A 2-Part Study to Investigate the Dose-Ranging Safety and Pharmacokinetics, Followed by the Efficacy and Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children ≥ 2 Years Old and Young Adults With Dravet Syndrome

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the safety, tolerability, and efficacy of ZX008 (fenfluramine hydrochloride) when added to adjunctive antiepileptic stiripentol treatment in children and young adults with Dravet syndrome.

Detailed Description
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This is a multicenter, 2-cohort trial to first assess the pharmacokinetic and safety profile of a single dose of ZX008 (fenfluramine hydrochloride) oral solution when added to a standard Dravet syndrome treatment regimen containing valproate (VPA) and clobazam (CLB), with or without stiripentol (STP) (Cohort 1), followed by a randomized, double-blind, placebo-controlled parallel group evaluation of the efficacy, safety, and tolerability of ZX008 as adjunctive therapy for seizures in children and young adults with Dravet syndrome (Cohort 2).

Official Title
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A Multicenter, 2-Cohort Trial to First Assess the Pharmacokinetic and Safety Profile of a Single Dose of ZX008 (Fenfluramine Hydrochloride) Oral Solution When Added to Standard of Care (Cohort 1), Followed by a Randomized, Double-blind, Placebo-controlled Parallel Group Evaluation of the Efficacy, Safety, and Tolerability of ZX008 as Adjunctive Antiepileptic Therapy to Stiripentol Treatment in Children and Young Adults With Dravet Syndrome (Cohort 2)

Conditions
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Dravet Syndrome

Intervention / Treatment
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* Drug: ZX008 (Fenfluramine Hydrochloride)
* Drug: Matching Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Subject must be male or non-pregnant, non-lactating female, aged 2 to 18 years (inclusive). Subject must have documented medical history to support a clinical diagnosis of Dravet syndrome, where convulsive seizures are not completely controlled by current antiepileptic drugs. Subject must be receiving a therapeutically relevant and stable dose of stiripentol (STP) plus clobazam (CLB) and/or valproate (VPA), and for at least 4 weeks prior to screening and be expected to remain stable throughout the study (Cohort 2 only). Subject must be receiving a stable dose of CLB and VPA, administered twice daily (BID), to be eligible for Dose Regimen 1 and 2, or subject must be receiving a stable dose of CLB, VPA, and STP, administered BID, to be eligible for Dose Regimen 3 (Cohort 1 only). Key Exclusion Criteria: Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study medication. Subject has pulmonary arterial hypertension. Subject has a current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction, or stroke. Subject has a 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 is receiving concomitant therapy with: centrally acting anorectic agents; monoamine-oxidase inhibitors; any centrally acting compound with clinically appreciable amount of serotonin agonist or antagonist properties, including serotonin reuptake inhibition; triptans, atomoxetine, or other centrally acting noradrenergic agonists; cyproheptadine, and/or cytochrome P450 (CYP) 2D6/3A4/2B6 inhibitors/substrates. Subject is currently taking carbamazepine ,oxcarbazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as maintenance therapy. Subject has a positive result on urine tetrahydrocannabinol (THC) panel or whole blood cannabidiol (CBD) at the Screening Visit. Subject has a clinically significant condition, or has had clinically relevant symptoms or a clinically significant illness in the 4 weeks prior to the Screening Visit, other than epilepsy, that would negatively impact study participation, collection of study data, or pose a risk to the subject.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 2: ZX008 0.5 mg/kg/day<br>ZX008 0.5 mg/kg/day (maximum 20 mg/day) dose supplied as an oral solution administered twice a day (BID) in equally divided doses with food. | Drug: ZX008 (Fenfluramine Hydrochloride)<br>* ZX008 0.5 mg/kg/day (maximum 20 mg/day). ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 and provided in concentrations of 2.5 mg/mL. *Note: The 0.5 mg/kg/day dose of ZX008 fenfluramine hydrochloride in this study is equivalent to 0.4 mg/kg/day (maximum 17 mg/day) dose of fenfluramine base.<br>|
| Placebo Comparator: Cohort 2: Matching Placebo<br>Matching placebo administered twice a day (BID) in equally divided doses with food. | Drug: Matching Placebo<br>* Matching Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Convulsive Seizure Frequency (CSF) From the Baseline Period (Baseline) to the Combined Titration + Maintenance (T+M) Period | Monthly (28 day) convulsive seizure frequency (CSF) was based on electronic diary data obtained for each participant. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). The number of convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day CSF. | 15 weeks (combined Titration + Maintenance Period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved ≥ a 50% Reduction in Convulsive Seizure Frequency From Baseline to the Combined Titration + Maintenance Period | Percentage of participants who achieved ≥ a 50% reduction in convulsive seizure frequency from Baseline compared to the combined Titration + Maintenance Periods in the ZX008 0.5 mg/kg/day vs placebo groups. | 15 weeks (combined Titration + Maintenance Period) | 
| Longest Convulsive Seizure-Free Interval (Days) | Comparison of the duration of the longest convulsive seizure-free interval (days) during the combined Titration + Maintenance Periods for the ZX008 0.5 mg/kg/day and placebo groups. | 15 weeks (combined Titration + Maintenance Period) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Seizure, Tonic clonic, Epilepsy, Myoclonic, Encephalopathy