Treatment of Sunflower Syndrome With ZX008 (Fenfluramine Hydrochloride) in Children and Young Adults (Ages 4-25).
Condition: Photosensitive Epilepsy
MeSH terms: Epilepsy; Epilepsy, Reflex
Intervention: Fenfluramine Hydrochloride
Intervention description: 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.
Intervention MeSH terms: Fenfluramine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 4 Years
Maximum age: 25 Years
Healthy volunteers: No
Keywords: Sunflower Syndrome; Epilepsy

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.