A Trial of Two Fixed Doses of ZX008 (Fenfluramine HCl) in Children and Young Adults With Dravet Syndrome
Condition: Dravet Syndrome; Seizure Disorder
MeSH terms: Seizures; Epilepsies, Myoclonic; Epilepsy; Syndrome
Intervention: ZX008 (Fenfluramine Hydrochloride); Matching Placebo
Intervention description: ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5. The product is sugar free and is intended to be compatible with a ketogenic diet.; Placebo solution for ZX008. The product is sugar free and is intended to be compatible with a ketogenic diet.
Intervention MeSH terms: Fenfluramine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 262.0
Sex: All
Minimum age: 2 Years
Maximum age: 18 Years
Healthy volunteers: No
Keywords: seizure; tonic-atonic; clonic; epilepsy; myoclonic; encephalopathy

Summary:

      Study 1 and Study 3 are the prospective, merged analyses of 2 identical double-blind,
      placebo-controlled studies, ZX008-1501 and ZX008-1502, to assess the efficacy, safety, and
      pharmacokinetics of ZX008 when used as adjunctive therapy in pediatric and young adult
      subjects with Dravet syndrome. Study 1501 and Study 1502 were conducted in parallel; Study
      1501 was conducted at approximately 30 study sites in North America; Study 1502 was conducted
      at approximately 30 study sites in Europe, Asia and Australia. Upon completion of the
      Baseline Period after initial Screening and Baseline charting of seizure frequency, subjects
      who qualified for the studies were randomized (1:1:1) in a double-blind manner to receive
      either 1 of 2 doses of ZX008 (0.2 mg/kg/day or 0.8 mg/kg/day; maximum dose: 30 mg/day) or
      placebo. Randomization was stratified by age group (< 6 years, ≥6 to 18 years) to achieve
      balance across treatment arms, with the target of 25% of subjects in each age group. All
      subjects were titrated to their randomized dose over a 14-day Titration Period. Following
      titration, subjects continued treatment at their randomly assigned dose over a 12-week
      Maintenance Period. Subjects exiting the study underwent a 2-week taper, unless they enrolled
      in a follow-on study. Subjects were followed for post-study safety monitoring.
    

Eligibility criteria:

        Key Inclusion Criteria:

          -  Male or non-pregnant, non-lactating female, age 2 to 18 years, inclusive as of the day
             of the Screening Visit.

          -  Clinical diagnosis of Dravet syndrome, where convulsive seizures are not completely
             controlled by current antiepileptic drugs.

          -  Must have a minimum # of convulsive seizures per 4-week period for past 12 weeks prior
             to screening.

          -  All medications or interventions for epilepsy must be stable for at least 4 weeks
             prior to screening and expected to remain stable throughout the study.

          -  No cardiovascular or cardiopulmonary abnormality based on ECHO, ECG or physical
             examination.

          -  Parent/caregiver is willing and able to be compliant with diary completion, visit
             schedule and study drug accountability.

        Key Exclusion Criteria:

          -  Pulmonary arterial hypertension.

          -  Current or past history of cardiovascular or cerebrovascular disease, such as cardiac
             valvulopathy, myocardial infarction or stroke.

          -  Current or past history of glaucoma.

          -  Moderate or severe hepatic impairment.

          -  Receiving concomitant therapy with: anorectic agents; monoamine-oxidase inhibitors;
             medications that act via serotonin including serotonin reuptake inhibitors;
             atomoxetine, or other centrally-acting noradrenergic agonist; or cyproheptadine.

          -  Currently receiving or has received stiripentol in the past 21 days prior to
             Screening.

          -  Currently taking carbamazepine, oxcarbamazepine, eslicarbazepine, phenobarbital, or
             phenytoin, or has taken any of these within the past 30 days.

          -  Positive result on tetrahydrocannabinol (THC) or cannabidiol (CBD) test at the
             Screening Visit.

          -  A clinically significant medical condition,that would interfere with study
             participation, collection of study data, or pose a risk to the subject.