Treatment of Sunflower Syndrome With ZX008 (Fenfluramine Hydrochloride) in Children and Young Adults (Ages 4-25).

NCT03790137 | Completed Phase 3 Results FDA Drug

• 1 other identifier: 12112018
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Photosensitive Epilepsy

Keywords

Sunflower Syndrome; Epilepsy

Outcome Measures

Primary Outcomes (2)

• % Change in Frequency of Handwaving Episodes

  The number of handwaving episodes (seizures) per day were recorded on a seizure diary by either the subject or the parent of the subject. One handwaving episode was defined as the period starting from when the hand first came up toward the face, until there was a brief pause in waving. Subjects and their caregivers were instructed to record the total number of handwaving episodes each day during a one month baseline, and during the 3 month treatment period. The baseline seizure frequency was calculated as an average of the reported handwaving episodes per day during the baseline period. This number was compared to the average episodes per day for the final month of the study (month 3 of treatment with fenfluramine) for each patient. The median percent change in frequency of handwaving episodes across all patients is reported below.

  Month 3

• Change in Frequency of Generalized Tonic-clonic Seizures

  Daily seizure logs will be maintained by either the subject or the parent of the subject and used to calculate seizure frequency. Frequency of Generalized Tonic-clonic seizures was recorded as an average number of seizures/day. The average number of tonic-clonic seizures per day during the baseline period was compared to the average number of tonic-clonic seizures per day during the final month (month 3) for each patient that had experienced at least one tonic-clonic seizure in their lifetime.

  Month 3

Secondary Outcomes (11)

• Change in Spike Frequency on EEG

  Month 3

• Number of Patients That Experienced a Photoparoxysmal Response on EEG

  Month 3

• Changes in Cognitive Functioning Determined by the Weschler Abbreviated Scale of Intelligence (WASI-II Subtests)

  Month 3 (~84 days after the first dose of fenfluramine.)

• Changes in Cognitive Functioning Determined by the Weschler Intelligence Scale for Children (WISC-V) -Processing Speed Subtests.

  Month 3 (approximately 84 days after the first dose of fenfluramine)

• Changes in Quality of Life Determined by the Quality of Life in Childhood Epilepsy Questionnaire(QOLCE-16)

  Month 3 (approximately 84 days after first dose of fenfluramine)

Study Arms (1)

Treatment group

EXPERIMENTAL

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.

Drug: Fenfluramine Hydrochloride

Interventions

Fenfluramine Hydrochloride DRUG

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.

Also known as: ZX008

Treatment group

Eligibility Criteria

• Age: 4 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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 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.

Sponsors & Collaborators

• Elizabeth Anne Thiele: lead
• Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.: collaborator

Study Sites (1)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Related Publications (9)

• 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.

  PMID: 3932858 BACKGROUND

• Ames FR. "Self-induction" in photosensitive epilepsy. Brain. 1971;94(4):781-98. doi: 10.1093/brain/94.4.781. No abstract available.

  PMID: 5132972 BACKGROUND

• 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.

  PMID: 6854340 BACKGROUND

• 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.

  PMID: 24556582 BACKGROUND

• 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.

  PMID: 8892363 BACKGROUND

• 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.

  PMID: 21474289 BACKGROUND

• 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.

  PMID: 2463643 BACKGROUND

• 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.

  PMID: 14124883 BACKGROUND

• Patel S, Geenen KR, Dowless D, Bruno PL, Thiele EA. Follow-up to low-dose fenfluramine for Sunflower syndrome: A non-randomized controlled trial. Dev Med Child Neurol. 2023 Jul;65(7):961-967. doi: 10.1111/dmcn.15492. Epub 2022 Dec 23.

  PMID: 36562419 DERIVED

Related Links

• Zogenix Announces Positive Top-line Results from Pivotal Phase 3

MeSH Terms

Conditions

Epilepsy, Reflex; Epilepsy

Interventions

Fenfluramine

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Phenethylamines; Ethylamines; Amines; Organic Chemicals

Results Point of Contact

• Title: Dr. Elizabeth Thiele
• Organization: Massachusetts General Hospital

ethiele@mgh.harvard.edu

6177266540

Study Officials

• Elizabeth Thiele, M.D., Ph.D.

  Director, Pediatric Epilepsy Program

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director, Pediatric Epilepsy Program

Study Record Dates

• First Submitted: December 12, 2018
• First Posted: December 31, 2018
• Study Start: May 31, 2019
• Primary Completion: November 25, 2021
• Study Completion: July 19, 2024
• Last Updated: November 6, 2024
• Results First Posted: February 8, 2023

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)