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

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ClinicalTrials.gov Identifier: NCT03790137
Recruitment Status : Not yet recruiting
First Posted : December 31, 2018
Last Update Posted : December 31, 2018
Sponsor:
Collaborator:
Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
Information provided by (Responsible Party):
Elizabeth Thiele, Massachusetts General Hospital

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 10 patients with Sunflower Syndrome who will be taking ZX008.


Condition or disease Intervention/treatment Phase
Photosensitive Epilepsy Drug: Fenfluramine Hydrochloride Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label Treatment of ZX008 (Fenfluramine Hydrochloride) in Pediatric and Adult Epilepsy Patients (Ages 4-25) With Sunflower Syndrome.
Estimated Study Start Date : February 2019
Estimated Primary Completion Date : February 2020
Estimated Study Completion Date : February 2020


Arm Intervention/treatment
Experimental: Treatment group
The treatment group will include approximately 10 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 up to 6 months.
Drug: Fenfluramine Hydrochloride
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 0.8 mg/kg/day, or a total maximum dose of 30 mg/day. The subject will remain on a dose of 0.8 mg/kg/day, 30 mg/day, or maximum tolerated daily dose for a 6 week maintenance period.
Other Name: ZX008




Primary Outcome Measures :
  1. Change in Frequency of Absence Seizures Associated with Hand Waving. [ Time Frame: Subject Seizure frequency will be recorded at 28 days, 56 Days and 84 Days after the patient's first dose of study drug. Completion of the primary outcome measure will be determined 84 days after the patient's first dose. ]
    Daily seizure logs will be maintained by either the subject or the parent of the subject and used to calculate seizure frequency. Frequency of absence seizures associated with hand waving will be compared from baseline to 28, 56, and 84 days after the first dose.

  2. Change in Frequency of Generalized Tonic-clonic seizures [ Time Frame: Subject Seizure frequency will be recorded at 28 days, 56 Days and 84 Days after the patient's first dose of study drug. Completion of the primary outcome measure will be determined 84 days after the patient's first dose. ]
    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 will be compared from baseline to 28, 56, and 84 days after the first dose.


Secondary Outcome Measures :
  1. Changes in EEG Patterns [ Time Frame: EEGs will be conducted at baseline visit and 84 days after the patient's first dose of study drug. Completion of the secondary outcome measure will be determined 84 days after the patient's first dose. ]
    The investigators will read and interpret pre-drug and post-drug EEGs. Results will be compared.

  2. Changes in Cognitive Functioning determined by the Weschler Abbreviated Scale of Intelligence (WASI-II subtests) [ Time Frame: Completion of the secondary outcome measure will be determined 84 days after the first dose. ]
    The Weschler Abbreviated Scale of Intelligence (WASI-II subtests) will be administered at baseline and 84 days after the start of the first dose of study drug. Results of these cognitive tests will be compared between baseline and 84 days post initial dose.

  3. Changes in Cognitive Functioning determined by the Weschler Intelligence Scale for Children (WISC-V) -Working Memory subtests. [ Time Frame: Completion of the secondary outcome measure will be determined 84 days after the first dose. ]
    The Weschler Intelligence Scale for Children (WISC-V) -Working Memory subtests will be administered at baseline and 84 days after the start of the first dose of study drug. Results of these cognitive tests will be compared between baseline and 84 days post initial dose.

  4. Changes in Cognitive Functioning determined by the Weschler Intelligence Scale for Children (WISC-V) -Processing Speed subtests. [ Time Frame: Completion of the secondary outcome measure will be determined 84 days after the first dose. ]
    The Weschler Intelligence Scale for Children (WISC-V) -Processing Speed subtests will be administered at baseline and 84 days after the start of the first dose of study drug. Results of these cognitive tests will be compared between baseline and 84 days post initial dose.

  5. Changes in Quality of Life determined by the Pediatric Quality of Life Inventory (PedsQL) [ Time Frame: Quality of life questionnaires will be administered after the baseline period and 84 days after the patient's first dose of study drug. Completion of the secondary outcome measure will be determined 84 days after the first dose. ]
    The Pediatric Quality of Life Inventory (PedsQL) will be administered at baseline, and 84 days after the first dose. This questionnaire assesses mood, social relationships, and behaviors. Results will be compared.

  6. Changes in Self-Concept determined by The Beck Self Report Inventory. [ Time Frame: Quality of life questionnaires will be administered after the baseline period and 84 days after the patient's first dose of study drug. Completion of the secondary outcome measure will be determined 84 days after the first dose. ]
    The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose. This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior. Results will be compared.

  7. Changes in Executive functioning determined by The Behavioral Rating Inventory of Executive Function (BRIEF) questionnaire. [ Time Frame: Quality of life questionnaires will be administered after the baseline period and 84 days after the patient's first dose of study drug. Completion of the secondary outcome measure will be determined 84 days after the first dose. ]
    The Behavioral Rating Inventory of Executive Function (BRIEF) questionnaire will be administered at baseline, and 84 days after the first dose. This questionnaire assesses executive function. Results will be compared.



Information from the National Library of Medicine

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Ages Eligible for Study:   4 Years to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03790137


Contacts
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Contact: Elizabeth Thiele 617-726-0241 ethiele@mgh.harvard.edu
Contact: Patricia Bruno, RN, BSN 617-724-7551 pbruno@mgh.harvard.edu

Sponsors and Collaborators
Elizabeth Thiele
Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
Investigators
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Principal Investigator: Elizabeth Thiele, M.D., Ph.D. Director, Pediatric Epilepsy Program

Additional Information:
Publications:
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Responsible Party: Elizabeth Thiele, Director, Pediatric Epilepsy Program, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT03790137     History of Changes
Other Study ID Numbers: 12112018
First Posted: December 31, 2018    Key Record Dates
Last Update Posted: December 31, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Individual participant data (IPD) will not be made available to other researchers.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Elizabeth Thiele, Massachusetts General Hospital:
Sunflower Syndrome
Epilepsy

Additional relevant MeSH terms:
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Epilepsy
Epilepsy, Reflex
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Fenfluramine
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents
Physiological Effects of Drugs