, the subject may experience 
extra sleepiness, slow or difficult breathing, a drop in blood pressure, 
feeling sick to their stomach, vomiting (throwing up), restlessness, 
or not knowing where they are when they wake up.  
• Questionnaires:  A questionnaire may contain questions that are 
sensitive in nature.  The subject and/or their caregiver/parent may 
refuse to answer any question that makes them feel uncomfortable.  
If the subject has concerns after completing the questionnaire, they 
should talk to their study doctor. 
• Reproductive risks:  The subject should not become pregnant or 
father a baby while on this study because it is not known whether 
the drugs in this study can affect an unborn baby.  Females should 
not breastfeed a baby while on this study.  It is important to 
understand that if the subject is able to become pregnant or father a 
baby they need to use birth control while on this study.  The subject 
should check with their study doctor about what kind of birth control 
methods to use and how long to use them.  Some methods might not 
be approved for use in this study. If the subject is capable of having 
a baby, their blood will be tested to confirm that they are not 
pregnant.   
• Unknown Risks: The experimental treatment may have side effects 
that no one knows about yet.  The study staff will let the subject 
know if they learn anything that might make the subject change their 
mind about participating in the study. 
 
As with all studies, there is a potential to breach confidentiality. 
Assigning a study number and keeping the log in a safe physical or 
electronic place will reduce the risk. 


Detailed Protocol Version Date 02/21/2020 
 
23
 
Additionally, if the study treatment does not work for the subject, they 
may see no change or an increase in their seizures. ZX008 may cause 
unpleasant side effects or reactions. Since ZX008 is an investigational 
medication, there may be risks and side effects that are unknown.  
 
Pregnancy/Birth Control 
 
Women 
If this subject is a female who is not able to have children, i.e. they 
are permanently sterile (when a female is unable to have children after 
surgical removal of female reproductive organ), they do not need to 
use any birth control methods.   
 
Taking ZX008 may involve unknown risks to a pregnant female, an 
embryo, fetus (unborn baby), or nursing infant.  Therefore, if the 
subject is pregnant, planning to become pregnant, or are 
breastfeeding a child, the subject cannot take part in this study.   
 
Before entering the study, a blood pregnancy test will be done for all 
women who are able to become pregnant.  This test might not detect 
an early pregnancy.  Pregnancy tests will be repeated during the 
study.   
 
Any female in the study who is sexually active and is able to have 
children must use, with her partner, approved methods of highly 
effective birth control from the time of signing informed consent 
through 90 days after the last dose of study drug.  If the subject is 
already using a method of birth control, the study doctor or study staff 
will discuss with the subject whether their current method of birth 
control is acceptable for use during this study.  Methods of effective 
birth control include surgical sterilization (for example, “vasectomy”); 
hormonal contraceptives such as birth control pills, the patch, 
intrauterine device, etc.   
 
If during the study, the subject becomes pregnant, they should tell the 
study doctor as soon as possible.  The study medication will be 
stopped, the subject will be discontinued from the study, and the 
study doctor will ask that the subject give updates about the outcome 
of the pregnancy. 
 
Men 
If the subject is a male and sexually active with a partner who is able 
to have children, the subject and his partner should be compliant with 


Detailed Protocol Version Date 02/21/2020 
 
24
a highly effective method of birth control consistently from the time of 
signing informed consent through 90 days after the last dose of study 
drug.  Acceptable methods of birth control include condom for the 
subject plus hormonal contraceptives, such as birth control pills, the 
patch, intrauterine device, etc. for their partner; or surgical 
sterilization (for example, “vasectomy”). The study doctor will discuss 
and suggest the appropriate method of birth control for the subject 
while they are in this study.  
 
If during the study, the subject’s partner becomes pregnant, they 
should tell the study doctor as soon as possible.  In this situation, the 
study doctor can either withdraw the subject from the study or if not, 
he/she will ask the subject to give updates about the outcome of their 
partner’s pregnancy.   
 
Alternatively, true abstinence is acceptable when it is in line with the 
subject’s preferred and usual lifestyle. If a subject is usually not 
sexually active but becomes active, they, with their partner, they must 
comply with the contraceptive requirements detailed above. 
 
Male subjects should not donate sperm and female subjects should 
refrain from egg donation for the duration of the study and for at least 
90 days after the last day of study medication administration. 
 
 
VIII. POTENTIAL BENEFITS 
 
Potential benefits to participating subjects include the possibility for a 
reduction in seizure frequency and/or severity.  
 
This study will elucidate the effects of fenfluramine hydrochloride 
(ZX008) on the improvement of seizures in children and young adults 
with Sunflower Syndrome.  Additionally, should the investigation drug 
be effective, this study will provide new information about the safety, 
tolerability, and appropriate dosing for ZX008 in the treatment of 
Sunflower Syndrome.  
 
IX. MONITORING AND QUALITY ASSURANCE 
 
The LPI and clinical research nurses will review all data relating to 
safety and tolerability throughout the study to monitor compliance and 
assess subject safety. 
 


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25
Reporting of Adverse Events:  The Institution and Investigator shall 
follow the same standards as a normal healthcare professional to 
report observed or reported adverse events to the FDA 
(https://www.accessdata.fda.gov/scripts/medwatch/) and notification 
regarding any serious adverse events (SAEs) or ECHO findings 
consistent with cardiac valvulopathy or pulmonary hypertension to 
ZOGENIX either by phone at 1-866-964-3649 or via email 
Zogenix@druginfo.com 
 
All problems having to do with subject safety related to the treatment 
drug will be documented, including adverse events (AE) and serious 
adverse events (SAE). Some SAEs might necessitate withdrawing from 
the study. Serious adverse events would be those which could result in 
death, are life threatening, require inpatient hospitalization, result in a 
persistent or significant disability/incapacity, or any other adverse 
event that, based upon appropriate medical judgment, may jeopardize 
the subject’s health and may require medical or surgical intervention. 
If the subject is withdrawn from the treatment due to an adverse 
event, the subject will be followed as frequently as necessary until 
resolution of the event.   
 
Unexpected serious related adverse reactions will be reported to FDA 
as soon as possible, but no later than 15 calendar days following the 
initial receipt of information, as per FDA regulations. Unexpected fatal 
or life-threatening suspected adverse reactions will be reported to FDA 
as soon as possible, but no later than 7 calendar days following the 
initial receipt of the information, as per FDA regulations. Included in 
the report, will be: 
 
• A detailed description of the adverse event 
• The basis for determining that the event is unexpected in nature, 
severity, or frequency 
• The basis for determining that the event is related or possibly 
related to the research procedures 
• The basis for determining that the research places subjects at an 
increased risk of harm (i.e., a serious adverse event) 
• Whether any changes to the research or other corrective actions 
are warranted 
 
In addition to reporting adverse events to the Partner’s IRB, the LPI 
will also report them to the FDA in the form of a written IND safety 
report. The IND safety report will be submitted on form 3500A and 
accompanied by form 1571.  
 


Detailed Protocol Version Date 02/21/2020 
 
26
The LPI will also monitor the adherence to the protocol and to Good 
Clinical Practice, the progress of enrollment, and make sure that study 
drug is being stored, dispensed, and accounted for according to 
specifications. The subjects will be closely monitored for side effects 
during the treatment period.  
 
Parents/subjects are instructed how to administer the study drug at 
each study visit.  
The subject will be withdrawn from the treatment for any of the 
following reasons:  
 
1. Development of signs or symptoms indicative of cardiac 
valvulopathy or regurgitation (mitral, aortic, tricuspid, pulmonary 
valves), or pulmonary hypertension for which the local cardiologist 
and the investigator believe the benefit of continued participation 
does not outweigh the risk. 
2. Subject is noncompliant with procedures set forth in the protocol in 
an ongoing or repeated manner. 
3. Subject experiences an AE or SAE that warrants withdrawal from 
the treatment. 
4. Clinically significant worsening of seizures, judged by investigator 
or caregiver such that treatment outside of the protocol and 
treatments other than ZX008 are assumed to be in the subject’s 
best interest. Frequent or increased use of rescue medication may 
be considered indicative of worsening seizures. 
5. It is the investigator’s opinion that it is not in the subject’s best 
interest to continue in the treatment.


Detailed Protocol Version Date 02/21/2020  27 
 
 
X. REFERENCES 
 
1. Aicardi, J. & Gastaut, H. (1985). Treatment of self-induced  
photosensitive epilepsy with Fenfluramine. New England Journal 
of Medicine, 313 (22), 1419. https://doi.org/ 
10.1056/NEJM198511283132218 
2. Ames, F.R. (1971). “Self-induction” in Photosensitive Epilepsy. Brain,  
 
94 (4), 781-798. https://doi.org/10.1093/brain/94.4.781 
3. Ames. F.R. & Saffer, D. (1983). The Sunflower Syndrome: A New Look  
 
at “Self-induced” Photosensitive Epilepsy. Journal of the  
 
Neurological Sciences, 59 (1), 1-11.  
https://doi.org/10.1016/0022-510X(83)90076-X 
4. Belcastro, V. & Striano, P. (2014). Self-induction seizures in sunflower  
 
epilepsy: a video- EEG report. Epileptic Disord, 16 (1), 93-95.  
 
https://doi.org/10.1684/epd.2014.0630 
5. Boel, M. & Casaer, P. (1996). Add-On Therapy of Fenfluramine in  
 
Intractable Self-Induced Epilepsy. Neuropediatrics, 27 (4), 171- 
 
173. https://doi.org/10.1055/s-2007-973781 
6. Chieffo, D., Battaglia, D., Lettori, D., Del Re, M., Brogna, C., Dravet,  
 
C., Mercuri, E., & Guzzetta, F. (2011). Neuropsychological  
 
development in children with Dravet syndrome. Epilepsy  
 
Research, 95 (1-2), 86-93. https://doi.org/10.1016/j.eplepsyre 
s.2011.03.005 
7. Fuller, R.W., Snoddy, H.D., & Robertson, D.W. (1988). Mechanisms of  
 
effects of d-Fenfluramine on brain serotonin metabolism in rats:  
 
Uptake inhibition versus release. Pharmacology Biochemistry and  
 
Behavior, 30 (3), 715-721. https://doi.org/10.1016/0091- 
 
3057(88)90089-5 
8. Livingston, S. & Torres, I.C. (1964). Photic epilepsy: report of an  
unusual case and review of the literature. Clinical Pediatrics, 3,  
304-307. https://doi.org/10.1177/000992286400300511 
9. Zogenix Announces Positive Top-line Results from Pivotal Phase 3  
 
Clinical Trial of ZX008 in Dravet Syndrome. (2017, September  
 
27). Retrieved from https://globenewswire.com/news- 
 
release/2017/09/29/1134829/0/en/Zogenix-Announces-Positive- 
 
Top-line-Results-from-Pivotal-Phase-3-Clinical-Trial-of-ZX008-in- 
 
Dravet-Syndrome.html