Overview

This study is a pilot non-controlled clinical trial with adjunctive fenfluramine for the treatment of five different types of developmental and epileptic encephalopathies (DEEs) focused on epileptic and "non-epileptic outcomes": SYNGAP1 and STXBP1 encephalopathies, inv-dup(15) encephalopathy, multifocal or bilateral malformations of cortical development, and continuous spikes and waves during sleep. The main goal is to assess changes in seizure frequency comparing before and after treatment with fenfluramine in five specific types of developmental and epileptic encephalopathies (DEEs). Secondary objectives of this study are the analysis of changes in seizure intensity and duration, and "non-epileptic outcomes" such as variations in cognitive activity, level of alertness, impulsivity/self-control, gait stability and other alterations that might be detected during the interview and physical examination.

Eligibility

GENERAL INCLUSION CRITERIA:

• Age between 2 and 35 years (both included).
• Diagnosis of epilepsy associated with some degree of intellectual disability, starting before 11 years of age.
• All patients will have a phenotype consistent with their genetic, electroclinical or neuroimaging diagnosis.

SPECIFIC INCLUSION CRITERIA PER GROUP:

        ---GROUP 1: Non-controlled epilepsy after failing at least 3 antiseizure medications, with
        a minimum of 4 countable seizures with motor semiology per month during the baseline period
        of 3 months.
          -  Group 1A: Patients with genetic testing showing a pathogenic or likely pathogenic
             variant in main synaptopathy genes (SYNGAP1 and STXBP1).
          -  Group 1B: Patients with genetic testing showing a pathogenic or likely pathogenic
             inverted duplication of chromosome 15 [inv-dup (15)].
          -  Group 1C: Patients with neuroimaging showing multifocal or bilateral malformations of
             cortical development.
               -  GROUP 2:
        Electroclinical diagnosis of Continuous Spikes and Waves during Sleep (CSWS) syndrome, with
        baseline video-EEG monitoring showing epileptiform activity occupying at least 50% of slow
        sleep tracing, after failing at least 3 antiseizure medications.
        ADDITIONAL INCLUSION CRITERIA:
        In addition, all subjects must meet all of the following inclusion criteria to be enrolled
        into the study:
          -  Subject is male or non-pregnant, non-lactating female. Female subjects of childbearing
             potential must not be pregnant or breast-feeding. Female subjects of childbearing
             potential must have a negative urine or serum pregnancy test at screening and during
             the study.
          -  Receiving at least 1 concomitant antiseizure medications (ASMs) and up to 4
             concomitant ASMs, inclusive. Ketogenic Diet (KD) and Vagus Nerve Stimulation (VNS) are
             permitted but do not count towards the total number of ASMs. Rescue medications for
             seizures are not counted towards the total number of ASMs.
          -  All medications or interventions for epilepsy (including ketogenic diet and vagal
             nerve stimulation) must be stable for at least 4 weeks prior to screening and are
             expected to remain stable throughout the study.
          -  Subject has been informed of the nature of the study and informed consent has been
             obtained from the legally responsible parent/guardian.
          -  Subject has provided assent in accordance with Institutional Review Board (IRB)/Ethics
             Committee requirements, if capable.
          -  Subject's parent/caregiver is willing and able to be compliant with diary completion,
             visit schedule and study drug accountability.
        EXCLUSION CRITERIA
        Subjects who meet any of the following exclusion criteria will not be enrolled into the
        study:
          -  Subject has a known hypersensitivity to fenfluramine or any of the excipients in the
             study medication.
          -  Subject has only non-motor seizures (such as absences), for group 1.
          -  Subject has pulmonary arterial hypertension.
          -  Subject has current or past history of cardiovascular or cerebrovascular disease.
          -  Subject has current or recent history of Anorexia Nervosa, bulimia, or depression
             within the prior year that required medical treatment or psychological treatment for a
             duration greater than 1 month.
          -  Subject has a current or past history of glaucoma.
          -  Subject has moderate or severe renal or hepatic impairment.
          -  Subject is receiving concomitant therapy with any of the following: centrally-acting
             anorectic agents; monoamine-oxidase inhibitors; any centrally-acting compound with
             clinically appreciable amount of serotonin agonist or antagonist properties, including
             serotonin reuptake inhibition; other centrally-acting noradrenergic agonists.
          -  Subject is currently receiving an investigational product.
          -  Subject has participated in another clinical trial within the past 30 days (calculated
             from that study's last scheduled visit).
          -  Subject is at imminent risk of self-harm or harm to others.
          -  Subject is unwilling or unable to comply with scheduled visits, drug administration
             plan, laboratory tests, other study procedures, and study restrictions.
          -  Subject is institutionalized in a general nursing home (i.e., in a facility that does
             not provide skilled epilepsy care).
          -  Subject does not have a reliable caregiver who can provide seizure diary information
             throughout the study.
          -  Subject has a severe clinically significant condition.