<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03790137</url>
  </required_header>
  <id_info>
    <org_study_id>12112018</org_study_id>
    <nct_id>NCT03790137</nct_id>
  </id_info>
  <brief_title>Treatment of Sunflower Syndrome With ZX008 (Fenfluramine Hydrochloride) in Children and Young Adults (Ages 4-25).</brief_title>
  <official_title>An Open-Label Treatment of ZX008 (Fenfluramine Hydrochloride) in Pediatric and Adult Epilepsy Patients (Ages 4-25) With Sunflower Syndrome.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Elizabeth Anne Thiele</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Massachusetts General Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Sunflower Syndrome (also referred to as Self-induced Photosensitive Epilepsy) is a rare&#xD;
      epileptic disorder characterized by a distinctive seizure that manifests itself in a highly&#xD;
      stereotyped physical behavior. Seizure types associated with Sunflower Syndrome include&#xD;
      absence seizures and generalized tonic-clonic seizures. Individuals with Sunflower Syndrome&#xD;
      obsessively seek out a light source, stare at the light source, and wave one hand in front of&#xD;
      their eye(s). Electroencephalogram (EEG) features include generalized spike and wave&#xD;
      discharges interictally, and typically strong photoparoxysmal response during photic&#xD;
      stimulation.&#xD;
&#xD;
      Currently, Sunflower syndrome is poorly characterized in medical literature and is often&#xD;
      misunderstood at the clinical level. The name self-induced photosensitive epilepsy may be a&#xD;
      misnomer as research concerning the neurochemical and neuropsychological pathways cannot&#xD;
      conclusively determine that it is self-induced (conscious behavior) as the name implies.&#xD;
      Although some reports have concluded that the hand waiving induces the seizure, these&#xD;
      findings are not consistent throughout scientific literature. In fact, an EEG report found&#xD;
      that the seizures can begin simultaneously with the hand waving. This suggests that the hand&#xD;
      waving may in fact be part of the seizure, not the cause.&#xD;
&#xD;
      There are no treatments specifically approved for the treatment of Sunflower Syndrome in the&#xD;
      United States. Broad spectrum anticonvulsant medications, including sodium valproate,&#xD;
      lamotrigine, levetiracetam, and clobazam, have not shown full efficacy in seizure prevention&#xD;
      in patients with Sunflower Syndrome. Accordingly, there remains a significant unmet need for&#xD;
      an approved treatment for children and adults with Sunflower Syndrome.&#xD;
&#xD;
      Because this epilepsy typically does not respond to anticonvulsant medications, and because&#xD;
      Aicardi described the successful treatment with fenfluramine of at least one child with this&#xD;
      syndrome, the investigators of this study will investigate if fenfluramine is an effective,&#xD;
      safe and well tolerated treatment for Sunflower Syndrome.&#xD;
&#xD;
      The primary objective of this study is to determine the efficacy of ZX008 on seizure&#xD;
      frequency in children and young adults with Sunflower Syndrome. The goal of treatment is to&#xD;
      provide a 30 percent or greater reduction of generalized tonic-clonic seizures and/or hand&#xD;
      waving associated with absence seizures.&#xD;
&#xD;
      Secondary objectives of the study include evaluation of the effect of ZX008 (fenfluramine&#xD;
      hydrochloride) on EEG patterns and quality of life. Patients with Sunflower Syndrome often&#xD;
      experience low self-esteem, bullying due to the unusual motor movements associated with their&#xD;
      seizures, school performance issues, anxiety, and depression.&#xD;
&#xD;
      The study population will include pediatric and young adult patients seen by Elizabeth A.&#xD;
      Thiele, M.D., Ph.D. at MGH's Pediatric Epilepsy Clinic who were identified as candidates. The&#xD;
      Principal Investigator (PI) will follow up to 20 patients with Sunflower Syndrome who will be&#xD;
      taking ZX008.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">May 31, 2019</start_date>
  <completion_date type="Anticipated">October 2023</completion_date>
  <primary_completion_date type="Actual">November 25, 2021</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>% Change in Frequency of Handwaving Episodes</measure>
    <time_frame>Month 3</time_frame>
    <description>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.&#xD;
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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Frequency of Generalized Tonic-clonic Seizures</measure>
    <time_frame>Month 3</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Spike Frequency on EEG</measure>
    <time_frame>Month 3</time_frame>
    <description>The investigators will read and interpret pre-drug (baseline) and post-drug EEGs (month 3 of core study) for the first 9 patients. The average number of spikes/hour across these patients will be reported for both pre- and post-treatment EEGs.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Patients That Experienced a Photoparoxysmal Response on EEG</measure>
    <time_frame>Month 3</time_frame>
    <description>The investigators will read and interpret pre- (baseline) and post-treatment (month 3) EEGs. The number of patients that experienced a photoparoxysmal response during the EEGs will be reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Cognitive Functioning Determined by the Weschler Abbreviated Scale of Intelligence (WASI-II Subtests)</measure>
    <time_frame>Month 3 (~84 days after the first dose of fenfluramine.)</time_frame>
    <description>The Weschler Abbreviated Scale of Intelligence (WASI-II subtests) will be administered to the first 10 patients 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.&#xD;
The WASI-II measures cognitive functioning through 2 subtests, vocabulary and matrix reasoning. The raw scores on these subtests are combined to give a composite full-scale IQ (FSIQ) that is scaled to an average of 100 and standard deviation of 15.&#xD;
Maximum raw scores for the subtests are as follows (higher values are considered better and minimum score on each is 0).&#xD;
Vocabulary:&#xD;
ages 7-11: 47 ages 12-14: 53 ages 15-25: 59&#xD;
Matrix Reasoning:&#xD;
ages 6-8: 24 ages 9-25: 30</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Cognitive Functioning Determined by the Weschler Intelligence Scale for Children (WISC-V) -Processing Speed Subtests.</measure>
    <time_frame>Month 3 (approximately 84 days after the first dose of fenfluramine)</time_frame>
    <description>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 (Month 3; visit 5). Results of these cognitive tests will be compared between baseline and 84 days post initial dose.&#xD;
Raw scores for the coding and symbol search subtests will be used to evaluate processing speed. The maximum raw scores are as follows (the minimum score is 0 and higher scores are considered better).&#xD;
Coding:&#xD;
ages 6-7: 65 ages 8-16: 119&#xD;
Symbol search:&#xD;
ages 6-7: 45 ages 8-16: 60</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Quality of Life Determined by the Quality of Life in Childhood Epilepsy Questionnaire(QOLCE-16)</measure>
    <time_frame>Month 3 (approximately 84 days after first dose of fenfluramine)</time_frame>
    <description>The Quality of Life in Childhood Epilepsy Questionnaire will be administered at baseline, and 84 days after the first dose (Month 3; visit 5). This questionnaire assesses mood, social relationships, and behaviors. Results will be compared.&#xD;
The QOLCE assesses quality of life across 4 domains of functioning: cognitive, emotional, social and physical. Scores range from 0-100. Composite scores are calculated as a mean across all measures.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Executive Functioning Determined by The Behavioral Rating Inventory of Executive Function (BRIEF) Questionnaire.</measure>
    <time_frame>Month 3 (approximately 84 days after the first dose of fenfluramine)</time_frame>
    <description>The Behavioral Rating Inventory of Executive Function (BRIEF) questionnaire will be administered at baseline, and 84 days after the first dose of fenfluramine (Month 3; Visit 5). This questionnaire assesses executive function across 8 clinical scales:&#xD;
Inhibit&#xD;
Shift&#xD;
Emotional Control&#xD;
Initiate&#xD;
Working Memory&#xD;
Plan/Organize&#xD;
Organization of Materials&#xD;
Monitor&#xD;
Item level scores are rated on a 3 point Likert Scale from 1-3:&#xD;
Never&#xD;
Sometimes&#xD;
Often&#xD;
The Global Executive Composite (GEC) score is the total score of all 8 clinical subscales. The item scores are summed for each scale and raw scores are converted to Tscores. The mean of the GEC score will be reported.&#xD;
T scores from 60 to 64 are considered mildly elevated. T scores from 65 to 69 are considered potentially clinically elevated. T scores at or above 70 are considered clinically elevated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Self-Concept Determined by The Beck Self Report Inventory.</measure>
    <time_frame>Month 3 (approximately 84 days after first dose of fenfluramine)</time_frame>
    <description>The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.&#xD;
The raw scores for subscales are calculated in the following manner:&#xD;
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.&#xD;
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.&#xD;
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.&#xD;
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.&#xD;
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.&#xD;
Raw scores will be translated into T-scores.&#xD;
T-scores for BYI are as follows:&#xD;
55 or less = average&#xD;
55-59 = mildly elevated&#xD;
60-69 = moderately elevated&#xD;
70+ = extremely elevated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Anxiety Determined by the Beck Self Report Inventory</measure>
    <time_frame>Month 3</time_frame>
    <description>The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.&#xD;
The raw scores for subscales are calculated in the following manner:&#xD;
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.&#xD;
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.&#xD;
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.&#xD;
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.&#xD;
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.&#xD;
Raw scores will be translated into T-scores.&#xD;
T-scores for BYI are as follows:&#xD;
55 or less = average&#xD;
55-59 = mildly elevated&#xD;
60-69 = moderately elevated&#xD;
70+ = extremely elevated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Depression Determined by the Beck Self Report Inventory</measure>
    <time_frame>Month 3</time_frame>
    <description>The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.&#xD;
The raw scores for subscales are calculated in the following manner:&#xD;
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.&#xD;
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.&#xD;
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.&#xD;
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.&#xD;
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.&#xD;
Raw scores will be translated into T-scores.&#xD;
T-scores for BYI are as follows:&#xD;
55 or less = average&#xD;
55-59 = mildly elevated&#xD;
60-69 = moderately elevated&#xD;
70+ = extremely elevated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Anger Determined by the Beck Self Report Inventory</measure>
    <time_frame>Month 3</time_frame>
    <description>The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.&#xD;
The raw scores for subscales are calculated in the following manner:&#xD;
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.&#xD;
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.&#xD;
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.&#xD;
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.&#xD;
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.&#xD;
Raw scores will be translated into T-scores.&#xD;
T-scores for BYI are as follows:&#xD;
55 or less = average&#xD;
55-59 = mildly elevated&#xD;
60-69 = moderately elevated&#xD;
70+ = extremely elevated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Disruptive Behavior Determined by the Beck Self Report Inventory</measure>
    <time_frame>Month 3</time_frame>
    <description>The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.&#xD;
The raw scores for subscales are calculated in the following manner:&#xD;
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.&#xD;
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.&#xD;
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.&#xD;
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.&#xD;
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.&#xD;
Raw scores will be translated into T-scores.&#xD;
T-scores for BYI are as follows:&#xD;
55 or less = average&#xD;
55-59 = mildly elevated&#xD;
60-69 = moderately elevated&#xD;
70+ = extremely elevated</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Photosensitive Epilepsy</condition>
  <arm_group>
    <arm_group_label>Treatment group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fenfluramine Hydrochloride</intervention_name>
    <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.</description>
    <arm_group_label>Treatment group</arm_group_label>
    <other_name>ZX008</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subject is male or non-pregnant, non-lactating female, age 4 to 25 years, inclusive as&#xD;
             of the day of the screening visit. Female subjects of childbearing potential must have&#xD;
             a negative serum pregnancy test at screening. Subjects of childbearing or&#xD;
             child-fathering potential must be willing to use medically acceptable forms of birth&#xD;
             control, which includes abstinence, while in this study and for 90 days after the last&#xD;
             dose of study drug.&#xD;
&#xD;
          -  Subjects must have a diagnosis of Sunflower Syndrome, where seizures are not&#xD;
             completely controlled by their current treatment plan.&#xD;
&#xD;
          -  Subjects must experience seizures including absence seizures and/or generalized&#xD;
             tonic-clonic seizures which involve seeking out a light source, staring at the light&#xD;
             source, and waving one hand in front of their eye(s). Subject's must experience an&#xD;
             average of 6 hand waving associated with absence seizures and/or generalized&#xD;
             tonic-clonic seizures per week.&#xD;
&#xD;
          -  Evidence of EEG in the medical history that shows generalized spike and wave&#xD;
             discharges between seizures and a strong photoparoxysmal response during photic&#xD;
             stimulation. Acceptable evidence includes a copy of the EEG trace, EEG report, or&#xD;
             physician note that appropriately describes the EEG findings.&#xD;
&#xD;
          -  All medications or interventions for epilepsy must be stable for at least 4 weeks&#xD;
             prior to screening and are expected to remain stable until Month 3.&#xD;
&#xD;
          -  Subject and/or parent/guardian has been informed of the nature of the study and&#xD;
             informed consent has been obtained from the subject and/or legally responsible&#xD;
             parent/guardian.&#xD;
&#xD;
          -  Subject has provided assent in accordance with Institutional Review Board (IRB)/Ethics&#xD;
             Committee requirements, if capable.&#xD;
&#xD;
          -  Subjects parent/caregiver is willing and able to be compliant with diary completion,&#xD;
             visit schedule, and study drug accountability.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subject has a known hypersensitivity to fenfluramine hydrochloride or any other&#xD;
             ingredients in the investigational drug,&#xD;
&#xD;
          -  Subject's etiology of seizures is a degenerative neurological disease.&#xD;
&#xD;
          -  Subject is pregnant.&#xD;
&#xD;
          -  Subject is not willing to comply with a method of birth control acceptable to the PI&#xD;
             during the study and for 90 days following completion of the study.&#xD;
&#xD;
          -  Subject is breastfeeding.&#xD;
&#xD;
          -  Subject has a history of drug or alcohol abuse.&#xD;
&#xD;
          -  Subject has pulmonary arterial hypertension.&#xD;
&#xD;
          -  Subject has current or past history of cardiovascular or cerebrovascular disease, such&#xD;
             as cardiac valvulopathy, myocardial infarction or stroke, or clinically significant&#xD;
             structural cardiac abnormality, including but not limited to mitral valve prolapse,&#xD;
             atrial or ventricular septal defects, patent ductus arteriosis, and patent foramen&#xD;
             ovale with reversal of shunt. (note: bicuspid valve is not considered exclusionary,&#xD;
             but may be associated with the following diseases, which are exclusionary: coarctation&#xD;
             of the aorta, Turner syndrome, supravalvular aortic stenosis, subvalvular aortic&#xD;
             stenosis, patent ductus arteriosus, Sinus of Valsalva aneurysm, ventricular septal&#xD;
             defect, Shone's complex, ascending aortic aneurysm, Loeys-Dietz syndrome, ACTA2&#xD;
             mutation familial thoracic aortic aneurysm syndrome, and MAT2A mutation familial&#xD;
             thoracic aortic aneurysm syndrome).&#xD;
&#xD;
          -  Subject has current or recent history of anorexia nervosa, bulimia, or depression&#xD;
             within the prior year that required medical treatment or psychological treatment for a&#xD;
             duration greater than 1 month.&#xD;
&#xD;
          -  Subject has a current or past history of glaucoma.&#xD;
&#xD;
          -  Subject has had an anoxic episode requiring resuscitation within 6 months of the&#xD;
             screening visit.&#xD;
&#xD;
          -  Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild&#xD;
             hepatic impairment (elevated liver enzymes &lt; 3x upper limit of normal (ULN) and/or&#xD;
             elevated bilirubin &lt;2x ULN) may be entered into the study after review and approval by&#xD;
             the Medical Monitor in conjunction with the sponsor, in consideration of comorbidities&#xD;
             and concomitant medications.&#xD;
&#xD;
          -  Subject has severe renal impairment (estimated glomerular filtration rate&#xD;
             &lt;30mL/min/1.73m2)&#xD;
&#xD;
          -  Subject is receiving concomitant therapy with: centrally-acting anorectic agents;&#xD;
             monoamine-oxidase inhibitors; any centrally-acting compound with clinically&#xD;
             appreciable amount of serotonin agonist or antagonist properties, including serotonin&#xD;
             reuptake inhibition; other centrally-acting noradrenergic agonists, including&#xD;
             atomoxetine; or cyproheptadine. (Note: Short-term medication requirements for&#xD;
             prohibited medications will be handled on a per case basis by the medical monitor.)&#xD;
&#xD;
          -  Subject has positive result (as defined in the laboratory manual) on urine&#xD;
             tetrahydrocannabinol (THC) Panel or whole blood cannabidiol (CBD) at the screening&#xD;
             visit.&#xD;
&#xD;
          -  Subject has been taking felbamate for less than 1 year prior to screening and/or does&#xD;
             not have stable liver function and hematology laboratory tests, and/or the dose has&#xD;
             not been stable for at least 60 days prior to the screening visit.&#xD;
&#xD;
          -  Subject is known to be human immunodeficiency virus (HIV) positive.&#xD;
&#xD;
          -  Subject is known to have active viral hepatitis (B or C).&#xD;
&#xD;
          -  Subject is currently receiving an investigational medicinal product.&#xD;
&#xD;
          -  Subject has participated in another clinical trial within the past 30 days (calculated&#xD;
             from that study's last scheduled visit). Participation in non-treatment trials will be&#xD;
             reviewed by the medical monitor.&#xD;
&#xD;
          -  Subject is at imminent risk of self-harm or harm to others, in the investigator's&#xD;
             opinion.&#xD;
&#xD;
          -  Subject is unwilling or unable to comply with scheduled visits, drug administration&#xD;
             plan, laboratory tests, other study procedures, and study restrictions.&#xD;
&#xD;
          -  Subject is institutionalized in a general nursing home (i.e., in a facility that does&#xD;
             not provide skilled epilepsy care).-Subject does not have a reliable caregiver who can&#xD;
             provide seizure diary information throughout the study.&#xD;
&#xD;
          -  Subject has a clinically significant condition, or has had clinically relevant&#xD;
             symptoms or a clinically significant illness in the 4 weeks prior to the Screening&#xD;
             Visit, other than epilepsy, that would negatively impact study participation,&#xD;
             collection of study data, or pose a risk to the subject.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>4 Years</minimum_age>
    <maximum_age>25 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Elizabeth Thiele, M.D., Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Director, Pediatric Epilepsy Program</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>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</url>
    <description>Zogenix Announces Positive Top-line Results from Pivotal Phase 3</description>
  </link>
  <reference>
    <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>
    <PMID>3932858</PMID>
  </reference>
  <reference>
    <citation>Ames FR. &quot;Self-induction&quot; in photosensitive epilepsy. Brain. 1971;94(4):781-98. doi: 10.1093/brain/94.4.781. No abstract available.</citation>
    <PMID>5132972</PMID>
  </reference>
  <reference>
    <citation>Ames FR, Saffer D. The sunflower syndrome. A new look at &quot;self-induced&quot; photosensitive epilepsy. J Neurol Sci. 1983 Apr;59(1):1-11. doi: 10.1016/0022-510x(83)90076-x.</citation>
    <PMID>6854340</PMID>
  </reference>
  <reference>
    <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>
    <PMID>24556582</PMID>
  </reference>
  <reference>
    <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>
    <PMID>8892363</PMID>
  </reference>
  <reference>
    <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>
    <PMID>21474289</PMID>
  </reference>
  <reference>
    <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>
    <PMID>2463643</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>14124883</PMID>
  </reference>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>December 12, 2018</study_first_submitted>
  <study_first_submitted_qc>December 27, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 31, 2018</study_first_posted>
  <results_first_submitted>November 25, 2022</results_first_submitted>
  <results_first_submitted_qc>January 11, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">February 8, 2023</results_first_posted>
  <last_update_submitted>January 11, 2023</last_update_submitted>
  <last_update_submitted_qc>January 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Elizabeth Anne Thiele</investigator_full_name>
    <investigator_title>Director, Pediatric Epilepsy Program</investigator_title>
  </responsible_party>
  <keyword>Sunflower Syndrome</keyword>
  <keyword>Epilepsy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Epilepsy</mesh_term>
    <mesh_term>Epilepsy, Reflex</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fenfluramine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Individual participant data (IPD) will not be made available to other researchers.</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>February 21, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/37/NCT03790137/Prot_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>After signing consent and enrolling in the study, all patients underwent a baseline echocardiogram, as well as baseline labs. If there were abnormal findings, patients were excluded from participation due to concerns of cardiac toxicity with fenfluramine.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Treatment Group</title>
          <description>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 undergo a one month baseline, and then will take the investigational new drug, fenfluramine, for at least 84 days (~3 months). They will remain on treatment beyond the core study if fenfluramine is deemed effective and well-tolerated.&#xD;
Fenfluramine: Fenfluramine will be supplied to the treatment group as an oral solution. Subjects will receive their daily dose of Fenfluramine in two doses (one in the morning and one in the evening). After a four week baseline, all 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 (total maximum dose: 26 mg/day). The subjects will remain on a maximum dose for the duration of the core study.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="19"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Treatment Group</title>
          <description>The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome 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 during the core study and may proceed to an extension phase of the study if there is perceived benefit.&#xD;
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 0.7 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 for the duration of the core study.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="20"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="11.9" lower_limit="7" upper_limit="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>% Change in Frequency of Handwaving Episodes</title>
        <description>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.&#xD;
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.</description>
        <time_frame>Month 3</time_frame>
        <population>One patient withdrew from the study 3 days after starting study medication. This patient developed a rash, which was not thought to be related to study medication. The patient chose not to challenge the drug at an allergists office, and instead withdrew from the study. The other 19 patients completed the core study, but only 17 provided analyzable seizure data.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment Group</title>
            <description>The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.</description>
          </group>
        </group_list>
        <measure>
          <title>% Change in Frequency of Handwaving Episodes</title>
          <description>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.&#xD;
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.</description>
          <population>One patient withdrew from the study 3 days after starting study medication. This patient developed a rash, which was not thought to be related to study medication. The patient chose not to challenge the drug at an allergists office, and instead withdrew from the study. The other 19 patients completed the core study, but only 17 provided analyzable seizure data.</population>
          <units>% change in hand waving episodes</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-66.2" lower_limit="-78.7" upper_limit="-31.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>The frequency of HWE for each patient was reported as episodes/day, as determined by dividing the total number of seizures experienced over a given time period by the number of days for which seizures were recorded. Paired t-tests were performed to compare each patient's baseline seizure frequency to their seizure frequency in the last month of treatment. Change in seizure frequency is reported as percent change from baseline. An alpha of 0.05 was used for statistical significance.</non_inferiority_desc>
            <p_value>&lt;0.001</p_value>
            <method>t-test, 1 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change in Frequency of Generalized Tonic-clonic Seizures</title>
        <description>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.</description>
        <time_frame>Month 3</time_frame>
        <population>10 of the 20 patients reported having a generalized tonic-clonic seizure at some point in their lives.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment Group</title>
            <description>The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Frequency of Generalized Tonic-clonic Seizures</title>
          <description>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.</description>
          <population>10 of the 20 patients reported having a generalized tonic-clonic seizure at some point in their lives.</population>
          <units>tonic-clonic seizures/day</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0" lower_limit="0" upper_limit="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Spike Frequency on EEG</title>
        <description>The investigators will read and interpret pre-drug (baseline) and post-drug EEGs (month 3 of core study) for the first 9 patients. The average number of spikes/hour across these patients will be reported for both pre- and post-treatment EEGs.</description>
        <time_frame>Month 3</time_frame>
        <population>The investigators read and interpreted pre-drug and post-drug EEGs for the first 9 patients that completed the core study. The remaining 10 patients did not undergo EEGs as part of this study, due to safety concerns during the COVID-19 pandemic.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment Group</title>
            <description>The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Spike Frequency on EEG</title>
          <description>The investigators will read and interpret pre-drug (baseline) and post-drug EEGs (month 3 of core study) for the first 9 patients. The average number of spikes/hour across these patients will be reported for both pre- and post-treatment EEGs.</description>
          <population>The investigators read and interpreted pre-drug and post-drug EEGs for the first 9 patients that completed the core study. The remaining 10 patients did not undergo EEGs as part of this study, due to safety concerns during the COVID-19 pandemic.</population>
          <units>spikes/hour</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Pre-Treatment</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="73.9" lower_limit="0" upper_limit="277.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Post-Treatment</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="50.4" lower_limit="0" upper_limit="187.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Patients That Experienced a Photoparoxysmal Response on EEG</title>
        <description>The investigators will read and interpret pre- (baseline) and post-treatment (month 3) EEGs. The number of patients that experienced a photoparoxysmal response during the EEGs will be reported.</description>
        <time_frame>Month 3</time_frame>
        <population>The investigators read and interpreted pre-drug and post-drug EEGs for the first 9 patients that completed the core study. The remaining 10 patients did not undergo EEGs as part of this study, due to safety concerns during the COVID-19 pandemic.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment Group</title>
            <description>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 undergo a one month baseline, and then will take the investigational new drug, fenfluramine, for at least 84 days (~3 months). They will remain on treatment beyond the core study if fenfluramine is deemed effective and well-tolerated.&#xD;
Fenfluramine: Fenfluramine will be supplied to the treatment group as an oral solution. Subjects will receive their daily dose of Fenfluramine in two doses (one in the morning and one in the evening). After a four week baseline, all 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 (total maximum dose: 26 mg/day). The subjects will remain on a maximum dose for the duration of the core study.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients That Experienced a Photoparoxysmal Response on EEG</title>
          <description>The investigators will read and interpret pre- (baseline) and post-treatment (month 3) EEGs. The number of patients that experienced a photoparoxysmal response during the EEGs will be reported.</description>
          <population>The investigators read and interpreted pre-drug and post-drug EEGs for the first 9 patients that completed the core study. The remaining 10 patients did not undergo EEGs as part of this study, due to safety concerns during the COVID-19 pandemic.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline EEG (pre-treatment)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 3 EEG (post-treatment)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Cognitive Functioning Determined by the Weschler Abbreviated Scale of Intelligence (WASI-II Subtests)</title>
        <description>The Weschler Abbreviated Scale of Intelligence (WASI-II subtests) will be administered to the first 10 patients 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.&#xD;
The WASI-II measures cognitive functioning through 2 subtests, vocabulary and matrix reasoning. The raw scores on these subtests are combined to give a composite full-scale IQ (FSIQ) that is scaled to an average of 100 and standard deviation of 15.&#xD;
Maximum raw scores for the subtests are as follows (higher values are considered better and minimum score on each is 0).&#xD;
Vocabulary:&#xD;
ages 7-11: 47 ages 12-14: 53 ages 15-25: 59&#xD;
Matrix Reasoning:&#xD;
ages 6-8: 24 ages 9-25: 30</description>
        <time_frame>Month 3 (~84 days after the first dose of fenfluramine.)</time_frame>
        <population>9 of the first 10 patients completed the core study. The second 10 patients did not undergo neuropsychological testing as part of this study due to safety concerns during the COVID-19 pandemic.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment Group</title>
            <description>The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Cognitive Functioning Determined by the Weschler Abbreviated Scale of Intelligence (WASI-II Subtests)</title>
          <description>The Weschler Abbreviated Scale of Intelligence (WASI-II subtests) will be administered to the first 10 patients 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.&#xD;
The WASI-II measures cognitive functioning through 2 subtests, vocabulary and matrix reasoning. The raw scores on these subtests are combined to give a composite full-scale IQ (FSIQ) that is scaled to an average of 100 and standard deviation of 15.&#xD;
Maximum raw scores for the subtests are as follows (higher values are considered better and minimum score on each is 0).&#xD;
Vocabulary:&#xD;
ages 7-11: 47 ages 12-14: 53 ages 15-25: 59&#xD;
Matrix Reasoning:&#xD;
ages 6-8: 24 ages 9-25: 30</description>
          <population>9 of the first 10 patients completed the core study. The second 10 patients did not undergo neuropsychological testing as part of this study due to safety concerns during the COVID-19 pandemic.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="97.89" spread="13.53"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="106.22" spread="11.64"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Cognitive Functioning Determined by the Weschler Intelligence Scale for Children (WISC-V) -Processing Speed Subtests.</title>
        <description>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 (Month 3; visit 5). Results of these cognitive tests will be compared between baseline and 84 days post initial dose.&#xD;
Raw scores for the coding and symbol search subtests will be used to evaluate processing speed. The maximum raw scores are as follows (the minimum score is 0 and higher scores are considered better).&#xD;
Coding:&#xD;
ages 6-7: 65 ages 8-16: 119&#xD;
Symbol search:&#xD;
ages 6-7: 45 ages 8-16: 60</description>
        <time_frame>Month 3 (approximately 84 days after the first dose of fenfluramine)</time_frame>
        <population>9 of the first 10 patients underwent neuropsychological testing as part of the core study. The remaining patients did not undergo this testing due to safety concerns during the COVID-19 pandemic.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment Group</title>
            <description>The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Cognitive Functioning Determined by the Weschler Intelligence Scale for Children (WISC-V) -Processing Speed Subtests.</title>
          <description>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 (Month 3; visit 5). Results of these cognitive tests will be compared between baseline and 84 days post initial dose.&#xD;
Raw scores for the coding and symbol search subtests will be used to evaluate processing speed. The maximum raw scores are as follows (the minimum score is 0 and higher scores are considered better).&#xD;
Coding:&#xD;
ages 6-7: 65 ages 8-16: 119&#xD;
Symbol search:&#xD;
ages 6-7: 45 ages 8-16: 60</description>
          <population>9 of the first 10 patients underwent neuropsychological testing as part of the core study. The remaining patients did not undergo this testing due to safety concerns during the COVID-19 pandemic.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="89.63" spread="9.12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="92.14" spread="10.48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Quality of Life Determined by the Quality of Life in Childhood Epilepsy Questionnaire(QOLCE-16)</title>
        <description>The Quality of Life in Childhood Epilepsy Questionnaire will be administered at baseline, and 84 days after the first dose (Month 3; visit 5). This questionnaire assesses mood, social relationships, and behaviors. Results will be compared.&#xD;
The QOLCE assesses quality of life across 4 domains of functioning: cognitive, emotional, social and physical. Scores range from 0-100. Composite scores are calculated as a mean across all measures.</description>
        <time_frame>Month 3 (approximately 84 days after first dose of fenfluramine)</time_frame>
        <population>8 of the first 9 patients completed this testing as part of the core study. The remaining patients did not undergo this testing due to safety concerns during the COVID-19 pandemic.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment Group</title>
            <description>The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Quality of Life Determined by the Quality of Life in Childhood Epilepsy Questionnaire(QOLCE-16)</title>
          <description>The Quality of Life in Childhood Epilepsy Questionnaire will be administered at baseline, and 84 days after the first dose (Month 3; visit 5). This questionnaire assesses mood, social relationships, and behaviors. Results will be compared.&#xD;
The QOLCE assesses quality of life across 4 domains of functioning: cognitive, emotional, social and physical. Scores range from 0-100. Composite scores are calculated as a mean across all measures.</description>
          <population>8 of the first 9 patients completed this testing as part of the core study. The remaining patients did not undergo this testing due to safety concerns during the COVID-19 pandemic.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="60.41" spread="18.88"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="60.76" spread="17.48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Executive Functioning Determined by The Behavioral Rating Inventory of Executive Function (BRIEF) Questionnaire.</title>
        <description>The Behavioral Rating Inventory of Executive Function (BRIEF) questionnaire will be administered at baseline, and 84 days after the first dose of fenfluramine (Month 3; Visit 5). This questionnaire assesses executive function across 8 clinical scales:&#xD;
Inhibit&#xD;
Shift&#xD;
Emotional Control&#xD;
Initiate&#xD;
Working Memory&#xD;
Plan/Organize&#xD;
Organization of Materials&#xD;
Monitor&#xD;
Item level scores are rated on a 3 point Likert Scale from 1-3:&#xD;
Never&#xD;
Sometimes&#xD;
Often&#xD;
The Global Executive Composite (GEC) score is the total score of all 8 clinical subscales. The item scores are summed for each scale and raw scores are converted to Tscores. The mean of the GEC score will be reported.&#xD;
T scores from 60 to 64 are considered mildly elevated. T scores from 65 to 69 are considered potentially clinically elevated. T scores at or above 70 are considered clinically elevated.</description>
        <time_frame>Month 3 (approximately 84 days after the first dose of fenfluramine)</time_frame>
        <population>7 of the first 9 patients provided pre- and post-treatment responses to the BRIEF questionnaire. The remaining patients did not undergo this testing due to safety concerns during the COVID-19 pandemic.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment Group</title>
            <description>The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Executive Functioning Determined by The Behavioral Rating Inventory of Executive Function (BRIEF) Questionnaire.</title>
          <description>The Behavioral Rating Inventory of Executive Function (BRIEF) questionnaire will be administered at baseline, and 84 days after the first dose of fenfluramine (Month 3; Visit 5). This questionnaire assesses executive function across 8 clinical scales:&#xD;
Inhibit&#xD;
Shift&#xD;
Emotional Control&#xD;
Initiate&#xD;
Working Memory&#xD;
Plan/Organize&#xD;
Organization of Materials&#xD;
Monitor&#xD;
Item level scores are rated on a 3 point Likert Scale from 1-3:&#xD;
Never&#xD;
Sometimes&#xD;
Often&#xD;
The Global Executive Composite (GEC) score is the total score of all 8 clinical subscales. The item scores are summed for each scale and raw scores are converted to Tscores. The mean of the GEC score will be reported.&#xD;
T scores from 60 to 64 are considered mildly elevated. T scores from 65 to 69 are considered potentially clinically elevated. T scores at or above 70 are considered clinically elevated.</description>
          <population>7 of the first 9 patients provided pre- and post-treatment responses to the BRIEF questionnaire. The remaining patients did not undergo this testing due to safety concerns during the COVID-19 pandemic.</population>
          <units>T Score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="61.29" spread="13.62"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 3 Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="58.50" spread="15.84"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Self-Concept Determined by The Beck Self Report Inventory.</title>
        <description>The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.&#xD;
The raw scores for subscales are calculated in the following manner:&#xD;
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.&#xD;
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.&#xD;
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.&#xD;
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.&#xD;
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.&#xD;
Raw scores will be translated into T-scores.&#xD;
T-scores for BYI are as follows:&#xD;
55 or less = average&#xD;
55-59 = mildly elevated&#xD;
60-69 = moderately elevated&#xD;
70+ = extremely elevated</description>
        <time_frame>Month 3 (approximately 84 days after first dose of fenfluramine)</time_frame>
        <population>7 of the first 9 patients provided pre- and post-treatment responses to the Beck Self Report Inventory. The remaining patients did not undergo this testing due to safety concerns during the COVID-19 pandemic.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment Group</title>
            <description>The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Self-Concept Determined by The Beck Self Report Inventory.</title>
          <description>The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.&#xD;
The raw scores for subscales are calculated in the following manner:&#xD;
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.&#xD;
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.&#xD;
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.&#xD;
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.&#xD;
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.&#xD;
Raw scores will be translated into T-scores.&#xD;
T-scores for BYI are as follows:&#xD;
55 or less = average&#xD;
55-59 = mildly elevated&#xD;
60-69 = moderately elevated&#xD;
70+ = extremely elevated</description>
          <population>7 of the first 9 patients provided pre- and post-treatment responses to the Beck Self Report Inventory. The remaining patients did not undergo this testing due to safety concerns during the COVID-19 pandemic.</population>
          <units>T-Score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="44.43" spread="13.43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 3 Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="52.88" spread="14.23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Anxiety Determined by the Beck Self Report Inventory</title>
        <description>The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.&#xD;
The raw scores for subscales are calculated in the following manner:&#xD;
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.&#xD;
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.&#xD;
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.&#xD;
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.&#xD;
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.&#xD;
Raw scores will be translated into T-scores.&#xD;
T-scores for BYI are as follows:&#xD;
55 or less = average&#xD;
55-59 = mildly elevated&#xD;
60-69 = moderately elevated&#xD;
70+ = extremely elevated</description>
        <time_frame>Month 3</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment Group</title>
            <description>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.&#xD;
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 0.7 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Anxiety Determined by the Beck Self Report Inventory</title>
          <description>The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.&#xD;
The raw scores for subscales are calculated in the following manner:&#xD;
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.&#xD;
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.&#xD;
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.&#xD;
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.&#xD;
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.&#xD;
Raw scores will be translated into T-scores.&#xD;
T-scores for BYI are as follows:&#xD;
55 or less = average&#xD;
55-59 = mildly elevated&#xD;
60-69 = moderately elevated&#xD;
70+ = extremely elevated</description>
          <units>T score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="47.29" spread="8.20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 3 Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="45.13" spread="5.91"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Depression Determined by the Beck Self Report Inventory</title>
        <description>The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.&#xD;
The raw scores for subscales are calculated in the following manner:&#xD;
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.&#xD;
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.&#xD;
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.&#xD;
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.&#xD;
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.&#xD;
Raw scores will be translated into T-scores.&#xD;
T-scores for BYI are as follows:&#xD;
55 or less = average&#xD;
55-59 = mildly elevated&#xD;
60-69 = moderately elevated&#xD;
70+ = extremely elevated</description>
        <time_frame>Month 3</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment Group</title>
            <description>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 undergo a one month baseline, and then will take the investigational new drug, fenfluramine, for at least 84 days (~3 months). They will remain on treatment beyond the core study if fenfluramine is deemed effective and well-tolerated.&#xD;
Fenfluramine: Fenfluramine will be supplied to the treatment group as an oral solution. Subjects will receive their daily dose of Fenfluramine in two doses (one in the morning and one in the evening). After a four week baseline, all 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 (total maximum dose: 26 mg/day). The subjects will remain on a maximum dose for the duration of the core study.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Depression Determined by the Beck Self Report Inventory</title>
          <description>The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.&#xD;
The raw scores for subscales are calculated in the following manner:&#xD;
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.&#xD;
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.&#xD;
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.&#xD;
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.&#xD;
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.&#xD;
Raw scores will be translated into T-scores.&#xD;
T-scores for BYI are as follows:&#xD;
55 or less = average&#xD;
55-59 = mildly elevated&#xD;
60-69 = moderately elevated&#xD;
70+ = extremely elevated</description>
          <units>T score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="49.29" spread="12.38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 3 Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="47.13" spread="11.72"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Anger Determined by the Beck Self Report Inventory</title>
        <description>The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.&#xD;
The raw scores for subscales are calculated in the following manner:&#xD;
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.&#xD;
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.&#xD;
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.&#xD;
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.&#xD;
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.&#xD;
Raw scores will be translated into T-scores.&#xD;
T-scores for BYI are as follows:&#xD;
55 or less = average&#xD;
55-59 = mildly elevated&#xD;
60-69 = moderately elevated&#xD;
70+ = extremely elevated</description>
        <time_frame>Month 3</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment Group</title>
            <description>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 undergo a one month baseline, and then will take the investigational new drug, fenfluramine, for at least 84 days (~3 months). They will remain on treatment beyond the core study if fenfluramine is deemed effective and well-tolerated.&#xD;
Fenfluramine: Fenfluramine will be supplied to the treatment group as an oral solution. Subjects will receive their daily dose of Fenfluramine in two doses (one in the morning and one in the evening). After a four week baseline, all 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 (total maximum dose: 26 mg/day). The subjects will remain on a maximum dose for the duration of the core study.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Anger Determined by the Beck Self Report Inventory</title>
          <description>The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.&#xD;
The raw scores for subscales are calculated in the following manner:&#xD;
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.&#xD;
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.&#xD;
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.&#xD;
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.&#xD;
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.&#xD;
Raw scores will be translated into T-scores.&#xD;
T-scores for BYI are as follows:&#xD;
55 or less = average&#xD;
55-59 = mildly elevated&#xD;
60-69 = moderately elevated&#xD;
70+ = extremely elevated</description>
          <units>T score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="45.00" spread="7.87"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 3 Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="41.75" spread="5.52"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Disruptive Behavior Determined by the Beck Self Report Inventory</title>
        <description>The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.&#xD;
The raw scores for subscales are calculated in the following manner:&#xD;
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.&#xD;
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.&#xD;
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.&#xD;
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.&#xD;
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.&#xD;
Raw scores will be translated into T-scores.&#xD;
T-scores for BYI are as follows:&#xD;
55 or less = average&#xD;
55-59 = mildly elevated&#xD;
60-69 = moderately elevated&#xD;
70+ = extremely elevated</description>
        <time_frame>Month 3</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment Group</title>
            <description>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 undergo a one month baseline, and then will take the investigational new drug, fenfluramine, for at least 84 days (~3 months). They will remain on treatment beyond the core study if fenfluramine is deemed effective and well-tolerated.&#xD;
Fenfluramine: Fenfluramine will be supplied to the treatment group as an oral solution. Subjects will receive their daily dose of Fenfluramine in two doses (one in the morning and one in the evening). After a four week baseline, all 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 (total maximum dose: 26 mg/day). The subjects will remain on a maximum dose for the duration of the core study.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Disruptive Behavior Determined by the Beck Self Report Inventory</title>
          <description>The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.&#xD;
The raw scores for subscales are calculated in the following manner:&#xD;
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.&#xD;
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.&#xD;
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.&#xD;
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.&#xD;
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.&#xD;
Raw scores will be translated into T-scores.&#xD;
T-scores for BYI are as follows:&#xD;
55 or less = average&#xD;
55-59 = mildly elevated&#xD;
60-69 = moderately elevated&#xD;
70+ = extremely elevated</description>
          <units>T score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="44.14" spread="5.08"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 3 Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="43.50" spread="5.76"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse event data were collected between Baseline and Month 3 of the study (~84 days after the first dose of fenfluramine).</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Treatment Group</title>
          <description>The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Reduced Appetite</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Nocturnal Enuresis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Viral Illness</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Shortness of Breath</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Chest Pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Seasonal Allergies</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Rhinorrhea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>irritability</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>palilalia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>low serum calcium level</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>rash</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>acne exacerbation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Elizabeth Thiele</name_or_title>
      <organization>Massachusetts General Hospital</organization>
      <phone>6177266540</phone>
      <email>ethiele@mgh.harvard.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03790137
org study id: 12112018
nct id: NCT03790137
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: % Change in Frequency of Handwaving Episodes
time frame: Month 3
description: 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.
measure: Change in Frequency of Generalized Tonic-clonic Seizures
time frame: Month 3
description: 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.
measure: Change in Spike Frequency on EEG
time frame: Month 3
description: The investigators will read and interpret pre-drug (baseline) and post-drug EEGs (month 3 of core study) for the first 9 patients. The average number of spikes/hour across these patients will be reported for both pre- and post-treatment EEGs.
measure: Number of Patients That Experienced a Photoparoxysmal Response on EEG
time frame: Month 3
description: The investigators will read and interpret pre- (baseline) and post-treatment (month 3) EEGs. The number of patients that experienced a photoparoxysmal response during the EEGs will be reported.
measure: Changes in Cognitive Functioning Determined by the Weschler Abbreviated Scale of Intelligence (WASI-II Subtests)
time frame: Month 3 (~84 days after the first dose of fenfluramine.)
description: The Weschler Abbreviated Scale of Intelligence (WASI-II subtests) will be administered to the first 10 patients 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.
The WASI-II measures cognitive functioning through 2 subtests, vocabulary and matrix reasoning. The raw scores on these subtests are combined to give a composite full-scale IQ (FSIQ) that is scaled to an average of 100 and standard deviation of 15.
Maximum raw scores for the subtests are as follows (higher values are considered better and minimum score on each is 0).
Vocabulary:
ages 7-11: 47 ages 12-14: 53 ages 15-25: 59
Matrix Reasoning:
ages 6-8: 24 ages 9-25: 30
measure: Changes in Cognitive Functioning Determined by the Weschler Intelligence Scale for Children (WISC-V) -Processing Speed Subtests.
time frame: Month 3 (approximately 84 days after the first dose of fenfluramine)
description: 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 (Month 3; visit 5). Results of these cognitive tests will be compared between baseline and 84 days post initial dose.
Raw scores for the coding and symbol search subtests will be used to evaluate processing speed. The maximum raw scores are as follows (the minimum score is 0 and higher scores are considered better).
Coding:
ages 6-7: 65 ages 8-16: 119
Symbol search:
ages 6-7: 45 ages 8-16: 60
measure: Changes in Quality of Life Determined by the Quality of Life in Childhood Epilepsy Questionnaire(QOLCE-16)
time frame: Month 3 (approximately 84 days after first dose of fenfluramine)
description: The Quality of Life in Childhood Epilepsy Questionnaire will be administered at baseline, and 84 days after the first dose (Month 3; visit 5). This questionnaire assesses mood, social relationships, and behaviors. Results will be compared.
The QOLCE assesses quality of life across 4 domains of functioning: cognitive, emotional, social and physical. Scores range from 0-100. Composite scores are calculated as a mean across all measures.
measure: Changes in Executive Functioning Determined by The Behavioral Rating Inventory of Executive Function (BRIEF) Questionnaire.
time frame: Month 3 (approximately 84 days after the first dose of fenfluramine)
description: The Behavioral Rating Inventory of Executive Function (BRIEF) questionnaire will be administered at baseline, and 84 days after the first dose of fenfluramine (Month 3; Visit 5). This questionnaire assesses executive function across 8 clinical scales:
Inhibit
Shift
Emotional Control
Initiate
Working Memory
Plan/Organize
Organization of Materials
Monitor
Item level scores are rated on a 3 point Likert Scale from 1-3:
Never
Sometimes
Often
The Global Executive Composite (GEC) score is the total score of all 8 clinical subscales. The item scores are summed for each scale and raw scores are converted to Tscores. The mean of the GEC score will be reported.
T scores from 60 to 64 are considered mildly elevated. T scores from 65 to 69 are considered potentially clinically elevated. T scores at or above 70 are considered clinically elevated.
measure: Changes in Self-Concept Determined by The Beck Self Report Inventory.
time frame: Month 3 (approximately 84 days after first dose of fenfluramine)
description: The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.
The raw scores for subscales are calculated in the following manner:
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.
Raw scores will be translated into T-scores.
T-scores for BYI are as follows:
55 or less = average
55-59 = mildly elevated
60-69 = moderately elevated
70+ = extremely elevated
measure: Changes in Anxiety Determined by the Beck Self Report Inventory
time frame: Month 3
description: The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.
The raw scores for subscales are calculated in the following manner:
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.
Raw scores will be translated into T-scores.
T-scores for BYI are as follows:
55 or less = average
55-59 = mildly elevated
60-69 = moderately elevated
70+ = extremely elevated
measure: Changes in Depression Determined by the Beck Self Report Inventory
time frame: Month 3
description: The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.
The raw scores for subscales are calculated in the following manner:
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.
Raw scores will be translated into T-scores.
T-scores for BYI are as follows:
55 or less = average
55-59 = mildly elevated
60-69 = moderately elevated
70+ = extremely elevated
measure: Changes in Anger Determined by the Beck Self Report Inventory
time frame: Month 3
description: The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.
The raw scores for subscales are calculated in the following manner:
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.
Raw scores will be translated into T-scores.
T-scores for BYI are as follows:
55 or less = average
55-59 = mildly elevated
60-69 = moderately elevated
70+ = extremely elevated
measure: Changes in Disruptive Behavior Determined by the Beck Self Report Inventory
time frame: Month 3
description: The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.
The raw scores for subscales are calculated in the following manner:
Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.
Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.
Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.
Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.
Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.
Raw scores will be translated into T-scores.
T-scores for BYI are as follows:
55 or less = average
55-59 = mildly elevated
60-69 = moderately elevated
70+ = extremely elevated
arm group label: Treatment group
arm group type: Experimental
description: 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.
intervention type: Drug
intervention name: Fenfluramine Hydrochloride
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.
arm group label: Treatment group
other name: ZX008
criteria: 
gender: All
minimum age: 4 Years
maximum age: 25 Years
healthy volunteers: No
last name: Elizabeth Thiele, M.D., Ph.D.
role: Principal Investigator
affiliation: Director, Pediatric Epilepsy Program
facility: 
country: United States
url: 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
description: Zogenix Announces Positive Top-line Results from Pivotal Phase 3
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.
PMID: 3932858
citation: 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
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.
PMID: 6854340
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.
PMID: 24556582
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.
PMID: 8892363
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.
PMID: 21474289
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.
PMID: 2463643
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.
PMID: 14124883
responsible party type: Sponsor-Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Elizabeth Anne Thiele
investigator title: Director, Pediatric Epilepsy Program
mesh term: Epilepsy
mesh term: Epilepsy, Reflex
mesh term: Fenfluramine
sharing ipd: No
ipd description: Individual participant data (IPD) will not be made available to other researchers.
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 