Clinical trial NCT03790137: Treatment of Sunflower Syndrome With ZX008 (Fenfluramine Hydrochloride) in Children and Young Adults (Ages 4-25).
Official title: An Open-Label Treatment of ZX008 (Fenfluramine Hydrochloride) in Pediatric and Adult Epilepsy Patients (Ages 4-25) With Sunflower Syndrome.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Photosensitive Epilepsy
Keywords: Sunflower Syndrome
Epilepsy
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
First posted: 2018-12-31
Enrollment: 20
Sex: ALL
Minimum age (years): 4
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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.
* 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 hand waving 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.

Exclusion Criteria:

* 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 PI 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 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 has positive result (as defined in the laboratory manual) on urine tetrahydrocannabinol (THC) Panel or whole blood cannabidiol (CBD) at the screening visit.
* 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.
* 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.

Primary outcomes:
measure: % Change in Frequency of Handwaving Episodes
timeFrame: Month 3
measure: Change in Frequency of Generalized Tonic-clonic Seizures
timeFrame: Month 3
Secondary outcomes:
measure: Change in Spike Frequency on EEG
timeFrame: Month 3
measure: Number of Patients That Experienced a Photoparoxysmal Response on EEG
timeFrame: Month 3
measure: Changes in Cognitive Functioning Determined by the Weschler Abbreviated Scale of Intelligence (WASI-II Subtests)
timeFrame: Month 3 (~84 days after the first dose of fenfluramine.)
measure: Changes in Cognitive Functioning Determined by the Weschler Intelligence Scale for Children (WISC-V) -Processing Speed Subtests.
timeFrame: Month 3 (approximately 84 days after the first dose of fenfluramine)
measure: Changes in Quality of Life Determined by the Quality of Life in Childhood Epilepsy Questionnaire(QOLCE-16)
timeFrame: Month 3 (approximately 84 days after first dose of fenfluramine)
measure: Changes in Executive Functioning Determined by The Behavioral Rating Inventory of Executive Function (BRIEF) Questionnaire.
timeFrame: Month 3 (approximately 84 days after the first dose of fenfluramine)
measure: Changes in Self-Concept Determined by The Beck Self Report Inventory.
timeFrame: Month 3 (approximately 84 days after first dose of fenfluramine)
measure: Changes in Anxiety Determined by the Beck Self Report Inventory
timeFrame: Month 3
measure: Changes in Depression Determined by the Beck Self Report Inventory
timeFrame: Month 3
measure: Changes in Anger Determined by the Beck Self Report Inventory
timeFrame: Month 3
measure: Changes in Disruptive Behavior Determined by the Beck Self Report Inventory
timeFrame: Month 3
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
Study officials:
affiliation: Director, Pediatric Epilepsy Program
name: Elizabeth Thiele, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Aicardi J, Gastaut H. Treatment of self-induced photosensitive epilepsy with fenfluramine. N Engl J Med. 1985 Nov 28;313(22):1419. doi: 10.1056/NEJM198511283132218. No abstract available.
citation: Ames FR. "Self-induction" in photosensitive epilepsy. Brain. 1971;94(4):781-98. doi: 10.1093/brain/94.4.781. No abstract available.
citation: Ames FR, Saffer D. The sunflower syndrome. A new look at "self-induced" photosensitive epilepsy. J Neurol Sci. 1983 Apr;59(1):1-11. doi: 10.1016/0022-510x(83)90076-x.
citation: Belcastro V, Striano P. Self-induction seizures in sunflower epilepsy: a video-EEG report. Epileptic Disord. 2014 Mar;16(1):93-5. doi: 10.1684/epd.2014.0630.
citation: Boel M, Casaer P. Add-on therapy of fenfluramine in intractable self-induced epilepsy. Neuropediatrics. 1996 Aug;27(4):171-3. doi: 10.1055/s-2007-973781.
citation: Chieffo D, Battaglia D, Lettori D, Del Re M, Brogna C, Dravet C, Mercuri E, Guzzetta F. Neuropsychological development in children with Dravet syndrome. Epilepsy Res. 2011 Jun;95(1-2):86-93. doi: 10.1016/j.eplepsyres.2011.03.005. Epub 2011 Apr 6.
citation: Fuller RW, Snoddy HD, Robertson DW. Mechanisms of effects of d-fenfluramine on brain serotonin metabolism in rats: uptake inhibition versus release. Pharmacol Biochem Behav. 1988 Jul;30(3):715-21. doi: 10.1016/0091-3057(88)90089-5.
citation: LIVINGSTON S, TORRES IC. PHOTIC EPILEPSY: REPORT OF AN UNUSUAL CASE AND REVIEW OF THE LITERATURE. Clin Pediatr (Phila). 1964 May;3:304-7. doi: 10.1177/000992286400300511. No abstract available.